Ethanolamine → N-Methyl-N-methoxy2-(S)-hydroxy-3-cyclobutyl Propanamide

A mixture of 11.40 g (61.5 mmol) of N-methyl-N-methoxy 2-oxo-3-cyclobutyl propanamide (from Step B) and 250 mL 0.5 N (R)-Alpine Borane® solution in THF was concentrated and stirred at rt for 5 days. The mixture was cooled to 0° C. and quenched with 6.8 mL (75.0 mmol) of isobutyraldehyde. The resulting mixture was diluted with 200 mL of ether and treated with 7.5 mL (125 mmol) of ethanolamine. The precipitate that formed was filtered and the filtrate was concentrated. Flash chromatography on 500 g of silica gel using 9:1 v/v CH2Cl2 as the eluant afforded 11.48 g (99%, 91% ee) of the title compound: 1H NMR (500 MHz) δ1.59-1.70 (m, 2H), 1.67 (s, 1H), 1.77-1.83 (m, 2H), 1.82-1.92 (m, 1H), 2.03-2.13 (m, 2H), 2.53-2.60 (m, 1H), 3.23 (s, 3H), 3.72 (s, 3H), 4.31 (app d, J=5.5, 1H); HPLC: Chiralpak AS 4.6×250 mm column, 75/25 hexanes/iPrOH, 0.5 mL/min, 210 nm. Retention Times: (S)-Enantiomer, 13.3 min; (R)-enantiomer, 17.2 min.

1. concentrationwas concentrated
2. temperatureThe mixture was cooled to 0° C.
3. customThe precipitate that formed
4. filtrationwas filtered
5. concentrationthe filtrate was concentrated

ORD record

ord-6e07ea31f64e4961ad1b38c510a01b55

Source dataset

uspto-grants-2002_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06399619B1