* 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.
With hydrogen; acetic acid In water at 20℃; for 18 h;
EXAMPLE 20B methyl 2-fluoro-4-formylbenzoate EXAMPLE 20A (310 mg, 1.73 mmol) was dissolved in 60percent aqueous acetic acid (10 mL) with warming. Raney nickel (60 mg) was added and the mixture was stirred under hydrogen at ambient temperature for 18 hours. Solid material was filtered off and the filtrate concentrated. The residue was purified on silica gel using 1:4 ethyl acetate/hexane to give the title compound (220 mg, 70percent). MS (DCI): m/z 183 (M+H)+.
70%
Stage #1: Heating / reflux Stage #2: With hydrogen In water at 20℃; for 18 h;
EXAMPLE 17B methyl 2-fluoro-4-formyl-benzoate EXAMPLE 17A (310 mg, 1.73 mmol) was dissolved in 60percent aqueous acetic acid (10 mL) with gentle heating. Raney nickel (60 mg) was added and the mixture stirred under hydrogen at ambient temperature for 18 hours. Solid material was filtered off and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (1:4 ethyl acetate/hexane) to give 220 mg (70percent) of the title compound. MS (DCI): m/z 183 (M+H)+.
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 15 - 25℃; for 0.25 h; Stage #2: at 40℃; for 2 h;
Step (i) Potassium carbonate (3.70 g, 26.7 mmol ) was added to a solution of 4-cyano-2- fluorobenzoic acid (4 g, 24.3 mmol) in DMF (350 mL). After stirring at RT for 15 minutes, iodomethane (1.66 mL, 26.7 mmol) was added. The flask was stoppered, and the mixture stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM (50 mL) and brine (50 mL). The organic phase was passed tlirough silica and concentrated to give methyl 4-cyano-2-fluorobenzoate (4.1 g, 94percent). NMR (300 MHz, CDC13) δ ppm 3.96 (s, 311 ) 7.44-7.48 (m, 111) 7.49-7.53 (m, 111) 8.01- 8.05 (m, 1H)
94%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25 h; Stage #2: at 40℃; for 2 h;
Potassium carbonate (3.70 g, 26.7 mmol) was added to a solution of 4-cyano-2-fluorobenzoic acid (4 g, 24.3 mmol) in DMF (350 mL). After stirring at RT for 15 minutes, iodomethane (1.66 mL, 26.7 mmol) was added. The flask was stoppered, and the mixture stirred at 40° C. for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM (50 mL) and brine (50 mL). The organic phase was passed through silica and concentrated to give methyl 4-cyano-2-fluorobenzoate (4.1 g, 94percent). 1H NMR (300 MHz, CDCl3) δ ppm 3.96 (s, 3H) 7.44-7.48 (m, 1H) 7.49-7.53 (m, 1H) 8.01-8.05 (m, 1H)
30%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h;
Example 42 4-fluoromethyl-3-[4-(tetrahydropyran-4-yloxymethyl)phenoxy]benzamide (42a) methyl 4-cyano-2-fluorobenzoate 4-Cyano-2-fluorobenzoic acid (5.15 g, 31.2 mol) was dissolved in dimethylformamide (50 mL), potassium carbonate (6.47 g, 46.8 mmol) and methyl iodide (3.88 mL, 62.4 mmol) were added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title object compound as a white powder (1.70 g, yield 30percent). 1H-NMR (CHCl3, 400 MHz) δ: 3.97 (3H, s), 7.48 (1H, dd, J=9.8, 1.5 Hz), 7.52 (1H, dd, J=8.1, 1.5 Hz), 8.05 (1H, dd, J=8.1, 7.3 Hz).
With dicyanozinc In N,N-dimethyl-formamide at 80℃;
EXAMPLE 20A methyl 4-cyano-2-fluorobenzoate A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyanide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (100 mL) was purged with nitrogen and the mixture stirred at 80° C. overnight. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The solid was purified on silica gel using 1:5 ethyl acetate/hexane to afford the title compound (6.1 g, 80percent). MS (DCI): m/z 180 (M+H)+.
STEP 2: To a solution of methyl 4-bromo-2-fluorobenzoate (9.1 mmol) in DMF (50 mL) was added zinc cyanide (641 mg, 5.5 mmol) followed by tetrakis(triphenyphosphine)palladium(0) (1.05 g, 0.91 mmol). The mixture was heated to 100 °C and stirred for 3 h. At that point, additional tetrakis(triphenyphosphine)- palladium(O) (500 mg, 0.43 mmol) was added. The mixture was stirred a further 30 min and was then cooled to room temperature. Water and ethyl acetate were added, and insoluble solids were removed by filtration through celite. The layers were then separated. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with 10percent aqueous lithium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (10percent ethyl acetate in hexanes) to provide methyl 4-cyano-2-fluorobenzoate (1.36 g, 7.6 mmol, 84percent yield). 1H NMR (400 MHz, CDCl3): 8.06 (dd, IH), 7.53 (dd, IH), 7.47 (dd, IH), 3.98 (s, 3H); MS (EI) for C9H6FNO2: 179 (M+).
