CN106316921B - A kind of preparation method of acemetacin - Google Patents
A kind of preparation method of acemetacin Download PDFInfo
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- CN106316921B CN106316921B CN201610687351.3A CN201610687351A CN106316921B CN 106316921 B CN106316921 B CN 106316921B CN 201610687351 A CN201610687351 A CN 201610687351A CN 106316921 B CN106316921 B CN 106316921B
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- acemetacin
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- hydrogen chloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
- C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
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Abstract
The present invention relates to a kind of preparation method of anti-anti-inflammation and analgesic drugs, in particular to a kind of preparation method of acemetacin belongs to chemical pharmaceutical technology field.This method prepares acetic acid and hydrogen chloride acidolysis solution the following steps are included: being passed through hydrogen chloride in acetic acid, constant temperature stirs after putting into the acemetacin tert-butyl ester in above-mentioned acidolysis solution, carry out acidolysis reaction, cool down after completion of the reaction, stand still for crystals, filtering, push up wash, refine after obtain finished product acemetacin.
Description
Technical field
The present invention relates to a kind of preparation method of anti-anti-inflammation and analgesic drugs, in particular to a kind of preparation side of acemetacin
Method belongs to chemical pharmaceutical technology field.
Background technique
Acemetacin, chemical name are 1- (4- chlorobenzene formacyl) -5- methoxyl group -2- Methyl-1H-indole -3- acetic acid carboxylic
Methyl ester, structural formula are as follows:
This product is a kind of Non-steroidanalgetic drug, and chemical structure is the precursor of Indomethacin similar to Indomethacin
Medicine generates its Indomethacin through metabolism in vivo after oral and plays a role.Its main feature is that digestive tract side effects and Indomethacin ratio
More significant reduction.It is mainly used for rheumatic, rheumatoid arthritis, osteoarthritis, curative for effect, potential applicability in clinical practice is wide.
It is considered as improving antiphlogistic effects in nonsteroidal anti-inflammatory drug of new generation and improving most what a drug in terms of tolerance.At present
The preparation method of acemetacin reported in the literature, through esterification, is made with such as mostly using Indomethacin as starting material
The acemetacin ester of the protecting groups such as tert-butyl, benzyl, pyranose, then take off ester through hydrogenolysis or acidolysis and obtain acemetacin.Such as beauty
State patent US3910952A is disclosed with 4- methoxyl group phenylhydrazine and 4-Oxyvalerate ethyoxyl benzyl ester through cyclization, acylation reaction, system
Acemetacin benzyl ester is obtained, then sloughs benzyl through palladium carbon catalytic hydrogenolysis and acemetacin is made, the method reaction specificity is good, can be made
The higher product of purity, but hydrogenation makees catalyst using precious metal palladium, it is at high cost, height is required to process equipment, market is competing
It is poor to strive power, brings difficulty to large-scale production.Another United States Patent (USP) US4600783 discloses a kind of preparation side of acemetacin
Method is using Indomethacin as raw material, under the potassium alkaline environmental condition of chlorinating benzyl triethylamine catalysis, with the tertiary fourth of monoxone
The acemetacin tert-butyl ester is made through esterification in ester.A Xi is obtained using the method acidolysis of such as methanesulfonic acid, benzene sulfonic acid, sulfuric acid
Mei Xin.The sulfonic acid substance that the method uses has gene caution structure, contains genotoxicity impurity in product, pharmacologically secondary to make
With strong, should not use.And the method for sulfuric acid solution actually get be acemetacin and Indomethacin mixture, selection
Property is very poor, and two kinds of substances are difficult to separate, and product purity is low.It is a kind of disclosed in another United States Patent (USP) US4603210 to prepare A Xi
The pungent method of U.S. under the conditions of potassium fluoride and sodium carbonate alkaline environment, is passed through with chloroacetic acid tert-butyl ester using Indomethacin as raw material
The acemetacin tert-butyl ester is made in esterification.Acemetacin is obtained using the method for such as trifluoroacetic acid, formic acid acidolysis again.This
Trifluoroacetic acid used in method is expensive, is unsuitable for industrialized production, and the method by-product of formic acid acidolysis is more, after
Handle complicated, yield is low.Comprehensive existing document at present can be seen that the preparation of the acemetacin tert-butyl ester be easy, yield it is also higher.
But when acid hydrolyzation sloughs tert-butyl, various existing methods all hardly result in purer product.When using acid stronger acid acid
Xie Shi, obtained even mixture.Acid hydrolyzation produces the main reason for acemetacin purity is not high, is the acemetacin tert-butyl ester
It is poor that acidolysis takes off de-tert-butylation reaction specificity.There are two the alkoxy center that can be broken, i.e., tertiary fourths for acemetacin tert-butyl ester tool
Alkoxy and ethyoxyl.In acid condition, tertiary butane oxygroup is more easily broken off compared with ethyoxyl, obtains acemetacin.But ethoxy
Base can also be broken, and obtained product is Indomethacin.Acemetacin tert-butyl ester acidolysis reaction by acid type, acid it is dense
The influence of the factors such as degree, reaction temperature, acidolysis time is very big, and reaction condition is difficult to control.Therefore, it selects acidolysis agent appropriate, close
The solvent system and reaction condition of reason are the key that solve acemetacin tert-butyl ester acidolysis selectivity, and determine tert-butyl ester acid
Solution prepares the key of acemetacin product quality.
Summary of the invention
A kind of preparation method of acemetacin provided by the present invention, comprising the following steps:
Step (1): being passed through the acetum that hydrogen chloride prepares hydrogen chloride in acetic acid, in the acetum of the hydrogen chloride
The mass ratio of hydrogen chloride and acetic acid is 1:5 to 1:20；
Step (2): add in the acidolysis solution using the acetum of hydrogen chloride made from step 1 as acidolysis solution
Enter phosphorus trichloride or alchlor as catalyst, constant temperature stirs after putting into the acemetacin tert-butyl ester, carries out acidolysis reaction, keeps
Reaction temperature two hours or more；
Step (3): cool down after completion of the reaction, stand still for crystals, filtering, pushing up and wash to obtain crude product acemetacin；
Step (4): crude product acemetacin is refining to obtain finished product acemetacin.
Further, the temperature of the acidolysis reaction is 20 DEG C -90 DEG C.Further, the acemetacin tert-butyl ester
The mass ratio that feeds intake with acetic acid is 1:1.5-10.Further, the acemetacin tert-butyl ester and phosphorus trichloride or alchlor
The mass ratio that feeds intake of catalyst is 1: 0.005-0.05.Further, the subtractive process is as follows: acemetacin crude product is molten
In hot toluene solvent, cool down after dissolution, until crystallization is completely, obtains acemetacin finished product after filtering, drying.
A kind of preparation method of acemetacin provided by the present invention, using the acemetacin tert-butyl ester hydrogen chloride acetic acid
In solution, and suitable phosphorus trichloride is added or alchlor carries out catalysis acidolysis reaction, obtains acemetacin.This acid hydrolysis method
Reaction specificity it is good, selectivity is high, and the fracture of acemetacin tert-butyl ester ethyoxyl (generating Indomethacin) reaction is reduced to
Bottom line, not only acidolysis reaction high conversion rate, and Indomethacin content is few in product, relative to other synthetic methods, produces
Quality and yield have extremely clear superiority.
Specific embodiment
The present invention is further described below with reference to specific implementation example, but the scope of protection of the present invention is not limited thereto.
The many documents of preparation method of the intermediate acemetacin tert-butyl ester used in the present invention have been reported that, commercially available product also can be used, be
It better understands and implements the present invention, provide a kind of preparation method of acemetacin tert-butyl ester in instances, but the present invention adopts
The acemetacin tert-butyl ester does not depend on the preparation method of the acemetacin tert-butyl ester described in example uniquely.
Example 1: the preparation of the acemetacin tert-butyl ester
Toluene 850kg, chloroacetic acid tert-butyl ester 48kg are successively pumped into reactor tank, Indomethacin 100kg, carbon are successively put into
Sour sodium 35kg, chlorinating benzyl triethylamine 8kg, stirring are warming up to 75 DEG C, insulation reaction 4 hours.Add water 300kg, stir 10 minutes,
Layering.Organic phase adds water 300kg, stirs 10 minutes, layering.Toluene is evaporated off in organic phase, is cooled to room temperature, is added
Methanol 400kg, temperature rising reflux to dissolved clarification, decrease temperature crystalline, rejection filter, 80 DEG C of drying obtain acemetacin tert-butyl ester 125kg, yield
95%, HPLC content: 99.6%.
