CN104628577B - The synthetic method of Bisolvon - Google Patents
The synthetic method of Bisolvon Download PDFInfo
- Publication number
- CN104628577B CN104628577B CN201510034747.3A CN201510034747A CN104628577B CN 104628577 B CN104628577 B CN 104628577B CN 201510034747 A CN201510034747 A CN 201510034747A CN 104628577 B CN104628577 B CN 104628577B
- Authority
- CN
- China
- Prior art keywords
- bisolvon
- hydrogen chloride
- method preparing
- reaction
- 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.)
- Active
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to the preparation method of a kind of Bisolvon, the method is with 2 amino 3,5 dibromo benzaldehydes and N methyl cyclohexylamine are raw material, at catalyst and next step synthesis bromhexine free alkali of reducing agent existence condition, the bromhexine free alkali of generation and hydrogen chloride salt-forming reagent carry out salt-forming reaction and prepare Bisolvon；Wherein, sulfonic acid type catalyst Amberlyst 15 (H) selected by catalyst.The method significantly reducing reactions steps, shorten the production cycle, improve reaction yield, reduce production cost, the preparation method of the present invention is without using hypertoxicity reagent, and reaction condition is gentle, and to equipment without particular/special requirement, environmental pollution is little.
Description
Technical field
The invention belongs to chemical medicine synthesis field, a kind of method being specifically related to synthetic hydrochloric acid bromhexine.
Background technology
Bisolvon, chemical name is Bromhexine Hydrochloride, structure
Formula is as follows:
The Novel mucous dissolubility expectorant agent of the structure synthesis of its effective ingredient proposed according to medicinal plants Adhatoda vasica Nees,
There is the stronger effect dissolving glutinous expectorant, mucopolysaccharide Study On Fiber Differentiation and the cracking of apoplexy due to phlegm, the synthesis of suppression mucopolysaccharide can be made, make apoplexy due to phlegm
Sialic acid content reduces, thus reduces the viscosity of expectorant, makes sputum be prone to expectoration.Clinically for acute/chronic bronchitis, asthma,
Bronchiectasis, emophysematous treatment.
The preparation method of existing Bisolvon crude drug mainly has following several:
Method one (J. Label. Compd. Radiopharm 2005;48:429 434.): with 2-amino-3,5-
Dibromobenzoic acid is raw material, through condensing agent dicyclohexylcarbodiimide (DCC), catalyst DMAP (DMAP) and work
Agent N-hydroxy-succinamide (HOSu) activates, and is directly condensed prepares N-methyl-N-cyclohexyl-2-ammonia with N-methylcyclohexylamine
Base-3,5-dibromobenzene Methanamide, then prepare bromhexine free alkali through lithium borohydride reduction.
Method two (CN102617359B, CN102531922B, CN102924295B): 2-nitro bromobenzyl and N-methyl cyclohexane
Amine is initiation material, occurs aminating reaction to generate N-(2-nitrobenzyl)-N-methylcyclohexylamine, and this intermediate is under raney ni catalysis
Anti-raw ortho position nitro hydrogenation reduction reaction generates N-(2-amino benzyl)-N-methylcyclohexylamine, then obtains bromhexine trip through bromine bromo
From alkali, salt is become to obtain Bisolvon with hydrogen chloride.Or similar can also use hydrazine hydrate that nitro is reduced into amino, then with
Bromine generation substitution reaction, becomes salt to obtain Bisolvon with hydrogen chloride.This synthesis technique severe reaction conditions, makes in building-up process
With the reagent such as hydrazine hydrate, bromine, hydrazine hydrate toxicity is relatively big, and serious to personnel and environmental hazard, the use of simple substance bromine causes giving up
Water difficult treatment.
Method three (CN104003887A): with 2-amino-3,5-dibromo benzaldehyde is raw material, and aldehyde radical reduction is obtained 2-ammonia
Base-3,5-dibromobenzene methanol, then obtain 6 with double (trichloromethyl) carbonate reaction, 8-bis-bromo-1H-benzo [d] [1,3] oxazines-
2 (4H)-one, last and N-methylcyclohexylamine carries out open loop and prepares bromhexine free alkali.
Method four (CN102531922B): triacetic acid borate and 2-amino-3,5-dibromobenzene methanol reacts, and generates 2-ammonia
Base-3,5-dibromobenzene methanol chelate, then react generation bromhexine free alkali, last and hcl reaction with N-methylcyclohexylamine
Generate Bisolvon.
Method five (CN104003887A): with 2-amino-3,5-dibromobenzene methanol, as raw material, uses thionyl chloride to carry out
Chloro, then carry out aminating reaction with N-methylcyclohexylamine and obtain bromhexine free alkali, hydrochloric acid becomes salt to obtain Bisolvon.Or
Similar also can react with N-methylcyclohexylamine through p-methyl benzene sulfonic chloride catalysis under the conditions of-70 DEG C, becomes salt to prepare with hydrochloric acid
Bisolvon.This route operating procedure is few, but initiation material 2-amino-3,5-dibromobenzene methanol prices is expensive, sets production
Standby condition requires height.
In above-mentioned syntheti c route, there is initiation material or intermediate is not easy to obtain, intermediate is unstable, be difficult to monitor, reaction
Condition is harsh, the problems such as environmental pollution is big.
Summary of the invention
The technical problem to be solved is to provide a kind of method preparing Bisolvon.The synthesis side of the present invention
Method technique is simple, and reaction condition is gentle, and raw material is easy to get, and product yield is high, and environmental pollution is little.
For solve above-mentioned technical problem, the present invention by the following technical solutions:
Specifically, a kind of method preparing Bisolvon, the method comprises the steps:
(1) 2-amino-3,5 dibromo benzaldehyde and N-methylcyclohexylamine are carried out under catalyst and reducing agent existence condition
Reductive amination process one-step synthesis bromhexine free alkali；
(2) bromhexine free alkali and hydrogen chloride salt-forming reagent carry out salt-forming reaction and prepare Bisolvon.
Wherein, the reducing agent in step (1) is sodium borohydride or potassium borohydride, preferably sodium borohydride.
Reaction dissolvent in step (1) is oxolane, Isosorbide-5-Nitrae-dioxane or isopropyl ether, preferably oxolane.
Catalyst in step (1) is solid acid catalyst, preferably Amberlyst 15 (H), Amberlyst 15
(H) being a kind of sulfonic acid type catalyst, No. CAS is 9037-24-5, buys in Chengdu bass spy reagent company limited.
In step (1), reaction temperature is 10 ~ 40 DEG C, preferably 25 ~ 30 DEG C.
In step (1), 2-amino-3, the molal weight of 5 dibromo benzaldehydes and N-methylcyclohexylamine than for 1:1.1 ~
1.3, sodium borohydride and 2-amino-3, the molal weight ratio of 5 dibromo benzaldehydes is 2 ~ 3:1, the addition of catalyst and 2-amino-
The mass ratio of 3,5 dibromo benzaldehydes is 80 ~ 90mg:1g.
In the salt-forming reaction of step (2), described hydrogen chloride salt-forming reagent be hydrogen chloride gas, the alcoholic solution of hydrogen chloride or
The ethereal solution of hydrogen chloride；It is preferably the ethereal solution of hydrogen chloride；The more preferably 1,4-dioxane solution of hydrogen chloride.
Compared with prior art, the present invention, by changing synthetic route and reaction condition, uses raw material 2-cheap and easy to get
Amino-3,5 dibromo benzaldehydes and N-methylcyclohexylamine are at catalyst and next step synthesis bromhexine of reducing agent existence condition, significantly
Decrease reactions steps, shorten the production cycle；The Amberlyst 15 (H) using cheap environmental protection makees catalyst, shortens anti-
Between Ying Shi, improve reaction yield；Catalyst Amberlyst 15 (H) recyclable recycling, reduces production cost simultaneously；
The preparation method of the present invention is without using hypertoxicity reagent, and reaction condition is gentle, and to equipment without particular/special requirement, environmental pollution is little.
Detailed description of the invention
The 1,4-dioxane solution (content 4M) of hydrogen chloride is purchased from Shanghai Jing Chun biochemical technology limited company.
The preparation of embodiment 1 Bisolvon
(1) preparation of bromhexine free alkali
Take 2-amino-3,5 dibromo benzaldehyde and the N-methyl of 2.7g (0.0239mol) of 6.0 g (0.0215 mol)
Cyclohexylamine, adds the oxolane of 100mL, and at 25 DEG C, stirring makes its mix homogeneously, is then sequentially added into 0.5g
Amberlyst 15 (H), 1.7g sodium borohydride (0.0447mol), continue stirring, by TLC method, (HSGF254 silica gel plate launches
Agent: VPetroleum ether:VEthyl acetate=9:1) monitoring reaction process, after reaction terminating, filters mixture, adds 30mL saturated in filtrate
Saline solution, stratification, ether extraction (3 × 50mL), merge organic facies, washing, saturated common salt is washed, and anhydrous sodium sulfate is done
Dry, filter, concentrate and remove solvent, column chromatography (petroleum ether: ethyl acetate=9:1) obtains pale yellow oily liquid body 4.7g, yield
58%。
(2) preparation of Bisolvon
In the round-bottomed flask of 100mL, add 4.7g bromhexine, under condition of ice bath, add the Isosorbide-5-Nitrae-two of 20mL hydrogen chloride
Oxygen six ring solution (4M), continues stirring 30 ~ 60min, filters after adding, filter cake ethyl acetate is washed, and obtains Bisolvon
Crude product 4.8g, then with 20mL dehydrated alcohol recrystallization, obtain Bisolvon 4.3g, with raw material 2-amino-3,5-dibromobenzene
The productivity that formaldehyde calculates is 48%, fusing point 235-237 DEG C.
1H-NMR (CD3OD, 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 Bisolvon.
