Conivaptan syntheses

As Of 2009, conivaptan HCl (1) is one of three vasopressin receptor antagonists approved for use in the treatment of hyponatremia worldwide. The U.S. approval of 1 was preceded by the 2006 approval of mozavaptan hydrochloride (2) in Japan. In 2009, tolvaptan (3) joined 1 as an FDA-approved agent for the treatment of hyponatremia. In this chapter, the pharmacological profile and synthesis of conivaptan hydrochloride (1) is examined in detail. 

In 2005, the Yamanouchi process group (postacquisition by Astellas) reported further refinements of their initial synthesis of conivaptan HCl (1), leading to a process for the multikilogram synthesis of l.34 Key features of this second-generation process route included (1) improved overall yield, (2) increased synthetic convergence, (3) elimination of the use of chlorinated solvents, and (4) elimination of the Raney nickel hydrogenation. 

Initial efforts to prepare benzoic acid 28 from methyl or ethyl 4-aminobenzoate and biphenyl-2-carboxylic acid (27) afforded poor yields of 28 (48% and 7%, respectively). However, acylation of 4-aminobenzoic acid with biphenyl-2-carbonyl chloride was found to provide 28 in excellent yield (95%) when DMAP was employed as a base. Selective acylation of the anilinic nitrogen of 26 with benzoic acid 28 was accomplished in analogy with the first-generation process synthesis by conversion of 28 to the corresponding acid chloride (SOCl2, CH3CN) followed by acylation of 26 in acetonitrile. Subsequent addition of ethanolic hydrogen chloride to the reaction mixture resulted in the precipitation of conivaptan HCl (1), which was isolated in 90% yield. 

Through their refinements to the synthesis of 1, the Astellas process group ultimately developed a multikilogram-scale process for the production of 1, which both decreased the cost and increased the safety of the synthesis relative to earlier discovery and process routes.34 The resulting process additionally provided conivaptan HCl (1) in 56% overall yield from cyanobenzazepinone 19, representing a four-fold increase in yield relative to the first-generation process synthesis and sixfold increase in yield relative to the initial discovery route. 

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See also in sourсe #XX -- [ , , , , , ]

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