Large-Scale Asymmetric Synthesis of the 3,6,7,8-Tetrahydrochromeno[7,8-d]imidazole BYK 405879: A Promising Candidate for the Treatment of Acid-Related Diseases

Abstract

A process for the synthesis of the potassium-competitive acid blocker BYK 405879 (8) was established based on the approach used in medicinal chemistry (asymmetric hydrogenation of prochiral ketone 15 and Mitsunobu cyclization of the resulting alcohol 34). Several critical reaction steps were optimized. The synthesis of prochiral ketones was accomplished using ethyl 3-(2-methylphenyl)-3-oxopropanoate instead of 1-[1-(2-methylphenyl)vinyl]pyrrolidine, a reagent that was difficult to prepare and possesses limited shelf life. The catalyst loading of the asymmetric hydrogenation step was reduced significantly from a S/C ratio of 100:1 to a S/C ratio of 2500:1 by benzyl protection of ketone 15. After the Mitsunobu cyclization, the removal of byproduct was easily accomplished through acid-base extraction, and pure BYK 405879 (8) was then obtained by means of crystallization in the presence of succinic acid.

Development of a Pilot-Plant-Scale Synthesis of an Alkylated Dihydrobenzothiadiazole S,S-Dioxide: Incorporation of a Late-Stage Mitsunobu Reaction

“…As mentioned previously, we were encouraged by reports of the successful use of Mitsubobu conditions on preparative scales. – In reviewing these cases, we noted that some of the successful applications involved use in an early-stage reaction of the process where high purity product was not required, was performed on scales that allowed chromatography to be an option, , or upgrade of the crude product was easily achieved by a reslurry . However, there were other examples that used approaches similar to what we were proposing and relied on an acid−base extraction of product away from the Mitsunobu byproduct. ,,,, In our case, we planned to develop a telescoped process that combined the Mitsunobu reaction to generate 10 with N -Boc deprotection of 10 and hoped that at low pH, 11 could be extracted into the aqueous phase, enabling a scaleable method to separate 11 from the triphenylphosphine oxide and hydrazine dicarboxylate byproducts…”

“…In light of the newly issued guidance on acceptable levels of potentially genotoxic impurities (PGI) in API, we reasoned that the Mitsunobu reaction was worth evaluating before a decision was made to forego this transformation for an alkylation strategy. There have been reports on the successful execution of Mitsunobu reactions on scale. − …”

Asymmetric homogeneous hydrogenations at scale

“…The reaction outcome was still susceptible to the exact structure of the substrate; some analogues gave competing reactions. 342,343 Earlier results with ferrocene-based bisphosphines (7) and BINAP (10) systems under hydrogen required protection of the phenolic hydroxy group. 344 Merck has used an asymmetric hydrogen transfer reaction to prepare the phenylethanol derivative 207 (Scheme 74); the asymmetric hydrogenation approach has been discussed (Scheme 68).…”

Tetrahydrochromenoimidazoles as Potassium-Competitive Acid Blockers (P-CABs): Structure−Activity Relationship of Their Antisecretory Properties and Their Affinity toward the hERG Channel

“…This heterocyclic scaffold emerged from the systematic investigation of possible variations of the well-known imidazo[1,2-a]pyridine motif. 5 In comparison to the isomeric imidazo[1,2-a]pyridines 1, represented by 3 (BYK 311319), 5 the respective benzimidazoles 2, represented by 4 (BYK 405879), 14,15 possess a lower pK a value, resulting in a more selective accumulation in the parietal cell and a better safety profile. Enantiopure P-CABs belonging to both structural classes can be prepared in an analogous manner (asymmetric reduction of ketones followed by Mitsunobu cyclization of the resulting diols), and the large scale synthesis of the candidate 4 was based on this synthetic strategy.…”