March 25, 2013

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The following patent record is from the CAplusSM database.


Patent Number: US 8338621
Title: Method for the preparation of 2-oxo-1-pyrrolidine derivatives such as levetiracetam, brivaracetam and seletracetam
Inventor(s): Surtees, John; Bouvy, Didier; Thomas, Antoine; Combret, Yves; Frank, Michael; Schmidt, Gunther
Patent Assignee(s): UCB Pharma, S.A., Belg.
Source: Eur. Pat. Appl., 32 pp. CODEN: EPXXDW
Language: English

The invention relates to alternative processes for the preparation of 2-oxo-1-pyrrolidine derivs. I [R1 = H, alkyl or alkenyl; R2 = alkyl or alkenyl; X = CN, CO2H, -COOR3 or -CONR4R5, wherein R3 = alkyl; R4 and R5 independently = H or alkyl]. Particularly, the invention relates to alternative processes for the synthesis of levetiracetam, brivaracetam and seletracetam. The method involves condensation of optically pure II [Y = halo, sulfonate or N2+; R2 and X are defined as above] with III to provide diastereoisomerically pure I.  Alternative preparation of I via condensation of II with IV followed by cyclization was provided. For instance, (S)-2-(2-oxopyrrolidin-1-yl)butanamide (levetiracetam) was prepared via condensation reaction of (R)-2-bromobutyramide with pyrrolidin-2-one using NaOMe in THF, albeit with substantial racemization. However, a similar reaction of optically pure (R)-Me 2-(triflyloxy)butyrate with pyrrolidin-2-one and NaOMe in PhMe gave the Me ester intermediate of levetiracetam with an 89.26% level of the desired (S)-isomer, in 74% yield. Levetiracetam was also prepared by the reaction between (R)-2-bromobutyramide and Me 4-aminobutyrate hydrochloride to generate intermediate hydrochloride salt of Me 4-(1-carbamoylpropylamino)butyrate in 49% yield. This amino ester underwent cyclization in the presence of 2-hydroxypyridine at 80? to give levetiracetam with 98.6% (S)-isomer. The invention processes advantageously minimize the number of separation steps required to obtain the desired 2-oxo-1-pyrrolidine derivs.

Please note:  Abstracts and Titles for patent records in CAplus are routinely enhanced to better describe the claimed invention. The title of the U.S. granted patent is Process for the preparation of 2-oxo-1-pyrrolidine derivatives. In this example, the US granted patent includes Guy Duchene as an inventor. CAS originally indexed the published application EP 1806339 as the first published record of the invention which only included Surtees, John; Bouvy, Didier; Thomas, Antoine; Combret, Yves; Frank, Michael; Schmidt, Gunther as inventors at that time.

 View the full-text here.

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