Water → HCID 54751762, compound

364 g of benzyl (3S,4R)-3-(N-cyclopropyl)carbamoyl-4-hydroxypyrrolidine-1-carboxylate (1.20 mol) was suspended in 1.46 L of dehydrated tetrahydrofuran. While this suspension was stirred, 3.07 L of a 1.17 M tetrahydrofuran solution of borane-tetrahydrofuran complex in (3.59 mol) was added dropwise at an internal temperature of 20 to 43° C. The mixture was stirred at an internal temperature of 41 to 46° C. for 8 hours. Subsequently, the mixture was allowed to cool under stirring and then cooled in an ice bath while kept stirred. 364 mL of water was then added dropwise at an internal temperature of 15 to 25° C. Subsequently, 726 g of triethylamine was added dropwise at an internal temperature of 16 to 18° C. The mixture was then heated and stirred for 14 hours under reflux. Subsequently, the reaction mixture was allowed to cool under stirring and concentrated under reduced pressure. To the resulting residue, 1.09 L of water was added to dissolve the solid and the solution was extracted with 2.55 L of ethyl acetate. The organic layer was washed with 1.82 L of water and extracted with 1.50 L of 2 mol/L hydrochloric acid. A 2 mol/L sodium hydroxide solution (1.67 L) was then added to the aqueous layer under stirring until pH 12. The mixture was extracted with 2.55 L of ethyl acetate and the organic layer was washed with 1.82 L of 28% brine. To this layer, 255 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The resulting solid was separated by filtration and washed with 0.55 L of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure to give 345 g of a crude product of the title compound as a faint yellow oil. This product was used in the subsequent step without further purification.

1. stirringThe mixture was stirred at an internal temperature of 41 to 46° C. for 8 hours
2. temperatureto cool
3. stirringunder stirring
4. temperaturecooled in an ice bath
5. stirringwhile kept stirred
6. temperatureThe mixture was then heated
7. stirringstirred for 14 hours
8. temperatureunder reflux
9. temperatureto cool
10. stirringunder stirring
11. concentrationconcentrated under reduced pressure
12. additionTo the resulting residue, 1.09 L of water was added
13. dissolutionto dissolve the solid
14. extractionthe solution was extracted with 2.55 L of ethyl acetate
15. washThe organic layer was washed with 1.82 L of water
16. extractionextracted with 1.50 L of 2 mol/L hydrochloric acid
17. additionA 2 mol/L sodium hydroxide solution (1.67 L) was then added to the aqueous layer
18. stirringunder stirring until pH 12
19. extractionThe mixture was extracted with 2.55 L of ethyl acetate
20. washthe organic layer was washed with 1.82 L of 28% brine
21. additionTo this layer, 255 g of anhydrous sodium sulfate was added
22. stirringthe mixture was stirred for 1 hour
23. customThe resulting solid was separated by filtration
24. washwashed with 0.55 L of ethyl acetate
25. concentrationconcentrated under reduced pressure

ORD record

ord-54db5b5273ed46fa8d2644263cc9772f

Source dataset

uspto-grants-2010_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07667049B2