CN102977047A - Refining method of crude epalrestat product - Google Patents
Refining method of crude epalrestat product Download PDFInfo
- Publication number
- CN102977047A CN102977047A CN2012104920780A CN201210492078A CN102977047A CN 102977047 A CN102977047 A CN 102977047A CN 2012104920780 A CN2012104920780 A CN 2012104920780A CN 201210492078 A CN201210492078 A CN 201210492078A CN 102977047 A CN102977047 A CN 102977047A
- Authority
- CN
- China
- Prior art keywords
- epalrestat
- crude product
- drying
- product
- purification
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
The invention discloses a refining method of a crude epalrestat product, which comprises the following steps of: firstly, dissolving the crude epalrestat product into a tetrahydrofuran solvent, heating to completely dissolve the crude epalrestat product, and stopping heating after the crude epalrestat product is completely dissolved; then adding isopropyl ether so that a small amount of red solids are separated out, further heating to completely dissolve the red solids, then stopping heating, naturally cooling, crystallizing and filtering, and then drying to obtain initially refined epalrestat; and then adding the tetrahydrofuran solvent, heating till the initially refined epalrestat is completely dissolved, stopping heating, then slowly adding petroleum ether so that a small amount of red solids are separated out, continuously heating till the red solids are completely dissolved, then stopping heating, naturally cooling, crystallizing and filtering, and then drying to obtain a refined epalrestat product. The refining method disclosed by the invention can be used for obtaining the high-purity epalrestat and has the advantages that the solvent raw material is available, reaction condition is mild, operation is simple and yield is high, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of method of purification of medicine, belong to the pharmaceutical chemistry field, particularly relate to a kind of process for purification of epalrestat crude product.
Background technology
Epalrestat in 1992 in Japanese Initial Public Offering, be a kind of non-competitive aldose reductase inhibitor of reversibility of carboxylic-acid, diabetic complication is had obvious curative effects.And the chronic complicating diseases of the eye that diabetes cause, kidney, nerve, blood vessel and heart, organ, be the patient final occur blind, lower limb are gangrenous, uremia, cerebral apoplexy or myocardial infarction even life-threatening immediate cause.
Existing known some metabolic pathway and signal transduction pathway etc. play a very important role in the evolution of diabetic complication.As under normal circumstances, intracellular glucose only about 5% enters the polyvalent alcohol passage, and under diabetic disease states, the polyvalent alcohol passage activates, about 30% glucose enters this passage, can cause that NADPH exhausts in the cell, indirect activation DAG-PKC signal path, cause osmotic 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 safely and efficiently medicine for the treatment of one of diabetic complication through clinical confirmation.
By the investigation to document, generally reach the Epalrestat of total impurities about 0.3% in the prior art, and in experiment, find that single solvent can't obtain total impurities less than 0.1% high purity Epalrestat.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of process for purification of epalrestat crude product.Can obtain the high purity Epalrestat by technical solution of the present invention, and all kinds of SOLVENTS raw material that adopts is easy to get, reaction conditions is gentle, and easy and simple to handle, yield is higher, is applicable to suitability for industrialized production.
In order to address the above problem, the technical solution used in the present invention is:
The invention provides a kind of process for purification of epalrestat crude product, described process for purification may further comprise the steps:
A, primary purification: at first with the epalrestat dissolving crude product in solvents tetrahydrofurane, being heated to 50～70 ℃ dissolves the epalrestat crude product fully, stopped heating after dissolving fully, then slowly add the solvent isopropyl ether, there is a small amount of red solid to separate out after the adding, continue to be heated to 50～70 ℃, make red solid dissolve rear stopped heating fully, naturally cooling crystallization 5～6h, filter behind the crystallization, obtain the wet product of epalrestat after the filtration, the wet product of epalrestat that obtain after filtering are carried out drying, the epalrestat after being made with extra care for the first time after the drying;
Described epalrestat crude product and solvents tetrahydrofurane between the two the ratio of add-on be 1g:1～10ml; Described epalrestat crude product and solvent isopropyl ether between the two the ratio of add-on be 1g:3～15ml;
B, secondary refining:
Epalrestat after step a is for the first time refining adds solvents tetrahydrofurane, being heated to 50～70 ℃ dissolves epalrestat fully, stopped heating after dissolving fully, then slowly add the solvent sherwood oil, there is a small amount of red solid to separate out after adding sherwood oil, continue to be heated to 50～70 ℃, make its red solid dissolve rear stopped heating fully, naturally cooling crystallization 5～6h, filter behind the crystallization, obtain the wet product of epalrestat after the filtration, the wet product of epalrestat that obtain after filtering are carried out drying, obtain the epalrestat highly finished product after the drying;
Described after first refining epalrestat and the solvents tetrahydrofurane of adding between the two the ratio of add-on be 1g:1～10ml; Described after first refining epalrestat and the solvent sherwood oil between the two the ratio of add-on be 1g:1～8ml.
