CN103012167A - Preparation method of ambroxol hydrochloride - Google Patents
Preparation method of ambroxol hydrochloride Download PDFInfo
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- CN103012167A CN103012167A CN2012105432587A CN201210543258A CN103012167A CN 103012167 A CN103012167 A CN 103012167A CN 2012105432587 A CN2012105432587 A CN 2012105432587A CN 201210543258 A CN201210543258 A CN 201210543258A CN 103012167 A CN103012167 A CN 103012167A
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Abstract
The invention discloses a preparation method of ambroxol hydrochloride. According to the preparation method, a 'one-pot reaction' is adopted in the reaction, so that the separation of an intermediate is avoided, the operation is simple, the production period is short, the production cost is reduced, and the method is suitable for industrial production and application; the operation in refining the ambroxol hydrochloride is easy to carry out; and the ambroxol hydrochloride with purity more than 99.9% can be simply obtained by one-time recrystallization, so that the demand on preparation production can be met.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of preparation method of Ambroxol HCl, specifically refer to a kind of technique that adopts one kettle way to prepare Ambroxol HCl.
Background technology
Ambroxol HCl, chemical name is: the Ambroxol hydrochloride, chemical structural formula is:
。
Ambroxol HCl is the mucolytic by the research and development of German Boehringer Ingelheim company, is 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, and it has determined curative effect, low toxin.Ambroxol HCl can act on secretory cell, regulates the secretion of slurries and mucus, and serous secretion is increased, the mucus dissolved dilution, and can strengthen the swing of cilium, and increase the removing ability of mucus haulage system, make sputum be easy to discharge.
Ambroxol HCl also is a kind of respiratory system protective material, has that anti-oxidant, inflammation-inhibiting medium discharges, lax airway smooth muscle, promotes the effects such as synthetic and secretion of pulmonary surfactant.Ambroxol HCl can also increase the drug level of microbiotic in air flue, thereby improves antibiotic curative effect.
Disclose a kind of synthetic route of Ambroxol HCl in " Ambroxol HCl technological innovation " that Yuan Chunhu delivers, with 2-amino-3, the 5-dibromo benzaldehyde is starting raw material, makes Ambroxol HCl through two-step reaction, and detailed process is
A kind of synthetic method of Ambroxol HCl is disclosed in " synthesizing of Ambroxol HCl " literary composition that the people such as Yu Qian deliver, wherein 3,5-two bromo-2-aminobenzaldehydes and the condensation of trans-4-amino hexalin, condensation product is refining with zellon, obtain anti--4-[(2-ammonia-3,5-dibromobenzene methylene radical) amino] hexalin (schiff bases), add sodium borohydride reduction after it is dissolved in anhydrous methanol, then get the Transbroncho crude product through aftertreatments such as extractions, make the Ambroxol HCl crude product with the concentrated hydrochloric acid reaction, make the Ambroxol HCl finished product through the crystal again.Reaction scheme is:
The disclosed routes of people such as the method reaction scheme and Yuan Chunhu are identical, and intermediate is anti--4-[(2-ammonia-3,5-dibromobenzene methylene radical) amino] hexalin also needs to separate separately.In addition, use the multi-solvents such as methylene dichloride, zellon in the method, will certainly cause to a certain degree pollution to environment.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of Ambroxol HCl, the method reaction process adopts " one kettle way " to carry out, reaction times is short, intermediate need not to separate, easy and simple to handle, greatly reduce simultaneously use kind and the usage quantity of solvent, reduced the pollution to environment.
Technical problem to be solved by this invention solves by the following technical programs.
A kind of preparation method of Ambroxol HCl operates by following reaction scheme,
, wherein, III is the product schiff bases of condensation reaction, II is the product Transbroncho alkali of reduction reaction, and I is the product Ambroxol HCl that obtains behind the Transbroncho alkali salify, and this reaction process adopts one kettle way to carry out, the intermediate III is not separated with II, and reaction process is not changed solvent.
