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CAS No. : | 321-23-3 | MDL No. : | MFCD01930221 |
Formula : | C6H3BrFNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VQCWSOYHHXXWSP-UHFFFAOYSA-N |
M.W : | 220.00 | Pubchem ID : | 2783362 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 42.92 |
TPSA : | 45.82 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.9 cm/s |
Log Po/w (iLOGP) : | 1.57 |
Log Po/w (XLOGP3) : | 2.45 |
Log Po/w (WLOGP) : | 2.92 |
Log Po/w (MLOGP) : | 2.06 |
Log Po/w (SILICOS-IT) : | 0.81 |
Consensus Log Po/w : | 1.96 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.09 |
Solubility : | 0.181 mg/ml ; 0.000822 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.06 |
Solubility : | 0.193 mg/ml ; 0.000879 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.92 |
Solubility : | 0.266 mg/ml ; 0.00121 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.85 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | 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 |
---|---|---|
97% | Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25 h; Inert atmosphere Stage #2: at 0 - 20℃; for 18 h; |
General procedure: Preparation 100: 4-bromo-2-ethoxy-1 -nitrobenzene To a cooled (0°C) solution of EtOH (0.07 mL, 1 .193 mmol) in THF (5 mL) was added NaH (60percent suspension in mineral oil, 68 mg, 1 .705 mmol). The reaction mixture was stirred under nitrogen at 0 for 15 minutes. 2-fluoro-4-bromo-nitrobenzene (250 mg, 1 .136 mmol) was added and the reaction mixture stirred for a further 18 hours, whilst warming slowly to room temperature. The reaction mixture was concentrated in vacuo. Ether (20 mL) and HCI (0.5 M, 20 mL) were added. The aqueous layer was basified with aqueous saturated NaHC03 solution and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried (MgS04) and concentrated in vacuo, to give the title compound (270 mg, 97percent). 1 H NMR (500 MHz, CDCI3): δ 7.74 (d, J = 8.5 Hz, 1 H), 7.24 (d, J = 2.0 Hz, 1 H), 7.17 (dd, J = 8.5, 2.0 Hz, 1 H), 4.1 9 (q, J = 7.0 Hz, 2H), 1 .50 (t, J = 7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | at 20℃; for 2 h; | 4-Bromo-2-fluoro-1-nitro-benzene (15.0 g, 68.2 mmol) was dissolved in ethanol (150 ml), and sodium ethoxide (14.0 g, 205 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, and then diluted with water. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (16.0 g, 95percent). [1293] 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J=8.4 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.15 (dd, J=8.8, 2.0 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 1.48 (t, J=7.2 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | for 2 h; | 62A: 4-bromo-2-ethoxy-l-nitrobenzene; [00479] To a solution of 4-bromo-2-fluoro-l-nitrobenzene (3 g, 13.6 mmol) and EtOH (50 mL) was added NaOEt (21percent w/w, 50 mL). The mixture stirred for 2 h before concentrating in vacuo. The residue purified by flash chromatography (0- 100percent EtoAc/Hexane) to afford 62A (3 g, 90percent) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (t, 3 H) 4.19 (q, 2 H) 7.22 (dd, 2 H) 7.71 - 7.81 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With ammonia In methanol at 20℃; for 18 h; | 5-Bromo-2-nitro aniline 2-Fluoro-4-bromo-1-nitrobenzene (0.5 g, 2.2 mmol) was added to methanolic ammonia (10 mL) and stirred at r.t. for 18 h. The reaction mixture was then concentrated in vacuo and the residue was triturated with isohexane, yielding the title compound (0.48 g, 97percent) as a yellow solid. δH (d6-DMSO) 7.88 (d, J 8.8 Hz, 1H), 7.53 (br s, 2H), 7.25 (d, J 3.0 Hz, 1H), 6.75 (dd, J 9.2, 2.0 Hz, 1H). |
91% | With ammonia In methanol at 0 - 20℃; for 12 h; Sealed tube | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (5 g, 22.7 mmol) in MeOH (5 mL), maintained at 0°C in a sealed tube, was added methanolic ammonia (15 mL). The reaction mixture was stirred at room temperature for 12 h, then concentrated. The crude residue was triturated with pentane and Et20 to afford the title compound (4.5 g, 91percent), which was used for the next step without any further purification. H (400 MHz, CD3OD) 7.93 (d,J9.1 Hz, 1H), 7.18 (d,J2.1 Hz, 1H), 6.74 (dd,J9.2, 2.1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | at 110℃; | 4-Bromo-2-fluoro-nitrobenzene (5.6 g, 20.9 mmol) and aniline (2.5 g, 72.2 mmol) are added to 50 ml. of anhydrous NMP. The reaction is heated to 1 10 °C overnight. After cooling to room temperature and removing the solvent, the compound is purified via column chromatography (silica, cyclohexane/ethyl acetate 9:1 ) and obtained as an orange solid in 92percent yield (5.7 g). H-NMR (400 MHz, CD2CI2): δ = 9.48 (s, 1 H), 8.06 (d, 1 H), 7.46 (t, 2H), 7.30 (t, 4H), 6.89 (d, 1 H). |
88% | at 50℃; for 30 h; Inert atmosphere | 4-bromo-2-fluoronitrobenzene (1.0 g, 4.3 mmol) and aniline (490 mg, 5.2 mmol) are suspended in 1 -methyl-2-pyrrolidon (2 ml_). The mixture is purged with argon, then heated to 50°C for 15 h. Additional aniline (350 mg, 3.7 mmol) is added to the reaction. The mixture is stirred at 50°C for 15 h. After cooling to room temperature the mixture is diluted with 2 ml. of methanol and 15 ml_ of water. The obtained precipitate is filtered and washed twice with methanol/water-solution (2:1 ). The solid is dried at 60°C under vacuum. The desired product is obtained in 88percent yield (1 .1 g). 1H-NMR (400 MHz, CD2CI2): δ = 6.89 (d, 1 H), 7.32-7.26 (m, 3H), 7.33 (s, 1 H), 7.46 (t, 2H), 8.05 (d, 1 H), 9.47 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 20℃; | To a solution of 4-bromo-2-fluoro-1-nitro-benzene (2.0 g, 9.09 mmol) in methanol (50 ml) was added sodium methanolate (30 percent in methanol) (1.64 g, 9.09 mmol). The reac.not. tion mixture was stirred at room temperature overnight. The reaction mixture was con- centrated and the residue was dissolved in water (30 ml) and extracted twice with ethyl acetate. The combined organic phases were washed with water. The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness to yield a crystalline solid (2.1 g, 99 percent). 1H-NMR (DMSOd6): δ [ppm] 7.9 (d, 1 H), 7.6 (s, 1 H), 7.3 (d, 1 H), 4.0 (s, 3H). |
98% | at 60℃; for 1 h; | MeONa (1.0 mL, 5.0 mmol)Was added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.01 g, 4.58 mmol)In MeOH (10mL) solution,The reaction was stirred at 60 ° C in an oil bath for 1 h.The solvent was removed under reduced pressure,The residue was dissolved in CH2Cl2 (30 mL)The insoluble material was removed by filtration,The filtrate was concentrated,To give the object as a yellow solid (1.05 g, 98percent). |
89.7% | at 20℃; | 18.4 g (83.64 mmol) of 2-fluoro-4-bromonitrobenzene (Aldrich) are almost fully dissolved in 300 mL of anhydrous methanol. 19.9 mL (106.22 mmol) of a 30percent solution of sodium methoxide in methanol are added dropwise and the mixture is stirred overnight at room temperature. The methanol is evaporated off under reduced pressure, the medium is taken up in ethyl acetate and water, and the aqueous phase is then acidified by adding aqueous 1N HCl. After separation of the phases by settling, the organic phase is washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum. 17.4 g of the expected product are obtained in the form of a yellow solid. Yield=89.7percent. |
73% | at 20℃; for 15 h; | 4-Bromo-2-methoxy-1-nitrobenzene (4e). To asolution of 4-Bromo-2-fluoro-1-nitrobenzene (400 mg, 2.0 mmol) in methanol (5 mL) wasadded sodium methoxide 5.0Min methanol (480 L, 2.4 mmol) and then stirred at roomtemperature for 15 h. The reaction mixture was diluted with ethyl acetate, washed with waterand brine, and dried over anhydrous MgSO4. The crude material was purified by silica gelchromatography (6percent ethyl acetate in hexanes) to give 4e (380 mg, 73percent). 1H NMR (600 MHz, Acetone-d6) δ 7.80 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.6, 1.9 Hz, 1H),4.04 (s, 3H); 13C NMR (150 MHz, Acetone-d6) δ 154.1, 139.9, 128.4, 127.3, 124.3, 118.3, 57.6;IR (Neat) (cm-1): 3108, 2990, 2957, 2855, 1611, 1567, 1523, 1441, 1396, 1344, 1304, 1258,1189, 1005, 872, 858. 1H NMR data correspond with those reported in the literature [12]. |
9.5 g | at 25℃; for 8 h; Inert atmosphere; Reflux | Step 2 4-Bromo-2-methoxy-1-nitrobenzene (compound 12-4) Compound 12-3 (10.0 g, 46 mmol, commercially available) was dissolved in 150 ml of anhydrous methanol at room temperature, sodium methoxide (4.37 g, 81 mmol) was added, and the reaction mixture was heated to reflux and vigorously stirred for 8 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product compound 12-4 (9.5 g) which was used directly in the next step. MS m/z (ESI): 231.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.8 g | Stage #1: With sodium In methanol at 0℃; for 1 h; Stage #2: at 20℃; |
At 0 ° C, sodium metal (1.0 g) was chopped and slowly added to 30 mL.In anhydrous methanol, after 1 h of reaction, 2-fluoro-4-bromo-1-nitrobenzene (10.0 g) was added.After reacting at room temperature overnight, the target product is obtained by post-treatment and separation and purification.(white solid, 9.8 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | at 60℃; for 1 h; | To 4-bromo-2-fluoro-1-nitrobenzene (8.0 g, 36.4 mmol) was added 0.5 N sodium methoxide (105 mL, 52.5 mmol). The mixture was stirred at 60° C. for 1 h. The MeOH was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (8.1 g, 34.9 mmol, 96percent) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (d, J=8.61 Hz, 1H), 7.23 (d, J=2.01 Hz, 1H), 7.16 (dd, J=8.61, 1.83 Hz, 1H), 3.95 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | at -40℃; for 1 h; | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.0 g, 4.54 mmol) in THF (20 mL) was added vinyl magnesium bromide (1M in THF, 13.62 mL, 13.62 mmol) slowly at -40° C. The reaction mixture was maintained at this temperature for 60 min. After completion of the reaction saturated aqueous NH4Cl solution was added and the mixture was extracted with EtOAc (2*20 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. Flash chromatography (silica, EtOAc:petroleum ether 9:1) gave 5-bromo-7-fluoro-1H-indole as a gummy solid (0.24 g, 25percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 3-chloro-benzenecarboperoxoic acid In 1,2-dichloro-ethane for 10h; Reflux; | General procedure for the oxidation of aromatic amines with m-CPBA: General procedure: m-CPBA(1.7 g, 8.0 mmol, 85%) was dissolved in 1,2-dichloroethane (15.0 mL) in a threeneckflask equipped with a condenser and heated to reflux (at rt in case of 1b).Then, the substrate aromatic amine (2.0 mmol) dissolved in 1,2-dichloroethane(5.0 mL) was added dropwise to the refluxing peracid solution. After 10 h, themixture was cooled to rt and quenched with saturated aqueous Na2S2O3. Thesolvent was removed under reduced pressure and the residue was treated with10% NaOH solution followed by extraction with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous Na2SO4. Removal of thesolvent under vacuum afforded the crude product, which was purified bycolumn chromatography using hexane/ethyl acetate as eluant. |
75% | With dihydrogen peroxide; trifluoroacetic acid In water at 75℃; Inert atmosphere; | 4-Bromo-2-fluoro-1-nitrobenzene (14). This compound was preparedfollowing a literature procedure.39 To a solution of 13 (1.26 g,6.6 mmol) in TFA (13 mL) was added aq·H2O2 (30%, 3.4 mL, 33 mmol)dropwise over 30 min, and the resulting mixture was stirred at 75 °C for1 h. After completion monitored by TLC, the mixture was poured intoice (20 mL), the pale yellow precipitate was obtained and filtered,washed by cold water and dried under reduced pressure to get thedesired compound 14 without further purification (1.09 g, 75%). Rf(hexane/ethyl acetate 10:1): 0.45; 1H NMR (400 MHz, CDCl3): δ 7.97(1H, t, J=8.0 Hz), 7.50 (1H, dd, J=2.0, 10.0 Hz), 7.47-7.44 (1H, m);13C NMR (100 MHz, CDCl3): δ 155.4 (d, JCF=268 Hz), 136.4, 129.4 (d,JCF=9.0 Hz), 128.1 (d, JCF=4.0 Hz), 127.1 (d, JCF=2.0 Hz), 122.1(d, JCF=24.0 Hz). The spectroscopic data matched that reported in theliterature.39 |
72% | With water; dihydrogen peroxide In trifluoroacetic acid for 1h; Heating; |
71% | With dihydrogen peroxide; trifluoroacetic acid In water at 20℃; for 1.5h; Reflux; | |
56% | With dihydrogen peroxide In water | |
51% | With sodium borate; acetic acid Heating; | 4-Bromo-2-fluoro-nitrobenzene (2) A suspension of sodium perborate tetrahydrate (20.24 g, 0.13 mol)in glacial acetic acid (80 mL) was stirred at 65 °C. 4-Bromo-2-fluoro-aniline (5 g, 26.31 mmol, 1 eq) in35 mL acetic acid was dropwise added over 5 h. The reaction was heated overnight, andsubsequently, another portion of NaBO3.4 H2O (12.2 g, 78.9 mmol) was added. After fullconsumption of the starting material, the reaction mixture was cooled to room temperature, the solidfiltered off, and the filtrate quenched with ice-cold water (600 mL). Then, the precipitate wasfiltrated and purified with column chromatography (hexane/chloroform, 2:1) to give the product asyellow solid 2 (2.96 g, 51%). TLC (hexane/CHCl3 (2:1)): Rf = 0.32. 1H NMR (400 MHz, CDCl3)δH = 8.01-7.93 (m, 1H), 7.50 (dd, J = 10.1, 1.9 Hz, 1H), 7.48-7.44 (m, 1H). 13C NMR (101 MHz, CDCl3)δC = 155.48 (d, J = 269.9 Hz), 136.60 (d, J = 7.2 Hz), 129.56 (d, J = 8.9 Hz), 128.24 (d, J = 4.3 Hz), 127.28 (d,J = 2.5 Hz), 122.21 (d, J = 23.6 Hz). LR-MS (EI): m/z = 219 (calcd. 219 for C6H379BrFNO2+ [M]+) |
40% | With sulfuric acid; dihydrogen peroxide; acetic acid | 16 8-(3-Chloro-phenyl-1,2,3,3a-tetrahydro-5H-pyrrolo[1,2-a]quinoxalin-4-one EXAMPLE 16 8-(3-Chloro-phenyl-1,2,3,3a-tetrahydro-5H-pyrrolo[1,2-a]quinoxalin-4-one To a mixture of acetic acid (500 ml), 30% hydrogen peroxide (250 ml), and concentrated sulfuric acid (10 ml) was added 4-bromo-2-fluoroaniline (50 g, 0.26 mol) at 85+-5° C. over 20 minutes. The reaction mixture was allowed to cool to room temperature and filtered. The solution was diluted with water and extracted with EtOAc (2*100 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The semisolid residue was filtered and the crude 4-bromo-2-fluoro-1-nitro-benzene was sublimed in vacuo to afford 4-bromo-2-fluoro-1-nitro-benzene (23 g, 40%): mp 82-83° C.; 1H-NMR (DMSO-d6) δ7.64-7.70 (m, 1H), 8.0 (dd, 1H, J=11.0, 1.98 Hz), 8.1 (t, 1H, J=8.57 Hz), MS (EI) m/z 219/221 (M+). |
40% | With sulfuric acid; dihydrogen peroxide; acetic acid | 16 8-(3-Chloro-phenyl-1,2,3,3a-tetrahydro-5H-pyrrolo[1,2-a]quinoxalin-4-one EXAMPLE 16 8-(3-Chloro-phenyl-1,2,3,3a-tetrahydro-5H-pyrrolo[1,2-a]quinoxalin-4-one To a mixture of acetic acid (500 ml), 30% hydrogen peroxide (250 ml), and concentrated sulfuric acid (10 ml) was added 4-bromo-2-fluoroaniline (50 g, 0.26 mol) at 85+-5° C. over 20 minutes. The reaction mixture was allowed to cool to room temperature and filtered. The solution was diluted with water and extracted with EtOAc (2*100 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The semisolid residue was filtered and the crude 4-bromo-2-fluoro-1-nitro-benzene was sublimed in vacuo to afford 4-bromo-2-fluoro-1-nitro-benzene (23 g, 40%): mp 82-83° C.; 1H-NMR (DMSO-d6) δ 7.64-7.70 (m, 1H), 8.0 (dd, 1H, J=11.0, 1.98 Hz), 8.1 (t, 1H, J=8.57 Hz); MS (EI) m/z 219/221 (M+). |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at -10 - 20℃; for 10h; | 33.a Example 33 S-Cyano-furan-l-carboxylic acid [2-(4-meihyl-piperidin-l-yl)-4-(l,2,3,6-tetrahydro- pyridin-4-yl)-phenyl]-amide dihydrochloride; EPO a) l-(5-Bromo-2-nitro-phenyl)-4-methyl-piperidine A solution of 4-bromo-2-fluoro-phenylamine (3.00 g, 15.8 mmol) in 15 niL of DCM is added dropwise to a suspension of 3-chloroperoxybenzoic acid (19 g, 57-86%) in 200 niL of DCM at -10 °C and the mixture is allowed to attain RT and stirred for 10 h. The reaction is then washed with saturated aqueous NaHCO3 (2 x 150 mL) and brine (100 mL), and the organic layer dried over Na2SO4 and evaporated. MeOH (10 mL) was then added to the crude residue to precipitate a white solid that was removed by filtration and the filtrate was concentrated to give 4-bromo-2-fluoro-l-nitro-benzene. This product was dissolved in 100 mL of DCM, cooled to 0 °C, and 4-methylpiperidine (5.00 g, 50.8 mmol) was added and the solution was stirred for 10 h at RT. The reaction was diluted with 100 mL of DCM, washed with brine (3 x 100 mL), and the organic layer dried over Na2SO4 and concentrated. The crude oil was purified by elution from a 20-g solid phase extraction (SPE) cartridge (silica) with 50% DCM/hexanes to give 3.4 g (72 %) of the title compound as a yellow oil: Mass spectrum (ESI, m/z): Calcd. for C12H15BrN2O2, 299.0 (M+H), found 299.1. | |
With m-chloroperoxybenzoic acid In methanol; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran | 13.a 5-Cyano-furan-2-carboxylic Acid [2-(4-methyl-piperidin-1-yl)-4-pyridin-4-yl-phenyl]-amide bis(trifluoroacetic acid salt) a) 1-(5-Bromo-2-nitro-phenyl)-4-methyl-piperidine A solution of 4-bromo-2-fluoro-phenylamine (3.00 g, 15.8 mmol) in 15 mL of DCM is added drop wise to a suspension of 3-chloroperoxybenzoic acid (19 g, 57-86%) in 200 mL of DCM at -10° C. and the mixture is allowed to attain RT and stirred for 10 h. The reaction is then washed with saturated aqueous NaHCO3 (2*150 mL) and brine (100 mL), and the organic layer dried over Na2SO4 and evaporated. MeOH (10 mL) was then added to the crude residue to precipitate a white solid that was removed by filtration and the filtrate was concentrated to give 4-bromo-2-fluoro-1-nitro-benzene. | |
With dihydrogen peroxide; trifluoroacetic anhydride In dichloromethane; water at 0 - 20℃; | 8 To a solution of hydroxy peroxide (30% in H2O, 46.5 ml_, 480 mmol) under N2 at 00C, trifluoroacetic anhydride (76.8 mL, 550 mmol) in 160 mL dichloromethane was added drop wisely over one and half hour. After addition, 4-bromo-2-fluorobenzenamine (10 g, 52.6 mmol) in 160 mL dichloromethane was added dropwise and the reaction mixture was gradually warmed up to room temperature and stirred over night. The mixture was extracted by dichloromethane and dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure to yield 4-bromo-2-fluoro-1 -nitrobenzene (10.59 g). 400MHz 1H NMR (CDCI3) δ 8.0 (t, 1 H), 7.4-7.6 (m, 2H); MS+ 219, 221. | |
With dihydrogen peroxide; trifluoroacetic anhydride In dichloromethane at 0 - 20℃; | 4 To a solution of hydroxy peroxide (46.5 ml, 480 mmol) under 00C, trifluoroacetic anhydride (76.8 ml, 550 mmol) in 160 ml dichloromethane was added drop wisely over one and half hour. After addition, 4-bromo-2-fluorobenzenamine (10 g, 52.6 mmol) in 160 ml dichloromethane was added dropwise and the reaction mixture was gradually warmed up to room temperature and stirred over night. The mixture was extracted by dichloromethane and dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure to yield 4-bromo-2-fluoro-1 -nitrobenzene (10.59 g). 400 MHz 1H NMR (CDCI3) δ 8.0 (t, 1 H), 7.4-7.6 (m, 2H); MS+ 219, 221. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | In tetrahydrofuran; at -40℃; for 1h; | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.0 g, 4.54 mmol) in THF (20 mL) was added vinyl magnesium bromide (1M in THF, 13.62 mL, 13.62 mmol) slowly at -40 C. The reaction mixture was maintained at this temperature for 60 min. After completion of the reaction saturated aqueous NH4Cl solution was added and the mixture was extracted with EtOAc (2*20 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. Flash chromatography (silica, EtOAc:petroleum ether 9:1) gave 5-bromo-7-fluoro-1H-indole as a gummy solid (0.24 g, 25%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In ethanol; water monomer; at 20℃; for 48h; | [0443j Step A: Preparation of 5 -bromo-N-methyl-2-nitro-aniline: A suspension of 4- bromo-2-fluoro-1-nitro-benzene (5.0 g, 22.7 mmol) in 95% ethanol (20 mL) was treated with 40% methylamine in water (5.9 mL, 68 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 2 days. Water (200 mL) was added. The resulting mixture was stirred at ambient temperature for 10 minutes. Ethyl acetate (100 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give 5-bromo-N-methyl-2-nitro-aniline (5.2 g, 99%) as solid. |
98% | In tetrahydrofuran; methanol; at 45℃; for 12h; | To the mixture of 4-bromo-2-fluoro-l -nitrobenzene (25.0 g, 113.0 mmol) in MeOH (100.0 mL) and THF (50.0 mL) was added MeNH2 (67.5 mL, 135.0 mmol, 2 M in THF) dropwise. The mixture was stirred at 10 C for 12 hours. Then more MeNH2 (60.0 mL, 2 M in THF) was added to the mixture and the mixture was stirred at 45 C for 12 hours. The mixture was concentrated in vacuo to give residue. Water (200.0 mL) added to the mixture and the mixture was extracted with EtOAc (200.0 mL x 2). The organic layers were washed with brine and dried over anhydrous Na2S04, filtered and the filtrate was concentrated in vacuo to give 5-bromo-A-methyl-2-nitroaniline (25.5 g, 98% yield) as a yellow solid. 1HNMR (400 MHz, CDCl3) 7.95 (d, J= 9.2 Hz, 2H), 6.93 (d, 7= 1.6 Hz, 1H), 6.71-6.68 (m, 1H), 7.48 (s, 1H), 2.94 (d, 7= 5.2 Hz, 3H). |
