A Biocatalytic Route to the Novel Antiepileptic Drug Brivaracetam
| Autor: | Célal Ates, Arnaud Schule, Christophe Joseph Szczepaniak, Christophe Maréchal, John O’Rourke, Nicolas Carly, Alain Merschaert |
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| Rok vydání: | 2016 |
| Předmět: |
010405 organic chemistry
Organic Chemistry Ph control Substituent Enantioselective synthesis Antiepileptic drug Substrate (chemistry) Brivaracetam 010402 general chemistry 01 natural sciences 0104 chemical sciences Solvent chemistry.chemical_compound chemistry Yield (chemistry) medicine Organic chemistry Physical and Theoretical Chemistry medicine.drug |
| Zdroj: | Organic Process Research & Development. 20:1566-1575 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/acs.oprd.6b00094 |
| Popis: | An asymmetric synthesis of the novel antiepileptic drug Brivaracetam 1 is described. The stereochemistry of the 4-n-propyl substituent is introduced by a biocatalytic resolution of (rac)-methyl 2-propylsuccinate 4-tert-butyl ester 4. The selection of the resolution substrate and the screening of enzymes were carried out from our in-house screening platform. The development and scale-up of the best conditions, including solvent media, pH control, workup, and enzyme supply, led up to a successful demonstration conducted at 1 kg scale in a 10 L vessel. The chiral intermediate (R)-2-propylsuccinic acid 4-tert-butyl ester 6 was reproducibly obtained in 42% yield and 97% ee all along the development. The control of the stereochemistry via the biocatalytic resolution allowed the production of Brivaracetam 1 within the required commercial quality specifications. |
| Databáze: | OpenAIRE |
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