Above-mentioned preparation method, the solvent of described reaction process is selected from and can makes 2-amino-3, alcohol, ketone, the nitrile of 5-dibromo benzaldehyde and trans-4-amino hexalin and product schiff bases homogenizing thereof, specifically be selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, acetone, acetonitrile, the ethylene glycol one or more, particular methanol, ethanol.Whole reaction process is not changed solvent.
The preparation method of above-mentioned Ambroxol HCl, the operation steps of described reaction process is:
A. condensation: 2-amino-3,5-dibromo benzaldehyde and trans-4-amino hexalin stir in solvent, and the temperature control reaction gets schiff bases solution;
B. reduction: the schiff bases solution temperature control with step a obtains, add sodium borohydride or lithium aluminum hydride under the agitation condition, the temperature control reaction gets the Transbroncho alkaline solution;
C. salify: with the Transbroncho alkaline solution cooling that step b obtains, regulate pH value with hydrochloric acid soln under the agitation condition, the temperature control reaction is filtered, and washs, and drying gets Ambroxol HCl.
Above-mentioned preparation method, 2-amino-3 among the step a, the mol ratio of 5-dibromo benzaldehyde and trans-4-amino hexalin is 1:1-2, preferred 1:1.2; Temperature of reaction is 40 ℃-solvent boiling point temperature, preferred 60 ℃-65 ℃; Reaction times is 3-8h.
Above-mentioned preparation method, the sodium borohydride that adds among the step b or the molar weight of lithium aluminum hydride are the 2-amino-3 among the step a, 5-dibromo benzaldehyde 1.1-1.5 times, and preferred 1.2 times; Temperature of reaction is 0 ℃-40 ℃, preferred 20 ℃-30 ℃; Reaction times is 6h.Preferred 20 ℃-30 ℃ of temperature can make temperature of reaction and carries out fast herein, and the temperature low reaction is slower, reaction not exclusively, the high reaction of temperature is violent, can produce more impurity.
Above-mentioned preparation method, the Transbroncho alkaline solution is cooled to 10 ℃-20 ℃ among the step c.
Above-mentioned preparation method, regulating the pH value among the step c is 1-4, preferred 2-3.When the pH value was 2-3, products obtained therefrom was that white and yield are higher, and pH value too low production color is partially yellow, and too the high product yield is on the low side for the pH value.
Above-mentioned preparation method, the temperature of step c reaction is 0 ℃-20 ℃, preferred 0 ℃-5 ℃, the time of reaction is 2-6h.When temperature of reaction was 0 ℃-5 ℃, product yield was higher.
The preparation method of above-mentioned Ambroxol HCl, the operation steps of described reaction process is preferably:
A. condensation: 2-amino-3,5-dibromo benzaldehyde and trans-4-amino hexalin stir in solvent, and the temperature control reaction gets schiff bases solution;
B. reduction: the schiff bases solution temperature control with step a obtains, add sodium borohydride or lithium aluminum hydride under the agitation condition, the temperature control reaction gets the Transbroncho alkaline solution;
C. salify: with the Transbroncho alkaline solution cooling that step b obtains, regulate pH value with hydrochloric acid soln under the agitation condition, the temperature control reaction is filtered, and washs, and drying gets the Ambroxol HCl crude product;
D. refining: add solvent in the Ambroxol HCl crude product that obtains to step c, heating, stir, activated carbon decolorizing, the temperature control crystallization filters, washing, drying namely gets the Ambroxol HCl finished product.
Above-mentioned preparation method, solvent is the mixed solvent of methyl alcohol and other solvent in the steps d, described other solvent is selected from one or more in water, propyl alcohol, Virahol, butanols, ethylene glycol, acetone, acetonitrile, ethylene glycol, methylene dichloride, chloroform, sherwood oil, the isopropyl ether, preferably water; The volume ratio of methyl alcohol and other solvent is 1:1-19, preferred 1:1.
Above-mentioned preparation method, the temperature of crystallization is-5 ℃ ~ 10 ℃ in the steps d, preferred 0 ℃ ~ 5 ℃, the time of crystallization is 4-10h, preferred 8h.When recrystallization temperature was 0 ℃ ~ 5 ℃, yield was higher and energy consumption is lower.
