CN104628577A - Method for synthesizing bromhexine hydrochloride - Google Patents
Method for synthesizing bromhexine hydrochloride Download PDFInfo
- Publication number
- CN104628577A CN104628577A CN201510034747.3A CN201510034747A CN104628577A CN 104628577 A CN104628577 A CN 104628577A CN 201510034747 A CN201510034747 A CN 201510034747A CN 104628577 A CN104628577 A CN 104628577A
- Authority
- CN
- China
- Prior art keywords
- bromhexine
- bromhexine hydrochloride
- prepare
- hydrogenchloride
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 Cc1c(*)cc(*)cc1COC(*)(*)C=* Chemical compound Cc1c(*)cc(*)cc1COC(*)(*)C=* 0.000 description 2
- KGHIESUBWNHHHF-UHFFFAOYSA-N [BH+]c(cc(C)cc1CN(C)C2CCCCC2)c1N Chemical compound [BH+]c(cc(C)cc1CN(C)C2CCCCC2)c1N KGHIESUBWNHHHF-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a method for preparing bromhexine hydrochloride. The method comprises the steps of synthesizing bromhexine free alkali from 2-amino-3,5-dibromo benzaldehyde and N-methyl cyclohexylamine in the presence of a catalyst and a reducer in one step, and enabling the produced bromhexine free alkali to undergo salt forming reaction with a hydrogen chloride salt forming reagent, thereby preparing bromhexine hydrochloride, wherein the catalyst is a sulfonic acid type catalyst Amberlyst<R>15(H). According to the method, the number of reaction steps is greatly reduced, the production cycle is shortened, the reaction yield is increased, and the production cost is reduced; the method disclosed by the invention has no need of using virulent reagents, is mild in reaction conditions and little in environmental pollution, and is free from special requirements on equipment.
Description
Technical field
The invention belongs to chemical medicine synthesis field, be specifically related to a kind of method of synthetic hydrochloric acid bromhexine.
Background technology
Bromhexine hydrochloride, chemical name is Bromhexine Hydrochloride, and structural formula is as follows:
The Novel mucous solvability Eradicates phlegm agent of the structure synthesis of its effective constituent proposed according to medicinal plant Adhatoda vasica Nees, stronger dissolving is had to stick the effect of phlegm, the mucopolysaccharide Study On Fiber Differentiation in phlegm and cracking can be made, suppress the synthesis of mucopolysaccharide, sialic acid content in phlegm is reduced, thus reduce the viscosity of phlegm, make sputum be easy to expectoration.Clinically for acute/chronic bronchitis, asthma, bronchiectasis, emophysematous treatment.
The preparation method of existing bromhexine hydrochloride bulk drug mainly contains following several:
Method one (J. Label. Compd. Radiopharm 2005; 48:429 – 434.): with 2-amino-3,5-dibromobenzoic acid is raw material, activate through condensing agent dicyclohexylcarbodiimide (DCC), catalyzer DMAP (DMAP) and activator N-hydroxy-succinamide (HOSu), direct and N-methylcyclohexylamine condensation obtains N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzene methane amide, then through the obtained bromhexine free alkali of lithium borohydride reduction.
Method two (CN102617359B, CN102531922B, CN102924295B): 2-nitro bromobenzyl and N-methylcyclohexylamine are starting raw material, there is amination reaction and generate N-(2-nitrobenzyl)-N-methylcyclohexylamine, this intermediate anti-raw ortho position nitro hydrogenation reduction reaction under raney ni catalysis generates N-(the amino benzyl of 2-)-N-methylcyclohexylamine, obtain bromhexine free alkali through bromine bromo again, obtain bromhexine hydrochloride with hydrogenchloride salify.Or nitroreduction is become amino by the similar hydrazine hydrate that also can use, then with bromine generation substitution reaction, obtain bromhexine hydrochloride with hydrogenchloride salify.This synthesis technique severe reaction conditions, employs the reagent such as hydrazine hydrate, bromine in building-up process, hydrazine hydrate toxicity is comparatively large, to personnel and environmental hazard serious, the use of simple substance bromine causes wastewater treatment difficulty.
Method three (CN104003887A): with 2-amino-3,5-dibromo benzaldehyde is raw material, aldehyde radical reduction is obtained 2-amino-3,5-dibromobenzene methyl alcohol, 6 are obtained again with two (trichloromethyl) carbonate reaction, 8-bis-bromo-1H-benzo [d] [1,3] oxazines-2 (4H)-one, last and N-methylcyclohexylamine carries out open loop and obtains bromhexine free alkali.
Method four (CN102531922B): nitrilotriacetic boric acid ester and 2-amino-3,5-dibromobenzene methyl alcohol reacts, and generates amino-3, the 5-dibromobenzene methyl alcohol inner complexs of 2-, react with N-methylcyclohexylamine and generate bromhexine free alkali, last and hcl reaction generates bromhexine hydrochloride.
