CN107556204A - A kind of synthetic method of ambroxol hydrochloride - Google Patents
A kind of synthetic method of ambroxol hydrochloride Download PDFInfo
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- CN107556204A CN107556204A CN201610537395.8A CN201610537395A CN107556204A CN 107556204 A CN107556204 A CN 107556204A CN 201610537395 A CN201610537395 A CN 201610537395A CN 107556204 A CN107556204 A CN 107556204A
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- added dropwise
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- bromination
- ambroxol hydrochloride
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- 0 *c1cc(CBr)c(*)c(*)c1 Chemical compound *c1cc(CBr)c(*)c(*)c1 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N Cc(cccc1)c1N Chemical compound Cc(cccc1)c1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a kind of synthetic method of ambroxol hydrochloride.The step of method, is as follows：In first step bromination reaction, o-toluidine plus water are cooled, hydrobromic acid solution reaction is added dropwise, temperature control is added dropwise bromine, hydrogen peroxide and sodium hydroxide solution reaction, filters to obtain 2,4 dibromo 6 (bromomethyl) aniline at 30~60 DEG C.In second step aminating reaction, (bromomethyl) aniline of 2,4 dibromo 6 is warming up to 90~110 DEG C with secondary addition DMF, potassium carbonate, trans cvclohexvl hydramine by made from, is incubated 2~6hrs, adds toluene, stirring and crystallizing.Filtering, obtains ambroxol.The invention provides a kind of new technology of ambroxol hydrochloride synthesis, in phenyl ring part, reaction condition is dexterously controlled, chlorine is replaced with bromo to the halogen of ring and side chain respectively, successively bromination, a step is completed, so that the Ligature of phenyl ring and hexamethylene ring is selectively more preferable, yield is higher.
Description
(1) technical field
The present invention relates to a kind of synthetic method of ambroxol hydrochloride, especially one kind to replace chlorine using bromo, respectively to ring with
Side chain priority bromination, the new technology that a step is completed.
(2) background technology
Ambroxol hydrochloride is the new of mid-term Germany Boehringer Ingelheim companies exploitation listing the 1980s
Medicine, it is mucolytic agent, can increase the secretion of respiratory mucosa serous gland, reduces mucus glands secrete, is glued so as to reduce sputum
Degree, promote the secretion of pulmonary surfactant, increase bronchus ciliary movement, sputum is easy to expectoration.Being mainly used in treatment has
Phlegm but the patient brought up is not easy because sputum is sticky, or is dispelled for the acute and chronic broncho-pulmonary disease of expectoration dysfunction
Phlegm is treated, especially the disease such as AECB, temper of panting tracheitis, bronchial astehma.
The technique of past synthetic hydrochloric acid ambroxol mainly has following several method：
1. using acid or its homologue on stupid ring, amine, reducing agent sodium borohydride etc. is formed by imines with the amine of hexamethylene ring
Reduction.The shortcomings that this method is to need oxidation operation, and dangerous big, wastewater flow rate is big, esterification reduction, operating difficulties, route length, is received
Rate is low, and cost is high；It is as follows
2. utilizing benzaldehyde, imines, reducing agent sodium borohydride etc. is formed by imine reduction with the amine of hexamethylene ring.This method
Shortcoming is synthesizing benzaldehyde, benzoic acid or derivatives thereof, it is necessary to which oxidation operation, dangerous big, wastewater flow rate is big, and yield is low；Imines
Reduction amination, wastewater flow rate is big, there is hydrogen generation, course of reaction poor controllability in production process.It is as follows
My company is passed through to be studied for many years, and in summary each bar process route feature, is directed to green chemical industry technique always
Research and development, therefore chlorine is replaced using bromo in the present invention, respectively to ring and side chain priority bromination, the friendly process synthesis skill that a step is completed
Art, this technology are that a new technology has no report.
(3) content of the invention
The invention provides a kind of new technology of ambroxol hydrochloride synthesis, in phenyl ring part, reaction condition is dexterously controlled,
Chlorine is replaced with bromo to the halogen of ring and side chain respectively, successively bromination, a step is completed so that the Ligature of phenyl ring and hexamethylene ring selects
Selecting property is more preferable, and yield is higher.This technique does not add organic solvent, and waste water is recyclable to be applied mechanically, and is that an Atom economy is good, is received
Rate is high, and cost is low, free of contamination friendly process synthetic route.
