Sodium Hydroxide → Enalapril Maleate

Participants

Reaction Steps

A mixture of 3 g. of L-alanyl-L-proline, 5 g of ethyl 2-oxo-4-phenyl-butanoate, 13 g. of 3A molecular sieves, and 3.6 g. of Raney nickel in 85 ml of ethanol is hydrogenated at 25° C. and at 40 psig of hydrogen until uptake of hydrogen ceases. The solids are filtered, washed with 80 ml. of ethanol and the filtrates are combined. Assay by high pressure liquid chromatography shows an 87:13 ratio of diastereoisomers in favor of the desired product. Ethanol is removed under vacuum to afford an oil which is dissolved in 60 ml. of water and 20 ml. of ethyl acetate. The pH of the stirred two-phase mixture is adjusted to 8.6 with 50% NaOH. The layers are separated and the water phase is extracted with 2×20 ml more of ethyl acetate. The water phase is adjusted to pH 4.25 with hydrochloric acid, 12 g. of NaCl is dissolved in the water, and product is extracted with 5× 12 ml of ethyl acetate. The extracts are combined and dried with Na2SO4. The desired product, N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline, is crystallized as its maleate salt by addition of 1.86 g. of maleic acid. After stirring for 4 hours, the salt is filtered, washed with ethyl acetate and dried to afford 5.2 g. of pure product, m.p. 150°-151° C.

Provenance & Evidence