CN111285822A - Preparation method of febuxostat crystal form A - Google Patents
Preparation method of febuxostat crystal form A Download PDFInfo
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- CN111285822A CN111285822A CN201811506146.8A CN201811506146A CN111285822A CN 111285822 A CN111285822 A CN 111285822A CN 201811506146 A CN201811506146 A CN 201811506146A CN 111285822 A CN111285822 A CN 111285822A
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- febuxostat
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- 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- 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 discloses a preparation method of febuxostat medicinal crystal form A, which comprises the steps of dissolving febuxostat in acetonitrile solvent, heating, stirring and dissolving; adding or not adding seed crystal after full dissolution, cooling by stages and carrying out heat preservation and crystallization; filtering and drying to obtain the product. The preparation process is stable, the method is simple and convenient to operate, the repeatability is good, the impurity removal effect is good, the yield is high, the crystal form stability is good, and the solvent can be recycled and reused, so that the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of febuxostat crystal form A.
Background
Febuxostat is a drug developed and developed by the company of imperial japan for treating hyperuricemia with gout symptoms, which is approved by EMEA in the european union in 4 months in 2004, approved by FDA in the us in 2 months in 2009, and marketed in china in 2013.
Febuxostat is a non-purine selective xanthine oxidase/xanthine dehydrogenase inhibitor, can inhibit the oxidation state and reduction state of xanthine oxidase, and is used for treating diseases related to hyperuricemia. Febuxostat is mainly metabolized by the liver, so that adverse reactions of allopurinol caused by kidney metabolism and excretion can be better avoided.
The chemical name of febuxostat is 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-thiazole formic acid, and the febuxostat has the following chemical structural formula:
japanese Imperial corporation, U.S. Pat. No. 6,97474, describes A, B, C, D, G of the present compound and amorphous compounds and their preparation, mainly using methanol-water or isopropanol-water as solvent. Wherein the infrared characteristic absorption wavelength of the febuxostat crystal form A is 1676cm-1And 2231cm-1And the characteristic absorption peaks of the X-ray powder diffraction characteristic 2 theta are 6.62 degrees, 7.18 degrees, 12.80 degrees, 13.26 degrees, 16.48 degrees, 19.58 degrees, 21.92 degrees, 22.68 degrees, 25.84 degrees, 26.70 degrees, 29.16 degrees and 36.70 degrees. Chinese patent CN1975047B introduces H, I, J three crystal forms and a preparation method thereof, and the crystal forms are mainly prepared by recrystallization of two types of organic solvents containing cyano groups, such as acetonitrile or butyronitrile; european patent EP2399911 describes Form I, II, tert-amyl alcohol solvates and processes for their preparation; patent CN101891703B discloses a preparation method of febuxostat N-type crystal form, wherein the solvent is N, N-dimethylformamide or N, N-dimethylacetamide; patent CN101386605 discloses febuxostat crystal form K, and the crystallization solvent is 1, 4-dioxane or a mixed system of 1, 4-dioxane and one solvent of n-hexane, petroleum ether and cyclohexane.
In example 7 of chinese invention patent CN101139325, a method for preparing crystal form a with acetone is disclosed, although the process is simple, the yield is low, only 50%.
The method for preparing the medicinal crystal form A disclosed in the Chinese patent CN1275126A is characterized in that methanol-water is used as a solvent for crystallization, the crystallization conditions are controlled rigorously, the operable space is narrow, a methanol solvate, a hydrate or a crystal form C is easily formed, the reproducibility of the obtained crystal form A is poor, and the industrial mass production is difficult to realize.
World patent WO2011139886a2 discloses the use of mixed solvents of alcohols, which result in a product that is not form a.
The prior art discloses a method for preparing febuxostat products by using isopropanol, but the prepared crystal forms are not febuxostat crystal form A, in other words, a unique specified crystal form cannot be obtained in an isopropanol system by using a general crystallization method, and particularly, febuxostat crystal form A cannot be obtained. Therefore, other process condition control is required to be assisted to obtain the product with the unique determined crystal form.
At present, febuxostat has a plurality of reported crystal forms, wherein the crystal form A is relatively stable, and the dissolution rate of the tablet is better. Therefore, the need exists in the art for developing a preparation method of febuxostat crystal form a, which can obtain a single febuxostat crystal form a, has stable process, mild crystallization conditions and low cost, and is very suitable for industrial mass production.
