반응 #50022

반응 방정식

(S)-pyroglutamic acid

methanol

THF

acetone oxime

→

1-(1-methyl-5-oxo-2(S)-pyrrolidinyl)-1,3-butanedione-3-oxime

용매

hexane

반응 조건

실험 절차

reacting the starting material, (S)-pyroglutamic acid, of formula (5), ##STR17## with methanol as the esterifying reagent at from -10° C. to 60° C. for from 4-to-48 hours, to prepare the (S)-pyroglutamic add ester of formula (6), ##STR18## wherein R1 is methyl; (b) reacting the compound of formula (6) with an excess of a salt of the dianion of acetone oxime in a solution of THF:hexane, at a temperature of from -10° C. to ambient temperature, with vigorous mixing of the reagents, to form the intermediate product, 1-(1-methyl-5-oxo-2(S)-pyrrolidinyl)-1,3-butanedione-3-oxime, which is not isolated, but which is cyclized and dehydrated by reaction with a strong acid at ambient-to-reflux temperature for from 0.5-to-3 hours, to produce the novel 5(S)-(3-methyl-5-isoxazolyl)-2-pyrrolidinone compound of formula (7), ##STR19## (c) reducing the compound of formula (7) with a reducing agent known to reduce lactams to cyclic amines, particularly an agent selected from the group consisting of lithium aluminum hydride, NaBH4 /BF3, NaBH4 /CH3SO3H, NaBH4 /camphor sulfonic acid, borane/dimethyl sulfide, and borane/THF, to give the 3-methyl-5-(2(S)-pyrrolidinyl)isoxazole compound of formula (8), ##STR20## which is not isolated; then (d) immediately treating the reaction product from step (c) with the N-alkylating agent formaldehyde and formic acid at ambient or an elevated temperature, and isolating the desired product of formula (1), wherein Alk is methyl, in high chiral purity.

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