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.

Optimization of Drug-Like Properties of Nonsteroidal Glucocorticoid Mimetics and Identification of a Clinical Candidate

“…A highly optimized, large-scale enantiopure synthesis of (R)-39 was published recently. 23 The pure enantiomers showed an approximately 2-fold improved potency against GR compared to the racemic mixtures as expected ( Table 5). The maximum transrepression efficacy remained at 87% and 88%, respectively, which translated into a desirable dissociation profile with maximum effects at 2 μM of 27% and 33% for the MMTV reporter gene assay (vs dexamethasone at 100%) and 44% and 39% for osteocalcin production (vs dexamethasone at 100%), respectively.…”

Electronically Activated Organoboron Catalysts for Enantioselective Propargyl Addition to Trifluoromethyl Ketones

“…[11e,12] Towards this end, Fandrick et al have reported what is, as far as we know, the only available method for catalytic enantioselective propargyl group addition to trifluoromethyl ketones. [12] Homopropargyl alcohol 4 was synthesized by reaction of ketone 1 with silyl-protected propargyl-B(pin) compound 2 [13,14] promoted by a catalyst generated in situ from 27 mol % N - iso -propyl-L-proline ( 3 ) and 25 mol % Et 2 Zn (Scheme 2a).…”

“…as well. To obtain the enantiomer for synthesis of the biologically active enantiomer of BI 653048, [11e,12] we used the aminophenol ligand derived from D-valine and obtained ent - 6 in nearly the same yield and e.r. (Scheme 3).…”

Synthesis of two potent glucocorticoid receptor agonists labeled with carbon‐14 and stable isotopes

“…A second synthesis was devised to furnish [ 14 C]‐( 2 ) in five steps with a specific activity of 58 mCi/mmol and a radiochemical purity of 99.9% using carbon‐14 labeled carbon dioxide (Scheme ). The key intermediate [ 14 C]‐( 15 ) containing an N ‐(4‐methoxyphenyl)ethyl amide was first synthesized from enolization of trifluoromethylketone ( 12 ) followed by bromine–magnesium exchange, and then electrophile trapping reaction with [ 14 C]‐carbon dioxide to [ 14 C]‐( 13 ) was accomplished in 71% radiochemical yield . The acid [ 14 C]‐( 13 ) was then converted to the acyl chloride using thionyl chloride and reacted with ( S )‐1‐(4‐methoxyphenyl)ethylamine ( 14 ) to give [ 14 C]‐( 15 ) in 95% radiochemical yield.…”