Chemical development of the vasopressin receptor 2 antagonist SR-121463*
István Hermecz,1, Andrea Sánta-Csutor2, Csaba Gönczi2,
Gergely Héja2, Éva Csikós2, Kálmán
Simon3, Ágota Smelkó-Esek3, and Benjámin Podányi3
1Preclinical Development, 2Synthetic Development, 3Preclinical
Analytical Development Laboratories; Chinoin Pharmaceutical and Chemical
Works Ltd., H-1045 Budapest, Tó u. 1-5, Hungary
Abstract: 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.
*Plenary lecture presented at the Hungarian-German-Italian-Polish
Joint Meeting on Medicinal Chemistry, Budapest, Hungary, 2 6 September
2001. Other presentations are published in this issue, pp.
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