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CAS No. : | 118072-93-8 | MDL No. : | MFCD00867791 |
Formula : | C5H10N2O7P2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XRASPMIURGNCCH-UHFFFAOYSA-N |
M.W : | 272.09 | Pubchem ID : | 68740 |
Synonyms : |
Zoledronate;CGP42446A;GP42446A;CGP-4244;ZA;ZOL 446;CGP 42446
|
Chemical Name : | (1-Hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl)diphosphonic acid |
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 5.0 |
Molar Refractivity : | 51.47 |
TPSA : | 172.73 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -11.02 cm/s |
Log Po/w (iLOGP) : | -1.47 |
Log Po/w (XLOGP3) : | -4.31 |
Log Po/w (WLOGP) : | -1.12 |
Log Po/w (MLOGP) : | -3.54 |
Log Po/w (SILICOS-IT) : | -3.88 |
Consensus Log Po/w : | -2.86 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 1.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 1.22 |
Solubility : | 4530.0 mg/ml ; 16.6 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 1.29 |
Solubility : | 5350.0 mg/ml ; 19.7 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 1.98 |
Solubility : | 25700.0 mg/ml ; 94.4 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.14 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P501-P202-P201-P264-P280-P302+P352-P308+P313-P337+P313-P305+P351+P338-P362+P364-P332+P313-P405 | UN#: | N/A |
Hazard Statements: | H315-H319-H361 | 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 |
---|---|---|
99% | Stage #1: With phosphoric acid; phosphorus trichloride In 1,2-propylene cyclic carbonate; PEG 600 (polyethylene glycol) at 40 - 60℃; Stage #2: With water In 1,2-propylene cyclic carbonate; PEG 600 (polyethylene glycol) at 85℃; for 18 h; |
Example 7Preparation of Zoledronic Acid; In a mixture of 20 ml of propylene carbonate and 15 ml of PEG 600 was dissolved 7.44 g of phosphorous acid at 40° C. 2-(1H-imidazol-1-yl)acetic acid (3.0 g) was added while stirring and the reaction mixture was heated to 40° C. To the resulting solution was added 9 ml of phosphorus trichloride. The reaction mixture was heated to 60° C. and stirred at 55-60° C. for 4 hours.Water (40 ml) was gradually added to the reaction mixture under stirring (hydrogen chloride is liberated). The reaction mixture was stirred at 85° C. for 18 hours, cooled down to 0° C. and the product was precipitated by addition of ethanol (150 ml). The precipitate was filtered off, washed with ethanol (1.x.40 ml) and dried at 60° C. for 10 hours to give 6.85 g (99percent) of zoledronic acid monohydrate. |
99% | Stage #1: With phosphorous acid; phosphorus trichloride In 1,2-propylene cyclic carbonate; PEG 600 at 40 - 60℃; Stage #2: With water In 1,2-propylene cyclic carbonate; PEG 600 at 85℃; for 18 h; |
In a mixture of 20 ml of propylene carbonate and 15 ml of PEG 600 was dissolved 7.44 g of phosphorous acid at 40°C. 2-(1H-imidazol-1-yl)acetic acid (3.0 g) was added while stirring and the reaction mixture was heated to 40°C. To the resulting solution was added 9 ml of phosphorus trichloride. The reaction mixture was heated to 60°C and stirred at 55-60°C for 4 hours. Water (40 ml) was gradually added to the reaction mixture under stirring (hydrogen chloride is liberated). The reaction mixture was stirred at 85°C for 18 hours, cooled down to 0°C and the product was precipitated by addition of ethanol (150 ml).The precipitate was filtered off, washed with ethanol (1 x 40 ml) and dried at 60°C for 10 hours to give 6.85 g (99percent) of zoledronic acid monohydrate. |
87.3% | Stage #1: at 50 - 55℃; for 6 h; Stage #2: at 70 - 80℃; for 3 h; |
(1) crude productFor 2L into reaction by adding imidazole -1 - acetic acid 110g, phosphorous acid 286g, phosphorus trichloride 480g, heating to 50 - 55 °C, thermal insulation reaction 6h. Reaction finishes, dropping purified water 770 ml, then completing, heating up to 70 - 80 °C, stirring reaction 3h, adding activated carbon to 11g, the decolorization 30min, filter when, after filtering, reaction bottle for 200 ml purified water leaching, washing the filter cake washing. The filtrate is cooled to the room temperature after the dropping funnel in turn, slowly adding containing 320g reaction bottle of isopropanol, stirring at the room temperature crystallization 4h. Filtering, cake 110g anhydrous ethanol wash once, 60 °C drying by blowing 3h. Be zoledronate crude 200.1g, yield 84.3percent, purity 99.8percent.(2) the finished productThe reaction flask is added to the purification water 2.24 kg, zoledronate crude 140g, stirring, warming to reflux, after dissolving the sample all, adding activated carbon to 7g, decoloring 30min, heat filter, the filtrate stirring at the room temperature crystallization 2h, 0 - 5 °C stirring crystallization 2h. Filtering, washing clean reaction kettle mother liquor, washing the filter cake, the filter cake is for 100 ml cold purified water wash once, 60 °C drying by blowing 3h, obtaining white zoledronate crystalline powder 130.3g, yield 87.3percent, purity 99.9percent. |
85.6% | Stage #1: With phosphorous acid; phosphorus trichloride In N,N'- dimethylethyleneurea (DMEU) at 40 - 60℃; Stage #2: With water In N,N'- dimethylethyleneurea (DMEU) at 80 - 100℃; |
A mixture of 1-imidazolylacetic acid (25g; 0.1538mol) and H3PO3 (18.9g; 0.2306mol) in N,N'-dimethylethyleneurea (DMEU) (150ml) is heated to a temperature of from 4O0C to 500C. PCl3 (26ml; 0.3076mol) is slowly added to the resulting suspension. The resulting mixture is heated to a temperature of from 500C to 6O0C and stirred until reaction is complete by HPLC. Water is slowly added to the reaction mixture and the resulting solution is heated, with stirring, to a temperature of from 800C to 1000C until the reaction is complete. The reaction mixture is cooled to ambient temperature and the pH is adjusted to pH 8.0 to 9.0 with aqueous sodium hydroxide solution. The resulting solution is filtered and the pH of the solution is adjusted to pH 1.5 to 2.0. Ethanol is added and precipitation of solids occurs. The solid is filtered, washed and dried under vacuum at a temperature of from 45°C to 550C to a constant weight. 25.7g of zoledronic acid is obtained (molar yield: 85.6percent) with a HPLC purity higher than 99.5percent in area. [The yield was calculated on dry basis]The product was characterized as follows:1H NMR (D2O) δ=4.71 (t, 2H, CH2); 7.28 (dd., IH3CH); 7.44 (dd., IH, CH); 8.62 (s., IH, CH)31P NMR (D2O) δ= 16.03 |
83% | Stage #1: at 55℃; Stage #2: at 8 - 70℃; for 14 - 15 h; Stage #3: With sodium hydroxide In water at 30 - 40℃; |
Example 1 - Zoledronic Acid; EPO <DP n="7"/>A suspension of 1-imidazol-l-yl acetic acid (200 g) in methanesulfonic acid 98-99 percent (240 ml) is added slowly and blending phosphorous trichloride (856 ml).The temperature is increased until reaching 55 0C, reflux is observed.Once the phosphorous trichloride aggregate is finished, the aggregate of water (171 ml) is started, thus increasing the exothermy, which is evidenced through a larger volume of reflux.During the reaction hydrogen chloride is released.The mass in suspension slowly dissolves and the solution turns very viscous, thus making the agitation difficult.After 12 hours reaction at 55-70 0C, water is slowly added (805 ml), in a period of 2-3 hours at a temperature between 8 and 25 0C, with which a fluid solution is achieved.It is then heated at 105 - 112 0C over 3 hours and the solution is filtered to eliminate impurities.The resulting solution is partially neutralized at a temperature of 30 - 40 0C with a sodium hydroxide aqueous solution 50 percent (w/v) until obtaining a pH of 0.25 +/- 0.03It is then cooled down to 0-5 0C, maintaining this temperature over at least 2 hours the precipitate being filtered.The same is washed by resuspension once in water (500 ml) and twice in methanol (500 ml each time).The precipitate may be dried in a stove at 50 - 60 0C, thus obtaining the raw zoledronic acid with a potentiometric titre equal to or exceeding 98 percent.It may also be used humid to prepare the trihydrate form.The output is 83 percent. |
75% | Stage #1: With phosphorous acid In diphenylether at 70℃; for 1 h; Stage #2: With phosphorus trichloride In diphenylether at 70℃; for 6 h; Stage #3: With water In diphenylether; toluene at 25℃; |
The suspension of (1-imidazoyl)ethanoic acid (10.0 g) and phosphorous acid (19.5 g) in diphenyl ether (50 ml) was heated up to 70° C. for 1 hour. Phosphorous trichloride (20 ml) was slowly added to reaction mass at 70° C. temperature and maintained reaction temperature for another 6 hours. Reaction mass was cooled to 25° C. followed by addition of water (150 ml) and toluene (30 ml). Reaction mixture was again heated to 70° C. and charged charcoal in hazy biphasic solution, stirred, filtered through Hyflo bed, washed the bed with hot water (30 ml). Layers was separated from filtrate, aqueous layer was washed with toluene (20 ml) and combined organic layer was then back extracted with water (20 ml) and mixed with main aqueous layer. The water (140 ml) was distilled out from combined aqueous layer at atmospheric pressure in 2 hours and then refluxed the concentrated mass for 13 hours. Reaction mass was cooled to 25° C. followed by addition of methanol (50 ml) in 1 hours. The reaction mixture was stirred and again cooled to 0° C. followed filtration. The filtrate was washed with chilled 1:2 mixture (30 ml) of water and methanol and dried at 60° C. to get Zoledronic Acid. Yield: 19.0 gm (75percent) |
74% | Stage #1: With phosphorus trichloride In methanesulfonic acid at 80 - 110℃; for 8.5 h; Stage #2: for 24 h; |
Example 3Preparation of [1- hydroxy -2-(l H-imidazol-l -yl) ethylidenejbisphosphonic acid6.3 g (0.05 mol) imidazol-l-yl-acetic acid is dissolved in 14 ml methanesulfonic acid while stirring. After 30 minutes of stirring, 13.6 ml (0.16 mol) phosphorus trichloride is added dropwise, then the mixture is stirred for 3 hours at 80 °C. The mixture is left to cool down to room temperature, then 36 ml water is added dropwise. The mixture is warmed to 105-110 °C and then, stirred for 5 hours. Then the reaction mixture is purified with 0.75 g activated carbon and then filtered, washed with 5 ml water and then, 10 M NaOH solution is added droppwise until pH is 1.8. The suspension is stirred for 1 day then the precipitated product is filtered, washed with water and dried. Yield: 10.1 g (74 percent), Free acid content: 23 percent, Purity: 83 percentThe product is recrystallized with a 5 X excess of 1 N HCl. Yield: 6.3 g (46 percent), Free acid content: 98 percent, Purity: 98 percent |
72% | Stage #1: With phosphorous acid; trichlorophosphate In silicon oil at 80℃; for 17 h; Stage #2: With water In silicon oil at 80 - 100℃; for 16 h; |
Examples; CRYSTAL FORMS OF ZOLEDRONIC ACID (ZLD-Ac); Preparation of ZLD-AC crystal form I; General procedure for the preparation of ZLD-AC crystal form I starting from 1- Imidazoleacetic acid (IAA), Phosphorous acid (H3PO3) and Phosphorous oxychloride (POC13) (Examples 1-9, see Table 1) :; A cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, is loaded with 1-IMIDAZOLEACETIC acid (IAA), Phosphorous acid and a diluent (Toluene/Chlorobenzene/PEG-400/Silicon oil). The obtained suspension is heated to 75°C-80°C and Phosphorous oxychloride is added drop- wise. The reaction mixture is then heated to 75°C-100°C for 1-34 hours. Then water is added at 80°C-100°C. The mixture is stirred vigorously for about 15 minutes. [In some cases, when Silicon oil is used as a diluent, there is a need to add Toluene in order to improve the separation between the oily phase and the aqueous phase]. Then the phases are separated. The aqueous phase is put in a clean reactor and heated to 95°C-100°C for 13.5-19 hours. Then it is cooled to 5°C and absolute Ethanol is added to obtain a precipitate after stirring at 5°C for 2.5-4 hours [In some cases a precipitate of Zoledronic acid is obtained without adding absolute Ethanol as an anti-solvent]. The white product is then filtered, washed with absolute Ethanol and dried in a vacuum oven at 50°C for 17-24 hours to obtain Zoledronic acid crystal form I (LOD BY TGA=6. 3percent-9. 3percent).; ZLD HPLC METHOD: COLUMN: PHENOMENEX PHENYL-HEXYL 5UM, 250X4.6MM MOBILE PHASE: 40MM OCTANSULFONIC ACID SODIUM SALT IN 1percent HCLO4, 0.2percent H3PO4 : METHANOL (85:15) DETECTION: 220NM STABILITY WAS MEASURED VERSUS THE PRESENCE OF FORM II. P THE STABILITY DATA FOR EXAMPLE 4 IN THE TABLE ABOVE IS: |
70.7% | Stage #1: With phosphorous acid In sulfolane at 75℃; for 0.5 h; Stage #2: With phosphorus trichloride In sulfolane at 35 - 67℃; for 3 h; Stage #3: With water In sulfolane at 0 - 100℃; for 8 h; |
Preparation of zoledronic acid monohydrate A suspension of 1-imidazolylacetic acid (50g, 0. 396mol) and phosphorous acid (48.7g, 0. 594mol) in sulfolan (180ml) is heated to 75°C for 30 min. The mixture is cooled to 35-40° C and then gradually introduced phosphorous trichloride (117ml, 1. 346mol) while maintaining the temperature between 35-45°C. The mixture is heated to 63-67°C for 3hrs, whereby white solid results. It is then cooled to 0-5°C and quenched by slow addition of water (500ml) at 0-5°C over a period of 1 hr. The resulting clear solution is heated at 100°C for 3hrs, cooled to ambient temperature and charcoalized. To the charcoalized solution is added acetone (800ml). The mixture is then stirred for 4hrs at 20- 25°C and the crystallized product is filtered, washed sequentially with chilled water (200ml), acetone (100ml) and dried in air oven at 55-60°C until water content is between. |
70% | Stage #1: With phosphonic Acid; phosphorus trichloride In sulfolane at 25 - 65℃; for 0.0625 h; Microwave irradiation Stage #2: With water In sulfolane at 150℃; for 0.166667 h; Microwave irradiation |
3.8 mmol (1 equiv) of the respective carboxylic acid (658 mg 3-pyridylacetic acid hydrochloride for 1, 478 mg imidazol-1-yl-acetic acid for 2, 339 mg β-alanine for 3, 392 mg γ-aminobutyric acid for 4, 499 mg 6-aminohexanoic acid for 5) were added to 11.4 mmol (3 equiv) H3PO3 in a dry flask. 1.6 mL of distilled sulfolane was added and the contents were heated briefly to dissolve the solids. The solution was cooled down to approximately 25-35 °C, and 11.4 mmol (3 equiv) of PCl3 were immediately added. The flask was then placed in a Milestone Ethos Synth Microwave Synthesis Labstation and fitted with a condenser through which cold water was passed. The following microwave programs were applied:For synthesis of 1: 3 min ramp to 65 °C, followed by 15 s at 65 °C. For synthesis of 2: 3 min ramp to 65 °C, followed by 45 s at 65 °C.For synthesis of 3: 3 min ramp to 65 °C, followed by 15 s at 65 °C.For synthesis of 4: 3 min ramp to 65 °C, followed by 4 min at 65 °C.For synthesis of 5: 3 min ramp to 65 °C, followed by 4 min at 65 °C.The power was automatically adjusted to reach and maintain the temperature designated by the program, which is determined by a built-in IR sensor in the microwave reactor. For the synthesis of intermediates 1 and 2, the power fluctuated between 0 and a max of 300-400 W, while for 3, 4, and 5, the max power was typically 200-300 W.The solid mixture after microwave irradiation consists of intermediate phosphorus compound together with a yellow-orange unwanted side product which can be removed by centrifugation before or after hydrolysis. The reaction mixture was quenched with 6 mL of H2O, yielding a clear solution that was then transferred to a 50 mL sealed quartz reaction vessel and was hydrolyzed to the bisphosphonic acid in the microwave reactor with a 6 min ramp to 150 °C, followed by 4 min at 150 °C. The power applied fluctuated between 0 and a max of 450-500 W. The pH of the hydrolysis mixtures for acids 1, 3, 4, and 5 was adjusted15 with NaOH and the mixture then aged at 0-5 °C until crystallization of the products was complete. Acids 4 and 5 were precipitated as monosodium salts by stirring with 2-5 mL ethanol for 1-2 h at room temperature. Acid 2 was precipitated by the addition of 9 mL acetone to the acidic hydrolysis mixture and stirring for 3-4 h at room temperature. The white crystalline products were then filtered and washed with cold H2O and acetone or ethanol and then dried under vacuum at 45 °C to constant weight.15 with NaOH and the mixture then aged at 0-5 °C until crystallization of the products was complete. Acids 4 and 5 were precipitated as monosodium salts by stirring with 2-5 mL ethanol for 1-2 h at room temperature. Acid 2 was precipitated by the addition of 9 mL acetone to the acidic hydrolysis mixture and stirring for 3-4 h at room temperature. The white crystalline products were then filtered and washed with cold H2O and acetone or ethanol and then dried under vacuum at 45 °C to constant weight. |
59% | Stage #1: With phosphorous acid; trichlorophosphate In silicon oil at 80℃; for 34 h; Stage #2: With water In toluene; silicon oil at 80 - 100℃; for 16 h; |
Examples; CRYSTAL FORMS OF ZOLEDRONIC ACID (ZLD-Ac); Preparation of ZLD-AC crystal form I; General procedure for the preparation of ZLD-AC crystal form I starting from 1- Imidazoleacetic acid (IAA), Phosphorous acid (H3PO3) and Phosphorous oxychloride (POC13) (Examples 1-9, see Table 1) :; A cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, is loaded with 1-IMIDAZOLEACETIC acid (IAA), Phosphorous acid and a diluent (Toluene/Chlorobenzene/PEG-400/Silicon oil). The obtained suspension is heated to 75°C-80°C and Phosphorous oxychloride is added drop- wise. The reaction mixture is then heated to 75°C-100°C for 1-34 hours. Then water is added at 80°C-100°C. The mixture is stirred vigorously for about 15 minutes. [In some cases, when Silicon oil is used as a diluent, there is a need to add Toluene in order to improve the separation between the oily phase and the aqueous phase]. Then the phases are separated. The aqueous phase is put in a clean reactor and heated to 95°C-100°C for 13.5-19 hours. Then it is cooled to 5°C and absolute Ethanol is added to obtain a precipitate after stirring at 5°C for 2.5-4 hours [In some cases a precipitate of Zoledronic acid is obtained without adding absolute Ethanol as an anti-solvent]. The white product is then filtered, washed with absolute Ethanol and dried in a vacuum oven at 50°C for 17-24 hours to obtain Zoledronic acid crystal form I (LOD BY TGA=6. 3percent-9. 3percent).; ZLD HPLC METHOD: COLUMN: PHENOMENEX PHENYL-HEXYL 5UM, 250X4.6MM MOBILE PHASE: 40MM OCTANSULFONIC ACID SODIUM SALT IN 1percent HCLO4, 0.2percent H3PO4 : METHANOL (85:15) DETECTION: 220NM STABILITY WAS MEASURED VERSUS THE PRESENCE OF FORM II. P THE STABILITY DATA FOR EXAMPLE 4 IN THE TABLE ABOVE IS: |
53% | Stage #1: With phosphoric acid; phosphorus trichloride In sulfolane at 54 - 88℃; for 5.55 - 7.35 h; Stage #2: With water In sulfolane for 3 - 4 h; Heating / reflux |
