反应详情

With cooling with ice, oxalyl chloride (15.7 ml, 0.18 mol) was dropwise added to a dichloromethane (200 ml) solution of 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (35 g, 0.15 mol) synthesized according to the method described in J. Med. Chem., 30, 1711-1715 (1987), then a catalytic amount of N,N-dimethylformamide was added, followed by stirring as such for 1 hour, then warming up to room temperature and further stirring for 1 hour. The reaction liquid was dried to solidness under reduced pressure (toluene azeotropy three times). This was dissolved in dichloromethane (100 ml), and the solution was dropwise added to a dichloromethane (150 ml) solution containing tert-butanol (43 ml, 0.45 mol) with cooling with ice. Triethylamine (31.4 ml, 0.225 mol) was further dropwise added at the same temperature, followed by stirring at room temperature for 16 hours. Water was added to the reaction liquid, and the dichloromethane layer was collected, and this was washed with water and saturated brine. After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1→1:1→1:2→1:3, v/v) to obtain the entitled compound (including mixture of optical isomers) (34.227 g in total, 79%). This was used in the next, reaction as such.

1. customsynthesized
2. stirringfurther stirring for 1 hour
3. customThe reaction liquid
4. dry with materialwas dried to solidness under reduced pressure (toluene azeotropy three times)
5. dissolutionThis was dissolved in dichloromethane (100 ml)
6. additionthe solution was dropwise added to a dichloromethane (150 ml) solution
7. temperaturewith cooling with ice
8. stirringby stirring at room temperature for 16 hours
9. customthe dichloromethane layer was collected
10. washthis was washed with water and saturated brine
11. dry with materialAfter drying over anhydrous sodium sulfate and concentration under reduced pressure
12. customthe resulting residue was purified by silica gel column chromatography (eluent, n-hexane
13. customethyl acetate=3:1→1:1→1:2→1:3, v/v) to obtain
14. additionthe entitled compound (including mixture of optical isomers) (34.227 g in total, 79%)
15. customreaction as such