CN105820057A - Method for preparing metoprolol - Google Patents
Method for preparing metoprolol Download PDFInfo
- Publication number
- CN105820057A CN105820057A CN201610255204.9A CN201610255204A CN105820057A CN 105820057 A CN105820057 A CN 105820057A CN 201610255204 A CN201610255204 A CN 201610255204A CN 105820057 A CN105820057 A CN 105820057A
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- Prior art keywords
- reaction
- solution
- metoprolol
- water
- epoxychloropropane
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- 0 C*CCc1ccc(C)cc1 Chemical compound C*CCc1ccc(C)cc1 0.000 description 1
- PAUSMGCEIQNQDW-UHFFFAOYSA-N CC(C)NCC(CCc1ccc(CCNC)cc1)O Chemical compound CC(C)NCC(CCc1ccc(CCNC)cc1)O PAUSMGCEIQNQDW-UHFFFAOYSA-N 0.000 description 1
- UEOWFGJMGUIGHC-UHFFFAOYSA-N COCCc(cc1)ccc1OCC1OC1 Chemical compound COCCc(cc1)ccc1OCC1OC1 UEOWFGJMGUIGHC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/27—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms
- C07D301/28—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms by reaction with hydroxyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epoxy Compounds (AREA)
Abstract
The invention relates to a method for preparing metoprolol. The method comprises the following steps: preparing p-hydroxyphenethyl methyl ether and a sodium hydroxide solution into a weakly alkaline solution, heating to 90-100 DEG C, mixing the solution with epoxy chloropropane, sending the mixture into a pipe reactor, reacting to obtain a solution containing compounds disclosed as structural formula (II), carrying out reduced pressure distillation under slightly negative pressure conditions after the reaction solution flows out of the pipe reactor to obtain a mixed solution of the compounds disclosed as structural formula (II) and water, and directly carrying out ammonolysis reaction on the mixed solution and isopropylamine in water, thereby obtaining the metoprolol. The pH value is regulated to accurately control the alkali consumption, thereby achieving the goal of reducing the ring opening side reaction between the epoxy chloropropane and intermediate II. The pipe continuous reaction is carried out at high temperature to greatly shorten the time and correspondingly reduce the ring opening side reaction, thereby enhancing the quality and yield of the product. The compounds (II) directly enter the next reaction, and thus, the operation is simple and environment-friendly.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to a kind of metoprolol, a kind of method preparing metoprolol.
Background technology
Metoprolol (Metoprolol, another name metoprolol, metoprolol, metoprolol, metoprolol etc.) is that one is clinically used for treating various hypertension (can share) and anginal common medicine with diuretic and vasodilation.Its chemical name is 1-isopropylamino-3-[p-(2-methoxyethyl) phenoxy group]-2-propanol, 1-[4-(2-methoxyethyl) pHenoxy]-3-propan-2-ylamino-propan-2-ol.Metoprolol is second filial generation beta-blocker, alternative retardance β1receptor, weakens the increase of heart adrenergic tension force and the cardiac damage that causes；Also can reduce heart rates, therefore it can treat irregular rapid heart rate.Metoprolol also can reduce myocardial contraction intensity and hypertension.By heart rates and the myocardial contraction intensity of slowing down, metoprolol decreases myocardium requirementing keto quantity.Throat pain may be caused when oxygen demand exceedes supply, therefore metoprolol is the most helpful for treatment throat pain.
The document report of synthesis metoprolol and intermediate is more, such as patent at present: us2005107635, us5082969, wo9822426, wo2007141593, cn200810115092.2, cn102503843, cn102381995.Principal synthetic routes is:
Us5082969 synthesis II, under conditions of alkalescence, to methoxy ethyl phenol and epichlorohydrin reaction, reaction obtains for 15-20 hour at low temperatures, and the response time is long, and produces more ring-opened byproducts；Wo9822426 Yu us2005107635 reacts in water, improves reaction temperature, and by distilation II, the response time is 3-5 hour, and produces operation inconvenience.
Methoxy ethyl phenol is become after salt by wo2007141593 with alkali, then low-temp reaction, the time is longer.Cn102381995 improves, and after first high temperature becomes salt, then with the epoxychloropropane low-temp reaction shortening response time to 4 hours, but the response time is also aobvious the longest.
Cn200810115092.2, employs phase transfer catalyst, but has also used the organic solvents such as substantial amounts of dichloromethane or isopropanol, add cost, also increase risk of environmental pollution.
Therefore, if being provided that a kind of method synthesizing metoprolol, to overcome the above-mentioned deficiency that metoprolol etc. is synthesized, will have very important significance.