80%
at 80℃;
EXAMPLE 17A methyl 4-cyano-2-fluoro-benzoate A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyanide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in N,N-dimethylformamide (100 mL) was stirred at 80° C. overnight. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The residue was purified by flash chromatography on silica gel (1:5 ethyl acetate/hexane) to afford 6.1 g (80percent) of the title compound. MS (DCI): m/z 180 (M+H)+.
Preparation of methyl 4-(aminomethyl)-2-fluorobenzoate: A solution of 4-cyano-2-fluorobenzoic acid (4.02 g, 24.36 mmol, Aldrich) in methanol (50 mL) was treated with p-toluenesulfonic acid monohydrate (0.46 g, 2.43 mmol) and heated to reflux overnight. The solvent was removed and the reaction residue was extracted with EtOAc, washed with saturated Na2CO3, brine and dried over Na2SO4 to give Methyl 4-cyano-2-fluorobenzoate (4.46 g, 95percent).
With potassium carbonate In acetone for 20 h; Reflux
Example 33A Methyl 4-cyano-2-fluorobenzoate 13.20 g (79.9 mmol) of 4-cyano-2-fluorobenzoic acid are dissolved in 300 ml of acetone. Then 22.10 g (159.9 mmol) of potassium carbonate and 9.08 ml (95.9 mmol) of dimethyl sulfate are successively added. The mixture is stirred at reflux temperature for 20 h. The reaction mixture is then mixed with 300 ml of water and the acetone is removed in a rotary evaporator. Several extractions with dichloromethane are carried out. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is then removed in vacuo. The remaining solid is used further without further purification. 16.1 g (84percent of theory) of the title compound are obtained as a colorless solid. GC-MS (method 7): Rt=6.23 min; [M]+ (EIpos): m/z=179 1H-NMR (300 MHz, DMSO-d6): δ=3.90 (s, 3H), 7.83 (dd, 1H), 8.01-8.08 (m, 2H).
84%
With potassium carbonate In acetone for 20 h; Reflux
4-cyano-2-fluoro-benzoic acid 13.20 g (79.9 mmol) was dissolved in acetone 300 mL. Then, 22.10 g of potassium carbonate A (159.9 mmol) and dimethyl sulfate 9.08 ml (95.9 mmol) were added consecutively. The mixture was refluxed at a temperature of 20 hour Stirred . Then, the reaction mixture was mixed with 300 mL of water, and the acetone on a rotary evaporator It was removed. It can in turn was extracted with dichloromethane. The combined organic phases are washed with a saturated aqueous sodium chloride solution, and sulfuric acid Dried over sodium. Then, the solvent was removed in vacuo. The remaining solid was used without further purification. The title compound was 16.1 g (84percent of theory) as a colorless solid
STEP 3: To a flask containing methyl 4-cyano-2-fluorobenzoate (1.61 g, 9.0 mmol) was added fuming nitric acid (15 mL) followed by concentrated sulfuric acid (4 mL). The mixture was heated to 45 °C for 15 h before cooling to room temperature. The solution was then poured into ice water and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated to provide methyl 4-cyano-2-fluoro-5-nitrobenzoate (859 mg, 3.83 mmol, 43percent yield). <n="450"/>1H NMR (400 MHz, CDCl3): 8.95 (d, IH), 7.72 (d, IH), 4.04 (s, 3H); MS (EI) for C9H5FN2O4: 224 (M+).
Example 26 4-hydroxymethyl-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenylamino}benzamide (26a) methyl 4-cyano-2-fluorobenzoate To 4-cyano-2-fluorobenzoic acid (1.00 g, 6.06 mmol) were added toluene (10 mL) and methanol (10 mL), and 2.0 M trimethylsilyldiazomethane/diethyl ether solution (about 5 mL) was added dropwise. The reaction mixture was evaporated under reduced pressure to give the title object compound as a slightly yellow powder (1.11 g, yield 100%). (0694) 1H-NMR (CDCl3, 400 MHz) delta: 3.97 (3H, s), 7.44-7.48 (1H, m), 7.50-7.55 (1H, m), 8.02-8.08 (1H, m).
