CN114890964A - Crystal preparation method of epalrestat crystal form B - Google Patents
Crystal preparation method of epalrestat crystal form B Download PDFInfo
- Publication number
- CN114890964A CN114890964A CN202210705290.4A CN202210705290A CN114890964A CN 114890964 A CN114890964 A CN 114890964A CN 202210705290 A CN202210705290 A CN 202210705290A CN 114890964 A CN114890964 A CN 114890964A
- Authority
- CN
- China
- Prior art keywords
- epalrestat
- crystal form
- crystal
- preparation
- evaporation
- 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.)
- Pending
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 86
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 title claims abstract description 71
- 229950010170 epalrestat Drugs 0.000 title claims abstract description 68
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000002425 crystallisation Methods 0.000 claims abstract description 14
- 230000008025 crystallization Effects 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims description 38
- 238000001704 evaporation Methods 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 230000008020 evaporation Effects 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 16
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 16
- 239000002994 raw material Substances 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 9
- 238000004090 dissolution Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000007738 vacuum evaporation Methods 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 230000007547 defect Effects 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 26
- 239000012065 filter cake Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000012467 final product Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229940118148 Aldose reductase inhibitor Drugs 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 241000219295 Portulaca Species 0.000 description 1
- 206010074268 Reproductive toxicity Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000007696 reproductive toxicity Effects 0.000 description 1
- 231100000372 reproductive toxicity Toxicity 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- -1 salt compound Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a crystal preparation method of epalrestat crystal form B. The epalrestat crystal form B is a main epalrestat commercial crystal form product at present, but the industrial preparation of the epalrestat crystal form B at present has the defects of adoption of a harmful reagent, low yield, low product purity and the like. Aiming at the technical defects, the invention provides a preparation method of epalrestat crystal form B, which is characterized in that the crystal form A or amorphous epalrestat is dissolved in an alcohol reagent, and a high-purity crystal form B product can be obtained by an evaporation-cooling coupled crystallization technology. The method has high yield, and no harmful reagent is used in the preparation process, so that the method is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of preparation of crystal form medicines, and particularly relates to a crystal preparation method of epalrestat crystal form B.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Epalrestat (CAS number: 82159-09-9) with molecular formula C 15 H 13 NO 3 S 2 Molecular weight is 319.40, and chemical structural formula is shown in the following table. Epalrestat as aldose reductase inhibitor can be used for treating peripheral nerve disorder and abnormal heartbeat caused by diabetes,originally developed and marketed by the japanese portulaca.
The epalrestat crystal form A has poor water solubility, so that the in vivo dissolution and the release amount are low, and the bioavailability of the medicine is further influenced. The polymorphism is a ubiquitous phenomenon of a medicament and has an important effect on improving the physicochemical property of the medicament. Different crystal forms of the same drug often have different indexes such as solubility, stability and the like, and further the clinical curative effect of a preparation product is influenced. Related researches show that epalrestat not only has polymorphism, but also can form eutectic products with other components. Through a large amount of researches, researchers find and prepare other crystal forms of epalrestat products. Among them, patent JP2005298424A discloses a preparation method of epalrestat crystal form B, but because the solvent dosage in the preparation process is very large, the preparation efficiency of crystal form B is very low, and it is difficult to meet the actual industrial demand. Patent CN105272934A provides a preparation method of epalrestat crystal form C, and crystal form C product with purity over 99.9% can be obtained by two refining processes of methyl butanone, methyl isobutyl ketone, formic acid and acetic acid. The boiling point of the solvent for preparing the crystal form C is high, so that the residual solvent in the product is easy to exceed the standard, and the crystal form C lacks clinical data, so that the application and popularization of the crystal form C are greatly limited. In patent CN113277962A, epalrestat-metformin salt hydrate is successfully prepared by adopting acetone-water solvent system, which greatly improves the dissolution rate of epalrestat and simultaneously reduces the hygroscopicity of metformin, however, the new salt compound is still in the preclinical research stage at present, and finally there are still many uncertainties on whether to successfully come into the market.
The preparation of the epalrestat crystal form B serving as an important crystal form product of epalrestat which is already commercially produced still has a plurality of defects, and the large-scale application of the epalrestat crystal form B is limited to a certain extent. In patent CN107629021A, a mixed solvent system of methanol and tetrahydrofuran is adopted, so that the solvent dosage required by the preparation of the crystal form B is reduced to 14 times, but because tetrahydrofuran has certain reproductive toxicity, certain harm is brought to operators in the use process, and the application and popularization of the method are limited. The patent CN108191788A obtains the epalrestat crystal form B product by using low-carbon alcohol such as methanol, ethanol and the like to carry out high-temperature pulping operation. The process yield is low due to the long residence time in the high temperature zone, and is not suitable for industrial scale-up. Although the process yield can be improved by adding acid or alkali reagents, the addition of the acid or alkali reagents can cause the local pH change to be violent and cause the impurity content to be increased, thereby bringing great uncertainty to the quality stability of the product. Therefore, it is very important to find a preparation method of epalrestat crystal form B crystal which is convenient for industrial application, high in process yield and stable in quality.
Disclosure of Invention
Based on the technical background, the invention aims to provide a method for stably and efficiently preparing epalrestat crystal form B, and in order to realize the technical aim, the invention provides the following technical scheme:
in a first aspect of the present invention, there is provided a process for preparing crystal form B of epalrestat, said process comprising the steps of:
dissolving the epalrestat raw material in an alcohol solvent, wherein the solid-to-liquid ratio in the solution after the dissolution is 0.01-0.05 g/g; transferring the solution into a crystallizer for first-stage evaporation, stopping evaporation when the mass of the distillate reaches 20-30% of that of the alcohol solvent, and growing crystals at the constant temperature at the end point of the temperature for 30-60 min;
carrying out two-stage evaporation, and stopping evaporation when the total weight of the distillate of the two-stage evaporation reaches 45-65% of the mass of the alcohol solvent;
cooling to 0-5 ℃, wherein the cooling rate is 1-2 ℃/min, and growing the crystal for 60-90 min;
and filtering the reaction system in the crystallizer to obtain a solid part, namely the epalrestat crystal form B.
In the above preparation method, the epalrestat used as raw material comprises crystal form or main crystal form epalrestat raw material; in a preferred embodiment, the preparation method adopts epalrestat crystal form A and/or amorphous epalrestat as preparation raw materials;
in one embodiment, the epalrestat raw material is epalrestat crystal form a, or the content of the crystal form a is 60% or more;
in another embodiment, the epalrestat raw material is amorphous epalrestat, or the amorphous content is 60% or more;
in another embodiment, the epalrestat raw material contains 60% or more of form a and amorphous epalrestat.
Preferably, the alcohol solvent is a mixed solvent including but not limited to one or more of methanol, ethanol, n-propanol and isopropanol.
Preferably, the epalrestat raw material is added with an alcohol solvent and then is continuously stirred and dissolved for 30-60 min at the temperature of 60-70 ℃ to obtain the solution.
Preferably, the first-stage evaporation adopts a vacuum evaporation crystallization mode, and the vacuum degree is 0.06-0.08 Mpa.
Preferably, the two-stage evaporation is also crystallized by vacuum evaporation, and the vacuum degree is 0.04-0.06 MPa.
Preferably, in the above preparation method, after the reaction system in the crystallizer is filtered, the method further comprises the steps of washing and drying the solid part.
Furthermore, the reagent used for washing is selected from volatile organic reagents with low cost, and can be completely removed in the drying process, and the feasible washing reagent is verified to be one of methanol, ethanol, n-propanol and isopropanol.
Furthermore, the drying mode preferably adopts low-temperature drying, such as vacuum drying, the drying temperature is 40-50 ℃, the vacuum degree is 0.08-0.1 MPa, and the drying time is 7-12 hours.
