4-Methylmorpholine → (3S,5R)-5-Biphenyl-4-ylmethyl-3-hydroxymethyl-3-methyl-pyrrolidin-2-one

Temperature

0 °C

(3R,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid (25.0 g, 80.8 mmol) was combined with THF (500 mL) and NMM (25 mL, 230 mmol). The resulting mixture was cooled at 0° C. (jacket temp set at −5° C.) and isobutyl chloroformate (21.0 mL, 162 mmol) was added dropwise via addition funnel, while maintaining the internal temperature below 5° C.). The mixture was stirred at 0° C. for 20 minutes. Sodium borohydride (12.2 g, 323 mmol) dissolved in water (40 mL) was added dropwise and the mixture was stirred at 0° C. for 20 minutes (>98% conversion). The reaction was quenched with 1M aqueous HCl (300 mL) and the mixture was stirred at room temperature for 1 hour. Most of solvent was distilled off, leaving a white slurry. The slurry was stirred for 60 minutes and then filtered (small particles, slow filtration) to yield the title compound as a white solid (23 g; >98% purity).

1. additionwas added dropwise via addition funnel
2. temperaturewhile maintaining the internal temperature below 5° C.)
3. additionwas added dropwise
4. stirringthe mixture was stirred at 0° C. for 20 minutes (>98% conversion)
5. customThe reaction was quenched with 1M aqueous HCl (300 mL)
6. stirringthe mixture was stirred at room temperature for 1 hour
7. distillationMost of solvent was distilled off
8. customleaving a white slurry
9. stirringThe slurry was stirred for 60 minutes
10. filtrationfiltered
11. filtration(small particles, slow filtration)

ORD record

ord-29176f2baa354b889f52355ca6b0e7a7

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09096577B2