Example 1; [0022] An oven-dried 250 ml_ 4-neck RB flask was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet and two 1/8 inch polytetrafluoroethylene (PTFE) feeding lines. The system was flushed with nitrogen for 30 minutes. Under nitrogen protection, imidazoIe-1-ylacetic acid (15.97 g, 0.13 mole), sulfolane (70 ml_) and phosphorous acid (2.67 g, 0.033 mol) were charged to the RB flask. The reaction mixture was mixed at 210 RPM and heated to 600C. PCI3 (9.18 g, 0.067mol) was added slowly (1.3 mL/mn) via a masterflex tubing pump. Five minutes were allowed for mixing. Alternately fed were 26 wtpercent phosphorous acid sulfolane solution (30.7 g, 10.23 g each addition at 1.6 mL/min) and PCI3 (27.5 g, 9.18 g each portion at 1.3 mL/min). Three to five minutes of mixing were allowed between additions. The addition took 1 hr 3 min and temperature was maintained between 600C and 670C. After addition was complete, the temperature of the reaction mixture was raised to 800C and was held at this temperature for 4 hours. Then the temperature of the reaction mixture was raised to 880C and held for 30 minutes. Ambient temperature water (50 g) was added in to quench the reaction. The solution was refluxed for 3 hrs <n="13"/>. temperature, the product was vacuum-filtered and rinsed with 38 g of acetone. Zoledronic acid was obtained as a white crystalline solid (24.1 g, 95.3wtpercent purity by quantitative NMR, 65percent yield). Example 2; [0023] An oven-dried 250 mL 4-neck RB flask was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet and two 1/8 inch PTFE feeding lines. The system was flushed with nitrogen for 30 minutes. Under nitrogen protection, imidazole-1-ylacetic acid (15.97 g, 0.13 mole), sulfolane (70 mL) and phosphorous acid (2.67 g, 0.033 mol) were charged to the RB flask. The reaction mixture was mixed at 300 RPM and heated to 600C. PCI3 (9.18 g, 0.067mol) was added in slowly (1.3 mL/min) via a masterflex tubing pump. Five minutes were allowed for mixing. Alternately fed were 26 wtpercent phosphorous acid sulfolane solution (30.7 g, 10.23 g each addition at 1.6 mL/min) and PCI3 (27.5 g, 9.18 g each portion at 1.3 mL/min. Three to five minutes of mixing were allowed between additions. The addition took 1 hr 6 min and temperature was maintained between 54 and 64°C. After addition was complete, the temperature of the reaction mixture was raised to 800C and held for 4 hours. Then the temperature of the reaction mixture was raised to 880C and held for 30 minutes. This slurry was transferred via 3/8" PTFE tubing using nitrogen pressure into 100 mL of pre-heated (80°C) water under mixing. The resultant water solution was heated to refluxing and held at that temperature for 4 hr. It was then slowly cooled to room temperature then to 1-2°C and held for 1.5 hr at this temperature. The product was collected via vacuum filtration. The cake was rinsed with acetone (20 g) and zoledronic acid was obtained as a white crystalline solid (19.1 g, 98.3 wtpercent purity by quantitative NMR, 53percent yield). Example 3; [0024] An oven-dried 250 mL 4-neck RB flask was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet and two 1/8 inch PTFE feeding lines. The system was flushed with nitrogen for 30 minutes. Under nitrogen protection, imidazole-1-ylacetic acid (15.9 g, 0.13 mole), sulfolane (70 mL) and phosphorous acid (2.67 g, 0.033 mol) were charged to the RB flask. The reaction mixture was mixed and heated to 6O0C. PCI3 (36.7 g, 0.267 mol) and phosphorous acid (8.0 g, 0.098 mol) in <n="14"/>- . mL/min respectively. Reaction temperature remained between 6O0C and 67°C during feeding, After addition of PCI3 and phosphorous acid, the reaction slurry was heated to 800C and held at that temperature for 4 hours. This slurry was then transferred via 3/8" PTFE tubing using nitrogen pressure into 50 m._ of pre-heated (8O0C) water under mixing. The resultant water solution was heated to refluxing and held at that temperature for 4 hr. It was then slowly cooled to 48-500C. Acetone (200 ml_) was added in slowly and then it was cooled to 1-2°C and held for 2 hr at this temperature. The product was collected via vacuum filtration. The cake was rinsed with acetone (35 g) and zoledronic acid was obtained as a white crystalline solid (22.1 g, 98.6 wtpercent purity by quantitative NMR, 61 percent yield). Example 4; [0025] A 2.5 L resin-kettle was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet, two 1/8 inch PTFE tubing as PCI3 and phosphorous acid sulfolane solution feeding lines. The system was dried under a stream of nitrogen. Under nitrogen, imidazoleacetic acid (79.92 g, 0.63 mol), phosphorous acid (13.90 g, 0.17 mol) and sulfolane (350 ml_) were added to the resin-kettle and mixed at 200 RPM. The mixture was heated to 62°C then PCI3 (36.7 g, 0.267 mol) was added in slowly (1.3 mL/min) using a masterflex tubing pump. The slurry was mixed for 5 minutes. Phosphorous acid (40.0 g, 0.49 mol) was dissolved in 114.0 g of sulfolane at 500C. Alternately, this solution (30.8 g each time at 1.6 mL/min) and 147 g (1.07 mol) of PCI3 (29.5 g each portion at 1.3 mL/min) were fed into the reactor while the reaction temperature was maintained at 60-640C. Three to five minutes mixing time was allowed between each addition. Toward the second half of the alternate addition, addition rates were increased to 2.0 mL/min for PCI3 and 2.5 mL/min for phosphorous acid solution respectively. The addition took 3 hr and 21 minutes. After the addition was complete, the phosphorous acid line was rinsed with 30 mL of sulfolane and this was added into the resin-kettle reactor. The reaction temperature was then raised to 800C and maintained for 4 hours. The resulting slurry was then quenched into 250 g of water pre-heated to 800C under mixing. The aqueous solution was refluxed for 4 hours and cooled slowly to room temperature resulting in a slurry. Acetone (1 L) was added slowly into the slurry and the mixture was cooled further to 1-2 0C. After mixing for 2 hours at this temperature, the product was vacuum <n="15"/>, hour. Zoledronic acid was obtained as a white, crystalline solid (109.6 g). |
53% | Stage #1: With phosphorus trichloride In methanesulfonic acid at 80℃; for 3 h; Stage #2: With water In methanesulfonic acid at 26 - 110℃; for 5 h; Stage #3: With sodium hydroxide In water for 5 h; |
6.3 g (0.05 mol) of imidazol-1-yl-acetic acid was dissolved in 21 ml of methanesulfonic acid with stirring. 13.6 ml (0.16 mol) of phosphorus trichloride was added dropwise and the mixture was stirred at 80 °C for 3 h. After cooling to 26 °C, 36 ml of water was added dropwise, the temperature was elevated to 105-110 °C and the contents of the flask were stirred at this temperature for 5 h. Next, the mixture was stirred with 0.75 g of activated carbon for 30 min, filtered and the solid washed with 5 ml of water. To the combined water phase was added dropwise 10 N NaOH solution to attain pH 1.8. The suspension obtained was stirred for 5 h, the solid filtered, washed with 5 ml of water and dried to afford 9.7 g (71percent) of a crude mixture consisting of a 26-74percent mixture of ZA and ZA-Na. Recrystallization from 48.5 ml of 1 N hydrochloric acid furnished 7.2 g (53percent) of ZA comprising 99percent of the acid (Table 1, entry 7); 31P NMR (5percent NaOH/D2O) 16.0 [P8 (5percent NaOD/D2O) 16.2]. |
50% | Stage #1: With phosphorous acid; trichlorophosphate In silicon oil at 80℃; for 26 h; Stage #2: With water In ethanol; silicon oil at 0 - 97℃; for 43.5 h; |
PREPARALION OF ZLD-AC CRYSTAL FORM XNII; Example 18 :; A 3L reactor equipped with A mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was loaded with 1-IMIDAZOLEACETIC acid (70. OG, 0. 56MOLE), Phosphorous acid (136. 7g, 1.67mole) and Silicon oil (M-350) (490ML). The suspension was heated to 80°C and Phosphorous oxychloride (194. 4ML, 2.08mole) was added drop-wise during 4 hours. The reaction mixture was stirred at 80°C for 22 hours. Then water (490ML) was added slowly at 80°C. The mixture was stirred vigorously for about 30 minutes. Then the silicon oil phase and the aqueous phase were separated. The aqueous phase was put in a clean reactor and heated to 97°C for 17.5 hours. Then absolute Ethanol (490ML) was added and the solution was stirred at reflux (87°C) for 2 hours. The solution was then cooled to 70°C-72°C during about 1 hour and was kept at this temperature for 1 hour. After cooling to 25°C during 2.5 hours and stirring at this temperature for 1 hour, half of the product was filtered, washed with small amount of cold water and dried in a vacuum oven at 50°C for 20 hours to obtain 50.8g of Zoledronic acid crystal form XVIII (MS- 507-CROP I, LOD by TGA=1.9percent). The rest of the suspension was cooled to 0°C during 2 hours and was stirred at this temperature for about 16 hours. Then the product was filtered and dried in a vacuum oven at 50°C for 24 hours to obtain 26g of Zoledronic acid crystal form XVIII (MS-507-CROP II, LOD by TGA=1. 0percent). The overall yield of the process is 50percent purity by HPLC 97.7percent. |
49% | Stage #1: With hydrogenchloride; phosphorus trichloride In water at 0 - 5℃; for 2.5 h; Stage #2: for 6 h; Reflux |
Example II. Preparation of [l-hydroxy-2-(lH-imidazol-l-yl)- ethylidene]bisphosρhonic acid.A solution of lH-imidazole-1 -acetic acid [26 g (0.206 moles) of lH-imidazole-1- acetic acid in the mixture of 18 ml of water and 18 ml of hydrochloric acid (35percent)] is added dropwise for 30 minutes at the temperature 0-5 0C to 108 ml of phosphorus trichloride (PCl3) cooled to the temperature 0-5 0C. The mixture is mixed at 0-50C for 1 hour. Then, the mixture is heated to 800C and maintained at this temperature for 1 hour. The excess of phosphorus trichloride is then distilled off under the reduced pressure. 200 ml of water is added to the reaction residues and the hydrolysis is performed while maintaining boiling for 6 hours, afterwards 1 g of activated charcoal, 5 g of Hyflo Super CeI are added and mixed while boiling for 30 minutes. The mixture is filtered and the filter is washed with 20 ml of water. The filtrate is concentrated under the reduced pressure to the volume of 100 ml. 150 ml of 95percent ethanol is added to the concentrated filtrate at 70°C. The mixture is cooled while mixing to 250C and crystallization is performed until the temperature reaches 20-250C for 4 hours. The formed precipitate is filtered off, washed twice with 30 ml of water-ethanol mixture (1:1.5) and dried at 5O0C. 29.3 g (49percent) of [l-hydroxy-2-(lH-imidazol-l-yl)-ethylidene]bisρhosphonic acid monohydrate is obtained. ΗPLC 100.00percent , TGA 6.30percentXPRD: 12.05; 12.77; 15.69; 18.80; 20.84; 21.25; 21.71; 22.09; 25.71; 27.50; 29.19; 32.42; 32.88 ° (+,- 0,02 °) 2 ψ1H NMR (D2O): 5=4.670-4.709 ppm (t, 2H, J=9.65); 7.379 (s,lH); 7.540 (s, IH);8.719 (s, IH)13C NMR: 5=55.56 ppm; 74.81-76.90 (t); 121.13; 126.83; 138.7131P NMR: 5=14.36 ppm15 g of [l-hydroxy-2-(l/-r-imidazol-l-yl)-ethylidene]bisphosphonic acid is suspended in 300 ml of water, heated to the boiling point and mixed while boiling for 15 minutes. Then, the mixture is cooled to 70°C and 300 ml of ethanol is added for about 1-1.5 hour. The mixture is cooled to 20-25°C. After 14 hours of mixing in20-25°C the precipitate is filtered off, washed twice with 15 ml of water and once with 15 ml of ethanol and dried for 6 hours at 55°C. 12.78 g (85percent) of [l-hydroxy-2-(lH-imidazol-l-yl)-ethylidene]bisphosphonic acid monohydrate is obtained.ΗPLC 100.00percent, TGA 6.24percentXPRD: 12.05; 12.78; 15.72; 18.70; 20.82; 21.23; 21.70; 22.08; 25.70; 27.51; 29.14;32.32; 32.88 ° (+,- 0.02 °) 2 ψ 1H NMR (D2O): 5=4.470-4.497 ppm (t, 2H, J=9.62); 7.164 (s,lH); 7.367 (s, IH);8.421 (s, IH)13C NMR: 5=53.00 ppm; 72.59 (t); 118.47; 123.66; 138.7131P NMR: 5=14.21 ppm |
49% | Stage #1: With hydrogenchloride; phosphorus trichloride In water at 0 - 80℃; for 2.5 h; Stage #2: for 6 h; Heating |
EXAMPLE II Preparation of [1-hydroxy-2-(1H-imidazol-1-yl)-ethylidene]bisphosphonic acid A solution of 1H-imidazole-1-acetic acid [26 g (0.206 moles) of 1H-imidazole-1-acetic acid in the mixture of 18 ml of water and 18 ml of hydrochloric acid (35percent)] is added dropwise for 30 minutes at the temperature 0-5° C. to 108 ml of phosphorus trichloride (PCl3) cooled to the temperature 0-5° C. The mixture is mixed at 0-5° C. for 1 hour. Then, the mixture is heated to 80° C. and maintained at this temperature for 1 hour. The excess of phosphorus trichloride is then distilled off under the reduced pressure. 200 ml of water is added to the reaction residues and the hydrolysis is performed while maintaining boiling for 6 hours, afterwards 1 g of activated charcoal, 5 g of Hyflo Super Cel are added and mixed while boiling for 30 minutes. The mixture is filtered and the filter is washed with 20 ml of water. The filtrate is concentrated under the reduced pressure to the volume of 100 ml. 150 ml of 95percent ethanol is added to the concentrated filtrate at 70° C. The mixture is cooled while mixing to 25° C. and crystallization is performed until the temperature reaches 20-25° C. for 4 hours. The formed precipitate is filtered off, washed twice with 30 ml of water-ethanol mixture (1:1.5) and dried at 50° C. 29.3 g (49percent) of [1-hydroxy-2-(1H-imidazol-1-yl)-ethylidene]bisphosphonic acid monohydrate is obtained. HPLC 100.00percent , TGA 6.30percent XPRD: 12.05; 12.77; 15.69; 18.80; 20.84; 21.25; 21.71; 22.09; 25.71; 27.50; 29.19; 32.42; 32.88° (+,-0.02°) 2ψ 1H NMR (D2O): δ=4.670-4.709 ppm (t, 2H, J=9.65); 7.379 (s, 1H); 7.540 (s, 1H); 8.719 (s, 1H) 13C NMR: δ32 55.56 ppm; 74.81-76.90 (t); 121.13; 126.83; 138.71 |
28% | With phosphoric acid; phosphorus trichloride In diethylene glycol dimethyl ether; water at 50 - 100℃; for 8 - 11 h; Heating / reflux | Example 3:Preparation of Zoledronic Acid:[0019] A 1.5 liter kettle reactor, fitted with a heating mantle, mechanical stirrer, dropping funnel, thermocouple and condenser with nitrogen inlet adapter, was charged with imidazoleacetic acid (100 g, 0.793 mol), diglyme (400 ml), and 85percent phosphoric acid (55 ml). Phosphorus trichloride (330 g, 2.41 mol) was slowly added to the reaction mass resulting in an exotherm and the evolution of hydrogen chloride. The temperature was allowed to rise to 700C and the solution was stirred until the evolution of HCl subsided. The temperature of the reaction mass was increased to 85°C and a white solid began to form, float and adhere to the stirrer shaft. After about 1 hour, stirring became impossible and the stirring motor was stopped. The reaction mass was heated for 5 more hours at 85°C and then cooled to ambient temperature, producing a solid homogeneous white mass. <n="8"/>[0020] Water was slowly added to the white mass (320 ml) that resulted in an exotherm and HCl evolution. The water slowly dissolved the mass in a gradual and uniform fashion, eventually liberating the stirrer. After the mass substantially dissolved, the solution was refluxed for 5 hours, then cooled and stripped to a gum with a rotary evaporator, collecting 420 g of water (pH 0.65). More water (250 ml) was added and stripped, collecting 166 g of water (pH 1.87). Water (250 ml) was again added and stripped, collecting 316 g (pH 2.14). The flask was removed from the rotary evaporator, water (150 ml) was added and the mixture was heated to 90-950C during which time all solids dissolved. The solution was seeded with zoledronic acid monohydrate crystals and slowly cooled to room temperature then chilled to 30C with an ice bath. The resulting crystalline solid was filtered, rinsed with acetone (200 + 100 ml) and dried under a nitrogen stream giving a crop of 52.4 g. Acetone was also added to the filtrate (200 ml) and the solution was left in a freezer overnight giving a second crop of crystals (12.0 g) which, after washing with acetone and drying, was combined with the first crop for a total yield of 64.4 g (28percent). The NMR indicated the presence of traces of diglyme, acetone and H3PO3 impurities. Example 4:Preparation of Zoledronic Acid:[0021 ] A 5 liter cylindrical jacketed reactor was fitted with a mechanical stirrer, thermocouple, nitrogen inlet adapter and a condenser with a caustic scrubber. This was charged with imidazoleacetic acid (0.333 kg, 2.64 mol) and diglyme (1.00 1). The slurry was heated to 500C while stirring (100 rpm) under a slow nitrogen purge (1 1/min). Additional diglyme (0.26 1) and 85percent phosphoric acid (0.304 kg) were added to the reaction mass. Using a Masterflex pump and Teflon tubing, phophorus trichloride (1.04 kg total, 7.57 mol) was pumped into the reaction mass, slowly (2 ml/min) at first and then at an increased rate (40 ml/min), after the water in the phosphoric acid had been depleted. During addition of the PCl3, the temperature was raised to about 65°C and a white mass gradually formed, causing the stirrer to bind. The jacket temperature was increased to 850C causing PCl3 to reflux. The refluxing slowed and then stopped as the white mass expanded. The reactor was allowed to stand at about 80°C for four hours, after which the jacket temperature was set at 150C overnight.[0022] The reactor jacket temperature was increased to 500C and water (0.95 kg total) was slowly (2-5 ml/min) added with a Masterflex pump. The water dissolved the white mass on contact, liberating HCl in an exothermic reaction. After about 250 g of water was added to the reaction mass, the stirrer became unbound and stirring was resumed (100 rpm). The water <n="9"/>addition rate was slowly increased to 40 ml/min. The reaction mass was then heated at about 1000C for 4 hours and then cooled to room temperature.[0023] The reaction mass was drained and rotary evaporated to yield a gum. Water was added to the gum and stripped several times until the distillates pH rose above 1. The resulting aqueous solution (1.2 kg, 1.6 1) was stirred in a beaker and acetone (1.5 1) was slowly added. The mixture was allowed to stand 16 hours to complete crystallization. The solid was filtered, thoroughly washed with acetone and dried in a nitrogen stream to give crude Zoledronic acid (0.202 g, 0.74 mol, 28percent yield). |
7% | With phosphoric acid; phosphorus trichloride In water; PEG 400 at 70 - 85℃; for 11 h; Heating / reflux | Example 6:(Comparative) Preparation of Zoledronic Acid in PEG-400:[0025] Example 3 was repeated substituting PEG-400 (400ml) for diglyme. After the addition of phosphorus trichloride and increased temperature of the reaction mass, a solid formed that eventually returned to solution upon further heating. The yield of zoledronic acid was 7 percent (isolated yield). 1HNMR (D2O/NaOD): 7.72 (s, 1 H); 7.22 (s, 1 H); 6.87 (s, 1 H); 4.82 (O-H, 7.02 H); 4.45 (m, 2 H). 31P NMR (D2O/NaOD): 17.0 (m). Not only was there a substantial decrease in yield, but the product purity deteriorated as well. |
Yield | Reaction Conditions | Operation in experiment |
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89% | at 70 - 80℃; Heating / reflux | Example 3 - Zoledronic Acid Monohydrate; The raw humid zoledronic acid (equivalent to 90.3 g raw product), obtained according to Example 1, is suspended in water (3050 ml). The suspension is heated at reflux, with agitation. EPO <DP n="9"/>Water is added up to a total volume of 3750 ml, by which a total dissolution is obtained.The heating is then interrupted and the agitation, allowing it to slowly cool down to ambient temperature.Once the inside temperature is around 70 - 800C a frank crystallization starts.Once the ambient temperature is reached, it is cooled down to 2 - 5 0C, maintained at that temperature during 1 'Λ hours, filtered and the precipitate is washed with ice water.It is dried in a stove with air flow at 5°C - 60 0C.169.3 g (89 percent) colorless crystals are obtained.The loss through dissection (6.8percent) confirms that this is a monohydrate.This substance, by diffraction with X-rays, dust method, presents peaks at the following values of 20 12.1; 12.8; 15.7; 18.9 +/- 0.2, coincident with those described for the form I (US 2005/0054616).Figure I A shows its diffractogram of dust X-rays and figure IV A the lay-out of the atoms in the unitary cell of the crystalline network for this form. |
Yield | Reaction Conditions | Operation in experiment |
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99% | Example 7Preparation of Zoledronic Acid; In a mixture of 20 ml of propylene carbonate and 15 ml of PEG 600 was dissolved 7.44 g of phosphorous acid at 40 C. 2-(1H-imidazol-1-yl)acetic acid (3.0 g) was added while stirring and the reaction mixture was heated to 40 C. To the resulting solution was added 9 ml of phosphorus trichloride. The reaction mixture was heated to 60 C. and stirred at 55-60 C. for 4 hours.Water (40 ml) was gradually added to the reaction mixture under stirring (hydrogen chloride is liberated). The reaction mixture was stirred at 85 C. for 18 hours, cooled down to 0 C. and the product was precipitated by addition of ethanol (150 ml). The precipitate was filtered off, washed with ethanol (1×40 ml) and dried at 60 C. for 10 hours to give 6.85 g (99%) of zoledronic acid monohydrate. | |
99% | In a mixture of 20 ml of propylene carbonate and 15 ml of PEG 600 was dissolved 7.44 g of phosphorous acid at 40C. 2-(1H-imidazol-1-yl)acetic acid (3.0 g) was added while stirring and the reaction mixture was heated to 40C. To the resulting solution was added 9 ml of phosphorus trichloride. The reaction mixture was heated to 60C and stirred at 55-60C for 4 hours. Water (40 ml) was gradually added to the reaction mixture under stirring (hydrogen chloride is liberated). The reaction mixture was stirred at 85C for 18 hours, cooled down to 0C and the product was precipitated by addition of ethanol (150 ml).The precipitate was filtered off, washed with ethanol (1 x 40 ml) and dried at 60C for 10 hours to give 6.85 g (99%) of zoledronic acid monohydrate. | |
