CN113956239A - Azelastine hydrochloride, and preparation method and application thereof - Google Patents
Azelastine hydrochloride, and preparation method and application thereof Download PDFInfo
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- YEJAJYAHJQIWNU-UHFFFAOYSA-N azelastine hydrochloride Chemical compound Cl.C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 YEJAJYAHJQIWNU-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 229960004335 azelastine hydrochloride Drugs 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000006722 reduction reaction Methods 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- RHGFRDGVBQGEMQ-UHFFFAOYSA-N 1-methylazepan-2-one hydrochloride Chemical compound [Cl-].C[NH+]1CCCCCC1=O RHGFRDGVBQGEMQ-UHFFFAOYSA-N 0.000 claims abstract description 24
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 17
- 239000011591 potassium Substances 0.000 claims abstract description 17
- 238000006482 condensation reaction Methods 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims abstract description 16
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- YWECCEXWKFHHQJ-UHFFFAOYSA-N 2-(4-chlorobenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(Cl)C=C1 YWECCEXWKFHHQJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 43
- 239000000047 product Substances 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 claims description 23
- 229960004574 azelastine Drugs 0.000 claims description 23
- 238000010992 reflux Methods 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 239000012071 phase Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000000243 solution Substances 0.000 description 21
- 238000003756 stirring Methods 0.000 description 14
- 239000008213 purified water Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 238000004811 liquid chromatography Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- BDSINYHJZLINDJ-UHFFFAOYSA-N 2-[2-(4-chlorophenyl)acetyl]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)CC1=CC=C(Cl)C=C1 BDSINYHJZLINDJ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 238000011003 system suitability test Methods 0.000 description 4
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 3
- BHSJZGRGJYULPA-UHFFFAOYSA-N 1-methylazepan-4-one;hydrochloride Chemical compound Cl.CN1CCCC(=O)CC1 BHSJZGRGJYULPA-UHFFFAOYSA-N 0.000 description 3
- RTGDFNSFWBGLEC-TVPGTPATSA-N 2-morpholin-4-ylethyl (z)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(\C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-TVPGTPATSA-N 0.000 description 3
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 3
- 239000012670 alkaline solution Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- -1 hexahydro-1-methyl-1H-azepin-4-yl Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- 229940097496 nasal spray Drugs 0.000 description 2
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical compound [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical class [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- NLXGCQIEVZYDRS-UHFFFAOYSA-N 4-[(4-chlorophenyl)methyl]-2h-phthalazin-1-one Chemical compound C1=CC(Cl)=CC=C1CC1=NNC(=O)C2=CC=CC=C12 NLXGCQIEVZYDRS-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010029098 Neoplasm skin Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a preparation method of azelastine hydrochloride, belonging to the technical field of pharmacy. The method comprises the following steps: mixing 1-methylhexahydro-4H-azepinone hydrochloride and benzoyl hydrazine for reaction to obtain acylhydrazone; mixing the acylhydrazone, the potassium borohydride and the water for a reduction reaction to obtain a reduction product; carrying out acidolysis on the reduction product to obtain an acidolysis product; and mixing the acidolysis product with 2- (p-chlorobenzoyl) benzoic acid for condensation reaction to obtain the azelastine hydrochloride. In the reduction reaction, potassium borohydride and water are added, wherein the water is used as a catalyst, so that the reduction reaction is rapidly carried out and is fully reduced, and the purity and the yield of the target compound are greatly improved.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to azelastine hydrochloride and a preparation method and application thereof.
