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Synfacts 2013; 9(1): 0009
DOI: 10.1055/s-0032-1317725
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of TAK-733

Contributor(s):
Philip Kocienski
Zhao Y * et al. Takeda California, San Diego, Millenium Pharmaceuticals Inc., Cambridge and IRIX Pharmaceuticals, Greenville, USA
Process Research and Kilogram Synthesis of an Investigational, Potent MEK Inhibitor.

Org. Process Res. Dev. 2012;
16: 1652-1659
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Publication History

Publication Date:
17 December 2012 (online)

 
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Key words

TAK-733 - MEK inhibitors - 3-fluoropyridone - cascade reaction

Significance

MEK kinases regulate the pathway that mediates proliferative and anti-apoptotic signaling factors that promote tumor growth and metastasis. TAK-733 is an MEK kinase inhibitor that entered phase I clinical trials for the treatment of cancer. A noteworthy feature of this short synthesis (25% yield overall) is the one-pot, three-step synthesis of the fluoropyridone D, in which the fluorine atom is present at the outset.


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Comment

The reaction of F with the nosylate G gave a mixture of N- and O-alkylation products (8:1) from which the desired N-alkylation product was isolated by crystallization. The mixture of N-methyl pyrrolidine (NMP) and methanol used in the final deprotection step, helped to ensure formation of the desired polymorph. The nine-step discovery synthesis (3% overall yield) is also presented.


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