CN106631828A - Preparation method of bromhexine hydrochloride - Google Patents
Preparation method of bromhexine hydrochloride Download PDFInfo
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- CN106631828A CN106631828A CN201611156387.5A CN201611156387A CN106631828A CN 106631828 A CN106631828 A CN 106631828A CN 201611156387 A CN201611156387 A CN 201611156387A CN 106631828 A CN106631828 A CN 106631828A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
- C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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Abstract
The invention provides a preparation method of bromhexine hydrochloride. The method comprises the steps that 2-amino-3, 5-dibromo-benzene and N-methyl cyclohexane are used as the raw material, and bromhexine hydrochloride is obtained after reductive amination and salification. The reaction process comprises the steps that the transient state is generated by the reaction in-situ of 2-amino-3, 5-dibromo-benzene and N-methyl cyclohexane, and N-methyl cyclohexane and titanate; the generated transient state and a reducing agent create a reduction reaction, and bromhexine free alkaili is generated; the bromhexine free alkaili is salified and bromhexine hydrochloride is prepared. The reaction steps of the bromhexine hydrochloride are reduced by the method, the process is simple, easy to operate, and the reaction condition is mild, the required raw materials are easily obtainable, and industrial production is facilitated; the bromhexine hydrochloride is good in yield, high in purity, less in impurity content, and the safety and the effectiveness of drugs are guaranteed.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular to a kind of preparation method of bromhexine hydrochloride.
Background technology
Bromhexine hydrochloride (Bromhexine Hydrochloride, N- (2- amino -3,5- dibromo-benzyls)-N- methyl rings
Hexylamine hydrochloride) it is the medicine developed by Boehringer Ingelheim company, clinically for acute/chronic bronchitis, asthma, a gas
Enlargement of pipe, emophysematous treatment, are particularly suited for the difficult person that the viscous productive cough of white goes out, and draw because sputum extensively blocks bronchium
The grade disease out of breath risen.
At present, it is relatively more with regard to the synthesis technique document report of bromhexine hydrochloride, and comprehensive literature analysis finds, report
The synthetic method of bromhexine hydrochloride include it is following several, its synthetic route is as follows：
Route one
Route two
Route three
The condensing agent being related in the technique of route one is mostly dicyclohexylcarbodiimide (DCC), its hexamethylene of accessory substance two
Base urea (DCU) toxicity is big, and removal difficulty is larger, the drug safety of its residual venture influence bromhexine hydrochloride.The reaction of route two
Type is relatively simple, but processing step is long, cumbersome, long the production cycle；And be related in technical process security risk compared with
Big halogenating agent, the requirement to consersion unit is higher；Meanwhile, halogenating agent activity is higher, and the bromine on phenyl ring may be caused former
Son is substituted and produces side reaction, affects product quality.
Although the technique of route three is relatively simple：Under acetic acid catalytic condition, heating, toluene point water carry out condensation reaction, contract
The short production cycle.But the toluene of the route point water step needs pyroreaction, degree consersion unit to have high demands；Also exist simultaneously
Incomplete risk is reacted, there is security risk in industrialized production.
To sum up, there is provided a kind of preparation method of bromhexine hydrochloride, process is simple is easy to operate, reaction condition is gentle, reaction
Yield preferably, has preferably industrialization basis to become those skilled in the art's problem demanding prompt solution.
The content of the invention
The invention provides a kind of preparation method of bromhexine hydrochloride, the preparation method process is simple is easy to operate, reaction
Mild condition, yield is good, and purity is high, and impurity content is few, and needed raw material is easy to get, with good industrialization basis.
A kind of preparation method of bromhexine hydrochloride of the present invention, comprises the steps：
a：2- amino -3,5- dibromo benzaldehydes, N-methylcyclohexylamine and titanate esters react in a solvent generation transition state；
b：Transition state described in reducing agent in-situ reducing, generates bromhexine free alkali；
c：The bromhexine free alkali prepares bromhexine hydrochloride into salt；
Reaction equation is：
Preferably, the R is the straight chained alkyl or branched alkyl of C1-C6.
