Dihydropyridines → Ethyl orthoformate

Participants

Reaction Steps

The title compound can be obtained starting from stoichiometric amounts of 4-formyl-3-methoxybenzonitrile (Example 10A), 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and allyl 4,4,4-trifluoro-3-oxobutanoate [Moseley, J. D., Tetrahedron Lett. 46, 3179-3181 (2005)]. This entails firstly the dihydropyridine synthesis being carried out in ethanol without addition of additives at the reflux temperature overnight. The initially resulting intermediate allyl 4-(4-cyano-2-methoxyphenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-3-carboxylate can then be dehydrated with acetic acid in a literature-based process [cf. Moseley, J. D., Tetrahedron Lett. 46, 3179-3181 (2005)]. Subsequently, allyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-(trifluoromethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxylate can be obtained by reaction with triethyl orthoformate in analogy to the synthesis of Example 29A. Final allyl ester cleavage using Wilkinson's catalyst [tris(triphenylphosphine)rhodium(I) chloride] in acetic acid affords the title compound [cf. Moseley, J. D., Tetrahedron Lett. 46, 3179-3181 (2005)].

Provenance & Evidence