Hydrochloric Acid → (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-(4-chlorophenyl-sulfonylamino)pyrrolidine

Temperature

5 °C

In an atmosphere of nitrogen,(2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-azidopyrrolidine (49.4 g) was dissolved in ethyl acetate (500 ml) followed by addition of triphenylphosphine (60.75 g, 0.232 mol) at 20°-30° C. (foaming took place). After completion of addition, the mixture was warmed to 40°-45° C. and stirred for 30 minutes. The mixture was diluted with water (16.5 ml) and warmed and stirred at 60°-65° C. for 1.5 hours to provide a reaction mixture containing (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-aminopyrrolidine. This reaction mixture was cooled to 5°-10° C. and adjusted to pH 3.5 with 1N hydrochloric acid (ca. 350 ml). After phase separation, the organic layer was washed with 1% hydrochloric acid (125 ml). The aqueous layer was combined and adjusted to pH 7.0 with triethylamine (ca. 20 ml) (pH prior to adjustment: 1.5). This aqueous solution was cooled to 5° C. and ethyl acetate (475 ml) and triethylamine (70.5 g, 0.696 mol) were added thereto in that order. Then, at 5°-10° C., 4-chlorobenzenesulfonyl chloride (49 g, 0.232 mol) was added in 3 successive portions and the mixture was stirred at 5° C. for 1 hour. The reaction mixture was adjusted to pH 2.0 with 6N-hydrochloric acid. After phase separation, the organic layer was washed with 1% hydrochloric acid (125 ml). The aqueous layer was combined and adjusted to pH 7.0 with 24% aqueous sodium hydroxide solution. The aqueous solution was extracted with ethyl acetate (500 ml) and the extract was washed with a saturated aqueous sodium chloride solution (125 ml). The ethyl acetate layer was concentrated to 187.5 ml under reduced pressure and the concentrate was stirred at 20°-25° C. for 1.5 hours for crystallization and ripening. To this solution was added diisopropyl ether (562.5 ml) dropwise and the mixture was stirred for 1 hour. The resulting crystal was collected by filtration and washed with diisopropyl ether (100 ml). The washed crystal was dried in vacuo overnight to provide (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-(4-chlorophenyl-sulfonylamino)pyrrolidine (51.51 g) as a crystal.

1. additionAfter completion of addition
2. temperaturethe mixture was warmed to 40°-45° C.
3. temperaturewarmed
4. stirringstirred at 60°-65° C. for 1.5 hours
5. customto provide a reaction mixture
6. temperatureThis reaction mixture was cooled to 5°-10° C.
7. customAfter phase separation
8. washthe organic layer was washed with 1% hydrochloric acid (125 ml)
9. stirringthe mixture was stirred at 5° C. for 1 hour
10. customAfter phase separation
11. washthe organic layer was washed with 1% hydrochloric acid (125 ml)
12. extractionThe aqueous solution was extracted with ethyl acetate (500 ml)
13. washthe extract was washed with a saturated aqueous sodium chloride solution (125 ml)
14. concentrationThe ethyl acetate layer was concentrated to 187.5 ml under reduced pressure
15. stirringthe concentrate was stirred at 20°-25° C. for 1.5 hours for crystallization
16. additionTo this solution was added diisopropyl ether (562.5 ml) dropwise
17. stirringthe mixture was stirred for 1 hour
18. filtrationThe resulting crystal was collected by filtration
19. washwashed with diisopropyl ether (100 ml)
20. customThe washed crystal was dried in vacuo overnight

ORD record

ord-c29eea278d8441f5842c6010c0e7f9f9

Source dataset

uspto-grants-1997_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05675011