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Synfacts 2011(12): 1267-1267  
DOI: 10.1055/s-0031-1289315
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of PF-03463275

Contributor(s):Philip Kocienski
M. A. Berliner*, S. P. A. Dubant, T. Makowski, K. Ng, B. Sitter, C. Wager, Y. Zhang
Pfizer Global Research and Development, Groton, USA; Pfizer Global Research and Development, Sandwich, UK
Use of an Iridium-Catalyzed Redox-Neutral Alcohol-Amine Coupling on Kilogram Scale for the Synthesis of a GlyT1 Inhibitor
Org. Process Res. Dev.  2011,  15:  1052-1062  
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Publication History

Publication Date:
18 November 2011 (online)

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Key words

PF-03463274 - glycine transporter type 1 inhibitors - iridium-catalyzed hydrogen borrowing

Significance

PF-03463275 is a glycine transporter type 1 (GlyT1) inhibitor that has potential for the treatment of schizophrenia. The synthesis depicted features the first kilogram-scale application of iridium-catalyzed hydrogen borrowing to achieve the operational equivalent of reductive amination in the union of C and D to give E. The only byproduct of the reaction is water.

Comment

An extensive optimization study achieved a S/C of ≥2000 (i.e. lower than 0.05 mol% of catalyst), but the reaction tended to stall thereby requiring a second charge of catalyst. After this work was complete the authors discovered that water and a tertiary amine are essential for high catalyst activity resulting in high rates and complete conversion on a single charge.

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