87.3% | (1) crude productFor 2L into reaction by adding imidazole -1 - acetic acid 110g, phosphorous acid 286g, phosphorus trichloride 480g, heating to 50 - 55 C, thermal insulation reaction 6h. Reaction finishes, dropping purified water 770 ml, then completing, heating up to 70 - 80 C, stirring reaction 3h, adding activated carbon to 11g, the decolorization 30min, filter when, after filtering, reaction bottle for 200 ml purified water leaching, washing the filter cake washing. The filtrate is cooled to the room temperature after the dropping funnel in turn, slowly adding containing 320g reaction bottle of isopropanol, stirring at the room temperature crystallization 4h. Filtering, cake 110g anhydrous ethanol wash once, 60 C drying by blowing 3h. Be zoledronate crude 200.1g, yield 84.3%, purity 99.8%.(2) the finished productThe reaction flask is added to the purification water 2.24 kg, zoledronate crude 140g, stirring, warming to reflux, after dissolving the sample all, adding activated carbon to 7g, decoloring 30min, heat filter, the filtrate stirring at the room temperature crystallization 2h, 0 - 5 C stirring crystallization 2h. Filtering, washing clean reaction kettle mother liquor, washing the filter cake, the filter cake is for 100 ml cold purified water wash once, 60 C drying by blowing 3h, obtaining white zoledronate crystalline powder 130.3g, yield 87.3%, purity 99.9%. |
85.6% | A mixture of 1-imidazolylacetic acid (25g; 0.1538mol) and H3PO3 (18.9g; 0.2306mol) in N,N'-dimethylethyleneurea (DMEU) (150ml) is heated to a temperature of from 4O0C to 500C. PCl3 (26ml; 0.3076mol) is slowly added to the resulting suspension. The resulting mixture is heated to a temperature of from 500C to 6O0C and stirred until reaction is complete by HPLC. Water is slowly added to the reaction mixture and the resulting solution is heated, with stirring, to a temperature of from 800C to 1000C until the reaction is complete. The reaction mixture is cooled to ambient temperature and the pH is adjusted to pH 8.0 to 9.0 with aqueous sodium hydroxide solution. The resulting solution is filtered and the pH of the solution is adjusted to pH 1.5 to 2.0. Ethanol is added and precipitation of solids occurs. The solid is filtered, washed and dried under vacuum at a temperature of from 45C to 550C to a constant weight. 25.7g of zoledronic acid is obtained (molar yield: 85.6%) with a HPLC purity higher than 99.5% in area. [The yield was calculated on dry basis]The product was characterized as follows:1H NMR (D2O) delta=4.71 (t, 2H, CH2); 7.28 (dd., IH3CH); 7.44 (dd., IH, CH); 8.62 (s., IH, CH)31P NMR (D2O) delta= 16.03 | |
83% | Example 1 - Zoledronic Acid; EPO <DP n="7"/>A suspension of 1-imidazol-l-yl acetic acid (200 g) in methanesulfonic acid 98-99 % (240 ml) is added slowly and blending phosphorous trichloride (856 ml).The temperature is increased until reaching 55 0C, reflux is observed.Once the phosphorous trichloride aggregate is finished, the aggregate of water (171 ml) is started, thus increasing the exothermy, which is evidenced through a larger volume of reflux.During the reaction hydrogen chloride is released.The mass in suspension slowly dissolves and the solution turns very viscous, thus making the agitation difficult.After 12 hours reaction at 55-70 0C, water is slowly added (805 ml), in a period of 2-3 hours at a temperature between 8 and 25 0C, with which a fluid solution is achieved.It is then heated at 105 - 112 0C over 3 hours and the solution is filtered to eliminate impurities.The resulting solution is partially neutralized at a temperature of 30 - 40 0C with a sodium hydroxide aqueous solution 50 % (w/v) until obtaining a pH of 0.25 +/- 0.03It is then cooled down to 0-5 0C, maintaining this temperature over at least 2 hours the precipitate being filtered.The same is washed by resuspension once in water (500 ml) and twice in methanol (500 ml each time).The precipitate may be dried in a stove at 50 - 60 0C, thus obtaining the raw zoledronic acid with a potentiometric titre equal to or exceeding 98 %.It may also be used humid to prepare the trihydrate form.The output is 83 %. | |
75% | The suspension of (1-imidazoyl)ethanoic acid (10.0 g) and phosphorous acid (19.5 g) in diphenyl ether (50 ml) was heated up to 70 C. for 1 hour. Phosphorous trichloride (20 ml) was slowly added to reaction mass at 70 C. temperature and maintained reaction temperature for another 6 hours. Reaction mass was cooled to 25 C. followed by addition of water (150 ml) and toluene (30 ml). Reaction mixture was again heated to 70 C. and charged charcoal in hazy biphasic solution, stirred, filtered through Hyflo bed, washed the bed with hot water (30 ml). Layers was separated from filtrate, aqueous layer was washed with toluene (20 ml) and combined organic layer was then back extracted with water (20 ml) and mixed with main aqueous layer. The water (140 ml) was distilled out from combined aqueous layer at atmospheric pressure in 2 hours and then refluxed the concentrated mass for 13 hours. Reaction mass was cooled to 25 C. followed by addition of methanol (50 ml) in 1 hours. The reaction mixture was stirred and again cooled to 0 C. followed filtration. The filtrate was washed with chilled 1:2 mixture (30 ml) of water and methanol and dried at 60 C. to get Zoledronic Acid. Yield: 19.0 gm (75%) | |
74% | Example 3Preparation of [1- hydroxy -2-(l H-imidazol-l -yl) ethylidenejbisphosphonic acid6.3 g (0.05 mol) imidazol-l-yl-acetic acid is dissolved in 14 ml methanesulfonic acid while stirring. After 30 minutes of stirring, 13.6 ml (0.16 mol) phosphorus trichloride is added dropwise, then the mixture is stirred for 3 hours at 80 C. The mixture is left to cool down to room temperature, then 36 ml water is added dropwise. The mixture is warmed to 105-110 C and then, stirred for 5 hours. Then the reaction mixture is purified with 0.75 g activated carbon and then filtered, washed with 5 ml water and then, 10 M NaOH solution is added droppwise until pH is 1.8. The suspension is stirred for 1 day then the precipitated product is filtered, washed with water and dried. Yield: 10.1 g (74 %), Free acid content: 23 %, Purity: 83 %The product is recrystallized with a 5 X excess of 1 N HCl. Yield: 6.3 g (46 %), Free acid content: 98 %, Purity: 98 % | |
72% | Examples; CRYSTAL FORMS OF ZOLEDRONIC ACID (ZLD-Ac); Preparation of ZLD-AC crystal form I; General procedure for the preparation of ZLD-AC crystal form I starting from 1- Imidazoleacetic acid (IAA), Phosphorous acid (H3PO3) and Phosphorous oxychloride (POC13) (Examples 1-9, see Table 1) :; A cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, is loaded with 1-IMIDAZOLEACETIC acid (IAA), Phosphorous acid and a diluent (Toluene/Chlorobenzene/PEG-400/Silicon oil). The obtained suspension is heated to 75C-80C and Phosphorous oxychloride is added drop- wise. The reaction mixture is then heated to 75C-100C for 1-34 hours. Then water is added at 80C-100C. The mixture is stirred vigorously for about 15 minutes. [In some cases, when Silicon oil is used as a diluent, there is a need to add Toluene in order to improve the separation between the oily phase and the aqueous phase]. Then the phases are separated. The aqueous phase is put in a clean reactor and heated to 95C-100C for 13.5-19 hours. Then it is cooled to 5C and absolute Ethanol is added to obtain a precipitate after stirring at 5C for 2.5-4 hours [In some cases a precipitate of Zoledronic acid is obtained without adding absolute Ethanol as an anti-solvent]. The white product is then filtered, washed with absolute Ethanol and dried in a vacuum oven at 50C for 17-24 hours to obtain Zoledronic acid crystal form I (LOD BY TGA=6. 3%-9. 3%).; ZLD HPLC METHOD: COLUMN: PHENOMENEX PHENYL-HEXYL 5UM, 250X4.6MM MOBILE PHASE: 40MM OCTANSULFONIC ACID SODIUM SALT IN 1% HCLO4, 0.2% H3PO4 : METHANOL (85:15) DETECTION: 220NM STABILITY WAS MEASURED VERSUS THE PRESENCE OF FORM II. P THE STABILITY DATA FOR EXAMPLE 4 IN THE TABLE ABOVE IS: | |
70.7% | Preparation of zoledronic acid monohydrate A suspension of 1-imidazolylacetic acid (50g, 0. 396mol) and phosphorous acid (48.7g, 0. 594mol) in sulfolan (180ml) is heated to 75C for 30 min. The mixture is cooled to 35-40 C and then gradually introduced phosphorous trichloride (117ml, 1. 346mol) while maintaining the temperature between 35-45C. The mixture is heated to 63-67C for 3hrs, whereby white solid results. It is then cooled to 0-5C and quenched by slow addition of water (500ml) at 0-5C over a period of 1 hr. The resulting clear solution is heated at 100C for 3hrs, cooled to ambient temperature and charcoalized. To the charcoalized solution is added acetone (800ml). The mixture is then stirred for 4hrs at 20- 25C and the crystallized product is filtered, washed sequentially with chilled water (200ml), acetone (100ml) and dried in air oven at 55-60C until water content is between. | |
70% | 3.8 mmol (1 equiv) of the respective carboxylic acid (658 mg 3-pyridylacetic acid hydrochloride for 1, 478 mg imidazol-1-yl-acetic acid for 2, 339 mg beta-alanine for 3, 392 mg gamma-aminobutyric acid for 4, 499 mg 6-aminohexanoic acid for 5) were added to 11.4 mmol (3 equiv) H3PO3 in a dry flask. 1.6 mL of distilled sulfolane was added and the contents were heated briefly to dissolve the solids. The solution was cooled down to approximately 25-35 C, and 11.4 mmol (3 equiv) of PCl3 were immediately added. The flask was then placed in a Milestone Ethos Synth Microwave Synthesis Labstation and fitted with a condenser through which cold water was passed. The following microwave programs were applied:For synthesis of 1: 3 min ramp to 65 C, followed by 15 s at 65 C. For synthesis of 2: 3 min ramp to 65 C, followed by 45 s at 65 C.For synthesis of 3: 3 min ramp to 65 C, followed by 15 s at 65 C.For synthesis of 4: 3 min ramp to 65 C, followed by 4 min at 65 C.For synthesis of 5: 3 min ramp to 65 C, followed by 4 min at 65 C.The power was automatically adjusted to reach and maintain the temperature designated by the program, which is determined by a built-in IR sensor in the microwave reactor. For the synthesis of intermediates 1 and 2, the power fluctuated between 0 and a max of 300-400 W, while for 3, 4, and 5, the max power was typically 200-300 W.The solid mixture after microwave irradiation consists of intermediate phosphorus compound together with a yellow-orange unwanted side product which can be removed by centrifugation before or after hydrolysis. The reaction mixture was quenched with 6 mL of H2O, yielding a clear solution that was then transferred to a 50 mL sealed quartz reaction vessel and was hydrolyzed to the bisphosphonic acid in the microwave reactor with a 6 min ramp to 150 C, followed by 4 min at 150 C. The power applied fluctuated between 0 and a max of 450-500 W. The pH of the hydrolysis mixtures for acids 1, 3, 4, and 5 was adjusted15 with NaOH and the mixture then aged at 0-5 C until crystallization of the products was complete. Acids 4 and 5 were precipitated as monosodium salts by stirring with 2-5 mL ethanol for 1-2 h at room temperature. Acid 2 was precipitated by the addition of 9 mL acetone to the acidic hydrolysis mixture and stirring for 3-4 h at room temperature. The white crystalline products were then filtered and washed with cold H2O and acetone or ethanol and then dried under vacuum at 45 C to constant weight.15 with NaOH and the mixture then aged at 0-5 C until crystallization of the products was complete. Acids 4 and 5 were precipitated as monosodium salts by stirring with 2-5 mL ethanol for 1-2 h at room temperature. Acid 2 was precipitated by the addition of 9 mL acetone to the acidic hydrolysis mixture and stirring for 3-4 h at room temperature. The white crystalline products were then filtered and washed with cold H2O and acetone or ethanol and then dried under vacuum at 45 C to constant weight. | |
59% | Examples; CRYSTAL FORMS OF ZOLEDRONIC ACID (ZLD-Ac); Preparation of ZLD-AC crystal form I; General procedure for the preparation of ZLD-AC crystal form I starting from 1- Imidazoleacetic acid (IAA), Phosphorous acid (H3PO3) and Phosphorous oxychloride (POC13) (Examples 1-9, see Table 1) :; A cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, is loaded with 1-IMIDAZOLEACETIC acid (IAA), Phosphorous acid and a diluent (Toluene/Chlorobenzene/PEG-400/Silicon oil). The obtained suspension is heated to 75C-80C and Phosphorous oxychloride is added drop- wise. The reaction mixture is then heated to 75C-100C for 1-34 hours. Then water is added at 80C-100C. The mixture is stirred vigorously for about 15 minutes. [In some cases, when Silicon oil is used as a diluent, there is a need to add Toluene in order to improve the separation between the oily phase and the aqueous phase]. Then the phases are separated. The aqueous phase is put in a clean reactor and heated to 95C-100C for 13.5-19 hours. Then it is cooled to 5C and absolute Ethanol is added to obtain a precipitate after stirring at 5C for 2.5-4 hours [In some cases a precipitate of Zoledronic acid is obtained without adding absolute Ethanol as an anti-solvent]. The white product is then filtered, washed with absolute Ethanol and dried in a vacuum oven at 50C for 17-24 hours to obtain Zoledronic acid crystal form I (LOD BY TGA=6. 3%-9. 3%).; ZLD HPLC METHOD: COLUMN: PHENOMENEX PHENYL-HEXYL 5UM, 250X4.6MM MOBILE PHASE: 40MM OCTANSULFONIC ACID SODIUM SALT IN 1% HCLO4, 0.2% H3PO4 : METHANOL (85:15) DETECTION: 220NM STABILITY WAS MEASURED VERSUS THE PRESENCE OF FORM II. P THE STABILITY DATA FOR EXAMPLE 4 IN THE TABLE ABOVE IS: | |
53 - 65% | Example 1; [0022] An oven-dried 250 ml_ 4-neck RB flask was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet and two 1/8 inch polytetrafluoroethylene (PTFE) feeding lines. The system was flushed with nitrogen for 30 minutes. Under nitrogen protection, imidazoIe-1-ylacetic acid (15.97 g, 0.13 mole), sulfolane (70 ml_) and phosphorous acid (2.67 g, 0.033 mol) were charged to the RB flask. The reaction mixture was mixed at 210 RPM and heated to 600C. PCI3 (9.18 g, 0.067mol) was added slowly (1.3 mL/mn) via a masterflex tubing pump. Five minutes were allowed for mixing. Alternately fed were 26 wt% phosphorous acid sulfolane solution (30.7 g, 10.23 g each addition at 1.6 mL/min) and PCI3 (27.5 g, 9.18 g each portion at 1.3 mL/min). Three to five minutes of mixing were allowed between additions. The addition took 1 hr 3 min and temperature was maintained between 600C and 670C. After addition was complete, the temperature of the reaction mixture was raised to 800C and was held at this temperature for 4 hours. Then the temperature of the reaction mixture was raised to 880C and held for 30 minutes. Ambient temperature water (50 g) was added in to quench the reaction. The solution was refluxed for 3 hrs <n="13"/>. temperature, the product was vacuum-filtered and rinsed with 38 g of acetone. Zoledronic acid was obtained as a white crystalline solid (24.1 g, 95.3wt% purity by quantitative NMR, 65% yield). Example 2; [0023] An oven-dried 250 mL 4-neck RB flask was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet and two 1/8 inch PTFE feeding lines. The system was flushed with nitrogen for 30 minutes. Under nitrogen protection, imidazole-1-ylacetic acid (15.97 g, 0.13 mole), sulfolane (70 mL) and phosphorous acid (2.67 g, 0.033 mol) were charged to the RB flask. The reaction mixture was mixed at 300 RPM and heated to 600C. PCI3 (9.18 g, 0.067mol) was added in slowly (1.3 mL/min) via a masterflex tubing pump. Five minutes were allowed for mixing. Alternately fed were 26 wt% phosphorous acid sulfolane solution (30.7 g, 10.23 g each addition at 1.6 mL/min) and PCI3 (27.5 g, 9.18 g each portion at 1.3 mL/min. Three to five minutes of mixing were allowed between additions. The addition took 1 hr 6 min and temperature was maintained between 54 and 64C. After addition was complete, the temperature of the reaction mixture was raised to 800C and held for 4 hours. Then the temperature of the reaction mixture was raised to 880C and held for 30 minutes. This slurry was transferred via 3/8" PTFE tubing using nitrogen pressure into 100 mL of pre-heated (80C) water under mixing. The resultant water solution was heated to refluxing and held at that temperature for 4 hr. It was then slowly cooled to room temperature then to 1-2C and held for 1.5 hr at this temperature. The product was collected via vacuum filtration. The cake was rinsed with acetone (20 g) and zoledronic acid was obtained as a white crystalline solid (19.1 g, 98.3 wt% purity by quantitative NMR, 53% yield). Example 3; [0024] An oven-dried 250 mL 4-neck RB flask was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet and two 1/8 inch PTFE feeding lines. The system was flushed with nitrogen for 30 minutes. Under nitrogen protection, imidazole-1-ylacetic acid (15.9 g, 0.13 mole), sulfolane (70 mL) and phosphorous acid (2.67 g, 0.033 mol) were charged to the RB flask. The reaction mixture was mixed and heated to 6O0C. PCI3 (36.7 g, 0.267 mol) and phosphorous acid (8.0 g, 0.098 mol) in <n="14"/>- . mL/min respectively. Reaction temperature remained between 6O0C and 67C during feeding, After addition of PCI3 and phosphorous acid, the reaction slurry was heated to 800C and held at that temperature for 4 hours. This slurry was then transferred via 3/8" PTFE tubing using nitrogen pressure into 50 m._ of pre-heated (8O0C) water under mixing. The resultant water solution was heated to refluxing and held at that temperature for 4 hr. It was then slowly cooled to 48-500C. Acetone (200 ml_) was added in slowly and then it was cooled to 1-2C and held for 2 hr at this temperature. The product was collected via vacuum filtration. The cake was rinsed with acetone (35 g) and zoledronic acid was obtained as a white crystalline solid (22.1 g, 98.6 wt% purity by quantitative NMR, 61 % yield). Example 4; [0025] A 2.5 L resin-kettle was fitted with a mechanic stirrer, K-thermocouple, condenser, nitrogen inlet and outlet, two 1/8 inch PTFE tubing as PCI3 and phosphorous acid sulfolane solution feeding lines. The system was dried under a stream of nitrogen. Under nitrogen, imidazoleacetic acid (79.92 g, 0.63 mol), phosphorous acid (13.90 g, 0.17 mol) and sulfolane (350 ml_) were added to the resin-kettle and mixed at 200 RPM. The mixture was heated to 62C then PCI3 (36.7 g, 0.267 mol) was added in slowly (1.3 mL/min) using a masterflex tubing pump. The slurry was mixed for 5 minutes. Phosphoro... | |
53% | 6.3 g (0.05 mol) of imidazol-1-yl-acetic acid was dissolved in 21 ml of methanesulfonic acid with stirring. 13.6 ml (0.16 mol) of phosphorus trichloride was added dropwise and the mixture was stirred at 80 C for 3 h. After cooling to 26 C, 36 ml of water was added dropwise, the temperature was elevated to 105-110 C and the contents of the flask were stirred at this temperature for 5 h. Next, the mixture was stirred with 0.75 g of activated carbon for 30 min, filtered and the solid washed with 5 ml of water. To the combined water phase was added dropwise 10 N NaOH solution to attain pH 1.8. The suspension obtained was stirred for 5 h, the solid filtered, washed with 5 ml of water and dried to afford 9.7 g (71%) of a crude mixture consisting of a 26-74% mixture of ZA and ZA-Na. Recrystallization from 48.5 ml of 1 N hydrochloric acid furnished 7.2 g (53%) of ZA comprising 99% of the acid (Table 1, entry 7); 31P NMR (5% NaOH/D2O) 16.0 [P8 (5% NaOD/D2O) 16.2]. | |
50% | PREPARALION OF ZLD-AC CRYSTAL FORM XNII; Example 18 :; A 3L reactor equipped with A mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was loaded with 1-IMIDAZOLEACETIC acid (70. OG, 0. 56MOLE), Phosphorous acid (136. 7g, 1.67mole) and Silicon oil (M-350) (490ML). The suspension was heated to 80C and Phosphorous oxychloride (194. 4ML, 2.08mole) was added drop-wise during 4 hours. The reaction mixture was stirred at 80C for 22 hours. Then water (490ML) was added slowly at 80C. The mixture was stirred vigorously for about 30 minutes. Then the silicon oil phase and the aqueous phase were separated. The aqueous phase was put in a clean reactor and heated to 97C for 17.5 hours. Then absolute Ethanol (490ML) was added and the solution was stirred at reflux (87C) for 2 hours. The solution was then cooled to 70C-72C during about 1 hour and was kept at this temperature for 1 hour. After cooling to 25C during 2.5 hours and stirring at this temperature for 1 hour, half of the product was filtered, washed with small amount of cold water and dried in a vacuum oven at 50C for 20 hours to obtain 50.8g of Zoledronic acid crystal form XVIII (MS- 507-CROP I, LOD by TGA=1.9%). The rest of the suspension was cooled to 0C during 2 hours and was stirred at this temperature for about 16 hours. Then the product was filtered and dried in a vacuum oven at 50C for 24 hours to obtain 26g of Zoledronic acid crystal form XVIII (MS-507-CROP II, LOD by TGA=1. 0%). The overall yield of the process is 50% purity by HPLC 97.7%. | |
