Development of a Phase Transfer Catalyzed Asymmetric Synthesis for an Estrogen Receptor Beta Selective Agonist
| Autor: | Ulf-H. Dolling, Khateeta M. Emerson, Adrian Goodyear, Debra J. Wallace, Karel M. J. Brands, Steven F. Oliver, Cameron J. Cowden, Sarah E. Brewer, Michael S. Ashwood, Gavin W. Stewart, Jeremy P. Scott, Andrew D. Gibb |
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| Rok vydání: | 2007 |
| Předmět: |
chemistry.chemical_classification
Agonist medicine.drug_class Stereochemistry Organic Chemistry Enantioselective synthesis Hydrazone Alkylation Combinatorial chemistry Stereocenter chemistry.chemical_compound chemistry Methyl vinyl ketone medicine Michael reaction Physical and Theoretical Chemistry Estrogen receptor beta |
| Zdroj: | Organic Process Research & Development. 12:723-730 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/op700178q |
| Popis: | A practical asymmetric synthesis of the estrogen receptor beta selective agonist (7β-9aβ)-1,4-dichloro-2-hydroxygibba-1(10a),2,4,4b-tetraen-6-one (1), proceeding by way of six isolated intermediates and without recourse to chromatography, is described. Highlights of the process route developed are two chemoselective chlorinations, a lithiated hydrazone alkylation and an asymmetric Michael addition of indanone 11 to methyl vinyl ketone (using 15 mol % of cinchonine-derived catalyst 20g) to set the all-carbon quaternary asymmetric stereocenter. The challenges addressed in scaling the latter heterogeneous biphasic phase transfer reaction to 44 mol (14 kg) scale are discussed in detail. Overall, the chemistry developed has been used to prepare >6 kg of drug candidate 1 in 18% overall yield and with >99% ee. |
| Databáze: | OpenAIRE |
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