97% | In tetrahydrofuran; at 20℃; for 0.166667h; | [00328] Step 1. 4-Bromo-2-fluoro- 1 -nitrobenzene 16-A (5.5 g, 25 mmol) was added to a solution of methyl amine in THF (37.5 mL, 2 M). The mixture was stirred at room temperature for 10 min, quenched with a sat. NFLCl aqueous solution (10 mL). The aqueous mixture was extracted with EtOAc (30 mL x 3), and the combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2S04, concentrated to provide the intermediate 16-B as a yellow oil (5.6 g, 97%). LC-MS: m/z = 231.0 [M+H]+. |
95% | In ethanol; at 20℃; for 0.583333h; | 2M Methylamine in ethanol (4.9 ml; 9.73 mmol; 2.00 eqf.) is dropped in over 5 min at rt to the stirred solution of 4-bromo-2-fluoro-1 -nitrobenzene (1.07 g; 4.86 mmol; 1.00 eq.) in ethanol (10.00 ml). RM is stirred at rt for 30 min, then solvent is evaporated and residue is triturated with water to remove methylamine hydrofluoride. The remaining residue is collected by filtration, washed with water and dried at 60 C in an oven to give 5-bromo-N-methyl-2- nitroaniline (1.07 g; 4.62 mmol; yield 95.0%; 100% by UPLC) as orange thin needles. |
95% | In ethanol; | 4-Bromo-2-fluoro-l -nitrobenzene (23 g, 105 mmol) was dissolved in EtOH(20 mL), Με Η2 (250 mL, 33%,in EtOH) was added, the mixture was stirred at R.T overnight, The mixture was detected by LC-MS, the starting material was consumed, evaporated the solvent, the crude was dissolved in EtOAc (300 mL) and washed with water (200 mL x 2) and brine (200 mL),dried with Na2S04, filtered and the organic phase was evaporated the solvent, 23 g of the target compound was obtained as yellow solid (95 % yield). NMR (400 MHz, CDCb) δ 8.03 (d, J= 9.2 Hz, 2H), 7.01(s, 1H), 6.76 (d, J= 9.2 Hz, 1H), 3.02(s, 3H); LC-MS (ESI+): m/z 232.1 (M+H)+ . |
95% | In ethanol; at 20℃; | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (23 g, 105 mmol) in EtOH (50 mL) was added MeNH2 (250 ml, 33% in EtOH). After the addition, the mixture was stirred at rt overnight. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in EtOAc (300 mL), washed with water (200 mL×2) and brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (23 g, 95% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=9.2 Hz, 2H), 7.01 (s, 1H), 6.76 (d, J=9.2 Hz, 1H), 3.02 (s, 3H). LC/MS (ESI, m/z): [M+1]+=231.1 |
95% | With potassium carbonate; In tetrahydrofuran; dichloromethane; at 20℃; for 16h; | To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (1, 300 g, 1.36 mol) in DCM (3 L) were added K2CO3 (0.94 Kg, 6.8 mol) and methylamine (2M in THF) (2.04 L, 4.09 mol) at RT and stirred for 16 h. Two batches of the reaction were combined. After completion of reaction, the reaction mixture was diluted with water (3.0 L) and extracted with DCM (2.5 L x 2). The combined organic layer was washed with saturated sodium bicarbonate solution (1.5 L x 2) and brine (1.5 L x 2). The organic layer was dried over sodium sulphate, filtered and solvent removed under reduced pressure to obtain 5-bromo-N-methyl-2-nitroaniline (2, 600 g, 95% yield) as a yellow solid. LCMS (ES+): m/z 231.1 [M+H]+ |
95% | With potassium carbonate; In tetrahydrofuran; dichloromethane; at 20℃; for 16h; | To a stirred solution of 4-bromo-2-fluoro-l -nitrobenzene (300 g, 1.36 mol) in DCM (3 L) were added K2CO3 (0.94 Kg, 6.8 mol) and methylamine (2M in THF) (2.04 L, 4.09 mol) at room temperature and stirred for 16 h. Two batches of the reaction were combined. After completion of reaction, the reaction mixture was diluted with water (3.0 L) and extracted with DCM (2 x 2.5 L). The combined organic layer was washed with saturated sodium bicarbonate solution (2 x 1.5 L) and brine (2 x 1.5 L). The organic layer was dried over sodium sulphate, filtered and solvent removed under reduced pressure to obtain 5-bromo-N-methyl-2-nitroaniline (600 g, 95% yield) as a yellow solid. LCMS (ES+): 231.1 [M+H]+ |
95% | In tetrahydrofuran; dichloromethane; at 20℃; for 18h; | To a 1 L round bottomed flask were added 4-bromo-2-fluoro-l -nitrobenzene (16 g, 73 mmol) and DCM (400 mL). To this mixture was added methylamine (2.0 M solution in THF) (88 mL, 180 mmol). Upon addition of amine, the solution rapidly changed from a pale yellow to a bright orange solution. The reaction mixture was stirred at room temperature under a closed system. After 18 h, the reaction mixture was filtered through a plug of SiCh (250 g), with 2: 1 Hex:EtOAc as eluent. The filtrate was concentrated and dried in vacuo to afford the title compound (16 g, 69 mmol, 95 % yield) as a yellow solid. ’H NMR (500 MHz, METHANOL-d4) 6 8.05 (d, J=9.1 Hz, 1H), 7.18 (d, J=1.9 Hz, 1H), 6.85-6.78 (m, 1H), 3.02 (s, 3H). Analytical LC/MS (Method 3): Observed Mass: 232.9; Retention Time: 0.97 min. |
95% | In tetrahydrofuran; dichloromethane; at 20℃; for 18h; | To a 1 L round bottomed flask were added 4-bromo-2-fluoro-l -nitrobenzene (16 g, 73 mmol) and DCM (400 mL). To this mixture was added methylamine (2.0 M solution in THF) (88 mL, 180 mmol). Upon addition of amine, the solution rapidly changed from a pale yellow to a bright orange solution. The reaction mixture was stirred at room temperature under a closed system. After 18 h, the reaction mixture was filtered through a plug of SiCh (250 g), with 2: 1 Hex:EtOAc as eluent. The filtrate was concentrated and dried in vacuo to afford the title compound (16 g, 69 mmol, 95 % yield) as a yellow solid. ’H NMR (500 MHz, METHANOL-d4) 6 8.05 (d, J=9.1 Hz, 1H), 7.18 (d, J=1.9 Hz, 1H), 6.85-6.78 (m, 1H), 3.02 (s, 3H). Analytical LC/MS (Method 3): Observed Mass: 232.9; Retention Time: 0.97 min. |
94% | In ethanol; at 20℃; for 1h; | To a solution of 11 (25.0 g, 114 mmol) in EtOH (100 mL) was added methylamine (40% in MeOH, 34.8 mL, 341 mmol) at rt. The mixture was stirred at rt for 1 h and then cooled to 0 C. The precipitate was collected by filtration, and washed with EtOH and IPE successively to give the title compound (24.8 g, 94%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.95 (3H, d, J = 4.9 Hz), 6.83 (1H, dd, J = 9.1, 1.9 Hz), 7.17 (1H, d, J = 1.9 Hz), 7.98 (1H, d, J = 9.1 Hz), 8.23 (1H, br s). |
93% | In dichloromethane; at 13℃; for 10h; | The methylamine aqueous solution (30 ml, 250 mmol, 33 wt %) is added to the 4 - bromo -2 - fluoro -1 - nitrobenzene (10.22 g, 46 . 45 mmol) in DCM (50 ml) solution, room temperature (13 C) reaction under 10 h. The reaction solution concentrated under reduced pressure, to obtain the product as a yellow solid (10 g, 93%). |
93% | In ethanol; at 20℃; for 16h;Sealed tube; | Into a sealed tube were added 4-bromo-2-fluoro-1-nitrobenzene (46 g, 209 mmol) and methylamine (30% in ethanol, 500 mL) at room temperature. After stirring for an additional 16 h, the resulting solution was concentrated under reduced pressure. The residue was triturated with water (1 L) and filtered. The filter cake was collected and dried under vacuum to afford 5-bromo- N-methyl-2-nitroaniline (45 g, 93%) as an orange solid. 1H NMR (400 MHz, DMSO-d6) d 8.25 (br s, 1H), 8.02-7.94 (m, 1H), 7.17 (t, J = 2.9 Hz, 1H), 6.83 (dd, J = 9.1, 2.2 Hz, 1H), 2.95 (d, J = 4.7 Hz, 3H). LC/MS (ESI, m/z): [(M + 1)]+ = 231.15, 233.15 |
92% | In ethanol; at 23℃; for 0.5h;Inert atmosphere; | Methylamine (56.6 mL, 455 mmol, 33% wt in EtOH) was added to a mixture of 4-bromo-2-fluoro-1-nitro-benzene (50.0 g, 227 mmol) in EtOH (455 mL) at 23 C under nitrogen. The mixture was stirred at 23 C for 30 min, filtered and washed with cold EtOH (200 mL) to provide the title compound as a solid (48.2 g, 92%). m/z (ES+) [M+H]+= 231.0, LCMS (A05); tR = 2.51 min; .1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 4.3 Hz, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 9.1, 2.1 Hz, 1H), 2.95 (d, J = 5.0 Hz, 3H) |
90.6% | With potassium carbonate; potassium iodide; In dichloromethane; at 80℃; for 18h; | 4-bromo-2-fluoro-1-nitrobenzene (5.000 g, 22.727 mmol), methanamine (0.777 g, 25.000 mmol), potassium carbonate (6.282 g, 45.455 mmol) and potassium iodide (0.377 g, 2.273 mmol) were dissolved in dichloromethane (100 mL) at room temperature, after which the resulting solution was stirred at 80 for 18 hours, and then a reaction was finished bylowering a temperature to room temperature. Hexane was put into the reaction mixture and stirred, after which a precipitated solid was filtered and dried to obtain a title compound (4.760 g, 90.6%) in a yellow solid form. |
83% | In tetrahydrofuran; at 15℃; for 0.166667h; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS321-23-3) was added to a solution of methylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C. for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 6.82 (dd, J=8.4, 1.6 Hz, 1H), 2.95 (d, J=4.8 Hz, 3H). |
83% | at 15℃; for 0.166667h;Inert atmosphere; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid.1H NMR (400MHz, DMSO-d6) d 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H). |
83% | at 15℃; for 0.166667h;Inert atmosphere; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) d 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H). |
83% | In tetrahydrofuran; at 15℃; for 0.166667h; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid.1H NMR (400MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H). |
83% | In tetrahydrofuran; at 15℃; for 0.166667h; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CASNo.321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (d, J= 9.2 Hz, 1H), 7.16 (d, J= 1.6 Hz, 1H), 6.82 (dd, J= 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H). |
83% | In tetrahydrofuran; at 15℃; for 0.166667h; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CASNo.321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (d, J= 9.2 Hz, 1H), 7.16 (d, J= 1.6 Hz, 1H), 6.82 (dd, J= 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H). |
77% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 20h; | j00417j To a solution of 4-bromo-2-fluoro-1-nitrobenzene (5.0 g, 22.7 mmol) in N,Ndimethylformamide (80 mL) was added methylamine (2 M in tetrahydrofuran, 22.7 mL) and potassium carbonate (3.93 g, 28.4 mmol). The mixture was stirred at room temperature for 20 hours, then poured into water (50 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give compound B-73 (4.0 g, 77% yield) as a yellow solid. LCMS (B): tR=0.777 mi, (ES) mlz (M+H) =231.0. ‘H-NMR (CD3C1, 400 MHz): 8.03 (d, J=9.2 Hz, 2H), 7.02 (d, J=1.6 Hz, 1H), 6.78 (dd, J11.2 Hz, J21.2 Hz, 1H), 3.02 (s, 3H). |
74.3% | With potassium carbonate; In tetrahydrofuran; at 90℃; for 6h; | Step A5-bromo-N-methyl-2-nitroaniline[00302] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), a 2 M methylamine solution in THF (5.00 mL, 10.00 mmol) and K2C03 (2.51 g, 18.18 mmol) in DMF (20 mL) was heated at 90 C for 3 h. More methylamine solution in THF (10.00 mL, 20.00 mmol) was added and the reaction mixture was heated at 90 C for 3 h. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with a 5% aq. LiCI solution (3x100 mL). The organic layer was concentrated onto Celite and purified by column chromatography (silica gel, 0-40% EtOAc/hexane) to obtain 5-bromo-N-methyl-2- nitroaniline (1.56 g, 6.75 mmol, 74.3 % yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.94 (d, 3 H) 6.82 (dd, J=9.07, 2.05 Hz, 1 H) 7.16 (d, =1.95 Hz, 1 H) 7.98 (d, J=9.07 Hz, 1 H) 8.24 (d, .7=4.19 Hz, 1 H). |
In ethanol; at 0 - 20℃; for 0.416667h; | To a solution of 4-bromo-2-fluoro-1 -nitrobenzene (10 g, 45.45 mmol) in 20 ml of ethanol under 00C, 30 ml methylamine (33 wt% in ethanol) was added dropwise. After addition, reaction mixture was gradually warmed up to room temperature and stirred for 25 minutes. The mixture was concentrated under reduced pressure to yield N-methyl-(5-bromo- 2-nitrophenyl)amine (9.13 g). 400 MHz 1H NMR (CDCI3) δ 8.0 (d, 1H), 7.0 (d, 1H), 6.7 (dd, 1 H); MS+ 230, 232. | |
In ethanol; acetonitrile; at 20℃; for 4h; | To a stirred partial solution of 4-bromo-2-fluoronitrobenzene (9.2 g; Aldrich) in acetonitrile (140 ml) was added a solution of 8M methylamine in ethanol (86 ml). The reaction was stirred at room temperature for 4 hr and then evaporated to dryness. The residue was partitioned between EtOAc (500 ml) and water (500 ml). The aqueous phase was separated off and extracted with EtOAc (500 ml). The organic phases were combined, washed with water (500 ml) and brine, dried (magnesium sulphate) and evaporated to give the title compound (9.47 g) as an orange-brown solid. | |
In 1,4-dioxane; methanol; at 90℃; for 3.5h;Inert atmosphere; | To a round bottom flask was added added 4-bromo-2-fluoro- 1 -nitrobenzene (11.8 g, 53.7 mmol), anhydrous 1,4 Dioxane (100 mL), and a 2.0 M solution of methyl amine in methanol (56.4 mL, 113 mmol). The reaction mixture was then heated to 90C while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 3.5 hours. The crude reaction mixture was then allowed to cool to room temperature, and concentrated to give 5-bromo-N-methyl-2-nitroaniline (1-1). MS (M)+: observed = 230.9, calculated = 231.05. | |
In methanol; ethanol; at 23℃; for 13h; | S-bromo-N-methyl-2-nitroaniiine (1-2)A solution of 4-Bromo-2-ftuoronitrobenzene (1-1, 10.5 g, 47.7 mmol) in EtOH(100 ml) was treated with Methylamine (2M in MeOH, 28.6 ml, 573 mmol, 1.2 eq) and the resulting dark maroon solution was stirred at 23 deg C for 13 h. The reaction was then concentrated in vacuo, and the residual yellow-orange solid was partitioned between EtOAc (2x250 ml) and water (300 ml). The combined organic layers were dried over Na2S04 and concentrated, leaving the title compound, 5-bromo-N-methyl-2-nitroaniline (1-2), as a bright orange solid. 1HNM (300 MHz, CDC13) δ 8.03 (d, IH, J=9.15 Hz), 7.01 (sd, IH, J=l,83 Hz), 6.77 (dd, IH, J=7.02 Hz), 3.02 (d, 3H, J=4.88 Hz). LRMS m/z: Calc'd for C7H7BrN202 (M+H) 232.1, found 232.8. | |
With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; | Intermediate IX(5-Bromo-2-nitro-phenyl)-methyl-amine Methylamine (2 M in tetrahydrofuran, 11.4 mL) was added to a mixture of 4-bromo-2-fluoro-1-nitro-benzene (2.50 g) and K2CO3 (1.90 g) in N,N-dimethylformamide (40 mL). The resulting mixture was stirred at ambient temperature overnight. Then, the mixture was concentrated under reduced pressure and dichloromethane was added. The resulting mixture was washed with 0.5 M aqueous HCl solution and brine and dried (MgSO4). The solvent was removed to give the product as a solid.Yield: 2.60 g (99% of theory); Mass spectrum (ESI+): m/z=231/233 (Br) [M+H]+. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 85℃;Sealed vial; | [000202] 4-Bromo-2-fluoronitrobenzene (Aldrich, 1 eqvt), methylamine (2 eqvt), and hunig's base (3 eqvt) in DMF (1 Molar in substrate) were placed in a sealed vial and heated to 85 C overnight. The crude mixture was diluted with water, and the product collected by filtration. Purification by chromatography (gradient: 92:8 hexanes:ethyl acetate to 68:32 hexanes:ethyl acetate) provided the title compound. 1HNMR (DMSO-d6, 400 MHz) δ 8.22 (bd, J = 4.4 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2 Hz, 1H), 6.80 (dd, J = 9.2, 2.4 Hz, 1H), 2.92 (d, J = 4.8 Hz). | |
24.8 g | In methanol; ethanol; at 20℃; for 1h; | Example 2 1- (2-Cyclopropyl-l-methyl-lH-benzimidazol-6-yl) -4- ( (4- fluorobenzyl ) oxy) pyridin-2 ( 1H) -one A) 5-Bromo-N-methyl-2-nitroaniline To a solution of 4-bromo-2-fluoro-l-nitrobenzene (25 g) in EtOH (100 ml) was added methylamine (40% in MeOH, 34.8 ml) at room temperature. The mixture was stirred at room temperature for 1 h. After being stirred, the reaction mixture was cooled to 0C, and the precipitate was collected by filtration and washed with EtOH (0C) and IPE. The solid was dried to give the title compound (24.8 g) as a yellow solid. XH NMR (300 MHz, DMSO-d6) : δ 2.95 (3H, d, . J = 4.9 Hz), 6.83 (1H, dd, J = 1.9, 9.1 Hz), 7.17 (1H, d, J = 1.9 Hz), 7.98 (1H, d, J = 9.1 Hz) , 8.23 (1H, brs) . |
24.8 g | In methanol; ethanol; at 20℃; for 1h; | A) 5-Bromo-N-methyl-2-nitroaniline [0294] To a solution of 4-bromo-2-fluoro-1-nitrobenzene (25 g) in ethanol (100 mL) was added methylamine (40% in methanol, 34.8 mL) at room temperature, and the mixture was stirred for 1 hr. The obtained mixture was cooled to 0C, and the resulting precipitate was collected by filtration and washed with ice-cooled ethanol and diisopropyl ether. The obtained solid was dried to give the title compound (24.8 g) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 2.95 (3H, d, J = 4.9 Hz), 6.83 (1H, dd, J = 9.1, 1.9 Hz), 7.17 (1H, d, J = 1.9 Hz), 7.98 (1H, d, J = 9.1 Hz), 8.23 (1H, brs). |
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 2h; | [0007991 To a stirred solution of the compound 1 (2 g, 1 eq)) in DMF (20 mL), methyl amine 2 M solution in THF (9.19 mL, 2 eq) and DIPEA (3.53 g, 3 eq) were added and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3 X 25 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product 2 (2 g) and used as such for the next step without further purification. | |
In methanol; at 80℃; for 15h; | A mixture of 4-bromo-2-fluoro-1-nitrobenzene (4.0 g, 18.26 mmol) in 30 mLMeNH2/MeOH was stirred at 80 C for 15 h, and poured into H20 (100 mL). The mixture wasextracted with EA (30 mL x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to afford 5-bromo-N-methyl-2-nitroaniline (3.8 g, 90 %) as a yellow solid. LC-MS m/z: 232.9 [M+H]+. Purity (214 nm): 88.0%; tR = 1.89 min | |
In ethanol; at 0 - 20℃; for 0.416667h; | To a solution of bromo-2-fluoro-1- nitrobenzene (10 g, 45.45 mmol) in 20 ml of ethanol under O0C, 30 ml methylamine (33 wt% <n="67"/>in ethanol) was added dropwise. After addition, reaction mixture was gradually warmed up to room temperature and stirred for 25 minutes. The mixture was concentrated under reduced pressure to yield N-methyl-(5-bromo-2-nitrophenyl)amine (9.13 g). 400 MHz 1H NMR (CDCI3) δ 8.0 (d, 1 H), 7.0 (d, 1 H), 6.7 (dd, 1 H); MS+ 230, 232. | |
In ethanol; | 4-Bromo-2-fluoro-1-nitrobenzene (23 g, 105 mmol) was dissolved in EtOH (20 mL), Me Eh (250 mL, 33% in EtOH) was added, the mixture was stirred at R.T overnight. When LC- MS showed the starting material was consumed, the solvent was evaporated and the resulting crude was dissolved in EtOAc (300 mL) and washed with water (200 mL x 2) and brine (200 mL), dried over anhydrous Na2S04. The solid was filtered and the filtrate was concentrated to give the crude product 5-bromo-N-methyl-2-nitroaniline as yellow solid (23 g, 95 % yield). 1H NMR (400 MHz, CDCb) δ 8.03 (d, J= 9.2 Hz, 2H), 7.01 (s, 1H), 6.76 (d, J= 9.2 Hz, 1H), 3.02 (s, 3H). LC-MS (ESI+): m/z 232.1 (M+H)+. | |
In methanol; ethanol; at 20℃; for 1h; | To a solution of 4-bromo-2-fluoro-1 -nitrobenzene (0.50 g, 2.28 mmol), in EtOH (10 ml_), methylamine (40% wt/v in methanol, 1 .0 ml.) was added and stirred at room temperature for 1 hour. The precipitated material was filtered under vacuum, washed with hexanes and dried to obtain 5-bromo-N-methyl-2-nitroaniline. 1 H NMR (400 MHz, DMSO-d6) d: 8.24 (brs,1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.16 (d, J = 2 Hz 1 H), 6.82 (dd, J = 2 Hz and 9.2 Hz, 1 H), 2.94 (d, J = 4.8 Hz, 3H). | |
With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 25℃; for 18h;Inert atmosphere; | Step A: 5-Bromo-N-methyl-2-nitroaniline Under a protection of nitrogen, to a solution of 4-bromo-2-fluoro-1-nitroaniline (15.0g, 68.18mmol) and potassium carbonate (11.31g, 81.82mmol) in DMF (250mL) was added dropwise methylamine in tetrahydrofuran (2M, 68.18mL) at 25C, and it was stirred at 25C for 18 hours. The reaction solution was poured into 500mL water, and it was stirred for 10 minutes. The precipitated solid was filtered and dried to give the title compound. 1H NMR (400MHz, CHLOROFORM-d) δ=8.03 (d, J=9.4 Hz, 2H), 7.01 (s, 1H), 6.77 (dd, J=1.8, 9.2 Hz, 1H), 3.02 (d, J=5.1 Hz, 3H). | |
In tetrahydrofuran; at 20℃; | To a solution of 4-bromo-2-fluoro-1-nitro-benzene (1 g, 4.55 mmol) in THF (15 mL) was added methanamine (6.82 mL, 13.64 mmol) (2 M solution in THF), and the mixture was stirred at 20 C. for 2 hours. (0305) The mixture was concentrated to give the crude product (1200 mg, 4.97 mmol) as a solid. LCMS Rt=0.815 min in 1.5 min chromatography, MS ESI calcd. for C7H8BrN2O2 [M+H]+ 231.0, found 230.7. | |
In tetrahydrofuran; at 20℃; | To a solution of 4-bromo-2-fluoro-1-nitro-benzene (1 g, 4.55 mmol) in THF (15 mL) was added methanamine (6.82 mL, 13.64 mmol) (2 M solution in THF), and the mixture was stirred at 20 C. for 2 hours. (0305) The mixture was concentrated to give the crude product (1200 mg, 4.97 mmol) as a solid. LCMS Rt=0.815 min in 1.5 min chromatography, MS ESI calcd. for C7H8BrN2O2 [M+H]+ 231.0, found 230.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In methanol; at 20℃; | To a solution of 4-bromo-2-fluoro-1-nitro-benzene (2.0 g, 9.09 mmol) in methanol (50 ml) was added sodium methanolate (30 % in methanol) (1.64 g, 9.09 mmol). The reac¬ tion mixture was stirred at room temperature overnight. The reaction mixture was con- centrated and the residue was dissolved in water (30 ml) and extracted twice with ethyl acetate. The combined organic phases were washed with water. The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness to yield a crystalline solid (2.1 g, 99 %). 1H-NMR (DMSOd6): delta [ppm] 7.9 (d, 1 H), 7.6 (s, 1 H), 7.3 (d, 1 H), 4.0 (s, 3H). |
98% | In methanol; dichloromethane; at 60℃; for 1h; | MeONa (1.0 mL, 5.0 mmol)Was added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.01 g, 4.58 mmol)In MeOH (10mL) solution,The reaction was stirred at 60 C in an oil bath for 1 h.The solvent was removed under reduced pressure,The residue was dissolved in CH2Cl2 (30 mL)The insoluble material was removed by filtration,The filtrate was concentrated,To give the object as a yellow solid (1.05 g, 98%). |
89.7% | With methanol; at 20℃; | 18.4 g (83.64 mmol) of 2-fluoro-4-bromonitrobenzene (Aldrich) are almost fully dissolved in 300 mL of anhydrous methanol. 19.9 mL (106.22 mmol) of a 30% solution of sodium methoxide in methanol are added dropwise and the mixture is stirred overnight at room temperature. The methanol is evaporated off under reduced pressure, the medium is taken up in ethyl acetate and water, and the aqueous phase is then acidified by adding aqueous 1N HCl. After separation of the phases by settling, the organic phase is washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum. 17.4 g of the expected product are obtained in the form of a yellow solid. Yield=89.7%. |
73% | In methanol; at 20℃; for 15h; | 4-Bromo-2-methoxy-1-nitrobenzene (4e). To asolution of 4-Bromo-2-fluoro-1-nitrobenzene (400 mg, 2.0 mmol) in methanol (5 mL) wasadded sodium methoxide 5.0Min methanol (480 L, 2.4 mmol) and then stirred at roomtemperature for 15 h. The reaction mixture was diluted with ethyl acetate, washed with waterand brine, and dried over anhydrous MgSO4. The crude material was purified by silica gelchromatography (6% ethyl acetate in hexanes) to give 4e (380 mg, 73%). 1H NMR (600 MHz, Acetone-d6) delta 7.80 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.6, 1.9 Hz, 1H),4.04 (s, 3H); 13C NMR (150 MHz, Acetone-d6) delta 154.1, 139.9, 128.4, 127.3, 124.3, 118.3, 57.6;IR (Neat) (cm-1): 3108, 2990, 2957, 2855, 1611, 1567, 1523, 1441, 1396, 1344, 1304, 1258,1189, 1005, 872, 858. 1H NMR data correspond with those reported in the literature [12]. |
9.5 g | In methanol; at 25℃; for 8h;Inert atmosphere; Reflux; | Step 2 4-Bromo-2-methoxy-1-nitrobenzene (compound 12-4) Compound 12-3 (10.0 g, 46 mmol, commercially available) was dissolved in 150 ml of anhydrous methanol at room temperature, sodium methoxide (4.37 g, 81 mmol) was added, and the reaction mixture was heated to reflux and vigorously stirred for 8 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product compound 12-4 (9.5 g) which was used directly in the next step. MS m/z (ESI): 231.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | for 2h; | 62A: 4-bromo-2-ethoxy-l-nitrobenzene; [00479] To a solution of 4-bromo-2-fluoro-l-nitrobenzene (3 g, 13.6 mmol) and EtOH (50 mL) was added NaOEt (21% w/w, 50 mL). The mixture stirred for 2 h before concentrating in vacuo. The residue purified by flash chromatography (0- 100% EtoAc/Hexane) to afford 62A (3 g, 90%) as an oil. 1H NMR (400 MHz, CDCl3) delta ppm 1.49 (t, 3 H) 4.19 (q, 2 H) 7.22 (dd, 2 H) 7.71 - 7.81 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 90℃; for 12h; Inert atmosphere; | 142 Preparation of N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide To a solution of 4-bromo-2-fluoro-1-nitrobenzene (2.2 g, 10 mmol, 1 eq.) and 3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (3.81g, 15 mmol, 1.5 eq.) in dioxane (80 mL) was added KOAc (1.96 g, 20 mmol, 2 eq.), followed by Pd(dppf)Cl2(408 mg, 0.5 mmol, 0.05 eq.) under N2protection. The mixture was stirred at 90 °C for 12 h, then cooled to r.t. and concentrated. The resulting residue was purified via column chromatography(PE/EA=20/1~ 5/1, v/v) to afford 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane as a white solid (2.1 g, 78.6% yield). |
70% | With potassium acetate In dichloromethane at 100℃; for 18h; | B.1 General Procedure B: Formation of a boronate from an aryl or heteroaryl halide; A mixture of an aryl or heteroaryl halide (preferably 1 equiv), a suitable base (such as KOAc or TEA) (1-10 equiv, preferably 1.5-6 equiv), bis(pinacolato)diboron or pinacolborane (1-5 equiv, preferably 1-1.5 equiv), and a suitable solvent (such as 1,4-dioxane or DMF) is degassed under N2/vacuum purge. Then a catalyst (for example, [l,r-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with DCM (1 : 1)) (0.02-0.20 equiv, preferably 0.04-0.10 equiv) is added. The reaction is heated at about 80-120 0C (preferably 100 0C) for about 1-24 h (preferably 2-18 h) then is cooled to ambient temperature. The mixture is optionally concentrated under reduced pressure, diluted with or partitioned between water and an organic solvent (for example, EtOAc or DCM), and filtered to remove insoluble material, washing with additional solvent. The layers are separated and the aqueous layer is optionally extracted with additional organic solvent. The combined organic layers may be optionally washed with brine, dried over Na2SO4 or MgSO4, then decanted or filtered prior to concentrating under reduced pressure. The crude product is purified by crystallization or trituration from an appropriate solvent or solvents, or by chromatography to give the target compound.Illustration of General Procedure BPreparation No.B.l : 2-(3-Fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-[l,3>2]dioxaborolaneA mixture of 4-bromo-2-flouronitrobenzene (20.0 g, 90.9 mmol; 3B Medical Systems), KOAc (26.8 g, 0.273 mol; J.T.Baker), bis(pinacolato)diboron (23.1 g, 90.9 mmol), and 1,4-dioxane (200 mL) was degassed under N2/vacuum purge. Then [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II) complex with DCM (1:1) (3.0 g, 3.6 mmol) was added and the reaction was heated at about 100 0C for about 18 h. The reaction was then cooled to ambient temperature and concentrated under reduced pressure. The mixture was partitioned between water (100 mL) and DCM (100 mL) then filtered to remove any solid, washing with additional DCM (200 mL). The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography using heptane/DCM (stepwise gradient, 9:1 to 4:1 to 2:1) to give the title compound (19.4 g, 70%): 1H NMR (DMSO-d6, 400 MHz) δ 8.15 (m, IH), 7.67 (m, 2H), 1.33 (s, 12H). |
4224 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,2-dimethoxyethane at 100℃; for 14h; Inert atmosphere; | 283.A (A) 2-(3-Fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (A) 2-(3-Fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A mixture of 4-bromo-2-fluoro-1-nitrobenzene (5011 mg), bis(pinacolato)diboron (8676 mg), potassium acetate (6706 mg), PdCl2(dppf) CH2Cl2 adduct (930 mg) and DME (50 mL) was stirred under nitrogen atmosphere at 100° C. for 14 hours. The reaction mixture was diluted with ethyl acetate (50 mL), and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (4224 mg). 1H NMR (300 MHz, CDCl3) δ 1.36 (12H, s), 7.64-7.73 (2H, m), 7.97-8.04 (1H, m). |
4224 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,2-dimethoxyethane at 20 - 100℃; for 14h; Inert atmosphere; | 283.A 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In a nitrogen atmosphere at 100 ° C,4-Bromo-2-fluoro-1-nitrobenzene(5011 mg),Pinacol boronic ester (8676mg) double frequency,Potassium acetate (6706 mg),PdCl2 (dppf) CH2Cl2 adduct (930 mg) and DME (50 mL) was stirred at room temperature for 14 hours.The reaction mixture was diluted with ethyl acetate (50 mL) and the insoluble material was removed by filtration.After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4224 mg). |
1.6 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 12h; Inert atmosphere; | 44.44-1 Step 44-1: Preparation of 2-(3-fluoro-4-nitrophenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane 4-bromo-2-fluoro-1-nitrobenzene (2 g, 7.88 mmol) under nitrogenAnd bis (pinacolato) diboron(4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane), 2.1 g, 9.45 mmol)Was dissolved in 60 mL of 1,4-dioxane solution,Pd(dppf)2Cl2 (1.3 g, 1.58 mmol)And potassium acetate (3.1 g, 31.5 mmol)Was added.The reaction mixture was stirred at 80° C. for 12 hours.When the reaction was completed, extraction was performed using distilled water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 1.6 g of the title compound. |
1.6 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 12h; Inert atmosphere; | 44.44-1 Step 44-1: Preparation of 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4-Bromo-2-fluoro-1-nitrobenzene (2 g, 7.88 mmol) and bis(pinacolato)diboron (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane); 2.1 g, 9.45 mmol) were dissolved in 60 mL of a 1,4-dioxane solution in the presence of nitrogen, and then Pd(dppf)2Cl2 (1.3 g, 1.58 mmol) and potassium acetate (3.1 g, 31.5 mmol) were added to obtain a reaction mixture. The reaction mixture was stirred at 80°C for 12 hours. When the reaction was completed, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 1.6 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | at 60℃; for 1h; | To 4-bromo-2-fluoro-1-nitrobenzene (8.0 g, 36.4 mmol) was added 0.5 N sodium methoxide (105 mL, 52.5 mmol). The mixture was stirred at 60 C. for 1 h. The MeOH was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (8.1 g, 34.9 mmol, 96%) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta ppm 7.74 (d, J=8.61 Hz, 1H), 7.23 (d, J=2.01 Hz, 1H), 7.16 (dd, J=8.61, 1.83 Hz, 1H), 3.95 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 1h; | EXAMPLE 13 4-bromo-2-fluoro-1 -nitrobenzene A. Synthesis of Compound of Formula (8).[0452] To a suspension of 4-bromo-2-fluoro-l -nitrobenzene (2.0 g) in ACN (15 mL) was added 0.56 g of <strong>[1001-53-2]N-acetylethylenediamine</strong> followed by 0.96 mL of NN-diisopropylethylamine. The mixture was stirred at 60 0C for 1 h. After cooling down to room temperature N-(2-(5- <n="56"/>bromo-2-nitrophenylamino)ethyl)acetamide was filtered out as yellow precipitate. Product was used in the next step without further purification.1H NMR (DMSO-d6, 400 MHz) delta 8.32 (broad t, IH); 8.12 (broad t, IH); 7.99 (d, IH); 7.38 (d, IH); 6.84 (dd, IH); 3.43 (quartet, 2H); 3.27 (quartet, 2H); and 1.82 (s, 3H).MS (ESI) m/z 301.9, 628.9, 626.9 (base peak). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide at 80℃; for 22h; Inert atmosphere; | 13 5-Bromo-N-ethyl-2-nitroaniline (53a) To a solution of 4-bromo-2-fluoro-1-nitrobenzene (52) (500 mg, 2.27 mmol) and potassium carbonate (628 mg, 4.55 mmol) in anhydrous DMF (5 mL) was added 2 M being quenched with water (10 mL), the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 5: 95 to 10:90) to afford 53a (520.0 mg, 93%) as a yellow solid; 1H NMR (0550) (CDCl3, 500 MHz) 8.03 (1 H, d, J = 9.2 Hz), 7.97 (1 H, br), 7.01 (1 H, d, J = 1.5 Hz), 6.75 (1 H, dd, J = 9.2, 1.5 Hz), 3.36-3.30 (2 H, m), 1.38 (3 H, t, J = 7.6 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calculated for C 798H10Br N 812O2 and C8H10 Br N2O2244.9921, 246.9900; found 244.9920, 246.9898. |
93% | With potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide at 80℃; for 22h; | 16.O Example 16 - General Procedure for the Preparation of 5-Bromo-N-alkyl-2-nitroaniline- Method O (0564) 5-Bromo-N-ethyl-2-nitroaniline (57a) To a solution of 4-bromo-2-fluoro-1-nitrobenzene (56) (500 mg, 2.27 mmol) and potassium carbonate (628 mg, 4.55 mmol) in anhydrous DMF (5 mL) was added 2 M (0566) ethanamine in THF (2.3 mL, 4.55 mmol). The resulting mixture was stirred at 80 C for 22 h. After being quenched with water (10 mL), the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 5: 95 to 10:90) to afford 57a (520.0 mg, 93%) as a yellow solid; 1H NMR (0567) (CDCl3, 500 MHz) 8.03 (1 H, d, J = 9.2 Hz), 7.97 (1 H, br), 7.01 (1 H, d, J = 1.5 Hz), 6.75 (1 H, dd, J = 9.2, 1.5 Hz), 3.36-3.30 (2 H, m), 1.38 (3 H, t, J = 7.6 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calculated for C 79 (0568) 8H10 Br N 1 (0569) 2O2 and C8H 8 (0570) 10 Br N2O2244.9921, 246.9900; found 244.9920, 246.9898. |
88% | In ethanol at 20℃; for 2h; | 6 To a solution of 4-bromo-2-fluoro-1-nitro-benzene (2 g, 9.09 mmol) in Ethanol (15 mL) was added ethanamine (3725.62 mg, 27.27 mmol) and the mixture was stirred at 20° C. for 2 hours. The mixture was cooled to 0° C., the solid formed was collected by filtration, washed with z-Pr2O (20 mL) and dried in oven to give the product of 5-bromo-N-ethyl-2-nitro-aniline (1950 mg, 7.96 mmol, 88% yield) as a solid. Rt=0.857 min in 1.5 min chromatography, MS ESI calcd. for C8H10BrN2O2 [M+H+2]+ 247.0, found 246.8. |
88% | In ethanol at 20℃; for 2h; | 6 To a solution of 4-bromo-2-fluoro-1-nitro-benzene (2 g, 9.09 mmol) in Ethanol (15 mL) was added ethanamine (3725.62 mg, 27.27 mmol) and the mixture was stirred at 20° C. for 2 hours. The mixture was cooled to 0° C., the solid formed was collected by filtration, washed with z-Pr2O (20 mL) and dried in oven to give the product of 5-bromo-N-ethyl-2-nitro-aniline (1950 mg, 7.96 mmol, 88% yield) as a solid. Rt=0.857 min in 1.5 min chromatography, MS ESI calcd. for C8H10BrN2O2 [M+H+2]+ 247.0, found 246.8. |
80% | In ethanol at 20℃; for 1h; | 52 5.1.51 5-Bromo-N-methyl-2-nitroaniline (12a) General procedure: To a solution of 11 (25.0 g, 114 mmol) in EtOH (100 mL) was added methylamine (40% in MeOH, 34.8 mL, 341 mmol) at rt. The mixture was stirred at rt for 1 h and then cooled to 0 °C. The precipitate was collected by filtration, and washed with EtOH and IPE successively to give the title compound (24.8 g, 94%) as a yellow solid. |
In ethanol at 85℃; for 15h; | 26.3 Step 26.3: (5-Bromo-2-nitro-phenyl)-ethyl-amine; A mixture of 4-bromo-2-fluoro-nitrobenzene (6 g, 27.3 mmol), methylamine (2M in MeOH, 34.1 ml_, 68.2 mmol, 2.5 eq) and EtOH (80 ml.) is stirred for 15 h at 85°C, allowed to cool and concentrated. The residue purified by trituration to afford 6 g of the title compound as an yellow solid: tR= 5.13 min (System 1 ). | |
4.45 g | Stage #1: 4-bromo-2-fluoronitrobenzene; ethylamine In tetrahydrofuran at 20 - 50℃; for 4h; Stage #2: With potassium carbonate In ethanol; water at 50℃; for 2h; | 20.A A) 5-Bromo-N-ethyl-2-nitroaniline Example 20 1- (2-Cyclopropyl-l-ethyl-lH-benzimidazol-6-yl ) -4- ( (4- fluorobenzyl) oxy) pyridin-2 ( 1H) -one A) 5-Bromo-N-ethyl-2-nitroaniline The mixture of 4-bromo-2-fluoro-l-nitrobenzene (5 g) and ethylamine (2 M in THF, 17.05 ml) was stirred at room temperature for 2 h and at 50°C for 2 h. After concentration of the mixture, the residue was quenched with saturated NaHC03 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgS04 and concentrated in vacuo. The progress of the reaction was followed by NMR, but 4-bromo-2-fluoro-l- nitrobenzene was remained. The resulting residue was dissolved in EtOH (25 ml), and heated with potassium carbonate (6.28 g) and ethylamine (15.6 M in water, 1.47 ml) at 50°C for 2 h. The resulting suspension was filtered. The precipitate was washed with EtOH and water and dried to give the title compound (4.45 g) as a pale yellow solid. XH NMR (300 MHz, CDC13) : δ 1.06 (3H, t, J = 7.5 Hz), 3.25 (2H, td, J = 5.1, 7.1 Hz), 6.74 (1H, dd, J = 1.9, 9.0 Hz), 7.01 (1H, d, J =1.9 Hz), 7.92-8.11 (2H, m) . |
In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 0 - 20℃; | 5-bromo-N-ethyl-2-nitroaniline: To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (7000 mg, 31.83 mmol) in N-Methyl-2-pyrrolidinone (70 mL) was added 2.0 M ethylamine in THF (3731 mg, 82.73 mmol) at 0oC dropwise. The reaction mixture was stirred at ambient temperature for 6-8 hours, and after completion of reaction as indicated by TLC water (100 mL) was added and stirred for 30 min. The obtained orange solid was filtered, washed with water and dried to give the title compound (7100 mg, 91.10 % yield) which was used for the next step without purification. MS (ESI): m/z 246 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | |
80% | With sodium hydroxide In ethanol; water at 20℃; Inert atmosphere; | 3.4. General Procedure 1 for the Synthesis of (4-Methoxybenzyl)(2-Nitrophenyl)sulfanes (1b-1r) General procedure: The following description is for a 30 mmol scale reaction. The solvent quantities andflask size were adjusted accordingly for smaller-scale reactions.A 500 mL round-bottomed flask equipped with a stir bar was loaded with the 1-fluoro-2-nitrobenzene derivative (1 equiv.) and 200 mL of ethanol and placed under anatmosphere of argon. (4-methoxyphenyl)methanethiol (1 equiv.) was added with a syringe,followed by a dropwise addition of NaOH (1 equiv.) dissolved in 10 mL of H2O. Thereaction mixture was stirred at room temperature until TLC indicated the completion ofthe reaction (typically within 2 h). After removing the solvent under reduced pressure,the residue was diluted with 150 mL of H2O and extracted twice with dichloromethane.The organic phases were combined, dried over MgSO4, filtered, and concentrated. Theresulting crude product was purified by recrystallization or column chromatography asdescribed below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 16h; | To a suspension of 4-bromo-2-fluoro-1-nitrobenzene (3.0 g) in acetonitrile (100 mL) was added 3.7 g of methylamine hydrochloride followed by 12 mL of N,N-diisopropylethylamine. The mixture was stirred at 60 C. for 16 hours. After cooling down to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate (100 mL) and washed 3 times with water, then brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, providing 5-bromo-N-methyl-2-nitroaniline as an orange solid. The product was used in the next step without further purification. | |
With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h;Microwave irradiation; | [00318] To a solution of 4-bromo-2-fluoro-l -nitrobenzene (10 g, 45.7 mmol) in DMSO (50 mL) was added TEA (18.47 g, 183 mmol), methylamine hydrochloride (6.1 g, 91.4 mmol) and the reaction mixture was heated under microwave conditions at 120 C for 3 h. The mixture was cooled, extracted with ethyl acetate; the combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude product was used in next step without further purification. (10.5 g, yield 98%) MS (ESf) e/z: 231.1. | |
With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h; | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.7 mmol) in DMSO (50 mL) were added triethylamine (18.47 g, 183 mmol) and methylamine hydrochloride (6.1 g, 91.4 mmol). The reaction mixture was heated at 120 C for 3 hours. After cooling, the mixture was extracted with ethyl acetate (100 mL x 3), the combined organic layers washed with brine, dried over Na2SO4, and concentrated in vacuo to yield a crude product which was used in next step without further purification (10.5 g, 98%). LCMS (mlz): 231.1 (M+1). |
With N-ethyl-N,N-diisopropylamine; at 50℃; for 1h; | To a solution of 4-bromo-2- fluoro-1-nitrobenzene (1 g, 4.55 mmol) in CH3CN (25 mL) was added DIEA (2.94 g, 22.7 mmol, 3.96 mL) and methanamine (1.23 g, 18.3 mmol, HCl). The mixture was stirred at 50 C for 1 hour. TLC indicated the starting material was consumed completely and one new spot was formed. The reaction mixture was partitioned between Ethyl acetate (25 mL) and H2O (25 mL). The organic phase was separated, washed with sat. NaCl (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 29a. 1H NMR (400 MHz, CD3Cl) d 11.25 - 11.44 (m, 1H), 8.04 (br d, J = 9.0 Hz, 1H), 8.01 - 8.08 (m, 1H), 7.02 (s, 1H), 6.78 (br d, J = 8.6 Hz, 1H), 3.63 - 3.71 (m, 1H), 3.07 - 3.13 (m, 1H), 3.01 - 3.05 (m, 3H), 1.46 (d, J = 6.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 130℃;Inert atmosphere; microwave irradiation; | 4-Bromo-2-fluoro-1 -nitrobenzene (500mg, 2.27mmol), 2-nitro-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)aniline (660mg, 2.50mmol) and K2CO2 (940mg, 6.81 mmol) were suspended in DME-H2O (4:1 , 15mL) and purged with nitrogen. The solution was degassed by sonication before Pd(dppf)CI2 (185mg, 10mol%) was added. The mixture was heated to 130C for 10min under microwave irradiation. The cooled mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2x50mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resulting black solid was absorbed onto silica and purified by column chromatography (4:1 to 1 :1 petrol-EtOAc) to give the product as an orange solid (285mg, 45%).1H NMR (DMSO): 8.43 (1 H, d, J 2.3), 8.19 (1 H, t, J 8.5), 7.96 (1 H, dd, J 4.8 and 2.1), 7.92 (1 H, d, J 2.0), 7.79-7.73 (3 H, m) and 7.15 (1 H, d, J 8.8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 1.5h; | 146.A Step A(5-bromo-2-nitroph 2H-pyran-4-ylamine[00358] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), tetrahydro-2H-pyran-4-amine (0.920 g, 9.09 mmol) and K2C03 (2.51 g, 18.18 mmol) in DMF (20 mL) was heated at 90 °C for 90 min. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with a 5% aq. LiCI solution (3x100 mL). The organic layer was concentrated onto Celite and purified by column chromatography (silica gel, 0-40% EtOAc/hexane) obtain (5-bromo-2-nitrophenyl)tetrahydro-2H-pyran-4-ylamine (2.68 g, 8.90 mmol, 98 % yield) as a yellow solid: H NMR (400 MHz, DMSO-d6) δ ppm 1.45 - 1.67 (m, 2 H) 1.91 (dd, J=12.51 , 1.95 Hz, 2 H) 3.49 (td, J=11.43, 2.05 Hz, 2 H) 3.77 - 4.03 (m, 3 H) 6.84 (dd, J=9.09, 1.95 Hz, 1 H) 7.42 (d, J=1.86 Hz, 1 H) 7.85 - 8.06 (m, 2 H); ES LC-MS m/z =301.4 (Br79, M+H)+; ES LC-MS m/z =303.4 (Br81, M+H)+. |
92% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; | |
92% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; |
92% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; | |
With potassium carbonate | ||
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 16h; Sealed tube; | 1 Step 1: N-(5-bromo-2-nitrophenyl)tetrahydro-2H-pyran-4-amine To a solution of 4-bromo-2-fluoro- 1 -nitrobenzene (1.1 g, 4.95 mmol) and tetrahydro-2H-pyran-4-amine (500 mg, 4.95 mmol) in DMF (6 mL) was added K2C03 (1.37 g, 9.9 mmol) and the mixture stirred in sealed tube at 85°C for 16h. After cooling, water (100 mL) was added to the mixture and extracted with DCM (3x50 mL). The combined organic layers were washed with water (2x50 mL), brine (50 mL) and dried over anhydrous Na2S04 then filtered and concentrated to yield the title compound which was directly used for next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With ammonia; In methanol; at 20℃; for 18h; | 5-Bromo-2-nitro aniline 2-Fluoro-4-bromo-1-nitrobenzene (0.5 g, 2.2 mmol) was added to methanolic ammonia (10 mL) and stirred at r.t. for 18 h. The reaction mixture was then concentrated in vacuo and the residue was triturated with isohexane, yielding the title compound (0.48 g, 97%) as a yellow solid. deltaH (d6-DMSO) 7.88 (d, J 8.8 Hz, 1H), 7.53 (br s, 2H), 7.25 (d, J 3.0 Hz, 1H), 6.75 (dd, J 9.2, 2.0 Hz, 1H). |
91% | With ammonia; In methanol; at 0 - 20℃; for 12h;Sealed tube; | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (5 g, 22.7 mmol) in MeOH (5 mL), maintained at 0C in a sealed tube, was added methanolic ammonia (15 mL). The reaction mixture was stirred at room temperature for 12 h, then concentrated. The crude residue was triturated with pentane and Et20 to afford the title compound (4.5 g, 91%), which was used for the next step without any further purification. H (400 MHz, CD3OD) 7.93 (d,J9.1 Hz, 1H), 7.18 (d,J2.1 Hz, 1H), 6.74 (dd,J9.2, 2.1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine In ethanol at 100℃; for 0.5h; Microwave irradiation; | 53.1 EXAMPLE 532-[2-(1 ,3-benzothiazol-5-yl)-1 H-imidazol-4-yl]-1 -[2-(methyloxy)ethyl]-1 H-benzimidazole-6- carbonitrile hydrochlorideStep 1 . 5-bromo-N-[2-(methyloxy)ethyl]-2-nitroaniline: 4-bromo-2-fluoro-1 -nitrobenzene (0.3 g, 1.336 mmol), 2-(methyloxy)ethylamine (0.1 17 ml_, 1.336 mmol), and DIEA (0.238 ml_, 1 .336 mmol) in Ethanol (5 mL) were irradiated by microwave at 100°C for 30 min. The reaction mixture was partitioned between dichloromethane and brine. The aqueous layer was extracted with DCM twice. The combined DCM layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified via Biotage (SNAP Cartridge KP Sil 25 g, 0-10% EtOAc/Hexane) to yield 5-bromo-N-[2-(methyloxy)ethyl]-2-nitroaniline (0.374 g, 1.286 mmol, 96 % yield). 1H NMR (400 MHz, CDCI3) δ 8.22 (br. s., 1 H), 8.04 (d, J = 9.1 Hz, 1 H), 7.05 (d, J = 1.5 Hz, 1 H), 6.78 (dd, 1 H), 3.69 (t, 2 H), 3.48 (t, 2 H), 3.45 (s, 3 H); MS (m/z) 275.1 (M+H)+. |
89% | With triethylamine In ethanol at 80℃; for 3h; | 32.1 Preparation of 5-bromo-N-(2-methoxyethyl)-2-nitroaniine TEA (0.9 mL, 5.90 mmol) was added to a rt stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (1 g, 4.54 mmol) and 2-methoxyethan-1 -amine (0.5 g, 5.54 mmol) in ethanol (5 mL) and the reaction mixture was heated at 80°C for 3h. The resulting mixture was poured into water (50 mL) and extracted with EtOAc (30 mL X 3). The combined EtOAc layers were washed with brine (30 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using 20% EtOAc in hexane as eluent. Product fractions were combined and concentrated to dryness to afford the title compound (1.1 g, 89%) as a solid. 1 H NMR (400 MHz, DMSO) δ ppm 8.22 (t, J = 4.8 Hz, 1 H), 7.99 (d, J = 2 Hz, 1 H), 7.31 (d, J = 2 Hz,1 H), 7.86 (dd, Jt J2 = 2 Hz, 1 H), 3.60-3.51 (m, 4H), 3.32 (d, J = 9.6 Hz, 3H). |
With potassium carbonate |
In 1,2-dichloro-ethane at 80℃; for 12h; Inert atmosphere; | ||
1160 mg | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 15℃; for 3h; | 16 To a solution of 4-bromo-2-fluoro-1-nitro-benzene (1 g, 4.55 mmol) in THF (5 mL) was added 2-methoxyethanamine (512.11 mg, 6.82 mmol) and DIEA (1174.55 mg, 9.09 mmol). The resulting mixture was stirred at 15° C. for 3 hours to give a solution. EtOAc (30 mL) and water (15 mL) was added to the reaction solution. After separation, the organic layer was washed with brine (15 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by silica gel column with EtOAc in PE (0% to 10% to 20% to 30%) to give the product (1160 mg, 4.22 mmol) as a solid. 1H NMR (400 MHz, CDCl3) δH 8.23 (br s, 1H), 8.04 (d, 1H), 7.04 (d, 1H), 6.78 (dd, 1H), 3.71-3.67 (m, 2H), 3.50-3.46 (m, 2H), 3.45 (s, 3H). |
1160 mg | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 15℃; for 3h; | 16 To a solution of 4-bromo-2-fluoro-1-nitro-benzene (1 g, 4.55 mmol) in THF (5 mL) was added 2-methoxyethanamine (512.11 mg, 6.82 mmol) and DIEA (1174.55 mg, 9.09 mmol). The resulting mixture was stirred at 15° C. for 3 hours to give a solution. EtOAc (30 mL) and water (15 mL) was added to the reaction solution. After separation, the organic layer was washed with brine (15 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by silica gel column with EtOAc in PE (0% to 10% to 20% to 30%) to give the product (1160 mg, 4.22 mmol) as a solid. 1H NMR (400 MHz, CDCl3) δH 8.23 (br s, 1H), 8.04 (d, 1H), 7.04 (d, 1H), 6.78 (dd, 1H), 3.71-3.67 (m, 2H), 3.50-3.46 (m, 2H), 3.45 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With caesium carbonate In N,N-dimethyl-formamide at 0 - 25℃; for 16h; Inert atmosphere; | 4.1 Step 1: Preparation of 1- j2-(5-Bromo-2-nitro-phenoxy)-ethylj-pyrrolidine (126-3): To asolution of 4-bromo-2-fluoro-1-nitro-benzene 126-2 (38 g, 172 mmol) inN,N-dimethyl formamide (380 mL) was added cesium carbonate (168.83 g, 518 mmol) followed by 2-pyrrolidin-1-yl-ethanol 126-1 (22.18 g, 190 mmol) drop-wise at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (3.8 L). The solid precipitate was collected by filtration and dried over vacuum. The solid obtained was further suspended in hexane (190 mL) and stirred for 15 mm, filtered and dried to obtain 126-3 as a yellow solid 41.9 g (77 %). |
With caesium carbonate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.8 g | At 0 C, sodium metal (1.0 g) was chopped and slowly added to 30 mL.In anhydrous methanol, after 1 h of reaction, 2-fluoro-4-bromo-1-nitrobenzene (10.0 g) was added.After reacting at room temperature overnight, the target product is obtained by post-treatment and separation and purification.(white solid, 9.8 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With iron(0); ammonia hydrochloride In ethanol; lithium hydroxide monohydrate at 90℃; | 36.1 first step Compound 1 (2.0 g, 9.1 mmol, 1 eq.) was dissolved in ethanol (10 mL) and water (4 ml), then Fe2.5g (5.0eq, 46mmol) and NH4Cl (4.9g, 10.0eq, 91mmol) were added to the reaction solution, and the reaction was stirred at 90°C overnight. After the reaction was completed, the reaction solution was filtered through a sand core funnel padded with diatomaceous earth, and the filter cake was washed three times with 50 mL of ethanol. After concentration under reduced pressure, the residue was extracted with EA, and the organic phases were combined.Spin dry to obtain compound 2 as a light brown solid (1.78 g, 77.8% yield). |
With dichloro-λ2-stannane dihydrate In ethyl acetate | ||
With iron(0); glacial acetic acid In ethanol at 80℃; for 1h; | 126.1 Step 1: Synthesis of 4-bromo-2-fluoroaniline (2): To a stirred solution of 4-bromo-2- fluoro-1 -nitrobenzene (1, 9.0 g, 13.64 mmol) and acetic acid (1 1.5 g, 0.57 mol) in ethanol (60 mL) was added iron powder (15.9 g, 0.285 mol). The reaction mixture was stirred at 80 °C for 1 h. After completion of the reaction, reaction mixture was diluted with EtOAc and filtered through celite bed. The filtrate was concentrated under reduced pressure to get the crude compound and it was used for the next step directly (6.0 g, 76.5%); LCMS (ESI positive ion) m/z: calculated: 188.96; observed: 192.0 (M+l). |
With iron(0); ammonia hydrochloride In ethanol; lithium hydroxide monohydrate at 90℃; for 2h; | 82.1 Step 1 : Preparation of 4-bromo-2-fluoroaniline To a stirred solution of 4-bromo-2-fluoro-l -nitrobenzene (10 g, 45.5 mmol) in EtOH (50 mL)AVater (20 mL) was added iron (12.7 g, 230 mmol) and NH4C1 (24.3 g, 455 mmol). The reaction mixture was stirred at 90 °C for 2 h. After 2 h the reaction mixture was filtered over Celite. The filter cake was washed with EtOH (300 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (S1O2, Petroleum ether/EtOAc=10: l to 5: 1) to afford 4-bromo-2-fluoroaniline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-(4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid; 4-bromo-2-fluoronitrobenzene With potassium carbonate In water; acetonitrile at 70℃; for 48h; Stage #2: With hydrogenchloride In water; ethyl acetate | 4A 2-(l-(5-bromo-2-nitrophenyl)-4-(førM)utoxycarbonyl)piperazin-2-yl)acetic acid 4-Bromo-2-fluoro-l -nitrobenzene (5.3 g, 24.1 mmol) was dissolved in acetonitrile (70 mL) and water (10 mL). To this mixture, potassium carbonate (1Og, 72.3 mmol) and 2-(4- (te/t-butoxycarbonyl)piperazin-2-yl)acetic acid (7.1g, 28.9 mmol) were added. The resulting mixture was heated at 70 0C for 2 days. The mixture thus obtained was concentrated and ethyl acetate was added. 1 NHCl was then added slowly to the reaction solution until pΗ=6. The water layer was separated and washed multiple times with ethyl acetate. The organic layers thus obtained were combined and concentrated. The crude material thus obtained was purified by silica gel chromatography eluting with a gradient of 0% to 10% of methanol in dichloromethane to afford the title compound. 1H NMR (300 MHz, DMSO-J6) δ ppm 12.28 (br s), 7.71 - 7.83 (m, 1 H), 7.56 - 7.66 (m, 1 H), 7.30 - 7.40 (m, 1 H), 3.56 - 3.82 (m, 3 H), 3.33 - 3.44 (m, 1 H), 2.99 - 3.24 (m, 2 H), 2.87 (m, , 1 H), 2.32 - 2.47 (m, 1 H), 2.17 - 2.29 (m, 1 H), 1.32 - 1.51 (s, 9 H); MS (DCI+) m/z 444.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; | The suspension of 4-bromo-2-fluoronitrobenzene (21.8 g, 100 mmoL), 4- bromo-2-iodophenol (29.7 g, 100 mmoL) and K2C03 (28 g, 200 mol) in DMF (250 mL) was heated to 50 C overnight. The reaction mixture was then cooled and poured into water. The resulting precipitate was collected by filtration, washed with water and dried in vacuo. The crude product was recrystallized from methanol to give the desired Int-6a (40 g). MS (ESI) m/e (M+H)+: 498, 500 and 502. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In 1,2-dichloro-ethane at 80℃; for 12h; Inert atmosphere; | 4.1.2.3.4 Scheme 2 5-Bromo-N-cyclopropyl-2-nitroaniline (68) A solution of compound 56 (10 g, 45.45 mmol) and cyclopropanamine (6.3 mL, 90.91 mmol) in 1,2-dichloroethane (20 mL) was heated to 80 °C for 12 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature and poured into 50 mL of water and extracted with dichloromethane (3 * 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and excess solvent removed via rotary evaporator to give compound 68 (11.57 g, 45.0 mmol, 99% yield) as a red solid. 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.96 (d, J = 9.1 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 9.1, 2.0 Hz, 1H), 2.60-2.50 (m, 1H), 0.97-0.88 (m, 2H), 0.69-0.61 (m, 2H). |
99% | In 1,2-dichloro-ethane at 80℃; for 12h; | 5-bromo-N-cyclopropyl-2-nitroaniline (48) A solution of compound 47 (10 g, 45.45 mmol) and cyclopropanamine (6.3 mL, 90.91 mmol) in 1,2-dichloroethane (20 mL) was heated to 80 °C for 12 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature and poured into 50 mL of water and extracted with dichloromethane (3 * 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and excess solvent was removed via rotary evaporator to give compound 48 (11.57 g, 45.0 mmol, 99% yield) as a red solid. 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.96 (d, J = 9.1 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 9.1, 2.0 Hz, 1H), 2.60-2.50 (m, 1H), 0.97-0.88 (m, 2H), 0.69-0.61 (m, 2H). |
87% | In 1,2-dichloro-ethane at 80℃; for 12h; | 77.a Example 77 (a) Compound 77A (10g, 45.45mmol) was dissolved in 30ml of DCE, added cyclopropylamine (6.29ml, 90.91mmol), heated to reflux at 80°C for 12h, and monitored the reaction with a TLC panel. After the reaction, the solvent was evaporated and 40mlH2O Extract with DCM/40ml*2, combine the organic layers, wash once with 100ml saturated brine, dry with anhydrous sodium sulfate, and evaporate the solvent to obtain 10.2g of yellow solid, compound 77B, with a yield of 87%. |
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 14h; | 321.A Step A. (5-bromo-2-nitro-phenyl)-cyclopropylamine:To solution of 4-bromo-2-fluoronitrobenzene (2.0 g, 0.0091 mol) in DMF (10 ml) was added carefully DIPEA (3.25 ml, 0.0182 mol) and cyclopropylamine (0.7 ml, 0.0091 mol) and the resulting solution was stirred at room temperature for 14h. The reaction was quenched with ice-water and extracted with diethyl ether (3 x 100 ml). The combined organic layers were washed with brine dried over Na2S04 and concentrated under vacuum to afford the title compound (5-bromo-2-nitro-phenyl)-cyclopropylamine as a yellow solid. 0¾ΒΓΝ202; 1H NMR (400 MHz, DMSO- | |
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 191.1 Step 1: Synthesis of 5-bromo-N-cyclopropyl-2-nitroaniline (3): [000628j To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzenel(2 g,1 eq), cyclopropylamine (0.5 18 g,leq)in DMF (10 mL), DIPEA (2.34 g,2eq) was added and stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3 X 50 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 2% EtOAc-hexane to afford the title compound 3. LCMS (mlz):257.00 (M+1). | |
In 1,2-dichloro-ethane at 80℃; for 12h; | ||
With N-ethyl-N,N-diisopropylamine In acetonitrile at 50℃; for 1h; Inert atmosphere; | 22 Synthesis of 5-bromo-N-cyclopropyl-2-nitroaniline (22a). To a mixture of 4- bromo-2-fluoro-1-nitrobenzene (2 g, 9.09 mmol) and cyclopropanamine (2.08 g, 36.36 mmol, 2.52 mL) in CH3CN (10 mL) was added DIEA (5.87 g, 45.45 mmol, 7.92 mL) under N2. The mixture was stirred at 50 °C for 1 hour. TLC indicated that the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give 22a.1H NMR (400 MHz, CDCl3) d 7.72 (dd, J = 9.0, 2.0 Hz, 1H), 6.56 (dd, J = 9.0, 2.0 Hz, 1H), 4.57 (s, 7H), 3.01 (br s, 2H), 2.27 - 2.36 (m, 1H), 0.57 - 0.70 (m, 2H), 0.28 - 0.38 (m, 2H). | |
In 1,2-dichloro-ethane at 80℃; for 3h; Inert atmosphere; | 1.31 o a mixture of 4-bromo-2-fluoro-1-nitrobenzene (5 g, 22.73 mmol, 1 eq.) in DCE (50 mL) was added cyclopropanamine (2.60 g, 45.46 mmol, 3.15 mL, 2 eq.) in one portion at 80 °C under nitrogen. The mixture was stirred at 80 °C for 3 h. LCMS showed that the reaction was complete. The reaction was poured into was water (50 mL). The aqueous phase was extracted with DCM (3 x 3 x 50 mL). The combined organic phase was washed with brine (2 x 40 mL) dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (5.8 g, crude) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate In tetrahydrofuran at 100℃; for 4h; | 4.1 Methyl 3-((5-bromo-2-nitrophenyl)amino)propanoate {Step 1): A solution of 4-bromo-2-fluoro-l -nitrobenzene (10 g, 45.5 mol), methyl 3-aminopropanoate hydrochloride (6.4 g, 45.5 mol) and K2C03 (19 g, 136.5 mol) in THF (250 mL) was heated at 100 °C for 4 hrs. The mixture was extracted with ethyl acetate (100 mL), washed with brine (150 mL), dried and concentrated to give the residue, which was purified by CombiFlash (PE:EA=2:1) to give methyl 3-((5-bromo-2-nitrophenyl)amino)propanoate (12 g, yield 88 %). 1H NMR (300 MHz, CDC13) δ 2.70-2.75 (t, J = 6.6 Hz, 2H), 3.58-3.65 (m, 2H), 3.74 (s, 3H), 6.76-6.80 (m, 1H), 7.02-7.03 (d, J = 2.1 Hz, 1H), 8.01-8.04 (d, J = 9.0 Hz, 2H), 8.20-8.22 (br, 1H). |
88% | With potassium carbonate In tetrahydrofuran at 100℃; for 4h; | |
65.2% | With potassium carbonate In tetrahydrofuran at 100℃; for 4.5h; Sealed tube; | 33.1 Step 1: Compound TDI01265-1 (2 g, 9.1 mmol), methyl 3-aminopropanoate hydrochloride (1.27 g, 9.1 mmol), potassiumcarbonate (3.8 g, 27.3 mmol) and tetrahydrofuran (30 mL) were added to a 50 mL sealed tube. The reaction was warmedto 100°C for 4.5 h. LC-MS indicated the reaction was complete. The reaction solution was filtered, and the filtrate wascollected, and concentrated under reduced pressure to give a solid, which was purified by column chromatography(petroleum ether : ethyl acetate=20:1∼8:1) to afford TDI01265-2 (1.8 g, yellow solid, yield: 65.2%).1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.79 (dd, J = 9.1, 1.9 Hz,1H), 3.75 (s, 3H), 3.62 (dd, J = 12.4, 6.5 Hz, 2H), 2.73 (t, J = 6.6 Hz, 2H). MS m/z (ESI): 305.1 [M+H]. |
3.3 g | With potassium carbonate In tetrahydrofuran at 75℃; | 4.1 Step 1: methyl 3-((5 -bromo-2-nitrophenyl)amino)propanoate (B3 3-2) A mixture of 4-bromo-2-fluoro-1-nitrobenzene (2.2 g, 10 mmol), methyl 3- aminopropanoate hydrochloride (1.7 g, 12 mmol) and K2C03 (4.1 g, 30 mmol) in THF (40 mL) was stirred at 75 °C overnight. After cooling to room temperature, the mixture was treated with brine (50 mL) and extracted with ethyl acetate (40 mL * 2). The combined organic layers were dried over Na2504, filtered and concentrated to give the title compound as a yellow solid (3.3 g). ‘H NMR (400 MHz, CDC13) ö 8.22 (br s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.79 (d, J =8.4 Hz, 1H), 3.75 (s, 3H), 3.63 (t, J = 5.2 Hz, 2H), 2.75 (d, J = 6.0 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; at 70℃; | a) 1,1-Dimethylethyl (3S)-3-[(5-bromo-2-nitrophenyl)amino]methyl}-l- pyrrolidinecarboxylate4-Bromo-2-fluoro-l -nitrobenzene (5 g), 1,1-dimethylethyl (35)-3-(aminomethyl)-l- pyrrolidinecarboxylate (5 g) and TEA (4.1 g) were dissolved in 50 mL DMSO and stirred at 70 C overnight. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over sodium sulfate and evaporated to dryness to afford the titled compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 13h; | 140.A Step A5-bromo-N-[4- 2-nitroaniline[00334] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), a 4- (methyloxy)aniline (1.187 g, 9.64 mmol) and K2C03 (2.51 g, 18.18 mmol) in DMF (20 mL) was heated at 90 °C for 5 h. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with a 5% aq. LiCI solution (3x100 mL). The organic layer was concentrated to obtain 5-bromo-N-[4-(methyloxy)phenyl]-2-nitroaniline (2.92 g, 9.04 mmol, 99 % yield) as a dark orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 - 3.83 (m, 3 H) 6.91 - 6.98 (m, 2 H) .7.00 - 7.07 (m, 2 H) 7.24 - 7.31 (m, 2 H) 8.01 - 8.06 (m, 1 H) 9.46 (s, 1 H); ES LC-MS m/z =323.3 (Br79, M+H)+; ES LC-MS m/z =325.2 (Br81, M+H)+. |
68.2% | Stage #1: 4-methoxy-aniline With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Cooling with ice; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran at 30 - 40℃; | 1.1 Step 1 - Synthesis of 5-bromo-N-(4-methoxyphenyl)-2-nitroaniline Step 1 - Synthesis of 5-bromo-N-(4-methoxyphenyl)-2-nitroanilineTo a solution of 4-methoxyaniline (560 mg, 4.6 mmol) in anhydrous THF (10 mL) was added NaH (273 mg, 6.8 mmol) little by little at ice-bath, and then the mixture was allowed to stir at room temperature for 30 minutes. After 4-bromo-2-fluoro-l -nitrobenzene (1.0 g, 4.6 mmol) in THF was added dropwise, the mixture was allowed to stir at 30-40 °C overnight. After the reaction mixture was quenched with water, the mixture was extracted with EtOAc. The organic phase was dried with Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with PE : EtOAc = 20 : 1) to provide 5-bromo-N- (4-methoxyphenyl)-2-nitroaniline (1.0 g, yield: 68.2%). 1H-NMR (CDC13, 400 MHz) δ 9.34 (s, 1H), 7.98-8.00 (m, 1H), 7.26-7.35 (m, 2H), 6.73-6.82 (m, 3H), 3.78 (s, 3H). |
68.2% | Stage #1: 4-methoxy-aniline With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Cooling with ice; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran at 30 - 40℃; | 1.1 Synthesis of 5-bromo-N-(4-methoxyphenyl)-2-nitroaniline Synthesis of 5-bromo-N-(4-methoxyphenyl)-2-nitroaniline To a solution of 4-methoxyaniline (560 mg, 4.6 mmol) in anhydrous THF (10 mL) was added NaH (273 mg, 6.8 mmol) little by little at ice-bath, and then the mixture was allowed to stir at room temperature for 30 minutes. After 4-bromo-2-fluoro-l -nitrobenzene (1.0 g, 4.6 mmol) in THF was added dropwise, the mixture was allowed to stir at 30-40 °C overnight.After the reaction mixture was quenched with water, the mixture was extracted with EtOAc. The organic phase was dried with Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with PE : EtOAc = 20 : 1) to provide 5-bromo-N- (4-methoxyphenyl)-2-nitroaniline (1.0 g, yield: 68.2%). 1H- MR (CDC13, 400 MHz) δ 9.34 (s, 1H), 7.98-8.00 (m, 1H), 7.26-7.35 (m, 2H), 6.73-6.82 (m, 3H), 3.78 (s, 3H). (M+H)+: 323 / 325. |
In N,N-dimethyl-formamide at 80℃; for 18h; | II Intermediates (5-bromo-2-nitro-iV-phenylaniline) and 5-bromo-N-(4-methoxyphenyl)-2- nitroaniline General procedure: A mixture of 4-bromo-2-fluoro-l -nitrobenzene (1.14 g, 1 eq) and aniline (1 eq) in DMF (30 mL) was heated at 80 °C and the reaction progression checked by1C MS. After 18 h the reaction was cooled down to room temperature, diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The organic1ayers were collected, washed with H20 (2 x 50 mL), brine (1 x 50 mL) and dried (MgSC^). The solvent was removed under reduced pressure and the crude product was used in the next reaction without further purification. 1-497,1C MS [M + 1] + m/z 293.00; 1-498,1C MS [M + 1]+ m/z 323.00 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 3h; | 132.A Step A5-bromo-N itroaniline[00306] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), cyclopentylamine (0.897 mL, 9.09 mmol) and K2C03 (2.51 g, 18.18 mmol) in DMF (20 mL) was heated at 90 °C for 3 h. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with a 5% aq. LiCI solution (3x100 mL). The organic layer was concentrated to obtain 5-bromo-N-cyclopentyl-2-nitroariiline (2.58 g, 9.05 mmol, 100 % yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 - 1.77 (m, 6 H) 2.06 (dq, =12.08, 5.96 Hz, 2 H) 4.08 (sxt, J=6.38 Hz, 1 H) 6.84 (dd, J=9.12, 2.00 Hz, 1 H) 7.27 (d, J=2.05 Hz, 1 H) 7.95 - 8.04 (m, 2 H); ES LC-MS m/z =285.1 (Br79, M+H)+; ES LC-MS m/z =287.2 (Br81, M+H)+ |
In 1,2-dichloro-ethane at 80℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | 141.A Step A5-bromo-2-n lethyl]aniline[00338] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), (1 R)-1 - phenylethanamine (1 .102 g, 9.09 mmol) and K2C03 (2.51 g, 18.18 mmol) in DMF (20 mL) was heated at 90 °C for 2 h. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with a 5% aq. LiCI solution (3x100 mL). The organic layer was concentrated to obtain an orange oil, which later crystallized under vacuo to obtain 5- bromo-2-nitro-N-[(1 R)-1-phenylethyl]aniline (2.88 g, 8.97 mmol, 99 % yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, 3 H) 4.95 (quin, J=6.68 Hz, 1 H) 6.83 (dd, J=9.07, 1 .95 Hz, 1 H) 7.03 (d, J=2.05 Hz, 1 H) 7.22 - 7.30 (m, 1 H) 7.32 - 7.39 (m, 2 H) 7.40 - 7.46 (m, 2 H) 7.99 (d, J=9.07 Hz, 1 H) 8.31 (d, J=6.63 Hz, 1 H). |
With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.0833333h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 3h; | 171.A Step A1, 1-dimethylethyl 3-[(5- 1-pyrrolidinecarboxylate[00434] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), a 1 ,1- dimethylethyl 3-amino-1 -pyrrolidinecarboxylate (1.693 g, 9.09 mmol) and K2C03 (2.51 g, 18.18 mmol) in DMF (20 mL) was heated in a 90°C sand bath for 3 hours. The resulting mixture was diluted with EtOAc (200 mL) and washed with a 5% LiCI solution (3x100 mL). The organic layer was concentrated to obtain a solid. The sample was purified by silica gel chromatography (0-30 % EtOAc in hexanes to yield 1 , 1-dimethylethyl 3-[(5-bromo-2-nitrophenyl)amino]-1- pyrrolidinecarboxylate as a yellow solid (3.2 g, 91 % yield). 1H NMR (400 MHz, DMSO-cfe) δ ppm 7.89 - 8.07 (m, 2 H) 7.39 (s, 1 H) 6.90 (dd, J=9.1 , 1.9 Hz, 1 H) 4.40 (dd, .7=14.9, 5.8 Hz, 1 H) 3.65 (dd, J=10.8, 6.1 Hz, 1 H) 3.36 - 3.44 (m, 1 H) 3.30 - 3.41 (m, 2 H overlapping H20) 3.22 (dd, J=10.9, 4.9 Hz, 1 H) 2.14 - 2.29 (m, 1 H) 1.82 - 2.05 (m, 1 H) 1.40 (s, 9 H). ES-LCMS: 286.2 (M+1-BOC). |
80% | With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 16h; Sealed tube; | 1 Step 1: tert-butyl 3-((5-bromo-2-nitrophenyl)amino)pyrrolidine-l-carboxylate To a solution of 4-bromo-2-fluoro- 1 -nitrobenzene (500 mg, 2.27 mmol) and tert- butyl 3-aminopyrrolidine-l-carboxylate (390 mg, 2.27 mmol) in DMSO (5 mL) was added DIPEA (351 mg, 2.72 mmol) and the solution stirred in a sealed bottle at room temperature for 16h. After LCMS analysis indicated completion of the reaction, the solution was diluted with water (100 mL) and DCM (100 mL). The organic layer was washed by water (30 mLX 2) and brine (30 mL) and dried over anhydrous Na2S04 before being filtered and concentrated to yield the desired product (670 mg Yield 80%). The material was used in the next step without further purification. LCMS (m/z): 386.1 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 26h; | Step A5-bromo-2-ni henyl]aniline[00447] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (1.353 g, 6.15 mmol), 3-(1 ,3-oxazol-5-yl)aniline (0.985g, 6.15 mmol) and K2C03 (1.7 g, 12.3 mmol) in DMF (13.5 mL) was heated at 90 C for 26 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with a 5% LiCI solution (3x100 mL). The organic layer was concentrated and the residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to obtain 5-bromo-2- nitro-N-[3-(1 ,3-oxazol-5-yl)phenyl]aniline as bright red - orange solid (1.18g, 53%). 1H NMR (400 MHz, DMSO-c/s) δ ppm 9.54 (s, 1 H) 8.48 (s, 1 H) 8.07 (d, .7=9.2 Hz, 1 H) 7.75 (s, 1 H) 7.71 (s, 1 H) 7.59 - 7.64 (m, 1 H) 7.53 - 7.58 (m, 1 H) 7.36 (d, J=8.0 Hz, 1 H) 7.23 (d, J=2.0 Hz, 1 H) 7.07 (dd, J=9.0, 2.0 Hz, 1 H). ES-LCMS: 360.0 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In tetrahydrofuran at 90℃; for 6h; | 133.A Step A5-bromo-N-( -nitroaniline[00310] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), isopropylamine (0.774 mL, 9.09 mmol) and K2C03 (2.51 g, 18.18 mmol) in DMF (20 mL) was stirred at room temperature overninght. The resulting mixture was diluted with ethyl acetate and washed with a 5% aq. LiCI solution (3x100 mL). The organic layer was concentrated to obtain 5-bromo-N-(1-methylethyl)-2-nitroaniline (2.32 g, 8.95 mmol, 98 % yield) as a bright orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (d, 6 H) 3.93 - 4.02 (m, 1 H) 6.83 (dd, J=9.12, 2.00 Hz, 1 H) 7.29 (d, J=1.95 Hz, 1 H) 7.90 (d, J=7.71 Hz, 1 H) 7.99 (d, J=9.07 Hz, 1 H); ES LC-MS m/z =259.2 (Br79, M+H)+; ES LC-MS m/z =261.2 (Br81, M+H)+. |
98.8% | With potassium carbonate In dichloromethane for 16h; | Step 1: 5-bromo-N-isopropyl-2-nitro-aniline (3) To a solution of 4-bromo-2-fluoro-1-nitro-benzene (1, 2.4 g, 10.91 mmol) in DCM (25 mL) was added isopropylamine (2, 644.9 mg, 10.91 mmol, 0.933 mL) and potassium carbonate (3.02 g, 21.8 mmol). After 16 h, the reaction was diluted with DCM (50 mL) and washed with water (3 x 40 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to obtain 5- bromo-N-isopropyl-2-nitro-aniline (3, 2.8 g, 10.78 mmol, 98.8% yield) as a bright yellow solid. The material was used in the next step without purification. LCMS (ES+): m/z 261 [M+H]+ |
96% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 4.1.5.1. 5-Bromo-N-isopropyl-2-nitroaniline(9) An orange mixtureof 4-bromo-2-fluoro-1 enitrobenzene 8 (4 g, 18.18 mmol), isopropylamine(1.7 mL, 20 mmol) and K2CO3 (2.51 g, 36.36 mmol) inDMF (40 mL) was stirred at room temperature overnight. The resulting mixture was diluted with water and the mixture was extracted by ethyl acetate, and the combined organic layers werewashed by water and brine, dried by anhydrous magnesium sulphate. The solvent was evaporated, and the residue was purified bysilica gel column chromatography to obtain 9 (4.52 g, 96%) as abright orange solid. 1H NMR (400 MHz, DMSO-d6) d 8.08e7.77 (m,2H), 7.20 (d, J 2.5 Hz, 1H), 6.76 (dd, J 9.1, 2.3 Hz, 1H), 4.08-3.77(m, 1H), 1.23 (dd, J 6.4, 2.3 Hz, 6H). 13C NMR (101 MHz, DMSO)d 145.12, 131.60, 130.47, 128.55, 118.48, 117.14, 44.09, 22.51. |
87% | In N,N-dimethyl-formamide for 13h; Inert atmosphere; | 1.1 Step 1: Synthesis of 5-bromo-N-isopropyl-2-nitroaniline Under a nitrogen atmosphere, propyl-2-amine (4.3 mL, 50.00 mmol) was added dropwise to a solution of 4-bromo-2-fluoro-1-nitrobenzene (10.01 g, 41.50 mmol) in DMF (100 mL) The reaction was carried out for 13 h. Then add EtOAc to the reaction(800 mL), washed with H2O (100 mL×6).The product was isolated as a yellow solid (10.21 g, 87%). |
In 1,2-dichloro-ethane at 80℃; for 12h; Inert atmosphere; | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Cooling with ice; | 1 Step 1 Synthesis of 5-bromo-N-isopropyl-2-nitroaniline In an ice bath, potassium carbonate (5.02 g, 36.36 mmol) and isopropylamine (1.55 mL, 18.18 mmol) were sequentially added into the solution of 4-bromo-2-fluoro-1-nitrobenzene (4.00 g, 18.18 mmol) in anhydrous DMF (40 mL), the reaction mixture was warmed to room temperature naturally, and the mixture was stirred overnight. The reaction was quenched by adding water, extracted with ethyl acetate (100 mL×3), the combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 4.62 g of a yellow solid, which was directly used in the next step without purification. | |
With N-ethyl-N,N-diisopropylamine In [D3]acetonitrile at 50℃; for 2h; Inert atmosphere; | 20 Synthesis of 5-bromo-N-isopropyl-2-nitroaniline (20a). To a mixture of 4-bromo- 2-fluoro-1-nitrobenzene (1 g, 4.55 mmol) and propan-2-amine (1.07 g, 18.2 mmol, 1.56 mL) in CH3CN (20 mL) was added DIEA (2.94 g, 22.7 mmol, 3.96 mL) under N2. The mixture was stirred at 50 °C for 2 hours. TLC indicated the starting material was consumed completely and one new spot was formed. The reaction mixture was concentrated under reduced pressure, and the residue was diluted in water (20 mL), and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (30 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give 20a.1H NMR (400 MHz, CDCl3) d 8.03 (d, J = 9.0 Hz, 2H), 6.97 - 7.11 (m, 1H), 6.68 - 6.76 (m, 1H), 3.74 - 3.87 (m, 1H), 1.32 - 1.36 (m, 6H). | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; | ||
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 19h; | 165.A Step A2-[(5-bromo-2-nitrophenyl)amino]ethanol[00418] A solution of 4-bromo-2-fluoro-1 -nitrobenzene (8 g, 36.4 mmol), DIPEA (12.70 mL, 72.7 mmol), and ethanolamine (3.30 mL, 54.5 mmol) in Ν,Ν-dimethylformamide (DMF) (68 mL) was maintained with stirring at room temperature for 19 hours. The mixture was poured into water and stirred vigorously. Solids were collected by vacuum filtration to afford 2-[(5- bromo-2-nitrophenyl)amino]ethanol as a yellow solid (10.13 g, 36.5 mmol, 100 % yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (t, J=5.2 Hz, 1 H) 7.98 (d, J=9.0 Hz, 1 H) 7.30 (d, J=2.0 Hz, 1 H) 6.83 (dd, J=9.0, 2.0 Hz, 1 H) 5.01 (t, J=5.3 Hz, 1 H) 3.62 (q, J=5.5 Hz, 2 H) 3.41 (q, J=5.5 Hz, 2 H). |
95% | With triethylamine In ethanol at 80℃; for 2h; | 55.1 Preparation of 2-((5-bromo-2-nitrophenyl)amino)ethan-1-ol TEA (2.9 mL, 20.55 mmol) was added to a rt stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (1.5 g, 6.85 mmol) and 2-aminoethan-1-ol (0.51 g, 8.22 mmol) in ethanol (15 mL) and the reaction mixture was heated at 80 °C for 2 h. The resulting mixture was then diluted with water (100 mL) and extracted with EtOAc (40 mL X 3). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford the title compound (1.7 g, 95%) as an oil. [M+H]+262.94. |
89% | In ethanol at 110℃; for 0.333333h; Irradiation; | 127.1 Step 12- j(5-bromo-2-nitrophenyl)aminoj ethanol Step 12- j(5-bromo-2-nitrophenyl)aminoj ethanolA solution of 2-aminoethanol (350 mg, 5.73 mmol) and 4-bromo-2-fluoro-1-nitrobenzene(315 mg, 1.432 mmol) in ethanol (4 mL) was irradiated (Biotage Personal Chemistry unit,300 W) at 110 °C for 20 minutes. The red-orange solution was concentrated under vacuum,and the residue purified by flash chromatography (silica gel eluted with hexanes-ethylacetate, 90:10 - 60:40) to provide the titled compound (331 mg, 89%). ‘H NMR (300 MHz,DMSO-d6) ppm 3.41 (q, J=5.6 Hz, 2 H), 3.63 (q, J=5.6 Hz, 2 H), 4.99 (t, J=5.2 Hz, 1 H),6.83 (dd, J=9.1, 2.0 Hz, 1 H), 7.30 (d, J=2.0 Hz, 1 H), 7.99 (d, J=9.1 Hz, 1 H), 8.29 (t, J=5.0Hz, 1 H). |
89% | In ethanol at 110℃; for 0.333333h; Microwave irradiation; | 127.1 Step 1 2-[(5-bromo-2-nitrophenyl)amino]ethanol Step 1 2-[(5-bromo-2-nitrophenyl)amino]ethanol A solution of 2-aminoethanol (350 mg, 5.73 mmol) and 4-bromo-2-fluoro-1-nitrobenzene (315 mg, 1.432 mmol) in ethanol (4 mL) was irradiated (Biotage Personal Chemistry unit, 300 W) at 110° C. for 20 minutes. The red-orange solution was concentrated under vacuum, and the residue purified by flash chromatography (silica gel eluted with hexanes-ethyl acetate, 90:10-60:40) to provide the titled compound (331 mg, 89%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.41 (q, J=5.6 Hz, 2H), 3.63 (q, J=5.6 Hz, 2H), 4.99 (t, J=5.2 Hz, 1H), 6.83 (dd, J=9.1, 2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.99 (d, J=9.1 Hz, 1H), 8.29 (t, J=5.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.2% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 10h; | Step A5-bromo-N-[3-(4-morpholinyl)phenyl]-2-nitroaniline [00326] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), a 3-(4- morpholinyl)aniline (1.632 g, 9.16 mmol) and K2C03 (2.51 g, 18.18 mmol) in DMF (10 mL) was heated at 90 C for 10 h. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with a 5% aq. LiCI solution (3x100 mL). The organic layer was concentrated onto Celite and purified by column chromatography (silica gel, 0-50% EtOAc/hexane) to obtain 5-bromo-N-[3-(4-morpholinyl)phenyl]-2-nitroaniline (2.26 g, 5.98 mmol, 65.2 % yield) as a bright orange solid: 1H NMR (400 MHz, DMSO-cfe) delta ppm 3.10 - 3.17 (m, 4 H) 3.70 - 3.77 (m, 4 H) 6.78 (dd, =7.72, 1.47 Hz, 1 H) 6.86 (dd, J=8.26, 2.10 Hz, 1 H) 6.91 (t, J=2.00 Hz, 1 H) 6.99 (dd, J=9.09, 2.05 Hz, 1 H) 7.20 (d, J=2.05 Hz, 1 H) 7.30 (t, J=8.06 Hz, 1 H) 8.04 (d, J=9.09 Hz, 1 H) 9.43 (s, 1 H); ES LC-MS m/z =378.2 (Br79, M+H)+; ES LC-MS m/z =380.2 (Br81, M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 6h; | Step A(5-bromo-2-nitrop nyl]methyl}amine[00414] A solution of 4-bromo-2-fluoro-1 -nitrobenzene (3.43 g, 15.60 mmol) and [4-(4- morpholinyl)phenyl]methyl}amine (3 g, 15.60 mmol) in N,N-dimethylformamide (35 mL) was treated with DIPEA (8.18 mL, 46.8 mmol) and maintained with stirring at room temperature for 6 hours. The solution was poured into water, stirred for 45 minutes, and solids collected via vacuum filtration to afford (5-bromo-2-nitrophenyl)<strong>[214759-74-7][4-(4-morpholinyl)phenyl]methyl}amine</strong> (5.49 g, 14.00 mmol, 90 % yield) as an orange solid. LCMS (m/z, ES+) = 393 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium acetate In 1,4-dioxane; water at 90℃; for 1.5h; | 136.A; 139.A Step A2,4-difluoro-N-[5-(3-fluoro-4-nitrophenyl)-2-(methyloxy)-3-pyridinyl]benzenesulfonamide[00318] A degassed mixture of 4-bromo-2-fluoro-1 -nitrobenzene (0.413 g, 1.877 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (1 g, 2.346 mmol), Pd(dppf)2CI2 CH2CI2 adduct (0.153 g, 0.188 mmol) and potassium acetate (0.553 g, 5.63 mmol) in 1 ,4-dioxane (20 mL) and water (5 mL) was heated at 90 °C for 90 minutes. The reaction mixture was allowed to cool to room temperature then diluted with EtOAc (100 mL) and washed with a sat. NaCI solution (100 mL). The organic layer was concentrated. The residue was dissolved in CH2CI2l concentrated onto Celite and purified by column chromatography (silica gel, 0-50% EtOAc/hexane) to obtain 2,4- difluoro-N-[5-(3-fluoro-4-nitrophenyl)-2-(methyloxy)-3-pyridinyl]benzenesulfona (705 mg, 1.605 mmol, 85 % yield) as a yellow solid: H NMR (400 MHz, DMSO-d6) δ ppm 3.62 - 3.69 (m, 3 H) 7.20 (td, =8.49, 2.24 Hz, 1 H) 7.54 - 7.62 (m, 1 H) 7.70 - 7.80 (m, 2 H) 7.99 (dd, 12.93, 1.80 Hz, 1 H) 8.07 (d, J=2.34 Hz, 1 H) 8.24 (t, =8.39 Hz, 1 H) 8.52 (d, J=2.34 Hz, 1 H) 10.40 (s, 1 H); ES LC-MS m/z =440.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; | Step A(R)-5-bromo-N- -2-nitroaniline[00224] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), (R)-2- methyl-1-phenylpropan-l-amine, Hydrochloride (1.357 g, 9.09 mmol) and K2CO3 (2.51 g,18.18 mmol) in DMF (20 mL) (1.51 g) The mixture was heated overnight at 90°C. The mixture was allowed to cool to room temperature then diluted with EtOAc. The mixture was then washed with 5percent LiCI solution 3 x 100 mL then brine. The organic layer was dried with Na2S04, filtered and purified by silica gel chromatography (0-20 percent EtOAc in hexanes). Fractions containing the product were combined and concentrated to obtain 3.48 g of a yellow oil. The sample was dissolved in DMF (20mL) and (R)-2-methyl-1-phenylpropan-1 -amine, Hydrochloride (543 mg) was added followed by K2C03 (1.51 g). The mixture was heated overnight at 90°C.The mixture was allowed to cool to room temperature then diluted with EtOAc. The mixture was then washed with 5percent LiCI solution 3 x 100 mL then brine. The organic layer was dried with Na2S04, filtered and purified by silica gel chromatography (0-20 percent EtOAc in hexanes) to obtain (R)-5-bromo-N-(2-methyl-1-phenylpropyl)-2-nitroaniline as a yellow oil, (3.11 g, 8.11 mmol as 0.3 ethyl acetate, 89 percent yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.55 (d, J=7.2 Hz, 1 H) 7.99 (d, J=9.0 Hz, 1 H) 7.30 - 7.44 (m, 4 H) 7.22 - 7.30 (m, 1 H) 7.04 (d, J=2.0 Hz, 1 H) 6.81 (dd, J=9.1 , 2.0 Hz, 1 H) 4.65 (t, J=7.0 Hz, 1 H) 2.07 - 2.24 (m, 1 H) 0.68 - 1.07 (m, 6 H). LCMS: m/z 349.1 (M+H+).Step B |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h; | a) To a solution of 4-bromo-2-fluoro-nitrobenzene (5.8 g, 25.6 mmol) and (lR)-l- (2,4-dichlorophenyl)ethanamine (prepared from Example 1, 5.1 g, 26.8 mmol) in anhydrous dimethyl sulfoxide (DMSO, 55 mL) was added potassium carbonate (K2CO3, 7.4 g, 53.1 mmol). The reaction mixture was heated at 120 C for 1 h. After cooling to room temperature, the mixture was diluted with deionized water (750 mL) and the flask was rinsed with z'PrOH (25 mL). The mixture was stirred for 30 min, and a bright yellow solid was obtained. The solid was collected by filtration, and dried in vacuo to give the desired product (9.7 g, 25.0 mmol, 94%). MS: (ES) m/z calculated for Ci4H12BrCl2 202 [M + H]+ 388.9, found 390. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 2-methyl-3-buten-2-ol With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Reflux; Inert atmosphere; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran; mineral oil at 20℃; for 16h; | 1 Synthesis of 325 Synthesis of 325 Under an argon atmosphere, a tetrahydrofuran (15 ml) solution of 324 (3.1 g, 36 mmol) was added dropwise to a tetrahydrofuran (30 ml) suspension of 60% sodium hydride (1.44 g, 36 mmol) at room temperature, and the mixture was heated at reflux for 30 minutes. The reaction solution was cooled to 0 to 5°C and a tetrahydrofuran (15 ml) solution of 323 (7.2 g, 33 mmol) was added dropwise, and the solution was stirred at room temperature for 16 hours. The reaction solution was poured into a cooled aqueous ammonium chloride solution, and then the solution was extracted with ethyl acetate. The extraction liquid was dried and the solvent was distilled off under reduced pressure, and then the residue was purified by silica gel flash column chromatography (eluting solvent: n-hexane → ethyl acetate/n-hexane = 1/50, 1/20) to obtain 325 (8.46 g, 90%) as a yellow oily substance. APCI-MS m/z 303/305[M+NH4]+ |
Stage #1: 2-methyl-3-buten-2-ol With sodium hydride In tetrahydrofuran for 0.5h; Reflux; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: isopropyl alcohol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran; mineral oil at 0 - 20℃; for 18h; | |
88% | With caesium carbonate for 2h; Reflux; | A23 Preparation of intermediate 65 A mixture of 4-bromo-2-fluoro-1-nitrobenzene (3.00 g, 13.60 mmol) and Cs2CO3 (13.50 g, 41.40 mmol) in iPrOH (30 mL) was stirred and refluxed for 2 h. The mixture was cooled down to rt and filtered on a pad of celite. The cake was washed with iPrOH and the filtrate was evaporated in vacuo. The residue was taken-up in EtOAc and water. The layers were separated and the aqueous organic layer was washed withwater, dried over MgSO4, filtered off and evaporated in vacuo to give an orange liquid. The residue (3.6 g) was purified by column chromatography on silica gel (irregular SiOH, 15-40 jim, 120 g, dry loading on celite, mobile phase: heptane/DCM, gradient:from 80% heptane, 20%DCM to 50% heptane, 50% DCM). The desired fraction were collected and evaporated to dryness to give 3.12 g of intermediate 65 (88% yield,yellow liquid (which crystalized on standing)). |
87% | Stage #1: isopropyl alcohol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; | A Step A, 4-Bromo-2-isopropoxy-1-nitrobenzene To a suspension of NaH (60%, 1.5 g, 36.4 mmol) in THF (100 mL) under nitrogen at 0 °C was added i-PrOH (2.6 mL, 34.1 mmol) dropwise. The mixture was stirred at room temperature for 0.5 hour, followed by the addition of 4-bromo-2-fluoro-1-nitrobenzene (5 g, 22.7 mmol). The reaction mixture was stirred under nitrogen at room temperature for 0.5 h. Ice- water was added to quench the reaction, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica column chromatography (gradient elution: 0 - 1% EtOAc in petroleum ether) to give the title compound as a yellow oil (5.1 g, yield: 87%). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.6 Hz, 1 H), 7.23 (s, 1 H), 7.14 (dd, J= 8.6, 1.7 Hz, 1 H), 4.67 (dquin, J= 12.1, 6.0 Hz, 1 H), 1.42 (s, 3 H), 1.41 (s, 3 H) ppm |
79% | at 60℃; for 16h; | 10 Preparation of compound 10-d 2-Fluoro-4-bromonitrobenzene (5.0 g, 22.83 mmol) was dissolved in isopropanol (100 mL) and cesium carbonate(37.2 g, 114.16 mmol) was added thereto. The reaction mixture was stirred at 60 °C for 16 hours. The reactionmixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The residuewas dissolved in ethyl acetate (150 mL) and then water (150 mL) was added. The separated organic phase was driedover anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue wasrecrystallized from petroleum ether (100 mL) to deliver a yellow solid 10-d (4.7 g, yield: 79%). This product was usedwithout further purification |