Background
Azelastine hydrochloride, chemical name 4- (4-chlorobenzyl) -2- (hexahydro-1-methyl-1H-azepin-4-yl) -1- (2H) -phthalazine hydrochloride, azelastine hydrochloride nasal spray is trade name isepan, is local antihistamine, is one of the representative therapeutic drugs to allergic rhinitis medical treatment as antihistamine, not only the curative effect is good, the security is high, and its nasal spray is convenient to carry, can accomplish the advantage of using medicine at any time. In addition, the Chinese medicinal composition has good curative effect on allergic skin tumor itch, eczema and various dermatitis in recent years, and has huge market capacity, wide market prospect and strong market competitiveness. Azelastine hydrochloride has the following structural formula:
in the prior art, the following method is adopted for the synthetic route of azelastine hydrochloride:
the method comprises the following steps: n-methylpiperidine-4-ketone is used as a raw material, azelastine hydrochloride is synthesized through ring expansion, hydrazide reaction, condensation and other reactions, and the total reaction yield is 48.6%; the second method comprises the following steps: chinese patent CN101987884A discloses that N-methylhexahydroazepin-4-one hydrochloride and 4- (4-chlorobenzyl) -1- (2H) -phthalazinone are used as raw materials to synthesize azelastine hydrochloride by one step through condensation; the third method comprises the following steps: chinese patent CN102391253A discloses that N-methyl hexahydro-azepin-4-one hydrochloride is used as an initial raw material to react with benzoyl hydrazine to form acylhydrazone, the acylhydrazone is reduced by potassium borohydride and condensed with 2- (p-chlorophenyl acetyl) benzoic acid to form 4- (4-chlorobenzyl) -2- (hexahydro-1-methyl-1H-azepin-4-yl) -1- (2H) -phthalazine hydrochloride, the total yield is 70-80%, and the content of the product obtained after recrystallization is 99.1% at most. Namely, the synthesis method in the prior art has the problems of low yield and purity.
Disclosure of Invention
In view of the above, the present invention aims to provide a preparation method of azelastine hydrochloride. The preparation method provided by the invention has the advantages of high yield and high purity.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of azelastine hydrochloride, which comprises the following steps:
mixing 1-methylhexahydro-4H-azepinone hydrochloride and benzoyl hydrazine for reaction to obtain acylhydrazone;
mixing the acylhydrazone, the potassium borohydride and the water for a reduction reaction to obtain a reduction product;
carrying out acidolysis on the reduction product to obtain an acidolysis product;
and mixing the acidolysis product with 2- (p-chlorobenzoyl) benzoic acid for condensation reaction to obtain the azelastine hydrochloride.
Preferably, the molar ratio of the 1-methylhexahydro-4H-azepinone hydrochloride to the benzoyl hydrazine is 1: (0.7-1.1).
Preferably, the molar ratio of the potassium borohydride to the 1-methylhexahydro-4H-azepinone hydrochloride is (2.0-4.0): 1.
Preferably, the molar ratio of the water to the 1-methylhexahydro-4H-azepinone hydrochloride is (8.0-19.0): 1.
preferably, after the reduction reaction, the reduction system is subjected to reduced pressure concentration, water quenching reaction and ethyl acetate extraction in sequence to obtain an organic phase, the pH value of the organic phase is adjusted to be less than or equal to 3, and water is added for extraction and layering to obtain a water phase, namely the reduction product.
Preferably, the acid hydrolysis conditions include: using concentrated hydrochloric acid, wherein the molar ratio of the concentrated hydrochloric acid to 1-methylhexahydro-4H-azepinone hydrochloride is (7.0-10.0): 1, the mass concentration of the concentrated hydrochloric acid is 37.0-37.5%.
Preferably, the acidolysis is carried out under the condition of reflux, and the acidolysis time is 1-3 h.
Preferably, the molar ratio of the 2- (p-chlorobenzoyl) benzoic acid to the 1-methylhexahydro-4H-azepinone hydrochloride is (0.6-1.0): 1.
Preferably, the conditions of the condensation reaction include: and (4) refluxing, wherein the pH value is 6-8, and the time is 2-8 h.
Preferably, after the condensation reaction, the obtained condensation reaction product is subjected to vacuum concentration, the pH value is adjusted to be more than or equal to 9, the obtained condensation reaction product is filtered, washed and dried to obtain azelastine free alkali, the azelastine free alkali is mixed with a salifying solvent, activated carbon is added for filtering, the obtained filtrate and acid are salified and then are subjected to crystallization, recrystallization and drying in sequence to obtain the azelastine hydrochloride, and the solvents used for crystallization and recrystallization independently comprise one or more of absolute ethyl alcohol, an ethanol aqueous solution, an isopropanol aqueous solution or an acetone aqueous solution.
