CN106397442B

Movatterモバイル変換

Info

Publication number: CN106397442B
Application number: CN201510459549.1A
Authority: CN
Inventors: 张福利; 吴立前; 裘鹏程; 焦慧荣; 蒋敏; 陈梦柯; 陈辉; 柯彬; 王磊
Original assignee: Shanghai Institute of Pharmaceutical Industry; China National Medicines Guorui Pharmaceutical Co Ltd
Current assignee: Shanghai Institute of Pharmaceutical Industry; China National Medicines Guorui Pharmaceutical Co Ltd
Priority date: 2015-07-28
Filing date: 2015-07-28
Publication date: 2020-03-27
Anticipated expiration: 2035-07-28
Also published as: CN106397442A

Abstract

Translated fromChinese

本发明公开了一种瑞加德松的纯化方法。该方法包括下列步骤：在碱水溶液的作用下，将含杂质A的瑞加德松粗品与极性有机溶剂混合，析晶，即可；其中，所述的瑞加德松粗品中杂质A的含量为0.1％～1.0％。本发明的纯化方法能够高效除去瑞加德松粗品中的杂质A，得到的瑞加德松产品中杂质A含量在0.10％以下，最低含量在0.04％以下，进一步提高瑞加德松产品的HPLC纯度，使最后得到瑞加德松产品的HPLC纯度在99.80％以上；产品质量好，完全符合ICH Q3a的杂质限量标准。

The invention discloses a purification method of Regardson. The method comprises the following steps: under the action of the alkaline aqueous solution, mixing the regadesone crude product containing impurity A with a polar organic solvent, and crystallization; The content is 0.1% to 1.0%. The purification method of the invention can efficiently remove the impurity A in the regadesone crude product, the content of the impurity A in the obtained regadesone product is below 0.10%, the minimum content is below 0.04%, and the HPLC of the regadesone product is further improved. Purity, so that the HPLC purity of the finally obtained Regardson product is more than 99.80%; the product quality is good and fully meets the ICH Q3a impurity limit standard.

Description

Purification method of regadenoson

Technical Field

The invention provides a purification method of regadenoson.

Background

Regadenoson, common english name Regadenoson, chemical name 1- (6-amino-9- β -D-ribofuranosyl-9H-purin-2-yl) -N-methyl-1H-pyrazole-4-carboxamide, formula C₁₅H₁₈N₈O₅And a molecular weight of 390.35 CAS registry number 875148-45-1, adenosine A, co-developed by CV Therapeutics and Astellas Pharma, USA_2AReceptor agonists by activation of adenosine A_2AThe receptor expands coronary artery blood vessels, increases coronary artery blood flow to assist in diagnosing coronary artery disease, is marketed in the united states 4 months 2008 for radionuclide myocardial perfusion imaging, and has the following structure:

patent CN102260311A reports that the synthesis method of regadenoson is: taking 2-chloroadenosine 2 as an initial raw material, preparing 2-hydrazino adenosine 3 by hydrazine hydrate substitution, then condensing and closing with 2-formyl 3-oxo ethyl propionate to obtain a compound 4, and hydrolyzing the compound 4 by methylamine aqueous solution to obtain the regadenoson 1, wherein the specific synthetic route is as follows:

the patent also discloses a purification method of the regadenoson, which comprises the following specific steps: dissolving the crude product of the regadenoson in dimethyl sulfoxide, adding pure water into the solution, filtering the slurry formed by the solution, washing a filter cake by water and ethanol in sequence, and finally drying to obtain the product of the regadenoson.

Patent CN101668768A discloses a preparation method and a purification method of regadenoson, wherein the synthetic route of the preparation method of the crude product is shown in the above reaction equation, and the patent also discloses a purification method of regadenoson, which specifically comprises the following steps: dissolving the crude product of the regadenoson in dimethyl sulfoxide to obtain a solution, maintaining the temperature at 78-88 ℃, adding the solution into pure water to form slurry, filtering the slurry, washing a filter cake by water and ethanol in sequence, and finally drying to obtain the regadenoson product.

