CN103333074B - Production method of bromhexine hydrochloride - Google Patents
Production method of bromhexine hydrochloride Download PDFInfo
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Abstract
The invention relates to a production method of bromhexine hydrochloride. The production method is characterized by comprising the following steps of: 1) carrying out a condensation reaction between 3,5-dibromo-2-aminobenzalcohol and N-methyl cyclohexane in the presence of glacial acetic acid as a catalyst, thereby generating N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzylamine; 2) salifying the generated N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzylamine with hydrochloric acid to obtain bromhexine hydrochloride; and 3) decoloring and refining the obtained bromhexine hydrochloride in an alcoholic solution to obtain a pure product, wherein an azeotropic water-carrying agent is added to the condensation reaction in the step 1), and water in the reaction mixed solution in the reaction process is removed immediately through distillation.
Description
Technical field
The invention belongs to field of medicine and chemical technology, particularly a kind of production method of expectorant bromhexine hydrochloride.
Background technology
Bromhexine hydrochloride, another name hydrochloric acid bromine hexylamine, bisolvon, bromhexine, Broncokin, English name is Bromhexine Hydrochloride, and chemical name is Bromhexine Hydrochloride, molecular formula: C
14h
20br
2n
2hCl, molecular weight: 412.60, structural formula:
Bromhexine hydrochloride is commonly use expectorant both at home and abroad, has stronger glutinous phlegm solvency action, and polysaccharide fiber element in phlegm can be made to decompose fracture, suppress the synthesis of acidic mucopolysaccharide albumen, reduction phlegm viscosity, is beneficial to expectoration.Clinically be applicable to the patient that chronic bronchitis, asthma, bronchiectasis, silicosis etc. have the not easily expectoration of sticky phlegm.Bromhexine hydrochloride clinical application security is good, determined curative effect, is included in " Chinese Pharmacopoeia ", " National essential drugs list " and " national basic medical insurance, work-related injury insurance and birth insurance Drug catalogue ".
Existing multiple bromhexine hydrochloride synthesis technology route, but there is the problem such as poor product quality and environmental pollution, also there is the problem of quality stability difference, in preparation process thereof process and prolonged storage, its active constituent content reduces very fast, is unfavorable for ensuring drug quality and the security of medication, validity.2010 version " Chinese Pharmacopoeia " improve bromhexine hydrochloride related substance standard, specify that single impurity peak area must not be greater than the main peak area (0.2%) of contrast solution, each impurity peak area and 1.5 times (0.3%) of contrast solution main peak area must not be greater than.And original synthetic technology and process for purification gained bromhexine hydrochloride often need through repeatedly refining crystallization, just can reach standards of pharmacopoeia requirement, cause the waste of the resources such as artificial, the energy and raw and auxiliary material, both improve product cost, and be not suitable with again the requirement of industrialization continuous seepage.Therefore, improve bromhexine hydrochloride synthesis technology, to improve the quality of products and quality stability is a urgent task of research department and manufacturing enterprise.In recent years, many research work have made unremitting effort for improving bromhexine hydrochloride synthesis technology and quality product and constant product quality.
Patent CN101817754B discloses a kind of multifunctional reaction still production bromhexine hydrochloride method of installing special still bottom valve, for ensureing quality product, need refine, three refining total recoverys 62.5%, total yield of products 38.54% through three dehydrated alcohols; Patent CN102531922A improves condensation catalyst kind and reaction conditions, use 3,5-bis-bromo-2-amino-benzene methyl alcohol and nitrilotriacetic boric acid ester react generation 3,5-bis-bromo-2-amino-benzene methyl alcohol inner complex, react with N-methylcyclohexylamine again and generate bromhexine base, condensation reaction yield 80%, salify-refining yield 80%, method employs by public security department's control precursor chemicals diacetyl oxide; Patent CN102617359A is with 3, the bromo-2-aminobenzaldehyde of 5-bis-is starting raw material, 3 are generated through reduction reaction, 5-bis-bromo-2-amino-benzene methyl alcohol, react with chlorinating agent, generate 2,4-bromo-6-chloromethyl aniline reacts with N-methylcyclohexylamine and generates bromhexine base, then salify, yield 85 ~ 90%, refined recovery rate 70 ~ 80%, this method starting raw material 3,5-bis-bromo-2-aminobenzaldehyde is the raw material preparing expectorant Transbroncho of future generation, use chlorinating agent to reaction anhydrous condition and equipment requirements higher, and there are intermediates and easily to degrade instability problem.Above-mentioned patented method respectively has feature, but all still small-scale test data in lab provided.
