CN106631754A - Preparation method of p-methyl cinnamic acid - Google Patents
Preparation method of p-methyl cinnamic acid Download PDFInfo
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- CN106631754A CN106631754A CN201611234992.XA CN201611234992A CN106631754A CN 106631754 A CN106631754 A CN 106631754A CN 201611234992 A CN201611234992 A CN 201611234992A CN 106631754 A CN106631754 A CN 106631754A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The invention belongs to the technical field of medicine synthesis and in particular relates to a preparation method of an ozagrel key intermediate, namely p-methyl cinnamic acid. The method comprises the following steps: taking p-tolualdehyde as a raw material and alcohol as a reaction solvent; reacting under the protection of nitrogen gas and under a heating condition of sodium alcoholate and/or a sodium alcoholate alcohol solution and acetate; after reacting, concentrating until an oily product is obtained; adding an alkali solution and reacting and hydrolyzing; adding an acid for acidifying and carrying out acid regulation to obtain the p-methyl cinnamic acid. The preparation method provided by the invention has the advantages of moderate reaction conditions, simplicity in operation, high yield, high product purity, low raw material cost and the like, has the advantages of environment friendliness, greenness and environment protection, and is suitable for industrial production.
Description
Technical field
The invention belongs to medical synthesis technical field, and in particular to a kind of ozagrel key intermediate is to methyl cinnamic acid
Preparation method.
Background technology
To methyl cinnamic acid, CAS 1866-39-3, molecular formula C10H10O2, it is in the middle of the key intermediate of ozagrel
Body.It is as follows to methyl cinnamic acid structural formula：
。
Ozagrel（Ozagrel）It is the strength thromboxane A z of first listing in the world（TXAz）Synthetase inhibitors,
The joint study of Japanese Ono and Kissei pharmaceutical industries Co., Ltd. is in the antithrombotic of Initial Public Offering in 1988；Suitable for treatment
The adjoint dyskinesia of Acute thrombostic cerebral infarction and cerebral infarction, and improve the postoperative cerebrovascular convulsion of subarachnoid hemorrhage
Contraction is shunk and concurrent symptoms of cerebral ischemia.Ozagrel is one of maximum kind of amplification in antithrombotic reagent, there is multiple doses at present
Type is listed at home, including tablet, capsule, parenteral solution etc., very important status is occupied in anti-thrombotic drugs.
Be Perkin reaction methods to methyl cinnamic acid conventional synthesis, i.e., with p-tolyl aldehyde and acetic acid anhydride reactant, with
Sodium acetate is that reaction temperature more than catalyst, but 160 DEG C and side reaction are more, is not suitable for very much industrialized production.In addition, with right
Tolyl aldehyde and malonic acid react, and need pyridine and piperidines to be catalyst；Because all cacodorous taste of two catalyst, institute
With in reaction and post processing to the healthy unfavorable of producers；In addition, because being not reaction raw materials, causing reaction to finish
Two catalyst to be also discharged into environment and pollute environment.Patent CN102633624A discloses preparation to methyl cinnamic acid
Method, still reacted with p-tolyl aldehyde and malonic acid, though replacing pyridine and piperidines by catalyst of DBU, be because DBU
Price is high and needs recovery and recrystallization to make post processing relatively complicated.
The content of the invention
In order to solve above-mentioned technical problem, the invention provides a kind of preparation method to methyl cinnamic acid.The method
With p-tolyl aldehyde and methyl acetate as raw material, react in the case where sodium methoxide is alkali effect, process through hydrolysis etc. and obtain to first
Base cinnamic acid.This synthetic method avoid reaction in high temperature, avoid using the catalyst pyridine and piperazine of prior synthesizing method
Pyridine；It is simple to operate, do not need special production to set so that the preparation method environmental protection, greatly reduce the pollution to environment
It is standby, it is easy to industrialized production；Gained is to methyl cinnamic acid high income, and purity is high.
The present invention is achieved through the following technical solutions：
A kind of preparation method to methyl cinnamic acid, comprises the steps：
With p-tolyl aldehyde as raw material, alcohol is reaction dissolvent, in sodium alkoxide and/or sodium alkoxide alcoholic solution and acetic acid esters under nitrogen protection
React under heating condition, reaction is finished and is concentrated into grease, add aqueous slkali reaction hydrolysis, add sour acid adjustment and obtain to methyl
Cinnamic acid.
In the above-mentioned preparation method to methyl cinnamic acid, the reaction dissolvent alcohol is methyl alcohol, ethanol, propyl alcohol or butanol
In one or more；The sodium alkoxide is one or two in sodium methoxide, caustic alcohol, and the sodium alkoxide alcoholic solution is sodium methoxide
And/or the alcoholic solution of caustic alcohol；The acetic acid esters is the one kind in methyl acetate, ethyl acetate, propyl acetate or butyl acetate.
