CN110305027A - A method of producing the Aceclofenac tert-butyl ester - Google Patents
A method of producing the Aceclofenac tert-butyl ester Download PDFInfo
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- CN110305027A CN110305027A CN201910501748.2A CN201910501748A CN110305027A CN 110305027 A CN110305027 A CN 110305027A CN 201910501748 A CN201910501748 A CN 201910501748A CN 110305027 A CN110305027 A CN 110305027A
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- butyl
- butyl ester
- tert
- aceclofenac
- producing
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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 present invention relates to a kind of methods for producing the Aceclofenac tert-butyl ester.This method comprises: C14H10Cl2NNaO2, bromo-acetic acid tert-butyl, catalyst iodine compound and 4-butyl ammonium hydrogen sulfate are reacted in water, slow cooling crystallization, is filtered, washed, dries.This method has many advantages, such as mild reaction condition, high income, the discharge for reducing waste liquid and the toxic action for avoiding organic solvent to human body.
Description
Technical field
The invention belongs to Aceclofenac tert-butyl ester preparation field, in particular to a kind of side for producing the Aceclofenac tert-butyl ester
Method.
Background technique
Very much, main useful C14H10Cl2NNaO2 and halogen acetic acid uncle now concerning the synthetic route report of the Aceclofenac tert-butyl ester
Butyl ester back flow reaction (Qilu pharmaceutical Affairs 2009 Vol.28, No.10) (reactional equation in acetone
Formula is as follows), there are C14H10Cl2NNaO2 and chloroacetic acid tert-butyl ester back flow reaction (Jiang Nili, Fan Penggao, the Cheng Guohou in acetonitrile.Vinegar chlorine
Synthesis [J] Chinese Journal of Pharmaceuticals .2005 (07) of fragrant acid)；C14H10Cl2NNaO2 and chloroacetic acid tert-butyl ester flow back in DMF
React (Qin Bingchang, Chen Jing, Zhang Youjuan.The synthesis Chinese Journal of Pharmaceuticals of Aceclofenac, 2008,39 (6): 408-409.),
Such organic solvent waste disposal amount of method is big, and separating difficulty is big, and process safety coefficient is low, is unfavorable for industrial production.
Summary of the invention
It is existing to overcome technical problem to be solved by the invention is to provide a kind of method for producing the Aceclofenac tert-butyl ester
Organic solvent waste disposal amount is big in Aceclofenac tert-butyl ester preparation process in technology, product separating difficulty is big and process safety system
The low defect of number.
A kind of method producing the Aceclofenac tert-butyl ester of the invention, comprising:
C14H10Cl2NNaO2, the bromo-acetic acid tert-butyl, catalysis for being 1:1.1-1.7:0.03-0.09:0.08-0.15 by molar ratio
Agent iodide and 4-butyl ammonium hydrogen sulfate (phase transfer catalyst) react in water, and slow cooling crystallization, is filtered, washed, dries
It is dry, the Aceclofenac tert-butyl ester is obtained, wherein the mass ratio of C14H10Cl2NNaO2 and water is 1:4-6.
The iodide are potassium iodide.
The reaction temperature is 55-70 DEG C, reaction time 2-3h.
The cleaning solvent is ethyl alcohol, and dosage is 2-4 times of C14H10Cl2NNaO2 quality.
The drying temperature is 60-70 DEG C.
The molar ratio of the C14H10Cl2NNaO2 and bromo-acetic acid tert-butyl is 1:1-1.5.
Beneficial effect
Present invention employs nucleophilic substitution, the Aceclofenac tert-butyl ester generated in aqueous solvent is precipitated from water, easily
In observation, bulk temperature is lower than the boiling point of water, and process safety, waste liquid is few and is easily handled, and take water as a solvent to go well
Except the inorganic salts sodium bromide generated in reaction process, avoid using when organic solvent the step of elder generation's filtering inorganic salt；Phase is added to turn
Shifting catalyst 4-butyl ammonium hydrogen sulfate can make material dispersion uniform, and reaction is abundant, and 4-butyl ammonium hydrogen sulfate price is excellent honest and clean.
