CN103086907A - Aceclofenac preparation method - Google Patents
Aceclofenac preparation method Download PDFInfo
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- CN103086907A CN103086907A CN2013100462383A CN201310046238A CN103086907A CN 103086907 A CN103086907 A CN 103086907A CN 2013100462383 A CN2013100462383 A CN 2013100462383A CN 201310046238 A CN201310046238 A CN 201310046238A CN 103086907 A CN103086907 A CN 103086907A
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- aceclofenac
- butyl ester
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- acidolysis
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Abstract
The invention relates to an aceclofenac preparation method and belongs to the chemical pharmaceutical field. The method comprises a step that acidolysis of aceclofenac tert-butyl ester is carried out in a mixed solution comprising a low-molecular-weight organic acid and hydrogen halide to obtain aceclofenac. The method which allows the acidolysis of aceclofenac tert-butyl ester to be carried out in the mixed solution comprising the low-molecular-weight organic acid and hydrogen halide has the advantages of high selectivity, reduction of the fracture of the ethoxy group in aceclofenac tert-butyl ester to a lowest limit, high acidolysis reaction conversion rate, extremely-low content of diclofenac in obtained aceclofenac, easy aceclofenac refining, and high aceclofenac purity.
Description
Technical field
The present invention relates to a kind of preparation method of anti-inflammation analgesis medicament, particularly a kind of preparation method of Aceclofenac, belong to chemical pharmacy field.
Background technology
Aceclofenac, chemical name are 2-((2,6-dichlorophenyl) amino) phenylacetyl ethoxyacetic acid, English name: Aceclofenac, and structural formula is:
this product is a new synthetic orally active non_steroidal anti_inflammatory drug (NSAIDs), belong to toluylic acid class anti-inflammatory, analgesic, analgesic, structurally, with diclofenac, Warner-Lambert) is relevant with the fragrant acid of fragrant chlorine, in clinical practice, its pharmacological action is compared with other non-steroid medicines (NSAIDs), it is in urgency, in the chronic inflammatory diseases experimental model to have obviously anti-inflammatory action widely, powerful analgesia and analgesic and stomach toxicity act as feature, the Aceclofenac preparation method of bibliographical information, be starting raw material mainly with diclofenac sodium greatly, through esterification, make with such as benzyl, cycloalkyl, pyranyl, the Aceclofenac ester of the protecting groups such as the tertiary butyl.Take off ester through hydrogenolysis or acidolysis again and obtain Aceclofenac, the USP4548952 report through condensation reaction, makes aceclofenac benzyl ester with diclofenac sodium and alpha-halogen Yi Suan Benzyl ester, then sloughs benzyl through palladium carbon catalytic hydrogenolysis and make Aceclofenac.This method reaction specificity is good, can obtain the higher degree product, once becoming the main production method that generally adopts both at home and abroad, but hydrogenation uses precious metal palladium to make catalyzer, cost is higher, and limited by processing unit, brings difficulty to large-scale commercial production, at present, this technique is eliminated gradually; In the last few years, use the Aceclofenac tert-butyl ester, the method of sloughing the tertiary butyl through acidolysis plays people's concern, and many reports are arranged, and CN2007192213 discloses a kind of preparation method of Aceclofenac, under the existence of triethylamine, diclofenac and bromo-acetic acid tert-butyl are made the Aceclofenac tert-butyl ester through condensation, then make Aceclofenac with the formic acid acidolysis, and this method by product is more, aftertreatment is complicated, and yield is very low;＜＜Chinese Journal of Pharmaceuticals〉〉 101-8255(2005) 07-0393-02 report diclofenac sodium, chloroacetic acid tert-butyl ester and acetonitrile back flow reaction 24h, obtain the Aceclofenac tert-butyl ester, then obtain Aceclofenac with hydrochloric acidolysis.It is actual that this method obtains is the mixture of diclofenac and Aceclofenac, and be difficult to separate,＜＜Chinese Journal of Pharmaceuticals〉〉 1001-8255(2008) the 06-0408-02 report, with diclofenac sodium, chloroacetic acid tert-butyl ester at DMF(N, dinethylformamide) in, back flow reaction makes the Aceclofenac tert-butyl ester, with acetic acid acidolysis under aluminum trichloride (anhydrous) exists, make Aceclofenac again.This method is had relatively high expectations to reaction conditions.After reaction, aluminum chloride is difficult for removing, and can react with Aceclofenac, generates Aceclofenac aluminium salt.Extremely difficulty is