CN107641074A - The production method of mexiletine hydrochloride - Google Patents
The production method of mexiletine hydrochloride Download PDFInfo
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Abstract
A kind of production method of mexiletine hydrochloride is provided, it includes etherification step：Make 2,6 xylenols are dissolved in solid-liquid heterogeneous reaction system and obtain mixed liquor, chlroacetone is set to be mixed with the mixed liquor, back flow reaction obtains ether ketone, and wherein solid-liquid heterogeneous reaction system includes solvent, solid-liquid phase transfer accelerator, inorganic base and alkali halide；Amination reduction step：Ether ketone is set to be contacted with ammonia methanol to carry out amination reduction reaction under conditions of suitable for reaction, so as to obtain ether amines；Salt-forming steps：Ether amines are made to obtain mexiletine hydrochloride with hcl reaction in a solvent.The method of the present invention improves reaction efficiency and productivity ratio, has the advantages of production cost is low, resource consumption is few, production efficiency is high.
Description
Technical field
The invention belongs to chemosynthesis technical field, it is usually directed to the production method of mexiletine hydrochloride.
Background technology
Mexiletine hydrochloride, English name：Mexiletine Hydrochloride, it is commonly called as mexiletine, chemical name：(±)-1-
(2,6- dimethyl phenoxy) -2- propylamin hydrochlorides (CAS No：5370-01-4), molecular formula：C11H17NOHCl, molecular weight：
215.72 structural formula is as follows：
Its structure of mexiletine hydrochloride is similar to lidocaine, has been originally found anticonvulsant action, by the proof medicine pair
Arrhythmia cordis caused by coronary artery ligation has good effectiveness, is clinically mainly used in treating acute and chronic room property at present
Arrhythmia cordis.
Mainly there are two kinds of technique productions mexiletine hydrochlorides the country at present, and the first is with 2,6- xylenols and epoxy third
Alkane obtains ether alcohol after carrying out etherification reaction, and ether ketone is aoxidized to obtain by sodium dichromate, then is reduced through amination, the U.S. west of hydrochloric acid is obtained into salt
Rule.It is to be etherified to obtain ether ketone with 2,6- xylenols and chlroacetone, then is reduced through amination, obtains hydrochloric acid into salt for second
Mexiletine.
There is more deficiency in above two production technology, in the first production technology, toxic articles weight chromium has been used
Therefore sour sodium simultaneously introduces pollutant effulent；In second of production technology, solid-liquid two phase reaction is used when preparing ether ketone, is made
By the use of high boiling polar aprotic solvent dimethylformamide (DMF) as reaction dissolvent come dissolving salt and organic matter, but
The general boiling point of polar non-solute used is higher, is difficult to be removed from mixture after the completion of reaction, and reclaim purification ratio
It is more difficult, it is more much higher than common alcohol, hydrocarbon price.
Therefore, a kind of production technology of mexiletine hydrochloride environmentally friendly, resource consumption is few how is studied, is this area
Technical staff's technical problem urgently to be resolved hurrily.
The content of the invention
In order to solve the above problems, 2,6- xylenols are dissolved in solid-liquid heterogeneous reaction system by the present invention to be obtained
Mixed liquor, 2,6- xylenols and chlroacetone are etherified to obtain ether ketone in mixed liquor, then are reduced through amination, obtained into salt
A kind of mexiletine hydrochloride, there is provided the production method for the mexiletine hydrochloride that production cost is low, resource consumption is few, production efficiency is high.This
Invention specifically comprises the following steps：
Etherification step：2,6- xylenols is dissolved in solid-liquid heterogeneous reaction system and obtain mixed liquor, make chlorine third
Ketone mixes with the mixed liquor, and back flow reaction obtains ether ketone, wherein the solid-liquid heterogeneous reaction system includes solvent, solid liquid phase
Shift accelerator, inorganic base and alkali halide
Amination reduction step：The ether ketone is set to be contacted with ammonia methanol under conditions of suitable for reaction anti-to carry out amination reduction
Should, so as to obtain ether amines；
Salt-forming steps：The ether amines are made to obtain mexiletine hydrochloride with hcl reaction in a solvent.
In some embodiments, in described production method, the solvent in the etherification step is varsol.
In some embodiments, in described production method, the solvent in the etherification step is selected from by chloroform, dichloro
At least one of group that methane, 1,2- dichloroethanes, acetonitrile, benzene,toluene,xylene and acetone form.
In some embodiments, in described production method, the solid-liquid phase transfer accelerator is quaternary ammonium salt or four fourths
Base ammonium salt.
In some embodiments, in described production method, the solid-liquid phase transfer accelerator is selected from by tetrabutyl bromine
Change at least one of group of ammonium, tetrabutylammonium chloride, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide composition.
In some embodiments, in described production method, when the chlroacetone mixes with the mixed liquor, described 2,
The mass ratio of 6- xylenols and the chlroacetone is 2: 1 to 1: 1.
In some embodiments, in described production method, 2,6- xylenols described in the mixing liquid with
The mass ratio of the inorganic base is 3: 1 to 1: 1.
In some embodiments, in the production method, chlroacetone is made to be mixed with the mixed liquor in the etherification step
Close and the mixed liquor is added drop-wise to carry out by the mixed solution form with 1,2- dichloroethanes and chlroacetone.
In some embodiments, in described production method, the condition bag of reaction is suitable in the amination reduction step
It is zero to include under 0.8-1.5MPa Hydrogen Vapor Pressures 80-120 DEG C of keeping temperature to Hydrogen Vapor Pressure.
In some embodiments, in described production method, the solvent in the salt-forming steps is ethyl acetate, first
At least one of group of alcohol, ethanol and acetone composition.
Beneficial effect：
In the production method of mexiletine hydrochloride of the present invention, it is etherified in the solid-liquid heterogeneous reaction system
Reaction, etherification reaction generating rate is improved, maximize production efficiency, resource consumption is few, and can be produced into recycling design, reduction
This.
Embodiment
Now describe the various exemplary embodiment of the present invention in detail, the detailed description is not considered as the limit to the present invention
System, and it is understood as the more detailed description to certain aspects of the invention, characteristic and embodiment.
It should be understood that heretofore described term is only to describe special embodiment, being not intended to limit this hair
It is bright.In addition, for the number range in the present invention, it is thus understood that specifically disclose the scope upper and lower bound and they it
Between each median.Median and any other statement value in any statement value or stated ranges or in the scope
Each less scope between interior median is also included in the present invention.These small range of upper and lower bounds can be independent
Ground is included or excluded in the range of.
Unless otherwise stated, all technologies used herein and scientific terminology have the routine in field of the present invention
The identical meanings that technical staff is generally understood that.Although the present invention only describes preferable method and material, the present invention's
Implement or can also be used and similar or equivalent any method described herein and material in testing.The institute mentioned in this specification
There is document to be incorporated by reference into, to the disclosure and description method related to the document and/or material.It is incorporated to any
When document conflicts, it is defined by the content of this specification.
It is open term, i.e., on "comprising" used herein, " comprising ", " having ", " containing " etc.
Mean including but not limited to.Any or all combinations on "and/or" used herein, including the things.Unless
It is otherwise noted, otherwise % refers to quality percent by volume.
Exist in the prior art and obtain ether alcohol after carrying out etherification reaction with 2,6- xylenols and expoxy propane, through overweight
Sodium chromate aoxidizes to obtain ether ketone, then is reduced through amination, obtains mexiletine hydrochloride into salt.The reaction equation of this method is as follows.
The requirement of current environmental protection is increasingly strict, due to the method use toxic articles sodium dichromate and therefore introducing
Pollutant effulent, therefore its application is extremely restricted.Need more environment-friendly alternative.
The present invention is to be etherified to obtain ether ketone with 2,6- xylenols and chlroacetone, then reduces through amination, obtained into salt
It is as follows to the method for mexiletine hydrochloride, its course of reaction.
In current such a production technology, used when preparing ether ketone during solid-liquid two phase reaction and used high boiling polarity
Non-protonic solvent dimethylformamide (DMF) comes dissolving salt and organic matter as reaction dissolvent, but aprotic, polar used is molten
The general boiling point of agent is higher, is difficult to be removed from mixture after the completion of reaction, and recovery purification is relatively difficult, than common
Alcohol, hydrocarbon price are much higher.
An aspect of of the present present invention is overcome in the production method of the mexiletine hydrochloride of above-mentioned deficiency offer, in the etherification step
In, 2,6- xylenols are put into solid-liquid heterogeneous reaction system, and 2,6- xylenols Anion-adsorption exists in a solvent
The surface of inorganic base, solid-liquid phase transfer accelerator act on inorganic base surface and 2,6- xylenols anion, and generation has 2,
6- xylenols anion and the ion pair of solid-liquid phase transfer accelerator cation composition, ion pair pass through solid-liquid circle
Face, into liquid phase, ion pair and the chlroacetone being blended in the mixed solution react, and generate ether ketone.Meanwhile by solid liquid phase
Transfer accelerator cation is replaced out.In certain embodiments, the solvent in the solid-liquid heterogeneous reaction system is non-
Polar solvent, preferably varsol, such as the solvent are 1,2- dichloroethanes.In certain embodiments, it is non-in the solid-liquid
Solvent in homogeneous reaction system is free chloroform, dichloromethane, 1,2- dichloroethanes, acetonitrile, benzene,toluene,xylene and third
At least one of group of ketone composition.In certain embodiments, in the solid-liquid heterogeneous reaction system, solid-liquid phase transfer promotees
It is quaternary ammonium salt to enter agent.In certain embodiments, solid-liquid phase transfer accelerator is specially in the solid-liquid heterogeneous reaction system
In the group that free TBAB, tetrabutylammonium chloride, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide form extremely
Few one kind.In certain embodiments, the inorganic base in the solid-liquid heterogeneous reaction system is potassium carbonate or saleratus；
In some embodiments, the alkali halide in the solid-liquid heterogeneous reaction system is sodium bromide or KI.
In some embodiments, the chlroacetone and the process that the mixed liquor mixes are by by 1,2- dichloroethanes
The mixed liquor is added drop-wise to the mixed solution form of chlroacetone to carry out.
In some embodiments, when the chlroacetone mixes with the mixed liquor, the chlroacetone and the mixed liquor
In the mass ratioes of 2, the 6- xylenols be 1: (1-2), it is preferable that the chlroacetone and 2, the 6- xylenols
Mass ratio be 1: 1,1: 1.5 or 1: 2.
In some embodiments, wherein the matter of 2,6- xylenols described in the mixing liquid and the inorganic base
Amount is than being 3: 1 to 1: 1.In some embodiments, during the etherificate, 2,6- described in the mixing mixing liquid
The mass ratio of xylenol and the inorganic base is 0.5: 1 to 1.5: 1.Inorganic base is potassium carbonate or saleratus, it is preferable that
The mass ratio of 2, the 6- xylenols and the potassium carbonate is 2.5: 1 to 1.5: 1.2, the 6- xylenols with it is described
The mass ratio of saleratus is 0.5: 1 to 1: 1.For example, the mass ratio of 2, the 6- xylenols and the potassium carbonate is 2.5
: 1,2: 1 or 1: 1.The mass ratio of 2, the 6- xylenols and the saleratus is 0.5: 1,0.75: 1 or 1: 1.
In some embodiments, it is 2, the 6- xylenols, the inorganic base, described in the etherification procedure
Chlroacetone and the ratio of quality of solid phase transfer accelerator are：(6-8)∶(3-4)∶(4-5)∶1；Preferably, 2, the 6- bis-
The ratio that methylphenol, the inorganic base, the chlroacetone and the solid phase shift the quality of accelerator is (6-7): 3: 4: 1, more
Preferably, the ratio of 2, the 6- xylenols, the inorganic base, the chlroacetone and the quality of solid phase transfer accelerator
For 6: 3: 4: 1.With the increase of solid phase transfer accelerator proportion, the rate of recovery of reaction product ether ketone rises, and works as
The ratio that 2, the 6- xylenols, the inorganic base, the chlroacetone and the solid phase shift the quality of accelerator is 6: 3: 4
: when 1, the rate of recovery of ether ketone reaches highest.
Further, in certain embodiments, it is 2, the 6- xylenols, described inorganic in the etherification procedure
Alkali, the chlroacetone, the alkali halide and be (6-8): (3-4) with the ratio of quality of solid phase transfer accelerator:
(4-5)∶(0.1-0.3)∶1.So that it is adsorbed onto the solid-liquid phase transfer accelerator on inorganic base surface, 2,6- xylenol anion
Reach optimal ratio with the ion pair of solid-liquid phase transfer accelerator cation composition, and ion pair and chlroacetone and match somebody with somebody ratio, make
Obtain 2, the 6- xylenols described in mixed liquor fully to react with the chlroacetone, the productivity ratio of ether ketone maximizes.
Further, in certain embodiments, in the etherification procedure, 2, the 6- xylenols, described 1,
2- dichloroethanes, the inorganic base, the alkali halide, the solid phase shift the quality of accelerator and the chlroacetone
Than for：(12-13)∶(36-37)∶(6-8)∶(0.2-1)∶(1-2)∶(7-9).The etherification procedure is in the chloroethenes of 1,2- bis-
Carried out in alkane solvents, add the solubility of the solid phase transfer accelerator and the inorganic base so that 2,6- xylenols
Accelerator is shifted with the solid phase and the inorganic base fully contacts；Alkali halide is bromine in the system of the etherification reaction
Change sodium or KI, wherein, bromine is a kind of preferable accelerator so that bromide ion has strong sucking action with hydrogen ion,
So that reaction can be carried out rapidly, sodium bromide or KI produce initial radical in reaction system, shorten luring for reaction
Lead the phase, accelerate course of reaction.It is 2, the 6- xylenols, 1, the 2- dichloroethanes, described inorganic in etherification procedure
Alkali, the alkali halide, the ratio of quality of solid phase transfer accelerator and the chlroacetone are：(12-13)∶(36-
37): (6-8): (0.2-1): (1-2): (7-9), the then etherification reaction progress that is swift in response, and in the chloroethenes of 1,2- bis-
Ensure that the solid phase transfer accelerator and inorganic base have higher relative concentration in alkane solvents, and cause to obtain 2,6- diformazans
Base phenol shifts accelerator with the solid phase and the inorganic base fully contacts, and maximizes 2,6- xylenols and chlroacetone
Produce the efficiency of ether ketone.And in above-mentioned mass ratio, each Ingredient Amount is moderate, the useless consumption of raw material will not be produced.For example,
In the etherification procedure, the quality of 2, the 6- xylenols is 122, and the quality of 1, the 2- dichloroethanes is 366, described
The quality of inorganic base is 61, and the quality of the alkali halide is 3, and the quality of the solid phase transfer accelerator is 16 and described
When the quality of chlroacetone is 80, the quality that production obtains ether ketone in etherification procedure is 170.
In some embodiments, in the production method of the mexiletine hydrochloride, ammonia described in the amination reduction step
The concentration 5-20% of methanol, more preferably preferably 5-15%, 10-15%.
Embodiment
Embodiment 1
Etherification step：By in 122 parts of 2,6- xylenols and 366 parts of 1,2- dichloroethanes input reactors, 61 are added
The potassium carbonate, 3 parts of sodium bromides, 16 parts of TBABs of part, are warming up to backflow, and 40 parts of 1,2- dichloroethanes and 80 parts of chlorine are added dropwise
Acetone mixed solution, drop Bi Jixu back flow reactions 2 hours.Solid slag is filtered out, 1,2- dichloroethanes is reclaimed, obtains 170 parts of ether ketone.
Amination reduction step：170 parts of smart ketone, 385 parts of 10% ammonia methanol, 6 parts of Raney's nickel are put into hydriding reactors, into kettle
Hydrogen is passed through to 1.2MPa, is warming up to 100 DEG C, it is 1.2MPa to be incubated and keep Hydrogen Vapor Pressure, terminates until inhaling hydrogen, is cooled to 30
Below DEG C, sedimentation reclaims ammonia methanol to the greatest extent after removing catalyst.Vacuum ＜ 0.09MPa are controlled, collect 110 DEG C of cuts about 160
Part spermine.
Salt-forming steps：By in 582 parts of 160 parts of spermine, ethyl acetate input reactors, about 1mol/L chlorination is slowly added dropwise
Hydroacetic acid ethyl ester solution to pH value is about 3-5, is refrigerated to less than 5 DEG C, after filtering 60 DEG C dry 179.2 parts of mexiletine hydrochlorides into
Product.
Embodiment 2
Etherification step：By in 120 parts of 2,6- xylenols and 360 parts of 1,2- dichloroethanes input reactors, 200 are added
Part saleratus, 2 parts of KIs, 10 parts of TBABs, are warming up to backflow, and 600 parts of 1,2- dichloroethanes and 70 parts are added dropwise
Chlroacetone mixed solution, drop Bi Jixu back flow reactions 2 hours.Solid slag is filtered out, 1,2- dichloroethanes is reclaimed, obtains 170 parts of ether ketone.
Amination reduction step：170 parts of smart ketone, 342 parts of 10% ammonia methanol, 11.4 parts of Raney's nickel are put into hydriding reactors, to
Hydrogen is passed through in kettle to 1.2MPa, is warming up to 100 DEG C, it is 1.2MPa to be incubated and keep Hydrogen Vapor Pressure, terminates until inhaling hydrogen, cools
To less than 30 DEG C, sedimentation reclaims ammonia methanol to the greatest extent after removing catalyst.Vacuum ＜ 0.09MPa are controlled, collect 110 DEG C of cuts about
163 parts of spermine.
Salt-forming steps：By in 489 parts of 163 parts of spermine, methanol input reactors, about 1mol/L hydrogen chloride second is slowly added dropwise
Acetate solution to pH value is about 3-5, is refrigerated to less than 5 DEG C, and 143 parts of mexiletine hydrochloride finished products are dried to obtain for 60 DEG C after filtering.
