Reaction equation
[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.CO.[CH3:12][C:13](=[N:15][OH:16])[CH3:14].[CH2:17]1COCC1>CCCCCC>[CH3:17][N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7](=[O:9])[CH2:12][C:13](=[N:15][OH:16])[CH3:14]Participants
Reactant 4
Product 1
Reagents, catalysts & solvents 1
Procedure
reacting the starting material, (S)-pyroglutamic acid, of formula (5), ##STR18## with methanol as the esterifying reagent at from -10° C. to 60° C. for from 4-to-48 hours, to prepare the (S)-pyroglutamic acid ester of formula (6), ##STR19## 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), ##STR20## (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), ##STR21## which is not isolated; then (d) immediately treating the reaction product from step (c) with the N-alkylating agent formaldehyde in the presence of formic acid at ambient or an elevated temperature, and isolating the desired product of formula (1), wherein Alk is methyl, in high chiral purity.
Sources & evidence
- ORD record
- ord-1d754ce665ea49da9f270652ca087d36
- Source dataset
- uspto-grants-1996_05
- Patent number
- US05516912
Linked notes
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