Preparation 22: 4-Cyano-2-fluorobenzoic acid methyl esterSufficient methanol (ca. 10 mL) was added to a stirred suspension of 4-cyano-2- fluorobenzoic acid (2 g, 12.11 mmol) in toluene (5 mL) to give a clear solution. Trimethylsilyldiazomethane (7.87 mL of a 2 M solution in hexane, 15.75 mmol) was added dropwise, until the persistence of a yellow colour, after which the solution was stirred for a further 10 min and AcOH then added until a colourless solution was again obtained. The reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous Na2CO1 (2 x 20 mL) and brine (20 mL) and dried (MgSO4). Evaporation of the solvent afforded the title ester: & (CDCl3) 3.98 (3H, s), 7.47 (IH, dd), 7.53 (IH, dd), 8.06 ( IH, t).
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 3.5h;
STEP 2: To a solution of methyl 4-bromo-2-fluorobenzoate (9.1 mmol) in DMF (50 mL) was added zinc cyanide (641 mg, 5.5 mmol) followed by tetrakis(triphenyphosphine)palladium(0) (1.05 g, 0.91 mmol). The mixture was heated to 100 C and stirred for 3 h. At that point, additional tetrakis(triphenyphosphine)- palladium(O) (500 mg, 0.43 mmol) was added. The mixture was stirred a further 30 min and was then cooled to room temperature. Water and ethyl acetate were added, and insoluble solids were removed by filtration through celite. The layers were then separated. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with 10% aqueous lithium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (10% ethyl acetate in hexanes) to provide methyl 4-cyano-2-fluorobenzoate (1.36 g, 7.6 mmol, 84% yield). 1H NMR (400 MHz, CDCl3): 8.06 (dd, IH), 7.53 (dd, IH), 7.47 (dd, IH), 3.98 (s, 3H); MS (EI) for C9H6FNO2: 179 (M+).
80%
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 80℃;
EXAMPLE 17A methyl 4-cyano-2-fluoro-benzoate A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyanide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in N,N-dimethylformamide (100 mL) was stirred at 80 C. overnight. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The residue was purified by flash chromatography on silica gel (1:5 ethyl acetate/hexane) to afford 6.1 g (80%) of the title compound. MS (DCI): m/z 180 (M+H)+.
Preparation of methyl 4-(aminomethyl)-2-fluorobenzoate: A solution of 4-cyano-2-fluorobenzoic acid (4.02 g, 24.36 mmol, Aldrich) in methanol (50 mL) was treated with p-toluenesulfonic acid monohydrate (0.46 g, 2.43 mmol) and heated to reflux overnight. The solvent was removed and the reaction residue was extracted with EtOAc, washed with saturated Na2CO3, brine and dried over Na2SO4 to give Methyl 4-cyano-2-fluorobenzoate (4.46 g, 95%).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃;
Step 1: methyl-4-cyano-2-fluorobenzoate4-Cyano-2-fluorobenzoic acid (1 g; 6.06 mmol) was suspended in MeOH (10 ml.) and 1-(3- dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.39 g; 7.27 mmol; 1 .20 eq.) and 4-dimethylaminopyridine (70 mg; 0.61 mmol; 0.10 eq.) were added. The mixture was stirred at RT overnight.Solvents were concentrated and the resulting mixture was taken up into EtOAc (20 ml_) and washed with 0.1 N HCI solution (10 ml_), 0.1 N NaOH solution (10 ml.) and brine (2x10 ml_), dried over MgSO4 and evaporated. The isolated solid was washed with cyclohexane and a mixture of cyclohexane / EtOAc (3:1 ) then dried, affording the title compound as an off-white solid. 1H-NMR (DMSO-d6, 300MHz) delta 8.12-8.05 (m, 2H), 7.87 (dd, J = 1.32 Hz, J = 8.10 Hz, 1 H), 3.93 (s, 3H). GC/MS Rt 3.08 min: 179 (M+H)+. HPLC (Method A) Rt 2.83 min (Purity: 97%).
With hydrogenchloride; In 1,4-dioxane; at 20℃;
Preparation 90 4-Cyano-2-fluoro-benzoic acid methyl ester Add 4N hydrochloride in 1,4-dioxane (100 mL, 400 mmol) to 4-cyano-2-fluoro-benzoic acid (10.0 g, 60.5 mmol) in methanol (100 mL). Stir the reaction mixture at room temperature overnight. Concentrate the reaction mixture. Purify the residue by column chromatography (silica gel) eluding with 20% ethyl acetate/hexane to give the title compound (6.8 g, 38.0 mmol).
4-Cyano-2-fluorobenzoic acid (ABCR, 16 g; 96.90 mmol) was suspended in 300 ml_ of DCM. Oxalyl chloride (9 ml 106.59 mmol) was added, followed by DMF (0.5 ml_). After 3 hours at RT the yellow solution was evaporated under reduced pressure and the resulting yellow oil was taken up in anhydrous THF (150 ml_) and added dropwise to a 4C solution of methanol (50 mL) and triethylamine (25.80 ml 193.79 mmol; 2 eq.). An HCI solution (0.1 N, 200 mL) was added and the product was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with a semi-saturated NaHCO3 solution (200 mL), water (200 mL) and dried over MgSO4. Evaporation under reduced pressure gave the title compound as a light yellow solid (17.84 g, quantitative). HPLC (Method A) Rt 2.81 min (Purity: 93.9%).
