CN103073438A - Ambroxol hydrochloride compound refining method - Google Patents
Ambroxol hydrochloride compound refining method Download PDFInfo
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Abstract
The invention relates to an ambroxol hydrochloride compound refining method, comprising a step of synthesizing an ambroxol hydrochloride crude product and a step of refining ambroxol hydrochloride, wherein the refining step comprises the following steps: 1) adding water and the ambroxol hydrochloride crude product into a reaction bottle, heating to a temperature of 70-75 DEG C and stirring, and dissolving the crude product, so as to obtain an ambroxol hydrochloride crude product solution; adding active carbon into the ambroxol hydrochloride crude product solution, decolorizing and filtering in a thermal insulating manner, and collecting filtrate; 2) cooling the filtrate to a temperature of 55-60 DEG C, carrying out thermal insulation and stirring; 3) cooling the filtrate to a temperature of 45-48 DEG C, controlling a stirring speed of 15 r/min, adding seed crystal, and crystallizing for 1 hour by controlling a temperature and a stirring speed; 4) cooling to a temperature of 20-25 DEG C and crystallizing for 20 minutes, slowly cooling to a temperature of 10 DEG C for 1.5 hours again after a crystallizing process, and obtaining an ambroxol hydrochloride fine product by leaching and drying. With the adoption of the ambroxol hydrochloride compound refining method provided by the invention, the ambroxol hydrochloride only contains an impurity B in five know impurities; and a content of the impurity B is controlled below 0.005%.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to a kind of process for purification of Ambroxol HCl compound.
Background technology
Ambroxol HCl (ambroxol hydrochloride) claim again AMB, chemistry is called the amino 3.5-dibromo-benzyl of trans-4-[(2-) amino] the hexalin hydrochloride, structural formula is as follows, is the mucolytic by the research and development of German Boehringer Ingelheim company.This medicine went on the market in Germany in early 1980s, in succession go on the market in many countries such as France, Italy, Japan, Spain subsequently, be used for the treatment of eliminating the phlegm of the various acute and chronic respiratory tract diseases of and expectoration dysfunction undesired with the sputum secretion, its curative effect certainly, untoward reaction is little, ranks forefront in the emphasis hospital administration rank of China's main cities in recent years always.
Ambroxol HCl is respiratory mucus conditioning agent of new generation, has the superior usefulness of eliminating the phlegm, and the synthetic of alveolar surfactant had significant promoter action with secretion.The mucus that Ambroxol HCl can stimulate the bronchorrhea glandular secretion to be easier to flow makes the sputum dilution, and toughness reduces, and can increase generation and the secretion of pulmonary surfactant, thereby reduce Raw air way resistance, reduce the sticking power of mucus, activate the mucociliary function, promote mucociliary to rotate.Compare with s-generation expelling phlegm drugs with the first-generation, Ambroxol HCl is except having powerful mucolysis effect, and its maximum characteristics are that it can stimulate alveolar type II cells, promotes the synthetic and secretion of alveolar surfactant, thereby effectively increase the mucus running, promote expectoration.
The Ambroxol HCl preparation of selling in the market has oral preparations and injection two large types, and wherein, injection liquid divides import and domestic two kinds, and the validity period of Imported Ambroxol Hydrochloride injection liquid is 5 years, and the validity period of domestic ambroxol hydrochloride injection only has 2 years.Why like this, be because the related substance growth in the injection is too fast, the scope that is above standard (total impurities must not cross 1.0%).In addition, the Ambroxol HCl raw material of selling on the domestic market does not have oral and differentiation injection stage, and purity only requires more than 99.0%; The quality standard that does not also have injection stage Ambroxol HCl raw material in the Chinese Pharmacopoeia; In the quality standard of Ambroxol HCl raw material, only control total impurities under the related substance item and do not have the segmentation criteria of concrete Control of Impurities.
European Pharmacopoeia version Ambroxol HCl in 2002 bulk drug quality standard is listed 5 known impurities, is respectively:
Impurity A: chemical name is: (2-amino-3,5-dibromo-benzyl) methyl alcohol, molecular formula is: C
7H
7Br
2NO, slightly water-soluble.
Impurity B: chemical name is: trans-4-[6, and 8-two bromo-Isosorbide-5-Nitrae-dihydroquinazolines-3 (H)] the hexalin hydrochloride, molecular formula is: C
14H
18Br
2N
2O HCl, water-soluble.
