CN111072499A - Synthesis process of ambroxol hydrochloride - Google Patents
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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Abstract
The invention relates to a synthesis process of ambroxol hydrochloride, which comprises the following steps: carrying out bromination reaction on methyl o-aminobenzoate under the action of molecular bromine and hydrogen peroxide to generate a compound 3; carrying out ester amine condensation on the compound 3 and trans-4-aminocyclohexanol in a condensing agent to generate a compound 2; then carbonyl reduction is carried out to generate ambroxol hydrochloride through salification. The method has the advantages of mild conditions, simple steps, environmental friendliness, easy storage of raw materials, high yield and suitability for industrial production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a synthesis process of ambroxol hydrochloride.
Background
Ambroxol hydrochloride, chemical name: trans-4- [ (2-amino-3, 5-dibromobenzyl) amino ] -cyclohexanol hydrochloride, the chemical structural formula is:
ambroxol hydrochloride is a mucus dissolving agent developed by German Boringer Vangelhine company, is used for eliminating phlegm for treating various acute and chronic respiratory diseases accompanied with abnormal sputum secretion and phlegm elimination dysfunction, and has the advantages of definite curative effect, low toxicity and the like. The ambroxol hydrochloride can act on secretory cells, regulate the secretion of serous fluid and mucus, increase the secretion of serous fluid, dissolve and dilute the mucus, strengthen the swing of cilia, increase the clearing capacity of a mucus transportation system and easily discharge sputum.
Ambroxol hydrochloride is also a respiratory system protective agent, and has the effects of resisting oxidation, inhibiting the release of inflammatory mediators, relaxing airway smooth muscles, promoting the synthesis and secretion of lung surfactant and the like. The ambroxol hydrochloride can also increase the drug concentration of antibiotics in the airway, thereby improving the curative effect of the antibiotics.
A synthetic route of ambroxol hydrochloride is disclosed in 'ambroxol hydrochloride technical innovation' published in Yuan Chun Hu, 2-amino-3, 5-dibromobenzaldehyde is used as a starting material, and ambroxol hydrochloride is prepared through two-step reaction, wherein the specific process is that
The product trans-4- [ (2-amino-3, 5-dibromobenzylidene) amino ] cyclohexanol obtained by the first step of condensation reaction of the method needs to be separated independently, but the property is unstable, hydrolysis is easy to occur, the storage is difficult, the quality is difficult to guarantee even after refining, and the reaction time of the step is 10-15 hours, and the time is long; the second step of the method is to introduce hydrogen chloride gas for salt formation, and the operation is not easy in the actual production; and the sodium borohydride aqueous solution is adopted, so that the reducibility is strong, the water absorption and oxidation are very easy in the air, the storage condition requirement is strict, and the sodium borohydride aqueous solution and the air are highly toxic substances, so that the sodium borohydride aqueous solution is greatly harmful to a human body after being contacted for a long time and cannot adapt to large-scale production.
In the text entitled "synthesis of ambroxol hydrochloride", published by the same inventor, 3, 5-dibromo-2-aminobenzaldehyde and trans-4-aminocyclohexanol are condensed, the condensation product is refined by tetrachloroethylene to obtain trans-4- [ (2-amino-3, 5-dibromobenzylidene) amino ] cyclohexanol (Schiff base), the obtained product is dissolved in anhydrous methanol, then sodium borohydride is added for reduction, then the obtained product is subjected to extraction and other post-treatments to obtain a crude ambroxol hydrochloride product, the crude ambroxol hydrochloride product is reacted with concentrated hydrochloric acid to obtain a crude ambroxol hydrochloride product, and the crude ambroxol hydrochloride product is obtained by water refining. The reaction route is as follows:
the reaction route of the method is the same as that disclosed by Yuan Chun Hu et al, and the intermediate trans-4- [ (2-ammonia-3, 5-dibromobenzylidene) amino ] cyclohexanol also needs to be separated separately. In addition, sodium borohydride is used as a reducing agent, water absorption and oxidation are easy to occur in the air, the storage condition is strict, and the sodium borohydride is a highly toxic substance, so that the sodium borohydride is harmful to a human body after being contacted for a long time and cannot adapt to large-scale production.