It is further preferred that the straight chained alkyl is methyl, ethyl, n-propyl, normal-butyl, the branched alkyl is isopropyl
Base, isobutyl group.
Preferably, in step a, 2- amino -3,5- dibromo benzaldehydes and the N-methylcyclohexylamine mole
Than for 1:0.8～1:4,2- amino -3,5- dibromo benzaldehydes are 1 with the mol ratio of the titanate esters:1～1:3.
It is further preferred that 2- amino -3,5- dibromo benzaldehydes are 1 with the mol ratio of the N-methylcyclohexylamine:2
～1:3.
Preferably, in step a, the solvent is molten selected from alcohols solvent, ether solvent, halogenated hydrocarbon solvent, nitrile
One or more in agent and sulfoxide type solvents.
It is further preferred that it is methyl alcohol, ethanol, isopropanol, n-butanol, tetrahydrofuran, Isosorbide-5-Nitrae-dioxy that the solvent is selected from
One or more in six rings, dichloromethane.
Preferably, in step b, one kind in sodium borohydride, potassium borohydride, the lithium borohydride of the reducing agent or
Several, 2- amino -3,5- dibromo benzaldehydes are 1 with the mol ratio of the reducing agent:0.3～1:3, it is step a, described
Step b, the reaction temperature of step c are -10～50 DEG C.
It is further preferred that the reaction temperature of step a, step b, step c is 20～30 DEG C.
Compared with prior art, beneficial effects of the present invention：
With 2- amino -3,5- dibromo benzaldehydes and N-methylcyclohexylamine are raw material to the present invention, Jing reduction aminations, are prepared into salt
Bromhexine hydrochloride.Bromhexine hydrochloride is prepared using the present invention, the reactions steps of bromhexine hydrochloride are shortened, and needed raw material is easy
.In the present invention, 2- amino -3, the aldehyde radical in 5- dibromo benzaldehyde structures can be with N- methyl rings at a temperature of -10～50 DEG C
Hexylamine and titanate esters react transition state of the generation containing ethylidene ether structure, and gained transition state need not isolate and purify, can direct quilt
Reducing agent reduction generates bromhexine free alkali.The technique can carry out in same reaction vessel, it is to avoid it is right to need in prior art
The step of intermediate product carries out isolated or purified.Present invention process is simple, easy to operate, and reaction condition is gentle, and needed raw material is easy
, be conducive to industrialized production.
Bromhexine hydrochloride yield is prepared using the present invention good, purity is high, impurity content is few, ensure that medicine it is safe,
Effectively.
Description of the drawings
Fig. 1 is the high resolution mass spectrum figure of bromhexine hydrochloride.
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of bromhexine hydrochloride.
Specific embodiment
Detailed description below can make more detailed description, but subject of the present invention model to present disclosure
Enclose and be not limited to specific examples below, every technology realized based on present invention, technique belong to the model of the present invention
Enclose.
Embodiment 1
Raw material in the present embodiment derives from commercially available.By 2.0g 2- amino -3,5- dibromo benzaldehydes, 1.2g N- methyl
Cyclohexylamine is dissolved in 20ml methyl alcohol, 4g tetraisopropyl titanates is slowly dropped in reactant liquor under the conditions of being stirred at room temperature, after adding
Continue that reaction 5h is stirred at room temperature；0.3g sodium borohydrides are dividedly in some parts in reactant liquor, reaction 2h is stirred at room temperature.TLC detection reactions
Completely.After reaction terminates, add 20ml water quenchings to go out reaction in reactant liquor, separate out a large amount of solids, filtration, filter cake ethyl acetate
Washing 3 times, merging filtrate and washing lotion, ethyl acetate extracts to obtain organic phase, has with sodium carbonate liquor, saturated common salt water washing successively
Machine phase.
Under room temperature, stirring condition, 5ml 6N hydrochloric acid, stirring and crystallizing 3h are instilled in above-mentioned organic phase.Filter one white
Solid, ethyl alcohol recrystallization, drying obtain 2.3g bromhexine hydrochlorides, yield：78%.HRMS-ESI(m/z):375.0051(M+H+)；1H-NMR (400MHz, CD3OD) δ=7.70 (d, 1H), 7.48 (d, 1H), 4.50 (d, 1H), 4.23 (d, 1H), 3.40～
3.34 (m, 1H), 2.70 (s, 3H), 2.18～2.09 (m, 2H), 1.97 (s, 2H), 1.76～1.57 (m, 3H), 1.47～1.37
(m, 2H), 1.27～1.24 (m, 1H) ppm.
