4-Methylmorpholine → HCID 13685963, compound

Participants

Reaction Steps

N-Carbobenzoxy-L-prolyl-DL-valinol was prepared by reacting 9.97 g (40 mmol) N-carbobenzoxy-L-proline, 5.46 g (40 mmol) isobutyl chloroformate, 4.05 g (40 mmol) N-methylmorpholine, and 4.13 g (40 mmol) DL-valinol substantially according to the mixed anhydride procedure described in Example 1. A portion, 1.00 g, of crude product was dissolved in 120 mL ethyl acetate, and 80 mL n-hexane were added. This solution was stirred vigorously and seeded with a crystal of N-carbobenzoxy-L-prolyl-L-valinol. After 5 minutes, crystalline product (100 mg) was separated by filtration. High performance liquid chromatography (HPLC) indicated that the product contained 76% N-carbobenzoxy-L-prolyl-D-valinol (L-D isomer) and 24% N-carbobenzoxy-L-prolyl-L-valinol (L-L isomer). HPLC analysis was conducted using a 4.6 mm ID×25 cm column packed with 5-6 μm diameter particles of porous silica, and a linear gradient (3→100% B in 30 minutes), using 1-chlorobutane as solvent A and 1:1 methanol/acetonitrile as solvent B. A first peak (11.2 minutes) was the desired L-D isomer, and a second peak (11.6 minutes) was the L-L isomer, characterized in Example 2 above. HPLC separation was repeated with a series of 5 mg injections to give a total of 64 mg (0.19 mmol) pure N-carbobenzoxy-L-prolyl-D-valinol. This product could also be isolated directly from the crude reaction product by a series of fractional crystallizations from ethyl acetate/n-hexane, then ethanol/n-hexane. Pure N-carbobenzoxy-L-prolyl-D-valinol melted at 118.0°-118.2°, α25D-27.6°, (C=1.01 g/100 mL in acetone).

Provenance & Evidence