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Preparation method of articaine hydrochloride

A technology of articaine hydrochloride and concentrated hydrochloric acid, applied in the field of preparation of articaine hydrochloride, can solve the problems of insufficient product purity and many impurities, and achieve the effects of high product yield, reduction of industrial pollution and simplified operation

Active Publication Date: 2012-01-18
蚌埠丰原涂山制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are more impurities in the product prepared by this method, which may be due to an amido exchange reaction on the methyl ester group, resulting in insufficient product purity.

Method used

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  • Preparation method of articaine hydrochloride
  • Preparation method of articaine hydrochloride
  • Preparation method of articaine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] The preparation of embodiment 1 articaine hydrochloride

[0019] 1. Preparation of intermediate compound B

[0020] synthetic route:

[0021]

[0022] Add 12.5L of a mixed solution of sodium methoxide and methanol (prepared from 1kg of sodium metal) into the reaction kettle, control the temperature at 4°C and stir, then add 3.3L of methyl thioglycolate and 3.2L of 2-methacrylonitrile dropwise in sequence. After the dropwise addition, it was naturally raised to room temperature and reacted for 48 hours to obtain an orange-red liquid.

[0023] TLC inspection: silica gel G-254 plate, developer ethyl acetate / petroleum ether=1 / 1, observed under ultraviolet light.

[0024] After cooling to 4°C, concentrated hydrochloric acid was added dropwise to the reaction mixture to adjust the pH to 7 (about 2.8 L) while stirring, and 5.5 L of 30% hydrogen peroxide was added dropwise while stirring. After the addition was completed, the reaction mixture was naturally raised to room t...

Embodiment 2

[0052] Example 2 Large-scale production of articaine hydrochloride crude product

[0053] Put n-propylamine and 1 / 3 dimethyl sulfoxide into the hydrogenation reaction kettle, dissolve the intermediate compound C in the remaining dimethyl sulfoxide, and then add the mixture into the autoclave. Add the solution of intermediate compound 3 dropwise under stirring at 0-5°C. After the dropwise addition is complete, keep stirring at natural temperature for 22±2 hours, and control the end point of the reaction with a thin layer. Add ice-purified water, separate and extract with ethyl acetate, wash with saturated brine, and collect the organic phase. After the organic phase was dried with anhydrous sodium sulfate for 10 hours, the sodium sulfate was filtered off and the organic phase was collected. The organic phase was concentrated in ethyl acetate at 60-70°C under vacuum. After concentration, cool, add acetone to dissolve the oil, add concentrated hydrochloric acid dropwise, and ad...

Embodiment 3

[0057] Example 3 Refined large-scale production of articaine hydrochloride

[0058] Put the crude articaine hydrochloride and absolute ethanol into the dissolving pot, heat and dissolve at 65-75°C, add medicinal charcoal after the dissolution is complete, keep warm for 30 minutes for decolorization, and filter into the crystallization tank. Cool to 0-10°C, crystallize for 4 hours and discharge. Centrifugal filtration, drying, packaging. The feed liquid is filtered by a centrifuge, and the wet product is put into a drum oven, dried at 60-70°C for 10 hours, and packaged. (Table 2)

[0059] Table 2 The refinement and inspection of articaine hydrochloride crude product

[0060]

[0061]

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Abstract

The invention provides a preparation method of articaine hydrochloride. The preparation method comprises the following steps of: reacting methyl mercaptoacetate with 2-metyl acrylonitrile used as starting raw materials in a mixed solution of sodium methoxide and methanol, after the reaction is finished, adjusting the pH value to 7 with concentrated hydrochloric acid, dropwise adding hydrogen peroxide, then dropwise adding concentrated hydrochloric acid to the reaction system, and concentrating under reduced pressure to obtain an intermediate compound B; dissolving the compound B in dichloromethane containing pyridine, dropwise adding alpha-chloropropionyl chloride, washing the reaction product, drying and concentrating to obtain an intermediate compound C; and dissolving the compound C with dimethyl sulfoxide, dropwise adding to a dimethyl sulfoxide solution containing n-propylamine, reacting at room temperature, mixing the product with ice water, extracting with ethyl acetate, drying, concentrating to obtain an oil product, dissolving with acetone, adjusting the pH value to 5-6 with concentrated hydrochloric acid, crystallizing, filtering and drying to obtain a crude product of the articaine hydrochloride. The method has the advantages that the operation is easy, the separation and purification are convenient, the product yield is high, the product purity is more than 99%, the industrial pollution is low, and the method is suitable for mass production.

Description

technical field [0001] The present invention relates to the method of compound, specifically, relate to a kind of preparation method of articaine hydrochloride. Background technique [0002] Local anesthetics are a class of drugs widely used in surgical clinics. Although there are many kinds of local anesthetics available in clinical practice, with the continuous improvement of people's health needs and quality of life, higher requirements are put forward for the use of local anesthetics, which have good curative effect, low side effects and safe use. It is convenient and can adapt to the needs of different parts and different surgical anesthesia. [0003] Oral Special Local Injection Anesthetic Compound Articaine Hydrochloride Injection is the only oral special local anesthetic currently available in the domestic market. Articaine and lidocaine belong to the same amide class of local injection anesthetics. Compared with other local anesthetics, the main characteristics o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38
Inventor 马其胜朱学娟李保琴孙鹏
Owner 蚌埠丰原涂山制药有限公司
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