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Trimetazidine hydrochloride intermediate preparation method

A technology for trimetazidine hydrochloride and an intermediate, which is applied in the field of chemical synthesis, can solve the problems of being unsuitable for industrialized production, poor production and operation safety, high environmental pressure, etc., and achieves a technology that is beneficial to industrialized reactions, has low toxicity, and reduces three wastes. The effect of emissions

Active Publication Date: 2017-11-24
JIANGSU TOHOPE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Although the yield of this process route is higher and the product purity obtained is better, it uses highly toxic reagent dimethyl sulfate in the alkylation reaction, and dimethyl sulfate not only has strong irritation, but also has The strong carcinogenic effect makes the safety of production operation very poor, and the pressure on the environment is also great
In addition, the highly irritating phosphorus oxychloride formylation reagent and the dimethylformamide reagent that is difficult to remove in the post-treatment process are used in the formylation reaction, which makes the production operation more difficult. In view of the above factors, this route is not suitable for industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Add 250ml of toluene, (27.2g, 0.15mol) 1,2,3-trichlorobenzene (II) and 1.0g of cuprous iodide into a 500ml reaction bottle, stir until the mixture is uniform, then start to add the (36.7 g, 0.68mol) methanol solution of sodium methoxide. After the dropwise addition, the temperature was raised to reflux, and the reflux reaction was maintained for 5 hours. layer (including intermediate (Ⅲ)) to be reacted in the next step.

[0034] Put the organic layer containing the intermediate (Ⅲ) obtained above into a 500ml reaction flask, add (13.5g, 0.23mol) anhydrous magnesium chloride, add 35.4g paraformaldehyde in batches, start to drop after the addition (38.6g, 0.28mol) potassium carbonate, heated to reflux after the dropwise addition, and reacted for 5 hours. After the reaction, the reaction solution was cooled to room temperature, and then the reaction solution was slowly added dropwise to an appropriate amount of water, and kept stirring for 30 minutes. Separate the layers,...

Embodiment 2

[0036] Add 250ml of toluene, (27.2g, 0.15mol) 1,2,3-trichlorobenzene (II) and 0.5g of cuprous iodide into a 500ml reaction flask, stir until evenly mixed, then start to add dropwise the containing (40.5 g, 0.75mol) methanol solution of sodium methoxide. After the dropwise addition, the temperature was raised to reflux, and the reflux reaction was maintained for 5 hours. After the reaction, the reaction solution was cooled to room temperature, 250ml of water was added, stirred for 30 minutes, and the organic mixture was collected. layer (including intermediate (Ⅲ)) to be reacted in the next step.

[0037] Put the organic layer containing the intermediate (Ⅲ) obtained above into a 500ml reaction flask, add (13.5g, 0.23mol) anhydrous magnesium chloride, add 35.4g paraformaldehyde in batches, start to drop after the addition (38.6g, 0.28mol) potassium carbonate, heated to reflux after the dropwise addition, reacted for 45 hours, cooled the reaction solution to room temperature aft...

Embodiment 3

[0039] Add 250ml of toluene, (27.2g, 0.15mol) 1,2,3-trichlorobenzene (II) and 1.5g of cuprous iodide into a 500ml reaction bottle, stir until evenly mixed, then start to add dropwise the containing (40.5 g, 0.75mol) methanol solution of sodium methoxide, after the dropwise addition, start to heat up to reflux, keep the reflux reaction for 3~6 hours, after the reaction, cool the reaction solution to room temperature, add 250ml of water, stir for 30 minutes, let it stand for stratification, Collect the organic layer (including intermediate (Ⅲ)) for the next step reaction.

[0040] Put the above-obtained organic layer containing intermediate (Ⅲ) in a 500ml reaction flask, add (17.9g, 0.30mol) anhydrous magnesium chloride, add 40.8g paraformaldehyde in batches, and start adding dropwise (62.2g, 0.45mol) of potassium carbonate, heated to reflux after the dropwise addition, reacted for 5 hours, cooled the reaction solution to room temperature after the reaction, then slowly added th...

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Abstract

The invention discloses a trimetazidine hydrochloride intermediate preparation method. The method takes 1,2,3-trichlorobenzene (II) as a starting raw material; a nucleophilic substitution reaction is performed under catalysis of a catalyst in a methanol solution of sodium methylate for obtaining an intermediate (III); and then a Duff reaction is performed on the intermediate (III), and finally an intermediate (I) is obtained. The solvent used in the method provided by the invention has low toxicity, and can be recycled and reused, so that the three-waste (waste gas, waste water and industrial residue) emission is reduced. The method simplifies the operation steps, reduces the production cost and is more beneficial to industrial reactions. The post-treatment process of the method is simpler, so that on the basis of increasing impurity removing efficiency, the complexity of the technological process is reduced further.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation method of trimetazidine hydrochloride intermediate 2,3,4-trimethoxybenzaldehyde. Background technique [0002] Trimetazidine hydrochloride, CAS registration number: 13171-25-0, chemical name 1-[(2,3,4-trimethoxyphenyl)methyl]-piperazine hydrochloride, chemical structure is as follows: [0003] . [0004] Trimetazidine hydrochloride is an anti-angina pectoris drug successfully developed by the French company Sevier. It can promote myocardial metabolism and myocardial energy production, and at the same time reduce myocardial oxygen consumption, thereby improving the balance between supply and demand of myocardial oxygen, and can also increase the risk of coronary heart disease. Arterial blood flow reserve, delay exercise-induced myocardial ischemia, and significantly reduce the frequency of angina pectoris. [0005] CN102850296B reacts 2,3,4-trimethoxybenzaldehyd...

Claims

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Application Information

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IPC IPC(8): C07C47/575C07C45/00
CPCC07C41/16C07C45/00C07C47/575C07C43/2055
Inventor 陆惠刚龚利锋顾晔袁跃华邹振荣
Owner JIANGSU TOHOPE PHARMA
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