The invention provides a preparation method of azelastine hydrochloride, which comprises the following steps: mixing 1-methylhexahydro-4H-azepinone hydrochloride and benzoyl hydrazine for reaction to obtain acylhydrazone; mixing the acylhydrazone, the potassium borohydride and the water for a reduction reaction to obtain a reduction product; carrying out acidolysis on the reduction product to obtain an acidolysis product; and mixing the acidolysis product with 2- (p-chlorobenzoyl) benzoic acid for condensation reaction to obtain the azelastine hydrochloride. In the reduction reaction, potassium borohydride and water are added, wherein the water is used as a catalyst, so that the reduction reaction is rapidly carried out and is fully reduced, and the purity and the yield of the target compound are greatly improved. The data of the embodiment show that the yield of azelastine hydrochloride prepared by the preparation method provided by the invention is 95.00-95.96%, the total molar yield is 73.11-74.91%, and the HPLC purity is 99.95-99.98%.
Furthermore, the method can separate out all benzoic acid at room temperature during acidolysis to achieve the separation effect, does not need to use organic solvents such as dichloromethane and the like for extraction, reduces the pressure of environmental protection, and simultaneously, the quality of the final product is not influenced.
Furthermore, the invention uses ethanol water solution, isopropanol water solution or acetone water solution for refining during crystallization and recrystallization, and the small amount of water is beneficial to removing inorganic impurities in the finished product and improving the product quality.
Drawings
FIG. 1 is a liquid chromatography chromatogram of azelastine hydrochloride prepared in example 2;
FIG. 2 is a diagram of the liquid chromatography system adaptation spectrum of azelastine hydrochloride prepared in example 2;
fig. 3 is a liquid chromatography system adaptation spectrum of azelastine hydrochloride prepared in comparative example 1.
Detailed Description
The invention provides a preparation method of azelastine hydrochloride, which comprises the following steps of;
mixing 1-methylhexahydro-4H-azepinone hydrochloride and benzoyl hydrazine for reaction to obtain acylhydrazone;
mixing the acylhydrazone, the potassium borohydride and the water for a reduction reaction to obtain a reduction product;
carrying out acidolysis on the reduction product to obtain an acidolysis product;
and mixing the acidolysis product with 2- (p-chlorobenzoyl) benzoic acid for condensation reaction to obtain the azelastine hydrochloride.
The reaction principle of the preparation method of azelastine hydrochloride is shown as formula I:
the invention mixes 1-methylhexahydro-4H-azepinone hydrochloride and benzoyl hydrazine for reaction to obtain acylhydrazone.
In the present invention, the molar ratio of the 1-methylhexahydro-4H-azepinone hydrochloride to the benzoyl hydrazine is preferably 1: (0.7 to 1.1), more preferably 1: (0.7-0.8).
In the invention, the reaction temperature is 20-40 ℃ and the reaction time is 1-2 h. In the invention, the reaction is preferably carried out in an organic solvent, the organic solvent is preferably methanol, and the amount of the methanol is not particularly limited, so that the reaction materials can be completely dissolved.
After the reaction, the temperature of the obtained product system is preferably reduced to below 20 ℃, the KOH methanol solution is dripped, the stirring reaction is continued for 1-2 hours, and the concentration of the KOH methanol solution is preferably 1 mol/L. In the invention, the dripping speed is preferably 80-120 mL/min.
After the acylhydrazone is obtained, the acylhydrazone, the potassium borohydride and the water are mixed for reduction reaction to obtain a reduction product
In the invention, the molar ratio of the potassium borohydride to the 1-methylhexahydro-4H-azepinone hydrochloride is preferably (2.0-4.0): 1, and more preferably (2.0-3.0): 1.
In the invention, the molar ratio of the water to the 1-methylhexahydro-4H-azepinone hydrochloride is preferably (8.0-19.0): 1, more preferably (11.0 to 14.0): 1. In the present invention, the water is preferably purified water.
In the invention, preferably, the acylhydrazone is cooled to below 10 ℃, and then the potassium borohydride and the water are sequentially added.
In the invention, the temperature of the reduction reaction is preferably 40-reflux temperature, and the time is preferably 1-3 h.
In the invention, after the reduction reaction, the method preferably further comprises the steps of sequentially carrying out reduced pressure concentration, water quenching reaction and ethyl acetate extraction on the obtained reduction system to obtain an organic phase, adjusting the pH value of the organic phase to be less than or equal to 3, and then adding water for extraction and layering to obtain a water phase, namely the reduction product.
In the present invention, the concentration under reduced pressure is used for removing the organic solvent, and the specific parameters of the concentration under reduced pressure are not particularly limited, and may be in a manner known to those skilled in the art.