In order to improve bromhexine hydrochloride quality stability, improve patient medication security, validity, patent CN102775316A takes to decolour in ethanol, n-butanol mixed solvent, and the method for crystallisation by cooling drip acetonitrile solution in filtrate after, yield 87 ~ 90%, content 99.5 ~ 90.8%, again the pH adjusting agents such as vehicle and citric acid such as gained novel crystallization and N.F,USP MANNITOL are formed composition, to improve bromhexine hydrochloride quality stability, aforesaid method adopts mixed solvent decolouring and drips the crystallization of special solvent acetonitrile, brings the recycling difficulty of solvent; Patent CN 102924295A uses the method for water ratio more than 30% alcoholic solvent crystallization, the rate of recovery is greater than 60%, optimal conditions can reach more than 80%, product purity reaches more than 99.8%, the new crystallographic stability obtained and the solvability in water are better than the crystal formation that prior art produces, be conducive to preparation bromhexine hydrochloride injection formulation, but this method rate of recovery is on the low side, increases mother liquid disposal quantity and difficulty; Recently disclosed patent CN103145564A takes to decolour in ethanol, methanol mixed solvent, drips the method for crystallisation by cooling after aqueous acetone solution, there is recycling difficulty and the rate of recovery problem on the low side of a large amount of mixed solvent equally in filtrate.
For overcoming above-mentioned defect of the prior art, the present invention is studied reaction conditions, conversion unit is improved simultaneously, through the improvement of the present invention to preparation technology, the present invention has prepared the high-quality bromhexine hydrochloride bulk drug that a kind of content is greater than 99.9%, quality stability is good, make reaction yield bring up to 85 ~ 90% from general 75 ~ 80%, refining yield reaches 92 ~ 95% from 85 ~ 90% raisings simultaneously.
Summary of the invention
The invention provides a kind of production method of bromhexine hydrochloride, described method steps is as follows:
1) 3,5-bis-bromo-2-amino-benzene methyl alcohol and N-methylcyclohexylamine are that catalyzer carries out condensation reaction with glacial acetic acid, generate amino-3, the 5-dibromobenzene methylamines (bromhexine) of N-methyl-N-cyclohexyl-2-;
2) amino-3, the 5-dibromobenzene methylamines of the N-methyl-N-cyclohexyl-2-generated and hydrochloric acid salify obtain bromhexine hydrochloride;
3) gained bromhexine hydrochloride decolorizing and refining in alcoholic solution obtains sterling.
Wherein, add azeotropic aqua in the condensation reaction of step 1), described azeotropic aqua is selected from: the organic solvent such as benzene,toluene,xylene, hexanaphthene, prioritizing selection toluene.Add-on is add-on is 1 ~ 2% of reaction system gross weight.
Wherein, the condensation reaction of step 1), the water in reaction process in reaction mixture distills removal in time.This reaction preferred is carried out in the back flow reaction tank of the specially designed connection division box of the present invention, and the water in reaction process in reaction mixture is removed in time through this device.
The condensation reaction of step 1) is carried out in a solvent, and namely described solvent is reactant N-methylcyclohexylamine.In step 1), the part by weight of each reactant is: 3,5-bis-bromo-2-amino-benzene methyl alcohol: N-methylcyclohexylamine: glacial acetic acid==1:1.10 ~ 1.30:0.50 ~ 0.60, preferred 1:1.18 ~ 1.21:0.51 ~ 0.52.
Wherein, step 2) salt-forming reaction be the hydrochloric acid adding 10-30% in reaction mixture after the reaction of step 1) completes, add-on is 3, the 1-1.5 of 5-bis-bromo-2-amino-benzene methyl alcohol molar weight doubly, salification process needs to add necessary solvent to be made to mix, solvent is selected from: acetone, methyl alcohol or ethanol, and add-on is about 1.2 ~ 1.6 times of 3,5-bis-bromo-2-amino-benzene methanol weight.
Wherein, the purification step of step 3) is step 2) the bromhexine hydrochloride crude product that obtains is placed in alcoholic solution and adds gac and carry out decolorizing and refining, described alcoholic solution is selected from: the low-alcohol solutions such as methyl alcohol, ethanol, Virahol, be preferably ethanolic soln, the weight proportion of each composition of this step is: bromhexine hydrochloride crude product: lower alcohol: activated carbon=1:8 ~ 16:0.03 ~ 0.08, be preferably bromhexine hydrochloride crude product: ethanol: activated carbon=1:11 ~ 12:0.05, need the pH value regulating alcoholic solution in treating process, make solution ph reach 2 ~ 3.
Preferably, preparation method of the present invention is as follows:
To in reactor, drop into N-methylcyclohexylamine, add 3,5-bis-bromo-2-amino-benzene methyl alcohol under stirring, stirring and dissolving, more slowly drip glacial acetic acid, finally add toluene; Open esterification to install pipes valve and water coolant and freezing refrigerant respective valves, carry out being heated to reflux water-dividing; Slowly heat up, until reaction end (point water terminates), reaction final temp is about 170 ~ 180 DEG C later.
Pre-thermal crystalline reactor, and form negative pressure, be transferred in this reactor by upper step reaction gained reaction product, solvent fraction is to the greatest extent steamed in decompression, cooling, add acetone solution under stirring, then use the hydrochloric acid soln regulator solution pH=2 of 15%, be cooled to less than 10 DEG C crystallizations 5 ~ 8 hours, filter, filter cake washing with acetone, dry bromhexine hydrochloride crude product, mother liquor recyclable part bromhexine hydrochloride crude product.
In refining reaction device, add ethanol, add bromhexine hydrochloride crude product under stirring, use hydrochloric acid conditioning solution pH=2 ~ 3, after heating for dissolving, repetition measurement pH value of solution=2 ~ 3 are constant.Then add gac, reflux 1 hour, phegma filters, cooling crystallization, filters, and washing is dry, obtains refining sterling.
The present invention, while the preparation method providing above-mentioned bromhexine hydrochloride, also provides a kind of conversion unit, and this conversion unit is through the result of the present inventor's research, is particularly suitable for condensation step of the present invention.
Equipment of the present invention can be called: the back flow reaction tank (or be called: distillation and reflux secondary division box) of band division box.
The composition structure of this equipment is shown in Fig. 2: it is by condenser 1; Distillation column 2; Reactor 3; Glass trap 4; Polytetrafluoroethylbellows bellows 5,6; Emptying valve 7,10; Glass visor 8,9; Diverter valve 11,12; Y tube 13; U-shaped pipe 14,16; J-shaped pipe 15; Threeway 17; Chilled brine import 18; Chilled brine outlet 19; Circulating cooling water inlet 20; Circulating cooling water out 21 forms;
3, 5-bis-bromo-2-amino-benzene methyl alcohol and N-methylcyclohexylamine and catalyzer glacial acetic acid carry out condensation reaction in condensation reaction pot 3, generate N-methyl-N-cyclohexyl-2-amino-3, 5-dibromobenzene methylamine and water, the azeotropic aqua added, the moisture equal solvent that N-methylcyclohexylamine and reaction generate is by the polynary azeotrope of thermosetting, fractionation is carried out by distillation column 2, low-boiling azeotrope (moisture content is higher) is through distillation column 2 capital U-shaped pipe connecting 14, corrugated tube 5, J-shaped pipe 15, the gas phase channel that threeway 17 forms enters telescopic condenser 1 and is cooled, form liquid-phase reflux, constantly by the reverse heating of polynary azeotrope in reflux course, because N-methylcyclohexylamine boiling point (149 DEG C) is higher, and the boiling point of water (100 DEG C) is lower, lower boiling high-moisture azeotrope rises and is enriched in telescopic condenser 1 first half, water droplet is formed through condensation, water droplet is suspended on telescopic condenser 1 barrel, when water droplet is condensed into the enough large globule, will fast landing under gravity, flow into phlegma in the glass trap 4 being arranged on below, most of water layering in first step water trap 4 that reaction generates is separated by diverter valve 12, telescopic condenser 1 is installed on 3 ~ 4 meters of eminences above reactor, and to swing back in the vertical direction 5 ~ 10 ° of angles relative to reactor 3, distillation column 2, making more to be conducive to the enough large globule quick landing on rear side of barrel of water droplet cohesion formation enters in water trap 4, the globule that can reduce formation contacts with the polynary azeotrope gas phase of rising chance of being heated, and also can reduce the globule and enter in visor 9 with condensate flow by the liquid channel of threeway 17, J-shaped pipe connecting 15, corrugated tube 6, U-shaped pipe connecting 16, visor 8, Y tube 13 composition, enter the water in visor 9 and organic phlegma layering, water layer is discharged by diverter valve 11, realizes secondary and divides water, because the proportion of water is larger than organic phlegma, organic phlegma return velocity is controlled by regulating temperature of reaction, make the Y tube 13 of setting effectively prevent the globule from rising with phlegma and flow to distillation column 2, organic phlegma containing saturation moisture after two fraction water flows into distillation column 2 top, with the polynary azeotrope gas phase countercurrent flow fractionation of rising in post, what to make after distillation column 2 fractionation backflow return reactor is that organic phlegma water ratio of major ingredient reaches denier with N-methylcyclohexylamine, again condensation reaction is participated in, avoid, decrease the generation of side reaction, improve reaction yield and quality product, reduce waste discharge, meet environmental protection requirement.
Condenser in distillation and reflux secondary division box preferably adopts telescopic condenser, install in the mode of Fig. 2 signal, can effectively stop to use the phenomenons such as other pattern condensers (such as shell and tube, chip and rotary vane type etc.) issuable hydrops, emulsification, both made vapour, liquid be separated shunting, and be conducive to again moisture content enrichment condensation and form large water drop, device takes polynary organic solvent azeotropic thing gas phase by distillation column 2 top through U-shaped pipe connecting 14, corrugated tube 5, J-shaped pipe 15, the gas phase channel that threeway 17 forms enters from the lower end of telescopic condenser 1, instead of entering from telescopic condenser 1 side upper end perforate (installing emptying valve 7 position Fig. 2) in the installation of condenser routine, to prevent polynary organic solvent azeotropic thing gas phase to be just rapidly cooled into phlegma once enter condenser, moisture is scattered in phlegma with the vaporific form of fine liquid particles, and fast along with under condensate stream, define the organic phlegma of supersaturation water, be unfavorable for that moisture is separated removing, polynary organic solvent azeotropic thing gas phase enters telescopic condenser 1 from lower end, more be conducive to moisture content to be enriched in telescopic condenser 1 upper part and to be condensed into water droplet, also be conducive to water droplet be suspended on condenser barrel and form large water drop under solvent azeotrope gas phase raising force holder arch, also only have the globule when being formed enough large, be greater than adhesive power and air-flow holder arch power at gravity, the globule just quick landing enters in water trap 4 to carry out layering to divide water, in addition, polynary organic solvent azeotropic thing gas phase enters telescopic condenser 1 from lower end, it also avoid phlegma undercooling, increase the kinetic viscosity of phlegma, unfavorable layering and Fen Shui, when also avoiding causing the organic solvent condensate liquid containing saturation moisture to flow into distillation column 2 top, because temperature is too low, the temperature difference is too large, distillation column fractionation efficiency can be reduced, increase energy consumption, cause unnecessary waste, do not meet resource-effective requirement.
Medication chemistry produce in, improve reaction yield namely mean economize on resources, reduce consume and pollute, the raising of reaction yield is necessarily along with the minimizing of reaction impurities and the lifting of quality product.Focus technology measure of the present invention is carrying out in condensation reaction, add appropriate azeotropic aqua and employing distillation and reflux secondary division box, the moisture that in timely removing reactor, reaction generates, avoid, reduce side reaction generation, positive reaction is carried out smoothly, reduce refuse to produce and discharge from source, effectively can reduce the finished product relative substance content, improve reaction yield and quality product.
The synergy of azeotropic aqua and distillation and reflux secondary division box; greatly can reduce the N-methylcyclohexylamine water ratio being back to reactor; make manufacture gained bromhexine hydrochloride crude product can obtain through primary purification the high-quality bromhexine hydrochloride bulk drug fine work that content is greater than 99.9%, quality stability is good; total recovery can reach more than 85%; decrease pollution substance discharge with because repeatedly refining lost labor, the energy and raw and auxiliary material; reduce costs, meet environment protection and energy-saving and cost-reducing requirement.
In purification step, adding acid regulates pH value to be 2-3, it is another important process technical improvements of the present invention, object makes bromhexine 100 ﹪ become hydrochloride, because the free thermally-stabilised difference of bromhexine, quality product and quality stability can be had a strong impact on, the free bromhexine stopping residual parcel in crude product is needed to enter finished product, both refining yield (reaching as high as more than 95%) can be improve to a certain extent, turn improve quality product and quality stability, thus can accomplish that namely can obtain content through primary purification is greater than 99.9 ﹪, the high-quality bromhexine hydrochloride bulk drug that quality stability is good, reduce and cause manually because of repeatedly refining, the waste of the energy and raw and auxiliary material, economize on resources, reduce costs, be applicable to suitability for industrialized production.
Accompanying drawing explanation
Shown in accompanying drawing 1 is bromhexine hydrochloride synthetic chemistry reaction formula (structural formula).
Shown in accompanying drawing 2 is distillation and reflux secondary division box structural representation, and wherein 1 is telescopic condenser, specification: 3M
2; 2 is distillation columns, the specification of post: ￠ 150 ~ 200mm, high 2M; 3 is reactors, specification: 500L; 4 is glass traps; 5,6 is polytetrafluoroethylbellows bellows; 7,10 is emptying valves; 8,9 is glass visors; 11,12 is diverter valves; 13 is Y tubes; 14,16 is U-shaped pipe; 15 is that J-shaped pipe, 17 is for threeway;
In diagram, 18 is the chilled brine import such as (or freezing ethylene glycol other refrigerant); 19 is chilled brine other refrigerants such as (or) freezing ethylene glycol outlet; 20 is circulating cooling water inlet; 21 is circulating cooling water out.
Accompanying drawing 3a, Fig. 3 b, Fig. 3 c are 20101201,20101202,20,101,203 3 product batch number bromhexine hydrochloride product infrared spectrograms respectively.
Accompanying drawing 4 is that 20101201,20101202,20,101,203 3 product batch number bromhexine hydrochloride product contents analyze HPLC collection of illustrative plates.
Fig. 4 a bromhexine hydrochloride reference substance, Fig. 4 b bromhexine hydrochloride 101201 trial-product
Fig. 4 c bromhexine hydrochloride 101202 trial-product, Fig. 4 d bromhexine hydrochloride 101203 trial-product
Accompanying drawing 5 is 20101201,20101202,20,101,203 3 product batch number bromhexine hydrochloride product Related substance HPLC collection of illustrative plates.
Fig. 5 a bromhexine hydrochloride Related substance reference substance, Fig. 5 b Related substance 101201 trial-product, Fig. 5 c Related substance 101202 trial-product, Fig. 5 d Related substance 101203 trial-product
Embodiment
Embodiment 1
Prepare Bromhexine Hydrochloride crude product.
Charge ratio:
| Material name | Quantity (Kg) | Material name | Quantity (Kg) |
| Reduzate | 94 | Toluene | 3±1 |
| Glacial acetic acid | 49±1 | 30% hydrochloric acid | 48±5 |
| N-methylcyclohexylamine | 114±1 | Water | 48±5 |
| Ethanol | 125±1 |
In 300L electrically heated reactor, drop into N-methylcyclohexylamine, add reduzate under stirring, stirring and dissolving, more slowly drip glacial acetic acid, finally add toluene; Open esterification to install pipes valve and water coolant and freezing refrigerant respective valves, carry out chuck and be heated to reflux water-dividing; Slowly heat up, until reaction end (point water terminates), the last kettle temperature that controls of reaction is about 170 ~ 180 DEG C later.
Preheating 1000L salify crystallizing pan, and make to form negative pressure (vacuum tightness-0.08Mpa) in pot, reaction gained material is transferred in the salify crystallizing pan of preheating, solvent fraction is to the greatest extent steamed in decompression (vacuum tightness-0.08Mpa), cooling, adds dissolve with ethanol under stirring, then uses the hydrochloric acid soln regulator solution pH=2 of 15%, be cooled to less than 10 DEG C crystallizations 5 ~ 8 hours, filter, filter cake washing with acetone, dry, dry to obtain bromhexine hydrochloride crude product about 100 ~ 110Kg, through refining after the assay was approved.Ethanol mother liquor recyclable part bromhexine hydrochloride crude product, reclaim ethanol through distillation, detect qualified after apply mechanically.
Embodiment 2
Prepare Bromhexine Hydrochloride crude product.