However, the inventor of the present application repeated the above-mentioned methods for synthesizing and purifying CN102260311A and CN101668768A, and found that the crude regadenoson product contains an impurity with a content of > 0.1%, so that the final regadenoson product does not meet the impurity limit standard of ICH Q3a (note: the standard requires that the content of single impurity of the drug is less than 0.1%), and cannot meet the quality requirement of the drug. Therefore, there is a need in the art for a purification method of regadenoson to solve the above technical problems.

Disclosure of Invention

The invention aims to solve the technical problem of providing a purification method of regadenoson, aiming at overcoming the defects that the regadenoson product obtained by the existing purification method of the regadenoson crude product with impurity A as the main impurity has high impurity A content and poor quality, the regadenoson product with impurity A content less than 0.1 percent and meeting the medicine quality requirement and the like. The purification method can efficiently remove the impurity A in the crude product of the regadenoson, the content of the impurity A in the obtained regadenoson product is below 0.10 percent, the lowest content is below 0.04 percent, the HPLC purity of the regadenoson product is further improved, and the HPLC purity of the finally obtained regadenoson product is above 99.80 percent; the product has good quality and completely meets the impurity limit standard of ICH Q3 a.

The inventors isolated, purified and structurally identified impurities in the regadenoson products obtained in the methods disclosed in the above-mentioned CN102260311A and CN101668768A patents, and confirmed that the structural formula of the impurities is as follows, and named as impurity a:

after the intensive research and analysis of the inventors, the cause of the impurity a is mainly: in both the above processes for the preparation of regadenoson, compound 4 undergoes a hydrolysis side reaction simultaneously with the aminolysis in aqueous methylamine solution, thus producing impurity a with properties very similar to those of the regadenoson product.

The inventor prepares crude regadenoson HPLC purity of 99.58% and impurity A content of 0.35% according to the two synthetic routes; repeating the two purification methods to obtain the product of the regadenoson, wherein the HPLC purity of the product of the regadenoson is 99.60 percent, and the content of the impurity A is 0.33 percent; it can be seen that the above two purification methods have difficulty in removing impurity a. Moreover, the main impurity in the regadenoson product prepared by the two synthesis methods is the impurity A, and the existence of the impurity A has great influence on the quality of the regadenoson product, so that the effective control and removal of the impurity are the key points for obtaining the regadenoson product meeting the quality requirement of medicines. In addition, the presence of this impurity may cause serious side reactions, and thus, there is a strong need in the art for a method for effectively removing impurity a from the product of regadenoson, in order to solve the above technical problems.

The invention mainly solves the technical problem through the following technical scheme.

The invention provides a purification method of regadenoson, which comprises the following steps: under the action of alkaline water, mixing the crude product of the regadenoson containing the impurity A with a polar organic solvent, and crystallizing; wherein, the content of the impurity A in the crude product of the regadenoson is 0.1 to 1.0 percent.

In the purification method, the HPLC purity of the crude regadenoson product is not particularly limited as long as the main impurity in the crude regadenoson product is impurity a, preferably the HPLC purity of the crude regadenoson product is 98.0% to 99.8%, more preferably 99.0% to 99.8%, and most preferably 99.5% to 99.7%. The content of the impurity A is preferably 0.1-0.5%.

The purification method is preferably any one of the following modes:

the first method is as follows: mixing the crude product of the regadenoson with a polar organic solvent, adding an alkaline aqueous solution at the temperature of 50-80 ℃ (preferably 65-80 ℃), and crystallizing;

the second method comprises the following steps: mixing the crude product of the regadenoson with a solvent at the temperature of 50-80 ℃ (preferably 65-80 ℃), and crystallizing; the solvent is a mixed solution of a polar organic solvent and an alkaline water solution.

In the present invention, the polar organic solvent preferably includes a protic polar organic solvent and/or an aprotic polar organic solvent. The protic polar organic solvent may be a protic polar organic solvent as is conventional in the art, preferably C₁～C₄The alcohol solvent of (1). Said C₁～C₄The alcoholic solvent of (a) is preferably one or more of methanol, ethanol, isopropanol and n-butanol, more preferably one or more of methanol, ethanol and isopropanol. When said C is₁～C₄When the alcohol solvent is n-butanol, it is generally necessary to use the alcohol solvent in combination with another protic polar organic solvent and/or the aprotic polar organic solvent of the present invention. The other protic polar organic solvent is preferably one or more of methanol, ethanol and isopropanol. The aprotic polar organic solvent may be an aprotic polar organic solvent which is conventional in the art, and preferably one or more of a ketone solvent, a sulfoxide solvent and an amide solvent. The ketone solvent is preferably acetone. The sulfoxide solvent is preferably dimethyl sulfoxide. The amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide.

In the present invention, the alkali in the aqueous alkali solution is preferably an inorganic alkali and/or an organic alkali. The inorganic base may be an inorganic base conventional in the art, preferably one or more of an alkali metal hydroxide, an alkaline earth metal hydroxide and an alkali metal carbonate, more preferably an alkali metal hydroxide and/or an alkali metal carbonate. The alkali metal hydroxide is preferably sodium hydroxide and/or potassium hydroxide. The alkaline earth metal hydroxide is preferably calcium hydroxide. The alkali metal carbonate is preferably sodium carbonate and/or potassium carbonate. The organic base may be any organic base conventional in the art, preferably C₁～C₆Of an alkylamine of (a). Said C₁～C₆The alkylamine of (a) is preferably one or more of methylamine, dimethylamine, diethylamine and triethylamine. The molar concentration of the aqueous alkali solution is preferably 0.01 to 1 mol/L.

In the first embodiment, the volume/mass ratio of the polar organic solvent to the crude regadenoson product is preferably 3 to 20mL/g, more preferably 6 to 10 mL/g. The ratio of the alkaline aqueous solution with the molar concentration of 0.01-1 mol/L to the volume mass of the regadenoson is preferably 3-20 mL/g, more preferably 3-15 mL/g. The addition is preferably dropwise. The dropping speed is preferably controlled to be between 50 and 80 ℃ (preferably 65 to 80 ℃), and is generally 1mL/min to 10 mL/min.

In the second embodiment, the solvent is a mixed solution of a polar organic solvent and an aqueous alkali solution, wherein the volume ratio of the polar organic solvent to the aqueous alkali solution is preferably 1:1 to 10:1, and more preferably 1:1 to 3: 1. The volume and mass ratio of the solvent to the crude product of the regadenoson is preferably 40mL/g to 80 mL/g.

In the first or second mode, the crystallization is preferably performed by stirring. The time for crystallization is preferably 1 to 3 hours. The temperature for crystallization is preferably room temperature (10-30 ℃).

In the first or second mode, after the crystallization, the method preferably further comprises the following steps: filtering the system after crystallization, and sequentially using water and C₁～C₄Washing the filter cake with the alcohol solvent, and drying to obtain the product of the regadenoson. Wherein, said C₁～C₄The alcoholic solvent of (b) is preferably methanol and/or ethanol. Said water or said C₁～C₄The alcohol solvent of (2) is preferably 5mL/g to 10mL/g in comparison with the crude product of regadenoson in terms of volume and mass. The drying method may be a method conventional in the art, and preferably vacuum drying. The temperature of the vacuum drying is preferably 45-55 ℃.

In the invention, the crude regadenoson product can be prepared according to a conventional preparation method of the crude regadenoson product in the field, preferably according to a method described in embodiments 2-4 of a patent CN102260311 or a patent CN101668768, and the HPLC purity of the crude regadenoson product is generally between 98% and 99.8%; the content of the impurity A is generally between 0.1 and 1.0 percent.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows:

the purification method can efficiently remove the impurity A in the crude product of the regadenoson, the content of the impurity A in the obtained regadenoson product is below 0.10 percent, the lowest content is below 0.04 percent, the HPLC purity of the regadenoson product is further improved, and the HPLC purity of the finally obtained regadenoson product is above 99.80 percent; the product has good quality and completely meets the impurity limit standard of ICH Q3 a.

