CN104402737A

CN104402737A - New method for preparing bromhexine hydrochloride

Info

Publication number: CN104402737A
Application number: CN201410544731.2A
Authority: CN
Inventors: 黄道飞; 费志刚; 徐骥; 崔正华
Original assignee: NINGBO TEAM PHARM Co Ltd
Current assignee: NINGBO TEAM PHARM Co Ltd
Priority date: 2014-10-13
Filing date: 2014-10-13
Publication date: 2015-03-11

Abstract

The invention provides a new method for preparing bromhexine hydrochloride. The method is characterized by including following steps: with 2-amino-3,5-dibromophenylmethanol as a raw material, carrying out a reaction with a bromination reaction to generate 2,4-dibromo-6-bromomethylaniline, carrying out a condensation reaction between the 2,4-dibromo-6-bromomethylaniline and N-methylcyclohexylamine, and carrying out a salification reaction with hydrochloric acid to obtain the bromhexine hydrochloride. The starting raw materials in the method are low in cost and are easy to obtain. The method is simple in operation, is environmental-friendly, is high in yield of a finished product and is high in purity of the finished product.

Description

A kind of novel method preparing bromhexine hydrochloride

Technical field

The invention belongs to medical art, be specifically related to a kind of novel method preparing bromhexine hydrochloride.

Background technology

Bromhexine hydrochloride, another name hydrochloric acid bromine hexylamine, bromhexine, must cloperastine, Broncokin, English Bromhexine Hydrochloride by name, chemistry Bromhexine Hydrochloride by name, chemical structural formula is:

Bromhexine hydrochloride has stronger dissolving to stick phlegm effect, the polysaccharide fiber element in phlegm can be made to decompose, by suppressing goblet cell and mucus body of gland synthesis glycoprotein, the sialic acid in sputum is reduced, reduce phlegm viscosity, be beneficial to expectoration, the clinical patient being applicable to the not easily expectoration of the sticky phlegm such as bronchitis, asthma, pulmonary emphysema.

Although bromhexine hydrochloride is the old medicine of a listing many decades, the synthetic route report about it is a lot, and different operational paths causes quality product uneven, and the danger that most operational path intermediate controls is comparatively large, and environmental pollution is more serious.

In the preparation method of existing document or patent report, the preparation method of bromhexine hydrochloride mainly contains four:

Method one: patent CN10187754A with adjacent nitro bromobenzyl and N-methylcyclohexylamine for starting raw material, reaction generates N-(2-nitrobenzyl)-N-methylcyclohexylamine, under raney ni catalysis, reduction generates N-(2-aminobenzyl)-N-methylcyclohexylamine, react with bromine again and generate bromhexine free alkali, last salify.The adjacent nitro bromobenzyl of this method starting raw material is expensive, and comparatively large to human body pungency, manufacturer is domestic almost not to be had, and not easily buys; Raney's nickel reduction has certain risk aborning, easily catches fire, and causes work safety accident hidden danger; And the bromhexine free alkali purity that obtains of bromination is very low subsequently, and causing bromhexine hydrochloride repeatedly to refine can be qualified, and the reaction formula of this patent route is as follows:

Method two: patent CN103333074A obtains bromhexine free alkali with amino-3, the 5-dibromobenzene methyl alcohol of 2-and N-methylcyclohexylamine in next step legal system of toluylic acid catalysis, and rear and hydrochloric acid salify obtains bromhexine hydrochloride.The method needs to use pyroreaction still (interior temperature needs more than 180 DEG C) in the industrial production, operates more dangerous, and toluylic acid is easy toxogen material processed, is subject to management and control.

Method three: patent DE2456033, reacts through Tosyl chloride catalysis and N-methylcyclohexylamine at-78 DEG C for starting raw material with 2-amino 3,5-dibromobenzene methyl alcohol, with bromhexine hydrochloride obtained after HCl salify.Though this route step is shorter, require very high to production unit, production cost is high, is not suitable for scale operation.

