CN102516197A - Preparation of high purity epalrestat - Google Patents
Preparation of high purity epalrestat Download PDFInfo
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- CN102516197A CN102516197A CN2011104189875A CN201110418987A CN102516197A CN 102516197 A CN102516197 A CN 102516197A CN 2011104189875 A CN2011104189875 A CN 2011104189875A CN 201110418987 A CN201110418987 A CN 201110418987A CN 102516197 A CN102516197 A CN 102516197A
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- epalrestat
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Abstract
The invention provides a preparation method of high purity epalrestat. The preparation method comprises the following steps: 1, reacting a-methyl cinnaldehyde with 3-carboxymethylrhodanine under an alkaline condition to obtain crude epalrestat; 2, dissolving the crude epalrestat under an acidic condition, refluxing, filtering, and carrying out cooling crystallization to obtain crude refined epalrestat; and 3, dissolving the crude refined epalrestat by an organic solvent, refluxing, filtering, and carrying out cooling crystallization to obtain refined epalrestat. The preparation method of the high purity epalrestat has a technological effect on the reduction of contents of impurities.
Description
Technical field
The present invention relates to a kind of preparation method of high purity epalrestat, belong to the pharmaceutical chemistry technical field.
Background technology
Epalrestat in 1992 in Japanese Initial Public Offering, be a kind of aldose reductase inhibitor of the non-competing type of reversibility of carboxylic-acid, diabetic complication is had obvious curative effects; And the chronic complicating diseases of the eye that mellitus cause, kidney, nerve, blood vessel and heart, organ; Be that final generation of patient lost one's sight lower limb gangrene, uremia; Stroke or myocardial infarction, even life-threatening immediate cause.
Existing known some metabolic pathway and signal transduction pathway etc. play crucial effect in the evolution of diabetic complication.As under normal circumstances, intracellular glucose only about 5% gets into the polyvalent alcohol passage, and under diabetic disease states; The polyvalent alcohol passage activates; About 30% glucose gets into this passage, can cause that NADPH exhausts in the cell, indirect activation DAG-PKC signal path; Cause infiltration stress, the reduction of inositol metabolic disturbance and cytolemma Na+-K+-ATP enzymic activity.And epalrestat can be intervened the polyvalent alcohol passage, and it is treatment one of a diabetic complication medicine safely and efficiently through clinical confirmation.
Summary of the invention
The objective of the invention is to overcome the weak point of prior art, a kind of preparation method of high purity epalrestat is provided, can reduce the content of related substances in the epalrestat bulk drug and other impurity, improve the quality of product.
The preparation method of high purity epalrestat of the present invention comprises the steps:
1) with a-methyl phenylacrolein, 3-ethyloic if tannin reacts under alkaline condition and obtains the epalrestat bullion; 2) under acidic conditions with behind dissolving crude product, backflow, filtration, the cooling crystallization the thick elaboration of epalrestat;
3) with organic solvent after with thick elaboration dissolving, backflow, filtration, cooling crystallization the epalrestat elaboration,
Reaction solvent in the said step 1) is an amine solvent, and said amine solvent is selected from ammoniacal liquor, three
Ethamine, diethylamine or pyridine.
Organic solvent in the said step 3) is selected from methyl alcohol, Virahol, ethanol or acetone.
Described step 2) acid in and the weight ratio of bullion are (18 ~ 25): 1
Described step 2) acid in and the weight ratio of bullion are (20 ~ 25): 1.
Organic solvent in the described step 3) is (17 ~ 26) with the weight ratio of thick elaboration: 1.
Organic solvent in the described step 3) is (19 ~ 26) with the weight ratio of thick elaboration: 1.
Method of the present invention is the 2nd) step is with the 3rd) increased " filtrations " before the step crystallization and operate, the 3rd goes on foot and has changed recrystallization temperature.The 2nd) usage quantity of step acetic acid is 18 ~ 25 times of bullion, and filter operation should be carried out while hot, and purpose is to remove not allow impurity.The 3rd) usage quantity of step organic solvent is 17 ~ 26 times of thick elaboration, and filter operation should be carried out while hot, and purpose is to remove not allow impurity, is cooled to 30 ~ 40 ℃ and filters, the epalrestat elaboration.
The preparation method of high purity epalrestat of the present invention has the technique effect of the content that reduces impurity, is embodied in:
1) reduced the content of Z-isomer, the content of Z-isomer is between 0.24 ~ 0.26 in the finished product epalrestat that prior art is produced, and the content of Z-isomer is between 0.04 ~ 0.07 in the finished product epalrestat that process for purification of the present invention makes;
2) reduced total assorted content, the total assorted content of the finished product epalrestat that prior art is produced is about 0.3, and the total impurities content of the finished product epalrestat that process for purification of the present invention makes is lower than 0.1;
3) process for purification of the present invention is the 2nd) step and the 3rd) go on foot the operation that adds filtered while hot in the reaction, can insolubles be removed, improve the quality of products.
Embodiment
Embodiment 1Preparation high purity epalrestat
The preparation method of the epalrestat of present embodiment may further comprise the steps:
1) with 20g 3-ethyloic if tannin, 15.2g a-methyl phenylacrolein adds in the still, dissolves with the Virahol of 68.6g; Drip the triethylamine of 16.4g, drip and finish, behind the reflux 1h; Be cooled to 10 ℃ of filtrations,, obtain the epalrestat bullion with putting into oven for drying behind the Virahol flushing product
25G;
2) the epalrestat bullion is dissolved with 450g98% formic acid, behind the reflux 30min, filtered while hot is cooled to 49 ℃ of filtrations, and product is put into oven for drying, obtains the thick elaboration of epalrestat
10G;
3) the thick elaboration of epalrestat is dissolved with the 260g Virahol, behind the reflux 10min, filtered while hot is cooled to 30 ℃ of filtrations, and product is put into oven for drying.
4) sampling of oven dry back detects, and qualified back packing places shady and cool lucifuge place to preserve.
Embodiment 2Preparation high purity epalrestat
The preparation method of the epalrestat of present embodiment may further comprise the steps:
1) with the 1kg3-ethyloic if tannin, 0.76kg a-methyl phenylacrolein adds in the still, dissolves with the Virahol of 3.43kg; Drip the ammoniacal liquor of 0.82kg, drip and finish, behind the reflux 1h; Be cooled to 10 ℃ of filtrations,, obtain the epalrestat bullion with putting into oven for drying behind the Virahol flushing product
1.4Kg;
2) the epalrestat bullion is dissolved with 28kg98% formic acid, behind the reflux 30min, filtered while hot is cooled to 49 ℃ of filtrations, and product is put into oven for drying, obtains the thick elaboration of epalrestat
0.96Kg;
3) the thick elaboration of epalrestat is used the 16.32kg dissolve with methanol, behind the reflux 10min, filtered while hot is cooled to 30 ℃ of filtrations, and product is put into oven for drying.
4) sampling of oven dry back detects, and qualified back packing places shady and cool lucifuge place to preserve.
Embodiment 3Preparation high purity epalrestat
1) with 20g 3-ethyloic if tannin, 15.2g a-methyl phenylacrolein adds in the still, dissolves with the Virahol of 68.6g; Drip the diethylamine of 16.4g, drip and finish, behind the reflux 1h; Be cooled to 10 ℃ of filtrations,, obtain epalrestat bullion 25 g with putting into oven for drying behind the Virahol flushing product;
2) the epalrestat bullion is dissolved with 525g98% formic acid, behind the reflux 30min, filtered while hot is cooled to 49 ℃ of filtrations, and product is put into oven for drying, obtains thick elaboration 13 g of epalrestat;
3) the thick elaboration of epalrestat is dissolved with the 247g Virahol, behind the reflux 10min, filtered while hot is cooled to 30 ℃ of filtrations, and product is put into oven for drying.
4) sampling of oven dry back detects, and qualified back packing places shady and cool lucifuge place to preserve.
Embodiment 4Preparation high purity epalrestat
1) with the 1kg3-ethyloic if tannin, 0.76kg a-methyl phenylacrolein adds in the still, dissolves with the Virahol of 3.43kg; Drip the pyridine of 0.82kg; Drip and finish, behind the reflux 1h, be cooled to 10 ℃ of filtrations; With putting into oven for drying behind the Virahol flushing product, obtain epalrestat bullion 1.4 kg;
2) the epalrestat bullion is dissolved with 35kg98% formic acid, behind the reflux 30min, filtered while hot is cooled to 49 ℃ of filtrations, and product is put into oven for drying, obtains thick elaboration 0.9 kg of epalrestat;
3) the thick elaboration of epalrestat is used the 18.9kg dissolve with methanol, behind the reflux 10min, filtered while hot is cooled to 30 ℃ of filtrations, and product is put into oven for drying.
4) sampling of oven dry back detects, and qualified back packing places shady and cool lucifuge place to preserve.
Claims (5)
1. the preparation method of a high purity epalrestat is characterized in that, comprises the steps:
1) with a-methyl phenylacrolein, 3-ethyloic if tannin reacts under alkaline condition and obtains the epalrestat bullion; 2) under acidic conditions with behind dissolving crude product, backflow, filtration, the cooling crystallization the thick elaboration of epalrestat;
3) with organic solvent after with thick elaboration dissolving, backflow, filtration, cooling crystallization the epalrestat elaboration,
Reaction solvent in the said step 1) is an amine solvent, and said amine solvent is selected from ammoniacal liquor, three
Ethamine, diethylamine or pyridine.
2. the organic solvent in the said step 3) is selected from methyl alcohol, Virahol, ethanol or acetone.
3. the preparation method of high purity epalrestat according to claim 1 is characterized in that, described step 2) in acid and the weight ratio of bullion be (18 ~ 25): 1
The preparation method of high purity epalrestat according to claim 2 is characterized in that, described step 2) in acid and the weight ratio of bullion be (20 ~ 25): 1.
4. the preparation method of high purity epalrestat according to claim 1 is characterized in that, the organic solvent in the described step 3) is (17 ~ 26) with the weight ratio of thick elaboration: 1.
5. the preparation method of high purity epalrestat according to claim 1 is characterized in that, the organic solvent in the described step 3) is (19 ~ 26) with the weight ratio of thick elaboration: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104189875A CN102516197A (en) | 2011-12-15 | 2011-12-15 | Preparation of high purity epalrestat |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104189875A CN102516197A (en) | 2011-12-15 | 2011-12-15 | Preparation of high purity epalrestat |
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| CN102516197A true CN102516197A (en) | 2012-06-27 |
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| CN2011104189875A Pending CN102516197A (en) | 2011-12-15 | 2011-12-15 | Preparation of high purity epalrestat |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977047A (en) * | 2012-11-28 | 2013-03-20 | 开封明仁药业有限公司 | Refining method of crude epalrestat product |
| CN105061355A (en) * | 2015-09-16 | 2015-11-18 | 宁夏康亚药业有限公司 | Refining method of high-purity epalrestat |
| CN105272934A (en) * | 2015-10-09 | 2016-01-27 | 扬子江药业集团江苏海慈生物药业有限公司 | Epalrestat C crystal form and preparation method thereof |
| JP2017043605A (en) * | 2015-08-28 | 2017-03-02 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Process for preparing epalrestat |
| CN107629021A (en) * | 2017-10-19 | 2018-01-26 | 扬子江药业集团南京海陵药业有限公司 | A kind of Epalrestat crystal formation B industrialized process for preparing |
| CN108191788A (en) * | 2018-01-24 | 2018-06-22 | 石家庄四药有限公司 | B crystal form epalrestat and preparation method thereof |
| CN113651770A (en) * | 2021-08-19 | 2021-11-16 | 山东达因海洋生物制药股份有限公司 | Novel crystal form of epalrestat, preparation method and application thereof |
| CN114456125A (en) * | 2022-03-10 | 2022-05-10 | 山东达因海洋生物制药股份有限公司 | Preparation method of small-particle-size epalrestat crystals |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1743321A (en) * | 2005-04-15 | 2006-03-08 | 扬子江药业集团 | Method for preparing thiazolidine acetate coprising phenyl propylidene |
-
2011
- 2011-12-15 CN CN2011104189875A patent/CN102516197A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1743321A (en) * | 2005-04-15 | 2006-03-08 | 扬子江药业集团 | Method for preparing thiazolidine acetate coprising phenyl propylidene |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977047A (en) * | 2012-11-28 | 2013-03-20 | 开封明仁药业有限公司 | Refining method of crude epalrestat product |
| CN102977047B (en) * | 2012-11-28 | 2015-06-17 | 开封明仁药业有限公司 | Refining method of crude epalrestat product |
| JP2017043605A (en) * | 2015-08-28 | 2017-03-02 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Process for preparing epalrestat |
| JP2022000462A (en) * | 2015-08-28 | 2022-01-04 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Method of preparing epalrestat |
| CN105061355A (en) * | 2015-09-16 | 2015-11-18 | 宁夏康亚药业有限公司 | Refining method of high-purity epalrestat |
| CN105061355B (en) * | 2015-09-16 | 2016-07-06 | 宁夏康亚药业有限公司 | A kind of process for purification of high-purity epalrestat |
| CN105272934A (en) * | 2015-10-09 | 2016-01-27 | 扬子江药业集团江苏海慈生物药业有限公司 | Epalrestat C crystal form and preparation method thereof |
| CN107629021A (en) * | 2017-10-19 | 2018-01-26 | 扬子江药业集团南京海陵药业有限公司 | A kind of Epalrestat crystal formation B industrialized process for preparing |
| CN108191788A (en) * | 2018-01-24 | 2018-06-22 | 石家庄四药有限公司 | B crystal form epalrestat and preparation method thereof |
| CN108191788B (en) * | 2018-01-24 | 2022-05-06 | 石家庄四药有限公司 | Crystal form B epalrestat and preparation method thereof |
| CN113651770A (en) * | 2021-08-19 | 2021-11-16 | 山东达因海洋生物制药股份有限公司 | Novel crystal form of epalrestat, preparation method and application thereof |
| CN114456125A (en) * | 2022-03-10 | 2022-05-10 | 山东达因海洋生物制药股份有限公司 | Preparation method of small-particle-size epalrestat crystals |
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Application publication date: 20120627 |