Ambroxol HCl preparation method's of the present invention advantage is:
1) the method for the invention adopts the mode of " treating different things alike " to carry out condensation, reduction, salt-forming reaction, avoided obtaining step by step intermediate complicated loaded down with trivial details last handling process and corresponding operation, simple to operate, the simultaneous reactions time shortens, shorten the production cycle, reduced energy consumption and cost;
The reaction process of 2) " treating different things alike " in the method for the invention need not to change solvent, greatly reduced use kind and the usage quantity of solvent, thereby has reduced the environmental pollution that toxicity that dissolvent residual causes and organic solvent cause;
3) treating process easy handling in the preferred method of the present invention only need carry out a recrystallization and can obtain purity at the product more than 99.9%, and yield can reach more than 80%, and other quality index all meets medicinal standard, is suitable for use as medicinal raw material.
Embodiment
The present invention is further detailed explanation below in conjunction with specific embodiment.
Embodiment 1
With 100ml methyl alcohol, 2-amino-3,5-dibromo benzaldehyde (10.0g, 35.9mmol), trans-4-amino hexalin (5.0g, 43.4mmol) joins in the reactor, be heated to backflow (60 ℃～65 ℃) under stirring, insulation reaction 6h, the TLC monitoring reaction is complete, then be cooled to 30 ℃～40 ℃, add sodium borohydride (2.1g, 55.5mmol), finish, insulation reaction 6h, the TLC monitoring reaction is complete, be incubated completely, reaction solution is cooled to 10 ℃～20 ℃, stir lower to hydrochloric acid soln adjust pH=1, be cooled to 5 ℃～10 ℃, insulation reaction 6h filters rinsing, dry, get Ambroxol HCl crude product 12.1g, yield 81.4%, purity 99.30%.
Get Ambroxol HCl crude product 10g, stir the lower 30% methanol aqueous solution 70ml that slowly adds, be heated to backflow, to all dissolvings, activated carbon decolorizing, cooling in 0 ℃～5 ℃ insulation crystallization 8h, is filtered, rinsing, drying gets Ambroxol HCl finished product 8.45g, yield 84.5%.
Embodiment 2
With 100ml methyl alcohol, 2-amino-3,5-dibromo benzaldehyde (10.0g, 35.9mmol), trans-4-amino hexalin (5.0g, 43.4mmol) joins in the reactor, be heated to backflow (60 ℃～65 ℃) under stirring, insulation reaction 3h, the TLC monitoring reaction is complete, then be cooled to 30 ℃～35 ℃, add sodium borohydride (1.63g, 43.1mmol), finish, insulation reaction 6h, the TLC monitoring reaction is complete, be incubated completely, reaction solution is cooled to 10 ℃～20 ℃, stir lower to hydrochloric acid soln adjust pH=2, be cooled to 0 ℃～5 ℃, insulation reaction 4h filters rinsing, dry, get Ambroxol HCl crude product 13.0g, yield 87.5%, purity 99.48%.
Get Ambroxol HCl crude product 10g, stir the lower 50% methanol aqueous solution 70ml that slowly adds, be heated to backflow, to all dissolvings, activated carbon decolorizing, cooling in 0 ℃～5 ℃ insulation crystallization 8h, is filtered, rinsing, drying gets Ambroxol HCl finished product 8.48, yield 84.8%.
Embodiment 3
With 100ml methyl alcohol, 2-amino-3,5-dibromo benzaldehyde (10.0g, 35.9mmol), trans-4-amino hexalin (4.53g, 39.3mmol) joins in the reactor, be heated to backflow (60 ℃～65 ℃) under stirring, insulation reaction 8h, the TLC monitoring reaction is complete, then be cooled to 20 ℃～30 ℃, add lithium aluminum hydride (1.63g, 43.0mmol), finish, insulation reaction 6h, the TLC monitoring reaction is complete, be incubated completely, reaction solution is cooled to 10 ℃～20 ℃, stir lower to hydrochloric acid soln adjust pH=2, be cooled to 10 ℃～15 ℃, insulation reaction 5h filters rinsing, dry, get Ambroxol HCl crude product 12.3g, yield 82.8%, purity 99.27%.
