Preparation method of etoricoxib crystal form IV

Abstract

The invention provides a preparation method of an etoricoxib crystal form IV. The method comprises the following steps: firstly, adding an etoricoxib crude product into an organic solvent, and heating until solid is dissolved and clarified; the preparation method comprises the following steps: dissolving etoricoxib in an ether solvent, adding an organic alkali, slowly cooling until the solution is slightly turbid, growing crystals (adding a small amount of ether solvent, and repeatedly heating and cooling to grow the crystals, or adding crystals to grow the crystals), and crystallizing to obtain the single crystal form IV etoricoxib. The method is easy and convenient to operate, good in reproducibility, high in yield, high in impurity removal capacity and suitable for industrial production, and the prepared final product is good in stability and meets the medicinal requirement.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a method for preparing etoricoxib crystal form IV. Background Technology

[0002] Etoricoxib (5-chloro-6'-methyl-3-[4-(methanesulfonyl)phenyl]-2,3'-bipyridine) is a selective inhibitor of cyclooxygenase-2 (COX-2) with anti-inflammatory, antipyretic, and analgesic effects. Its structural formula is as follows:

[0003] Currently, etoricoxib preparations have been launched in many countries and regions. The preparation type is film-coated tablets, and it is mainly used in clinical practice to treat the symptoms and signs of acute and chronic osteoarthritis, acute gouty arthritis, primary dysmenorrhea, etc.

[0004] As an oral formulation, crystal form is a key quality attribute of etoricoxib. More than ten crystal forms have been reported in the literature: the original patent CN01810137.2 reported eight pharmaceutically usable crystal forms, including crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, hemihydrate, sesquihydrate and amorphous; and patent WO2005085199A1 reported seven crystal forms, including crystal form IX, crystal form X, crystal form XI, crystal form XII, crystal form XIII, crystal form XIV and crystal form XVI.

[0005] Existing literature has extensively studied etoricoxib crystal forms, but reports mainly focus on the preparation methods of crystal forms I and V. Methods for preparing crystal form IV are less frequently reported in published literature. The original study CN01810137.2 reported that etoricoxib can be recrystallized from toluene to obtain crystal form IV, but this method requires strict control of crystallization and dropping rates; otherwise, it is easy to transform into other crystal forms, making industrialization difficult. WO2001037833 reported that etoricoxib crystal form I or II can be recrystallized from a mixed solvent of toluene and n-heptane at temperatures below 45°C to prepare crystal form IV, but the use of highly toxic toluene as a crystallization solvent still makes it unsuitable for commercial production. Therefore, it is essential to develop a method suitable for industrial production of etoricoxib crystal form IV. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a method for preparing etoricoxib crystal form IV. First, crude etoricoxib is added to an organic solvent and heated until the solid dissolves completely. Then, an organic base is added, and the solution is slowly cooled until it becomes slightly turbid. Following crystal growth (by adding a small amount of ether solvent and repeatedly heating and cooling to grow crystals; or by adding seed crystals to grow crystals) and crystallization steps, crystal form IV etoricoxib is obtained. This method is simple to operate, has good reproducibility, high yield, and strong impurity removal capabilities, making it suitable for industrial production. The final product prepared has good stability and meets pharmaceutical requirements.

[0007] The etoricoxib form IV involved in this invention refers to a single crystal form with characteristic absorption peaks in its X-ray powder diffraction pattern at 2θ values ​​of 13.31±0.2°, 15.09±0.2°, 16.45±0.2°, 17.11±0.2°, 17.75±0.2°, 18.67±0.2°, 18.86±0.2°, 19.40±0.2°, 19.79±0.2°, 21.61±0.2°, 22.26±0.2°, 22.78±0.2°, 23.54±0.2°, and 24.84±0.2°.

