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CAS No. : | 119141-88-7 | MDL No. : | MFCD09907604 |
Formula : | C17H19N3O3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 345.42 | Pubchem ID : | - |
Synonyms : |
(S)-Omeprazole;(-)-Omeprazole;(–)-Omeprazole
|
Chemical Name : | (S)-6-Methoxy-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole |
Num. heavy atoms : | 24 |
Num. arom. heavy atoms : | 15 |
Fraction Csp3 : | 0.29 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 93.7 |
TPSA : | 96.31 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.82 cm/s |
Log Po/w (iLOGP) : | 1.64 |
Log Po/w (XLOGP3) : | 2.23 |
Log Po/w (WLOGP) : | 3.61 |
Log Po/w (MLOGP) : | 0.91 |
Log Po/w (SILICOS-IT) : | 3.16 |
Consensus Log Po/w : | 2.31 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.52 |
Solubility : | 0.105 mg/ml ; 0.000303 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.89 |
Solubility : | 0.0447 mg/ml ; 0.000129 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -6.47 |
Solubility : | 0.000117 mg/ml ; 0.000000337 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.58 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P270-P280-P301+P310+P330-P305+P351+P338+P310-P405-P501 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49 % ee | With dihydrogen peroxide In water; acetonitrile at 20℃; for 5.5 h; | 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1 H- benzimidazole (4a) and the (salen)manganese complex 2a - e are dissolved in acetonitrile. The reaction temperature is adjusted, then 30percent aqueous H2O2 is added dropwise and the mixture is stirred for several hours. Then the reaction mixture is transferred portion-wise into a cold (0 0C) 10percent aqueous solution of Na2SO3 and stirred for additional 15 min. The obtained mixture is extracted with dichloromethane. The organic phase is dried over Na2SO4 and concentrated yielding an oily residue which is analyzed by chiral and achiral HPLC analytical method.Typically, runs were carried out on 0.5 - 6 mmol scale of the starting material 4a in acetonitrile (1 mmol 4a in 10 mL MeCN). The amounts of added reagents, temperature and reaction time in particular examples are indicated in Tables 1 to 3. Also the results are indicated in Tables 1-3. |
80 % ee | Stage #1: at 50 - 55℃; for 1 h; Stage #2: With N-ethyl-N,N-diisopropylamine In toluene at 25 - 30℃; for 0.0833333 h; Stage #3: With Cumene hydroperoxide In toluene at 20℃; for 4 h; |
0.495 g (1.5 mmol) of the compound of formula III, 5 ml of dried toluene and 1 mmol of a chiral ligand (166.1 mg of the methyl ester of (S)-mandelic acid (general formula IV: X = OMe, Y = H, rVc)) were placed in a 3 -neck 50-ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated in an oil bath to a temperature in the range of 50 to 55 °C. Then, 0.15 ml of Ti(Oz-Pr)4 (general formula V: Z = Ti, R5 = i-Pr) were added to this mixture at once. The resulting mixture was stirred at a temperature in the range of 50 to 55 °C for 1 hour. Then, the temperature of the reaction mixture was maintained at 25 to 30 °C and 85 μ of diisopropylethylamine were added to the reaction mixture. The mixture was stirred for 5 minutes and 0.25 ml of 88percent cumene hydroperoxide were added to the solution. The resulting reaction mixture was stirred at the room temperature for 4 hours. The reaction was terminated by addition of 5 ml of a 5percent aqueous solution of Na2S203 and diluted with 5 ml of toluene. The resulting mixture was filtered through filtration paper. The two-phase filtrate was divided in a separating funnel and the toluene fraction was extracted with additional 5 ml of water. After drying with anhydrous magnesium sulfate the toluene solution was evaporated to dryness in a rotational vacuum evaporator. The resulting evaporation residue was chromatographed on silica gel. Chloroform : methanol : 25percent NH OH in the (10 : 1 : 0.1) proportion was used as the eluent. The fractions of the product were combined, evaporated in a rotational vacuum evaporator and analyzed in a HPLC system on a chiral phase (CHIRALPAK AD-H.(R).); mobile phase 50percent of hexane : 50percent of ethanol, detection 302 nm).Esomeprazole (formula I) with the enantiomeric excess of 80 percent was obtained. |
67.7 % ee | Stage #1: at 50 - 55℃; for 1 h; Stage #2: With N-ethyl-N,N-diisopropylamine In toluene at 25 - 30℃; for 0.0833333 h; Stage #3: With Cumene hydroperoxide In toluene at 20℃; for 4 h; |
(R)-omeprazole was prepared with the same procedure as described in example 1. 1 mmol (200 mg) of (jf?)-3-chloromandelic acid methyl ester (general formula ent-TV: X = OMe, Y = 3-Cl) was used as the chiral ligand.(/?)-omeprazole (formula ent-I) with the enantiomeric excess of 67.6 percent was obtained. |
83.7 % ee | With oxygen; NADP In aq. phosphate buffer; isopropyl alcohol at 25℃; for 24 h; Enzymatic reaction | General procedure: The Activity FIOP and enantioselectivity (percent ee) of the 53 exemplary non-naturally occurring monooxygenase polypeptides of Table 2B in carrying out the biocatalytic conversion of the substrate compound (1) (pyrmetazole) to the product compound (2) ((R)- or (S)-omeprazole) were determined that following general HTP assay conditions: 5 g/L pyrmetazole substrate, 10 μL of lysate of the engineered CHMO polypeptide, 1 g/L KRED of SEQ ID NO: 268, 0.5 g/L NADP, in a solution of 50 mM potassium phosphate buffer, 10percent (v/v) IPA, pH 9.0, 25° C. reaction temperature and 24 h reaction time (with 400 rpm stirring). Further details of the HTP assay methods are described in the Examples. |
82.5 % ee | With C64H64N4O6Ti2; dihydrogen peroxide In water; ethyl acetate at 0℃; for 24 h; | General procedure: Sulfide (OMS or LPS, 100 mol) and the Ti-salalen catalyst(1.1 mol) were dissolved in the solvent (typically: EtOAc, 6.0 mL),the mixture was thermostatted at desired temperature (typically 0 °C, or −20 to +20 °C for variable-temperature measurements),and 30percent aqueous hydrogen peroxide (0.105 mmol of H2O2) was then introduced in one portion. Stirring (500 rpm) was continued at that temperature (typically 24 h). For low-temperature experiments, the reaction times were about 30 h at −10 °C and up to 10 days at −20 °C. To analyze the reaction outcome, 20 L aliquots of the reaction mixture were taken to a vial and immediately carefully evaporated to dryness with a stream of compressed air during ca. 15–20 s. The remaining solid was dissolved in 0.20 mL of 1percent Et3N solution in isopropyl alcohol, and the contents of residual sulfide, (R)- and(S)-sulfoxide, and sulfone, were analyzed by chiral HPLC as noted above. |
71.5 % ee | With C68H72N4O10Ti2; dihydrogen peroxide In water; ethyl acetate at 0℃; for 24 h; | General procedure: Sulfide (OMS or LPS, 100 mol) and the Ti-salalen catalyst(1.1 mol) were dissolved in the solvent (typically: EtOAc, 6.0 mL),the mixture was thermostatted at desired temperature (typically 0 °C, or −20 to +20 °C for variable-temperature measurements),and 30percent aqueous hydrogen peroxide (0.105 mmol of H2O2) was then introduced in one portion. Stirring (500 rpm) was continued at that temperature (typically 24 h). For low-temperature experiments, the reaction times were about 30 h at −10 °C and up to 10 days at −20 °C. To analyze the reaction outcome, 20 L aliquots of the reaction mixture were taken to a vial and immediately carefully evaporated to dryness with a stream of compressed air during ca. 15–20 s. The remaining solid was dissolved in 0.20 mL of 1percent Et3N solution in isopropyl alcohol, and the contents of residual sulfide, (R)- and(S)-sulfoxide, and sulfone, were analyzed by chiral HPLC as noted above. |
68 % ee | With dihydrogen peroxide; acetic acid In methanol; water at 0℃; for 12 h; | General procedure: The appropriate catalyst 5 (10 molpercent) and sulfide (1.0 mmol) were dissolved in CH3OH/H2O (1:1) (5 mL) and this solution was cooled to 0 °C. Subsequently the additive HOAc (2.0 mmol) and the oxidant hydrogen peroxide (1.5 mmol, 30percent, w/w) were added. The mixture was stirred for 12 h and then was treated with 10 mL of saturated ammonium chloridesolution and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated to give pure sulfoxides through flash column chromatography on silica gel (hexane/ethyl acetate(10:1)). All the products in the paper are known compounds that exhibited spectroscopic data identical to those reported in the literature [34]. The ee was determined by HPLC on chiral column (Daicel,Chiralpak, OD-H). The configuration of sulfoxides product from these reactions was proven to be (S) by comparing the specific rotation with the literature values [35]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67 % ee | With dihydrogen peroxide In water; acetonitrile at -10℃; for 5 h; | 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1 H-benzimidazole (4a) (0.987 g , 3 mmol) and manganese complex of (R,R)-1 ,2-bis(3,5-di-te/f-butyl-2-hydoxybenzyl- amino)cyclohexane (10c) (96 mg, 5 mol percent) are dissolved in acetonitrile (45 ml). The reaction mixture is cooled to -100C and 30percent aqueous H2O2 (13.8 ml, 45 mol equiv) is added dropwise over 3 hours period. The reaction mixture is stirred for additional 2 hours. HPLC analysis shows formation of 56percent of sulfoxide (1a) with 67percent ee (S-enriched) and 5percent of sulfone. |
9 % ee | With dihydrogen peroxide In water; acetonitrile at 0 - 20℃; for 3.5 h; | 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1 H- benzimidazole (4a) and a preformed salan (10b) - metal complex are dissolved in acetonitrile. The reaction temperature is adjusted and 30percent aqueous H2O2 is added dropwise. The mixture is stirred for several hours. Then, it is poured portionwise into a cold (0 0C) 10percent aqueous Na2SO3 and stirred for additional 15 min and extracted with dichloromethane. The organic phase is dried over Na2SO4 and concentrated yielding an oily residue which is analyzed by chiral and achiral HPLC.Typically, runs were carried out on 1 mmol scale of the starting material 4a in acetonitrile (1 mmol 4a in 10 mL MeCN). The amounts of added reagents, temperature and reaction time in particular examples are indicated in Table 4. Also the results are indicated in Table 4. |
75.1 % ee | Stage #1: With titanium(IV) isopropylate; C69H72N6O3 In water; toluene at 50℃; for 1 h; Inert atmosphere Stage #2: With p-cumenyl hydroperoxide; N-ethyl-N,N-diisopropylamine In water; toluene at 25℃; for 0.5 h; |
Titanium tetraisopropoxide (66.7 mg, 0.235 mmol) and water (8.0 mg, the total amount of water is 8.47 mg, 0.47 mmol) were added to a solution of L1 (67.1 mg, 0.065 mmol) in toluene (20 mL) at 25 C. After stirring at that temperature for 1 h, pyrmetazol (165.0 mg, 0.5 mmol) was added. Then, the mixture was heated to 50 Cand maintained for 1 h. After the mixture was cooled to 25 C, N,N-diisopropylethylamine (16.8 mg, 0.13 mol) and cumene hydroperoxide (80percent in cumene, 110.5 mg,0.65 mmol) were added subsequently. After stirring at 25 C for 1 h, a small sample of reaction mixture was taken for HPLC analysis for conversion and selectivity, and the product was isolated by preparative thin-layer chromatography (TLC; eluent: CH2Cl2/MeOH 25/1) for determination of the enantiomeric purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: omeprazole With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate; water; triethylamine In acetone at 35 - 40℃; Large scale; Stage #2: With (S)-Mandelic acid In acetone at 35 - 40℃; for 2h; Large scale; Stage #3: With sodium hydrogencarbonate In dichloromethane; water for 0.5h; Large scale; | |
inclusion complexation with (S)-(-)-2,2'-dihydroxy-1,1'-binaphthyl; | ||
With diethylamine In methanol Chiral high performance liquid chromatography; Resolution of racemate; | 15 Preparation of S-Omeprazole from rac-Omeprazole by means of Chiral High Performance Liquid Chromatography (HPLC). Omeprazole (10.0373 g; 29.058 mmol) was placed in a volumetric flask (500 mL) with 0.1% diethylamine (DEA) in methanol, dissolved by means of sonication, and brought to volume. The solution was injected onto a Waters Delta Prep 4000 HPLC under the following conditions: Column: Chiralpak AD Column Dimensions: 20 mm×250 mm; 10 μm particle size Detection: 280 nm Flow rate: 10 mL/minute Mobile Phase: 100% Methanol Injection Volume: 10 mL The fractions of the S-omeprazole enantiomer were collected into a flask containing sodium carbonate (10 g). After collection, the sodium carbonate was removed by filtration and the solvent removed by rotary evaporation. The resulting oil was used directly in subsequent experiments (see Examples 1 and 2). |
In methanol Chiral high performance liquid chromatography; Resolution of racemate; | 16 Preparation of S-Omeprazole from rac-Omeprazole by means of Chiral High Performance Liquid Chromatography (HPLC). Omeprazole (0.7307 g; 2.115 mmol) was dissolved in methanol (37 mL). The solution was injected onto a Waters Delta Prep 4000 HPLC under the following conditions: Column: Chiralpak AD Column Dimensions: 20 mm×250 mm; 10 μm particle size Detection: 280 nm Flow rate: 10 mL/minute Mobile Phase: 100% Methanol Injection Volume: 10 mL The fractions of the S-omeprazole enantiomer were collected into a flask and the methanol removed by nitrogen purge to produce an oil. The oil was used directly in a subsequent experiment (see Example 3). | |
Stage #1: omeprazole With sodium hydroxide In methanol at 25 - 30℃; Stage #2: With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate; (S)-Mandelic acid; triethylamine | ||
98 % ee | With Escherichia coli DMSO reductase In methanol; aq. phosphate buffer at 37℃; for 3h; Resolution of racemate; Darkness; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.2% | To the 1000 mL three-necked round bottom flask, 50 mL of ufiprazole and 250 mL of toluene were added and heated in an oil bath at 65-70 C,After clarification of the solution, use a pipette to the reaction solution2 mL of the catalyst D-tartrate was added in turn, tetraisopropyl titanate 2.3mL and high purity water 0.5mL, stirring 50min, cold bath, cooling to 2-5 drop N, N-diisopropylethylamine 1.3mL,Slowly dripping Hydrogen peroxide cumene 27mL, reaction 24h, TLC detection reaction is complete, adding sodium hydroxide 18g and pure water 300mL stirring2.0h, the filtrate was washed three times with toluene 300mL, separated, the aqueous phase was collected, and the pH of the solution was adjusted to 7-8 with acetic acid. Dichloromethane 300mL * 3 extraction, combined organic phase into the 2500mL single-mouth bottle,The dichloromethane was removed under reduced pressure,dry,To obtain the flocculent flocculent yellowish solid esomeprazole 52g,Yield 99.2%. | |
95.6% | With C23H48NO(1+)*2H(1+)*O40PW12(3-); dihydrogen peroxide; sodium hydrogencarbonate; (1S,2S)-cyclohexane-1,2-diammonium 2,3-dihydroxysuccinate; In water; acetone; at 28℃; for 15h; | To a solution of 33 g (about 0.1 mol) of thioether precursor of formula (I) in 200 ml of acetone was added 11 g of sodium bicarbonate, 3.0 g of quaternary ammonium phosphotungstovanadate, 28 g of (1S, 2S) - 1,2-cyclohexanediamine-D-tartaric acid salt, 40 ml of a 40% aqueous solution of hydrogen peroxide was slowly added dropwise while stirring, and the reaction temperature was controlled at 28 C and maintained at that temperature for 15 hours. The filtrate was poured into water, stirred for 30 minutes, filtered, washed with water, and dried to obtain 33.1 g of (S)-(-)-omeprazole in a yield of 95.6% |
94% | With C64H64N4O6Ti2; dihydrogen peroxide; In water; ethyl acetate; at 0℃; for 24h; | General procedure: Sulfide (OMS or LPS, 100 mol) and the Ti-salalen catalyst(1.1 mol) were dissolved in the solvent (typically: EtOAc, 6.0 mL),the mixture was thermostatted at desired temperature (typically 0 C, or -20 to +20 C for variable-temperature measurements),and 30% aqueous hydrogen peroxide (0.105 mmol of H2O2) was then introduced in one portion. Stirring (500 rpm) was continued at that temperature (typically 24 h). For low-temperature experiments, the reaction times were about 30 h at -10 C and up to 10 days at -20 C. To analyze the reaction outcome, 20 L aliquots of the reaction mixture were taken to a vial and immediately carefully evaporated to dryness with a stream of compressed air during ca. 15-20 s. The remaining solid was dissolved in 0.20 mL of 1% Et3N solution in isopropyl alcohol, and the contents of residual sulfide, (R)- and(S)-sulfoxide, and sulfone, were analyzed by chiral HPLC as noted above. |
92.7% | 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-lH- benzimidazole (30 g, 90.19 mmol), toluene (242 mL) and D-tartaric acid di-w-propionamide (12.96 g, 54.71 mmol) were added into a reaction flask. The reaction mixture was warmed to 70 <n="40"/>0C and stirred for 10 minutes and then cooled to 55-60 0C. To the resulting solution was added titanium (IV) tetraisopropoxide (7.78 g, 27.36 mmol). The resulting mixture was stirred for 60 minutes and then water (0.16 mL, 9.019 mmol) was added thereinto. The resulting solution was further stirred for 30 minutes and cooled 30 0C. To the solution was added triethylamine (3.8 mL, 27.36 mmol). The resulting solution was stirred for 30 minutes and then cumyl hydroperoxide (19.4 mL, 107.8 mmol) was added thereinto. The reaction was kept at 30 0C over 43 hours. To the resulting solution was added 10% aqueous sodium hydroxide. The aqueous phase was separated and extracted twice with toluene. The pH of the aqueous layer was adjusted to about 9 with glacial acetic acid. The resulting aqueous phase was extracted with dichlormethane. The resulting organic phase was washed twice with saturated aqueous brine, dried over anhydrous sodium sulfate and filtered. The combined organic phase was evaporated to dryness under reduced pressure to give S-(-)-levo-omeprazole (29.2 g, 92.7%, ee: 95.2%). | |
92% | General procedure: In a typical experiment, Ti(Oi-Pr)4 (0.9 mL, 3 mmol) was added to a solution of (S,S)-DBzTA 5i (1.969 g, 6 mmol) and pyrmetazol (3.29 g, 10 mmol) in toluene (20 mL) at 80 C. The solution was stirred for 60 min., after which water (54 mg, 3 mmol) was added to the mixture, and the solution was stirred for another 60 min. Next, the temperature was adjusted to 30 C, after which cumene hydroperoxide (80 %, 3.6 mL, 20 mmol) was slowly added. After 1 h at 30 C, the solution was added to aqueous sodium hydroxide (1.2 g NaOH in 20 mL water), stirred for 1 h, and extracted with water (20 mL × 3). The aqueous phase was adjusted to pH 8 with acetic acid, separated, and extracted with dichloromethane (20 mL × 3). The combined organic solutions were dried over anhydrous Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (2:1) as the eluent to afford the sulfoxide. | |
92% | With AD-mix beta; dichloro[(-)-sparteine-N,N']copper(II); Cumene hydroperoxide; C14H17F6N3S; In ethyl acetate; at 20℃; for 1.5h;Catalytic behavior; | General procedure: (1), in cleanliness,Add 5 mol of toluene to the dried glass reaction flask.Turn on the stirring and add the intermediate product Ome Thiol.0.5 mol chiral thiourea catalyst (R1 = R2 = CF3, R3 = ethyl),Add 0.5 mol of chiral hawkskin-copper complex,Add 0.4mol of CAA6,0.9 mol of cumene hydroperoxide was added dropwise at room temperature.Stir for 1.5 h. (2), after treatment: ammonia extraction twice,The aqueous layer was collected and 25 mol of dichloromethane was added.The glacial acetic acid is adjusted to pH=8-9, and the organic layer is collected.Dry over anhydrous sodium sulfate,Filtration and concentration of the filtrate under reduced pressure until solventless distillation.Add 20 mol of ethyl acetate,Stir to a homogeneous phase,Then cool down to 0 ~ 10 C, slowly add 10mol of drinking water,There is a lot of solid precipitation,filter,An esomeprazole solid is obtained. |
91.5% | With titanium(IV) isopropylate; tert.-butylhydroperoxide; (R,R)-hydroxybenzoin; isopropyl alcohol; In dichloromethane; water; at 5 - 20℃; | (R, R) -1,2-diphenyl-1,2-ethanediol, 2.14 g (10mmol) was added to 100 ml of dichloromethane, 1.42 g (5 mmol) of titanium tetraisopropoxide and 1.2 g of isopropyl alcohol (20 mmOl) were added dropwise, and 33.0 g of omeprazole sulfur Ether (0.1 m omicron 1), dissolved at room temperature after stirring, cooled to 5 -10 C, dropping 7 0% t-butyl hydroperoxide aqueous solution (0.2 mol), the mixture was stirred at 5-10 C for 2.0-2.5 hours and 10 ml of aqueous ammonia (10%) was added to terminate the reaction. 10% acetic acid aqueous solution to adjust rhoH- = 8-9, stratified, the water phase extracted with dichloromethane 3 times, combined with organic phase, Na2S04 dry Filtered and concentrated to give 31.6 g of a white solid, 91.5% yield; 98.5% purity and 0.56% impurity sulfone. value of 99.65%. |
90% | With tert.-butylhydroperoxide; In water; toluene; at -20℃; for 12h; | Titanium tetraisopropoxide (4.5 mg, 0.016 mmol) was added to a solution of (R,R)-1,2-bis-(2-bromophenyl)ethane-1,2-diol (12 mg, 0.032 mmol) in toluene (2 ml) at 25 C. The solution was stirred for 10 minutes, water (5.7 mg, 0.32 mmol) was added, and the solution was then stirred for another 10 minutes. 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole (105 mg, 0.32 mol) was subsequently added to the solution, and the temperature was adjusted to -20 C. Thereafter, t-butyl hydroperoxide (70%, 96 mul, 0.064 mmol) was slowly added. After 12 hours at -20 C., the solution was extracted three times with aqueous ammonium hydroxide (12.5% NH3, 3×5 ml). Thereafter, methyl isobutyl ketone (5 ml) was added to the combined aqueous extracts. Then, the pH of the aqueous phase was adjusted using acetic acid, the aqueous phase was separated and extracted with an additional amount of methyl isobutyl ketone (5 ml). The organic solution was cooled to -10 C. over night, and the neutral form of S-omeprazole was precipitated as a solid to obtain the title compound (99 mg, 90% yield). The enantiomeric excess of S-omeprazole was 94%. Purification using methyl isobutyl ketone yielded S-omeprazole, and the enantiomeric excess was >99%. |
87% | With Aspergillus niger catalase; oxygen; NADP; In aq. phosphate buffer; isopropyl alcohol; at 25℃; for 48h;pH 9.0;Enzymatic reaction; | Example 6 Process for Production of Esomeprazole at 30 g Scale Using an Engineered CHMO Polypeptide (0318) This example illustrates a process for preparing esomeprazole in enantiomeric excess at a 30 g scale via a biocatalytic conversion of the substrate pyrmetazole using an engineered CHMO polypeptide of the disclosure (e.g., a polypeptide of SEQ ID NO: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78. 80. 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, or 158). (0319) A. Biocatalytic Reaction Protocol: (0320) A 1 L multi-neck jacketed reactor vessel equipped with baffle and overhead stirrer, fitted with an anchor shaped agitator was charged with a pre-mixed powder of 30 g pyrmetazole (from Sinojie (HK) Ltd.) and 1.5 g of an esomeprazole ?seed? (prepared in a previous enzymatic reaction), and then 517 mL of 0.05 M potassium phosphate at pH 9.0 (?buffer solution?). This reaction mixture was stirred at 150 rpm at 25 C. for 10 min in order to obtain a well-suspended slurry. A three way tap was attached to the necks of the vessel. The tap was fitted with 2 rubber balloons filled with oxygen and a vacuum line for conducting degassing steps prior to the start of the reaction. Vacuum was applied to the vessel (30 mbar, obtained within 5 min) and the evacuated flask was filled with oxygen via the three way tap. This evacuation-gas-filling cycle was repeated two more times. The reaction vessel under positive oxygen pressure then was charged sequentially with the following: 24 mL IPA (HPLC grade); 60 mg NADP in 4 mL buffer solution (pH 9.0); 300 mg ketoreductase of SEQ ID NO: 268 in 15 mL buffer solution (pH 9.0); 600 mg CHMO of SEQ ID NO: 158 in 40 mL buffer solution (pH 9.0); and 1.2 mL of catalase (Aspergillus niger catalase solution in buffer stabilized with sodium chloride and sorbitol with stated activity of 25000 ClU/g; available from Sigma-Aldrich). Catalase is added to neutralize peroxide that may form during the reaction and negatively affect the performance of the CHMO. The above reaction mixture was stirred at 25 C. for 48 hours. The stir rate was 300 rpm in the beginning and increased stepwise as shown in Table 8 below. The course of the reaction was followed by taking periodic 0.3 mL samples from the reaction mixture which were quenched in 10 mL MeOH and analyzed using HPLC as described below. For the purpose of tracking the process, t=0 was set at the time at which the CHMO was added. Samples were also taken and tested for peroxide during course of reaction but no peroxide was detected. The in-process reaction profile based on the sample analyzes is summarized in Table 8 below. A % conversion of >99% within 36 hours can be estimated from the kinetic profile of the reaction. In comparable runs a conversion of 98% was determined after 32 h (with a rate of conversion of 1%/h constantly at the latter stage of the reaction) and similar kinetic profile could be obtained in repetitive runs with the described experimental set-up. The reaction mixture 48 hours after start was taken for product work-up and isolation as described below. [table-us-00009-en] TABLE 8 Reaction Profile Time Stirring speed (h) % Conversion (rpm) 0 5 300 2 17.6 350 4 30.7 350 6 43.3 350 7.5 50.1 400 22.5 87.8 450 26 92.3 450 28 94.3 450 30 96.1 450 44 99.6 450 (0322) B. Reaction Work-Up Protocol: (0323) To the reaction mixture was added 165 mL (5.5 volumes) of methyl isobutyl ketone (?MIBK?), the jacket temperature was adjusted to 48 C. and the mixture was stirred at 300 rpm. After 25 min the internal temperature showed 45 C. and the slurry was completely dissolved. Mixing was stopped and after 20 min the phases were separated. The lower aqueous layer was slightly turbid with a yellowish color. The upper organic layer appeared to be an emulsion and was brown in color. The aqueous layer was drained and collected. The organic layer was subsequently drained and submitted to a warm filtration over Celite applying vacuum (the temperature of the jacket filter was adjusted to 45 C.). The aqueous phase was transferred back to the heated vessel and 45 mL of MIBK was added. Stirring at 300 rpm for 30 min and phase separation within 20 min afforded a lower slightly turbid, yellowish aqueous layer and a brownish upper organic phase. The aqueous layer was drained and discarded. The organic layer was drained and collected. The solution was submitted to warm Celite filtration after the first filtration was completed (same filter and Celite layer). The organic phases were combined and separated from the aqueous layer that was formed during filtration. The aqueous layer was discarded and the organic phase was transferred back to the vessel. The temperature was adjusted to 15 C. and the solution stirred at 150 rpm for 1 hour. The p... |