According to the process for purification of above-mentioned epalrestat crude product, the crude product of epalrestat described in the step a and solvents tetrahydrofurane between the two the ratio of add-on be 1g:2～4ml; Described epalrestat crude product and solvent isopropyl ether between the two the ratio of add-on be 1g:6～8ml.
According to the process for purification of above-mentioned epalrestat crude product, the wet product of the epalrestat that will obtain after will filtering described in the step a carry out drying, and its drying temperature is 50～150 ℃, and be 1～10h time of drying.
According to the process for purification of above-mentioned epalrestat crude product, the epalrestat after first refining described in the step b and the solvents tetrahydrofurane of adding between the two the ratio of add-on be 1g:2～4ml; Described after first refining epalrestat and the solvent sherwood oil between the two the ratio of add-on be 1g:2～4ml.
According to the process for purification of above-mentioned epalrestat crude product, the wet product of the epalrestat that will obtain after will filtering described in the step b carry out drying, and its drying temperature is 50～150 ℃, and be 1～10h time of drying.
According to the process for purification of above-mentioned epalrestat crude product, the purity of the described epalrestat highly finished product of step b 〉=99.9%.
Positive beneficial effect of the present invention:
1, technical solution of the present invention is by refining through twice with the epalrestat crude product, namely make with extra care for the first time through tetrahydrofuran (THF) and isopropyl ether respectively, carry out secondary refining through tetrahydrofuran (THF) and sherwood oil again, make its epalrestat crude product carry out refinement treatment twice, the purity of the finished product epalrestat after making it refining is greater than 99.9%.
2, can obtain the high purity Epalrestat by technical solution of the present invention, and all kinds of SOLVENTS raw material that adopts in the treating process is easy to get, reaction conditions is gentle, and easy and simple to handle, yield is higher, is applicable to suitability for industrialized production.
Four, description of drawings:
Fig. 1: the collection of illustrative plates of epalrestat usual production;
Fig. 2: the collection of illustrative plates after adopting tetrahydrofuran (THF) and isopropyl ether to Epalrestat usual production primary purification;
Illustrate: after the epalrestat crude product is refining through tetrahydrofuran (THF) and isopropyl ether, removes retention position in the high performance liquid chromatograph and be positioned at impurity peaks before and after the 14min;
Fig. 3: the collection of illustrative plates after epalrestat crude product process tetrahydrofuran (THF) and sherwood oil are refining;
Illustrate: after the epalrestat crude product is refining through tetrahydrofuran (THF) and sherwood oil, removes retention position in the high performance liquid chromatograph and be positioned at impurity peaks about 5min;
Fig. 4: the epalrestat crude product adopts the collection of illustrative plates after tetrahydrofuran (THF)+isopropyl ether, tetrahydrofuran (THF)+sherwood oil are made with extra care successively; It is the collection of illustrative plates of gained epalrestat highly finished product of the present invention.
Five, embodiment:
Further set forth the present invention below in conjunction with embodiment, but do not limit content of the present invention.
Embodiment 1:
The process for purification of epalrestat crude product of the present invention, the detailed step of this process for purification is as follows:
A, primary purification: at first epalrestat crude product 10g is dissolved among the solvents tetrahydrofurane 30ml, being heated to 55～65 ℃ dissolves the epalrestat crude product fully, stopped heating after dissolving fully, then slowly add solvent isopropyl ether 70ml, there is a small amount of red solid to separate out after the adding, continue to be heated to 55～65 ℃, make red solid dissolve rear stopped heating fully, naturally cooling crystallization 5h filters behind the crystallization, obtain the wet product of epalrestat after the filtration, the wet product of epalrestat that obtain after filtering are carried out drying, and drying temperature is 100 ℃, and be 1h time of drying, epalrestat 8.0g after being made with extra care for the first time after the drying, its yield are 80.0%;
B, secondary refining:
Epalrestat 8.0g after step a is for the first time refining adds solvents tetrahydrofurane 24ml, being heated to 55～65 ℃ dissolves epalrestat fully, stopped heating after dissolving fully, then slowly add solvent sherwood oil 16ml, there is a small amount of red solid to separate out after adding sherwood oil, continue to be heated to 55～65 ℃, make its red solid dissolve rear stopped heating fully, naturally cooling crystallization 5h filters behind the crystallization, obtain the wet product of epalrestat after the filtration, the wet product of epalrestat that obtain after filtering are carried out drying, and drying temperature is 100 ℃, and be 1h time of drying, obtain epalrestat highly finished product 6.0g after the drying, its yield is 75.0%.
Embodiment 2:
The process for purification of epalrestat crude product of the present invention, the detailed step of this process for purification is as follows:
A, primary purification: at first epalrestat crude product 10g is dissolved among the solvents tetrahydrofurane 40ml, being heated to 50～55 ℃ dissolves the epalrestat crude product fully, stopped heating after dissolving fully, then slowly add solvent isopropyl ether 80ml, there is a small amount of red solid to separate out after the adding, continue to be heated to 50～55 ℃, make red solid dissolve rear stopped heating fully, naturally cooling crystallization 5.5h filters behind the crystallization, obtain the wet product of epalrestat after the filtration, the wet product of epalrestat that obtain after filtering are carried out drying, and drying temperature is 90 ℃, and be 2h time of drying, epalrestat 8.1g after being made with extra care for the first time after the drying, its yield are 81.0%;
B, secondary refining:
Epalrestat 8.1g after step a is for the first time refining adds solvents tetrahydrofurane 32.4ml, being heated to 50～55 ℃ dissolves epalrestat fully, stopped heating after dissolving fully, then slowly add solvent sherwood oil 32.4ml, there is a small amount of red solid to separate out after adding sherwood oil, continue to be heated to 50～55 ℃, make its red solid dissolve rear stopped heating fully, naturally cooling crystallization 5.5h filters behind the crystallization, obtain the wet product of epalrestat after the filtration, the wet product of epalrestat that obtain after filtering are carried out drying, and drying temperature is 90 ℃, and be 2h time of drying, obtain epalrestat highly finished product 6.3g after the drying, its yield is 77.8%.
Embodiment 3:
The process for purification of epalrestat crude product of the present invention, the detailed step of this process for purification is as follows:
A, primary purification: at first epalrestat crude product 10g is dissolved among the solvents tetrahydrofurane 20ml, being heated to 65～70 ℃ dissolves the epalrestat crude product fully, stopped heating after dissolving fully, then slowly add solvent isopropyl ether 60ml, there is a small amount of red solid to separate out after the adding, continue to be heated to 65～70 ℃, make red solid dissolve rear stopped heating fully, naturally cooling crystallization 6h filters behind the crystallization, obtain the wet product of epalrestat after the filtration, the wet product of epalrestat that obtain after filtering are carried out drying, and drying temperature is 120 ℃, and be 1h time of drying, epalrestat 8.22g after being made with extra care for the first time after the drying, its yield are 82.2%;
B, secondary refining:
Epalrestat 8.22g after step a is for the first time refining adds solvents tetrahydrofurane 16.5ml, being heated to 65～70 ℃ dissolves epalrestat fully, stopped heating after dissolving fully, then slowly add solvent sherwood oil 24.7ml, there is a small amount of red solid to separate out after adding sherwood oil, continue to be heated to 65～70 ℃, make its red solid dissolve rear stopped heating fully, naturally cooling crystallization 6h filters behind the crystallization, obtain the wet product of epalrestat after the filtration, the wet product of epalrestat that obtain after filtering are carried out drying, and drying temperature is 120 ℃, and be 1h time of drying, obtain epalrestat highly finished product 6.5g after the drying, its yield is 79.1%.
Claims (6)
1. the process for purification of an epalrestat crude product is characterized in that, described process for purification may further comprise the steps:
A, primary purification: at first with the epalrestat dissolving crude product in solvents tetrahydrofurane, being heated to 50～70 ℃ dissolves the epalrestat crude product fully, stopped heating after dissolving fully, then slowly add the solvent isopropyl ether, there is a small amount of red solid to separate out after the adding, continue to be heated to 50～70 ℃, make red solid dissolve rear stopped heating fully, naturally cooling crystallization 5～6h, filter behind the crystallization, obtain the wet product of epalrestat after the filtration, the wet product of epalrestat that obtain after filtering are carried out drying, the epalrestat after being made with extra care for the first time after the drying;
Described epalrestat crude product and solvents tetrahydrofurane between the two the ratio of add-on be 1g:1～10ml; Described epalrestat crude product and solvent isopropyl ether between the two the ratio of add-on be 1g:3～15ml;
B, secondary refining:
Epalrestat after step a is for the first time refining adds solvents tetrahydrofurane, being heated to 50～70 ℃ dissolves epalrestat fully, stopped heating after dissolving fully, then slowly add the solvent sherwood oil, there is a small amount of red solid to separate out after adding sherwood oil, continue to be heated to 50～70 ℃, make its red solid dissolve rear stopped heating fully, naturally cooling crystallization 5～6h, filter behind the crystallization, obtain the wet product of epalrestat after the filtration, the wet product of epalrestat that obtain after filtering are carried out drying, obtain the epalrestat highly finished product after the drying;
Described after first refining epalrestat and the solvents tetrahydrofurane of adding between the two the ratio of add-on be 1g:1～10ml; Described after first refining epalrestat and the solvent sherwood oil between the two the ratio of add-on be 1g:1～8ml.
2. the process for purification of epalrestat crude product according to claim 1 is characterized in that: the crude product of epalrestat described in the step a and solvents tetrahydrofurane between the two the ratio of add-on be 1g:2～4ml; Described epalrestat crude product and solvent isopropyl ether between the two the ratio of add-on be 1g:6～8ml.
3. the process for purification of epalrestat crude product according to claim 1 is characterized in that: the wet product of the epalrestat that will obtain after will filtering described in the step a carry out drying, and its drying temperature is 50～150 ℃, and be 1～10h time of drying.
4. the process for purification of epalrestat crude product according to claim 1 is characterized in that: described in the step b first after refining epalrestat and the solvents tetrahydrofurane of adding between the two the ratio of add-on be 1g:2～4ml; Described after first refining epalrestat and the solvent sherwood oil between the two the ratio of add-on be 1g:2～4ml.
5. the process for purification of epalrestat crude product according to claim 1 is characterized in that: the wet product of the epalrestat that will obtain after will filtering described in the step b carry out drying, and its drying temperature is 50～150 ℃, and be 1～10h time of drying.
