Development of a Large Scale Asymmetric Synthesis of the Glucocorticoid Agonist BI 653048 BS H3PO4

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• 作者：Jonathan T. Reeves ; 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 J盲ger ; 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
• 刊名：The Journal of Organic Chemistry
• 出版年：2013
• 出版时间：April 19, 2013
• 年：2013
• 卷：78
• 期：8
• 页码：3616-3635
• 全文大小：1109K
• 年卷期：v.78,no.8(April 19, 2013)
• ISSN：1520-6904

文摘

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H₃PO₄ (1路H₃PO₄) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine鈥搈agnesium 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.