Embodiment 2
Raw material in the present embodiment derives from commercially available.By 2.0g 2- amino -3,5- dibromo benzaldehydes, 4g N- methyl rings
Hexylamine is dissolved in 20ml methyl alcohol, 2g tetraisopropyl titanates is slowly dropped in reactant liquor under 10 DEG C of stirring conditions, after adding
Continue at 10 DEG C of stirring reactions 5h；0.3g sodium borohydrides are dividedly in some parts in reactant liquor, reaction 2h is stirred at room temperature.TLC detections are anti-
Should be complete.After reaction terminates, add 20ml water quenchings to go out reaction in reactant liquor, separate out a large amount of solids, filtration, filter cake acetic acid second
Ester washing 3 times, merging filtrate and washing lotion, ethyl acetate extracts to obtain organic phase, successively with sodium carbonate liquor, saturated common salt water washing
Organic phase.
Under 10 DEG C of stirring conditions, 10ml 6N hydrochloric acid, stirring and crystallizing 3h are instilled in above-mentioned organic phase.Filter one white
Color solid, ethyl alcohol recrystallization, drying obtain 2.1g bromhexine hydrochlorides, yield：71%.
Embodiment 3
Raw material in the present embodiment derives from commercially available.By 2.0g 2- amino -3,5- dibromo benzaldehydes, 1.2g N- methyl
Cyclohexylamine is dissolved in 20ml isopropanols, and 4g tetraisopropyl titanates are slowly dropped in reactant liquor under 30 DEG C of stirring conditions, plus
Continue that reaction 5h is stirred at room temperature after complete；0.3g sodium borohydrides are dividedly in some parts in reactant liquor, in 30 DEG C of stirring reactions 2h.TLC is examined
Survey reaction complete.After reaction terminates, add 20ml water quenchings to go out reaction in reactant liquor, separate out a large amount of solids, filtration, filter cake second
Acetoacetic ester washing 3 times, merging filtrate and washing lotion, ethyl acetate extracts to obtain organic phase, successively with sodium carbonate liquor, saturated aqueous common salt
Washing organic phase.
Under 30 DEG C of stirring conditions, 5ml 6N hydrochloric acid, stirring and crystallizing 3h are instilled in above-mentioned organic phase.Filter one white
Solid, ethyl alcohol recrystallization, drying obtain 2.4g bromhexine hydrochlorides, yield：81%.
Embodiment 4
Raw material in the present embodiment derives from commercially available.By 2.0g 2- amino -3,5- dibromo benzaldehydes, 1.2g N- methyl
Cyclohexylamine is dissolved in 20ml methyl alcohol, 4.9g butyl titanates is slowly dropped in reactant liquor under 0 DEG C of stirring condition, after adding
Continue at 0 DEG C of stirring reaction 6h；0.3g sodium borohydrides are dividedly in some parts in reactant liquor, reaction 2h is stirred at room temperature.TLC detection reactions
Completely.After reaction terminates, add 20ml water quenchings to go out reaction in reactant liquor, separate out a large amount of solids, filtration, filter cake ethyl acetate
Washing 3 times, merging filtrate and washing lotion, ethyl acetate extracts to obtain organic phase, has with sodium carbonate liquor, saturated common salt water washing successively
Machine phase.
Under 0 DEG C of stirring condition, 5ml 6N hydrochloric acid, stirring and crystallizing 3h are instilled in above-mentioned organic phase.Filter white solid
Body, ethyl alcohol recrystallization, drying obtain 2.0g bromhexine hydrochlorides, yield：68%.
