124445-98-3Relevant articles and documents
Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4
Reeves, Jonathan T.,Fandrick, Daniel R.,Tan, Zhulin,Song, Jinhua J.,Rodriguez, Sonia,Qu, Bo,Kim, Soojin,Niemeier, Oliver,Li, Zhibin,Byrne, Denis,Campbell, Scot,Chitroda, Ashish,Decroos, Phil,Fachinger, Thomas,Fuchs, Victor,Gonnella, Nina C.,Grinberg, Nelu,Haddad, Nizar,Jaeger, Burkhard,Lee, Heewon,Lorenz, Jon C.,Ma, Shengli,Narayanan, Bikshandarkoil A.,Nummy, Larry J.,Premasiri, Ajith,Roschangar, Frank,Sarvestani, Max,Shen, Sherry,Spinelli, Earl,Sun, Xiufeng,Varsolona, Richard J.,Yee, Nathan,Brenner, Michael,Senanayake, Chris H.
, p. 3616 - 3635 (2013/06/04)
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.