Mix, S- (+)-Methyl mandelate 60.6 g, Toluene 250 ml and Titanium isopropoxide 15 ml, into a 500 ml R. B. Flask assembly and stir to make a clear solution under Nitrogen atmosphere. Heat the reaction mixture to 40C and maintain for 17 hr. Cool to 25-30C and charge Omeprazole sulfide 50 g and Diisopropylethylamine 1.35 ml to it and stir for 10-15 minutes. Add Cumene hydroperoxide (-80 % solution in cumene) 28 ml slowly through addition funnel to the reaction mixture at 25-30C. Stir the reaction mixture at 25-30C for 2.0 hr. Filter the solid and wash with Toluene 50 ml. Collect the filtrate and charge 12.5 % ammonia solution 300 ml, to the filtrate and stir the mixture for 15 minutes. Back extract the Toluene layer with 12.5% Ammonia solution; 200 ml and add Methyl isobutyl ketone 250 ml, to the combined aqueous layer. Adjust the pH of the solution to 7.3-7. 6 by adding Glacial Acetic acid at 25-30 C. Stir the content for 30 min. Separate the organic layer and extract the aq. layer with Methyl isobutyl ketone ; 50 ml. Charge sodium hydroxide solution (50% w/v) 11 ml to combined organic layer and stir the mixture for 15 minutes. Distil off solvent completely under vacuum at 55-60 C. Add Acetonitrile; 300 ml, to the residue and stir the content at 25-30C. Filter the product under nitrogen atmosphere and wash the cake with Acetonitrile 50 ml. Dry the product in vacuum at 50-55C. Yield of Esomeprazole sodium (22.4 g) with enantiomeric excess > 98%. | ||
Mix, Toluene 120 L, Omeprazole sulfide 30 Kg, followed by 204 ml Water, D- (-)- Diethyl tartrate 9.4 L and Titanium isopropoxide 7.98 Kg, into a 500 L reaction assembly and stir to make a homogenous suspension under Nitrogen atmosphere. Heat the reaction mixture to 50-52C and maintain for 1 hour. Cool to 15-20C and charge Diisopropylethylamine 3.56 Kg to it and stir for 10-15 minutes. Add Cumene hydroperoxide (-80 % solution in cumene) 16.37 Kg slowly through addition funnel to the reaction mixture at 0 to 5C. Stir the reaction mixture at 25-30C for 2.0 hr. Charge 12.5 % ammonia solution 240 L, to it and stir for 10-15 minutes. Back extract the Toluene layer with 12.5% Ammonia solution; 60 L and add Methyl isobutyl ketone 120 L, to the combined aqueous layer. Adjust the pH of the solution to 7.3-7. 6 by adding Glacial Acetic acid at 25-30 C. Stir the content for 30 min. Separate the organic layer and extract the aq. layer with Methyl isobutyl ketone ; 30 L. Charge sodium methoxide solution (30% w/v) about 15 Kg to combined organic layer and stir the mixture for 15 minutes. Distil off solvent completely under vacuum at 55-60 C. Add Acetonitrile; 90 L to the residue and stir the content at 25-30C. Filter the product under nitrogen atmosphere and wash the cake with Acetonitrile 60 L. Dry the product in vacuum at 50-55C. Yield of Esomeprazole sodium = about 18 Kg. Sulfone content: 4.0 % | ||
EXAMPLE 1; Preparation of (S)-5/6-methoxy-1-benzyloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleTo a solution of 2-[2-(3,5-dimethyl-4-methoxypyridyl)methylthio]-5-methoxy-benzimidazole 2 (10 g) in 50.0 mL toluene under an inert atmosphere, was added (D)-diethyl tartrate (2.75 g). The mixture was heated to 50-55 C. and stirred for 30 minutes. Titanium (IV) isopropoxide (1.73 g) was added and the temperature was maintained at 50-55 C. for an additional 60 minutes. The reaction mixture was cooled to 0-5 C. whereupon diisopropylethylamine (1.33 g) and 80% cumene hydroperoxide (6.93 g) were added while keeping the temperature below 10 C. The reaction mixture was stirred at 0-10 C. for 2-4 hours until the reaction was complete. The reaction mixture was warmed to room temperature, filtered through Celite and extracted with 12-14% ammonium hydroxide. The aqueous and methyl isobutyl ketone (MIBK, 30 mL) phases were cooled to 0-5 C. The pH was adjusted to 7.3 to 7.8 with acetic acid and phases were separated. The aqueous phase was extracted with MIBK. The combined organic phases were washed with brine and vacuum distilled to 40 mL to give a solution of (S)-(-)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole in MIBK. The sulfoxide solution was diluted with dichloromethane (30 mL) and triethylamine (4.61 g). The mixture was cooled to 0-10 C. and 95% benzyl chloroformate (6.0 g) was added while keeping the temperature below 10 C. After stirring for 1-4 hours, water (30 mL) and ethyl acetate (30 mL) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases was washed with brine and saturated sodium bicarbonate, vacuum distilled to 30 mL and filtered through Celite. The filtrate was stirred while 80 mL of heptanes was added dropwise whereupon the suspension was cooled to 0-5 C. and maintained at this temperature for 1-2 hours. The suspension was filtered, washed with heptanes/ethyl acetate (4/1) and dried under vacuum at room temperature to afford (S)-5/6-methoxy-3-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole. Weight: 11.5 g. Purity: 99% by HPLC. Chiral purity: 99.5% (S-form) by HPLC. Ratio of 5- and 6-methoxy products: 1:1. The analytical data were consistent with the assigned structure.H-NMR (400 MHz, CDCl3):5-Methoxy isomer: delta/ppm=2.18 (3H, s), 2.32 (3H, s), 3.73 (3H, s), 3.76 (3H, s), 4.67 (2H, dd, J=13, 38 Hz), 5.54 (2H, s), 6.95-7.01 (1H, m), 7.38 (1H, d, J=2 Hz), 7.40-7.43 (2H, m), 7.47-7.59 (2H, m), 7.68 (1H, d, J=9 Hz), 8.05 (1H, s);6-Methoxy isomer: 6/ppm=2.18 (3H, s), 2.32 (3H, s), 3.73 (3H, s), 3.83 (3H, s), 4.67 (2H, dd, J=13, 38 Hz), 5.53 (2H, s), 6.95-7.01 (1H, m), 7.29 (1H, d, J=2 Hz), 7.40-7.43 (2H, m), 7.47-7.59 (2H, m), 7.75 (1H, d, J=9 Hz), 8.05 (1H, s). | ||
In a 500 ml flask, 18.8 gm diethyl (-)-D-tartrate, 12.9 gm titanium(IV) isopropoxide and 0.33 ml water were taken at room temperature, and 50 gm 5-methoxy[(2-(4-methoxy)- 3,5-dimethyl-2-pyridinyl] methylsulfenyl]-lH-benzimidazole (also termed as pyrmetazole or PMT) was added and the mixture was heated to 70-75 degrees for 1 hour. After cooling to 40 degrees, 3 gm diisopropyl ethyl amine and 34.6 gm (80%) cumene <n="24"/>hydroxide were added and maintained mixture under stirring. The reaction was monitored, after completion of reaction 100 ml toluene and 31.6 gm NaOH solution were added to the mixture. The mixture then stirred for 0.5 hours at heating and then cooled to room temperature and further to 0-5 degree Celsius. Layers were separated and toluene layer washed with water. The aqueous layer neutralized with cone. Hydrochloric acid and esomeprazole free base was extracted using dichloromethane. The dichloromethane layers, dried, and evaporated to obtain esomeprazole free base. | ||
5.6 g | The 5 - methoxy -2 - (4 - methoxy - 3, 5 - dimethyl -2 - pyridyl) methyl thio - 1H - benzimidazole 5.67g added to the 100 ml three-opening in the bottle, the toluene is added to 25 ml, stirring, heated to 65 C, then adding purified water 90uL, D - tartaric acid diethyl ester 2.3g and tetraisopropyl titanate 28g, stirring 1h, cooling. T=30 C when, adding N, N - diisopropyl ethylamine 1.6g, after 15min, for 30min slowly dropping hydrogen peroxide in 2.5 ml. TLC detection after the reaction, a small amount of raw material remaining. For 12% of ammonia water extraction 3 times, the combined aqueous phase, by adding dichloromethane, then adjusting the pH to acetic acid for 8 the left and the right, liquid, organic phase with pure water and saturated salt water all 20 ml wash once, dried with anhydrous sodium sulfate, filtered, concentrated to obtain brown oil of 5.6g. | |
36.7 g | Omeprazole thioether 50 g (0.152 mol)Toluene 220g mixed with stirring,The solution layer was a white suspension.And stirred at 20 to 25 CDiethyl D-tartrate (63 g, 0.304 mol)And 43 g (0.152 mol) of (IV) isopropyl ester,The reaction solution was yellow turbid liquid.after that0.68 g (0.038 mol) of purified water was added,20 ~ 25 and then stirring 10min.After heating to 45 ~ 55 ,Insulation reaction 1 hour,The color gradually darkens to brown.Cooling to 25 ~ 30 ,20 g (0.155 mol) of N, N-diisopropylethylamine was added,Stir for 0.5 hours.Continue to cool,And stirred at -2 to 4 C for 1 hour.Then, 25 g (0.135 mol) of cumene hydroperoxide (85%) was added with stirring,The stirring was continued at -2 to 4 C for 7 hours,Simultaneously, the reaction solution was detected by HPLC,Sulfone content of 3.8%,Omeprazole thioether content of 11.2%Stop the reaction. To the above reaction solution was added 100 g of triethylamine,Stirring 10min after adding purified water 150g,Stir quickly for 30 minutes,Static stratification,The organic phase was extracted twice with the same amount of triethylamine and water as described above.Combine the aqueous phase and filter.12 g of glacial acetic acid was added dropwise at -3 to 2 C,Adjust the material liquid pH = 8 ~ 9,And maintain the pH value of half hour re-measured the same,The same temperature to continue stirring 6h,Precipitate a large amount of white solid.Filtered and washed three times with 100 g x 3 purified water,Filter dry.Dried to give esomeprazole 36.7 g. | |
The resulting organic phase was heated to 55 C with stirring,Adding 6.2 grams of diethyl D-tartrate, 4.3 g of titanium isopropoxide, Keep heating for 1 hour, remove the heating, down to room temperature, plus N,N-diisopropyl Diamine 1.9 g,11.4 g of cumene hydroperoxide was slowly added dropwise, and the reaction was stirred for 4 hours(Sampling detection,EsomeprazoleThe thioether content is in1.0% or less),To the reaction solution was added 15% aqueous ammonia 100 ml twice in two mixing, combined ammonia water, ammonia phase with 100 ml of methylene chloride backwash once. | ||
148.2 g | In a 3000 mL three-necked round bottom flask,Add 270 ml of methanol,2-Mercapto-5-methoxybenzimidazole 90. 0 g (0.50 mol),Stirring,Add an aqueous sodium hydroxide solution (40.0 g sodium hydroxide/100 ml purified water).Stir the reaction at room temperature for 1 hour.2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride 110 g (0.50 mol) was added,Methyl tert-butyl ether (900 ml) was heated to 35-45 C for 3 hours.After the reaction,Cool the feed to room temperature,Purified water 250 ml*2 was added twice to the remaining stock solution.Obtained methyl sulfide tert-butyl ether solution,The water bath is heated to 50-60C,Addition of 62.5 g (0.30 mol) of D-(-)-diethyl tartrate,Tetraisopropyl titanate 43.0 g (0.15 mol),Insulation for 1 hourAfter cooling to 25-35C,Triethylamine 15.0 g (0.15 mol) was added,72.0 g (0.475 mol) of cumene hydroperoxide was added dropwise.5h, heat preservation reactionAfter the reaction,Add 15% ammonia water 400ml to the reaction solution.Stir for 20min,Extraction liquid, The organic layer was extracted twice with 15% aqueous ammonia 400ml*2.Combined ammonia layer,Add activated carbon 12 g to decolorize at room temperature for 4 hours.filter,Ammonia layer is added with ethyl acetate 900 ml,Ice bath cooling to 5-15 C,The glacial acetic acid was added dropwise to adjust the pH to 7. 5-8. 5,Dividing fluid,The aqueous layer was extracted with ethyl acetate 450ml for the second extraction.Combine the ethyl acetate layers,Wash 400 ml*2 twice with saturated saline solution.Ethyl acetate extraction phase,Temperature control 35 ~ 45 C vacuum concentration,Light brown oil 148.2 g,Add acetone 900 ml,Stir so that the oil is completely dissolved,Transfer the feed solution to a 2000 ml three-neck round bottom flask.Sodium hydroxide solution (18.1 g of sodium hydroxide/1. 8 g of purified water) was added,Heating reflux 60min,The crystal was dropped to 0-10C and stirred for 6h.Suction filtrationAcetone 50ml wash cake,Filter cake 35-45 C / -0. 095MPa vacuum drying 12h,120.7 g of esomeprazole sodium was obtained.Yield 65.7%.HPLC: 99.6%,Ee%: 99.7%. | |
163 g | 2) adding 38.5 g of titanium tetraisopropoxide to the dichloromethane phase,6-g D-tartrate, heated to refluxAfter reacting for 1 h, the temperature was lowered to 20 C and 15.2 g of triethylamine was added.Temperature control -20 ~ -15 C,Adding 95g of 80wt% cumene hydroperoxide anda solution of 95 ml of dichloromethane,2h drop,Reaction 2h. Wash the dichloromethane phase by adding 300 ml of water.Set the liquid to obtain the methylene chloride phase,The methylene chloride phase was concentrated under reduced pressure at a temperature of 20 to 25 C until no droplets were distilled off.An oil of 163 g was obtained. | |
With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate; In water; toluene; at 50℃; for 1.33333h;Inert atmosphere; | (1) 21.62 kg of the intermediate I obtained in Example 1 (containing 64.54 mol of omeprazole thioether) was added to 87.7 kg.Toluene (the amount of toluene is 4 times the mass of omeprazole thioether), the temperature is raised to 50 C, stirred and dissolved, and then transferred to a 500 L reactor.Turn on nitrogen protection.(2) The temperature was raised to 50±3C, and 169g of purified water and 5.47kg of D-tartrate dibasic acid were added, and the reaction was kept for 20 minutes.Slowly add dropwise a solution of isopropyl titanate toluene (5.79 kg of isopropyl titanate dissolved in 7.4 kg of toluene) to maintain the temperature of the reaction solution.The reaction was stirred at 50 ± 3 C for 50 min to 60 min. Among them, water added, D-diethyl tartrate, isopropyl titanate and omeprazole sulfurThe molar ratio of ether was 0.14:0.4:0.3:1.(3) Cool down to 15 to 20 C and add 2.66 kg of triethylamine. Continue to cool down, slowly add peroxide at 10~15 CHydrogen cumene toluene solution (11.28 kg of cumene hydroperoxide dissolved in 29.3 kg of toluene), after the addition is completed, the temperature is raised to 25 ~The reaction was carried out at 30 C to obtain esmeprazole. The molar ratio of triethylamine to omeprazole thioether added was 0.3:1.After 2 hours, the sample was monitored by TLC method (extension agent ethyl acetate), and the concentration of intermediate I in the reaction solution was low.In the control solution, the concentration of the intermediate I was spotted, and the chiral oxidation reaction was terminated to obtain Esomeprazole, which was used to enter the potassium salt.should. If the spot concentration of the intermediate I is higher than the concentration of the intermediate I spot in the control solution, the reaction is continued. Sampling every 30 minutes,Until the concentration of the control solution is lower than the spot concentration. |
Yield | Reaction Conditions | Operation in experiment |
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87% | In water | 15 EXAMPLE 15PREPARATION OF ESOMEPRAZOLE SODIUM; Esomeprazole obtained in example 14 (54.5 g; 157.78 mmol), was dissolved in a solution of aqueous NaOH (136.24 g; 4.88 % w/w) and DM water (30 ml). The solution was washed with methylene chloride twice (200 ml x 2). The aqueous layer was filtered and concentrated completely under reduced pressure to yield viscous mass. Ethanol was added to the viscous mass and concentrated under reduced pressure. Thereafter, ethyl acetate was added and concentrated to dryness under reduced pressure to yield solid mass. Further, ethyl acetate (400 ml) was added and stirred the mixture under reflux for 30 min. Cooled the reaction mass to 20-300C and stirred for 3 h. The separated solid was filtered, washed with ethyl acetate and dried under reduced pressure at 40°C to yield esomeperazole sodium. Yield - 50.6 g (87 %) Enantiomeric excess - 99.96 %. |
Stage #1: sodium hydroxide; esomeprazole In methanol; water at 30 - 31℃; for 0.666667h; Stage #2: In acetone for 1h; | 1 EXAMPLE 1Preparation of Crystalline Esomeprazole Sodium Form J50 ml of methanol was taken into a round bottom flask and a mixture of 12.75 g sodium hydroxide and 11 ml of water was added to it and stirred for clear dissolution at 31° C. 110 g of esomeprazole was dissolved in 550 ml of methanol and the solution was added to the above methanolic sodium hydroxide solution. The mass was subjected to stirring at a temperature of 30° C. for 40 minutes, followed by the addition of 5.5 g of carbon with simultaneous stirring. The reaction mass was filtered through a Celite bed, and washed with 550 ml of methanol. The filtrate was subjected to distillation at a temperature of 30° C. under a vacuum of 200 torr. The residue was co-distilled with 1650 ml of acetone in three equal lots at 35° C. To the obtained residue, 220 ml of acetone was added and stirred for one hour. The separated solid was filtered and dried at 34° C. for 12 hours to afford 61.5 g of the title compound.Moisture content: 1.35% w/w.Specific optical rotation [α]D20=+43.220.Purity by HPLC 99.99%.Particle size distribution: D10 less than 3 μm, D50 less than 10 μm, D90 less than 30 μm.Bulk density: Before tapping: 0.428 g/ml. After tapping: 0.630 g/ml. | |
Stage #1: sodium hydroxide; esomeprazole In methanol; dichloromethane at 26℃; for 1h; Stage #2: In dichloromethane at 29℃; for 1.5h; | 9 EXAMPLE 9Conversion of Esomeprazole Sodium Crystalline Form J to Crystalline Form K3.47 g of sodium hydroxide and 105 ml of methanol were taken into a round bottom flask and stirred at 29° C. A solution of 30 g of esomeprazole in 150 ml of dichloromethane was added to the above methanolic sodium hydroxide solution and stirred for 1 hour at 26° C. The mass was then distilled under a vacuum of 300 mm Hg at 38° C. The remaining residue was then co-distilled with 450 ml of dichloromethane in three equal lots. To the residue obtained, 60 ml of dichloromethane was added and stirred at 29° C. for 1.5 hours. The separated solid was filtered and washed with 30 ml of dichloromethane to give 32.2 g of Form J of esomeprazole sodium.The crystalline Form J obtained above was further dried at 34° C. for 9 hours to yield 18.5 g of crystalline Form K of esomeprazole sodium. |
Stage #1: sodium hydroxide; esomeprazole In methanol; acetonitrile at 26℃; for 1h; Stage #2: In dichloromethane at 29℃; for 1.5h; | 10 EXAMPLE 10Conversion of Esomeprazole Sodium Crystalline Form J to Crystalline Form K3.47 g of sodium hydroxide and 105 ml of methanol were taken into a round bottom flask and stirred at 29° C. A solution of 30 g of esomeprazole in 150 ml of acetonitrile was added to the above methanolic sodium hydroxide solution and stirred for 1 hour at 26° C. The reaction mass was then distilled under a vacuum of 300 mm Hg at 38° C. The residue was then co-distilled with 450 ml of acetonitrile in three equal lots. To the residue obtained, 60 ml of dichloromethane was added and stirred at 29° C. for 1.5 hours. The separated solid was filtered and washed with 30 ml of acetonitrile to give 42.6 g of Form J of esomeprazole sodium.The crystalline Form J obtained above was further dried at 34° C. for 9 hours to yield 25.6 g of crystalline Form K of esomeprazole sodium. | |
In methanol at 5 - 30℃; for 11.25 - 11.5h; | 1.III; 2.III Step-lll:; Methanol (26 ml) is added to the residue (13.1 gm, obtained in step-ll) under stirring at 25 - 300C, the contents are cooled to 10 - 150C and then the solution of sodium hydroxide (3.25 gm) in methanol is added for 15 - 30 minutes at 100C. The resulting mass is stirred for 20 minutes, the temperature of the mass is raised to 25 - 300C and then stirred for 10 hours at 25 - 300C. The reaction mass is cooled to 5 - 100C and then stirred for 1 hour. Filtered the solid, washed with chilled methanol (13 ml) followed by diisopropyl ether (50 ml) and then dried at 50 - 550C to give 10.2 gm of esomeprazole sodium salt (enantiomeric purity: 100%).; Methanol (26 ml) is added to the residue (13.5 gm, obtained in step-ll) under stirring at 25 - 300C, the contents are cooled to 10 - 150C and then the solution of sodium hydroxide (3.25 gm) in methanol is added for 15 - 30 minutes at 100C. The resulting mass is stirred for 20 minutes, the temperature of the mass is raised to 25 - 300C and then stirred for 10 hours at 25 - 300C. The reaction mass is cooled to 5 - 100C and then stirred for 1 hour. Filtered the solid, washed with chilled methanol (13 ml) followed by diisopropyl ether (50 ml) and then dried at 50 - 550C to give 10.4 gm of esomeprazole sodium salt (enantiomeric purity: 100%). |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In dichloromethane; 4-methyl-2-pentanone at 0 - 10℃; for 1 - 4h; | 1 EXAMPLE 1; Preparation of (S)-5/6-methoxy-1-benzyloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleTo a solution of 2-[2-(3,5-dimethyl-4-methoxypyridyl)methylthio]-5-methoxy-benzimidazole 2 (10 g) in 50.0 mL toluene under an inert atmosphere, was added (D)-diethyl tartrate (2.75 g). The mixture was heated to 50-55° C. and stirred for 30 minutes. Titanium (IV) isopropoxide (1.73 g) was added and the temperature was maintained at 50-55° C. for an additional 60 minutes. The reaction mixture was cooled to 0-5° C. whereupon diisopropylethylamine (1.33 g) and 80% cumene hydroperoxide (6.93 g) were added while keeping the temperature below 10° C. The reaction mixture was stirred at 0-10° C. for 2-4 hours until the reaction was complete. The reaction mixture was warmed to room temperature, filtered through Celite and extracted with 12-14% ammonium hydroxide. The aqueous and methyl isobutyl ketone (MIBK, 30 mL) phases were cooled to 0-5° C. The pH was adjusted to 7.3 to 7.8 with acetic acid and phases were separated. The aqueous phase was extracted with MIBK. The combined organic phases were washed with brine and vacuum distilled to 40 mL to give a solution of (S)-(-)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole in MIBK. The sulfoxide solution was diluted with dichloromethane (30 mL) and triethylamine (4.61 g). The mixture was cooled to 0-10° C. and 95% benzyl chloroformate (6.0 g) was added while keeping the temperature below 10° C. After stirring for 1-4 hours, water (30 mL) and ethyl acetate (30 mL) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases was washed with brine and saturated sodium bicarbonate, vacuum distilled to 30 mL and filtered through Celite. The filtrate was stirred while 80 mL of heptanes was added dropwise whereupon the suspension was cooled to 0-5° C. and maintained at this temperature for 1-2 hours. The suspension was filtered, washed with heptanes/ethyl acetate (4/1) and dried under vacuum at room temperature to afford (S)-5/6-methoxy-3-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole. Weight: 11.5 g. Purity: 99% by HPLC. Chiral purity: 99.5% (S-form) by HPLC. Ratio of 5- and 6-methoxy products: 1:1. The analytical data were consistent with the assigned structure.H-NMR (400 MHz, CDCl3):5-Methoxy isomer: δ/ppm=2.18 (3H, s), 2.32 (3H, s), 3.73 (3H, s), 3.76 (3H, s), 4.67 (2H, dd, J=13, 38 Hz), 5.54 (2H, s), 6.95-7.01 (1H, m), 7.38 (1H, d, J=2 Hz), 7.40-7.43 (2H, m), 7.47-7.59 (2H, m), 7.68 (1H, d, J=9 Hz), 8.05 (1H, s);6-Methoxy isomer: 6/ppm=2.18 (3H, s), 2.32 (3H, s), 3.73 (3H, s), 3.83 (3H, s), 4.67 (2H, dd, J=13, 38 Hz), 5.53 (2H, s), 6.95-7.01 (1H, m), 7.29 (1H, d, J=2 Hz), 7.40-7.43 (2H, m), 7.47-7.59 (2H, m), 7.75 (1H, d, J=9 Hz), 8.05 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine;dmap; In tetrahydrofuran; at 60℃; for 6h; | To a solution (10 mL) of [(S)-5-METHOXY-2- [ [ (4-METHOXY-] 3,5-dimethyl-2-pyridyl) methyl] sulfinyl]-lH-benzimidazole (1.34 g) synthesized by the method described in Example 1 of Japanese Patent Application under PCT laid-open under kohyo No. 10-504290 in tetrahydrofuran were added 2- [[ (CHLOROCARBONYL)] (methyl) amino] ethyl ethyl carbonate (0.9 mL) obtained in Reference Example 34, triethylamine (1.08 mL) and 4-dimethylaminopyridine (0.010 g), and the mixture was stirred at [60C] for 6 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane=1 : 2, then 1: 1) to give a 3: 2 mixture (0.92 g) of the title compound and ethyl [2- [ [ [ (S)-6-METHOXY-2- [ [ (4-METHOXY-3,] 5-dimethyl-2- pyridyl) [METHYL] SULFINYL]-LH-BENZIMIDAZOL-1-] yl] carbonyl] (methyl) amino] ethyl carbonate as a pale-yellow amorphous solid. [1H-NMR] [(CDC13)] : 1.25-1. 34 (3H, m), 2.10-2. 30 (3H, m), 2.23 (3H, [S),] 2.99-3. 23 (3H, m), 3.40-3. 85 (2H, m), 3.69 (6/5H, s), 3.71 (9/5H, s), 3.86 (6/5H, s), 3.88 (9/5H, s), 4.14-4. 25 (2H, m), 4.38-4. 60 (2H, m), 4.79-5. 05 (2H, m), 6.92-7. 08 (7/5H, m), 7.33 (3/5H, d, J=9.3Hz), 7. 65 [(LH,] m), 8.21 (lH, s). | |
With dmap; triethylamine; In tetrahydrofuran; at 60℃; for 6h; | To a solution of <strong>[119141-88-7](S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole</strong> (1.34 g) synthesized by a method described in Synthetic Example 1 of JP-A 10-504290 in tetrahydrofuran (10 mL) were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.9 mL) obtained in Reference Synthetic Example 34, triethylamine (1.08 mL) and 4-dimethylaminopyridine (0.010 g), and stirred at 60C for 6 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate : hexane = 1 : 2, then 1 : 1) to give a mixture of 3 : 2 of title compound and ethyl 2-[[[(S)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl] carbonyl] (methyl) amino] ethyl carbonate as pale yellow amorphous solid (0.92 g).1H-NMR(CDCl3) : 1.25-1.34(3H,m), 2.10-2.30(3H,m), 2.23(3H,s), 2.99-3.23(3H,m), 3.40-3.85(2H,m), 3.69(6/5H,s), 3.71(9/5H,s), 3.86(6/5H,s), 3.88(9/5H,s), 4.14-4.25(2H,m), 4.38-4.60(2H,m), 4.79-5.05(2H,m), 6.92-7.08 (7/5H,m), 7.33(3/5H,d,J=9.3Hz), 7.65 (1H,m), 8.21(1H,s). | |
With triethylamine;dmap; In tetrahydrofuran; at 60℃; for 6h; | To a solution (10 mL) of <strong>[119141-88-7](S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole</strong> (1.34 g) synthesized by the method described in Synthetic Example 1 of JP-A-10-504290 in tetrahydrofuran were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.9 mL) obtained in Reference Example 34, triethylamine (1.08 mL) and 4-dimethylaminopyridine (0.010 g), and the mixture was stirred at 60C for 6 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give a 3:2 mixture (0.92 g) of the title compound and ethyl 2-[[[(S)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as a pale-yellow amorphous solid.1H-NMR(CDCl3) : 1.25-1.34 (3H,m), 2.10-2.30 (3H,m), 2.23(3H,s), 2.99-3.23(3H,m), 3.40-3.85(2H,m), 3.69 (6/5H,s), 3.71 (9/5H,s), 3.86 (6/5H,s), 3.88 (9/5H,s), 4.14-4.25 (2H,m), 4.38-4.60(2H,m), 4.79-5.05(2H,m), 6.92-7.08(7/5H,m), 7.33(3/5H,d,J=9.3Hz), 7.65(1H,m), 8.21 (1H, s). |
With dmap; triethylamine; In tetrahydrofuran; at 60℃; for 6h; | Synthetic Example 57 Ethyl 2-[[[(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate (0731) (0732) To a solution (10 mL) of <strong>[119141-88-7](S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole</strong> (1.34 g) synthesized by the method described in Synthetic Example 1 of Japanese Patent Application under PCT laid-open under kohyo No. 10-504290 in tetrahydrofuran were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.9 mL) obtained in Reference Example 34, triethylamine (1.08 mL) and 4-dimethylaminopyridine (0.010 g), and the mixture was stirred at 60 C. for 6 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give a 3:2 mixture (0.92 g) of the title compound and ethyl 2-[[[(S)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as a pale-yellow amorphous solid. (0733) 1H-NMR (CDCl3): 1.25-1.34 (3H, m), 2.10-2.30 (3H, m), 2.23 (3H, s), 2.99-3.23 (3H, m), 3.40-3.85 (2H, m), 3.69 (6/5H, s), 3.71 (9/5H, s), 3.86 (6/5H, s), 3.88 (9/5H, s), 4.14-4.25 (2H, m), 4.38-4.60 (2H, m), 4.79-5.05 (2H, m), 6.92-7.08 (7/5H, m), 7.33 (3/5H, d, J=9.3 Hz), 7.65 (1H, m), 8.21 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With magnesium methanolate; In methanol; at 20℃; for 1h; | o a 1000 mL four-necked flask was added 20 g of magnesium powder and 600 mL of anhydrous methanol, Slow heating to keep the methanol solution slightly boiling, Until all the magnesium residue is dissolved, slow cooling to get methanol magnesium methanol solution, sealed in the dryer to be used; To the 500 mL flask was added <strong>[119141-88-7]esomeprazole</strong> 50 g of a methanol solution of magnesium methoxide, Stirring at room temperature for 1h, remove most of the methanol under reduced pressure to get the target product <strong>[119141-88-7]esomeprazole</strong> magnesium, The reaction yield was 100.0%. |
86.5% | With hydrogenchloride; ammonium hydroxide; magnesium chloride; In water; at 0 - 5℃; for 2h;pH 7 - 8.5; | The above-mentioned aqueous ammonia water bath cooling, 0-5 C low-cost dilute hydrochloric acid to adjust the pH in 7.0-8.5, stirring by adding magnesium chloride solution (19 grams, dissolved in 40 grams of water), dropping the process of precipitation of white solid, drop finished, 0-5 C The crystals were further stirred for 2 hours, filtered and washed with water to give 17 g of a white solid. The resulting white solid was added to 100 g of absolute ethanol, stirred until fully dissolved, and the appropriate amount of activated carbon was decolorized, and the filtrate was stirred slowly. 500 g of purified water was added dropwise. A large amount of white solid was precipitated and the crystals were stirred for 3 hours. And dried to give 11.2 g of <strong>[119141-88-7]esomeprazole</strong> magnesium in 86.5% yield (based on 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride), 99.7% Purity 100%. |
74.7% | 3) adding 300 ml of methanol to the above oil,Add 770g of 5wt%Magnesium methoxide in methanol solution,Temperature control 25 ~ 30 C for 2h,Then, 4,500 ml of methyl tert-butyl ether was added dropwise with vigorous stirring.2h plus,Cool down to -5 to 0 C,Crystal growth 2h,filter,Esomeprazole magnesium wet product.Temperature control 30 ~ 35 C,The wet product is refined in a mixed solution of 1500 ml of water and 50 ml of methanol.Stir for 1h,filter,35:40 C dried <strong>[119141-88-7]esomeprazole</strong> magnesium trihydrate 159.5g,The yield is 74.7%.The purity is 99.76%, and the optical purity is 99.6%. |
Magnesium metal (2.08 grams) was suspended in a mixture of methanol (150.00 ml) and dichloromethane (5.0 ml) and cooled to a temperature OF 5-10C. Then, TO THE RESULTING REACTION MIXTURE CRUDE ESOMEPRAZOLE (50.0 GRAMS) ] DISSOLVED IN METHANOL (150.0 ml) was added. The resulting reaction mixture was slowly decomposed by adding water (900 ml) and stirred until a solid results. The resulting solid mass was filtered and washed with water (300 ml). The wet solid was suspended in acetone (200 ml) and stirred at a temperature of 0-5C until the solid separated. The separated solid was filtered and washed with acetone (50 ml). Further the wet solid was dissolved in methanol (300 ml) and filtered. Then by expelling the resulting filtrate white solid was isolated. The isolated white solid was recrystallised from a mixture of water (175 ml) and acetone (175 ml). The crystallized solid was dried at a temperature OF 60-65C to afford the title compound. [Weight: 8.5 grams). | ||
With magnesium sulfate; In DMF (N,N-dimethyl-formamide); hexane; acetic acid butyl ester; water; at 5 - 30℃; for 20h; | S-Omeprazole (10 gm), MGS04. 7H2O (5.5 gm), n-butyl acetate (200 ML), dimethylformamide (150 mi) and water (2.0 mi) are mixed and stirred for 15 hours between 20C and 30C. The solution is cooled to 5C, n-hexane (100 ml) is added and the contents are stirred for 5 hours between 5C AND10C. The separated crystals are filtered to give 7.3 gm of S-omeprazole magnesium hemihydrate. | |
With magnesium; In methanol; dichloromethane; for 12h;Product distribution / selectivity; | Example 6; Magnesium (0.18 gm) was dissolved in methanol (50 ml) and dichloromethane (0.5 ml) was added. The reaction mass was stirred at 25C for 5 hours under nitrogen. Then <strong>[119141-88-7]esomeprazole</strong> (3.0 gm) obtained as in example 3 was added and stirred for 12 hours. Water (20 ml) was added to reaction mass and stirred for 15 minutes. The precipitated solid was filtered and the solid was recrystallized from acetone and methanol to obtain 2.5 gm of <strong>[119141-88-7]esomeprazole</strong> magnesium dihydrate (enantiomeric excess: 99.6%, optical rotation: -128 (c = 0.5% methanol)). | |
With magnesium methanolate; In methanol; at 20℃; for 1h; | A stoichiometric amount of 7.6 wt.-% methanolic solution of magnesium methanolate (18.1 mL) was added to the solution of 9.0 g of <strong>[119141-88-7]esomeprazole</strong> (99.28% e.e.) in 100 mL of methanol. The obtained reaction mixture was stirred at room temperature for 1 hour allowing to form <strong>[119141-88-7]esomeprazole</strong> magnesium salt in the meantime. After addition of 0.4 mL of water the reaction mixture was further stirred for 30 min. The formed inorganic solid salts were separated from the liquid by filtration through a layer of diatomite filter medium (Celite). The volume of filtrate was then reduced by evaporation of methanol forming an <strong>[119141-88-7]esomeprazole</strong> magnesium solution with concentration 40-45 wt.-%. A mixture of 51 mL of acetone and 2.9 mL of water was added to the concentrate. The mixture was seeded with a 0.05 g of <strong>[119141-88-7]esomeprazole</strong> magnesium dihydrate form B. After a few minutes a precipitate was formed and the suspension was stirred for 4 hours. The product was filtered off, washed twice with 10 mL of a mixture of acetone and methanol (4/1(V/V)). The wet filter cake was dried for 20 hours at reduced pressure (200 mbar). 8.00 g of <strong>[119141-88-7]esomeprazole</strong> magnesium dihydrate form B was obtained (99.84% e.e. determined by chiral HPLC, 100% purity determined by HPLC, 6.1% of water content determined by Karl-Fisher, 1.98% of residual solvents content (methanol, acetone) as determined by GC). | |
With magnesium methanolate; In methanol; at 20℃; for 0.5h;Inert atmosphere; | 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1 /-/-benzimidazole (4a) (9.87 g, 30 m m o l ) a n d (R,R)-(-)-Lambda/,Lambda/'-bis(3,5-di-tert-butylsalicylidene)-1 ,2-cyclohexanediamino- manganese(lll) chloride (2a) (0.953 g, 5 mol%) are dissolved in acetonitrile (225 ml). The reaction mixture is cooled to -100C and 30% aqueous H2O2 (92 ml, 30 mol eqiuv) is added dropwise over 6 hours. The reaction mixture is stirred for additional 8 hours. HPLC analysis shows formation of 62% of sulfoxide with 52% ee (S-enriched). 10% Aqueous Na2SO3 (1 I) is slowly added to the reaction mixture. The mixture is extracted with ethyl acetate (2 x 1 I). The combined organic phases are dried over Na2SO4 and concentrated. The resulting oily residue is dissolved in methanol (50 ml) and purified by HPLC chromatography (ChiralPak AD, 20 mum particle size, eluent methanol).Combined fractions containing S-omeprazole are concentrated to reach concentration of ca. 400 mg of S-omeprazole / 1 ml of MeOH. 6% Solution of Mg(OMe)2 in MeOH (prepared from 0.1 2 g of magnesium tu rnings and 9 ml of MeOH with added catalytic amount of dichloromethane) is added to the concentrated solution of S-omeprazole. The reaction mixture is stirred for half an hour at room temperature under inert atmosphere. Then it is slowly poured into methyl t-butyl ether (320 ml) under vigorous stirring. The formed suspension is cooled to -100C and kept at this temperature for an hour. After filtration and washing with methyl t-butyl ether (32 ml) the solid is dried at 40 0C under vacuum to get 3.63 g of S-omeprazole magnesium salt with 99.6 % ee and 0.14% of sulfone. | |
With magnesium methanolate; In methanol; at 25 - 30℃;Inert atmosphere; | Example 2 Magnesium turnings (1.02 gm) are dissolved and reacted with methanol (90 ml) at 40 C. with a catalytic amount of methylene dichloride, the resulting solution is stirred for 5-6 hours at 35-40 C. under nitrogen atmosphere and then cooled to 25-30 C. To the resulting magnesium methoxide solution added <strong>[119141-88-7]esomeprazole</strong> (30 gm) and then the contents are stirred for 30 minutes at 25-30 C. Distilled off methanol completely under vacuum at below 40 C. and then co-distilled two times with methylene dichloride (each time 150 ml). To the residue added methylene dichloride (1500 ml) and anhydrous Na2SO4 (30 gm) at 25-30 C., the contents are stirred for 15 minutes, the resulting mass is passed on hi-flow and washed the bed with methylene dichloride (150 ml). The resulting filtrate is distilled under vacuum at below 40 C. and then co-distilled with methanol (75 ml). To the resulting residue added methanol (240 ml) and water (4.5 ml), stirred for 15 minutes at 25-30 C. and then distilled under vacuum at below 40 C. until the mass volume reaches to 60 ml. To the resulting mass added acetone (100 ml) slowly at 35-40 C., stirred for 10 minutes, and again added acetone (120 ml), stirred for 10 minutes and then cooled to 25 C. The mass is stirred for 2 hours at 20-25 C., further cooled down to 5 C. and stirred for 30 minutes at 5-10 C. Filtered the material, washed with acetone (30 ml) and then dried at 45-50 C. for 4-5 hours to give 16.8 gm of <strong>[119141-88-7]esomeprazole</strong> magnesium dihydrate (Assay by HPLC: 99.7%; content of trihydrate form: Not detected). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In acetonitrile; at 20℃; for 2h; | Esomeprazole (1.0 g, 2.9 mmol) was dissolved in acetonitril (20 ML) at room temperature. 1-Adamantan amine (0.86 g, 5.7 mmol) was added to the solution whereupon a white solid precipitated. The reaction slurry was stirred at room temperature for additional two hours. The formed precipitate was filtered off, washed with acetonitril (10 ml), and dried. 1.13 g (83 %) of the title compound was obtained. 1H NMR (400 MHZ, CD2C12) : 1.48 (bs, 18H), 2.14 (s, 3H), 2.18 (s, 3H), 3.66 (s, 3H), 3.78 (s, 3H), 4.46 (d, 1H), 4.66 (d, 1H), 6.88 (d, 1H), 6.95 (m, 1H), 7.52 (d, 1H), 8.15 (s, 1H) The prepared compound was analysed by XRPD resulting in the diffractogram shown in Figure 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-(2-adamantyl)amine; esomeprazole In ethyl acetate Stage #2: In ethyl acetate; acetonitrile at 20℃; | 3 Esomeprazole (0.5 g, 1.4 mmol) was dissolved in a solution of 2-Adamantanamine (0.44 g, 2.9 mmol) and ethyl acetate (10 ml). The obtained solution was concentrated to about 4 ml and acetonitrile (10 ml) was added. The resulting mixture was concentrated once more to about half, whereupon a white solid started to precipitate. The reaction slurry was stirred at room temperature over night. The precipitated product was filtered off and washed with acetonitrile. 0.1 g of the title compound was obtained. 1H-NMR (400 MHZ, CD30D) : 1.64 (d, 2H), 1.77-1. 88 (m, 8H), 1.93 (d, 2H), 2.02 (d, 2H), 2.16 (s, 3H), 2.25 (s, 3H), 3.10 (bs, 1H), 3.70 (s, 3H), 3.86 (s, 3H), 4.69 (d, 1H), 4.84 (d, 1H), 6.92 (dd, 1H), 7.11 (d, 1H), 7.52 (d, 1H), 8. 15 (s, 1H) The prepared compound was analysed by XRPD resulting in the diffractogram shown in Figure 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With barium dihydroxide In methanol at 25 - 30℃; for 1 - 2h; | 1 Example 1 : A First Preparation Of (S .-OMEPRAZOLE BARIUM in crystalline form (S) -OMEPRAZOLE FREE BASE (5G,) WAS ADDED TO METHANOL (25ML) AND STIRRED AT 25- 30°C. Barium hydroxide (4.6g) dissolved in methanol (40ML) was slowly added to the above solution in 10 minutes at 25-30°C. The reaction mixture was further stirred for 1 to 2 hours, the obtained solid was filtered and washed with methanol. The product was air DRIED AT 40 TO 45°C FOR 8 TO 10 HOURS TO GET (S) -OMEPRAZOLE BARIUM (5.2G). HPLC Purity = 98.56%, Chiral Purity by HPLC= 99.89 %. MC% w/w by KF = 4.12 %. XRD, IR spectra are as shown in Figure I and II respectively, as shown in the accompanying drawings. | |
With barium dihydroxide In water; acetone at 25 - 30℃; for 4 - 5h; | 3 Example 3: Preparation Of (S)-OMEPRAZOLE barium in amorphous form (S) -OMEPRAZOLE FREE BASE (5G,) WAS ADDED TO ACETONE (60ML) AND STIRRED AT 25-30° C. Barium hydroxide octahydrate (4.6) and water (15ML) were then added to the above mixture at 25-30°C. The reaction mixture was further stirred for 4 to 5 hours, and then filtered to remove suspended solid material. The solvent was recovered under reduced pressure to obtain the product as a foam. The product was dried at 40 to 45°C under reduced pressure for 2 to 3 hours to get (S)-OMEPRAZOLE barium (4.2g). HPLC Purity = 99. 43%, Chiral Purity by HPLC= 99.99 %, MC% w/w by KF = 2.66 %. XRD, IR spectra are as shown in Figure IV and V respectively, as shown in the accompanying drawings | |
With barium dihydroxide In methanol | 10 Esomerprazole free base 52.1gm was suspended in 5 volume methanol. A solution of barium hydroxide (prepared by dissolving 49 gm barium hydroxide in 8 volume methanol) was added to the esomeprazole solution in methanol. The mixture was stirred overnight and then filtered. The precipitate was dried to get 50 gm esomeprazole barium. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol at 10 - 50℃; for 3h; | 2 Example 2; (S)-5-MethOxy-2-[[(3, 5-dimethyl-4-nitro-2-pyridinyl) methyl] sulfinyl]-1 H- benzimidazole (ee: 95%, 10 gm) is mixed with methanol (100 ml) and the contents are cooled to 10°C. Sodium methoxide solution (20 ml, 30% in methanol) is added and heated to 50°C. The contents are maintained at this temperature for 3 hours, cooled to 25°C and water (100 ml) is added. The pH of the reaction mass is adjusted to 8.0 with acetic acid. Then the reaction mass is extracted with methylene dichloride (100 ml), the layers are separated and the methylene dichloride layer is washed with water (100 ml). Methylene dichloride layer is dried with sodium sulfate, methylene dichloride solvent is distilled off to obtain (S)-5-MethOxy-2-[[(4-methOxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H- benzimidazole as residue. The residue is dissolved in methanol (30 ml), cooled to 10°C and then potassium hydroxide (1.5 gm) in methanol (10 mi) is added slowly for 15 minutes. The reaction mass is stirred for 12 hours and the solid obtained is filtered to obtain potassium salt of (S)-5-Methoxy-2- [ [ (4-methoxy-3, 5- dimethyl-2-pyridinyl) methyl] sulfinyl]-1 H-benzimidazole (ee: 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium hydroxide; In methanol; at 10℃; for 12.25h; | Example 2; (S)-5-MethOxy-2-[[(3, 5-dimethyl-4-nitro-2-pyridinyl) methyl] sulfinyl]-1 H- benzimidazole (ee: 95%, 10 gm) is mixed with methanol (100 ml) and the contents are cooled to 10C. Sodium methoxide solution (20 ml, 30% in methanol) is added and heated to 50C. The contents are maintained at this temperature for 3 hours, cooled to 25C and water (100 ml) is added. The pH of the reaction mass is adjusted to 8.0 with acetic acid. Then the reaction mass is extracted with methylene dichloride (100 ml), the layers are separated and the methylene dichloride layer is washed with water (100 ml). Methylene dichloride layer is dried with sodium sulfate, methylene dichloride solvent is distilled off to obtain (S)-5-MethOxy-2-[[(4-methOxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H- benzimidazole as residue. The residue is dissolved in methanol (30 ml), cooled to 10C and then potassium hydroxide (1.5 gm) in methanol (10 mi) is added slowly for 15 minutes. The reaction mass is stirred for 12 hours and the solid obtained is filtered to obtain potassium salt of (S)-5-Methoxy-2- [ [ (4-methoxy-3, 5- dimethyl-2-pyridinyl) methyl] sulfinyl]-1 H-benzimidazole (ee: 95%). |
84.33% | With potassium hydroxide; In methanol; toluene; at 10 - 30℃; for 2.5h; | (1) The <strong>[119141-88-7]esomeprazole</strong> reaction solution obtained in Example 2 was cooled to below 10 C, and potassium hydroxide methanol was slowly added.a solution (5.92 kg of potassium hydroxide dissolved in 40 kg of methanol) to precipitate a solid;(2) The temperature was raised to 25 to 30 C and the reaction was stirred for 2 hours. Filtration, filter cake mixed with 14.6kg of toluene and 14.6kg of methanolThe solution is beaten for 30 minutes and filtered;(3) The filter cake is dried under reduced pressure at 40 to 45 C to obtain 21.5 kg of Esomeprazole potassium having a purity of 97.216% (see Figure 2).Crude (intermediate 2, containing 20.90g of Esomeprazole potassium, molecular weight 384, ie 54.427mol), sampled for inspection, in line with the middleThe body 2 quality control standard enters the refining process. If it is unqualified, rework will be carried out until it meets the intermediate 2 quality control standard.(The intermediate 2 quality control standard: if there is impurity peak in the chromatogram of the test solution, containing intermediate I (OmiLazosole) should not be larger than the main peak area of the impurity control solution (0.5%), and the impurity D with a relative peak retention time of about 0.95 is pressed.The area normalization method shall not exceed 3.0%, and the other single impurity peaks shall be calculated according to the area normalization method, not exceeding 1.5%, and impurities.The total amount does not exceed 5.0%, the ratio of the optical isomer peak area to the sum of the areas of the optical isomer and the <strong>[119141-88-7]esomeprazole</strong> peak areaCalculated, no more than 1.0%, as shown in Figure 2.Rework treatment method: the obtained intermediate 2 is added to a 2 times mass volume of a toluene/methanol mixed solution, and beating 1Hours, filtered. The filter cake was dried under reduced pressure at 40 to 45 C.The crude product (Intermediate 2) yield was 84.33% ((54.427 / 64.54) * 100%). |
With potassium hydroxide; In methanol; at 5 - 25℃; for 14.5h; | Example 4; The residue (4.5 gm) obtained as in example 3 was dissolved in methane) (25 ml) at 25C and the solution was cooled to 5-10C. Potassium hydroxide solution in methanol (1.5 gm in 8 ml methanol) was added slowly for 30 min. During addition of potassium hydroxide solution, solid was thrown out. The temperature was raised to 25C, stirred for 14 hours, filtered and dried to obtain 4.5 gm of potassium salt of (S)-5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2- pyridyl)methylsulfinyl] 1-H-benzimidazole (Esomeprazole potassium) (Eantiomeric excess: 99.6%). |
With potassium hydroxide; In dichloromethane; water; for 2h;Product distribution / selectivity; | EXAMPLE 3[0076] Preparation of 5-Methoxy-2-[(S)-(4-methoxy-3,5-dimethyl-2- pyridinylmethyl)sulfmyl]-lH-benzimidazole potassium.[0077] Esomeprazole (10 g) was dissolved in methylene dichloride (50 ml). A solution of potassium hydroxide solution (1.46 grams of potassium hydroxide dissolved in 25 ml of water) was added to the solution and stirred for 120 minutes. The aqueous layer was separated and concentrated in a rotary evaporator under vacuum below 400C. To the residue, acetone (200 ml) was added and stirred. Acetone was distilled out completely in a rotary evaporator under vacuum to obtain <strong>[119141-88-7]esomeprazole</strong> potassium solid (5.5 g). XRD confirmed the <strong>[119141-88-7]esomeprazole</strong> potassium was form X having a characteristic d-spacing value at 16.6 and 2-Theta value 5.3. [0078] HPLC purity: 99.5 %EXAMPLE 4[0079] Preparation of 5-Methoxy-2-[(S)-(4-methoxy-3,5-dimethyl-2- pyridinylmethyl)sulfmyl]-lH-benzimidazole potassium.[0080] Esomeprazole (10 g) was dissolved in methylene dichloride (50 ml). A solution of potassium hydroxide solution (1.46 grams of potassium hydroxide dissolved in 25 ml of water) was added to the solution and stirred for 120 minutes. The aqueous layer was separated and spray dried in a spray drier to obtain <strong>[119141-88-7]esomeprazole</strong> potassium solid (3.8 gm). XRD confirmed the <strong>[119141-88-7]esomeprazole</strong> potassium was Form X having a characteristic d- spacing value at 16.6 and 2-Theta value 5.3. [0081] HPLC purity: 99.55% | |
With potassium hydroxide; In methanol; butanone;Cooling with ice; | 4.47 g (13.5 mmol) of the compound of formula III, 45 ml of dried toluene and 2.21 g (13.35 mmol) of (5)-mandelic acid methyl ester (general formula IV: X = OMe, Y = H; IVc) were placed in a 3-neck 100-ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated in an oil bath to a temperature in the range of 50 to 55 C. Then, 1.37 ml of Ti(Oz'-Pr)4 (general formula V: Z = Ti, R5 = z-Pr; 3.3 mmol) were added to this mixture at once. The resulting mixture was stirred at a temperature in the range of 50 to 55 C for 1 hour. Then, the reaction mixture was maintained at a temperature of +5 to 10 C and 2.14 ml of 88% cumene hydroperoxide were added. The reaction mixture was stirred at a temperature of +5 to 10 C for 4 hours. Then 75 ml of a 12.5% solution of ammonium hydroxide were added to the reaction mixture. The resulting suspension was filtered through filtration paper. The filtration cake was washed with 15 ml of a 12.5% solution of ammonium hydroxide. The toluene fraction was separated and the aqueous fraction was placed in an Erlenmeyer flask, 75 ml of dichloromethane were added and it was carefully acidified with acetic acid to pH 8-9 under stirring and cooling with ice. The dichloromethane fraction was separated in a separating funnel, washed with 15 ml of water, dried with anhydrous sodium sulfate and evaporated in an evaporator. 3.51 g of crude <strong>[119141-88-7]esomeprazole</strong> were obtained and mixed with 75 ml of ethylmethylketone. 5.2 ml of a KOH solution in methanol (3 g of KOH in 25 ml of methanol) were added to the mixture cooled with ice. After seeding the solution was left to crystallize at the temperature of +5 C for 5 hours. The crystalline product was extracted and air dried. 2.93 g of the potassium salt of <strong>[119141-88-7]esomeprazole</strong> were obtained, which provided 1.15 g of the potassium salt of <strong>[119141-88-7]esomeprazole</strong> after repeated crystallization.-NMR (250 MHz, DMSO): 8.22 (s, IH), 7.31 (d, 8.9 Hz, IH), 6.96 (d, 2.3 Hz, IH), 6.55 (dd, 2.3 Hz, 8.6 Hz, IH), 4.78 (d, 13.1 Hz, IH), 4.38 (d, 13.1 Hz, IH), 3.72 (s, 3H), 3.69 (s, 3H), 2.23 (s, 3H), 3.20 (s, 3H).HPLC chemical purity: 99.85 %. HPLC on the chiral phase (CHIRALPAK AD-H, mobile phase 50% hexane : 50% ethanol, detection 302 nm): enantiomeric excess 99.8 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In acetonitrile at 20℃; for 2h; | 2 Example 2: S-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) -methyl] sulfinyl]-lH- benzimidazole tert-butyl ammonium salt.; Esomeprazole sodium salt was dissolved in water and esomeprazole was precipitated by the addition of carbon dioxide. Esomeprazole (1.0 g, 2.9 mmol) was dissolved in acetonitril (10 ml) at room temperature. Tert-butylamine (0.42 g, 5.7 mmol) was added and the mixture was stirred at room temperature for 2 h. The formed precipitate was filtered off and washed with acetonitril (5 ml). 714 mg (59%) of the title compound was obtained. Optical rotation [α]D20 +26.1 (1% solution in water) 1H-NMR (500 MHz, CDC13) : 1.15 (s, 9H), 2.20 (s, 3H), 2.22 (s, 3H), 3.68 (s, 3H), 3.83 (s, 3H), 3.14 (bs, 3H), 4.69-4. 80 (m, 2H), 6.90-6. 94 (m, 1H), 7.01 (d, 1H), 7.52 (d, 1H), 8.20 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In methanol;Chiral supercritical fluid chromatography; Resolution of racemate;Purification / work up; | Preparation of R-Omeprazole and S-Omeprazole from rac-Omeprazole by means of Chiral Supercritical Fluid Chromatography. Omeprazole (2517.6 mg; 7.289 mmol) was placed in a volumetric flask (100 mL) with 0.4% triethylamine (TEA) in methanol, dissolved by means of sonication, and brought to volume. The solution was injected onto a Berger Multigram Supercritical Fluid System under the following conditions: Column: Chiralpak AS-H SFC Column Dimensions: 20 mm×250 mm; 5 mum particle size Column Temperature: 35 C. Column Pressure: 100 bar Detection: 302 nm Flow rate: 50 mL/minute Mobile Phase: 75:25 Carbon Dioxide: Methanol with 0.4% TEA Injection Volume: 0.75 mL The fractions of each enantiomer were collected into separate ice chilled flasks. After collection, the solvent was removed by rotary evaporation and the resulting oils were used directly in a subsequent experiment (see Example 4). | |
With N,N-dimethyl-ethanamine; In ethanol;Chiral supercritical fluid chromatography; Resolution of racemate;Purification / work up; | Preparation of R-Omeprazole and S-Omeprazole from rac-Omeprazole by means of Chiral Supercritical Fluid Chromatography. Omeprazole (2463.0 mg; 7.130 mmol) was placed in a volumetric flask (200 mL) with 0.3% dimethylethylamine (DMEA) in ethanol, dissolved by means of sonication, and brought to volume. The solution was injected onto a Berger Multigram Supercritical Fluid System under the following conditions: Column: Chiralpak AS-H SFC Column Dimensions: 20 mm×250 mm; 5 mum particle size Column Temperature: 35 C. Column Pressure: 150 bar Detection: 302 nm Flow rate: 50 mL/minute Mobile Phase: 75:25 Carbon Dioxide: Ethanol with 0.3% DMEA Injection Volume: 1.0 mL The fractions of each enantiomer were collected into separate ice chilled flasks. After collection, the solvent was reduced by rotary evaporation to approximately 10 ml, and the diluted products used in a subsequent experiment (see Examples 7 and 8) | |
With N,N-dimethyl-ethanamine; In methanol;Chiral supercritical fluid chromatography; Resolution of racemate;Purification / work up; | Preparation of R-Omeprazole and S-Omeprazole from rac-Omeprazole by means of Chiral Supercritical Fluid Chromatography. Omeprazole (2552.4 mg; 7.389 mmol) was placed in a volumetric flask (100 mL) with 0.3% dimethylethylamine (DMEA) in methanol, dissolved by means of sonication, and brought to volume. The solution was injected onto a Berger Multigram Supercritical Fluid System under the following conditions: Column: Chiralpak AS-H SFC Column Dimensions: 20 mm×250 mm; 5 mum particle size Column Temperature: 35 C. Column Pressure: 100 bar Detection: 302 nm Flow rate: 50 mL/minute Mobile Phase: 75:25 Carbon Dioxide: Methanol with 0.3% DMEA Injection Volume: 0.75 mL The fractions of each enantiomer were collected into separate ice chilled flasks. After collection, the solvent was removed by rotary evaporation. The resulting oils were used in a subsequent experiment (see Example 6). |
at 20℃;Resolution of racemate; | Racemic mixtures of omeprazole were resolved and separated into (S)- and (R)-enantiomers using chiral column chromatography. The omeprazole mixture were dissolved in methanol and diluted to a concentration of about 22-25 g/L. About 0.01 v/v % of diethylamine was also added to the mixtures. The chromatographic separation was carried out under the following conditions: Stationary phase: CHIRALPAK AD, 20 mum particle size Column length: 250-350 mm Mobile phase: methanol Loading: mLOAD/SCOLUMN=175-220 mg/cm2, Flow rate=3.8-4.2 cm/min. Temperature: room temperature Flow rate during S-enantiomer elution: 5.7-6.2 cm/min. Flow rate during R-enantiomer elution: 9.0-11.8 cm/min. UV detector: 325 nm Run time: 22-26 min. | |
With CHIRALPAK AD; diethylamine; In methanol;Resolution of racemate; | Example 1; Preparation of neutral esomeprazole Neutral racemic omeprazole of chemical purity of 99.91 % (commercially available) was dissolved in 0.005 % solution of diethylamine in methanol (24 g omeprazole per L) and the solution was loaded to column (ChiralPak AD, 20 mum particle size, column length 350 mm). Products were eluted by methanol and S-enantiomer was collected first. The prepared solution was injected several times to the top of chromatographic column until the wanted quantity was obtaining. The collected main fractions were evaporated at the temperature below 40C under reduced pressure until the concentration of 100 - 300 g/l of active substance was reached. | |
With diethylamine; In methanol;Resolution of racemate;Product distribution / selectivity; | Racemic mixture of omeprazole is resolved and separated into S- and R-enantiomer using chiral column chromatography. Omeprazole is dissolved in methanol and diluted to a concentration of about 22 - 25 g / L. About 0.01 % (V/V) of diethylamine is also added to the solution. The chromatographic separation is carried out under the following conditions: Stationary phase: CHIRALPAK AD, 20 mum particle sizeColumn length: 250-350 mmColumn diameter : 5 cmMobile phase: methanolLoading: mLOAD/ SCOLUMN = 175-220 mg/cm2, Linear velocity = 3.8-4.2 cm/min.Temperature: room temperatureLinear velocity during S-enantiomer elution: 5.7-6.2 cm/min.Linear velocity during R-enantiomer elution: 9.0-11.8 cm/min.UV detector: 325 nmRun time: 22-26 min; Example 3 7.2 kg of omeprazole is resolved and separated into S- and R-enantiomers using chiral column chromatography. Omeprazole is dissolved in methanol and diluted to a concentration of about 22 - 25 g / L. About 0.01 % (V/V) of diethylamine is also added to the solution. The chromatographic separation is carried out under the analogous conditions as described in Example 2 using a column of length 300 mm and of diameter 15 cm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium methylate; In methanol; at 20℃; for 1h; | To 50 mL of <strong>[119141-88-7]esomeprazole</strong> was added to a 1000 mL flask, Add 200mL of methanol to dissolve, then add sodium methoxide 8g,Stirred at room temperature for 1 h,TLC monitoring raw material reaction is complete,The methanol was removed under reduced pressure,Add 200 mL of acetone to the flask,The mixture was stirred for 1h, filtered and the filter cake was dried in vacuo to give 53g of the white crystalline powder <strong>[119141-88-7]esomeprazole</strong> sodium, the yield was 100%. |
95.2% | With sodium hydroxide; In methanol; at 25℃; for 1h; | 700 g (2.03 mol) of the purple oil obtained in Example 8 was added, and 500 ml of the product was addedAnhydrous methanol stirring dissolved, then add 700ml anhydrous methanol and 90g (2.25mol)Sodium hydroxide was stirred at 25 C for 1 hour and then 4500 ml of methyl tert-butyl ether was added,10 stirring about 12 hours, a solid precipitation, filtration, vacuum drying, get Esso US657.1 g of crude oxazole sodium, molar yield 88.1%, HPLC purity 98.2%, ee value 99.94%. The reaction flask was charged with 500 g (1.36 mol) of the crude <strong>[119141-88-7]esomeprazole</strong> sodium of Example 9,1000ml of methylene chloride and 1000ml of water, stirring down to about 0 ; slowly addedGlacial acetic acid, the pH value adjusted to 6.5-6.8 (about 100ml), plus, stirring extraction 0.5Hour, the liquid, the water phase with dichloromethane and then extract twice 500ml / times * 2. Merge all organicThe mixture was dried over 40 g of anhydrous sodium sulfate for 2 hours, filtered and the solvent was evaporated under reduced pressure to givePurple oil. Add 350ml of anhydrous methanol stirring dissolved, then add 500ml anhydrousMethanol and 60.0 g (1.50 mol) of sodium hydroxide were added and stirred for 1 hour before addition2700ml methyl tert-butyl ether, 10 or so for 12 hours, a large number of solid precipitation, tooAnd dried under reduced pressure to obtain 476.0 g of estradiol sodium, the molar yield was 95.2%, and the HPLCPurity 99.7%, ee value 99.97%. |
94.82% | With sodium methylate; In methanol; at 40℃; for 6h; | To <strong>[119141-88-7]esomeprazole</strong> in 34.5g (100 mmol), was added to 60m1 of methanol was stirred solution, was added dropwise 27% sodium methoxide solution 60g, reaction 6h 40 , filtered and the filtrate was concentrated under reduced pressure, the obtained crude product were added 100ml of ethyl acetate, after stirring suction filtration, the filter cake was washed with acetone, and dried to obtain 34.8 g of <strong>[119141-88-7]esomeprazole</strong> sodium, yield 94.82%, purity 99.33%, impurity sulfone 0.38% [HPLC method, conditions as above], melting point: 247.6 ~ 249.2C. |
87% | With sodium hydroxide; In water;Product distribution / selectivity; | EXAMPLE 15Preparation of Esomeprazole SodiumEsomeprazole obtained in example 14 (54.5 g; 157.78 mmol), was dissolved in a solution of aqueous NaOH (136.24 g; 4.88% w/w) and DM water (30 ml). The solution was washed with methylene chloride twice (200 ml×2). The aqueous layer was filtered and concentrated completely under reduced pressure to yield viscous mass. Ethanol was added to the viscous mass and concentrated under reduced pressure. Thereafter, ethyl acetate was added and concentrated to dryness under reduced pressure to yield solid mass. Further, ethyl acetate (400 ml) was added and stirred the mixture under reflux for 30 min. Cooled the reaction mass to 20-30 C. and stirred for 3 h. The separated solid was filtered, washed with ethyl acetate and dried under reduced pressure at 40 C. to yield <strong>[119141-88-7]esomeprazole</strong> sodium.Yield-50.6 g (87%)Enantiomeric excess-99.96%. |
87.5% | With sodium hydroxide; In methanol; for 2h; | [...] crude preparation:Taking 2.8 kg intermediate, for 5L methanol dissolved, dropping 10% methanol solution of sodium hydroxide 2.35L, stirring 2h. The pressure of the steam to about the quality of the product 1 times the volume of the remaining methanol, dropping 23L ethyl acetate, stirring 5h, filtering, drying, be 1.57 kg white solid.[...] refining:In the bag the essence dries, 10L three mouth bottle I add methanol 6.9L, opening stirring, input 1.37 kg [...] crude, heating to 40 C, dissolves clear, adding 140g activated carbon stirring 30 minutes, to take advantage of the heat filter to the 10L three mouth bottle II, concentrated under reduced pressure to a predetermined scale, shut off the vacuum, after the natural cooling to room temperature, 0 C continuously stirring 5 hours, filtered, for 300 ml ethyl acetate washing the filter cake, the filter cake collected, into the hot air circulation in the oven, the oven temperature 35 C drying, then into the drying in the vacuum drying box, shall be [...] works, yield: 87.5%. M.p. 246 - 249 C, in accordance with the import quality standard detecting HPLC chemical purity 99.91%, ee %=99.7%, |
87.8% | With sodium hydroxide; In ethanol; at 25℃; for 1h; | 700 g (2.03 mol) of the purple oily product obtained in Example 7,Add with 500ml of anhydrous ethanol stirring dissolved,A mixed solution of 700 ml of absolute ethanol and 90 g (2.25 mol) of sodium hydroxide was added,25 C for 1 hour and then add 4000ml of methyl tert-butyl ether (<strong>[119141-88-7]esomeprazole</strong> sodium insoluble solvent, can promote crystallization)Stirring at about 10 C for 12 hours,There is solid precipitation,filter,Vacuum drying,To obtain 654.8 g of crude <strong>[119141-88-7]esomeprazole</strong> sodium,The molar yield was 87.8%HPLC purity 98.4%Ee value of 99.92% |
65.7% | With sodium hydroxide; In water; acetone; at 0 - 10℃; for 7h;Reflux; | In a 3000 mL three-necked round bottom flask,Add 270 ml of methanol,2-Mercapto-5-methoxybenzimidazole 90. 0 g (0.50 mol),Stirring,Add an aqueous sodium hydroxide solution (40.0 g sodium hydroxide/100 ml purified water).Stir the reaction at room temperature for 1 hour.2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride 110 g (0.50 mol) was added,Methyl tert-butyl ether (900 ml) was heated to 35-45 C for 3 hours.After the reaction,Cool the feed to room temperature,Purified water 250 ml*2 was added twice to the remaining stock solution.Obtained methyl sulfide tert-butyl ether solution,The water bath is heated to 50-60C,Addition of 62.5 g (0.30 mol) of D-(-)-diethyl tartrate,Tetraisopropyl titanate 43.0 g (0.15 mol),Insulation for 1 hourAfter cooling to 25-35C,Triethylamine 15.0 g (0.15 mol) was added,Cumyl hydroperoxide was added dropwise 72.0 g (0.475mol),Insulation dropwise. The reaction 1. 5h,After the reaction,Add 15% ammonia water 400ml to the reaction solution.Stir for 20min,Extraction liquid, The organic layer was extracted twice with 15% aqueous ammonia 400ml*2.Combined ammonia layer,Add activated carbon 12 g to decolorize at room temperature for 4 hours.filter,Ammonia layer is added with ethyl acetate 900 ml,Ice bath cooling to 5-15 C,The glacial acetic acid was added dropwise to adjust the pH to 7. 5-8. 5,Dividing fluid,The aqueous layer was extracted with ethyl acetate 450ml for the second extraction.Combine the ethyl acetate layers,Wash 400 ml*2 twice with saturated saline solution.Ethyl acetate extraction phase,Temperature control 35 ~ 45 C vacuum concentration,Light brown oil 148.2 g,Add acetone 900 ml,Stir so that the oil is completely dissolved,Transfer the feed solution to a 2000 ml three-neck round bottom flask.Sodium hydroxide solution (18.1 g of sodium hydroxide/1. 8 g of purified water) was added,Heating reflux 60min,The crystal was dropped to 0-10C and stirred for 6h.Suction filtrationAcetone 50ml wash cake,Filter cake 35-45 C / -0. 095MPa vacuum drying 12h,120.7 g of <strong>[119141-88-7]esomeprazole</strong> sodium was obtained.Yield 65.7%.HPLC: 99.6%,Ee%: 99.7%. |
52% | With sodium methylate; In methanol; acetone; butanone; at 20 - 27℃;Product distribution / selectivity; | Example 16: Preparation of <strong>[119141-88-7]esomeprazole</strong> sodium using acetone/methyl ethyl ketone and a solution of sodium methoxide in methanol A solution of <strong>[119141-88-7]esomeprazole</strong> (19.5 g, 56.5 mmol; 1 .3% sulfone,1 .05% R- enantiomer) in methyl ethyl ketone (60 ml_) and acetone (60 ml_) was cooled to 15 C. 30% sodium methoxide in methanol (10.7 ml_, 57.6 mmol) was added in 15 min. Subsequently, the solution was stirred at 27 C. A solid started to crystallize. The resulting slurry was stirred overnight at room temperature. The solid was collected by filtration, rinsed with acetone (2 chi 20 ml_) and dried under reduced pressure at 50 C to yield <strong>[119141-88-7]esomeprazole</strong> sodium. Yield: 10.8 g (52%). Sulfone content: 0.05%. R-enantiomer content: 0.00%. |
With sodium hydroxide; In methanol; at 5 - 25℃; for 14.5h; | Example 6; The residue (6.5 gm) obtained as in example 5 was dissolved in methanol (40 ml) at 25C and the solution was cooled to 5-10C. Potassium hydroxide solution in methanol (2.0 gm in 10 ml methanol) was added slowly for 30 min. During addition of potassium hydroxide solution, solid was thrown out. The temperature was raised to 25C, stirred for 14 hours, filtered and dried to obtain 6.2 gm of potassium salt of (S)-5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2- pyridyl)methylsulfinyl]-1 H-benzimidazole (Esomeprazole potassium) (Enantiomeric excess: 99.4%). | |
With sodium hydroxide; In water; for 0.25h;Product distribution / selectivity; | Mix, S- (+)-Methyl mandelate 60.6 g, Toluene 250 ml and Titanium isopropoxide 15 ml, into a 500 ml R. B. Flask assembly and stir to make a clear solution under Nitrogen atmosphere. Heat the reaction mixture to 40C and maintain for 17 hr. Cool to 25-30C and charge Omeprazole sulfide 50 g and Diisopropylethylamine 1.35 ml to it and stir for 10-15 minutes. Add Cumene hydroperoxide (-80 % solution in cumene) 28 ml slowly through addition funnel to the reaction mixture at 25-30C. Stir the reaction mixture at 25-30C for 2.0 hr. Filter the solid and wash with Toluene 50 ml. Collect the filtrate and charge 12.5 % ammonia solution 300 ml, to the filtrate and stir the mixture for 15 minutes. Back extract the Toluene layer with 12.5% Ammonia solution; 200 ml and add Methyl isobutyl ketone 250 ml, to the combined aqueous layer. Adjust the pH of the solution to 7.3-7. 6 by adding Glacial Acetic acid at 25-30 C. Stir the content for 30 min. Separate the organic layer and extract the aq. layer with Methyl isobutyl ketone ; 50 ml. Charge sodium hydroxide solution (50% w/v) 11 ml to combined organic layer and stir the mixture for 15 minutes. Distil off solvent completely under vacuum at 55-60 C. Add Acetonitrile; 300 ml, to the residue and stir the content at 25-30C. Filter the product under nitrogen atmosphere and wash the cake with Acetonitrile 50 ml. Dry the product in vacuum at 50-55C. Yield of Esomeprazole sodium (22.4 g) with enantiomeric excess > 98%.; Example 2-Preparation of a salt of <strong>[119141-88-7]esomeprazole</strong> by following a known process involving Titanium catalyst complexed with a bidentate ligand Preparation of sodium salt of 5-methoxy-2- [ (S)- (4-methoxy-3, 5-dimethyl-2- pvridinylmethyl) sulphinyl]-lH-benzimidazole (csomprazole sodium)- Mix, Toluene 120 L, Omeprazole sulfide 30 Kg, followed by 204 ml Water, D- (-)- Diethyl tartrate 9.4 L and Titanium isopropoxide 7.98 Kg, into a 500 L reaction assembly and stir to make a homogenous suspension under Nitrogen atmosphere. Heat the reaction mixture to 50-52C and maintain for 1 hour. Cool to 15-20C and charge Diisopropylethylamine 3.56 Kg to it and stir for 10-15 minutes. Add Cumene hydroperoxide (-80 % solution in cumene) 16.37 Kg slowly through addition funnel to the reaction mixture at 0 to 5C. Stir the reaction mixture at 25-30C for 2.0 hr. Charge 12.5 % ammonia solution 240 L, to it and stir for 10-15 minutes. Back extract the Toluene layer with 12.5% Ammonia solution; 60 L and add Methyl isobutyl ketone 120 L, to the combined aqueous layer. Adjust the pH of the solution to 7.3-7. 6 by adding Glacial Acetic acid at 25-30 C. Stir the content for 30 min. Separate the organic layer and extract the aq. layer with Methyl isobutyl ketone ; 30 L. Charge sodium methoxide solution (30% w/v) about 15 Kg to combined organic layer and stir the mixture for 15 minutes. Distil off solvent completely under vacuum at 55-60 C. Add Acetonitrile; 90 L to the residue and stir the content at 25-30C. Filter the product under nitrogen atmosphere and wash the cake with Acetonitrile 60 L. Dry the product in vacuum at 50-55C. Yield of Esomeprazole sodium = about 18 Kg. Sulfone content: 4.0 % | |
Example 1.1; Preparation of <strong>[119141-88-7]esomeprazole</strong> sodium salt modification C; Esomeprazole-K (11.89 g) was dissolved in water (50 ml) and toluene (80 ml) was added.Then, the pH was adjusted to approximately 7 by adding acetic acid (5.89 ml, 25% v/v).The two phases were mixed for 10 minutes and then allowed to separate. The water phasewas removed and the remaining organic phase was washed with aqueous NaCl-solution(50 ml ,10%). After phase separation, methanol (4.24 ml) was added to the toluene phaseand, then 1 eq NaOH (1.52 ml, aq, 45%) was added. The solution was seeded with 25 mgEso-Na. The crystallisation was left over night with stirring, the crystals were filtered offby vacuum filtration and quickly washed twice with toluene (2x10 ml). The resulting wetfilter cake was dried shortly, e.g 2-5 minutes, in air before the analysis. | ||
Example 1.3; Preparation of <strong>[119141-88-7]esomeprazole</strong> sodium salt modification H; Esomeprazole-K (11.89 g) was dissolved in water (50 ml) and toluene (80 ml) was added.Then, the pH was adjusted to approximately 7 by adding acetic acid (5.89 ml, 25% v/v).The two phases were mixed for 10 minutes and then allowed to separate. The water phasewas removed and the remaining organic phase was washed with aqueous NaCl-solution(50 ml ,10%). After phase separation, 2-propanol (3.6 ml) was added to the toluene phaseand, then 1 eq NaOH (1.52 ml, aq, 45%) was added. The solution was seeded with 53 mgEso-Na. The crystallisation was left over night with stirring, the crystals were filtered offby vacuum filtration and quickly washed twice with toluene (2x10 ml). The resulting wetfilter cake was dried shortly, e.g'2-5 minutes, in air before the analysis. | ||
Example 1.2; Preparation of <strong>[119141-88-7]esomeprazole</strong> sodium salt modification E ; Esomeprazole-K (11.89 g) was dissolved in water (50 ml) and toluene (80 ml) was added.Then, the pH was adjusted to approximately 7 by adding acetic acid (5.89 ml, 25% v/v).The two phases were mixed for 10 minutes and then allowed to separate. The water phasewas removed and the remaining organic phase was washed with aqueous NaCl-solution(50 ml ,10%). After phase separation, ethanol (11.1 ml) was added to the toluene phaseand, then 1 eq NaOH (1.52 ml, aq, 45%) was added. The solution was seeded with 55 mgEso-Na. The crystallisation was left over night with stirring, the crystals were filtered offby vacuum filtration and quickly washed twice with toluene (2x10 ml). The resulting wetfilter cake was dried shortly, e.g 2-5 minutes, in air before the analysis. | ||
With sodium hydroxide; In methanol; at 10 - 30℃; for 10.25h; | Esomeprazole (100 gm) is dissolved in methanol (150 ml) at 25 - 300C, the solution is cooled to 100C and then the solution of sodium hydroxide (13 gm) in methanol (135 ml) is added for 15 minutes at 10 - 150C. The mass temperature is raised to 25 - 300C, stirred for 10 hours at 25 - 300C, the resulting mass is cooled to 100C and then stirred for 1 hour at 10 - 150C. Filtered the solid, washed the bed with chilled methanol and then dried at 45 - 500C to give 66 gm of <strong>[119141-88-7]esomeprazole</strong> sodium salt. | |
With sodium hydroxide; In methanol; at 15 - 30℃;Product distribution / selectivity; | Example 3; Preparation of <strong>[119141-88-7]esomeprazole</strong> sodium Form P 15 g of of sodium hydroxide was dissolved in methanol (300 ml). The obtained solution was added to 650 ml of <strong>[119141-88-7]esomeprazole</strong> concentrate (containing 130 g of <strong>[119141-88-7]esomeprazole</strong>) obtained as described in Example 1. The reaction mixture was stirred at the temperature between 15C - 30C allowing <strong>[119141-88-7]esomeprazole</strong> sodium salt to form (reaction time 0.5 - 1 h). The solution containing <strong>[119141-88-7]esomeprazole</strong> sodium salt was cooled to -5 C and seeded with a 0.04 g of <strong>[119141-88-7]esomeprazole</strong> sodium obtained in Example 2. The formed suspension was cooled to -10 C and stirred at the same temperature overnight. The crystals were filtered off by vacuum filtration. The obtained product was dried at the temperature below 35C under reduced pressure to get 61 g of <strong>[119141-88-7]esomeprazole</strong> sodium Form P with identical XRD diffractogram as in Example 2 (100.0 area % chromatographic purity, sodium 6.3 % per dry substance, methanol 10.0 % (w / w)). | |
With sodium hydroxide; In methanol; at 25 - 35℃; for 2h;Product distribution / selectivity; | EXAMPLE 1; To a solution of methanol (175 ml) and sodium hydroxide (8.7 g) in a four-neck round-bottom flask, <strong>[119141-88-7]esomeprazole</strong> (50 g) (dissolved in methanol (175 ml)) is added and the contents are stirred for about 2 hours at about 25C to 350C. The reaction mass is then subjected to distillation at about 7O0C. The residue is cooled to 25C to 35C. Ethyl acetate (250 ml) is added and the solution is subjected to distillation at about 250C to 35C under vaccum. The process of charging ethyl acetate and distilling is repeated twice using 250 ml of ethyl acetate to meet the specification that methanol content in the reaction mass must be less than 5%. To the resulting residue, which is substantially free of methanol, ethyl acetate (250 ml) is charged and stirred for about one hour at about 25C to 3O0C. The separated solid is filtered and washed with ethyl acetate (100 ml). The above wet compound is charged in a round bottom flask containing ethyl acetate (250 ml) and stirred for about one hour at 25C to 35C. The compound is filtered, washed with ethyl acetate (100 ml), and suction dried to afford <strong>[119141-88-7]esomeprazole</strong> sodium. | |
With sodium hydroxide; In methanol; at 10 - 30℃; | Reference Example 1 Esomeprazole (100 gm) is dissolved in methanol (150 ml) at 25-30 C., the solution is cooled to 10 C. and then the solution of sodium hydroxide (13 gm) in methanol (135 ml) is added for 15 minutes at 10-15 C. The mass temperature is raised to 25-30 C., stirred for 10 hours at 25-30 C., the resulting mass is cooled to 10 C. and then stirred for 1 hour at 10-15 C. Filtered the solid, washed the bed with chilled methanol and then dried at 45-50 C. to give 66 gm of <strong>[119141-88-7]esomeprazole</strong> sodium salt. | |
With sodium hydroxide; In methanol; at 0 - 25℃; for 13.5h; | Example 3The 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]1-H-benzimidazole (40 gm, <strong>[119141-88-7]esomeprazole</strong>:R-omeprazole=11:1) obtained as in example 1 was dissolved in methanol (80 ml) at 25 C. and the solution was cooled to 10 C. Sodium hydroxide solution in methanol (10 gm in 120 ml methanol) was added slowly for 30 min. The contents were stirred for 3 hours at 5-10 C. The temperature was raised to 20-25 C. for 10 hours and then cooled to 0 C. and stirred for 2 hours at 0-5 C. The solid obtained was collected by filtration and the solid was washed with chilled methanol (20 ml) and diisopropylether (100 ml) to obtain 26 gm of sodium salt of (S)-5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]1-H-benzimidazole (Esomeprazole sodium) (Enantiomeric excess: 99%). | |
With sodium hydroxide; In 3-methyl-butan-2-one; water; acetonitrile; | 3.28 g (10 mmol) of the compound of formula III, 35 ml of dried toluene and 1.10 g (6.67 mmol) of (5)-mandelic acid methyl ester (general formula IV: X = OMe, Y = H; IVc) were placed in a 3-neck 100-ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated in an oil bath to a temperature in the range of 50 to 55 C. Then, 0.98 ml of Ti(Oz-Pr)4 (general formula V: Z = Ti, R5 = z-Pr; 3.3 mmol) were added to this mixture at once. The resulting mixture was stirred at a temperature in the range of 50 to 55 C for 1 hour. Then, the temperature of the reaction mixture was maintained at 25 to 30 C and 0.426 g of diisopropylethylamine (3.3 mmol) and then 1.67 ml of 88% cumene hydroperoxide were added to the reaction mixture. The reaction mixture was stirred at a temperature of 28 to 34 C for 2 hours. Then, 20 ml of a 12.5% solution of ammonium hydroxide were added to the reaction mixture at the room temperature. The resulting suspension was filtered through filtration paper. The filtration cake was washed with 15 ml of a 12.5% solution of ammonium hydroxide.The aqueous fraction was placed in an Erlenmeyer flask, 15 ml of dichloromethane were added and it was carefully acidified with acetic acid under stirring and cooling. The dichloromethane fraction was separated in a separating funnel, washed with 5 ml of water, dried with anhydrous sodium sulfate and evaporated in an evaporator. 1.85 g of crude <strong>[119141-88-7]esomeprazole</strong> was obtained and dissolved in a mixture of isopropylmethylketone and acetonitrile and 500 mg of a 50% aqueous solution of NaOH were added. After concentration in a rotational vacuum evaporator 0.86 g of the sodium salt of <strong>[119141-88-7]esomeprazole</strong> were obtained (general formula II, M = Na). The enantiomeric excess was determined to be 95% by means of the HPLC method on a chiral phase described in example 1. | |
With sodium hydroxide; In water; acetonitrile; at 50℃; for 12h; | 34.5 g of (S) - (-) - omeprazole was added to 200 ml of acetonitrile, 10 g of a 50% aqueous sodium hydroxide solution was added,50 C for 12 hours, cooling to room temperature, filtration, and washing the filter cake with acetone, 40-45 C drying to obtain <strong>[119141-88-7]esomeprazole</strong> sodium crude 29.6 grams. | |
657.1 g | With sodium hydroxide; In ethanol; tert-butyl methyl ether; water; at 35℃; for 13h; | 700 g (2.03 mol) of the purple oily substance obtained in Example 8 was dissolved in 500 ml of anhydrous methanol with stirring, Then add 700ml of anhydrous methanol and 90g (2. 25m1l) of sodium hydroxide mixed solution, stirring at 25 C for 1 hour and then add 4500ml of methyl tert-butyl ether, 10 C about 12 hours stirring, a solid The crude product of <strong>[119141-88-7]esomeprazole</strong> sodium was 657.lg, the molar yield was 88.1%, the purity of HPLC was 98.2%, and the purity was 99.94%. |
476 g | With sodium hydroxide; In ethanol; at 25℃; for 1h; | 700g (2.03mol) of the purple oil obtained in Example 7,Was added with 500ml of anhydrous ethanol was stirred and dissolved, then add 700ml of anhydrous ethanol and 90g (2.25mol) of sodium hydroxide mixed solution, stirred at 25 C for 1 hour and then added 4000ml of methyl tert-butyl ether (<strong>[119141-88-7]esomeprazole</strong> Sodium solubles, can promote crystallization), stirred at about 10 for 12 hours, the solid precipitated, filtered and dried under reduced pressure to give crude <strong>[119141-88-7]esomeprazole</strong> sodium 654.8g, molar yield of 87.8%, HPLC purity of 98.4% , ee value 99.92%. The reaction flask was charged with 500 g (1.36 mol) of crude <strong>[119141-88-7]esomeprazole</strong> sodium of Example 9,1000ml of methylene chloride and 1000ml of pure water, stirring to cool to about 0 C; Slowly add glacial acetic acid, the pH value adjusted to 6.5-6.8 (about 100ml), add Bi, stirring for 0.5 hours, liquid separation, aqueous Extract twice more with methylene chloride 500ml / time * 2. All organic phases were combined, dried over 40 g of anhydrous sodium sulfate for 2 hours, filtered and the solvent evaporated under reduced pressure to give a purple oil again. 350ml of anhydrous methanol was added and dissolved with stirring, and then a mixed solution of 500ml of anhydrous methanol and 60.0g (1.50mol) of sodium hydroxide was added. After stirring for 1 hour, 2700ml of methyl tert-butyl ether was added and stirred for 12 hours at about 10 C, A large amount of solid was precipitated, filtered and dried under reduced pressure to obtain 476.0 g of finished <strong>[119141-88-7]esomeprazole</strong> sodium product with a molar yield of 95.2%, an HPLC purity of 99.7% and an ee value of 99.97%. |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: esomeprazole With methylmagnesium bromide In tetrahydrofuran; diethyl ether at 20℃; for 2h; Stage #2: With water In tetrahydrofuran; diethyl ether at 0℃; | 2 Preparation of Magnesium S-Omeprazole from S-Omeprazole and Methyl Magnesium Bromide via a Grignard Reaction. S-Omeprazole (103.06 mg, 0.30 nmol) was separated from rac-omeprazole free base by means of chiral HPLC (see Example 15) and dissolved in sufficient deoxygenated tetrahydrofuran in a clean, dry Schlenk flask (25 mL). Methyl magnesium bromide (2.0 mL, 6.0 mmol, 3.0 Min diethyl ether) was added slowly by syringe. Immediately, the evolution of a gas was observed and the reaction was allowed to stir under ambient conditions for two hours. A small quantity of ice cold water was added to the flask resulting in a vigorous exothermic reaction. Additional water was added and a yellow solid formed. The contents of the flask were transferred to a 1 L separatory funnel with water, diethyl ether, and tetrahydrofuran. An emulsion formed and concentrated ammonium hydroxide was added to the separatory funnel in an amount sufficient to dissipate the emulsion. | |
Stage #1: esomeprazole With magnesium ethylate In methanol; ethanol for 18h; Stage #2: With water for 6h; | 8 Preparation of Magnesium S-Omeprazole from S-Omeprazole and Magnesium Ethoxide. Magnesium ethoxide (100.61 mg, 0.8792 mmol in 20 mL methanol) was combined with S-omeprazole (500 mg in 10 mL ethanol, 1.448 mmol) obtained from the chiral separation of rac-omeprazole (SFC; see Example 13). The solution was allowed to stir for approximately 18 hours. A small portion of water was added (0.1 mL) and the solution was allowed to stir for an additional two hours. Any particulate matter was removed by filtration through 0.45 μm PTFE and the solvent removed by rotary evaporation. Acetone (18 mL) was added and the solution allowed to stir for approximately one hour. The acetone was removed by rotary evaporation. The resulting solid product was characterized by means of X-ray powder diffraction. TABLE 4 Positions and intensities of the major peaks in the X-ray powder diffraction of magnesium S-omeprazole as taught in Example 8. d-value/ Relative Intensity 15.1 vs 12.5 m 10.8 m 10.0 m 8.5 m 7.8 m 5.1 vs 4.8 vs 4.3 m 4.1 m 3.8 m 3.4 m 2.9 m | |
Stage #1: esomeprazole With magnesium methanolate In methanol for 48h; Stage #2: With water In methanol for 0.5h; | 3 Preparation of Magnesium S-Omeprazole from S-Omeprazole and Magnesium Methoxide. Magnesium metal (14.429 mg, 0.5937 mmol) was placed in a small, dry Schlenk flask with methanol (5 mL). The flask was fitted with a nitrogen purge and the solution warmed to 40° C. to dissolve the metal. S-Omeprazole, separated from rac-omeprazole free base by chiral HPLC (see Example 16; 0.09954 g, 0.2882 mmol), was dissolved in methanol (7 mL) and added to the Schlenk flask. The solution was stirred under nitrogen for 48 hours. Water (8 μL) was added to the Schlenk flask and stirred for 30 minutes to facilitate the precipitation of magnesium salts. The magnesium salts were removed by filtration through a Whatman No.4 paper filter. Any remaining solids were removed from the pink supernatant solution by filtration through 0.45-μm polytetrafluoroethylene (PTFE). The solution was concentrated by rotary evaporation. Acetone (10 mL) was added and the solution placed under refrigeration for 2 days. |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 1-(S)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(S)-sulfinyl]-1H-benzimidazole With methanol; sodium hydroxide; water at 25℃; for 3.16667h; Stage #2: With acetic acid In methanol; water | 3 Example 3; Methanol (150 ml) was added to the product (8.1 gm) obtained as in example 2 and stirred for .30 min at 25°C, then sodium hydroxide solution (2.5 gm in 10 ml water) was added slowly for 10 min. The contents were'stirred for 3 hours at 25°C. Then methanol was distilled off to obtain a residue. To the residue was added water (50 ml), the pH was adjusted to 6.8 with acetic acid and the product was extracted with methylenechloride. The layers were separated. The methylene chloride layer was washed with 5% aq. sodium chloride (50 ml), dried with sodium sulfate and the solvent was distilled to obtain 4.5 gm residue containing (S)-5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2- pyridyl) methylsulfinyl]1-H-benzimidazole (Esomeprazole). |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 1-(S)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(S)-sulfinyl]-1H-benzimidazole; 1-(S)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(S)-sulfinyl]-1H-benzimidazole With methanol at 25℃; for 0.5h; Stage #2: With methanol; sodium hydroxide; water at 25℃; for 3.16667h; Stage #3: With water; acetic acid In methanol | 5 Example 5; Treat the mother liquor (containing 1-(R)-camphor sulfonyl-(6- and 5-)-methoxy- 2- [(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(S)-sulfinyl]-1H-benzimidazole in 3.2 : 1 ratio) from example 3 as follows: The solvent was distilled to obtain a residue. The residue was dissolved in methylene chloride (100 ml) and washed with water (2 x 50 ml). The organic layer was distilled, methanol (80 ml) was added to the residue obtained and stirred for 30 min at 25°C. Then sodium hydroxide solution (3.0 gm in 10 ml water) was added slowly for 10 min. The contents were stirred for 3 hours at 25°C. Then methanol was distilled off to obtain a residue. To the residue was added water (50 ml), the pH was adjusted to 6.8 with acetic acid and the product was extracted with methylene chloride (3 X 50 ml). The layers were separated. The methylene chloride layer was washed with 5% aq. sodium chloride (50 ml), dried with sodium sulfate and the solvent was distilled to obtain 6.5 gm residue containing (S)-5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]- 1 H-benzimidazole (Esomeprazole). |
Yield | Reaction Conditions | Operation in experiment |
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With formaldehyd; triethylamine In dichloromethane | 2.1 Synthesis of (S)1-Hydroxymethyl-(5-methoxy)- and (S)1-hydroxymethyl-(6-methoxy)-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (isomer mixture 1:2) Example 2.1 Synthesis of (S)1-Hydroxymethyl-(5-methoxy)- and (S)1-hydroxymethyl-(6-methoxy)-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (isomer mixture 1:2) (S)5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (3.5 g; 10 mmol) and triethyl amine (100 mg; 1 mmol) were dissolved in methylene chloride (50 ml). A formaldehyde solution (5 M;10 ml; 50 mmol) was added and the mixture was shaken violently for 2 minutes. After separation the organic was dried over sodium sulphate, filtered and concentrated at reduced pressure. The slightly red residue (ca 4 g) was an isomeric mixture (ratio 1:2) of the title compounds. This oil was used without purification in the subsequent reactions. 1H-NMR (500 MHz, CDCl3, δ): 7.97, 7.93, 7.56, 7.44, 7.15, 7.05, 6.99, 6.95, 6.11, 5.68, 4.89, 3.89, 3.73, 2.32, 2.30, 2.17, 2.15. |
Yield | Reaction Conditions | Operation in experiment |
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99% | With sodium hydroxide; In water; toluene;pH 11.5 - 12.0;Product distribution / selectivity; | 5.0 g of S-omeprazole*(S)-[1 ,1'-Binaphthalen]-2,2'-diol complex were dissolved in a H2O/toluene mixture by addition of NaOH 10%. The pH was adjusted to 11.5-12.0 and the organic phase was separated. The process was repeated until it was verified that no (S)-(-)-[1 ,1'-Binaphthalen]-2,2'-diol remained into the aqueous phase. The pH of the aqueous phase was adjusted to 7.0-7.5 and it was extracted with CH2CI2. The organic phase was separated, evaporated until dryness and 2.7 g of esomeprazole (yield 99%) were obtained. 1H RMN (400 MHz, CDCI3): delta 12.2 (1 H, wide signal), 8.18 (1 H, s), 7.3-7.7 (1 H, wide signal), 6.7-7.2 (1 H, wide signal), 6.92 (1 H, dd, J=8.9 Hz, J'=2.1 Hz), 4.80 (1 H, d, J=13.6 Hz), 4.74 (1 H, d, J=13.6 Hz), 3.83 (3H, s), 3.67 (3H, s), 2.23 (3H, s), 2.20 (3H,s). |
99% | With sodium hydroxide; In tert-butyl methyl ether; water;pH 11.3;Product distribution / selectivity; | 5.0 g of the S-omeprazole*(S)-[1 ,1'-Binaphthalen]-2,2'-diol complex prepared in Example 1 , were dissolved in a water/tert-butylmethyl ether mixture by addition of NaOH 10%. The pH was adjusted to 11.3 and the organic phase was separated. The pH of the aqueous phase was adjusted to 7.3 and it was extracted with dichloromethane. The organic phase was separated, evaporated until dryness and 2.7 g of esomeprazole (yield 99%) were EPO <DP n="13"/>obtained. |
99% | With sodium hydroxide; water; In toluene;pH 11.5 - 12;Product distribution / selectivity; | Example 4Preparation of Esomeprazole Starting from the S-omeprazole.(S)-[1,1'-Binaphthalen]-2,2'-diol complex in toluene5.0 g of S-omeprazole.(S)-[1,1'-Binaphthalen]-2,2'-diol complex were dissolved in a H2O/toluene mixture by addition of NaOH 10%. The pH was adjusted to 11.5-12.0 and the organic phase was separated. The process was repeated until it was verified that no (S)-(-)-[1,1'-Binaphthalen]-2,2'-diol remained into the aqueous phase. The pH of the aqueous phase was adjusted to 7.0-7.5 and it was extracted with CH2Cl2. The organic phase was separated, evaporated until dryness and 2.7 g of esomeprazole (yield 99%) were obtained. 1H RMN (400 MHz, CDCl3): delta 12.2 (1H, wide signal), 8.18 (1H, s), 7.3-7.7 (1H, wide signal), 6.7-7.2 (1H, wide signal), 6.92 (1H, dd, J=8.9 Hz, J'=2.1 Hz), 4.80 (1H, d, J=13.6 Hz), 4.74 (1H, d, J=13.6 Hz), 3.83 (3H, s), 3.67 (3H, s), 2.23 (3H, s), 2.20 (3H, s). |
99% | With sodium hydroxide; water; In tert-butyl methyl ether;pH 11.3;Product distribution / selectivity; | Example 6Preparation of Esomeprazole Starting from the S-omeprazole.(S)-[1,1'-Binaphthalen]-2,2'-diol complex in tert-butylmethyl ether5.0 g of the S-omeprazole.(S)-[1,1'-Binaphthalen]-2,2'-diol complex prepared in Example 1, were dissolved in a water/tert-butylmethyl ether mixture by addition of NaOH 10%. The pH was adjusted to 11.3 and the organic phase was separated. The pH of the aqueous phase was adjusted to 7.3 and it was extracted with dichloromethane. The organic phase was separated, evaporated until dryness and 2.7 g of esomeprazole (yield 99%) were obtained. |
95% | 65.0 g of the inclusion complex (optical purity: 99.4% ee) of esomeprazole and (S)-(-)-binol obtained in Example 15, and 300 ml of isopropyl acetate were added sequentially to 300 ml of an aqueous solution containing 4.95 g of sodium hydroxide, which was stirred at room temperature for 30 min. The organic layer was separated and the aqueous layer was further extracted with 150 ml of isopropyl acetate. The organic layers were combined and concentrated to recover 25 g of (S)-(-)-binol therefrom (recovery ratio: 85%). To the aqueous layer, on the other hand, 300 ml of dichloromethane was added, the pH of the resulting mixture was adjusted to 8.0 with 1N acetic acid, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure to obtain 33.7 g of the title compound in the form of a foaming material (yield: 95%). Specific linear luminosity: [alpha]D20 = - 146.9 (c=1 , THF).Optical purity: 99.4% ee (chiral HPLC).1H-NMR (CDCl3, ppm): delta 2.14 (s, 3H), 2.24 (s, 3H), 3.72 (s, 3H), 3.86 (s, 3H), 4.76 (dd, 2H), 6.96 (dd, 1H), 7.04 (br. s, 1H), 7.29 (s, 1H), 7.56(br. s, 1H), 8.23(s, 1H). IR (KBr, cm-1): 3529, 3349, 1628, 1590, 1571, 1465, 1414, 1398, 1270, 1211, 1156.4, 1079, 1048, 1029, 837, 625, 518. | |
92% | With sodium hydroxide; In dichloromethane; water;pH 11.5 - 12.0;Product distribution / selectivity; | 1.0 g of S-omeprazole*(S)-[1 ,1'-Binaphthalen]-2,2'-diol complex was dissolved in a water/methylene chloride mixture by addition of NaOH 10%. The pH was adjusted to 11.5-12.0 and the organic phase was separated. The pH of the aqueous phase was adjusted to 7.0-7.5 and it was extracted with CH2CI2. The organic phase was separated, evaporated until dryness and 0.5 g of esomeprazole (yield 92%) were obtained. |
92% | With sodium hydroxide; water; In dichloromethane;pH 11.5 - 12;Product distribution / selectivity; | Example 5Preparation of Esomeprazole Starting from the S-omeprazole*(S)-[1,1'-Binaphthalen]-2,2'-diol complex in methylene chloride1.0 g of S-omeprazole.(S)-[1,1'-Binaphthalen]-2,2'-diol complex was dissolved in a water/methylene chloride mixture by addition of NaOH 10%. The pH was adjusted to 11.5-12.0 and the organic phase was separated. The pH of the aqueous phase was adjusted to 7.0-7.5 and it was extracted with CH2Cl2. The organic phase was separated, evaporated until dryness and 0.5 g of esomeprazole (yield 92%) were obtained. |
87% | 65.0 g of the inclusion complex (optical purity: 99.4% ee) of esomeprazole and (S)-(-)-binol obtained in Example 15, and 300 ml of isopropyl acetate were added sequentially to 300 ml of an aqueous solution containing 4.95 g of sodium hydroxide, which was stirred at room temperature for 30 min. The organic layer was separated and the aqueous layer was further extracted with 150 ml of isopropyl acetate. Then, 30 ml of isopropyl alcohol was added to the aqueous layer, the pH of the resulting mixture was adjusted to 8.0 with 1N acetic acid and stirred at 5-10 C for 20 hrs. The precipitated solids were filtered, washed sequentially with 100 ml of water and 100 ml of n-hexane, and dried at room temperature under a reduced pressure, to obtain 30.9 g of the title compound as a white-yellow solid (yield: 87%). The proton nuclear magnetic resonance(1H-NMR) and infrared ray (IR) spectra of the product were identical to those obtained in Example 16.M.p.: 70 C .Specific linear luminosity: [alpha]D20 = -150.7 (c=0.5, CHCl3). Optical purity: 99.5% ee (chiral HPLC). |
Yield | Reaction Conditions | Operation in experiment |
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With strontium diisopropoxide In isopropyl alcohol at 20℃; for 1 - 2h; | 3 Esomeprazole free base (5 g) was dissolved in isopropanol (50 ml) at room temperature and a solution of strontium isopropoxide (5 g) dissolved in isopropanol (50 ml) was slowly added. The reaction mixture was stirred at room temperature for about 1 to about 2 hours and the reaction mass was quenched in water. The precipitated solids were filtered and the wet cake was washed with water (25 ml). The wet cake was air dried at a temperature ranging from about 40°C to about 45°C to provide esomeprazole strontium salt (4.0 g). (HPLC Purity > 98.9%, > 99.7% ee) |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: methanol; magnesium In dichloromethane at 40 - 45℃; for 2 - 3h; Stage #2: esomeprazole In methanol; dichloromethane at 5 - 10℃; for 3h; | 40 The procedure is carried out as described in Raju et al, Organic Process Research & Development 2006, 10, 33-35, which is hereby incorporated by reference in its entirety. A solution of magnesium methoxide was prepared by adding magnesium turnings (1.31 g, 0.054 mol) and dichloromethane (5 mL) to methanol (150 mL) and stirring under nitrogen atmosphere for 2-3 hours, at 40-45° C. The solution was cooled to 5-10° C. and added to a stirred mixture of esomeprazole (42.0 g, 0.121 mol) and methanol (150.0 mL), and stirring was maintained for 3 hours. Water (2.0 mL) was added and stirring was continued for 1 hour and the solution was filtered. The mother liquor was distilled under reduced pressure at 35° C. Acetone (400 mL) was added and the mixture was stirred for 1 hour at 25-35° C. The precipitate was filtered and washed with acetone (200 mL), dissolved in methanol (222 mL) and water (8 mL) and stirred for about 30 minutes at 25-30° C. and filtered. The filtrate was suspended in water and stirred at 0-5° C. for about 45 minutes, filtered, washed with water (300 mL) and dried under reduced pressure to yield esomeprazole magnesium salt. | |
Stage #1: methanol With magnesium Stage #2: esomeprazole With magnesium methanolate In methanol |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydrogencarbonate In dichloromethane; water for 0.25 - 0.5h; | 38 The procedure was carried out as described in Raju et al, Organic Process Research & Development 2006, 10, 33-35, which is hereby incorporated by reference in its entirety. Esomeprazole mandalate salt (7.5 g) was suspended in a mixture of dichloromethane (80 mL) and 5% sodium bicarbonate (80 mL) and stirred for 15-30 minutes. The organic phase was separated, and the solvent was removed under reduced pressure to afford 7.3 g of esomperazole. |
Yield | Reaction Conditions | Operation in experiment |
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100% | In methanol; water | 1 Examples Example 1 - Preparation of esomeprazole arginine salt; (5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole arginine) 3.0 g (0.017 mole) of L-arginine were dissolved in a mixture of 110 ml of water and 60 ml of methanol. 6.0 g (0.017 mole) of esomeprazole were added and it was stirred until a solution was obtained. Any undissolved particles are filtered off to get a clear solution. The product was isolated by lyophilization. The obtained freeze dried product was further dried under reduced pressure at room temperature and subsequently at 30-35° for 3 hours. The amorphous salt of esomeprazole arginine was produced with 100 % yield and characterized by the following analyses: 1H-NMR (300 MHz, DMSO-d6): 1.5 (m, 4H, CH2-arginine), 2.18 (s, 3H, CH3), 2.20 (s, 3H, CH3), 3.07 (m, 2H, CH2-arginine), 3.15 (m, 1H, CH-arginine), 3.68 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 4.55 (d, JHA,B= 13.4Hz, 1H, HA), 4.77 (d, JHA,B= 13.4Hz, 1H, HB), 6.77 (dd, JH6,7=8.8Hz, JH4.7=2.4Hz, 1H, H7), 7.05 (d, JH4,7=2.4Hz, 1H, H4), 7.45 (d, JH6,7=8.8Hz, 1H, H6), 8.19 (s, 1H, H6,) HPLC (Chiral purity) = 100.0% Moisture content (KF) = 0.84% (KF = according to Karl Fischer) The amorphous form of the salt was indicated by the X-ray powder diffraction pattern and DSC (plain halo effect and glass transition at about 40°C). |
Yield | Reaction Conditions | Operation in experiment |
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100 % ee | Stage #1: esomeprazole magnesium salt With acetic acid In methanol; water at 15 - 20℃; Stage #2: With sodium hydroxide In water Stage #3: With acetic acid In methanol; water at 15 - 20℃; | 2.a a) 40.0 g (0.0974 mole) of 5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulphinyl]-1H-benzimidazole magnesium salt trihydrate were dissolved in 400 ml of methanol at 15-20°C. The pH value of the solution was adjusted to 8.0 with 6% acetic acid and the solution was diluted with 200 ml of water. The esomeprazole was extracted with methylene chloride and the extracts were treated with activated charcoal. After concentrating the extracts, 225 ml of water were added and the pH value was adjusted to 12.0 with 20% sodium hydroxide. The layers were separated. 50 ml of methanol were added to the aqueous layer, and then the product was precipitated with 25 % acetic acid at 15 - 20°C and filtered. The wet precipitate was re-slurried in alkaline water for one hour, filtered and dried under reduced pressure at room temperature and subsequently at 30-35° for 5 hours. 20.5 g of amorphous form of esomeprazole were obtained and characterized by the following analyses: 1H-NMR (300 MHz, DMSO-d6): 2.17 (s, 3H, CH3), 2.19 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 4.64 (d, JHA,B= 13.4Hz, 1H, HA), 4.76 (d, JHA,B= 13.4Hz,1H, HB), 6.88 (dd, JH6,7=8.8Hz, JH4.7=2.4Hz, 1H, H7), 7.08 (d, JH4,7=2.4Hz, 1H, H4), 7.52 (d, JH6,7=8.8Hz, 1H, H6), 8.18 (s, 1H, H6,) HPLC (Chiral purity) = 100.0% Moisture content (KF) = 0.89% |
With acetic acid In water at 20℃; | 3 EXAMPLE 3: PREPARATION OF AMORPHOUS ESOMEPRAZOLE FROMESOMEPRAZOLE MAGNESIUM BY SPRAY DRYINGMagnesium salt of esomeprazole (5g) was dissolved in water (250ml) at room temperature. The pH of the mixture was adjusted to about 9-10 with acetic acid. The aqueous layer was further treated with methylene dichloride (100 ml). The organic layer was separated off and evaporated under vacuum at about 30°C to about 40°C to obtain a residue. The residue was dissolved in acetone (50ml) and the solution was spray dried using spray drier equipment. The solution was sprayed with about 2 kg/cm nitrogen pressure. Further the input temperature was maintained at about 40-45°C and the outlet temperature was maintained at about 30-35°C. The solid was collected from the spray drier and dried at about 30-35°C under vacuum to afford Esomeprazole base (3.5 g) in amorphous form. |
Yield | Reaction Conditions | Operation in experiment |
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With acetic acid In tetrahydrofuran; water at 0 - 30℃; for 2h; | 2 Example 2; Tetrahydrofuran (250 ml) and water (500 ml) were added to esomeprazole potassium salt (50 gm) at 25 - 3O0C, cooled to 200C and then the pH is adjusted to 7.5 - 8.0 with acetic acid. The reaction mass was cooled to 50C, stirred for 2 hours at 0 - 50C, filtered the mass, washed with 50 ml of chilled mixture of water and tetrahydrofuran (2 : 1 ) and again washed with water (100 ml). To the wet cake obtained was added water (100 ml) at 250C and then stirred for 30 minutes. Subsequently, the water was removed by lyophilization at about -600C. After isolation from the lyophilization vessel there were obtained 26.2 gm of amorphous esomeprazole (HPLC Purity: 99.87%, water content: 2.5%). | |
With acetic acid; diethylamine In water | 1.6 Example 1.6Preparation of esomeprazole non-salt modification GEsomeprazol-K (7.9g) was dissolved in purified water (35 ml) at room temperature. Diethanol amine (4.14g) was mixed with 30 ml water and added to the Esomeprazol-K solution. Aqueous acetic acid (20%) (0.88 ml) was added to the solution (0.1 ml/min). Seed crystals were added to initiate crystallisation. After this, 7.32 ml aqueous acetic acid (20%) was added slowly (0.0365 ml/min). The slurry was aged over night before 0.5 ml acetic acid was added (20%, 0.1 ml/min), then 30 ml water was added and finally 1.5 ml aqueous acetic acid (20%, 0.1 ml/min)). The slurry was filtered off and washed with water (4x30 ml) and dried at 25 C under vacuum over night yielding 6.1g of modification G. | |
With acetic acid; methylamine In ethanol; water at 10 - 30℃; | 1.7 Example 1.7 Preparation of esomeprazole non-salt modification B Esomeprazol-K (5.95g) was dissolved in purified water (50 ml) at room temperature and methyl amine in ethanol (33%, 5 ml) was added. To the solution was added aqueous acetic acid (25%) (4.94 ml). After a few minutes, addition of 4.8 ml acetic acid (25%) was started. The acid was added in portions during 20 minutes. The crystallisation started spontaneously but lumps were formed. The temperature was increased to 30 C during 10 minutes, then cooled down quickly to 10 C and finally heated again to 25 C. After 4 hours at 25 C more crystals were formed and the lumps were gradually transformed into a slurry which was left over night. The crystals were then filtered off, washed with water and dried under vacuum and 20 C. |
With ammonia; acetic acid In water | 1.1 Example 1.1Preparation of esomeprazole non-salt modification BEsomeprazol-K (7.9g) was dissolved in purified water (65ml) at room temperature and aqueous ammonia (3.9 ml, 25%) was added. After this, 6.0 ml aqueous acetic acid (20%) was added slowly (0.0365 ml/min). The slurry was aged for one hour before more acetic acid was added (2.2 ml, 0.0365 ml/min). The slurry was left over night and before filtration, 80 ml water was added to dilute the slurry. The slurry was filtered off and washed with water (4x30 ml) and dried at 20 C under vacuum over night. | |
With ammonia; acetic acid In water at 10℃; for 2h; | 1.2 Example 1.2 Preparation of esomeprazole non-salt modification CEsomeprazol-K (7.84g) was dissolved in purified water (65 ml) at room temperature and ammonia (aq),(3.9 ml, 25%) was added. The solution was cooled to 10 C. Aqueous acetic acid (25%) (6.56 ml) was added to the solution slowly (0.0365 ml/min). Seed crystals were added when 0.6 ml acid had been added to initiate crystallisation. The substance was allowed to crystallise for 2 hours at 1O C. Then, the slurry was filtered off and washed with water (3x20 ml) and dried in air. XRPD analysis showed a new form called modification C. | |
With ammonia; acetic acid In water for 72h; | 1.5 Example 1.5Preparation of esomeprazole non-salt modification GEsomeprazol-K (7.89g) was dissolved in purified water (65 ml) at room temperature and ammonia (aq),(3.9 ml, 25%) was added. Aqueous acetic acid (25%) (8.2 ml) was added to the solution slowly (0.0365 ml/min). Seed crystals were added to initiate crystallisation. The substance was allowed to crystallise for 3 days. Then, the slurry was filtered off and washed with water (2x30 ml) and dried at 25 C under vacuum. XRPD analysis showed a new form called modification G. | |
With ammonia; acetic acid In water at 20 - 30℃; | 1.3 Example 1.3Preparation of esomeprazole non-salt modification EEsomeprazol-K (5.98g) was dissolved in purified water (50 ml) at room temperature and ammonia (aq),(3 ml, 25%) was added. To the solution was added aqueous acetic acid (25%) (2.5 ml). Seed crystals were added to initiate crystallisation. The solution was heated to 3O C and after 30 minutes more acetic acid was added (1.0 ml). The crystallisation started and larger lumps were formed, which gradually were transformed to a white slurry. After 3 hours more acetic acid was added (1.5 ml) and the resulting slurry was left over night. The crystals were then filtered off, washed with water and dried under vacuum and 20 C. | |
With ethanolamine; acetic acid In water | 1.4 Example 1.4Preparation of esomeprazole non-salt modification EEsomeprazol-K (7.9g) was dissolved in purified water (65 ml) at room temperature and ethanol amine (3.9 ml) was added. Aqueous acetic acid (20%) (8.5 ml) was slowly added to the solution (0.0365 ml/min). Seed crystals were added to initiate crystallisation. After this, 2.5 ml aqueous acetic acid (20%) was added in four portions every 30 minutes. Finally, the slurry was aged over night before, the slurry was filtered off and washed with water (3x30 ml) and dried at 25 C under vacuum over night. The product (5.5g) was a white, crystalline, powder. | |
Stage #1: esomeprazole potassium In tetrahydrofuran; water at 25 - 30℃; Stage #2: With acetic acid In tetrahydrofuran; water at 0 - 20℃; for 2 - 3h; | 1 Example 1 Example 1 Tetrahydrofuran (250 ml) and water (500 ml) are added to esomeprazole potassium salt (50 gm) at 25-30° C., cooled to 20° C. and then the pH is adjusted to 7.5-8.0 with acetic acid. The reaction mass is cooled to 5° C., stirred for 2 to 3 hours at 0-5° C., filtered the mass, washed with 50 ml of chilled mixture of water and tetrahydrofuran (2:1) and again washed with water (100 ml). The wet cake is dried at 30-35° C. under vacuum to reach the moisture content to 25-30%. The solid is again dried in rotovapour at 25-30° C. under nitrogen atmosphere to give 26.3 gm of amorphous esomeprazole hydrate (HPLC Purity: 99.92%, Moisture Content: 4.0%). | |
Stage #1: esomeprazole potassium In water; acetonitrile at 25 - 30℃; Stage #2: In water; acetonitrile at 0 - 20℃; for 2 - 3h; | 2 Example 2 Example 2 Acetonitrile (250 ml) and water (700 ml) are added to esomeprazole potassium salt (50 gm) at 25-30° C., cooled to 20° C. and then the pH is adjusted to 7.5-8.0 with acetic acid. The reaction mass is cooled to 5° C., stirred for 2 to 3 hours at 0-5° C., filtered the mass, washed with 50 ml of chilled mixture of water and acetonitrile (3:1) and again washed with water (100 ml). The wet cake is dried at 30-35° C. to reach the moisture content to 30-35%. The solid is again dried in rotovapour at 25-30° C. under nitrogen atmosphere to give 26.1 gm of amorphous esomeprazole hydrate (HPLC Purity: 99.91%, Moisture Content: 4.1%). | |
With water; acetic acid In tetrahydrofuran at 0 - 5℃; for 2h; | 2 EXAMPLE 2; Tetrahydrofuran (250 ml) and water (500 ml) were added to esomeprazole potassium salt (50 gm) at 25-30° C., cooled to 20° C. and then the pH is adjusted to 7.5-8.0 with acetic acid. The reaction mass was cooled to 5° C., stirred for 2 hours at 0-5° C., filtered the mass, washed with 50 ml of chilled mixture of water and tetrahydrofuran (2:1) and again washed with water (100 ml). To the wet cake obtained was added water (100 ml) at 25° C. and then stirred for 30 minutes. Subsequently, the water was removed by lyophilization at about -60° C. After isolation from the lyophilization vessel there were obtained 26.2 gm of amorphous esomeprazole (HPLC Purity: 99.87%, water content: 2.5%). | |
With ammonium chloride In water at 20℃; | 4 EXAMPLE 4: ALTERNATE PROCESS FOR PREPARATION OF AMORPHOUSESOMEPRAZOLE FROM ESOMEPRAZOLE POTASSIUM BY SPRAY DRYINGPotassium salt of esomeprazole (5 gm) was dissolved in water (250ml) at about room temperature and treated with ammonium chloride solution (5 %). The aqueous layer was further treated with methylene dichloride. The organic layer was separated off and evaporated under vacuum at about 30°C to about 40°C. The residue was dissolved in acetone (50ml) and the solution was spray dried using spray drier equipment. The solution was sprayed with about 2 kg/cm2 nitrogen pressure. Further the input temperature was maintained at about 40-45°C and the outlet temperature was maintained at about 30-35°C. The solid was collected from the spray drier and dried at about 30-35°C under vacuum to afford Esomeprazole base (3.3 g) in amorphous form.Purity by Chiral HPLC: 99.8%, R-isomer: 0.05%. |
Yield | Reaction Conditions | Operation in experiment |
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98% | Example 20: Isolation of (S)-omeprazoleTo a suspension of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2-ethanediol] (2.5 g, 2.7 mmol, 99.3% e.e.) in toluene (23 ml) was added aqueous sodium hydroxide (1.5 M, 1.9 ml, 2.83 mmol) and the mixture was heated at 80 0C to effect complete dissolution. The biphasic mixture was cooled to approximately 70 0C and the aqueous phase was decanted. The organic phase was extracted with water (2 x 4 ml) at approximately 70 0C and the combined aqueous phases were washed with toluene (2 x 6 ml) at ambient temperature and stripped on a rotary evaporator (40 0C, 10 min). After cooling to 0 0C and seeding with (S)-omeprazole (100 mg), a solution of glacial acetic acid (163 mul, 2.83 mmol) in water (3 ml) was added dropwise over 1 h with vigorous stirring. Stirring was continued for a further 1 h at 0 0C and the mixture was filtered. The collected solid was washed with water (2 x 5 ml) and dried in vacuo at ambient temperature to afford (S)-omeprazole (867 mg, 98%, 99.7% e.e.) as a white solid.Rf (SiO2, CH2CI2/MeOH 9:1 ) 0.50.IR (KBr: w weak, m medium, s strong) 3059w, 3005w, 2904w, 2802w, 1627s,1587m, 1567m, 1511 m, 1472m, 1408s, 1311m, 1271w, 1204ss, 1186m, 1158m, 1112w, 1077m, 1016s, 966m, 885w, 822m, 810m and 430m.1H NMR (400 MHz, CDCI3) 8.22 (s, 1 H), 7.53 (broad s, 1 H), 7.03 (broad s, 1 H), 6.96 (dd, J = 2.4 and 8.8 Hz, 1 H), 4.79 (d, J = 13.6 Hz, 1 H), 4.69 (d, J = 13.6 Hz, 1 H), 3.85 (s, 3 H), 3.70 (s, 3 H), 2.24 (s, 3 H) and 2.22 (s, 3 H). | |
95% | Example 21 : Isolation of (S)-omeprazoleTo a suspension of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2-ethanediol] (2.5 g, 2.7 mmol, 99.3% e.e.) in toluene (23 ml) was added aqueous potassium hydroxide (1.5 M, 2.24 ml, 2.83 mmol) and the mixture was heated at 80 0C to effect complete dissolution. The biphasic mixture was cooled to approximately 70 0C and the aqueous phase was decanted. The organic phase was extracted with water (2 x 4 ml) at approximately 70 0C and the combined aqueous phases were washed with toluene (2 x 6 ml) at ambient temperature and stripped on a rotary evaporator (40 0C, 10 min). After cooling to 0 0C and seeding with (S)-omeprazole (100 mg), a solution of glacial acetic acid (163 mul, 2.83 mmol) in water (3 ml) was added dropwise over 1 h with vigorous stirring. Stirring was continued for a further 1 h at 0 0C and the mixture was filtered. The collected solid was washed with water (2 x 5 ml) and dried in vacuo at ambient temperature to afford (S)-omeprazole (885 mg, 95%, 99.8% e.e.) as a white solid. | |
84% | Example 22: Isolation of (S)-omeprazoleTo a suspension of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2-ethanediol] (2.2 g, 2.4 mmol, 99.3% e.e.) in dichloromethane (13 ml) was added aqueous sodium hydroxide (1.5 M, 1.6 ml, 2.5 mmol) and the mixture was heated to reflux temperature to effect complete dissolution. The aqueous phase was decanted and the organic phase was extracted with water (2 x 4 ml) at approximately 40 0C and the combined aqueous phases were washed with dichloromethane (2 x 5 ml) at ambient temperature. Dichloromethane (8.2 ml) was replaced and, to the biphasic mixture at 0 0C, a solution of glacial acetic acid (144 mul, 2.50 mmol) in water (3 ml) was added dropwise over 1 h with vigorous stirring. The organic phase was decanted, was washed with water (2 x 5 ml) and was concentrated in vacuo to afford (S)-omeprazole (687 mg,84%, 99.8% e.e.) as a white solid foam. |
Yield | Reaction Conditions | Operation in experiment |
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96% | Example 23: Isolation of (S)-omeprazoleTo a suspension of (S)-omeprazol 2 [(S)-1 ,1 ,2-triphenyl-1 ,2-ethanediol] (2.2 g, 2.4 mmol, 99.3% e.e.) in dichloromethane (13 ml) was added aqueous sodium hydroxide (1.5 M, 1.64 ml, 2.5 mmol) and the mixture was heated to <n="18"/>reflux temperature to effect complete dissolution. The aqueous phase was decanted and the organic phase was extracted with water (2 x 4 ml) at approximately 40 0C and the combined aqueous phases were washed with dichloromethane (2 x 5 ml_) at ambient temperature and stripped on a rotary evaporator (40 0C, 10 min). After cooling to 0 0C and seeding with (S)- omeprazol (100 mg), a solution of ammonium acetate ( 0.2 g, 2.6 mmol) in water (3 ml) was added dropwise over 1 h with vigorous stirring. Stirring was continued for a further 1 h at 0 0C and the mixture was filtered. The collected solid was washed with water (2 x 5 ml_) and dried in vacuo at ambient temperature to afford (S)-omeprazol (788 mg, 96%, 99.8% e.e.) as a white solid.Example 24: Recovery of (S)-1 ,1 ,2-triphenyl-1 ,2-ethanediolThe organic phase decanted after separation of aqueous (S)-omeprazole sodium salt (2.7 mmol) was washed with aqueous sodium hydroxide (1 M, 5.4 ml, 5.4 mmol) and with water (2 x 5 ml) at approximately 70 0C. The solution was concentrated to a volume of 4.5 ml and, after heating to redissolve the resulting suspension, was stirred at ambient temperature for 1 h. After further cooling to 0 0C for 30 min, the mixture was filtered and the solid collected was washed with toluene (3 x 1 ml at 0 0C) and dried in vacuo to give (S)-1 ,1 ,2- triphenyl-1 ,2-ethanediol (1.25g, 80%, 99.9% e.e.) as a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
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With 1,2:4,5-di-O-cyclohexylidene-D-fructopyranose; Cumene hydroperoxide; vanadium(V) oxytripropoxide; N-ethyl-N,N-diisopropylamine; In water; ethyl acetate; at 20 - 55℃; for 20.1667 - 20.25h;Product distribution / selectivity; | Example 2; Preparation of 5-methoxy-2-|'[('4-methoxy-3,5-dimethyl-2-pyridinvDmethyll sulfinyl] -lH-benzimidazole; To a suspension of vanadium oxytripropoxide (1.2 g) in ethyl acetate (200 ml), l,2:4,5-Dz-O-cyclohexylidene-/>fructopyranose (1.0 g) was added and the mixture was stirred for 10-15 minutes at room temperature under nitrogen atmosphere. 5- Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-7/-rbenzimidazole <n="11"/>(10 g) was added to the resulting mixture and the temperature was raised up to 50- 550C. Water (0.02 ml) was added to the said mixture and stirred for one hour. The reaction mass was cooled between 25-3O0C and added lambdazetaiV-diisopropylethylamine (0.7 g) followed by addition of cumene hydroperoxide (2.6 g) dropwise over a period of one hour. The reaction mass was further stirred for 18 hours at said temperature. Triethylamine (20 ml) was added to the resulting mixture and was extracted with water. The organic layer was separated and the aqueous layer was further extracted from dichloromethane at pH 8.0 to 8.5. The organic layer was combined and distilled under vacuum to obtain the product as oily mass. Yield = 4.0 gEnantiomeric excess = 67percent. | |
With Oxone; ethylenediaminetetraacetic acid; sodium hydrogencarbonate; 1,2:4,5-di-O-cyclohexylidene-beta-D-erythro-hexo-2,3-diulopyranose; In acetonitrile; at -10 - 20℃; for 3.16667 - 3.25h;Product distribution / selectivity; | Example 3; Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinvDmethvpi sulfinyl] -l//-benzimidazole; 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-7J/ benzimidazole (10 g) was taken in acetonitrile (150 ml) and to this add l,2:4,5-/J)/-O-cyclohexylidene- beta-D-erythro hexo-2,3-diulopyranose (10.2 g) was added under an nitrogen atmosphere. The reaction mixture was stirred at 15-2O0C for 10-15 minutes. Ethylenediaminetetracetic acid solution (10 ml) was added at the same temperature and the reaction mixture was cooled to -15 to -1O0C. Oxone (22.8 g) and sodium bicarbonate (2.1 g) was added to the reaction mixture over a period of one hour. After the addition, the resulting mixture was stirred for additional two hours. To the resulting reaction mixture, water (100 ml) and dichloromethane (200 ml) was added and stirred for few minutes. The organic layer was separated off, distilled under reduced pressure to obtain the oily residue. Yield = 3.5 gEnantiomeric excess = 77percent. | |
With dihydrogen peroxide;[MnCl((1R,2R)-N,N'-bis(3,5-di-tert-butylsalicylidene)diphenylethanediamine(-2H))]; In water; acetonitrile; at 20℃; for 5.5h;Product distribution / selectivity; | 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1 H- benzimidazole (4a) and the (salen)manganese complex 2a - e are dissolved in acetonitrile. The reaction temperature is adjusted, then 30percent aqueous H2O2 is added dropwise and the mixture is stirred for several hours. Then the reaction mixture is transferred portion-wise into a cold (0 0C) 10percent aqueous solution of Na2SO3 and stirred for additional 15 min. The obtained mixture is extracted with dichloromethane. The organic phase is dried over Na2SO4 and concentrated yielding an oily residue which is analyzed by chiral and achiral HPLC analytical method.Typically, runs were carried out on 0.5 - 6 mmol scale of the starting material 4a in acetonitrile (1 mmol 4a in 10 mL MeCN). The amounts of added reagents, temperature and reaction time in particular examples are indicated in Tables 1 to 3. Also the results are indicated in Tables 1-3. |
0.495 g (1.5 mmol) of the compound of formula III, 5 ml of dried toluene and 104.1 mg (1.0 mmol) of (<;S)-lactic acid methyl ester (general formula IV: X = OMe, IVc) were placed in a 3- neck 50ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated up in an oil bath to a temperature in the range of 50 to 55 0C. Then, 0.15 ml OfTi(OPr)4 were added to this mixture at a time. The resulting mixture was stirred at a temperature in the range of 50 to 55 0C for 1 hour. Then, the reaction mixture was maintained at a temperature of 25 to 30 0C and 85 mul of diisopropylethylamine were added to the reaction mixture. The mixture was stirred for 5 minutes and 0.25 ml of 88percent cumene hydroperoxide were added to the solution. The resulting reaction mixture was stirred at the room temperature for 4 hours. The reaction was terminated by addition of 5 ml of a 5percent aqueous solution of Na2S2O3 and diluted with 5 ml of toluene. The resulting mixture was filtered through filtration paper. The two-phase filtrate was separated in a separating funnel and the toluene fraction was extracted with anther 5 ml of water. After drying with anhydrous magnesium sulfate the toluene solution was evaporated in a rotary vacuum evaporator until dry. The resulting evaporation residue (0.55g) was subjected to chromatography on 16.0 g of silica gel. Chloroform : methanol : 25percent NH4OH in the ratio of (10 : 1 : 0,1) were used as the eluent. The fractions containing the compound of formula Ia were combined, evaporated in a rotary vacuum evaporator and analyzed with HPLC on the chiral phase (CHIRALPAK AD-H.(R)., mobile phase 50percent hexane : 50percent ethanol, detection 302 nm): (.^-omeprazole has the enantomeric excess of 56.0 percent. | ||
0.495 g (1.5 mmol) of the compound of formula III, 5 ml of dried toluene and 1 mmol of a chiral ligand (166.1 mg of the methyl ester of (S)-mandelic acid (general formula IV: X = OMe, Y = H, rVc)) were placed in a 3 -neck 50-ml flask, which was equipped with a magnetic stirrer and a thermometer. The mixture in the flask was heated in an oil bath to a temperature in the range of 50 to 55 °C. Then, 0.15 ml of Ti(Oz-Pr)4 (general formula V: Z = Ti, R5 = i-Pr) were added to this mixture at once. The resulting mixture was stirred at a temperature in the range of 50 to 55 °C for 1 hour. Then, the temperature of the reaction mixture was maintained at 25 to 30 °C and 85 mu of diisopropylethylamine were added to the reaction mixture. The mixture was stirred for 5 minutes and 0.25 ml of 88percent cumene hydroperoxide were added to the solution. The resulting reaction mixture was stirred at the room temperature for 4 hours. The reaction was terminated by addition of 5 ml of a 5percent aqueous solution of Na2S203 and diluted with 5 ml of toluene. The resulting mixture was filtered through filtration paper. The two-phase filtrate was divided in a separating funnel and the toluene fraction was extracted with additional 5 ml of water. After drying with anhydrous magnesium sulfate the toluene solution was evaporated to dryness in a rotational vacuum evaporator. The resulting evaporation residue was chromatographed on silica gel. Chloroform : methanol : 25percent NH OH in the (10 : 1 : 0.1) proportion was used as the eluent. The fractions of the product were combined, evaporated in a rotational vacuum evaporator and analyzed in a HPLC system on a chiral phase (CHIRALPAK AD-H.(R).); mobile phase 50percent of hexane : 50percent of ethanol, detection 302 nm).Esomeprazole (formula I) with the enantiomeric excess of 80 percent was obtained. | ||
(R)-omeprazole was prepared with the same procedure as described in example 1. 1 mmol (200 mg) of (jf?)-3-chloromandelic acid methyl ester (general formula ent-TV: X = OMe, Y = 3-Cl) was used as the chiral ligand.(/?)-omeprazole (formula ent-I) with the enantiomeric excess of 67.6 percent was obtained. | ||
General procedure: In a typical experiment, Ti(Oi-Pr)4 (0.9 mL, 3 mmol) was added to a solution of (S,S)-DBzTA 5i (1.969 g, 6 mmol) and pyrmetazol (3.29 g, 10 mmol) in toluene (20 mL) at 80 °C. The solution was stirred for 60 min., after which water (54 mg, 3 mmol) was added to the mixture, and the solution was stirred for another 60 min. Next, the temperature was adjusted to 30 °C, after which cumene hydroperoxide (80 percent, 3.6 mL, 20 mmol) was slowly added. After 1 h at 30 °C, the solution was added to aqueous sodium hydroxide (1.2 g NaOH in 20 mL water), stirred for 1 h, and extracted with water (20 mL .x. 3). The aqueous phase was adjusted to pH 8 with acetic acid, separated, and extracted with dichloromethane (20 mL .x. 3). The combined organic solutions were dried over anhydrous Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel with ethyl acetate/petroleum ether (2:1) as the eluent to afford the sulfoxide. | ||
With oxygen; NADP; In aq. phosphate buffer; isopropyl alcohol; at 25℃; for 24h;pH 9.0;Enzymatic reaction; | General procedure: The Activity FIOP and enantioselectivity (percent ee) of the 53 exemplary non-naturally occurring monooxygenase polypeptides of Table 2B in carrying out the biocatalytic conversion of the substrate compound (1) (pyrmetazole) to the product compound (2) ((R)- or (S)-omeprazole) were determined that following general HTP assay conditions: 5 g/L pyrmetazole substrate, 10 muL of lysate of the engineered CHMO polypeptide, 1 g/L KRED of SEQ ID NO: 268, 0.5 g/L NADP, in a solution of 50 mM potassium phosphate buffer, 10percent (v/v) IPA, pH 9.0, 25° C. reaction temperature and 24 h reaction time (with 400 rpm stirring). Further details of the HTP assay methods are described in the Examples. | |
With C64H64N4O6Ti2; dihydrogen peroxide; In water; ethyl acetate; at 0℃; for 24h; | General procedure: Sulfide (OMS or LPS, 100 mol) and the Ti-salalen catalyst(1.1 mol) were dissolved in the solvent (typically: EtOAc, 6.0 mL),the mixture was thermostatted at desired temperature (typically 0 °C, or ?20 to +20 °C for variable-temperature measurements),and 30percent aqueous hydrogen peroxide (0.105 mmol of H2O2) was then introduced in one portion. Stirring (500 rpm) was continued at that temperature (typically 24 h). For low-temperature experiments, the reaction times were about 30 h at ?10 °C and up to 10 days at ?20 °C. To analyze the reaction outcome, 20 L aliquots of the reaction mixture were taken to a vial and immediately carefully evaporated to dryness with a stream of compressed air during ca. 15?20 s. The remaining solid was dissolved in 0.20 mL of 1percent Et3N solution in isopropyl alcohol, and the contents of residual sulfide, (R)- and(S)-sulfoxide, and sulfone, were analyzed by chiral HPLC as noted above. | |
With C68H72N4O10Ti2; dihydrogen peroxide; In water; ethyl acetate; at 0℃; for 24h; | General procedure: Sulfide (OMS or LPS, 100 mol) and the Ti-salalen catalyst(1.1 mol) were dissolved in the solvent (typically: EtOAc, 6.0 mL),the mixture was thermostatted at desired temperature (typically 0 °C, or ?20 to +20 °C for variable-temperature measurements),and 30percent aqueous hydrogen peroxide (0.105 mmol of H2O2) was then introduced in one portion. Stirring (500 rpm) was continued at that temperature (typically 24 h). For low-temperature experiments, the reaction times were about 30 h at ?10 °C and up to 10 days at ?20 °C. To analyze the reaction outcome, 20 L aliquots of the reaction mixture were taken to a vial and immediately carefully evaporated to dryness with a stream of compressed air during ca. 15?20 s. The remaining solid was dissolved in 0.20 mL of 1percent Et3N solution in isopropyl alcohol, and the contents of residual sulfide, (R)- and(S)-sulfoxide, and sulfone, were analyzed by chiral HPLC as noted above. | |
With dihydrogen peroxide; acetic acid; In methanol; water; at 0℃; for 12h; | General procedure: The appropriate catalyst 5 (10 molpercent) and sulfide (1.0 mmol) were dissolved in CH3OH/H2O (1:1) (5 mL) and this solution was cooled to 0 °C. Subsequently the additive HOAc (2.0 mmol) and the oxidant hydrogen peroxide (1.5 mmol, 30percent, w/w) were added. The mixture was stirred for 12 h and then was treated with 10 mL of saturated ammonium chloridesolution and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated to give pure sulfoxides through flash column chromatography on silica gel (hexane/ethyl acetate(10:1)). All the products in the paper are known compounds that exhibited spectroscopic data identical to those reported in the literature [34]. The ee was determined by HPLC on chiral column (Daicel,Chiralpak, OD-H). The configuration of sulfoxides product from these reactions was proven to be (S) by comparing the specific rotation with the literature values [35]. |
Yield | Reaction Conditions | Operation in experiment |
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Example 12.- Preparation of esomeprazole, S-isomer of the compound of general formula (II) wherein R2 is 5-methoxy, R4 and R6 are methyl, and R5 is methoxy 26 mg (0.17 mmol) of 4 -methoxy-2,3,5-trimethylpiridine were dissolved in 0.5 ml of anhydrous tetrah ydrofuran at room temperature under under inert atmosphere and the solution was then cooled below -90C. 0.10 ml of a 1.7M solution of terc-butyl lithium (0.17 mmol) were added dropwise and the temperature was maintained below -80C. After 30 minutes at this temperature, the mixture was slowly added to a solution 6 mg (0.017 mmol) of the F1 isomer of (-)-menthyl 5-methoxy-2-benzimidazolylsulphinate, as obtained in Example 11, in 1 ml de tetrahydrofuran cooled below -80C as well. Once the addition was completed, the resulting mixture was allowed to stand up to -20 C, then 5 ml of water were slowly added and it was allowed to reach room temperature. The reaction mixture was analyzed by HPLC and 92% conversion occurred. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol at 25 - 30℃; for 0.666667 - 0.833333h; | 25 EXAMPLE 25: PREPARATION OF ESOMEPRAZOLE LITHIUM AMORPHOUS FORM Esomeprazole free base (10 gm) of Formula I and methanol (100 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Lithium hydroxide (1.2 gm) dissolved in methanol (40 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 30 minutes. The resultant clear solution was distilled completely at 50 °C under vacuum to obtain 13.5 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 24. | |
