反应详情

A solution of trans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol (60 mg, 0.156 mmol) produced in Example (92a) in dichloromethane (5 mL) was stirred at an external temperature of 0° C. under a nitrogen atmosphere. Triethylamine (0.065 mL, 0.468 mmol) and methanesulfonyl chloride (0.018 mL, 0.233 mmol) were added in that order to the mixture, followed by stirring for 30 minutes under the same conditions. Saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then washed with ethyl acetate and water and extracted with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was dissolved again in dimethylsulfoxide (3 mL), and then tetrabutylammonium iodide (12 mg, 0.032 mmol) and potassium cyanide (34 mg, 0.522 mmol) were added thereto and the mixture was stirred for 2 hours at an external temperature of 70° C. Ethyl acetate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed twice with water and then once with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 8 mg of trans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)acetonitrile as a colorless oil, and 19 mg of trans-1-(2-chloromethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil.

1. washwas then washed with ethyl acetate and water
2. extractionextracted with ethyl acetate
3. washThe separated organic layer was washed with brine
4. dry with materialdried over anhydrous sodium sulfate
5. filtrationThe desiccant was filtered off
6. concentrationthe filtrate was concentrated under reduced pressure
7. dissolutionThe resultant residue was dissolved again in dimethylsulfoxide (3 mL)
8. stirringthe mixture was stirred for 2 hours at an external temperature of 70° C
9. washThe separated organic layer was washed twice with water
10. dry with materialonce with brine, and dried over anhydrous sodium sulfate
11. filtrationThe desiccant was filtered off
12. concentrationthe filtrate was concentrated under reduced pressure
13. customThe resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane)