CN110305027B - Method for producing aceclofenac tert-butyl ester - Google Patents
Method for producing aceclofenac tert-butyl ester Download PDFInfo
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- CN110305027B CN110305027B CN201910501748.2A CN201910501748A CN110305027B CN 110305027 B CN110305027 B CN 110305027B CN 201910501748 A CN201910501748 A CN 201910501748A CN 110305027 B CN110305027 B CN 110305027B
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- tert
- butyl ester
- butyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a method for producing aceclofenac tert-butyl ester. The method comprises the following steps: reacting diclofenac sodium, tert-butyl bromoacetate, catalyst iodide and tetrabutylammonium hydrogen sulfate in water, slowly cooling, crystallizing, filtering, washing and drying. The method has the advantages of mild reaction conditions, high yield, reduction in waste liquid discharge, avoidance of toxic effect of organic solvents on human bodies and the like.
Description
Technical Field
The invention belongs to the field of preparation of aceclofenac tert-butyl ester, and particularly relates to a method for producing aceclofenac tert-butyl ester.
Background
There are many reports on the synthetic route of tert-butyl acetochlorophenol, which mainly uses the reflux reaction of diclofenac sodium and tert-butyl haloacetate in acetone (Qialu pharmaceutical affaises 2009 Vol.28, No.10) (the reaction equation is as follows), and uses the reflux reaction of diclofenac sodium and tert-butyl chloroacetate in acetonitrile (Jiannieli, Vanpongao, Cheng Guo. the synthesis of aceclofenac [ J ]. China journal of pharmaceutical industry 2005 (07)); the method has the advantages of large discharge amount of organic waste solvents, large separation difficulty, low process safety factor and no contribution to industrial production, and is used for carrying out reflux reaction on diclofenac sodium and chloroacetic acid tert-butyl ester in DMF (Qinpiprochang, old, Zixuan, synthesis of aceclofenac, J.Med.Industrials, 2008,39 (6): 408-409).
Disclosure of Invention
The invention aims to solve the technical problem of providing a method for producing aceclofenac tert-butyl ester, and overcomes the defects of large organic waste solvent discharge amount, large product separation difficulty and low process safety factor in the preparation process of the aceclofenac tert-butyl ester in the prior art.
The invention relates to a method for producing aceclofenac tert-butyl ester, which comprises the following steps:
reacting diclofenac sodium, tert-butyl bromoacetate, catalyst iodide and tetrabutylammonium hydrogen sulfate (phase transfer catalyst) in a molar ratio of 1:1.1-1.7:0.03-0.09:0.08-0.15 in water, slowly cooling, crystallizing, filtering, washing and drying to obtain the aceclofenac tert-butyl ester, wherein the mass ratio of the diclofenac sodium to the water is 1: 4-6.
The iodide is potassium iodide.
The reaction temperature is 55-70 ℃, and the reaction time is 2-3 h.
The washing solvent is ethanol, and the dosage of the washing solvent is 2-4 times of that of diclofenac sodium.
The drying temperature is 60-70 ℃.
The molar ratio of the diclofenac sodium to the tert-butyl bromoacetate is 1: 1-1.5.
Advantageous effects
The method adopts nucleophilic substitution reaction, the tert-butyl chlorophenol acetate generated in solvent water is separated out from the water, the observation is easy, the integral temperature is lower than the boiling point of the water, the process is safe, the waste liquid is less and easy to treat, the water is used as the solvent, the inorganic salt sodium bromide generated in the reaction process can be well removed, and the step of filtering the inorganic salt in advance when the organic solvent is used is avoided; the addition of phase transfer catalyst tetrabutylammonium bisulfate can disperse the material homogeneously and react fully, and the tetrabutylammonium bisulfate has low cost. Has good application prospect. The invention has low cost, no pollution and environmental protection.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the teaching of the present invention, and these equivalents also fall within the scope of the claims appended to the present application.
