4-(CHLORO-DIFLUORO-METHOXY)-PHENYLAMINE

167 g of 4-nitro-chlorodifluoromethoxybenzene was charged into the autoclave followed by 200 g of ethyl acetate and 15 g of Raney nickel. After the replacement of nitrogen and hydrogen, the pressure in the autoclave is kept at about 2~3 MPa with hydrogen and reacted at 30-40 ° C. When the pressure of the system is no longer changing, the reaction is maintained for 1 hour. The sample is analyzed and controlled to be less than 0.5percent Hydrogenation reaction liquid filtered catalyst, the first atmospheric pressure recovery of most of the solvent, and then vacuum distillation, the target product 4- (chlorodifluoromethoxy) aniline 92.6g, a yield of 64.2percent.167 g of 4-nitro-chlorodifluoromethoxybenzene was charged into the autoclave followed by 200 g of ethyl acetate and 15 g of Raney nickel. After the replacement of nitrogen and hydrogen, the pressure in the autoclave is kept at about 2~3 MPa with hydrogen and reacted at 30-40 C. When the pressure of the system is no longer changing, the reaction is maintained for 1 hour. The sample is analyzed and controlled to be less than 0.5% Hydrogenation reaction liquid filtered catalyst, the first atmospheric pressure recovery of most of the solvent, and then vacuum distillation, the target product 4- (chlorodifluoromethoxy) aniline 92.6g, a yield of 64.2%.N-(4-(chlorodifluoromethoxy)phenyl)-1, 2-dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxamide (4). To a mixture of 1, 2-dimethyl-4-(pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carboxylic acid (4d, 15 mg, 0.056 mmol, 1 eq) and HATU (25.51 mg, 0.067 mmol, 1.2 eq), DIPEA (14.45 mg, 0.112 mmol, 19.48 uL, 2 eq) in DMF (1 mL) at 20 C. was added 4-[chloro(difluoro)methoxy]aniline (1h, 16.24 mg, 0.084 mmol, 1.5 eq). The mixture was stirred at 20 C. for 16 hours. The mixture was concentrated in vacuo. LCMS showed desired MS. The mixture was poured into water and extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product. The residue was purified by prep-HPLC (TFA condition, column: Nano-Micro UniSil 5-100 C18 ULTRA 100*250 mm 5 um; mobile phase: [water (0.1%TFA)-ACN]; B %: 25%-50%, 11 min) to afford the title compound 4 as a white solid. MS mass calculated for [M+H]+ (C21H16ClF2N5O2) requires m/z 444.1, LCMS found m/z 444.1. 1H NMR (400 MHz, MeOD-d4) delta 9.33-9.25 (m, 3H), 8.48 (s, 1H), 8.25 (s, 1H), 7.88 (d, J=9.0 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 4.07 (s, 3H), 2.85 (s, 3H).4-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxamide (3e). To a solution of 4-bromo-2-(difluoromethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid (3d, 110 mg, 0.361 mmol, 1 eq) in DMF(3 mL) was added DIPEA (93.20 mg, 0.721 mmol, 125.61 uL, 3 eq) and HATU (205.65 mg, 0.541 mmol, 1.2 eq). The mixture was stirred at 25 C. for 0.5 hr before (1R, 4R)-9-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-hydroxy-1-methyl-1, 2, 3, 4-tetrahydrobenzo[4, 5]imidazo[1, 2-a]pyridine-7-carboxamide (49i). To a solution of (1R, 4R)-9-bromo-4-hydroxy-1-methyl-1, 2, 3, 4-tetrahydrobenzo[4, 5]imidazo [1, 2-a]pyridine-7-carboxylic acid (49h, 10 mg, 0.031 mmol), 4-[chloro(difluoro)methoxy]aniline (1h, 7.14 mg, 0.037 mmol) in DMF (1 mL) was added HATU (14.03 mg, 0.037 mmol) and DIEA (11.92 mg, 0.092 mmol, 16.07 uL). The mixture was stirred at 15 C. for 5 hr. LCMS showed desired ms was detected. TLC (ethyl acetate:methanol=10:1, Rf=0.40) showed a new spot was formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (10 mL) and extracted with EtAOc (10 mL*3). The combined organic layers were washed with brine, dried over Ns2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, ethyl acetate:methanol=10:1) to give 49i as a white solid. 1H NMR (400 MHz, CDCl3-d) delta 8.09 (d, J=1.3 Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 7.71 (d, J=8.9 Hz, 2H), 7.25 (s, 1H), 5.46 (br t, J=5.8 Hz, 1H), 5.18 (br s, 1H), 2.76-2.60 (m, 1H), 2.39-2.17 (m, 2H), 1.96-1.86 (m, 1H), 1.53 (d, J=6.6 Hz, 3H).7-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-1-cyclopropyl-2-(difluoromethyl)-1H-benzo[d]imidazole-5-carboxamide (15g). A mixture of 15e (18 mg, 0.054 mmol, 1 eq), 1h (15.79 mg, 0.082 mmol, 1.5 eq), HATU (31.01 mg, 0.082 mmol, 1.5 eq) and DIEA (21.08 mg, 0.163 mmol, 3 eq) in DMF (1 mL) was stirred at 15 C. for 2 hr. LCMS showed a peak with desired MS. The reaction mixture was concentrated, and the crude product was purified by prep-TLC (petroleum ether:ethyl acetate=2:1, Rf=0.5) to give 15g as a yellow solid. 1H NMR (400 MHz, CDCl3-d) delta 8.20 (d, J=1.5 Hz, 1H), 8.16 (d, J=1.5 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.30 (br s, 2H), 7.04 (s, 1H), 3.72 (br s, 1H), 1.47-1.42 (m, 2H), 1.37 (br d, J=4.4 Hz, 2H).N-(4-(chlorodifluoromethoxy)phenyl)-1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxamide (1). To a solution of 1-methyl-7-(pyrimidin-5-yl)-1H-benzo[d]imidazole-5-carboxylic acid (1g, 0.04 g, 0.157 mmol, 1 eq) and

Molecular Weight:193.58
XLogP3:2.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:193.0105978
Monoisotopic Mass:193.0105978
Topological Polar Surface Area:35.2
Heavy Atom Count:12
Complexity:148
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes