Methyl 2-bromo-5-fluorobenzoate

Methyl 2-bromo-5-fluorobenzoate (159-1). Trimethylsilyl diazomethane (338 ml, 676 mmol, 2.0 M in diethyl ether) was added dropwise to a stirred, 0°C solution of 2-bromo-5-fluorobenzoic acid (74 g, 338 mmol) in MeOH (676ml) until a yellow color persisted. Acetic acid was added dropwise until the yellow color dissipated. The solvent was removed in vacuo, and the resisdue was dissolved in CH2Cl2, then filtered through a plug of silica gel, eluting with CH2Cl2. The solvent was removed in vacuo to afford 77 g, 98 percent of 159-1 as a yellow oil.Trimethylsilyl diazomethane (338 ml, 676 mmol, 2.0 M in diethyl ether) was added dropwise to a stirred, 0°C solution of 2-bromo-5-fluorobenzoic acid (74 g, 338 mmol) in MeOH (676ml) until a yellow color persisted. Acetic acid was added dropwise until the yellow color dissipated. The solvent was removed in vacuo, and the resisdue was dissolved in CHDBU(1.7 equiv, 1.16 mL, 7.76 mmol) was added to a solution of 2-bromo-5-fluorobenzoic acid (1.0 equiv, 1.0 g, 4.57 mmol) and iodomethane (2.0 equiv, 0.57 mL, 9.14mmol) in CHPreparation 6; test-butyl [2- (aminomethyl)-4-fluorobenzyl] carbamate; (a) Methyl 2-bromo-5-fluorobenzoate; To a solution of 2-bromo-5-fluorobenzoic acid (3.0 g, 13.7 mmol) in methanol (4 mL) was added HCl-saturated methanol (70 mL). The reaction mixture was stirred for 24 hours and then concentrated. The excess of HC1 was removed by co-evaporation from methanol to give the sub-title compound (97percent), which was used in the next step without further purification. 1H NMR (500 MHz, CDC13) 6 3.96 (s, 3H), 7.09 (dt, 1H), 7.55 (dd, 1H), 7.65 (dd, 1H)General procedure: To a solution of 2-bromo-4-fluorobenzoic acid (2.17 g, 10.00 mmol) in methanol (10 mL) was added sulfuric acid (1.63 mL, 30 mmol) , the reaction mixture was refluxed for 4 h.The solvent was removed in vacuo.The mixture was diluted with diethyl ether, and washed water (50 mL * 3) and brine (50 mL * 3), dried over MgSOIn the nitrogen atmosphere, 2-bromo-5-fluorobenzoic acid (50.0 g) was added, Sulfuric acid (7 ml) and methanol (500 ml) was stirred at reflux temperature for 8 hours.After the reaction solution was cooled to room temperature, The methanol was distilled off under reduced pressure, And then an aqueous solution of ethyl acetate and sodium hydrogencarbonate was added thereto to carry out liquid separation.The solvent of the organic layer was evaporated under reduced pressure to give methyl 2-bromo-5-fluorobenzoate (50.0 g).Step 1. methyl 2-bromo-5-fluorobenzoate (0904) (0905) To a solution of 2-bromo-5-fluorobenzoic acid (4.00 g, 18.26 mmol) in MeOH (120 mL, anhydrous) was added SOCl2 (3.26 g, 27.40 mmol) dropwise at 0 °C and the mixture was heated at 68 °C for 18 h. TLC (petroleum ether: EtOAc = 5:1) confirmed the desired product. The mixture was concentrated and the residue was mixed with EtOAc (200 mL), washed by NaHCO3 (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated to give methyl 2-bromo-5-fluorobenzoate as a colorless oil. Yield: 2.7 g LCMS method C: Rt = 0.77 min.Step 2: 2-(2-bromo-5-fluorophenyl)propan-2-ol (0906) To a solution of 2-bromo-5-fluorobenzoate (2.70 g, 11.59 mmol) in THF (85 mL, anhydrous) at 0 C under N2 was added MeMgBr (9.66 mL, 28.97 mmol, 3.0 M in Et2O) dropwise, and the mixture was stirred at 23-28 C for 4 h. The mixture was quenched by aq. sat. NH4Cl (80 mL) and extracted by EtOAc (60 mL). The organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by ISCO column chromatography on silica gel (13% EtOAc in petroleum ether) to give 2-(2-bromo-5-fluorophenyl)propan-2-ol as a colorless oil. Yield: 2.5 g (94%).1H NMR (CDCl3): delta 7.42-7.57 (m, 2H), 6.77-6.88 (m, 1H), 1.75 (s, 6H).Preparation 6; test-butyl [2- (aminomethyl)-4-fluorobenzyl] carbamate; (a) Methyl 2-bromo-5-fluorobenzoate; To a solution of 2-bromo-5-fluorobenzoic acid (3.0 g, 13.7 mmol) in methanol (4 mL) was added HCl-saturated methanol (70 mL). The reaction mixture was stirred for 24 hours and then concentrated. The excess of HC1 was removed by co-evaporation from methanol to give the sub-title compound (97%), which was used in the next step without further purification. 1H NMR (500 MHz, CDC13) 6 3.96 (s, 3H), 7.09 (dt, 1H), 7.55 (dd, 1H), 7.65 (dd, 1H)General procedure: To a solution of 2-bromo-4-fluorobenzoic acid (2.17 g, 10.00 mmol) in methanol (10 mL) was added sulfuric acid (1.63 mL, 30 mmol) , the reaction mixture was refluxed for 4 h.The solvent was removed in vacuo.The mixture was diluted with diethyl ether, and washed water (50 mL * 3) and brine (50 mL * 3), dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (80/1) as eluant to afford colorless liquid. Yield: 88.3%.This compound was prepared according to the general procedure reported by Baker.13 The spectral data were consistent with that reported in the literature. (for 96; the methyl ester was obtained by reacting 2-bromo-5-fluorobenzoic acid with methanol under catalysis with sulfuric acid: 1H NMR: 7.8, m, 1H, 7.65, m, 1H, 7.4, m, 1H, 3.85, s, 3H), To a solution of (R)-tert-butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4, 5-dihydro-1, 2, 4-triazin-3-yl)piperidin-3-ylcarbamate (18, 30 mg) in dichloromethane (1 mL) was added TFA (0.5 mL), and the mixture was stirred at RT for 3 h. The mixture was carefully neutralized with NaHCO3 (aq, saturated), and extracted with CH2Cl2 (10 mL×3). The combined extracts were dried over Na2SO4 and concentrated to give the crude product. This was purified by column chromatography on silica gel, and eluted with 92:6:2 dichloromethane-methanol-ammonia to provide (R)-3-(3-aminopiperidin-1-yl)-4-(3-fluorobenzyl)-6-methyl-1, 2, 4-triazin-5(4H)-one (19). MS: m/z, 396 (100%, M+1), 398 (100%).In the nitrogen atmosphere, 2-bromo-5-fluorobenzoic acid (50.0 g) was added, Sulfuric acid (7 ml) and methanol (500 ml) was stirred at reflux temperature for 8 hours.After the reaction solution was cooled to room temperature, The methanol was distilled off under reduced pressure, And then an aqueous solution of ethyl acetate and sodium hydrogencarbonate was added thereto to carry out liquid separation.The solvent of the organic layer was evaporated under reduced pressure to give Step 1. General procedure: 10 g of methyl 5-bromo-2-iodobenzoate (2-1) and 5 g of naphthalene-1-boronic acid (2-2) were dissolved in 100 mL of tetrahydrofuran (THF) and 25 mL of water, and 1 g of Pd(PPh3)4 and 12 g of K2CO3 were added dropwise thereto. The reaction solution was stirred under reflux at a temperature of 65 C. for 6 hours. After the reaction solution was cooled to room temperature, the THF was removed under reduced pressure, and the mixture was extracted three times using ethyl acetate. The organic solution was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The residue obtained therefrom was purified by column chromatography to obtain 8.3 g (yield: 83%) of Intermediate 2-3.

Molecular Weight:233.03
XLogP3:3.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:231.95352
Monoisotopic Mass:231.95352
Topological Polar Surface Area:26.3
Heavy Atom Count:12
Complexity:174
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes