title: Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4.
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.
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut, 06877-0368, USA. jonathan.reeves@boehringer-ingelheim.com
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Reeves
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Fandrick
authors.forename: Zhulin
authors.initials: Z
authors.lastname: Tan
authors.forename: Jinhua J
authors.initials: JJ
authors.lastname: Song
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Bo
authors.initials: B
authors.lastname: Qu
authors.forename: Soojin
authors.initials: S
authors.lastname: Kim
authors.forename: Oliver
authors.initials: O
authors.lastname: Niemeier
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Li
authors.forename: Denis
authors.initials: D
authors.lastname: Byrne
authors.forename: Scot
authors.initials: S
authors.lastname: Campbell
authors.forename: Ashish
authors.initials: A
authors.lastname: Chitroda
authors.forename: Phil
authors.initials: P
authors.lastname: DeCroos
authors.forename: Thomas
authors.initials: T
authors.lastname: Fachinger
authors.forename: Victor
authors.initials: V
authors.lastname: Fuchs
authors.forename: Nina C
authors.initials: NC
authors.lastname: Gonnella
authors.forename: Nelu
authors.initials: N
authors.lastname: Grinberg
authors.forename: Nizar
authors.initials: N
authors.lastname: Haddad
authors.forename: Burkhard
authors.initials: B
authors.lastname: Jäger
authors.forename: Heewon
authors.initials: H
authors.lastname: Lee
authors.forename: Jon C
authors.initials: JC
authors.lastname: Lorenz
authors.forename: Shengli
authors.initials: S
authors.lastname: Ma
authors.forename: Bikshandarkoil A
authors.initials: BA
authors.lastname: Narayanan
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Nummy
authors.forename: Ajith
authors.initials: A
authors.lastname: Premasiri
authors.forename: Frank
authors.initials: F
authors.lastname: Roschangar
authors.forename: Max
authors.initials: M
authors.lastname: Sarvestani
authors.forename: Sherry
authors.initials: S
authors.lastname: Shen
authors.forename: Earl
authors.initials: E
authors.lastname: Spinelli
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Sun
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Varsolona
authors.forename: Nathan
authors.initials: N
authors.lastname: Yee
authors.forename: Michael
authors.initials: M
authors.lastname: Brenner
authors.forename: Chris H
authors.initials: CH
authors.lastname: Senanayake
mesh_terms: D000577:Amides / Q000737:chemistry*; D001549:Benzamides / Q000737:chemistry*; D005938:Glucocorticoids / Q000819:agonists* / Q000737:chemistry*; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000577:Amides; C582735:BI 653048 BS H3PO4; D001549:Benzamides; D005938:Glucocorticoids; D011725:Pyridines; D011758:Pyrroles