[0008] The technical solution of the present invention is: a method for preparing coxib-based crystal form IV, characterized by comprising the following steps: (1) Add crude etoricoxib to an organic solvent and heat to 50-90°C until the solid is completely dissolved; (2) Add an organic base, slowly cool down to 40~60℃ and the solution becomes slightly turbid, then add a small amount of ether solvent and then grow crystals; (3) Raise the temperature to 50~90℃, then lower it to 40~60℃, repeat the raising and lowering operation 1~3 times in total; (4) After the last cooling, maintain the temperature at 40~60℃ to grow crystals, then cool down to -10~10℃ and keep warm to precipitate crystals; filter and dry to obtain crystal form IV etoricoxib with a single crystal form.

[0009] The organic solvent is a low-grade aliphatic lipid compound such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate, or a low-grade aliphatic ketone compound such as acetone, methyl ethyl ketone, methyl butyl ketone, and methyl isobutyl ketone, or a mixture of the above solvents. The low-grade aliphatic lipid and ketone compounds have moderate polarity, ensuring the solvent's impurity removal ability while also forming weak dipole-dipole interactions with the sulfonyl and aromatic rings in the etoricoxib molecule. This helps improve the orderliness of the etoricoxib molecule stacking, forming a single crystal nucleus structure.

[0010] The organic base refers to triethylamine, pyridine, N,N-dimethylaminopyridine, diisopropylethylamine, DBU, etc., or mixtures of the above organic bases. The molar ratio of the above organic bases to etoricoxib is (0.01~0.1):1. The organic base molecule temporarily acts as a "molecular template" by forming a weak hydrogen bond (CH…N) with the oxygen atom of the sulfonyl group, guiding the sulfonyl group to adopt the spatial orientation of crystal form IV, thereby forming a crystal form IV nucleus. Furthermore, experiments have shown that without the induction of an organic base, it is difficult to form the target crystal nucleus, resulting in the precipitated product having crystal form I.

[0011] Ether solvents refer to chain-like lower ether compounds such as diethyl ether, isopropyl ether, and methyl tert-butyl ether, or epoxides such as tetrahydrofuran and 1,4-dioxane, or mixtures of the above ether solvents. The use of ether solvents reduces solvent polarity, thereby reducing the solubility of etoricoxib in the solvent system and ensuring that the target crystal nucleus does not dissolve during the oscillatory crystallization process. During crystal precipitation, some etoricoxib molecules form crystal form I nuclei without the induction of an organic base, leading to mixed crystals. We unexpectedly discovered that in a specific solvent system (esters / ketones and triethylamine), oscillatory crystallization can transform crystal form I crystals into the target crystal form through recrystallization, ensuring the uniformity of the crystal form.

[0012] The mass ratio of the organic solvent to etoricoxib is (3~20):1; the mass ratio of the ether solvent to the organic solvent is (0.02~0.05):1. The crystal growth time after adding the ether solvent is not less than 0.5 h. The heating and cooling operation is as follows: heat to increase the temperature, cool to decrease the temperature (oscillation to induce crystallization). The crystal growth time after heating / cooling is 0.5~5 h.

[0013] In addition to using lipid or ketone solvents, the present invention also provides a method for preparing etoricoxib crystal form IV using C1-C4 fatty alcohol solvents, characterized by comprising the following steps: (1) Add crude etoricoxib to a C1-C4 fatty alcohol solvent and heat to 50-90°C until the solid is completely dissolved; (2) Add organic base; cool to 30~70℃, add a small amount of etoricoxib type IV seed crystals, and keep warm to grow crystals; (3) Continue cooling to -10~10℃ and keep warm for 1~4 hours to allow crystals to precipitate. (4) Filter and dry to obtain the single crystal form IV etoricoxib.

[0014] The C1-C4 fatty alcohol solvents refer to methanol, ethanol, isopropanol, n-butanol, tert-butanol, etc., or mixtures thereof. The mass ratio of the above alcohol solvents to etoricoxib is (4~20):1. Alcohol solvents are more polar than ester / ketone solvents, making it difficult for them to spontaneously form crystal form IV nuclei through the induction of organic bases. Therefore, seed crystals need to be added when the solution is metastable, and sufficient crystallization must be ensured to obtain etoricoxib in a single crystal form IV. Compared to long-chain alcohols, C1-C4 molecules are smaller in size, can be embedded in lattice channels without being trapped, and perfectly extricate themselves after drying, avoiding lattice collapse.

[0015] The specific types and amounts of organic bases used are the same as above. The mass ratio of seed crystals to etoricoxib is (0.5~3):100. The crystal growth time is no less than 0.5 hours.

[0016] The technical effects of this invention are: 1. Compared with existing methods, the preparation method of etoricoxib crystal form IV provided by the present invention is simple to operate, does not require precise temperature control, and uses materials with relatively low toxicity, making it more suitable for industrialized production.

[0017] 2. The etoricoxib prepared by this invention has a purity of over 99.9% and good stability, and its quality does not decrease during long-term storage. Attached Figure Description Figure 1 The XRD pattern obtained in Example 1 is the etoricoxib XRD pattern. Figure 2 The HPLC chromatogram of etoricoxib obtained in Example 1; Figure 3 The XRD pattern obtained in Example 2 is the etoricoxib XRD pattern. Figure 4 The image shows the HPLC chromatogram of etoricoxib obtained in Example 2. Detailed Implementation

[0018] The following examples are used to further explain the essence of the present invention, but are not intended to limit the scope of the invention.

[0019] Example 1: Add 50g of crude etoricoxib (purity 98.7%) to 180g of isopropyl acetate, stir and heat to 60-70℃ until the solid is completely dissolved; add 0.7g of triethylamine; slowly cool to 50-55℃, stir until the solution is slightly turbid, add 3.6g of methyl tert-butyl ether, and maintain the temperature for crystal growth for 1 hour; heat to 60-70℃ and then cool down to 50-55℃, repeating the heating and cooling operation once (for a total of 2 times); maintain the temperature at 50-55℃ and stir for crystal growth for 1 hour; continue to cool to 5℃ and maintain the temperature for crystal precipitation for 2 hours; filter and dry to obtain 47.85g of etoricoxib crystal form IV. Product yield 95.7%, purity 99.96% (HPLC chromatogram see [reference needed]). Figure 2 The sample contained 752 ppm of isopropyl acetate residue, 15 ppm of methyl tert-butyl ether residue, and no detectable triethylamine. The melting point was 133.7-134.4℃. XRD patterns are shown below. Figure 1 .

[0020] The stability of the above samples was investigated (under conditions of 30±2℃ and 65±5%RH), and the specific results are shown in Table 1. Table 1 shows that the samples exhibited good stability and their quality did not decrease during long-term storage.

[0021] Table 1. Results of sample stability study in Example 1

[0022] Example 2: Add 50g of crude etoricoxib (purity 98.7%) to 220g of ethanol, stir and heat to 55-65℃ until the solid is completely dissolved; add 0.7g of triethylamine, cool to 50-55℃, stir until the solution is slightly turbid, add 0.5g of etoricoxib crystal form IV seed crystals, and maintain the temperature for 1.5h to allow crystals to grow; continue cooling to -5℃ and maintain the temperature for 3h to allow crystals to precipitate; filter and dry to obtain 46.85g of etoricoxib crystal form IV. Product yield 93.7%, purity 99.97% (HPLC chromatogram see [reference needed]). Figure 4 Ethanol residue 687 ppm, triethylamine not detected, melting point 133.7-134.5℃; XRD pattern see [reference needed]. Figure 3 .

[0023] The stability of the above samples was investigated (under conditions of 30±2℃ and 65±5%RH), and the specific results are shown in Table 2. Table 2 shows that the samples exhibited good stability and their quality did not decrease during long-term storage.