Preferably, in the above-mentioned preparation method to methyl cinnamic acid, the reaction dissolvent alcohol is methyl alcohol, to methylbenzene first
Aldehyde and methanol weight ratio are 1:1-5；The sodium alkoxide is sodium methoxide, and p-tolyl aldehyde and sodium methoxide weight ratio are 1:0.45-
1.35；The acetic acid esters is 1 for the weight ratio of methyl acetate, p-tolyl aldehyde and methyl acetate:0.62-2.47.
In the above-mentioned preparation method to methyl cinnamic acid, the temperature reacted under the heating condition is 20-65 DEG C；It is preferred that
For 50-65 DEG C.
In the above-mentioned preparation method to methyl cinnamic acid, the time reacted under the heating condition is 10-35 hours.
In the above-mentioned preparation method to methyl cinnamic acid, the aqueous slkali is sodium hydroxide solution, potassium hydroxide solution, carbonic acid
One kind in sodium solution, solution of potassium carbonate；The acidifying acid be concentrated hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid,
One kind in citric acid.
Preferably, in the above-mentioned preparation method to methyl cinnamic acid, the aqueous slkali be sodium hydroxide solution, the acid
Change acid is concentrated hydrochloric acid.The concentration of the sodium hydroxide solution is 10 ~ 30%；The concentration of the concentrated hydrochloric acid is Chinese Pharmacopoeia annex
Specified in concentration.
Preferably, the above-mentioned preparation method detailed step to methyl cinnamic acid is：P-tolyl aldehyde, methyl alcohol and acetic acid
After methyl esters stirs, nitrogen protection is cooled to less than 0 DEG C, and stirring is dividedly in some parts sodium methoxide；50-65 is to slowly warm up to after adding
DEG C reaction, reaction is finished and is concentrated into grease, adds sodium hydroxide solution to react 2 hours, adds concentrated hydrochloric acid acid adjustment to obtain to first
Base cinnamic acid.
Its synthetic route is as follows：
。
Beneficial effects of the present invention are：
（1）With p-tolyl aldehyde and methyl acetate as raw material, directly with solid sodium methylate as alkali, it is to avoid sodium methoxide solution
Transport and preparation.
（2）With methyl alcohol as solvent reaction, the solvent of concentration and recovery repeatedly set can give birth to for meeting environmental protection in production
The requirement of product.
（3）The preparation method avoids the use of the foul smelling smell catalyst such as pyridine and piperidines in tradition reaction, reduces
Pollution to environment；And the product no foul smell for obtaining, obtain high-quality ozagrel for follow-up smoothly reaction and provide
May.
（4）Reclaiming applying mechanically for methyl alcohol makes the cost of material to methyl cinnamic acid lower.
（5）It is obtained to methyl cinnamic acid high income, purity is high.
Specific embodiment
With reference to specific embodiment, the invention will be further described, so that those skilled in the art know more about this
It is bright, but and it is not so limited the present invention.
Embodiment 1
Methyl alcohol 240g, methyl acetate 81.4g and p-tolyl aldehyde 120g are added in 1L reaction bulbs, logical nitrogen is protected under stirring
Shield, is cooled to less than 0 DEG C.Sodium methoxide 56.7g is dividedly in some parts, rear solution is added and is to slowly warm up to 60 ~ 65 DEG C.Thin layer monitoring reaction
Finish, concentration removes solvent, add NaOH 40g and deionized water 300g, 20 ~ 30 DEG C are reacted 2 hours, then use concentrated hydrochloric acid
120g adjusts solution ph 1 ~ 2.Filter, drying obtains off-white color to methyl cinnamic acid 154.2g；Molar yield 95.1%, liquid-phase pure
Degree 99.5%.
Embodiment 2
Methyl alcohol 360g, methyl acetate 81.4g and p-tolyl aldehyde 120g are added in 1L reaction bulbs, logical nitrogen is protected under stirring
Shield, is cooled to less than 0 DEG C.Sodium methoxide 59.4g is dividedly in some parts, rear solution is added and is to slowly warm up to 50 ~ 60 DEG C.Thin layer monitoring reaction
Finish, concentration removes solvent, add NaOH 40g and deionized water 300g, 20 ~ 30 DEG C are reacted 2 hours, then use concentrated hydrochloric acid
135g adjusts solution ph 1 ~ 2.Filter, drying obtains off-white color to methyl cinnamic acid 152.3g；Molar yield 93.9%, liquid-phase pure
Degree 99.4%.
Embodiment 3
Methyl alcohol 360g, methyl acetate 88.8g and p-tolyl aldehyde 120g are added in 1L reaction bulbs, logical nitrogen is protected under stirring
Shield, is cooled to less than 0 DEG C.Sodium methoxide 56.7g is dividedly in some parts, rear solution is added and is to slowly warm up to 50 ~ 60 DEG C.Thin layer monitoring reaction
Finish, concentration removes solvent, add NaOH 40g and deionized water 300g, 20 ~ 30 DEG C are reacted 2 hours, then use concentrated hydrochloric acid
120g adjusts solution ph 1 ~ 2.Filter, drying obtains off-white color to methyl cinnamic acid 151.6g；Molar yield 93.5%, liquid-phase pure
Degree 99.6%.