removed, and affects the purity of product.Comprehensive existing document can be found out, the preparation of the Aceclofenac tert-butyl ester is easy, yield is also higher, but when sloughing the tertiary butyl with acidization, but be difficult to obtain purer product, sometimes or even mixture, the specificity that the Aceclofenac tert-butyl ester is sloughed tertiary butyl reaction with acidization is poor, because the Aceclofenac tert-butyl ester has two the alkoxyl group centers that can rupture, be uncle's fourth alkoxyl group and oxyethyl group, wherein uncle's fourth alkoxyl group is than the easier acidolysis fracture of oxyethyl group, the product that obtains is Aceclofenac, but oxyethyl group also can rupture, and the product that obtains is but diclofenac.simultaneously, the oxyethyl group fracture also can further occur in Aceclofenac, the same diclofenac that generates, the experiment proved that, Aceclofenac tert-butyl ester acidolysis reaction, be subjected to the kind of the acid of using, the concentration of acid, temperature of reaction, the impact of the factors such as acidolysis time, the degree of acidolysis is difficult to control, as long as acidolysis intensity is enough large, under certain condition, the Aceclofenac tert-butyl ester and Aceclofenac are with thorough acidolysis, final product can be all diclofenac, under existing acidolysis process condition, the crude product purity that obtains is very poor, bring very big difficulty to aftertreatment, especially Aceclofenac and diclofenac similar performance, be difficult to separate with usual way, often to just can obtain qualified product through complicated treating process, therefore, select suitable acidolysis agent, rational solvent systems and reaction conditions, to solve optionally key of Aceclofenac tert-butyl ester acidolysis, this is also to adopt the acidolysis of the Aceclofenac tert-butyl ester to prepare Aceclofenac quality and Eco-power deciding step.
Summary of the invention
The present invention is for providing a kind of preparation method of Aceclofenac.
the preparation method of a kind of Aceclofenac provided by the present invention, comprise and adopt the acidolysis of the Aceclofenac tert-butyl ester, the Aceclofenac tert-butyl ester is carried out acidolysis and obtain Aceclofenac in the mixed solution of low molecular organic acids and hydrogen halide, in the mixed solution of described low molecular organic acids and hydrogen halide, the mass ratio of hydrogen halide and low molecular organic acids is 5-20%, described acidolysis temperature is 60 ℃-90 ℃, described low molecular organic acids is formic acid or acetic acid or propionic acid or butyric acid or trifluoroacetic acid or trichoroacetic acid(TCA), described hydrogen halide is hydrogenchloride or hydrogen bromide, the mass ratio that feeds intake of the described Aceclofenac tert-butyl ester and low molecular organic acids is 1:1.5-10, acidolysis is fully by filtration, dry, obtain the Aceclofenac crude product, the Aceclofenac crude product is dissolved in the hot toluene solvent, cooling, complete to crystallization, filter, obtain the Aceclofenac highly finished product after drying.
The preparation method of Aceclofenac provided by the invention, adopt the Aceclofenac tert-butyl ester to carry out acidolysis in the mixed solution of low molecular organic acids and hydrogen halide, this acid hydrolysis method selectivity is high, the fracture of Aceclofenac tert-butyl ester oxyethyl group has been reduced to bottom line, the acidolysis reaction transformation efficiency is high, in product, diclofenac content is few, and product is easily refining, and purity is high.
Embodiment
In order to explain more fully enforcement of the present invention, embodiment of the present invention is provided, these embodiments are only to elaboration of the present invention, do not limit the scope of the invention.although in preparation method's documents and materials of the intermediate Aceclofenac tert-butyl ester used, many reports are arranged in the present invention, those skilled in the art can obtain easily, the intermediate Aceclofenac tert-butyl ester also can adopt commercially available obtaining, in order better to understand and enforcement the present invention, a kind of preparation method of the intermediate Aceclofenac tert-butyl ester is provided in an embodiment, but the preparation method of the Aceclofenac tert-butyl ester shown in the not unique embodiment of depending on of the Aceclofenac tert-butyl ester that adopts in the preparation method of a kind of Aceclofenac of the present invention, in following examples, hydrogen halide content refers to the mass ratio of hydrogen halide and low molecular organic acids, hydrogen halide can be hydrogenchloride or hydrogen bromide.
The preparation of embodiment 1:2-((2,6-dichlorophenyl) amino) the phenylacetyl ethoxyacetic acid tert-butyl ester (the Aceclofenac tert-butyl ester)
With the diclofenac sodium shown in the formula II, the halogen acetic acid tert-butyl ester with shown in the formula III represents with chloroacetic acid tert-butyl ester in following formula, be dissolved in varsol or ketones solvent or ether solvent, add phase-transfer catalyst, carry out esterification, obtain the Aceclofenac tert-butyl ester shown in the formula IV through aftertreatment.
The halogen acetic acid tert-butyl ester that uses, can be chloroacetic acid tert-butyl ester or bromo-acetic acid tert-butyl, the phase-transfer catalyst that uses is quaternary ammonium compound, can be for as benzyl halide triethylamine, tetrabutyl halogeno-amine, the varsol that uses can be alkane or aromatic hydrocarbons or halocarbon, and ketones solvent can be acetone or butanone etc., ether solvent refers to ether or methyl tertiary butyl ether, and concrete preparation example is as follows:
In 85L toluene suction retort, add the 40Kg diclofenac sodium, 20Kg chloroacetic acid tert-butyl ester, 0.1Kg chlorinating benzyl triethylamine.Be warming up to backflow, reacted 6 hours.Be cooled to 75 ℃ and add water 50Kg, stirring reaction 20 minutes.Standing 20 minutes.Divide except water layer.Reclaim under reduced pressure toluene is to doing.Add the 60L dissolve with methanol.Slow cooling is to room temperature, and is complete to crystallization, filters, and a small amount of methyl alcohol pushes up to be washed, and drains.80 ℃ of oven dry.Get the Aceclofenac tert-butyl ester 48.4 Kg, yield 94%.
Example 2: the preparation of Aceclofenac
75 ㎏ formic acid are dropped in retort, add Aceclofenac tert-butyl ester 40Kg, stirring and dissolving passes into hydrogenchloride, to the content (w/w) of hydrogenchloride be 6%.Control temperature 60 C, continued stirring reaction 5 hours, be cooled to 20 ℃, standing 3 hours complete to crystallization, and the top is washed, and drains, and 80 ℃ of oven dry get 32.9 Kg Aceclofenac, yield 95.32%.Crude product is dissolved in 120L toluene, is heated to more than 90 ℃.Filter, be cooled to room temperature.Complete to crystallization, to filter, a small amount of toluene wash is drained.Get 31.4 Kg Aceclofenac elaboration.Refining yield 92%.HPLC content 99.72%.
Example 3: the preparation of Aceclofenac
75 ㎏ formic acid are dropped in retort, add Aceclofenac tert-butyl ester 40Kg, stirring and dissolving, passing into hydrogenchloride to the content (w/w) of hydrogenchloride is 10%, controls simultaneously 80 ℃ of temperature of charge, continued stirring reaction 5 hours, be cooled to 20 ℃, crystallization processed in standing 3 hours is complete, and the top is washed, drain 80 ℃ of oven dry.Get 32.5 Kg Aceclofenac, yield 94.6% is dissolved in crude product in 120L toluene, is heated to more than 90 ℃, filters, and is cooled to room temperature, and crystallization is complete, filters, and a small amount of toluene wash is drained to get about 30.5 Kg Aceclofenac elaboration.Refining yield 93.4%.HPLC content 99.70%.
Example 4: the preparation of Aceclofenac
75 ㎏ formic acid are dropped in retort, add Aceclofenac tert-butyl ester 40Kg, stirring and dissolving, passing into hydrogenchloride to the content (w/w) of hydrogenchloride is 18%, controls simultaneously 75 ℃ of temperature of charge.Continued stirring reaction 5 hours, and be cooled to 20 ℃, standing 3 hours complete to crystallization, and the top is washed, and drains, and 80 ℃ of oven dry get 32.3 Kg Aceclofenac, yield 94%.In crude product 120L toluene, be heated to more than 90 ℃, filter, be cooled to room temperature, crystallization is complete, filters, and a small amount of toluene wash is drained to get about 29.7 Kg Aceclofenac elaboration.Refining yield 92%.HPLC content 99.78%.
Example 5: the preparation of Aceclofenac
75 ㎏ formic acid are dropped in retort, add Aceclofenac tert-butyl ester 40Kg, stirring and dissolving passes into hydrogen bromide, to the content (w/w) of hydrogen bromide be 10%.Control 90 ℃ of temperature, continued stirring reaction 5 hours, be cooled to 20 ℃, standing 3 hours complete to crystallization, and the top is washed, and drains, and 80 ℃ of oven dry get 32.9 Kg Aceclofenac, yield 95.8%.Crude product is dissolved in 120L toluene, is heated to more than 90 ℃.Filter, be cooled to room temperature.Complete to crystallization, to filter, a small amount of toluene wash is drained.Get 30.9Kg Aceclofenac elaboration.Refining yield 94%.HPLC content 99.85%.