Charge ratio:
| Material name | Quantity (Kg) | Material name | Quantity (Kg) |
| Reduzate | 188 | Toluene | 5±1 |
| Glacial acetic acid | 98±1 | 30% hydrochloric acid | 96±5 |
| N-methylcyclohexylamine | 228±1 | Water | 96±5 |
| Methyl alcohol | 250±1 |
In 500L electrically heated reactor, drop into N-methylcyclohexylamine, add reduzate under stirring, stirring and dissolving, more slowly drip glacial acetic acid, finally add toluene; Open esterification to install pipes valve and water coolant and freezing refrigerant respective valves, carry out chuck and be heated to reflux water-dividing; Slowly heat up, until reaction end (point water terminates), the last kettle temperature that controls of reaction is about 170 ~ 180 DEG C later.
Preheating 1000L salify crystallizing pan, and make to form negative pressure (vacuum tightness-0.08Mpa) in pot, reaction gained material is transferred in the salify crystallizing pan of preheating, solvent fraction is to the greatest extent steamed in decompression (vacuum tightness-0.08Mpa), cooling, adds dissolve with methanol under stirring, then uses the hydrochloric acid soln regulator solution pH=2 of 15%, be cooled to less than 10 DEG C crystallizations 5 ~ 8 hours, filter, filter cake methanol wash, dry, dry to obtain bromhexine hydrochloride crude product about 200 ~ 220Kg, through refining after the assay was approved.Methanol mother liquor recyclable part bromhexine hydrochloride crude product, reclaim methyl alcohol through distillation, detect qualified after apply mechanically.
Embodiment 3
Condensation-salify workshop section: prepare Bromhexine Hydrochloride crude product.
Charge ratio:
| Material name | Quantity (Kg) | Material name | Quantity (Kg) |
| Reduzate | 188 | Toluene | 5±1 |
| Glacial acetic acid | 98±1 | 30% hydrochloric acid | 96±5 |
| N-methylcyclohexylamine | 228±1 | Water | 96±5 |
| Acetone | 300±1 |
In 500L electrically heated reactor, drop into N-methylcyclohexylamine, add reduzate under stirring, stirring and dissolving, more slowly drip glacial acetic acid, finally add toluene; Open esterification to install pipes valve and water coolant and freezing refrigerant respective valves, carry out chuck and be heated to reflux water-dividing; Slowly heat up, until reaction end (point water terminates), the last kettle temperature that controls of reaction is about 170 ~ 180 DEG C later.
Preheating 1000L salify crystallizing pan, and make to form negative pressure (vacuum tightness-0.08Mpa) in pot, reaction gained material is transferred in the salify crystallizing pan of preheating, solvent fraction is to the greatest extent steamed in decompression (vacuum tightness-0.08Mpa), cooling, adds acetone solution under stirring, then uses the hydrochloric acid soln regulator solution pH=2 of 15%, be cooled to less than 10 DEG C crystallizations 5 ~ 8 hours, filter, filter cake washing with acetone, dry, dry to obtain bromhexine hydrochloride crude product about 220 ~ 240Kg, through refining after the assay was approved.Acetone mother liquor recyclable part bromhexine hydrochloride crude product, reclaim acetone through distillation, detect qualified after apply mechanically.
Embodiment 4
Preparation bromhexine hydrochloride sterling.
Charge ratio:
| Material name | Weight ratio | Charging capacity |
| Crude product | 1 | 30Kg |
| Methyl alcohol | 10 | 300±5Kg |
| Gac | 0.05 | 1.5Kg |
| Hydrochloric acid | In right amount |
In 500L decolorizing and refining pot, add 270 ± 5Kg methyl alcohol, add bromhexine hydrochloride crude product 30Kg under stirring, use appropriate hydrochloric acid regulator solution pH=2 ~ 3, after heating for dissolving, repetition measurement pH value of solution=2 ~ 3 are constant.Then add gac 1.5Kg, be heated to backflow, insulation backflow 1 hour.Backflow terminates, and press filtration is to crystallizing pan while hot, and filter and terminate with 30Kg methanol wash Decolouring pot, strainer and pipeline, washing lotion is incorporated in crystallizing pan.Be cooled to temperature about 10 DEG C in pot, feed liquid is filtered, filter cake methanol wash, fully dries, in revolution vacuum drier, carry out drying, drying temperature 80 DEG C, vacuum tightness about-0.08Mpa, dry 5-8 hour, obtain highly finished product and be about 27-28kg, the recyclable bromhexine hydrochloride crude product of refinement mother liquor, reclaims methyl alcohol and applies mechanically after distillation process detection is qualified.Embodiment 5
Preparation bromhexine hydrochloride sterling.
