CN101607918B - Method for preparing metoprolol - Google Patents
Method for preparing metoprolol Download PDFInfo
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- CN101607918B CN101607918B CN200810115092.2A CN200810115092A CN101607918B CN 101607918 B CN101607918 B CN 101607918B CN 200810115092 A CN200810115092 A CN 200810115092A CN 101607918 B CN101607918 B CN 101607918B
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- metoprolol
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- benzene
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- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960002237 metoprolol Drugs 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 7
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims abstract description 6
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 22
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 claims description 6
- 229960003742 phenol Drugs 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 2
- ZBOQQGAVXCUYJM-UHFFFAOYSA-N butanedioic acid;1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound OC(=O)CCC(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 ZBOQQGAVXCUYJM-UHFFFAOYSA-N 0.000 claims 1
- UEOWFGJMGUIGHC-UHFFFAOYSA-N 2-[[4-(2-methoxyethyl)phenoxy]methyl]oxirane Chemical compound C1=CC(CCOC)=CC=C1OCC1OC1 UEOWFGJMGUIGHC-UHFFFAOYSA-N 0.000 abstract 2
- FAYGEALAEQKPDI-UHFFFAOYSA-N 4-(2-methoxyethyl)phenol Chemical compound COCCC1=CC=C(O)C=C1 FAYGEALAEQKPDI-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000000967 suction filtration Methods 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 230000006837 decompression Effects 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- -1 amido propyl alcohol class Chemical class 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- UKBBZNRSHOCRNP-UHFFFAOYSA-N 1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol;hydrochloride Chemical compound Cl.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 UKBBZNRSHOCRNP-UHFFFAOYSA-N 0.000 description 1
- UEOWFGJMGUIGHC-UHFFFAOYSA-O COCCc(cc1)ccc1OCC1[OH+]C1 Chemical compound COCCc(cc1)ccc1OCC1[OH+]C1 UEOWFGJMGUIGHC-UHFFFAOYSA-O 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing metoprolol, which comprises the following steps that: p-hydroxyphenethylmethyl ether and epoxy chloropropane react under the action of a phase transfer catalyst to obtain 1-(2,3-epoxypropoxy)-4-(2-methoxyethyl)-benzene; and in the presence of isopropanol, the 1-(2,3-epoxypropoxy)-4-(2-methoxyethyl)-benzene reacts with isopropyl amine to obtain metoprolol alkali.
Description
Technical field
The present invention relates to a kind of preparation method of metoprolol, particularly a kind of method of preparing metoprolol under phase-transfer catalyst effect.
Background technology
Metoprolol is a kind of amido propyl alcohol class medicine, selectivity β
1receptor-blocking agent is one for the treatment of hypertension, coronary heart disease, chronic heart failure and ARR common drug.It with have the suprarenin of excitation and norepinephrine to be at war with, and at the guarded by location heart of acceptor, suppress cardiac contractile force, avoid being overexcited and stoping nerve impulse.Itself can also guarantee the contraction of heart wall unstriated muscle.
The chemical name of metoprolol is 1-isopropylamino-3-[p-(2-methoxy ethyl) phenoxy group]-2-propyl alcohol, molecular formula is C
15h
25nO
3.Mainly to utilize metoprolol hydrochloride, tartrate and succinate clinically.
US2005107635 and CN97199796.9 disclose formula II compound and preparation method thereof.
In patent US2005107635 and CN97199796.9, reported the synthetic method of formula II compound, at condition Formula Il I compound and the epichlorohydrin reaction of sodium hydroxide or potassium hydroxide, obtained, and by the Methods For Purification product of underpressure distillation.Experimental study shows to adopt the yield of the disclosed method synthesis type of patent II compound method more of the present invention low.The method of preparation formula II compound disclosed by the invention, post-treating method is simple, and purity is higher, and synthetic formula I compound yield is high then, and HPLC purity is high.
Formula II compound purity is not high will finally cause reducing the yield of formula I compound, and production cost significantly rises, and is therefore necessary to develop a kind of method of easy handling, economical and efficient ground preparation I compound.
Summary of the invention
The object of this invention is to provide a kind of method of preparing metoprolol (formula I compound).
The present invention further provides the preparation method of formula I compound, wherein formula III is raw material, and the phase-transfer catalyst described in during preparation I compound is Tetrabutyl amonium bromide and polyoxyethylene glycol (PEG400).
The present invention further provides the method for preparation formula II compound, wherein temperature of reaction is 75-85 ℃.
The method that the present invention further provides refining formula I compound, during by formula I compound crude product recrystallization, solvent used is anhydrous methanol.
The present invention further provides the method for formula I compound salify, its Chinese style I compound becomes the solvent of ester with succsinic acid with hydrochloric acid be acetone.
Route of the present invention is simple and convenient and aftertreatment is simple compared with the disclosed synthetic route of patent, is suitable for laboratory preparation and suitability for industrialized production, and the product purity of preparation is high, consuming cost is lower.
