Scalable Asymmetric Syntheses of Foslevodopa and Foscarbidopa Drug Substances for the Treatment of Parkinson’s Disease
| Autor: | Rajarathnam E. Reddy, Soma Ghosh, Eric A. Voight, John R. Bellettini, Selvakumar Balaraman, Abhishek Ashok, Jianguo Ji, Brian J. Kotecki, David R. Hill, Timothy B. Towne, James P. Stambuli, Benoit Cardinal-David, Minshan Shou, Mark A. Matulenko, Alexander D Huters, Vincent S. Chan, Russell C. Klix, Justin A. Simanis |
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| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Levodopa Parkinson's disease Double bond Chemistry Organic Chemistry Enantioselective synthesis Carbidopa Parkinson Disease Prodrug medicine.disease Combinatorial chemistry Pharmaceutical Preparations medicine Humans Moiety Hydrogenation Hydrazine (antidepressant) medicine.drug |
| Zdroj: | The Journal of Organic Chemistry. 87:1986-1995 |
| ISSN: | 1520-6904 0022-3263 |
| Popis: | Foslevodopa (FLD, levodopa 4'-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4'-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki-Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety. |
| Databáze: | OpenAIRE |
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