The main reagents indicate the source.
| CAS | Name(s) | Specification of | Manufacturer of the product |
| 5292-43-3 | Bromoacetic acid tert-butyl ester | 99.5％ | Longsheng chemical engineering in salt city |
| 32503-27-8 | Tetrabutylammonium hydrogen sulfate | Analytical purity | Aladdin |
| 7681-11-0 | Potassium iodide | Analytical purity | Chinese medicine reagent |
| 61-17-5 | Ethanol | Analytical purity | Chinese medicine reagent |
Example 1
Adding 100g of water into a 250ml three-neck flask, starting stirring, adding 20g (80%, 50.31mmol) of crude diclofenac sodium (DOS5), adding 16.7g (85.64mmol, 1.7eq) of tert-butyl bromoacetate, 0.6g (3.614mmol, 0.07eq) of potassium iodide and 1.6g (4.713mmol, 0.09eq) of tetrabutylammonium hydrogen sulfate, starting heating, heating to 60 ℃, starting heat preservation, controlling the temperature to be 60-65 ℃, preserving heat for 2 hours, slowly cooling to 5-15 ℃, preserving heat for half an hour, carrying out vacuum filtration to obtain a tan solid, washing the solid to be grey white by using ethanol with the mass of 3 times of that of DOS5, and drying at 60 ℃ for 30 hours to obtain 17.3g of tert-butyl aceclofenate. The yield was 94.5% and the liquid phase purity was 99.62%.
Example 2
Adding 500g of water into a 1000ml three-neck flask, starting stirring, adding 100g (80%, 251.6mmol) of diclofenac sodium crude product (DOS5), adding 73.6g (377.4mmol, 1.5eq) of tert-butyl bromoacetate, 2.9g (17.61mmol, 0.07eq) of potassium iodide, 7.7g (22.64mmol, 0.09eq) of tetrabutylammonium hydrogen sulfate, starting heating, heating to 60 ℃, starting heat preservation, controlling the temperature to be 60-65 ℃, preserving heat for 2.5 hours, slowly cooling to 5-15 ℃, preserving heat for half an hour, carrying out vacuum filtration to obtain a brown yellow solid, washing the solid to be off-white by using 3 times of ethanol in mass of DOS5, and drying at 60 ℃ for 30 hours to obtain 88.7g of tert-butyl aceclofenate. The yield was 94.16% and the liquid phase purity was 99.43%.
Comparative example 1
For example, the preparation method in patent CN 101531607a is as follows: adding 20g of diclofenac sodium, 0.6g of sodium iodide, 11.3g of chloroacetic acid tert-butyl ester and 140ml of acetonitrile into a reaction bottle, heating to 77-78 ℃, refluxing for 2h, filtering out sodium chloride after the reaction is finished, distilling out acetonitrile at the normal pressure of 77-82 ℃, then evaporating acetonitrile in vacuum, adding methanol, refluxing to refine the intermediate, cooling, crystallizing, and drying in vacuum (45-55 ℃, the vacuum degree is more than or equal to 0.09MPa) to obtain 23.1g of white crystals, wherein the yield is 89.6%.
Claims (3)
1. A method for producing tert-butyl aceclofenac, comprising:
reacting diclofenac sodium, tert-butyl bromoacetate, catalyst iodide and tetrabutylammonium hydrogen sulfate in a molar ratio of 1:1.1-1.7:0.03-0.09:0.08-0.15 in water, slowly cooling, crystallizing, filtering, washing and drying to obtain aceclofenac tert-butyl ester, wherein the mass ratio of the diclofenac sodium to the water is 1:4-6, and the iodide is potassium iodide.
2. The process according to claim 1, wherein the reaction temperature is 55-70 ℃ and the reaction time is 2-3 hours.
3. The method of claim 1, wherein the molar ratio of diclofenac sodium to t-butyl bromoacetate is from 1:1 to 1.5.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910501748.2A CN110305027B (en) | 2019-06-11 | 2019-06-11 | Method for producing aceclofenac tert-butyl ester |
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| CN201910501748.2A CN110305027B (en) | 2019-06-11 | 2019-06-11 | Method for producing aceclofenac tert-butyl ester |
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| CN110305027A CN110305027A (en) | 2019-10-08 |
| CN110305027B true CN110305027B (en) | 2022-07-22 |
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| CN111848426B (en) * | 2020-07-17 | 2023-02-10 | 宁波斯迈克制药有限公司 | Industrial production method of aceclofenac |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2020145A6 (en) * | 1990-05-29 | 1991-07-16 | Prodesfarma Sa | Process for obtaining esters of 2-(2,6- dichlorophenyl)amino)phenylacetoxyacetic acid |
| CN103086907A (en) * | 2013-02-06 | 2013-05-08 | 河南东泰制药有限公司 | Aceclofenac preparation method |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2020145A6 (en) * | 1990-05-29 | 1991-07-16 | Prodesfarma Sa | Process for obtaining esters of 2-(2,6- dichlorophenyl)amino)phenylacetoxyacetic acid |
| CN103086907A (en) * | 2013-02-06 | 2013-05-08 | 河南东泰制药有限公司 | Aceclofenac preparation method |
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