CN102381995A - Preparation method of metoprolol - Google Patents
Preparation method of metoprolol Download PDFInfo
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- CN102381995A CN102381995A CN201010267321XA CN201010267321A CN102381995A CN 102381995 A CN102381995 A CN 102381995A CN 201010267321X A CN201010267321X A CN 201010267321XA CN 201010267321 A CN201010267321 A CN 201010267321A CN 102381995 A CN102381995 A CN 102381995A
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- metoprolol
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- IUBSYMUCCVWXPE-UHFFFAOYSA-N CC(C)NCC(COc1ccc(CCOC)cc1)O Chemical compound CC(C)NCC(COc1ccc(CCOC)cc1)O IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a preparation method of metoprolol. Reaction of methoxy ethyl phenol and sodium hydroxide liquor is carried out at the temperature ranging from 30 DEG C to 80 DEG C to generate methoxy sodium ethyl phenate. When the temperature is reduced to a range between 0 DEG C and 40 DEG C, epichlorohydrin is added for reaction to obtain compound II. Due to isopropyl alcohol, the compound II is reacted with isopropyl amine to obtain metoprolol. Compared with the prior art, fewer by-products are generated during preparation of the compound II, reaction time is short, and the obtained product can be reacted with the isopropyl amine to prepare the metoprolol without being purified.
Description
Technical field
The present invention relates to the preparation method of medicine synthetic technical field, especially metoprolol.
Background technology
Metoprolol is a kind of optionally β1Shou Tizuzhiji, is the common drug of treatment hypertension, coronary heart disease, myocardial infarction.Metoprolol can weaken the effect of the catecholamine relevant with physiology and mental load, reduces heart rate, CO and blood pressure.
The chemical name of metoprolol is (±) 1-isopropylamino-3-[right-(2-methoxyethyl) phenoxy]-2-propyl alcohol, and acceptable clinically salt mainly contains hydrochloride, tartrate, SUMATRIPTAN SUCCINATE.
The preparation of metoprolol mainly comprised for two steps, and methoxy ethyl phenol and epichlorohydrin reaction are made compound I I, made metoprolol (I) with the Isopropylamine reaction again.
US5082969 discloses the compound method of compound I I, under the condition of sodium hydroxide, methoxy ethyl phenol and epoxy chloropropane is made 0-25 ℃ of reaction in 15-20 hour.
Also to disclose the content of gained compound I I be 75-80% to US5082969 in addition, and the content of by-product compounds III is 15-20%
CN97199796.9 discloses the compound method of compound I I, under the condition of sodium hydroxide or Pottasium Hydroxide, methoxy ethyl phenol and epoxy chloropropane is reacted 4 hours at 50-70 ℃, and the product underpressure distillation obtains compound III.
In the present invention, obtain as drawing a conclusion through experimental study:
1. during preparation compound I I: improve temperature of reaction, can shorten the reaction times, but by product III increases, product needed underpressure distillation purify () of CN97199796.9; Temperature of reaction reduces, and by product III reduces (15-20%), but needs to prolong the reaction times (of US5082969).
2. the preparation of compound I I can be reacted in two steps, methoxy ethyl phenol is reacted under comparatively high temps with sodium hydroxide earlier make the methoxy ethyl sodium phenylate, and sodium salt reacts at a lower temperature with epoxy chloropropane and makes compound I I.Improve temperature when becoming sodium salt and can not produce side reaction, sodium salt and epoxy chloropropane reaction under lower temperature can effectively reduction by product III (Fig. 1 compares with CN97199796.9), simultaneously, the reaction times also shortens and (US5082969 compares) greatly.
3. compared with present technology, the present invention can reduce production of by-products, shortens the reaction times simultaneously, and products obtained therefrom need not distillation and purifies, and can drop into next step reaction.
Summary of the invention
The present invention relates to the preparation method of metoprolol.The present invention relates to the preparation of the represented metoprolol of formula (I) specifically
The preparation technology of metoprolol of the present invention comprises:
(1) methoxy ethyl phenol and sodium hydroxide solution are reacted under 30-80 ℃, generate methoxy ethyl phenol sodium salt.Be cooled to 0-40 ℃, add epichlorohydrin reaction, get compound I I.
(2) in the presence of Virahol, compound I I and Isopropylamine reaction obtain metoprolol.
Among the present invention, to reaction times of methoxy ethyl phenol and sodium hydroxide solution be 0-2 hour.
Reaction times to methoxy ethyl phenol sodium salt and epoxy chloropropane is 1-4 hour.
The invention provides a kind of preparation method of simple and effective metoprolol.Compare with CN97199796, our gained compound I I purity is high, need not make with extra care.To compare purity suitable with US5082969, but the reaction times shortens (shortening to 5 hours by 20 hours) greatly.
Description of drawings:
Fig. 1 is the high-efficient liquid phase chromatogram of compound I I according to the invention.
Below in conjunction with specific examples the present invention is further described.
Embodiment
Embodiment 1
In the 50L reaction kettle, add the 19.2L purified water, slowly add 0.9kg sodium hydroxide and be stirred to complete dissolving.Adding is warming up to 60 ℃ to methoxy ethyl phenol 3Kg, is stirred to the full continued reaction 1 hour of dissolving.Be cooled to 30 ℃, add the 2L epoxy chloropropane.Temperature control continues reaction 4 hours for 30 ℃.Use the 8L ethyl acetate extraction, ethyl acetate layer is successively with purified water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.Filter,, collect filtrating with the ETHYLE ACETATE washing.Remove solvent under reduced pressure to not going out, get compound I I 3.8Kg, yield 92.6%.Purity 79.78% (Fig. 1).