50.8% | With sodium ethanolate at 60℃; for 16h; | 4 Step 4: Synthesis of 4-bromo-2-isopropoxy-1-nitrobenzene (4-8) : To the isopropanol solution (50 ml) of 4-bromo-2-fluoro-1-nitrobenzene (5.0g, 22.7 mmol) was added sodium ethoxide (22.7 mmol) and heated for 60 °C for 16 hours. TLC and LCMS of the reaction indicated complete consumption of starting material. Isopropanol was evaporated from the reaction mixture, and the resulting residue and extracted by ethyl acetate (2X50 ml). The combined organic layers were dried over Na2SO4 and evaporated to get crude material, which was purified by using isolera columns chromatography to afford 4- bromo-2-isopropoxy-1-nitrobenzene (3g, 11.5mmol, 50.8% yield). |
With caesium carbonate at 85℃; for 1.5h; | 8.1 Method 1 4-(1-Methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline Method 1 4-(1-Methylpiperidin-4-yl)-2-(propan-2-yloxy)aniline A mixture of 10.0 g of 4-bromo-2-fluoro-1-nitrobenzene, 44.4 g of caesium carbonate and 100 ml of isopropanol is heated at 85° C. (bath) for 1 h 30, and then left to cool to ambient temperature. The mixture is concentrated under vacuum and the residue is taken up with 400 ml of water and 300 ml of ethyl acetate. The aqueous phase is extracted with 100 ml of ethyl acetate and the combined organic phases are washed twice with 200 ml of water. The organic phases are dried over magnesium sulfate and concentrated under vacuum, so as to obtain 11.59 g of crude 4-bromo-1-nitro-2-(propan-2-yloxy)benzene in the form of a yellow oil which crystallizes. TLC: Rf=0.52 (dichloromethane/heptane (1/1)). |
|
With caesium carbonate at 85℃; for 1.5h; | III.8.1 A mixture of 10.0 g of 4-bromo-2-fluoro-1 -nitrobenzene, 44.4 g of caesium carbonate and 100 ml of isopropanol is heated at 85 °C (bath) for 1 h 30, and then left to cool to ambient temperature. The mixture is concentrated under vacuum and the residue is taken up with 400 ml of water and 300 ml of ethyl acetate. The aqueous phase is extracted with 100 ml of ethyl acetate and the combined organic phases are washed twice with 200 ml of water. The organic phases are dried over magnesium sulfate and concentrated under vacuum, so as to obtain 1 1 .59 g of crude 4-bromo-1 -nitro-2-(propan-2-yloxy)benzene in the form of a yellow oil which crystallizes. TLC: Rf = 0.52 (dichloromethane/heptane (1 /1 )). | |
4.5 g | With caesium carbonate at 60℃; | 1 step 1:4-bromo-2-isopropoxy-1-nitrobenzene 4-bromo-2-fluoro-1-nitrobenzene (5.0 g) and cesium carbonate (22.1 g) were added to 50 in turnIn milliliters of isopropanol, react at 60 ° C overnight, concentrate under reduced pressure to remove solventThe resulting residue was dissolved in a small amount of ethyl acetate and water.Extracted with ethyl acetate, and the extract was washed with brine.After drying and concentrating anhydrous sodium sulfate,The residue obtained was flash chromatographed on silica gel ( petroleum ether: ethyl acetate,The title product (light yellow solid, 4.5 g) was obtained after 4:1, v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; | |
80% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; | (5-Bromo-2-nitrophenyl)(2-fluorophenyl)sulfane (18) (5-Bromo-2-nitrophenyl)(2-fluorophenyl)sulfane (18) Cesium carbonate (4.3 g, 13.2 mmol) was added to a solution of 4-bromo-2-fluoronitrobenzene 16 (2.42, 11 mmol, Aldrich) and 2-fluorobenzene thiol 17 (1.4 g, 11 mmol, Aldrich) in DMF (60 mL), and the mixture was stirred for 5 h at room temperature. Water (200 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and washed sequentially with water (100 mL) and then brine (100 mL). The organic phase was separated, dried, and concentrated to yield a yellow solid that was purified by silica gel chromatography (hexanes/EtOAc 8:1 to 3:1) to give 18 (2.88 g, 80%). 1H NMR (CDCl3, 400 MHz) δ 8.17 (d, J=8.0 Hz, 1H), 7.68-7.60 (m, 2H), 7.41-7.29 (m, 3H), 6.95 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With caesium carbonate; In N,N-dimethyl-formamide; at 40℃; for 48h; | [00381] Step 1. To a stirred solution of 4-bromo-2-fluoro- l-nitro-benzene (208.2 mg, 0.946 mmol) and 2,2-difluoropropan- l-ol (100 mg, 1.041 mmol) in DMF (6 mL, 77.5 mmol) was added cesium carbonate (244 mg, 0.75 mmol). The reaction mixture was stirred for 48 h at 40C. The mixture was diluted with EtOAc, then washed with aq. Sat. NaHC03, H20, and brine. The organic layer was dried over sodium sulfate and solvent was removed in vacuo. The crude product was purified by flash column chromatography using gradient elution (EtOAc in Heptanes, 0 to 40%). Removal of solvents afforded 168.3 mg of intermediate 103- B as a yellow solid (60%). LC-MS: m/z = 295.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | General procedure: Preparation 100: 4-bromo-2-ethoxy-1 -nitrobenzene To a cooled (0C) solution of EtOH (0.07 mL, 1 .193 mmol) in THF (5 mL) was added NaH (60% suspension in mineral oil, 68 mg, 1 .705 mmol). The reaction mixture was stirred under nitrogen at 0 for 15 minutes. 2-fluoro-4-bromo-nitrobenzene (250 mg, 1 .136 mmol) was added and the reaction mixture stirred for a further 18 hours, whilst warming slowly to room temperature. The reaction mixture was concentrated in vacuo. Ether (20 mL) and HCI (0.5 M, 20 mL) were added. The aqueous layer was basified with aqueous saturated NaHC03 solution and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried (MgS04) and concentrated in vacuo, to give the title compound (270 mg, 97%). 1 H NMR (500 MHz, CDCI3): delta 7.74 (d, J = 8.5 Hz, 1 H), 7.24 (d, J = 2.0 Hz, 1 H), 7.17 (dd, J = 8.5, 2.0 Hz, 1 H), 4.1 9 (q, J = 7.0 Hz, 2H), 1 .50 (t, J = 7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In 1-methyl-pyrrolidin-2-one; at 110℃; | 4-Bromo-2-fluoro-nitrobenzene (5.6 g, 20.9 mmol) and aniline (2.5 g, 72.2 mmol) are added to 50 ml. of anhydrous NMP. The reaction is heated to 1 10 C overnight. After cooling to room temperature and removing the solvent, the compound is purified via column chromatography (silica, cyclohexane/ethyl acetate 9:1 ) and obtained as an orange solid in 92% yield (5.7 g). H-NMR (400 MHz, CD2CI2): delta = 9.48 (s, 1 H), 8.06 (d, 1 H), 7.46 (t, 2H), 7.30 (t, 4H), 6.89 (d, 1 H). |
92% | In dimethyl sulfoxide; at 130℃; for 16h; | Take 2-fluoro-4-bromonitrobenzene (4-Bromo-2-fluoro-1-nitrobenzene, 10 g,46.1 millimolar), aniline (5.2 grams, 55.3 millimoles),Dimethyl sulfoxide (DMSO, 130 ml) was reacted at 130 C for 16 hours.Return to room temperature and distill off the solvent under reduced pressureExtracted with ethyl acetate and saline solution,The organic layer was dehydrated with anhydrous magnesium sulfate and then dried with a rotary concentrator.The red liquid was obtained in 12.4 g, and the yield was 92%. |
88% | In 1-methyl-pyrrolidin-2-one; at 50℃; for 30h;Inert atmosphere; | 4-bromo-2-fluoronitrobenzene (1.0 g, 4.3 mmol) and aniline (490 mg, 5.2 mmol) are suspended in 1 -methyl-2-pyrrolidon (2 ml_). The mixture is purged with argon, then heated to 50C for 15 h. Additional aniline (350 mg, 3.7 mmol) is added to the reaction. The mixture is stirred at 50C for 15 h. After cooling to room temperature the mixture is diluted with 2 ml. of methanol and 15 ml_ of water. The obtained precipitate is filtered and washed twice with methanol/water-solution (2:1 ). The solid is dried at 60C under vacuum. The desired product is obtained in 88% yield (1 .1 g). 1H-NMR (400 MHz, CD2CI2): delta = 6.89 (d, 1 H), 7.32-7.26 (m, 3H), 7.33 (s, 1 H), 7.46 (t, 2H), 8.05 (d, 1 H), 9.47 (s, 1 H). |
57% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 50℃; for 48h; | To a solution of 105 (10 g, 45.5 mmol) and aniline (5.08 g 54.5mmol) in 100 mL NMP, potassium acetate was added (18.8 g, 136.4 mmol). The reaction mixture was stirred for 48 h at 50C. The reaction was diluted with 500 ml of water. The formed residue was filtered off, washed with H20, dried, and washed with an ice-cold mixture of hexane/ Et20 2: 1 to give (5-bromo-2- nitrophenyl)phenylamine (126) (7.63 g, 57%), 1H-NMR (DMSO-d6 , 400 MHz): 9.47 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.47 (dd, Ji = J2 = 8.0 Hz, 2H), 7.37-7.33 (m, 2H), 7.27 (dd, Ji = J2 =7.6Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.02 (dd, = 8.8 Hz, J2 = 2.0 Hz), |
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 60℃; for 4h; | Aniline (930 mg, 10.0 mmol) was added to a solution of DIPEA (1.94 g, 15.0 mmol) and 4-bromo-2-fluoro-l -nitrobenzene (2.2 g, 10.0 mmol) in DMSO (16 mL). The reaction mixture was stirred at 60C for 4h. Upon completion, the mixture was diluted with water (50 mL), and the resulting precipitate collected by filtration, washed with water and dried in vacuo. The crude product was used in next step without further purification. LCMS (m/z): 293.1/294.1 [M+H]+/ [M+2H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: diethyl malonate With sodium hydride In hexane; dimethyl sulfoxide at 60℃; for 0.25h; Stage #2: 4-bromo-2-fluoronitrobenzene In hexane; dimethyl sulfoxide at 80℃; for 4.5h; | Diethyl 2-(5-Bromo-2-Nitrophenyl) Malonate (2). To a solution of 20 ml n-hexane, add 5.0 g 60% NaH (125 mmol) and stir 2 min, then remove suspension. Slowly add 90 ml DMSO and 13.5 g diethyl malonate (100 mmol). Control the temperature under 40 oC. Then put mixture heated at 60 oC for 15 min and cooled down to rt. Add 11.0 g 1 (50 mmol) by drop. The mixture was heated at 80 oC for 4.5 h and then cooled to rt. Add 100 ml saturated NH4Cl solution to stop the reaction. Three times extraction with acetyl acetate (EA) were performed and washed with saturated NaCl solution, then dry with Na2SO4. Remove EA by evaporation and obtained 17.9 g Diethyl 2-(5-Bromo-2-Nitrophenyl) Malonate (2) and proceed to next step without purification. Yellow solidyield: 99.0%, mp. 70-72oC, HPLC: 99.1%. HRMS (ESI) m/z calcd for [C13H14BrNO6+H]+ 381.9902; found, 381.9901 [M+Na]+, 383.9882 [M+Na]+. |
67.2% | In N,N-dimethyl-formamide Heating; Alkaline conditions; | |
17.9 g | Stage #1: diethyl malonate With sodium hydride In hexane; dimethyl sulfoxide at 40 - 60℃; for 0.25h; Stage #2: 4-bromo-2-fluoronitrobenzene In hexane; dimethyl sulfoxide at 80℃; for 4.5h; | 2 - nitro -3 - bromophenylacetic c b acid ethyl ester synthesis To is provided with a 20 ml hexane, the magnetic coil and a thermometer of the 250 ml three-necked bottle added 60% NaH (5.0g, 125mmol), after the step of stirring 2min, remove supernatant. Slowly adding DMSO solvent 90 ml, adjusting the stirring speed to moderate, constant voltage used in the dropping funnel slowly adds by drops third acid diethyl ester (13.5g, 100mmol), produced in the process of dropping a large amount of hydrogen and the exothermic (temperature control in 40 °C within), at the same time keep the internal and external pressure are a. After dropping the reaction liquid is put into the 60 °C oil bath to continue stirring 15min, taken out and cooled to the room temperature. Gradual dissolved in 50 ml DMSO solution of the raw materials in the 2 - fluoro -4 - bromo nitrobenzene (11.0g, 50mmol), solution immediately turned into a deep black red, together with the condenser tube, the device is put into the 80 °C oil desire reaction 4.5h. Stopping the reaction, cooling to room temperature, for 100 ml saturated NH4Cl solution quenching reaction. Extracted with ethyl acetate 3 times, acetic acid ethyl ester level saturated NaCl solution for washing 2 times, Na2SO4Drying and put 5h; turns on lathe does organic solvent, after cooling to separate out 17.9g 2 - nitro -3 - bromophenylacetic c diethyl malonate, yellow crystal, directly into the next step reaction. |
92 g | With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 12h; Inert atmosphere; | 10 Synthesis of Intermediate B40 A mixture of 4-bromo-2-fluoro-l -nitrobenzene (B39; 65.3 g, 297 mmol), diethyl malonate (52 g, 327 mmol), and CS2CO3(116 g, 356 mmol) in dimethylformamide (650 mL) was stirred for 12 h at 50 °C under an atmosphere of nitrogen. The reaction was then quenched by the addition of water/ice (1.5 L), and the resulting solution was extracted with ethyl acetate (3 x 1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:5) to afford 1,3- diethyl 2-(5-bromo-2-nitrophenyl) propanedioate (B40; 92 g) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; In ethanol; water; at 20 - 85℃; for 18h; | 4-Bromo-2-fuoro-l-nitrobenzene (1.00 g, 4.54 mmoi), ethyl 2- ibenzylarrsino)acetate (0.87 g, 4.5 mmoi), and potassium carbonate (0.78 g, 5.7 mmoi) in ethanol (15 m L) and water (11 mL) were heated at 85 "C for 10 h then stirred at rt for 8 h. The reaction mixture was diluted with water and brine then washed with methylene chloride. The resultant aqueous layer was filtered to afford 99 as an orange solid (1.28 g, 72%):*'H NM R (300 M Hz, DMSO- ): delta 7.57 (d, J = 8.6 Hz, 1H), 7.37-7.21 (m, 6H), 6.97 (dd, J - 8.7, 2,0 Hz.. 1H), 4.52 (s, 2H), 3.40 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In ethanol; at 20℃; for 2h; | 4-Bromo-2-fluoro-1-nitro-benzene (15.0 g, 68.2 mmol) was dissolved in ethanol (150 ml), and sodium ethoxide (14.0 g, 205 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, and then diluted with water. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (16.0 g, 95%). [1293] 1H NMR (400 MHz, CDCl3): delta 7.72 (d, J=8.4 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.15 (dd, J=8.8, 2.0 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 1.48 (t, J=7.2 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In acetonitrile at 80℃; | 126 Ethyl (3R)-3 -(5 -bromo-2-nitro-anilino)-3 - [2-chloro-6-(difluoromethoxy)phenyllpropanoate General procedure: To a solution of Intermediate 118 (5 g, 17.06 mmol) in MeCN (50 mL) was added potassium carbonate (7.06 g, 51.18 mmol) and 1 -bromo-2,5-difluoro-4-nitrobenzene (4.86g, 20.47 mmol). The reaction mixture was stirred at 80°C for 16h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (Si02, 20 % EtOAc in hexane) to afford the title compound (6g, 69%) as a yellow viscous liquid. Intermediate 126 was prepared from Intermediate 118 (9.3g, 28.3 mmol) and 4-bromo-2-fluoro-nitrobenzene (7.4g, 34 mmol), using the same procedure described forpreparation of Intermediate 119. The reaction was stirred overnight at 80°C and purified by chromatography (Si02, 10% EtOAc in hexane). Intermediate 126 was obtained as a yellow oil (12.5g, 90%).LCMS (ESj 493.0/495.0 (M+H) |
90% | With potassium carbonate In acetonitrile at 80℃; | INTERMEDIATE 15 ethyl (3R)-3 -(5 -bromo-2-nitro-anilino)-3 - [2-chloro-6-(difluoromethoxy)phenyllpropanoate Intermediate 15 was prepared, using the same procedure described for preparation of Intermediate 5, from Intermediate 4 (9.3g, 28.3 mmol) and 4-bromo-2-fluoro-nitrobenzene (7.4g, 34 mmol). The reaction was stirred overnight at 80°C and purified by chromatography (Si02, 10% EtOAc in hexane). Intermediate 15 was obtained as a yellow oil (12.5g, 90% yield).LCMS (ESj 495 (M+H):_To a solution of Intermediate 4 (5 g, 17.06 mmol) in MeCN (50 mL) was added potassium carbonate (7.06 g, 51.18 mmol) and 1 -bromo-2,5-difluoro-4-nitrobenzene (4.86 g, 20.47 mmol). The reaction mixture was stirred at 80°C for 16h. After completion ofreaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (Si02, 20 % EtOAc in hexane) to afford the title compound (6g, 69% yield) as a yellow viscous liquid.LCMS (ES+) RT 3.42 mm, 510.90/512.90/514.90 (M+H) |
90% | With potassium carbonate In acetonitrile at 80℃; | Ethyl (3i?)-3-(5-bromo-2-nitroanilino)-3-[2-chloro-6-(difluoromethoxy)phenyl]- propanoate To a solution of Intermediate 4 (9.3 g, 28.3 mmol) in acetonitrile (80 mL) were added potassium carbonate (11.73 g, 84.9 mmol) and 4-bromo-2-fluoro-l -nitrobenzene (7.4 g, 34 mmol). The reaction mixture was stirred at 80°C overnight, then diluted with EtOAc (150 mL) and washed with water (150 mL). The organic layer was separated and dried over anhydrous sodium sulphate, then filtered and concentrated under reduced pressure. The residue was purified by chromatography (S1O2, 10% EtOAc in hexane) to afford the title compound (12.5 g, 90%) as a yellow oil. LCMS Method 1 (ES+) 493 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | Stage #1: N-(2-Hydroxyethyl)phthalimide With potassium <i>tert</i>-butylate In tetrahydrofuran for 0.0833333h; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran at 20℃; for 14h; Stage #3: isopropyl chloroformate | 147.1 Stepisopropyl 12-(5-bromo-2-nitrophenoxy)ethylj carbamate Stepisopropyl 12-(5-bromo-2-nitrophenoxy)ethylj carbamateN-(2-Hydroxyethyl)phthalimide (0.2 17 g, 1.14 mmol) was added to a suspension of potassium tert-butoxide (0.153 g, 1.36 mmol) in tetrahydrofuran (5 mL). The suspension was stirred for 5 minutes, then 4-bromo-2-fluoronitrobenzene (0.25 g, 1.14 mmol) was added. The mixture was stirred at room temperature for 14 hours and then concentrated under vacuum. The residue was taken up in CHC13 (20 mL) and washed with 8% aqueous H2S04 (10 mL). The organic layer was dried (MgSO4) and filtered. To the filtrate was added anhydrous hydrazine (0.15 mL, 4.8 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was filtered with a CHC13 (10 mL) rinse. The combined filtrate and washing was concentrated under vacuum, and the residue was taken up in aqueous 10% K2C03 (20 mL) and CH2C12 (20 mL). This mixture was stirred at room temperature as a solution of isopropyl chloroformate in toluene (1 M, 3.42 mL, 3.42 mmol) was added. After 45 minutes, the aqueous layer was separated and extracted with CH2C12 (10 mL), and the combined organic phases were concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluted with heptanes-ethyl acetate, 90:10 - 60:40) to provide the titled compound (116 mg, 29%). ‘H NMR (300 MHz, CDC13) 5 ppm 1.23 (d, J = 6.1 Hz, 6H), 3.63 (q, J = 5.2 Hz, 2H), 4.18 (t, J = 4.9 Hz, 2H), 4.91 (sept, J = 6.2 Hz, 1H), 5.19 (br m, 1H), 7.20 (dd, J = 8.5, 2.0 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H); MS (ESI) m/z 347/349 (M+H). |
29% | Stage #1: N-(2-Hydroxyethyl)phthalimide With potassium <i>tert</i>-butylate In tetrahydrofuran for 0.0833333h; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran at 20℃; for 14h; Stage #3: isopropyl chloroformate Further stages; | 147.1 Example 147 isopropyl [2-(5-bromo-2-nitrophenoxy)ethyl]carbamate Step 1 isopropyl [2-(5-bromo-2-nitrophenoxy)ethyl]carbamate N-(2-Hydroxyethyl)phthalimide (0.217 g, 1.14 mmol) was added to a suspension of potassium tert-butoxide (0.153 g, 1.36 mmol) in tetrahydrofuran (5 mL). The suspension was stirred for 5 minutes, then 4-bromo-2-fluoronitrobenzene (0.25 g, 1.14 mmol) was added. The mixture was stirred at room temperature for 14 hours and then concentrated under vacuum. The residue was taken up in CHCl3 (20 mL) and washed with 8% aqueous H2SO4 (10 mL). The organic layer was dried (MgSO4) and filtered. To the filtrate was added anhydrous hydrazine (0.15 mL, 4.8 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was filtered with a CHCl3 (10 mL) rinse. The combined filtrate and washing was concentrated under vacuum, and the residue was taken up in aqueous 10% K2CO3 (20 mL) and CH2Cl2 (20 mL). This mixture was stirred at room temperature as a solution of isopropyl chloroformate in toluene (1 M, 3.42 mL, 3.42 mmol) was added. After 45 minutes, the aqueous layer was separated and extracted with CH2Cl2 (10 mL), and the combined organic phases were concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluted with heptanes-ethyl acetate, 90:10-60:40) to provide the titled compound (116 mg, 29%). 1H NMR (300 MHz, CDCl3) δ ppm 1.23 (d, J=6.1 Hz, 6H), 3.63 (q, J=5.2 Hz, 2H), 4.18 (t, J=4.9 Hz, 2H), 4.91 (sept, J=6.2 Hz, 1H), 5.19 (br m, 1H), 7.20 (dd, J=8.5, 2.0 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H); MS (ESI) m/z 347/349 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Step 14-bromo-1-nitro-2-(2-phenoxyethoxy)benzene<strong>[122-99-6]2-Phenoxyethanol</strong> (345 mg, 2.500 mmol) was added to a suspension of potassium tertbutoxide (306 mg, 2.73 mmol) in tetrahydrofuran (10 mL). The suspension was stirred for 10 minutes, then 4-bromo-2-fluoronitrobenzene (500 mg, 2.273 mmol) was added, and stirring was continued at room temperature for 41 hours. The mixture was concentrated under vacuum, and the residue was diluted with water (15 mL) and extracted with ethyl acetate (2x30 mL). The combined extract was dried (MgSO4), concentrated under vacuum and purified by flash chromatography (silica gel eluted with hexanes-ethyl acetate, 100:0-90:10) to provide the titled compound (546 mg, 7 1%). ?H NMR (300 MHz, DMSO-d6) 5 ppm 4.354.42 (m, 2H), 4.44 - 4.50 (m, 2H), 6.91 - 6.95 (m, 2H), 6.96 - 7.02 (m, 1H), 7.21 (dd, J = 8.8,1.7 Hz, 1H), 7.27 - 7.35 (m, 2H), 7.38 (d, J = 1.7 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H). | |
