CN105820057B - A kind of method for preparing Metoprolol - Google Patents
A kind of method for preparing Metoprolol Download PDFInfo
- Publication number
- CN105820057B CN105820057B CN201610255204.9A CN201610255204A CN105820057B CN 105820057 B CN105820057 B CN 105820057B CN 201610255204 A CN201610255204 A CN 201610255204A CN 105820057 B CN105820057 B CN 105820057B
- Authority
- CN
- China
- Prior art keywords
- reaction
- solution
- structural formula
- water
- mixed
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
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
-
- 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
Abstract
A kind of method for preparing Metoprolol of the present invention, is configured to weakly alkaline solution by para hydroxybenzene ethyl methyl ether and sodium hydroxide solution, is heated to 90~100 DEG C of temperature, is reacted after being mixed with epoxychloropropane into pipeline reactor, and reaction is obtained containing structural formula（Ⅱ）After the solution of shown compound, reaction solution outflow pipeline reactor, the vacuum distillation under slightly band condition of negative pressure obtains structural formula（Ⅱ）Shown compound and the mixed solution of water, then will contain structural formula（Ⅱ）Shown compound and the mixed solution of water directly carry out ammonolysis reaction with isopropylamine in water, obtain Metoprolol.The present invention accurately controls the consumption of alkali by adjusting pH value, to reach the open loop side reaction for reducing epoxychloropropane and intermediate II.Carry out pipeline successive reaction at high temperature simultaneously, the time is greatly shortened, open loop side reaction is also accordingly reduced, the quality and yield of product is improved, and（Ⅱ）The next step is directly entered, simple environment protection is operated.
Description
Technical field
The invention belongs to medicinal chemistry art, it is related to a kind of Metoprolol, specifically a kind of Metoprolol for preparing
Method.
Background technology
Metoprolol (Metoprolol, alias metoprolol, metoprolol, Betaloc, metoprolol etc.) is one
Plant and be clinically used for treating various hypertension (can share with diuretics and vasodilator) and anginal common medicine.Its chemistry
Name is 1- isopropylaminos -3- [p- (2- methoxyethyls) phenoxy group] -2- propyl alcohol, 1- [4- (2-methoxyethyl)
pHenoxy]-3-propan-2-ylamino-propan-2-ol.Metoprolol is second generation beta-blocker, alternative
Block β1receptor, weaken cardiac damage caused by the increase of heart adrenergic tension force；Also heart rates can be reduced, therefore it
Irregular heart rate can be treated too fast.Metoprolol can also reduce myocardial contraction intensity and hypertension.By slowing down heart rates
With myocardial contraction intensity, Metoprolol reduces myocardium requirementing keto quantity.It may trigger sore-throat when oxygen demand exceedes supply, therefore
Metoprolol is also helpful for treatment sore-throat.
The document report of synthesis Metoprolol and intermediate is more at present, such as patent：us2005107635、us5082969、
wo9822426、wo2007141593、cn200810115092.2、cn102503843、cn102381995.Principal synthetic routes
For：
Us5082969 synthesis II, under conditions of alkalescence, to methoxy ethyl phenol and epichlorohydrin reaction, low
Temperature lower reaction is obtained for 15-20 hours, and the reaction time is long, and the more ring-opened byproducts of production；Wo9822426 with
Us2005107635 reacts in water, improves reaction temperature, II by distilation, and the reaction time is 3-5 hour, and is given birth to
Produce operation inconvenience.
To methoxy ethyl phenol and alkali into after salt in wo2007141593, then low-temp reaction, the time is longer.
Cn102381995 is improved, and first high temperature shortens the reaction time to 4 hours into after salt, then with epoxychloropropane low-temp reaction, but
Reaction time also shows slightly long.
Cn200810115092.2, has used phase transfer catalyst, but has also used substantial amounts of dichloromethane or isopropanol etc.
Organic solvent, adds cost, also increases risk of environmental pollution.
Therefore, if a kind of method for synthesizing Metoprolol can be provided, to overcome above-mentioned reaction synthesis Metoprolol etc. no
Foot, will have very important significance.
The content of the invention
It is described the invention provides a kind of method for preparing Metoprolol for above-mentioned technical problem of the prior art
This method for preparing Metoprolol many, the work that to solve to prepare the method time length of Metoprolol, byproduct in the prior art
The complicated technical problem of skill.