In the present invention, it is preferable to adjust the pH to 3 or less by using concentrated hydrochloric acid, and the concentration and the amount of the concentrated hydrochloric acid are not particularly limited in the present invention, and the pH can be 3 or less.
After obtaining the reduction product, the invention carries out acidolysis on the reduction product to obtain the acidolysis product.
In the present invention, the acid hydrolysis conditions preferably include: using concentrated hydrochloric acid, wherein the molar ratio of the concentrated hydrochloric acid to 1-methylhexahydro-4H-azepinone hydrochloride is (7.0-10.0): 1, the mass concentration of the concentrated hydrochloric acid is 37.0% -37.5%, and the molar ratio of the concentrated hydrochloric acid to 1-methylhexahydro-4H-azepinone hydrochloride is more preferably (8.4-8.6): 1.
the present invention preferably adds the concentrated hydrochloric acid to the reduction product.
In the invention, the acidolysis is preferably carried out under the condition of reflux, and the acidolysis time is preferably 1-3 h.
After the acidolysis is finished, the method preferably further comprises the steps of naturally cooling to room temperature, filtering a filter cake, washing with purified water and collecting a water phase in sequence to obtain the acidolysis product.
After an acidolysis product is obtained, the acidolysis product and 2- (p-chlorobenzoyl) benzoic acid are mixed for condensation reaction to obtain the azelastine hydrochloride.
In the present invention, the molar ratio of 2- (p-chlorobenzoyl) benzoic acid to 1-methylhexahydro-4H-azepinone hydrochloride is preferably (0.6-1.0): 1, and more preferably (0.8-1.0): 1.
In the present invention, the conditions of the condensation reaction preferably include: and (4) refluxing, wherein the pH value is 6-8, and the time is 2-8 h.
In the invention, the pH value is preferably adjusted by using an inorganic alkaline solution, the inorganic alkaline solution is preferably a methanol solution of NaOH, the concentration and the dosage of the methanol solution of NaOH are not particularly limited, and the pH value can be adjusted to be 6-8.
In the invention, preferably, after the condensation reaction, the obtained condensation reaction product is subjected to reduced pressure concentration, pH value adjustment is not less than 9, filtering, water washing and drying in sequence to obtain azelastine free alkali, the azelastine free alkali is mixed with a salifying solvent, activated carbon is added for filtering, the obtained filtrate and acid are salified and then are subjected to crystallization, recrystallization and drying in sequence to obtain the azelastine hydrochloride, and the solvents used for crystallization and recrystallization independently comprise one or more of absolute ethyl alcohol, an ethanol aqueous solution, an isopropanol aqueous solution or an acetone aqueous solution.
In the present invention, the concentration under reduced pressure serves to remove the solvent of the inorganic alkaline solution.
In the invention, the pH value is preferably adjusted to be more than or equal to 9 by using NaOH aqueous solution, the concentration and the dosage of the NaOH aqueous solution are not particularly limited, and the pH value can be more than or equal to 9. In a specific embodiment of the invention, the mass content of the NaOH aqueous solution is preferably 5-10%. The effect of adjusting the pH value to be more than or equal to 9 in the invention is to completely separate out the azelastine free alkali.
In the present invention, the drying is preferably vacuum drying, the temperature of the vacuum drying is preferably 80 ℃, the time of the vacuum drying is not particularly limited, and the moisture can be completely removed.
In the present invention, the salt-forming solvent preferably comprises one or more of ethanol, acetone, isopropanol. The dosage of the salifying solvent is not specially limited, and the azelastine free base can be completely dissolved.
In the present invention, it is preferable to further include heating to reflux after the addition of the activated carbon. In the present invention, the time of the reflux is preferably 30 min.
In the invention, the acid is preferably concentrated hydrochloric acid, the concentration and the dosage of the concentrated hydrochloric acid are not particularly limited, and the azelastine free base can be completely salified.
In the present invention, the solvent used for the crystallization preferably includes one or more of absolute ethanol, an aqueous ethanol solution, an aqueous isopropanol solution, or an aqueous acetone solution. In the present invention, the volume percentage of the ethanol aqueous solution is preferably 95%, the volume percentage of the isopropanol aqueous solution is preferably 95%, and the volume percentage of the acetone aqueous solution is preferably 90%. The invention has no special limitation on the dosage of the solvent, and can realize crystallization.
The crystallization is preferably followed by drying, the temperature of the drying is preferably 50 ℃, the drying time is not particularly limited, and the solvent used for the crystallization can be completely removed.
In the present invention, the solvent used for recrystallization is preferably the same as the solvent used for crystallization, and is not described again.
In the present invention, the drying is preferably vacuum drying, the temperature of the vacuum drying is preferably 80 ℃, the time of the vacuum drying is not particularly limited, and the solvent used for the recrystallization can be completely removed.
In order to further illustrate the present invention, the following examples are given to describe the preparation method of azelastine hydrochloride provided by the present invention in detail, but they should not be construed as limiting the scope of the present invention.
Example 1
Benzoyl hydrazine (313.0g, 2.30mol) and 3.1L methanol were added to the reaction vessel, stirred at room temperature until clear, and then 1-methylhexahydro-4H-azepinone hydrochloride (499.0g, 3.05mol) was added and reacted at 30 ℃ for 2 hours. Cooling the reaction liquid to below 20 ℃, dropwise adding 3.06L of 1mol/L potassium hydroxide/methanol mixed solution, and stirring at room temperature for reaction for 2 hours after dropwise adding; slowly adding potassium borohydride (494.0g, 9.16mol) at the temperature below 10 ℃, then adding purified water (762.5g, 42.36mol), heating to 55 ℃ after the addition, and keeping the temperature for reaction for 3 hours. Concentrating under reduced pressure to remove methanol, adding purified water 3.1L to the residue, extracting with ethyl acetate 6.2L once, separating ethyl acetate layer, washing water layer with ethyl acetate twice, 3.1L each time, mixing ethyl acetate layers, adding concentrated hydrochloric acid to adjust pH to 3, adding purified water 3.2L, separating, retaining water phase, discarding organic phase, washing water phase with ethyl acetate twice, 3.1L each time, and collecting water phase.
Adding concentrated hydrochloric acid (2226.5g, 21.96mol) into the water phase, heating to reflux, carrying out heat preservation reaction for 3 hours, cooling to room temperature, washing a filter cake obtained by suction filtration with 0.2L of purified water twice, collecting filtrate, adding 2- (p-chlorophenyl acetyl) benzoic acid (669.0g, 2.44mol) into the filtrate, cooling to below 10 ℃, adjusting the pH to 7 with saturated solution of saturated sodium hydroxide methanol, heating to reflux, carrying out heat preservation reaction for 6 hours, carrying out reduced pressure concentration to remove methanol, adding 5% sodium hydroxide solution into the residue to adjust the pH to 9, precipitating a large amount of solid, carrying out suction filtration, and drying at 50 ℃.
Adding the solid into acetone, heating to reflux, keeping the temperature and stirring for 30 minutes, adding activated carbon, refluxing and decoloring for 30 minutes, filtering to remove the activated carbon and insoluble substances while the solution is hot, cooling the filtrate to room temperature, adjusting the pH value to 3 by using concentrated hydrochloric acid, separating out a large amount of solid, performing suction filtration, and drying at 50 ℃ to obtain a crude azelastine hydrochloride product (984.0g, 2.35mol), wherein the yield is 77.05 percent, and the HPLC purity is 99.70 percent.
Adding the crude azelastine hydrochloride into a 95% ethanol solution, stirring, heating to reflux, adding activated carbon, refluxing and decolorizing for 30min, filtering, stirring the filtrate at room temperature, crystallizing, filtering, and vacuum drying at 80 deg.C to obtain refined azelastine hydrochloride (934.8g, 2.23 mol). The yield was 95.00%, the total molar yield was 73.11%, and the HPLC purity was 99.95%.
Example 2
Benzoyl hydrazine (560.0g, 4.11mol) and 5.6L methanol were added to the reaction vessel, stirred at room temperature until clear, and then 1-methylhexahydro-4H-azepinone hydrochloride (893.0g,5.46mol) was added and reacted at 30 ℃ for 2 hours. Cooling the reaction liquid to below 20 ℃, dropwise adding 5.5L of 1mol/L potassium hydroxide/methanol mixed solution, and stirring at room temperature for reaction for 2 hours after dropwise adding; slowly adding potassium borohydride (884.0g, 16.39mol) at the temperature below 10 ℃, then adding purified water (1365.0g, 75.83mol), heating to 55 ℃ after the addition, and keeping the temperature for reaction for 3 hours. Concentrating under reduced pressure to remove methanol, adding purified water 5.5L to the residue, extracting with ethyl acetate 11L once, separating ethyl acetate layer, washing water layer with ethyl acetate twice, 5L each time, combining ethyl acetate layers, adding concentrated hydrochloric acid to adjust pH to 2, adding purified water 5.5L, separating, retaining water phase, discarding organic phase, washing water phase with ethyl acetate twice, 5.5L each time, and collecting water phase.
Adding concentrated hydrochloric acid (3990.7g, 39.36mol) into the water phase, heating to reflux, carrying out heat preservation reaction for 3 hours, cooling to room temperature, carrying out suction filtration on a filter cake, washing twice with 0.5L of purified water, collecting filtrate, adding 2- (p-chlorophenyl acetyl) benzoic acid (1200.0g, 4.39mol) into the filtrate, cooling to below 10 ℃, adjusting the pH to 7 with saturated solution of saturated sodium hydroxide methanol, heating to reflux, carrying out heat preservation reaction for 6 hours, carrying out vacuum concentration to remove methanol, adding 5% sodium hydroxide solution into the residue, adjusting the pH to 10, precipitating a large amount of solid, carrying out suction filtration, and drying at 50 ℃.
Adding the solid into acetone, heating to reflux, keeping the temperature and stirring for 30 minutes, adding activated carbon, refluxing and decoloring for 30 minutes, filtering to remove the activated carbon and insoluble substances while the solution is hot, cooling the filtrate to room temperature, adjusting the pH value to 2 by using concentrated hydrochloric acid, separating out a large amount of solid, performing suction filtration, and drying at 50 ℃ to obtain a crude azelastine hydrochloride product (1782.0g, 4.26mol), wherein the molar yield is 78.02% and the HPLC purity is 99.80%.
Adding the crude azelastine hydrochloride into a 95% ethanol solution, stirring and heating to reflux and clear, adding activated carbon, refluxing and decoloring for 30 minutes, performing suction filtration, stirring and crystallizing filtrate at room temperature, performing suction filtration, and performing vacuum drying at 80 ℃ to obtain a refined azelastine hydrochloride product (1710.0g, 4.09mol) with the yield of 95.96%. The total molar yield was 74.91%, with an HPLC purity of 99.98%.
FIG. 1 is a liquid chromatography chromatogram of azelastine hydrochloride obtained in example 2, wherein liquid detection data are shown in Table 1, and Table 1 is a liquid chromatography data of azelastine hydrochloride obtained in example 2
| Peak number | Name of Compound | Retention time | Area of | Height | Number of theoretical plate | Tailing factor | Degree of | Area% | |
| 1 | Azelastine | 1.810 | 164478 | 9538 | 10573 | 1.04 | -- | 100.00 | |
| Total of | 164478 | 9538 | 100.00 |
The liquid chromatography system suitability test was performed on azelastine hydrochloride obtained in example 2, and the results are shown in fig. 2 and table 2.
Table 2 results of liquid chromatography system suitability test of azelastine hydrochloride prepared in example 2
| Peak number | Name of Compound | Retention time | Area of | Height | Number of theoretical plate | Tailing factor | Degree of | Area% | |
| 1 | EP impurity A | 3.996 | 165099 | 22791 | 6885 | 1.16 | -- | 0.12 | |
| 2 | EP impurity B | 4.462 | 97004 | 12416 | 7487 | -- | 2.3 | 0.07 | |
| 3 | EP impurity D | 9.254 | 1003498 | 76078 | 10992 | 1.03 | 17.1 | 0.73 | |
| 4 | EP impurity C | 9.830 | 401448 | 29394 | 11444 | 1.02 | 1.6 | 0.29 | |
| 5 | Azelastine | 11.588 | 135252398 | 3999579 | 6034 | 1.01 | 3.6 | 97.96 | |
| 6 | Impurity F | 12.821 | 1094222 | 50685 | 8250 | -- | 2.1 | 0.79 | |
| 7 | EP impurity E | 25.933 | 51187 | 1500 | 12014 | 1.20 | 17.4 | 0.04 | |
| Total of | 138064855 | 4192441 | 100.00 |
As can be seen from FIGS. 1-2 and tables 1-2, azelastine hydrochloride was prepared in this example.
Comparative example 1
Adding N-methylhexahydroazepin-4-one hydrochloride (16.37g, 0.10mol) and benzoyl hydrazine (14.98g, 0.11mol) into a reaction kettle, stirring and reacting for 5 hours at room temperature, and then cooling to 20 ℃; dropwise adding 50mL of 2mol/LKOH methanol solution, adding potassium borohydride (7.01g, 0.13mol), continuously cooling and stirring for 30min, and then stirring and reacting at 40 ℃ for 6 h; extracting with dichloromethane for three times, each time with 10mL, drying with anhydrous sodium sulfate, adding ether solution containing HCl to form salt, and desolventizing; 1000ml of purified water and 2- (p-chlorophenyl acetyl) benzoic acid (27.47g, 0.10mol) were added thereto, and the pH was adjusted to 7 with a 20 wt% NaOH solution, and the mixture was refluxed for 2 hours with stirring, cooled with stirring, and adjusted to 9 with a 20 wt% NaOH solution, whereby no solid precipitated. The purity is as follows: 0.09%, yield 0.
Table 3 shows the data of the liquid chromatography chromatogram of azelastine hydrochloride prepared in comparative example 1.
TABLE 3 liquid chromatography data for azelastine hydrochloride prepared in comparative example 1
| Peak number | Name of Compound | Retention time | Area of | Height | Number of theoretical plate | Tailing factor | Degree of | Area% | |
| 1 | Azelastine EP impurity A | 2.105 | 574003 | 91524 | 3230 | 1.72 | -- | 11.11 | |
| 2 | Azelastine EP impurity B | 2.475 | 2093487 | 347431 | 3743 | 1.12 | 2.4 | 40.53 | |
| 3 | 3.640 | 1929952 | 290574 | 5865 | 0.97 | 6.6 | 37.37 | ||
| 4 | 4.171 | 98189 | 13464 | 6615 | -- | 2.7 | 1.90 | ||
| 5 | 4.460 | 23463 | 2751 | 6072 | -- | 1.3 | 0.45 | ||
| 6 | 4.769 | 143399 | 17208 | 6521 | 0.98 | 1.3 | 2.78 | ||
| 7 | 5.764 | 28981 | 2615 | 6925 | 0.72 | 3.9 | 0.56 | ||
| 8 | Azelastine EP impurity D | 6.233 | 96307 | 9168 | 7506 | 0.90 | 1.7 | 1.86 | |
| 9 | Azelastine EP impurity C | 6.610 | 9576 | 1024 | 9904 | 0.97 | 1.4 | 0.19 | |
| 10 | 7.246 | 9408 | 712 | 5910 | -- | 2.0 | 0.18 | ||
| 11 | 7.539 | 6285 | 600 | 7417 | -- | 0.8 | 0.12 | ||
| 12 | Azelastine | 8.981 | 4709 | 317 | 1037 | -- | 2.0 | 0.09 | |
| 13 | 9.324 | 16236 | 740 | 3547 | -- | 0.4 | 0.31 | ||
| 14 | 10.140 | 37870 | 2309 | 8578 | 0.87 | 1.5 | 0.73 | ||
| 15 | 11.710 | 29727 | 1342 | 6836 | 1.19 | 3.1 | 0.58 | ||
| 16 | 13.123 | 4936 | 261 | 10036 | 0.99 | 2.6 | 0.10 | ||
| 17 | 14.824 | 29408 | 824 | 3716 | 1.24 | 2.3 | 0.57 | ||
| 18 | 16.347 | 16488 | 369 | 3750 | 0.77 | 1.5 | 0.32 | ||
| 19 | Azelastine EP impurity E | 21.461 | 12490 | 392 | 9527 | 1.07 | 5.3 | 0.24 | |
| Total of | 5164914 | 783626 | 100.00 |
The results of the liquid chromatography system suitability test of azelastine hydrochloride prepared in comparative example 1 are shown in fig. 3 and table 4.
Table 4 liquid chromatography system suitability test results for azelastine hydrochloride prepared in comparative example 1
| Peak number | Name of Compound | Retention time | Area of | Height | Number of theoretical plate | Tailing factor | Degree of | Area% | |
| 1 | Azelastine EP impurity A | 2.046 | 77833 | 14507 | 3703 | 1.35 | -- | 0.08 | |
| 2 | Azelastine EP impurity B | 2.453 | 31846 | 5148 | 3033 | 1.02 | 2.6 | 0.03 | |
| 3 | Azelastine EP impurity D | 6.232 | 142172 | 12593 | 6924 | -- | 15.8 | 0.14 | |
| 4 | Azelastine EP impurity C | 6.614 | 62317 | 5523 | 7173 | -- | 1.2 | 0.06 | |
| 5 | Azelastine | 9.061 | 101041899 | 3999797 | 5726 | 1.35 | 6.2 | 99.64 | |
| 6 | Azelastine EP impurity E | 21.508 | 46984 | 1378 | 9026 | 0.95 | 18.0 | 0.05 | |
| Total of | 101403051 | 4038946 | 100.00 |
Tables 1 and 3 correspond to azelastine hydrochloride obtained in example 2 and comparative example 1, respectively, and it can be seen that the purity of azelastine hydrochloride is reduced from 99.98% to 0.09%, thus proving that the method of the present invention can obtain high-purity azelastine hydrochloride, and the method of the present invention is superior to the prior art.
Comparative example 2
As in example 2, except that no purified water was added after the addition of potassium borohydride, the purity and yield data obtained are supplemented. No product spot was detected by TLC, and the product was not sufficiently pure to be obtained as a liquid, i.e. azelastine hydrochloride was not obtained, with a yield of 0.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be construed as the protection scope of the present invention.
Claims (10)
1. The preparation method of azelastine hydrochloride is characterized by comprising the following steps:
mixing 1-methylhexahydro-4H-azepinone hydrochloride and benzoyl hydrazine for reaction to obtain acylhydrazone;
mixing the acylhydrazone, the potassium borohydride and the water for a reduction reaction to obtain a reduction product;
carrying out acidolysis on the reduction product to obtain an acidolysis product;
and mixing the acidolysis product with 2- (p-chlorobenzoyl) benzoic acid for condensation reaction to obtain the azelastine hydrochloride.
2. The preparation method according to claim 1, wherein the molar ratio of 1-methylhexahydro-4H-azepinone hydrochloride to benzoyl hydrazine is 1: (0.7-1.1).
3. The preparation method of claim 1, wherein the molar ratio of the potassium borohydride to the 1-methylhexahydro-4H-azepinone hydrochloride is (2.0-4.0): 1.
4. The preparation method according to claim 1 or 3, wherein the molar ratio of water to 1-methylhexahydro-4H-azepinone hydrochloride is (8.0-19.0): 1.
5. the preparation method of claim 1, wherein after the reduction reaction, the reduction system is subjected to reduced pressure concentration, water quenching reaction and ethyl acetate extraction in sequence to obtain an organic phase, the pH value of the organic phase is adjusted to be less than or equal to 3, water is added for extraction and layering, and the obtained water phase is the reduction product.
6. The method as claimed in claim 1, wherein the acid hydrolysis conditions include: using concentrated hydrochloric acid, wherein the molar ratio of the concentrated hydrochloric acid to 1-methylhexahydro-4H-azepinone hydrochloride is (7.0-10.0): 1, the mass concentration of the concentrated hydrochloric acid is 37.0-37.5%.
7. The method as claimed in claim 1 or 6, wherein the acid hydrolysis is carried out under reflux for 1 to 3 hours.
8. The preparation method according to claim 1, wherein the molar ratio of 2- (p-chlorobenzoyl) benzoic acid to 1-methylhexahydro-4H-azepinone hydrochloride is (0.6-1.0): 1.
9. The method according to claim 1, wherein the conditions of the condensation reaction include: and (4) refluxing, wherein the pH value is 6-8, and the time is 2-8 h.
10. The preparation method according to claim 1, characterized in that after the condensation reaction, the obtained condensation reaction product is subjected to vacuum concentration, pH value is adjusted to be not less than 9, filtering, water washing and drying in sequence to obtain azelastine free base, the azelastine free base is mixed with a salifying solvent, activated carbon is added for filtering, the obtained filtrate and acid are salified and then subjected to crystallization, recrystallization and drying in sequence to obtain the azelastine hydrochloride, and the solvent used for crystallization and recrystallization independently comprises one or more of absolute ethyl alcohol, an ethanol aqueous solution, an isopropanol aqueous solution or an acetone aqueous solution.
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| CN86107627A (en) * | 1985-11-11 | 1987-07-15 | 阿斯塔厂股份公司化学工厂 | The preparation method of novel 4-benzyl-1-(2H)-phthalazinone derivatives |
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