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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: 2014-07-02
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°C in a 5L reactor, stir for 6 hours, and react Finish. Evaporate methanol and triethylamine as solvents under reduced pressure at 40°C, raise the temperature and collect fractions at 110-112°C with a pressure of 2mmHg to obtain a colorless and transparent liquid that is 1-(2,6-dimethylphenoxy) 1.66Kg of isopropanol, the yield is 92.2%.

[0030] NMR data: 1 H-NMR (CDCl3, 400MHz): δ (ppm) = 7.02 (d, 2H, J = 7.2Hz), 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=3.2Hz), 2.29(s, 6H), 1.27(d, 3H, J=6.4Hz).

[0031] Step 2: Dissolve 1.66Kg of 1-(2,6-dimethylphenoxy)isopropanol and 1.06Kg of methanesulfonyl chloride in 5L of dry dichloromethane, cool in an ice-water bath to 0°C, and at 0°C, Add 1.02Kg of triethylamine dropwise in the system, after the dropwise addition, continue to stir for 30 minut...

Embodiment 2

[0045] Step 1: Weigh 1.22Kg of 2,6-dimethylphenol, 726g of propylene oxide and 100g of triethylamine, dissolve in 2.5L of methanol, heat to 80°C in a 5L reactor, stir for 3 hours, and react Finish. Evaporate methanol and triethylamine as solvents under reduced pressure at 40°C, raise the temperature and collect fractions at 110-112°C with a pressure of 2mmHg to obtain a colorless and transparent liquid that is 1-(2,6-dimethylphenoxy) 1.72Kg of isopropanol, the productive rate is 95.6%.

[0046] Step 2: 1.72Kg of 1-(2,6-dimethylphenoxy)isopropanol and 1.26Kg of methanesulfonyl chloride were dissolved in 6L of dry toluene, cooled to 0°C in an ice-water bath, and poured into the system at 35°C Add 1.11Kg of triethylamine dropwise to the mixture, after the dropwise addition, continue to stir for 45 minutes, a large amount of white solids are precipitated, filter, first wash the filter cake with toluene, combine the filtrate and washing liquid to obtain an organic phase, and then ...

Embodiment 3

[0059] Step 1: Weigh 1.22Kg of 2,6-dimethylphenol, 878g of propylene oxide and 73.2g of triethylamine, dissolve in 2.5L of ethanol, heat to 100°C in a 5L reactor, and stir for 2 hours. The reaction is over. Evaporate the solvent ethanol and triethylamine under reduced pressure at 40°C, raise the temperature and collect the distillate with a pressure of 2mmHg and 110-112°C to obtain a colorless and transparent liquid which is 1-(2,6-dimethylphenoxy) 1.58Kg of isopropanol, the productive rate is 87.8%.

[0060] Step 2: Dissolve 1.58Kg of 1-(2,6-dimethylphenoxy)isopropanol and 1.50Kg of methanesulfonyl chloride in 6L of dry dichloromethane, cool in an ice-water bath to 0°C, and at 5°C, Add 1.33Kg of triethylamine dropwise in the system, after the dropwise addition, continue to stir for 60 minutes, a large amount of white solids are separated out, filter, wash the filter cake with dichloromethane earlier, combine the filtrate and washing liquid to obtain the organic phase, and th...

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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, in particular 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 as follows: [0003] [0004] Mexiletine hydrochloride is a sodium channel blocker antiarrhythmic drug, which is mainly used clinically for acute and chronic ventricular arrhythmias and ventricular arrhythmias that are ineffective for lidocaine treatment. It was developed and marketed by Boehringer Ingelheim Pharmaceutical Co., Ltd. in Germany. In 1968, Boehringer Ingelheim Pharmaceutical Co., Ltd. obtained the patent right of the compound of this product. In 1976, mexiletine hydrochloride ordinary tablets and capsul...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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