49% | Example II. Preparation of [l-hydroxy-2-(lH-imidazol-l-yl)- ethylidene]bisphosrhohonic acid.A solution of lH-imidazole-1 -acetic acid [26 g (0.206 moles) of lH-imidazole-1- acetic acid in the mixture of 18 ml of water and 18 ml of hydrochloric acid (35%)] is added dropwise for 30 minutes at the temperature 0-5 0C to 108 ml of phosphorus trichloride (PCl3) cooled to the temperature 0-5 0C. The mixture is mixed at 0-50C for 1 hour. Then, the mixture is heated to 800C and maintained at this temperature for 1 hour. The excess of phosphorus trichloride is then distilled off under the reduced pressure. 200 ml of water is added to the reaction residues and the hydrolysis is performed while maintaining boiling for 6 hours, afterwards 1 g of activated charcoal, 5 g of Hyflo Super CeI are added and mixed while boiling for 30 minutes. The mixture is filtered and the filter is washed with 20 ml of water. The filtrate is concentrated under the reduced pressure to the volume of 100 ml. 150 ml of 95% ethanol is added to the concentrated filtrate at 70C. The mixture is cooled while mixing to 250C and crystallization is performed until the temperature reaches 20-250C for 4 hours. The formed precipitate is filtered off, washed twice with 30 ml of water-ethanol mixture (1:1.5) and dried at 5O0C. 29.3 g (49%) of [l-hydroxy-2-(lH-imidazol-l-yl)-ethylidene]bisrhohosphonic acid monohydrate is obtained. EtaPLC 100.00% , TGA 6.30%XPRD: 12.05; 12.77; 15.69; 18.80; 20.84; 21.25; 21.71; 22.09; 25.71; 27.50; 29.19; 32.42; 32.88 (+,- 0,02 ) 2 theta1H NMR (D2O): 5=4.670-4.709 ppm (t, 2H, J=9.65); 7.379 (s,lH); 7.540 (s, IH);8.719 (s, IH)13C NMR: 5=55.56 ppm; 74.81-76.90 (t); 121.13; 126.83; 138.7131P NMR: 5=14.36 ppm15 g of [l-hydroxy-2-(l/-r-imidazol-l-yl)-ethylidene]bisphosphonic acid is suspended in 300 ml of water, heated to the boiling point and mixed while boiling for 15 minutes. Then, the mixture is cooled to 70C and 300 ml of ethanol is added for about 1-1.5 hour. The mixture is cooled to 20-25C. After 14 hours of mixing in20-25C the precipitate is filtered off, washed twice with 15 ml of water and once with 15 ml of ethanol and dried for 6 hours at 55C. 12.78 g (85%) of [l-hydroxy-2-(lH-imidazol-l-yl)-ethylidene]bisphosphonic acid monohydrate is obtained.EtaPLC 100.00%, TGA 6.24%XPRD: 12.05; 12.78; 15.72; 18.70; 20.82; 21.23; 21.70; 22.08; 25.70; 27.51; 29.14;32.32; 32.88 (+,- 0.02 ) 2 theta 1H NMR (D2O): 5=4.470-4.497 ppm (t, 2H, J=9.62); 7.164 (s,lH); 7.367 (s, IH);8.421 (s, IH)13C NMR: 5=53.00 ppm; 72.59 (t); 118.47; 123.66; 138.7131P NMR: 5=14.21 ppm | |
49% | EXAMPLE II Preparation of [1-hydroxy-2-(1H-imidazol-1-yl)-ethylidene]bisphosphonic acid A solution of 1H-imidazole-1-acetic acid [26 g (0.206 moles) of 1H-imidazole-1-acetic acid in the mixture of 18 ml of water and 18 ml of hydrochloric acid (35%)] is added dropwise for 30 minutes at the temperature 0-5 C. to 108 ml of phosphorus trichloride (PCl3) cooled to the temperature 0-5 C. The mixture is mixed at 0-5 C. for 1 hour. Then, the mixture is heated to 80 C. and maintained at this temperature for 1 hour. The excess of phosphorus trichloride is then distilled off under the reduced pressure. 200 ml of water is added to the reaction residues and the hydrolysis is performed while maintaining boiling for 6 hours, afterwards 1 g of activated charcoal, 5 g of Hyflo Super Cel are added and mixed while boiling for 30 minutes. The mixture is filtered and the filter is washed with 20 ml of water. The filtrate is concentrated under the reduced pressure to the volume of 100 ml. 150 ml of 95% ethanol is added to the concentrated filtrate at 70 C. The mixture is cooled while mixing to 25 C. and crystallization is performed until the temperature reaches 20-25 C. for 4 hours. The formed precipitate is filtered off, washed twice with 30 ml of water-ethanol mixture (1:1.5) and dried at 50 C. 29.3 g (49%) of [1-hydroxy-2-(1H-imidazol-1-yl)-ethylidene]bisphosphonic acid monohydrate is obtained. HPLC 100.00% , TGA 6.30% XPRD: 12.05; 12.77; 15.69; 18.80; 20.84; 21.25; 21.71; 22.09; 25.71; 27.50; 29.19; 32.42; 32.88 (+,-0.02) 2theta 1H NMR (D2O): delta=4.670-4.709 ppm (t, 2H, J=9.65); 7.379 (s, 1H); 7.540 (s, 1H); 8.719 (s, 1H) 13C NMR: delta32 55.56 ppm; 74.81-76.90 (t); 121.13; 126.83; 138.71 | |
28% | With phosphoric acid; phosphorus trichloride; In diethylene glycol dimethyl ether; water; at 50 - 100℃; for 8 - 11h;Heating / reflux;Product distribution / selectivity; | Example 3:Preparation of Zoledronic Acid:[0019] A 1.5 liter kettle reactor, fitted with a heating mantle, mechanical stirrer, dropping funnel, thermocouple and condenser with nitrogen inlet adapter, was charged with imidazoleacetic acid (100 g, 0.793 mol), diglyme (400 ml), and 85% phosphoric acid (55 ml). Phosphorus trichloride (330 g, 2.41 mol) was slowly added to the reaction mass resulting in an exotherm and the evolution of hydrogen chloride. The temperature was allowed to rise to 700C and the solution was stirred until the evolution of HCl subsided. The temperature of the reaction mass was increased to 85C and a white solid began to form, float and adhere to the stirrer shaft. After about 1 hour, stirring became impossible and the stirring motor was stopped. The reaction mass was heated for 5 more hours at 85C and then cooled to ambient temperature, producing a solid homogeneous white mass. <n="8"/>[0020] Water was slowly added to the white mass (320 ml) that resulted in an exotherm and HCl evolution. The water slowly dissolved the mass in a gradual and uniform fashion, eventually liberating the stirrer. After the mass substantially dissolved, the solution was refluxed for 5 hours, then cooled and stripped to a gum with a rotary evaporator, collecting 420 g of water (pH 0.65). More water (250 ml) was added and stripped, collecting 166 g of water (pH 1.87). Water (250 ml) was again added and stripped, collecting 316 g (pH 2.14). The flask was removed from the rotary evaporator, water (150 ml) was added and the mixture was heated to 90-950C during which time all solids dissolved. The solution was seeded with zoledronic acid monohydrate crystals and slowly cooled to room temperature then chilled to 30C with an ice bath. The resulting crystalline solid was filtered, rinsed with acetone (200 + 100 ml) and dried under a nitrogen stream giving a crop of 52.4 g. Acetone was also added to the filtrate (200 ml) and the solution was left in a freezer overnight giving a second crop of crystals (12.0 g) which, after washing with acetone and drying, was combined with the first crop for a total yield of 64.4 g (28%). The NMR indicated the presence of traces of diglyme, acetone and H3PO3 impurities. Example 4:Preparation of Zoledronic Acid:[0021 ] A 5 liter cylindrical jacketed reactor was fitted with a mechanical stirrer, thermocouple, nitrogen inlet adapter and a condenser with a caustic scrubber. This was charged with imidazoleacetic acid (0.333 kg, 2.64 mol) and diglyme (1.00 1). The slurry was heated to 500C while stirring (100 rpm) under a slow nitrogen purge (1 1/min). Additional diglyme (0.26 1) and 85% phosphoric acid (0.304 kg) were added to the reaction mass. Using a Masterflex pump and Teflon tubing, phophorus trichloride (1.04 kg total, 7.57 mol) was pumped into the reaction mass, slowly (2 ml/min) at first and then at an increased rate (40 ml/min), after the water in the phosphoric acid had been depleted. During addition of the PCl3, the temperature was raised to about 65C and a white mass gradually formed, causing the stirrer to bind. The jacket temperature was increased to 850C causing PCl3 to reflux. The refluxing slowed and then stopped as the white mass expanded. The reactor was allowed to stand at about 80C for four hours, after which the jacket temperature was set at 150C overnight.[0022] The reactor jacket temperature was increased to 500C and water (0.95 kg total) was slowly (2-5 ml/min) added with a Masterflex pump. The water dissolved the white mass on contact, liberating HCl in an exothermic reaction. After about 250 g of water was added to the reaction mass, the stirrer became unbound and stirring was resumed (100 rpm). The water <n="9"/>addition rate was slowly increased to 40 ml/min. The reaction mass was then heated at about 1000C for 4 hours and then cooled to room temperature.[0023] The reaction mass was drained and rotary evaporated to yield a gum. Water was added to the gum and stripped several times until the distillates pH rose above 1. The resulting aqueous solution (1.2 kg, 1.6 1) was stirred in a beaker and acetone (1.5 1) was slowly added. The mixture was allowed to stand 16 hours to complete crystallization. The solid was filtered, thoroughly washed with acetone and dried in a nitrogen stream to give crude Zoledronic acid (0.202 g, 0.74 mol, 28% yield). |
7% | With phosphoric acid; phosphorus trichloride; In water; PEG 400; at 70 - 85℃; for 11h;Heating / reflux;Product distribution / selectivity; | Example 6:(Comparative) Preparation of Zoledronic Acid in PEG-400:[0025] Example 3 was repeated substituting PEG-400 (400ml) for diglyme. After the addition of phosphorus trichloride and increased temperature of the reaction mass, a solid formed that eventually returned to solution upon further heating. The yield of zoledronic acid was 7 % (isolated yield). 1HNMR (D2O/NaOD): 7.72 (s, 1 H); 7.22 (s, 1 H); 6.87 (s, 1 H); 4.82 (O-H, 7.02 H); 4.45 (m, 2 H). 31P NMR (D2O/NaOD): 17.0 (m). Not only was there a substantial decrease in yield, but the product purity deteriorated as well. |
A suspension of imidazol-1-ylacetic acid, compound of formula 2 (50g, 0. 396mol) and phosphorous acid (48.7g, 0. 594mol) in sulfolan (180ml) was heated to 75 C for 30 min. The mixture was cooled to 35-40 C and phosphorous trichloride (117ml, 1. 346mol) was gradually introduced while maintaining the temperature between 35-45 C. The mixture was heated to 63-67 C for 3 hours, whereby white solid results. It was then cooled to 0- 5'C and quenched by slow addition of water (500ml) at 0-5 C over a period of 1 hour. The resulting clear solution was heated at 100 C for 3 hours, cooled to ambient temperature and charcoalized. Acetone was added to the charcoalized solution. The mixture was then stirred for 4 hours at 20-25 C and the crystallized product was filtered, washed sequentially with chilled water, acetone and dried to obtain zoledronic acid. | ||
Preparation of zoledronic acid monohydrate A suspension of 1-imidazolylacetic acid (20g, 0. 159mol) and phosphorous acid (19.6g, 0. 239mol) in 1,2-dimethoxyethane (72m1) is heated to 75 C for 30 minutes. The mixture is cooled to 35-40 C and then gradually introduced phosphorous trichloride (48ml, 0. 543mol) while maintaining the temperature between 35-45 C. The mixture is heated to 63-67 C for 3 hrs, whereby white solid results. It is then cooled to 0-5 C and quenched by slow addition of water (160ml) at 0-5 C over a period of 1 hr. The resulting clear solution is heated at 100 C for 3 hrs, cooled to ambient temperature and charcoalized. To the charcoalized solution is added acetone (320ml). The mixture is then stirred for 4 hours at 20-25 C, the crystallized product is filtered, washed sequentially with chilled water (80ml), acetone (80ml) and dried in air oven at 55-60 C until water content is between 6.2-7. 2% w/w. Appearance: white crystalline solid, purity >99.5%, meeting specification as per IHS. | ||
Imidazol-1-ylacetic acid (50 gm), phosphorous acid (150 gm) and n-octane (1000 mL) were taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-950C. Phosphorus trichloride (250 gm) was then added to the reaction mixture and allowed to heat at 90- 950C. The reaction mixture was cooled and distilled water (500 mL) was added to it. The reaction mixture was further heated to 90-950C and then cooled to room temperature, filtered through celite bed. Aqueous layer was separated and methanol (2000 mL) was EPO <DP n="11"/>added to it. The solution was cooled to 0-5 C and stirred for 4-5 hrs. The precipitated solid was filtered, washed with methanol and dried under vacuum yielding 70 gm of product. | ||
Imidazol-1-ylacetic acid (50 gm), phosphorous acid (150 gm) and 1,4-dioxane (1000 mL) were taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-950C. Phosphorus trichloride (250 gm) was then added to the reaction mixture and allowed to heat at 90- 95C. The reaction mixture was cooled and distilled water (500 mL) was added to it. The reaction mixture was further heated to 90-950C and then cooled to RT and filtered through celite bed. Methanol (2000 mL) was added to the filtrate and cooled to 0-50C and stirred for 4-5 hrs. The precipitated solid was filtered, washed with methanol and dried under vacuum to yield 56.0 gm of product. | ||
Example- 3: Preparation of zoledronic acid; A mixture of imidazol-1-yl acetic acid (100 gm) and phosphorous acid (324 gm) was heated under stirring to about 60-800C to get a homogeneous solution. Phosphorous trichloride (324 gm) was added slowly at a temperature of about 750C to the homogeneous solution. The resultant mass was stirred for 6 hours and cooled. A solution of hydrochloric acid (9N, 465 ml) was added over 30 minutes and the entire mass was heated at 75-8O0C for about 12 hours, treated with activated carbon (3.8 gm) and filtered. Acetone (1200 ml) was added to the filtrate and the resultant mixture was cooled to 15-2O0C. After complete precipitation of the product, the mass was filtered and the wet cake was washed with acetone (300 ml) and dried at 50-6O0C to get zoledronic acid as a white crystalline solid. Yield: 161 gmHPLC Purity: 99.92% | ||
Example-5: Preparation of zoledronic acid; A mixture of imidazol-1-yl acetic acid (100 gm) and phosphorous acid (324 gm) was heated under stirring to about 60-800C to get a homogeneous solution. Phosphorous oxychloride (364 gm) was added slowly at a temperature of about 750C to the homogeneous solution. The resultant mass was stirred for 5 hours and cooled. A solution of hydrochloric acid (9N, 465 ml) was added over 30 minutes and the entire mass was heated at 9O0C for about 12 hours, cooled and filtered. Acetone (1200 ml) was added to the filtrate and the resultant mixture was cooled to 15-2O0C. After complete precipitation of the product, the mass was filtered and the <n="10"/>wet cake was washed with acetone (300 ml) and dried at 50-600C to get crystals of zoledronic acid.Yield: 170 gmHPLC Purity: 99.92% | ||
Imidazol-1-ylacetic acid (50 gm), phosphorous acid (150 gm) and n-octane (1000 mL) were taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-95 C. Phosphorus trichloride (250 gm) was then added to the reaction mixture and allowed to heat at 90-95 C.The reaction mixture was cooled and distilled water (500 mL) was added to it. The reaction mixture was further heated to 90-95 C. and then cooled to room temperature, filtered through celite bed. Aqueous layer was separated and methanol (2000 mL) was added to it. The solution was cooled to 0-5 C. and stirred for 4-5 hrs. he precipitated solid was filtered, washed with methanol and dried under vacuum yielding 70 gm of product. | ||
Take the above compounds Intermediate 2 3.15g (0.025mol), H3PO4 2.45g (0.025mol) and polyethylene glycol 400 0.5h the reaction at 100 , after cooling to 65 deg.] C of 15g (0.037mol), was slowly added dropwise phosphorus trichloride was added 0.025 mol (2.2 mL), addition was complete, the reaction was continued 3h 100 , followed by addition of 30mL of concentrated hydrochloric acid was refluxed for 5h, the reaction was completed, cooled to room temperature, the reaction solution was poured into 3 of ethanol with a white solid was precipitated, filtered, and dried in vacuo to give the compound . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydroxide; In methanol; for 16h;Heating / reflux;Product distribution / selectivity; | Example 16:; A 250ml flask was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (4. 8G), Sodium hydroxide (0.7g) and Methanol (10 volumes per grams OF ZLD-AC) (48ML). The reaction mixture was heated to reflux temperature for 16 hours. Then it was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (2X10ML) and dried in a vacuum oven at 50C for 22 hours to give 4.8g (99%) of Zoledronate monosodium crystal form XV (LOD by TGA=0.8%). Purity by HPLC 99. 9%. |
98% | With sodium hydroxide; In ethanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | Preparation of ZLD-NA crystal form XVI; Example 37:; A solution of sodium hydroxide (0.7g) in a mixture of water (50% V/V)/ETHANOL (50% v/v, 10 volumes per grams of ZLD-Ac form 1) (14ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> (4. 8G) in a mixture of water (50% V/V)/ETHANOL (50% v/v, 10 volumes per grams of ZLD-Ac form I) (81ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice- bath. The precipitate was then filtered, washed with absolute Ethanol (2X20ML) and dried in a vacuum oven at 50C for 18 hours to give 5.2g (98%) of Zoledronate monosodium crystal form XVI (LOD by TGA=9. 9%). Purity by HPLC 99. 95%. |
96% | With sodium hydroxide; In ethanol; for 16h;Heating / reflux;Product distribution / selectivity; | Preparation OF ZLD-AC crystal form XV; Example 15:; A 250ML flask was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (4. 8G), Sodium hydroxide (0.7g) and absolute Ethanol (10 volumes per grams OF ZLD-AC) (48ML). The reaction mixture was heated to reflux temperature for 16 hours. Then it was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with absolute Ethanol (2X20ML) and dried in a vacuum oven at 50C for 23 hours to give 4. 9G (96%) of Zoledronate monosodium crystal form XV in a mixture with <strong>[118072-93-8]Zoledronic acid</strong> crystal form I (LOD by TGA=5. 8%). |
94% | With sodium hydroxide; In water; isopropyl alcohol; for 16h;Heating / reflux;Product distribution / selectivity; | Example 38 :; A solution of sodium hydroxide (0. 7g) in a mixture of WATER (50% V/V)/IPA (50% V/V, 10 volumes per grams of ZLD-Ac form I) (15ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> (5. 0G) in A mixture of water (50% V/V)/IPA (50% v/v, 10 volumes per grams OF ZLD-AC form I) (85ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with IPA (2x20ml) and dried in a vacuum oven at 50C for 24 hours to give 5.2g (94%) of Zoledronate monosodium crystal form XVI (LOD by TGA=9.8%). Purity by HPLC 99.9%. |
89% | With sodium hydroxide; In methanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | Example 39:; A solution of sodium hydroxide (0.7g) in a mixture of water (50% v/v) /Methanol (50% v/v, 10 volumes per grams OFZLD-AC form I) (14ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form I (4.8g) in a mixture of water (50% V/V)/ETHANOL (50% v/v, 10 volumes per grams OF ZLD-AC form 1) (81ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (LX25ML) and dried in a vacuum oven at 50C for 25.5 hours to give 4.8g (89%) of Zoledronate monosodium crystal form XVI (LOD by TGA=11. 1%). Purity by HPLC 99. 9%. |
83% | With sodium hydroxide; In ethanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | Example 33:; A solution of sodium hydroxide (0.7g) in a mixture of water (80% V/V)/ETHANOL (20% v/v, 10 volumes per grams of ZLD-Ac) (36ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form I (4. 8G) in a mixture of water (80% v/v) /Ethanol (20% v/v, 10 volumes per grams of ZLD-Ac) (202ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with absolute Ethanol (2X20ML) and dried in a vacuum oven at 50C for 22 hours to give 4.7g (83%) of Zoledronate monosodium crystal form VIII (LOD by TGA=15. 5%). Purity by HPLC 99.9% |
