Purification method of imrecoxib bulk drug

Abstract

The invention provides a method for purifying an imrecoxib bulk drug, which comprises the following steps: 1) dissolving an imrecoxib bulk drug crude product in a solvent to form a solution, in the presence of a porous medium, applying an oxygen-containing oxide to the solution, and converting an isomeride, namely an impurity 10, of the bulk drug into an epoxide; (2) the reaction liquid is subjected to aftertreatment, a crude drug refined product is obtained, and the porous medium is activated carbon or porous carbon fibers. According to the method provided by the invention, the content of the impurity 10 can be reduced to 0.1% or below, and the post-treatment is simple.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and relates to a method for preparing etoricoxib and its intermediates. Background Technology

[0002] Imrecoxib (molecular weight 369.477) is a selective cyclooxygenase (COX-2) inhibitor used to relieve pain symptoms of osteoarthritis and is also widely used for axial spondylitis, gout, perioperative analgesia, and other diseases. The structural formula of imrecoxib is shown in Formula I. In the mainstream synthetic route of imrecoxib, an isomer of imrecoxib—imrecoxib impurity ARXZ10 (hereinafter referred to as impurity 10) shown in Formula II—is generated. This is because the intermediate used in the synthesis (an N,N-disubstituted p-tolueneacetamide derivative, structure of Formula III) undergoes competitive elimination of the 3- and 5-hydrogen positions after cyclization of the five-membered ring, releasing an H2O. The 3-hydrogen elimination generates imrecoxib, while the 5-hydrogen elimination yields impurity ARXZ10.

[0003]

[0004] High-performance liquid chromatography (HPLC) analysis revealed that impurity 10 in the product of etoricoxib exceeded 0.3%. Due to its highly similar structure to the target product, effective separation through physical property differences, such as recrystallization or column chromatography, is impossible. For example, according to the method for removing this impurity disclosed in CN109553564A, the crude product is recrystallized with ethanol (this step was omitted in the comparative example), the recrystallized crude crystals are then dissolved in dichloromethane, filtered through diatomaceous earth, and the filtrate is crystallized with n-hexane. This is claimed to reduce the impurity content to pharmaceutical standards. However, the inventors repeatedly performed this operation, and the results showed that the entire process did not reduce the impurity 10 content at all; in fact, it slightly increased it.

[0005] Therefore, there is a need in this field to find an effective method for removing isomer impurities from erixib. Summary of the Invention

[0006] This invention proposes a method for purifying etoricoxib raw material, overcoming the shortcomings of existing technologies that cannot effectively remove etoricoxib isomers.

[0007] The method for purifying etoricoxib raw material according to the present invention includes the following steps:

[0008] 1) Dissolve the crude arbutin raw material in a solvent to form a solution. In the presence of a porous medium, apply an oxygen-containing oxide to the solution to convert impurity 10 into an epoxide.

[0009] 2) Post-process the reaction solution to obtain the refined drug substance.

[0010] The porous medium is activated carbon or porous carbon fiber.

[0011] In some embodiments, the oxygen-containing oxide is oxygen, air, or peroxide.

[0012] In some embodiments, the peroxide is selected from the group consisting of hydrogen peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, and peracetic acid.

[0013] Preferably, the porous medium is activated carbon, and its amount is 0.5-15% of the crude drug mass.

[0014] In some embodiments, the solvent is one or more of ethanol, isopropanol, ethyl acetate, methyl acetate, acetone, acetonitrile, pyridine, N,N-dimethylformamide, and dioxane.

[0015] In some embodiments, the post-treatment includes: slowly cooling the reaction solution and then crystallizing it at 1–10°C.

[0016] In some embodiments, the post-processing includes: washing the reaction solution with dilute hydrochloric acid, separating the aqueous phase, drying, and concentrating to remove the solvent.

[0017] Further, the post-processing includes:

[0018] 2-1) Reduced pressure concentration removes most of the solvent, and the active pharmaceutical ingredient is then dissolved in ethyl acetate;

[0019] 2-2) Wash the solution with dilute hydrochloric acid to remove the epoxide;

[0020] 2-3) Concentrate to remove ethyl acetate, and obtain refined raw material.

[0021] In the presence of a porous medium, this invention converts impurity 10 in the active pharmaceutical ingredient into an epoxide using oxygen or a peroxide. It exhibits excellent selectivity for the oxidizing target. The presence of the porous medium or carrier facilitates the smooth progress of the reaction. Furthermore, the medium can simultaneously adsorb other impurities, making post-processing very simple. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the specific implementation methods or related technologies of this application, the accompanying drawings used in the description of the specific implementation methods or related technologies will be briefly introduced below. Obviously, the accompanying drawings described below are only some implementation methods of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort, wherein:

[0023] Figure 1 This is an HPLC chromatogram of crude etoricoxib in the reaction solution of Example 1 before reaction;

[0024] Figure 2 This is the HPLC chromatogram obtained after 2 hours of reaction in Example 1;

[0025] Figure 3 This is the HPLC chromatogram of the refined etoricoxib product obtained in Example 1. Detailed Implementation

[0026] The technical concept of the present invention will be described in detail below with reference to specific embodiments. It is readily understood that the embodiments described in this disclosure are merely illustrative and not all possible implementations of the present invention. Those skilled in the art, upon obtaining the description of the basic concept of the present invention in this disclosure and in conjunction with the given embodiments, can obtain other ways of implementing the present invention without creative effort, and can also make creative improvements based on the basic concept of the present invention. All such variations or improvements fall within the scope defined by the claims of this application.

[0027] According to the general concept of the present invention, crude etoricoxib is oxidized with an oxygen-containing oxide to convert impurity 10 into an epoxy compound, as shown in the following reaction formula:

[0028]

[0029] In this invention, oxygen-containing oxides refer to substances that exert their oxidizing effect through the presence of oxygen. Oxides suitable for this invention include oxygen, air, and peroxides. The preferred peroxide is one of hydrogen peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, and peracetic acid. Theoretically, the possibility of using other peroxides is not excluded; however, compounds such as tert-butyl peroxide, benzoyl peroxide, and 1,1-bis(tert-butylperoxide)cyclohexane have disadvantages in terms of material availability and ease of post-reaction separation.

[0030] When oxygen is used as the oxidant, oxygen is introduced into the reactor in a predetermined amount, and the reaction can be carried out in a closed system, such as an autoclave. During the reaction, the autoclave is maintained at a temperature of 40–80°C for 1–6 hours, with an excess of 0.2–3.0 times the oxygen. When air is used as the oxidant, it is preferable to carry out the reaction in an open system, with air continuously introduced into the reactor for 2–10 hours under stirring, and the temperature controlled at 40–80°C, preferably not exceeding 50°C.

[0031] When using a peroxide oxidant, the reaction is carried out at atmospheric pressure and a temperature of 40–70°C. The amount of peroxide added can be 0.2–0.5 eq of the etoricoxib active pharmaceutical ingredient. If the amount added is equal to that of impurity 10, the concentration of peroxide in the system will be too low, resulting in low reaction efficiency. Nitrogen protection is preferred during the reaction, especially for industrial-scale production.

[0032] Solvents that can be used in this invention include ethanol, isopropanol, dichloromethane, ethyl acetate, methyl acetate, acetone, acetonitrile, pyridine, N,N-dimethylformamide (DMF), dioxane, etc. Ethanol, dioxane, DMF, and pyridine are preferred, with ethanol being the most preferred due to its simpler post-processing.

[0033] HPLC analysis showed that the excess of oxides did not lead to the oxidation of the arbutin active pharmaceutical ingredient itself. This means that although both arbutin and impurity 10 have carbon-carbon double bonds in their five-membered rings, the double bonds at positions 3 and 4 of the arbutin five-membered ring are not easily oxidized, while the double bonds at positions 4 and 5 of impurity 10 can be oxidized. The inventors understand that a possible reason is that the carbon-carbon double bonds of arbutin form a highly conjugated structure with the two benzene rings, resulting in high stability and resistance to oxidation. Other possible reasons include differences in steric hindrance.

[0034] It is understood that although the temperature ranges for the reaction are given above, these ranges should be preferred rather than exclusive. Under certain reaction conditions, such as suitable solvents and closed systems, temperatures above 80°C are also possible. If the reaction time is allowed to be long enough, temperatures below 40°C can also complete the reaction of the present invention.

[0035] The inventors discovered that introducing activated carbon into the reaction system promotes the reaction's smooth progress, while the reaction proceeds much more slowly without activated carbon. The inventors hypothesize that this might be because the activated carbon acts as a reaction interface during the reaction. To verify this hypothesis, the inventors experimented with substances such as diatomaceous earth and molecular sieves, but the results showed that these porous media did not exhibit the same effect as activated carbon. However, after receiving the teachings of this disclosure, it is entirely possible to find other media materials to replace activated carbon, such as porous carbon fibers, carbon nanotubes, and multilayer graphene powder. These should be covered within the scope defined by the claims of this application.

[0036] The activated carbon used in this invention should be prepared from high-quality charcoal, achieving a pharmaceutical-grade cleanliness. It can be in powder, columnar, honeycomb, or granular form.

[0037] Powdered activated carbon typically has a mesh size between 200 and 325 mesh and a specific surface area of ​​not less than 600 m². 2 / g.

[0038] These columnar activated carbons are available in diameters of Φ1.5mm, Φ3.0mm, Φ3.5mm, Φ4.0mm, and Φ5.0mm, offering the advantage of easy regeneration for industrial-scale applications. This type of activated carbon is suitable for all oxide applications.

[0039] The size of honeycomb activated carbon is suitable for a range of no more than 100 mm on each side, such as a cuboid no more than 100 mm × 100 mm × 100 mm, or a cylinder with a diameter and height no more than 100 mm. The pore size can range from 1.5 to 5 mm. Honeycomb activated carbon has a large specific surface area, is not easily clogged, and is suitable for industrial-scale applications using gaseous oxidants. In this case, the activated carbon is arranged in a fixed bed in the reactor, with an aeration device installed below the fixed bed. A stirring device is also preferably installed in the reactor to keep the reaction liquid constantly disturbed.

[0040] Granular activated carbon can have a particle size between 1-3 mm. This form can be used as both an oxygen / air oxidant and a peroxide oxidant, and will be stirred together with the reactants in a closed or open system.

[0041] The reaction process can be tracked using high-performance liquid chromatography (HPLC). The reaction can be stopped when the content of impurity 10 is detected to be no more than 0.1% by mass. In one specific embodiment of the invention, the test solution is prepared as follows: An appropriate amount of the crude solution is accurately weighed and placed in a 20ml volumetric flask. 2ml of acetonitrile is added to dissolve the solution, which is then diluted with a solvent and shaken well to prepare a solution containing approximately 0.5mg / ml of etoricoxib.

[0042] The detection was performed under the following chromatographic conditions:

[0043] Instrument: High-performance liquid chromatograph, equipped with a UV detector

[0044] Column: Octadecylsilane-bonded silica gel as the packing material (Waters Sunfire C18, 4.6 × 150 mm, 3.5 μm or equivalent column).

[0045] Mobile phase A: 0.1% phosphoric acid solution

[0046] Mobile phase B: Acetonitrile-methanol (90:10)

[0047] Flow rate: 1.0 ml / min

[0048] Detection wavelength: 218nm

[0049] Column temperature: 40℃

[0050] Injection volume: 20 μL

[0051] Solvent: Acetonitrile: Acetonitrile-water (40:60) (v / v)

[0052] After the reaction is stopped, the activated carbon is removed by hot filtration. The reaction solution is then post-treated in two ways. One method is to slowly cool the reaction solution and then crystallize it at 1–10°C. This method is simple to operate, but it results in the loss of some active pharmaceutical ingredient in the mother liquor. The other method is to concentrate under reduced pressure to remove most of the solvent, then dissolve the product in ethyl acetate, and wash the solution twice with a small amount of dilute hydrochloric acid to separate the aqueous phase. After drying and concentration to remove the solvent, the product is obtained. This method avoids recrystallization, results in less loss of active pharmaceutical ingredient, and has a high product yield.

[0053] Example 1

[0054] Add 300ml of 95% ethanol to a 500ml three-necked flask, start stirring, purge with nitrogen three times while continuously introducing nitrogen, heat to 60-65℃, and add 17.59g of crude etoricoxib (approximately...

[0055] 0.0476 mol) was stirred until dissolved, 2 g of powdered pharmaceutical charcoal was added, followed by a mixture of 2 g of hydrogen peroxide (approximately 30%, approximately 0.0176 mol) and 4 g of 95% ethanol. The mixture was kept at 60–65 °C with stirring. After 2 hours, the reaction was stopped. A sample of the reaction solution was taken for HPLC analysis, and the content of isomer impurity 10 was found to be 0.05%. The reaction solution was exported, filtered while hot, and then divided into two equal portions. One portion was taken and allowed to cool naturally to 0–10 °C and maintained for crystallization for 1 hour. The wet product was collected by filtration and vacuum dried. After drying, 7.35 g of the purified isomer 10 product, a slightly yellow powder, was obtained, with a yield of 83.57% (purity 99.57%, isomer impurity 10: 0.06%).

[0056] Example 2

[0057] Take another 150 ml of the reaction solution from Example 1, concentrate it under reduced pressure to about 20 ml, dissolve it in 80 ml of ethyl acetate, wash it twice with 8 ml of 5% dilute hydrochloric acid, wash it once with a small amount of sodium bicarbonate aqueous solution, then dry it and concentrate the solvent under vacuum to obtain 8.38 g of purified etoricoxib, with a yield of 95.28% (purity 99.52%, isomer impurities 10:0.06%).