Impurity C: chemical name is: trans-4-{[(E)-and 2-amino-3, the 5-dibromo-benzyl] amino } hexalin, molecular formula is: C
13H
16Br
2N
2O is slightly soluble in water.
Impurity D: chemical name is: cis-4-[(2-amino-3,5-dibromo-benzyl) amino] the hexalin hydrochloride, molecular formula is: C
13H
18Br
2N
2O HCl, slightly water-soluble.
Impurity E: chemical name is: (2-amino-3,5-dibromo phenyl) formaldehyde, molecular formula is: C
7H
5Br
2NO.Water-soluble hardly.
But in Imported Ambroxol Hydrochloride injection liquid quality standard, related substance is also just calculated the content of impurity with external standard method, trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] total amount of hexalin hydrochloride (impurity B) and (2-amino-3,5-dibromo phenyl) formaldehyde (impurity E) must not persalt Transbroncho labelled amount 1%.
For reducing foreign matter content, the process for purification of CN102153482A injection stage Ambroxol HCl, the method is: get purity and be the Ambroxol HCl raw material more than 99.0%, the ratio with 1: 5.5～9.2, the aqueous ethanolic solution that adds 70.2%～88% volume ratio, the g/ml of unit; Heat back and heat up in a steamer to abundant dissolving; Stopped heating, crystallisation by cooling is separated out Ambroxol HCl; The filtering solvent obtains crystallization, is drying to obtain.Impurity B is no more than 0.03% in the Ambroxol HCl raw material of the injection stage that the present invention makes, and impurity E is no more than 0.002%, and the total impurities beyond removal of impurity B and the E is no more than 0.03%; Purity reaches more than 99.9%.
Although aforesaid method has reduced the content of impurity to a certain extent, yet still contain known impurities B and E and a certain amount of removal of impurity B and E total impurities in addition in the Ambroxol HCl after aforesaid method is processed.The inventor is after having carried out a large amount of research to the bulk drug Ambroxol HCl, find to adopt aqueous solvent can make Ambroxol HCl only contain a impurity B in 5 known impurity in conjunction with gradient cooling crystallization etc. pleasantly surprisedly, and the content of impurity B can be controlled at below 0.005%, product purity is increased to 99.9%, thereby has finished the present invention.
Summary of the invention
The object of the present invention is to provide a kind of process for purification of Ambroxol HCl compound, the method can reduce kind and the content of impurity significantly.
For realizing purpose of the present invention, the present invention adopts following technical scheme:
A kind of process for purification of Ambroxol HCl compound comprises synthesizing of Ambroxol HCl crude product and making with extra care of Ambroxol HCl, it is characterized in that described refining comprising the steps:
1) add entry and Ambroxol HCl crude product in reaction flask, be warming up to 70 ℃ of-75 ℃ of stirrings, dissolving crude product obtains the crude product solution of Ambroxol HCl; Add gac in crude product solution, keep 70 ℃ of-75 ℃ of decolourings, insulation is filtered, and collects filtrate;
2) the filtrate temperature is down to 55 ℃-60 ℃, keeps this temperature, stir;
3) again with filtrate greenhouse cooling to 45 ℃-48 ℃, 15 rev/mins of control stirring velocitys add the Ambroxol HCl crystal seed, control this temperature and stirring velocity growing the grain 1 hour;
4) and then with ℃ of-25 ℃ growing the grains of greenhouse cooling to 20 20 minutes, growing the grain finishes again slow cooling to 10 ℃ growing the grain 1.5 hours, suction filtration, dry Ambroxol HCl elaboration.
The present invention adopts gradient cooling, pass through process optimization, select 55 ℃-60 ℃ and 45 ℃ of-48 ℃ of two main thermogrades crystallization of lowering the temperature, make the product more times remain on the steady district of crystal growth Jie, avoided in the Crystallization Process impurity to be wrapped in the lattice and separated out together, by the mode of this kind control crystallization, can make Ambroxol HCl only contain a impurity B in 5 known impurity, and the content of impurity B can be controlled at below 0.005%, product purity is increased to 99.9%.
Further, the synthetic of Ambroxol HCl crude product of the present invention comprises the steps:
A) take formula (I) compound as starting raw material, DMAP and 4-dimethylamino hexalin are catalyzer, and reaction obtains intermediate under the condition of dehydrated alcohol and potassium hydroxide existence and to Trans-4-Amino Cyclohexanol;
B) under the condition that etoh solvent, water and Glacial acetic acid exist, intermediate and concentrated hydrochloric acid reaction are generated Ambroxol HCl.