DE2207460 uses trans-4-aminocyclohexanol to react with compound 4 to obtain compound 3, then passes through LiAlH4Reduction in tetrahydrofuran to give compound 2, and final reduction with Br2Bromination gives the product, the reaction equation is as follows:
the method uses LiAlH4Reduction reaction, the danger is higher; when molecular bromine is used as a brominating reagent, the theoretical utilization rate of the molecular bromine in the reaction process is only 50 percent, and the molecular bromine is industrially generatedIn terms of production, the method is a waste of resources, and the other half of molecular bromine generates corrosive hydrogen bromide in the reaction process, so that the corrosive hydrogen bromide severely corrodes industrial equipment, the service life of the industrial equipment is greatly reduced, and the method is not favorable for large-scale production.
In the preparation method of ambroxol hydrochloride disclosed in CN103012167A, 2-amino-3, 5-dibromobenzaldehyde and trans-4-aminocyclohexanol are used as raw materials, and the method is carried out by a one-pot method, although the route is simple and convenient to operate and short in reaction time, lithium aluminum hydride or sodium borohydride is used for reduction reaction, so that the reaction risk is increased, the cost is increased, and the method is not suitable for industrial production.
Therefore, there is still a need in the art for a method for synthesizing ambroxol hydrochloride, which is simple, mild in conditions, environment-friendly, easy in raw material storage and high in yield.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a synthesis process of ambroxol hydrochloride, which has high yield and is environment-friendly. The technical scheme of the invention is as follows:
the synthesis process of ambroxol hydrochloride is characterized by comprising the following operation steps:
1) carrying out bromination reaction on methyl anthranilate to generate a compound 3;
2) carrying out ester amine condensation on the compound 3 and trans-4-aminocyclohexanol to generate a compound 2;
3) reducing the compound 2 by carbonyl group, and salifying to obtain ambroxol hydrochloride;
in the step 1), the brominating agent is molecular bromine, the mass fraction is 30%, and the oxidant is hydrogen peroxide; the mass ratio of methyl anthranilate to molecular bromine is 1: 1.0-1.4; the reaction solvent is dichloromethane and water, the volume ratio of the dichloromethane to the water is 2:1, and the volume ratio of the hydrogen peroxide to the dichloromethane is 1: 10. Wherein the mass ratio of methyl anthranilate to molecular bromine is 1: 1.1.
In the step 2), the reaction solvent comprises N, N-dimethylformamide, dichloromethane, tetrahydrofuran, dioxane or a mixture thereof; the condensation catalyst is DIC and DMAP; the organic base comprises triethylamine or pyridine; the reaction molar ratio of the compound 3, the trans-4-aminocyclohexanol, the DIC and the organic base is 1: 1-1.2: 0.3-0.5: 1-3, the amount ratio of the compound 3 to the DMAP substance is 1: 0.05-0.15, and the reaction time is 1-3 hours at room temperature. Wherein, the reaction solvent is N, N-dimethylformamide; the reaction molar ratio of the compound 3, the trans-4-aminocyclohexanol, the DIC and the organic base is 1:1.2:0.4:1.5, and the weight ratio of the compound 3 to the DMAP substance is 1: 0.10.
In the step 3), the carbonyl reducing agent is hanster 1, 4-dihydropyridine, the catalyst is trifluoromethanesulfonic anhydride, and the mixture is stirred at room temperature for reaction; the salifying step is as follows: dissolving with acetone, dropwise adding concentrated hydrochloric acid under stirring at room temperature to obtain light yellow precipitate, stirring at room temperature, filtering, washing with acetone to obtain light yellow crude product, recrystallizing with water, decolorizing with activated carbon, and drying to obtain white ambroxol hydrochloride; the mass ratio of the compound 2, the trifluoromethanesulfonic anhydride and the hanster 1, 4-dihydropyridine is 1: 0.05-0.2: 1-2. Wherein the mass ratio of the compound 2, the trifluoromethanesulfonic anhydride and the hanster 1, 4-dihydropyridine is 1: 0.08-0.12: 1-1.5, and more preferably, the mass ratio of the compound 2, the trifluoromethanesulfonic anhydride and the hanster 1, 4-dihydropyridine is 1:0.1: 1.2.
Compared with the prior art, the beneficial technical effects of the invention are as follows:
1. the method takes methyl anthranilate as a starting material, has simple reaction steps, can finish ambroxol hydrochloride by only three steps, and has high reaction yield and high purity;
2. the molecular bromine is used as a bromination reagent, the hydrogen peroxide is used as an oxidant, and hydrogen bromide generated in the reaction process is oxidized into molecular bromine which is recycled in a reaction system, so that the utilization rate of bromine atoms is improved, half of the molecular bromine can be theoretically saved, and meanwhile, the hydrogen bromide generated in the bromination process is avoided, so that the severe corrosion to industrial equipment is avoided, and the service life of the industrial equipment is greatly reduced;
3. the invention takes DIC and DMAP as the amide condensing agent, avoids the disadvantages of using toxic reagent acyl chloride or other expensive amide condensing agents in the prior art, has high reaction yield and purity, does not have the racemization problem, has simple post-treatment, reduces the cost and is suitable for large-scale industrial production;
4. the carbonyl adopts hans ester 1, 4-dihydropyridine as a reducing agent, has the characteristics of easy preparation, low toxicity, easy storage compared with a stabilizing agent and the like, and has the best catalytic effect, higher yield and better selectivity when hans ester 1, 4-dihydropyridine is used as the reducing agent and trifluoromethanesulfonic anhydride is used as a catalyst.
Detailed Description
The technical solution of the present invention is further described in the following non-limiting examples. Wherein, the Hans ester 1, 4-dihydropyridine is synthesized as follows: adding 20mmol of formaldehyde, 20mmol of ammonium carbonate, 44mmol of ethyl acetoacetate, 40-50 mL of water and 22g of PEG-400 into a three-necked bottle, installing a thermometer and a reflux condenser tube on the bottle mouth, heating and stirring by using an oil bath, reacting for 2h at 70-75 ℃, and tracking the reaction by Thin Layer Chromatography (TLC) every 15-30 min (the volume ratio of a developing agent is ethyl acetate: petroleum ether is 3: 5). And cooling after the reaction is finished, carrying out reduced pressure filtration (mother liquor recovery), washing a filter cake for 2-3 times by using 50mL of distilled water, washing for 2-3 times by using warm 60mL of petroleum ether, and drying a product to obtain the target product 1, 4-dihydropyridine derivative with the yield of 92% and the purity of 98.9%.
Example 1: synthesis of Compound 3
30mmol of methyl anthranilate was weighed into a three-necked flask, and 60mL of methylene chloride and 42mL of water were added thereto and sufficiently stirred. 60mL of dichloromethane are added into the constant pressure funnel, 33mmol of molecular bromine is accurately weighed and added into the constant pressure funnel, and a dichloromethane solution of bromine is slowly dropped. And (3) slowly dropwise adding 12mL of uniformly mixed solution of 30% hydrogen peroxide and 18mL of water in mass fraction into the reaction system while dropwise adding molecular bromine, fully stirring, and tracking the reaction process by TLC. After the reaction was completed, water was added to the system until the solid was completely dissolved, followed by liquid separation and washing of the aqueous phase with dichloromethane until colorless and transparent. An appropriate amount of sodium bicarbonate solid and 50mL of dichloromethane were slowly added to the aqueous phase, stirred well, and extracted to obtain an organic phase. Washing the organic phase with water to neutrality, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain solid product as the crude product. The crude product was recrystallized from ethanol/water to give 8.985g of solid in 96.86% yield and 99.92% purity.
Example 2: synthesis of Compound 3
30mmol of methyl anthranilate was weighed into a three-necked flask, and 60mL of methylene chloride and 42mL of water were added thereto and sufficiently stirred. 60mL of dichloromethane are added into the constant pressure funnel, 42mmol of molecular bromine is accurately weighed and added into the constant pressure funnel, and a dichloromethane solution of bromine is slowly dropped. And (3) slowly dropwise adding 12mL of uniformly mixed solution of 30% hydrogen peroxide and 18mL of water in mass fraction into the reaction system while dropwise adding molecular bromine, fully stirring, and tracking the reaction process by TLC. After the reaction was completed, water was added to the system until the solid was completely dissolved, followed by liquid separation and washing of the aqueous phase with dichloromethane until colorless and transparent. An appropriate amount of sodium bicarbonate solid and 50mL of dichloromethane were slowly added to the aqueous phase, stirred well, and extracted to obtain an organic phase. Washing the organic phase with water to neutrality, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain solid product as the crude product. The crude product was recrystallized from ethanol/water to give 8.393g of a solid in 90.21% yield and 99.62% purity.
Example 3: synthesis of Compound 3
30mmol of methyl anthranilate was weighed into a three-necked flask, and 60mL of methylene chloride and 42mL of water were added thereto and sufficiently stirred. Adding 60mL of dichloromethane into a constant pressure funnel, accurately weighing 30mmol of molecular bromine, adding the molecular bromine into the constant pressure funnel, and slowly dropwise adding a dichloromethane solution of the bromine. And (3) slowly dropwise adding 12mL of uniformly mixed solution of 30% hydrogen peroxide and 18mL of water in mass fraction into the reaction system while dropwise adding molecular bromine, fully stirring, and tracking the reaction process by TLC. After the reaction was completed, water was added to the system until the solid was completely dissolved, followed by liquid separation and washing of the aqueous phase with dichloromethane until colorless and transparent. An appropriate amount of sodium bicarbonate solid and 50mL of dichloromethane were slowly added to the aqueous phase, stirred well, and extracted to obtain an organic phase. Washing the organic phase with water to neutrality, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain solid product as the crude product. The crude product was recrystallized from ethanol/water to give 8.319g of a solid in 89.27% yield and 99.46% purity.
Example 4: synthesis of Compound 2
Suspending 20mmol of compound 3, 24mmol of trans-4-aminocyclohexanol, 8mmol of DIC and 2mmol of DMAP in a reaction bottle containing 100mL of N, N-dimethylformamide, dropwise adding a mixed solution of 30mmol of pyridine and 50mL of N, N-dimethylformamide under the stirring of ice water bath, continuing stirring for 1 hour after dropwise adding is finished within 20 minutes, and then heating to room temperature and stirring for 2 hours. Stopping stirring, adding the reaction solution into water for pulping, performing ice-bath crystallization, filtering, and drying under reduced pressure to obtain 4.222g of compound 2 as a solid, wherein the yield is 96.14%, and the purity is 99.86%.
Example 5: synthesis of Compound 2
Suspending 20mmol of compound 3, 20mmol of trans-4-aminocyclohexanol, 6mmol of DIC and 1mmol of DMAP in a reaction bottle filled with 100mL of dichloromethane, dropwise adding a mixed solution consisting of 20mmol of triethylamine and 50mL of dichloromethane while stirring in an ice water bath, continuing stirring for 1 hour after dropwise adding is finished within 20 minutes, and then heating to room temperature and stirring for 2 hours. Stopping stirring, adding the reaction solution into water for pulping, crystallizing in ice bath, filtering, and drying under reduced pressure to obtain 3.669g of compound 2 as a solid, wherein the yield is 82.14%, and the purity is 98.17%.
Example 6: synthesis of Compound 2
Suspending 20mmol of compound 3, 24mmol of trans-4-aminocyclohexanol, 10mmol of DIC and 3mmol of DMAP in a reaction bottle filled with 100mL of tetrahydrofuran, dropwise adding a mixed solution consisting of 60mmol of diisopropylethylamine and 50mL of tetrahydrofuran while stirring in an ice water bath, continuing stirring for 1 hour after dropwise adding is finished within 20 minutes, and then heating to room temperature and stirring for 2 hours. Stopping stirring, adding the reaction solution into water for pulping, performing ice-bath crystallization, filtering, and drying under reduced pressure to obtain 3.922g of compound 2 as a solid, wherein the yield is 88.74 percent, and the purity is 99.24 percent.
Example 7: synthesis of Compound 2
Suspending 20mmol of compound 3, 24mmol of trans-4-aminocyclohexanol, 6mmol of DIC and 3mmol of DMAP in a reaction bottle filled with 100mL of dioxane, dropwise adding a mixed solution consisting of 30mmol of pyridine and 50mL of dioxane under the stirring of ice-water bath, continuing stirring for 1 hour after the dropwise adding is finished within 20 minutes, and then heating to room temperature and stirring for 2 hours. Stopping stirring, adding the reaction solution into water, pulping, crystallizing in ice bath, filtering, and drying under reduced pressure to obtain solid 4.066g of compound 2, wherein the yield is 92.18%, and the purity is 99.43%.
Example 8: synthesis of ambroxol hydrochloride
Adding 10mmol of compound 2 and 1mmol of trifluoromethanesulfonic anhydride into a round-bottom flask in sequence, dissolving in 50mL of toluene, stirring for 0.5h, adding 12mmol of hans-ester 1, 4-dihydropyridine, stirring at room temperature for reaction for 1h, adding 20mL of water, separating out an organic phase, washing with water, washing with saturated salt water, drying the organic phase, concentrating under reduced pressure, adding 100mL of acetone for dissolution, dropwise adding 5mL of concentrated hydrochloric acid while stirring at room temperature to generate a light yellow precipitate, stirring at room temperature for 1h, filtering, and washing with acetone to obtain a light yellow crude product. Recrystallizing with water, decolorizing with activated carbon, and drying to obtain 2.345g of ambroxol hydrochloride with yield of 96.85% and purity of 99.84%.
Example 9: synthesis of ambroxol hydrochloride
Adding 10mmol of compound 2 and 0.8mmol of trifluoromethanesulfonic anhydride into a round-bottom flask in sequence, dissolving in 50mL of toluene, stirring for 0.5h, adding 10mmol of hans-ester 1, 4-dihydropyridine, stirring at room temperature for reaction for 1h, adding 20mL of water, separating out an organic phase, washing with water, washing with saturated salt water, drying the organic phase, concentrating under reduced pressure, adding 100mL of acetone for dissolution, dropwise adding 5mL of concentrated hydrochloric acid while stirring at room temperature to generate a light yellow precipitate, stirring at room temperature for 1h, filtering, and washing with acetone to obtain a light yellow crude product. Recrystallizing with water, decolorizing with activated carbon, and drying to obtain 2.197g of white ambroxol hydrochloride with yield of 90.41% and purity of 99.48%.
Example 10: synthesis of ambroxol hydrochloride
Adding 10mmol of compound 2 and 1.2mmol of trifluoromethanesulfonic anhydride into a round-bottom flask in sequence, dissolving in 50mL of toluene, stirring for 0.5h, adding 15mmol of hans-ester 1, 4-dihydropyridine, stirring at room temperature for reaction for 1h, adding 20mL of water, separating out an organic phase, washing with water, washing with saturated salt water, drying the organic phase, concentrating under reduced pressure, adding 100mL of acetone for dissolution, dropwise adding 5mL of concentrated hydrochloric acid while stirring at room temperature to generate a light yellow precipitate, stirring at room temperature for 1h, filtering, and washing with acetone to obtain a light yellow crude product. Recrystallizing with water, decolorizing with activated carbon, and drying to obtain 2.216g of white ambroxol hydrochloride with yield of 91.25% and purity of 99.56%.
Example 11: synthesis of ambroxol hydrochloride
Adding 10mmol of compound 2 and 0.5mmol of trifluoromethanesulfonic anhydride into a round-bottom flask in sequence, dissolving in 50mL of toluene, stirring for 0.5h, adding 10mmol of hans-ester 1, 4-dihydropyridine, stirring at room temperature for reaction for 1h, adding 20mL of water, separating out an organic phase, washing with water, washing with saturated salt water, drying the organic phase, concentrating under reduced pressure, adding 100mL of acetone for dissolution, dropwise adding 5mL of concentrated hydrochloric acid while stirring at room temperature to generate a light yellow precipitate, stirring at room temperature for 1h, filtering, and washing with acetone to obtain a light yellow crude product. Recrystallizing with water, decolorizing with activated carbon, and drying to obtain 2.115g of ambroxol hydrochloride with yield of 86.84% and purity of 99.28%.
Example 12: synthesis of ambroxol hydrochloride
Adding 10mmol of compound 2 and 2mmol of trifluoromethanesulfonic anhydride into a round-bottom flask in sequence, dissolving in 50mL of toluene, stirring for 0.5h, adding 20mmol of hans-ester 1, 4-dihydropyridine, stirring at room temperature for reaction for 1h, adding 20mL of water, separating out an organic phase, washing with water, washing with saturated salt water, drying the organic phase, concentrating under reduced pressure, adding 100mL of acetone for dissolution, dropwise adding 5mL of concentrated hydrochloric acid while stirring at room temperature to generate a light yellow precipitate, stirring at room temperature for 1h, filtering, and washing with acetone to obtain a light yellow crude product. Recrystallizing with water, decolorizing with activated carbon, and drying to obtain 2.164g of white ambroxol hydrochloride with yield of 88.96% and purity of 99.38%.
Comparative example 1: synthesis of Compound 3
30mmol of methyl anthranilate was weighed into a three-necked flask, and 60mL of 1, 1-dichloroethane and 42mL of water were added thereto and sufficiently stirred. 30mL of 1, 1-dichloroethane is added into the constant pressure funnel, 33mmol of molecular bromine is accurately weighed and added into the constant pressure funnel, and the 1, 1-dichloroethane solution of the bromine is slowly dropped. And (3) slowly dropwise adding 12mL of uniformly mixed solution of 30% hydrogen peroxide and 18mL of water in mass fraction into the reaction system while dropwise adding molecular bromine, fully stirring, and tracking the reaction process by TLC. After the reaction was completed, water was added to the system until the solid was completely dissolved, followed by liquid separation and washing of the aqueous phase with dichloromethane until colorless and transparent. An appropriate amount of sodium bicarbonate solid and 50mL of dichloromethane were slowly added to the aqueous phase, stirred well, and extracted to obtain an organic phase. Washing the organic phase with water to neutrality, drying with anhydrous sodium sulfate, filtering, and distilling under reduced pressure to obtain solid product as the crude product. The crude product was recrystallized from ethanol/water to give 7.554g of a solid in 73.58% yield and 90.28% purity.
Comparative example 2: synthesis of Compound 2
Suspending 20mmol of compound 3, 24mmol of trans-4-aminocyclohexanol and 24mmol of 2-methoxy-4, 6-dichloro-1, 3, 5-triazine in a reaction bottle containing 100mL of N, N-dimethylformamide, dropwise adding a mixed solution of 30mmol of N-methylcyclohexylamine and 50mL of N, N-dimethylformamide under stirring in an ice-water bath, continuing stirring for 1 hour after the dropwise addition is finished within 20 minutes, and then heating to room temperature and stirring for 2 hours. Stopping stirring, adding the reaction solution into water for pulping, performing ice-bath crystallization, filtering, and drying under reduced pressure to obtain 3.388g of compound 2 as a solid, wherein the yield is 71.63%, and the purity is 92.71%.
Comparative example 3: synthesis of ambroxol hydrochloride
Adding 10mmol of compound 2 and 1mmol of trifluoromethanesulfonic anhydride into a round-bottom flask in sequence, dissolving in 50mL of dichloromethane, stirring for 0.5h, adding 12mmol of hans-ester 1, 4-dihydropyridine, stirring at room temperature for reaction for 1h, adding 20mL of water, separating out an organic phase, washing with water, washing with saturated salt water, drying the organic phase, concentrating under reduced pressure, adding 100mL of acetone for dissolution, dropwise adding 5mL of concentrated hydrochloric acid while stirring at room temperature to generate a light yellow precipitate, stirring at room temperature for 1h, filtering, and washing with acetone to obtain a light yellow crude product. Recrystallizing with ethanol, decolorizing with activated carbon, and drying to obtain 1.593g of white ambroxol hydrochloride with yield of 64.85% and purity of 98.43%.
It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (10)
1. The synthesis process of ambroxol hydrochloride is characterized by comprising the following operation steps:
1) carrying out bromination reaction on methyl anthranilate to generate a compound 3;
2) carrying out ester amine condensation on the compound 3 and trans-4-aminocyclohexanol to generate a compound 2;
3) reducing the compound 2 by carbonyl group, and salifying to obtain ambroxol hydrochloride;
2. the process for synthesizing ambroxol hydrochloride according to claim 1, wherein in step 1), the brominating agent is molecular bromine with a mass fraction of 30%, and the oxidizing agent is hydrogen peroxide.
3. The ambroxol hydrochloride synthesis process according to claim 2, characterized in that in step 1), the mass ratio of methyl anthranilate to molecular bromine is 1: 1.0-1.4; the reaction solvent is dichloromethane and water, the volume ratio of the dichloromethane to the water is 2:1, and the volume ratio of the hydrogen peroxide to the dichloromethane is 1: 10.
