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Preparation method of mexiletine hydrochloride

A technology of mexiletine hydrochloride and its production method, which is applied in the production field of mexiletine hydrochloride, can solve problems such as the existence of production technology, hidden dangers of industrial production safety, and hidden dangers of safety, and achieve low production costs, significant economic value, and improved quality. Effect

Active Publication Date: 2012-07-25
FOSHAN PRIZEN MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The Catalog of Highly Toxic Chemicals issued by the State Administration of Work Safety, the Ministry of Public Security, the State Environmental Protection Administration, the Ministry of Health, the State Administration of Quality Supervision, Inspection and Quarantine, the Ministry of Railways, the Ministry of Communications, and the Civil Aviation Administration of China Announcement No. 2 in 2003 (2002 Edition) ", sodium dichromate is listed as No. 27 highly toxic chemicals; secondly, there are potential safety hazards in the production process, which is catalyzed by Raney-Ni at 10Kg / cm 2 Hydrogenation under pressure, because Raney-Ni is extremely flammable, brings safety hazards to industrial production

Method used

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  • Preparation method of mexiletine hydrochloride
  • Preparation method of mexiletine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Step 1: Weigh 1.22Kg of 2,6-dimethylphenol, 580g of propylene oxide and 70g of triethylamine, dissolve in 2.5L of methanol, heat to 60℃ in a 5L reactor, and stir for 6 hours to react End. The solvent methanol and triethylamine were distilled off under reduced pressure at 40°C, and the temperature was increased to collect the fraction with a pressure of 2mmHg and 110~112°C to obtain a colorless and transparent liquid, namely 1-(2,6-dimethylphenoxy) Isopropanol was 1.66 Kg, and the yield was 92.2%.

[0030] NMR data: 1 H-NMR (CDCl3, 400MHz): δ (ppm) = 7.02 (d, 2H, J = 7.2 Hz), 6.92-6.95 (m, 1H), 4.18-4.27 (m, 1H), 3.72-3.75 (m, 1H), 3.63-3.67 (m, 1H), 2.63 (d, 1H, J=3.2 Hz), 2.29 (s, 6H), 1.27 (d, 3H, J=6.4 Hz).

[0031] Step 2: Dissolve 1.66Kg of 1-(2,6-dimethylphenoxy)isopropanol and 1.06Kg of methanesulfonyl chloride in 5L of dry dichloromethane, cool to 0℃ in an ice water bath, and at 0℃, Add 1.02Kg of triethylamine to the system dropwise. After the addition is complete...

Embodiment 2

[0045] Step 1: Weigh 1.22Kg of 2,6-dimethylphenol, 726g of propylene oxide and 100g of triethylamine, dissolve it in 2.5L of methanol, heat it to 80°C in a 5L reactor, and stir for 3 hours to react. End. The solvent methanol and triethylamine were distilled off under reduced pressure at 40°C, and the temperature was increased to collect the fraction with a pressure of 2mmHg and 110~112°C to obtain a colorless and transparent liquid, namely 1-(2,6-dimethylphenoxy) The isopropanol was 1.72 Kg, and the yield was 95.6%.

[0046] Step 2: Dissolve 1.72Kg of 1-(2,6-dimethylphenoxy)isopropanol and 1.26Kg of methanesulfonyl chloride in 6L of dry toluene, cool to 0℃ in an ice water bath, and add to the system at 35℃ 1.11Kg of triethylamine was added dropwise to the medium. After the addition, continue to stir for 45 minutes. A large amount of white solid precipitates out. Filter, first wash the filter cake with toluene, combine the filtrate and washing liquid to obtain the organic phase, ...

Embodiment 3

[0059] Step 1: Weigh 1.22Kg of 2,6-dimethylphenol, 878g of propylene oxide and 73.2g of triethylamine, dissolve them in 2.5L of ethanol, heat to 100°C in a 5L reactor, and stir for 2 hours. The reaction is over. The solvent ethanol and triethylamine were distilled off under reduced pressure at 40°C, and the temperature was raised to collect the fraction with a pressure of 2mmHg and 110~112°C to obtain a colorless and transparent liquid, namely 1-(2,6-dimethylphenoxy) Isopropanol was 1.58Kg, and the yield was 87.8%.

[0060] Step 2: 1-(2,6-Dimethylphenoxy)isopropanol 1.58Kg and methanesulfonyl chloride 1.50Kg are dissolved in 6L of dry dichloromethane, cooled to 0℃ in an ice water bath, at 5℃, 1.33Kg of triethylamine was added dropwise to the system. After the addition, the stirring was continued for 60 minutes. A large amount of white solid precipitated out. Filter. First wash the filter cake with dichloromethane. Combine the filtrate and the washing solution to obtain an organi...

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Abstract

The invention provides a preparation method of mexiletine hydrochloride. The preparation method comprises the following steps of: reacting 2,6-xylenol seriving as a raw material with epoxypropane under the action of a catalysis amount of triethylamine for carrying out hydroxypropylation to obtain 1-(2,6-dimethylphenoxy) isopropanol; carrying out sulfonylation with methanesulfonyl chloride or paratoluensulfonyl chloride based on triethylamine as an acid-binding agent to obtain 1-(2,6-dimethylphenoxy) isopropyl methanesulfonate or 1-(2,6-dimethylphenoxy)isopropyl p-toluenesulfonate; then substituting with ammonia to generate 1-(2,6-dimethylphenoxy) isopropamide; and carrying out salification on 1-(2,6-dimethylphenoxy) isopropamide and hydrochloric acid to obtain mexiletine hydrochloride. The preparation method is simple in reaction operation, available in raw material, easy to post-treat and high in yield and is environment-friendly; intermediate products are unnecessary to purify; and the purity of the obtained product mexiletine hydrochloride can reach more than 99.5%, and the yield is more than 45%.

Description

Technical field [0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a production method of mexiletine hydrochloride. Background technique [0002] Mexiletine hydrochloride, English name: Mexiletine Hydrochloride, commonly known as slow heart rhythm, chemical name: 1-(2,6-dimethylphenoxy)-2-propylamine hydrochloride (CAS No: 5370-01-4), Molecular formula: C 11 H 17 NO·HCl, molecular weight: 215.72, structural formula is as follows: [0003] [0004] Mexiletine hydrochloride is an antiarrhythmic drug of the sodium channel blocker class. It is mainly used clinically for acute and chronic ventricular arrhythmias and ventricular arrhythmias that are ineffective to lidocaine treatment. It was developed and marketed by the German Boehringer Ingelheim Pharmaceutical Co., Ltd. In 1968, Boehringer Ingelheim Pharmaceutical Co., Ltd. obtained the patent right for the compound of this product. In 1976, common mexiletine hydrochloride tablets ...

Claims

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Application Information

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IPC IPC(8): C07C217/54C07C213/02
Inventor 胡文辉唐星兰小兵余加进
Owner FOSHAN PRIZEN MEDICAL TECH
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