Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4

  • J Org Chem. 2013 Apr 19;78(8):3616-35. doi: 10.1021/jo400079z.
Jonathan T Reeves  1 ,  Daniel R Fandrick ,  Zhulin Tan ,  Jinhua J Song ,  Sonia Rodriguez ,  Bo Qu ,  Soojin Kim ,  Oliver Niemeier ,  Zhibin Li ,  Denis Byrne ,  Scot Campbell ,  Ashish Chitroda ,  Phil DeCroos ,  Thomas Fachinger ,  Victor Fuchs ,  Nina C Gonnella ,  Nelu Grinberg ,  Nizar Haddad ,  Burkhard Jäger ,  Heewon Lee ,  Jon C Lorenz ,  Shengli Ma ,  Bikshandarkoil A Narayanan ,  Larry J Nummy ,  Ajith Premasiri ,  Frank Roschangar ,  Max Sarvestani ,  Sherry Shen ,  Earl Spinelli ,  Xiufeng Sun ,  Richard J Varsolona ,  Nathan Yee ,  Michael Brenner ,  Chris H Senanayake
Affiliations
  • 1. Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut, 06877-0368, USA. [email protected]
PMID: 23544738 DOI: 10.1021/jo400079z
Abstract

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.

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