Oxalyl chloride (9.0 ml_, 106.6 mmol) and DMF (0.5 ml.) were added into a suspension of 4- cyano-2-fluorobenzoic acid (ABCR, 16 g, 96.9 mmol) in anhydrous DCM (300 ml.) The resulting mixture was stirred at RT, and then evaporated under reduced pressure. The residue was taken up with anhydrous THF (150 ml.) and added dropwise into a solution of methanol (50 ml.) and triethylamine (25.8 ml_, 193.8 mmol) at 4C. The reaction mixture was diluted with a 0.1 N aqueous solution of HCI (200 ml.) and extracted with EtOAc (3x100 ml_). The combined organic layers were washed with a semi-saturated aqueous solution of NaHCO3 (200 ml.) and water (200 ml_), dried (MgSO4) and concentrated under vacuum to give the title compound as a pale yellow solid (17.8 g, quantitative). HPLC (Method A) Rt 2.81 min (Purity: 93.9%).
Preparation 18: 4-Cyano-2-fluorobenzoic acid methyl ester: A suspension of 4-cyano-2-fluorobenzoic acid (2 g, 12.11 mmol) was suspended in toluene (5 mL) and sufficient MeOH added (ca 10 mL) to give a clear solution. Trimethylsilyldiazomethane (7.87 mL of a 2 M solution in hexane, 15.75 mmol) was added dropwise, giving a yellow solution which was stirred a further 10 min. Acetic acid was then added dropwise until a colourless solution was obtained which was then diluted with EtOAc (50 mL). The organic solution was washed with saturated aqueous Na2CO3 (20 mL) and brine (20 mL) then dried (MgSO4). Evaporation of the solvent afforded the title ester: deltaH (CDCl3) 3.98 (3H, s), 7.47 (IH, dd), 7.53 (IH, dd), 8.06 (IH, t).
With hydrogenchloride; In 1,4-dioxane; at 70℃; for 1h;
Reference Example 1 Methyl 4-cyano-2-fluorobenzoate A 4 M hydrochloric acid dioxane solution (70.0 mL, 280 mmol) was added to a methanol (70.0 mL) solution of 4-cyano-2-fluorobenzoic acid (10.0 g, 60.6 mmol), and the mixture was stirred for one hour at 70 C. The reaction mixture was cooled to room temperature, and then the solvent was distilled off under reduced pressure. Thus, a crude product of the title compound was obtained.
With chloro-trimethyl-silane; at 60℃; for 4h;
A mixture of 4-cyano-2-fluorobenzoic acid (5.0 g, 30 mmol) (1 ) and chlorotrimethylsilane (13.5 mL, 106 mmol) in MeOH (100 mL) was stirred at 60C for 4 h and then (0603) concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with satd. aq. NaHC03 (200 mL), dried over MgS04, filtered and concentrated in vacuo to afford the title compound (2) (5.2 g, 97%) as a pale yellow solid: 1H NMR (400 MHz, DMSO-c/6) delta: 8.07 - 8.01 (2H, m), 7.83 (1 H, dd), 3.90 (3H, s)
With dicyanozinc;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 80℃;
EXAMPLE 20A methyl 4-cyano-2-fluorobenzoate A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyanide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (100 mL) was purged with nitrogen and the mixture stirred at 80 C. overnight. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated. The solid was purified on silica gel using 1:5 ethyl acetate/hexane to afford the title compound (6.1 g, 80%). MS (DCI): m/z 180 (M+H)+.
With hydrogen; acetic acid;nickel; In water; at 20℃; for 18h;
EXAMPLE 20B methyl 2-fluoro-4-formylbenzoate EXAMPLE 20A (310 mg, 1.73 mmol) was dissolved in 60% aqueous acetic acid (10 mL) with warming. Raney nickel (60 mg) was added and the mixture was stirred under hydrogen at ambient temperature for 18 hours. Solid material was filtered off and the filtrate concentrated. The residue was purified on silica gel using 1:4 ethyl acetate/hexane to give the title compound (220 mg, 70%). MS (DCI): m/z 183 (M+H)+.
70%
EXAMPLE 17B methyl 2-fluoro-4-formyl-benzoate EXAMPLE 17A (310 mg, 1.73 mmol) was dissolved in 60% aqueous acetic acid (10 mL) with gentle heating. Raney nickel (60 mg) was added and the mixture stirred under hydrogen at ambient temperature for 18 hours. Solid material was filtered off and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (1:4 ethyl acetate/hexane) to give 220 mg (70%) of the title compound. MS (DCI): m/z 183 (M+H)+.