Claims (9)
1. a kind of preparation method to methyl cinnamic acid, comprises the steps：
With p-tolyl aldehyde as raw material, alcohol is reaction dissolvent, in sodium alkoxide and/or sodium alkoxide alcoholic solution and acetic acid esters under nitrogen protection
React under heating condition, reaction is finished and is concentrated into grease, add aqueous slkali reaction hydrolysis, add sour acid adjustment and obtain to methyl
Cinnamic acid.
2. the preparation method to methyl cinnamic acid according to claim 1, it is characterised in that the reaction dissolvent alcohol is first
One or more in alcohol, ethanol, propyl alcohol or butanol；The sodium alkoxide is one or two in sodium methoxide, caustic alcohol, described
Sodium alkoxide alcoholic solution is the alcoholic solution of sodium methoxide and/or caustic alcohol；The acetic acid esters is methyl acetate, ethyl acetate, propyl acetate
Or the one kind in butyl acetate.
3. the preparation method to methyl cinnamic acid according to claim 2, it is characterised in that the reaction dissolvent alcohol is first
Alcohol, p-tolyl aldehyde and methanol weight ratio are 1:1-5；The sodium alkoxide is sodium methoxide, p-tolyl aldehyde and sodium methoxide weight
Than for 1:0.45-1.35；The acetic acid esters is 1 for the weight ratio of methyl acetate, p-tolyl aldehyde and methyl acetate:0.62-
2.47。
4. the preparation method to methyl cinnamic acid according to claim 1, it is characterised in that react under the heating condition
Temperature be 20-65 DEG C.
5. the preparation method to methyl cinnamic acid according to claim 4, it is characterised in that react under the heating condition
Temperature be preferably 50-65 DEG C.
6. the preparation method to methyl cinnamic acid according to claim 1, it is characterised in that react under the heating condition
Time be 10-35 hours.
7. the preparation method to methyl cinnamic acid according to claim 1, it is characterised in that the aqueous slkali is hydroxide
One kind in sodium solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate；The acidifying acid be concentrated hydrochloric acid, sulfuric acid,
One kind in phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, citric acid.
8. the preparation method to methyl cinnamic acid according to claim 7, it is characterised in that the aqueous slkali is hydroxide
Sodium solution, the acidifying acid is concentrated hydrochloric acid.
9. the preparation method to methyl cinnamic acid according to claim 1, it is characterised in that detailed step is：To methyl
After benzaldehyde, methyl alcohol and methyl acetate stir, nitrogen protection is cooled to less than 0 DEG C, and stirring is dividedly in some parts sodium methoxide；Add
After be to slowly warm up to 50-65 DEG C of reaction, reaction is finished and is concentrated into grease, adds sodium hydroxide solution to react 2 hours, is added dense
Hydrochloric acid acid adjustment is obtained to methyl cinnamic acid.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4618698A (en) * | 1984-06-16 | 1986-10-21 | Bayer Aktiengesellschaft | Process for the preparation of a mixture of an optionally substituted cinnamic acid ester and an optionally substituted β-alkoxy-β-phenyl-propionic acid ester, and a process for the preparation of optionally substituted cinnamic acid |
| CN102351689A (en) * | 2011-10-31 | 2012-02-15 | 滨州泓瑞医药科技有限公司 | Preparation technique of p-hydroxy-cinnamic acid |
| CN102627559A (en) * | 2012-03-22 | 2012-08-08 | 湖北远成药业有限公司 | Preparation method of methyl 4-methylcinnamate |
| CN105601496A (en) * | 2015-12-31 | 2016-05-25 | 济南诚汇双达化工有限公司 | Preparation method of 3,4-dimethoxy phenylpropionic acid |
-
2016
- 2016-12-28 CN CN201611234992.XA patent/CN106631754A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4618698A (en) * | 1984-06-16 | 1986-10-21 | Bayer Aktiengesellschaft | Process for the preparation of a mixture of an optionally substituted cinnamic acid ester and an optionally substituted β-alkoxy-β-phenyl-propionic acid ester, and a process for the preparation of optionally substituted cinnamic acid |
| CN102351689A (en) * | 2011-10-31 | 2012-02-15 | 滨州泓瑞医药科技有限公司 | Preparation technique of p-hydroxy-cinnamic acid |
| CN102627559A (en) * | 2012-03-22 | 2012-08-08 | 湖北远成药业有限公司 | Preparation method of methyl 4-methylcinnamate |
| CN105601496A (en) * | 2015-12-31 | 2016-05-25 | 济南诚汇双达化工有限公司 | Preparation method of 3,4-dimethoxy phenylpropionic acid |
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Application publication date: 20170510 |