The beneficial effects of one or more technical schemes are as follows:
1. in order to overcome the defects of the prior art, the invention carries out systematic research on the crystallization process of epalrestat, and adopts an evaporation-cooling coupled crystallization technology to stably convert other crystal form products into the crystal form B, so that the yield of the product is over 90 percent, and the purity can reach over 99.9 percent. Meanwhile, the epalrestat crystal product obtained by the invention has the advantages of no aggregation, uniform particle size distribution and good quality reproducibility among batches.
2. The preparation process provided by the invention is simple and convenient, can be completed only by a crystallizer and a low-carbon alcohol reagent, and is suitable for industrial amplification production.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
Figure 1 is the XRD diffraction pattern of the product of example 1.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.
Example 1
Adding 10g of epalrestat crystal form A into a three-necked bottle filled with 500g of methanol solvent, stirring and dissolving at 60 ℃, continuously stirring for 60 minutes, filtering and decoloring; transferring the filtrate into crystallizer, maintaining the temperature of the solution at 30 deg.C, starting vacuum pump to perform evaporation crystallization operation, controlling the vacuum degree of the system at 0.06MPa, and when the distillate reaches the temperature of the filtrateWhen 150g, stopping evaporating the solvent, growing the crystal at constant temperature and stirring for 30 minutes; then, the vacuum degree of the system is controlled to be 0.04MPa, the solvent is continuously evaporated, and when the total amount of the distillate is 325g, the evaporation operation is stopped; then the temperature of the solution system is reduced to 5 ℃ at the speed of 2 ℃/min, and then the crystal is grown for 60 min. Suction filtration is carried out, the filter cake is washed by methanol and dried for 7 hours under the vacuum condition of 40 ℃, and the vacuum degree is 0.08 MPa. The yield of the final product is 92.3 percent, the HPLC purity is 99.92 percent, and the product granularity D 50 And 8.76 microns.
The XRD diffraction result of the product in this example is shown in fig. 1, and compared with the diffraction pattern of the reference product of crystal form B, the two have substantially the same characteristic diffraction peak, and it can be determined that the product is the product of crystal form B. The products prepared in the following examples were compared in the same manner, and were identified as the product of form B.
Example 2
Adding 10g of amorphous epalrestat into a three-necked bottle containing 1000g of ethanol solvent, stirring and dissolving at 70 ℃, continuously stirring for 30 minutes, filtering and decoloring; transferring the filtrate into a crystallizer, keeping the temperature of the solution at 40 ℃, starting a vacuum pump to perform evaporative crystallization operation, controlling the vacuum degree of the system to be 0.08MPa, stopping evaporating the solvent when the distillate reaches 300g, growing crystals at constant temperature and stirring for 60 minutes; then controlling the vacuum degree of the system to be 0.06MPa, continuously evaporating the solvent, and stopping evaporation operation when the total amount of the distillate is 500 g; then the temperature of the solution system is reduced to 0 ℃ at the speed of 1 ℃/min, and then the crystal growth is carried out for 90 min. Filtering, washing the filter cake with ethanol, and drying at 50 deg.C under vacuum condition for 12 hr with vacuum degree of 0.1 MPa. The yield of the final product is 91.8%, the HPLC purity is 99.94%, and the product granularity D 50 Is 7.85 microns.
Example 3
Adding 20g of epalrestat crystal form A into a three-necked bottle filled with 1000g of isopropanol solvent, stirring and dissolving at 65 ℃, continuously stirring for 50 minutes, filtering and decoloring; transferring the filtrate into crystallizer, maintaining the temperature of the solution at 40 deg.C, starting vacuum pump to perform evaporation crystallization operation, controlling the vacuum degree of the system at 0.07MPa, stopping evaporation of the solvent when the distillate reaches 200g, growing crystal at constant temperature, and stirring45 minutes; then controlling the vacuum degree of the system to be 0.05MPa, continuing to evaporate the solvent, and stopping evaporation when the total amount of the distillate is 650 g; then the temperature of the solution system is reduced to 2 ℃ at the speed of 1 ℃/min, and then the crystal growth is carried out for 70 min. Filtering, washing the filter cake with isopropanol, and drying at 55 deg.C under vacuum condition for 10 hr with vacuum degree of 0.09 MPa. The yield of the final product is 90.3%, the HPLC purity is 99.93%, and the product granularity D 50 Is 6.56 microns.
