* 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.
Step 2; Preparation of Methyl 2-amino-4-trifluoromethylbenzoate; Add a solution of methyl 2-nitro-4-trifluoromethylbenzoate (106 g, 425 mmol) in ethyl. acetate (2.2 L) to a slurry of 10percent palladium on carbon (11.0 g) in ethyl acetate (200 mL)and stir the suspension at room temperature under an atmosphere of hydrogen at 60 psifor 3 h. Filter the suspension through a pad of Celite.(R). and wash the pad with additionalethyl acetate. Remove the solvents under reduced pressure and purify the residue bycolumn chromatography on silica gel, eluting with isohexane/ethyl acetate (9:1), toprovide the title compound as a white crystalline solid (84 g, 95percent).
93%
With hydrogen In ethyl acetate at 20℃; for 18 h;
Step 2. Methyl 2-Amino-4-(trifluoromethyl)benzoate: A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10percent Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite.(R). and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93percent): 1H-NMR (DMSO-d6) δ 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
93%
With hydrogen In ethyl acetate at 20℃; for 18 h;
A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10percent Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93percent): 1H-NMR (DMSO-d6) ? 3.79 (s, 3H), 6.75 (dd,J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
93%
With hydrogen In ethyl acetate at 20℃; for 18 h;
Step 2. Methyl 2-Amino-4-(trifluoromethyl)benzoate; A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10percent Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite.(R). and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93percent): 1H-NMR (DMSO-d6) δ 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
91%
Stage #1: With tin(ll) chloride In dichloromethane; ethyl acetate at 20℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water; ethyl acetate
B. 2-Amino-4-trifluoromethyl-benzoic acid methyl ester. A solution of 2-nitro-4-trifluoromethylbenzoic acid methyl ester (4.3 g, 0.017 mol) was dissolved in a mixture of DCM (20 mL) and EtOAc (20 mL) followed by addition of SnCl2.2H2O (19 g, 0.086 mol). The mixture was stirred overnight at room temperature, then was neutralized by shaking with a satd. aq. NaHCO3 solution. The resulting salts were removed by filtration through a pad of diatomaceous earth. The filtrate was extracted with DCM (3*). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (3.38 g, 91percent). TLC (silica, 50percent EtOAc/hexanes): Rf=0.60. HPLC (reverse phase): RT=9.31 min. 1H NMR (500 MHz, CDCl3): 7.95 (d, J=8.3 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J=9.3 Hz, 1H), 5.91 (br s, 2H), 3.90 (s, 3H).
67%
With sodium dithionite In ethanol; water at 50℃; for 3 h;
A mixture of methyl 2-nitro-4- (trifluoromethyl) benzoate (2.49 g 0.01 mol), sodium hydrosulfite (8.71 g, 0.05 mol), ethanol (20 ml) and water (20 ml) was heated at 50 0C for 3 h. Water was added and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 5percent ethyl acetate/n-hexane to give 1.46 g(6.67 mmol 67percent) of the title compound as a white powder. 1H NMR (CDCl3) δ. 3.90 (s, 3H), 5.50-6,20 (brs, 2H), 6.85 (d, J = 8.48 Hz, IH), 6.90 (s, IH), 7.95 (d, J = 8.48 Hz, IH) . MS Calcd. : 219; Found: 220 (M+H) .
With TMSCH2N2 In tetrahydrofuran; hexane at 20℃; for 1 h;
Example 74 5- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-8-trifluoromethyl-2, 3,4, 5-tetrahydro- benzo [b] azepine-1-carboxylic acid isopropyl ester The titled compounds was prepared following the procedures described in Example 1 by replacing 2-Amino-benzoic acid methyl ester with 2-Amino-4- trifluoromethyl-benzoic acid methyl ester in Example 1, step 1. MS (ES+): 585 (M+H). Preparation of 2-Amino-4-trifluoromethyl-benzoic acid methyl ester: A solution of 2-amino-4-trifluoromethyl-benzoic acid (9.15g, 44.6 mmol) in THF/MeOH (300 ml/75. 0 ml) was treated with trimethylsilyldiazonium methane (2.00 M in hexane, 23.0 ml) and stirred at room temperature for an hour. The reaction was quenched by acetic acid (3.00 ml). The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography eluting with 0-10percent ethyl acetate in hexane to provide 8. 55g (88percent) white crystalline of the titled compound. The structure was confirmed by lH- 4 NMR.