Summary of the invention
For above-mentioned technical problem of the prior art, the invention provides a kind of method preparing metoprolol, the described this method prior art to be solved preparing metoprolol is prepared the method time length of metoprolol, side-product many, the technical problem of complex process.
The invention provides a kind of method preparing metoprolol, comprise the following steps:
1) para hydroxybenzene ethyl methyl ether is weighed, para hydroxybenzene ethyl methyl ether and sodium hydroxide solution are configured to weakly alkaline solution, the pH of described weakly alkaline solution is between 8-10, it is heated to temperature 90～100 DEG C, then after static mixer mixes, enter pipeline reactor with the epoxychloropropane being heated to 90～100 DEG C to react, described para hydroxybenzene ethyl methyl ether is 1:1.1～1:1.4 with the mol ratio of epoxychloropropane, the pressure carrying out reacting in pipeline reactor is 0.1～0.5MPa, reaction temperature is 100～120 DEG C, keep 10-30min, reaction obtains the solution containing the compound shown in structure formula II,
2) after reactant liquor flows out pipeline reactor, reduce pressure under the pressure of-0.04～-0.08MPa the Distillation recovery epoxychloropropane mixture with water, obtain the compound of the structural formula shown in (II) and the mixed solution of water, then by containing the compound of the structural formula shown in (II) mixed solution with water, directly and 2-aminopropane. carries out ammonolysis reaction in water, obtains metoprolol.
Further, in step 1) in, according to the weakly alkaline solution flow of para hydroxybenzene ethyl methyl ether be 40～60 kgs/hour, epoxychloropropane flow be 7～14 kgs/hour, pump into static mixer respectively, flow through after static mixer is sufficiently mixed with the speed of 2～3 meter per seconds, enter pipeline reactor.
Further, in step 2) in, the compound containing the structural formula shown in (II) that will be cooled to room temperature is directly inputted to aminating reaction still with water mixed liquid body, pump into the isopropylamine solution that mass percent concentration is 50～80% simultaneously, (II) compound of the structural formula shown in and mol ratio 1:1.5 of 2-aminopropane .～1:1.8, it is input in aminating reaction still according to the flow of 10～16 kgs/hour, reaction 3～5h, then overflow to next reactor continues reaction, keeping reaction temperature is 10～20 DEG C, until reaction terminates, extract reaction solution with organic solvent extracting, waste water reclamation 2-aminopropane., after concentration, crystallisation by cooling obtains metoprolol.
The present invention accurately controls, by regulation pH value, the open loop side reaction that the consumption of alkali reaches to reduce epoxychloropropane with intermediate II.Meanwhile, use and at high temperature carry out pipeline successive reaction, time is greatly shortened, decreases open loop side reaction the most accordingly, improve quality and the yield of product, and II is directly entered the next step, operates simple environment protection.With existing document ratio, II response time is short, and by-product is few, it is not necessary to purifies and can react with 2-aminopropane., and is responded and all carry out in water, and this route yield height, low cost, operation simply, are that an environmental protection can the process route of industrialized production.
The present invention compares with prior art, and its technological progress is significant.Instant invention overcomes the response time in the method for prior art synthesis metoprolol long, the shortcoming such as easy open loop, it is provided that a kind of response time is short, and by-product is few, and operation is simple, environmental protection can the process route of industrialized production.
Detailed description of the invention
In order to make those skilled in the art be more fully understood that the present invention, the present invention will be further described by the following examples, but these embodiments do not limit the scope of the invention.
Embodiment 1
Para hydroxybenzene ethyl methyl ether and 10% sodium hydroxide solution be configured to the weakly alkaline solution that pH value is 8, be heated to 98～100 DEG C standby；In the still of epoxychloropropane, add epoxychloropropane, be heated to 98～100 DEG C standby；nullThe weakly alkaline solution flow of para hydroxybenzene ethyl methyl ether is 50 kgs/hour，Epoxychloropropane flow is 10.1 kgs/hour，Both are by mol ratio 1:1.2 (calculating by hydroxyethyl methyl phenyl ethers anisole)，Pump into static mixer respectively，Reach to be sufficiently mixed requirement when flowing through static mixer with the speed of 2 meter per seconds，Subsequently into pipeline reactor，The temperature controlling the reactant liquor in reactor is 115～120 DEG C，Stress control 0.45～0.5MPa，In pipeline, reaction time is 10min，After reaction terminates，Slightly band negative pressure (-0.04～-0.05Mpa) carries out steam distillation，Reclaim unreacted epoxychloropropane，Obtain the mixed solution of II and water，Be cooled to room temperature II enters directly into aminating reaction still with water mixed liquid body，Reaction 3 hours it is simultaneously in aminating reaction still with the isopropylamine solution of 70% that flow is 11.4 kgs/hour (material II and 2-aminopropane. by mole theory ratio for 1:1.5)，Overflow to again in next reactor，Continue reaction，Holding reaction temperature is room temperature，Until reaction terminates，With toluene extractive reaction liquid，After concentrating part toluene，Crystallisation by cooling obtains sterling metoprolol 20.3 kgs/hour，Yield 84%.