Example 2: the preparation of acemetacin
250kg acetic acid is put into reactor tank, is passed through hydrogen chloride under stirring, until the content (w/w) of hydrogen chloride is 16%.Add
Enter phosphorus trichloride 0.5kg, acemetacin tert-butyl ester 100kg, 80 DEG C of temperature control are stirred 5 hours, are cooled to 20 DEG C, stand 2 hours extremely
Crystallization is complete.It filters, top is washed, and 80 DEG C of drying obtain 82.8kg acemetacin.Yield 93.98%.Crude product is dissolved in 360kg toluene
In, it is heated to dissolved clarification, puts into active carbon 1kg, is stirred 20 minutes.It filters, is cooled to room temperature, stand 2 hours, mistakes complete to crystallizing
Filter, a small amount of toluene washing, is drained, and 80 DEG C of drying obtain 80.6kg acemetacin fine work.Refine yield 97.34%, HPLC content
99.86%。
Example 3: the preparation of acemetacin
250kg acetic acid is put into reactor tank, is passed through hydrogen chloride under stirring, until the content (w/w) of hydrogen chloride is 15%.Add
Enter 2.0 kg of phosphorus trichloride, acemetacin tert-butyl ester 100kg, 80 DEG C of temperature control are stirred 5 hours, are cooled to 20 DEG C, stand 2 hours extremely
Crystallization is complete.It filters, top is washed, and 80 DEG C of drying obtain 82.3kg acemetacin, yield 93.41%.Crude product is dissolved in 360kg toluene
In, it is heated to dissolved clarification, puts into active carbon 1kg, is stirred 20 minutes, is filtered, room temperature is cooled to, 2 hours is stood and extremely crystallizes completely, mistake
Filter, a small amount of toluene washing, is drained, and 80 DEG C of drying obtain 80.4kg acemetacin fine work.Refine yield 97.69%, HPLC content
99.89%。
Example 4: the preparation of acemetacin
250kg acetic acid is put into reactor tank, is passed through hydrogen chloride under stirring, until the content (w/w) of hydrogen chloride is 12%.Add
Enter 5.0 kg acemetacin tert-butyl ester 100kg of phosphorus trichloride, 80 DEG C of temperature control are stirred 5 hours, are cooled to 20 DEG C, stand 2 hours extremely
Crystallization completely, filters, and top is washed, and 80 DEG C of drying obtain 82.1kg acemetacin, yield 93.19%.Crude product is dissolved in 360kg toluene
In, it is heated to dissolved clarification, puts into active carbon 1kg, is stirred 20 minutes, is filtered, room temperature is cooled to, 2 hours is stood and extremely crystallizes completely, mistake
Filter, a small amount of toluene washing, is drained, and 80 DEG C of drying obtain 80.2kg acemetacin fine work.Refine yield 97.68%, HPLC content
99.83%。
Example 5: the preparation of acemetacin
250kg acetic acid is put into reactor tank, is passed through hydrogen chloride under stirring, until the content (w/w) of hydrogen chloride is 8%.It is added
Alchlor 0.5Kg, acemetacin tert-butyl ester 100kg, 80 DEG C of temperature control are stirred 5 hours, are cooled to 20 DEG C, stand 2 hours to knot
Brilliant to filter completely, top is washed, and 80 DEG C of drying obtain 81.9kg acemetacin, yield 92.96%.Crude product is dissolved in 360kg toluene,
It is heated to dissolved clarification, puts into active carbon 1kg, is stirred 20 minutes, is filtered, room temperature is cooled to, 2 hours is stood and extremely crystallizes filtering completely,
A small amount of toluene washing, is drained, and 80 DEG C of drying obtain 79.8kg acemetacin fine work.Refine yield 97.44%.HPLC content
99.79%。
Example 6: the preparation of acemetacin
250kg acetic acid is put into reactor tank, is passed through hydrogen chloride under stirring, until the content (w/w) of hydrogen chloride is 5%.It is added
Acemetacin tert-butyl ester 100kg, 80 DEG C of temperature control are stirred 5 hours, are cooled to 20 DEG C, are stood 2 hours to crystallizing completely, are filtered, top
It washes, 80 DEG C of drying obtain 80.7kg acemetacin, yield 91.6%.Crude product is dissolved in 360kg toluene, dissolved clarification is heated to, is put into
Active carbon 1kg is stirred 20 minutes, is filtered, and room temperature is cooled to, and stands 2 hours to filtering completely is crystallized, a small amount of toluene washing is taken out
Dry, 80 DEG C of drying obtain 78.7kg acemetacin fine work.Refine yield 97.52%.HPLC content 99.76%.
