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Synfacts 2015; 11(1): 0004
DOI: 10.1055/s-0034-1379645
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a Key Building Block for HCV Protease Inhibitor Telaprevir

Contributor(s):
Philip Kocienski
Tanoury GJ, * Chen M, Dong Y, Forslund R, Jurkauskas V, Jones AD, Belmont D. Vertex Pharmaceuticals, Boston, USA
Stereoselective Lithiation and Carboxylation of Boc-Protected Bicyclopyrrolidine: Synthesis of a Key Building Block for HCV Protease Inhibitor Telaprevir.

Org. Process Res. Dev. 2014;
18: 1234-1244
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Publication History

Publication Date:
15 December 2014 (online)

 
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Key words

telaprevir - stereoselective lithiation - carboxylation - classical resolution

Significance

The target molecule H is a fragment of the HCV protease inhibitor telaprevir. A large-scale process for the synthesis of H entails a stereoselective lithiation–carboxylation of A to give rac-C followed by a resolution with (S)-1,2,3,4-tetrahydronaphthalen-1-amine (D). Two hundred kilograms of the target molecule H were manufactured in 27% overall yield by this route.


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Comment

An enantioselective synthesis of C via asymmetric lithiation–carboxylation using a variety of chiral diamine ligands was also investigated. For example the chiral diamine ligand (–)-cytisine developed by O’Brien and co-workers (J. Am. Chem. Soc. 2002, 124, 11870) provided ent-C in 44% yield and er > 99:1 after crystallization. However, this route was not pursued owing to the high cost and uncertain supply of (–)-cytisine.


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