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Synfacts 2013; 9(7): 0689
DOI: 10.1055/s-0033-1338916
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the Glucocorticoid Agonist BI 653048 BS H3PO4

Contributor(s):
Philip Kocienski
Reeves JT * et al. Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA and Boehringer Ingelheim GmbH & Co., Ingelheim am Rhein, Germany
Development of a Large Scale Asymmetric Synthesis of the Glucocorticoid Agonist BI 653048 BS H3PO4 .

J. Org. Chem. 2013;
78: 3616-3635
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Publication History

Publication Date:
17 June 2013 (online)

 
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Key words

BI 65308 BS H3PO4 - glucocorticoid agonist - asymmetric propargylation - organocatalysis - trifluoromethyl ketones

Significance

BI 653048 BS H3PO4 is a glucocorticoid agonist that is a candidate for the treatment of rheumatoid arthritis. In the synthesis depicted, the key step is the zinc-mediated asymmetric propargylation of trifluoromethyl ­ketone A using propargyl boronate C and proline-derived ligand B. The synthesis delivered 94 kg of the API in 17.6% overall yield.


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Comment

A detailed exploration of the mechanism of the zinc-mediated propargylation of the trifluoromethyl ketone I is described in an accompanying paper (J. Org. Chem. 2013, 78, 3592) that includes a zinc-catalyzed variant. In the case of the zinc-catalyzed reaction, water is an essential component. The target molecule is isolated as a 1:1 complex (not a salt) with phosphoric acid.


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