4-Methylmorpholine → HCID 22825258, compound

Participants

Reaction Steps

A solution of Z-Ala-OH (118.5 g, 0.53 mol, 1.05 eq.) in DMF (400 mL) was placed in a 2-l 3-neck creased round bottom flask fitted with a thermometer, mechanical stirrer, dropping funnel and immersed in a dry ice-acetone bath at -15°. The reaction was carried out under an atmosphere of N2, cooled to -15° and precooled (-20°) N-methylmorpholine (80.9 g, 0.80 mol, 1.58 eq.) added. After stirring for 4 min at -15°, the reaction mixture was cooled to -25° and precooled (-20°) isobutylchloroformate (72.5 g, 0.53 mol, 1.05 eq.) added portionwise over a 2 min period (temperature must not exceed -15°). The reaction mixture stirred for an additional 4 min at -25° and a precooled (-20°) solution of H-Glu(OtBu)-Asn-OtBu (189 g, 0.506 mol) in DMF (350 mL)-CH2Cl2 (150 mL) added as rapidly as possible while maintaining -15° to -20° (4 minutes). After the addition was complete the reaction mixture was stirred at -15° for 30 min and at 25° for 3 h. The reaction mixture was filtered and the filter cake washed with DMF (2×50 mL). The filtrate was evaporated in vacuo and the resultant syrup immediately poured into H2O (3.5 l). The suspension was stirred for 18 h and the product collected by filtration and washed with H2O (2×500 mL) and dried in vacuo. A total of 575.6 g (98.3%) was prepared in 2 batches. Recrystallization from EtOH (3.5 l):H2O (5 l) gave 533.4 g (91.1%); mp 174°-176°; [α]D25 -35.48° (c 1, MeOH); Rf 0.25 (CHCl3 :MeOH:AcOH; 80 -20-5).

Provenance & Evidence