Method five (CN104003887A): with amino-3, the 5-dibromobenzene methyl alcohol of 2-as raw material, uses thionyl chloride to carry out chloro, then carries out amination reaction with N-methylcyclohexylamine and obtain bromhexine free alkali, and hydrochloric acid salify obtains bromhexine hydrochloride.Or similar also can react through p-methyl benzene sulfonic chloride catalysis and N-methylcyclohexylamine under-70 DEG C of conditions, obtains bromhexine hydrochloride with hydrochloric acid salify.This route operation steps is few, but amino-3, the 5-dibromobenzene methanol prices of starting raw material 2-are expensive, high to production unit conditional request.
In above-mentioned syntheti c route, there is starting raw material or intermediate is not easy to obtain, intermediate is unstable, be difficult to monitoring, severe reaction conditions, the problems such as environmental pollution is large.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of method preparing bromhexine hydrochloride.Synthetic method craft of the present invention is simple, and reaction conditions is gentle, and raw material is easy to get, and product yield is high, and environmental pollution is little.
For solving the problems of the technologies described above, the present invention by the following technical solutions:
Particularly, a kind of method preparing bromhexine hydrochloride, the method comprises the steps:
(1) amino-3,5 dibromo benzaldehydes of 2-and N-methylcyclohexylamine carry out reductive amination process one-step synthesis bromhexine free alkali under catalyzer and reductive agent existence condition;
(2) bromhexine free alkali and hydrogenchloride salt-forming reagent carry out salt-forming reaction and obtain bromhexine hydrochloride.
Wherein, the reductive agent in step (1) is sodium borohydride or POTASSIUM BOROHYDRIDE, is preferably sodium borohydride.
Reaction solvent in step (1) is tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or isopropyl ether, is preferably tetrahydrofuran (THF).
Catalyzer in step (1) is solid acid catalyst, be preferably Amberlyst 15 (H), Amberlyst 15 (H) is a kind of sulfonic acid type catalyzer, and No. CAS is 9037-24-5, buys in the special reagent company limited of Chengdu bass.
In step (1), temperature of reaction is 10 ~ 40 DEG C, is preferably 25 ~ 30 DEG C.
In step (1), 2-amino-3, the molar mass of 5 dibromo benzaldehydes and N-methylcyclohexylamine is than being 1:1.1 ~ 1.3, sodium borohydride and 2-amino-3, the molar mass ratio of 5 dibromo benzaldehydes is 2 ~ 3:1, the mass ratio of the add-on of catalyzer and amino-3,5 dibromo benzaldehydes of 2-is 80 ~ 90mg:1g.
In the salt-forming reaction of step (2), described hydrogenchloride salt-forming reagent is hydrogen chloride gas, the alcoholic solution of hydrogenchloride or the ethereal solution of hydrogenchloride; Be preferably the ethereal solution of hydrogenchloride; Be more preferably the Isosorbide-5-Nitrae-dioxane solution of hydrogenchloride.
Compared with prior art, the present invention, by changing synthetic route and reaction conditions, uses amino-3,5 dibromo benzaldehydes of raw material 2-cheap and easy to get and N-methylcyclohexylamine at catalyzer and next step synthesis bromhexine of reductive agent existence condition, greatly reduce reactions steps, shorten the production cycle; Use the Amberlyst 15 (H) of cheap environmental protection to make catalyzer, shorten the reaction times, improve reaction yield; Catalyst A mberlyst 15 (H) recyclable recycling, reduces production cost simultaneously; Preparation method of the present invention is without the need to using hypertoxicity reagent, and reaction conditions is gentle, and to equipment without particular requirement, environmental pollution is little.
Embodiment
Isosorbide-5-Nitrae-the dioxane solution (content 4M) of hydrogenchloride is purchased from Shanghai Jing Chun biochemical technology limited-liability company.
The preparation of embodiment 1 bromhexine hydrochloride
(1) preparation of bromhexine free alkali
Get the 2-amino-3 of 6.0 g (0.0215 mol), the N-methylcyclohexylamine of 5 dibromo benzaldehydes and 2.7g (0.0239mol), add the tetrahydrofuran (THF) of 100mL, stirring at 25 DEG C makes it mix, then add 0.5g Amberlyst 15 (H) successively, 1.7g sodium borohydride (0.0447mol), continue to stir, with TLC method (HSGF254 silica-gel plate, developping agent: V
sherwood oil: V
ethyl acetate=9:1) monitor reaction process, after reaction terminating, mixture is filtered, 30mL saturated aqueous common salt is added, stratification, extracted with diethyl ether (3 × 50mL) in filtrate, merge organic phase, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filter, concentrated except desolventizing, column chromatography (sherwood oil: ethyl acetate=9:1) obtains pale yellow oily liquid body 4.7g, yield 58%.
