3-Morpholinone, 5,6-dimethyl-, (5R,6S)- synthesis

Yield:1605312-85-3 14%

Reaction Conditions:

Stage #1: (2S,3R)-3-amino-butan-2-ol hydrochloride;chloroacetyl chloridewith N-ethyl-N,N-diisopropylamine in tetrahydrofuran at 0 - 20; for 3 h;Inert atmosphere;
Stage #2: with sodium hydride in tetrahydrofuran;mineral oil at 20;

Steps:

32 Preparation 32: (5R,6S)-5,6-Dimethyl-morpholin-3-one

Preparation 32: (5R,6S)-5,6-Dimethyl-morpholin-3-oneTo a solution of (25,3R)-3-amino-butan-2-ol hydrochloride (2.8 g, 22.5 mmol) in THF (15 mL) was added DIPEA (8 mL, 45 mmol) and the reaction mixture was cooled to 0 °C in a water/ice bath. Slowly chloroacetyl chloride (2.2 mL, 27 mmol) was added to the reaction mixture which was allowed to warm to room temperature and stirred under nitrogen for 3 h. The mixture wasevaporated and partitioned between saturated aqueous NH4CI (40 mL) and 20% isopropyl alcohol in chloroform (3 x 20 mL) and the combined organic extracts were dried and evaporated. The crude material was dissolved in THF (20 mL) followed by the slow addition of NaH (60% dispersed in mineral oil) (1.2 g, 29.3 mmol) and the mixture stirred at room temperature overnight. The mixture was then concentrated in vacuo. Chromatography (5i02,gradient elution, 0 - 20%, (2 M NH3 in MeOH) in DCM) gave the title compound (392 mg, 14%) as a white solid. MS: [M+H] = 130. iH NMR (400 MHz, DMSO-d6): 8.07 (iH, 5), 3.95 (2H, 5), 3.89-3.77 (iH, m), 3.30-3.23 (iH, m), 1.08-1.02 (6H, m).

References:

WO2014/60767,2014,A1 Location in patent:Page/Page column 122