Gergely Heja

Chemical development of the vasopressin receptor 2 antagonist SR-121463

A facile convergent total synthesis of the selective, potent, and orally active V2 non-peptide 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 NaBH4 in the presence of CCl3COOH. 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.

Ring transformation of 1-[(1,2,4-oxadiazol-3-yl)methyl]isoquinolines into 2-acylaminopyrazolo[5,1-a]isoquinolines

Selective reduction of 1-[(1,2,4-oxadiazol-3-yl)methyl]-3,4-dihydroisoquinolines (8) gives the tetrahydro derivatives (12) which readily isomerize to 2-acylaminopyrazolo[5,1-a]isoquinolines (13). Compounds (13) were also obtained by reaction of the isoquinolinylacetamide oxime (11) with esters (6). A comparision of ring transformations in the series of compounds (8) and (12) indicated that both followed the same mechanism. This provided further support to the proposed1a extension of the Type-2 Boulton–Katritzky scheme.