background and overview[1]
methoxyethyl 3-nitrophenylidene acetoacetate is a pharmaceutical intermediate that can be used to prepare nimodipine. nimodipine is a dihydropyridine calcium channel antagonist, which is characterized by its ability to pass through the blood-brain barrier and effectively act on cerebral blood vessels. it is effective in the treatment of cerebral infarction, migraine, stroke, arachnoid hemorrhage and sudden deafness. the therapeutic effect also plays a great role in promoting memory enhancement and treating alzheimer’s disease.
preparation[1]
suspend 200kg of methoxyethyl acetoacetate and 185.1kg of 3-nitrobenzaldehyde in 800l of isopropyl alcohol. then add 5.65kg of p-anisic acid and 5.05kg of 33% dimethylamine in ethanol solution, and heat at about 35°c for about 30 minutes to obtain a solution. the reaction mixture was cooled to 20/25°c, then it was cooled with running water for about 12 hours and with brine at about 0°c for a further 24 hours, then centrifuged and washed with isopropanol. after drying, 327 kg of methoxyethyl 3-nitrophenylidene acetoacetate was obtained in a yield of approximately 91%.
apply[1]
suspend 490kg methoxyethyl 3-nitrophenylidene acetoacetate and 244.4kg 3-aminocrotonic acid isopropyl ester in 1500l isopropyl alcohol, and use 3kg p-anisic acid and 2.5kg 33% dimethyl treatment of amines with ethanol solutions. after heating, a solution was obtained which was refluxed for about 10 hours, after which it was cooled first with water and then in brine at about 0° c. and the resulting precipitate was centrifuged. by recrystallization from isopropanol, 657 kg of nimodipine was obtained in about 94% yield.
references
[1] us6015906 – dimethylamine benzoate or p-anisate catalysed process for the preparation of 4-(nitrophenyl)-dihydropyridines