The technical solution adopted by the present invention is as follows：
1. bromination
168g water is added into 1000ml four-hole bottles, 168.7g (1mol) o-toluidine, cools to 0~20 DEG C, is added dropwise
48% hydrobromic acid solution 168.5g (1mol), stir about 30 minutes, reaction system are faint yellow supernatant liquid；Temperature control is 30~60
DEG C, bromine 239.7g (1.5mol) is added dropwise, moment is added dropwise, solution has red, and about 3 seconds, red disappeared, and is added dropwise；Temperature control
At 30~60 DEG C, 27% hydrogen peroxide 31.5g (0.25mol) is added dropwise；60 DEG C~90 DEG C are kept stable at, continues that 27% dioxygen is added dropwise
Water 63g (0.5mol), is added dropwise, and is incubated 1~2 hour.10~20 DEG C are cooled to, 30% sodium hydroxide solution 133.3g is added dropwise
(1mol), PH=7 is adjusted, separates out a large amount of solids, filtered, washing obtains faint yellow solid 2,4- bis- bromo- 6- (bromomethyl) aniline.
Reaction equation is as follows：
2：Amination is coupled
The solid 333.5g (0.97mol) that the first step obtains is added in 2000 flasks, added in 1000mlDMF,
158.7g (1.15mol) potassium carbonate, 115.2g (1mol) trans cvclohexvl hydramine is added, is warming up to 90~110 DEG C, insulation 2~
6hrs, HPLC detect raw material 2, and 4- bis- bromo- 6- (bromomethyl) aniline residue is less than 0.3%, stop reaction, and insulation is filtered off except carbon
The solid of sour potassium and KBr, it is concentrated under reduced pressure near dry, addition 1000ml toluene, stirring and crystallizing.Filtering, drying obtain ambroxol
344.7g solid.Reaction equation is as follows：
3：Into salt
The drying solid 344.7g (0.912mol) that second step is obtained, 2000ml flasks are added to, add 1000g first
Alcohol, the concentrated hydrochloric acid 100.4g, ph for being added dropwise 34.8% are about 1, stir 1 hour, filter, washing, drying obtain 359.2g crystal into
Product solid.Reaction equation is as follows：
Reaction temperature described in the first step is carried out at 30 DEG C~60 DEG C, preferably 40 DEG C~50 DEG C.
The described reaction time is 1~5 hour, preferably 1~3 hour.
Compared with the prior art, its advantage is embodied in the present invention：The step of bromination one is completed, and technique does not add organic solvent,
Waste water is recyclable to be applied mechanically, and is that an Atom economy is good, high income, cost is low, free of contamination friendly process synthetic route.
(4) embodiment：
Technical scheme, but protection scope of the present invention not limited to this are illustrated with specific embodiment below.
Embodiment 1
First step bromination
168g water is added into 1000ml four-hole bottles, 168.7g (1mol) o-toluidine, cools to 0~20 DEG C, is added dropwise
34.8% concentrated hydrochloric acid solution 104.8g (1mol), stir about 30 minutes, reaction system are faint yellow supernatant liquid；Temperature control 30~
60 DEG C, bromine 239.7g (1.5mol) is added dropwise, moment is added dropwise, solution has red, and about 3 seconds, red disappeared, and is added dropwise；Control
27% hydrogen peroxide 31.5g (0.25mol) is added dropwise at 30~60 DEG C in temperature；60 DEG C~90 DEG C are kept stable at, continues to be added dropwise 27% pair
Oxygen water 63g (0.5mol), is added dropwise, and is incubated 1~2 hour.10~20 DEG C are cooled to, 30% sodium hydroxide solution is added dropwise
133.3g (1mol), PH=7 is adjusted, separates out a large amount of solids, filtered, washing obtains faint yellow solid 2, bromo- 6- (the bromine first of 4- bis-
Base) aniline, dry 333.5g, HPLC detection purity 99%, yield 97%.