Example 4
Adding 10g of epalrestat crystal form A into a three-necked bottle filled with 250g of n-propanol solvent, stirring and dissolving at 70 ℃, continuously stirring for 45 minutes, filtering and decoloring; transferring the filtrate into a crystallizer, keeping the temperature of the solution at 35 ℃, starting a vacuum pump to perform evaporative crystallization operation, controlling the vacuum degree of the system to be 0.08MPa, stopping evaporating the solvent when the distillate reaches 50g, growing crystals at constant temperature and stirring for 30 minutes; then controlling the vacuum degree of the system to be 0.06MPa, continuously evaporating the solvent, and stopping evaporation operation when the total amount of the distillate is 125 g; then the temperature of the solution system is reduced to 1 ℃ at the speed of 1 ℃/min, and then the crystal growth is carried out for 80 min. Filtering, washing the filter cake with n-propanol, and drying at 50 deg.C under vacuum condition for 9 hr with vacuum degree of 0.1 MPa. The yield of the final product is 91.7%, the HPLC purity is 99.94%, and the product granularity D 50 And 9.21 microns.
Example 5
Adding 10g of amorphous epalrestat into a three-necked bottle containing 400g of methanol solvent, stirring and dissolving at 65 ℃, continuously stirring for 60 minutes, filtering and decoloring; transferring the filtrate into a crystallizer, keeping the temperature of the solution at 30 ℃, starting a vacuum pump to perform evaporation crystallization operation, controlling the vacuum degree of the system to be 0.06MPa, stopping evaporating the solvent when the distillate reaches 40g, growing crystals at constant temperature, and stirring for 50 minutes; then controlling the vacuum degree of the system to be 0.05MPa, continuing to evaporate the solvent, and stopping evaporation when the total amount of the distillate is 180 g; then the temperature of the solution system is reduced to 0 ℃ at the speed of 2 ℃/min, and then the crystal growth is carried out for 90 min. Suction filtration is carried out, the filter cake is washed by methanol and dried for 8 hours under the vacuum condition of 40 ℃, and the vacuum degree is 0.09 MPa. The yield of the final product is 90.6%, the HPLC purity is 99.94%, and the product granularity D 50 And 9.64 microns.
Example 6
Adding 20g of amorphous epalrestat into a three-necked bottle containing 500g of ethanol solvent, stirring and dissolving at 70 ℃, continuously stirring for 45 minutes, filtering and decoloring; transferring the filtrate into a crystallizer, keeping the temperature of the solution at 30 ℃, starting a vacuum pump to perform evaporation crystallization operation, controlling the vacuum degree of the system to be 0.07MPa, stopping evaporating the solvent when the distillate reaches 125g, growing crystals at constant temperature, and stirring for 40 minutes; then controlling the vacuum degree of the system to be 0.05MPa, continuing to evaporate the solvent, and stopping evaporation operation when the total amount of the distillate is 250 g; then the temperature of the solution system is reduced to 5 ℃ at the speed of 1.5 ℃/min, and then the crystal growth is carried out for 60 min. Filtering, washing the filter cake with ethanol, and drying at 45 deg.C under vacuum condition for 12 hr with vacuum degree of 0.09 MPa. The yield of the final product is 90.2%, the HPLC purity is 99.93%, and the product granularity D 50 And 8.63 microns.
Example 7
Adding 20g of amorphous epalrestat into a three-necked bottle filled with 500g of isopropanol solvent, stirring and dissolving at 60 ℃, continuously stirring for 40 minutes, filtering and decoloring; transferring the filtrate into a crystallizer, keeping the temperature of the solution at 35 ℃, starting a vacuum pump to perform evaporative crystallization operation, controlling the vacuum degree of the system to be 0.08MPa, stopping evaporating the solvent when the distillate reaches 150g, growing crystals at constant temperature and stirring for 30 minutes; then controlling the vacuum degree of the system to be 0.04MPa, continuously evaporating the solvent, and stopping evaporation operation when the total amount of the distillate is 300 g; then the temperature of the solution system is reduced to 0 ℃ at the speed of 2 ℃/min, and then the crystal is grown for 60 min. Filtering, washing the filter cake with isopropanol, and drying at 50 deg.C under vacuum condition for 12 hr with vacuum degree of 0.08 MPa. The yield of the final product is 92.6 percent, the HPLC purity is 99.92 percent, and the product granularity D 50 And 7.53 microns.
Example 8
Adding 10g of epalrestat crystal form A into a three-necked bottle filled with 200g of n-propanol solvent, stirring and dissolving at 70 ℃, continuously stirring for 60 minutes, filtering and decoloring; transferring the filtrate into a crystallizer, keeping the temperature of the solution at 40 deg.C, starting a vacuum pump to perform evaporation crystallization, and controlling the vacuum of the systemThe temperature is 0.07MPa, when the distillate reaches 60g, the solvent is stopped to evaporate, and the crystal is grown at constant temperature and stirred for 40 minutes; then controlling the vacuum degree of the system to be 0.05MPa, continuing to evaporate the solvent, and stopping evaporation when the total amount of the distillate is 110 g; then the temperature of the solution system is reduced to 5 ℃ at the speed of 2 ℃/min, and then the crystal growth is carried out for 70 min. And (4) carrying out suction filtration, washing a filter cake by using n-propanol, and drying for 10 hours at the temperature of 55 ℃ under the vacuum condition, wherein the vacuum degree is 0.09 MPa. The yield of the final product is 92.1 percent, the HPLC purity is 99.91 percent, and the product granularity D 50 8.46 microns.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of crystal form B of epalrestat is characterized by comprising the following steps:
dissolving the epalrestat raw material in an alcohol solvent, wherein the solid-to-liquid ratio in the solution after the dissolution is 0.01-0.05 g/g; transferring the solution into a crystallizer for first-stage evaporation, stopping evaporation when the mass of the distillate reaches 20-30% of that of the alcohol solvent, and growing crystals at the constant temperature at the end point of the temperature for 30-60 min;
carrying out two-stage evaporation, and stopping evaporation when the total weight of the distillate of the two-stage evaporation reaches 45-65% of the mass of the alcohol solvent;
cooling to 0-5 ℃, wherein the cooling rate is 1-2 ℃/min, and growing the crystal for 60-90 min;
and filtering the reaction system in the crystallizer to obtain a solid part, namely the epalrestat crystal form B.
2. A process for the preparation of crystalline form B epalrestat according to claim 1 wherein epalrestat as starting material comprises epalrestat starting material in crystalline form or predominantly in crystalline form;
preferably, the preparation method adopts epalrestat crystal form A and/or amorphous epalrestat as preparation raw materials.
3. The method for preparing the crystal of epalrestat crystal form B according to claim 2, wherein the epalrestat raw material is epalrestat crystal form a, or the content of the crystal form a is 60% or more;
or the epalrestat raw material is amorphous epalrestat, or the amorphous content is 60% or more;
or, in the epalrestat raw material, the contents of the crystal form A and the amorphous epalrestat are 60 percent or more.
4. The process for preparing epalrestat form B crystals of claim 1, wherein the alcoholic solvent is a mixed solvent including but not limited to one or more of methanol, ethanol, n-propanol and isopropanol.
5. The method for preparing the crystal of epalrestat crystal form B according to claim 1, wherein the solution is obtained by adding an alcohol solvent to the epalrestat raw material and continuously stirring and dissolving the mixture at 60-70 ℃ for 30-60 min.