Charge ratio:
| Material name | Weight ratio | Charging capacity |
| Crude product | 1 | 50Kg |
| Ethanol | 12 | 600±5Kg |
| Gac | 0.05 | 2.5Kg |
| Hydrochloric acid | In right amount |
In 1000L decolorizing and refining pot, add 550 ± 5Kg95% ethanol, add bromhexine hydrochloride crude product 50Kg under stirring, use appropriate hydrochloric acid regulator solution pH=2 ~ 3, after heating for dissolving, repetition measurement pH value of solution=2 ~ 3 are constant.Then add gac 2.5Kg, be heated to backflow, insulation backflow 1 hour.Backflow terminates, and is filtered hot to crystallizing pan, and filter and terminate with 50Kg95% washing with alcohol Decolouring pot, strainer and pipeline, washing lotion is incorporated in crystallizing pan.Be cooled to temperature about 10 DEG C in pot, feed liquid is filtered, filter cake 95% washing with alcohol, fully dries, in revolution vacuum drier, carry out drying, drying temperature 80 DEG C, vacuum tightness about-0.08Mpa, dry 5-8 hour, obtain highly finished product and be about 45-47kg, the recyclable bromhexine hydrochloride crude product of refinement mother liquor, reclaims ethanol and applies mechanically after distillation process detection is qualified.
Embodiment 6
Bromhexine hydrochloride accelerated stability test result.
One, test method
1, sample lot number: 101201,101202,101203
2, sample packaging: plastics bag
3, stability conditions: temperature 40 ± 2 DEG C; RH75 ± 5%
4, test period: in December, 2010 ~ 2011 year June
5, test basis: " Chinese Pharmacopoeia " version in 2010 two
6, number of times is detected: 0 month, 1 month, 2 months, 3 months, 6 months.
Two, test-results: see attached list 1, subordinate list 2, subordinate list 3.
Three, conclusion (of pressure testing)
By 6 months accelerated stability tests, product purity kept more than 99.0%, and each impurity summation is less than 0.1%, and result shows that three batch samples all meet the regulation of " Chinese Pharmacopoeia " version in 2010 two.
Embodiment 7
Bromhexine hydrochloride long-term stable experiment result.
Four, test method
1, sample lot number: 101201,101202,101203
2, sample packaging: plastics bag
3, stability conditions: temperature 25 ± 2 DEG C; RH60 ± 10%
4, test period: in December, 2010 ~ 2012 year December
5, test basis: " Chinese Pharmacopoeia " version in 2010 two
6, number of times is detected: 0 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months
Five, test-results: see attached list 4, subordinate list 5, subordinate list 6.
Six, conclusion (of pressure testing)
By 24 months long-term stable experiments, product purity kept more than 99.0%, and each impurity summation is less than 0.1%, and result shows that three batch samples all still meet the regulation of " Chinese Pharmacopoeia " version in 2010 two, and its long-term stable experiment is also proceeding.
Embodiment 8
Ten lot number quality condition statistic datas that bromhexine hydrochloride is produced in the recent period see attached list 7.
Statistic data shows, is better than version " Chinese Pharmacopoeia " standard-required in 2010, single impurity < 0.05%, each impurity summation < 0.1% according to the bromhexine hydrochloride quality condition that patent of invention method is produced.
