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Synfacts 2012; 8(5): 0467
DOI: 10.1055/s-0031-1290833
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of PF-3635659

Contributor(s):
Philip Kocienski
Dillon BR, * Roberts DF, * Entwistle DA, Glossop PA, Knight CJ, Laity DA, James K, Praquin CF, Strang RS, Watson CA. L. Pfizer Global Research and Development, Sandwich, UK
Development of a Scalable Synthesis of a Geminal Dimethyl Tertiary Amine as an Inhaled Muscarinic Antagonist for the Treatment of COPD.

Org. Process Res. Dev. 2012;
16: 195-203
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Further Information

Publication History

Publication Date:
18 April 2012 (online)

 
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Key words

PF-3635659 - muscarinic M3 antagonists - Bouveault reaction - gem-dimethylation - zirconium tetrachloride

Significance

Chronic obstructive pulmonary disease (COPD) is projected to become the third leading cause of death worldwide by 2020. PF-3635659 is a once-daily, inhaled muscarinic M3 antagonist that has entered phase II clinical trials for the treatment of COPD. The synthesis depicted delivered 2.6 kg of the hydrochloride salt and benefited from crystalline intermediates at every stage.


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Comment

A noteworthy feature of the synthesis is the reaction of amide F with MeMgBr in the presence of ZrCl4 (a variant of the classical Bouveault reaction) to give the sterically encumbered gem-dimethyl amine G in 74% yield on an 8.2 mol scale. Late-stage demethylation of the phenol methyl ether G using methionine in methanesulfonic acid avoided the genetic toxicity problems of the more commonly used boron tribromide.


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