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With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane;Inert atmosphere;
Conversion 4, step 4C; Preparation of 5-(2-chloro-5-fluoro-benzyloxy)-3-{4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2- trifluoro-acetylj-aminol-benzoylaminoj-indazole-i-carboxylic acid tert-butyl ester; Triphenylphosphine (146 mg, 0.557 mmol) in DCM (2 mL), cooled at 4C, in a nitrogen atmosphere was treated with neat diisopropyl azodicarboxylate (0.106 mL, 0.5208 mmol) while stirring. After 20 minutes the colourless solution was treated with 5-hydroxy-3-{4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]- benzoylamino}-indazole-1-carboxylic acid tert-butyl ester (82 mg, 0.5108 mmol) in DCM (2 mL). After 2 hours the crude was purified by flash chromatography over silica gel (DCM:EtOH:35% NH4OH 95:5:0.5) and 108 mg of title compound were obtained as a white solid in 59 % yield. ESI(+) MS: m/z 790 (MH+).
The solution of 2-chloro-5-fluoro-benzoic acid (4.00 g, 23.0 mmol) in THE (200 ml) was added triethylamine (4.14 ml, 29.9 mmol). At -30 C, the mixture was added ethyl chloroformate (2.62 ml, 27.8 mmol) and stirred for 10 min. The solution was added sodium borohydrate (2.60 g, 68.9 mmol) and stirred for 5 min. The mixture was added H2O (10 ml) and stirred for 20 min at room temperature. The solution was concentrated in vacuo and the residue was added CHCl3 and 1 N HClaq. The organic layer was washed with 1 N NaOHaq and dried over Na2SO4. The solution was removed in reduced pressure. The residue was washed with n-hexane to give alcohol as a colorless solid. To the CH2Cl2 suspention of dimethylsulfoxide (2.43 ml, 34.2 mmol) was added a solution of oxalyl chloride (1.47 ml, 17.1 mmol) in 50 ml of dry CH2Cl2 at -78 C, and the resulting mixture was stirred for 20 min. CH2Cl2 (15 ml) solution of the alcohol was added at -78 C. The mixture was allowed to warm to -40 C for 1 h. The mixture was added triethylamine (7.89 ml, 57.0 mmol), allowed to warm to room temperature, and was treated with 0.1 N HClaq. The organic layer was washed with saturated Na2CO3aq, dried over Na2SO4, and concentrated in vacuo to give the title compound (1.33 g, 37%) as a colorless solid after trituration with n-hexane. 1H NMR (400 MHz, CDCl3) delta 7.22-7.28 (1H, m), 7.41-7.47 (1H, m), 7.58-7.64 (1H, m), 10.42 (1H, d, J = 3.2 Hz). MS (EI) m/z 158 M+.
The solution of 2-chloro-5-fluoro-benzoic acid (4.00 g, 23.0 mmol) in THE (200 ml) was added triethylamine (4.14 ml, 29.9 mmol). At -30 C, the mixture was added ethyl chloroformate (2.62 ml, 27.8 mmol) and stirred for 10 min. The solution was added sodium borohydrate (2.60 g, 68.9 mmol) and stirred for 5 min. The mixture was added H2O (10 ml) and stirred for 20 min at room temperature. The solution was concentrated in vacuo and the residue was added CHCl3 and 1 N HClaq. The organic layer was washed with 1 N NaOHaq and dried over Na2SO4. The solution was removed in reduced pressure. The residue was washed with n-hexane to give alcohol as a colorless solid. To the CH2Cl2 suspention of dimethylsulfoxide (2.43 ml, 34.2 mmol) was added a solution of oxalyl chloride (1.47 ml, 17.1 mmol) in 50 ml of dry CH2Cl2 at -78 C, and the resulting mixture was stirred for 20 min. CH2Cl2 (15 ml) solution of the alcohol was added at -78 C. The mixture was allowed to warm to -40 C for 1 h. The mixture was added triethylamine (7.89 ml, 57.0 mmol), allowed to warm to room temperature, and was treated with 0.1 N HClaq. The organic layer was washed with saturated Na2CO3aq, dried over Na2SO4, and concentrated in vacuo to give the title compound (1.33 g, 37%) as a colorless solid after trituration with n-hexane. 1H NMR (400 MHz, CDCl3) delta 7.22-7.28 (1H, m), 7.41-7.47 (1H, m), 7.58-7.64 (1H, m), 10.42 (1H, d, J = 3.2 Hz). MS (EI) m/z 158 M+.
With methanol; sodium tetrahydroborate; at 20℃; for 1h;
To a solution of methyl 2-chloro-5-fluorobenzoate (23, 35.0 g, 185.6 mmol) in dry THF (150 mL) was added NaBH4 (21.2 g, 557 mmol). Methanol (40 mL) was added dropwise at RT. After the addition, the mixture was stirred at RT for 1 h. Water (300 mL) was slowly added. The mixture was extracted with CH2Cl2 (200 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give (2-chloro-5-fluorophenyl)methanol (24).
With phosphorus tribromide; In 1,2-dimethoxyethane; at 0 - 20℃; for 3h;
To a solution of <strong>[261762-59-8](2-chloro-5-fluorophenyl)methanol</strong> (24, 25.5 g, 159 mmol) in dry DME (200 mL) at 0 C. was added a solution of PBr3 (25.8 g, 95.2 mmol) in dry DME (150 mL) dropwise. The mixture was then slowly warmed up to RT and stirred at RT for another 3 h. The mixture was diluted with water (300 mL), and extracted with 1:1 petroleum-ether-EtOAc (200 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give 2-(bromomethyl)-1-chloro-4-fluorobenzene (25).
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