In methanol; dichloromethane at 25 - 30℃; for 3.16667 - 3.33333h; | 31 EXAMPLE 31: PREPARATION OF ESOMEPRAZOLE LITHIUM CRYSTALLINE FORM L6 Esomeprazole free base (10 gm) of Formula I and dichloromethane (100 ml) was charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Lithium hydroxide (1.2 gm) dissolved in methanol (30 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The resultant clear solution was distilled to remove about 80-90% of the original volume at 50°C under vacuum, dichloromethane (100 ml) was charged and the mixture was stirred at 25-30°C for 30-60 minutes. The formed solid was filtered and was washed with dichloromethane (20 ml). The solid obtained was dried at 70°C under vacuum for 2-3 hours to afford 7.5 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 30. | |
In methanol; ethyl acetate at 25 - 30℃; for 3.16667 - 3.33333h; | 32 EXAMPLE 32: PREPARATION OF ESOMEPRAZOLE LITHIUM CRYSTALLINE FORM L7 Esomeprazole free base (10 gm) of Formula I and ethyl acetate (100 ml) was charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Lithium hydroxide (1.2gm) dissolved in methanol (50 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The resultant clear solution was distilled to remove about 80-90% of the original volume at 50°C under vacuum, ethyl acetate (100 ml) was added and the mixture was stirred at 25-30°C for 30-60 minutes. The solid was filtered and washed with ethyl acetate (20 ml). The solid obtained was dried at 70°C under vacuum for 2-3 hours to afford 12.8 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 31. |
In methanol; isopropyl alcohol at 25 - 30℃; for 3.16667 - 3.33333h; | 28 EXAMPLE 28: PREPARATION OF ESOMEPRAZOLE LITHIUM CRYSTALLINE FORM L3 Esomeprazole free base (10 gm) of Formula I and isopropyl alcohol (100 ml) was charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Lithium hydroxide (1.2 gm) dissolved in methanol (30 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The resultant clear solution was distilled until about 80-90% of its original volume was removed at 50°C under vacuum, isopropyl alcohol (100 ml) was charged and the mixture was stirred at 25-30°C for 30-60 minutes. The formed solid was filtered and was washed with isopropyl alcohol (20 ml). The solid obtained was dried at 70°C under vacuum to afford 2.1 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 27. | |
In toluene at 25 - 30℃; for 3.16667 - 3.33333h; | 27 EXAMPLE 27: PREPARATION OF ESOMEPRAZOLE LITHIUM CRYSTALLINE FORM L2 Esomeprazole free base (10 gm) of Formula I and toluene (100 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Lithium hydroxide (1.2 gm) dissolved in toluene (30 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The resultant clear solution was distilled until about 80-90% of its original volume was removed at 50°C under vacuum, toluene (100 ml) was added and the mixture was stirred at 25-30°C for 30-60 minutes. The formed solid was filtered and the solid was washed with toluene (20 ml). The solid obtained was dried at 70°C under vacuum for 3-4 hours to afford 5 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 26. | |
In methanol; acetonitrile at 25 - 30℃; for 3.16667 - 3.33333h; | 29 EXAMPLE 29: PREPARATION OF ESOMEPRAZOLE LITHIUM CRYSTALLINE FORM L4 Esomeprazole free base (10 gm) of Formula I and acetonitrile (100 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Lithium hydroxide (1.2 gm) dissolved in methanol (30 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The resultant clear solution was distilled to remove about 80-90% of the original volume at 50°C under vacuum, acetonitrile (100 ml) was added and the mixture was stirred at 25-30°C for 30-60 minutes. The formed solid was filtered and was washed with acetonitrile (20 ml). The solid obtained was dried at 70°C under vacuum for 2-3 hours to afford 6.2 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 28. | |
In tetrahydrofuran; methanol at 25 - 30℃; for 3.16667 - 3.33333h; | 30 EXAMPLE 30: PREPARATION OF ESOMEPRAZOLE LITHIUM CRYSTALLINE FORM L5 Esomeprazole free base (10 gm) of Formula I and tetrahydrofuran (100 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Lithium hydroxide (1.2 gm) dissolved in methanol (30 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The resultant clear solution was distilled to remove about 80-90% of the original volume at 50°C under vacuum, tetrahydrofuran (THF) (100 ml) was added and the mixture was stirred at 25-30°C for 30-60 minutes. The formed solid was filtered and washed with tetrahydrofuran (20 ml). The solid obtained was dried at 70°C under vacuum for 2-3 hours to afford 6 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 29. | |
In methanol; acetone at 25 - 30℃; for 3.16667 - 3.33333h; | 26 EXAMPLE 26: PREPARATION OF ESOMEPRAZOLE LITHIUM CRYSTALLINE FORM L1 Esomeprazole free base (10 gm) of Formula I and acetone (100 ml) of were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Lithium hydroxide (1.2 gm) dissolved in methanol (30 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The resultant clear solution was distilled until about 80-90% of the original volume was removed at 50°C under vacuum, acetone (100 ml) was charged, and the mixture was stirred 25-30°C for 30-60 minutes. The solid that formed was filtered and was washed with acetone (20 ml). The solid obtained was dried at 70°C under vacuum for 3-4 hours to afford 4 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 25. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; toluene for 12.3333 - 12.5h; | 14 EXAMPLE 14: PREPARATION OF ESOMEPRAZOLE POTASSIUM CRYSTALLINE FORM P1 Potassium hydroxide (16.2 gm) and methanol (300 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10-15 minutes. Esomeprazole free base (100 g) of Formula I dissolved in methanol (150 ml) was added slowly over a period of 10-20 minutes. Toluene (150 ml) was added slowly for 10 minutes and stirred for 12 hours. Formed solid was filtered and the solid was washed with toluene (100 ml). Solid obtained was dried at 40-50°C under vacuum to afford 80 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 13. | |
In methanol; dichloromethane at 25 - 30℃; for 3.16667 - 3.33333h; | 18 EXAMPLE 18: PREPARATION OF ESOMEPRAZOLE POTASSIUM CRYSTALLINE FORM P5 Esomeprazole free base (10 gm) of Formula I and dichloromethane (70 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Potassium hydroxide (1.623 gm) dissolved in methanol (35 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The solution obtained was distilled completely at 55°C under vacuum, and dichloromethane (60 ml) was charged and distilled to dryness. To the residue, dichloromethane (60 ml) was added and stirred at 25-30°C for 45-60 minutes. The solid was filtered and was washed with dichloromethane (35 ml). The solid obtained was dried at 65°C under vacuum to afford 3.4 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 17. | |
In methanol; water; ethyl acetate at 20 - 30℃; for 4.16667 - 6.33333h; | 15 EXAMPLE 15: PREPARATION OF ESOMEPRAZOLE POTASSIUM CRYSTALLINE FORM P2 Esomeprazole free base (13.3 gm) of Formula I and ethyl acetate (85.2 ml) was charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Potassium hydroxide (1.72 gm) dissolved in 4 ml of water was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 2-3 hours followed by addition of methanol (2 ml). The resulting solution was stirred at 20-30°C for 2-3 hours. The solution was distilled completely at 50°C under vacuum to afford a foamy yellow solid that was scraped from the flask to afford 11.2 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 14. |
In methanol; isopropyl alcohol at 25 - 30℃; for 3.16667 - 3.33333h; | 20 EXAMPLE 20: PREPARATION OF ESOMEPRAZOLE POTASSIUM CRYSTALLINE FORM P7 Esomeprazole free base (10 gm) of Formula I and isopropyl alcohol (70 ml) was charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. A mixture of methanolic potassium hydroxide solution (KOH (1.623 gm) dissolved in methanol (35 ml)) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The separated solid was filtered and the solid was washed with isopropyl alcohol (35 ml). The solid obtained was dried at 60-70°C under vacuum for about 3 hours to afford 5.3 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 19. | |
In methanol; toluene at 25 - 30℃; for 3.16667 - 3.33333h; | 16 EXAMPLE 16: PREPARATION OF ESOMEPRAZOLE POTASSIUM CRYSTALLINE FORM P3 Esomeprazole free base (10 gm) of Formula I and toluene (70 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Potassium hydroxide (1.623 gm) dissolved in methanol (35 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The resulting solution was distilled completely at 60 °C under vacuum and toluene (2x60 ml) was charged and distilled to dryness. To the obtained residue, toluene (35 ml) was charged and stirred for 20-30 minutes. The solid was filtered and was washed with toluene (35 ml). The solid obtained was dried at 65°C under vacuum to afford the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 15. | |
In methanol; acetonitrile at 25 - 30℃; for 3.16667 - 3.33333h; | 17 EXAMPLE 17: PREPARATION OF ESOMEPRAZOLE POTASSIUM CRYSTALLINE FORM P4 Esomeprazole free base (10 gm) of Formula I and acetonitrile (70 ml) was charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Potassium hydroxide (1.623 gm) dissolved in methanol (35 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The formed solid was filtered and was washed with acetonitrile (35 ml). The solid obtained was dried at 60-70°C under vacuum for 3 hours to afford 3.9 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 16. | |
In methanol; acetone at 25 - 30℃; for 3.16667 - 3.33333h; | 19 EXAMPLE 19: PREPARATION OF ESOMEPRAZOLE POTASSIUM CRYSTALLINE FORM P6 Esomeprazole free base of Formula I and acetone (70 ml) was charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. A mixture of methanolic potassium hydroxide solution (KOH (1.623 gm) dissolved in methanol (35 ml)) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. Formed solid was filtered and the solid was washed with acetone (35 ml). The solid obtained was dried at 60°C under vacuum for 3 hours to afford 5.3 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 18. |
Yield | Reaction Conditions | Operation in experiment |
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In water at 25 - 30℃; for 3.16667 - 3.33333h; | 21 EXAMPLE 21: PREPARATION OF ESOMEPRAZOLE CALCIUM CRYSTALLINE FORM K1 Esomeprazole free base (14.8) of Formula I and water (70 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Calcium chloride (1.6 gm) dissolved in water (40 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The formed solid was filtered and was washed with water (35ml). The solid obtained was dried at 60°C under vacuum to afford 7.7 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 20. | |
In methanol; butan-1-ol at 25 - 30℃; for 3.16667 - 3.33333h; | 22 EXAMPLE 22: PREPARATION OF ESOMEPRAZOLE CALCIUM CRYSTALLINE FORM K2 Esomeprazole free base (10 gm) of Formula I, n-butanol (35 ml) and methanol (70 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Calcium chloride (1.6 gm) dissolved in methanol (40 ml) was added slowly at 25-30°C over a period of 10-20 minutes and was stirred for 3 hours. The unwanted solid was filtered and washed with n-butanol (15 ml). The clear filtrate obtained was distilled completely at 50 °C under vacuum to obtain a semi-solid residue. To the residue, ethyl acetate (80 ml) was added and distilled completely at 60°C under vacuum to afford a residue. To the resultant residue ethyl acetate (35 ml) was charged and stirred at 20-30°C for 30 minutes. The solid was filtered and washed with ethyl acetate (35 ml). The solid obtained was dried at 50 °C under vacuum for 3-4 hours to afford 20 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 21. | |
In methanol; toluene at 25 - 30℃; for 3.16667 - 3.33333h; | 23 EXAMPLE 23: PREPARATION OF ESOMEPRAZOLE CALCIUM CRYSTALLINE FORM K3 Esomeprazole free base (10 gm) of Formula I, toluene (35 ml) and methanol (70 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Calcium chloride (1.6 gm) dissolved in methanol (40 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The unwanted solid was filtered and the solid was washed with toluene (15 ml). The clear filtrate obtained was distilled completely at 50 °C under vacuum to afford a solid residue. To the residue, toluene (35 ml) was charged and distilled completely at 60 °C under vacuum to obtain a residue. To the residue, toluene (60 ml) was charged and stirred at 20-30°C for 30 minutes. The solid was filtered and was washed with toluene (35 ml). The solid obtained was dried at 50°C under vacuum for 2-3 to afford 11.8 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 22. |
In methanol at 25 - 30℃; for 3.16667 - 3.33333h; | 24 EXAMPLE 24: PREPARATION OF ESOMEPRAZOLE CALCIUM CRYSTALLINE FORM K4 Esomeprazole free base (10 gm) of Formula I and methanol (70 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Calcium chloride (1.6 gm) dissolved in methanol (40 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The unwanted solid was filtered and the solid was washed with methanol (35 ml). The filtrate obtained was distilled completely at 60°C under vacuum to afford a residue. To the residue, methanol (50 ml) was charged and distilled completely at 50-60°C under vacuum to obtain a residue. To the residue, acetone (70 ml) was charged and stirred at 30°C for 30 minutes. The solid was filtered and was washed with acetone (35 ml). The solid obtained was dried at 60°C under vacuum for 3-4 hours to afford 15.6 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 23. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; ethyl acetate at 25 - 30℃; for 3.16667 - 3.33333h; | 7 EXAMPLE 7: PREPARATION OF ESOMEPRAZOLE BARIUM AMORPHOUS FORM Esomeprazole free base (10 gm) of Formula I and ethyl acetate (100 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Barium hydroxide (9.1 gm) dissolved in methanol (20 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The formed solid was filtered and the solid was washed with ethyl acetate (40 ml). The solid obtained was dried at 50-60°C under vacuum to afford 9 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 6. | |
In methanol; dichloromethane at 25 - 30℃; for 3.16667 - 3.33333h; | 11 EXAMPLE 11: PREPARATION OF ESOMEPRAZOLE BARIUM CRYSTALLINE FORM B4 Barium hydroxide (9.1 g) and methanol (20 ml) was charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Esomeprazole free base (10 g) of Formula I dissolved in dichloromethane (100 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The obtained solution was poured in to a glass tray and allowed to evaporate to dryness overnight to afford 13.4 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 10. | |
In methanol; toluene at 25 - 30℃; for 3.16667 - 3.33333h; | 10 EXAMPLE 10: PREPARATION OF ESOMEPRAZOLE BARIUM CRYSTALLINE FORM B3 Barium hydroxide (9.1 g) and methanol (20 ml) was charged into a clean and dry 4 neck round bottom flask and stirred for 10 minutes. Esomeprazole free base of Formula I (10 g) dissolved in toluene (100 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The obtained solution was poured into a glass tray and allowed to evaporate to dryness overnight to afford 13.3 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 9. |
In methanol; acetonitrile at 25 - 30℃; for 3.16667 - 3.33333h; | 13 EXAMPLE 13: PREPARATION OF ESOMEPRAZOLE BARIUM CRYSTALLINE FORM B6 Barium hydroxide (9.1 gm) and methanol (20 ml) were charged into a clean and dry 4 neck round bottom flask, followed by stirring for 10 minutes. Esomeprazole free base (10 gm) of Formula I dissolved in acetonitrile (100 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 2-3 hours. The solution obtained was poured into a glass tray and allowed to evaporate to dryness overnight to afford 12.2 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 12. | |
In tetrahydrofuran; methanol at 25 - 30℃; for 3.16667 - 3.33333h; | 12 EXAMPLE 12: PREPARATION OF ESOMEPRAZOLE BARIUM CRYSTALLINE FORM B5 Barium hydroxide (9.1 gm) and methanol (20 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Esomeprazole free base (10 g) of Formula I dissolved in tetrahydrofuran (THF) (100 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The obtained solution was poured into a glass tray and allowed to evaporate to dryness overnight to afford 14 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 11. | |
In acetone at 25 - 30℃; for 3.16667 - 3.33333h; | 9 EXAMPLE 9: PREPARATION OF ESOMEPRAZOLE BARIUM CRYSTALLINE FORM B2 Barium hydroxide (9.1 g) and acetone (40 ml) was charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Esomeprazole free base (10 g) of Formula I dissolved in acetone (100 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The obtained solution was poured into a glass tray and allowed to evaporate to dryness overnight to afford 13 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 8. | |
In methanol at 25 - 30℃; for 3.16667 - 3.33333h; | 8 EXAMPLE 8: PREPARATION OF ESOMEPRAZOLE BARIUM CRYSTALLINE FORM B1 Barium hydroxide (9.1 g) and methanol (100 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for a period of 10 minutes. Esomeprazole free base (10 g) of Formula I dissolved in methanol (100 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The obtained solution was poured into a glass tray and allowed to evaporate to dryness overnight to afford 14 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 7. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; butan-1-ol at 25 - 30℃; for 1.16667 - 1.33333h; | 1 EXAMPLE 1: PREPARATION OF ESOMEPRAZOLE COPPER CRYSTALLINE FORM C1 Esomeprazole free base (20 gm) of Formula I and n-butanol (200 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Copper sulfate (12.2 gm) dissolved in methanol (100 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 60 minutes. The formed solid was filtered and the solid was washed with n-butanol (100 ml). Solid obtained was dried at 50°C under vacuum for 2-3 hours to afford 16 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 1. | |
In methanol; dichloromethane at 25 - 30℃; for 3.16667 - 3.33333h; | 3 EXAMPLE 3: PREPARATION OF ESOMEPRAZOLE COPPER AMORPHOUS FORM Esomeprazole free base (20 gm) of Formula I and dichloromethane (100 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Copper sulfate (6.1 gm) dissolved in methanol (50 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 3 hours. The solvents were distilled completely at 40°C under vacuum to afford 5.8 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 3. | |
In methanol; N,N-dimethyl-formamide at 25 - 30℃; for 1.16667 - 1.33333h; | 2 EXAMPLE 2: PREPARATION OF ESOMEPRAZOLE COPPER CRYSTALLINE FORM C2 Esomeprazole free base (20 gm) of Formula I and N,N-dimethylformamide (DMF) (200 ml) were charged into a clean and dry 4 neck round bottom flask followed by stirring for 10 minutes. Copper sulfate (12.2 g) dissolved in methanol (100 ml) was added slowly at 25-30°C over a period of 10-20 minutes and stirred for 60 minutes. The formed solid was filtered and the solid was washed with methanol (100 ml). Solid obtained was dried at 50°C under vacuum for 2-3 hours to afford 17 g of the title compound, characterized by a PXRD pattern substantially in accordance with Fig. 2. |
Yield | Reaction Conditions | Operation in experiment |
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With diethylamine In water at 20 - 25℃; for 12h; | 11.b Variant (b) 50 g (0.1447 moles) (S)-omeprazole was dissolved in 500 ml of water with 18 ml diethylamine. A solution of 13.32 g (0.0723 moles) magnesium bromide in 200 ml of water was gradually added, and the mixture was stirred for 12 hours at 20-25°C. The product was filtered and washed with 100 ml of water. The wet product was macerated in 500 ml water, filtered and dried to obtain 45.0 g of (S)-omeprazole magnesium as amorphous form. | |
With Arg In water at 20 - 25℃; for 12h; | 11.c Variant (c) 5.0 g (0.01447 moles) (S)-omeprazole was dissolved in a solution of 50 ml water and 2.52 g (0.01447 moles) arginine. A solution of 1.33 g (0.0072 moles) magnesium bromide in 20 ml water was gradually added, and the mixture was stirred for 12 hours at 20-25°C. The product was filtered and washed with 10 ml of water. The wet product was macerated in 50 ml water, filtered and dried to obtain 4.6 g of (S)-omeprazole magnesium as amorphous form. |
Yield | Reaction Conditions | Operation in experiment |
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99.5 % ee | With Dowex 50W, H(1+) form In ethanol at 0℃; for 0.5h; | 2 Example 2; Optical resolution of racemic omeprazole; A solution of N-benzylcinchoninium chloride (5.9 g) in ethanol/water (9:1, 100 ml) was passed through an Ambersep 900 OH (11 g) column. To the obtained solution omeprazole (4.6 g) was added. After stirring the mixture at room temperature for 1 hour, the mixture was evaporated in vacuo to dryness at a temperature of 45°C. To the obtained solid mass was then added toluene (20 ml), and the resulting mixture was evaporated to dryness. The resulting pale yellow solid (9.7 g) was dissolved in 114 ml of n-butanol/2-propanol (1:7). After stirring the mixture at room temperature overnight, crystals deposited out therein were obtained through a filtration to give 4.7 g of enriched (S)-omeprazole N-benzylcinchoninium salt. The material was twice recrystallized from n-butanol/2-propanol (1:7) to give 3.3 g of (S)-omeprazole N-benzylcinchoninium salt (m.p. 203-205°C, 98.5% d.e. (determined by chiral HPLC), [α] +52° (1.0, methanol)). By concentrating the mother liquor and washings and allowing recrystallization to proceed at room temperature for 24 hours, 0.6 g of (S)-omeprazole N-benzylcinchoninium salt was recoverd. The obtained salt (3.2 g) was dissolved in 25 ml of ethanol. To the solution was added Dowex 50W, H+ form under stirring in an ice bath to a pH value of 4, and the mixture was stirred at a temperature of 0°C for 0.5 hours. The reaction mixture was filtered, washed with 2 x 5 ml of ethanol, and the filtrate was evaporated in vacuo to give a semisolid mass. Solidified mass was recrystallized from toluene/cyclohexane (1:3) to give 0.85 g of (S)-omeprazole (99.5% e.e. (determined by chiral HPLC)). |
Yield | Reaction Conditions | Operation in experiment |
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99% | With hydrogenchloride In ethanol; water at 0℃; for 1h; | 1 Examples Example 1; Optical resolution of racemic omeprazole; To a solution of omeprazole (5.92 g) in 200 ml of methanol, a methanolic solution of N-benzylcinchoninium hydroxide (7.2 g in 100 ml MeOH) was added. After stirring the mixture at room temperature for 0.5 hours, the solution was evaporated in vacuo to dryness at a temperature of 45°C. The resulting pale yellow solid of diastereomeric pair salt (13.2 g, m.p. 183-186°C) was twice recrystallized from n-butanol/2-propanol (1:7) to give 5.2 g of (S)-omeprazole N-benzylcinchoninium salt (m.p. 205-207°C, 99% d.e. determined by chiral HPLC). A second crop (0.7 g, m.p. 202-204°C, 98.5% d.e. determined by chiral HPLC) was obtained by concentrating the combined mother liquor and washings, and twice allowing recrystallization to proceed at room temperature for 24 hours. The obtained salt (5.2 g) was dissolved in a mixture of 25 ml of ethanol and 2.5 ml of water. To the solution was added 0.3 N hydrochloric acid solution under stirring in an ice bath to a pH value of 3-3.5, and the mixture was stirred at a temperature of 0°C for 1 hour. The solvent was evaporated in vacuo to give a semisolid mass, to which 20 ml of ethyl acetate were added. After stirring the mixture at room temperature, the solid was filtered off. N-Benzylcinchoninium chloride was thus recovered in a yield of 99 % having a purity of 99 % (determined by HPLC). The organic layer was separated and evaporated, and the obtained solidified mass was recrystallized from toluenecyclohexane (1:3) to give 2.1 g of (S)-omeprazole (m.p. 65-80°C, 99 % e.e. (determined by chiral HPLC), [α] -41.5° (0.17, methanol)). |
Yield | Reaction Conditions | Operation in experiment |
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99 % ee | Stage #1: (S)-omeprazole N-methylcinchonidinium salt With hydrogenchloride In water; toluene at 5 - 10℃; for 1h; Stage #2: With sodium hydroxide In water; toluene Stage #3: With acetic acid In toluene at 5℃; for 0.5h; | 4 Example 4; Optical resolution of racemic omeprazole; Analogously to example 2, a dimethylformamide solution of N-methylcinchoninium iodide was used. After stirring the reaction mixture at room temperature for 1 hour, the mixture was evaporated in vacuo to dryness and then washed with diethyl ether (2 x 20 ml) to obtain a pale yellow solid (m.p. 118-129°C, [α] +104° (1.0, methanol)). The resulting salt was twice recrystallized from 2-butanone and a small volume of ethanol to obtain crystalline (S)-omeprazole N-methylcinchoninium salt (m.p. 110-125°C, 99% d.e. (determined by chiral HPLC), [α] +21° (0.7, methanol)). To a suspension of the obtained salt (2.5 g) in toluene (70 ml) was added 3% aqueous hydrochloric acid at a temperature of 5-10°C to a pH value of 3. The mixture was stirred, filtered and the organic phase was decanted. The organic phase was extracted with 10 % sodium hydroxide solution (2 x 10 ml) and after cooling to 5°C acidified with glacial acetic acid with vigorous stirring. Stirring was continued for 0.5 h, then the solution was seeded with (S)-omeprazole (100 mg) at 5°C and filtered. The collected solid was washed with water (2 x 5 ml) and dried in vacuo at ambient temperature to afford (S)-omeprazole (0.95 g, 99% e.e.) as a slightly brown solid. |
