Chemical development of the vasopressin receptor 2 antagonist SR-121463

Abstract

A facile convergent total synthesis of the selective, potent, and orally active V 2 nonpeptide antagonist, SR-121463, was developed by modification of the discovery route. One of the late intermediates, the sulfonyl chloride 1, was synthesized from 3-hydroxybenzoic acid (19) by regioselective sulfonation, O-methylation and amidation in four steps. Another late intermediate, indolin-2-one 2, was prepared from p-phenetidine (8) through the indolin-2-one 16, where the cyclohexanone moiety of 27 was introduced into the active 3-methylene group of 16 by sequential transformation using methyl acrylate and KOtBu. After formation of the cyclic ketal moiety of 13, its ring-opening was achieved by using NaBH 4 in the presence of CCl 3 COOH. The morpholino group in 2 was introduced in accordance with the discovery approach, starting from the 2-hydroxyethoxy derivative 14 through the tosyloxy derivative 15 with morpholine in a one-pot reaction. In this way, the indolin-2-one 2 was synthesized from 8 in six steps. Finally, acylation of the indolin-2-one 2 was achieved with the sulfonyl chloride 1 in the presence of KOtBu in dimethyl sulfoxide (DMSO) at room temperature. This synthetic route proved to be applicable for the large-scale synthesis of SR-121463.

Hydrothermal treatments of two cowpea (Vigna unguiculata L. Walp) varieties: effect of micronisation on physicochemical and structural characteristics

“…As a result, the spirocyclic compound 1 became available through a novel protocol, based on latest radical chemistry of aromatic azides, which, besides providing a strongly enhanced yield of 1 , employs a more convenient azido precursor and also results in highly minimized atom waste. Furthermore, this protocol compares favourably even with other reported non‐radical methods 1b,c,4–6…”

Radical Cyclization Approach to Spirocyclohexadienones

“…Spirocyclohexadienones such as spirooxindole 1 and spirodihydroquinolone 4 are pivotal intermediates in the preparation of biologically active compounds (Figure ). Reduction of spirocyclohexadienone 1 provides spirocyclohexanone 2 , a key intermediate in the synthesis of the potent and selective vasopressin inhibitor SR121463A 3 . Spirodihydroquinolone 4 is a key intermediate in the preparation of aza -galanthamine 5 .…”

Spirocyclic Scaffolds in Medicinal Chemistry

“…The development of this drug candidate discontinued in 2009 after phase III clinical study. Several alternative routes to the spirocyclic 2-oxindole core of this drug candidate were developed, which were primarily based on bis-alkylation followed by intramolecular Claisen condensation. , However, we consider the so-called discovery route to this molecule rather intriguing from the synthetic standpoint. According to this approach, acyl hydrazine 155 underwent a Brunner-type Fischer indole synthesis upon treatment with n -butyllithium and subsequent heating at 180 °C.…”