With sulfuric acid; nitric acid; at 45.0℃; for 15.0h;
STEP 3: To a flask containing methyl 4-cyano-2-fluorobenzoate (1.61 g, 9.0 mmol) was added fuming nitric acid (15 mL) followed by concentrated sulfuric acid (4 mL). The mixture was heated to 45 C for 15 h before cooling to room temperature. The solution was then poured into ice water and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated to provide methyl 4-cyano-2-fluoro-5-nitrobenzoate (859 mg, 3.83 mmol, 43% yield). <n="450"/>1H NMR (400 MHz, CDCl3): 8.95 (d, IH), 7.72 (d, IH), 4.04 (s, 3H); MS (EI) for C9H5FN2O4: 224 (M+).
With diiodomethane; isopentyl nitrite;copper(l) iodide; In tetrahydrofuran; for 4h;Heating / reflux;
STEP 5: To a solution of methyl 5-amino-4-cyano-2-fluorobenzoate (437 mg, 2.2 mmol) in THF (13 mL) was added copper(I) iodide (419 mg, 2.2 mmol), diiodomethane (890 uL, 1 1 mmol), and isoamyl nitrite (890 uL, 6.6 mmol). The solution was heated to reflux for 4 h and was then allowed to cool to room temperature. After dilution with ethyl acetate, water was added and the mixture was filtered through celite. The biphasic filtrate was partitioned. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was then subject to column chromatography to provide impure methyl 4-cyano-2-fluoro-5- iodobenzoate (452 mg, ~ 63% purity, ~ 0.93 mmol). The remainder of the material consisted primarily of methyl 4-cyano-2-fluorobenzoate and was carried forward into the subsequent reaction without further purification. 1H NMR (400 MHz, CDCl3): 8.44 (d, IH), 7.43 (d, IH), 3.97 (s, 3H); MS (EI) for C9H5FINO2: 305 (M+).
Step 2: methyl 4-[amino(hydroxyimino)methyl]-2-fluorobenzoate To a solution of <strong>[175596-01-7]methyl 4-cyano-2-fluorobenzoate</strong>, obtained in Step 1 (486.8 mg; 2.72 mmol) in abs. EtOH (6 ml_) was added hydroxylamine (0.8 ml 13.6 mmol; 5 eq.) (50% in water) and the mixture was heated at 74C overnight. After cooling, a product precipitated. The precipitate was filtered off and dried under vacuum to afford Intermediate 1 as an off-white solid (267.10 mg; 46%). 1H-NMR (DMSO-d6, 300MHz) delta 10.09 (s, 1 H), 7.92 (t, J = 7.91 Hz, 1 H), 7.69 (dd, J = 1.70 Hz, J = 8.10 Hz, 1 H), 7.64 (dd, J = 1.51 , J = 12.81 , 1 H), 6.05 (s, 2H), 3.90 (s, 3H). HPLC (Method B) Rt 2.99 min (Purity: 100%).
With hydroxylamine; In ethanol; water; at 20 - 75℃;
Methyl 4-cyano-2-fluorobenzoate, obtained in step 1 (17.76 g; 99.13 mmol) was suspended in EtOH (200 mL). Hydroxylamine (50% in water, 30 mL; 495.67 mmol) was added and the resulting yellow suspension was heated at 750C for 1 hour and stirred at RT overnight. The suspension was filtered, the remaining residue was rinsed twice with ethanol (50 mL) and dried under vacuum, affording the title compound as a colorless solid. 1H NMR: (DMSO-dbeta, 300 MHz) delta 10.09 (s, 1 H), 7.95-7.89 (m, 1 H), 7.70-7.62, m, 2H), 6.05 (s, 2H), 3.89 (s, 3H). LC/MS (Method A): 210.9 (M-H)"; 212.9 (M+H)+. HPLC (Method A), Rt: 0.97 min (purity: 100%).