Get Ambroxol HCl crude product 10g, stir lower methyl alcohol and acetone (volume ratio 1:3) the mixing solutions 200ml of slowly adding, be heated to backflow, to all dissolvings, activated carbon decolorizing, cooling in-5 ℃～0 ℃ insulation crystallization 4h, is filtered, rinsing, drying gets Ambroxol HCl finished product 8.06g, yield 80.6%.
Embodiment 4
With 100ml ethanol, 2-amino-3,5-dibromo benzaldehyde (10.0g, 35.9mmol), trans-4-amino hexalin (5.0g, 43.4mmol) joins in the reactor, be heated to backflow (75 ℃～80 ℃) under stirring, insulation reaction 4h, the TLC monitoring reaction is complete, then be cooled to 10 ℃～20 ℃, add sodium borohydride (2.1g, 55.5mmol), finish, insulation reaction 6h, the TLC monitoring reaction is complete, be incubated completely, reaction solution is cooled to 10 ℃～20 ℃, stir lower to hydrochloric acid soln adjust pH=3, be cooled to 10 ℃～15 ℃, insulation reaction 3h filters rinsing, dry, get Ambroxol HCl crude product 12.6g, yield 84.8%, purity 99.35%.
Get Ambroxol HCl crude product 10g, stir lower methyl alcohol and acetone (volume ratio 1:5) the mixing solutions 220ml of slowly adding, be heated to backflow, to all dissolvings, activated carbon decolorizing, cooling in 0 ℃～5 ℃ insulation crystallization 6h, is filtered, rinsing, drying gets Ambroxol HCl finished product 8.48g, yield 84.8%.
Embodiment 5
With the 100ml Virahol, 2-amino-3,5-dibromo benzaldehyde (10.0g, 35.9mmol), trans-4-amino hexalin (5.0g, 43.4mmol) joins in the reactor, be heated to backflow (80 ℃～85 ℃) under stirring, insulation reaction 5h, the TLC monitoring reaction is complete, then be cooled to 20 ℃～30 ℃, add sodium borohydride (2.1g, 55.5mmol), finish, insulation reaction 6h, the TLC monitoring reaction is complete, be incubated completely, reaction solution is cooled to 10 ℃～20 ℃, stir lower to hydrochloric acid soln adjust pH=4, be cooled to 0 ℃～5 ℃, insulation reaction 2h filters rinsing, dry, get Ambroxol HCl crude product 12.8g, yield 86.2%, purity 99.18%.
Get Ambroxol HCl crude product 10g, stir lower methyl alcohol and methylene dichloride (volume ratio 1:6) the mixing solutions 280ml of slowly adding, be heated to backflow, to all dissolvings, activated carbon decolorizing, cooling in 0 ℃～5 ℃ insulation crystallization 6h, is filtered, rinsing, drying gets Ambroxol HCl finished product 8.26g, yield 82.6%.
Embodiment 6
With 100ml methyl alcohol, 2-amino-3,5-dibromo benzaldehyde (10.0g, 35.9mmol), trans-4-amino hexalin (4.14g, 35.9mmol) joins in the reactor, be heated to backflow (60 ℃～65 ℃) under stirring, insulation reaction 6h, the TLC monitoring reaction is complete, then be cooled to 10 ℃～20 ℃, add sodium borohydride (1.49g, 39.5mmol), finish, insulation reaction 6h, the TLC monitoring reaction is complete, be incubated completely, reaction solution is cooled to 10 ℃～20 ℃, stir lower to hydrochloric acid soln adjust pH=4, be cooled to 0 ℃～5 ℃, insulation reaction 4h filters rinsing, dry, get Ambroxol HCl crude product 11.8g, yield 79.4%, purity 99.32%.