(2) preparation of bromhexine hydrochloride
4.7g bromhexine is added in the round-bottomed flask of 100mL, under condition of ice bath, add the Isosorbide-5-Nitrae-dioxane solution (4M) of 20mL hydrogenchloride, add rear continuation stirring 30 ~ 60min, filter, filter cake ethyl acetate is washed, and obtains the crude product 4.8g of bromhexine hydrochloride, then uses 20mL dehydrated alcohol recrystallization, obtain bromhexine hydrochloride 4.3g, with the productive rate of amino-3, the 5-dibromo benzaldehydes calculating of raw material 2-for 48%, fusing point 235-237 DEG C.
1h-NMR (CD
3oD, 400MHz): δ 1.13-2.14 (m, 10H), 2.66 (s, 3H), 3.29-3.32 (m, 1H), 4.16-4.17 (m, 1H), 4.45-4.46 (m, 1H), 7.41-7.43 (m, 1H), 7.65-7.67 (m, 1H). through with standard substance comparison after, determine that the product obtained is bromhexine hydrochloride.
Claims (10)
1. prepare a method for bromhexine hydrochloride, it is characterized in that, the method comprises the steps:
(1) amino-3,5 dibromo benzaldehydes of 2-and N-methylcyclohexylamine carry out reductive amination process one-step synthesis bromhexine free alkali under catalyzer and reductive agent existence condition;
(2) bromhexine free alkali and hydrogenchloride salt-forming reagent carry out salt-forming reaction and obtain bromhexine hydrochloride.
2. prepare the method for bromhexine hydrochloride as claimed in claim 1, it is characterized in that, the reductive agent described in step (1) is sodium borohydride or POTASSIUM BOROHYDRIDE.
3. prepare the method for bromhexine hydrochloride as claimed in claim 2, it is characterized in that, reductive agent is preferably sodium borohydride.
4. prepare the method for bromhexine hydrochloride as claimed in claim 1, it is characterized in that, the reaction solvent in step (1) is tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or isopropyl ether.
5. prepare the method for bromhexine hydrochloride as claimed in claim 4, it is characterized in that, the reaction solvent in step (1) is preferably tetrahydrofuran (THF).
6. prepare the method for bromhexine hydrochloride as claimed in claim 1, it is characterized in that, the catalyzer described in step (1) is solid acid catalyst.
7. prepare the method for bromhexine hydrochloride as claimed in claim 6, it is characterized in that, the preferred Amberlyst 15 (H) of the catalyzer described in step (1).
8. prepare the method for bromhexine hydrochloride as claimed in claim 1, it is characterized in that, in step (1), temperature of reaction is 10 ~ 40 DEG C, is preferably 25 ~ 30 DEG C.
9. prepare the method for bromhexine hydrochloride as claimed in claim 1, it is characterized in that, 2-amino-3, the molar mass of 5 dibromo benzaldehydes and N-methylcyclohexylamine is than being 1:1.1 ~ 1.3, sodium borohydride and 2-amino-3, the molar mass ratio of 5 dibromo benzaldehydes is 2 ~ 3:1, and the mass ratio of the add-on of catalyzer and amino-3,5 dibromo benzaldehydes of 2-is 80 ~ 90mg:1g.
10. prepare the method for bromhexine hydrochloride as claimed in claim 1, it is characterized in that, the hydrogenchloride salt-forming reagent described in step (2) is hydrogen chloride gas, the alcoholic solution of hydrogenchloride or the ethereal solution of hydrogenchloride; Be preferably the ethereal solution of hydrogenchloride; Be more preferably the Isosorbide-5-Nitrae-dioxane solution of hydrogenchloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510034747.3A CN104628577B (en) | 2015-01-24 | 2015-01-24 | The synthetic method of Bisolvon |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510034747.3A CN104628577B (en) | 2015-01-24 | 2015-01-24 | The synthetic method of Bisolvon |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104628577A true CN104628577A (en) | 2015-05-20 |
| CN104628577B CN104628577B (en) | 2016-12-07 |
Family
ID=53207873
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510034747.3A Active CN104628577B (en) | 2015-01-24 | 2015-01-24 | The synthetic method of Bisolvon |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104628577B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461659A (en) * | 2014-09-28 | 2016-04-06 | 韶远科技（上海)有限公司 | Amplifiable synthetic method of aminobenzylamine compounds |
| CN106631828A (en) * | 2016-12-14 | 2017-05-10 | 成都新恒创药业有限公司 | Preparation method of bromhexine hydrochloride |
| CN109535010A (en) * | 2018-12-27 | 2019-03-29 | 广州品红制药有限公司 | A kind of preparation method of bromhexine hydrochloride |
| CN112194585A (en) * | 2020-10-29 | 2021-01-08 | 济南久隆医药科技有限公司 | Synthetic method of bromhexine hydrochloride |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333074A (en) * | 2013-07-02 | 2013-10-02 | 浙江万邦药业股份有限公司 | Production method of bromhexine hydrochloride |
-
2015
- 2015-01-24 CN CN201510034747.3A patent/CN104628577B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333074A (en) * | 2013-07-02 | 2013-10-02 | 浙江万邦药业股份有限公司 | Production method of bromhexine hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| 李付刚 等: "含溴医药的制备方法与生产现状(一)", 《精细与专用化学品》 * |
| 蒲洁琨 等: "盐酸溴己新的合成", 《中国医药工业杂志》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461659A (en) * | 2014-09-28 | 2016-04-06 | 韶远科技（上海)有限公司 | Amplifiable synthetic method of aminobenzylamine compounds |
| CN106631828A (en) * | 2016-12-14 | 2017-05-10 | 成都新恒创药业有限公司 | Preparation method of bromhexine hydrochloride |
| CN109535010A (en) * | 2018-12-27 | 2019-03-29 | 广州品红制药有限公司 | A kind of preparation method of bromhexine hydrochloride |
| CN109535010B (en) * | 2018-12-27 | 2021-10-26 | 广州一品红制药有限公司 | Preparation method of bromhexine hydrochloride |
| CN112194585A (en) * | 2020-10-29 | 2021-01-08 | 济南久隆医药科技有限公司 | Synthetic method of bromhexine hydrochloride |
| CN112194585B (en) * | 2020-10-29 | 2022-09-09 | 济南久隆医药科技有限公司 | Synthetic method of bromhexine hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104628577B (en) | 2016-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102617359B (en) | Method for preparing bromhexine hydrochloride | |
| CN104628577A (en) | Method for synthesizing bromhexine hydrochloride | |
| CN102924424B (en) | Method for synthesizing doxepin hydrochloride | |
| CN103601686A (en) | Method for synthesizing fluorine-containing pyrimidine compounds by virtue of one-pot method | |
| CN101863858A (en) | Synthetic method of bentazone | |
| CN103242197B (en) | Preparation method of ultraviolet absorbent intermediate etocrilene (ETO) | |
| CN103497226A (en) | Refinement method of methylamino abamectin benzoate | |
| CN102976961B (en) | Method for preparing methoxamine hydrochloride | |
| CN101654419A (en) | Preparation method of fluvoxamine maleate | |
| DE10212301A1 (en) | Process for the preparation of aryl aminopropanols | |
| CN101012147A (en) | Method of preparing R-(+)-3-chlorophenylpropanol | |
| CN105646285B (en) | One kind dimension Lactel sieve intermediate and its preparation method and application | |
| CN103601645A (en) | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof | |
| CN108164423B (en) | Preparation method of naftifine hydrochloride | |
| CN111777520B (en) | Synthesis method of multi-substituted dimethylamino phenyl acetic acid compound | |
| CN104447355A (en) | Novel method for preparing bromhexine hydrochloride | |
| CN106748966A (en) | A kind of synthetic method of Ramipril key intermediate | |
| CN109810059A (en) | A kind of preparation method of left-handed hydrochloric acid demethyl benzene ring pelargonate | |
| CN102936205B (en) | Synthesis method of tapentadol | |
| CN103288650A (en) | Hydrochloric acid 1-amino-3, 5-dimethyl adamantane preparation method | |
| CN104557604B (en) | Synthetic method for 5-acetylsalicylamide | |
| CN103242289A (en) | Preparation method of N,N-diallyl-(1R,2R)-2-aminomethyl-1-(2-thienyl)cyclopropanecarboxamide hydrochloride | |
| CN111303073A (en) | Method for preparing pesticide mefenacet by using benzothiazolone and 2-halogenated-N-methyl-N-phenyl acetamide | |
| CN104311469A (en) | Synthetic method of substituted indole-3-acetic acid | |
| CN101134740A (en) | Method for synthesizing ketorolac ammonia butanetriol key intermediate compound benzoyl pyrrole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20181114 Address after: 201203 room 304, Harley Road, Zhangjiang hi tech park, Pudong New Area, Shanghai, 1043 Patentee after: Shanghai Ding Ya pharmaceutical chemistry Science and Technology Ltd. Address before: 201203 Room 301, Harley Road, Zhangjiang hi tech park, Pudong New Area, Shanghai, 1043 Patentee before: SHANGHAI MOXUE PHARMACEUTICAL CO., LTD. |
|
| TR01 | Transfer of patent right |