Method four: patent CN102617359A with amino-3, the 5-dibromo benzaldehydes of 2-for starting raw material, through sodium borohydride reduction, amino-3, the 5-dibromobenzene methyl alcohol of obtained 2-, then through sulfur oxychloride chlorination, with N-methylcyclohexylamine condensation, obtain bromhexine hydrochloride with hydrochloric acid salify.This highway route design is ingenious, and without the need to using harsh equipment and reaction conditions in large production, compare above three routes, present method has some superiority; But that studies this route according to us found that, this route has following three weakness: one, a large amount of uses of sulfur oxychloride are to the serious corrosion of workshop appliance; Two, when-3,5-dibromobenzene methyl alcohol chlorination amino to 2-, find that the bromine of 3,5 is replaced by chlorine, cause in whole finished product, occurring the impurity being difficult to refining removing; Three, this route methods total recovery is not high, reacts uneconomical.

Summary of the invention

The object of this invention is to provide a kind of novel method preparing bromhexine hydrochloride, advantage of the present invention: starting raw material is easy to get, operational path shorter (2 step), reaction conditions is gentle, and environmental pollution is low, and product yield is high, and purity is good.

Method of the present invention comprises the following steps:

(1) amino-3, the 5-dibromobenzene methyl alcohol of 2-and brominated reagent react the bromo-6-bromotoluidine of generation 2,4-bis-.

(2) 2, the 4-bis-bromo-6-bromotoluidines that obtain of step (1) and N-methylcyclohexylamine carry out condensation reaction, then with hydrochloric acid salify, and obtained bromhexine hydrochloride.

In step (1), described brominated reagent is Hydrogen bromide, hydrogen bromide acetic acid solution, phosphorus tribromide, preferred Hydrogen bromide.

In step (1), reaction solvent is benzene, toluene, methylene dichloride etc., preferred toluene; Solvent load is 10 ~ 25 times (volume mass is than mL/g) of amino-3, the 5-dibromobenzene methyl alcohol of 2-, preferably 15 times.

In step (1), temperature of reaction is 0 ~ 100 DEG C, preferably 80 ~ 85 DEG C; Reaction times is 1 ~ 24h, preferred 10h.

In step (2), the mol ratio of the bromo-6-bromotoluidine of 2,4-bis-and N-methylcyclohexylamine is 1: 1 ~ 8, preferably 1: 4.5.

In step (2), temperature of reaction is-20 ~ 30 DEG C, preferably-4 ~ 4 DEG C; Reaction times is 1 ~ 10h, preferred 6h.

The achievement that the present invention is useful:

1., through ultimate analysis, UV spectrum, infrared spectra, mass spectrum, proton nmr spectra, carbon spectrum analysis, confirm that product prepared by the present invention is bromhexine hydrochloride, its structural formula is:

Molecular formula is C ₁₄h ₂₀br ₂n ₂hCl, molecular weight: 412.60.

2. synthesis step of the present invention shorter (2 step), reaction conditions is gentle, and environmentally friendly, quality product is high.

3. the key intermediate 2 of the present invention's generation, the bromo-6-bromotoluidine of 4-bis-, also there is no its chemical substance digit recognition number (No. CAS) at present, find when we study, unstable during this compound Individual existence, but it is more stable in toluene system, so when aftertreatment, the bromo-6-bromotoluidine of this key intermediate 2,4-bis-is not separated, but in toluene system, directly participate in next step reaction, further simplify production operation.

4. compared with disclosed bromhexine hydrochloride production technique, production efficiency of the present invention is high, and technological operation is simple, is applicable to heavy industrialization continuous seepage.

The method synthetic route that the present invention proposes is as follows:

Embodiment

The present invention is described by the following specific embodiments, and by embodiment, the present invention may be better understood, but scope of the present invention is not by the restriction of these embodiments.

