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

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H₃PO₄ (<b>1·H</b>_<b>3</b><b>PO</b>_<b>4</b>) is presented. A key trifluoromethyl ketone intermediate <b>22</b> containing an <i>N</i>-(4-methoxyphenyl)­ethyl amide was prepared by an enolization/bromine–magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone <b>22</b> 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

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

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H₃PO₄ (<b>1·H</b>_<b>3</b><b>PO</b>_<b>4</b>) is presented. A key trifluoromethyl ketone intermediate <b>22</b> containing an <i>N</i>-(4-methoxyphenyl)­ethyl amide was prepared by an enolization/bromine–magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone <b>22</b> 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