A Scalable Synthesis of CE-157119 HCl Salt, an SRI/5-HT_2A Antagonist

Abstract

A scalable synthesis of CE-157119 HCl salt (1), an SRI/5-HT 2A antagonist, was developed via the regioselective S N Ar etherification between a phenol and an N-methylamide. This early development route shortened the original 5-step synthesis to three steps, eliminated all chromatography and increased the overall yield from 15% to 34%. The process was implemented for API manufacture from 100-g scale to multikilogram scale.

Survey of Solvent Usage in Papers Published inOrganic Process Research&Development1997–2012

“…An example of replacing DMF with 2-MeTHF in an S N Ar reaction has been published by Pfizer. 27 In the original medicinal chemistry synthesis, aryl fluoride 7 underwent reaction with phenol 9 using potassium carbonate as base and DMF as solvent at 100 °C. The reaction produced a 4:1 mixture of the desired bis aryl ether 10 and its regioisomer 12 (Scheme 3).…”

Amine-boranes as Dual-Purpose Reagents for Direct Amidation of Carboxylic Acids

“…Borane complexes of other gaseous amines, methylamine ( 1b ) and dimethylamine ( 1c ), with acids 2a , 2b , 2c , and 2f (4-chloro-2,5-difluorobenzoic acid), provided the corresponding 2°- ( 3ba , 3bb , 3bc , and 3bf , respectively) and 3°- ( 3ca , 3cb , and 3cc , respectively) amides in 92–99% yields. Amide 3bf , prepared from 1b and 4-chloro-2,5-difluorobenzoic acid ( 2f ), is a critical pharmaceutical intermediate for the production of CE-157119 HCl salt.…”

“…Borane complexes of other gaseous amines, methylamine (1b) and dimethylamine (1c), with acids 2a, 2b, 2c, and 2f (4-chloro-2,5-difluorobenzoic acid), provided the corresponding 2°-(3ba, 3bb, 3bc, and 3bf, respectively) and 3°-(3ca, 3cb, and 3cc, respectively) amides in 92−99% yields. Amide 3bf, prepared from 1b and 4-chloro-2,5difluorobenzoic acid (2f), is a critical pharmaceutical intermediate 32 for the production of CE-157119 HCl salt. Amide products containing a wide range of N-substitutions were obtained in 53−91% yield from either 2a or 2b, demonstrating the reaction's compatibility with aliphatic 1°amines with 1°-(3da), 2°-(3ia), or 3°-(3ea, 3eb, 3ha) alkyl substituents, as well as acyclic (3fa) and cyclic (3ga) 2°amines.…”

A generally applicable quantitative reactivity model for nucleophilic aromatic substitution built from simple descriptors

“…As a test of the ESP/LUMO model's potential utility in realworld synthetic planning, we sought to validate its predictions against SNAr reactions used to prepare clinical candidate active pharmaceutical ingredients (APIs). These include recent reports on branebrutinib, 127 an EGFR T790 M inhibitor, 128 a Nav1.7 inhibitor, 129 a tyrosine kinase inhibitor, 130 an SRI/5-HT2A antagonist, 131 an RoRγ inverse agonist, 132 and merestinib 133 (Fig. 12).…”

“…In the first case, synthesis of the target SRI/5-HT2A antagonist requires a site selective SNAr to install an aryl ether ortho to a carbonyl functionality. 131 This was initially performed using an aldehyde moiety; however, the relatively poor site selectivity meant column chromatography was required to purify the intermediate. Further process developments identified an N-methylamide as a more selective alternative that retained key for progressing to the target API.…”