Drawings

FIG. 1 is an HPLC chromatogram of crude regadenoson of example 1.

FIG. 2 is HPLC chromatogram of purified regadenoson product of example 1.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The crude product of regadenoson in the following examples is prepared by the method described in patent CN102260311 or patent CN101668768 examples 2-4, and the HPLC purity is 98-99.8%; the content of the impurity A is 0.1-1.0%.

The specific conditions for HPLC testing of crude and product regadenoson in the following examples are as follows:

adopting a Thermo UltiMate 3000 high performance liquid chromatograph; chromatography column Waters X-bridge C18 column (4.6 mm. times.150 mm, 3.5 μm); mobile phase 20mmol/L potassium dihydrogen phosphate solution (pH 6.8) (a), acetonitrile (B); gradient elution (0 → 5min, a 95%; 5 → 20min, a 95% → 85%; 20 → 30min, a 85% → 40%; 30 → 38min, a 40%; 38 → 38.1min, a 40% → 95%; 38.1 → 45min, a 95%); the detection wavelength is 245 nm; the flow rate is 1.0 ml/min; column temperature 25 deg.C

Example 1

Taking 1g of a crude product of the regadenoson (the HPLC purity is 99.58 percent, and the content of the impurity A is 0.35 percent), adding 6mL of LDMSO to dissolve the crude product, heating the crude product to about 80 ℃, dropwise adding 9mL of a sodium hydroxide aqueous solution with the concentration of 0.1mol/L, gradually separating out a white solid in the dropwise adding process, naturally cooling the crude product to room temperature after the dropwise adding is finished, stirring the solution for 2 hours, filtering the solution, washing a filter cake by using 10mL of pure water and 10mL of ethanol in sequence, and performing vacuum drying at 50 ℃ to obtain 0.97g of the regadeno. HPLC results showed 99.89% regadenoson and 0.05% impurity a.

Example 2

Taking 1g of a crude product of the regadenoson (the HPLC purity is 98.0%, the content of the impurity A is 1.0%), adding 20mL of LDMSO to dissolve the crude product, heating the crude product to about 70 ℃, dropwise adding 3mL of a 0.5mol/L potassium carbonate aqueous solution, gradually separating out a solid in the dropwise adding process, naturally cooling the crude product to room temperature after the dropwise adding is finished, stirring the crude product for 3 hours, filtering the solution, washing a filter cake by using 10mL of pure water and 10mL of ethanol in sequence, and performing vacuum drying at 55 ℃ to obtain 0.85g of the regadenoson product. The HPLC results showed that the content of regadenoson was 99.87% and the content of impurity a was 0.03%.

Example 3

Taking 1g of a crude product of the regadenoson (the HPLC purity is 99.50 percent, the content of the impurity A is 0.45 percent), adding 10mL of DMMF to dissolve the crude product, heating the crude product to about 70 ℃, dropwise adding 6mL of a sodium carbonate aqueous solution with the concentration of 0.1mol/L, gradually separating out a solid in the dropwise adding process, naturally cooling the crude product to room temperature after the dropwise adding is finished, stirring the solution for 2 hours, filtering the solution, washing a filter cake by using 10mL of pure water and 10mL of ethanol in sequence, and performing vacuum drying at 50 ℃ to obtain 0.95g of the regadeno. HPLC results showed that the content of regadenoson was 99.89% and the content of impurity a was 0.04%.

Example 4

2g of crude regadenoson (with HPLC purity of 99.58 percent and impurity A content of 0.35 percent) is taken, 80mL of 0.01mol/L potassium hydroxide aqueous solution/methanol mixed solvent (with volume ratio of 10/1) is added, the mixture is heated to about 75 ℃, the solid is completely dissolved, then the mixture is naturally cooled to room temperature, the mixture is stirred for 1h, the filtration is carried out, 10mL of pure water and 10mL of ethanol are sequentially used for washing a filter cake, and the vacuum drying at 50 ℃ is carried out to obtain 1.86g of the regadenoson product. The HPLC results showed a content of 99.88% for regadenoson and 0.05% for impurity a.

Example 5

2g of a crude product of the regadenoson (the HPLC purity is 98.0%, the content of the impurity A is 1.0%) is taken, 80mL (the volume ratio is 1/1) of a dimethylamine aqueous solution/n-butanol mixed solvent of 1mol/L is added, the mixture is heated to about 50 ℃, the solid is completely dissolved, then the mixture is naturally cooled to room temperature, the mixture is stirred for 2 hours, the filtration is carried out, 10mL of pure water and 10mL of ethanol are used for washing a filter cake, and the vacuum drying is carried out at 45 ℃ to obtain 1.81g of the regadenoson product. The HPLC results showed that the content of regadenoson was 99.82% and the content of impurity a was 0.09%.

Example 6

0.8g of crude regadenoson (HPLC purity 99.80%, impurity A content 0.16%) is taken, 64mL (volume ratio of 1/10) of 1mol/L triethylamine water solution/acetone mixed solvent is added, the mixture is heated to about 68 ℃ to completely dissolve the solid, then the solid is naturally cooled to room temperature, the mixture is stirred for 1h, filtered, 8mL of pure water and 8mL of ethanol are used for washing a filter cake, and vacuum drying is carried out at 50 ℃ to obtain 0.65g of the regadenoson product. The HPLC results showed that the content of regadenoson was 99.91% and the content of impurity a was 0.06%.

Example 7

Taking 1g of a crude product of the regadenoson (the HPLC purity is 98.0%, the content of the impurity A is 1.0%), adding 3mL of N, N-dimethylacetamide, heating to about 68 ℃, dropwise adding 15mL of a calcium hydroxide aqueous solution with the concentration of 0.01mol/L, gradually separating out a solid in the dropwise adding process, naturally cooling to room temperature after dropwise adding, stirring for 3h, filtering, washing a filter cake by using 10mL of pure water and 10mL of ethanol in sequence, and performing vacuum drying at 50 ℃ to obtain 0.85g of the regadenoson product. The HPLC results showed that the content of regadenoson was 99.87% and the content of impurity a was 0.04%.

Fig. 1 and table 1 show HPLC spectra of crude regadenoson prepared by the method described in example 2 of patent CN102260311A, and information on retention time, peak height, peak area, relative area, etc. Wherein 1, 2 and 3 correspond to the information of retention time, peak height, peak area, relative area and the like of each component in the regadenoson product. 1 represents impurity a, 2 represents regadenoson, and 3 represents other impurities.

Fig. 2 and table 2 show information on retention time, peak height, peak area, relative area, etc. of the HPLC chromatogram of the regadenoson product obtained in example 1. Wherein, 1, 2 and 3 correspond to the information of retention time, peak height, peak area, relative area and the like of each component in the regadenoson product. 1 represents impurity a, 2 represents regadenoson, and 3 represents other impurities.

TABLE 1

TABLE 2

Comparative example 1

Taking 1g of a crude product of the regadenoson (the HPLC purity is 99.58 percent, and the content of the impurity A is 0.35 percent), adding 6mL of LDMSO to dissolve the crude product, heating the crude product to about 80 ℃, dropwise adding 9mL of pure water, gradually separating out a white solid in the dropwise adding process, naturally cooling the crude product to room temperature after the dropwise adding is finished, stirring the crude product for 2 hours, filtering the solution, washing a filter cake by using 10mL of pure water and 10mL of ethanol in sequence, and performing vacuum drying at 50 ℃ to obtain 0.97g of the regadenoson. The HPLC results showed that the regadenoson content was 99.62% and the impurity a content was 0.33%.

Claims

Translated fromChinese

1.一种瑞加德松的纯化方法，其特征在于，其包括下列步骤：在碱水溶液的作用下，将含杂质A的瑞加德松粗品与极性有机溶剂混合，析晶，即可；其中，所述的瑞加德松粗品中杂质A的含量为0.1％～1.0％；所述的碱水溶液的摩尔浓度为0.01mol/L～1mol/L；所述的瑞加德松粗品的HPLC纯度为98.0％～99.8％；1. a purification method of Regardson, it is characterized in that, it may further comprise the steps: under the effect of alkaline aqueous solution, the crude product of Regardson containing impurity A is mixed with polar organic solvent, crystallization, get final product Wherein, the content of impurity A in the described Ruigadesone crude product is 0.1%～1.0%; The molar concentration of the described alkaline aqueous solution is 0.01mol/L～1mol/L; HPLC purity is 98.0%～99.8%;

所述的纯化方法，其为下列任一方式：Described purification method, it is any of the following ways:

方式一：将所述的瑞加德松粗品与极性有机溶剂混合后，在50℃～80℃的温度下，加入碱水溶液，析晶，即可；Method 1: after mixing the crude regadesone product with a polar organic solvent, at a temperature of 50°C to 80°C, add an alkaline aqueous solution to crystallize;

方式二：在50～80℃的温度下，将所述的瑞加德松粗品与溶剂混合，析晶，即可；所述的溶剂为极性有机溶剂与碱水溶液的混合溶液；Method 2: at a temperature of 50 to 80 ° C, the crude regadesone product is mixed with a solvent, and then crystallized; the solvent is a mixed solution of a polar organic solvent and an aqueous alkali solution;

所述的极性有机溶剂包括质子性极性有机溶剂和/或非质子性极性有机溶剂；所述的碱水溶液中的碱为无机碱和/或有机碱；Described polar organic solvent includes protic polar organic solvent and/or aprotic polar organic solvent; the alkali in described alkali aqueous solution is inorganic alkali and/or organic alkali;

所述的质子性极性有机溶剂为C₁～C₄的醇类溶剂；所述的非质子性极性有机溶剂为酮类溶剂、亚砜类溶剂和酰胺类溶剂中的一种或多种；所述的无机碱为碱金属氢氧化物、碱土金属氢氧化物和碱金属的碳酸盐中的一种或多种；所述的有机碱为C₁～C₆的烷基胺；The protic polar organic solvent is a C₁ -C₄ alcohol solvent; the aprotic polar organic solvent is one or more of ketone solvents, sulfoxide solvents and amide solvents ; the inorganic base is one or more of alkali metal hydroxide, alkaline earth metal hydroxide and alkali metal carbonate; the organic base is C₁ -C₆ alkylamine;

方式一中，所述的极性有机溶剂与所述的瑞加德松粗品的体积质量为3～20mL/g；所述的摩尔浓度为0.01mol/L～1mol/L的碱水溶液与所述的瑞加德松的体积质量比为3～20mL/g；In the first mode, the volume mass of the polar organic solvent and the crude regadesone product is 3～20mL/g; the molar concentration of the alkaline aqueous solution is 0.01mol/L～1mol/L and the The volume-to-mass ratio of regadesone is 3 to 20 mL/g;

方式二中，所述的溶剂为极性有机溶剂与碱水溶液的混合溶液，其中所述的极性有机溶剂与碱水溶液的体积比为1:1～10:1；所述的溶剂与所述的瑞加德松粗品的体积质量比为40mL/g～80mL/g；In the second mode, the solvent is a mixed solution of a polar organic solvent and an aqueous alkali solution, wherein the volume ratio of the polar organic solvent to the aqueous alkali solution is 1:1 to 10:1; The volume-to-mass ratio of the crude regadesone is 40mL/g～80mL/g;

2.如权利要求1所述的纯化方法，其特征在于，所述的瑞加德松粗品中杂质A的含量为0.1％～0.5％。2 . The purification method according to claim 1 , wherein the content of impurity A in the crude regardson product is 0.1% to 0.5%. 3 .

3.如权利要求1所述的纯化方法，其特征在于，所述的瑞加德松粗品的HPLC纯度为99.0％～99.8％。3 . The purification method according to claim 1 , wherein the HPLC purity of the regadesone crude product is 99.0% to 99.8%. 4 .

4.如权利要求3所述的纯化方法，其特征在于，所述的瑞加德松粗品的HPLC纯度为99.5％～99.7％。4 . The purification method according to claim 3 , wherein the HPLC purity of the regadesone crude product is 99.5% to 99.7%. 5 .

5.如权利要求1所述的纯化方法，其特征在于，方式一或方式二中，所述的析晶的方法为搅拌析晶；所述的析晶的时间为1～3h；和/或，所述的析晶的温度为10～30℃。5. The purification method according to claim 1, wherein, in the first mode or the second mode, the crystallization method is stirring crystallization; the crystallization time is 1～3h; and/or , the temperature of the crystallization is 10～30℃.

6.如权利要求1所述的纯化方法，其特征在于，所述的C₁～C₄的醇类溶剂为甲醇、乙醇、异丙醇和正丁醇中的一种或多种；当所述的C₁～C₄的醇类溶剂为正丁醇时，所述的正丁醇与其他质子性极性有机溶剂和/或所述的非质子性极性有机溶剂混合使用；所述的其他质子性极性有机溶剂为甲醇、乙醇和异丙醇中的一种或多种；所述的酮类溶剂为丙酮；所述的亚砜类溶剂为二甲亚砜；所述的酰胺类溶剂为N,N-二甲基甲酰胺和/或N,N-二甲基乙酰胺；所述的碱金属氢氧化物为氢氧化钠和/或氢氧化钾；所述的碱土金属氢氧化物为氢氧化钙；所述的碱金属的碳酸盐为碳酸钠和/或碳酸钾；和/或，所述的C₁～C₆的烷基胺为甲胺、二甲胺、二乙胺和三乙胺中的一种或多种。6 . The purification method according to claim 1 , wherein the alcohol solvent of C₁ to C₄ is one or more of methanol, ethanol, isopropanol and n-butanol; When the C₁ -C₄ alcoholic solvent is n-butanol, the n-butanol is mixed with other protic polar organic solvents and/or the aprotic polar organic solvents; the other The protic polar organic solvent is one or more of methanol, ethanol and isopropanol; the ketone solvent is acetone; the sulfoxide solvent is dimethyl sulfoxide; the amide solvent It is N,N-dimethylformamide and/or N,N-dimethylacetamide; the alkali metal hydroxide is sodium hydroxide and/or potassium hydroxide; the alkaline earth metal hydroxide is calcium hydroxide; the carbonate of the alkali metal is sodium carbonate and/or potassium carbonate; and/or the alkylamine of C₁ -C₆ is methylamine, dimethylamine, diethylamine and one or more of triethylamine.

7.如权利要求1所述的纯化方法，其特征在于，方式一中，所述的加入的方式为滴加；和/或，所述的滴加的速度为控制反应体系温度在50～80℃之间。7. The purification method according to claim 1, wherein, in the first mode, the method of adding is dropwise; and/or, the speed of the dropwise addition is to control the temperature of the reaction system at 50-80 between °C.

8.如权利要求1所述的纯化方法，其特征在于，方式一或方式二中，所述的析晶结束后，还进一步包括下列步骤：将析晶结束后的体系，过滤，依次用水和C₁～C₄的醇类溶剂洗涤滤饼，干燥，即得瑞加德松产品。8. purification method as claimed in claim 1 is characterized in that, in mode one or mode two, after described crystallization finishes, also further comprises the following steps: by the system after crystallization finishes, filter, successively use water and The filter cake is washed with a C₁ -C₄ alcoholic solvent, and dried to obtain the Regardson product.