Example 7: the preparation of acemetacin
250kg acetic acid is put into reactor tank, is passed through hydrogen chloride under stirring, until the content (w/w) of hydrogen chloride is 16%.Add
Enter 2.0 Kg of alchlor, acemetacin tert-butyl ester 100kg, 60 DEG C of temperature control are stirred 5 hours, are cooled to 20 DEG C, stand 2 hours extremely
Crystallization completely, filters, and top is washed, and 80 DEG C of drying obtain 82.1kg acemetacin, yield 93.19%.Crude product is dissolved in 360kg toluene
In, it is heated to dissolved clarification, puts into active carbon 1kg, is stirred 20 minutes, is filtered, room temperature is cooled to, 2 hours is stood and extremely crystallizes completely, mistake
Filter, a small amount of toluene washing, is drained, and 80 DEG C of drying obtain 80.5kg acemetacin fine work.Refine yield 98.05%.HPLC content
99.83%。
Example 8: the preparation of acemetacin
250kg acetic acid is put into reactor tank, is passed through hydrogen chloride under stirring, until the content (w/w) of hydrogen chloride is 16%.Add
Enter 5.0 Kg of alchlor, acemetacin tert-butyl ester 100kg, 40 DEG C of temperature control are stirred 5 hours, are cooled to 20 DEG C, stand 2 hours extremely
Crystallization completely, filters, and top is washed, and 80 DEG C of drying obtain 81.9kg acemetacin, yield 92.96%.Crude product is dissolved in 360kg toluene
In, it is heated to dissolved clarification, puts into active carbon 1kg, is stirred 20 minutes, is filtered, room temperature is cooled to, 2 hours is stood and extremely crystallizes completely, mistake
Filter, a small amount of toluene washing, is drained, and 80 DEG C of drying obtain 80.1kg acemetacin fine work.Refine yield 97.80%.HPLC content
99.79%。
Example 9: the preparation of acemetacin
250kg acetic acid is put into reactor tank, is passed through hydrogen chloride under stirring, until the content (w/w) of hydrogen chloride is 12%.Add
Enter 3.0 Kg of alchlor, acemetacin tert-butyl ester 100kg, 60 DEG C of temperature control are stirred 5 hours, are cooled to 20 DEG C, stand 2 hours extremely
Crystallization completely, filters, and top is washed, and 80 DEG C of drying obtain 81.7kg acemetacin, yield 92.73%.Crude product is dissolved in 360kg toluene
In, it is heated to dissolved clarification, puts into active carbon 1kg, is stirred 20 minutes, is filtered, room temperature is cooled to, 2 hours is stood and extremely crystallizes completely, mistake
Filter, a small amount of toluene washing, is drained, and 80 DEG C of drying obtain 80.0kg acemetacin fine work.Refine yield 97.92%.HPLC content
99.81%。
Example 10: the preparation of acemetacin
250kg acetic acid is put into reactor tank, is passed through hydrogen chloride under stirring, until the content (w/w) of hydrogen chloride is 12%.Add
Enter 3.0 Kg of phosphorus trichloride, acemetacin tert-butyl ester 100kg, 40 DEG C of temperature control are stirred 5 hours, are cooled to 20 DEG C, stand 2 hours extremely
Crystallization completely, filters, and top is washed, and 80 DEG C of drying obtain 81.8kg acemetacin, yield 92.85%.Crude product is dissolved in 360kg toluene
In, it is heated to dissolved clarification, puts into active carbon 1kg, is stirred 20 minutes, is filtered, room temperature is cooled to, 2 hours is stood and extremely crystallizes completely, mistake
Filter, a small amount of toluene washing, is drained, and 80 DEG C of drying obtain 79.6kg acemetacin fine work.Refine yield 97.3%.HPLC content
99.89%。
After the embodiment that the present invention will be described in detail, one of ordinary skilled in the art is clearly understood that, is not being taken off
It is lower from above-mentioned claim and spirit to carry out various change and modify, it is all according to the technical essence of the invention to the above reality
Example is applied, made any simple modification, equivalent change and modification belong to the range of technical solution of the present invention, and the present invention is also
It is not only restricted to the embodiment of example in specification.
Claims (5)
1. a kind of preparation method of acemetacin, it is characterised in that the following steps are included:
Step (1): the acetum that hydrogen chloride prepares hydrogen chloride, chlorination in the acetum of the hydrogen chloride are passed through in acetic acid
The mass ratio of hydrogen and acetic acid is 1:5 to 1:20；
Step (2): using the acetum of hydrogen chloride made from step 1 as acidolysis solution, in the acidolysis solution, three are added
Phosphorus chloride or alchlor put into the acemetacin tert-butyl ester, constant temperature stirring carries out acidolysis reaction, keeps as acid hydrolysis catalyst
Reaction temperature two hours or more；
Step (3): cool down after completion of the reaction, stand still for crystals, filtering, pushing up and wash to obtain crude product acemetacin；
Step (4): crude product acemetacin is refining to obtain finished product acemetacin.
2. a kind of preparation method of acemetacin according to claim 1, it is characterised in that: acidolysis in the step (2)
The temperature of reaction is 20 DEG C -90 DEG C.
3. a kind of preparation method of acemetacin according to claim 1, it is characterised in that: the A Xi of the step (2)
The mass ratio that feeds intake of the pungent tert-butyl ester of U.S. and acetic acid is 1:1.5-10.
4. a kind of preparation method of acemetacin according to claim 1, it is characterised in that: the A Xi of the step (2)
The mass ratio that feeds intake of the pungent tert-butyl ester of U.S. and phosphorus trichloride or alchlor is 1:0.005-0.05.
5. a kind of preparation method of acemetacin according to claim 1, it is characterised in that: purification in the step (4)
Process is as follows: acemetacin crude product being dissolved in hot toluene solvent, is cooled down after dissolution, until crystallization is completely, after filtering, drying
Obtain acemetacin finished product.
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| CN108440374B (en) * | 2018-05-22 | 2022-01-18 | 荆楚理工学院 | Preparation method of acemetacin |
| CN111960986A (en) * | 2019-05-19 | 2020-11-20 | 河南东泰制药有限公司 | Preparation method of acemetacin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85102265A (en) * | 1985-04-01 | 1985-12-20 | 郑州大学 | The new anti-inflammatory pain new technique for synthesizing |
| DE4236098A1 (en) * | 1991-11-18 | 1993-05-19 | Orion Yhtymae Oy | Prodn. of acemetacin from indomethacin |
| CN101123878A (en) * | 2003-07-29 | 2008-02-13 | 信号研发控股有限责任公司 | L-threonine derivatives of high therapeutic index |
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2016
- 2016-08-19 CN CN201610687351.3A patent/CN106316921B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85102265A (en) * | 1985-04-01 | 1985-12-20 | 郑州大学 | The new anti-inflammatory pain new technique for synthesizing |
| DE4236098A1 (en) * | 1991-11-18 | 1993-05-19 | Orion Yhtymae Oy | Prodn. of acemetacin from indomethacin |
| CN101123878A (en) * | 2003-07-29 | 2008-02-13 | 信号研发控股有限责任公司 | L-threonine derivatives of high therapeutic index |
Non-Patent Citations (1)
| Title |
|---|
| 《Chemical structure and antiinflammatory activity in the group of substituted indole-3-acetic acids》;Boltze, K. H.et al.;《Arzneimittel-Forschung》;19801231;第30卷(第8A期);第1314-25页 |
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