With hydroxylamine; In ethanol; water; for 18h;Reflux;
A mixture of <strong>[175596-01-7]methyl 4-cyano-2-fluorobenzoate</strong> (2) (1 .0 g, 5.6 mmol) and 50% (0607) aq. hydroxylamine (6.84 mL, 1 12 mmol) in EtOH (30 mL) was stirred at reflux for 18 h. The reaction mixture was cooled to RT, diluted with H20 (20 mL) and extracted with EtOAc (60 mL). The organic solution was washed with brine (100 mL), dried over MgS04, filtered and concentrated in vacuo to give methyl 2-fluoro-4-(//'- hydroxycarbamimidoyl) benzoate (3) (260 mg, 22%) as a 1 :1 mixture of methyl and ethyl esters that was progressed without purification: m/z 227, 213 [M+H]+ (ES+)
Step (i) Potassium carbonate (3.70 g, 26.7 mmol ) was added to a solution of 4-cyano-2- fluorobenzoic acid (4 g, 24.3 mmol) in DMF (350 mL). After stirring at RT for 15 minutes, iodomethane (1.66 mL, 26.7 mmol) was added. The flask was stoppered, and the mixture stirred at 40 C for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM (50 mL) and brine (50 mL). The organic phase was passed tlirough silica and concentrated to give methyl 4-cyano-2-fluorobenzoate (4.1 g, 94%). NMR (300 MHz, CDC13) delta ppm 3.96 (s, 311 ) 7.44-7.48 (m, 111) 7.49-7.53 (m, 111) 8.01- 8.05 (m, 1H)
94%
Potassium carbonate (3.70 g, 26.7 mmol) was added to a solution of 4-cyano-2-fluorobenzoic acid (4 g, 24.3 mmol) in DMF (350 mL). After stirring at RT for 15 minutes, iodomethane (1.66 mL, 26.7 mmol) was added. The flask was stoppered, and the mixture stirred at 40 C. for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM (50 mL) and brine (50 mL). The organic phase was passed through silica and concentrated to give methyl 4-cyano-2-fluorobenzoate (4.1 g, 94%). 1H NMR (300 MHz, CDCl3) delta ppm 3.96 (s, 3H) 7.44-7.48 (m, 1H) 7.49-7.53 (m, 1H) 8.01-8.05 (m, 1H)
30%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;
Example 42 4-fluoromethyl-3-[4-(tetrahydropyran-4-yloxymethyl)phenoxy]benzamide (42a) methyl 4-cyano-2-fluorobenzoate 4-Cyano-2-fluorobenzoic acid (5.15 g, 31.2 mol) was dissolved in dimethylformamide (50 mL), potassium carbonate (6.47 g, 46.8 mmol) and methyl iodide (3.88 mL, 62.4 mmol) were added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title object compound as a white powder (1.70 g, yield 30%). 1H-NMR (CHCl3, 400 MHz) delta: 3.97 (3H, s), 7.48 (1H, dd, J=9.8, 1.5 Hz), 7.52 (1H, dd, J=8.1, 1.5 Hz), 8.05 (1H, dd, J=8.1, 7.3 Hz).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
Intermediate 70: Methyl 4-cvano-2-fluorobenzoate A solution of 4-cyano-2-fluoro benzoic acid (4.00 g, 24.2 mmol) in dry DMF (40 ml) was treated with methyl iodide (20.62 g, 14.5 mmol), potassium carbonate (5.02 g, 36.3 mmol) and the reaction mixture was stirred at RT for 12 h. The reaction mixture was filtered and filtrate was concentrated. The crude was diluted with ethyl acetate and extracted with water.The organic layer was washed with brine and dried over Na2SO4 and evaporated under vacuum. The title compound was obtained as a yellow solid.1 H NMR(DMSO-d6, 400MHz) delta 8.00-8.05 (2H, m) 7.80 -7.82 (1 H, d), 3 .88 (3H, s). HPLC (Condition B): Rt 5.67 min (HPLC purity 99.0%).
With hydrogen;palladium on activated charcoal; In tetrahydrofuran; at 20℃; for 12h;
Intermediate 71 : Methyl 4-([(terf-butoxycarbonyl)aminolmethyl)-2-fluorobenzoate A solution of <strong>[175596-01-7]methyl 4-cyano-2-fluorobenzoate</strong> (intermediate 70, 4.00 g, 24.2 mmol) in dry THF (40ml) was treated with Boc anhydride (3.65 g, 16.7 mmol), palladium on carbon 10% (1 g) and the reaction mixture was stirred at RT for 12 h under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The title compound was obtained as colorless liquid (2.6 g), used without purification for the next step.
With potassium carbonate; dimethyl sulfate; In water; acetone;
Example 15A Methyl 4-cyano-2-fluorobenzoate 13.20 g (79.9 mmol) of 4-cyano-2-fluorobenzoic acid are dissolved in 300 ml of acetone. Then 22.10 g (159.9 mmol) of potassium carbonate and 9.08 ml (95.9 mmol) of dimethyl sulfate are successively added. The mixture is stirred at reflux temperature for 20 h. The reaction mixture is then mixed with 300 ml of water and the acetone is removed in a rotary evaporator. Several extractions with dichloromethane are carried out. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is then removed in vacuo. The remaining solid is used further without further purification. 16.1 g (84% of theory) of the title compound are obtained as a colorless solid. GC-MS (method 5): Rt=6.23 min; [M]+ (Elpos): m/z=179 1H-NMR (300 MHz, DMSO-d6): delta=3.90 (s, 3H), 7.83 (dd, 1H), 8.01-8.08 (m, 2H).
