CN116514666A - Preparation method of bromhexine hydrochloride - Google Patents
Preparation method of bromhexine hydrochloride Download PDFInfo
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- CN116514666A CN116514666A CN202210083627.2A CN202210083627A CN116514666A CN 116514666 A CN116514666 A CN 116514666A CN 202210083627 A CN202210083627 A CN 202210083627A CN 116514666 A CN116514666 A CN 116514666A
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- Prior art keywords
- bromhexine hydrochloride
- reaction
- dibromo
- crude product
- aminobenzaldehyde
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- 229960002335 bromhexine hydrochloride Drugs 0.000 title claims abstract description 48
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 39
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- RCPAZWISSAVDEA-UHFFFAOYSA-N 2-amino-3,5-dibromobenzaldehyde Chemical compound NC1=C(Br)C=C(Br)C=C1C=O RCPAZWISSAVDEA-UHFFFAOYSA-N 0.000 claims abstract description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000012043 crude product Substances 0.000 claims abstract description 21
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 17
- 235000019253 formic acid Nutrition 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 claims abstract description 15
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 11
- 239000000047 product Substances 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000007858 starting material Substances 0.000 abstract description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000003638 chemical reducing agent Substances 0.000 abstract description 4
- 239000011591 potassium Substances 0.000 abstract description 4
- 229910052700 potassium Inorganic materials 0.000 abstract description 4
- 239000012279 sodium borohydride Substances 0.000 abstract description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract description 4
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical group C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- GHUMSGGCKVMYGH-UHFFFAOYSA-N (2-amino-3,5-dibromophenyl)methanol Chemical compound NC1=C(Br)C=C(Br)C=C1CO GHUMSGGCKVMYGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960003870 bromhexine Drugs 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- MCJGPOZFMWWPGB-UHFFFAOYSA-N 2,4-dibromo-6-[(cyclohexylamino)methyl]aniline Chemical compound NC1=C(Br)C=C(Br)C=C1CNC1CCCCC1 MCJGPOZFMWWPGB-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- -1 N-methyl-N-cyclohexyl-2-amino-3, 5-dibromobenzamide hydrochloride Chemical group 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 208000026435 phlegm Diseases 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- WUESWDIHTKHGQA-UHFFFAOYSA-N cyclohexylurea Chemical class NC(=O)NC1CCCCC1 WUESWDIHTKHGQA-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
- C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of bromhexine hydrochloride. The preparation method comprises the following steps: in the presence of formic acid, 3, 5-dibromo-2-amino benzaldehyde and N-methyl cyclohexylamine undergo reductive amination reaction, hydrochloric acid is added for salifying reaction, a bromhexine hydrochloride crude product is obtained, and the bromhexine hydrochloride crude product is refined to obtain the bromhexine hydrochloride; the molar ratio of formic acid to 3, 5-dibromo-2-aminobenzaldehyde is 1.0-5.0: 1, a step of; the molar ratio of the N-methyl cyclohexylamine to the 3, 5-dibromo-2-aminobenzaldehyde is 1.0-5.0: 1. the bromhexine hydrochloride crude product is prepared by one-step reaction, formic acid is used as a reducing agent, toluene is used as an entrainer, the reaction steps and time are shortened, the yield is improved, the use of sodium borohydride or potassium borohydride is avoided, and the reaction safety is improved. The product prepared by the method has few impurities and higher purity, and the crude product basically contains no other unknown impurities except a small amount of residual starting materials and is easy to purify. The method has the advantages of simple reaction operation, relatively mild conditions, less byproducts and high yield, and is suitable for industrial production and application.
Description
Technical Field
The invention relates to a preparation method of bromhexine hydrochloride, and belongs to the field of pharmaceutical chemicals.
Background
Bromhexine hydrochloride, the English name is Bromhexine Hydrochloride, the chemical name is N-methyl-N-cyclohexyl-2-amino-3, 5-dibromobenzamide hydrochloride, and the structural formula is as follows:
bromhexine hydrochloride is a phlegm-sticking dissolving agent, and is clinically mainly used for acute and chronic bronchitis, asthma, bronchiectasis and emphysema, and is especially suitable for white phlegm-sticking cough patients and critical emergency diseases caused by wide obstruction of small bronchi by sputum.
The existing production process route of bromhexine hydrochloride raw material medicine mainly comprises the following steps:
route one:
the process in the first route involves most of condensing agents such as Dicyclohexylcarbodiimide (DCC) or EDC, the byproducts are cyclohexyl urea derivatives, the toxicity is high, the residues are difficult to remove, the residual risks influence the medication safety of bromhexine hydrochloride, and meanwhile, the price of the starting materials and the condensing agents is high, so that the method is not suitable for industrial application.
Route two:
the second route has long process steps, complex operation and long production period; in addition, benzyl alcohol is replaced by thionyl chloride or TosCl in the process, and chlorinated impurities or sulfonate impurities are introduced besides the reaction steps, so that the impurities in the product are difficult to remove, and the control risk of the product is increased.
When the intermediate 3, 5-dibromo-2-amino benzyl alcohol reacts with thionyl chloride, bromine of the benzene ring is easily replaced by chlorine to generate corresponding impurities, and the purification difficulty of the product is increased. The limit of impurity I is specified in the standards of bromhexine hydrochloride related substances in the chinese pharmacopoeia of 2020 edition, and impurity I is a byproduct of substitution of one bromine on a benzene ring in bromhexine structure by chlorine, and its structure and properties are similar to bromhexine hydrochloride, and the impurities are as follows:
route three:
the process of the third route is simpler, potassium borohydride is used as a reducing agent, 3, 5-dibromo-2-aminobenzaldehyde is reduced to generate 3, 5-dibromo-2-aminobenzyl alcohol, condensation reaction is carried out under the catalysis of acetic acid, and hydrochloric acid is added to prepare bromhexine hydrochloride. The condensation step of the route needs about 180 ℃, has high temperature and high requirements on reaction equipment, and simultaneously has the risk of incomplete reaction, so that potential safety hazards exist in industrial production.
Route four:
in the fourth route, 3, 5-dibromo-2-aminobenzaldehyde is used as a starting material, reacts with cyclohexylamine to generate an imine intermediate, sodium borohydride is used for reduction to obtain 2-amino-3, 5-dibromo-N-cyclohexylbenzylamine, the 2-amino-3, 5-dibromo-N-cyclohexylbenzylamine reacts with a methylation reagent dimethyl sulfate to generate bromhexine, and hydrochloric acid is used for salifying to obtain bromhexine hydrochloride. Dimethyl sulfate is used in the route, is a highly toxic reagent and genotoxic impurities, has low quality control limit, and is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of bromhexine hydrochloride, which overcomes the defects in the prior art.
The preparation method of bromhexine hydrochloride provided by the invention comprises the following steps:
in the presence of formic acid, 3, 5-dibromo-2-amino benzaldehyde and N-methyl cyclohexylamine undergo reductive amination reaction, hydrochloric acid is added for salifying reaction, a bromhexine hydrochloride crude product is obtained, and the bromhexine hydrochloride crude product is refined to obtain the bromhexine hydrochloride;
in the preparation method, formic acid is used as a reducing agent, and the formic acid is dropwise added into a reaction system in a reflux state.
In the preparation method, the molar ratio of the formic acid to the 3, 5-dibromo-2-aminobenzaldehyde is 1.0-5.0: 1, preferably 1.0 to 3.0:1,.
In the preparation method, the molar ratio of the N-methyl cyclohexylamine to the 3, 5-dibromo-2-aminobenzaldehyde is 1.0-5.0: 1, preferably 1.0 to 3.0:1.
in the above preparation method, the solvent for the reductive amination reaction may be toluene or xylene, preferably toluene.
In the preparation method, the temperature of the reductive amination reaction is 60-160 ℃, preferably 100-140 ℃, and the reductive amination reaction is carried out in a reflux state to promote the generation of bromhexine;
the reductive amination reaction time is 5-20 h.
In the preparation method, the bromhexine hydrochloride crude product is refined in a recrystallization mode, so that related impurities can be effectively removed;
the solvent adopted for recrystallization is alcohol or aqueous solution thereof, and the alcohol is methanol or ethanol.
The preparation method has the following beneficial technical effects:
the invention takes 3, 5-dibromo-2-amino benzaldehyde as a starting material, and is used as a bromhexine starting material, and has the advantages of wide source, low cost and reliable quality.
The bromhexine hydrochloride crude product is prepared by one-step reaction, formic acid is used as a reducing agent, toluene is used as an entrainer, the reaction steps and time are shortened, the yield is improved, the use of sodium borohydride or potassium borohydride is avoided, and the reaction safety is improved.
The method has the advantages of simple reaction operation, relatively mild conditions, less byproducts and high yield, and is suitable for industrial production and application.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a crude bromhexine hydrochloride product prepared in example 1 of the present invention.
FIG. 2 is a high performance liquid chromatogram of bromhexine hydrochloride purified in example 4 of the present invention.
Detailed Description
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1: preparation of bromhexine hydrochloride crude product
Into the reaction flask were charged 100.0g of 3, 5-dibromo-2-aminobenzaldehyde and 600ml of toluene, and 81.1. 81.1g N-methylcyclohexylamine (the molar ratio of N-methylcyclohexylamine to 3, 5-dibromo-2-aminobenzaldehyde was 2.0:1) was added thereto, and the oil bath temperature was set at 140 ℃. After the reflux was started, 33.0g of formic acid (molar ratio of formic acid to 3, 5-dibromo-2-aminobenzaldehyde: 2.0:1) was added dropwise, and after the completion of the addition, the reflux reaction was maintained for 12 hours. Concentrating toluene under reduced pressure after the reaction is finished, adding ethyl acetate and water, cooling to 0-10 ℃, dropwise adding 40ml of hydrochloric acid, stirring for crystallization, performing suction filtration, washing a filter cake with water, washing with ethyl acetate for 1-2 times, and drying for 6h at 60 ℃ by blowing to obtain 134.6g of bromhexine hydrochloride crude product. Yield: 91%.
The bromhexine hydrochloride prepared in this example has a nuclear magnetic resonance hydrogen spectrum shown in figure 1.
LC-MS：377(M(-HCl)+1)； 1 H-NMR(500MHz，d 6 -DMSO)δ＝10.11(brs,1H)，7.67(d，2H)，5.88(brs，2H)，4.39～4.25(dd，2H)，3.31～3.28(m，1H)，2.53(s，3H)，2.17～2.15(m，2H)，1.86～1.81(m，2H)1.63-1.61(d，1H)1.51～1.47(m，2H)，1.26～1.25(m，2H)，1.10～1.24(m，1H)。
Example 2: preparation of bromhexine hydrochloride crude product
Into the reaction flask were charged 100.0g of 3, 5-dibromo-2-aminobenzaldehyde and 600ml of toluene, 73.0g of g N-methylcyclohexylamine (the molar ratio of N-methylcyclohexylamine to 3, 5-dibromo-2-aminobenzaldehyde was 1.8:1) and the oil bath temperature was set to 140 ℃. After the reflux was started, 33.0g of formic acid (molar ratio of formic acid to 3, 5-dibromo-2-aminobenzaldehyde: 2.0:1) was added dropwise, and after the completion of the addition, the reflux reaction was maintained for 10 hours. Concentrating toluene under reduced pressure after the reaction is finished, adding ethyl acetate and water, cooling to 0-10 ℃, dropwise adding 40ml of hydrochloric acid, stirring for crystallization, performing suction filtration, washing a filter cake with water, washing with ethyl acetate for 1-2 times, and drying for 6 hours at 70 ℃ by blowing to obtain 128.7g of bromhexine hydrochloride crude product. Yield: 87%.
Example 3: preparation of bromhexine hydrochloride crude product
Into the reaction flask were charged 100.0g of 3, 5-dibromo-2-aminobenzaldehyde and 600ml of toluene, 121.6. 121.6g N-methylcyclohexylamine (the molar ratio of N-methylcyclohexylamine to 3, 5-dibromo-2-aminobenzaldehyde was 1.5:1) was added, and the oil bath temperature was set at 130 ℃. 49.5g of formic acid (molar ratio of formic acid to 3, 5-dibromo-2-aminobenzaldehyde is 1.7:1) are added dropwise after reflux is started, and reflux reaction is maintained for 16h after the addition is completed. After the reaction is finished, the toluene is concentrated under reduced pressure, ethyl acetate and water are added, the temperature is reduced to 0-10 ℃, 40ml of hydrochloric acid is added dropwise, stirring crystallization is carried out for 1h, suction filtration is carried out, a filter cake is washed with water, then is washed with ethyl acetate, and blast drying is carried out for 6h at 70 ℃ to obtain 133.1g of bromhexine hydrochloride crude product. Yield: 90%.
Example 4 purification of bromhexine hydrochloride
Adding 40g of crude product prepared in the example 1 into a reaction bottle, adding 95% ethanol, stirring and heating to reflux, adding active carbon after the system is completely dissolved, decoloring for 30 minutes, filtering while the system is hot, cooling to room temperature, cooling to 0-5 ℃, crystallizing for 1h, filtering, leaching with ethanol, drying at 70 ℃ under reduced pressure for 5h to obtain 36.1g of white solid, and obtaining the yield: 90%, purity: 99.9% and high performance liquid chromatogram as shown in FIG. 2.
