Improved Synthesis of Methyl 2, 6-Dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1, 3, 2-doxaphosphorinan-2-yl)-1, 4-dihydropyridine-3-carboxylate (DHP-218)

抄録

Attempts were made to improve the synthesis of methyl 2, 6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1, 3, 2-dioxaphosphorinan-2-yl)-1, 4-dihydropyridine-3-carboxylate (DHP-218), a new calcium antagonist. 2-Acetonyl-2-oxo-1, 3, 2-dioxaphosphosphorinane (5a), the key intermediate, was prepared from the allenylphosphonate (2) via the enaminophosphonate (4) in a good yield. Subsequently, the Knoevenagel condensation using 5a and the imine (6a) gave the benzylideneacetonylphosphonate (7a) in a good yield without the use of the Horner-Emons reaction. This condensation also gave good results for other acetonylphopshonates. The final step gave DHP-218 in a good yield through a modified Hantzsch synthesis with the use of a dehydrating agent. The overall yield was increased from 1.7% to 22%.