With hydrogen;Raney Nickel; In methanol; under 2585.81 Torr; for 18h;
Preparation of methyl 4-(aminomethyl)-2-fluorobenzoate: A solution of 4-cyano-2-fluorobenzoic acid (4.02 g, 24.36 mmol, Aldrich) in methanol (50 mL) was treated with p-toluenesulfonic acid monohydrate (0.46 g, 2.43 mmol) and heated to reflux overnight. The solvent was removed and the reaction residue was extracted with EtOAc, washed with saturated Na2CO3, brine and dried over Na2SO4 to give Methyl 4-cyano-2-fluorobenzoate (4.46 g, 95%). This Methyl ester (1.03 g, 5.77 mmol) was combined with methanol (60 mL) and Raney Ni (2 spatula tip fulls were added after washing with methanol under argon). It was then put under Hydrogen at 50 PSI on a PARR shaker for 18 hrs. The reaction was filtered through celite and washed with methanol while being kept under N2. It was then purified by silica gel chromatography with methanol and methylene chloride to give methyl 4-(aminomethyl)-2-fluorobenzoate (247.6 mg, 23%) as off-white solid.
With ammonia; hydrogen; nickel; In methanol; ethanol; at 40℃; under 3142.81 Torr; for 18h;
Preparation 91 4-Aminomethyl-2-fluoro-benzoic acid methyl ester Add a slurry of Raney nickel in ethanol (1.2 g, 1.2 ml) to <strong>[175596-01-7]4-cyano-2-fluoro-benzoic acid methyl ester</strong> (5.8 g, 30.0 mmol) in 2N ammonia in methanol (580 mL). Purge with nitrogen gas (3*), purge with hydrogen gas (3*), and pressurize with hydrogen gas to 419 KPa. Heat the reaction at 40 C. for 18 hrs. Allow to cool to room temperature and filter the reaction mixture. Concentrate the filtrate to the crude title compound (6.9 g, 99%). MS (m/z): 184 (M+1).
Example 34A 3-Fluoro-4-(hydroxymethyl)benzonitrile 16.10 g (89.9 mmol) of <strong>[175596-01-7]methyl 4-cyano-2-fluorobenzoate</strong> are dissolved in 150 ml of methanol. Then 3.40 g (89.9 mmol) of sodium borohydride are added in portions. After the reaction has taken place (TLC check), the mixture is adjusted to pH 3 with dilute hydrochloric acid and extracted several times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution and dried with magnesium sulfate. The solvent is then removed in vacuo, and the residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 15:1?3:7). 3.70 g (27.2% of theory) of the title compound are obtained. GC-MS (method 7): Rt=6.51 min; [M]+ (EIpos): m/z=151 1H-NMR (300 MHz, DMSO-d6): delta=4.61 (s, 2H), 5.53 (s, 1H), 7.61-7.74 (m, 2H), 7.79 (dd, 1H).
27.2%
With methanol; sodium tetrahydroborate;
Methyl 4-cyano-2-fluoro-benzoate was dissolved 16.10 g (89.9 mmol) in 150 mL of methanol. Then, sodium borohydride 3.40 g (89.9 mmol) was added little by little. After the reaction was made (checked by TLC), the mixture was adjusted to pH 3 using dilute hydrochloric acid, and extracted several times with dichloromethane. The combined organic phases are washed with a saturated aqueous sodium chloride solution and dried using magnesium sulfate. Was purified by: - After that, the solvent is removed in vacuo, and column chromatography of the residue (7> 3 1: silica gel, mobile phase: cyclohexane / ethyl acetate 15). The title compound was obtained a 3.70 g (27.2% of theory).
With sodium borohydrid; In methanol; ethyl acetate;
Example 16A 3-Fluoro-4-(hydroxymethyl)benzonitrile 16.10 g (89.9 mmol) of <strong>[175596-01-7]methyl 4-cyano-2-fluorobenzoate</strong> are dissolved in 150 ml of methanol. Then 3.40 g (89.9 mmol) of sodium borohydride are added in portions. After the reaction has taken place (TLC check), the mixture is adjusted to pH 3 with dilute hydrochloric acid and extracted several times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution and dried with magnesium sulfate. The solvent is then removed in vacuo, and the residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 15:1?3:7). 3.70 g (27.2% of theory) of the title compound are obtained. GC-MS (method 5): Rt=6.51 min; [M]+ (Elpos): m/z=151 1H-NMR (300 MHz, DMSO-d6): delta=4.61 (s, 2H), 5.53 (s, 1H), 7.61-7.74 (m, 2H), 7.79 (dd, 1H).
