反応 #43514

反応方程式

Chloro-oxo-acetic acid methyl ester

1-tert-butoxycarbonyl-4-[2-(4-chloro-phenylsulfanyl)-5-trifluoromethyl-phenyl]-piperidine-4-ol

Tri-n-butyl tin hydride

2-[(cyano-dimethyl-methyl)-azo]-2-methyl-propionitrile

→

4-[2-(4-chloro-phenylsulfanyl)-5-trifluoromethyl-phenyl]-piperidine-1-carboxylic acid tert-butyl ester

収率 82.0%

溶媒

Ethyl acetate

acetonitrile

反応条件

後処理

1. 1
   その他to reach room temperature
2. 2
   その他the precipitated salts were removed by filtration through celite
3. 3
   洗浄The organic phase was washed with saturated aqueous sodium bicarbonate (40 mL), saturated aqueous sodium chloride (40 mL)
4. 4
   乾燥dried over magnesium sulfate
5. 5
   その他The volatiles were evaporated off
6. 6
   乾燥the crude material was dried in vacuo
7. 7
   workup.DISSOLUTIONThis material was dissolved in dry toluene (13 mL) under argon
8. 8
   workup.STIRRINGThe solution was stirred under argon at 90° C. for 3.5 h
9. 9
   その他The solvent was evaporated
10. 10
    その他the crude material was purified by chromatography on silica gel (eluent: ethyl acetate/heptane 1:9)

実験手順

Chloro-oxo-acetic acid methyl ester (1.37 g, 11.2 mmol) was added to a stirred solution of 1-tert-butoxycarbonyl-4-[2-(4-chloro-phenylsulfanyl)-5-trifluoromethyl-phenyl]-piperidine-4-ol (0.98 g, 2.0 mmol) and dimethyl-pyridin-4-yl-amine (DMAP, 0.44 g, 3.6 mmol) in dry acetonitrile (6.4 mL) at 0° C. under argon. The reaction mixture was allowed to reach room temperature and then stirred overnight. Ethyl acetate (40 mL) was added and the precipitated salts were removed by filtration through celite. The organic phase was washed with saturated aqueous sodium bicarbonate (40 mL), saturated aqueous sodium chloride (40 mL), and dried over magnesium sulfate. The volatiles were evaporated off, and the crude material was dried in vacuo. This material was dissolved in dry toluene (13 mL) under argon. Tri-n-butyl tin hydride (0.81 g, 3.0 mmol) and 2-[(cyano-dimethyl-methyl)-azo]-2-methyl-propionitrile (AIBN, 82 mg, 0.5 mmol) were added. The solution was stirred under argon at 90° C. for 3.5 h. The solvent was evaporated, and the crude material was purified by chromatography on silica gel (eluent: ethyl acetate/heptane 1:9) to produce 4-[2-(4-chloro-phenylsulfanyl)-5-trifluoromethyl-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (0.77 g, 82%). This oil was dissolved in methanol (8 mL) and hydrogen chloride in diethyl ether (2M, 8 mL) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated off and ethyl acetate (25 mL) was added. The organic phase was extracted with aqueous sodium hydroxide (2M, 8 mL) and washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, and the solvent was evaporated off. This material (588 mg) was dissolved in ethyl acetate (2.2 mL) and fumaric acid (183 mg, 1.58 mmol) dissolved in hot ethanol (96%, 4.4 mL) was added. The target compound was collected as a white solid. LC/MS (m/z) 372.1 (MH+); RT=2.54; purity (UV, ELSD): 97%, 100%; yield: 0.187 g (19%).

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