Practical and Scalable Method for Manufacturing AZD4604, A Potent and Selective JAK1 Inhibitor

Abstract

The development of a scalable process for the manufacture of a potent and selective JAK1 inhibitor intended for the inhaled treatment of asthma is described. The initial milligram-scale synthetic protocols were unsuitable for larger-scale synthesis, which led to a systematic evaluation of the reaction conditions to identify the optimized reaction conditions for the Suzuki/ Buchwald−Hartwig coupling, deprotection of the tosyl group, chemoselective nitro-reduction, and developing mild conditions for the amide coupling of a sensitive amino acid. This work also highlights mitigating critical issues associated with the synthesis of poorly soluble compounds, slurry-to-slurry metal-catalyzed coupling protocols. The optimized amide coupling conditions using chiral amino acid produced the desired active pharmaceutical ingredient (API) in high overall yield and good high-performance liquid chromatography (HPLC) purity.

Development of a Continuous Process for the Large-Scale Asymmetric Manufacture of (R)-3-Methoxy-2-(4-methylpiperazin-1-yl)propanoic Acid

“…The piperazine ring closure also resulted in partial racemization of methyl ester product 14 . Finally, hydrolysis of the ester 14 using LiOH resulted in complete racemization of the product 4 . During the course of this development, it also became apparent that sourcing of the required starting material 11 would be problematic.…”

“…The initial Campaign 1c manufacturing route to supply up to 1 kg of amino acid 4 in support of preclinical studies is shown in Scheme . − This route started with the cheap and readily available methyl acrylate ( 5 ), which readily underwent bromination to provide intermediate dibromo-ester 6 . This ester was converted to the corresponding methyl ether 7 by reaction with sodium methoxide (NaOMe) in MeOH.…”

“…Despite extensive investigations into the optimization of SFC for this purification, the method was found to suffer from low throughput and high solvent (MeOH) consumption. Also, the resolved amino acid was found to form a stable carbonate salt 10 under the chromatography conditions. − Subsequent treatment of carbonate salt 10 with aqueous hydrochloric acid (HCl) allowed for isolation of the corresponding crystalline hydrated dihydrochloride salt of amino acid 4 (Scheme ). The dihydrochloride salt was successfully used in subsequent amide formation to eventually afford AZD4604.…”

Discovery of the Potent and Selective Inhaled Janus Kinase 1 Inhibitor AZD4604 and Its Preclinical Characterization

“…To enable a rat DPI-PK study, a multigram synthesis route was developed . The obtained crystalline free base of compound 16 was amenable for micronization into a desired particle size (Figure ).…”

“…The chemical synthesis, purification, and crystallization of compounds 9 , 10 , and 16 have been reported previously. ,,,, Briefly, the condensation of 4-aminoindole derivatives 9 or 10 with appropriate 2-substituted 2-(4-methylpiperazin-1-yl)­acetic acids followed by purification by chromatography gave the corresponding racemates of 11 – 16 (Scheme ). Subsequent preparative chiral chromatography provided the separated enantiomers 11 – 16 (eutomers).…”