Toluene → (3R)-3-fluoro-N-(5-methyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxamide

Temperatur

-45 °C

5-Methylthiazol-2-amine (2.28 g, 20.0 mmol) was dissolved into dichloromethane (200 mL) and cooled to near −50° C. 20% Phosgene in toluene (12.6 mL, 24 mmol) was added rapidly over less than 30 seconds and stirred for 10 minutes more at −45° C. before the addition of diisopropylethylamine (17.4 mL, 100 mmol). The mixture was stirred for another 30 minutes near −45° C., (R)-3-fluoropyrrolidine hydrochloride (5.02 g, 40 mmol) was added, and after five minutes the cold bath was removed and the reaction warmed slowly to room temperature. The solution was quenched and stirred thoroughly with concentrated aqueous ammonium hydroxide (25 mL). The aqueous phase was separated and extracted with dichloromethane, and the combined organic phases were washed twice with water; each aqueous phase was back-extracted with dichloromethane. The combined organic phases were concentrated and then slurried in 3:1 hexanes/ethyl acetate. The solids were collected by filtration, rinsed with more 3:1 hexanes/ethyl acetate, and then slurried and rinsed first with 3:1 hexanes/dichloromethane, and then with 1:1 hexanes/dichloromethane to give the title compound.

1. temperaturecooled
2. customto near −50° C
3. customafter five minutes the cold bath was removed
4. temperaturethe reaction warmed slowly to room temperature
5. customThe solution was quenched
6. stirringstirred thoroughly with concentrated aqueous ammonium hydroxide (25 mL)
7. customThe aqueous phase was separated
8. extractionextracted with dichloromethane
9. washthe combined organic phases were washed twice with water
10. extractioneach aqueous phase was back-extracted with dichloromethane
11. concentrationThe combined organic phases were concentrated
12. filtrationThe solids were collected by filtration
13. washrinsed with more 3:1 hexanes/ethyl acetate
14. washrinsed first with 3:1 hexanes/dichloromethane

ORD-Eintrag

ord-6b47dbc0c7cc44919c7c3b535ba035c3

Quelldatensatz

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08383657B2