Get Ambroxol HCl crude product 10g, stir the lower 25% methanol aqueous solution 70ml that slowly adds, be heated to backflow, to all dissolvings, activated carbon decolorizing, cooling in 5 ℃～10 ℃ insulation crystallization 5h, is filtered, rinsing, drying gets Ambroxol HCl finished product 8.4g, yield 84.0%.
Embodiment 7
With 50ml methyl alcohol, the 50ml Virahol, 2-amino-3,5-dibromo benzaldehyde (10.0g, 35.9mmol), trans-4-amino hexalin (5.0g, 43.4mmol) joins in the reactor, be heated to backflow (60 ℃～65 ℃) under stirring, insulation reaction 6h, the TLC monitoring reaction is complete, then be cooled to 10 ℃～20 ℃, add sodium borohydride (1.49g, 39.4mmol), finish, insulation reaction 6h, the TLC monitoring reaction is complete, be incubated completely, reaction solution is cooled to 10 ℃～20 ℃, stir lower to hydrochloric acid soln adjust pH=2, be cooled to 0 ℃～5 ℃, insulation reaction 3h filters rinsing, dry, get Ambroxol HCl crude product 12.2g, yield 82.1%, purity 99.43%.
Get Ambroxol HCl crude product 10g, stir the lower 5% methanol aqueous solution 70ml that slowly adds, be heated to backflow, to all dissolvings, activated carbon decolorizing, cooling in 5 ℃～10 ℃ insulation crystallization 6h, is filtered, rinsing, drying gets Ambroxol HCl finished product 8.07g, yield 80.7%.
Embodiment 8
With 100ml acetone, 2-amino-3,5-dibromo benzaldehyde (10.0g, 35.9mmol), trans-4-amino hexalin (6.2g, 53.9mmol) joins in the reactor, be heated to backflow (60 ℃～65 ℃) under stirring, insulation reaction 6h, the TLC monitoring reaction is complete, then be cooled to 20 ℃～30 ℃, add sodium borohydride (1.63g, 43.1mmol), finish, insulation reaction 6h, the TLC monitoring reaction is complete, be incubated completely, reaction solution is cooled to 10 ℃～20 ℃, stir lower to hydrochloric acid soln adjust pH=2, be cooled to 0 ℃～5 ℃, insulation reaction 3h filters rinsing, dry, get Ambroxol HCl crude product 12.7g, yield 85.5%, purity 99.37%.
Get Ambroxol HCl crude product 10g, stir the lower 10% methanol aqueous solution 70ml that slowly adds, be heated to backflow, to all dissolvings, activated carbon decolorizing, cooling in 5 ℃～10 ℃ insulation crystallization 4h, is filtered, rinsing, drying gets Ambroxol HCl finished product 8.28g, yield 82.8%.
Embodiment 9
With 50ml methyl alcohol, 50ml ethanol, 2-amino-3,5-dibromo benzaldehyde (10.0g, 35.9mmol), trans-4-amino hexalin (5.37g, 46.7mmol) joins in the reactor, be heated to backflow (60 ℃～65 ℃) under stirring, insulation reaction 6h, the TLC monitoring reaction is complete, then is cooled to (10 ℃～20 ℃), add sodium borohydride (1.63g, 43.1mmol), finish insulation reaction 6h, the TLC monitoring reaction is complete, be incubated completely, reaction solution is cooled to 10 ℃～20 ℃, stir lower to hydrochloric acid soln adjust pH=2, be cooled to 0 ℃～5 ℃, insulation reaction 3h filters rinsing, dry, get Ambroxol HCl crude product 12.7g, yield 85.5%, purity 99.14%.
Get Ambroxol HCl crude product 10g, stir the lower 15% methanol aqueous solution 70ml that slowly adds, be heated to backflow, to all dissolvings, activated carbon decolorizing, cooling in 5 ℃～10 ℃ insulation crystallization 6h, is filtered, rinsing, drying gets Ambroxol HCl finished product 8.02g, yield 80.2%.