Disclosure of Invention
The invention discloses a preparation method of a single febuxostat crystal form A, which has the advantages of stable process, good repeatability, simple and convenient operation, good impurity removal effect, high product purity and yield, good crystal form stability, recyclable solvent and suitability for industrial production. The single crystal in the application refers to a mixed crystal or an amorphous and crystalline mixture which only contains one crystal form, but not two or more crystal forms.
The reflection angle 2 theta of the X-ray powder diffraction of the single febuxostat crystal form A is consistent with that disclosed by the prior art: characteristic absorption peaks at about 6.62, 7.18, 12.80, 13.26, 16.48, 19.58, 21.92, 22.68, 25.84, 26.70, 29.16, 36.70 °. The X-ray powder diffraction pattern is shown in FIG. 2.
The invention provides a preparation method of febuxostat crystal form A, which comprises the following steps:
① adding febuxostat into solvent containing acetonitrile, heating and stirring until all the febuxostat is dissolved;
②, carrying out hot filtration, cooling the temperature of the filtrate to 60-75 ℃, adding 0-2.0% of seed crystal into the reaction solution, wherein the seed crystal is febuxostat A crystal form, carrying out cooling by stages, finally cooling to 0-20 ℃, and carrying out heat preservation and crystallization;
③ separating, washing, and drying to obtain the final product.
Further, in step ① of the present invention, the solvent containing acetonitrile is anhydrous acetonitrile or acetonitrile-water mixed solvent, preferably acetonitrile-water mixed solvent.
Furthermore, the weight ratio of acetonitrile to water in the acetonitrile-water mixed solvent is 1: 1-20: 1.
Further, the weight ratio of the febuxostat to the acetonitrile-containing solvent in the step ① is 1:20 to 1:50, and preferably 1:20 to 1:30 in order to further improve the product yield.
In step ①, the mixture is heated and stirred until the mixture can be dissolved, and the temperature is generally 75-78 ℃.
Further, in the step ②, the temperature is reduced to 45-50 ℃ within 0.25-1.5 hours at the first stage, and is reduced to 0-20 ℃ within 0.25-1.5 hours at the second stage, in order to further improve the product yield, the preferable temperature reduction steps are that the temperature is reduced to 45-50 ℃ within 15-40 min at the first stage, the temperature is reduced to 0-20 ℃ within 15-30 min at the second stage, and in a preferable embodiment, the temperature reduction steps are that the temperature is reduced to 15-40 min within 15-40 min at the first stage, the temperature is reduced to 45-50 ℃ within 15-30 min at the second stage, and the temperature is reduced to 15-20 ℃.
In the cooling crystallization process, the total cooling time from the completion of the heat filtration to the completion of the crystallization is generally 0.5 to 3 hours, and 0.5 to 1.25 hours is preferred for improving the product yield.
Further, in the step ②, after the temperature is finally reduced to 0-20 ℃, stirring, preserving heat and crystallizing for 0.5-2 hours.
The drying mode in step ③ of the present invention may be a conventional method in the art, and in order to improve the crystal form uniqueness of the product, hot air circulation drying or vacuum drying is preferred, and the drying temperature is 30 to 80 ℃, and more preferably 60 to 80 ℃.
The drying time of the filter cake in step ③ of the invention can be properly adjusted according to actual conditions, and when hot air circulation drying or vacuum drying is adopted, the drying time is usually 8-20 hours.
The step ② of the present invention may be implemented by a conventional cooling method in the art, such as a high-low temperature control system circulating cooling device, wherein the high-low temperature control system circulating cooling device utilizes a refrigerator and a heater controlled by a microcomputer to achieve the heating, cooling and constant temperature, and the present invention preferably selects a program-controlled constant temperature circulating device SUNDI-935WN in view of the cooling effect and the automation control level.
After the crystallization of step ② of the present invention is complete, step ③ separates the precipitated crystals from the solution, which can be separated by any conventional separation method known in the art, such as filtration or centrifugation.
The febuxostat raw material used in the step ① of the invention can be in any crystal form or amorphous form, and a single febuxostat crystal form A can be obtained according to the preparation process.
Wherein, the febuxostat disclosed in the step ① or the febuxostat sample provided in the embodiment of the invention is prepared by a literature report method.
Wherein the seed crystals of step ② are preferably the single febuxostat crystal form a obtained without seed crystals according to the present invention.
By adopting the preparation method, the process operation can be simplified under the solvent system and the operation process, and the single high-purity febuxostat crystal form A can be obtained.
The single febuxostat crystal form A prepared by the invention is stable in the range of experimental conditions, and mutual transformation among the crystal forms can not occur.
The febuxostat anhydrous crystal form A prepared by the invention can be detected by a conventional crystal form detection method in the field, such as infrared spectrum absorption, X-ray powder diffraction, thermogravimetric analysis (TGA analysis), differential scanning calorimetry (DSC analysis) and other methods.
The single febuxostat crystal form A is detected to be the single febuxostat crystal form A through infrared spectrum absorption, X-ray powder diffraction, TGA analysis and DSC analysis.
Compared with the prior art, the invention brings the following beneficial technical effects:
the single crystal form A provided by the invention has good impurity removing effect, can obtain the crystal form A with high purity, and has high yield, thereby simplifying the process, improving the efficiency and saving the cost.
The invention provides a single febuxostat crystal form A, but not a hydrate, a solvate, a crystal form B, a crystal form C or a mixed crystal form. Compared with hydrate, the content of the active ingredients of the drug in the anhydrous crystal form is higher; compared with the mixed crystal form, the single crystal form is more beneficial to the control of the product quality and the establishment of the quality standard.
The preparation process is stable, the reproducibility is high, and the crystal forms prepared by repeated tests are all single febuxostat crystal form A. In the preparation process, the weight ratio of the febuxostat to the solvent is 1: 20-1: 50, and the solvent can be recycled in industrial mass production, so that the production cost is greatly reduced, and a green and safe production environment is created.
The process of the invention adopts low-temperature crystallization, the reaction condition is mild, the reaction temperature is raised to the boiling point temperature, the reaction does not need to be carried out for a long time under the high-temperature condition, the industrial mass production is more facilitated, and the obtained crystal form is stable, has higher purity and can be stored for a long time.
Drawings
FIG. 1 is an infrared absorption (IR) spectrum of a single febuxostat crystal form A prepared by the invention.
FIG. 2 is an X-ray powder diffraction pattern of a single febuxostat crystal form A prepared by the invention.
Fig. 3 is a Differential Scanning Calorimetry (DSC) profile of a single febuxostat crystal form a according to the present invention.
Figure 4 is a thermogravimetric analysis (TGA) profile of a single febuxostat crystal form a prepared in accordance with the present invention.
Detailed Description
The invention is illustrated below by means of some examples. It is to be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention, and that various changes and modifications obvious to those skilled in the art are also included within the scope of the present invention.
It should be noted that the experimental error of the X-ray powder diffraction pattern using Cu-K α radiation depends on the condition of the apparatus, the preparation of the sample and the purity of the sample, in particular, the X-ray diffraction pattern is generally changed with the condition of the apparatus, it is particularly pointed out that the relative intensities of the X-ray diffraction pattern may also be changed with the change of the experimental condition, so the order of the peak intensities cannot be the only or decisive factor, in addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should be taken into account, and usually the reflection angle 2 theta is allowed to have an error of + -0.2 deg., in addition, the whole shift of the peak angle is caused by the influence of the experimental factors such as the height of the sample, and usually a certain shift is allowed, therefore, the skilled person can understand that the single crystal form X-ray diffraction pattern obtained by the different preparation methods of the present invention does not have to be completely the same as the single crystal form X-ray diffraction pattern obtained by the different preparation methods of the present invention, as long as the reflection angle 2 theta is within the allowable error range of + -0.2 deg.
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the present invention in any way.
In the following embodiment, the step ② is implemented by using a common cooling method, namely a programmed temperature control circulating device SUNDI-935WN for Sn-free Guanya production, wherein the working temperature is-50-250 ℃, the maximum pump pressure is 2bar, the flow rate is 16-30L/min, the flow volume is 13.5L, and the liquid storage volume is 4.9L.
Example 1
5.0g of febuxostat and 100.0g of anhydrous acetonitrile are added into a 250ml three-neck jacketed bottle, heated and stirred, and the solution is heated to 78 ℃ for clarification. Hot filtering, cooling the filtrate to 65 deg.C, and cooling by stages. The cooling stage specifically comprises: cooling at the first stage for 15min, standing the reaction system, cooling from 65 ℃ to 45 ℃, and gradually adhering the solution to separate out granular solids in the process; cooling in the second stage, continuously standing and cooling to 20 ℃, and gradually increasing precipitated solids, wherein the cooling time in the second stage is 15 min; stirring, maintaining the temperature for 0.5 hr, and vacuum filtering. The wet product was dried in a hot air circulating drying oven at 80 ℃ for 8 hours to obtain 4.6g of a white powdery solid with a yield of 92.0%. The checking shows that the white powder solid has an infrared spectrum shown in figure 1, an X-ray powder diffraction pattern shown in figure 2, a single febuxostat crystal form A, an X-ray powder diffraction pattern shown in figure 2, a DSC pattern shown in figure 3 and a TGA pattern shown in figure 4.