In the 20L reaction kettle, add Virahol and compound I I, drip Isopropylamine, stir, be heated to backflow, reacted 1 hour.Remove solvent under reduced pressure to not going out, add 1.2L ETHYLE ACETATE, the refrigeration crystallization.Filter, obtain the 3.1Kg metoprolol, yield 79.4%.
Claims (3)
1. the preparation method of a metoprolol is characterized in that may further comprise the steps:
(1) methoxy ethyl phenol and sodium hydroxide solution are reacted, generate methoxy ethyl phenol sodium salt.Cooling adds epichlorohydrin reaction, gets 1-(2, the 3-glycidoxy)-4-(2-methoxy ethyl) benzene.
(2) in the presence of Virahol, 1-(2, the 3-glycidoxy)-4-(2-methoxy ethyl) benzene and Isopropylamine reaction obtain metoprolol.
2. according to the method for claim 1, be 30-80 ℃ to the temperature of reaction of methoxy ethyl phenol and sodium hydroxide solution, the reaction times is 0-2 hour.
3. according to the method for claim 1, be 0-40 ℃ to the temperature of reaction of methoxy ethyl phenol sodium salt and epoxy chloropropane, the reaction times is 1-4 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010267321.XA CN102381995B (en) | 2010-08-31 | 2010-08-31 | Preparation method of metoprolol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010267321.XA CN102381995B (en) | 2010-08-31 | 2010-08-31 | Preparation method of metoprolol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102381995A true CN102381995A (en) | 2012-03-21 |
| CN102381995B CN102381995B (en) | 2015-04-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010267321.XA Expired - Fee Related CN102381995B (en) | 2010-08-31 | 2010-08-31 | Preparation method of metoprolol |
Country Status (1)
| Country | Link |
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| CN (1) | CN102381995B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964258A (en) * | 2012-12-11 | 2013-03-13 | 上海奥博生物医药技术有限公司 | Preparation method of related substance J of metoprolol |
| CN105820057A (en) * | 2016-04-22 | 2016-08-03 | 上海应用技术学院 | Method for preparing metoprolol |
| CN111018724A (en) * | 2019-12-27 | 2020-04-17 | 江西美晶科技有限公司 | Metoprolol and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3998790A (en) * | 1970-02-18 | 1976-12-21 | Aktiebolaget Hassle | Phenoxy-hydroxypropylamines, their preparation, and method and pharmaceutical preparations for treating cardiovascular diseases |
| NL7908669A (en) * | 1978-11-29 | 1980-06-02 | Farmos Oy | PROCESS FOR PREPARING A THERAPEUTICALLY ACTIVE AMINE |
| EP0050885A2 (en) * | 1980-10-16 | 1982-05-05 | BLASCHIM S.p.A. | Process for preparing 1-amino-3-aryloxy-2-propanols and 1-amino-2-aryl-2-ethanols |
| CN1237958A (en) * | 1996-11-20 | 1999-12-08 | 阿斯特拉公司 | New manufacturing process of metoprolol |
| WO2005046568A2 (en) * | 2003-11-14 | 2005-05-26 | Ipca Laboratories Limited | Process for manufacture of metoprolol and salts thereof |
| CN101445436A (en) * | 2008-12-22 | 2009-06-03 | 天津市若围药物研究所 | Method for preparing medical compound chlorphenesin |
-
2010
- 2010-08-31 CN CN201010267321.XA patent/CN102381995B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3998790A (en) * | 1970-02-18 | 1976-12-21 | Aktiebolaget Hassle | Phenoxy-hydroxypropylamines, their preparation, and method and pharmaceutical preparations for treating cardiovascular diseases |
| NL7908669A (en) * | 1978-11-29 | 1980-06-02 | Farmos Oy | PROCESS FOR PREPARING A THERAPEUTICALLY ACTIVE AMINE |
| EP0050885A2 (en) * | 1980-10-16 | 1982-05-05 | BLASCHIM S.p.A. | Process for preparing 1-amino-3-aryloxy-2-propanols and 1-amino-2-aryl-2-ethanols |
| CN1237958A (en) * | 1996-11-20 | 1999-12-08 | 阿斯特拉公司 | New manufacturing process of metoprolol |
| WO2005046568A2 (en) * | 2003-11-14 | 2005-05-26 | Ipca Laboratories Limited | Process for manufacture of metoprolol and salts thereof |
| CN101445436A (en) * | 2008-12-22 | 2009-06-03 | 天津市若围药物研究所 | Method for preparing medical compound chlorphenesin |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964258A (en) * | 2012-12-11 | 2013-03-13 | 上海奥博生物医药技术有限公司 | Preparation method of related substance J of metoprolol |
| CN102964258B (en) * | 2012-12-11 | 2014-01-29 | 上海奥博生物医药技术有限公司 | Preparation method of related substance J of metoprolol |
| CN105820057A (en) * | 2016-04-22 | 2016-08-03 | 上海应用技术学院 | Method for preparing metoprolol |
| CN105820057B (en) * | 2016-04-22 | 2017-09-29 | 上海应用技术学院 | A kind of method for preparing Metoprolol |
| CN111018724A (en) * | 2019-12-27 | 2020-04-17 | 江西美晶科技有限公司 | Metoprolol and preparation method thereof |
| CN111018724B (en) * | 2019-12-27 | 2022-11-08 | 江西美晶科技有限公司 | Metoprolol and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102381995B (en) | 2015-04-15 |
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