Among the present invention, described formula (I) compound is 3, the amino cylite of 5-two bromo-2-di-acetyls, this compound can be bought or be synthetic with reference to the synthetic route of prior art, as " Graphical Synthetic Routes of Ambroxol " [Jia Weiyuan. Graphical Synthetic Routes of Ambroxol. Chinese Journal of Pharmaceuticals, the route of 1995,26(5): 235-237] reporting is synthetic.Also can be synthetic with reference to following method: in the anhydrous reaction flask of cleaning, add 27.9g2-amino-3, the 5-dibromo benzaldehyde, 250ml methylene dichloride 17.2g Acetyl Chloride 98Min., stir into homogeneous system, be cooled to 0-5 ℃, in reaction system, drip the 22.3g triethylamine, after having finished, keeps 30min 0-5 ℃, stirring reaction 3h.After reaction finishes, add 150ml water, standing demix behind the stirring 30min.Get the organic layer evaporated under reduced pressure.Add the dissolving of 200ml anhydrous methanol, be transferred in the hydrogenation reaction kettle, add the wet product catalyzer of Ranney-nickel 7g, temperature control 25-30 ℃, under the hydrogen pressure of 0.3MPa, stirring reaction 8h reacts complete, filters the washing of 20ml anhydrous methanol, merging filtrate, evaporated under reduced pressure.Add and to be chilled in advance 0-5 ℃ 40%HBr aqueous solution 150ml, temperature control 10-15 ℃, stirring reaction 6h adds the 200ml methylene dichloride after reaction finishes, and stirs 30min, standing demix, organic layer 20g anhydrous sodium sulfate drying, filtration, filtrate decompression evaporate to dryness and get final product.
Amino-3 from 2-in the prior art, 5-dibromobenzyl bromide or 2-acetamido-3,5-dibromobenzyl bromide set out the method for synthetic hydrochloric acid Transbroncho because amino is not protected, so above side reaction product can enter final product, affect quality product; And from 2-amino-3,5-dibromo benzaldehyde or ethyl benzoate set out the method for synthetic hydrochloric acid Transbroncho then because reduction reaction is difficult to carry out thoroughly and this intermediate physico-chemical property is closely similar with the finished product Ambroxol HCl, can become a kind of process contaminants and exist in the finished product, refining purifying is difficult to remove.The present invention is directed to the key issue of synthetic route, by further investigation and repetition test, designed a kind of brand-new synthesis route, developed a kind of to use safety, cheap and easy to get 3, the amino cylite of 5-two bromo-2-di-acetyls is as starting raw material, by the technique of the reaction synthetic hydrochloric acid Transbronchos such as condensation, hydrolysis, salify.
Mostly prior art is by condensation product is made with extra care; remove the incomplete impurity of reaction and by product; the present invention has developed new catalyzer and has solved this difficult problem; this catalyzer is comprised of 4-dimethylamino hexalin and DMAP; its mechanism is 4-dimethylamino hexalin and 3; the amino cylite reaction of 5-two bromo-2-di-acetyls generates metastable transition compound; reduced by 3; the activation energy of the amino cylite reaction of 5-two bromo-2-di-acetyls; so can rapidly and react Trans-4-Amino Cyclohexanol; generate the amino Transbroncho of two protections, substantially realize quantitative reaction, speed of reaction is fast; yield high (more than 95%); reduced former auxiliary consumption, reduced because of the excessive introducing impurity of supplementary material, quality product obviously improves.Reaction mechanism is as follows:
The present invention adopts new raw material safe, cheap and easy to get 3 first, the amino cylite of 5-two bromo-2-di-acetyls is starting raw material, adopt diacetyl group that the higher functional groups amino of the activity of this raw material is protected fully, katalysis by new catalyst, substantially stopped the generation of phenyl ring 2 bit amino side reactions, reaction product does not need to carry out recrystallization purifying and is directly used in next step reaction; Owing to adopting di-acetyl to carry out amido protecting, increase the solubleness of starting raw material in organic solvent simultaneously, reaction can be carried out in homogeneous phase solution, increased the probability that contacts between the molecule, obviously improved the reaction thoroughness.The purification refine step has been omitted in the design of operational path of the present invention, has reduced the product foreign matter content, and condensation product purity is brought up to more than 99% by about 92%, brings up to more than 70% by former 56%.
Industrialization can be implemented and realize to synthetic method of the present invention smoothly, keying action has been played in the exploitation of new catalyst, it is the technical barrier that this area faces that the condensation reaction of Ambroxol HCl technique is difficult to fully always, developed a kind of original creation new catalyst for this reaction in the technique condensation reaction of the present invention, consumption is few, and catalytic effect is fabulous.
Specifically, in the treating process of Ambroxol HCl of the present invention, the mass ratio of the volume of water and Ambroxol HCl crude product is 10.4:1 in the step 1).
Decolouring described in the step 1) is decolouring 10-30 minute, preferred 20 minutes.
Step 2) stirring velocity that stirs described in is 18-22 rev/min, and churning time is 25-35 minute; Preferred stirring velocity is 20 rev/mins, and churning time is 30 minutes.
The add-on of Ambroxol HCl crystal seed is the 2wt% of Ambroxol HCl crude product in the step 3).
In the building-up process of Ambroxol HCl crude product of the present invention, described step a) is: add Trans-4-Amino Cyclohexanol and dehydrated alcohol in reaction flask, stirring and dissolving, molten clear potassium hydroxide, DMAP and the 4-dimethylamino hexalin of adding successively later, control temperature 60 C～75 ℃ add formula (I) compound in batches, continue control temperature 60 C～75 ℃ reaction 1～3 hour, after reaction finishes, control temperature 45 C～55 a ℃ decompression steams anhydrous methanol, will concentrate the feed liquid cooling, crystallize out, growing the grain 1～3 hour, suction filtration, drying gets the Transbroncho intermediate.
Described step b) is: add ethanol, water, concentrated hydrochloric acid and Glacial acetic acid in reaction flask, control temperature 45 C～50 ℃ adding Transbroncho intermediate, stirring reaction 1～4 hour; Then be cooled to 20～30 ℃, add entry, crystallize out; Be cooled to again 0 ℃～5 ℃, growing the grain 2～4 hours, suction filtration, drying get Ambroxol HCl.
Above-mentioned steps a) in, described mass volume ratio to Trans-4-Amino Cyclohexanol and dehydrated alcohol is 1:15～22g/ml, preferred 1:17～19g/ml, more preferably 1:18g/ml;
Described mass ratio to Trans-4-Amino Cyclohexanol and potassium hydroxide is 1:1.5～1.7, preferred 1:1.65;
Described mass ratio to Trans-4-Amino Cyclohexanol and DMAP is 1:0.005～0.015, preferred 1:0.01;
Described mass ratio to Trans-4-Amino Cyclohexanol and 4-dimethylamino hexalin is 1:0.1～0.15, preferred 1:0.12;
Described mass ratio to Trans-4-Amino Cyclohexanol and the amino cylite of 3,5-, two bromo-2-di-acetyls is 1:2～6, preferred 1:4;
Described cooling is the period to be cooled to 5 ℃～10 ℃ in 1～2 hour, preferred 1.5 hours.
Above-mentioned steps b) in, the mass volume ratio of described intermediate and concentrated hydrochloric acid is 1:1～3g/ml, preferred 1:1.64g/ml;
The volume ratio of described ethanol, water, concentrated hydrochloric acid and Glacial acetic acid is 6.4:2.6:2.36:1;
Described stirring reaction is stirring reaction 2.5 hours; Described cooling is for being cooled to 25 ℃; Described growing the grain is growing the grain 3 hours.
Adding the volume of entry and the mass ratio of intermediate after the cooling is 3～4:1, preferred 3.33:1.
Compared with prior art, the present invention has following advantage:
(1) the present invention adopts gradient cooling, pass through process optimization, select 55 ℃-60 ℃, 45 ℃-48 ℃ of two main thermogrades crystallization of lowering the temperature, make the product more times remain on the steady district of crystal growth Jie, avoided in the Crystallization Process impurity to be wrapped in the lattice and separated out together, by the mode of this kind control crystallization, Ambroxol HCl only contains an impurity B in 5 known impurity, and the content of impurity B can be controlled at below 0.005%, product purity is increased to 99.9%;
(2) simultaneously, the present invention cooperates the synthesis technique of Ambroxol HCl crude product, adopt di-acetyl amino that main starting raw material activated nitrogen atom is protected fully, stopped the generation of phenyl ring 2 bit amino side reactions, difficult problems such as having overcome that the condensation side reaction is many in the prior art, productive rate is low, use that the sodium borohydride cost is high, catalytic hydrogenation processing condition harshness and potential safety hazard are large has formed that reaction scheme is short, mild condition, the little new synthetic process system of pollution;
(3) adopt the process for purification of Ambroxol HCl provided by the present invention that product dopant species and content are obviously reduced, purity improves, and 5 known impurity only contain one, and product purity reaches more than 99.9%; Total recovery is brought up to more than 67%; Single batch of production time shortens nearly 20 hours; Save solvent 91%; Cost is more than 30%.
