Total synthesis of SR 121463 A, a highly potent and selective vasopressin v(2) receptor antagonist

J Org Chem. 2001 Jun 1;66(11):3653-61. doi: 10.1021/jo0004658.

Abstract

SR 121463 A, 1, is a promising nonpeptide prototype for potent and selective antagonism of the vasopressin V(2) receptor subtype and, thus, a candidate for control of the clinically debilitating condition of hyponatremia and its associated syndromes. In the present work, we present a novel and stereoselective synthesis that stems from the preparation of three key intermediates: the substituted benzenesulfonyl chloride 2, the N-protected oxindole 3, and protected dibromide 4. The synthesis of 1 has been achieved in good overall yield, each step proceeding in greater than 80% yield. In addition, intermediate 2 and the syn isomer of 1 were prepared with complete control of stereochemistry. The latter reduction appears to proceed by lithium cation mediated chelation control. Molecular mechanics calculations with the MM3* and MMFF force fields underscore geometric and energetic aspects of the reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidiuretic Hormone Receptor Antagonists*
  • Gas Chromatography-Mass Spectrometry
  • Indicators and Reagents
  • Magnetic Resonance Spectroscopy
  • Morpholines / chemical synthesis*
  • Oxidation-Reduction
  • Spiro Compounds / chemical synthesis*
  • Stereoisomerism

Substances

  • Antidiuretic Hormone Receptor Antagonists
  • Indicators and Reagents
  • Morpholines
  • Spiro Compounds
  • satavaptan