Table 1 bromhexine hydrochloride accelerated stability test result (lot number: 101201)
Table 2 bromhexine hydrochloride accelerated test stability test result (lot number: 101202)
Table 3 bromhexine hydrochloride accelerated test stability test result (lot number: 101203)
Claims (7)
1. a preparation method for bromhexine hydrochloride, is characterized in that, comprises the steps:
1) 3,5-bis-bromo-2-amino-benzene methyl alcohol and N-methylcyclohexylamine are that catalyzer carries out condensation reaction with glacial acetic acid, generate amino-3, the 5-dibromobenzene methylamines of N-methyl-N-cyclohexyl-2-;
2) amino-3, the 5-dibromobenzene methylamines of the N-methyl-N-cyclohexyl-2-generated and hydrochloric acid salify obtain bromhexine hydrochloride;
3) gained bromhexine hydrochloride decolorizing and refining in alcoholic solution obtains sterling;
Wherein, step 1) condensation reaction in add azeotropic aqua, the water in reaction process in reaction mixture distills removal in time; Described azeotropic aqua is toluene, and add-on is 1 ~ 2% of reaction system gross weight; Step 1) condensation reaction carry out in a solvent, reactant N-methylcyclohexylamine itself is again reaction solvent; The part by weight of each reactant is: 3,5-bis-bromo-2-amino-benzene methyl alcohol: N-methylcyclohexylamine: glacial acetic acid=1:1.10 ~ 1.30:0.50 ~ 0.60.
2. preparation method according to claim 1, is characterized in that, the part by weight of each reactant is: 3,5-bis-bromo-2-amino-benzene methyl alcohol: N-methylcyclohexylamine: glacial acetic acid=1:1.18 ~ 1.21:0.51 ~ 0.52.
3. preparation method according to claim 1, it is characterized in that, wherein, step 2) salt-forming reaction be in step 1) reaction complete after reaction mixture in add 10 ~ 30% hydrochloric acid, add-on is 1 ~ 1.5 times of 3,5-bis-bromo-2-amino-benzene methyl alcohol molar weight, salification process needs to add necessary solvent to be made to mix, solvent is selected from: acetone, methyl alcohol or ethanol, and add-on is about 1.2 ~ 1.6 times of 3,5-bis-bromo-2-amino-benzene methanol weight.
4. preparation method according to claim 1, it is characterized in that, wherein, step 3) purification step be step 2) the bromhexine hydrochloride crude product that obtains is placed in alcoholic solution and adds gac and carry out decolorizing and refining, described alcoholic solution is selected from: methyl alcohol, ethanol, Virahol; The weight proportion of each composition of this step is: bromhexine hydrochloride crude product: lower alcohol: activated carbon=1:8 ~ 16:0.03 ~ 0.08, needs the pH value regulating alcoholic solution, make solution ph reach 2 ~ 3 in treating process.
5. preparation method according to claim 1, is characterized in that, described alcoholic solution is ethanolic soln, and the weight proportion of each composition of this step is: bromhexine hydrochloride crude product: ethanol: activated carbon=1:11 ~ 12:0.05.
6. preparation method according to claim 1, is characterized in that, preparation method is as follows:
To in reactor, drop into N-methylcyclohexylamine, add 3,5-bis-bromo-2-amino-benzene methyl alcohol under stirring, stirring and dissolving, more slowly drip glacial acetic acid, finally add toluene; Open esterification to install pipes valve and water coolant and freezing refrigerant respective valves, carry out being heated to reflux water-dividing; Slowly heat up, until reaction end, reaction final temp is 170 ~ 180 DEG C later;
Pre-thermal crystalline reactor, and form negative pressure, be transferred in this reactor by upper step reaction gained reaction product, solvent fraction is to the greatest extent steamed in decompression, cooling, add acetone solution under stirring, then use the hydrochloric acid soln regulator solution pH=2 of 15%, be cooled to less than 5 DEG C crystallizations 5 ~ 8 hours, filter, filter cake washing with acetone, dry bromhexine hydrochloride crude product, mother liquor recyclable part bromhexine hydrochloride crude product;
In refining reaction device, add ethanol, add bromhexine hydrochloride crude product under stirring, use hydrochloric acid conditioning solution pH=2 ~ 3, after heating for dissolving, repetition measurement pH value of solution=2 ~ 3 are constant; Then add gac, reflux 1 hour, phegma filters, cooling crystallization, filters, and washing is dry, obtains refining sterling.
7. preparation method according to claim 1, is characterized in that, the water for claim 1 distills the conversion unit of removal in time, forms by with lower device: condenser (1); Distillation column (2); Reactor (3); Glass trap (4); Polytetrafluoroethylbellows bellows (5,6); Emptying valve (7,10); Glass visor (8,9); Diverter valve (11,12); Y tube (13); U-shaped pipe (14,16); J-shaped pipe (15); Threeway (17); Chilled brine import (18); Chilled brine outlet (19); Circulating cooling water inlet (20); Circulating cooling water out (21).
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