6. the process for purification of epalrestat crude product according to claim 1 is characterized in that: the purity of the described epalrestat highly finished product of step b 〉=99.9%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210492078.0A CN102977047B (en) | 2012-11-28 | 2012-11-28 | Refining method of crude epalrestat product |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210492078.0A CN102977047B (en) | 2012-11-28 | 2012-11-28 | Refining method of crude epalrestat product |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102977047A true CN102977047A (en) | 2013-03-20 |
| CN102977047B CN102977047B (en) | 2015-06-17 |
Family
ID=47851441
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210492078.0A Active CN102977047B (en) | 2012-11-28 | 2012-11-28 | Refining method of crude epalrestat product |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102977047B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061355A (en) * | 2015-09-16 | 2015-11-18 | 宁夏康亚药业有限公司 | Refining method of high-purity epalrestat |
| CN106841463A (en) * | 2016-12-22 | 2017-06-13 | 扬子江药业集团南京海陵药业有限公司 | A kind of content assaying method of Epalrestat capsule |
| 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 (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005298424A (en) * | 2004-04-13 | 2005-10-27 | Sawai Pharmaceutical Co Ltd | Method for producing epalrestat crystal |
| JP2007099680A (en) * | 2005-10-04 | 2007-04-19 | Konica Minolta Chemical Co Ltd | Method for producing epalrestat |
| CN102516197A (en) * | 2011-12-15 | 2012-06-27 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation of high purity epalrestat |
-
2012
- 2012-11-28 CN CN201210492078.0A patent/CN102977047B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005298424A (en) * | 2004-04-13 | 2005-10-27 | Sawai Pharmaceutical Co Ltd | Method for producing epalrestat crystal |
| JP2007099680A (en) * | 2005-10-04 | 2007-04-19 | Konica Minolta Chemical Co Ltd | Method for producing epalrestat |
| CN102516197A (en) * | 2011-12-15 | 2012-06-27 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation of high purity epalrestat |
Non-Patent Citations (3)
| Title |
|---|
| 冯建鹏等: "高纯度依帕司他的制备方法", 《广东化工》, vol. 39, no. 11, 15 September 2012 (2012-09-15), pages 42 * |
| 周学良: "《精细化工产品手册 药物》", 31 December 2003, article "第十四章 激素及其有关药物 14512依帕司他", pages: 696 * |
| 盛荣等: "依帕司他的合成工艺改进", 《浙江大学学报》, vol. 32, no. 4, 31 December 2003 (2003-12-31), pages 356 - 358 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN106841463A (en) * | 2016-12-22 | 2017-06-13 | 扬子江药业集团南京海陵药业有限公司 | A kind of content assaying method of Epalrestat capsule |
| 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 |
| CN114456125B (en) * | 2022-03-10 | 2022-11-15 | 山东达因海洋生物制药股份有限公司 | Preparation method of small-particle-size epalrestat crystals |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102977047B (en) | 2015-06-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102977047B (en) | Refining method of crude epalrestat product | |
| CN103923024B (en) | A kind of process for purification of acipimox | |
| CN102701914B (en) | Method for extracting hydroxytyrosol from olive leaves | |
| CN102399630B (en) | Technology for refined rice bran oil rich in oryzanol | |
| CN102516197A (en) | Preparation of high purity epalrestat | |
| CN111960930A (en) | Method for separating and purifying cannabidiol from industrial cannabis sativa leaves | |
| CN104356111B (en) | A kind of method for preparing dabigatran etcxilate mesylate hydrolysis impurity | |
| CN103360411A (en) | Everolimus crystallization purification method | |
| CN103288801A (en) | Preparation method for high-purity esomeprazole sodium | |
| CN109824509B (en) | Method for extracting linoleic acid from achyranthes bidentata leaves | |
| CN102321143A (en) | Method for preparing high-purity betulin | |
| CN106046067A (en) | Synthetic method for 1,2-di-O-isopropylidene-3,5,6-tri-O-benzyl-D-glucofuranose | |
| WO2017015793A1 (en) | Method for separating diastereoisomer a of bedaquiline | |
| CN101781216A (en) | Novel process for preparing propylgallate directly from gallnuts | |
| CN101560188A (en) | Method for separating and purifying 2-methylimidazole crystal impurity | |
| CN103804266A (en) | Synthetic method of vildagliptin intermediate | |
| CN104230882B (en) | A kind of preparation method of duloxetine hydrochloride impurity | |
| CN102516179B (en) | Method for refining nizofenone fumarate and intermediate synthesizing method | |
| CN103058858A (en) | Method for extracting high-purity carnosic acid from rosemary | |
| CN104098458B (en) | A kind of preparation method of voglibose intermediate | |
| CN103408543B (en) | High purity citric acid and navoban compound | |
| CN110862429A (en) | Preparation method of sodium aescinate | |
| CN102250092B (en) | Preparation process of alkaloid tabersonine | |
| CN102746178B (en) | The preparation method of flutamide | |
| CN104262298B (en) | The novel process of separation and purification Lipstatin in a kind of streptomycete fermentation liquid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |