CN112321493A

CN112321493A - Etoricoxib purification method

Info

Publication number: CN112321493A
Application number: CN202011168670.6A
Authority: CN
Inventors: 刘超; 吴昆�; 杨以建; 叶子峥; 唐燕; 彭显峰; 戴萍
Original assignee: SICHUAN SUNRISE BIOPHARM Ltd
Current assignee: SICHUAN SUNRISE BIOPHARM Ltd
Priority date: 2020-10-28
Filing date: 2020-10-28
Publication date: 2021-02-05

Abstract

The invention discloses a method for purifying etoricoxib, which comprises the steps of adding a crude product of etoricoxib to be purified into a ketone solvent at room temperature, cooling and crystallizing, filtering and drying under the condition of adding or not adding a poor solvent after a solid is dissolved and becomes turbid, and further crystallizing an obtained sample to obtain a high-purity final product of etoricoxib.

Description

Etoricoxib purification method

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for purifying etoricoxib.

Background

Etoricoxib is a selective inhibitor of cyclooxygenase-2, has the effects of resisting inflammation, reducing fever and relieving pain, and has the following chemical structure.

Etoricoxib has been marketed in 84 countries and regions in the uk, spain, australia, china etc. in the form of film coated tablets, primarily for clinical use as a non-steroidal anti-inflammatory drug. The American college of rheumatology guidelines for gout diagnosis and treatment recommend etoricoxib as a drug for the treatment of acute gouty arthritis. Etoricoxib is also recommended to be selected by patients with gastrointestinal risks according to the Chinese osteoarthritis diagnosis and treatment guidelines and the expert opinion of orthopedic pain management in the bone science conference of the Chinese medical society.

At present, the method for synthesizing etoricoxib under the prior art conditions is mainly obtained by directly reacting an intermediate II and an intermediate III, most of post-treatment adopts salt formation and dissociation for purification (CN106632003A, CN104710349A, CN1443168A, WO2013144977 and the like), and after dissociation of part of documents, even treatment is carried out by adopting a reduced pressure concentration mode, so that the method has the advantages of complex steps, long period and high cost,

the concentration for a long time in the large-scale production not only wastes energy, manpower and the like, but also can increase other impurities in the sample, and although the obtained final product meets the requirements of the raw material medicines, the state is still white-like to yellow, and the color state of part of the sample even can not meet the basic requirements of the raw material medicines. Although patent CN109574919A does not adopt a purification method of dissociation after salt formation, the post-treatment process is very complicated, not only adopts two refining processes, but also uses metal or phosphorus trichloride having strong corrosion to equipment in the refining process, the purification steps are extremely complicated and not environment-friendly, and the safety of the raw material medicine is worthy of further confirmation. Although the refined product is detected, the related substances meet the requirements, the color of the obtained primary refined product is still yellow, the color of the secondary refined product is similar to white, and the final product obtained after crystal transformation is still similar to white. In bulk drugs, any substance that affects the safety and effectiveness of a drug is called an impurity. Although the above-mentioned documents do not explicitly indicate that the tedious purification steps are mainly aimed at removing color impurities and other related impurities contained in the sample, the present inventors have conducted a great deal of experimental verification that the color impurities contained in the crude product obtained by the synthesis of this main route are very difficult to remove. In addition, the original manufacturer of etoricoxib, namely default Shadong, also clearly specifies in the quality standard that the color of the etoricoxib raw material medicine is white to off-white. This also illustrates, on the other hand, the problem that etoricoxib drug substance is difficult to solve in the presence of color impurities.

Disclosure of Invention

The invention aims to provide a method for purifying etoricoxib, which has mild conditions and simple operation and avoids the complicated steps of salification and re-dissociation in the subsequent purification steps. The color of the high-purity sample prepared by the method is white, the absorbance of the sample is between 0 and 0.15, the HPLC purity is more than 99.9 percent, and the single maximum impurity is below 0.10 percent.

The invention discloses a method for purifying etoricoxib, which comprises the following steps:

1) under the condition of room temperature, adding the crude etoricoxib product to be purified into a ketone solvent with the volume of 2-10 times (mass volume times, the same below) until the solid is dissolved and becomes turbid;

2) cooling and crystallizing, filtering and drying under the condition of adding or not adding a poor solvent, further crystallizing the obtained sample to obtain a final product, namely the high-purity etoricoxib,

wherein, the ketone solvent in step 1) is selected from acetone, butanone, methyl isobutyl ketone, cyclohexanone, 2-butanone, cyclopropanone and any mixture thereof, and the poor solvent in step 2) is selected from water, n-hexane, n-heptane, cyclohexane and any mixture thereof.

Preferably, in the purification method of the present invention, the volume ratio of the ketone solvent to the poor solvent is: 1: 0 to 5, more preferably: 1: 0 to 1.

Preferably, the above-mentioned purification method of the present invention is preferably applied to the purification of crude etoricoxib obtained from a solvent selected from the group consisting of tetrahydrofuran, methanol, ethanol, isopropanol, water and any mixture thereof.

Preferably, in the purification method of the present invention, the ketone solvent is acetone or methyl isobutyl ketone, more preferably acetone, and the poor solvent is water or n-heptane, more preferably water.

Preferably, in the purification method of the present invention, the volume (ml or L) of the ketone solvent is 2 to 5 times, preferably 2 to 3 times of the mass (g or Kg) of etoricoxib.

Preferably, in the purification method of the present invention, in the step 2), the temperature for cooling and crystallizing is controlled to be-10 to 10 ℃, preferably 0 to 5 ℃.

Preferably, the high-purity etoricoxib obtained by the purification method of the present invention is prepared into a solution with a concentration of 0.1g/mL according to the first method of 0901, the first method of the general rules of the four ministry of the china pharmacopoeia 2015 edition, wherein the color of the solution is between yellow or yellow-green 0.5 and 1 standard colorimetric solutions. Or under the condition of 400nm wavelength, preparing a solution with the concentration of 0.1g/mL, and determining that the absorbance of the solution is between 0 and 0.15. Purity greater than or equal to 99.9% by HPLC, with individual maximum impurities below 0.10%.

In some embodiments, a method of the invention for purifying etoricoxib comprises:

under the condition of room temperature, adding the crude etoricoxib product to be purified into a ketone solvent of which the volume is 2-10 times that of the crude etoricoxib product, adding or not adding a poor solvent after the solid is dissolved and becomes turbid, cooling and crystallizing, filtering, and drying to obtain a sample;

wherein, the crude etoricoxib product to be purified is obtained from tetrahydrofuran, methanol, ethanol, isopropanol, water and any mixture thereof; the ketone solvent is selected from acetone, butanone, methyl isobutyl ketone, cyclohexanone, 2-butanone, cyclopropanone and any mixture thereof, and the poor solvent is selected from water, n-hexane, n-heptane, cyclohexane and any mixture thereof.

In the above embodiment, preferably, in the purification method of the present invention, the volume (ml) of the ketone solvent is 2 to 5 times of the mass (g) of etoricoxib, and preferably, the volume (ml) of the ketone solvent is 2 to 3 times of the mass (g) of etoricoxib.

In the above embodiment, in the purification method of the present invention, the volume ratio of the ketone solvent to the poor solvent is 1: 0 to 5, preferably 1: 0 to 1; the ketone solvent is preferably acetone, methyl isobutyl ketone or a mixture of the two, and more preferably acetone; the poor solvent is water or n-heptane, preferably, the poor solvent is water.

In the embodiment, the temperature for cooling crystallization is controlled to be-10 to 10 ℃, and preferably, the temperature for cooling crystallization is 0 to 5 ℃.

The purification method of the invention, wherein the crude etoricoxib to be purified can be prepared by the prior art, such as the method disclosed in organic. letters.2000,15(2): 2339-2341, which is incorporated by reference in its entirety, or can be purchased commercially.

The purification process of the invention, the "crystal transformation" described in step 2), was carried out with reference to the crystal transformation process of CN107056691A, example 2, which is incorporated herein by reference in its entirety. The detailed description is not repeated herein.

In the invention, the color of etoricoxib is determined by adopting the first method of 0901, the general rule of the four ministry of China pharmacopoeia 2015 edition, 1.0g of etoricoxib is taken, 10ml of methanol is added for dissolving, 0.1g/ml of methanol solution is prepared, the color of the solution is between yellow or yellow-green No. 0.5 and No. 1 standard colorimetric solutions, and the absorbance is measured under the condition of 400nm wavelength. The absorbance of the final etoricoxib products obtained in examples 1-4 was measured to be between 0 and 0.15.

In the present invention, the "volume amount" means the amount of L, i.e., L/Kg, or ml/g, of the volume of the solvent or poor solvent required per Kg of etoricoxib; for example, the volume L (ml) of the ketone solvent is 2-10 times of the mass kg (g) of solute etoricoxib.

In one embodiment, the present invention comprises the steps of:

under the condition of room temperature, adding the crude etoricoxib product to be purified into a ketone solvent with the volume of 2-10 times, adding or not adding a poor solvent after the solid is dissolved and becomes turbid, cooling and crystallizing, filtering, drying, and further crystallizing the obtained sample to obtain a final product.

Wherein the crude etoricoxib product to be purified is a crude product obtained from tetrahydrofuran, methanol, ethanol, isopropanol, water and any mixture thereof; the ketone solvent is selected from acetone, butanone, methyl isobutyl ketone, cyclohexanone, 2-butanone, cyclopropanone and any mixture thereof, and the poor solvent is selected from water, n-heptane, n-hexane, cyclohexane and any mixture thereof.

In the above embodiment, preferably, the volume amount of the ketone solvent is 2 to 3 times of the mass of etoricoxib, and the volume ratio of the ketone solvent to the poor solvent is 1: 0 to 5, preferably 1: 0 to 1; the ketone solvent is acetone, methyl isobutyl ketone or a mixture of the two, and acetone is more preferable; the poor solvent is water or n-heptane, preferably, the poor solvent is water; the temperature for cooling and crystallizing is-10 to 10 ℃, and preferably, the temperature for cooling and crystallizing is 0 to 5 ℃.

In a preferred embodiment, the purification process of the invention comprises the steps of:

adding the etoricoxib crude product to be purified into acetone or methyl isobutyl ketone with the volume of 2-3 times at room temperature, adding or not adding water or n-heptane after the etoricoxib crude product is dissolved and becomes turbid, cooling to 0-5 ℃, crystallizing, filtering, drying, and further crystallizing the obtained sample to obtain a final product, wherein the volume ratio of the ketone solvent to the poor solvent water or n-heptane is 1: 0 to 5, preferably 1: 0 to 1.

Etoricoxib obtained by the purification method of the invention is white crystalline powder, and the color of the solution prepared according to the requirements is between yellow or yellow-green 0.5 and 1 standard colorimetric solutions (first method of 0901 in the four ministry of general regulations in china pharmacopoeia 2015), and the absorbance of the etoricoxib is between 0 and 0.15. Purity (area normalization method) of etoricoxib is greater than or equal to 99.9% through HPLC detection, and single maximum impurities are all below 0.10%.

Currently, etoricoxib is widely used clinically, mainly in the form of film-coated tablets. Most literature reports that the purification method is only concerned about non-color impurities in etoricoxib, but not studied much about color impurities. Any substance that affects the safety and effectiveness of a drug should be well controlled. The inventor finds in practical research that etoricoxib can reach the specified quality standard easily, but color impurities are difficult to remove, particularly, after a crystal transformation step amplification test, the obtained solid particle size has a more obvious influence on the color, and the crystal transformation steps (CN109574919A, CN106632003A and the like) in the prior art are repeated, so that the obtained final product sometimes has a light yellow to off-white color, and cannot meet the quality standard requirements of raw material medicines. However, the inventor unexpectedly discovers that the ketone solvent has special solubility to the crude etoricoxib product to be purified, the solid is immediately dissolved after the etoricoxib is added into a certain amount of the ketone solvent at room temperature, and the solid can be separated out again after stirring. The purification of etoricoxib according to the method provided by the invention not only can effectively remove related substances in the crude product, but also can obviously remove color impurities in the solid, and finally, a white and high-purity sample is obtained through a crystal transformation step. The method has mild conditions and simple operation, avoids the complicated steps of salification and re-dissociation in the subsequent purification steps, and is suitable for industrial production.

Drawings

FIG. 1 is an HPLC chromatogram of a crude etoricoxib product;

FIG. 2 is a diagram showing the appearance of the final etoricoxib product obtained in comparative example 1 in the form of a pale yellow powder;

FIG. 3 is an HPLC chromatogram of the final product of toboxib obtained in comparative example 1 as a pale yellow powder;

FIG. 4 is an HPLC chromatogram of the final product of toboxib obtained in comparative example 2 as a pale yellow powder;

FIG. 5 is an appearance diagram of the final etoricoxib product obtained in example 1 in the form of a white powder;

FIG. 6 is an HPLC chromatogram of the final etoricoxib product obtained in example 1 as a white powder;

fig. 7 is an HPLC chromatogram of the final etoricoxib product obtained in example 2 as a white powder.

Detailed Description

The foregoing examples are merely exemplary for further explanation and understanding of the present invention, and are not intended to limit the scope of the present invention in any way. The crude etoricoxib product used in the following comparative examples and examples was prepared by the method disclosed in organic, letters.2000,15(2): 2339-2341, the crystal transformation process was performed by example 2 in CN107056691A to obtain the final etoricoxib product, which is incorporated by reference in its entirety and the examples herein are not repeated.

Comparative example 1

Weighing 15.6g of the crude etoricoxib product to be purified (the HPLC purity is 99.661%, the single maximum impurity is 0.282%, see figure 1), adding 60mL of methanol, heating to 55-60 ℃ for dissolution, adding 1.0g of activated carbon, heating, refluxing and stirring for 1 hour. And (2) carrying out hot filtration, gradually cooling the filtrate to 0-5 ℃ for crystallization, filtering, drying, carrying out crystal transformation on the obtained sample to obtain 11.6g of light yellow crystalline powder (shown in figure 2), wherein the color of the solution prepared according to the requirement is between yellow or yellow-green No. 2 and No. 3 standard colorimetric solutions (the first method of 0901 in the fourth division of the national pharmacopoeia 2015), and the absorbance is 0.305. The yield thereof was found to be 74.3%. Purity 99.972% by HPLC, single maximum impurity 0.021% (see fig. 3).

Comparative example 2

Weighing 19.0g of the crude etoricoxib product to be purified (the HPLC purity is 99.661%, and the single maximum impurity is 0.282%), adding 95mL of ethanol, heating to 55-60 ℃ to dissolve, adding 1.0g of activated carbon, heating, refluxing and stirring for 1 hour. And (2) carrying out hot filtration, gradually cooling the filtrate to 0-5 ℃ for crystallization, filtering, drying, carrying out crystal transformation on the obtained sample to obtain 13.8g of light yellow crystalline powder, wherein the color of the solution prepared according to the requirement is between yellow or yellow green No. 2 and No. 3 standard colorimetric solutions (the first method of 0901 of the four general rules of Chinese pharmacopoeia 2015), and the absorbance is 0.326. The yield thereof was found to be 72.6%. Purity 99.946% by HPLC, single maximum impurity 0.025% (see fig. 4).

Example 1

Weighing 20.0g of crude etoricoxib product to be purified (with HPLC purity of 99.661% and single maximum impurity of 0.282%), adding 50mL of acetone, stirring at room temperature, gradually dissolving the solid, slowly changing the latter system into turbidity, cooling to-5-0 ℃ for crystallization, filtering, drying, and crystallizing the obtained sample to obtain 16.1g of white crystalline powder (shown in figure 5). The color of the solution prepared according to the requirement is between yellow or yellow-green 0.5 and 1 standard colorimetric solution (the first method of 0901 in the four parts of the pharmacopoeia 2015 year edition), and the absorbance is 0.080. The yield thereof was found to be 80.5%. Purity 99.994% by HPLC, single maximum impurity 0.006% (see fig. 6).

Example 2

Weighing 16.0g of crude etoricoxib product to be purified (with HPLC purity of 99.661% and single maximum impurity of 0.282%), adding 40mL of acetone, stirring at room temperature, gradually dissolving the solid, slowly changing the rear system into turbidity, cooling to 0-5 ℃ for crystallization, adding 40mL of water, filtering, drying, and carrying out crystal transformation on the obtained sample to obtain 13.3g of white crystalline powder. The color of the solution prepared according to the requirement is between yellow or yellow-green 0.5 and 1 standard colorimetric solution (first method of 0901 in the four general rules of Chinese pharmacopoeia 2015), and the absorbance is 0.112. The yield thereof was found to be 83.1%. Purity 99.983% by HPLC, single maximum impurity 0.017% (see fig. 7).

Example 3

Weighing 36.3g of a crude product of etoricoxib to be purified (the HPLC purity is 99.750%, the single maximum impurity is 0.222%), adding 108mL of methyl isobutyl ketone, stirring at room temperature, gradually dissolving the solid, slowly changing the system to be turbid, cooling to 5-10 ℃ for crystallization, adding 108mL of water, filtering, drying, and crystallizing the obtained sample to obtain 30.5g of white crystalline powder. The color of the solution prepared according to the requirement is between yellow or yellow-green 0.5 and 1 standard colorimetric solution (the first method of 0901 in the four parts of the pharmacopoeia 2015 of China), and the absorbance is 0.105. The yield thereof was found to be 84.0%. Purity 99.974% by HPLC, single maximum impurity 0.018%.

Example 4

22.4g of crude etoricoxib product to be purified (with HPLC purity of 99.750% and single maximum impurity of 0.222%) is weighed, 155mL of acetone is added, stirring is carried out at room temperature, the solid is gradually dissolved, the rear system slowly becomes turbid, the temperature is reduced to 0-5 ℃ for crystallization, 77mL of n-heptane is added, filtering and drying are carried out, and 18.1g of white crystalline powder is obtained after crystal transformation of the obtained sample. The color of the solution prepared according to the requirement is between yellow or yellow-green 0.5 and 1 standard colorimetric solution (the first method of 0901 in the four general rules of Chinese pharmacopoeia 2015), and the absorbance is 0.093. The yield thereof was found to be 80.8%. Purity 99.985% by HPLC, single maximum impurity 0.012%.

Example 5

Weighing 0.78kg of crude etoricoxib product to be purified (HPLC purity is 99.625%, single maximum impurity is 0.269%), adding 1.95L of acetone, stirring at room temperature, gradually dissolving the solid, slowly changing the system to be turbid, cooling to 0-5 ℃ for crystallization, adding 1.95L of water, filtering, drying, and crystallizing the obtained sample to obtain 0.65kg of white crystalline powder. The color of the solution prepared according to the requirement is between yellow or yellow-green 0.5 and 1 standard colorimetric solution (first method of 0901 in the four general regulations of the Chinese pharmacopoeia 2015), and the absorbance is 0.081. The yield thereof was found to be 83.3%. Purity 99.987% by HPLC, single maximum impurity 0.010%.

The following table summarizes the results of the measurements of purity, yield, appearance, absorbance, single impurity, etc. of the etoricoxib final products (i.e., the products after crystal transformation) obtained in comparative examples 1-2 and examples 1-4.

Table: results of testing Etoricoxib final products of comparative examples 1-2 and examples 1-4

The data in the table show that the method not only solves the technical problem that the prior art can not remove colored impurities, but also has the double high technical effects of higher purity and higher yield compared with the method adopting ethanol, methanol and the like as crystallization solvents.

Claims

1. A method for purifying etoricoxib, comprising the steps of:

1) under the condition of room temperature, adding the etoricoxib crude product to be purified into a ketone solvent with the volume of 2-10 times of that of the etoricoxib crude product for dissolving;

2) and (3) under the condition of adding or not adding a poor solvent, cooling, crystallizing, filtering and drying to obtain a sample, and further crystallizing to obtain a final product.

2. The purification process according to claim 1, wherein the volume ratio of the ketone solvent to the poor solvent is: 1: 0 to 5, preferably: 1: 0 to 1.

3. The purification method according to claim 1, wherein the volume amount of the ketone solvent is 2-5 times, preferably 2-3 times of the mass of etoricoxib.

4. The purification process according to any one of claims 1 to 3, wherein the ketone solvent is selected from the group consisting of acetone, butanone, methyl isobutyl ketone, cyclohexanone, 2-butanone, cyclopropanone and any mixture thereof, preferably acetone or methyl isobutyl ketone, more preferably acetone.

5. Purification process according to any one of claims 1 to 3, the poor solvent being selected from water, n-hexane, n-heptane, cyclohexane and any mixture thereof, preferably water or n-heptane, more preferably water.

6. The purification method according to claim 1, wherein the temperature for cooling and crystallization is controlled to be-10 to 10 ℃, preferably 0 to 5 ℃.

7. The purification method according to claim 1, step 1), wherein the dissolution comprises a process of dissolving a solid and turning turbid.

8. The purification method according to claim 1, wherein the obtained high-purity etoricoxib is prepared into a solution with a concentration of 0.1g/mL according to the first method of 0901, the national pharmacopoeia 2015 edition of the general rules of the four ministry of the world, wherein the color of the solution is between yellow or yellow-green 0.5 and 1 standard colorimetric solution, or under the condition of a wavelength of 400nm, the solution with a concentration of 0.1g/mL is prepared, and the absorbance of the solution is 0-0.15, the purity of the solution is greater than or equal to 99.9% by HPLC (high performance liquid chromatography), and the single maximum impurity is less than 0.10%.

9. The purification process according to claim 1, wherein the crude etoricoxib to be purified is obtained from a solvent selected from the group consisting of tetrahydrofuran, methanol, ethanol, isopropanol, water and any mixture thereof.