Synthesis of N-protected-.alpha.-substituted-glycine racemic esters by zinc-mediated addition of organic halide to glycine cation equivalent
AssigneeG.D. Searle & Co.
InventorsNorman A. Abood, Roger A. Nosal
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Abstract
A method is described for synthesis of N-Boc-L-propargylglycine, a key intermediate used in the preparation of high-potency, orally-active renin inhibitors. This method involves reaction of an organic halide with a glycine cation equivalent, such as methyl N-Boc-2-acetoxyglycine, in the presence of zinc dust to give Boc-protected amino acid derivatives in high yield. Typically useful organic halides are allylic, benzylic and propargylic halides. Resolution of methyl N-Boc-propargylglycine with .alpha.-chymotrypsin provides N-Boc-L-propargylglycine in high yield.
Claims3
A method for preparing a naturally occurring or unnaturally occurring amino acid derivative, said method comprising reacting a mixture of elemental zinc and an N-protected-.alpha.-substituted-glycine cation derivative of Formula I:
- ##STR31## wherein G is the N-protecting group;
- wherein R.sup.1 is selected from the group consisting of hydrido, alkyl, cycloalkyl, alkoxyalkyl, acyl, aralkyl, aryl and aroyl;
- and wherein R.sup.2 is selected from the group consisting of alkyl, cycloalkyl, alkoxyalkyl, aralkyl and aryl;
- with an organic halide of Formula II:
- R.sup.3 X (II)
- wherein X is selected form the group consisting of chloro, bromo and iodo;
- and wherein R.sup.3 is a radical selected from the group consisting of alkly, cycloalkyl, alloxyalkyl, alkoxycarbonylalkyl, allyl, benzyl, propargyl and substituted-propargyl radicals of the formula:
- ##STR32## wherein each R.sup.4 and R.sup.5 is a radical independently selected from the group consisting of hydrido, alkyl, alkenyl and phenyl;
- wherein R.sup.6 is selected from the group consisting of hydrido, alkyl, benzyl and phenyl;
- wherein p is a number selected from zero through five, inclusive;
- and wherein q is a number selected from zero through five, inclusive;
- in a polar solvent to provide an N-protected-.alpha.-substituted-glycine racemic ester of Formula III:
- wherein G, R.sup.2 and R.sup.3 are as defined above, and recovering the ester of Formula III.
Dependencies are inferred from the claim text.