Embodiment 3
Etherification step：By in 130 parts of 2,6- xylenols and 370 parts of 1,2- dichloroethanes input reactors, 80 are added
Part potassium carbonate, 5 parts of sodium bromides, 20 parts of TBABs, are warming up to backflow, and 40 parts of 1,2- dichloroethanes and 90 parts of chlorine third are added dropwise
Ketone mixed solution, drop Bi Jixu back flow reactions 2 hours.Solid slag is filtered out, 1,2- dichloroethanes is reclaimed, obtains 175 parts of ether ketone.
Amination reduction step：175 parts of smart ketone, 405 parts of 10% ammonia methanol, 7 parts of Raney's nickel are put into hydriding reactors, into kettle
Hydrogen is passed through to 1.2MPa, is warming up to 100 DEG C, it is 1.2MPa to be incubated and keep Hydrogen Vapor Pressure, terminates until inhaling hydrogen, is cooled to 30
Below DEG C, sedimentation reclaims ammonia methanol to the greatest extent after removing catalyst.Vacuum ＜ 0.09MPa are controlled, collect 110 DEG C of cuts about 179
Part spermine.
Salt-forming steps：By in 610 parts of 179 parts of spermine, ethanol input reactors, about 1mol/L hydrogen chloride second is slowly added dropwise
Acetate solution to pH value is about 3-5, is refrigerated to less than 5 DEG C, and 157 parts of mexiletine hydrochloride finished products are dried to obtain for 60 DEG C after filtering.
In the case of without departing substantially from the scope or spirit of the invention, the embodiment of description of the invention can be done more
Kind is improved and change, and this will be apparent to those skilled in the art.Other realities obtained by the specification of the present invention
It is apparent obtain for technical personnel to apply mode.Present specification and embodiment are only exemplary.
Claims (10)
1. a kind of production method of mexiletine hydrochloride, it comprises the following steps：
Etherification step：2,6- xylenols is dissolved in solid-liquid heterogeneous reaction system and obtain mixed liquor, make chlroacetone with
The mixed liquor mixing, back flow reaction obtains ether ketone, wherein the solid-liquid heterogeneous reaction system includes solvent, solid-liquid phase transfer
Accelerator, inorganic base and alkali halide；
Amination reduction step：The ether ketone is set to be contacted with ammonia methanol to carry out amination reduction reaction under conditions of suitable for reaction,
So as to obtain ether amines；
Salt-forming steps：The ether amines are made to obtain mexiletine hydrochloride with hcl reaction in a solvent.
2. production method according to claim 1, wherein the solvent in the etherification step is varsol.
3. production method according to claim 1, wherein the solvent in the etherification step is selected from by chloroform, dichloromethane
At least one of group that alkane, 1,2- dichloroethanes, acetonitrile, benzene,toluene,xylene and acetone form.
4. production method according to claim 1, wherein solid liquid phase transfer accelerator is quaternary ammonium salt or tetrabutylammonium
Salt.
5. production method according to claim 1, wherein solid liquid phase transfer accelerator be selected from by TBAB,
At least one of group that tetrabutylammonium chloride, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide form.
6. production method according to claim 1, wherein when the chlroacetone mixes with the mixed liquor, 2, the 6- bis-
The mass ratio of methylphenol and the chlroacetone is 2:1 to 1:1.
7. production method according to claim 1, wherein 2,6- xylenols described in the mixing liquid and described
The mass ratio of inorganic base is 3:1 to 1:1.
8. production method according to claim 1, wherein making chlroacetone be mixed with the mixed liquor in the etherification step
Carried out by being added drop-wise to the mixed liquor in the form of the mixed solution of 1,2- dichloroethanes and chlroacetone.
9. production method according to claim 1, wherein the condition for being suitable to reaction in the amination reduction step is included in
80-120 DEG C of keeping temperature to Hydrogen Vapor Pressure is zero under 0.8-1.5MPa Hydrogen Vapor Pressures.
10. production method according to claim 1, wherein the solvent in the salt-forming steps is ethyl acetate, methanol, second
At least one of group of alcohol and acetone composition.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111978188A (en) * | 2020-09-02 | 2020-11-24 | 常州亚邦制药有限公司 | Preparation method of mexiletine hydrochloride impurity C |
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| CN111978188A (en) * | 2020-09-02 | 2020-11-24 | 常州亚邦制药有限公司 | Preparation method of mexiletine hydrochloride impurity C |
| CN111978188B (en) * | 2020-09-02 | 2022-03-08 | 常州亚邦制药有限公司 | Preparation method of mexiletine hydrochloride impurity C |
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Application publication date: 20180130 |
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