Claims (11)
1. the method preparing Bisolvon, it is characterised in that the method comprises the steps:
(1) 2-amino-3,5 dibromo benzaldehyde and N-methylcyclohexylamine carry out reduction amine under catalyst and reducing agent existence condition
Change reaction one-step synthesis bromhexine free alkali；
(2) bromhexine free alkali and hydrogen chloride salt-forming reagent carry out salt-forming reaction and prepare Bisolvon；
Wherein, the catalyst described in step (1) is Amberlyst 15 (H).
The method preparing Bisolvon the most as claimed in claim 1, it is characterised in that the reducing agent described in step (1)
For sodium borohydride or potassium borohydride.
The method preparing Bisolvon the most as claimed in claim 2, it is characterised in that reducing agent is sodium borohydride.
The method preparing Bisolvon the most as claimed in claim 1, it is characterised in that the reaction dissolvent in step (1) is
Oxolane, 1,4-dioxane or isopropyl ether.
The method preparing Bisolvon the most as claimed in claim 4, it is characterised in that the reaction dissolvent in step (1) is
Oxolane.
The method preparing Bisolvon the most as claimed in claim 1, it is characterised in that in step (1) reaction temperature be 10 ~
40℃。
The method preparing Bisolvon the most as claimed in claim 6, it is characterised in that in step (1) reaction temperature be 25 ~
30℃。
The method preparing Bisolvon the most as claimed in claim 1, it is characterised in that 2-amino-3,5 dibromo benzaldehydes and
The amount of the material of N-methylcyclohexylamine ratio for 1:1.1 ~ 1.3, sodium borohydride and 2-amino-3, the amount of the material of 5 dibromo benzaldehydes
Ratio is 2 ~ 3:1, the addition of catalyst and 2-amino-3, and the mass ratio of 5 dibromo benzaldehydes is 80 ~ 90mg:1g.
The method preparing Bisolvon the most as claimed in claim 1, it is characterised in that the hydrogen chloride described in step (2)
Salt-forming reagent is hydrogen chloride gas, the alcoholic solution of hydrogen chloride or the ethereal solution of hydrogen chloride.
The method preparing Bisolvon the most as claimed in claim 9, it is characterised in that the hydrogen chloride described in step (2)
Salt-forming reagent is the ethereal solution of hydrogen chloride.
11. methods preparing Bisolvon as claimed in claim 10, it is characterised in that the ethereal solution of described hydrogen chloride
1,4-dioxane solution for hydrogen chloride.
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 CN104628577A (en) | 2015-05-20 |
| CN104628577B true 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) |
Families Citing this family (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 |
| CN109535010B (en) * | 2018-12-27 | 2021-10-26 | 广州一品红制药有限公司 | Preparation 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333074B (en) * | 2013-07-02 | 2015-05-20 | 万邦德制药集团股份有限公司 | Production method of bromhexine hydrochloride |
-
2015
- 2015-01-24 CN CN201510034747.3A patent/CN104628577B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104628577A (en) | 2015-05-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104628577B (en) | The synthetic method of Bisolvon | |
| CN105820110B (en) | Mo Fanselin synthetic methods | |
| CN102659726B (en) | Method for synthesis of dronedarone | |
| CN103497226B (en) | Refinement method of methylamino abamectin benzoate | |
| CN100404497C (en) | Nitrile reducing process to prepare amine | |
| CN102010400B (en) | S-5-substituted-N-2'-(thiofuran-2-yl-) ethyl-1,2,3,4-tetranap-2-amine or chiral hydrochloric acid and application thereof to preparation of rotigotine | |
| CN102964268A (en) | Synthesis method of menthyl amide cooling agent | |
| CN101654419A (en) | Preparation method of fluvoxamine maleate | |
| CN112047883A (en) | Preparation method of cisatracurium besylate | |
| CN103896795B (en) | The preparation method and its usage of benzamide compound, its intermediate | |
| CN102199098B (en) | New synthesis method and application of (R)-N-benzyl-1-(4-methoxyphenyl)-2-propylamine | |
| CN108164423B (en) | Preparation method of naftifine hydrochloride | |
| CN104447355A (en) | Novel method for preparing bromhexine hydrochloride | |
| CN102050748B (en) | Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol | |
| CN111777520B (en) | Synthesis method of multi-substituted dimethylamino phenyl acetic acid compound | |
| CN101514163B (en) | Optically pure Sibutramine and process for preparing salt derivative thereof | |
| CN103242289B (en) | Preparation method of N,N-diallyl-(1R,2R)-2-aminomethyl-1-(2-thienyl)cyclopropanecarboxamide hydrochloride | |
| CN102164886A (en) | Process for the preparation of O-desmethylvenlafaxine | |
| CN112920053A (en) | Preparation method of chiral alpha-methyl aromatic ethylamine | |
| CN110790690A (en) | Synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid | |
| CN101407469A (en) | Preparation method of bupropion hydrochloride | |
| CN109942516A (en) | Compound R A is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone | |
| CN104003887A (en) | Preparation method of bromhexine hydrochloride | |
| CN104119238B (en) | A kind of preparation method of 4-(a chlorine difluoro-methoxy) aniline | |
| CN102993116A (en) | Preparation method of benzoxazine excitant |
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 |