反应详情

1.2 g (2.8 mmol) of a BOP reagent, 0.5 ml (3 mmol) of N,N-diisopropylethylamine, and 273 mg (2.8 mmol) of N,O-dimethylhydroxylamine hydrochloride were added to a dichloromethane solution containing 1 g (2.3 mmol) of Fmoc-Meser(Bzl) —OH. The obtained mixture was stirred at a room temperature over a day and a night. Thereafter, the reaction solution was successively washed with 1 N hydrochloric acid, a saturated sodium bicarbonate aqueous solution, and a saturated saline solution. The resultant was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2). 238 mg out of 850 mg of the obtained oily product was added to 2 ml of a THF solution, and the obtained solution was then added dropwise to 8 ml of a THF solution containing 10 mg (0.25 mmol) of aluminum lithium hydride at −78° C. The obtained mixture was stirred at −78° C. for 1.5 hours. Thereafter, 10 mg (0.25 mmol) of aluminum lithium hydride was further added to the reaction solution, and the obtained mixture was then stirred at −78° C. for 30 minutes. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution at −78° C., and the temperature of the mixture was increased to a room temperature. Thereafter, the mixture was filtrated with celite, and the filtrate was then extracted with dichloromethane. The extract was washed with a saturated saline solution, and was dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The generated oil product was dissolved in 5 ml of methanol without being purified. Thereafter, 100 mg (0.33 mmol) of 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one and 1 ml of acetic acid were added thereto. Thereafter, 135 mg (2.1 mmol) of sodium cyanoborohydride was added to the mixture under cooling on ice, and the temperature of the obtained mixture was increased to a room temperature, followed by stirring for 3 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2 to 2:1), so as to obtain a yellow foaming substance. This yellow foaming substance was dissolved in 5 ml of dichloromethane, and 1 ml of piperidine was then added to the solution. The obtained mixture was stirred at a room temperature. Four hours later, the reaction solution was concentrated, and 2 ml of 1 N hydrochloric acid and 2 ml of methanol were then added thereto, followed by stirring at 40° C. Six hours later, the reaction solution was neutralized with a 1 N sodium hydroxide aqueous solution under cooling on ice. A saturated sodium bicarbonate aqueous solution was added to the resultant, and the mixture was then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by amino TLC used for preparative separation (Fuji Silysia Chemical Ltd., PLCO5; dichloromethane:methanol=20:1), so as to obtain 48 mg (31%) of 7-((R)-3-benzyloxy-2-methylaminopropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a yellow foaming substance, as well as 28 mg (17%) of 7-((R)-4-benzyloxymethyl-3-methylimidazolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a yellow foaming substance.

1. washThereafter, the reaction solution was successively washed with 1 N hydrochloric acid
2. dry with materialThe resultant was dried over anhydrous sodium sulfate
3. distillationthe solvent was then distilled away under reduced pressure
4. customThe obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2)
5. addition238 mg out of 850 mg of the obtained oily product was added to 2 ml of a THF solution
6. additionthe obtained solution was then added dropwise to 8 ml of a THF solution
7. stirringThe obtained mixture was stirred at −78° C. for 1.5 hours
8. stirringthe obtained mixture was then stirred at −78° C. for 30 minutes
9. temperaturethe temperature of the mixture was increased to a room temperature
10. filtrationThereafter, the mixture was filtrated with celite
11. extractionthe filtrate was then extracted with dichloromethane
12. washThe extract was washed with a saturated saline solution
13. dry with materialwas dried over anhydrous sodium sulfate
14. concentrationfollowed by concentration under reduced pressure
15. dissolutionThe generated oil product was dissolved in 5 ml of methanol
16. customwithout being purified
17. temperatureunder cooling on ice
18. temperaturethe temperature of the obtained mixture was increased to a room temperature
19. stirringby stirring for 3 hours
20. extractionthe mixture was then extracted with dichloromethane
21. dry with materialThe extract was dried over anhydrous sodium sulfate
22. concentrationwas then concentrated
23. customThe obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2 to 2:1)
24. customso as to obtain a yellow foaming substance
25. stirringThe obtained mixture was stirred at a room temperature
26. concentrationFour hours later, the reaction solution was concentrated
27. addition2 ml of 1 N hydrochloric acid and 2 ml of methanol were then added
28. stirringby stirring at 40° C
29. customSix hours
30. temperatureunder cooling on ice
31. additionA saturated sodium bicarbonate aqueous solution was added to the resultant
32. extractionthe mixture was then extracted with dichloromethane
33. dry with materialThe extract was dried over anhydrous sodium sulfate
34. concentrationwas then concentrated
35. customThe obtained residue was purified by amino TLC
36. customused for preparative separation (Fuji Silysia Chemical Ltd., PLCO5; dichloromethane:methanol=20:1)