Chlorotrimethylsilane → Perindopril Erbumine

温度

22.5 °C

To (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (7.44 g) in dichloromethane (80 mL) at 20-25° C., trimethylchlorosilane (5.84 mL) and triethylamine (6.4 mL) were added and it was stirred at 20-25° C. for two hours. After two hours triethylamine (5.54 mL) was added, the suspension was cooled to −15° C., a suspension of N—((S)-1-carbetoxybutyl)-L-alanylchloride hydrochloride (11 g) in dichloromethane (80 mL), cooled to −15° C., was poured thereto and the stirring was continued at a temperature from 0° C. to −5° C. for two hours. The reaction solution was heated to 0° C., the precipitated triethylamine hydrochloride was filtered off and washed with dichloromethane (20 mL), water (66 mL) in which NaOH (1.6 g) had been dissolved was added to the filtrate and the pH was adjusted to 4.2 with a 20% NaOH solution. The organic phase was separated and the aqueous layer was washed two more times with dichloromethane (40 mL). The combined dichloromethane layers were evaporated, the residue was dissolved in isopropyl acetate (250 mL), the undissolved part was filtered off, and t-butylamine (4.4 mL) was added to the filtrate. The precipitated crystals were dissolved at the boiling point of the solution, the clear solution was cooled to 10-20° C. and it was continued with stirring for two hours. After two hours, the precipitated crystals were filtered off, washed with isopropyl acetate (30 mL) and dried at 35-40° C. in an air dryer. 15.3 g of perindopril erbumine in alpha form with a purity of more than 99% were obtained; the content of single impurities was not above 0.1%.

1. temperaturethe suspension was cooled to −15° C.
2. temperaturecooled to −15° C.
3. additionwas poured
4. waitthe stirring was continued at a temperature from 0° C. to −5° C. for two hours
5. temperatureThe reaction solution was heated to 0° C.
6. filtrationthe precipitated triethylamine hydrochloride was filtered off
7. washwashed with dichloromethane (20 mL), water (66 mL) in which NaOH (1.6 g)
8. dissolutionhad been dissolved
9. additionwas added to the filtrate
10. customThe organic phase was separated
11. washthe aqueous layer was washed two more times with dichloromethane (40 mL)
12. customThe combined dichloromethane layers were evaporated
13. dissolutionthe residue was dissolved in isopropyl acetate (250 mL)
14. filtrationthe undissolved part was filtered off
15. additiont-butylamine (4.4 mL) was added to the filtrate
16. dissolutionThe precipitated crystals were dissolved at the boiling point of the solution
17. temperaturethe clear solution was cooled to 10-20° C.
18. stirringwith stirring for two hours
19. waitAfter two hours
20. filtrationthe precipitated crystals were filtered off
21. washwashed with isopropyl acetate (30 mL)
22. customdried at 35-40° C. in an air dryer

ORDレコード

ord-4453f703f19d4e6fb61ccf640749cbd1

出典データセット

uspto-grants-2013_06

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08470869B2