81% | With sodium hydroxide; In methanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | Example 34:; A solution of sodium hydroxide (0.7g) in a mixture of water (80% V/V)/METHANOL (20% v/v, 10 volumes per grams OF ZLD-AC FPRM I) (36ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> (4.8g) in a mixture of water (80% V/V)/METHANOL (20% v/v, 10 volumes per grams of ZLD-Ac form 1) (202ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (LX20ML) and dried in a vacuum oven at 50C for 22 hours to give 4.7g (81%) OF ZOLEDRONATE monosodium crystal form VIII (LOD by TGA=16. 03%). Purity by HPLC 99.9%. |
64 - 72% | With sodium hydroxide; In water; at 3 - 94℃; for 17.5 - 66h;Product distribution / selectivity; | Example 31:; A 0. 5L reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (10. Og) and water (247ML). The suspension was heated to 94C to obtain a clear solution. A 40% aqueous solution of Sodium hydroxide (3.45g) was added drop-wise. The solution was then cooled to 4C during 2 hours and was stirred at this temperature for about 64 hours to obtain a massive precipitate. The white precipitate was filtered, washed with cold water (LXLOML) and dried in a vacuum oven at 50C for 26 hours to obtain 7.6g (64%) of Zoledronate monosodium crystal form VIII (LOD by TGA=15. 1%).; EXAMPLE 32- :; A 0. 5L reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (10. Og) and water (247ML). The suspension was heated to 94C to obtain a clear solution. A 40% aqueous solution of Sodium hydroxide (3.45g) was added drop-wise. The solution was then cooled to room temperature and stirred at this temperature for 16 hours. After cooling to 3C and stirring at this temperature for 1.5 hour, the white precipitate was filtered, washed with Methanol (2XL5ML) and dried in a vacuum oven at 50C for 25 hours to obtain 5.8g (49%) of Zoledronate monosodium crystal form VIII (LOD by TGA=15. 1%). The obtained Form VIII (2g) was recrystallized form water (34ml) to give 1.4g (72%) of <strong>[118072-93-8]Zoledronic acid</strong> crystal form VIII (LOD ) by TGA=11. 3%). Purity by HPLC 100.0%. |
10 - 79% | With sodium hydroxide; In water; isopropyl alcohol; for 16h;Heating / reflux;Product distribution / selectivity; | Example 35 :; A solution of sodium hydroxide (0.7g) in a mixture of water (80% v/v)/IPA (20% v/v, 10 volumes per grams of ZLD-Ac form I) (38ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> (5. 0G) in a mixture of water (80% v/v)/IPA (20% v/v, 10 volumes per grams OF ZLD-AC FONN I) (212ML) AT REFLUX temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with IPA (2X20ML) and dried in a vacuum oven at 50C for 24 hours to give 4.7g (79%) of Zoledronate monosodium crystal form VIII (LOD by TGA=15. 40%). Purity by HPLC 99.95%.; Example 36:; A solution of sodium hydroxide (0.7g) in a mixture of water (60% V/V)/IPA (40% v/v, 10 volumes per grams of ZLD-Ac form I) (19ml) was added drop-wise to A suspension of <strong>[118072-93-8]Zoledronic acid</strong> (5. 0G) in a mixture of water (60% V/V)/IPA (40% v/v, 10 volumes per grams OF ZLD-AC FORM I) (106ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with IPA (LX20ML) AND dried in a vacuum oven at 50C for 27 hours to give 0.6g (10%) of Zoledronate monosodium crystal form VIII (LOD by TGA=15.0%). |
With sodium hydroxide; In water; at 20 - 94℃; for 16h;Heating / reflux; | Preparation of ZLD-Na crystal form XVII; Example 40:; A 0. 5L reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (10. 0G) and water (247ML). The suspension was heated to 94C to obtain a clear solution. A 29% aqueous solution of Sodium hydroxide (3.45g) was added drop-wise. The solution was then cooled to room temperature and stirred at this temperature for 16 hours. After cooling to 3C the product was isolated by filtration. Further cooling of the mother-liquid led to the formation of A white precipitate. The precipitate was filtered and dried in a vacuum oven at 50C for 24 hours to obtain 0. 6G of Zoledronate monosodium crystal form XVII (LOD by TGA=10. 3%). | |
With sodium hydroxide; In water; at 20℃; | General procedure for the preparation of amorphous Zoledronate sodium; Example 72:; A 100ML flask was loaded with <strong>[118072-93-8]Zoledronic acid</strong> crystal form XII (2. 0g), Sodium hydroxide (0. 57G) and water (lOml). The reaction mixture was stirred at room temperature to obtain a clear solution. Then the solution was concentrated under vacuum to obtain a precipitate. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with water (2XLOML) and dried in a vacuum oven at 50C for 24 hours to give 0.76g of amorphous Zoledronate sodium. | |
With sodium hydroxide; In water; isopropyl alcohol; at 5 - 94℃; for 67h;pH 4.54;Product distribution / selectivity; | CRYSTAL FORMS OF ZOLEDRONATE MONOSODIUM (ZLD-NA); Preparation OL : ZLD-NA CRYSTAL FORM VI1 [I; Example 30 :; A 0. 5L reactor equipped with a mechanical stirrer, a thermometer and a reflux condenser was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (10.0g) and water (247ML). THE suspension was heated to 94C to obtain a clear solution. Sodium hydroxide (pearls, 1. 42g) was added. A pH test of the sodium salt showed PH=4. 54. The solution was cooled to 60C and IPA (10. 5ML) was added. The reaction mixture was cooled to room temperature during 2 hours and was stirred at this temperature for about 64 hours. After cooling to 5C and stirring at this temperature for 1 hour, the white precipitate was filtered, washed with cold water (LXLOML) and dried in a vacuum oven at 50C for 23.5 hours to obtain 7. 0g of Zoledronate monosodium crystal form VIII (pH=4. 32). Purity by HPLC 100.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With sodium hydroxide; In water; isopropyl alcohol; for 16h;Heating / reflux; | Example 54 :; A solution of sodium hydroxide (0.7g) in a mixture of water (60% v/v)/IPA (40% v/v, 10 volumes per grams of ZLD-Ac form XII) (19ml) was added drop-wise to A suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (4.98g) in A mixture of water (60% v/v)/IPA (40% v/v, 10 volumes per grams of ZLD-Ac) (106ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with IPA (LX20ML) and dried in a vacuum oven at 50C for 24 hours to give Zoledronate monosodium crystal form VIII (crop I). Then the precipitate from the mother-liquid was isolated by filtration as well, and dried in a vacuum oven at 50C for 24 hours to give 2. 8g (13%) of Zoledronate disodium crystal form VII (crop II). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydroxide; In methanol; water; for 19h;Heating / reflux; | Preparation OFZLD-NA2 CRYSTAL FORM XXV; Example 62:; A solution of sodium hydroxide (1.4g) in a mixture of water (80% v/v)/Methanol (20% V/V, 10 volumes per grams of ZLD-Ac form I) (38ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form I (5. 0G) in A mixture of water (80% V/V)/METHANOL (20% V/V, 10 volumes per grams of ZLD-Ac) (212ml) at reflux temperature. The reaction mixture was heated at REFLUX temperature for additional 19 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice- bath. The solution was then evaporated to dryness to obtain 6. LG (99%) of Zoledronate disodium crystal form XXV (LOD by TGA=7.4%). Purity by HPLC 99.9%. |
98% | With sodium hydroxide; In ethanol; water; for 18.5h;Heating / reflux;Product distribution / selectivity; | Example 55:; A solution of sodium hydroxide (1.4g) in a mixture of water (80% V/V)/ETHANOL (20% v/v, 10 volumes per grams OF ZLD-AC form 1) (38ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form I (5. 0G) in a mixture of water (80% v/v)/Ethanol (20% v/v, 10 volumes per grams of ZLD-Ac) (212ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 18. 5 hours. Then the reaction mixture was cooled to room temperature and the solution was evaporated to dryness to obtain 6.7g (98%) of Zoledronate disodium crystal form VII (LOD by TGA=16. 8%). Purity by HPLC 99. 9%. |
97% | With sodium hydroxide; In methanol; water; for 17h;Heating / reflux;Product distribution / selectivity; | Example 59 :; A solution of sodium hydroxide (1. 4g) in a mixture of water (20% V/V)/METHANOL (80% v/v, 10 volumes per grams of ZLD-Ac form 1) (lOml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form I (5. 0G) in a mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per grams OFZLD-AC) (53ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 17 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice- bath. The precipitate was then filtered, washed with Methanol (1X10M1) and dried in a vacuum oven at 50C for 26 hours to give 5.6g (97%) of Zoledronate disodium crystal form XIV (LOD by TGA=1.4%). Purity by HPLC 99.9%. |
94 - 96% | With sodium hydroxide; In ethanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | Example 44 :; A solution of sodium hydroxide (1.4g) in a mixture of WATER (X% V/V)/ETHANOL (Y% v/v, 10 volumes per grams of ZLD-Ac form 1) (10-15ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> fomr I (5. 0G) in a mixture of water (X% V/V)/ETHANOL (Y% v/v, 10 volumes per grams of ZLD-Ac) (53-85ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form V. Purity by HPLC 99.9%. ) |
94% | With sodium hydroxide; In methanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | Example 45:; A solution of sodium hydroxide (1.4g) in a mixture of water (X% V/V)/METHANOL (Y% v/v, 10 volumes per grams OF ZLD-AC FORM I) (15ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form I (5. 0G) in a mixture of water (X% V/V)/METHANOL (Y% v/v, 10 volumes per grams of ZLD-Ac) (85ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice- bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form V. Purity by HPLC 99.95%. |
93% | With sodium hydroxide; In methanol; water; for 21h;Heating / reflux;Product distribution / selectivity; | Preparation OF ZLD-NA2 crystal form XXVII; Example 63:; A 100ml flask was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (4.9g), Sodium hydroxide (1.4g), Methanol (50ML) and water (2. 5ML) [= 5% v/v water in Methanol]. The reaction mixture was heated to reflux temperature for 21 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with absolute Ethanol (2X75ML) and dried in a vacuum oven at 50C for 27.5 hours to give 5. 7G (93%) of Zoledronate disodium crystal form XXVII (LOD by TGA=5.3%). Purity by HPLC 99. 9%. |
92% | With sodium hydroxide; In DMF (N,N-dimethyl-formamide); water; for 16h;Heating / reflux;Product distribution / selectivity; | Preparation of ZLD-NA2 crystal form XIV; Example 58 :; A solution of sodium hydroxide (0. 7g) in a mixture of water (20% V/V)/DMF (80% v/v, 10 volumes per grams of ZLD-Ac form XII) (1 Oml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (4. 98G) in a mixture of water (20% V/V)/DMF (80% v/v, 10 volumes per grams OF ZLD-AC) (53ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with DMF (2X 1 OML) and dried in a vacuum oven at 50C for 24 hours to give 4. 8g (92%) of Zoledronate disodium crystal form XIV (LOD by TGA=1.9%). |
91% | With sodium hydroxide; In water; isopropyl alcohol; for 16h;Heating / reflux; | Preparation OF ZLD-NA2 crystal form X; Example 56:; A solution of sodium hydroxide (0.7g) in a mixture of water (20% V/V)/IPA (80% v/v, 10 volumes per grams of ZLD-Ac form XII) (10ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (4. 98G) in A mixture of water (20% V/V)/IPA (80% V/V, 10 volumes per grams of ZLD-Ac) (53ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with IPA (LX25ML) and dried in a vacuum oven at 50C for 24 hours to give 4. 7G (91 %) of Zoledronate disodium crystal form X (LOD by TGA=2. 6%). |
90 - 91% | With sodium hydroxide; In water; isopropyl alcohol; for 16h;Heating / reflux;Product distribution / selectivity; | Example 46:; A solution of sodium hydroxide (1.4g) in a mixture of water (X% V/V)/IPA (Y% V/V, 10 volumes per grams of ZLD-Ac form I) (10-15ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> (5. 0g) in a mixture of water (X% V/V)/IPA (Y% v/v, 10 volumes per grams of ZLD-Ac) (53-85ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form V. Purity by HPLC 99.95%. |
90% | With sodium hydroxide; In methanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | Example 64 :; A solution of sodium hydroxide (0. 7g) in a mixture of water (20% V/V)/METHANOL (80% V/V, 10 volumes per grams OF ZLD-AC form XII) (10ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (4.98g) in a mixture of water (20% V/V)/ Methanol (80% v/v, 10 volumes per grams OF ZLD-AC) (53ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (2X 15ML) and dried in a vacuum oven at 50C for 24 hours to give 4. 85g (90%) of Zoledronate disodium crystal form XXVII (LOD by TGA=7.5%). |
89 - 91% | With sodium hydroxide; In ethanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | CRYSTAL FORMS ORMS OF ZOLEDRONATE DISODIUM (ZLD-Na2) PREPARATION OF ZTI I)-NA2 CRYSTAL FORM V; EXAMPLE 41 :; A solution of sodium hydroxide (0.7g) in a mixture of water (X% V/V)/ETHANOL (Y% v/v, 10 volumes per grams OF ZLD-AC FORM XIP (10-15ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (4.98g) in a mixture of water (X% V/V)/ETHANOL (Y% v/v, 10 volumes per grams of ZLD-Ac) (53-85ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form V. |
89% | With sodium hydroxide; In ethanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | Example 53:; A solution of sodium hydroxide (0.7g) in a mixture of water (80% V/V)/ETHANOL or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac fonn XII) (38ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (4.98g) in a mixture of water (80% V/V)/ETHANOL or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD- Ac) (212ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form VII |
86% | With sodium hydroxide; In ethanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | Preparation of ZLD-Na2 crystal form VI; Example 47 ;: A solution of sodium hydroxide (0. 7g) in a mixture of water (60% V/V)/ETHANOL or Methanol (40% v/v, 10 volumes per GRAMS OFZLD-AC form XII) (19ML) was added drop- wise to a suspension OF ZOLEDROLLIC acid form XII (4. 98G) in A mixture of water (60% v/v) /Ethanol or Methanol (40% v/v, 10 volumes per grams OF ZLD-AC) (106ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form VI |
85% | With sodium hydroxide; In water; isopropyl alcohol; for 16h;Heating / reflux;Product distribution / selectivity; | Example 43:; -A solution of sodium hydroxide (0. 7g) in a mixture of water (X% V/V)/IPA (Y% v/v, 10 volumes per grams of ZLD-Ac form XII) (13-15ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> (4.98g) in a mixture of water (X% V/V)/IPA (Y% v/v, 10 volumes per grams OFZLD-AC FORM XII) (70-85ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form V. |
85% | With sodium hydroxide; In water; isopropyl alcohol; for 16h;Heating / reflux;Product distribution / selectivity; | Example 53:; A solution of sodium hydroxide (0.7g) in a mixture of water (80% V/V)/ETHANOL or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac fonn XII) (38ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (4.98g) in a mixture of water (80% V/V)/ETHANOL or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD- Ac) (212ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form VII |
85 - 88% | With sodium hydroxide; In methanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | fExample 42:; A solution of sodium hydroxide (0.7g) in a mixture of water (X% v/v)/Methanol (Y% v/v, 10 volumes per grams OF ZLD-AC form XII) (13-15ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (4.98g) in a mixture of water (X% V/V)/ Methanol (Y% v/v, 10 volumes per grams of ZLD-Ac) (70-85ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form V |
84% | With sodium hydroxide; In ethanol; water; for 19.5h;Heating / reflux; | Preparation OF ZLD-NAZ crystal form XIII; Example 57:; A solution of sodium hydroxide (1.4g) in a mixture of water (5% V/V)/ETHANOL (95% v/v, 10 volumes per grams of ZLD-Ac form I) (8ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form I (5. 0G) in a mixture of water (5% V/V)/ETHANOL (95% V/V, 10 volumes per grams of ZLD-Ac) (45ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 19.5 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Ethanol (LXLOML) and dried in a vacuum oven at 50C for 20 hours to give 4.9g (84%) OF ZOLEDRONATE DISODIUM crystal form XIII (LOD by TGA=3.4%). Purity by HPLC 99.9%. |
83% | With sodium hydroxide; In methanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | Example 53:; A solution of sodium hydroxide (0.7g) in a mixture of water (80% V/V)/ETHANOL or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac fonn XII) (38ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (4.98g) in a mixture of water (80% V/V)/ETHANOL or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD- Ac) (212ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form VII |
78% | With sodium hydroxide; In water; isopropyl alcohol; for 16h;Heating / reflux;Product distribution / selectivity; | Example 48:; A solution of sodium hydroxide (1. 4g) in a mixture of water (80% v/v) /IPA (20% v/v, 10 volumes per grams OF ZLD-AC FORM I (8ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> FORM I (5. 0g) in a mixture of water (80% v/v) /IPA (20% v/v, 10 volumes per grams of ZLD-Ac) (212ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature and the solution was evaporated to dryness. The obtained solid was dried in a vacuum oven at 50C for 5 hours to give 5. 2G (78%) of Zoledronate disodium crystal form VI (LOD by TGA=15. 4%). Purity by HPLC 99.9%. |
78% | With sodium hydroxide; In methanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | 7Preparation of ZLD-Na2 crystal form VI; Example 47 :; A solution of sodium hydroxide (0. 7g) in a mixture of water (60% V/V)/ETHANOL or Methanol (40% v/v, 10 volumes per GRAMS OFZLD-AC form XII) (19ML) was added drop- wise to a suspension OF ZOLEDROLLIC acid form XII (4. 98G) in A mixture of water (60% v/v) /Ethanol or Methanol (40% v/v, 10 volumes per grams OF ZLD-AC) (106ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate disodium crystal form VI |
24% | With sodium hydroxide; In water; isopropyl alcohol; at 5 - 80℃; for 20h;pH 7.35;Product distribution / selectivity; | Preparation of ZLD-Na2 crystal form VII; Example 50:; A 0. 5L reactor equipped with a mechanical stirrer, a thermometer and a reflux condenser was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (10. OG) and water (260ml). The suspension was heated to 80C to obtain a clear solution. Sodium hydroxide (pearls, 2. 84g) was added. A pH test of the sodium salt showed PH=7. 35. The solution was cooled to 60C and IPA (10. 5ML) was added. The reaction mixture was cooled to room temperature during 2 hours and was stirred at this temperature for about 16 hours. After cooling to 5C and stirring at this temperature for 2 hours, the solution was evaporated to dryness to obtain a white solid. The obtained solid was reslurred in water (50ML) and cooled to 4C. The product was then isolated by filtration and dried in a vacuum oven at 50C for 24 hours to obtain 3.2g of Zoledronate disodium crystal form VII (24%) (pH=7.27). Purity by HPLC 100.0%. |
22 - 23% | With sodium hydroxide; In water; at 4 - 92℃; for 3.5 - 16h;Product distribution / selectivity; | Example 51:; A 0. 5L reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (10. OG) and water (130ML). The suspension was heated to reflux temperature to obtain a clear solution. A 40% ; aqueous solution of Sodium hydroxide (6. 9g) was added drop-wise. The solution was then cooled to 4C during 2 hours and was stirred at this temperature for about 1.5 hours. The solution was concentrated to half of its volume to obtain a precipitate. The white precipitate was filtered and dried in a vacuum oven at 50C for 22 hours to obtain 2.7g (22%) of Zoledronate disodium crystal form VII (LOD by TGA=10.7%).; Example 52:; A 0. 5L reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and A dropping funnel, was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (10. OG) and water (130ML). The suspension was heated to reflux temperature (92C) to obtain A clear solution. A 40% aqueous solution of Sodium hydroxide (6.9g) was added drop-wise. The solution was then cooled to 25C was stirred at this temperature for about 16 hours. The solution was then concentrated to half of its volume to obtain a precipitate. The white precipitate was filtered and dried in a vacuum oven at 50C for 18.5 hours to obtain 2. 8g (23%) of Zoledronate disodium crystal form VII (LOD by TGA=10. 2%). Purity by HPLC 100.0%. |
