Chemistry:Bexlosteride
Bexlosteride is a potent and noncompetitive inhibitor of the enzyme 5α-reductase related to finasteride and dutasteride.[1] It is selective for the type I isoform of the enzyme.[1] It advanced to Phase III clinical trials, but development was halted at that stage, and it was never marketed.[2][3]
Synthesis
The synthesis of Bexlosteride has been reported in the literature.[4][5][6][7][8]
FGI of 6-Chloro-2-tetralone [17556-18-2] (1) to its enamine by reaction with pyrrolidine (or with the chiral amine 1-phenethylamine to ensure enantioselectivity) gives 1-(6-chloro-3,4-dihydronaphthalen-2-yl)pyrrolidine [54670-11-0] (2). Reaction with acrylamide [79-06-1] would be expected to be a 2-phase process. First a conjugate Michael addition occurs followed by displacement of pyrrolidine by the amide nitrogen to form an unsaturated lactam. The product of this step is called 8-chloro-1,4,5,6-tetrahydrobenzo[f]quinolin-3(2H)-one, PC10466539 (3). The lactam-olefin at the ring junction is reduced with triethylsilane in the presence of trifluoroacetic acid. The saturated lactam consists largely of racemic isomer with the trans ring junction. Alkylation of the lactam nitrogen with methyl halide in the presence of base gives 8-Chloro-4-methyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one [152323-03-0] (4). Treament with methanol opens the lactam ring to yield the corresponding methyl ester, PC10826711 (5). The amino-ester is next resolved via its ditoluyl tartrate salt giving PC10516975 (6). Finally, heating with sodium carbonate regenerates the lactam ring to afford Bexlosteride (7).
N.B. The starting tetralone finds dual use in the synthesis of 6-CAT.
See also
- 5α-Reductase inhibitor
- Izonsteride
References
- ↑ 1.0 1.1 Androgens and androgen receptor : mechanisms, functions, and clinical application. Boston: Kluwer Academic Publishers. 2002. ISBN 1-4020-7188-4. https://books.google.com/books?id=ODBLQc2BdDIC&q=Bexlosteride&pg=PA167.
- ↑ "Drug Profile: Bexlosteride". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800009929.
- ↑ Reaxys entry for bexlosteride: Reaxys Registry Number: 6635310
- ↑ Strategies for Organic Drug Synthesis and Design. New York: Wiley-Interscience. 2008. ISBN 978-0-470-19039-5. https://books.google.com/books?id=fEwl6Qev-mUC&q=Bexlosteride&pg=PA208.
- ↑ "Resolution of delta-Lactams Provides Access to Nonracemic Benzoquinolinones: The Synthesis of LY300502 and LY300503". The Journal of Organic Chemistry 61 (13): 4450–4454. June 1996. doi:10.1021/jo9601425. PMID 11667351.
- ↑ "Nonsteroidal inhibitors of human type I steroid 5-alpha-reductase". Journal of Medicinal Chemistry 36 (3): 421–3. February 1993. doi:10.1021/jm00055a014. PMID 8381185.
- ↑ "Unknown". Drugs of the Future 20 (2): 144. 1995.
- ↑ Audia JE, McQuaid LA, Neubauer BL, Rocco VP, US patent 5622962, issued 22 April 1997
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