2. Academic Validation
  3. Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4

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

Affiliation

  • 1 Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut, 06877-0368, USA. jonathan.reeves@boehringer-ingelheim.com
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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