With potassium carbonate; In acetone; for 20h;Reflux;
Example 33A Methyl 4-cyano-2-fluorobenzoate 13.20 g (79.9 mmol) of 4-cyano-2-fluorobenzoic acid are dissolved in 300 ml of acetone. Then 22.10 g (159.9 mmol) of potassium carbonate and 9.08 ml (95.9 mmol) of dimethyl sulfate are successively added. The mixture is stirred at reflux temperature for 20 h. The reaction mixture is then mixed with 300 ml of water and the acetone is removed in a rotary evaporator. Several extractions with dichloromethane are carried out. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent is then removed in vacuo. The remaining solid is used further without further purification. 16.1 g (84% of theory) of the title compound are obtained as a colorless solid. GC-MS (method 7): Rt=6.23 min; [M]+ (EIpos): m/z=179 1H-NMR (300 MHz, DMSO-d6): delta=3.90 (s, 3H), 7.83 (dd, 1H), 8.01-8.08 (m, 2H).
84%
With potassium carbonate; In acetone; for 20h;Reflux;
4-cyano-2-fluoro-benzoic acid 13.20 g (79.9 mmol) was dissolved in acetone 300 mL. Then, 22.10 g of potassium carbonate A (159.9 mmol) and dimethyl sulfate 9.08 ml (95.9 mmol) were added consecutively. The mixture was refluxed at a temperature of 20 hour Stirred . Then, the reaction mixture was mixed with 300 mL of water, and the acetone on a rotary evaporator It was removed. It can in turn was extracted with dichloromethane. The combined organic phases are washed with a saturated aqueous sodium chloride solution, and sulfuric acid Dried over sodium. Then, the solvent was removed in vacuo. The remaining solid was used without further purification. The title compound was 16.1 g (84% of theory) as a colorless solid
rac-4-([(2S,3S,4S)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino}methyl)-2-fluorobenzoic acid methyl ester[ No CAS ]
rac-4-([(2S,3S,4S)-2-(3-chloro-2-fluorophenyl)-3-(4-chloro-2-fluorophenyl)-3-cyano-4-(2,2-dimethylpropyl)pyrrolidine-1-carbonyl]amino}methyl)-2-fluorobenzoic acid[ No CAS ]
methyl 4-(aminocarbonothioyl)-2-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium hydrosulfide monohydrate; magnesium(II) chloride hexahydrate; In N,N-dimethyl-formamide; at 20℃; for 4h;
A sodium hydrogensulfide hydrate (9.22 g, 0.165 mol) was added to an N,N-dimethylformamide (74 mL) suspension of <strong>[175596-01-7]methyl 4-cyano-2-fluorobenzoate</strong> () (7.37 g, 41.1 mmol) and magnesium chloride hexahydrate (10.0 g, 49.4 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. Subsequently, water (148 mL) was added to the reaction mixture, and the precipitated solid was filtered. The solid thus obtained was added to 1 N aqueous hydrochloric acid solution (148 mL), and the mixture was stirred for 20 minutes. The solid in the reaction mixture was filtered to give the title compound (7.63 g, yield: 87%). 1H-NMR (500 MHz, DMSO-d6) delta ppm: 10.21 (1H, s), 9.75 (1H, s), 7.94-7.90 (1H, m), 7.79-7.72 (2H, m), 3.88-3.87 (3H, m).
methyl 2-fluoro-4-(hydroxymethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With water; acetic acid; at 15 - 25℃; under 15001.5 Torr; for 18h;Inert atmosphere;
Step (ii) Raney nickel (2.0 g) was added to a solution of <strong>[175596-01-7]methyl 4-cyano-2-fluorobenzoate</strong> (obtained as described in step (i) above) (10.1 g, 61.6 mmol) in acetic acid (200 ml.) and water (100 niL). The mixture was stirred at RT under argon at 20 bar. After 18 h the mixture was filtered through diatomaceous earth, washing through with water (1000 mL). The filtrate was extracted with EtOAc (3 chi 300 mL). The combined organic phases were dried and concentrated, adding toluene to assist removal of acetic acid, to give methyl 2- 11 uoro-4-( hydroxy meth) l)benzoate (crude, 6.06 g) which was used in the next step without further purification or characterisation.
With nickel; acetic acid; In water; acetic acid; at 20℃; under 15001.5 Torr; for 18h;Inert atmosphere;
Step (ii) Raney nickel (2.0 g) was added to a solution of <strong>[175596-01-7]methyl 4-cyano-2-fluorobenzoate</strong> (obtained as described in step (i) above) (10.1 g, 61.6 mmol) in acetic acid (200 mL) and water (100 mL). The mixture was stirred at RT under argon at 20 bar. After 18 h the mixture was filtered through diatomaceous earth, washing through with water (1000 mL). The filtrate was extracted with EtOAc (3*300 mL). The combined organic phases were dried and concentrated, adding toluene to assist removal of acetic acid, to give methyl 2-fluoro-4-(hydroxymethyl)benzoate (crude, 6.06 g) which was used in the next step without further purification or characterisation.
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