Embodiment
Below by specific embodiment summary of the invention of the present invention is described further, but does not therefore limit content of the present invention.
[embodiment 1]
(1) the Transbroncho intermediate is synthetic
In the anhydrous reaction flask of cleaning, add 10g to Trans-4-Amino Cyclohexanol, the dehydrated alcohol that adds 180ml, the rapid stirring dissolving, the molten clear 16.5g potassium hydroxide that adds successively later, 0.1gDMAP, 1.2g4-dimethylamino hexalin, the control temperature 60 C slowly adds 40g formula (I) compound in batches, continue control temperature 60 C reaction 3 hours, after reaction finishes, control temperature 45 C decompression steams the dehydrated alcohol of 110ml, with 1 hour time processed of concentrate feed hydraulic control slow cooling to 5 ℃, and growing the grain 1 hour, suction filtration, drying gets the Transbroncho intermediate, does not need refining next step reaction that is directly used in.Reaction formula is as follows:
(2) the Ambroxol HCl crude product is synthetic
The ethanol that in the anhydrous reaction flask of cleaning, adds 160ml, add 65ml water, the concentrated hydrochloric acid of 59ml and the Glacial acetic acid of 25ml, the control temperature 45 C adds 36g Transbroncho intermediate, stirring reaction 1 hour, then be cooled to about 20 ℃, slowly add the water of 120ml, product is separated out in a large number, feed liquid is cooled to 0 ℃ of growing the grain 2 hours, the Ambroxol HCl crude product of suction filtration, drying.Yield 71%.Its reaction formula is as follows:
(3) Ambroxol HCl is refining
The water that in reaction flask, adds 260ml, the Ambroxol HCl crude product that adds 25g, being warming up to 70 ℃ stirred 1 hour, product dissolves substantially, add the 2.0g gac, keep 70 ℃ of decolourings 20 minutes, insulation is filtered, collect filtrate, slowly the filtrate temperature is down to 55 ℃, keep 20 rev/mins of this temperature and stirring velocitys, stirred 30 minutes, and then slowly feed temperature being cooled to 45 ℃, 15 rev/mins of control stirring velocitys add 0.5g Ambroxol HCl crystal seed, control this temperature and stirring velocity growing the grain 1 hour, and then with greenhouse cooling to 20 ℃ growing the grain 20 minutes, growing the grain finished again slow cooling to 10 ℃ left and right sides growing the grain 1.5 hours, suction filtration, the dry Ambroxol HCl finished product that gets.MS, ' HNMR conforms to structure.
[embodiment 2]
(1) the Transbroncho intermediate is synthetic
In the anhydrous reaction flask of cleaning, add 10g to Trans-4-Amino Cyclohexanol, the anhydrous methanol that adds 190ml, the rapid stirring dissolving, the molten clear 15g potassium hydroxide that adds successively later, 0.05gDMAP, 1.0g4-dimethylamino hexalin, control 75 ℃ of temperature and slowly add in batches 60g formula (I) compound, continue 75 ℃ of reactions of control temperature 1 hour, after reaction finishes, control temperature 55 ℃ of decompressions steam the dehydrated alcohol of 120ml, with concentrate feed hydraulic control time 2 h processed slow cooling to 10 ℃, and growing the grain 3 hours, suction filtration, drying gets the Transbroncho intermediate, does not need refining next step reaction that is directly used in.Reaction formula is with embodiment 1.
(2) the Ambroxol HCl crude product is synthetic
The ethanol that in the anhydrous reaction flask of cleaning, adds 160ml, add 65ml water, the concentrated hydrochloric acid of 36ml and the Glacial acetic acid of 25ml, the control temperature 50 C adds 36g Transbroncho intermediate, stirring reaction 4 hours, then be cooled to about 30 ℃, slowly add the water of 108ml, product is separated out in a large number, feed liquid is cooled to 5 ℃ of growing the grains 4 hours, the Ambroxol HCl crude product of suction filtration, drying.Yield 73%.Its reaction formula is with embodiment 1.
(3) Ambroxol HCl is refining
The water that in reaction flask, adds 260ml, the Ambroxol HCl crude product that adds 25g, being warming up to 75 ℃ stirred 1 hour, product dissolves substantially, add the 2.0g gac, keep 75 ℃ of decolourings 20 minutes, insulation is filtered, collect filtrate, slowly the filtrate temperature is down to 60 ℃, keep 20 rev/mins of this temperature and stirring velocitys, stirred 30 minutes, and then slowly feed temperature being cooled to 48 ℃, 15 rev/mins of control stirring velocitys add 0.5g Ambroxol HCl crystal seed, control this temperature and stirring velocity growing the grain 1 hour, and then with greenhouse cooling to 25 ℃ growing the grain 20 minutes, growing the grain finished again slow cooling to 10 ℃ left and right sides growing the grain 1.5 hours, suction filtration, the dry Ambroxol HCl finished product that gets.MS, ' HNMR conforms to structure.
[embodiment 3]
(1) the Transbroncho intermediate is synthetic
In the anhydrous reaction flask of cleaning, add 10g to Trans-4-Amino Cyclohexanol, the dehydrated alcohol that adds 180ml, the rapid stirring dissolving, the molten clear 16.5g potassium hydroxide that adds successively later, 0.1gDMAP, 1.2g4-dimethylamino hexalin, the control temperature 70 C slowly adds 40g formula (I) compound in batches, continue control temperature 70 C reaction 2 hours, after reaction finishes, control temperature 50 C decompression steams the dehydrated alcohol of 110ml, with 1.5 hours time processed of concentrate feed hydraulic control slow cooling to 8 ℃, and growing the grain 2 hours, suction filtration, drying gets the Transbroncho intermediate, does not need refining next step reaction that is directly used in.Reaction formula is with embodiment 1.
(2) the Ambroxol HCl crude product is synthetic
The ethanol that in the anhydrous reaction flask of cleaning, adds 160ml, add 65ml water, the concentrated hydrochloric acid of 59ml and the Glacial acetic acid of 25ml, 48 ℃ of addings of control temperature 36g Transbroncho intermediate, stirring reaction 3 hours, then be cooled to about 25 ℃, slowly add the water of 120ml, product is separated out in a large number, feed liquid is cooled to 3 ℃ of growing the grains 3 hours, the Ambroxol HCl crude product of suction filtration, drying.Yield 76%.Reaction formula is with embodiment 1.
(3) Ambroxol HCl is refining
The water that in reaction flask, adds 260ml, the Ambroxol HCl crude product that adds 25g, being warming up to 72 ℃ stirred 1 hour, product dissolves substantially, add the 2.0g gac, keep 772 ℃ of decolourings 20 minutes, insulation is filtered, collect filtrate, slowly the filtrate temperature is down to 58 ℃, keep 20 rev/mins of this temperature and stirring velocitys, stirred 30 minutes, and then slowly feed temperature being cooled to 46 ℃, 15 rev/mins of control stirring velocitys add 0.5g Ambroxol HCl crystal seed, control this temperature and stirring velocity growing the grain 1 hour, and then with greenhouse cooling to 22 ℃ growing the grain 20 minutes, growing the grain finished again slow cooling to 10 ℃ left and right sides growing the grain 1.5 hours, suction filtration, the dry Ambroxol HCl finished product that gets.MS, ' HNMR conforms to structure.
[embodiment 4]
(1) the Transbroncho intermediate is synthetic
In the anhydrous reaction flask of cleaning, add 10g to Trans-4-Amino Cyclohexanol, the dehydrated alcohol that adds 170ml, the rapid stirring dissolving, the molten clear 17g potassium hydroxide that adds successively later, 0.15gDMAP, 1.5g4-dimethylamino hexalin, control 65 ℃ of temperature and slowly add in batches 20g formula (I) compound, continue 65 ℃ of reactions of control temperature 2.5 hours, after reaction finishes, control temperature 48 ℃ of decompressions steam the dehydrated alcohol of 105ml, with 1.8 hours time processed of concentrate feed hydraulic control slow cooling to 7 ℃, and growing the grain 2.5 hours, suction filtration, drying gets the Transbroncho intermediate, does not need refining next step reaction that is directly used in.Reaction formula is with embodiment 1.