75%
Stage #1: With hydrogenchloride In water at 80℃; for 63 h; Stage #2: With sodium hydroxide In water
Step 2: Methyl 2-amino-4-(trifluoromethyl)benzoate; To a mixture of 2-amino-4-(trifluoromethyl) benzoic acid (15O g, 0.73 mol) in MeOH (2.5 L) was added cone. HCl (0.5 L, 16.5 mol). The reaction mixture was allowed to stir at reflux. After 3 h, an additional portion of HCl (0.5 L, 16.5 mol) was added and the reaction was allowed to continue to stir at80 0C for 60 h. The reaction mixture was allowed to cool to rt and was concentrated. Water (0.5 L) was added to the residue, and the solution was basified with 10percent aqueous NaOH solution. The resulting precipitate was filtered to give methyl 2-amino-4-(trifluoromethyl)benzoate (12O g, 75percent) as a white solid.
75%
Stage #1: for 16 h; Heating / reflux Stage #2: With water; sodium carbonate In methanol; ethyl acetate
2-Amino-4-trifluoromethyl-benzoic acid methyl ester; To a solution of 2-amino-4-trifluoromethyl-benzoic acid (72.0 g, 351 mmol) in MeOH (1000 mL) was added dropwise concentrated sulfuric acid (50 mL). The mixture was heated to reflux for 16 h under nitrogen, allowed to cool to r.t., and then concentrated in vacuo to 1A of its volume. The mixture was taken up in EtOAc and washed with water, 10percent aqueous solution of sodium carbonate, and brine. It was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (silica gel 60, hexanes/EtOAc 9:1) furnished 2-amino-4-trifluoromethyl-benzoic acid methyl ester (57.8 g, 264 mmol, 75percent) as a white powder, m.p. 59 0C, ESI-MS: m/z 218 [M-H]".
Reference：
[1] Journal of Medicinal Chemistry, 1983, vol. 26, # 6, p. 865 - 869
[2] Patent: WO2005/37796, 2005, A1, . Location in patent: Page/Page column 82-83
[3] Patent: WO2010/65134, 2010, A1, . Location in patent: Page/Page column 60
[4] Patent: WO2006/108591, 2006, A1, . Location in patent: Page/Page column 66
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338
[6] Chinese Chemical Letters, 2017, vol. 28, # 6, p. 1248 - 1251
[7] Patent: WO2007/14054, 2007, A2, . Location in patent: Page/Page column 25
[8] Patent: WO2013/38390, 2013, A1, . Location in patent: Page/Page column 64
3
[ 186581-53-3 ]
[ 402-13-1 ]
[ 61500-87-6 ]
Yield
Reaction Conditions
Operation in experiment
5.34 g
Inert atmosphere
To a solution of 2-amino-4-(trifluoromethyl)benzoic acid (5 g) in THF (85 ml) was added diazomethane (48.7 ml) in ether until completion of the reaction. Nitrogen was bubbled into the reaction mixture for 15 minutes to remove the excess of diazomethane and the solvent was removed under reduced pressure to provide a light brown solid (5.34 g). The compound was used in the next without purification. LRMS (ES+) m/z 220.1 (M+H)+.
Reference：
[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 22, p. 3386 - 3396
[2] Patent: WO2013/74386, 2013, A2, . Location in patent: Page/Page column 69
[3] Patent: US9328138, 2016, B2, . Location in patent: Page/Page column 90
Reference：
[1] European Journal of Medicinal Chemistry, 2005, vol. 40, # 9, p. 897 - 907
10
[ 343-69-1 ]
[ 61500-87-6 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2005, vol. 40, # 9, p. 897 - 907
11
[ 61500-87-6 ]
[ 872624-52-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With iodine; silver sulfate In ethanol at 20℃; for 2 h;
Step 3; Preparation of methyl 2-amino-5-iodo-4-trifluoromethylbenzoate; Add a solution of methyl 2-amino-4-trifluoromethylbenzoate (178 g, 812 mmol) inethanol (3.3 L) to a suspension of iodine (206.1 g, 812 mmol) and silver(II) sulfate (253g, 812 mmol) in ethanol (5 L) at room temperature under an atmosphere of nitrogen andstir for 2 h. Filter the suspension through a pad of a Celite.(R)., wash the pad withadditional ethanol (2 L) and remove the solvents from the combined filtrates underreduced pressure at 40 °C. Dissolve the residue in ethyl acetate (7.5 L) and wash withsaturated sodium bicarbonate solution (3 x 1.5 L), water (3 x 1.5 L) and brine (2 L). Drythe organic phase over anhydrous magnesium sulfate, filter and remove the solvent underreduced pressure to give the title compound as a pale brown crystalline solid (276.0 g,99percent).