Embodiment 10
With the 100ml acetonitrile, 2-amino-3,5-dibromo benzaldehyde (10.0g, 35.9mmol), trans-4-amino hexalin (5.37g, 46.7mmol) joins in the reactor, be heated to backflow (60 ℃～65 ℃) under stirring, insulation reaction 6h, the TLC monitoring reaction is complete, then be cooled to 10 ℃～20 ℃, add sodium borohydride (1.63g, 43.1mmol), finish, insulation reaction 6h, the TLC monitoring reaction is complete, be incubated completely, reaction solution is cooled to 10 ℃～20 ℃, stir lower to hydrochloric acid soln adjust pH=2, be cooled to 0 ℃～5 ℃, insulation reaction 3h filters rinsing, dry, get Ambroxol HCl crude product 12.4g, yield 81.6%, purity 99.26%.
Get Ambroxol HCl crude product 10g, stir the lower 10% methanol aqueous solution 80ml that slowly adds, be heated to backflow, to all dissolvings, activated carbon decolorizing, cooling in 0 ℃～5 ℃ insulation crystallization 8h, is filtered, rinsing, drying gets Ambroxol HCl finished product 8.1g, yield 81.0%.
Embodiment 11
In order to investigate the quality product of the Ambroxol HCl that the method for the invention prepares, the inventor detects embodiment 1-10 gained Ambroxol HCl finished product, and its stability is investigated, and concrete outcome is as follows.
The quality examination result of the Ambroxol HCl finished product that table 1 prepares for embodiment 1-10:
Table 1
| Lot number | Outward appearance | Chromatographic purity (%) | Acidity | Clarity | Solution colour | Weight loss on drying (%) |
| Embodiment 1 | White crystalline powder | 99.938 | 5.3 | The solution clarification | Colourless | 0.14 |
| Embodiment 2 | White crystalline powder | 99.988 | 5.0 | The solution clarification | Colourless | 0.11 |
| Embodiment 3 | White crystalline powder | 99.949 | 5.0 | The solution clarification | Colourless | 0.18 |
| Embodiment 4 | White crystalline powder | 99.955 | 5.1 | The solution clarification | Colourless | 0.15 |
| Embodiment 5 | White crystalline powder | 99.916 | 5.2 | The solution clarification | Colourless | 0.25 |
| Embodiment 6 | White crystalline powder | 99.987 | 5.2 | The solution clarification | Colourless | 0.14 |
| Embodiment 7 | White crystalline powder | 99.985 | 5.1 | The solution clarification | Colourless | 0.12 |
| Embodiment 8 | White crystalline powder | 99.962 | 5.1 | The solution clarification | Colourless | 0.20 |
| Embodiment 9 | White crystalline powder | 99.920 | 5.0 | The solution clarification | Colourless | 0.10 |
| Embodiment 10 | White crystalline powder | 99.958 | 5.2 | The solution clarification | Colourless | 0.19 |
Can be found out that by data in the table 1 the Ambroxol HCl purity for preparing according to the method for the invention is all more than 99.9%, all other indexs also all meet medicinal standard.
The Ambroxol HCl finished product accelerated test result that table 2-table 4 prepares for embodiment 1-10.
Accelerated test condition: 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%.Commercially available back (internal packing is polyethylene plastic bag, and outer packaging is aluminium foil bag, sealing) is placed.
Detect respectively at sampling in 0,1,2,3,6 month.
Table 2
Table 3
Table 4
Can be found out by the accelerated test result, transfer postpone according to the Ambroxol HCl that the method for the invention prepares in the accelerated test condition, product purity does not obviously descend, and more than 99.8%, all other indexs also still meet medicinal standard.
The Ambroxol HCl finished product long-term stable experiment result that table 5-table 7 prepares for embodiment 1-10.
The long-term stable experiment condition: 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 5%, commercially available back (internal packing is polyethylene plastic bag, and outer packaging is aluminium foil bag, sealing) is placed.
Detect respectively at sampling in 0,3,6,9,12 month.
Table 5
。
Table 6
Table 7
Can be found out that by long-term test results transfer postpone according to the Ambroxol HCl that the method for the invention prepares in the test of long duration condition, considerable change does not appear in product purity, still more than 99.9%, all other indexs also still meet medicinal standard.