4. The process for synthesizing ambroxol hydrochloride according to claim 1, wherein in step 2), the reaction solvent is selected from the group consisting of N, N-dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, and a mixture thereof; the condensation catalyst is DIC and DMAP; the organic base comprises triethylamine or pyridine; the reaction molar ratio of the compound 3, the trans-4-aminocyclohexanol, the DIC and the organic base is 1: 1-1.2: 0.3-0.5: 1-3, the amount ratio of the compound 3 to the DMAP substance is 1: 0.05-0.15, and the reaction time is 1-3 hours at room temperature.
5. The process for synthesizing ambroxol hydrochloride according to claim 1, wherein in step 3), the carbonyl reducing agent is hanster 1, 4-dihydropyridine, the catalyst is trifluoromethanesulfonic anhydride, and the reaction is carried out with stirring at room temperature; the salifying step is as follows: dissolving with acetone, dropwise adding concentrated hydrochloric acid under stirring at room temperature to obtain light yellow precipitate, stirring at room temperature, filtering, washing with acetone to obtain light yellow crude product, recrystallizing with water, decolorizing with activated carbon, and drying to obtain white ambroxol hydrochloride.
6. The process for synthesizing ambroxol hydrochloride according to claim 5, wherein in the step 3), the mass ratio of the compound 2, trifluoromethanesulfonic anhydride and hanster 1, 4-dihydropyridine is 1: 0.05-0.2: 1-2.
7. The process for synthesizing ambroxol hydrochloride according to claim 3, wherein in step 1), the mass ratio of methyl anthranilate to molecular bromine is 1: 1.1.
8. The process for synthesizing ambroxol hydrochloride according to claim 4, wherein in the step 2), the reaction solvent is N, N-dimethylformamide; the reaction molar ratio of the compound 3, the trans-4-aminocyclohexanol, the DIC and the organic base is 1:1.2:0.4:1.5, and the weight ratio of the compound 3 to the DMAP substance is 1: 0.10.
9. The process for synthesizing ambroxol hydrochloride according to claim 6, wherein in the step 3), the mass ratio of the compound 2, trifluoromethanesulfonic anhydride and hanster 1, 4-dihydropyridine is 1: 0.08-0.12: 1-1.5.
10. The process for synthesizing ambroxol hydrochloride according to claim 9, wherein in step 3), the mass ratio of the compound 2, trifluoromethanesulfonic anhydride and hanster 1, 4-dihydropyridine is 1:0.1: 1.2.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112341347A (en) * | 2020-11-12 | 2021-02-09 | 中国药科大学 | Synthetic method of ambroxol hydrochloride |
| CN114380704A (en) * | 2020-10-22 | 2022-04-22 | 南开大学 | Synthetic method for preparing monobromoanilide compound |
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| CN101337897A (en) * | 2007-07-06 | 2009-01-07 | 江苏恒瑞医药股份有限公司 | Process for preparing ambroxol, analogue thereof or salts thereof |
| CN107915653A (en) * | 2017-12-04 | 2018-04-17 | 苏州大学 | Catalysis ester and amine carry out the method that reaction prepares acid amides |
| CN109535010A (en) * | 2018-12-27 | 2019-03-29 | 广州品红制药有限公司 | A kind of preparation method of bromhexine hydrochloride |
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| CN101337897A (en) * | 2007-07-06 | 2009-01-07 | 江苏恒瑞医药股份有限公司 | Process for preparing ambroxol, analogue thereof or salts thereof |
| CN107915653A (en) * | 2017-12-04 | 2018-04-17 | 苏州大学 | Catalysis ester and amine carry out the method that reaction prepares acid amides |
| CN109535010A (en) * | 2018-12-27 | 2019-03-29 | 广州品红制药有限公司 | A kind of preparation method of bromhexine hydrochloride |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114380704A (en) * | 2020-10-22 | 2022-04-22 | 南开大学 | Synthetic method for preparing monobromoanilide compound |
| CN112341347A (en) * | 2020-11-12 | 2021-02-09 | 中国药科大学 | Synthetic method of ambroxol hydrochloride |
| CN112341347B (en) * | 2020-11-12 | 2022-03-08 | 中国药科大学 | Synthetic method of ambroxol hydrochloride |
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