CN103073438B - Ambroxol hydrochloride compound refining method - Google Patents
Ambroxol hydrochloride compound refining method Download PDFInfo
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- CN103073438B CN103073438B CN 201310045450 CN201310045450A CN103073438B CN 103073438 B CN103073438 B CN 103073438B CN 201310045450 CN201310045450 CN 201310045450 CN 201310045450 A CN201310045450 A CN 201310045450A CN 103073438 B CN103073438 B CN 103073438B
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- 238000000034 method Methods 0.000 title claims abstract description 46
- -1 Ambroxol hydrochloride compound Chemical class 0.000 title claims abstract description 26
- 238000007670 refining Methods 0.000 title claims abstract description 17
- 229960000985 ambroxol hydrochloride Drugs 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 79
- 238000003756 stirring Methods 0.000 claims abstract description 51
- 239000012043 crude product Substances 0.000 claims abstract description 36
- 230000008569 process Effects 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000001816 cooling Methods 0.000 claims abstract description 26
- 239000000706 filtrate Substances 0.000 claims abstract description 19
- 239000013078 crystal Substances 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 15
- 238000009413 insulation Methods 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 229960005174 ambroxol Drugs 0.000 claims description 106
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 claims description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 40
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 33
- 238000000746 purification Methods 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 238000000967 suction filtration Methods 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 229960000583 acetic acid Drugs 0.000 claims description 10
- 239000012362 glacial acetic acid Substances 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 8
- 229960004756 ethanol Drugs 0.000 claims description 8
- 230000006837 decompression Effects 0.000 claims description 7
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- 238000010792 warming Methods 0.000 claims description 6
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- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 claims description 2
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 27
- 239000012535 impurity Substances 0.000 abstract description 26
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 abstract description 15
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 abstract description 8
- 229910052799 carbon Inorganic materials 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 238000002386 leaching Methods 0.000 abstract 1
- IMLXLGZJLAOKJN-UHFFFAOYSA-N 4-aminocyclohexan-1-ol Chemical compound NC1CCC(O)CC1 IMLXLGZJLAOKJN-UHFFFAOYSA-N 0.000 description 12
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- 238000012360 testing method Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 230000028327 secretion Effects 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 206010036790 Productive cough Diseases 0.000 description 4
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 210000003097 mucus Anatomy 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- RCPAZWISSAVDEA-UHFFFAOYSA-N 2-amino-3,5-dibromobenzaldehyde Chemical compound NC1=C(Br)C=C(Br)C=C1C=O RCPAZWISSAVDEA-UHFFFAOYSA-N 0.000 description 3
- 206010062717 Increased upper airway secretion Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 230000008676 import Effects 0.000 description 3
- 239000003580 lung surfactant Substances 0.000 description 3
- 208000026435 phlegm Diseases 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 0 *c(c(Br)c1)c(*=C)cc1Br Chemical compound *c(c(Br)c1)c(*=C)cc1Br 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000000420 mucociliary effect Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- JBDGDEWWOUBZPM-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]-1-cyclohexanol Chemical compound NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 JBDGDEWWOUBZPM-UHFFFAOYSA-N 0.000 description 1
- SDMXLAZIFYYECU-UHFFFAOYSA-N COC(CC1)CCC1N Chemical compound COC(CC1)CCC1N SDMXLAZIFYYECU-UHFFFAOYSA-N 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010062530 Increased bronchial secretion Diseases 0.000 description 1
- XBFISNPWDYRTRZ-UHFFFAOYSA-N N.Cl.[Br] Chemical compound N.Cl.[Br] XBFISNPWDYRTRZ-UHFFFAOYSA-N 0.000 description 1
- 240000005049 Prunus salicina Species 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 210000002588 alveolar type II cell Anatomy 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
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- 230000000762 glandular Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- 229940102398 methyl anthranilate Drugs 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
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- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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 the hydrochloric acid NA-872 again, 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, go on the market in succession 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 major types, and wherein, injection liquid divides import and homemade two kinds, and the validity period of import Ambroxol HCl injection liquid is 5 years, and the validity period of homemade Ambroxol HCl injection liquid has only 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-1,4-dihydroquinazoline-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 import Ambroxol HCl 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, this 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; Stop 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%.
Though 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 handled.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 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, this 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 water in reaction flask and the Ambroxol HCl crude product, 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 slowly to be cooled to 10 ℃ of growing the grains again 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 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) be starting raw material with formula (I) compound, 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 " Transbroncho graphical Synthetic Routes " [Jia Weiyuan. the Transbroncho graphical Synthetic Routes. Chinese Journal of Pharmaceuticals, 1995,26(5): 235-237] route of 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, reaction finishes, and filters the washing of 20ml anhydrous methanol, merging filtrate, evaporated under reduced pressure.Adding is chilled to 0-5 ℃ 40%HBr aqueous solution 150ml in advance, and temperature control 10-15 ℃, stirring reaction 6h, reaction finishes the back and adds the 200ml methylene dichloride, stirring 30min, standing demix, organic layer 20g anhydrous sodium sulfate drying filters, and the filtrate decompression evaporate to dryness is namely.
