反应详情

To a solution of 260 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetic acid in 20 ml of tetrahydrofuran were added 118 mg of 1-hydroxybenzotriazole, 167 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydro-chloride, 600 mg of (dibenzyl) [2-(4-piperidyl)ethyl]amine and 310 μl of triethylamine, and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over magnesium sulfate, and the solvent was evaporated therefrom. The resulting residue (385 mg) was dissolved in 10 ml of dichloroethane, 64 μl of 1-chloroethyl chloroformate was added thereto, and the mixture was stirred with heating under refluxing for 4.5 hours. The solvent was evaporated, 10 ml of methanol was added to the residue, and the mixture was stirred with heating under refluxing for 4.5 hours. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform-methanol). The resulting residue (22 mg) was dissolved in 0.1 ml of ethyl acetate, then 30 μl of a 4N HCl/ethyl acetate solution was added to the solution, and the mixture was stirred at room temperature. The solvent was evaporated therefrom, and the resulting solid was collected by filtration to give 14 mg of (Z)-4,4-difluoro-5-(2-{4-[2-(benzylamino)ethyl]piperidino)-2-oxoethylidene)-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine monohydrochloride as a colorless powder.

1. extractionthe mixture was extracted with ethyl acetate
2. washThe organic layer was washed with a saturated aqueous solution of NaCl
3. dry with materialdried over magnesium sulfate
4. customthe solvent was evaporated
5. dissolutionThe resulting residue (385 mg) was dissolved in 10 ml of dichloroethane
6. addition64 μl of 1-chloroethyl chloroformate was added
7. stirringthe mixture was stirred
8. temperaturewith heating
9. temperatureunder refluxing for 4.5 hours
10. customThe solvent was evaporated
11. addition10 ml of methanol was added to the residue
12. stirringthe mixture was stirred
13. temperaturewith heating
14. temperatureunder refluxing for 4.5 hours
15. temperatureAfter cooling to room temperature
16. additiona saturated aqueous solution of sodium bicarbonate was added
17. extractionthe mixture was extracted with ethyl acetate
18. washThe organic layer was washed with a saturated aqueous solution of NaCl
19. dry with materialdried over anhydrous magnesium sulfate
20. customthe solvent was evaporated
21. customThe residue was purified by silica gel column chromatography (eluting with chloroform-methanol)
22. dissolutionThe resulting residue (22 mg) was dissolved in 0.1 ml of ethyl acetate
23. addition30 μl of a 4N HCl/ethyl acetate solution was added to the solution
24. stirringthe mixture was stirred at room temperature
25. customThe solvent was evaporated
26. filtrationthe resulting solid was collected by filtration