- Preparation method of levetiracetam and intermediates thereof
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The invention provides a preparation method of levetiracetam and intermediates thereof. The specific steps are as follows: dropwise adding pyrrolidone into a toluene solution of sodium methoxide or sodium hydride, performing concentrating to dryness after a reaction is completed, adding toluene again, dropwise adding ethyl 2-bromobutyrate, and carrying out a reaction by heating to obtain a compound of a formula 3; adding a NaOH aqueous solution to the compound of the formula 3, performing heating until a reaction is completed, and dropwise adding concentrated hydrochloric acid to precipitate acompound of a formula 4; carrying out a reaction of the compound of the formula 4, R-(+)-phenylethylamine, and triethylamine to obtain a compound of a formula 6; performing hydrolysis by a NaOH solution, acidification by concentrated hydrochloric acid, and purification to a compound of a formula 7; and performing esterification by TsOH/EtOH to obtain a compound of a formula 8, and then performingammonia hydrolysis to obtain levetiracetam.
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Paragraph 0043; 0048-0051
(2020/01/08)
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- IMPROVED PROCESS FOR THE PREPARATION OF (S)-ALPHA-ETYL-2-OXO-1-PYRROLIDINEACETAMIDE AND (R)-ALPHA-ETHYL-2-OXO-1-PYRROLIDINEACETAMIDE
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A process provided for the preparation of the (S)- and (R)- alpha- ethyl-2-oxo-1- pyrrolidineacetamide of formula:(1) from (RS)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid of formula:(2) comprising: i) combining the (RS)-2 with a chiral base (resolving agent) in a resolution solvent and crystallizing from the said mixture the diastereomeric salt of (S)- or (R)-2 and chiral base; ii) regenerating (S)- or (R)-2 from the crystallized diastereomeric salt by treating with a suitable acid or acidic ion-exchange resin; iii) optionally regenerating (R)- or (S)-2 or their mixture (predominantly one enantiomer) from the crystallization mother liquor by treating with a suitable acid or acidic ion-exchange resin; iv) optionally epimerizing (RS)-2 by treating (R)- or (S)-2 or their mixture (predominantly one enantiomer) of step iii with an acid anhydride; V) optionally converting (RS)-2 of step iv into enantiomerically enriched (S)- or (R)-2 through steps i and ii; vi) formation of the mixed anhydride by reacting (R)- or (S)-2 with an alkyl or aryl sulfonyl halogen compound RSO2X in the presence of a suitable base; and vii) reacting the mixed anhydride with ammonia; wherein R represents C 1 to C 15 alkyl or aryl groups such as methyl, ethyl, p-toluenyl, 2,4,6-trimethylbenzyl, 2,4,6-trichloribenzyl, and X represents a halogen atom such as F, Cl and Br atoms.
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Page/Page column 13
(2008/06/13)
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