With sodium hydroxide; In water; at 25 - 92℃; for 16h;Product distribution / selectivity; | Example 61:; A 0. 5L reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form I (20. 0G) and water (260ML). The suspension was heated to reflux temperature (92C) to obtain a clear solution. A 40% aqueous solution of Sodium hydroxide (13. 8g) was added drop-wise. The solution was then cooled to 25C and was stirred at this temperature for about 16 hours. The solution was then concentrated to half of its volume to obtain a precipitate. After stirring at 0C for 72 hours, the white precipitate was filtered and dried in a vacuum oven at 50C for 23 hours to obtain 10.4g of Zoledronate disodium crystal form XIX. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydroxide; In ethanol; water; for 20h;Heating / reflux;Product distribution / selectivity; | Preparation of ZLD-Na3 crystal form XI; Example 70:; A 250ML flask was loaded with <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0G), Sodium hydroxide (1.4g), absolute Ethanol (50ML) and water (2. 5ML) [= 5% v/v water in Ethanol]. The reaction mixture was heated to reflux temperature for 20 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with absolute Ethanol (2X25ML) and dried in a vacuum oven at 50C for 24 hours to give 5.4g (86%) of Zoledronate trisodium crystal form XI (LOD by TGA=8. 9%). |
79 - 85% | With sodium hydroxide; In water; isopropyl alcohol; for 16h;Heating / reflux;Product distribution / selectivity; | PREPARATION OF ZLD-NA3 CRYSTAL FORM IX; Example 65:; A solution of sodium hydroxide (1.4g) in a mixture of water (20% V/V)/ETHANOL or Methanol or IPA (80% v/v, 10 volumes per grams OF ZLD-AC FORM XII) (LOML) WAS added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0g) in A mixture of water (20% v/v) /Ethanol or Methanol or IPA (80% v/v, 10 volumes per grams of ZLD-Ac) (53ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX; Example 66:; A solution of sodium hydroxide (1.4g) in a mixture of water (40% V/V)/ETHANOL or Methanol or IPA (60% v/v, 10 volumes per grams of ZLD-Ac form XII) (13ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0G) in a mixture of water (40% v/v) /Ethanol or Methanol or IPA (60% v/v, 10 volumes per grams OF ZLD-AC) (71ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX; TExample 67 :; A solution of sodium hydroxide (1.4g) in a mixture of water (50% V/V)/ETHANOL or Methanol or IPA (50% v/v, 10 volumes per grams of ZLD-Ac form XII) (15ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0G) in a mixture of water (50% V/V)/ETHANOL or Methanol or IPA (50% v/v, 10 volumes per grams OF ZLD-AC) (85ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX.; tqExample 68: A solution of sodium hydroxide (1.4g) in a mixture of water (60% V/V)/ETHANOL or Methanol or IPA (40% v/v, 10 volumes per grams OF ZLD-AC FORM XI (L9ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0G) in a mixture of water (60% V/V)/ETHANOL or Methanol or IPA (40% v/v, 10 volumes per grams OF ZLD-AC) (106ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX. ; sExample 69 :; A solution of sodium hydroxide (1. 4g) in A mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac form XII) (38ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0g) in a mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac) (212ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX |
64 - 88% | With sodium hydroxide; In methanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | PREPARATION OF ZLD-NA3 CRYSTAL FORM IX; Example 65:; A solution of sodium hydroxide (1.4g) in a mixture of water (20% V/V)/ETHANOL or Methanol or IPA (80% v/v, 10 volumes per grams OF ZLD-AC FORM XII) (LOML) WAS added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0g) in A mixture of water (20% v/v) /Ethanol or Methanol or IPA (80% v/v, 10 volumes per grams of ZLD-Ac) (53ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX; Example 66:; A solution of sodium hydroxide (1.4g) in a mixture of water (40% V/V)/ETHANOL or Methanol or IPA (60% v/v, 10 volumes per grams of ZLD-Ac form XII) (13ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0G) in a mixture of water (40% v/v) /Ethanol or Methanol or IPA (60% v/v, 10 volumes per grams OF ZLD-AC) (71ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX; TExample 67 :; A solution of sodium hydroxide (1.4g) in a mixture of water (50% V/V)/ETHANOL or Methanol or IPA (50% v/v, 10 volumes per grams of ZLD-Ac form XII) (15ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0G) in a mixture of water (50% V/V)/ETHANOL or Methanol or IPA (50% v/v, 10 volumes per grams OF ZLD-AC) (85ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX.; tqExample 68: A solution of sodium hydroxide (1.4g) in a mixture of water (60% V/V)/ETHANOL or Methanol or IPA (40% v/v, 10 volumes per grams OF ZLD-AC FORM XI (L9ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0G) in a mixture of water (60% V/V)/ETHANOL or Methanol or IPA (40% v/v, 10 volumes per grams OF ZLD-AC) (106ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX. ; sExample 69 :; A solution of sodium hydroxide (1. 4g) in A mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac form XII) (38ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0g) in a mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac) (212ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX |
58 - 84% | With sodium hydroxide; In ethanol; water; for 16h;Heating / reflux;Product distribution / selectivity; | PREPARATION OF ZLD-NA3 CRYSTAL FORM IX; Example 65:; A solution of sodium hydroxide (1.4g) in a mixture of water (20% V/V)/ETHANOL or Methanol or IPA (80% v/v, 10 volumes per grams OF ZLD-AC FORM XII) (LOML) WAS added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0g) in A mixture of water (20% v/v) /Ethanol or Methanol or IPA (80% v/v, 10 volumes per grams of ZLD-Ac) (53ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX; Example 66:; A solution of sodium hydroxide (1.4g) in a mixture of water (40% V/V)/ETHANOL or Methanol or IPA (60% v/v, 10 volumes per grams of ZLD-Ac form XII) (13ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0G) in a mixture of water (40% v/v) /Ethanol or Methanol or IPA (60% v/v, 10 volumes per grams OF ZLD-AC) (71ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX; TExample 67 :; A solution of sodium hydroxide (1.4g) in a mixture of water (50% V/V)/ETHANOL or Methanol or IPA (50% v/v, 10 volumes per grams of ZLD-Ac form XII) (15ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0G) in a mixture of water (50% V/V)/ETHANOL or Methanol or IPA (50% v/v, 10 volumes per grams OF ZLD-AC) (85ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX.; tqExample 68: A solution of sodium hydroxide (1.4g) in a mixture of water (60% V/V)/ETHANOL or Methanol or IPA (40% v/v, 10 volumes per grams OF ZLD-AC FORM XI (L9ML) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0G) in a mixture of water (60% V/V)/ETHANOL or Methanol or IPA (40% v/v, 10 volumes per grams OF ZLD-AC) (106ML) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX. ; sExample 69 :; A solution of sodium hydroxide (1. 4g) in A mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac form XII) (38ml) was added drop-wise to a suspension of <strong>[118072-93-8]Zoledronic acid</strong> form XII (5. 0g) in a mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac) (212ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50C for 24 hours to give Zoledronate trisodium crystal form IX |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethanol; water; at 20℃; for 24h; | Example 5: Preparation of the mutual salt of raloxifene and zoledronic acid ; 2.0 g of raloxifene was added to a mixture of 15 ml of water and 15 ml of ethanol, 1.0 g of zoledronic acid was added thereto, and the mixture was stirred at room temperature for 24 hours. The resulting mutual salt was isolated by filtration, washed with a mixture of 15 ml of water and 15 ml of ethanol, dried at 40C to obtain 2.4 g of the title compound as a cream-colored tetrahydrate. M. P. 235C Moisture content (Karl-Fisher titrator) 8.5% (theoretical value: 8. 81%) 'H-NMR (D20, ppm) : 5 8.62 (s, H), 7.40 (s, 1H), 7.27 (s, 1H), 7.21 (m, 3H), 7.02 (s, 1H), 6.69 (dd, 4H), 6.32 (dd, 4H), 4.59 (t, 2H), 3.95 (t, 2H), 3.24 (m, 4H), 2.72 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74 - 79% | Examples; CRYSTAL FORMS OF ZOLEDRONIC ACID (ZLD-Ac); Preparation of ZLD-AC crystal form I; General procedure for the preparation of ZLD-AC crystal form I starting from 1- Imidazoleacetic acid (IAA), Phosphorous acid (H3PO3) and Phosphorous oxychloride (POC13) (Examples 1-9, see Table 1) :; A cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, is loaded with 1-IMIDAZOLEACETIC acid (IAA), Phosphorous acid and a diluent (Toluene/Chlorobenzene/PEG-400/Silicon oil). The obtained suspension is heated to 75C-80C and Phosphorous oxychloride is added drop- wise. The reaction mixture is then heated to 75C-100C for 1-34 hours. Then water is added at 80C-100C. The mixture is stirred vigorously for about 15 minutes. [In some cases, when Silicon oil is used as a diluent, there is a need to add Toluene in order to improve the separation between the oily phase and the aqueous phase]. Then the phases are separated. The aqueous phase is put in a clean reactor and heated to 95C-100C for 13.5-19 hours. Then it is cooled to 5C and absolute Ethanol is added to obtain a precipitate after stirring at 5C for 2.5-4 hours [In some cases a precipitate of Zoledronic acid is obtained without adding absolute Ethanol as an anti-solvent]. The white product is then filtered, washed with absolute Ethanol and dried in a vacuum oven at 50C for 17-24 hours to obtain Zoledronic acid crystal form I (LOD BY TGA=6. 3%-9. 3%).; ZLD HPLC METHOD: COLUMN: PHENOMENEX PHENYL-HEXYL 5UM, 250X4.6MM MOBILE PHASE: 40MM OCTANSULFONIC ACID SODIUM SALT IN 1% HCLO4, 0.2% H3PO4 : METHANOL (85:15) DETECTION: 220NM STABILITY WAS MEASURED VERSUS THE PRESENCE OF FORM II. P THE STABILITY DATA FOR EXAMPLE 4 IN THE TABLE ABOVE IS: | |
69% | Examples; CRYSTAL FORMS OF ZOLEDRONIC ACID (ZLD-Ac); Preparation of ZLD-AC crystal form I; General procedure for the preparation of ZLD-AC crystal form I starting from 1- Imidazoleacetic acid (IAA), Phosphorous acid (H3PO3) and Phosphorous oxychloride (POC13) (Examples 1-9, see Table 1) :; A cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, is loaded with 1-IMIDAZOLEACETIC acid (IAA), Phosphorous acid and a diluent (Toluene/Chlorobenzene/PEG-400/Silicon oil). The obtained suspension is heated to 75C-80C and Phosphorous oxychloride is added drop- wise. The reaction mixture is then heated to 75C-100C for 1-34 hours. Then water is added at 80C-100C. The mixture is stirred vigorously for about 15 minutes. [In some cases, when Silicon oil is used as a diluent, there is a need to add Toluene in order to improve the separation between the oily phase and the aqueous phase]. Then the phases are separated. The aqueous phase is put in a clean reactor and heated to 95C-100C for 13.5-19 hours. Then it is cooled to 5C and absolute Ethanol is added to obtain a precipitate after stirring at 5C for 2.5-4 hours [In some cases a precipitate of Zoledronic acid is obtained without adding absolute Ethanol as an anti-solvent]. The white product is then filtered, washed with absolute Ethanol and dried in a vacuum oven at 50C for 17-24 hours to obtain Zoledronic acid crystal form I (LOD BY TGA=6. 3%-9. 3%).; ZLD HPLC METHOD: COLUMN: PHENOMENEX PHENYL-HEXYL 5UM, 250X4.6MM MOBILE PHASE: 40MM OCTANSULFONIC ACID SODIUM SALT IN 1% HCLO4, 0.2% H3PO4 : METHANOL (85:15) DETECTION: 220NM STABILITY WAS MEASURED VERSUS THE PRESENCE OF FORM II. P THE STABILITY DATA FOR EXAMPLE 4 IN THE TABLE ABOVE IS: | |
58% | Example 11:; A 250ML three-necked flask equipped with a mechanical stirrer, a reflux condenser and A dropping funnel, was loaded with 1-IMIDAZOLEACETIC acid hydrochloride (4.9g, 0.03mole), phosphorous acid (4.9g, 0.06mole) and Silicon oil (MERCK) (27ml). The suspension was heated to 75C and phosphorous oxychloride (10. 5ML, 0. 1 lmole) was added drop-wise during 30 minutes. The reaction mixture was then heated to 80C for 27 hours. Then WATER (27ML) AND toluene (30ML) were added at 80C. The mixture was stirred vigorously for about 15 minutes. Then the toluene phase (containing the silicon oil) and the aqueous phase were separated. The aqueous phase was put in a clean flask and heated to 90C for 16 hours. Then it was cooled to room temperature and absolute Ethanol (27ML) was added during the cooling process to obtain a white precipitate immediately. The mixture was stirred at 5C for 4 hours. The white product was then filtered, washed with absolute Ethanol (2XL5ML) and dried in a vacuum oven at 50C for 24 hours to obtain 4.9g (58%) of Zoledronic acid crystal form II (LOD by TGA=5. 2%). |
38% | Examples; CRYSTAL FORMS OF ZOLEDRONIC ACID (ZLD-Ac); Preparation of ZLD-AC crystal form I; General procedure for the preparation of ZLD-AC crystal form I starting from 1- Imidazoleacetic acid (IAA), Phosphorous acid (H3PO3) and Phosphorous oxychloride (POC13) (Examples 1-9, see Table 1) :; A cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, is loaded with 1-IMIDAZOLEACETIC acid (IAA), Phosphorous acid and a diluent (Toluene/Chlorobenzene/PEG-400/Silicon oil). The obtained suspension is heated to 75C-80C and Phosphorous oxychloride is added drop- wise. The reaction mixture is then heated to 75C-100C for 1-34 hours. Then water is added at 80C-100C. The mixture is stirred vigorously for about 15 minutes. [In some cases, when Silicon oil is used as a diluent, there is a need to add Toluene in order to improve the separation between the oily phase and the aqueous phase]. Then the phases are separated. The aqueous phase is put in a clean reactor and heated to 95C-100C for 13.5-19 hours. Then it is cooled to 5C and absolute Ethanol is added to obtain a precipitate after stirring at 5C for 2.5-4 hours [In some cases a precipitate of Zoledronic acid is obtained without adding absolute Ethanol as an anti-solvent]. The white product is then filtered, washed with absolute Ethanol and dried in a vacuum oven at 50C for 17-24 hours to obtain Zoledronic acid crystal form I (LOD BY TGA=6. 3%-9. 3%).; ZLD HPLC METHOD: COLUMN: PHENOMENEX PHENYL-HEXYL 5UM, 250X4.6MM MOBILE PHASE: 40MM OCTANSULFONIC ACID SODIUM SALT IN 1% HCLO4, 0.2% H3PO4 : METHANOL (85:15) DETECTION: 220NM STABILITY WAS MEASURED VERSUS THE PRESENCE OF FORM II. P THE STABILITY DATA FOR EXAMPLE 4 IN THE TABLE ABOVE IS: | |
Examples; CRYSTAL FORMS OF ZOLEDRONIC ACID (ZLD-Ac); Preparation of ZLD-AC crystal form I; General procedure for the preparation of ZLD-AC crystal form I starting from 1- Imidazoleacetic acid (IAA), Phosphorous acid (H3PO3) and Phosphorous oxychloride (POC13) (Examples 1-9, see Table 1) :; A cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, is loaded with 1-IMIDAZOLEACETIC acid (IAA), Phosphorous acid and a diluent (Toluene/Chlorobenzene/PEG-400/Silicon oil). The obtained suspension is heated to 75C-80C and Phosphorous oxychloride is added drop- wise. The reaction mixture is then heated to 75C-100C for 1-34 hours. Then water is added at 80C-100C. The mixture is stirred vigorously for about 15 minutes. [In some cases, when Silicon oil is used as a diluent, there is a need to add Toluene in order to improve the separation between the oily phase and the aqueous phase]. Then the phases are separated. The aqueous phase is put in a clean reactor and heated to 95C-100C for 13.5-19 hours. Then it is cooled to 5C and absolute Ethanol is added to obtain a precipitate after stirring at 5C for 2.5-4 hours [In some cases a precipitate of Zoledronic acid is obtained without adding absolute Ethanol as an anti-solvent]. The white product is then filtered, washed with absolute Ethanol and dried in a vacuum oven at 50C for 17-24 hours to obtain Zoledronic acid crystal form I (LOD BY TGA=6. 3%-9. 3%).; ZLD HPLC METHOD: COLUMN: PHENOMENEX PHENYL-HEXYL 5UM, 250X4.6MM MOBILE PHASE: 40MM OCTANSULFONIC ACID SODIUM SALT IN 1% HCLO4, 0.2% H3PO4 : METHANOL (85:15) DETECTION: 220NM STABILITY WAS MEASURED VERSUS THE PRESENCE OF FORM II. P THE STABILITY DATA FOR EXAMPLE 4 IN THE TABLE ABOVE IS: | ||
Examples; CRYSTAL FORMS OF ZOLEDRONIC ACID (ZLD-Ac); Preparation of ZLD-AC crystal form I; General procedure for the preparation of ZLD-AC crystal form I starting from 1- Imidazoleacetic acid (IAA), Phosphorous acid (H3PO3) and Phosphorous oxychloride (POC13) (Examples 1-9, see Table 1) :; A cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, is loaded with 1-IMIDAZOLEACETIC acid (IAA), Phosphorous acid and a diluent (Toluene/Chlorobenzene/PEG-400/Silicon oil). The obtained suspension is heated to 75C-80C and Phosphorous oxychloride is added drop- wise. The reaction mixture is then heated to 75C-100C for 1-34 hours. Then water is added at 80C-100C. The mixture is stirred vigorously for about 15 minutes. [In some cases, when Silicon oil is used as a diluent, there is a need to add Toluene in order to improve the separation between the oily phase and the aqueous phase]. Then the phases are separated. The aqueous phase is put in a clean reactor and heated to 95C-100C for 13.5-19 hours. Then it is cooled to 5C and absolute Ethanol is added to obtain a precipitate after stirring at 5C for 2.5-4 hours [In some cases a precipitate of Zoledronic acid is obtained without adding absolute Ethanol as an anti-solvent]. The white product is then filtered, washed with absolute Ethanol and dried in a vacuum oven at 50C for 17-24 hours to obtain Zoledronic acid crystal form I (LOD BY TGA=6. 3%-9. 3%).; ZLD HPLC METHOD: COLUMN: PHENOMENEX PHENYL-HEXYL 5UM, 250X4.6MM MOBILE PHASE: 40MM OCTANSULFONIC ACID SODIUM SALT IN 1% HCLO4, 0.2% H3PO4 : METHANOL (85:15) DETECTION: 220NM STABILITY WAS MEASURED VERSUS THE PRESENCE OF FORM II. P THE STABILITY DATA FOR EXAMPLE 4 IN THE TABLE ABOVE IS: | ||
With phosphoric acid; phosphorus trichloride; In 1,2-dichloro-ethane; at 50 - 80℃; for 6 - 6.5h; | Preparation of zoledronic acid. Into a 2L, three-necked RB flask was added 60g of imidazol-1-ylacetic acid hydrochloride prepared by the process described in step (ii), 105g of o-phosphoric acid and 250ml of ethylene dichloride. The reaction mass was heated to 50-55C and added 152g of phosphorous trichloride over a period of 2. 0-2. 5h keeping the temperature below 80C. After maintaining at 70-80C for 4h the reaction was quenched by adding 30ml of water and 165g of concentrated HC1. The reaction mass was heated to reflux temperature and maintained for 5-6h. The reaction mass was cooled to 25-30C, separated ethylene- dichloride layer, and treated the aqueous layer with carbon. Acetone (700ml) was added to the reaction mass and cooled to 5-10C. After maintaining for 2-3h reaction mass was filtered and the wet cake washed with 100ml of acetone. The Zoledronic acid so produced was dried at 50-60C to get 85g of white crystalline solid. Purity by HPLC is 98. 5%. A small sample was dissolved in 20 times refluxing water and cooled to 25-30C. Pure zoledronic acid was isolated by filtration. Purity by HPLC is 99.4%. | |
With phosphoric acid; phosphorus trichloride; In cyclohexane; at 50 - 80℃; for 8 - 8.5h; | Preparation of zoledronic acid. Into a 2L, three-necked RB flask was added 60g of imidazol-1-ylacetic acid hydrochloride prepared by the process described in step (i) of the Example 1, 105g of o- phosphoric acid and 250ml of cyclohexane. The reaction mass was heated to 50-55C and added 152g of phosphorous trichloride over a period of 2. 0-2. 5h keeping the temperature below 80C. After maintaining at 80C for 6h, the reaction was quenched by adding 100 ml of water and 165g of concentrated HCI. The reaction mass was heated to reflux temperature and maintained for 5-6h. The reaction mass was cooled to 25-30C, separated cyclohexane layer, and treated the aqueous layer with carbon. Acetone (700ml) was added to the reaction mass and cooled to 5-10C. After maintaining for 2-3h reaction mass was filtered and the wet cake washed with 100ml of acetone. Crude zoledronic acid was dried at 50-60C to get 80g as white crystalline solid. Purity by HPLC is 98.0%. The above crude zoledronic acid was taken into a 2L glass flask and added 1600ml of DM water. The reaction mass was heated to 90-95C and maintained for 2-3h to dissolve the solid. Carbon (lOg) was added to the reaction mass and filtered while hot. The filtrate was cooled to 25-30C and maintained for 3-4h before filtration. Wet cake was washed with water and dried at 50-60C till the moisture content reached 6-10%. Yield of pure zoledronic acid, as monohydrate was 70g. Purity by HPLC is 99.3%. | |
With phosphoric acid; phosphorus trichloride; In chlorobenzene; at 50 - 80℃; for 7 - 7.5h; | Preparation of zoledronic acid. Into a 200L glass flask containing 10. 5kg of o-phosphoric acid and 25L of chlorobenzene was added 6. 0 kg of imidazol-1-ylacetic acid hydrochloride prepared by the process described in step (i) of the Example 1. The reaction mass was heated to 50-55 C and added 15.2 kg of phosphorous trichloride over a period of 2.0-2. 5hr keeping the temperature below 80 C. After maintaining at 60-80 C for 5hr the reaction was quenched by adding 3.0 L of water and 16.5 kg of concentrated HC1. The reaction mass was heated to reflux temperature and maintained for 5-6hr. The reaction mass was cooled to 25-30 C, separated chlorobenzene layer, and treated the aqueous layer with carbon. Acetone (70.0 L) was added to the reaction mass and cooled to 5-10 C. After maintaining for 2-3hr reaction mass was filtered and the wet cake washed with 10. 0 L of acetone. Crude zoledronic acid was dried at 50-60 C to get 8.0 kg as white crystalline solid. Purity by HPLC is 99. 0%. The above crude zoledronic acid was taken into a 250-L, glass lined reactor and added 160 L of DM water. The reaction mass was heated to 90-95 C and maintained for 2-3hr to dissolve the solid. Carbon (1.0 kg) was added to the reaction mass and filtered while hot. The filtrate was cooled to 25-30 C and maintained for 3-4hr before filtration. Wet cake was washed with water and dried at 50-60 C till the moisture content reached 6- 10%. Yield of pure zoledronic acid, as monohydrate was 7. 0 Kg. Purity by HPLC is 99.8%. |
Yield | Reaction Conditions | Operation in experiment |
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98.7% | With hydrogenchloride; In ethanol; water; at 0 - 85℃;pH 1.7 - 3.7;Purification / work up; | Example 5:Recrystallization of Zoledronic Acid Monohydrate:[0024] A jacketed 3 liter flask, fitted with a stirrer, thermocouple and nitrogen adapter was charged with water (1.5 1) and 64.4 g of crude zoledronic acid monohydrate. The aqueous mixture was heated to 85C and all solids dissolved giving a pH of 1.7. Absolute ethanol (500 ml) and zoledronic acid monohydrate seeds were added to the aqueous mixture creating a slurry, which was slowly cooled with stirring. At 38C, the pH was adjusted from 3.7 to 1.7 with hydrochloric acid. At 180C, the aqueous mixture was adjusted to pH greater than 2. The slurry was stirred at O0C for about 4 hours then the solid was filtered, washed with ethanol (2 x 200 ml) and dried with nitrogen yielding 58.64 g of zoledronic acid monohydrate. The product was dried further in a vacuum drying oven at 5O0C, 1-2 in. nitrogen, giving a loss of 0.28 wt%. An NMR assay indicated a product purity of 92.2 wt % (on an anhydrous basis). Karl-Fischer titration indicated 6.46% water corresponding to 98.7 % zoledronic acid hydrate with the water to a zoledronic mole ratio of 1.06:1. 1H NMR (D2O/NaOD): 7.75 (s, IH); 7.23 (s, IH); 6.90 (s, IH); 4.82 (O-H, 7.35H); 4.46 (m, 2H); 31P (H coupled, D2O/NaOD): 16.83 (m). |
Examples of particularly preferred N-bisphophonates for use in the invention are: ... 1- Amino-2-(1-methylimidazol-4-yl)ethane-1,1-diphosphonic acid; 1- Amino-2-(1-benzylimidazol-4-yl)ethane-1,1-diphosphonic acid; 2-(1-Methylimidazol-2-yl)ethane-1,1-diphosphonic acid; 2-(1-Benzylimidazol-2-yl)ethane-1,1-diphosphonic acid; 2-(Imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid; 2-(Imidazol-1-yl)ethane-1,1-diphosphonic acid; 2-(4H-1,2,4-triazol-4-yl)-1-hydroxyethane-1,1-diphosphonic acid; 2-(Thiazol-2-yl)ethane-1,1-diphosphonic acid; ... | ||
The oral dosage form according to claim 6, wherein the bisphosphonate is selected from the group consisting of: ... 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid (ibandronate); 1-hydroxy-2-(3-pyridyl)ethylidene-1,1-bisphosphonic acid(risedronate); 1-hydroxyethylidene-1,1-bisphosphonic acid (etidronate); 1-hydroxy-3-(1-pyrrolidinyl)propylidene-1,1-bisphosphonic acid; 1-hydroxy-2-(1-imidazolyl)etylidene-1,1-bisphosphonic acid (zoledronate); 1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidene-1,1-bisphosphonic acid (minodronate); 1-(4-chlorophenylthio)methylidene-1,1-bisphosphonic acid (tiludronate); 1-(cycloheptylamino)methylidene-1,1-bisphosphonic acid (cimadronate, incadronate); and ... |
EXAMPLE 10 With stirring and under reflux, 8.6 g (0.053 mole) of imidazol-1-ylacetic acid hydrochloride, 7.1 ml of 85% phosphoric acid and 25 ml of chlorobenzene are heated to 100 C. Then 13.9 ml of phosphorus trichloride are added dropwise at 100 C., whereupon evolution of gas occurs. Over the course of 30 minutes a dense mass precipitates from the reaction mixture. The batch is heated for 3 hours to 100 C. and the supernatant chlorobenzene is removed by decantation. The residual viscous mass is heated for 3 hours to the boil, with stirring and under reflux, with 40 ml of 9N hydrochloric acid. The batch is then filtered hot with the addition of carbon and the filtrate is diluted with acetone, whereupon the crude 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid precipitates. This product is recrystallized from water. Melting point: 239 C. (dec.). Yield: 41% of theory. | ||
the bisphosphonates are selected from the group which comprises aminohydroxymethylidene bisphosphonic acids, ... 3-methylpentylamino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-(3-pyridinyl)-1-hydroxyethylidene-bisphosphonic acid, 1-hydroxy-2-(imidazol-1-yl)-ethylidene-1,1-bisphosphonic acid, cycloheptylaminomethylene diphosphonic acid, | ||
Examples of particularly preferred bisphophonates for use in the invention are: ... 1-Amino-2-(1-methylimidazol-4-yl)ethane-1,1-diphosphonic acid; 1-Amino-2-(1-benzylimidazol-4-yl)ethane-1,1-diphosphonic acid; 2-(1-Methylimidazol-2-yl)ethane-1,1-diphosphonic acid; 2-(1-Benzylimidazol-2-yl)ethane-1,1-diphosphonic acid; 2-(Imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid; 2-(Imidazol-1-yl)ethane-1,1-diphosphonic acid; 2-(4H-1,2,4-triazol-4-yl)-1-hydroxyethane-1,1-diphosphonic acid; 2-(Thiazol-2-yl)ethane-1,1-diphosphonic acid; ... |
Yield | Reaction Conditions | Operation in experiment |
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With water; at 30 - 73℃; for 0.166667h; | 5 g of anhydrous zoledronic acid was taken into a round bottomed flask equipped with a magnetic stirrer, condenser and oil bath, then 150 ml of water was added to it. The reaction mass was heated slowly to 73 C. to obtain a clear solution. The solution was filtered while hot to make it particle free. The clear filtrate was taken into a fresh round-bottomed flask and allowed to cool to 30 C. The reaction mass was stirred at 30 C. for 10 minutes. The separated solid was filtered under vacuum. The compound was suction dried under a vacuum of 600 mm Hg for 10 minutes to get 3.6 g of the title compound. Samples of this product were analyzed, to generate all of FIGS. 1-6. Moisture content: 15.5% (w/w). Melting point: 238+/-3 C. | |
With water; at 15 - 25℃; for 3.5h;Heating / reflux; | Example 2 - Zoledronic Acid Trihydrate; The raw humid zoledronic acid (equivalent to 30 g dry product), obtained in Example 1, is suspended in water (900 ml).The suspension is heated at reflux, thus obtaining a solution. EPO <DP n="8"/>This hot solution is slowly added and blended to a refrigerated container, containing water (50 ml).The inside temperature is adjusted by means of the flow of the refrigerant fluid and the volume of aggregate of the hot concentrated solution, in order to keep it between 15 and 25 0C.The aggregate requires around VA hours.Once all the zoledronic acid solution is added, it is cooled down to 0 - 5 0C maintaining this temperature over 2 - 3 hours, it is filtered, washed with ice water (30 ml) and dried with air flow at 50 - 600C.The obtained product presents the following physicochemical characteristics.Diffraction by X-rays (dust method)It presents peaks in at following values of 2Theta 9.2; 10.4; 14.7; 16.4 +/- 0.2.The diffractogram is the one shown in Figure I.Titre (potentiometric): 99 %Humidity (Loss by dissection): 16.6 %TGA_(Thermogravimetric Analysis):The obtained curve is shown in Figure II.DSC (Differential Scanning Calorimetry)The obtained curve is shown in Figure II.Infrared Spectrum (KBr)Absorption at 3578-3011; 1643.6; 1579.9; 1549.1; 1443.0; 1414.0; 1387.0; 1294.4; 1155.5; 966.5 cm"1Corresponds to Figure III. | |
With water; at 30℃; for 0.166667h; | EXAMPLE 1; PREPARATION OF ZOLEDRONIC ACID TRIHYDRATE5 g of anhydrous zoledronic acid was taken into a round bottomed flask equipped with a magnetic stirrer, condenser and oil bath, then 150 ml of water EPO <DP n="16"/>was added to it. The reaction mass was heated slowly to 73 C to obtain a clear solution. The solution was filtered while hot to make it particle free. The clear filtrate was taken into a fresh round-bottomed flask and allowed to cool to 30 C. The reaction mass was stirred at 30 C for 10 minutes. The separated solid was filtered under vacuum. The compound was suction dried under a vacuum of 600 mm Hg for 10 minutes to get 3.6 g of the title compound.Samples of this product were analyzed, to generate all of Figs. 1-6. Moisture content: 15.5 % (w/w) by the Karl Fischer method. Melting point: 238 +/- 3 C. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; water; | EXAMPLE 21 A solution of 0.121 g of tris(hydroxymethyl)methylamine in 2 ml of water is added to a solution of 0.141 g of 2-(imidazol-1-yl)-1-hydroxy-ethane-1,1-diphosphonic acid in 1 ml of water. The resulting solution is concentrated by evaporation in vacuo and triturated with 6 ml of warm methanol. After cooling, a cristalline precipitate is formed which is filtered off and dried for 1 hour in vacuo at 80 yielding pure mono-tris(hydroxymethyl)methylammonium 2-(imidazol-1-yl)-1-hydroxy-ethane-1,1-diphosphonate of m.p. 170-175. |
Yield | Reaction Conditions | Operation in experiment |
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89% | With water; at 70 - 80℃;Heating / reflux; | Example 3 - Zoledronic Acid Monohydrate; The raw humid zoledronic acid (equivalent to 90.3 g raw product), obtained according to Example 1, is suspended in water (3050 ml). The suspension is heated at reflux, with agitation. EPO <DP n="9"/>Water is added up to a total volume of 3750 ml, by which a total dissolution is obtained.The heating is then interrupted and the agitation, allowing it to slowly cool down to ambient temperature.Once the inside temperature is around 70 - 800C a frank crystallization starts.Once the ambient temperature is reached, it is cooled down to 2 - 5 0C, maintained at that temperature during 1 'Lambda hours, filtered and the precipitate is washed with ice water.It is dried in a stove with air flow at 5C - 60 0C.169.3 g (89 %) colorless crystals are obtained.The loss through dissection (6.8%) confirms that this is a monohydrate.This substance, by diffraction with X-rays, dust method, presents peaks at the following values of 20 12.1; 12.8; 15.7; 18.9 +/- 0.2, coincident with those described for the form I (US 2005/0054616).Figure I A shows its diffractogram of dust X-rays and figure IV A the lay-out of the atoms in the unitary cell of the crystalline network for this form. |
With water; In ethanol; at 60℃; for 2h; | Example 5: Process for Making the Crystalline Form of the Monohydrate of the Free Acid of Zoledronic Acid About 300 mg of the anhydrous form of zoledronic acid is suspended in about 1 mL of 96% ethanol. The suspension is equilibrated for about 2 hours at about 60C. The solid precipitate is then isolated by filtration. |
Yield | Reaction Conditions | Operation in experiment |
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In water; at 20 - 90℃; | Example 1 Process for Making the Crystalline Form of the 1:2 Calcium Salt of <strong>[118072-93-8]Zoledronic acid</strong> In a 2,500 mL 3-necked flask with mechanical stirrer, 50 g zoledronic acid and 1380 mL water are added. This mixture is heated to about 90C until everything goes into solution. To this clear solution a solution of 19 g calcium chloride dihydrate in 345 mL water is added. The mixture is cooled to room temperature and stirred over night. The precipitated Ca salt is then isolated by filtration, washing with water and dried in a vacuum oven at 50C over night. This gives 49.8 g Ca salt of the following composition: C: 18.93; H: 3.82; N: 8.65; P: 20.1; Ca: 6.36; H2O: 8.48. This corresponds to a trihydrate. m.p. >230C |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; In water; at 20℃; | Example 4 Process for Making the Crystalline Form of the 1:2 Magnesium Salt of Zoledronic Acid In a 500 mL three-necked flask, 2.9 g zoledronic acid are dissolved in 80 mL water and 10 mL NaOH 2 N. To this solution a solution of 0.408 g magnesium chloride hexahydrate in 80 mL ethanol is added at room temperature. The product crystallizes slowly during stirring the reaction mixture at room temperature. After stirring for some hours, the formed white precipitate is filtrated and washed with ethanol. Drying over night in a vacuum oven gives 2.79 g of a white product with the following composition: C: 17.87; H: 3.22; N: 8.22; P: 18.6; Mg: 1.45; H2O: 7.73. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate; In methanol; water; at 60℃;pH 7.4;Conversion of starting material; | Synthesis of 3-{3-[(tert-butoxycarbonyl)amino]-2-hydroxypropyl}-1-(2-hydroxy-2,2-diphosphonoethyl)-1H-imidazol-3-ium 9.8 mg of 29 was dissolved in 1 mL H2O and pH adjusted to 7.4 with Na2CO3. To this solution was added 32.7 mg of 4 in minimal MeOH. The reaction mixture was heated at 60 C. overnight, yielding compound 31 by 31P NMR and ESI-MS. 31P NMR (400 MHz, D2O): delta 14.11 (s). MS (negative ion ESI-MS, calculated 446.1093 m/z, found 443.9 m/z). |
Yield | Reaction Conditions | Operation in experiment |
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In water; isopropyl alcohol; at 20 - 75℃;Reflux;Product distribution / selectivity; | Example III. Preparation of [l-hydroxy-2-(lH-imidazol-l-yl)- ethylidene]bisphosphonic acid.A solution of lEta-imidazole-1-acetic acid [13 g (0.103 moles) of lH-imidazole-1- acetic acid in 9 ml of water and 9 ml of hydrochloric acid (35%)] is added for about 1 hour at the temperature 0-5 C to 54 ml of phosphorus trichloride (PCl3) cooled to the temperature 0-5 C. Then, the mixture is heated to 80-85C and maintained at this temperature for 2 hours. The excess of the phosphorus trichloride is then distilled off under the reduced pressure. 100 ml of water is added to the reaction residues and the hydrolysis is performed while maintaining boiling for 6 hours, the mixture is cooled to 85C, afterwards 1.3 g of activated charcoal, 1.3 g of Hyflo Super CeI are added and mixed for 30 minutes at 80-850C. The mixture is filtered and the precipitate on the filter is washed with 13 ml of water. 100 ml of isopropanol is added for 15 minutes to the filtrate at 65-550C. The mixture is cooled to 25C. After 18 hours of mixing at 20-250C the precipitate is filtered off, washed twice with 13 ml of water, once with 13 ml of water-isopropanol mixture (1:1) and once with 13 ml of isopropanol and dried for 5 hours at 500C.12.1 g (41%) of [l-hydroxy-2-(lH-imidazol-l-yl)-ethylidene]bisphosphonic acid monohydrate is obtained.EtaPLC 100% , TGA 6.02%XPRD: 12.04; 12.76; 15.67; 18.79; 20.81; 21.23; 21.69; 22.11; 25.70; 27.48; 29.17; 32.36; 32.87 (+,- 0.02 ) 2 theta1H NMR (D2O): 5=4.634-4.672 ppm (t, 2H, J=9.65); 7.330 (s,lH); 7.538 (s, IH);8.639 (s, IH)13C NMR: 6=55.84 ppm; 74.54-76.53 (t); 121.75; 126.50; 138.7931P NMR: delta=15.02 ppm 10 g of [l-hydroxy-2-(lH-imidazol-l-yl)-ethylidene]bisphosphonic acid is suspended in 200 ml of water, heated to the boiling point and mixed while boiling for 15 minutes. Then, the mixture is cooled to 70-750C and 200 ml of isopropanol is added for about 1-1.5 hour. The mixture is cooled to 20-250C. After 3 hours of mixing at 20-25C the precipitate is filtered off, washed twice with 10 ml of water and once with 10 ml of isopropanol and dried for 5 hours at 55C.9.35 g (93.5%) of [l-hydroxy-2-(lH-imidazol-l-yl)-ethylidene]bisphosphonic acid monohydrate is obtained.EtaPLC 100.00%, TGA 6.18%XPRD: 12.02; 12.76; 15.67; 18.80; 20.80; 21.24; 21.68; 22.12; 25.71; 27.51; 29.16; 32.31 ; 32.89 (+,- 0.02 ) 2 theta1H NMR (D2O): 5=4.675-4.713 ppm (t, 2H, J=9.63); 7.381 (s,lH); 7.542 (s, IH);8.719 (s, IH)13C NMR: 5=55.59 ppm; 74.82-76.91 (t); 121.14; 126.83; 138.7131P NMR: 5=13.24 ppm | |
In water;Reflux;Purification / work up; | Example 11; <strong>[118072-93-8]Zoledronic acid</strong> monohydrate (6.0 g) was suspended in water (100 ml) and the mixture was heated to reflux. Formed solution was cooled down to 20 C. and resulting crystalline suspension was stirred at 19-23 C. for additional 1.5 hours. Product was the filtered, washed with ethanol (10 ml) and dried at 60 C. to give 5.21 g (86.8%) of zoledronic acid monohydrate. | |
10 g of [1-hydroxy-2-(1H-imidazol-1-yl)-ethylidene]bisphosphonic acid is suspended in 200 ml of water, heated to the boiling point and mixed while boiling for 15 minutes. Then, the mixture is cooled to 70-75 C. and 200 ml of isopropanol is added for about 1-1.5 hour. The mixture is cooled to 20-25 C. After 3 hours of mixing at 20-25 C. the precipitate is filtered off, washed twice with 10 ml of water and once with 10 ml of isopropanol and dried for 5 hours at 55 C. 9.35 g (93.5%) of [1-hydroxy-2-(1H-imidazol-1-yl)-ethylidene]bisphosphonic acid monohydrate is obtained. HPLC 100.00%, TGA 6.18% XPRD: 12.02; 12.76; 15.67; 18.80; 20.80; 21.24; 21.68; 22.12; 25.71; 27.51; 29.16; 32.31; 32.89 (+,-0.02) 2theta 1H NMR (D2O): delta=4.675-4.713 ppm (t, 2H, J=9.63); 7.381 (s, 1H); 7.542 (s, 1H); 8.719 (s, 1H) 13C NMR: delta=55.59 ppm; 74.82-76.91 (t); 121.14; 126.83; 138.71 |
Yield | Reaction Conditions | Operation in experiment |
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A 50-mL round bottom flask charged with zoledronic acid (1.098 g, 4.035 mmol) and EtNiPr2 (2.81 mL, 4.0 eq.) in anhydrous DMF (25 mL) was heated at 42 C. for 15 min (during which n separation occurred) and to it was added a solution of 1-tert-butoxyformoxy-2'-isopropoxyformoxybenzylchloride (1.957 g, crude) in anhydrous DMF (10 mL). The resultant mixture was stirred and maintained at 42 C. for 24 hours as a heterogeneous suspension. A distillation head and a condenser were placed on the flask and the volatiles were distilled in high vacuum at 40 C. (oil bath). The residue was absorbed onto silica gel by mixing with MeOH (10 mL) and silica gel (15 g) followed by evaporation to dryness under high vacuum. This solid was added to a pre-packed column of silica gel (200 g) and eluded with CH3CN:MeOH (10:0->10:1->4:1->2:1->0:10). The fractions collected were checked by TLC and MS analyses. Two poured fractions showed the product mass after evaporation under reduced pressure gave 80 mg and 170 mg, respectively.The diacid (0.152 mg) was dissolved in CH3CN and passed through an ion exchange resin column (containing Amberlite IR-120 (Na) ion exchange resin which had been washed with water before loading) (40 g), eluded with deionized water. The fraction with slight tan color was freeze-dried to give 64 mg of a white fluffy solid. The product showed cis/trans mixture and a strong signal in negative MS-ESI. 31P NMR (300 MHz, D2O): delta 13.85 (s) and 13.51 (s); MS (ESI): 461.0 (M-H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogenchloride; In water; N,N-dimethyl-formamide; at 100℃; for 0.333333h;Sealed tube; Microwave irradiation; | 3.1. Crystalline manganese zoledronate nanoparticle (Mn-Zol) Synthesis. <strong>[118072-93-8]Zoledronic acid</strong> (5 mg, 0.019 mmol) and MnCI2-4H20 (10 mg, 0.05 mmol) were dissolved in a solvent mixture of DMF/H20 (5 mL/2 mL). After adding 0.15 mL 3M HCI, the resulting solution was sealed in a microwave vessel and placed in the microwave oven with the power set to 400 W and run time set to 5 minutes. After 20 minutes of heating at 100 C with stirring, the crystalline particles of Mn-Zol were isolated via centrifuge at 13000 rpm for 15 min. Before re-dispersing them in EtOH, they were washed once with water and three times with EtOH. Approximately 4.6 mg (70 %) particles of Mn-Zol were isolated from this procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; | Example 3 Preparation of Zoledronic, L-Lysine, and Water Complex 200 mg of zoledronic acid and 54 mg of L-lysine are slurried in 2 mL of tetrahydrofuran and 200 mul of water overnight. The solids gathered after filtration are dried and stored. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; | Example 4 Preparation of Zoledronic, DL-Lysine, and Water Complex 204 mg of zoledronic acid and 59 mg of DL-lysine are slurried in 2 mL of tetrahydrofuran and 200 mul of water overnight. The solids gathered after filtration are dried and stored. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | Example 6 Preparation of Zoledronic, Nicotinamide, and Water Complex by Solvent-Drop Grinding 99 mg of zoledronic acid is ground with 44 mg of nicotinamide and 40 mul of water is added to the solid mixture. The solids gathered after grinding are stored. | |
In water; | 99 mg of zoledronic acid was ground with 44 mg of nicotinamide and 40 mu of water was added to the solid mixture. The solids gathered after grinding were stored in screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 1 1 and FIG. 12, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | Example 8 Preparation of Zoledronic, Adenine, and Water Complex by Solvent-Drop Grinding 96 mg of zoledronic acid is ground with 65 mg of adenine and 60 muL of water is added to the solid mixture. The solids gathered after grinding are stored. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | Example 10 Preparation of Zoledronic and Glycine Complex 178 mg of zoledronic acid and 45 mg of glycine are slurried in 2 mL of water overnight. The solids gathered after filtration are dried and stored. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; In methanol; | Example 11 Preparation of Zoledronic Diammonia Water Complex 1.5 g of zoledronic acid is slurried in 7N ammonia in methanol overnight. The material is filtered and rinsed. The particulate material is dissolved in water with medium heat and left to evaporate at ambient conditions to obtain colorless blocks after 1 day. | |
With ammonia; In methanol; | 1 .5 g of zoledronic acid was slurried in 7N ammonia in methanol overnight. The material was filtered and rinsed. The particulate material was dissolved in water with medium heat and left to evaporate at ambient conditions to obtain colorless blocks after 1 day. The material was characterized by PXRD and FTIR corresponding to FIG. 17 and FIG. 18, respectively |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; In methanol; | Example 2 Preparation of Ammonium Zoledronic Salt and Water Complex 300 mg of zoledronic acid is slurried in 7N ammonia in methanol overnight. The material is filtered and rinsed. The particulate material is dissolved in water and left to evaporate at ambient conditions to obtain colorless plates after 1 week. | |
With ammonia; In methanol; | 300 mg of zoledronic acid was slurried in 7N ammonia in methanol overnight. The material was filtered and rinsed. The particulate material was dissolved in water and left to evaporate at ambient conditions to obtain colorless plates after 1 week. The material was characterized by PXRD and FTIR corresponding to FIG. 3 and FIG. 4, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.8% | for 0.333333h;Reflux; | ZL (0.05 mmol, 13.6 mg) and CuSO4*5H2O (0.10 mmol, 25.0 mg) were mixed in 5 mL distilled water. The mixture was refluxed for 20 min. Then, the resulting blue solution was filtered and left unperturbed to slowly concentrate. After several days, pale blue blocky crystals suitable for X-ray diffraction were obtained. Yield: 16.4 mg (47.8%). Anal. Calcd for C10H38Cu3N4O26P4: C,12.71; H, 4.05; N, 5.93%. Found: C, 12.70; H, 4.09; N, 5.88%. IR (KBr pellet, cm-1): 3444(w), 3167(w), 1627(s), 1400(s), 1279(m), 1151(s), 1077(s), 1031(m), 990(m), 965(w), 842(w), 638(w), 603(w). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | General procedure: Then, the BP ligand (0.1 mmol) [ZL 27.2 mg, IPrBP28.6 mg, MIBP 28.6 mg, EIBP 30.0 mg] was dissolvedin H2O (2 mL) and the resulting solution was treated withBa(OH)2·8H2O (31.5 mg, 0.1 mmol), which was kept stirringat 0 C for 10 min. A solution of [Pt(en)(H2O)(OSO3)](73.8 mg, 0.2 mmol in 2 mL of H2O) was then added to theobtained white suspension. After stirring for 6 h at 0 C, thesuspension was treated with additional Ba(OH)2·8H2O untilthe pH of reaction system reached a value of 5.0. Then, theresulting mixture was left stirring at 4 C overnight. Afterwards,the white precipitation (BaSO4) was removed bycentrifuge (2000 r/min, 10 min) and filtered by microporousmembrane filter. The resulting filtrate was taken todry by lyophilization and white powders were isolated.Unfortunately, suitable crystals of the four complexes forsingle-crystal X-ray diffraction were not obtained in spiteof great efforts over many attempts. The structures of complexes1-4 have been characterized by elemental analysis,IR, ESI-MS and 1H/13C/31P NMR spectra (Figs. S1-S4 inthe electronic supplementary material). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | A mixture of NiSO46H2O (0.263 g, 1 mmol) and H5-zdnH2O (0.145 g, 0.5 mmol) in H2O (16 ml) was stirred for 10 min. A solution of bpe (0.182 g, 1 mmol) in EtOH (2 ml) was added dropwise to the mixture to yield a light green precipitate. The resulting suspension was adjusted to a pH of 6.08 with ethylenediamine and continuously stirred for 20 min at room temperature. The resulting turquoise suspension was transferred to a 23-mL Teflon-lined stainless steel autoclave and heated to 180 C for 72 h. After the reaction system had been cooled slowly to room temperature, green block crystals were filtered off and dried at room temperature. Yield: 0.177 g (45 % based on Ni). Anal. calc. for C34H42N8Ni3O18P4 (%): C, 35.5; H, 3.7; N, 9.7. Found: C, 35.4; H, 3.6; N, 9.8. IR (KBr, cm-1): 3450(m), 3174(w), 3133(w), 3031(m), 2954(w), 2744(w), 2672(w), 2607(w), 1645(m), 1614(s), 1555(w), 1519(m), 1423(m), 1298(w), 1244(m), 1137(vs), 1077(s), 1014(m), 981(m), 898(m), 832(m), 671(w), 665(w), 604(w), 497(m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | General procedure: A mixture of NiSO46H2O (0.263 g, 1 mmol) and H5-zdnH2O (0.145 g, 0.5 mmol) in H2O (16 ml) was stirred for 10 min. A solution of bpe (0.182 g, 1 mmol) in EtOH (2 ml) was added dropwise to the mixture to yield a light green precipitate. The resulting suspension was adjusted to a pH of 6.08 with ethylenediamine and continuously stirred for 20 min at room temperature. The resulting turquoise suspension was transferred to a 23-mL Teflon-lined stainless steel autoclave and heated to 180 C for 72 h. After the reaction system had been cooled slowly to room temperature, green block crystals were filtered off and dried at room temperature. Yield: 0.177 g (45 % based on Ni). Anal. calc. for C34H42N8Ni3O18P4 (%): C, 35.5; H, 3.7; N, 9.7. Found: C, 35.4; H, 3.6; N, 9.8. IR (KBr, cm-1): 3450(m), 3174(w), 3133(w), 3031(m), 2954(w), 2744(w), 2672(w), 2607(w), 1645(m), 1614(s), 1555(w), 1519(m), 1423(m), 1298(w), 1244(m), 1137(vs), 1077(s), 1014(m), 981(m), 898(m), 832(m), 671(w), 665(w), 604(w), 497(m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydroxide; In ethanol; at 140℃; for 72h;pH 2.52;Autoclave; High pressure; | General procedure: CuCl2·2H2O (0.171 g, 1 mmol), H5zdn·H2O (0.145 g, 0.5 mmol), and bipy (0.156 g, 1 mmol) were successively added to 18 mL EtOH/H2O (1 : 1, v/v). The mixture was adjusted to pH 2.52 with 1.0 mol·L-1 NaOH and stirred continuously for 30 min. The resulting dark blue suspension was sealed in a 23-mL Teflon-lined stainless steel autoclave and heated at 140 C for 3 days under autogenous pressure. After cooling slowly to room temperature, the solution was filtered. The filtrate was allowed to stand at room temperature and blue block crystals grew during one week. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium hydroxide; In ethanol; at 140℃; for 72h;pH 2.52;Autoclave; High pressure; | CuCl2·2H2O (0.171 g, 1 mmol), H5zdn·H2O (0.145 g, 0.5 mmol), and bipy (0.156 g, 1 mmol) were successively added to 18 mL EtOH/H2O (1 : 1, v/v). The mixture was adjusted to pH 2.52 with 1.0 mol·L-1 NaOH and stirred continuously for 30 min. The resulting dark blue suspension was sealed in a 23-mL Teflon-lined stainless steel autoclave and heated at 140 C for 3 days under autogenous pressure. After cooling slowly to room temperature, the solution was filtered. The filtrate was allowed to stand at room temperature and blue block crystals grew during one week. Yield 67% (based on CuCl2). anal. Calcd for C25H27ClCu2N6O9P2: C, 38.49; H, 3.49; N, 10.77. Found: C, 38.41; H, 3.42; N, 10.82. Main IR bands (KBr, cm-1): 3420(s), 3092(w), 3055(w), 2704(w), 1981(w), 1640(s), 1580(m), 1521(m), 1431(s), 1342(w), 1294(w), 1228(m), 1103(s), 1000(s), 852(s), 774(m), 720(m), 643(m), 547(m), 493(w). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50%; 38% | With sodium hydroxide; In ethanol; at 140℃; for 72h;pH 3.03;Autoclave; High pressure; | CuSO4·5H2O (0.250 g, 1 mmol), H5zdn·H2O (0.145 g, 0.5 mmol) and bipy (0.156 g, 1 mmol) were successively added to 18 mL EtOH/H2O (1 : 1, v/v). The mixture was adjusted to pH 3.03 with 1.0 mol·L-1 NaOH and stirred continuously for 30 min. The resulting blue suspension was sealed in a 23 mL Teflon-lined stainless steel autoclave and heated at 140 C for 3 days under autogenous pressure. After cooling slowly to room temperature, the solution was filtered, and the filtrate was allowed to stand at room temperature. Slow evaporation for two weeks yielded a mixture of light blue plate crystals of 1 and dark blue block crystals of 4. Due to differences in color and shape, it was possible to separate them manually. Yield 50% for 1 and 38% for 4 (based on CuSO4). anal. Calcd for C15H18CuN4O11P2S: C, 30.65;H, 3.09; N, 9.53. Found: C, 30.59; H, 3.01; N, 9.60. anal. Calcd for C40H40Cu3N10O18P4S: C, 37.09; H, 3.11; N,10.81. Found: C, 37.15; H, 3.03; N, 10.76. Main IR bands (KBr, cm-1): 3109(w), 3070(s), 2967(m), 2811(w),1638(w), 1574(m), 1478(m), 1448(s), 1388(w), 1313(m), 1245(m), 1146(s), 1029(m), 930(s), 880(m), 776(m), 730(m), 635(m), 587(m), 548(m), 491(w) for 1, and 3438(s), 3152(w), 3109(w), 3038(w), 2829(m), 1955(w), 1634(m), 1610(s), 1545(m), 1473(m), 1448(s), 1366(w), 1310(m), 1252(s), 1030(m), 995(m), 893(w), 774(s), 737(m), 625(m), 553(m), 470(w) for 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In 1,4-dioxane; at 90℃; | A. Approximately 20-30 mg of <strong>[118072-93-8]Zoledronic acid</strong> (ZA) DLlysine water molecular complex prepared as in previous applications; Example 12 inPCTU.S. Pat. No. 1,123,427 and in Example 13 in U.S. application Set No. 12/847,568 was dissolved in acetic acid (0.6 mE) at 90 C. in a 7-mE glass vial. The hot solution was polish-filtered through a syringe filter to a clean pre-heated vial. Anti-solvent was added until the solution turned turbid. The resulting hot solution was stored in a refrigerator (4 C.) for 15 hours to achieve a rapid cooling and induce particle formation. The particulate material was isolated by filtration and dried at ambient temperature under vacuum (30 in Hg) for 15 hours. This novel form canobtained using a variety of anti-solvents such as dioxane, N-methylpyrrolidone (NMP), dimethylformamide (DMF) and dimethylacetamide (DMA). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | To a solution of Na2MoO42H2O (0.242 g, 1 mmol) in 10 mL of 1M CH3COONH4/CH3COOH buffer was added Mn(OAc)3.2H20 (0.070 g, 0.26 mmol) and zoledronic acid (0.137 g, 0.5 mmol). The solution was stirred for 5 mm then NH3 (33% in water) was added dropwise to pH = 7.5. The solution was left to evaporate and was filtered after 24 h in order to remove a pink precipitate. EDX measurements and IR spectroscopyindicated that the precipitate was a manganese BP complex that did not contain molybdenum. Greyish crystals of the title compound appeared after three days. Yield: 0.080 g (21% based on Mo). Anal. Calc. (found) for C10H52MnMo4N9O36P4 (M.W. = 1437 g mol-1): C 8.36 (8.88), H 3.65 (3.90), N 8.77 (8.78). IR (FTR): v (cm-i) = i575(m), i546 (w), i42i(s), i288 (w), ii36(s), iii2(sh), 1045(s), 1018(sh), 973(m), 915(s), 888(s), 790(s), 699(m), 656(m), 6i9(w), 560(w),529(m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With ammonium hydroxide; In aq. acetate buffer; at 130℃; for 24h;pH 6;Autoclave; | A mixture of(NH4)6Mo7O24.4H20 (0.248 g, 0.20 mmol), FeC13.6H20 (0.095 g,0.35 mmol) and zoledronic acid (0.201 g, 0.77 mmol) in 5 mL of 1 MCH3COONH4/CH3COOH buffer was stirred and the pH adjusted to 6 by addition of NH3(33% solution). The mixture was sealed in a 23 mL Teflon-lined stainless steel reactor andheated to 130C over a period of 4 h, kept at 130C for 20 h, then cooled to roomtemperature over a period of 36 h. Yellow crystals were collected by filtration and were washed with water.Yield: 0.3 15 g (67% based on Mo). Anal. Calc. (found) for C10H42FeMo4N9O31P4 (M.W. = 1348 g mo11): C 8.92 (8.87), H 3.14 (3.09), N 9.35 (9.36),Mo 28.46 (28.36), Fe 4.14 (4.21), P 9.19 (9.20). IR (FTR) : v (cm1) = 1652(w), 1575(m),1545(m), 1429(vs), 1394(s), 1313(w), 1284(m), 1138(s), 1118(s), 1042(vs), 977(s),948(m), 9 14(m), 869(s), 783(s), 708(s), 676(s), 621(s), 576(s), 5 16(s), 48 1(s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | 96 mg of zoledronic acid was ground with 65 mg of adenine and 60 LL of water was added to the solid mixture. The solids gathered after grinding were stored in screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 13 and FIG. 14, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | 178 mg of zoledronic acid and 45 mg of glycine were slurried in 2 mL of water overnight. The solids gathered after filtration were dried and stored in a screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 15 and FIG. 16, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; | 200 mg of zoledronic acid and 54 mg of L-lysine were slurried in 2 mL of tetrahydrofuran and 200 mu of water overnight. The solids gathered after filtration were dried and stored in a screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 5 and FIG. 6, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; | 204 mg of zoledronic acid and 59 mg of DL-lysine were slurried in 2 mL of tetrahydrofuran and 200 mu of water overnight. The solids gathered after filtration were dried and stored in a screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 7 and FIG. 8 respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79%Spectr. | With sodium carbonate; In water; at 20℃; for 19h; | [0094] Route B: Compound 1d (50.0 mg, 0.18 mmol, 1.00 eq.), [1-hydroxy-2-(1H-imidazol- 1-yl)ethane-1,1-diyl]bis(phosphonic acid), was dissolved in 4 mL water and the pH adjusted to 7.4 - 7.8 with Na2CO3 (s). To this solution was added 72.8 muL of 6 (0.93 mmol, 5 eq). The reaction mixture was stirred at RT overnight, and the reaction was monitored by 31P NMR. After 19 h, 79% of 3d yielded with ~15% of side products and less than 10% of starting materials was left. The solution of reaction mixture was washed with diethyl ether (3×), and the solvent of aqueous phase was removed in vacuo, giving 3d, which was used without further purification. The entire sample of 3d was dissolved in 2 mL of NH3?H2O. After stirring at RT for 30 hrs, chlorine was displaced and desired compound 4d was obtained according to MS. The solvent was removed in vacuo, and the residue was washed with diethyl ether and methanol, filtered, and dried, which was then subjected to SAX HPLC purification. SAX column (Macherey-Nagel 21.4 mm x 250 mm SP15/25 Nucleogel column), flow rate: 9 mL/min, UV-VIS detection at 230 nm. Sample was eluted with A: H2O, B: 0.5 M TEAB pH 7.5 using a gradient that was increased from 0-30% over 10 min, maintained at 30% from 10-15 min, and then increased to 100% of buffer B from 15-35 min. The biggest peak eluting from 13.5- 15.0 min was collected (the retention time has ±1.5 min error between different runs), and solvents were evaporated, yielding compound 4d for next step reaction.1H NMR (D2O): delta 8.76 (s, 1H), 7.45 (s, 1H), 7.33 (s, 1H), 4.53 (dd, J = 7.4, 6.8 Hz, 2H), 4.33 (d, J = 13.3 Hz, 1H), 4.11 - 4.07 (m, 2H), 3.21- 3.17 (m, 1H), 2.89 (brd, 1H).31P NMR (D2O): delta 13.9 (s, 2P). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81%Spectr. | With sodium carbonate; In methanol; water; at 50℃; for 60h; | [0093] Route A: Compound 1d (40.0 mg, 0.15 mmol, 1.00 eq.), [1-hydroxy-2-(1H-imidazol- 1-yl)ethane-1,1-diyl]bis(phosphonic acid), was dissolved in 3 mL water and the pH adjusted to 7.4 with Na2CO3 (s). To this solution was added 51 mg of 5 (0.29 mmol, 2 eq) in minimal MeOH. The reaction mixture was stirred at 50 C overnight, and the reaction was monitored by 31P NMR. After 19 h, 76% of 2d yielded. Thus, an additional 10.9 mg (0.06 mmol, 0.42 eq) of 5 in MeOH was added to the reaction mixture. After 41 h, less than 10% of starting materials was left and 81% of desired compound 2d yielded with ~15% of side products. The solvent was removed in vacuo, and the resulting white powder was washed with diethyl ether, filtered, and dried, giving 2d, which was used without further purification. The entire sample of 2d was dissolved in 50:50 water:TFA (v/v). After stirring at RT for overnight, Boc group was fully deprotected, and desired compound 4d was obtained according to 1H NMR. The solvent was removed in vacuo, and the residue was washed with diethyl ether and methanol, filtered, and dried, which was then subjected to SAX HPLC purification. SAX column (Macherey-Nagel 21.4 mm x 250 mm SP15/25 Nucleogel column), flow rate: 9 mL/min, UV-VIS detection at 230 nm. Sample was eluted with A: H2O, B: 0.5 M TEAB pH 7.5 using a gradient that was increased from 0-30% over 10 min, maintained at 30% from 10-15 min, and then increased to 100% of buffer B from 15-35 min. The biggest peak eluting from 12- 14 min was collected (the retention time has ±1.5 min error between different runs), and solvents were evaporated, yielding compound 4d for next step reaction.1H NMR (D2O): delta 8.76 (s, 1H), 7.45 (s, 1H), 7.33 (s, 1H), 4.53 (dd, J = 7.4, 6.8 Hz, 2H), 4.33 (d, J = 13.3 Hz, 1H), 4.11 - 4.07 (m, 2H), 3.21- 3.17 (m, 1H), 2.89 (brd, 1H).31P NMR (D2O): delta 14.02 (s, 2P). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; | A powder mixture of 3.51g of zoledronic acid and 1.95 g of L-carnitine were slurried overnight in 50 mL of isopropanol. The filtered and dried solids were stored in a screw cap vial for subsequent analysis. The material was characterized by PXRD and is shown in FIG 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | 158 mg of zoledronic acid and 237 mg of o-palmitoyl-L-carnitine were slurried in 2 ml of water overnight. The solids gathered after filtration were dried and stored in a screw cap vials for subsequent analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | 160 mg of zoledronic acid and 205 mg of o-myristoyl-L-carnitine were slurried in 2 ml of water overnight. The solids gathered after filtration were dried and stored in a screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 8 and 9 respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | 180 mg of zoledronic acid and 213 mg of o-lauroyl-L-carnitine were slurried in 2 ml of methanol overnight. The solids gathered after filtration were dried and stored in a screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 10 and 11 respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | 200 mg of zoledronic acid and 218 mg of o-decanoyl-L-carnitine were slurried in 2 ml of methanol overnight. The solids gathered after filtration were dried and stored in a screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 12 and 13 respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | 200 mg of zoledronic acid and 198 mg of o-octanoyl-L-carnitine were slurried in 2 ml of methanol overnight. The solids gathered after filtration were dried and stored in a screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 14J and 15 respectively. |
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P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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