[0024] Table 2. Results of sample stability study in Example 2

[0025] Comparative Example (Preparation method of etoricoxib crystal form IV reported in CN01810137.2): Add 55g of crude etoricoxib (98.7% purity) to 400mL of toluene, stir and heat to 34℃ until the solid is completely dissolved; cool the solution to 15-20℃ at a very slow rate, and crystal form IV solid precipitates out, taking about 1 hour and 13 minutes; continue to slowly lower the temperature to 0℃; add 700mL of n-heptane dropwise over about 5 hours and 5 minutes; filter and dry to obtain etoricoxib crystal form IV. Product yield: 94.1%, toluene residue: 752ppm, n-heptane residue: 833ppm.

[0026] Compared with the preparation method of the comparative example, the advantages of this invention are: 1) it does not require strict control of cooling and dropping rate, making it more suitable for commercial production; 2) the solvents used are all low-toxicity solvents, making them more suitable for use as raw materials for drug production.

Claims

1. A method for preparing coxib crystal form IV, characterized in that, Includes the following steps: (1) Add crude etoricoxib to an organic solvent and heat to 50-90°C until the solid is completely dissolved; the organic solvent is: a low-grade aliphatic lipid compound or a low-grade aliphatic ketone compound; (2) Add an organic base, slowly cool down to 40~60℃ and the solution becomes slightly turbid, then add an ether solvent and proceed with crystal growth; (3) Raise the temperature to 50~90℃, then lower it to 40~60℃, repeat the raising and lowering operation 1~3 times in total; (4) After the last cooling, maintain the temperature at 40~60℃ to grow crystals, then cool down to -10~10℃ and keep warm to precipitate crystals; After filtration and drying, a single crystal form, etocoxib, is obtained.

2. The method for preparing etoricoxib form IV as described in claim 1, characterized in that, The lower fatty lipid compounds are one or more selected from methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate.

3. The method for preparing etoricoxib form IV as described in claim 1, characterized in that, The lower aliphatic ketone compounds are one or more of acetone, methyl ethyl ketone, methyl butyl ketone, and methyl isobutyl ketone.

4. The method for preparing etoricoxib form IV as described in claim 1, characterized in that, The organic base is at least one of triethylamine, pyridine, N,N-dimethylaminopyridine, diisopropylethylamine, and DBU; the molar ratio of the organic base to etoricoxib is (0.01~0.1):

1.

5. The method for preparing etoricoxib form IV as described in claim 1, characterized in that, The ether solvent refers to one of diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, or a mixture of the above ether solvents.

6. The method for preparing etoricoxib form IV as described in claim 1, characterized in that, The mass ratio of the organic solvent to etoricoxib is (3-20):1; the mass ratio of the ether solvent to the organic solvent is (0.02~0.05):

1.

7. A method for preparing coxib crystal form IV, characterized in that, Includes the following steps: (1) Add crude etoricoxib to a C1-C4 fatty alcohol solvent and heat to 50-90°C until the solid is completely dissolved; (2) Add organic base; cool to 30~70℃, add etoricoxib type IV seed crystals, and keep warm to grow crystals; (3) Continue cooling to -10~10℃ and keep warm for 1~4 hours to allow crystals to precipitate. (4) Filter and dry to obtain a single crystal form IV etocoxib.

8. The method for preparing etoricoxib form IV as described in claim 7, characterized in that, The C1-C4 fatty alcohol solvents are one or more of methanol, ethanol, isopropanol, n-butanol, and tert-butanol.

9. The method for preparing etoricoxib form IV as described in claim 7, characterized in that, The mass ratio of the C1-C4 fatty alcohol solvent to etoricoxib is (4~20):

1.

10. The method for preparing etoricoxib form IV as described in claim 7, characterized in that, The mass ratio of the seed crystal to etoricoxib is (0.5~3):100; the crystal growth time is not less than 0.5h.

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