83%
With iodine; silver sulfate In ethanol at 20℃; for 1 h;
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester; A mixture of 2-amino-4-trifluoromethyl-benzoic acid methyl ester (51.5 g, 235 mmol), iodine (55.1 g, 217 mmol) and silver sulfate (73.3 g, 234 mmol) in EtOH (1560 mL) was stirred for 1 h at r.t. under nitrogen. The suspension was then filtered and the filtrate diluted with EtOAc and washed once with a 10percent aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (67.5 g, 196 mmol, 83percent) as a brown solid, m.p. 101-103 0C, ESI-MS: m/z 346 [M+H]+.
Reference：
[1] Patent: WO2006/2342, 2006, A1, . Location in patent: Page/Page column 56
[2] Patent: WO2006/108591, 2006, A1, . Location in patent: Page/Page column 10; 66
[3] Chinese Chemical Letters, 2017, vol. 28, # 6, p. 1248 - 1251
[4] Patent: WO2013/38390, 2013, A1, . Location in patent: Page/Page column 64; 65
[5] ChemMedChem, 2017, vol. 12, # 3, p. 197 - 201
methyl 2-amino-4-(trifluoromethyl)benzoate To a solution of 2-amino-4-(trifluoromethyl)benzoic acid (5 g) in THF (85 ml) was added diazomethane (48.7 ml) in ether until completion of the reaction. Nitrogen was bubbled into the reaction mixture for 15 minutes to remove the excess of diazomethane and the solvent was removed under reduced pressure to provide a light brown solid (5.34 g). The compound was used in the next without purification. LRMS (ES+) m/z 220.1 (M+H)+.
5.34 g
In tetrahydrofuran;Inert atmosphere;
To a solution of 2-amino-4-(trifluoromethyl)benzoic acid (5 g) in THF (85 ml) was added diazomethane (48.7 ml) in ether until completion of the reaction. Nitrogen was bubbled into the reaction mixture for 15 minutes to remove the excess of diazomethane and the solvent was removed under reduced pressure to provide a light brown solid (5.34 g). The compound was used in the next without purification. LRMS (ES+) m/z 220.1 (M+H)+.
2-amino-4-(trifluoromethyl)benzoic acid (0.50g, 2.44mmol) was dissolved in 40mL methanol and 8mL HClc were added slowly. The mixture was stirred and heated under reflux for 12h. Subsequently, the methanol was evaporated and the remaining residue suspended in water. This mixture was adjusted to an alkaline pH by adding a 10% NaOH solution and extracted with diethyl ether. The combined organic phases were dried over Na2SO4. After evaporation of the diethyl ether, the remaining solid was recrystalized in isohexane to give 0.50g (yield 93%) of a yellowish powder. mp: 62C; H NMR (400MHz, CDCl3) delta 3.89 (s, 3H, 1?-H); 5.90 (br s, 2H, NH); 6.84 (dd, 1H, 3J=8.2Hz, 4J=1.6Hz, 5-H); 6.89 (s, 1H, 3-H); 7.94 (dd, 1H, 3J=8.2Hz, 4J=1.6Hz, 6-H); C NMR (100MHz, CDCl3) delta 52.0 (C1?); 112.4 (q, 3J (C,F)=3.8Hz, C3); 113.1 (C1); 113.5 (q, 3J (C,F)=4.8Hz, C5); 123.6 (q, 1J (C,F)=273.2Hz, C8); 132.2 (C6); 135.5 (q, 2J (C,F)=31.6Hz, C4); 150.3 (C2); 113.1 (C1); 167.8 (C7); EI-MS (70eV): m/z (rel. int.)=219 [M+] (100), 200 (25), 187 (91), 160 (81); HR-EI-MS: m/z=219.0507; C9H8F3NO2 [M+] requires 219.0494.
88%
With TMSCH2N2; In tetrahydrofuran; hexane; at 20℃; for 1h;
Example 74 5- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-8-trifluoromethyl-2, 3,4, 5-tetrahydro- benzo [b] azepine-1-carboxylic acid isopropyl ester The titled compounds was prepared following the procedures described in Example 1 by replacing 2-Amino-benzoic acid methyl ester with 2-Amino-4- trifluoromethyl-benzoic acid methyl ester in Example 1, step 1. MS (ES+): 585 (M+H). Preparation of 2-Amino-4-trifluoromethyl-benzoic acid methyl ester: A solution of 2-amino-4-trifluoromethyl-benzoic acid (9.15g, 44.6 mmol) in THF/MeOH (300 ml/75. 0 ml) was treated with trimethylsilyldiazonium methane (2.00 M in hexane, 23.0 ml) and stirred at room temperature for an hour. The reaction was quenched by acetic acid (3.00 ml). The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography eluting with 0-10% ethyl acetate in hexane to provide 8. 55g (88%) white crystalline of the titled compound. The structure was confirmed by lH- 4 NMR.
75%
Step 2: Methyl 2-amino-4-(trifluoromethyl)benzoate; To a mixture of 2-amino-4-(trifluoromethyl) benzoic acid (15O g, 0.73 mol) in MeOH (2.5 L) was added cone. HCl (0.5 L, 16.5 mol). The reaction mixture was allowed to stir at reflux. After 3 h, an additional portion of HCl (0.5 L, 16.5 mol) was added and the reaction was allowed to continue to stir at80 0C for 60 h. The reaction mixture was allowed to cool to rt and was concentrated. Water (0.5 L) was added to the residue, and the solution was basified with 10% aqueous NaOH solution. The resulting precipitate was filtered to give methyl 2-amino-4-(trifluoromethyl)benzoate (12O g, 75%) as a white solid.
75%
2-Amino-4-trifluoromethyl-benzoic acid methyl ester; To a solution of 2-amino-4-trifluoromethyl-benzoic acid (72.0 g, 351 mmol) in MeOH (1000 mL) was added dropwise concentrated sulfuric acid (50 mL). The mixture was heated to reflux for 16 h under nitrogen, allowed to cool to r.t., and then concentrated in vacuo to 1A of its volume. The mixture was taken up in EtOAc and washed with water, 10% aqueous solution of sodium carbonate, and brine. It was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (silica gel 60, hexanes/EtOAc 9:1) furnished 2-amino-4-trifluoromethyl-benzoic acid methyl ester (57.8 g, 264 mmol, 75%) as a white powder, m.p. 59 0C, ESI-MS: m/z 218 [M-H]".
With hydrogenchloride; In water; for 12h;Heating / reflux;
2-amino-4-(trifluoromethyl)benzoic acid (2.51 g, 12.24 mmol) was dissolved in methanol (100 mL) and concentrated hydrochloric acid was added (20 ml_). The resulting solution was heated to reflux for 12 hours and then the volatiles removed under reduced pressure. The residue was partitioned between diethyl ether (2x100 mL) and sodium hydroxide solution (50 mL). This provided the desired compound methyl-2-amino-4- (trifluoromethyl)benzoate as a colourless oil (1.86 g). HPLC Rt = 3.15 minutes; m/z [M+H]+ = 220. 1H NMR (CD3OD) delta 7.88 (d, 1H), 7.00 (s, 1H), 6.72 (d, 1 H), 3.85 (s, 3H).
With sulfuric acid; at 20 - 65℃;
A solution of 2-amino-4-(trifluoromethyl)benzolic acid (75 g, 366 mmol) in MeOH (750ml) was treated dropwise with sulfuric acid (48.7 ml) over -15 minutes (exotherm temperature 34C) maintaining the temperature at 20C. The resulting mixture was heated to 65C for 24 hours. After cooling to RT, the mixture was diluted with water (750 ml) under stirring. The resulting precipitate was filtered and the solid was slurried in water (500 ml). Saturated sodium bicarbonate (1 L) was added to take the pH to pH9 and the mixture was extracted with diethyl ether (3 x 330 ml). The combined organic extracts were washed with brine (700 ml), dried (MgS04) and concentrated in vacuo to afford the title product. MS m/z 220[M+H]+.
A mixture of <strong>[61500-87-6]methyl 2-amino-4-(trifluoromethyl)benzoate</strong> (8.00 g, 0.036 mol), acetic anhydride (11.18 g, 0.109 mol) , pyridine (8.62 g, 0.109 mol) and chloroform (20 ml) was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo.The residue was diluted with water and extracted with ethyl acetate. The extracts were washed with IN hydrochloric acid and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 50% ethyl acetate/n-hexane to give 8.10 g (0.031 mol 86%) of the title compound as a white powder, mp 86-87 0C.1H NMR (CDCl3) delta 2.26 (s, 3H), 3.97 (s, 3H), 7.32 (dd, J = 1.41, 8.38 Hz, IH), 8.14 (d, J = 8.29 Hz, IH), 9.08 (s, IH), 11.11 (s, IH) .MS Calcd. : 261; Found: 262 (M+H) .
5.27 g
With pyridine; In 1,4-dioxane; at 80℃; for 60h;
Step 2: methyl 2-(acetylamino)-4-(trifluoromethyl)benzoate To a solution of the product from Step 1 (5.34 g) in dioxane (25 ml) was added acetic anhydride (6 ml) and pyridine (4 ml). After 60 hours of stirring at 80C, the solution was concentrated under reduced pressure and the residue was dissolved into ethyl acetate. The organic layer was washed with 2M sodium carbonate, 10% aqueous HCl, water and brine, dried over sodium sulfate and evaporated. The product was purified by flash chromatography (ISCO, 5%-20% ethyl acetate in hexanes) to provide a beige solid (5.27 g). LRMS (ES+) m/z 262.0 (M+H)+.
5.27 g
With pyridine; at 80℃; for 60h;
To a solution of the product from Step 1 (5.34 g) in dioxane (25 ml) was added acetic anhydride (6 ml) and pyridine (4 ml). After 60 hours of stirring at 80 C., the solution was concentrated under reduced pressure and the residue was dissolved into ethyl acetate. The organic layer was washed with 2M sodium carbonate, 10% aqueous HCl, water and brine, dried over sodium sulfate and evaporated. The product was purified by flash chromatography (ISCO, 5%-20% ethyl acetate in hexanes) to provide a beige solid (5.27 g). LRMS (ES+) m/z 262.0 (M+H)+
Tosyl chloride (12.4 g) was added to a pyridine (40 mL) solution of the compound (13.0 g) prepared in <Step 2> of Example 190. The reaction mixture was stirred at room temperature for two hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water, 1 N hydrochloric acid, and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Subsequently, n-hexane was added to the residue to solidify the resulting product. The title compound (18.9 g) was obtained as pale yellow crystals.
With pyridine; at 20℃; for 2h;
Tosyl chloride (12.4 g) was added to a pyridine (40 mL) solution of the compound (13.0 g) prepared in <Step 2> of Example 190. The reaction mixture was stirred at room temperature for two hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water, 1 N hydrochloric acid, and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Subsequently, n-hexane was added to the residue to solidify the resulting product. The title compound (18.9 g) was obtained as pale yellow crystals.
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 3102.97 Torr; for 3h;
Step 2; Preparation of Methyl 2-amino-4-trifluoromethylbenzoate; Add a solution of methyl 2-nitro-4-trifluoromethylbenzoate (106 g, 425 mmol) in ethyl. acetate (2.2 L) to a slurry of 10% palladium on carbon (11.0 g) in ethyl acetate (200 mL)and stir the suspension at room temperature under an atmosphere of hydrogen at 60 psifor 3 h. Filter the suspension through a pad of Celite and wash the pad with additionalethyl acetate. Remove the solvents under reduced pressure and purify the residue bycolumn chromatography on silica gel, eluting with isohexane/ethyl acetate (9:1), toprovide the title compound as a white crystalline solid (84 g, 95%).
93%
palladium-carbon; In ethyl acetate;
Step 2 Methyl 2-Amino-4-(trifluoromethyl)benzoate A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93%): 1H-NMR (DMSO-d6) delta 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
93%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 20℃; for 18h;
Step 2. Methyl 2-Amino-4-(trifluoromethyl)benzoate: A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93%): 1H-NMR (DMSO-d6) delta 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
93%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 20℃; for 18h;
A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93%): 1H-NMR (DMSO-d6) ? 3.79 (s, 3H), 6.75 (dd,J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
93%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 20℃; for 18h;
Step 2. Methyl 2-Amino-4-(trifluoromethyl)benzoate; A solution of methyl 2-nitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H2 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93%): 1H-NMR (DMSO-d6) delta 3.79 (s, 3H), 6.75 (dd, J=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, J=0.73 Hz, 1H), 7.83 (d, J=8.09 Hz, 1H).
91%
B. 2-Amino-4-trifluoromethyl-benzoic acid methyl ester. A solution of 2-nitro-4-trifluoromethylbenzoic acid methyl ester (4.3 g, 0.017 mol) was dissolved in a mixture of DCM (20 mL) and EtOAc (20 mL) followed by addition of SnCl2.2H2O (19 g, 0.086 mol). The mixture was stirred overnight at room temperature, then was neutralized by shaking with a satd. aq. NaHCO3 solution. The resulting salts were removed by filtration through a pad of diatomaceous earth. The filtrate was extracted with DCM (3*). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (3.38 g, 91%). TLC (silica, 50% EtOAc/hexanes): Rf=0.60. HPLC (reverse phase): RT=9.31 min. 1H NMR (500 MHz, CDCl3): 7.95 (d, J=8.3 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J=9.3 Hz, 1H), 5.91 (br s, 2H), 3.90 (s, 3H).
67%
With sodium dithionite; In ethanol; water; at 50℃; for 3h;
A mixture of methyl 2-nitro-4- (trifluoromethyl) benzoate (2.49 g 0.01 mol), sodium hydrosulfite (8.71 g, 0.05 mol), ethanol (20 ml) and water (20 ml) was heated at 50 0C for 3 h. Water was added and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 5% ethyl acetate/n-hexane to give 1.46 g(6.67 mmol 67%) of the title compound as a white powder. 1H NMR (CDCl3) delta. 3.90 (s, 3H), 5.50-6,20 (brs, 2H), 6.85 (d, J = 8.48 Hz, IH), 6.90 (s, IH), 7.95 (d, J = 8.48 Hz, IH) . MS Calcd. : 219; Found: 220 (M+H) .
With tin(ll) chloride; In dichloromethane; ethyl acetate; at 20℃; for 16h;
D. 2-Amino-4-trifluoromethylbenzoic acid methyl ester. To a stirred solution of 2-nitro-4-trifluoromethylbenzoic acid (6.0 g, 25 mmol) in dry DMF (30 mL) at 0 C. was added DBU (35 mL, 25 mmol) followed in 15 min by iodomethane (16 mL, 25 mmol). The reaction mixture was allowed to warm to ambient temperature and stir overnight, then was partitioned between water and EtOAc. The organic layer was washed with water and dried (MgSO4), and the resulting crude product was purified on silica gel (MPLC, hexanes/EtOAc) to provide the methyl ester as a yellow oil (5.7 g, 91%). This material was immediately dissolved in 3:1 EtOAc/DCM (50 mL), and SnCl2.2H2O (26 g, 110 mmol) was added with stirring. The mixture was held at ambient temperature for 16 h, then 5% aqueous NaHCO3 was added cautiously. The aqueous phase was extracted with DCM (3×), and the combined organic layers were dried (MgSO4). Filtration and concentration provided the aniline as a light yellow solid (4.5 g, 21 mmol, 84% for two steps). HPLC (reversed-phase): RT=9.38 min. 1H NMR (400 MHz, CDCl3): 7.95 (d, J=8.3 Hz, 1H), 6.91 (s, 1H), 6.85 (dd, J=8.6, 1.3 Hz, 1H), 6.2-5.5 (bs, 2H), 3.90 (s, 3H).
With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 20h;
First, 10% Pd-C (2.5 g) was added to a methanol (490 mL) solution of the compound (24.6 g) prepared in <Step 1> of Example 190, and the mixture was stirred in a hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was subjected to Celite filtration. The solvent was then distilled off under reduced pressure. The title compound (21.3 g) was obtained as gray-white crystals.
With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 20h;
First, 10%Pd-C (2.5 g) was added to a methanol (490 mL) solution of the compound (24.6 g) prepared in <Step 1> of Example 190, and the mixture was stirred in a hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was subjected to Celite filtration. The solvent was then distilled off under reduced pressure. The title compound (21.3 g) was obtained as gray-white crystals.
C. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-trifluoromethylbenzoic acid methyl ester. 4-Chlorosulfonyl-2,1,3-benzothiadiazole (1.77 g, 7.52 mmol) was added to a solution of 2-amino-4-trifluoromethylbenzoic acid methyl ester (1.50 g, 6.84 mmol) and pyridine (1.10 mL, 13.7 mmol) in DCM (10 mL). After standing overnight at room temperature, the reaction mixture was quenched with 1 N HCl and diluted with H2O. The aqueous layer was extracted with DCM (3*). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified by flash chromatography (hexanes/EtOAc) to provide the title compound (1.78 g, 62%). TLC (silica, 50% EtOAc/hexanes): Rf=0.47. MS (ESI): mass calculated for C15H10F3N3O4S2, 417.01; m/z found, 415.9/416.9/417.9 [M-H]-. HPLC (reverse phase): RT=9.95 min. 1H NMR (500 MHz, CDCl3): 11.33 (s, 1H), 8.41 (dd, J=7.1, 1.0 Hz, 1H), 8.23 (dd, J=8.9, 1.0 Hz, 1H), 8.04 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.72 (dd, J=8.8, 7.1 Hz, 1H), 7.20 (dd, J=8.3, 1.1 Hz, 1H), 3.96 (s, 3H).
With iodine; silver sulfate; In ethanol; at 20℃; for 2h;Product distribution / selectivity;
Step 3; Preparation of methyl 2-amino-5-iodo-4-trifluoromethylbenzoate; Add a solution of <strong>[61500-87-6]methyl 2-amino-4-trifluoromethylbenzoate</strong> (178 g, 812 mmol) inethanol (3.3 L) to a suspension of iodine (206.1 g, 812 mmol) and silver(II) sulfate (253g, 812 mmol) in ethanol (5 L) at room temperature under an atmosphere of nitrogen andstir for 2 h. Filter the suspension through a pad of a Celite, wash the pad withadditional ethanol (2 L) and remove the solvents from the combined filtrates underreduced pressure at 40 C. Dissolve the residue in ethyl acetate (7.5 L) and wash withsaturated sodium bicarbonate solution (3 x 1.5 L), water (3 x 1.5 L) and brine (2 L). Drythe organic phase over anhydrous magnesium sulfate, filter and remove the solvent underreduced pressure to give the title compound as a pale brown crystalline solid (276.0 g,99%).
83%
With iodine; silver sulfate; In ethanol; at 20℃; for 1h;
2-Amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester; A mixture of <strong>[61500-87-6]2-amino-4-trifluoromethyl-benzoic acid methyl ester</strong> (51.5 g, 235 mmol), iodine (55.1 g, 217 mmol) and silver sulfate (73.3 g, 234 mmol) in EtOH (1560 mL) was stirred for 1 h at r.t. under nitrogen. The suspension was then filtered and the filtrate diluted with EtOAc and washed once with a 10% aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (67.5 g, 196 mmol, 83%) as a brown solid, m.p. 101-103 0C, ESI-MS: m/z 346 [M+H]+.
With iodine; silver sulfate; In methanol; at 20℃;
<strong>[61500-87-6]2-Amino-4-trifluoromethyl-benzoic acid methyl ester</strong>, (48 g, 219 mmol) was dissolved in MeOH (750 ml). Silver sulfate (68.3 g, 219 mmol) and iodine (55.6 g, 219 mmol) was added and rinsed in with MeOH (50 ml). The reaction mixture was left for 1 hour at RT. The reaction mixture was filtered under vacuum and the filtrate concentrated in vacuo. The residue was taken up in MeOH (100 ml) and water (10 ml) and the mixture heated at 80C. The crude solution was hot filtered to remove residual inorganics and the warm filtrate was poured slowly into water (750 ml) with vigorous stirring. The mixture was left to particulate for 10 minutes and filtered to give the title compound as an orange solid. MS m/z 345[M+H]+.
c. Dimethyl 4-hydroxy-7-trifluoromethylquinoline-2,3-dicarboxylate Using a procedure similar to that described in Example 3c except starting with <strong>[61500-87-6]methyl 2-amino-4-trifluoromethylbenzoate</strong> and employing a five day reaction time to form the intermediate enamime adduct, the title compound was obtained (67%) as a tan crystalline solid, mp 210-210.5 C.; MS(CI): 330 (M+H). Analysis for C14 H10 F3 NO5 Calculated: C, 51.07; H, 3.06; N, 4.25 Found: C, 51.16; H, 3.23; N, 4.17
b. Methyl 2-amino-4-trifluoromethylbenzoate Using a procedure similar to that described in Example 8c except starting with 2-amino-4-trifluoromethylbenzoic acid, the title compound was obtained (86%), after chromatography (eluant: diethyl ether/hexane: 3/7) over silica gel, as a tan crystals, mp 62.5-63 C.; MS(CI): 220 (M+H). Analysis for C9 H8 F3 NO2 Calculated: C, 49.32; H, 3.68; N, 6.39 Found: C, 49.23; H, 3.75; N, 6.34 250-MHz 1 H NMR (DMSO-d6): 7.88 (d, J=8.4 Hz, 1H), 7.18 (s, 1H), 7.00 (br s, 2H), 6.79 (d, J=8.4 Hz, 1H), 3.84 (s, 3H).
With thionyl chloride;
Step 1 Synthesis of methyl 2-amino-4-(trifluoromethyl)benzoate First, 4.10 g of 2-amino-4-(trifluoromethyl)benzoic acid was dissolved in 70 ml of methanol, and 12 ml of thionyl chloride was then added dropwise to the solution at 0 C. The temperature was then raised, and the reaction mixture was stirred for 12 hours under reflux conditions. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in water and ethyl acetate. The resulting organic phase was washed with a saturated solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and then filtered.
2-Amino-4-(trifluoromethyl)benzoate (1.86 g, 8.5 mmol) was dissolved in pyridine (12 mL) and 4-chlorobenzenesulfonyl chloride (1.79 g, 8.5 mmol) was added. The resulting solution was heated to 80 0C in a microwave reactor for 10 minutes and then concentrated to dryness. The crude product was purified by column chromatography on silica gel. The column was eluted with 0% to 30% ethyl acetate in cyclohexane to afford methyl 2-[(4-chlorophenyl)sulfonyl]amino}-4-(trifluoromethyl)benzoate as a colourless oil (905 mg). HPLC Rt = 3.63 minutes; m/z [M+H]+ = 394. 1H NMR (CD3OD) delta 8.10 (d, 1 H), 7.91 (S, 1 H), 7.77 (d, 2H), 7.53 (d, 2H)1 7.44 (d, 1 H), 3.90 (s, 3H).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15℃;Cooling with ice;
8-(trifluoromethyl)-3,4-dihydro-lH-l-benzazepine-2,5-dione; Step 1 : Methyl 2-(4-methoxy-4-oxobutanamido)-4-(trifluoromethyl)benzoate; A 22 L reactor equipped with an overhead stirrer and a temperature probe was charged with <strong>[61500-87-6]methyl 2-amino-4-(trifluoromethyl)benzoate</strong> (680 g, 3.1 mol). DCM (5.4 L, 8 vol) was added to it and the resulting solution was cooled in an ice-water bath. DIEA (1.08 L, 6.2 mol, 2 equiv) was added to the solution. A solution of 4-chloro-4-oxo-butyrate (568 mL, 4.65 mol, 1.5 equiv) in DCM (1.4 L, 2 vol) was added dropwise maintaining the internal temperature below 15 0C (3 h). The ice-water bath was removed and the reaction was stirred for 3 h. The reaction was judged complete by EtaPLC analysis. Water (3.4 L, 5 vol) was added to the reaction and the biphasic mixture was stirred at ambient temperature overnight. The water layer was removed and saturated aqueous NaHCO3 (3.4 L, 5 vol) was added to the DCM layer. The mixture was stirred for 30 min. The two layers were separated and another 3.4 L (5 vol) of saturated aqueous NaHCO3 was added to the DCM layer. The mixture was stirred for 30 min. The two layers were separated and a 1 :1 mixture of brine/water (3.4 L, 5 vol) was added to the DCM layer. The biphasic mixture was stirred for 30 min. The two layers were separated and the DCM layer was pumped down to a low volume (ca. 1.4 L, 2 vol). THF (6.8 L, 10 vol) was added to the solution and the solvent was evaporated under reduced pressure to a low volume (ca. 1.4 L) to obtain Methyl 2-(4-methoxy-4- oxobutanamido)-4-(trifluoromethyl)benzoate [1.032 kg, theoretical yield, 3.1 mol] as a solution in THF.
methyl 2-isothiocyanato-4-trifluoromethylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91.1%
With sodium hydrogencarbonate; In dichloromethane; at 35℃;Cooling with ice;
Step 1: Methyl 2-isothiocyanato-4-trifluoromethylbenzoate Thiophosgene (1.595 ml; 20.186 mmol; 200.00 mol %) was added dropwise to a mixture of <strong>[61500-87-6]methyl 2-amino-4-trifluoromethylbenzoate</strong> (2.212 g; 10.093 mmol; 100.00 mol %) in 20 ml of dichloromethane and 20 ml of NaHCO3 solution with ice-cooling. The reaction mixture was slowly warmed to 35 C., stirred for 4-5 hours, 1 further equivalent and about 10 ml of NaHCO3 solution were added, the mixture was stirred at 35 C. overnight, 1 equivalent of thiophosgene and 10 ml of NaHCO3 solution were again added, and the mixture was stirred for a further 2 hours. The phases were separated, and the aqueous phase was extracted three times with DCM. The combined organic phases were dried over Na2SO4, the solvent was removed. Chromatographic purification of the residue on silica gel (eluent heptane/EA 5:1) gave 2.40 g of methyl 2-isothiocyanato-4-trifluoromethylbenzoate as yellow solid (yield 91.1%, content 100%). MS-FAB (M-31)+=230.0 Rf (polar method): 2.71 min (MS track).
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