The steps of the high performance liquid chromatography (China pharmacopoeia 2020 edition, four-part general rule 0512) are as follows:
test solution: the product is taken to be weighed accurately, dissolved in methanol and diluted to prepare a solution with the concentration of 2.5mg in each 1 ml.
Control solution: the sample solution was precisely measured and diluted with methanol to give a solution containing about 5. Mu.g per 1 ml.
Chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler; phosphate buffer solution (1.0 g of potassium dihydrogen phosphate is taken, 900ml of water is added for dissolution, 0.5mol/L sodium hydroxide solution is used for adjusting the pH value to 7.0, water is used for diluting to 1000ml, shaking is carried out), and acetonitrile (20:80) is taken as a mobile phase; column temperature is 40 ℃; the detection wavelength is 245nm; the sample volume was 10. Mu.l.
Comparative example 1 preparation of bromhexine hydrochloride Using route two in the background art
11.2g of 2-amino-3, 5-dibromobenzaldehyde and 20ml of absolute ethyl alcohol, 0.95g of sodium borohydride is added in portions under stirring, the temperature is controlled to be 40-50 ℃, and TLC monitoring is carried out on the completion of the reaction. 50ml of water is added into the reaction system, 2N hydrochloric acid is added dropwise under stirring to adjust the pH of the solution to 5-6, stirring is continued for 30 minutes, filtering is carried out, the filter cake is washed three times by water, and drying is carried out, thus obtaining 2-amino-3, 5-dibromobenzyl alcohol.
And adding the reduction product into 30ml of thionyl chloride in batches, keeping the ice bath at a temperature during the adding process, and stirring for 3-4 hours at room temperature after the adding is finished. After the completion, the excess thionyl chloride was concentrated under reduced pressure at normal temperature, 20ml of n-hexane was added to the residue, stirred for 20 minutes, filtered, washed with 20ml of n-hexane, and dried under reduced pressure at 30℃to give a yellow solid as a chlorinated intermediate.
The chlorinated intermediate is added into 11.3-g N-methyl cyclohexylamine, and then 20ml of absolute ethyl alcohol is added, and the mixture is stirred and reacted for 3 to 4 hours at normal temperature. After the reaction is finished, the reaction solution is concentrated under reduced pressure, 40ml of ethyl acetate is added into the residue, insoluble matters are removed by filtration, the pH value of the filtrate is adjusted to 5-6 by using a hydrogen chloride solution of ethyl acetate, the temperature is reduced to 0-5 ℃, stirring crystallization is carried out, filtration and drying are carried out, a bromhexine hydrochloride crude product is obtained, 6.8g of bromhexine hydrochloride is obtained by methanol recrystallization, and the yield is: 41%.
Comparative example 2 preparation of bromhexine hydrochloride by route three method in background art
100g of 3, 5-di-bromo-2-aminobenzaldehyde and 300ml of absolute ethyl alcohol are added into a reaction bottle, after being uniformly stirred, 9g of potassium borohydride is added in portions, the temperature is controlled to be not more than 50 ℃, the reaction is carried out for 3 hours under stirring, and TLC (thin layer chromatography) detects that the raw materials are completely reacted. Cooling the system to 0-10 ℃ for crystallization, carrying out suction filtration, washing a filter cake with water to be neutral, and drying to obtain 98.5g of solid with the yield: 97.8%, purity: 99.5%.
90g of the solid (3, 5-di-bromo-2-aminobenzyl alcohol), 97.2. 97.2g N-methylcyclohexylamine, 50.4g of acetic acid and 4.8g of toluene are added into a reaction bottle, and stirred, the temperature of the oil bath is raised to 150 ℃ and stirred for 12 hours, the temperature of the oil bath is raised to 5 ℃ per hour, and after the temperature is raised to 175 ℃, the reaction is continued for 12 hours until no liquid drops substantially, and the total reaction lasts for about 30 hours. Cooling to room temperature, adding 450ml of water, 112ml of concentrated hydrochloric acid and 200ml of ethyl acetate, stirring and cooling to 0-10 ℃, carrying out suction filtration, washing with water to be neutral, washing with 220ml of ethyl acetate, and drying to obtain 97.7g of yellow solid, wherein the yield is: 74% of bromhexine hydrochloride crude product.
Adding 95g of the crude product into a reaction bottle, adding 190 ml of 95% ethanol, heating to reflux, adding 3g of active carbon after complete dissolution, preserving heat and decoloring for 1 hour, filtering while the solution is hot, evaporating about 1/2 volume of ethanol from filtrate, naturally cooling to room temperature, cooling to 0-5 ℃ for stirring and crystallizing for 1 hour, filtering, leaching with 20ml of cold ethanol, and drying to obtain 83.1g of bromhexine hydrochloride, wherein the yield is as follows: 87%.
Comparison of bromhexine hydrochloride preparation process. The operation procedures, parameters and total yields of examples 1 and 4 and comparative examples 1 and 2 were compared, and the results are shown in table 3.
Table 3 comparison of the working procedures, parameters and overall yields of examples and comparative examples
As can be seen from the table, the method has the advantages of few steps, relatively mild conditions, and obviously better product purity and yield than the existing synthetic method. The bromhexine hydrochloride prepared by the method has the advantages of good quality, high yield and low cost, and is particularly suitable for industrial production.
The method has few steps and relatively mild conditions. The bromhexine hydrochloride prepared by the method has the advantages of good quality, high yield and low cost, and is particularly suitable for industrial production.
The above-described embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention.
Claims (7)
1. The preparation method of bromhexine hydrochloride comprises the following steps:
in the presence of formic acid, 3, 5-dibromo-2-amino benzaldehyde and N-methyl cyclohexylamine undergo reductive amination reaction, hydrochloric acid is added for salifying reaction, a bromhexine hydrochloride crude product is obtained, and the bromhexine hydrochloride crude product is refined to obtain the bromhexine hydrochloride;
the molar ratio of the formic acid to the 3, 5-dibromo-2-aminobenzaldehyde is 1.0-5.0: 1, a step of;
the molar ratio of the N-methyl cyclohexylamine to the 3, 5-dibromo-2-aminobenzaldehyde is 1.0-5.0: 1.
2. the method of manufacturing according to claim 1, characterized in that: the molar ratio of the formic acid to the 3, 5-dibromo-2-aminobenzaldehyde is 1.0-3.0: 1.
3. the preparation method according to claim 1 or 2, characterized in that: the molar ratio of the N-methyl cyclohexylamine to the 3, 5-dibromo-2-aminobenzaldehyde is 1.0-3.0: 1.
4. a production method according to any one of claims 1 to 3, characterized in that: the solvent for the reductive amination reaction is toluene or xylene, preferably toluene.
5. The method according to any one of claims 1 to 4, wherein: the temperature of the reductive amination reaction is 60-160 ℃, preferably 100-140 ℃;
the reductive amination reaction time is 5-20 h.
6. The production method according to any one of claims 1 to 5, characterized in that: refining the bromhexine hydrochloride crude product by adopting a recrystallization mode.
7. The method of manufacturing according to claim 6, wherein: the solvent adopted for recrystallization is alcohol or aqueous solution thereof, and the alcohol is methanol or ethanol.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617359A (en) * | 2012-02-24 | 2012-08-01 | 石家庄东方药业有限公司 | Method for preparing bromhexine hydrochloride |
| CN103333074A (en) * | 2013-07-02 | 2013-10-02 | 浙江万邦药业股份有限公司 | Production method of bromhexine hydrochloride |
| CN103396323A (en) * | 2013-08-07 | 2013-11-20 | 张嵩 | Production method of bromhexine hydrochloride |
| CN104447355A (en) * | 2014-10-13 | 2015-03-25 | 宁波天衡药业股份有限公司 | Novel method for preparing bromhexine hydrochloride |
| CN112194585A (en) * | 2020-10-29 | 2021-01-08 | 济南久隆医药科技有限公司 | Synthetic method of bromhexine hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617359A (en) * | 2012-02-24 | 2012-08-01 | 石家庄东方药业有限公司 | Method for preparing bromhexine hydrochloride |
| CN103333074A (en) * | 2013-07-02 | 2013-10-02 | 浙江万邦药业股份有限公司 | Production method of bromhexine hydrochloride |
| CN103396323A (en) * | 2013-08-07 | 2013-11-20 | 张嵩 | Production method of bromhexine hydrochloride |
| CN104447355A (en) * | 2014-10-13 | 2015-03-25 | 宁波天衡药业股份有限公司 | Novel method for preparing bromhexine hydrochloride |
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