Accompanying drawing explanation
Fig. 1 represents the formula I compound H PLC purity detecting figure of embodiment 1.
Fig. 2 represents the formula I compound H PLC purity detecting figure of embodiment 2.
Fig. 3 represents the formula I compound H PLC purity detecting figure of embodiment 3.
Fig. 4 represents the formula I compound H PLC purity detecting figure of embodiment 4.
Embodiment
Following embodiment is to describe in detail the present invention, and unrestricted the present invention.
Embodiment 1
In 250ml there-necked flask, add 8.8g sodium hydroxide and 80ml distilled water, stir.Add again 30.4g para hydroxybenzene ethyl methyl ether and 2.3g Tetrabutyl amonium bromide, drip 32ml epoxy chloropropane, dropwise and be heated to 75 ℃ of reactions 2 hours.TLC detection reaction, stops after completion of the reaction heating and is cooled to room temperature.Add 200ml dichloromethane extraction, organic phase anhydrous sodium sulfate drying.Suction filtration, filtrate decompression concentrates to obtain 1-(2,3-glycidoxy)-4-(2-methoxy ethyl)-benzene 38.5g, yield 92.4%.
In 500ml there-necked flask, add 1-(2,3-glycidoxy)-4-(2-methoxy ethyl)-benzene 38.5g and 200ml Virahol stirring and dissolving, then add 80ml Isopropylamine, reflux 2 hours.TLC detection reaction, stops after completion of the reaction heating and is cooled to room temperature.Concentrating under reduced pressure reaction solution, adds 250ml methylene dichloride to dissolve, washing, organic phase anhydrous sodium sulfate drying in residue.Suction filtration, filtrate decompression is concentrated, residue anhydrous methanol recrystallization.Suction filtration, filtration cakes torrefaction to constant weight obtains metoprolol 42.6g, yield: 86.9%.It is 99.68% that HPLC detects purity.
Embodiment 2
In 250ml there-necked flask, add 8.8g sodium hydroxide and 80ml distilled water, stir.Add again 30.4g para hydroxybenzene ethyl methyl ether and 3.0g polyoxyethylene glycol (PEG400), drip 32ml epoxy chloropropane, dropwise and be heated to 85 ℃ of reactions 2 hours.TLC detection reaction, stops after completion of the reaction heating and is cooled to room temperature.Add 200ml dichloromethane extraction, organic phase anhydrous sodium sulfate drying.Suction filtration, filtrate decompression concentrates to obtain 1-(2,3-glycidoxy)-4-(2-methoxy ethyl)-benzene 39.2g, yield 94.1%.
In 500ml there-necked flask, add 1-(2,3-glycidoxy)-4-(2-methoxy ethyl)-benzene 39.2g and 200ml Virahol stirring and dissolving, then add 81ml Isopropylamine, reflux 2 hours.TLC detection reaction, stops after completion of the reaction heating and is cooled to room temperature.Concentrating under reduced pressure reaction solution, adds 260ml methylene dichloride to dissolve, washing, organic phase anhydrous sodium sulfate drying in residue.Suction filtration, filtrate decompression is concentrated, residue anhydrous methanol recrystallization.Suction filtration, filtration cakes torrefaction to constant weight obtains metoprolol 44.6g, yield: 88.7%.It is 99.62% that HPLC detects purity.
Embodiment 3
In 250ml there-necked flask, add 8.8g sodium hydroxide and 80ml distilled water, stir.Add again 30.4g para hydroxybenzene ethyl methyl ether and 1.5g Tetrabutyl amonium bromide, drip 32ml epoxy chloropropane, dropwise and be heated to 80 ℃ of reactions 2 hours.TLC detection reaction, stops after completion of the reaction heating and is cooled to room temperature.Add 200ml dichloromethane extraction, organic phase anhydrous sodium sulfate drying.Suction filtration, filtrate decompression concentrates to obtain 1-(2,3-glycidoxy)-4-(2-methoxy ethyl)-benzene 38.9g, yield 93.5%.
In 500ml there-necked flask, add 1-(2,3-glycidoxy)-4-(2-methoxy ethyl)-benzene 38.9g and 200ml Virahol stirring and dissolving, then add 81ml Isopropylamine, reflux 2 hours.TLC detection reaction, stops after completion of the reaction heating and is cooled to room temperature.Concentrating under reduced pressure reaction solution, adds 250ml methylene dichloride to dissolve, washing, organic phase anhydrous sodium sulfate drying in residue.Suction filtration, filtrate decompression is concentrated, residue anhydrous methanol recrystallization.Suction filtration, filtration cakes torrefaction to constant weight obtains metoprolol 42.6g, yield: 85.3%.
In 500ml there-necked flask, add metoprolol 42.6g and 250ml acetone stirring and dissolving, then add 9.4g dimethyl diketone, reflux 2 hours.Stop heating and be cooled to room temperature.Suction filtration, 45 ℃ of vacuum-drying to constant weights of filter cake obtain white solid 46.9g, yield 90.4%.It is 99.73% that HPLC detects purity.
In 250ml there-necked flask, add 8.8g sodium hydroxide and 80ml distilled water, stir.Add again 30.4g para hydroxybenzene ethyl methyl ether and 2.0g polyoxyethylene glycol (PEG400), drip 32ml epoxy chloropropane, dropwise and be heated to 80 ℃ of reactions 2 hours.TLC detection reaction, stops after completion of the reaction heating and is cooled to room temperature.Add 200ml dichloromethane extraction, organic phase anhydrous sodium sulfate drying.Suction filtration, filtrate decompression concentrates to obtain 1-(2,3-glycidoxy)-4-(2-methoxy ethyl)-benzene 38.1g, yield 91.4%.
In 500ml there-necked flask, add 1-(2,3-glycidoxy)-4-(2-methoxy ethyl)-benzene 38.1g and 200ml Virahol stirring and dissolving, then add 79ml Isopropylamine, reflux 2 hours.TLC detection reaction, stops after completion of the reaction heating and is cooled to room temperature.Concentrating under reduced pressure reaction solution, adds 250ml methylene dichloride to dissolve, washing, organic phase anhydrous sodium sulfate drying in residue.Suction filtration, filtrate decompression is concentrated, residue anhydrous methanol recrystallization.Suction filtration, filtration cakes torrefaction to constant weight obtains metoprolol 42.3g, yield: 86.4%.
In 500ml there-necked flask, add metoprolol 42.3g and 250ml ethyl acetate stirring and dissolving, then add 16g concentrated hydrochloric acid, reflux 2 hours.Stop heating and be cooled to room temperature.Suction filtration, 45 ℃ of vacuum-drying to constant weights of filter cake obtain white solid 44.8g, yield 93.2%.It is 99.71% that HPLC detects purity.
Claims (4)
1. a preparation method for metoprolol (formula I compound), is characterized in that comprising the following steps:
(1) making para hydroxybenzene ethyl methyl ether and epoxy chloropropane be 75-85 ℃ in temperature of reaction is to react under phase-transfer catalyst effect with Tetrabutyl amonium bromide, obtain 1-(2,3-glycidoxy)-4-(2-methoxy ethyl)-benzene, the mass ratio of described para hydroxybenzene ethyl methyl ether and Tetrabutyl amonium bromide is 10: 1-20: 1;
(2), under the existence of Virahol, 1-(2,3-glycidoxy)-4-(2-methoxy ethyl)-benzene reacts with Isopropylamine, obtains metoprolol alkali.
2. method according to claim 1, is characterized in that the metoprolol of gained to change into hydrochloric acid metoprolol.
3. method according to claim 1, is characterized in that the metoprolol of gained to change into metroprolol succinate.
4. according to the method described in claim 2,3, the solvent that it is characterized in that the metoprolol of gained to change into metoprolol salt is acetone or ethyl acetate.
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| CN200810115092.2A CN101607918B (en) | 2008-06-16 | 2008-06-16 | Method for preparing metoprolol |
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| CN200810115092.2A CN101607918B (en) | 2008-06-16 | 2008-06-16 | Method for preparing metoprolol |
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| CN101607918A CN101607918A (en) | 2009-12-23 |
| CN101607918B true CN101607918B (en) | 2014-02-19 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432476A (en) * | 2010-09-29 | 2012-05-02 | 湖南康普医药研究院 | Method for preparing metoprolol succinate on scale |
| CN102503843B (en) * | 2011-10-28 | 2013-10-23 | 山东阿如拉药物研究开发有限公司 | Preparation method for metoprolol salt |
| CN102633660A (en) * | 2011-11-03 | 2012-08-15 | 北京华禧联合科技发展有限公司 | New crystal form of metoprolol succinate |
| CN106995381A (en) * | 2012-06-25 | 2017-08-01 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of Crystal form of metoprolol succinate and preparation method thereof |
| CN103102281A (en) * | 2013-02-20 | 2013-05-15 | 北京华素制药股份有限公司 | Synthesis method of metoprolol succinate |
| CN111018724B (en) * | 2019-12-27 | 2022-11-08 | 江西美晶科技有限公司 | Metoprolol and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1237958A (en) * | 1996-11-20 | 1999-12-08 | 阿斯特拉公司 | New manufacturing process of metoprolol |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050107635A1 (en) * | 2003-11-14 | 2005-05-19 | Mehra Janakraj K. | Metoprolol manufacturing process |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1237958A (en) * | 1996-11-20 | 1999-12-08 | 阿斯特拉公司 | New manufacturing process of metoprolol |
Non-Patent Citations (2)
| Title |
|---|
| 田建文等.相转移催化下合成对甲氧乙基苯基缩水甘油醚.《化学世界》.2006,第47-50页. |
| 相转移催化下合成对甲氧乙基苯基缩水甘油醚;田建文等;《化学世界》;20060125;第47-50页 * |
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