Second step amination is coupled
The solid 333.5g (0.97mol) that the first step obtains is added in 2000 flasks, added in 1000mlDMF,
121.9g (1.15mol) sodium carbonate, 115.2g (1mol) trans cvclohexvl hydramine is added, is warming up to 90~110 DEG C, insulation 2~
6hrs, HPLC detect raw material 2, and 4- bis- bromo- 6- (bromomethyl) aniline residue is less than 0.3%, stop reaction, and insulation is filtered off except carbon
The solid of sour potassium and KBr, it is concentrated under reduced pressure near dry, addition 1000ml toluene, stirring and crystallizing.Filtering, drying obtain ambroxol
344.7g, HPLC detect purity 99.5%, yield 94%.
3rd step is into salt
The drying solid 344.7g (0.912mol) that second step is obtained, 2000ml flasks are added to, add 1000g first
Alcohol, the concentrated hydrochloric acid 100.4g, ph for being added dropwise 34.8% are about 1, are stirred 1 hour, are filtered, and washing, drying obtains 359.2g crystal and consolidated
Body, yield about 95%, HPLC detection purity 99.7%.
Embodiment 2
First step bromination
168g water is added into 1000ml four-hole bottles, 168.7g (1mol) o-toluidine, cools to 0~20 DEG C, is added dropwise
34.8% concentrated hydrochloric acid solution 104.8g (1mol), stir about 30 minutes, reaction system are faint yellow supernatant liquid；Temperature control 30~
60 DEG C, bromine 239.7g (1.5mol) is added dropwise, moment is added dropwise, solution has red, and about 3 seconds, red disappeared, and is added dropwise；Control
27% hydrogen peroxide 31.5g (0.25mol) is added dropwise at 30~60 DEG C in temperature；60 DEG C~90 DEG C are kept stable at, continues to be added dropwise 27% pair
Oxygen water 63g (0.5mol), is added dropwise, and is incubated 1~2 hour.10~20 DEG C are cooled to, 30% sodium hydroxide solution is added dropwise
133.3g (1mol), PH=7 is adjusted, separates out a large amount of solids, filtered, washing obtains faint yellow solid 2, bromo- 6- (the bromine first of 4- bis-
Base) aniline, dry 330g, HPLC detection purity 99.2%, yield 96%.
Second step amination is coupled
The solid 333.5g (0.97mol) that the first step obtains is added in 2000 flasks, added in 1000mlDMF,
121.9g (1.15mol) sodium carbonate, 115.2g (1mol) trans cvclohexvl hydramine is added, is warming up to 90~110 DEG C, insulation 2~
6hrs, HPLC detect raw material 2, and 4- bis- bromo- 6- (bromomethyl) aniline residue is less than 0.3%, stop reaction, and insulation is filtered off except carbon
The solid of sour potassium and KBr, it is concentrated under reduced pressure near dry, addition 1000ml toluene, stirring and crystallizing.Filtering, drying obtain ambroxol
338g (0.894mol), HPLC detect purity 99%, yield 92.2%.
3rd step is into salt
The drying solid 337.4g (0.894mol) that second step is obtained, 2000ml flasks are added to, add 1000g first
Alcohol, the concentrated hydrochloric acid 98.2g, ph for being added dropwise 34.8% are about 1, are stirred 1 hour, are filtered, and washing, drying obtains 359.6g crystal and consolidated
Body, yield about 97%, HPLC detection purity 99.7%.
Embodiment 3
First step bromination
168g water is added into 1000ml four-hole bottles, 168.7g (1mol) o-toluidine, cools to 0~20 DEG C, is added dropwise
34.8% concentrated hydrochloric acid solution 104.8g (1mol), stir about 30 minutes, reaction system are faint yellow supernatant liquid；Temperature control 30~
60 DEG C, bromine 239.7g (1.5mol) is added dropwise, moment is added dropwise, solution has red, and about 3 seconds, red disappeared, and is added dropwise；Control
27% hydrogen peroxide 31.5g (0.25mol) is added dropwise at 30~60 DEG C in temperature；60 DEG C~90 DEG C are kept stable at, continues to be added dropwise 27% pair
Oxygen water 63g (0.5mol), is added dropwise, and is incubated 1~2 hour.10~20 DEG C are cooled to, 30% sodium hydroxide solution is added dropwise
133.3g (1mol), PH=7 is adjusted, separates out a large amount of solids, filtered, washing obtains faint yellow solid 2, bromo- 6- (the bromine first of 4- bis-
Base) aniline, dry 330g, HPLC detection purity 99.3%, yield 96%.
Second step amination is coupled
The solid 333.5g (0.97mol) that the first step obtains is added in 2000 flasks, added in 1000mlDMF,
121.9g (1.15mol) sodium carbonate, 115.2g (1mol) trans cvclohexvl hydramine is added, is warming up to 90~110 DEG C, insulation 2~
6hrs, HPLC detect raw material 2, and 4- bis- bromo- 6- (bromomethyl) aniline residue is less than 0.3%, stop reaction, and insulation is filtered off except carbon
The solid of sour potassium and KBr, it is concentrated under reduced pressure near dry, addition 1000ml toluene, stirring and crystallizing.Filtering, drying obtain ambroxol
320g (0.894mol), HPLC detect purity 99%, yield 92.2%.
3rd step is into salt
The drying solid 337.4g (0.894mol) that second step is obtained, 2000ml flasks are added to, add 1000g first
Alcohol, the concentrated hydrochloric acid 98.2g, ph for being added dropwise 34.8% are about 1, are stirred 1 hour, are filtered, and washing, drying obtains 359.6g crystal and consolidated
Body, yield about 97%, HPLC detection purity 99.7%.
Embodiment 4
First step bromination
168g water is added into 1000ml four-hole bottles, 168.7g (1mol) o-toluidine, cools to 0~20 DEG C, is added dropwise
34.8% concentrated hydrochloric acid solution 104.8g (1mol), stir about 30 minutes, reaction system are faint yellow supernatant liquid；Temperature control 30~
60 DEG C, bromine 239.7g (1.5mol) is added dropwise, moment is added dropwise, solution has red, and about 3 seconds, red disappeared, and is added dropwise；Control
27% hydrogen peroxide 31.5g (0.25mol) is added dropwise at 30~60 DEG C in temperature；60 DEG C~90 DEG C are kept stable at, continues to be added dropwise 27% pair
Oxygen water 63g (0.5mol), is added dropwise, and is incubated 1~2 hour.10~20 DEG C are cooled to, 30% sodium hydroxide solution is added dropwise
133.3g (1mol), PH=7 is adjusted, separates out a large amount of solids, filtered, washing obtains faint yellow solid 2, bromo- 6- (the bromine first of 4- bis-
Base) aniline, dry 336.9g, HPLC detection purity 99.5%, yield 98%.
Second step amination is coupled
The solid 333.5g (0.97mol) that the first step obtains is added in 2000 flasks, added in 1000mlDMF,
121.9g (1.15mol) sodium carbonate, 115.2g (1mol) trans cvclohexvl hydramine is added, is warming up to 90~110 DEG C, insulation 2~
6hrs, HPLC detect raw material 2, and 4- bis- bromo- 6- (bromomethyl) aniline residue is less than 0.3%, stop reaction, and insulation is filtered off except carbon
The solid of sour potassium and KBr, it is concentrated under reduced pressure near dry, addition 1000ml toluene, stirring and crystallizing.Filtering, drying obtain ambroxol
341.6g (0.904mol), HPLC detect purity 99%, yield 92.2%.
3rd step is into salt
The drying solid 341.6g (0.904mol) that second step is obtained, 2000ml flasks are added to, add 1000g first
Alcohol, the concentrated hydrochloric acid 98.2g, ph for being added dropwise 34.8% are about 1, are stirred 1 hour, are filtered, and washing, drying obtains 363.4g crystal and consolidated
Body, yield about 97%, HPLC detection purity 99.7%.
Embodiment 5
First step bromination
168g water is added into 1000ml four-hole bottles, the stupid amine of 168.7g (1mol) adjacent methyl, cools to 0~20 DEG C, is added dropwise
34.8% concentrated hydrochloric acid solution 104.8g (1mol), stir about 30 minutes, reaction system are faint yellow supernatant liquid；Temperature control 30~
60 DEG C, bromine 239.7g (1.5mol) is added dropwise, moment is added dropwise, solution has red, and about 3 seconds, red disappeared, and is added dropwise；Control
27% hydrogen peroxide 31.5g (0.25mol) is added dropwise at 30~60 DEG C in temperature；60 DEG C~90 DEG C are kept stable at, continues to be added dropwise 27% pair
Oxygen water 63g (0.5mol), is added dropwise, and is incubated 1~2 hour.10-20 DEG C is cooled to, 30% sodium hydroxide solution is added dropwise
133.3g (1mol), PH=7 is adjusted, separates out a large amount of solids, filtered, washing obtains faint yellow solid 2, bromo- 6- (the bromine first of 4- bis-
Base) aniline, dry 336.9g, HPLC detection purity 99.5%, yield 97%.
Second step amination is coupled
The solid 333.5g (0.97mol) that the first step obtains is added in 2000 flasks, added in 1000mlDMF,
121.9g (1.15mol) sodium carbonate, 115.2g (1mol) trans cvclohexvl hydramine is added, is warming up to 90~110 DEG C, insulation 2~
6hrs, HPLC detect raw material 2, and 4- bis- bromo- 6- (bromomethyl) aniline residue is less than 0.3%, stop reaction, and insulation is filtered off except carbon
The solid of sour potassium and KBr, it is concentrated under reduced pressure near dry, addition 1000ml toluene, stirring and crystallizing.Filtering, drying obtain ambroxol
352g (0.931mol), HPLC detect purity 99%, yield 95%.
3rd step is into salt
The drying solid 341.6g (0.931mol) that second step is obtained, 2000ml flasks are added to, add 1000g first
Alcohol, the concentrated hydrochloric acid 98.6g, ph for being added dropwise 34.8% are about 1, are stirred 1 hour, are filtered, and washing, drying obtains 374.4g crystal and consolidated
Body, yield about 97%, HPLC detection purity 99.7%.
Claims (3)
1. a kind of synthetic method of ambroxol hydrochloride, it is characterised in that as follows the step of method：Replace chlorine with bromo, respectively to ring and
Side chain priority bromination, a step are completed.
2. a kind of synthetic method of described ambroxol hydrochloride is required according to right 1, it is characterised in that：In first step bromination reaction
In, in phenyl ring part, respectively to ring and side chain priority bromination, one-step synthesis.For temperature control at 40~50 DEG C, the reaction time is 1~3 small
When.
3. a kind of synthetic method of described ambroxol hydrochloride is required according to right 1, it is characterised in that：It is coupled in second step amination
Pendant moiety halogen replaces chlorine with bromo in reaction, and for temperature control at 90~110 DEG C, the reaction time is 1~4 hour.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072500A (en) * | 2019-11-15 | 2020-04-28 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of ambroxol hydrochloride |
| CN113444001A (en) * | 2021-06-29 | 2021-09-28 | 江西荣兴药业有限公司 | Ambroxol hydrochloride production process |
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| ES8502963A1 (en) * | 1983-09-17 | 1985-02-01 | Espanola De Especialidades Far | Cyclohexyl-amine deriv. |
| CN104402737A (en) * | 2014-10-13 | 2015-03-11 | 宁波天衡药业股份有限公司 | New method for preparing bromhexine hydrochloride |
| CN104788326A (en) * | 2015-05-13 | 2015-07-22 | 济南康和医药科技有限公司 | Synthesis method of ambroxol hydrochloride |
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2016
- 2016-07-01 CN CN201610537395.8A patent/CN107556204A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8502963A1 (en) * | 1983-09-17 | 1985-02-01 | Espanola De Especialidades Far | Cyclohexyl-amine deriv. |
| CN104402737A (en) * | 2014-10-13 | 2015-03-11 | 宁波天衡药业股份有限公司 | New method for preparing bromhexine hydrochloride |
| CN104788326A (en) * | 2015-05-13 | 2015-07-22 | 济南康和医药科技有限公司 | Synthesis method of ambroxol hydrochloride |
Non-Patent Citations (1)
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| TUYEN NGUYEN VAN等: ""Total synthesis of four naturally occurring 2-azaanthraquinone antibiotics, 6-deoxy-8-methylbostrycoidin, 6-deoxybostrycoidin, 7- O-demethyl-6-deoxybostrycoidin and scorpinone"", 《TETRAHEDRON》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072500A (en) * | 2019-11-15 | 2020-04-28 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of ambroxol hydrochloride |
| CN111072500B (en) * | 2019-11-15 | 2022-12-06 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of ambroxol hydrochloride |
| CN113444001A (en) * | 2021-06-29 | 2021-09-28 | 江西荣兴药业有限公司 | Ambroxol hydrochloride production process |
| CN113444001B (en) * | 2021-06-29 | 2023-09-08 | 江西荣兴药业有限公司 | Ambroxol hydrochloride production process |
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