Example 6: the preparation of Aceclofenac
75 ㎏ acetic acid are dropped in retort, add Aceclofenac tert-butyl ester 40Kg, stirring and dissolving, pass into hydrogenchloride, to the content (w/w) of hydrogenchloride be 16%, control temperature 60 C, continued stirring reaction 5 hours, be cooled to 20 ℃, standing 3 hours complete to crystallization, and the top is washed, drain, 80 ℃ of oven dry get the 31.6Kg Aceclofenac, yield 92.0%.Crude product is dissolved in 120L toluene, is heated to more than 90 ℃, filter, be cooled to room temperature, complete to crystallization, to filter, a small amount of toluene wash is drained, and gets 29.2 Kg Aceclofenac elaboration.Refining yield 92.4%.HPLC content 99.82%.
Example 7: the preparation of Aceclofenac
75 ㎏ acetic acid are dropped in retort, add Aceclofenac tert-butyl ester 40Kg, stirring and dissolving passes into hydrogenchloride, to the content (w/w) of hydrogenchloride be 10%.Control simultaneously 80 ℃ of temperature of charge, continued stirring reaction 5 hours, be cooled to 20 ℃, crystallization processed in standing 3 hours is complete, and the top is washed, and drains, and 80 ℃ of oven dry get 31.5 Kg Aceclofenac, yield 91.7%.Crude product is dissolved in 120L toluene, is heated to more than 90 ℃, filter, be cooled to room temperature, crystallization is complete, filters, and a small amount of toluene wash is drained to get 29.1 Kg Aceclofenac elaboration.Refining yield 92.4%.HPLC content 99.80%.
Example 8: the preparation of Aceclofenac
120 ㎏ trifluoroacetic acids are dropped in retort, add Aceclofenac tert-butyl ester 40Kg, stirring and dissolving, pass into hydrogenchloride, to the content (w/w) of hydrogenchloride be 8%, control simultaneously 60 ℃ of temperature of charge, continued stirring reaction 5 hours, be cooled to 20 ℃, standing 3 hours complete to crystallization, and the top is washed, drain, 80 ℃ of oven dry get 33 Kg Aceclofenac, yield 96.1%.Crude product is dissolved in 120L toluene, is heated to more than 90 ℃, filter, be cooled to room temperature, crystallization is complete, filters, and a small amount of toluene wash is drained to get about 30.7Kg Aceclofenac elaboration.Refining yield 93%.HPLC content 99.74%
Example 9: the preparation of Aceclofenac
75 ㎏ acetic acid are dropped in retort, add Aceclofenac tert-butyl ester 40Kg, stirring and dissolving passes into hydrogen bromide, to the content (w/w) of hydrogen bromide be 16%.Stirring reaction was continued 5 hours in 80 ℃ of left and right of control temperature, was cooled to 20 ℃, and standing 3 hours complete to crystallization, and the top is washed, and drains, and 80 ℃ of oven dry get 30.2 Kg Aceclofenac, yield 88%.Crude product is dissolved in 120L toluene, is heated to more than 90 ℃, filter, be cooled to room temperature, complete to crystallization, to filter, a small amount of toluene wash is drained, and gets 27.2 Kg Aceclofenac elaboration.Refining yield 90%.HPLC content 99.6%
After describing embodiments of the present invention in detail, the personage who is familiar with this technology can be well understood to, can carry out various variations and modification not breaking away under above-mentioned claim and spirit, any simple modification, equivalent variations and modification that all foundations technical spirit of the present invention is done above embodiment, the scope that all belongs to technical solution of the present invention, and the present invention also is not subject to the embodiment of example in specification sheets.
Claims (7)
1. the preparation method of an Aceclofenac, comprise and adopt the acidolysis of the Aceclofenac tert-butyl ester, it is characterized in that: the Aceclofenac tert-butyl ester is carried out acidolysis and obtain Aceclofenac in the mixed solution of low molecular organic acids and hydrogen halide.
2. the preparation method of a kind of Aceclofenac according to claim 1, it is characterized in that: in the mixed solution of described low molecular organic acids and hydrogen halide, the mass ratio of hydrogen halide and low molecular organic acids is 5-20%.
3. the preparation method of a kind of Aceclofenac according to claim 1, it is characterized in that: described acidolysis temperature is 60 ℃-90 ℃.
4. the preparation method of a kind of Aceclofenac according to claim 1, it is characterized in that: described low molecular organic acids is formic acid or acetic acid or propionic acid or butyric acid or trifluoroacetic acid or trichoroacetic acid(TCA).
5. the preparation method of a kind of Aceclofenac according to claim 1, it is characterized in that: described hydrogen halide is hydrogenchloride or hydrogen bromide.
6. the preparation method of a kind of Aceclofenac according to claim 1, it is characterized in that: the mass ratio that feeds intake of the described Aceclofenac tert-butyl ester and low molecular organic acids is 1:1.5-10.
7. the preparation method of a kind of Aceclofenac according to claim 1 is characterized in that: acidolysis fully by filter, drying, obtain the Aceclofenac crude product, the Aceclofenac crude product is dissolved in the hot toluene solvent, and cooling is complete to crystallization, filter, obtain the Aceclofenac highly finished product after drying.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383745A (en) * | 2018-05-08 | 2018-08-10 | 鲁南制药集团股份有限公司 | A kind of preparation method of Aceclofenac |
| CN110305027A (en) * | 2019-06-11 | 2019-10-08 | 宁波斯迈克制药有限公司 | A method of producing the Aceclofenac tert-butyl ester |
| CN111960986A (en) * | 2019-05-19 | 2020-11-20 | 河南东泰制药有限公司 | Preparation method of acemetacin |
Citations (4)
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| US4548952A (en) * | 1983-03-21 | 1985-10-22 | Prodes, S.A. | 2-[(2,6-Dichlorophenyl)amino]phenylacetoxyacetyl derivatives and therapeutic compositions containing same |
| ES2020146A6 (en) * | 1990-05-29 | 1991-07-16 | Prodesfarma Sa | Process for obtaining 2-[(2,6-dichlorophenyl)amino]- phenylacetoxyacetic acid |
| WO2005073163A1 (en) * | 2004-01-30 | 2005-08-11 | J.B.Chemicals & Pharmaceuticals Ltd. | A process for the preparation of [2-(2,6-dichloro anilino) phenyl] acetoxy acetic acid |
| CN101531607A (en) * | 2009-01-20 | 2009-09-16 | 鲁南制药集团股份有限公司 | Improved method for preparing aceclofenac |
-
2013
- 2013-02-06 CN CN201310046238.3A patent/CN103086907B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4548952A (en) * | 1983-03-21 | 1985-10-22 | Prodes, S.A. | 2-[(2,6-Dichlorophenyl)amino]phenylacetoxyacetyl derivatives and therapeutic compositions containing same |
| ES2020146A6 (en) * | 1990-05-29 | 1991-07-16 | Prodesfarma Sa | Process for obtaining 2-[(2,6-dichlorophenyl)amino]- phenylacetoxyacetic acid |
| WO2005073163A1 (en) * | 2004-01-30 | 2005-08-11 | J.B.Chemicals & Pharmaceuticals Ltd. | A process for the preparation of [2-(2,6-dichloro anilino) phenyl] acetoxy acetic acid |
| CN101531607A (en) * | 2009-01-20 | 2009-09-16 | 鲁南制药集团股份有限公司 | Improved method for preparing aceclofenac |
Non-Patent Citations (1)
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| 姜妮丽: "醋氯芬酸的合成", 《中国医药工业杂志》, vol. 36, no. 7, 10 July 2005 (2005-07-10), pages 393 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383745A (en) * | 2018-05-08 | 2018-08-10 | 鲁南制药集团股份有限公司 | A kind of preparation method of Aceclofenac |
| CN108383745B (en) * | 2018-05-08 | 2021-12-28 | 鲁南制药集团股份有限公司 | Preparation method of aceclofenac |
| CN111960986A (en) * | 2019-05-19 | 2020-11-20 | 河南东泰制药有限公司 | Preparation method of acemetacin |
| CN110305027A (en) * | 2019-06-11 | 2019-10-08 | 宁波斯迈克制药有限公司 | A method of producing the Aceclofenac tert-butyl ester |
| CN110305027B (en) * | 2019-06-11 | 2022-07-22 | 宁波斯迈克制药有限公司 | Method for producing aceclofenac tert-butyl ester |
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