(2) the Ambroxol HCl crude product is synthetic
The ethanol that in the anhydrous reaction flask of cleaning, adds 160ml, add 65ml water, the concentrated hydrochloric acid of 108ml and the Glacial acetic acid of 25ml, 43 ℃ of addings of control temperature 36g Transbroncho intermediate, stirring reaction 2.5 hours, then be cooled to about 28 ℃, slowly add the water of 144ml, product is separated out in a large number, feed liquid is cooled to 2 ℃ of growing the grains 3.5 hours, the Ambroxol HCl crude product of suction filtration, drying.Yield 72%.Its reaction formula is with embodiment 1.
(3) Ambroxol HCl is refining
The water that in reaction flask, adds 260ml, the Ambroxol HCl crude product that adds 25g, being warming up to 74 ℃ stirred 1 hour, product dissolves substantially, add the 2.0g gac, keep 74 ℃ of decolourings 20 minutes, insulation is filtered, collect filtrate, slowly the filtrate temperature is down to 56 ℃, keep 20 rev/mins of this temperature and stirring velocitys, stirred 30 minutes, and then slowly feed temperature being cooled to 47 ℃, 15 rev/mins of control stirring velocitys add 0.5g Ambroxol HCl crystal seed, control this temperature and stirring velocity growing the grain 1 hour, and then with greenhouse cooling to 24 ℃ growing the grain 20 minutes, growing the grain finished again slow cooling to 10 ℃ left and right sides growing the grain 1.5 hours, suction filtration, the dry Ambroxol HCl finished product that gets.MS, ' HNMR conforms to structure.
Test example 1
This test example is for the content of the related substance of the Ambroxol HCl of the Ambroxol HCl that relatively adopts process for purification of the present invention to make and prior art.
Method: the mensuration of carrying out related substance according to European Pharmacopoeia version Ambroxol HCl in 2002 detection method.
Test 1: the Ambroxol HCl that the process for purification of the employing embodiment of the invention 1 makes;
Test 2: the Ambroxol HCl that the process for purification of the employing embodiment of the invention 2 makes;
Test 3: the Ambroxol HCl that the process for purification of the employing embodiment of the invention 3 makes;
Test 4: the Ambroxol HCl that the process for purification of the employing embodiment of the invention 4 makes;
Contrast 1: balcony Fuda, Zhejiang medication chemistry company limited produces, lot number 20111101;
Contrast 2: the Wuhan bio tech ltd production of prospering together;
Contrast 3: material chemical industry company limited produces in the Hubei;
Contrast 4: German Boehringer Ingelheim drugmaker produces;
Contrast 5: according to " synthesizing of Ambroxol HCl " [Yu Qian, Japanese plum army, Deng. synthesizing of Ambroxol HCl. Chinese Journal of Modern Applied Pharmacy, 2012,29(3): the 230-232] method of report " as starting raw material, making Ambroxol HCl through reactions such as bromo, reduction, oxidation, condensation, salifies with the 2-Methyl anthranilate " preparation.
Detected result sees the following form:
Table 1, the contrast of different Ambroxol HCl product impurity situation
As can be seen from the above table, compare than prior art, the hydrochloric acid ammonia bromine that adopts process for purification provided by the present invention to obtain only contains a kind of impurity B in 5 known impurity, and the content of impurity B can be controlled at below 0.005%.
Claims (10)
1. the process for purification of an Ambroxol HCl compound comprises synthesizing of Ambroxol HCl crude product and making with extra care of Ambroxol HCl, it is characterized in that, the refining of described Ambroxol HCl comprises the steps:
1) add entry and Ambroxol HCl crude product in reaction flask, be warming up to 70 ℃ of-75 ℃ of stirrings, dissolving crude product obtains the crude product solution of Ambroxol HCl; Add gac in crude product solution, keep 70 ℃ of-75 ℃ of decolourings, insulation is filtered, and collects filtrate;
2) the filtrate temperature is down to 55 ℃-60 ℃, keeps this temperature, stir;
3) again with filtrate greenhouse cooling to 45 ℃-48 ℃, 15 rev/mins of control stirring velocitys add the Ambroxol HCl crystal seed, control this temperature and stirring velocity growing the grain 1 hour;
4) and then with ℃ of-25 ℃ growing the grains of greenhouse cooling to 20 20 minutes, growing the grain finishes again slow cooling to 10 ℃ growing the grain 1.5 hours, suction filtration, dry Ambroxol HCl elaboration.