[0058] Example 3

[0059] Add 300 ml of 95% ethanol and 17.60 g of crude etoricoxib to a 500 ml three-necked flask, stir until dissolved, add 2 g of powdered pharmaceutical charcoal, stir continuously, heat to 60-65 °C, and continuously purge with air. After 2 hours, take a sample and monitor the crude solution by HPLC. The content of isomer impurity 10 is 0.08%. After the reaction is complete, filter while hot, then divide the solution into two equal parts. Take one part and let it cool naturally to 0-10 °C and maintain it for crystallization for 1 hour. Filter and collect the wet product, and dry under vacuum. After drying, 7.33 g of the purified etoricoxib product, a light yellow powder, is obtained, with a yield of 83.30% (purity 99.68%, isomer impurity 10: 0.04%).

[0060] Example 4

[0061] Take another 150 ml of the reaction solution from Example 3, concentrate it under reduced pressure to about 20 ml, dissolve it in 80 ml of ethyl acetate, wash it twice with 8 ml of 5% dilute hydrochloric acid, wash it once with a small amount of sodium bicarbonate aqueous solution, then dry it and concentrate the solvent under vacuum to obtain 8.36 g of purified etoricoxib, with a yield of 95.00% (purity 99.55%, isomer impurities 10:0.07%).

[0062] Comparative Example 1:

[0063] (1) Weigh 4.01 g of crude etoricoxib (purity 99.33%, isomer impurities 0.35%) and place it in a 100 ml three-necked flask. Add 48.03 g of anhydrous ethanol, heat to 70 °C to dissolve, cool to 0–10 °C, and maintain at 0–10 °C for 2 h to allow crystals to crystallize. Filter and collect the wet product, then vacuum dry. After drying, 3.13 g of yellow crude etoricoxib is obtained, with a yield of 78.05% (purity 99.13%, isomer impurities 0.34%).

[0064] (2) Weigh 3.51g of crude erectoxib (purity 98.91%, isomer impurities 0.36%) and place it in a 100ml three-necked flask. Add 22.16g of dichloromethane and stir magnetically to dissolve. Weigh 1.87g of diatomaceous earth and place it in a Buchner funnel lined with filter paper. Filter the dissolved crude solution and transfer the filtrate to another clean 100ml three-necked flask. Add 16.34g of n-hexane and crystallize at 20-30℃ for 1.5 hours. Filter, collect the wet product, and vacuum dry. After drying, 2.43g of off-white purified product is obtained, with a yield of 69.23% (purity 99.24%, isomer impurities 0.40%). This example can reduce colored impurities and has no effect on the content of impurity 10.

[0065] The technical solution of the present invention has been described above in conjunction with the embodiments. It should be noted that for those skilled in the art, other similar implementation methods based on the technical concept of the present disclosure without departing from the technical concept of the present disclosure are also within the protection scope of the embodiments of the present disclosure.

Claims

1. A method for purifying etoricoxib active pharmaceutical ingredient, wherein the active pharmaceutical ingredient comprises impurity 10 of formula II, characterized in that... include: 1) Dissolve the crude arbutin raw material in a solvent to form a solution. In the presence of a porous medium, apply an oxygen-containing oxide to the solution to convert impurity 10 into an epoxide. 2) Post-process the reaction solution to obtain the refined drug substance. The porous medium is activated carbon or porous carbon fiber.

2. The method according to claim 1, wherein, The oxygen-containing oxide is oxygen, air, or peroxide.

3. The method according to claim 1, wherein, The peroxide is selected from the group consisting of hydrogen peroxide, tert-butyl hydrogen peroxide, cumene hydrogen peroxide, and peracetic acid.

4. The method according to claim 1, wherein, The porous medium is activated carbon, and its dosage is 0.5-15% of the crude drug mass.

5. The method according to claim 4, wherein, The activated carbon is in the form of powder, columnar, honeycomb, or granular.

6. The method according to claim 1, wherein, The solvent is one or more of ethanol, isopropanol, ethyl acetate, methyl acetate, acetone, acetonitrile, pyridine, N,N-dimethylformamide, and dioxane.

7. The method according to claim 1, wherein, The oxidation reaction occurs at temperatures ranging from 40 to 80°C.

8. The method according to claim 1, wherein, The post-treatment includes: slowly cooling the reaction solution and then crystallizing it at 1–10°C.

9. The method according to claim 1, wherein, The post-processing includes: washing the reaction solution with dilute hydrochloric acid, separating the aqueous phase, drying, and concentrating to remove the solvent.

10. The method according to claim 9, wherein, The post-processing includes: 2-1) Reduced pressure concentration removes most of the solvent, and the active pharmaceutical ingredient is then dissolved in ethyl acetate; 2-2) Wash the solution with dilute hydrochloric acid to remove the epoxide; 2-3) Concentrate to remove ethyl acetate and obtain refined raw material.

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