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Novel method for preparing bromhexine hydrochloride

A technology of bromhexine hydrochloride and its production method, which is applied in the preparation of amino compounds, chemical instruments and methods, and the preparation of organic compounds, and can solve the problems of difficult refining and removal of impurities, corrosion of workshop equipment, and low overall yield, and achieve technological The effect of simple and feasible operation, short synthesis steps and simple process operation

Inactive Publication Date: 2015-03-25
NINGBO TEAM PHARMA
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  • Claims
  • Application Information

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Problems solved by technology

This route is ingeniously designed, and does not require harsh equipment and reaction conditions in large-scale production. Compared with the above three routes, this method has certain advantages; but according to the results of our research on this route, this route has the following three weaknesses: 1. 1. The extensive use of thionyl chloride is more serious to the corrosion of workshop equipment; 2. When 2-amino-3,5-dibromobenzyl alcohol is chlorinated, it is found that the bromine at the 3 and 5 positions is replaced by chlorine, resulting in the final product A impurity that is difficult to be purified and removed appears in the product; 3. The total yield of this route method is not high, and the reaction is uneconomical

Method used

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  • Novel method for preparing bromhexine hydrochloride
  • Novel method for preparing bromhexine hydrochloride
  • Novel method for preparing bromhexine hydrochloride

Examples

Experimental program
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Effect test

preparation example Construction

[0037] (1) Preparation of Schiff base

[0038]

Embodiment 1

[0040] 83.7g of 2-amino-3,5-dibromobenzaldehyde, 59.5g of cyclohexylamine, and 600mL of dichloromethane were heated to dissolve, 1.5g of formic acid was added, refluxed for 16h, TLC showed that the reaction was complete, the solvent was evaporated under reduced pressure, and Methanol 160mL, stirred at room temperature for 30min, solid precipitated, placed in refrigerator for 30min, filtered, washed with cold methanol (30mL×2), dried at 65°C under normal pressure to obtain 100.5g, molar yield: 91.2%.

Embodiment 2

[0042] 83.7g of 2-amino-3,5-dibromobenzaldehyde, 59.5g of cyclohexylamine, and 600mL of toluene, heated to reflux and separated water for 24h, TLC showed that the reaction was complete, evaporated the solvent under reduced pressure, added 160mL of methanol, filtered, and stirred at room temperature for 30min , precipitated solid, placed in the refrigerator for 30min, filtered, washed with cold methanol (30mL×2), dried at 65°C under normal pressure to obtain 100.5g, molar yield: 91.2%.

[0043] (2) Preparation of secondary amine

[0044]

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Abstract

The invention provides a novel method for preparing bromhexine hydrochloride. The method is characterized by comprising the following steps of reacting 2-amino-3,5-dibromobenzyl alcohol as a starting raw material and cyclohexylamine to obtain 2-amino-3,5-dibromo-N-cyclohexylbenzimide (referred to as Schiff base); reacting the Schiff base and a reducing agent to obtain 2-amino-3,5-dibromo-N-cyclohexyl-benzylamine (referred to as secondary amine); and reacting the secondary amine and a methylating reagent to obtain bromhexine base and then reacting the bromhexine base and hydrochloric acid to obtain bromhexine hydrochloride. The starting raw material used in the method is inexpensive and easily available, the process route is completely original, the steps are shorter, an intermediate has stable performance, and the bromhexine hydrochloride has the advantages of controllable quality, high yield and good purity.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a new preparation method of bromhexine hydrochloride. Background technique [0002] Bromhexine hydrochloride (English name: Bromhexine Hydrochloride, chemical name: N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzylamine hydrochloride) was first used as an Indian folk expectorant and cough medicine. The active ingredient of mouth flower. It was first synthesized by Keck in 1963, developed by Boehringer Inger Company and launched in 1965, and has been clinically used in Germany, Italy, Britain, France and other countries. It was produced in my country in 1973, and its quality standards were recorded in the Chinese Pharmacopoeia. [0003] Bromhexine hydrochloride is a derivative of Vasicine, a white or off-white crystalline powder, odorless, tasteless, slightly soluble in ethanol and chloroform, very slightly soluble in water, and its chemical structure is : [0004]...

Claims

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Application Information

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IPC IPC(8): C07C211/52C07C209/22C07C209/00
Inventor 黄道飞费志刚吕刚徐骥
Owner NINGBO TEAM PHARMA
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