6. The method for preparing epalrestat crystal form B according to claim 1, wherein the first-stage evaporation adopts a vacuum evaporation crystallization mode, and the vacuum degree is 0.06-0.08 MPa.
7. The method for preparing the crystal of epalrestat crystal form B according to claim 1, wherein the two-stage evaporation is performed by vacuum evaporation crystallization at a vacuum degree of 0.04-0.06 MPa.
8. The process for the preparation of epalrestat form B crystals of claim 1 further comprising the step of washing and drying the solid portion after filtering the reaction system in the crystallizer.
9. The process for preparing crystalline form B of epalrestat of claim 8 wherein the washing is with a reagent that includes, but is not limited to, one of methanol, ethanol, n-propanol, and isopropanol.
10. The method for preparing the crystal of epalrestat crystal form B according to claim 8, wherein the drying mode is preferably low-temperature drying, and further the drying mode is vacuum drying, the drying temperature is 40-50 ℃, the vacuum degree is 0.08-0.1 MPa, and the drying time is 7-12 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210705290.4A CN114890964A (en) | 2022-06-21 | 2022-06-21 | Crystal preparation method of epalrestat crystal form B |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210705290.4A CN114890964A (en) | 2022-06-21 | 2022-06-21 | Crystal preparation method of epalrestat crystal form B |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114890964A true CN114890964A (en) | 2022-08-12 |
Family
ID=82727404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210705290.4A Pending CN114890964A (en) | 2022-06-21 | 2022-06-21 | Crystal preparation method of epalrestat crystal form B |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114890964A (en) |
Citations (4)
| 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 |
| 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 |
| 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 |
-
2022
- 2022-06-21 CN CN202210705290.4A patent/CN114890964A/en active Pending
Patent Citations (4)
| 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 |
| 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 |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104788345B (en) | A kind of production method of high-purity hydrochloric acid metformin | |
| CN101914098B (en) | Preparation method of Meropenem trihydrate crystals | |
| CN112552167B (en) | Preparation method of calcium gluconate | |
| CN103167872B (en) | For the production of the method for VBT tartrate | |
| CN114890964A (en) | Crystal preparation method of epalrestat crystal form B | |
| CN108314696B (en) | Utilization method of 2-hydroxy-1, 3, 5-tri-O-benzoyl-alpha-D-ribofuranose crystallization mother liquor | |
| CN111548310B (en) | Levosimendan sodium crystal form and preparation method thereof | |
| CN109265413B (en) | Preparation method and refining method of difenidol hydrochloride | |
| CN100384853C (en) | Method for synthesizing ticarcillin sodium | |
| CN110483441B (en) | Preparation method of febuxostat crystal form A with low impurity content | |
| CN110697733B (en) | Method for producing high-purity solid cyanamide | |
| CN108484505B (en) | Preparation method of 2-methylimidazole | |
| CN114262331A (en) | Preparation method of sitagliptin phosphate monohydrate | |
| CN112358489A (en) | Production method of industrial penicillin sulfoxide product | |
| WO2014094659A1 (en) | Process for preparation of meropenem trihydrate crystals | |
| CN113135897B (en) | Rupatadine fumarate B crystal form and preparation method thereof | |
| CN114369073B (en) | Method for preparing high-purity hydrochlorothiazide | |
| CN116969886A (en) | Hydroxychloroquine sulfate crystal form C and preparation method and application thereof | |
| CN113527544B (en) | Preparation method of high-purity sugammadex sodium | |
| CN107501216B (en) | Novel synthesis method of high-stability bismuth citrate ranitidine | |
| CN113861164B (en) | Crystallization preparation method of nicotine | |
| CN114907286A (en) | Preparation method of high-purity epalrestat crystal | |
| CN106431943B (en) | Preparation method of bupropion hydrochloride crystal | |
| CN116143650A (en) | Crystallization method of tetracycline hydrochloride | |
| CN111187255B (en) | Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |