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Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4.
- Source :
-
The Journal of organic chemistry [J Org Chem] 2013 Apr 19; Vol. 78 (8), pp. 3616-35. Date of Electronic Publication: 2013 Apr 01. - Publication Year :
- 2013
-
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.
Details
- Language :
- English
- ISSN :
- 1520-6904
- Volume :
- 78
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of organic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23544738
- Full Text :
- https://doi.org/10.1021/jo400079z