Step-Economic Synthesis of Tamsulosin Hydrochloride via Continuous Chlorosulfonation and Biocatalytic Transamination

A new process was developed for the synthesis of (R)-tamsulosin in 4 chemical steps from readily available 4-methoxyphenylacetone using continuous chlorosulfonation and biocatalysis. Several conditions were tested for both batch and continuous chlorosulfonation of 4-methoxyphenylacetone. Continuous chlorosulfonation produced a white crystalline solid, while a brown solid or dark oil was consistently obtained when the reaction was performed in batch. Consequently, the sulfonamide intermediate was isolated as a white product in the continuous process, albeit in a slightly lower yield. Immobilized Escherichia coli whole cells overexpressing (R)-selective transaminases from Arthrobacter sp. (ArR-ATA and ArRmut-ATA, natural and engineered, respectively) and Aspergillus terreus (AtR-ATA), along with lyophilized amine transaminase (ATAs), were screened for the key asymmetric synthesis of the chiral amine intermediate. Under optimal conditions, conversions above 90% with >99% enantiomeric excess (ee) were achieved. Furthermore, for process intensification purposes, ATA-412 was covalently immobilized onto surface-activated mesoporous methacrylate beads, achieving quantitative immobilization yields. Immobilization and transamination were scaled up 30-fold, and the synthesized chiral amine intermediate was subjected to N-alkylation without isolation, yielding (R)-tamsulosin hydrochloride. Therefore, after scale-up, this synthesis shows a high potential to replace the current manufacturing process.