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Preparation method of Nimodipine

A nimodipine, reaction technology, applied in the field of preparation of nimodipine, can solve the problem of low process yield, achieve high yield, reduce raw material cost, and achieve good quality effects

Inactive Publication Date: 2016-07-06
QINGDAO HUANGDAO HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of the original process is low, and the impurity content of the finished product detected by HPLC is 0.4-1.0%.

Method used

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  • Preparation method of Nimodipine
  • Preparation method of Nimodipine
  • Preparation method of Nimodipine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Put 64kg of isopropanol and 0.4kg of triethylamine into the reaction tank, raise the temperature to 75°C, add 90kg of diketene dropwise for 1 hour, control the temperature at 80±2°C, and then keep the reaction at 90°C for 3 hours. Cool down to 0°C, pass ammonia for 5 hours, the amount of ammonia passed is 18kg, and stand for 3 hours to keep warm for reaction. Add 5.7 kg of anhydrous calcium chloride, stir to dissolve for 30 minutes, and stand still for 3 hours to separate water. Distilled under reduced pressure to obtain 125 kg of colorless oily isopropyl 3-aminocrotonate with a yield of 81.5% and a content of 98.8%.

[0021] Put 52kg of isopropyl 3-aminocrotonate, 100kg of 2-(3-nitrobenzylidene)-2-methoxyethyl acetoacetate and 105kg of methanol into the reaction tank, raise the temperature to 30°C, and keep the temperature for 1 hour. The reaction was carried out under reflux for 1 hour, and the methanol was distilled under reduced pressure until no more distillation ...

Embodiment 2

[0023] Put 65kg of isopropanol and 0.5kg of triethylamine into the reaction tank, raise the temperature to 75°C, add 90kg of diketene dropwise for 2 hours, control the temperature at 80±2°C, and then keep the reaction at 95°C for 3 hours. Cool down to 10°C, pass ammonia for 5 hours, the amount of ammonia passed is 18kg, and stand for 3 hours to keep warm for reaction. Add 4.3 kg of anhydrous magnesium sulfate, stir to dissolve for 30 minutes, and stand still for 3 hours to separate water. Distilled under reduced pressure to obtain 126 kg of colorless oily isopropyl 3-aminocrotonate with a yield of 82.2% and a content of 98.4%.

[0024] Put 56kg of isopropyl 3-aminocrotonate, 100kg of 2-(3-nitrobenzylidene)-2-methoxyethyl acetoacetate and 122kg of ethanol into the reaction tank, raise the temperature to 70°C, and keep the temperature for 1 hour. The reaction was refluxed for 1 hour, and the ethanol was distilled under reduced pressure until no more distillation occurred. Afte...

Embodiment 3

[0026] Put 65kg of isopropanol and 0.6kg of triethylamine into the reaction tank, raise the temperature to 75°C, add 90kg of diketene dropwise for 1.5 hours, control the temperature at 80±2°C, and then keep the reaction at 90°C for 3 hours. Cool down to 5°C, pass ammonia for 5 hours, the amount of ammonia passed is 20kg, and stand for 3 hours to keep warm for reaction. Add 5.0 kg of sodium chloride, stir to dissolve for 30 minutes, and stand still for 3 hours to separate water. Distilled under reduced pressure to obtain 126 kg of colorless oily isopropyl 3-aminocrotonate with a yield of 82.2% and a content of 98.1%.

[0027] Put 58kg of isopropyl 3-aminocrotonate, 100kg of 2-(3-nitrobenzylidene)-2-methoxyethyl acetoacetate and 102kg of isopropanol into the reaction tank, raise the temperature to 50°C and keep it warm for 1 hour , refluxed for 1 hour, and distilled isopropanol under reduced pressure until no longer distilled. After the reaction finishes, 74kg of isopropanol a...

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Abstract

The invention belongs to the pharmaceutical technical field, and more specifically to a preparation method of Nimodipine. The preparation method includes an ammonia ester reaction and a cyclization reaction. In the ammonia ester reaction, after an ammonia-filling reaction ends, firstly an inorganic salt is added to remove water from the ammonia ester reaction, and then isopropyl 3-aminocrotonate is obtained through rectification. The cyclization reaction is carried out on the isopropyl 3-aminocrotonate and 2-(3-nitrobenzylidene)-acetoacetate-2-methoxyethyl ester, and a fatty alcohol is used as a reaction solvent. The preparation method of the Nimodipine has the advantages that the finished product yield is high, the primary yield reaches 85-89%, the quality is good, the solvent can be recycled and reused, and the raw material cost can be greatly reduced. Total impurities detected by HPLC can decrease to 0.1-0.3% from 0.4-1.0% in the original technology.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a preparation method of nimodipine. Background technique [0002] The chemical name of Nimodipine is 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid-2-methoxyethyl -(1-methylethyl) ester, a calcium channel antagonist belonging to the dihydropyridine class, is suitable for improving blood circulation in cerebral vasospasm after subarachnoid hemorrhage of various causes and in the recovery period of acute cerebrovascular disease. The synthetic technique of nimodipine adopts the following steps at present: [0003] A. Urethane reaction: [0004] [0005] B. Cycling reaction [0006] [0007] [0008] Because the urethane reaction generates water in the process of passing through the ammonia, the reaction liquid after the completion of passing through the ammonia in the original process is directly rectified. Due to the existence of w...

Claims

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Application Information

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IPC IPC(8): C07D211/90
Inventor 卢彦敏
Owner QINGDAO HUANGDAO HOSPITAL OF TRADITIONAL CHINESE MEDICINE
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