CN102381995B - Preparation method of metoprolol - Google Patents
Preparation method of metoprolol Download PDFInfo
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- CN102381995B CN102381995B CN201010267321.XA CN201010267321A CN102381995B CN 102381995 B CN102381995 B CN 102381995B CN 201010267321 A CN201010267321 A CN 201010267321A CN 102381995 B CN102381995 B CN 102381995B
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- metoprolol
- reaction
- preparation
- methoxy ethyl
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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 technical field of pharmaceutical synthesis, especially the preparation method of metoprolol.
Background technology
Metoprolol is one optionally β1receptorblocker, is the common drug for the treatment of hypertension, coronary heart disease, myocardial infarction.Metoprolol can weaken the effect of the catecholamine relevant with physiology and mental load, reduces heart rate, heart output and blood pressure.
The chemical name of metoprolol is (±) 1-isopropylamino-3-[p-(2-methoxyethyl) phenoxy group]-2-propyl alcohol, and acceptable salt mainly contains hydrochloride, tartrate, succinate clinically.
The preparation of metoprolol mainly comprises two steps, obtains Compound II per to methoxy ethyl phenol and epichlorohydrin reaction, then reacts obtained metoprolol (I) with Isopropylamine.
US5082969 discloses the synthetic method of Compound II per, under the condition of sodium hydroxide, to react obtain for 15-20 hour methoxy ethyl phenol and epoxy chloropropane at 0-25 DEG C.
US5082969 also discloses the content of gained Compound II per is in addition 75-80%, and the content of by-product compounds III is 15-20%
CN97199796.9 discloses the synthetic method of Compound II per, and under the condition of sodium hydroxide or potassium hydroxide, react 4 hours to methoxy ethyl phenol and epoxy chloropropane at 50-70 DEG C, product underpressure distillation obtains compound III.
In the present invention, obtain as drawn a conclusion through experimental study:
1. when preparing Compound II per: improve temperature of reaction, can Reaction time shorten, but by product III increases, and (as described in CN97199796.9) is purified in product needed underpressure distillation; Temperature of reaction reduces, and by product III reduces (15-20%), but needs to extend the reaction times (as described in US5082969).
2. the preparation of Compound II per can be reacted in two steps, and react obtained to methoxy ethyl sodium phenylate at relatively high temperatures to methoxy ethyl phenol elder generation and sodium hydroxide, sodium salt reacts obtained Compound II per at a lower temperature with epoxy chloropropane again.Improve temperature during one-tenth sodium salt and can not produce side reaction, sodium salt and epoxy chloropropane react under comparatively low temperature effectively can reduce by product III (Fig. 1, compared with CN97199796.9), meanwhile, the reaction times also shortens and (compared with US5082969) greatly.
3. compared with the prior art, the present invention can reduce the generation of by product, simultaneously Reaction time shorten, and products obtained therefrom, without the need to distilation, 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 metoprolol represented by formula (I) specifically
The preparation technology of metoprolol of the present invention comprises:
(1) methoxy ethyl phenol and sodium hydroxide solution are reacted at 30-80 DEG C, generate methoxy ethyl phenol sodium salt.Be cooled to 0-40 DEG C, add epichlorohydrin reaction, obtain Compound II per.
(2) under the existence of Virahol, Compound II per and Isopropylamine react, and obtain metoprolol.
In the present invention, be 0-2 hour to the reaction times of methoxy ethyl phenol and sodium hydroxide solution.
Be 1-4 hour to the reaction times of methoxy ethyl phenol sodium salt and epoxy chloropropane.
The invention provides a kind of preparation method of simple and effective metoprolol.Compared with CN97199796, our gained Compound II per purity is high, does not need to refine.Purity is suitable compared with US5082969, but the reaction times shortens (shortening to 5 hours by 20 hours) greatly.
Accompanying drawing illustrates:
Fig. 1 is the high-efficient liquid phase chromatogram of Compound II per of the present invention.
Below in conjunction with specific examples, the invention will be further described.
Embodiment
Embodiment 1
In 50L reactor, add 19.2L purified water, slowly add 0.9kg sodium hydroxide and be stirred to entirely molten.Add methoxy ethyl phenol 3Kg, be warming up to 60 DEG C, be stirred to complete molten rear continuation reaction 1 hour.Be cooled to 30 DEG C, add 2L epoxy chloropropane.Temperature control 30 DEG C continues reaction 4 hours.Extract by 8L ethyl acetate, ethyl acetate layer washs with purified water, saturated nacl aqueous solution successively, anhydrous sodium sulfate drying.Filter, with ethyl acetate washing, collect filtrate.Removing solvent under reduced pressure to not going out, obtaining Compound II per 3.8Kg, yield 92.6%.Purity 79.78% (Fig. 1).
In 20L reactor, add Virahol and Compound II per, drip Isopropylamine, stir, be heated to backflow, react 1 hour.Removing solvent under reduced pressure to not going out, adding 1.2L ethyl acetate, refrigeration crystallization.Filter, obtain 3.1Kg metoprolol, yield 79.4%.
Claims (3)
1. a preparation method for metoprolol, is characterized in that comprising the following steps:
(1) react methoxy ethyl phenol and sodium hydroxide solution, generate methoxy ethyl phenol sodium salt, cooling, adds epichlorohydrin reaction, obtains 1-(2,3-glycidoxy)-4-(2-methoxy ethyl) benzene;
(2) under the existence of Virahol, 1-(2,3-glycidoxy)-4-(2-methoxy ethyl) benzene and Isopropylamine react, and obtain metoprolol.
2. the preparation method of metoprolol according to claim 1, it is characterized in that to the temperature of reaction of methoxy ethyl phenol and sodium hydroxide solution be 30-80 DEG C, the reaction times is 0-2 hour.
3. the preparation method of metoprolol according to claim 1, it is characterized in that to the temperature of reaction of methoxy ethyl phenol sodium salt and epoxy chloropropane be 0-40 DEG C, 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 CN102381995A (en) | 2012-03-21 |
| CN102381995B true CN102381995B (en) | 2015-04-15 |
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Family Applications (1)
| 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) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105820057B (en) * | 2016-04-22 | 2017-09-29 | 上海应用技术学院 | A kind of method for preparing Metoprolol |
| CN111018724B (en) * | 2019-12-27 | 2022-11-08 | 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 |
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| CN102381995A (en) | 2012-03-21 |
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Granted publication date: 20150415 Termination date: 20160831 |