Embodiment 5
Raw material in the present embodiment derives from commercially available.By 2.0g 2- amino -3,5- dibromo benzaldehydes, 2g N- methyl rings
Hexylamine is dissolved in 20ml1, in 4- dioxane, 4g tetraisopropyl titanates is slowly dropped into into reactant liquor under -10 DEG C of stirring conditions
In, -10 DEG C of stirring reactions 8h are continued at after adding；0.3g sodium borohydrides are dividedly in some parts in reactant liquor, reaction is stirred at room temperature
4h.TLC detection reactions are complete.After reaction terminates, add 20ml water quenchings to go out reaction in reactant liquor, separate out a large amount of solids, filtration,
Filter cake ethyl acetate is washed 3 times, merging filtrate and washing lotion, and ethyl acetate extracts to obtain organic phase, successively with sodium carbonate liquor, full
With brine It organic phase.
Under -10 DEG C of stirring conditions, 5ml 6N hydrochloric acid, stirring and crystallizing 3h are instilled in above-mentioned organic phase.Filter white
Solid, ethyl alcohol recrystallization, drying obtain 2.3g bromhexine hydrochlorides, yield：79%.
Embodiment 6
Raw material in the present embodiment derives from commercially available.By 2.0g 2- amino -3,5- dibromo benzaldehydes, 1.2g N- methyl
Cyclohexylamine is dissolved in 20ml methyl alcohol, and 4g tetraisopropyl titanates are slowly dropped in reactant liquor under 50 DEG C of stirring conditions, is added
After continue at 50 DEG C of stirring reactions 5h；0.5g potassium borohydrides are dividedly in some parts in reactant liquor, reaction 2h is stirred at room temperature.TLC is detected
Reaction is complete.After reaction terminates, add 20ml water quenchings to go out reaction in reactant liquor, separate out a large amount of solids, filtration, filter cake acetic acid
Ethyl ester washing 3 times, merging filtrate and washing lotion, ethyl acetate extracts to obtain organic phase, is washed with sodium carbonate liquor, saturated common salt successively
Wash organic phase.
Under 50 DEG C of stirring conditions, 5ml 6N hydrochloric acid, stirring and crystallizing 3h are instilled in above-mentioned organic phase.Filter white solid
Body, ethyl alcohol recrystallization, drying obtain 2.2g bromhexine hydrochlorides, yield：74%.
Embodiment 7
Comparative example：Bromhexine hydrochloride is prepared using the method for route in background technology one.
By 11g 2- amino -3,5- dibromobenzoic acids, 2g 4- dimethylamino pyridines and 5g N- hydroxysuccinimides
(HOSu) in being dissolved in 20mL dichloromethane, will be molten dissolved with the dichloromethane of 10g dicyclohexylcarbodiimides (DCC) under stirring condition
Liquid is slowly dropped in above-mentioned reactant liquor, continues stirring reaction, separates out a large amount of solids, continues to react 2h.By 18g N- methyl cyclohexanes
Amine is added in reactant liquor, stirring reaction 2h.TLC monitoring reactions are complete.Add 10mL 6N HCl that reaction is quenched in reactant liquor,
Filter, extract to obtain organic phase.
Under stirring condition, in above-mentioned organic phase 1.2g LiBH are dividedly in some parts4, after adding, it is heated to 40 DEG C of reactions.TLC
Monitoring reaction is complete.After reaction terminates, 20ml water quenchings are added to go out reaction in reactant liquor, dichloromethane extracts to obtain organic phase, according to
Secondary use sodium carbonate liquor, saturated common salt water washing organic phase.
Under stirring condition, 20ml 6N hydrochloric acid, stirring and crystallizing 3h are instilled in above-mentioned organic phase.Filter to obtain white solid, second
Alcohol is recrystallized, and obtains 9.5g bromhexine hydrochlorides, yield：62%.
Embodiment 8
Comparative example：Bromhexine hydrochloride is prepared using the method for route in background technology two.
11.2g 2- amino -3,5- dibromo benzaldehydes, 20ml absolute ethyl alcohols add in batches 0.95g, NaBH under stirring4,
Control temperature is at 10～40 DEG C, and heterogeneous reaction, TLC monitoring reactions are complete.After completion of the reaction, 50ml is added in reaction system
Water, the lower 2N hydrochloric acid that is added dropwise of stirring adjusts pH value of solution=5～6, continues to stir 30min, and solid is filtered, and filter cake is with water (20ml × 3)
Washing, is dried, and obtains reduzate for white solid.
Above-mentioned reduzate is dividedly in some parts in 30ml thionyl chlorides, 0～40 DEG C of keeping temperature during dropwise addition, is added dropwise
Finish stirring reaction under rear normal temperature, 3～4 hours reaction time.After completion of the reaction, will reduce pressure dense under excessive thionyl chloride normal temperature
Contracting, adds 20ml petroleum ethers in residue, stir 20min, filters, petroleum ether (10ml × 3) washing, drying under reduced pressure at 30 DEG C,
It is yellow solid to obtain chlorine band intermediate.
Above-mentioned chlorine band intermediate is dividedly in some parts in 11.34g N-methylcyclohexylamines, 20ml absolute ethyl alcohols is added, often
The lower stirring reaction of temperature.TLC monitors reaction process, 3～4 hours reaction time.After completion of the reaction, by the solvent under reduced pressure in reactant liquor
Concentration, 40ml ethyl acetate is added in residue, has solid to separate out, and continues to stir 20min, and solid is filtered, and filtrate is used
HCl/EA solution jumps pH=5～6, and stirring and crystallizing at being cooled to 0～5 DEG C is filtered, is dried, and obtains bromhexine hydrochloride crude product, methyl alcohol
It is recrystallized to give bromhexine hydrochloride about 6.8g, yield：41%.
Embodiment 9
Comparative example：Bromhexine hydrochloride is prepared using the method for route in background technology three.
Successively by 110g N-methylcyclohexylamines, 90g 2- amino -3,5- dibromo phenmethylols are added in reaction bulb, stirring
Under the conditions of add 50g glacial acetic acid and 60mL toluene in reactant liquor, a heating point water (about 110～120 DEG C of interior temperature, outer temperature about 130～
140 DEG C), TLC monitoring extent of reactions are no longer reduced to raw material.After reduced pressure concentration, the dissolving of 120mL ethanol is added, under stirring condition
Be added dropwise 6N HCl to solution system pH be 2, cooling crystallization overnight, is filtrated to get bromhexine hydrochloride crude product, be refining to obtain hydrochloric acid bromine oneself
New Testament 93g, yield：70%
Embodiment 10
The measure of impurity in bromhexine hydrochloride.Example 1-9 gained bromhexine hydrochlorides, determine impurity content.
Experimental technique：According to《Chinese Pharmacopoeia》(version in 2015, two) bromhexine hydrochloride【Check】Relevant substance-measuring under
Method is determined, and as a result be see the table below.
The dirt content test table of table 1
| Maximum single contaminant (%) | Total impurities (%) | |
| Embodiment 1 | 0.021 | 0.033 |
| Embodiment 2 | 0.037 | 0.058 |
| Embodiment 3 | 0.032 | 0.069 |
| Embodiment 4 | 0.043 | 0.062 |
| Embodiment 5 | 0.020 | 0.044 |
| Embodiment 6 | 0.041 | 0.072 |
| Embodiment 7 (comparative example) | 0.115 | 0.215 |
| Embodiment 8 (comparative example) | 0.076 | 0.144 |
| Embodiment 9 (comparative example) | 0.092 | 0.185 |
As shown in Table 1, maximum single contaminant and total impurities of the invention are better than process route one, the and of process route two
Process route three.
To sum up, the yield using the bromhexine hydrochloride obtained by the present invention is higher, and impurity content is less.And present invention process letter
Single, easy to operate, reaction condition is gentle, and needed raw material is easy to get, with good industrialization basis.
Above-described embodiment is only one of the preferred embodiment of the present invention, should not be taken to limit the protection model of the present invention
Enclose, as long as the body design thought and the change or polishing of having no essential meaning mentally made in the present invention, it is solved
Technical problem it is still consistent with the present invention, should be included within protection scope of the present invention.
