Process for preparing ACHPA
AssigneeMerck & Co., Inc.
InventorsPaul F. Schuda, William J. Greenlee, Prasun K. Chakravarty, Philip Escola
Life of this patent
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Abstract
Process comprising coupling of an acylimidazole-activated derivative of a reduced and protected phenylalanine with the magnesium salt of malonic acid monoethyl ester to produce the beta-ketoester, which is subsequently reduced with NaCNBH.sub.3 /THF in glacial acetic acid to afford a separable mixture of 3-S and 3-R 3-hydroxy-(4S)-4-(N-.alpha.-BOC)amino-5-cyclohexylpentanoic acid, such that large-scale, high yield production of optically-active ACHPA is significantly improved.
Claims2
A process for preparing (3S, 4S)-(N-.alpha.-BOC)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid ethyl ester comprising treatment of N-.alpha.-BOC-amino-3-hexahydrophenylpropionic acid with 1,1-carbonydiimidazole to form an acylimidazole-activated derivative of N-.alpha.-BOC-amino-3-hexahydrophenylpropionic acid, then
- (a) coupling said acylimidazole-activated derivative with the magnesium salt of malonic acid monoethylester to afford the .beta.-ketoester;
- (b) reducing said .beta.-ketoester using sodium cyanoborohydride in tetrahydrofuran and glacial acetic acid to produce a mixture of (3S,4S)-(N.alpha.-BOC)-4-amino-5cyclohexyl-3-hydroxypentanoic acid ethyl ester and (3S,4S)-(N.alpha.-BOC)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid ethyl ester;
- and
- (c) crystallizing off the (3R,4S) compound and purifying the remaining product to afford optically-pure (3S,4S)-(N.alpha.-BOC)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid.
Dependencies are inferred from the claim text.