It has a good application prospect.The present invention is at low cost, pollution-free, environmentally protective.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, those skilled in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
Main agents illustrate source.
| CAS | Title | Specification | Producer |
| 5292-43-3 | Bromo-acetic acid tert-butyl | 99.5% | Yancheng City dragon rises chemical industry |
| 32503-27-8 | 4-butyl ammonium hydrogen sulfate | It analyzes pure | Aladdin |
| 7681-11-0 | Potassium iodide | It analyzes pure | Traditional Chinese medicines reagent |
| 61-17-5 | Ethyl alcohol | It analyzes pure | Traditional Chinese medicines reagent |
Embodiment 1
100g water is added into the three-necked flask of 250ml, opens stirring, it is fragrant that 20g (80%, 50.31mmol) double chlorine are added
16.7g (85.64mmol, 1.7eq) bromo-acetic acid tert-butyl, 0.6g (3.614mmol, 0.07eq) is added in sour sodium crude product (DOS5)
Potassium iodide, 1.6g (4.713mmol, 0.09eq) 4-butyl ammonium hydrogen sulfate open heating, are warming up to 60 DEG C, start to keep the temperature, temperature
Control keeps the temperature 2 hours at 60-65 DEG C, slow cooling, until temperature is 5-15 DEG C, keeps the temperature half an hour, be filtered by vacuum brown color is solid
Body, by the ethanol washing of 3 times of DOS5 mass of solid to canescence, 60 DEG C drying 30 hours, obtain 17.3g Aceclofenac uncle
Butyl ester.Yield is 94.5%, liquid phase purity 99.62%.
Embodiment 2
500g water is added into the three-necked flask of 1000ml, opens stirring, 100g (80%, 251.6mmol) double chlorine are added
Fragrant acid sodium crude product (DOS5), addition 73.6g (377.4mmol, 1.5eq) bromo-acetic acid tert-butyl, 2.9g (17.61mmol,
0.07eq) potassium iodide, 7.7g (22.64mmol, 0.09eq) 4-butyl ammonium hydrogen sulfate open heating, are warming up to 60 DEG C, start to protect
Temperature, temperature are controlled at 60-65 DEG C, keep the temperature 2.5 hours, and slow cooling keeps the temperature half an hour until temperature is 5-15 DEG C, vacuum filtration
Yellow-brown solid, by the ethanol washing of 3 times of DOS5 mass of solid to canescence, 60 DEG C drying 30 hours, obtain 88.7g
The Aceclofenac tert-butyl ester.Yield is 94.16%, liquid phase purity 99.43%.
Comparative example 1
Such as in patent CN 101531607A the preparation method is as follows: in reaction flask put into C14H10Cl2NNaO2 20g, iodine
Change sodium 0.6g, chloroacetic acid tert-butyl ester 11.3g and acetonitrile 140ml, is heated to 77-78 DEG C of reflux 2h and filters out chlorine after reaction
Change sodium, 77-82 DEG C of first normal pressure distills out acetonitrile, rear evaporated in vacuo acetonitrile, and methanol eddy is added and refines intermediate, cooling crystallization,
It is dried in vacuo (45-55 DEG C, vacuum degree >=0.09MPa), obtains white crystals 23.1g, yield 89.6%.
Claims (4)
1. a kind of method for producing the Aceclofenac tert-butyl ester, comprising:
C14H10Cl2NNaO2, bromo-acetic acid tert-butyl, the catalyst iodine for being 1:1.1-1.7:0.03-0.09:0.08-0.15 by molar ratio
Compound and 4-butyl ammonium hydrogen sulfate react in water, and slow cooling crystallization, is filtered, washed, dries, and obtain the tertiary fourth of Aceclofenac
Ester, wherein the mass ratio of C14H10Cl2NNaO2 and water is 1:4-6.
2. method according to claim 1, which is characterized in that the iodide are potassium iodide.
3. method according to claim 1, which is characterized in that the reaction temperature is 55-70 DEG C, reaction time 2-3h.
4. method according to claim 1, which is characterized in that the molar ratio of the C14H10Cl2NNaO2 and bromo-acetic acid tert-butyl is
1:1-1.5。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910501748.2A CN110305027B (en) | 2019-06-11 | 2019-06-11 | Method for producing aceclofenac tert-butyl ester |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910501748.2A CN110305027B (en) | 2019-06-11 | 2019-06-11 | Method for producing aceclofenac tert-butyl ester |
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| CN110305027A true CN110305027A (en) | 2019-10-08 |
| CN110305027B CN110305027B (en) | 2022-07-22 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848426A (en) * | 2020-07-17 | 2020-10-30 | 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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2019
- 2019-06-11 CN CN201910501748.2A patent/CN110305027B/en active Active
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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848426A (en) * | 2020-07-17 | 2020-10-30 | 宁波斯迈克制药有限公司 | Industrial production method of aceclofenac |
| CN111848426B (en) * | 2020-07-17 | 2023-02-10 | 宁波斯迈克制药有限公司 | Industrial production method of aceclofenac |
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| CN110305027B (en) | 2022-07-22 |
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