Synthesis production method of bromhexini hydrochloride

A technology of bromhexine hydrochloride and production method, which is applied in the field of drug synthesis, can solve the problems of unstable performance of intermediates, rare starting materials, and low product yield, and achieve easy control, easy availability of starting materials, and product yield. high rate effect

Inactive Publication Date: 2015-05-13
KAMP PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The traditional synthesis process of bromhexine hydrochloride is complicated, the starting materials are rare, the performance of intermediates is unstable, the production cost is high, the product yield is low, the purity is poor, and the environmental pollution is serious

Method used

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  • Synthesis production method of bromhexini hydrochloride
  • Synthesis production method of bromhexini hydrochloride
  • Synthesis production method of bromhexini hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add 240g of water and 100g of 30% hydrochloric acid into the four-necked reaction flask, cool to below 0-5°C,

[0029] Add 160 g of bromine dropwise at 0-5°C (1 hour to complete the drop), after the drop is complete, stir and keep warm for 30 minutes to obtain hypobromous acid for later use. in another Add 440g of water into the reaction bottle, start stirring, and drop into methyl anthranilate 60 g, after cooling to 0--5°C. Slowly add hypobromous acid dropwise, control the temperature below 10°C, drop it in about 2 hours, continue to keep warm and stir for 1 hour, add 3000g of water, stir for 30 minutes, discharge the material and suction filter, rinse the filter cake with a large amount of drinking water, To neutrality, discharge and dry. 118g of the product is obtained. It is off-white or light yellow powder, with a melting point of 80~87°C. See figure 2 .

[0030]

[0031] Embodiment 2: the preparation of reduction

Embodiment 2

[0032] Put 200g of ethanol and 50g of calcium chloride into the reaction bottle under stirring, and stir until completely dissolved. Put 200g of ethanol into another reaction bottle, add 100g of bromide, 35g of potassium borohydride, stir at room temperature for 30 minutes, and start to add chlorine Calcium chloride ethanol solution, control the reaction temperature at 40±2°C, drop it after 2 hours, keep it warm for 2 hours. Cool down to 25°C, control the temperature below 25°C, slowly add 200 kg of 15% hydrochloric acid, adjust the pH value to 1-2, stir for 30 minutes to maintain the pH value, cool, filter with suction, and rinse the filter cake with drinking water until Neutral, tumble dry. The reduced product was 89g, white or light yellow powder, with a melting point of 135~143°C. See image 3 .

[0033]

[0034] Embodiment 3: Preparation of bromhexine hydrochloride crude product (condensation, salt formation)

Embodiment 3

[0035] Put 89g of reducing substance and 135.g of N-methylcyclohexylamine into the reaction flask in sequence, and start stirring for 30 minutes. The temperature is raised to reflux, and after reflux occurs, the water is separated by distillation until the water separation is completed. Continue to keep the reflux reaction for 2 hours, slowly raise the temperature to 170° C., and cool naturally. The temperature was lowered to 50°C, and 100 g of ethanol was sucked in. Then add 160 g of 15% hydrochloric acid until the pH reaches 1-2, and keep the pH constant for 30 minutes. Blowing and suction filtration, the filter cake was washed with 40 g of ethanol, drained, and dried. 100 g of crude bromhexine hydrochloride was obtained, with a melting point of 235-243°C. See Figure 4 .

[0036]

[0037] Embodiment 4: the refining of bromhexine hydrochloride

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Abstract

The present invention discloses synthetic production method of bromhexini hydrochloride. According to the method, methyl anthranilate is adopted as a starting raw material and is subjected to a bromine and hydrochloric acid bromination reaction to synthesize methyl 2-amino-3,5-dibromobenzoate, potassium borohydride and ethanol are adopted as raw materials to carry out a reduction reaction to synthesize 3,5-dibromo anthranilic alcohol, the 3,5-dibromo anthranilic alcohol and N-methyl cyclohexylamine are condensation to form bromhexine, hydrochloric acid is added to form a salt, a bromhexine hydrochloride crude product is synthesized, and re-crystallization with ethanol is performed to obtain the bromhexini hydrochloride. The method of the present invention has characteristics of short synthesis route, simple operation, easily available starting raw material, stable intermediate performance, high product yield and low production cost, and is suitable for industrial scale production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis and production method of bromhexine hydrochloride. Background technique [0002] Bromhexine hydrochloride alias: bromhexine, Bixiaotan, Bisouping, chemical name: N-(2-amino-3,5-dibromobenzyl)-N-cyclohexylmethylamine hydrochloride, English name Bromhexini Hydrochloridum N-(2-Amino-3,5-dibrombenzyl)-N-cyolohexylmethylamin-ehydrochloride. Molecular formula: C 14 h 20 Br 2 N 2 HCl, molecular weight: 412.60, chemical structural formula: see figure 1 . [0003] Bromhexine hydrochloride is a synthetic drug obtained through structural modification of Vasicine, and its hydrochloride is commonly used. It is white to off-white crystalline powder, easily soluble in methanol and ethanol, slightly soluble in water. It is mainly used for the mucus-producing cells of the trachea and bronchial mucosal glands to make them secrete low-viscosity small molecule mucin, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/53C07C209/18
Inventor 曾培安贺莲吴健民张静刘娟
Owner KAMP PHARMA
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