1-Butanol → Trandolaprilat

A solution of NaOH (6.5 g, 153.6 mmol; assay=94.52%), water (157 ml), ethanol (157 ml, technical grade, contains ˜5% 2-propanol) and Trandolapril (31.5 g, 72.94 mmol; assay=99.7%) was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 15 hours. After an in-process control showed an almost complete saponification (by HPLC), the clear solution was concentrated in vacuo to an amount of 167.05 g, and n-butanol (160 ml) was added to the concentrated product. This mixture was heated to an internal temperature ranging from about 60° C. to about 70° C., and 2N aqueous hydrochloric acid was added (150.4 mmol), whereupon the pH dropped down from 12.09 to 3.66. The organic layer was separated at an internal temperature of 66° C., and the aqueous layer was extracted again with n-butanol (80 ml) at an internal temperature of 65° C. The combined organic layers were washed twice with water (each 40 ml) at an internal temperature ranging from about 63° C. to about 65° C. The organic layer then obtained (total amount 306.4 g) was concentrated in vacuo at a temperature ranging from about 50° C. to about 60° C., whereupon after concentration to an amount of 190 g a white solid precipitated. This suspension was further concentrated in vacuo to an amount of 75.1 g, and 80 ml MTBE was added to complete the precipitation. The suspension was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 3.5 hours. After filtration, the wet product was washed twice with MTBE (each 80 ml) and dried in vacuo for 15 hours at 40° C. to give Trandolaprilat as disolvate with n-butanol (yield: 36.51 g, 66.67 mmol, 91.4%; assay (0.1N HClO4)=73.5%; HPLC purity=100%).

1. concentrationthe clear solution was concentrated in vacuo to an amount of 167.05 g, and n-butanol (160 ml)
2. additionwas added to the concentrated product
3. temperatureThis mixture was heated to an internal temperature
4. customranging from about 60° C. to about 70° C.
5. addition2N aqueous hydrochloric acid was added (150.4 mmol)
6. additionwhereupon the pH dropped down from 12.09 to 3.66
7. customThe organic layer was separated at an internal temperature of 66° C.
8. extractionthe aqueous layer was extracted again with n-butanol (80 ml) at an internal temperature of 65° C
9. washThe combined organic layers were washed twice with water (each 40 ml) at an internal temperature
10. customranging from about 63° C. to about 65° C
11. customThe organic layer then obtained (total amount 306.4 g)
12. concentrationwas concentrated in vacuo at a temperature
13. customranging from about 50° C. to about 60° C.
14. concentrationwhereupon after concentration to an amount of 190 g a white solid
15. customprecipitated
16. concentrationThis suspension was further concentrated in vacuo to an amount of 75.1 g, and 80 ml MTBE
17. additionwas added
18. customthe precipitation
19. waitranging from about 20° C. to about 25° C. for 3.5 hours
20. filtrationAfter filtration
21. washthe wet product was washed twice with MTBE (each 80 ml) and
22. customdried in vacuo for 15 hours at 40° C.

ORDレコード

ord-1d0aa1644b9c4e3699e3d1b0a6ab56fa

出典データセット

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07943655B2