反应详情

Under a nitrogen atmosphere and at −78° C., 3,4,5-trifluorophenyl magnesium bromide (prepared from 1-bromo-3,4,5-trifluorobenzene (11.7 g) and magnesium (1.48 g) according to the method described in Org. Synth., 2001, 79, 176) was added to a THF (140 mL) solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tertiery butyl ester (13.0 g) over 30 minutes. The reaction solution was stirred for 2 hours from −78° C. to −10° C. Afterwards, at −10° C., the resultant reaction was quenched with saturated ammonium chloride aqueous solution. Water was added to the reaction solution, and extraction with ethyl acetate was conducted. After drying the resulting extraction solution with magnesium sulfate, concentration under a vacuum was conducted. A 4 N hydrochloric acid ethyl acetate solution (150 mL) was added at room temperature to an ethyl acetate (150 mL) solution of the residue. The resultant reaction solution was stirred for 9 hours at room temperature. The reaction solution was concentrated under a vacuum, and after making the residue basic by adding saturated sodium bicarbonate solution, chloroform was added, and stirring was continued for 2 hours at room temperature. The organic layer was partitioned, and after drying with magnesium sulfate, the resultant was concentrated under a vacuum. 10% palladium on carbon (700 mg) was added to a methanol (200 mL) solution of the residue, and the resultant reaction solution was stirred for 9 hours under a hydrogen atmosphere and at room temperature. The reaction solution was filtered over celite, and the filtrate was concentrated under a vacuum. By purifying the residue by silica gel column chromatography (eluting solvent:heptane-ethyl acetate system), 5.47 g of the title compound was obtained. The physical property values are as follows.

1. customAfterwards, at −10° C., the resultant reaction
2. customwas quenched with saturated ammonium chloride aqueous solution
3. additionWater was added to the reaction solution, and extraction with ethyl acetate
4. customAfter drying
5. extractionthe resulting extraction solution
6. concentrationwith magnesium sulfate, concentration under a vacuum
7. additionA 4 N hydrochloric acid ethyl acetate solution (150 mL) was added at room temperature to an ethyl acetate (150 mL) solution of the residue
8. customThe resultant reaction solution
9. stirringwas stirred for 9 hours at room temperature
10. concentrationThe reaction solution was concentrated under a vacuum
11. additionby adding saturated sodium bicarbonate solution, chloroform
12. additionwas added
13. stirringstirring
14. waitwas continued for 2 hours at room temperature
15. customThe organic layer was partitioned
16. dry with materialafter drying with magnesium sulfate
17. concentrationthe resultant was concentrated under a vacuum
18. addition10% palladium on carbon (700 mg) was added to a methanol (200 mL) solution of the residue
19. customthe resultant reaction solution
20. stirringwas stirred for 9 hours under a hydrogen atmosphere and at room temperature
21. filtrationThe reaction solution was filtered over celite
22. concentrationthe filtrate was concentrated under a vacuum
23. customBy purifying the residue
24. washby silica gel column chromatography (eluting solvent:heptane-ethyl acetate system)