Example 2
5.0g of febuxostat and 250.0g of anhydrous acetonitrile are added into a 500ml three-neck jacketed bottle, heated and stirred, and the solution is heated to 75 ℃ for clarification. Hot filtering, cooling the filtrate to 70 deg.C, and cooling by stages. The cooling stage specifically comprises: cooling at the first stage, adding 0.1g of febuxostat crystal form A crystal seeds, cooling for 1.5 hours, standing the reaction system, cooling to 45 ℃, and gradually adhering the solution to the wall to separate out granular solids in the process; cooling in the second stage, keeping standing and cooling to 20 ℃, and gradually increasing precipitated solids, wherein the cooling time in the second stage is 1.5 hours; starting stirring, keeping the temperature for crystallization for 2 hours, and performing suction filtration. The wet product was dried in a vacuum oven at 80 ℃ for 8 hours to give 4.3g of a white powdery solid with a yield of 86.0%. As checked, the infrared spectrum of the white powdery solid was in accordance with the characteristic absorption wave number of FIG. 1, and the X-ray powder diffraction pattern was in accordance with 2. theta. of FIG. 2.
Example 3
50.0g of febuxostat, 1000.0g of anhydrous acetonitrile and 50.0g of purified water are added into a 2L three-neck jacketed bottle, heated and stirred, and the solution is heated to 78 ℃ for clarification. Hot filtering, cooling the filtrate to 65 deg.C, and cooling by stages. The cooling stage specifically comprises: cooling in the first stage for 40min, standing the reaction system, cooling to 45 deg.C, and separating out white solid with the addition of crystal seed; cooling in the second stage to precipitate a large amount of solid, standing and cooling to 20 deg.C for 30 min; starting stirring, keeping the temperature for crystallization for 1 hour, and performing suction filtration. The wet product was dried in a hot air circulating drying oven at 60 ℃ for 10 hours to obtain 47.1g of a white powdery solid with a yield of 94.2%. As checked, the infrared spectrum of the white powdery solid was in accordance with the characteristic absorption wave number of FIG. 1, and the X-ray powder diffraction pattern was in accordance with 2. theta. of FIG. 2.
Example 4
50.0g of febuxostat and 1000.0g of anhydrous acetonitrile are added into a 2L three-neck jacketed bottle, the mixture is heated and stirred, 500.0g of purified water is added under the reflux state at 78 ℃, and the solution is clarified. And (3) carrying out hot filtration, stirring the filtrate, cooling to 67 ℃, adding 0.5g of febuxostat crystal form A seed crystal into the clear liquid, and cooling by stages. The cooling stage specifically comprises: cooling at the first stage for 35min, standing the reaction system, cooling from 67 ℃ to 45 ℃, and gradually adhering the solution to separate out granular solids in the process; cooling in the second stage, continuously standing and cooling to 20 ℃, and gradually increasing precipitated solids, wherein the cooling time in the second stage is 30 min; starting stirring, keeping the temperature for crystallization for 2 hours, and performing suction filtration. The wet product was dried in a hot air circulating drying oven at 60 ℃ for 10 hours to obtain 47.5g of a white powdery solid with a yield of 95.0%. As checked, the infrared spectrum of the white powdery solid was in accordance with the characteristic absorption wave number of FIG. 1, and the X-ray powder diffraction pattern was in accordance with 2. theta. of FIG. 2.
Example 5
50.0g of febuxostat, 750.0g of anhydrous acetonitrile and 750.0g of purified water are added into a 3L three-neck jacketed bottle, heated and stirred, and the solution is heated to 78 ℃ for clarification. And (3) carrying out hot filtration, cooling the filtrate to 70 ℃, adding 1.0g of febuxostat crystal form A seed crystal, and cooling by stages. The cooling stage specifically comprises: cooling at the first stage for 30min, standing the reaction system, cooling to 45 ℃, and gradually precipitating granular solids from the solution by adherence in the process; cooling in the second stage, continuously standing and cooling to 20 ℃, and gradually increasing precipitated solids, wherein the cooling time in the second stage is 30 min; starting stirring, keeping the temperature for crystallization for 1 hour, and performing suction filtration. The wet product was dried in a hot air circulating drying oven at 60 ℃ for 10 hours to obtain 47.3g of a white powdery solid with a yield of 94.6%.