The invention provides a kind of method for preparing Metoprolol, comprise the following steps：
1) para hydroxybenzene ethyl methyl ether is weighed, it is molten that para hydroxybenzene ethyl methyl ether and sodium hydroxide solution are configured into alkalescent
Liquid, the pH of described weakly alkaline solution is heated to 90~100 DEG C of temperature, then with being heated to 90~100 DEG C between 8-10
Epoxychloropropane is reacted after being mixed through static mixer into pipeline reactor, described para hydroxybenzene ethyl methyl ether and ring
The mol ratio of oxygen chloropropane is 1：1.1~1:1.4, the pressure reacted in pipeline reactor is 0.1~0.5MPa, instead
It is 100~120 DEG C to answer temperature, keeps 10-30min, and reaction obtains the solution containing the compound shown in structural formula (II),
2) after reaction solution outflow pipeline reactor, epoxy chlorine is reclaimed in vacuum distillation under -0.04~-0.08MPa pressure
The mixture of propane and water, obtains the compound and the mixed solution of water of structural formula shown in (II), then will contain shown in (II)
The compound of structural formula and the mixed solution of water ammonolysis reaction is directly carried out in water with isopropylamine, obtain Metoprolol.
Further, in step 1) in, according to para hydroxybenzene ethyl methyl ether weakly alkaline solution flow for 40~60 kilograms/
Hour, epoxychloropropane flow are 7~14 kgs/hour, and static mixer is pumped into respectively, is flowed through with the speed of 2~3 meter per seconds
After static mixer is sufficiently mixed, into pipeline reactor.
Further, in step 2) in, the compound containing the structural formula shown in (II) that will be cooled to room temperature is mixed with water
Liquid is directly inputted to aminating reaction kettle, while being pumped into the isopropylamine solution that mass percent concentration is 50~80%, (II)
The compound of shown structural formula and the mol ratio 1 of isopropylamine:1.5~1:1.8, the flow according to 10~16 kgs/hour is defeated
Enter into aminating reaction kettle, react 3~5h, then overflow in next reactor continue react, keep reaction temperature be 10~
20 DEG C, until reaction terminates, use organic solvent extractive reaction liquid, Sewage treatment isopropylamine, after concentration, it is many that crystallisation by cooling obtains U.S.
Feel at ease.
The present invention carrys out the accurate consumption for controlling alkali by adjusting pH value and reaches reduction epoxychloropropane and intermediate II
Open loop side reaction.Meanwhile, using pipeline successive reaction is carried out at high temperature, the time is greatly shortened, also accordingly reduces out
Ring side reaction, improves the quality and yield of product, and II is directly entered the next step, operates simple environment protection.With existing literature
Than II reaction time is short, and accessory substance is few, can be reacted without purification with isopropylamine, and all reactions are carried out all in water, the road
Line high income, cost are low, operation is simple, be an environmental protection can industrialized production process route.
The present invention is compared with prior art, and its technological progress is significant.It is U.S. many instant invention overcomes prior art synthesis
The reaction time is long in the method felt at ease, and there is provided a kind of reaction time is short the shortcomings of easy open loop, accessory substance is few, and operation is simple,
Environmental protection can industrialized production process route.
Embodiment
In order that those skilled in the art more fully understand the present invention, the present invention is done furtherly by the following examples
It is bright, but these embodiments do not limit the scope of the invention.
Embodiment 1
Para hydroxybenzene ethyl methyl ether and 10% sodium hydroxide solution are configured to the weakly alkaline solution that pH value is 8, are heated to
98~100 DEG C standby；In the kettle of epoxychloropropane, add epoxychloropropane, be heated to 98~100 DEG C it is standby；Para hydroxybenzene
The weakly alkaline solution flow of ethyl methyl ether is 50 kgs/hour, and epoxychloropropane flow is 10.1 kgs/hour, and both massage
You match 1：1.2 (press and calculate hydroxyethyl methyl phenyl ethers anisole), are pumped into static mixer, static state are flowed through with the speed of 2 meter per seconds respectively
Reached during blender and be sufficiently mixed requirement, subsequently into pipeline reactor, control the temperature of reaction solution in reactor for 115~
120 DEG C, 0.45~0.5MPa of Stress control, reaction time is 10min in pipeline, after reaction terminates, slightly band negative pressure (-
0.04~-0.05Mpa) steam distillation is carried out, unreacted epoxychloropropane is reclaimed, the mixed solution of II and water is obtained, it is cold
But II and water mixed liquid body for arriving room temperature enter directly into aminating reaction kettle, with flow for 11.4 kgs/hour 70% it is different
(material II is 1 by mole theory ratio with isopropylamine to the propylamine aqueous solution:1.5) reacted 3 hours while entering in aminating reaction kettle,
Overflow to again in next reactor, continue to react, holding reaction temperature is room temperature, until reaction terminates, uses toluene extractive reaction
After liquid, concentrating part toluene, crystallisation by cooling obtains 20.3 kgs/hour of sterling Metoprolol, yield 84%.
40.0~40.5 DEG C of fusing point；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 are configured to the weakly alkaline solution that pH value is 10, are heated to
90~92 DEG C；In the kettle of epoxychloropropane, add epoxychloropropane, be heated to 90~92 DEG C it is standby；Para hydroxybenzene ethyl first
The weakly alkaline solution flow of ether is 40 kgs/hour, and epoxychloropropane flow is 7.5 kgs/hour, and both press mol ratio 1：
1.1, static mixer is pumped into respectively, is reached when flowing through static mixer with the speed of 2.2 meter per seconds and is sufficiently mixed requirement, then
Into pipeline reactor, the temperature for controlling reactor is 100-105 DEG C, 0.1~0.15MPa of Stress control, reacts and stops in pipeline
It is 25min to stay the time, after reaction terminates, and slightly band negative pressure (- 0.04~-0.08Mpa) carries out steam distillation, reclaims epoxy chloropropionate
Alkane, obtains the mixed solution of II and water, and II and water mixed liquid body for being cooled to room temperature enter directly into aminating reaction kettle, while pump
Enter 50% isopropylamine solution, flow is 16.0 kgs/hour (material II is 1 by mole theory ratio with isopropylamine:1.6),
Enter in aminating reaction kettle and react 2h, overflow in next reactor, continue to react, it is 15 DEG C to keep reaction temperature, until
Reaction terminates, with Toluene extractive reaction liquid, Sewage treatment isopropylamine, after concentrating part toluene, and it is U.S. many that crystallisation by cooling obtains sterling
Feel at ease 19.1 kgs/hour, yield 79%.
Embodiment 3
Para hydroxybenzene ethyl methyl ether and 10% sodium hydroxide solution are configured to the weakly alkaline solution that pH value is 9, are heated to
98~100 DEG C；In the kettle of epoxychloropropane, add epoxychloropropane, be heated to 90~92 DEG C it is standby；Para hydroxybenzene ethyl first
The weakly alkaline solution flow of ether is 60 kgs/hour, and epoxychloropropane flow is 13.9 kgs/hour, and both press mol ratio
1：1.4, static mixer is pumped into respectively, is reached when flowing through static mixer with the speed of 3 meter per seconds and is sufficiently mixed requirement, then
Into pipeline reactor, the temperature for controlling reactor is 110~115 DEG C, 0.2~0.3MPa of Stress control, reacts and stops in pipeline
It is 15min to stay the time, after reaction terminates, and slightly band negative pressure (- 0.04~-0.08Mpa) carries out steam distillation, reclaims epoxy chloropropionate
Alkane, obtains the mixed solution of II water, and the II of cooling enters directly into aminating reaction kettle with water mixed liquid body, while being pumped into 80%
Isopropylamine solution, flow is 11.3 kgs/hour, and (material II is 1 by mole theory ratio with isopropylamine:1.8) ammonia, is entered
Change in reactor and react 5h, overflow in next reactor, continue to react, it is 10 DEG C to keep reaction temperature, until reaction terminates,
With Toluene extractive reaction liquid, Sewage treatment isopropylamine, after concentrating part toluene, it is public that crystallisation by cooling obtains sterling Metoprolol 20.5
Jin/hour, yield 85%.
Claims (1)
1. a kind of method for 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 heated to 90~100 DEG C of temperature between 8-10, then with being heated to 90~100 DEG C of ring
Oxygen chloropropane is reacted after being mixed through static mixer into pipeline reactor, described para hydroxybenzene ethyl methyl ether and epoxy
The mol ratio of chloropropane is 1：1.1~1:1.4, it is public for 40~60 according to the weakly alkaline solution flow of para hydroxybenzene ethyl methyl ether
Jin/hour, epoxychloropropane flow are 7~14 kgs/hour, static mixer are pumped into respectively, with the speed stream of 2~3 meter per seconds
Cross after static mixer is sufficiently mixed, into pipeline reactor；The pressure reacted in pipeline reactor be 0.1~
0.5MPa, reaction temperature is 100~120 DEG C, keeps 10-30min, and reaction is obtained containing the compound shown in structural formula (II)
Solution,
2) after reaction solution outflow pipeline reactor is mixed, epoxy chlorine is reclaimed in vacuum distillation under -0.04MPa~-0.08Mpa pressure
The compound of propane and water, obtains the compound and the mixed solution of water of structural formula shown in (II), will be cooled to containing for room temperature
(II) compound of the structural formula shown in is directly inputted to aminating reaction kettle with water mixed liquid body, while it is dense to be pumped into mass percent
The isopropylamine solution for 50~80% is spent, the compound of the structural formula shown in (II) and the mol ratio 1 of isopropylamine:1.5~1:
1.8, it is input to according to 10~16 kgs/hour of flow in aminating reaction kettle, reacts 3~5h, then overflow to next reaction
Continue to react in kettle, it is 10~20 DEG C to keep reaction temperature, until reaction terminates, use organic solvent extractive reaction liquid, waste water is returned
Isopropylamine is received, after concentration, crystallisation by cooling obtains Metoprolol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610255204.9A CN105820057B (en) | 2016-04-22 | 2016-04-22 | A kind of method for preparing Metoprolol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610255204.9A CN105820057B (en) | 2016-04-22 | 2016-04-22 | A kind of method for preparing Metoprolol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105820057A CN105820057A (en) | 2016-08-03 |
| CN105820057B true CN105820057B (en) | 2017-09-29 |
Family
ID=56526418
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610255204.9A Active CN105820057B (en) | 2016-04-22 | 2016-04-22 | A kind of method for preparing Metoprolol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105820057B (en) |
Families Citing this family (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 (4)
| 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 |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1062888C (en) * | 1995-09-02 | 2001-03-07 | 龚循礼 | Long service life, corrosion-proof, and electric resistance reducing agent for earthing |
-
2016
- 2016-04-22 CN CN201610255204.9A patent/CN105820057B/en active Active
Patent Citations (4)
| 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 |
| 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 |
|---|
| Continuous and convergent access to vicinyl amino alcohols，Nobuta;Tomoya etal;《Chemical Communications (Cambridge》;20150824;第51卷(第82期);Supporting Information第14-15页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105820057A (en) | 2016-08-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI685488B (en) | Method for preparing intermediate of Azotomin (Azoxystyrin) | |
| CN110229162B (en) | Simple preparation method of Ruipab | |
| CN108586266B (en) | Synthesis process of dimethylamine borane | |
| CN105820057B (en) | A kind of method for preparing Metoprolol | |
| CN107641084A (en) | A kind of method for producing nitroparaffins co-production ketoxime | |
| CN111808054A (en) | Preparation method of ionic liquid and application of ionic liquid in cyclohexanone synthesis | |
| CN108164423B (en) | Preparation method of naftifine hydrochloride | |
| CN103896858B (en) | The preparation technology of cytosine | |
| CN114702425B (en) | Process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives and intermediates | |
| CN106543015A (en) | A kind of preparation method of metoprolol | |
| CN114369033A (en) | Green preparation method of N, N-dimethylamino ethyl acrylate | |
| CN110003023B (en) | Preparation method of environment-friendly N, N-dimethylformamide dimethyl acetal | |
| CN106432004A (en) | Synthesizing method of 3-sulfonyl alcohol compounds | |
| CN110642721B (en) | Preparation method of selegiline hydrochloride | |
| CN111675677B (en) | Synthesis process of N-methylmorpholine | |
| CN101659645B (en) | Method for preparing 3-fluorine-4 morpholinyl phenylamine | |
| US6818769B2 (en) | Process for the preparation of diamine single-sided condensation products | |
| CN113329994A (en) | Method for continuously preparing 5-cyanodiol | |
| CN108558838B (en) | Production method of estrogen receptor modulator intermediate | |
| CN110668951B (en) | Synthesis process of selegiline hydrochloride | |
| CN113651751B (en) | Preparation method of N-methoxycarbonyl-3-trifluoromethylpyridine-2-sulfonamide | |
| CN113831295B (en) | Method for synthesizing rosuvastatin ester by using continuous flow tubular reactor | |
| CN109384754B (en) | Preparation method of dronedarone hydrochloride | |
| CN114349650B (en) | Method for synthesizing fenoterol intermediate by adopting microfluid technology | |
| CN101671267A (en) | Method for directly converting addition product of sodium bisulfite of aldehyde or aliphatic methyl ketone into corresponding oxime |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200408 Address after: 322118 Hengdian Industrial Zone, Jinhua, Zhejiang, China, Dongyang Patentee after: ZHEJIANG APELOA JIAYUAN PHARMACEUTICAL Co.,Ltd. Address before: 200235 Xuhui District, Caobao Road, No. 120, Patentee before: JIAXING ZHONGHUA CHEMICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200630 Address after: 322118 Hengdian Industrial Zone, Jinhua, Zhejiang, China, Dongyang Co-patentee after: APELOA PHARMACEUTICAL Co.,Ltd. Patentee after: ZHEJIANG APELOA JIAYUAN PHARMACEUTICAL Co.,Ltd. Address before: 322118 Hengdian Industrial Zone, Jinhua, Zhejiang, China, Dongyang Patentee before: ZHEJIANG APELOA JIAYUAN PHARMACEUTICAL Co.,Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
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 |