Embodiment 1:

The synthesis of the bromo-6-bromotoluidine of (1) 2,4-bis-:

Amino-3, the 5-dibromobenzene methyl alcohol 11.2g of 2-are scattered in 160mL toluene, add the Hydrogen bromide 20.2g of 48% under stirring, and add and system temperature is risen to 80 ~ 85 DEG C of reaction 10h, system becomes clarification, and be chilled to room temperature, stratification, water layer 25mL toluene extracts; Combining methylbenzene layer, with the washing of water 100mL × 3, anhydrous sodium sulfate drying 1h, filters, filtrate is for subsequent use, and (intermediate is unstable, does not concentrate to be the toluene solution of the bromo-6-bromotoluidine of 2,4-bis-, do not purify, be directly used in the next step, yield is in 100%).

(2) preparation of bromhexine alkali

By above-mentioned 2, the toluene solution control Nei Wen-4 ~ 4 DEG C of the bromo-6-bromotoluidine of 4-bis-, slow dropping N-methylcyclohexylamine 20.4g, adds temperature control-4 ~ 4 DEG C reaction 30min, then rises to room temperature reaction 6h, TLC display reaction is complete, with the washing of water 100mL × 3, organic layer is evaporated to dry, obtains faint yellow bromhexine alkali 14.8g, molar yield: 98.5% (with amino-3, the 5-dibromobenzene methyl alcohol meters of 2-).

(3) preparation of bromhexine hydrochloride and refining

Bromhexine free alkali 14.8g is dissolved in 46mL dehydrated alcohol, temperature control 5 ~ 10 DEG C, drip concentrated hydrochloric acid and adjust system pH=1 ~ 2, stir 30min, in 0 ~ 4 DEG C of refrigeration 12h, filter, the washing of cold ethanol 7mL × 2, the washing of acetone 7mL × 2,65 DEG C of normal pressures are dried, and obtain bromhexine hydrochloride crude product 13.6g, molar yield: 84%.

Bromhexine hydrochloride crude product 13.1g, be scattered in 140mL methyl alcohol, reflux, to dissolving completely, adds gac 0.6g, continue backflow 30min, heat filter, filtrate, in 0 ~ 4 DEG C of refrigeration 8h, is filtered, cold methanol 4mL × 2 are washed, 80 DEG C of constant pressure and dry 8h, obtain bromhexine hydrochloride finished product 11.5g, molar yield: 88%.

¹H NMR(CDCl ₃)：δ10.13(br，1H)，7.66(s，2H)，5.90(br，2H)，4.24～4.39(dd，2H)，3.28(m，1H)，2.52(s，3H)，2.16(m，2H)，1.81(m，2H)，1.61(m，1H)，1.51(m，2H)，1.25(m，2H)，1.15(m，1H)ESI-MS：m/z 377.7(M+1)

HPLC：99.9％

。

Claims

1. prepare a novel method for bromhexine hydrochloride, the method comprises the steps:

(1) amino-3, the 5-dibromobenzene methyl alcohol of 2-and brominated reagent react the bromo-6-bromotoluidine of generation 2,4-bis-;

2. the preparation method of bromhexine hydrochloride according to claim 1, is characterized in that: the brominated reagent described in step (1) is Hydrogen bromide, hydrogen bromide acetic acid solution, phosphorus tribromide etc., preferred Hydrogen bromide.

3. the preparation method of bromhexine hydrochloride according to claim 1, is characterized in that: the reaction solvent described in step (1) is benzene, toluene, methylene dichloride etc., preferred toluene; Solvent load is 10 ~ 25 times (volume mass is than mL/g) of amino-3, the 5-dibromobenzene methyl alcohol of 2-, preferably 15 times.

4. the preparation method of bromhexine hydrochloride according to claim 1, is characterized in that: the temperature of reaction described in step (1) is 0 ~ 100 DEG C, preferably 80 ~ 85 DEG C; Reaction times is 1 ~ 24h, preferred 10h.

5. the preparation method of bromhexine hydrochloride according to claim 1, is characterized in that: the mol ratio of described in step (2) 2,4-bis-bromo-6-bromotoluidines and N-methylcyclohexylamine is 1: 1 ~ 8, preferably 1: 4.5.

6. the preparation method of bromhexine hydrochloride according to claim 1, is characterized in that: the temperature of reaction described in step (2) is-20 ~ 30 DEG C, preferably-4 ~ 4 DEG C; Reaction times is 1 ~ 10h, preferred 6h.