Claims (10)
1. a kind of preparation method of bromhexine hydrochloride, it is characterised in that：Comprise the steps：
a：2- amino -3,5- dibromo benzaldehydes, N-methylcyclohexylamine and titanate esters react in a solvent generation transition state；
b：Transition state described in reducing agent in-situ reducing, generates bromhexine free alkali；
c：The bromhexine free alkali prepares bromhexine hydrochloride into salt；
Reaction equation is：
2. the preparation method of a kind of bromhexine hydrochloride according to claim 1, it is characterised in that：The R is straight for C1-C6's
Alkyl group or branched alkyl.
3. the preparation method of a kind of bromhexine hydrochloride according to claim 2, it is characterised in that：The straight chained alkyl is first
Base, ethyl, n-propyl, normal-butyl, the branched alkyl is isopropyl, isobutyl group.
4. the preparation method of a kind of bromhexine hydrochloride according to claim 1-3 any one, it is characterised in that：The step
In rapid a, 2- amino -3,5- dibromo benzaldehydes are 1 with the mol ratio of the N-methylcyclohexylamine:0.8～1:4, the 2-
Amino -3,5- dibromo benzaldehydes are 1 with the mol ratio of the titanate esters:1～1:3.
5. the preparation method of a kind of bromhexine hydrochloride according to claim 4, it is characterised in that：2- amino-the 3,5-
Dibromo benzaldehyde is 1 with the mol ratio of the N-methylcyclohexylamine:2～1:3.
6. the preparation method of a kind of bromhexine hydrochloride according to claim 1-3 any one, it is characterised in that：The step
In rapid a, the one kind of the solvent in alcohols solvent, ether solvent, halogenated hydrocarbon solvent, nitrile solvents and sulfoxide type solvents
Or it is several.
7. the preparation method of a kind of bromhexine hydrochloride according to claim 6, it is characterised in that：It is first that the solvent is selected from
One or more in alcohol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4- dioxane, dichloromethane.
8. the preparation method of a kind of bromhexine hydrochloride according to claim 1-3 any one, it is characterised in that：The step
In rapid b, one or more of the reducing agent in sodium borohydride, potassium borohydride, lithium borohydride, 2- amino -3,5-
Dibromo benzaldehyde is 1 with the mol ratio of the reducing agent:0.3～1:3.
9. the preparation method of a kind of bromhexine hydrochloride according to claim 1-3 any one, it is characterised in that：The step
Rapid a, step b, the reaction temperature of step c are -10～50 DEG C.
10. the preparation method of a kind of bromhexine hydrochloride according to claim 9, it is characterised in that：It is step a, described
Step b, the reaction temperature of step c are 20～30 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114195657A (en) * | 2022-02-21 | 2022-03-18 | 江苏中渊化学品有限公司 | Synthetic method of bromhexine hydrochloride suitable for industrialization |
| CN115108939A (en) * | 2021-03-17 | 2022-09-27 | 成都施贝康生物医药科技有限公司 | Intermediate of trans-4- [ (2-amino-3, 5-dibromo benzyl) amino ] -adamantan-1-ol and preparation method thereof |
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| CN102617359A (en) * | 2012-02-24 | 2012-08-01 | 石家庄东方药业有限公司 | Method for preparing bromhexine hydrochloride |
| CN104003887A (en) * | 2014-07-03 | 2014-08-27 | 余中华 | Preparation method of bromhexine hydrochloride |
| CN104628577A (en) * | 2015-01-24 | 2015-05-20 | 上海默学医药科技有限公司 | Method for synthesizing bromhexine hydrochloride |
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| CN102617359A (en) * | 2012-02-24 | 2012-08-01 | 石家庄东方药业有限公司 | Method for preparing bromhexine hydrochloride |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115108939A (en) * | 2021-03-17 | 2022-09-27 | 成都施贝康生物医药科技有限公司 | Intermediate of trans-4- [ (2-amino-3, 5-dibromo benzyl) amino ] -adamantan-1-ol and preparation method thereof |
| CN114195657A (en) * | 2022-02-21 | 2022-03-18 | 江苏中渊化学品有限公司 | Synthetic method of bromhexine hydrochloride suitable for industrialization |
| CN114195657B (en) * | 2022-02-21 | 2022-05-06 | 江苏中渊化学品有限公司 | Synthetic method of bromhexine hydrochloride suitable for industrialization |
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Application publication date: 20170510 |