Preparation and application of methoxyethyl 3-nitrophenylidene acetoacetate_Kain Industrial Additive

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. Its characteristic is that it can pass through the blood-brain barrier and effectively act on the 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 an additional 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