反应详情

The tert-butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate (926 mg, 3.68 mmol) obtained in Step 4 of Example 1 was dissolved in dichloromethane (8 mL), a solution of triethylamine (0.66 mL, 4.78 mmol) and methanesulfonyl chloride (0.31 mL, 4.05 mmol) in dichloromethane (2 mL) was added dropwise under ice-cooling, followed by stirring under ice-cooling for 1 hour. The reaction liquid was diluted with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue (1.58 g) was dissolved in dichloromethane (20 mL), 1,8-diazabicyclo[4,3,0]-7-undecene (2.13 mL, 17.2 mmol) and 2-mercaptoethyl acetate (0.31 mL, 4.05 mmol) were added under ice-cooling, followed by stirring under ice-cooling for 3 hours. The reaction liquid was diluted with chloroform, and washed with a 1 N aqueous hydrochloric acid solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue (3.26 g) was dissolved in ethanol (20 mL), and then sodium ethoxide (2.0 g, 29.4 mmol) was added, followed by heating under reflux for 3 hours. The reaction liquid was concentrated under a reduced pressure, and the obtained residue was dissolved in chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=50:1→30:1) to give tert-butyl 4-[4-amino-5-(ethoxycarbonyl)thiophen-3-yl]piperidine-1-carboxylate (287 mg, 22.0%) as a pale yellow amorphous.

1. temperaturecooling
2. temperaturecooling for 1 hour
3. customThe reaction liquid
4. washthe organic layer was washed with saturated brine
5. dry with materialdried over anhydrous sodium sulfate
6. concentrationconcentrated under a reduced pressure
7. dissolutionThe obtained residue (1.58 g) was dissolved in dichloromethane (20 mL)
8. temperaturecooling
9. stirringby stirring under ice-
10. temperaturecooling for 3 hours
11. customThe reaction liquid
12. washwashed with a 1 N aqueous hydrochloric acid solution
13. washThe organic layer was washed with saturated brine
14. dry with materialdried over anhydrous sodium sulfate
15. concentrationconcentrated under a reduced pressure
16. dissolutionThe obtained residue (3.26 g) was dissolved in ethanol (20 mL)
17. temperatureby heating
18. temperatureunder reflux for 3 hours
19. customThe reaction liquid
20. concentrationwas concentrated under a reduced pressure
21. dissolutionthe obtained residue was dissolved in chloroform
22. washThe organic layer was washed with saturated brine
23. dry with materialdried over anhydrous sodium sulfate
24. concentrationconcentrated under a reduced pressure
25. customThe obtained residue was purified