In sum, the Ambroxol HCl product purity for preparing according to the method for the invention can reach more than 99.9%, and transfers postpone in accelerated test and test of long duration condition, and indices has no significant change, steady quality can satisfy the production requirement of drug product.
Claims (10)
1. the preparation method of an Ambroxol HCl operates by following reaction scheme,
, wherein, III is the product schiff bases of condensation reaction, II is the product Transbroncho alkali of reduction reaction, and I is the product Ambroxol HCl that obtains behind the Transbroncho alkali salify, it is characterized in that, reaction process is carried out in a kind of solvent system, and the intermediate III is not separated with II.
2. preparation method according to claim 1 is characterized in that, the solvent of described reaction process is selected from one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, acetone, acetonitrile, the ethylene glycol.
3. preparation method according to claim 1 is characterized in that, the operation steps of described reaction process is:
A. condensation: 2-amino-3,5-dibromo benzaldehyde and trans-4-amino hexalin stir in solvent, and the temperature control reaction gets schiff bases solution;
B. reduction: the schiff bases solution temperature control with step a obtains, add sodium borohydride or lithium aluminum hydride under the agitation condition, the temperature control reaction gets the Transbroncho alkaline solution;
C. salify: with the Transbroncho alkaline solution cooling that step b obtains, regulate pH value with hydrochloric acid soln under the agitation condition, the temperature control reaction is filtered, and washs, and drying gets Ambroxol HCl.
4. preparation method according to claim 3 is characterized in that, 2-amino-3 among the described step a, and the mol ratio of 5-dibromo benzaldehyde and trans-4-amino hexalin is 1:1-2, preferred 1:1.2; Temperature of reaction is 40 ℃-solvent boiling point temperature, preferred 60 ℃-65 ℃; Reaction times is 3-8h.
5. preparation method according to claim 3 is characterized in that, the sodium borohydride that adds among the described step b or the molar weight of lithium aluminum hydride are the 2-amino-3 among the step a, 5-dibromo benzaldehyde 1.1-1.5 times, and preferred 1.2 times; Temperature of reaction is 0 ℃-40 ℃, preferred 20 ℃-30 ℃; Reaction times is 6h.
6. preparation method according to claim 3 is characterized in that, the Transbroncho alkaline solution is cooled to 10 ℃-20 ℃ among the described step c; Regulating the pH value is 1-4, is preferably 2-3.
7. preparation method according to claim 3 is characterized in that, temperature of reaction is 0 ℃-20 ℃ among the described step c, preferred 0 ℃-5 ℃; Reaction times is 2-6h.
8. preparation method according to claim 3 is characterized in that, the operation steps of described reaction process is:
A. condensation: 2-amino-3,5-dibromo benzaldehyde and trans-4-amino hexalin stir in solvent, and the temperature control reaction gets schiff bases solution;
B. reduction: the schiff bases solution temperature control with step a obtains, add sodium borohydride or lithium aluminum hydride under the agitation condition, the temperature control reaction gets the Transbroncho alkaline solution;
C. salify: with the Transbroncho alkaline solution cooling that step b obtains, regulate pH value with hydrochloric acid soln under the agitation condition, the temperature control reaction is filtered, and washs, and drying gets the Ambroxol HCl crude product;
D. refining: add solvent in the Ambroxol HCl crude product that obtains to step c, heating, stir, activated carbon decolorizing, the temperature control crystallization filters, washing, drying namely gets the Ambroxol HCl finished product.
9. preparation method according to claim 8, it is characterized in that, solvent is the mixed solvent of methyl alcohol and other solvent in the described steps d, described other solvent is selected from one or more in water, propyl alcohol, Virahol, butanols, ethylene glycol, acetone, acetonitrile, ethylene glycol, methylene dichloride, chloroform, sherwood oil, the isopropyl ether, preferably water; The volume ratio of methyl alcohol and other solvent is 1:1-19, preferred 1:1.
