Sodium borohydride → (4R)-4-(1-Hydroxypropyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one

Temperature

0 °C

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-(3-methoxypropanoyl)pyrrolidin-2-one 1.20 (12 g, 39.30 mmol, 1.00 equiv), ethanol (100 mL), followed by the addition of NaBH4 (3.35 g, 88.16 mmol, 2.50 equiv) in several batches with stifling at 0° C. The resulting solution was stirred at 0° C. for 2 h, quenched by the addition of 100 mL of water/ice and extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane: methanol (200:1-80:1) to afford (4R)-4-(1-hydroxypropyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one as a mixture of diastereomers. The diastereomers were separated by chiral HPLC (CHIRALPAK IC), and the later eluting diastereomer was collected to afford (R)-4-((R)-1-hydroxy-3-methoxypropyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.21. This compound is the later eluting diastereomer under RP-HPLC conditions (Gemini column, water/acetonitrile/TFA).

1. customInto a 250-mL 3-necked round-bottom flask purged
2. temperaturemaintained with an inert atmosphere of nitrogen
3. customwith stifling at 0° C
4. customquenched by the addition of 100 mL of water/ice
5. extractionextracted with 3×300 mL of ethyl acetate
6. washwashed with 3×300 mL of brine
7. dry with materialdried over anhydrous sodium sulfate
8. concentrationconcentrated under vacuum
9. washeluting with dichloromethane: methanol (200:1-80:1)

ORD record

ord-a35e919962ae4d49bb8c5cff18d3b9bc

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09376441B2