Example 6
Adding 5.0kg of febuxostat and 125.0kg of anhydrous acetonitrile into a 200L reaction kettle, heating and stirring, heating to 76 ℃ and clarifying the solution. Hot filtering, cooling the filtrate to 72 deg.C under stirring, and cooling by stages. The cooling stage specifically comprises: cooling at the first stage for 30min, standing the reaction system, cooling to 45 ℃, and gradually precipitating granular solids from the solution by adherence in the process; cooling in the second stage, continuously standing and cooling to 20 ℃, and gradually increasing precipitated solids, wherein the cooling time in the second stage is 30 min; starting stirring, keeping the temperature for crystallization for 1 hour, and performing suction filtration. The wet product was dried in a hot air circulation drying oven at 60 ℃ for 12 hours to obtain 4.7kg of a white powder solid with a yield of 94.0%. As checked, the infrared spectrum of the white powdery solid was checked to be in agreement with the characteristic absorption wave number of FIG. 1, and the X-ray powder diffraction pattern was checked to be in agreement with 2. theta. of FIG. 2.
Claims (10)
1. A preparation method of febuxostat crystal form A is characterized by comprising the following steps:
① adding febuxostat into solvent containing acetonitrile, heating and stirring until all the febuxostat is dissolved;
②, carrying out hot filtration, cooling the temperature of the filtrate to 60-75 ℃, adding 0-2.0% of seed crystal into the reaction solution, wherein the seed crystal is febuxostat A crystal form, carrying out cooling by stages, finally cooling to 0-20 ℃, and carrying out heat preservation and crystallization;
③ separating, washing, and drying to obtain the final product.
2. The preparation method of febuxostat crystal form A according to claim 1, wherein the solvent containing acetonitrile in the step ① is anhydrous acetonitrile or a mixed solvent of acetonitrile and water, preferably a mixed solvent of acetonitrile and water, and further preferably the weight ratio of acetonitrile to water in the mixed solvent of acetonitrile and water is 1: 1-20: 1.
3. The preparation method of febuxostat crystal form A according to claim 1, wherein the weight ratio of the febuxostat to the acetonitrile-containing solvent in the step ① is 1: 20-1: 50, preferably 1: 20-1: 30.
4. The preparation method of febuxostat crystal form A according to claim 1, wherein in the step ①, the heating and stirring temperature is 75-78 ℃.
5. The method for preparing febuxostat crystal form A according to claim 1, wherein the temperature is reduced to 45-50 ℃ within 0.25-1.5 hours in the first stage, and is reduced to 0-20 ℃ within 0.25-1.5 hours in the second stage in the step ② in a segmented manner.
6. The preparation method of the febuxostat crystal form A according to claim 5, characterized in that the temperature is reduced to 0-20 ℃ within 15-40 min at the first stage cooling rate, and is reduced to 45-50 ℃ within 15-30 min at the second stage cooling rate in step ②, preferably within 15-40 min at the first stage cooling rate, and is reduced to 45-50 ℃ within 15-30 min at the second stage cooling rate, and is reduced to 15-20 ℃.
7. The preparation method of febuxostat crystal form A according to claim 1, wherein the temperature in the step ② is finally reduced to 0-20 ℃, and then the mixture is stirred, kept warm and crystallized for 0.5-2 hours.
8. The preparation method of febuxostat crystal form A according to claim 1, wherein the drying mode in the step ③ is hot air circulation drying or vacuum drying, preferably the drying temperature is 30-80 ℃, and more preferably the drying temperature is 60-80 ℃.
9. The method for preparing febuxostat crystal form A according to claim 1, wherein the drying time in the step ③ is 8-20 hours.
10. The preparation method of febuxostat crystal form A according to any one of claims 1-9, wherein the product obtained in step ③ is single febuxostat crystal form A.
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| JP2011020950A (en) * | 2009-07-15 | 2011-02-03 | Mitsutaka Kitamura | Method for producing crystal polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011020950A (en) * | 2009-07-15 | 2011-02-03 | Mitsutaka Kitamura | Method for producing crystal polymorph of 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid |
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Application publication date: 20200616 |