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A kind of preparation method of bromhexine hydrochloride

A technology of bromhexine hydrochloride and bromine, applied in the field of preparation of bromhexine hydrochloride, can solve problems such as complicated post-processing, low API purity, unstable intermediates and the like

Active Publication Date: 2021-10-26
GUANGZHOU YIPINHONG PHARMA +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] In summary, in the above or other preparation routes, there are high cost of raw materials or intermediates, unstable intermediates, harsh reactions, large environmental pollution, cumbersome post-processing, or low purity of the obtained API

Method used

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  • A kind of preparation method of bromhexine hydrochloride
  • A kind of preparation method of bromhexine hydrochloride
  • A kind of preparation method of bromhexine hydrochloride

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preparation example Construction

[0055] The invention provides a kind of preparation method of bromhexine hydrochloride, comprising the following steps:

[0056] (1) carry out bromination reaction after mixing 2-aminobenzoic acid ester compound, bromine, oxidizing agent and mixed solvent, generate 3,5-dibromo-2-aminobenzoic acid ester;

[0057] (2) Mixing the obtained 3,5-dibromo-2-aminobenzoic acid ester, a catalyst, a reducing agent and a solvent to perform a reduction reaction to generate 3,5-dibromo-2-aminobenzyl alcohol;

[0058] (3) carry out condensation reaction after the gained 3,5-dibromo-2-aminobenzyl alcohol, N-methylcyclohexylamine, mixed catalyst and solvent are mixed, generate bromhexine;

[0059] (4) Gained bromhexine and hydrochloric acid are carried out salt-forming reaction in solvent, generate bromhexine hydrochloride.

[0060] The invention mixes 2-aminobenzoic acid ester compounds, bromine, oxidizing agent and mixed solvent to perform bromination reaction to generate 3,5-dibromo-2-amino...

Embodiment 1

[0102] The raw materials in this example are all commercially available.

[0103] Synthesis of methyl 3,5-dibromo-2-aminobenzoate:

[0104] 26.50 kg of dichloromethane, 8.0 kg of purified water, and 3.02 kg of methyl 2-aminobenzoate were successively added into a 100L double-layer glass reactor, and stirred evenly. At room temperature, a solution of bromine (3.83 kg) in dichloromethane (5.3 kg) was slowly added to the reaction solution obtained above. Continue to stir for 10 minutes after the addition is complete, slowly add 2.50 kg of 30% hydrogen peroxide solution to the reaction solution, stir for 6 hours after the reaction is complete, slowly add 3.5 kg of 20% sodium sulfite solution to the reaction solution to quench the reaction, and separate phases , the organic phase was extracted once with 8.0 kg of purified water, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, the organic phase was concentrated under reduced pressure un...

Embodiment 2

[0136] The 3.02kg 2-aminobenzoic acid methyl ester among the embodiment 1 is replaced by 3.3kg 2-aminobenzoic acid ethyl ester, other conditions are exactly the same, finally bromhexine hydrochloride can be successfully prepared, and the yields of each step are equivalent.

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Abstract

The invention belongs to the field of organic synthesis and provides a preparation method of bromhexine hydrochloride. The present invention uses 2-aminobenzoate compounds as raw materials to obtain bromhexine hydrochloride after bromination reaction, reduction reaction, condensation reaction and salt-forming reaction, the synthetic route is short, the cost is low, the intermediate is stable, and it is environmentally friendly Pollution, high purity, high yield, in line with pharmaceutical standards, suitable for industrial expansion of production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a preparation method of bromhexine hydrochloride. Background technique [0002] Bromhexine hydrochloride, its chemical name is: N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzylamine hydrochloride, drug aliases: bromhexyl ammonium, benzyl cyclohexyl ammonium bromide , Bishouping, bromhexine hydrochloride, Bixiaophlegm, Bishuping, Bromhexylamine. This product is white or off-white crystalline powder; odorless and tasteless. This product is slightly soluble in ethanol or chloroform, very slightly soluble in water. This product can directly act on bronchial glands, promote the release of lysosomes of mucus secreting cells, and make the sticky sugar fibers in sputum differentiate and crack; it can also inhibit the synthesis of acid glycoproteins in mucous glands and goblet cells, making them Secrete low-viscosity small molecule glycoproteins, thereby reducing the viscosity...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C211/52C07C209/16C07C209/74C07C229/56C07C227/16C07C215/68C07C213/00
CPCC07C209/16C07C209/74C07C213/00C07C227/16C07C2601/14C07C229/56C07C215/68C07C211/52
Inventor 李捍雄兰小兵晏鑫星
Owner GUANGZHOU YIPINHONG PHARMA
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