Fusing point 40.0～40.5 DEG C；M/z:267[M]+；1H-NMR (CDCl3) δ: 1.08 [d, 6H, CH (CH3) 2], 2.27 (brs, 2H, OH, NH), 2.68～2.91 (m, 5H, CHCH2NH, CH2Ph, NHCH), 3.35 (s, 3H, OCH3), 3.56 (t, 2H, CH2OCH3), 3.95～3.99 (m, 2H, OCH2CH), 3.97～4.02 (m, 1H, CHOH), 6.83 (d, 2H, J=8.8Hz, Ar-H), 7.16 (d, 2H, Ar-H).
Embodiment 2
Para hydroxybenzene ethyl methyl ether and 10% sodium hydroxide solution be configured to the weakly alkaline solution that pH value is 10, be heated to 90～92 DEG C；In the still of epoxychloropropane, add epoxychloropropane, be heated to 90～92 DEG C standby；nullThe weakly alkaline solution flow of para hydroxybenzene ethyl methyl ether is 40 kgs/hour，Epoxychloropropane flow is 7.5 kgs/hour，Both are by mol ratio 1:1.1，Pump into static mixer respectively，Reach to be sufficiently mixed requirement when flowing through static mixer with the speed of 2.2 meter per seconds，Subsequently into pipeline reactor，The temperature controlling reactor is 100-105 DEG C，Stress control 0.1～0.15MPa，In pipeline, reaction time is 25min，After reaction terminates，Slightly band negative pressure (-0.04～-0.08Mpa) carries out steam distillation，Reclaim epoxychloropropane，Obtain the mixed solution of II and water，Be cooled to room temperature II enters directly into aminating reaction still with water mixed liquid body，Pump into the isopropylamine solution of 50% simultaneously，Flow be 16.0 kgs/hour (material II and 2-aminopropane. by mole theory than for 1:1.6),Enter into reaction 2h in aminating reaction still，Overflow in next reactor，Continue reaction，Keeping reaction temperature is 15 DEG C，Until reaction terminates，With toluene extractive reaction liquid，Waste water reclamation 2-aminopropane.，After concentrating part toluene，Crystallisation by cooling obtains sterling metoprolol 19.1 kgs/hour，Yield 79%.
Embodiment 3
Para hydroxybenzene ethyl methyl ether and 10% sodium hydroxide solution be configured to the weakly alkaline solution that pH value is 9, be heated to 98～100 DEG C；In the still of epoxychloropropane, add epoxychloropropane, be heated to 90～92 DEG C standby；nullThe weakly alkaline solution flow of para hydroxybenzene ethyl methyl ether is 60 kgs/hour，Epoxychloropropane flow is 13.9 kgs/hour，Both are by mol ratio 1:1.4，Pump into static mixer respectively，Reach to be sufficiently mixed requirement when flowing through static mixer with the speed of 3 meter per seconds，Subsequently into pipeline reactor，The temperature controlling reactor is 110～115 DEG C，Stress control 0.2～0.3MPa，In pipeline, reaction time is 15min，After reaction terminates，Slightly band negative pressure (-0.04～-0.08Mpa) carries out steam distillation，Reclaim epoxychloropropane，Obtain the mixed solution of II water，The II of cooling and water mixed liquid body enter directly into aminating reaction still，Pump into the isopropylamine solution of 80% simultaneously，Flow be 11.3 kgs/hour (material II and 2-aminopropane. by mole theory than for 1:1.8),Enter into reaction 5h in aminating reaction still，Overflow in next reactor，Continue reaction，Keeping reaction temperature is 10 DEG C，Until reaction terminates，With toluene extractive reaction liquid，Waste water reclamation 2-aminopropane.，After concentrating part toluene，Crystallisation by cooling obtains sterling metoprolol 20.5 kgs/hour，Yield 85%.
Claims (3)
1. the method preparing metoprolol, it is characterised in that comprise the following steps:
1) para hydroxybenzene ethyl methyl ether is weighed, para hydroxybenzene ethyl methyl ether and sodium hydroxide solution are configured to weakly alkaline solution, the pH of described weakly alkaline solution is between 8-10, it is heated to temperature 90～100 DEG C, then after static mixer mixes, enter pipeline reactor with the epoxychloropropane being heated to 90～100 DEG C to react, described para hydroxybenzene ethyl methyl ether is 1:1.1～1:1.4 with the mol ratio of epoxychloropropane, the pressure carrying out reacting in pipeline reactor is 0.1～0.5MPa, reaction temperature is 100～120 DEG C, keep 10-30min, reaction obtains the solution containing the compound shown in structure formula II,
(II)
2) after reactant liquor outflow pipeline reactor is mixed, reduce pressure under the pressure of-0.04MPa～-0.08Mpa the Distillation recovery epoxychloropropane compound with water, obtaining the compound of the structural formula shown in (II) and the mixed solution of water, then by containing the compound of the structural formula shown in (II) mixed solution with water, directly and 2-aminopropane. carries out ammonolysis reaction in water,Obtain metoprolol.
A kind of method preparing metoprolol the most according to claim 1, it is characterized in that: in step 1), according to the weakly alkaline solution flow of para hydroxybenzene ethyl methyl ether be 40～60 kgs/hour, epoxychloropropane flow be 7～14 kgs/hour, pump into static mixer respectively, flow through after static mixer is sufficiently mixed with the speed of 2～3 meter per seconds, enter pipeline reactor.
A kind of method preparing metoprolol the most according to claim 1, it is characterized in that: in step 2) in, the compound containing the structural formula shown in (II) that will be cooled to room temperature is directly inputted to aminating reaction still with water mixed liquid body, pump into the isopropylamine solution that mass percent concentration is 50～80% simultaneously, (II) compound of the structural formula shown in and mol ratio 1:1.5 of 2-aminopropane .～1:1.8, it is input in aminating reaction still according to the flow of 10～16 kgs/hour, reaction 3～5h, then overflow to next reactor continues reaction, keeping reaction temperature is 10～20 DEG C, until reaction terminates, extract reaction solution with organic solvent extracting, waste water reclamation 2-aminopropane., after concentration, crystallisation by cooling obtains metoprolol.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112645827A (en) * | 2020-12-25 | 2021-04-13 | 浙江普洛家园药业有限公司 | Method for continuously synthesizing metoprolol and salt thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5082969A (en) * | 1989-05-26 | 1992-01-21 | Esteve Quimica, S.A. | Industrial process for obtaining an aryloxypropanolamine |
| CN1128786A (en) * | 1995-09-02 | 1996-08-14 | 龚循礼 | Long service life, corrosion-proof, and electric resistance reducing agent for earthing |
| CN1128786C (en) * | 1996-11-20 | 2003-11-26 | 阿斯特拉公司 | New manufacturing process of metoprolol |
| CN102381995A (en) * | 2010-08-31 | 2012-03-21 | 扬子江药业集团北京海燕药业有限公司 | Preparation method of metoprolol |
| CN102503843A (en) * | 2011-10-28 | 2012-06-20 | 山东阿如拉药物研究开发有限公司 | Preparation method for metoprolol salt |
-
2016
- 2016-04-22 CN CN201610255204.9A patent/CN105820057B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5082969A (en) * | 1989-05-26 | 1992-01-21 | Esteve Quimica, S.A. | Industrial process for obtaining an aryloxypropanolamine |
| CN1128786A (en) * | 1995-09-02 | 1996-08-14 | 龚循礼 | Long service life, corrosion-proof, and electric resistance reducing agent for earthing |
| CN1128786C (en) * | 1996-11-20 | 2003-11-26 | 阿斯特拉公司 | New manufacturing process of metoprolol |
| CN102381995A (en) * | 2010-08-31 | 2012-03-21 | 扬子江药业集团北京海燕药业有限公司 | Preparation method of metoprolol |
| CN102503843A (en) * | 2011-10-28 | 2012-06-20 | 山东阿如拉药物研究开发有限公司 | Preparation method for metoprolol salt |
Non-Patent Citations (1)
| Title |
|---|
| TOMOYA ETAL: "Continuous and convergent access to vicinyl amino alcohols，Nobuta", 《CHEMICAL COMMUNICATIONS (CAMBRIDGE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112645827A (en) * | 2020-12-25 | 2021-04-13 | 浙江普洛家园药业有限公司 | Method for continuously synthesizing metoprolol and salt thereof |
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Denomination of invention: A method for preparing metoprolol Effective date of registration: 20210923 Granted publication date: 20170929 Pledgee: Dongyang sub branch of Bank of China Ltd. Pledgor: ZHEJIANG APELOA JIAYUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330001748 |