반응 #43514

반응 방정식

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

수율 82.0%

용매

Ethyl acetate

acetonitrile

반응 조건

후처리

1. 1
   기타to reach room temperature
2. 2
   기타the precipitated salts were removed by filtration through celite
3. 3
   세척The organic phase was washed with saturated aqueous sodium bicarbonate (40 mL), saturated aqueous sodium chloride (40 mL)
4. 4
   건조dried over magnesium sulfate
5. 5
   기타The volatiles were evaporated off
6. 6
   건조the 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
   기타The solvent was evaporated
10. 10
    기타the crude material was purified by chromatography on silica gel (eluent: ethyl acetate/heptane 1:9)

실험 절차

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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