71% | Step 1 4-bromo-1-nitro-2-(2-phenoxyethoxy)benzene <strong>[122-99-6]2-Phenoxyethanol</strong> (345 mg, 2.500 mmol) was added to a suspension of potassium tert-butoxide (306 mg, 2.73 mmol) in tetrahydrofuran (10 mL). The suspension was stirred for 10 minutes, then 4-bromo-2-fluoronitrobenzene (500 mg, 2.273 mmol) was added, and stirring was continued at room temperature for 41 hours. The mixture was concentrated under vacuum, and the residue was diluted with water (15 mL) and extracted with ethyl acetate (2*30 mL). The combined extract was dried (MgSO4), concentrated under vacuum and purified by flash chromatography (silica gel eluted with hexanes-ethyl acetate, 100:0-90:10) to provide the titled compound (546 mg, 71%). 1H NMR (300 MHz, DMSO-d6) delta ppm 4.35-4.42 (m, 2H), 4.44-4.50 (m, 2H), 6.91-6.95 (m, 2H), 6.96-7.02 (m, 1H), 7.21 (dd, J=8.8, 1.7 Hz, 1H), 7.27-7.35 (m, 2H), 7.38 (d, J=1.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In ethanol; at 120℃; for 0.166667h;Irradiation; | Step 11-(5-bromo-2-nitrophenyl)-4-<strong>[17766-28-8]cyclohexylpiperazine</strong>A mixture of 4-bromo-2-fluoronitrobenzene (204 mg, 0.927 mmol), 1 -<strong>[17766-28-8]cyclohexylpiperazine</strong> (328 mg, 1.947 mmol) and ethanol (4 mL) was irradiated at 120 C (Biotage PersonalChemistry unit, 300 W) for 10 minutes. The solution was cooled to room temperature andconcentrated under vacuum. The residue was purified by flash chromatography (silica geleluted with hexanes-ethyl acetate, 90:10 - 70:30) to provide the titled compound (300 mg,88%). ?H NMR (300 MHz, methanol-d4) ppm 1.08 - 1.39 (m, 5 H), 1.60 - 1.70 (m, 1 H),1.79 - 1.89 (m, 2 H), 1.90 - 2.01 (m, 2 H), 2.33 (tt, J=10.7, 3.2 Hz, 1 H), 2.65 - 2.77 (m, 4 H),3.03 - 3.10 (m, 4 H), 7.23 (dd, J=8.8, 2.0 Hz, 1 H), 7.41 (d, J=2.0 Hz, 1 H), 7.68 (d, J=8.8 Hz,1 H); MS (ESI) m/z 368/370(M+H). |
88% | In ethanol; at 120℃; for 0.166667h;Microwave irradiation; | Step 1 1-(5-bromo-2-nitrophenyl)-4-<strong>[17766-28-8]cyclohexylpiperazine</strong> A mixture of 4-bromo-2-fluoronitrobenzene (204 mg, 0.927 mmol), 1-<strong>[17766-28-8]cyclohexylpiperazine</strong> (328 mg, 1.947 mmol) and ethanol (4 mL) was irradiated at 120 C. (Biotage Personal Chemistry unit, 300 W) for 10 minutes. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluted with hexanes-ethyl acetate, 90:10-70:30) to provide the titled compound (300 mg, 88%). 1H NMR (300 MHz, methanol-d4) delta ppm 1.08-1.39 (m, 5H), 1.60-1.70 (m, 1H), 1.79-1.89 (m, 2H), 1.90-2.01 (m, 2H), 2.33 (tt, J=10.7, 3.2 Hz, 1H), 2.65-2.77 (m, 4H), 3.03-3.10 (m, 4H), 7.23 (dd, J=8.8, 2.0 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H); MS (ESI) m/z 368/370 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 50℃; for 3h; | 127.1 Step 1: 5-bromo-N-ethyl-2-nitroaniline (127a) General procedure: A solution of compound (30b) (180 mg, 0.47 mmol), (S)-pyrrolidin-3-yl-methanol (53 mg, 0.51 mmol) and DIPEA (140 μL, 0.78 mmol) in CH3CN (10 mL) was stirred at 50°C for 3 hours. The middle was then concentrated under reduced pressure. The crude was purified by flash preparative TLC on silica gel (DCM/MeOH 92/8) to give compound (30c) (100 mg, 0.21 mmol, 46%). According to the procedure described in example 30, step 3, 4-bromo-2-fluoro-1-nitrobenzene (220 mg, 1 mmol)was converted, by reaction with Ethylamine hydrochloride (82 mg, 1 mmol) and after purification by preparative TLC onsilica gel (DCM), to compound (127a) (244 mg, 1 mmol, 100%). 1H NMR (400 MHz, DMSO-d6) δ 1.22 (t, J = 7.1 Hz,3H), 3.36-3.40 (m, 2H), 6.82 (dd, J = 9.1/2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 9.1 Hz, 1H), 8.12 (bs, 1H).MS m/z ([M+H]+) 245/247. |
85% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 80℃; for 19h; | 32.A 5-bromo-N-ethyl-2-nitroaniline A solution of 4-bromo-2-fluoro-l -nitrobenzene (5.1 g, 23.18 mmol), ethanamine, HCl (1.890 g, 23.18 mmol) and DIEA (8.10 mL, 46.4 mmol) in DMA (25.8 mL) was heated to 80 °C for 19 h The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (3x15 mL), dried over MgS04, filtered and concentrated under reduced pressure. Obtained 5-bromo-N-ethyl-2-nitroaniline (5.1 g, 19.77 mmol, 85 % yield). Carried on without further purification. 1H NMR (400 MHz, CHLOROFORM- ) δ ppm 8.03 (d, J=9.0 Hz, 1H), 7.97 (br. S., 1H), 7.02 (d, J=1.8 Hz, 1H), 6.76 (dd, J=9.3, 2.0 Hz, 1H), 3.34 (qd, J=7.2, 5.0 Hz, 2H), 1.39 (t, J=7.3 Hz, 3H), LC/MS (ESI) m/e 245.0, 247.0 Br pattern [(M+H)+, calcd for C8H10BrN2O2 245.0]. |
With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 16h; | 12 Synthesis of 5-bromo-N-ethyl-2-nitroaniline (12a). To a solution of 4-bromo-2- fluoro-1-nitrobenzene (2 g, 9.09 mmol) and ethanamine (1.65 g, 36.53 mmol, 2.39 mL, HCl) in CH3CN (50 mL) was added DIEA (5.87 g, 45.45 mmol). Then the mixture was stirred at 60°C for 16 hours. TLC showed the reaction was completed. The mixture was concentrated in vacuum. The residue was extracted with EtOAc (50 mL+20 mL) and H2O (20 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuum to give 12a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.2% | With potassium carbonate In ethanol; water at 100℃; for 10h; | 4.1.1. General procedure for the preparation of 2a-f General procedure: To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1g, 4.55mmol), K2CO3 (0.78g, 5.68mmol) and different amino acid (5.45mmol) in ethanol (5ml) and water (4ml) were refluxed at 100°C for 10h. After cooling to the room temperature, pH value was adjusted to 2 with 1M HCl solution. The mixture was filtered and the precipitate was collected to afford 2a-g as golden yellow solid. 4.1.1.1 (5-Bromo-2-nitrophenyl)-d-alanine (2a) (0013) Golden yellow solid, yield 98.2%; ESI-MS m/z 287.9 [M+H]+; 1H NMR (300MHz, DMSO-d6) δ: 8.39 (d, J=6.8Hz, 1H), 8.02 (d, J=9.1Hz, 1H), 7.23 (s, 1H), 6.90 (dd, J=9.1, 1.7Hz, 1H), 4.62-4.46 (m, 1H), 1.46 (d, J=6.9Hz, 3H). |
91% | With potassium carbonate In ethanol; water for 10h; Reflux; | 4.2. (5-bromo-2-nitrophenyl)-D-alanine (2) To a solution of 4-Bromo-2-Fluoronitrobenzene (2.0 g, 9 mmol) and Potassium carbonate (1.38 g, 10 mmol) in Ethanol (15 mL) and water (6 mL) was added D-alanine (1.0 g,11 mmol), the mixture was heated to reflux for 10 h. after the reaction was completed, the solution was cooled to room temperature and pH value was adjusted to 2 with 1 M HCl solution. The precipitate was collected by filtration to afford (5-bromo-2-nitrophenyl)-D-alanine as golden yellow solid (2.37 g, 91 %) without further purification. ESI-MS m/z 289.2 [M + H]+; 1H NMR (300 MHz, DMSO) 8.39 (d, J = 6.8Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.23 (s, 1H), 6.90 (dd, J =9.1, 1.7 Hz, 1H), 4.62-4.46 (m, 1H), 1.46 (d, J = 6.9 Hz,3H). |
88% | With potassium carbonate In ethanol; water at 80℃; for 8h; | 1.a Example 1 (a) Compound 1A (25g, 113.64mmol), D-alanine (11.12g, 125.0mmol), potassium carbonate (17.25g, 125.0mmol) are dissolved in 500ml ethanol: water = 3:1 mixed solvent, 80 Heat to reflux at for 8 hours, monitor the reaction with a TLC plate, cool to room temperature after the reaction, evaporate the solvent, dissolve in water, adjust the pH to 1-2 with 1N HCl, a large amount of yellow solid precipitates, filter, and wash with 200ml petroleum ether The solid was dried in a vacuum drying oven to obtain 28.7 g of a yellow solid, namely compound 1B, with a yield of 88%. |
87% | With potassium carbonate In ethanol; water at 80℃; for 8h; | |
45.56 g | With potassium carbonate In ethanol; water for 16h; Reflux; | 1 N-(5-bromo-2-nitrophenyl)-D-alanine A solution of 35.6 g of 4-bromo-2-fluoronitrobenzene (CAS No. 321-23-3), 14.4 g of D-alanine and 27.95 g of potassium carbonate in 395 ml of ethanol and 175 ml of water was heated under reflux for 6 hours. After cooling to room temperature, the reaction mixture was acidified by addition of 1 N hydrochloric acid and the product formed was filtered off as a precipitate. This gave 45.56 g of N-(5-bromo-2-nitrophenyl)-D-alanine1H NMR (400 MHz, CDCl3): δ=1.46 (d, 3H); 4.52-4.62 (m, 1H); 6.89 (dd, 1H); 7.22 (d, 1H); 8.01 (d, 1H); 8.38 (d, 1H). |
17.36 g | With potassium carbonate In ethanol; water for 6h; Reflux; | Intermediate 11: N-(5-bromo-2-nitrophenyl)-D-alanine The 13.57g 4-bromo-2-fluoro-nitrobenzene, 5.49g D-alanine and 10.66g potassium carbonate solution in 150ml of ethanol and 60ml water was heated under reflux for 6 hours. After cooling to room temperature, by addition of 1M hydrochloric acid and the reaction mixture is acidified, and the product was isolated as a precipitate generated. To give 17.36g N-(5-bromo-2-nitrophenyl)-D-alanine. |
With potassium carbonate In ethanol; water at 20℃; for 12h; | ||
With potassium carbonate In ethanol; water for 8h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; Cooling with ice; | 4.1 Preparation 4: Preparation of Ν- (2-nitro-4-bromophenyl-6-phenoxy) _4-bromobenzenesulfonamide (compound 26) Step 1: 2.200g of 2-fluoro-4-bromonitrobenzene and 1.660g of K2C03 was added into a 100mL single-necked flask and added 30mL of DMF, DMF solution containing 1.040g of phenol was slowly dropped under ice-water bath, Dropping was completed and moved to the oil bath temperature 60 ° C for 12h. After completion of the reaction, ethyl acetate was added for extraction, washed with water three times, dried over anhydrous sodium sulfate and the filtrate was dried under reduced pressure. Obtained as a light yellow solid in 94% yield. |
94% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; | 6.1 step 1: 2.200 g of 2-fluoro-4-bromonitrobenzene and 1.660 g of K2CO3 were added to a 100-mL single-necked flask, 30 mL of DMF was added, and a DMF solution containing 1.040 g of phenol was slowly added dropwise in an ice-water bath. Move to the oil bath temperature of 60°C for 12 h.After the reaction was completed, ethyl acetate was added for extraction, washed with water three times, dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness under reduced pressure. Light yellow solid, yield 94%. |
90% | With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 3h; | 7 Example 7 (Scheme 13). Synthesis of ((S)-1-{(S)-2-[5-(4-iodo-3-phenoxy-phenyl)-lH-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (3(26)). A mixture of 4-bromo-2-fluoro- 1 -nitrobenzene (105) (7.0g, 31.8 mmol), phenol (3.1g, 33.4 mmol), K2CO3 (4.8 g, 35.0 mmol) in 50mL DMF was stirred at 75 °C for 3 h. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and water. The organic layer was washed successively with 2N aqueous NaOH, 2N aqueous HC1, saturated aqueous NaHCC>3, and brine, dried over Na2S04, and concentrated to give 4-bromo-l-nitro-2-phenoxybenzene (111) as orange crystals (8.4 g, 90%). 1H-NMR (CDCI3, 400 MHz): 8.05 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.46 (dd, Ji = J2 = 7.8 Hz, 1H), 7.25-7.30 (m, 2H), 7.08 (d, J = 7.8 Hz, 2H). |
88% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 75℃; for 3h; | Step 1: 4-bromo-1-nitro-2-phenoxy-benzene (2) Into a 50 mL pressure tube containing a well-stirred solution of 4-bromo-2-fluoro-1-nitro-benzene (1, 3 g, 13.64 mmol) in DMF (20 mL) was added phenol (1.28 g, 13.64 mmol, 1.20 mL) and potassium carbonate (3.77 g, 27.27 mmol, 1.65 mL) at 0 °C and the resulting mixture was stirred at 75 °C for 3 h. The reaction mixture was cooled to 0 °C and ice water (100 mL) was added. The precipitate was filtered, washed with water and dried under reduced pressure to afford 4-bromo- 1-nitro-2-phenoxy-benzene (2, 3.8 g, 12.02 mmol, 88% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J = 11.60 Hz, 1H), 7.59 (dd, J = 2.40, 11.80 Hz, 1H), 7.50-7.44 (m, 2H), 7.29-7.24 (m, 2H), 7.16-7.13 (m, 2H). |
Stage #1: 4-bromo-2-fluoronitrobenzene With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: phenol In N,N-dimethyl-formamide at 20℃; for 48h; | A Step A: 5-Bromo-2-nitrophenyl phenyl ether Step A: 5-Bromo-2-nitrophenyl phenyl ether To a stirred solution of 4-bromo-2-fluoro-l-nitrobenzene (300 mg, 1.36 mmol) in DMF (6.8 mL) was added cesium carbonate (1.33 g, 4.09 mmol). Stirring was continued at ambient temperature for 5 min, and to this mixture was added phenol (0.12 mL, 1.36 mmol). The reaction mixture was stirred at ambient temperature for 48 h, then partitioned between saturated aqueous sodium bicarbonate (100 mL) and EtOAc (100 mL). The aqueous layer was extracted further with EtOAc (2 x 100 mL) and the combined organic extracts were washed with water (3 x), then brine, then dried over a2S04, filtered, and concentrated in vacuo, to give the title compound in sufficient purity for use in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In ethanol; water; at 100℃; for 10h; | General procedure: To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1 g,4.55 mmol), K2CO3 (0.78 g, 5.68 mmol) and different amino acid(5.45 mmol) in ethanol (5 ml) and water (4 ml) were refluxed at100 C for 10 h. After cooling to the room temperature, pH valuewas adjusted to 2 with 1 M HCl solution. The mixture was filteredand the precipitate was collected to afford 2a-g as golden yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In ethanol; water at 100℃; for 10h; | 2 4.1.1. General procedure for the preparation of 2a-f General procedure: To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1 g,4.55 mmol), K2CO3 (0.78 g, 5.68 mmol) and different amino acid(5.45 mmol) in ethanol (5 ml) and water (4 ml) were refluxed at100 C for 10 h. After cooling to the room temperature, pH valuewas adjusted to 2 with 1 M HCl solution. The mixture was filteredand the precipitate was collected to afford 2a-g as golden yellowsolid. |
94% | With potassium carbonate In ethanol; water for 4h; Reflux; Inert atmosphere; | 4.1.2.1.1 Scheme 1 (5-Bromo-2-nitrophenyl)-l-alanine (57) To a solution of compound 56 (2g, 9.09mmol) and L-alanine (0.81g, 9.09mmol) in EtOH (10mL) was added K2CO3 (1.51g, 10.91mmol) in water (3mL). The mixture was heated to reflux for 4h and monitored by TLC. Upon completion, EtOH was evaporated. The residue was acidified with 1N aq. HCl to pH 3-4, diluted with water and extracted with EtOAc (3×50mL). Combined organic layers were washed with brine, and dried with Na2SO4 to afford compound 57 (2.48g, 8.58mmol, 94% yield) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.41 (d, J=7.0Hz, 1H), 8.02 (d, J=9.1Hz, 1H), 7.24 (s, 1H), 6.90 (d, J=9.5Hz, 1H), 4.62-4.52 (m, 1H), 1.45 (d, J=6.9Hz, 3H). |
With sodium hydrogencarbonate In ethanol; water at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 1.0h; | To a solution of 4-bromo-2-fluoro-1 -nitrobenzene (2.0 g, 9.09 mmol) in DME (20 mL) was added 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-one (prepared as in US20130053362, 4.53 g, 18.18 mmol), Cs2C03(2.96 g, 9.09 mmol), Pd(PPh3) (1.05 g, 0.909 mmol) and water (2 mL). The reaction mixture was degassed for 5 min and then heated to 80 C for 1 h. The mixture was cooled to rt. The solid was collected by filtration and washed with water. The title compound (2.2 g, 92%) was dried under reduced pressure and used in the next step without further purification.1H NMR (500 MHz, DMSO) delta 8.36 (d, J = 2.7 Hz, 1 H), 8.19 (t, J = 8.5 Hz, 1 H), 7.92 (dd, J = 2.7, 1.1 Hz, 1 H), 7.86 (dd, J = 13.6, 2.0 Hz, 1 H), 7.69 (dd, J = 8.7, 1.8 Hz, 1 H), 3.54 (s, 3H), 2.09 (s, 3H). MS (ESI) [M+H]+263.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | To a solution of <strong>[626220-76-6](2R)-1-methoxypropan-2-amine hydrochloride</strong> (343 mg, 2.73 mmol) in DMSO (3 mL), DIPEA (0.95 mL, 5.45 mmol) was added and the mixture was stirred 10 min at rt and then a solution of 4-bromo-2-fluoro-1-nitro-benzene (400 mg, 1.828 mmol) in DMSO (3 mL) was added dropwise and the reaction mixture was then stirred at rt. After 2h, starting material was still observed and more <strong>[626220-76-6](2R)-1-methoxypropan-2-amine hydrochloride</strong> (114 mg, 0.91 mmol) and DIPEA (0.63 mL, 3.64 mmol) were added and the mixture was stirred at 50 C for 1 h. To the mixture, saturated NaHC03(50 mL) and EtOAc (50 mL) were added and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na2S0 , filtered, and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a mixture of EtOAc in hexane as eluent to provide title compound (484 mg, 92%). 1 H NMR (500 MHz, CDCI3) delta 8.19 (d, J = 6.4 Hz, 1 H), 8.02 (d, J = 9.1 Hz, 1 H), 7.07 (d, J = 2.0 Hz, 1 H), 6.73 (dd, J = 9.1 , 2.0 Hz, 1 H), 3.88 - 3.79 (m, 1 H), 3.48 (dd, J = 5.0, 1.2 Hz, 2H), 3.41 (s, 3H), 1.33 (d, J = 6.5 Hz, 3H). MS (ESI) [M+H]+291.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20h; | a.) 21.0 g (100 mmol) 3-phenyl-1H-benzimidazol-2-one and 24.2 g (110 mmol) 4-bromo-2- fluoro-1-nitro-benzene, 27.6 g (200 mmol) potassium carbonate in DMF is stirred at 100 C for 20 h. The reaction mixture is poured in water and the water phase is extracted with (0803) dichloromethane. The organic phase is dried with magnesium sulfate and the solvent is removed in vacuum. Yield 23 g (56 %) 1H NMR (400 MHz, CDCl3): ^ = 8.11 (d, 1H), 7.92 (d, 1H), 7,79 (dd, 1H), 7.55.7.61 (m, 4H), 7.44-7.48 (m, 1H), 7.15-7.21 (m, 3H), 7.00-7.05 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 2-aminopyridine With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | 14 N-(5-Bromo-2-nitrophenyl)pyridin-2-amine (57f To a solution of pyridine-2-amine (257.0 mg, 2.73 mmol) in anhydrous THF (5 mL) was added potassium tert-butoxide (408 mg, 3.64 mmol) at 0C. The resulting mixture was purged with nitrogen and stirred at 0 C for 1 h.4-Bromo-2-fluoro-1-nitrobenzene (52) (400 mg, 1.82 mmol) was added and the reaction was stirred at 0C for 1 h. After being quenched with water (10 mL), the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 5:95 to 10:90) to afford 53f (418.3 mg, 78%) as an orange solid; 1H NMR (CDCl3, 500 MHz) 10.28 (1 H, br), 9.19 (1 H, d, J = 2.0 Hz), 8.40 (1 H, d, J = 5.1 Hz), 8.10 (1 H, d, J = 9.2 Hz), 7.67 (1 H, td, J = 8.9, 2.0 Hz), 7.07 (1 H, dd, J = 8.9, 2.0 Hz), 7.01 (1 H, dd, J = 7.1, 5.1 hz), 6.95 (1 H, d, J = 8.1 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calculated for C 7911H9 BrN3O2 and C11H 819 BrN3O2 293.9873, 295.9853; found 293.9863, 295.9883. |
78% | Stage #1: 2-aminopyridine With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran at 0℃; for 1h; | 17.P Example 17 - General Procedure for the Preparation of 5-Bromo-N-phenyl-2- nitroaniline-Method P (0582) N-(5-Bromo-2-nitrophenyl)pyridin-2-amine (57f) To a solution of pyridine-2-amine (257.0 mg, 2.73 mmol) in anhydrous THF (5 mL) was added potassium tert-butoxide (408 mg, 3.64 mmol) at 0C. The resulting mixture was purged with nitrogen and stirred at 0 C for 1 h.4-Bromo-2-fluoro-1-nitrobenzene (56) (400 mg, 1.82 mmol) was added and the reaction was stirred at 0C for 1 h. After being quenched with water (10 mL), the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 5:95 to 10:90) to afford 57f (418.3 mg, 78%) as an orange solid; 1H NMR (CDCl3, 500 MHz) 10.28 (1 H, br), 9.19 (1 H, d, J = 2.0 Hz), 8.40 (1 H, d, J = 5.1 Hz), 8.10 (1 H, d, J = 9.2 Hz), 7.67 (1 H, td, J = 8.9, 2.0 Hz), 7.07 (1 H, dd, J = 8.9, 2.0 Hz), 7.01 (1 H, dd, J = 7.1, 5.1 hz), 6.95 (1 H, d, J = 8.1 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calculated for C11H 79 (0584) 9 BrN3O2 and C 1 (0585) 11H 8 (0586) 9 BrN3O2 293.9873, 295.9853; found 293.9863, 295.9883. |
61% | Stage #1: 2-aminopyridine With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: 4-bromo-2-fluoronitrobenzene In tetrahydrofuran at 0℃; for 0.833333h; | 1.1 Synthesis Example 1 First, 8.8 g (91 mmol) of 2-aminopyridine and 20 g (180 mmol) of potassium t-butoxide were put into a three-neck flask, and the air in the flask was replaced with nitrogen. To this mixture was added 250 mE of tetrahydrofuran (abbreviation: THF), and stirring was performed at 0° C. for 1 hout After that, a mixture solution of 150 mE of THF and 21 g (91 mmol) of 4-bromo-2-fluoronitrobenzene was dropped, and stirring was performed at 00 C. for 50 minutes. Ethyl acetate and water were added to this reactionmixture, the resulting mixture was subjected to filtration, and the filtrate was subjected to extraction with ethyl acetate. The solution of the extract was washed with saturated brine. Then, magnesium sulfate was added and filtration was performed. The obtained filtrate was concentrated and filtrated through a filter aid filled with Celite (Catalog No. 531-16855, manufactured by Wako Pure Chemical Industries, Ltd. (the same applies to Celite in the following description)), alumina, and Celite in this order. The solvent in the filtrate was distilled oil, and the obtained residue was subjected to ultrasonic cleaning with hexane to give 16 g of the objective substance as an orange solid in a yield of 61%. A synthesis scheme of Step 1 is shown in (a-i) below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 5h; Inert atmosphere; | 3.2. General Method for Synthesis of Compounds 2a-c General procedure: 4-Bromo-2-fluoro-1-nitrobenzene (0.50 g, 2.28 mmol), piperidin-4-ylmethanol, 2-(piperazin-1-yl)ethanol and 3,4,5-trimethoxyphenol (2.28 mmol), K2CO3 (0.32 g, 2.28 mol) were mixed in DMF(10 mL) and heated at 90 °C under N2 for 5 h. After cooling, the reaction mixture was filtered toremove solid and the solvent was evaporated. The residue was dissolved in dichloromethane andwashed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue solid wasapplied on column of silica gel and then eluted with the mixed solvent of ethyl acetate and hexanes(3:1, v/v) to give the pure product as a white solid.1-(5-Bromo-2-nitrophenyl)piperidin-4-yl)methanol (2a). Yield: 0.61 g (85%), 1H-NMR (CDCl3) δ 1.50-1.53(m, 2H), 1.72 (s, 1H), 1.87 (d, J = 12.8 Hz, 2H), 2.89 (t, J = 12.4 Hz, 2H), 3.34 (d, J = 12.4 Hz, 2H), 3.60(d, J = 6.4 Hz, 2H), 7.10 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 5h; Inert atmosphere; | 3.2. General Method for Synthesis of Compounds 2a-c General procedure: 4-Bromo-2-fluoro-1-nitrobenzene (0.50 g, 2.28 mmol), piperidin-4-ylmethanol, 2-(piperazin-1-yl)ethanol and 3,4,5-trimethoxyphenol (2.28 mmol), K2CO3 (0.32 g, 2.28 mol) were mixed in DMF(10 mL) and heated at 90 °C under N2 for 5 h. After cooling, the reaction mixture was filtered toremove solid and the solvent was evaporated. The residue was dissolved in dichloromethane andwashed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue solid wasapplied on column of silica gel and then eluted with the mixed solvent of ethyl acetate and hexanes(3:1, v/v) to give the pure product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 5h; Inert atmosphere; | 3.2. General Method for Synthesis of Compounds 2a-c General procedure: 4-Bromo-2-fluoro-1-nitrobenzene (0.50 g, 2.28 mmol), piperidin-4-ylmethanol, 2-(piperazin-1-yl)ethanol and 3,4,5-trimethoxyphenol (2.28 mmol), K2CO3 (0.32 g, 2.28 mol) were mixed in DMF(10 mL) and heated at 90 °C under N2 for 5 h. After cooling, the reaction mixture was filtered toremove solid and the solvent was evaporated. The residue was dissolved in dichloromethane andwashed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue solid wasapplied on column of silica gel and then eluted with the mixed solvent of ethyl acetate and hexanes(3:1, v/v) to give the pure product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 5h; | A mixture of 4-bromo-2-fluoro-l-nitrobenzene (0.39, 1.36 mmol), <strong>[7664-66-6]4-(propan-2-yloxy)aniline</strong> (0.229,1 .43 mmol) and K2C03 (0.38 g, 2.73 mmol) in DMF (3 mL) was stirred at 90 C for 5h. Then thereaction mixture was diluted with EtOAc and washed with 5% aq. LiCI solution. The organic phasewas dried over Na2504, filtered, and concentrated in vacuo. The residue was purified by SiC2 columnchromatography (hexanes I EtOAc from 30:1 to 20:1) to give 0.43g (90%) of the product as orangesolid.1H NMR (500 MHz, CDCI3) O 9.37 (5, 1H), 8.04 (d, 1H), 7.12-7.17 (m, 3H), 6.93-6.97 (m, 2H), 6.81 (dd, 1H), 4.56 (sep, 1H), 1.36 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6100 mg | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 70℃; for 16h; | A mixture of A-20 (5000 mg, 22.73 mmol), 2,2,2- trifluoroethanamine hydrochloride (4620 mg, 34.09 mmol) and DIEA (8811.82 mg, 68.18 mmol) in THF (30 mL) was stirred at 70 C for 16 hours. After cooling to room temperature, the mixture was concentrated, then the mixture was diluted with H20 (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated to give the crude product that was purified by flash chromatography on silica gel (EtOAc in PE = 0 to 30% to 100%) to give the product A- 21 (6100 mg, 20.40 mmol). 1H NMR (CDC13, 400MHz) deltaH = 8.28 (br s, 1H), 8.09 (dd, 1H), 7.12 (s, 1H), 6.94 (dd, 1H), 4.08 - 3.86 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 12h; | N-(5-Bromo-2-nitrophenyl)-1H-pyrazol-4-amine (2a) General procedure: To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1, 2.19g, 10mmol) in DMF (50ml) and DIPEA (10ml) at 25°C was added 1H-pyrazol-4-amine (1.25g, 15mmol). Then the mixture was stirred at room temperature 12h. DMF and DIPEA were removed at reduced pressure and add water (100ml), and the residue was purified through a column chromatography on silica with chloroform/methanol (V:V 20:1) as a red solid. |
74.7% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 24h; | 1.1 Step 1) Synthesis of 5-bromo-2-nitro-N- (4-hydroxyphenyl) -aniline Dissolve 0.219 g (1 mmol) of 4-bromo-2-fluoronitrobenzene in 5 ml of DMF.0.11 g (1 mmol) of p-aminophenol was added sequentially,DIEA 0.26g (2mmol), after stirring at room temperature for 24h,Pour the reaction solution into 20 ml of water to precipitate a solid,Suction filtration to obtain a dark orange-red solid 0.23g,The yield was 74.7%. |
65% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 3h; Inert atmosphere; | 4-((5-Bromo-2-nitrophenyl)amino)phenol (16c). To a solution of 14(220 mg, 1 mmol) in anhydrous DMF (10 mL) was added K2CO3(207 mg, 1.5 mmol), followed by the addition of 4-aminophenol(120 mg, 1.1 mmol). The resulting mixture was heated to 90 °C andstirred for 3 h. After completion monitored by TLC, the mixture wasextracted with ethyl acetate (3×10 mL) and H2O. The combined organiclayer was dried over MgSO4 and concentrated in vacuo. The crudeproduct was purified by flash chromatography (hexane/ethyl acetate10:1→4:1) to give the product 16c as a pale orange solid (201 mg,65%); m.p. 151-152 °C; Rf (hexane/ethyl acetate 4:1): 0.30; 1H NMR(300 MHz, d6-DMSO): δ 9.65 (1H, br.s), 9.40 (1H, br.s), 8.02 (1H, d,J=9.0 Hz), 7.14 (2H, d, J=8.1 Hz), 6.92-6.84 (4H, m); 13C NMR(75 MHz, d6-DMSO): δ 156.1, 145.0, 131.0, 130.2, 129.0, 128.2, 127.7,119.4, 117.7, 116.3; HRMS (ESI+) Calc. for C12H9N2O3Br [M+Na]+330.9689/332.9668, found 330.9692/332.9672. IR (neat, cm-1): v3349, 3089, 1602, 1556, 1475, 1241, 1198, 747, 531. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 12h; | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1, 2.19g, 10mmol) in DMF (50ml) and DIPEA (10ml) at 25C was added <strong>[28466-26-4]1H-pyrazol-4-amine</strong> (1.25g, 15mmol). Then the mixture was stirred at room temperature 12h. DMF and DIPEA were removed at reduced pressure and add water (100ml), and the residue was purified through a column chromatography on silica with chloroform/methanol (V:V 20:1) as a red solid. (2.68g, 95.0% yield). mp 94-96C.1H NMR (400MHz, DMSO-d6) delta 13.03 (s, 1H, NH), 9.19 (s, 1H, NH), 8.03 (d, J=9.1Hz, 1H, Ar-H), 7.96-7.58 (m, 2H, Ar-H), 7.06 (d, J=2.0Hz, 1H, Ar-H), 6.93 (dd, J=9.1, 2.0Hz, 1H, Ar-H). 13C NMR (100MHz, DMSO-d6) delta 145.63, 136.48, 131.50, 130.93, 128.51, 125.80, 120.00, 119.94, 118.08. ESI-MS: m/z 281.1 [M-H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.6% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 12h; | General procedure: To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1, 2.19g, 10mmol) in DMF (50ml) and DIPEA (10ml) at 25C was added 1H-pyrazol-4-amine (1.25g, 15mmol). Then the mixture was stirred at room temperature 12h. DMF and DIPEA were removed at reduced pressure and add water (100ml), and the residue was purified through a column chromatography on silica with chloroform/methanol (V:V 20:1) as a red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; In dimethyl sulfoxide; at 65℃; | 2-Fluoro-4-bromonitrobenzene (7 g, 32 mmol) was dissolved in 8 mL of DMSO. <strong>[6967-12-0]6-Aminoindazole</strong> (4.7 g, 35 mmol) was then added, followed by 8 mL of triethylamine. The mixture was warmed to 65 C and allowed to stir overnight. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried using anhydrous Na2SC)4, filtered, and concentrated. The solid was washed with MTBE and used without further purification (8g, 75%). ESI MS [M-H]+ for C'nHxBr^CT, calcd 330.98, found 331.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydride In tetrahydrofuran at 0 - 25℃; for 2h; | 2.2.1 Preparation of Intermediate 2-2 To a solution of 4-bromo-2-fluoro-1-nitro-benzene 2-1 (12.0 g, 54.5 mmol, 1.0 eq.) and cyclopropanol (3.8 g, 65.5 mmol, 1.2 eq.) in THF (100 mL) was added NaH (2.6 g, 65.5 mmol, 60% purity, 1.2 eq.) at 0°C. The mixture was stirred at 25°C for 120 min. The reaction mixture was quenched by water at 25 °C and concentrated under reduced pressure to remove THF, and then the residue was recrystallized from water to give the pure product. Intermediate 2- 2 (13.6 g, 97% yield) was obtained as a yellow solid. |
97% | With sodium hydride In tetrahydrofuran at 0 - 25℃; for 2h; | 2.2.1 Preparation of Intermediate 2-2 To a solution of 4-bromo-2-fluoro-1-nitro-benzene 2-1 (12.0 g, 54.5 mmol, 1.0 eq.) and cyclopropanol (3.8 g, 65.5 mmol, 1.2 eq.) in THF (100 mL) was added NaH (2.6 g, 65.5 mmol, 60% purity, 1.2 eq.) at 0°C. The mixture was stirred at 25°C for 120 min. The reaction mixture was quenched by water at 25 °C and concentrated under reduced pressure to remove THF, and then the residue was recrystallized from water to give the pure product. Intermediate 2- 2 (13.6 g, 97% yield) was obtained as a yellow solid. |
76.72% | Stage #1: 4-bromo-2-fluoronitrobenzene With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.333333h; Stage #2: cyclopropanol In tetrahydrofuran; mineral oil at 20℃; for 2h; | 57 Synthesis of compound 57.1. To a solution of 4-bromo-2-fluoro-1-nitrobenzene (3.0g, 13.63mmol, 1.0eq) in tetrahydrofuran (30mL), was added sodium hydride (0.654g, 27.26mmol, 2eq) at 0°C and stirred for 20min. Cyclopropanol (0.869g, 14.99mmol, 1.1eq) was added and reaction mixture was stirred at room temperature for 2h. After completion of reaction, reaction mixture was transferred into ice, stirred and extracted with diethyl ether. Organic layer was combined, dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further purified by distillation to obtain pure 57.1. (2.7g, Yield: 76.72%). MS (ES): m/z 257.97 [M+H]+. |
With sodium hydride In 2-methyltetrahydrofuran; mineral oil at 0 - 20℃; for 16h; Inert atmosphere; | 4-Bromo-2-(cyclopropyloxy)- 1 -nitrobenzene 37 To a mixture of 4-bromo-2-cy cl opropoxy-1 -nitrobenzene (350 g, 1.59 mol) and cyclopropanol (166 g, 2.86 mol) in 2-MeTHF (3.5 L) was added NaH (60% pure, 114 g, 2.86 mol) at 0°C. The reaction mixture was stirred at rt for 16 h under N2atmosphere. The reaction was quenched with NH4CI (sat., aq., 2.5 L). The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 1 L). The combined organic extracts were washed with brine (2 L), and dried (Na2S04). The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 37 that was used without further purfication in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In dimethyl sulfoxide at 60 - 90℃; for 1.16667h; | 248.1 Step 1. A mixture of 4-bromo-2-fluoro-1-nitrobenzene (3.17 g, 14.41 mmol, Combi-blocks), 6-azaspiro[2.5]octane hydrochloride (2.447 g, 16.57 mmol, AstaTech) and potassium carbonate (5.97 g, 43.2 mmol, Aldrich) in 12 mL of DMSO was heated in an oil bath at 60 °C for 10 min then 90 °C for 1 h. The mixture was cooled to RT, treated with 20 mL of water and extracted with 2 x 50 mL of EtOAc. The combined organic extracts were washed with 2 x 5 mL of water and concentrated. The residue was purified on a silica gel column (15% to 45% EtOAc in heptane) to give 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane (4.26 g, 13.69 mmol, 95% yield) as an orange solid m/z ( ESI): 311.0/313.0 (M+H)+. |
95% | With potassium carbonate In dimethyl sulfoxide at 60 - 90℃; for 1.16667h; | 1 [0372] Intermediate 18: 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)aniline. [0373] Step 1: A mixture of 4-bromo-2-fluoro-1-nitrobenzene (3.17 g, 14.4 mmol, Combi-Blocks), 6- azaspiro[2.5]octane hydrochloride (2.45 g, 16.57 mmol, AstaTech) and potassium carbonate (5.97 g, 43.2 mmol, Sigma-Aldrich Corporation) in DMSO (12 mL) was heated in an oil bath at 60 oC for 10 min then heated to 90 oC for 1 h. The mixture was cooled to RT, treated with 20 mL of water, and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (2 x 5 mL), dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified on a silica gel column (15-45% EtOAc in heptane) to give 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane (4.26 g, 13.7 mmol, 95% yield) as an orange solid. m/z (ESI): 311.0/313.0 (M+H)+. |
With potassium carbonate In dimethyl sulfoxide at 60 - 90℃; for 1.16h; | 1 Step 1: A mixture of 4-bromo-2-fluoro-1-nitrobenzene (3.17 g, 14.4 mmol, Combi-Blocks), 6- azaspiro[2.5]octane hydrochloride (2.447 g, 16.57 mmol, AstaTech) and potassium carbonate (5.97 g, 43.2 mmol, Sigma-Aldrich Corporation) in DMSO (12 mL) was heated in an oil bath at 60 oC for 10 min then heated to 90 oC for 1 h. The mixture was cooled to RT, treated with 20 mL of water and extracted with of EtOAc (2 x 50 mL). The combined organic extracts were washed with water (2 x 5 mL), dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified on a silica gel column (15% to 45% EtOAc in heptane) to give 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane (4.26 g, 13.7 mmol, 95% yield) as an orange solid. m/z (ESI): 311.0/313.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In acetonitrile at 80℃; for 18h; | 4.A Step A. Intermediate 4A. Preparation of 5-bromo-N-(2,2-difluoroethyl)-2-nitroaniline To a 40 mL vial were added 4-bromo-2-fluoro-l -nitrobenzene (1.0 g, 4.6 mmol), and MeCN (20 mL). To this mixture was added 2,2-difluoroethan-l -amine (0.92 g, 12 mmol), the vial was capped and the reaction mixture was stirred at 80 °C. After 18 h, the reaction mixture was cooled, the solvent concentrated and the residue was purified by flash column chromatography (120 g silica gel cartridge; A = Hex, B = EtOAc; 35 min grad.; 0% B to 100%B; flow rate = 80 mL/min). The fractions corresponding to product were combined, concentrated and dried in vacuo to afford the title compound (1.2 g, 4.3 mmol, 93 % yield) as a yellow solid. ’H NMR (400 MHz, METHANOL-d4) 8 8.10-8.05 (m, 1H), 7.39-7.34 (m, 1H), 6.95-6.87 (m, 1H), 6.29-5.93 (m, 1H), 3.92-3.79 (m, 2H). Analytical LC/MS (Method 3): Observed Mass: 281.1; Retention Time: 0.98 min. |
93% | In acetonitrile at 80℃; for 18h; | 4.A Step A. Intermediate 4A. Preparation of 5-bromo-N-(2,2-difluoroethyl)-2-nitroaniline To a 40 mL vial were added 4-bromo-2-fluoro-l -nitrobenzene (1.0 g, 4.6 mmol), and MeCN (20 mL). To this mixture was added 2,2-difluoroethan-l -amine (0.92 g, 12 mmol), the vial was capped and the reaction mixture was stirred at 80 °C. After 18 h, the reaction mixture was cooled, the solvent concentrated and the residue was purified by flash column chromatography (120 g silica gel cartridge; A = Hex, B = EtOAc; 35 min grad.; 0% B to 100%B; flow rate = 80 mL/min). The fractions corresponding to product were combined, concentrated and dried in vacuo to afford the title compound (1.2 g, 4.3 mmol, 93 % yield) as a yellow solid. ’H NMR (400 MHz, METHANOL-d4) 8 8.10-8.05 (m, 1H), 7.39-7.34 (m, 1H), 6.95-6.87 (m, 1H), 6.29-5.93 (m, 1H), 3.92-3.79 (m, 2H). Analytical LC/MS (Method 3): Observed Mass: 281.1; Retention Time: 0.98 min. |
87% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere; | a Into a stirred solution of 4-bromo-2-fluoro-1 -nitrobenzene (2.20 g, 10 mmol), 2,2-di- flouroethane-1 -amine (0.81 1 g, 10 mmol) in DMF (10 ml), DIPEA (3.48 ml, 20 mmol) was added and stirred at room temperature for 16 h under argon atmosphere. After that time, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic ex tracts were washed with brine, dried over anhydrous MgSC and concentrated under reduced pressure. Product was purified by flash chromatography (silica gel, hexane/EtOAc 0-10%) to af- ford the title compound of the yellow solid (2.44 g, 87%). ESI-MS: 448.30 [M+H]+. |
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 16h; | 13 To a solution of 2,2-difluoroethanamine (552.68 mg, 6.82 mmol) and DIEA (1172.73 mg, 9.09 mmol) in THF (3 mL) was added 4-bromo-2-fluoro-1-nitro-benzene (1000 mg, 4.55 mmol) slowly and the solution was stirred at 20° C. for 16 hours. The mixture was concentrated to remove most of THF, and the residue was dissolved in EtOAc (10 mL), neutralized with sat.NaHCO3 to pH=8-9. The mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product (1200 mg, 4.27 mmol) as a solid. 1H NMR (400 MHz, CDCl3) δH 8.21 (br s, 1H), 8.07 (d, 1H), 7.09 (d, 1H), 6.89 (dd, 1H), 6.17-5.85 (m, 1H), 3.81-3.70 (m, 2H). | |
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 16h; | 13 To a solution of 2,2-difluoroethanamine (552.68 mg, 6.82 mmol) and DIEA (1172.73 mg, 9.09 mmol) in THF (3 mL) was added 4-bromo-2-fluoro-1-nitro-benzene (1000 mg, 4.55 mmol) slowly and the solution was stirred at 20° C. for 16 hours. The mixture was concentrated to remove most of THF, and the residue was dissolved in EtOAc (10 mL), neutralized with sat.NaHCO3 to pH=8-9. The mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product (1200 mg, 4.27 mmol) as a solid. 1H NMR (400 MHz, CDCl3) δH 8.21 (br s, 1H), 8.07 (d, 1H), 7.09 (d, 1H), 6.89 (dd, 1H), 6.17-5.85 (m, 1H), 3.81-3.70 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: α-methyl-2-pyridinemethanol With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Stage #2: 4-bromo-2-fluoro-1-nitro-benzene In tetrahydrofuran at 20℃; for 16h; | 1 Step 1 : 2-[(1S)-1-(5-bromo-2-nitrophenoxy)ethyl]pyridine To mixture of (1S)-1-(pyridin-2-yl)ethan-1-ol (1.0 g, 8.18 mmol) in THF (20 mL) at 0 (1080) °C, was added NaH (981 mg, 40.9 mmol). After 15 min, 4-bromo-2-fluoro-1- nitrobenzene (1.8 g, 8.18 mmol) was added and the mixture was stirred at RT. After (1081) 16 h, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed (brine), dried (Na2SO4) and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 20:1) to afford the title product (1.25 g, 50%) as a yellow liquid. LCMS (Method D): 5.01 min; m/z: 322.8 [M+H]+. |
50% | Stage #1: α-methyl-2-pyridinemethanol With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Stage #2: 4-bromo-2-fluoro-1-nitro-benzene In tetrahydrofuran at 20℃; for 16h; | 1 Step 1 : 2-[(1S)-1-(5-bromo-2-nitrophenoxy)ethyl]pyridine To mixture of (1S)-1-(pyridin-2-yl)ethan-1-ol (1.0 g, 8.18 mmol) in THF (20 mL) at 0 (1080) °C, was added NaH (981 mg, 40.9 mmol). After 15 min, 4-bromo-2-fluoro-1- nitrobenzene (1.8 g, 8.18 mmol) was added and the mixture was stirred at RT. After (1081) 16 h, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed (brine), dried (Na2SO4) and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 20:1) to afford the title product (1.25 g, 50%) as a yellow liquid. LCMS (Method D): 5.01 min; m/z: 322.8 [M+H]+. |
50% | Stage #1: α-methyl-2-pyridinemethanol With sodium hydride In tetrahydrofuran at 0℃; for 0.25h; Stage #2: 4-bromo-2-fluoro-1-nitro-benzene In tetrahydrofuran at 20℃; for 16h; | Step 1 : 2-[(1S)-1-(5-bromo-2-nitrophenoxy)ethyl]pyridine To mixture of (1S)-1-(pyridin-2-yl)ethan-1-ol (1.0 g, 8.18 mmol) in THF (20 mL) at 0 (1080) °C, was added NaH (981 mg, 40.9 mmol). After 15 min, 4-bromo-2-fluoro-1- nitrobenzene (1.8 g, 8.18 mmol) was added and the mixture was stirred at RT. After (1081) 16 h, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed (brine), dried (Na2SO4) and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (PE:EtOAc, 20:1) to afford the title product (1.25 g, 50%) as a yellow liquid. LCMS (Method D): 5.01 min; m/z: 322.8 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: benzyl-methyl-amine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.0833333h; Stage #2: 4-bromo-2-fluoro-1-nitro-benzene In tetrahydrofuran; mineral oil at 0 - 20℃; for 6h; | N-Benzyl-5-bromo-N-methyl-2-nitroaniline (14) To a solution ofN-benzylmethylamine(198 mg, 1.64 mmol) in tetrahydrofuran (7 mL) was added sodium hydride (60% dispersion in mineral oil, 82 mg, 2.05 mmol) at 0°C. After stirring at 0°Cfor 5 minutes, 4-bromo-2-fluoro-1-nitrobenzene(300 mg, 1.36 mmol)was added at 0°C. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the crude mixture was added to water and extracted with dichloromethane. The organic layer was dried over anhydrousNa2SO4andconcentrated under reduced pressure. The residue was purified by flash column chromatograph (0-10% ethyl acetate/hexane) to give the product as a yellow solid (458 mg, quantitative);1H NMR (400 MHz,CDCl3)δ7.65 (d,J= 8.4 Hz, 1H), 7.36 (dd,J= 7.2, 7.2 Hz, 2H), 7.29 (t,J= 7.2 Hz, 1H), 7.25 (d,J= 7.2 Hz, 2H), 7.21 (d,J= 2.0 Hz, 1H), 6.99 (dd,J= 8.4, 2.0 Hz, 1H), 4.37 (s, 2H), 2.77 (s, 3H);13C NMR (100 MHz, CDCl3)δ146.9, 136.5, 128.9, 127.94, 127.89, 127.8, 127.7, 122.9, 122.0, 58.6, 40.3; LC/MS (ESI+)m/z321.1 [M(79Br) + H]+, 323.0 [M(81Br) + H]+. |
100% | Stage #1: benzyl-methyl-amine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.0833333h; Stage #2: 4-bromo-2-fluoro-1-nitro-benzene In tetrahydrofuran; mineral oil at 0 - 20℃; for 6h; | N-Benzyl-5-bromo-N-methyl-2-nitroaniline (14) To a solution ofN-benzylmethylamine(198 mg, 1.64 mmol) in tetrahydrofuran (7 mL) was added sodium hydride (60% dispersion in mineral oil, 82 mg, 2.05 mmol) at 0°C. After stirring at 0°Cfor 5 minutes, 4-bromo-2-fluoro-1-nitrobenzene(300 mg, 1.36 mmol)was added at 0°C. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the crude mixture was added to water and extracted with dichloromethane. The organic layer was dried over anhydrousNa2SO4andconcentrated under reduced pressure. The residue was purified by flash column chromatograph (0-10% ethyl acetate/hexane) to give the product as a yellow solid (458 mg, quantitative);1H NMR (400 MHz,CDCl3)δ7.65 (d,J= 8.4 Hz, 1H), 7.36 (dd,J= 7.2, 7.2 Hz, 2H), 7.29 (t,J= 7.2 Hz, 1H), 7.25 (d,J= 7.2 Hz, 2H), 7.21 (d,J= 2.0 Hz, 1H), 6.99 (dd,J= 8.4, 2.0 Hz, 1H), 4.37 (s, 2H), 2.77 (s, 3H);13C NMR (100 MHz, CDCl3)δ146.9, 136.5, 128.9, 127.94, 127.89, 127.8, 127.7, 122.9, 122.0, 58.6, 40.3; LC/MS (ESI+)m/z321.1 [M(79Br) + H]+, 323.0 [M(81Br) + H]+. |
Tags: 321-23-3 synthesis path| 321-23-3 SDS| 321-23-3 COA| 321-23-3 purity| 321-23-3 application| 321-23-3 NMR| 321-23-3 COA| 321-23-3 structure
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