With Dowex 50W, H(1+) form In ethanol at 0℃; for 0.5h; | 3 Example 3; Optical resolution of racemic omeprazole; To a mixture of omeprazole (0.79 g) and sodium hydroxide (0.11 g) in methanol (35 ml) a solution of N-methylcinchonidinium iodide (1.0 g) in methanol (30 ml) was added. After stirring the mixture at room temperature for 1 hour, the mixture was cooled down in a refrigerator, filtered (Celite) and then evaporated in vacuo to dryness. The resulting pale yellow solid (m.p. 106-110°C, [α] -65° (1.0, methanol)) was dissolved in 82 ml of acetone/butyl acetate (7:1). After stirring the mixture at room temperature overnight, crystals deposited out therein were obtained through a filtration to give 0.7 g, of enriched (R)-omeprazole N-methylcinchonidinium salt. The material was recrystallized from acetone/butyl acetate (7:1) to give 0.5 g of enriched (R)-omeprazole N-methylcinchonidinium salt (m.p. 193-196°C, [α] -47° (1.0, methanol)). (S)-omeprazole N-methylcinchonidinium salt was obtained from the concentrated mother liquor, i.e. the filtrate after filtration of the crystalline mass. The crystalline (S)-omeprazole N-methylcinchoninium salt was twice recrystallized from 2-butanone/butylacetate (1:3) and a small volume of ethanol; m.p 95-107°C, 98.5% d.e. (determined by chiral HPLC). Liberation of (S)-omeprazole was accomplished analogously to example 2. |
Yield | Reaction Conditions | Operation in experiment |
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In a 100 ml flask, 7.5 gm diethyl (-)-D-tartrate and 5.16 gm titanium(IV) isopropoxide and 0.13 ml water were taken at room temperature, and the mixture was heated to 65 - 70 degrees for 1 hour. After cooling to room temperature, 10 gm 5-methoxy[(2-(4-methoxy)- 3,5-dimethyl-2-pyridinyl] methylsulfenyl]-lH-benzimidazole was added and heated until a clear solution was obtained. The mixture then stirred for 0.5 hours at heating and cooled to room temperature. 6.9 gm Cumene hydroperoxide was added slowly. After addition, the reaction was monitored by HPLC for the following with the results listed below: | ||
In a 100 ml flask, 7.5 gm diethyl (-)-D-tartrate, 20 ml methylene chloride, 5.16 gm titanium(IV) isopropoxide and 0.13 gm water were taken at room temperature, and the mixture was heated to 65 - 70 degrees for 1 hour. After cooling to room temperature, 10 gm PMT was added and heated until a clear solution was obtained. The mixture then <n="21"/>stirred for 0.5 hours at heating and cooled to room temperature. 6.9 gm Cumene hydroperoxide was added slowly. After addition, the reaction was monitored by HPLC for the following with the results listed below: | ||
With dihydrogen peroxide;Mn-complex of (R,R)-1,2-bis(3,5-di-tert-butyl-2-hydroxybenzylamino)cyclohexane; In water; acetonitrile; at -10℃; for 5h;Product distribution / selectivity; | 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1 H-benzimidazole (4a) (0.987 g , 3 mmol) and manganese complex of (R,R)-1 ,2-bis(3,5-di-te/f-butyl-2-hydoxybenzyl- amino)cyclohexane (10c) (96 mg, 5 mol %) are dissolved in acetonitrile (45 ml). The reaction mixture is cooled to -100C and 30% aqueous H2O2 (13.8 ml, 45 mol equiv) is added dropwise over 3 hours period. The reaction mixture is stirred for additional 2 hours. HPLC analysis shows formation of 56% of sulfoxide (1a) with 67% ee (S-enriched) and 5% of sulfone. |
With dihydrogen peroxide;Mn-complex of (S,S)-1,2-bis(2-hydroxybenzylamino)cyclohexane; In water; acetonitrile; at 0 - 20℃; for 3.5h; | 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1 H- benzimidazole (4a) and a preformed salan (10b) - metal complex are dissolved in acetonitrile. The reaction temperature is adjusted and 30% aqueous H2O2 is added dropwise. The mixture is stirred for several hours. Then, it is poured portionwise into a cold (0 0C) 10% aqueous Na2SO3 and stirred for additional 15 min and extracted with dichloromethane. The organic phase is dried over Na2SO4 and concentrated yielding an oily residue which is analyzed by chiral and achiral HPLC.Typically, runs were carried out on 1 mmol scale of the starting material 4a in acetonitrile (1 mmol 4a in 10 mL MeCN). The amounts of added reagents, temperature and reaction time in particular examples are indicated in Table 4. Also the results are indicated in Table 4. | |
Titanium tetraisopropoxide (66.7 mg, 0.235 mmol) and water (8.0 mg, the total amount of water is 8.47 mg, 0.47 mmol) were added to a solution of L1 (67.1 mg, 0.065 mmol) in toluene (20 mL) at 25 C. After stirring at that temperature for 1 h, pyrmetazol (165.0 mg, 0.5 mmol) was added. Then, the mixture was heated to 50 Cand maintained for 1 h. After the mixture was cooled to 25 C, N,N-diisopropylethylamine (16.8 mg, 0.13 mol) and cumene hydroperoxide (80% in cumene, 110.5 mg,0.65 mmol) were added subsequently. After stirring at 25 C for 1 h, a small sample of reaction mixture was taken for HPLC analysis for conversion and selectivity, and the product was isolated by preparative thin-layer chromatography (TLC; eluent: CH2Cl2/MeOH 25/1) for determination of the enantiomeric purity. | ||
19%Chromat. | With iron(III)-acetylacetonate; 2,4-dichloro-6-[(E)-[[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]imino]methyl]phenol; dihydrogen peroxide; p-N,N-dimethylaminobenzoic acid; In dichloromethane; water; at 15℃; for 1.5h; | General procedure: 79.3 mg (273 mumol) of S-dichloro chiral ligand and 32.2 mg (91.1 mumol) of iron(III) acetylacetonate were dissolved in 0.6 mL of ethyl acetate at 25° C., and stirred for more than 30 min. To the mixed solution were added 7.8 mg (45.5 mumol) of lithium 4-dimethylaminobenzoate and 0.3 mL of ethyl acetate, and the suspension was stirred for more than 30 min. 0.3 g (911 mumol) of sulfide A and 0.9 mL of ethyl acetate were added and the suspension was stirred for more than 30 min. After the mixture was cooled to ?5° C., 186 muL (1.82 mmol) of 30percent aqueous hydrogen peroxide solution was added dropwise for 2 min or more. After 4.5 hours, the reaction mixture was analyzed under HPLC analysis condition 1. sulfoxide A 88percent; sulfone A 11percent; sulfide A 0percent 98percent ee |
Yield | Reaction Conditions | Operation in experiment |
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98.1 % ee | Stage #1: S-omeprazole*(S)-[1.1'-binaphthalen]-2.2'-diol inclusion complex With sodium hydroxide In tert-butyl methyl ether; water at 20 - 30℃; Stage #2: With acetic acid In dichloromethane; water | 14 EXAMPLE 14Preparation of EsomeprazoleEsomeprazole-BINOL inclusion complex (100 g; 158.29 mmol; ee of 98.28%) was suspended in methyl t-butyl ether (1300 ml). Aqueous sodium hydroxide solution (2.2% w/w; 302 g) was added to the suspended mass at 20-30° C. and stirred till clear solution was obtained. Thereafter, organic layer was separated and the aqueous layer was extracted with methyl t-butyl ether for recovery of BINOL. The organic layers were combined, concentrated and recovered 44.4 g of BINOL. To the aqueous layer, methylene chloride (300 ml) was added and pH was adjusted to 7-8 with 10% v/v aqueous acetic acid. The organic layer was separated and washed with DM water and concentrated under reduced pressure to yield esomeprazole as a foamy solid mass.Yield-54.5 gEnantiomeric excess-98.1%. |
Yield | Reaction Conditions | Operation in experiment |
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Example 1; Water (580 ml) and 5% aqueous sodium chloride (70 ml) solution were added to the diastereomeric mixture of 1-(S)-camphor sulfonyl-5-methoxy-2- [(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1 H-benzimidazole and 1 -(S)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl- (R/S)-sulfinyl]-1 H-benzimidazole (35 gm, 9:1) obtained as in preparative example 1 at 25C, then sodium hydroxide solution (11 gm in 58 ml water) was added slowly for 30 minutes. The contents were stirred for 6 hours at 25C. To the reaction mass, was added dichloromethane (350 ml), the pH was adjusted to 7.0 with hydrochloric acid and the reaction mass was extracted with dichloromethane. The layers were separated. The organic layer was washed with 5% aqueous sodium chloride (70 ml), dried with sodium sulfate and the solvent was distilled to obtain 21 gm residue containing 5-Methoxy-2-[(3,5- dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]1-H-benzimidazole (esomeprazole :R-omeprazole = 11 :1 ). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydrogencarbonate In ethyl acetate at 5 - 10℃; for 0.5h; | 13 Example 13:Preparation of S-omeprazole (Esomeprazole); To a stirred solution of S-omeprazole-(R)-BNPPA complex (10 gm) in ethyl acetate (200 ml) was slowly added sodium bicarbonate (30 ml, 10%) at 5 to 10°C. The solution was stirred for 30 minutes at 5 to 10°C and layers were separated. The organic layer was washed with water and concentrated on a rotavapor. The residue obtained was dissolved in methanol (10 ml) and was added to ice cold water (50 ml) dropwise, stirred for 30 minutes. The solid obtained was collected by filtration and the solid was dried at 45 to 50°C deg C under vacuum for 12 hours to obtain 3 gm of esomeprazole (chiral purity: 84%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.8% | To 1000 mL Three-necked round bottom flask with esomeprazole sodium 60g and acetone 600mL, heated to 37-42 C, 56 mL of diethyl D-tartrate, 50 mL of tetraisopropyl titanate and 3 mL of high purity water were added successively, stirred for 20-40 min, 68 mL of triethylamine was added, S-mandelic acid 74g and acetone 20mL mixed solution and sodium methoxide 1.8g, stirring 6-8h pumping,The filter cake was transferred to a 250 mL three-necked round bottom flask, 19 g of sodium hydroxide and 300 mL of water was added, stirred for 1 h, filtered, and the filtrate was washed with toluene 200 mL * The aqueous phase was adjusted to pH 7-8 with glacial acetic acid and extracted with dichloromethane 300 mL * 3. The combined organic phases were washed with anhydrous sodium sulfate 20 g dry Drying, filtering the filtrate, removing the organic solvent in the filtrate under reduced pressure,And dried to obtain 40 g of a white fluffy solid esomeprazole (yield: 70.8%). | |
With acetic acid; In water; at 20℃;pH ~ 9 - 10; | EXAMPLE 2: PREPARATION OF AMORPHOUS ESOMEPRAZOLE FROMESOMEPRAZOLE SODIUM BY SPRAY DRYINGSodium salt of esomeprazole (5g) was dissolved in water (250ml) at about room temperature. The pH of the mixture was adjusted to about 9-10 with acetic acid. The aqueous layer was further treated with methylene dichloride (100 ml). The organic layer was separated off and evaporated under vacuum at about 30C to about 40C to obtain a residue. The residue was dissolved in acetone (50ml) was added and the solution was spray dried using spray drier equipment. The solution was sprayed with about 2 kg/cm2 nitrogen pressure. Further the input temperature was maintained at about 40-45C and the outlet temperature was maintained at about 30-35C. The solid was collected from the spray drier and dried at about 30-35C under vacuum to afford Esomeprazole base (3.5 g) in amorphous form.Purity by Chiral HPLC: 99.8%, R-isomer: 0.05%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.67 % ee | Stage #1: Camphorsulfonyl chloride; omeprazole With N-ethyl-N,N-diisopropylamine In dichloromethane at 5 - 10℃; for 0.5h; Stage #2: With acetic acid In dichloromethane at 5 - 10℃; Stage #3: With ammonia In dichloromethane | 1 Preparative Example 1 Racemate of 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]-1H-benzimidazole (100 gm) was dissolved in dichloromethane (1000 ml) and dimethyl amino pyridine (4 gm) at 25° C. and the solution was cooled to 0-5° C. N,N-diisopropylethylamine (85 ml) was added to the solution and cooled to 0-5° C. (S)-Camphor sulfonyl chloride (100 gm) dissolved in methylenechloride (150 ml) was added slowly for 30 minutes at 5-10° C. To the reaction mass, was added acetic acid (5 ml) at 5-10° C. The pH was adjusted to 6.5-7.0 with ammonia, and then ice-cooled water (500 ml) was added and stirred for 15 minutes at 25° C. The layers were separated. The organic layer was washed with 10% aqueous sodium chloride. The organic layer was distilled under reduced pressure to obtain a residue. The residue was stirred with ethanol (744 ml) for 20 hours at 25° C. The solid obtained was collected by filtration and the solid was washed with chilled ethanol (50 ml) and diisopropylether (200 ml) to obtain a diastereomeric mixture of 1-(S)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole and 1-(S)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole (120 gm, 13:7).The above solid (120 gm) was dissolved in tetrahydrofuran (1800 ml) at 25° C. for 30 minutes. Distilled off the solvent completely under vacuum and tetrahydrofuran (160 ml) was added. t-Butyl alcohol (160 ml) was slowly added to reaction mass for 15 minutes. Then the contents were stirred for 20 hours at 25° C. and cooled to 0-5° C. and stirred for 2 hours at 0-5° C. The solid obtained was collected by filtration and the solid was washed with chilled tetrahydrofuran and t-butyl alcohol mixture (20 ml, 1:1). Finally washed with diisopropylether (100 ml) to obtain a diastereomeric mixture of 1-(S)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole and 1-(S)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole (60 gm, 4:1).The above solid (60 gm) was dissolved in tetrahydrofuran (900 ml) and distilled off the solvent completely under vacuum. The contents were stirred with tetrahydrofuran (90 ml) and t-butyl alcohol mixture (90 ml) for 20 hours at 25° C. Cooled to 0-5° C. and stirred for 2 hours at 0-5° C. The solid obtained was collected by filtration and the solid was washed with chilled tetrahydrofuran and t-butyl alcohol mixture (20 ml, 1:1). Finally washed with diisopropylether (100 ml) to obtain a diastereomeric mixture of 1-(S)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole and 1-(S)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole (35 gm, 9:1).Example 1 Water (580 ml) and 5% aqueous sodium chloride (70 ml) solution were added to the diastereomeric mixture of 1-(S)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole and 1-(S)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole (35 gm, 9:1) obtained as in preparative example 1 at 25° C., then sodium hydroxide solution (11 gm in 58 ml water) was added slowly for 30 minutes. The contents were stirred for 6 hours at 25° C. To the reaction mass, was added dichloromethane (350 ml), the pH was adjusted to 7.0 with hydrochloric acid and the reaction mass was extracted with dichloromethane. The layers were separated. The organic layer was washed with 5% aqueous sodium chloride (70 ml), dried with sodium sulfate and the solvent was distilled to obtain 21 gm residue containing 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]1-H-benzimidazole (esomeprazole:R-omeprazole=11:1). |
Yield | Reaction Conditions | Operation in experiment |
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78% | Stage #1: omeprazole sodium With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate; water; triethylamine In acetone at 35 - 40℃; Large scale; Stage #2: With (S)-Mandelic acid In acetone at 35 - 40℃; for 2h; Large scale; Stage #3: With sodium hydrogencarbonate In dichloromethane; water for 0.5h; Large scale; |
Yield | Reaction Conditions | Operation in experiment |
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Titanium tetraisopropoxide (66.7 mg, 0.235 mmol) and water (8.0 mg, the total amount of water is 8.47 mg, 0.47 mmol) were added to a solution of L1 (67.1 mg, 0.065 mmol) in toluene (20 mL) at 25 C. After stirring at that temperature for 1 h, pyrmetazol (165.0 mg, 0.5 mmol) was added. Then, the mixture was heated to 50 Cand maintained for 1 h. After the mixture was cooled to 25 C, N,N-diisopropylethylamine (16.8 mg, 0.13 mol) and cumene hydroperoxide (80% in cumene, 110.5 mg,0.65 mmol) were added subsequently. After stirring at 25 C for 1 h, a small sample of reaction mixture was taken for HPLC analysis for conversion and selectivity, and the product was isolated by preparative thin-layer chromatography (TLC; eluent: CH2Cl2/MeOH 25/1) for determination of the enantiomeric purity. | ||
10.2%Chromat.; 88.3%Chromat. | With lithium 4-dimethylaminobenzoate; iron(III)-acetylacetonate; 2,4-dichloro-6-[(E)-[[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]imino]methyl]phenol; dihydrogen peroxide; In water; ethyl acetate; at -5℃; for 4.5h; | As described in Non-Patent Literature 1 and the like, when using titanium as a catalyst, there was a problem that it was necessary to increase the catalyst amount upon scaling up the reaction. Accordingly, experiments using 1 g, 20 g and 100 g of the starting sulfide A were conducted in a production method of the present invention. The reaction using 100 g is described below, but the reactions were similarly conducted using the corresponding amount of reagents in case of using 1 g or 20 g. (0149) 7.93 g (27.3 mmol) of S-dichloro chiral ligand, 8.04 g (22.77 mmol) of iron(III) acetylacetonate and 3.9 g (22.77 mmol) of lithium 4-dimethylaminobenzoate were suspended in 300 mL of ethyl acetate at room temperature, and stirred for more than 30 min. To the mixture were added 100 g (303.56 mmol) of sulfide A and 500 mL of ethyl acetate. After the mixture was cooled to ?5° C., 68.82 g (607.12 mmol) of 30percent aqueous hydrogen peroxide solution was added dropwise. After 8 hours, the reaction mixture was analyzed under HPLC analysis condition 3. (0150) The analysis results of the reactions in these various scales are shown in Table 5 below. [table-us-00005-en] Amount of Content (percent) Sulfide A Sulfoxide A Sulfone A Sulfide A percent ee 1 g 88.3 10.2 1.5 96.3 20 g 85.8 13.7 0.5 97.0 20 g 85.4 13.7 0.8 95.6 100 g 86.5 11.8 1.7 95.1 (0152) As described above, good reproducibility is observed in a production method of the present invention. It is understood that high yield and enantioselectivity can be maintained even in an increased scale, and it is not necessary to increase the amount of the catalyst. |
Yield | Reaction Conditions | Operation in experiment |
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92.3% | In tetrahydrofuran; at -5 - 5℃; for 3h; | (S)-l-phenylethyl ester of (S)-5-methoxy-1H-benzimidazole-2-sulfinic acid prepared in Example 5 was chargedwith 727. 7 g (2.30 mol) (Formula VI) and 450 ml of tetrahydrofuran, and thetemperature was lowered to -5 C. About 630 ml of the Grignard reagent (III)prepared by the method of Example 1 was added dropwise under mechanicalstirring, and the dropping temperature was controlled at -5 C to 0 C. Afterthe completion of the addition, the reaction was continued for 3 hours at about5 C. TLC was controlled (chloroform: methanol = 5: 1) and the startingmaterial was lost. THF was removed by evaporation under reduced pressure, and400 ml of dichloromethane was added to extract the desired product. Thereaction flask was placed in an ice-water bath (about 0 C) and 300 ml of 10%ammonium chloride solution (0 C to 5 C) Off. The organic phase was dried over anhydrous sodium sulfate (30 g), filtered andevaporated to give 733.2 g of a purple oil. The yield was 92.3%, HPLC puritywas 96.9%, and the value was 98. 84 / RTI & gt; |
733.2 g | In tetrahydrofuran; at -5 - 0℃; for 3h; | (S) -5-methoxy-1H-benzimidazole-2-sulfinic acid- (S) -1-phenylethyl ester prepared in Example 5 VI) and 450 ml of tetrahydrofuran were added and the temperature was lowered to -5 C. About 630 ml of Grignard reagent (III) prepared according to the method of Example 1 were added dropwise under mechanical stirring. The temperature of dropping was controlled at -5 C to 0 C. After the completion of the insulation was continued at -5 for about 3 hours, TLC control (chloroform: methanol = 5: 1), the raw material disappeared. The THF was removed under reduced pressure and 400 ml of dichloromethane was added to extract the target product. The reaction flask was placed in an ice-water bath (about 0 C) and quenched by adding 300 ml of a 10% ammonium chloride solution (0 C to 5 C) under mechanical stirring. The organic phase was separated by filtration and the organic phase was dried over 30 g of anhydrous sodium sulfate. The mixture was suction filtered and the organic solvent was distilled off to obtain 733.2 g of a purple oily product with a molar yield of 92.3%, an HPLC purity of 96.9% and an ee value of 98.84%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | Insulation at around 20 C,Nitrogen replacement reaction system,To a 1000 ml reaction flask was added 150 ml of tetrahydrofuran (hereinafter referred to as THF) and 68.0 g (2.80 mol) of magnesium shoulder (pretreated)Iodine 12.7 g (0.05 mol)Stirring for 1 hour,Heating up to 30 C,While slowly dissolving in 150 ml of THFOf a mixture of 464.3 g (2.50 mol 1) of 2- (chloromethyl) -4-methoxy-3,5-dimethylpyridine and 12.7 g (0.5 mol)Drop finished,Insulation at 30 C for 5 hours,Cool to 20 C to 25 C.among them,Magnesium shoulder pretreatment method is as follows: with 5% hydrochloric acid stirring washing for 30 minutes,Rapid filtration and leaching with acetone (to minimize the time with air contact),Vacuum drying immediately after use.A solution of 727.7 g (2.30 mol) of (S) -5-methoxy-1H-benzimidazole-2-sulfinic acid - (S) -1-phenylethyl ester prepared in Example 5 was added to the reaction vessel VI) and 450 ml of tetrahydrofuran,Cooling to -5 or so,Mechanical agitation,A mixture of about 630 ml of Grignard reagent (III) prepared according to the method of Example 1 was added dropwise,The dropping temperature was controlled at -5 C to 0 C,After the dropwise addition, the temperature was maintained at about -5 C for 3 hours,TLC in the control (chloroform: methanol = 5: 1), the raw material disappeared.The THF was distilled off under reduced pressure,The target product was extracted by the addition of 400 ml of dichloromethane,The reaction flask was placed in an ice-water bath (about 0 C), and 10% ammonium chloride solution (0 C to 5 C)To quench.Dispensing,The organic phase was dried with 30 g of anhydrous sodium sulfate,Filter,The organic solvent was distilled off,To give 733.2 g of a purple oil,The molar yield was 92.3%HPLC purity 96.9%Ee value of 98.84%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.2% | In tetrahydrofuran; at -15 - 0℃; for 1h; | A solution of 829.0 g (2.40 mol) of (S) -5-methoxy-1H-benzimidazole-2-sulfinic acid - (S) -1-phenylethyl ester prepared in Example 6 was added to the reaction vessel VI) and 450 ml of tetrahydrofuran, Cooling to -15 or so,Mechanical agitation,A mixture of about 630 ml of Grignard reagent (III) prepared according to Example 2 was added dropwise,The dropping temperature is controlled at -15 C to 0 C,After the dropwise addition, the reaction was continued at -15 C for 1 hour,TLC in the control (chloroform: methanol = 5: 1),Raw materials basically disappeared.The THF was distilled off under reduced pressure,The target product was extracted by the addition of 400 ml of dichloromethane,The reaction flask was placed in an ice-water bath (about 0 C) and quenched by adding 10 ml of a 10% ammonium chloride solution (0 C to 5 C) with mechanical stirring.Dispensing,The organic phase was dried with 30 g of anhydrous sodium sulfate,Filter,The organic solvent was distilled off,To give 747.7 g of a purple oil,Molar yield 90.2%, HPLC purity 96.5%, ee value 98.81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | In tetrahydrofuran; at -5 - 0℃; | The reaction vessel was charged with 727.7 g (2.30 mol) of (S) -5-methoxy Yl) -1H-benzimidazole-2-sulfinic acid- (S) -1-phenylethyl ester (Formula VI) and 450 ml of tetrahydrofuran, Cooling to -5 or so,Under mechanical agitation, about 630 ml was prepared by the procedure of Example 1Grignard reagent (III), dropping temperature control at -5 to 0 , after dripping continue to heat Reaction was carried out at about -5 C for 3 hours, and TLC was controlled (chloroform: methanol = 5: 1) and the starting material disappeared. The THF was removed by distillation under reduced pressure, and the target product was extracted with 400 ml of methylene chloride. The reaction flask was placed in ice water Bath (0 C or so) Mechanical addition 10% ammonium chloride solution (0 C to 5 C) 300 mlTo quench. The organic phase was washed with 30 g of anhydrous sodium sulfate, filtered and the organic solvent was distilled off Agent,733.2 g of a purple oil, 92.3% molar yield, 96.9% HPLC purity, eeValue of 98.84%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28 g | With sodium methylate In methanol at 65℃; for 2h; | Example Omeprazole20g placed in a 250ml three-necked flaskAdded 6.4 g of sodium methoxide,Methanol 100ml,3,5-Dimethyl-4-methoxy-2-chloromethylpyridine hydrochloride12.8g,The oil bath is stirred and heated to 65°C.Reaction for 2 hours,TLC showed complete reaction,Stop the reaction,Filter the reactants,The filter cake is washed with water until the solid is neutral.Dry cake product.Put the dried product,Add to a 100ml single-mouth flaskRecrystallize in ethanol/acetone (1:1),The target product 28g (compound 1) was obtained,The HPLC assay chemical purity 99.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With magnesium(II) chloride hexahydrate In water at 40℃; for 1h; Large scale; | 1.3; 2.3; 3.3 The third step is to mix the refined intermediate with deionized water, dissolve and filter, add esomeprazole as a seed crystal at a temperature of 40°C, and mix magnesium chloride hexahydrate and deionized water for 1 hour After the internal dripping is finished, stir for 12h, then cool to 5, stir for 30min, filter under reduced pressure, wash the obtained crystals with distilled water, and dry the obtained wet product at 40 and 4kPa to constant weight to obtain Esomelar Azole. The yield of this process was 92%. |
Tags: 119141-88-7 synthesis path| 119141-88-7 SDS| 119141-88-7 COA| 119141-88-7 purity| 119141-88-7 application| 119141-88-7 NMR| 119141-88-7 COA| 119141-88-7 structure
A188600[ 161796-78-7 ]
Sodium (S)-6-methoxy-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)benzo[d]imidazol-1-ide
Reason: Free-salt
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