The Improved Synthesis Of Cinepazide Maleate

Cinepazide maleate (1), a calcium antagonist, was developed by Sanofi-aventis Inc.. It was first launched as Vascoril in France in 1974.1 was indicated for the treatment of cardio-cerebro-vascular disease.The pathogenesis of cerebral infarction was summarized in this thesis. Here also introduced the commonly used medicines, and reviewed the progress of calcium antagonist developed in recent years.An improved route for the synthesis of the target was designed and studied in this thesis. After the synthesis of intermediate 3 from pyrrolidine via amidation and substitution, the compound was treated with chloroacetyl chloride and triphenylphosphine in a "one pot" manner to obtain compound 10’-HCl in a stable form. Eventually, it was brought into Wittig reaction with 3,4,5-trimethoxybenzaldehyde using LiOH as a base, and successively treated with maleic acid to give the target in more than 98% as the E-isomer in a large scale. Hence, the target was prepared in a total yield of 59.4% via a 5-step sequence. Moreover, one main metabolite of 1, compound 12 was similarly synthesized from compound 20.Meanwhile, the photolyzed impurity of the target, that is Z-form 11, was also prepared in this thesis for the sake of the convenient quality control. All the structures of the target and main key intermediates were determined by 1H NMR and ESI-MS.