2. the process for purification of Ambroxol HCl compound according to claim 1 is characterized in that, the synthetic of described Ambroxol HCl crude product comprises the steps:
A) take formula (I) compound as starting raw material, DMAP and 4-dimethylamino hexalin are catalyzer, obtain intermediate under the condition of dehydrated alcohol and potassium hydroxide existence with to amino ring alcohol reaction;
B) under the condition that etoh solvent, water and Glacial acetic acid exist, intermediate and concentrated hydrochloric acid reaction are generated Ambroxol HCl.
3. the process for purification of Ambroxol HCl compound according to claim 1 and 2 is characterized in that, in Ambroxol HCl refining, the mass ratio of the volume of water and Ambroxol HCl crude product is 10.4:1 in the step 1).
4. the process for purification of Ambroxol HCl compound according to claim 1 and 2 is characterized in that, the decolouring described in the step 1) is decolouring 10-30 minute, preferred 20 minutes.
5. the process for purification of Ambroxol HCl compound according to claim 1 and 2 is characterized in that step 2) described in the stirring velocity that stirs be 18-22 rev/min, churning time is 25-35 minute; Preferred stirring velocity is 20 rev/mins, and churning time is 30 minutes.
6. the process for purification of Ambroxol HCl compound according to claim 1 and 2 is characterized in that, the add-on of Ambroxol HCl crystal seed is the 2wt% of Ambroxol HCl crude product in the step 3).
7. the process for purification of Ambroxol HCl compound according to claim 2, it is characterized in that, in Ambroxol HCl crude product synthetic, described step a) is: add the pure and mild dehydrated alcohol of amino ring in reaction flask, stirring and dissolving, the molten clear potassium hydroxide that adds successively later, DMAP and 4-dimethylamino hexalin, control temperature 60 C～75 ℃ add formula (I) compound in batches, continue control temperature 60 C～75 ℃ reaction 1～3 hour, after reaction finishes, control temperature 45 C～55 a ℃ decompression steams anhydrous methanol, will concentrate the feed liquid cooling, crystallize out, growing the grain 1～3 hour, suction filtration, drying gets the Transbroncho intermediate.
8. according to claim 2 or the process for purification of 7 described Ambroxol HCl compounds, it is characterized in that, described step b) is: add ethanol, water, concentrated hydrochloric acid and Glacial acetic acid in reaction flask, control temperature 45 C～50 ℃ adding Transbroncho intermediate, stirring reaction 1～4 hour; Then be cooled to 20～30 ℃, add entry, crystallize out; Be cooled to again 0 ℃～5 ℃, growing the grain 2～4 hours, suction filtration, drying get Ambroxol HCl.
9. the process for purification of Ambroxol HCl compound according to claim 7 is characterized in that, in the step a), described mass volume ratio to the pure and mild dehydrated alcohol of amino ring is 1:15～22g/ml, preferred 1:17～19g/ml, more preferably 1:18g/ml;
Described mass ratio to amino ring alcohol and potassium hydroxide is 1:1.5～1.7, preferred 1:1.65;
Described mass ratio to amino ring alcohol and DMAP is 1:0.005～0.015, preferred 1:0.01;
Described mass ratio to amino ring alcohol and 4-dimethylamino hexalin is 1:0.1～0.15, preferred 1:0.12;
Described mass ratio to amino ring alcohol and formula (I) compound is 1:2～6, preferred 1:4;
Described cooling is the period to be cooled to 5 ℃～10 ℃ in 1～2 hour, preferred 1.5 hours.
10. the process for purification of Ambroxol HCl compound according to claim 8 is characterized in that, in the step b), the mass volume ratio of described intermediate and concentrated hydrochloric acid is 1:1～3g/ml, preferred 1:1.64g/ml;
The volume ratio of described ethanol, water, concentrated hydrochloric acid and Glacial acetic acid is 6.4:2.6:2.36:1;
Described stirring reaction is stirring reaction 2.5 hours; Described cooling is for being cooled to 25 ℃; Described growing the grain is growing the grain 3 hours;
Adding the volume of entry and the mass ratio of intermediate after the cooling is 3～4:1, preferred 3.33:1.
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