Methyl 2-amino-4-(trifluoromethyl)benzoate

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).Step 2. 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).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).B. 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 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 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.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 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 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) m.p. 60-62 C.; m.p. 60-62 C.; methyl 2-amino-3, 4-difluorobeazoate.N-bromosuccinimide (427 mg, 2.40 mmol) was added to a solution of methyl 2- amino-4-(trifluoromethyl)benzoate (500 mg, 2.28 mmol) in DMF (23 ml_). The reaction mixture was stirred at room temperature for 16 h before being poured into aqueous potassium carbonate (100 ml_). The resulting precipitate was collected by filtration and dried under vacuum to give 2-amino-5-bromo-4-methyl-benzoic acid methyl ester (615 mg, 82%) as a beige solid. (1153) M/Z (M[79Br]+H)+ = 298.0.General procedure: To a solution of methyl 2-amino-4-fluorobenzoate (1.64 g, 9.71 mmol) and methanesulfonyl chloride (5.28 mL, 115 mmol) in dichloromethane (100 mL) was added pyridine (7.86 mL, 97.1 mmol). The solution was stirred at room temperature for 18 hours. The reaction was quenched with 1N HCl and was stirred for 5 minutes. The mixture was extracted with DCM (3×). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography to afford methyl 4-fluoro-2-(methylsulfonamido)benzoate.General procedure: To a solution of methyl 2-amino-4-fluorobenzoate (1.64 g, 9.71 mmol) and methanesulfonyl chloride (5.28 mL, 115 mmol) in dichloromethane (100 mL) was added pyridine (7.86 mL, 97.1 mmol). The solution was stirred at room temperature for 18 hours. The reaction was quenched with 1N HCl and was stirred for 5 minutes. The mixture was extracted with DCM (3×). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography to afford methyl 4-fluoro-2-(methylsulfonamido)benzoate.General procedure: To a solution of methyl 2-amino-4-fluorobenzoate (1.64 g, 9.71 mmol) and methanesulfonyl chloride (5.28 mL, 115 mmol) in dichloromethane (100 mL) was added pyridine (7.86 mL, 97.1 mmol). The solution was stirred at room temperature for 18 hours. The reaction was quenched with 1N HCl and was stirred for 5 minutes. The mixture was extracted with DCM (3×). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography to afford methyl 4-fluoro-2-(methylsulfonamido)benzoate.

Molecular Weight:219.16
XLogP3:2.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:2
Exact Mass:219.05071298
Monoisotopic Mass:219.05071298
Topological Polar Surface Area:52.3
Heavy Atom Count:15
Complexity:242
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes