A Novel Synthesis of 5-HT4 Receptor Intestinal-Restrictive Bivalent Agonist: SIPI11588

Abstract

SIPI11588 is a 5-HT4 receptor agonist with potential bioactivity that significantly enhances whole-gut and colonic transit and defecation. The original linear synthetic route, starting from 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (3), involving seven steps (37.91% overall yield), suffers from poor atom economy, complex purification operations, and critical stability issues, thereby limiting preclinical studies. Herein, we established a convergent approach for the synthesis of SIPI11588 on a large scale. The route begins with 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (3), which underwent an amide condensation to obtain tert-butyl 4-((4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxamido)methyl)piperidine -1-carboxylate (10). Subsequently, a sequence of reactions, including deprotection, nucleophilic substitution, and hydrolysis, are performed in a one-pot process to generate 6-(4-((4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxamido)methyl)piperidin-1-yl)hexanoic acid (1), which was subjected to amide condensation with 1,1'-(butane-1,4-diyl)bis(3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)urea) hydrochloride (2) to achieve the target product SIPI11588 with a total yield of 39.57%. Compared with the original route, the new route shortens the process from 7 steps to 4 steps, simplifies the unit operations from 39 to 19 units, while eliminates complex processes, including frequent extraction, crystallization and column chromatography. This may represent a reliable, chromatography-free, and scalable approach suitable for preclinical development.