10. preparation method according to claim 8 is characterized in that, recrystallization temperature is-5 ℃ ~ 10 ℃ in the described steps d, preferred 0 ℃ ~ 5 ℃; The crystallization time is 4-10h, preferred 8h.
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| CN104803860A (en) * | 2015-05-12 | 2015-07-29 | 山东罗欣药业集团股份有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN104860832A (en) * | 2015-05-15 | 2015-08-26 | 苗怡文 | Drug ambroxol hydrochloride composition for treating respiratory system disease |
| CN104971057A (en) * | 2015-08-05 | 2015-10-14 | 青岛蓝盛洋医药生物科技有限责任公司 | Ambroxol hydrochloride composition capsule medicine for treating respiratory system diseases |
| CN105055321A (en) * | 2015-09-01 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal ambroxol hydrochloride composition dry suspension for treating coughs |
| CN105622437A (en) * | 2016-03-04 | 2016-06-01 | 中山福运生物科技有限公司 | Method for producing ambroxol hydrochloride |
| CN107488119A (en) * | 2016-06-13 | 2017-12-19 | 张家港市锦丰润尔发五金塑料厂 | The dibromo N of 2 amino 3,5（Anti- 4 hydroxyl ring ethyl）The preparation method of benzylamine |
| CN109134279A (en) * | 2017-08-15 | 2019-01-04 | 陶灵刚 | 1/10 water ambroxol compound of one kind and its pharmaceutical composition |
| CN109970579A (en) * | 2019-04-22 | 2019-07-05 | 浙江海洲制药有限公司 | A method of preparing ambroxol hydrochloride |
| 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 |
| CN111732518A (en) * | 2020-04-02 | 2020-10-02 | 河北宇辰医药科技有限公司 | Preparation method of cis-4- [ (2-amino-3, 5-dibromobenzyl) amino ] cyclohexanol |
| CN112279774A (en) * | 2019-07-24 | 2021-01-29 | 成都施贝康生物医药科技有限公司 | Dibromo benzyl derivative, stereoisomer or salt thereof, preparation method and application |
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| CN103739502B (en) * | 2014-01-17 | 2016-06-08 | 浙江浙邦制药有限公司 | A kind of separation and purification technique of ambroxol alkali |
| CN103755577A (en) * | 2014-01-17 | 2014-04-30 | 浙江浙邦制药有限公司 | Method for recovering ambroxol base from ambroxol hydrochloride refined mother solution |
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| CN104803860A (en) * | 2015-05-12 | 2015-07-29 | 山东罗欣药业集团股份有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
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| CN105055321A (en) * | 2015-09-01 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal ambroxol hydrochloride composition dry suspension for treating coughs |
| CN105622437A (en) * | 2016-03-04 | 2016-06-01 | 中山福运生物科技有限公司 | Method for producing ambroxol hydrochloride |
| CN107488119A (en) * | 2016-06-13 | 2017-12-19 | 张家港市锦丰润尔发五金塑料厂 | The dibromo N of 2 amino 3,5（Anti- 4 hydroxyl ring ethyl）The preparation method of benzylamine |
| CN109134279A (en) * | 2017-08-15 | 2019-01-04 | 陶灵刚 | 1/10 water ambroxol compound of one kind and its pharmaceutical composition |
| CN109970579A (en) * | 2019-04-22 | 2019-07-05 | 浙江海洲制药有限公司 | A method of preparing ambroxol hydrochloride |
| CN112279774A (en) * | 2019-07-24 | 2021-01-29 | 成都施贝康生物医药科技有限公司 | Dibromo benzyl derivative, stereoisomer or salt thereof, preparation method and application |
| CN112279774B (en) * | 2019-07-24 | 2023-05-30 | 成都施贝康生物医药科技有限公司 | Dibromobenzyl derivative, stereoisomer or salt thereof, preparation method and application |
| 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 |
| CN111732518A (en) * | 2020-04-02 | 2020-10-02 | 河北宇辰医药科技有限公司 | Preparation method of cis-4- [ (2-amino-3, 5-dibromobenzyl) amino ] cyclohexanol |
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