In the prior art from 2-amino-3,5-dibromo bromobenzyl or 2-acetamido-3,5-dibromo bromobenzyl set out the synthetic hydrochloric acid Transbroncho method since amino do not protect, so above side reaction product can enter final product, influence 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 technology of 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 made up 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, realize quantitative reaction substantially, speed of reaction is fast; yield height (more than 95%); reduced former auxilliary 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 active higher functional groups amino 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 adopt 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%.
Synthetic method of the present invention can smooth implementation and is realized industrialization, 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 technology is difficult to fully always, developed a kind of original creation new catalyst at this reaction in the technology 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, the control temperature adds formula (I) compound for 60 ℃～75 ℃ in batches, continue 60 ℃～75 ℃ reactions of control temperature 1～3 hour, after reaction finishes, 45 ℃～55 ℃ decompressions of control temperature steam anhydrous methanol, will concentrate the feed liquid cooling, separate out crystal, 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, the control temperature adds Transbroncho intermediate, stirring reaction 1～4 hour for 45 ℃～50 ℃; Be cooled to 20～30 ℃ then, add water, separate out crystal; Be cooled to 0 ℃～5 ℃ again, 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.
The volume that adds water after the cooling and the mass ratio of intermediate are 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 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, overcome that the condensation side reaction is many in the prior art, productive rate is low, used difficult problems such as sodium borohydride cost height, catalytic hydrogenation processing condition harshness and potential safety hazard are big, formed reaction scheme weak point, 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 reduces 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 the Trans-4-Amino Cyclohexanol of 10g, the dehydrated alcohol that adds 180ml, quick stirring and dissolving, the molten clear 16.5g potassium hydroxide that adds successively later, 0.1gDMAP, 1.2g4-dimethylamino hexalin, the control temperature slowly adds 40g formula (I) compound for 60 ℃ in batches, continue 60 ℃ of reactions of control temperature 3 hours, after reaction finishes, 45 ℃ of decompressions of control temperature steam the dehydrated alcohol of 110ml, and the 1 hour time processed of concentrate feed hydraulic control slowly is cooled to 5 ℃, 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 adds 36g Transbroncho intermediate for 45 ℃, stirring reaction 1 hour, be cooled to then about 20 ℃, slowly add the water of 120ml, product is separated out in a large number, feed liquid was 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 slowly to be cooled to 10 ℃ of left and right sides growing the grains again 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 the Trans-4-Amino Cyclohexanol of 10g, the anhydrous methanol that adds 190ml, quick stirring and dissolving, the molten clear 15g potassium hydroxide that adds successively later, 0.05gDMAP, 1.0g4-dimethylamino hexalin, the control temperature slowly adds 60g formula (I) compound for 75 ℃ in batches, continue 75 ℃ of reactions of control temperature 1 hour, after reaction finishes, 55 ℃ of decompressions of control temperature steam the dehydrated alcohol of 120ml, and the 2 hours time processed of concentrate feed hydraulic control slowly is cooled to 10 ℃, 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 adds 36g Transbroncho intermediate for 50 ℃, stirring reaction 4 hours, be cooled to then about 30 ℃, slowly add the water of 108ml, product is separated out in a large number, feed liquid was 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 slowly to be cooled to 10 ℃ of left and right sides growing the grains again 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 the Trans-4-Amino Cyclohexanol of 10g, the dehydrated alcohol that adds 180ml, quick stirring and dissolving, the molten clear 16.5g potassium hydroxide that adds successively later, 0.1gDMAP, 1.2g4-dimethylamino hexalin, the control temperature slowly adds 40g formula (I) compound for 70 ℃ in batches, continue 70 ℃ of reactions of control temperature 2 hours, after reaction finishes, 50 ℃ of decompressions of control temperature steam the dehydrated alcohol of 110ml, and the 1.5 hours time processed of concentrate feed hydraulic control slowly is cooled to 8 ℃, 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, the control temperature adds 36g Transbroncho intermediate for 48 ℃, stirring reaction 3 hours, be cooled to then about 25 ℃, slowly add the water of 120ml, product is separated out in a large number, feed liquid was 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 slowly to be cooled to 10 ℃ of left and right sides growing the grains again 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 the Trans-4-Amino Cyclohexanol of 10g, the dehydrated alcohol that adds 170ml, quick stirring and dissolving, the molten clear 17g potassium hydroxide that adds successively later, 0.15gDMAP, 1.5g4-dimethylamino hexalin, the control temperature slowly adds 20g formula (I) compound for 65 ℃ in batches, continue 65 ℃ of reactions of control temperature 2.5 hours, after reaction finishes, 48 ℃ of decompressions of control temperature steam the dehydrated alcohol of 105ml, and the 1.8 hours time processed of concentrate feed hydraulic control slowly is cooled to 7 ℃, 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, the control temperature adds 36g Transbroncho intermediate for 43 ℃, stirring reaction 2.5 hours, be cooled to then about 28 ℃, slowly add the water of 144ml, product is separated out in a large number, feed liquid was 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 slowly to be cooled to 10 ℃ of left and right sides growing the grains again 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. contemporary Chinese is used pharmacy, 2012,29(3): the 230-232] method of Bao Dao " 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 below 0.005%.
Claims (14)
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 water in reaction flask and the Ambroxol HCl crude product, 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, low whipping speed is to stir 25-35 minute under 18-22 rev/min the condition;
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 slowly to be cooled to 10 ℃ of growing the grains again 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) be starting raw material with formula (I) compound, 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.
5. the process for purification of Ambroxol HCl compound according to claim 4 is characterized in that, the decolouring described in the step 1) is decolouring 20 minutes.
6. 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 20 rev/mins, churning time is 30 minutes.
7. 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).
8. 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, the control temperature adds formula (I) compound for 60 ℃～75 ℃ in batches, continues 60 ℃～75 ℃ reactions of control temperature 1～3 hour, after reaction finishes, 45 ℃～55 ℃ decompressions of control temperature steam anhydrous methanol, will concentrate the feed liquid cooling, separate out crystal, growing the grain 1～3 hour, suction filtration, drying gets the Transbroncho intermediate.
9. according to the process for purification of claim 2 or 8 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, the control temperature adds Transbroncho intermediate, stirring reaction 1～4 hour for 45 ℃～50 ℃; Be cooled to 20～30 ℃ then, add water, separate out crystal; Be cooled to 0 ℃～5 ℃ again, growing the grain 2～4 hours, suction filtration, drying get Ambroxol HCl.
10. the process for purification of Ambroxol HCl compound according to claim 8 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;
Described mass ratio to amino ring alcohol and potassium hydroxide is 1:1.5～1.7;
Described mass ratio to amino ring alcohol and DMAP is 1:0.005～0.015;
Described mass ratio to amino ring alcohol and 4-dimethylamino hexalin is 1:0.1～0.15;
Described mass ratio to amino ring alcohol and formula (I) compound is 1:2～6;
Described cooling is to be cooled to 5 ℃～10 ℃ the period in 1～2 hour.
11. the process for purification of Ambroxol HCl compound according to claim 10 is characterized in that, in the step a), described mass volume ratio to the pure and mild dehydrated alcohol of amino ring is 1:17～19g/ml;
Described mass ratio to amino ring alcohol and potassium hydroxide is 1:1.65;
Described mass ratio to amino ring alcohol and DMAP is 1:0.01;
Described mass ratio to amino ring alcohol and 4-dimethylamino hexalin is 1:0.12;
Described mass ratio to amino ring alcohol and formula (I) compound is 1:4;
Described cooling is to be cooled to 5 ℃～10 ℃ the period in 1.5 hours.
12. the process for purification of Ambroxol HCl compound according to claim 11 is characterized in that, in the step a), described mass volume ratio to the pure and mild dehydrated alcohol of amino ring is 1:18g/ml.
13. the process for purification of Ambroxol HCl compound according to claim 9 is characterized in that, in the step b), the mass volume ratio of described intermediate and concentrated hydrochloric acid is 1:1～3g/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;
The volume that adds water after the cooling and the mass ratio of intermediate are 3～4:1.
14. the process for purification of Ambroxol HCl compound according to claim 13 is characterized in that, in the step b), the mass volume ratio of described intermediate and concentrated hydrochloric acid is 1:1.64g/ml;
The volume that adds water after the cooling and the mass ratio of intermediate are 3.33:1.
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| CN103755577B (en) * | 2014-01-17 | 2015-11-18 | 浙江浙邦制药有限公司 | A kind of method reclaiming Transbroncho alkali from Ambroxol HCl refinement mother liquor |
| CN104211604B (en) * | 2014-08-18 | 2016-05-11 | 江苏正大清江制药有限公司 | Eutectic of a kind of ambroxol and P-hydroxybenzoic acid and preparation method thereof |
| CN104211605B (en) * | 2014-08-18 | 2016-04-27 | 江苏正大清江制药有限公司 | A kind of Transbroncho and m-Salicylic acid eutectic and preparation method thereof |
| CN104829467A (en) * | 2015-04-14 | 2015-08-12 | 天津梅花生物医药科技有限公司 | Ambroxol hydrochloride dihydrate compound |
| CN104803860B (en) * | 2015-05-12 | 2017-08-08 | 山东罗欣药业集团股份有限公司 | A kind of ambroxol compound and its pharmaceutical composition |
| CN105997903A (en) * | 2015-05-15 | 2016-10-12 | 苗怡文 | Ambroxol hydrochloride composition serving as medicine for treating respiratory system diseases |
| CN106349088A (en) * | 2015-05-15 | 2017-01-25 | 苗怡文 | Method for preparing crystals of ambroxol hydrochloride compound for treating respiratory diseases |
| CN106631837B (en) * | 2016-12-22 | 2019-04-16 | 合肥久诺医药科技有限公司 | A kind of refining methd of Ambroxol Hydrochloride for Injection |
| CN110229111B (en) * | 2019-05-08 | 2022-03-15 | 梯尔希（南京）药物研发有限公司 | Ambroxol impurity and preparation method and application thereof |
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