A preparation method of parecoxib sodium and its intermediates

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of parecoxib sodium intermediate; the method comprises the steps of: (a) adding the crude product of the compound of formula (II) and an alkaline substance into solvent A for recrystallization, and separating out solid B; (b) mixing solid B with solvent C and stirring, and separating to obtain solid D; (c) drying solid D to obtain the refined product of the compound of formula (II). The refining method of the compound of formula (II) provided by the present invention can significantly improve the purity of the crude product of the compound of formula (II) in a high-yield manner; it has the advantages of simple operation, easy control of parameter conditions, and low cost in large-scale industrial production. The present invention also relates to a method for preparing parecoxib sodium by a one-pot method from valdecoxib, which does not require the separate isolation of parecoxib, and the production process is simpler, which is conducive to large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of parecoxib sodium and a parecoxib sodium intermediate (valdecoxib). Background Art

[0002] Parecoxib Sodium is a prodrug of Valdecoxib; Parecoxib Sodium is used for the short-term treatment of postoperative pain and can be clinically used for the treatment of moderate or severe postoperative acute pain.

[0003]

[0004] As shown in formula (I), a common route for synthesizing parecoxib sodium is to obtain the intermediate valdecoxib through a reaction, and then react it with propionic anhydride to obtain parecoxib, and then further prepare parecoxib sodium (for example, as described in CN104447600A).

[0005] During the preparation of valdecoxib, a small amount of chlorosulfonic acid attacks the meta-position of the benzene ring to generate a valdecoxib meta-position impurity. This impurity is an isomer of valdecoxib, with similar polarity and is difficult to remove. It will enter parecoxib sodium with the reaction transfer, generating a parecoxib sodium meta-position impurity, which directly affects the quality of the parecoxib sodium raw material drug. At the same time, the by-product of the sulfonation reaction is inorganic salt ammonium chloride, which will also reduce the content of valdecoxib. Summary of the Invention

[0006] In the first aspect of the present invention, a method for refining valdecoxib shown in formula (II) is provided, including the steps of:

[0007]

[0008] (a) Mixing the crude valdecoxib, an alkaline substance, and solvent A, performing recrystallization, and separating the precipitated solid B;

[0009] (b) Mixing the solid B with solvent C and stirring, and separating to obtain solid D;

[0010] (c) Drying the solid D to obtain the refined valdecoxib product.

[0011] In a specific embodiment of the present invention, the solvent A is an alcohol and water mixed solvent; the alcohol is selected from methanol, ethanol, isopropanol, or ethylene glycol.

[0012] The mass ratio of alcohol to water in the solvent A is (4 - 20):1, preferably (4 - 16):1, more preferably (4 - 12):1, and most preferably (4 - 8):1. For example, it can be 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1. Increasing the proportion of alcohol in the solvent A can improve the refining effect, but will reduce the yield of the refined product; the inventors of the present invention found that when the mass ratio of alcohol to water in the solvent A is not less than 4:1, the purity of the refined product can meet the requirements. For example, when using absolute ethanol to replace the solvent A, the yield of the refined product decreases significantly, but there is almost no need to improve the purity.

[0013] The mass ratio of the solvent A to the crude valdecoxib is (4 - 20):1, preferably (4 - 16):1, more preferably (4 - 13):1, and most preferably (4 - 10):1. For example, it can be 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1. Increasing the amount of the solvent A can improve the refining effect, but will reduce the yield of the refined product; the inventors of the present invention found that when the mass ratio of the solvent A to the crude valdecoxib is not less than 4:1, the purity of the refined product can meet the requirements.

[0014] When the alcohol in the solvent A is ethanol, the ethanol can be commercially available hydrated ethanol (including but not limited to 95% ethanol v / v), and at this time, the amounts of ethanol and water in the used hydrated ethanol are calculated according to the actual situation. That is, except as specifically pointed out, when using hydrated ethanol to constitute the solvent A; when considering the amount of water in the solvent A, the amount of water in the hydrated ethanol is included; when considering the amount of alcohol in the solvent A, the amount of water in the hydrated ethanol is not included.

[0015] In a specific embodiment of the present invention, the basic substance is selected from ammonia (NH3), triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide.

[0016] The mass ratio of the basic substance to the crude valdecoxib in the step (a) is (0.01 - 0.2):1, preferably (0.02 - 0.2):1, more preferably (0.05 - 0.2):1, and most preferably (0.05 - 0.15):1. For example, it can be 0.01:1, 0.02:1, 0.05:1, 0.1:1, 0.15:1, 0.2:1.

[0017] When the basic substance is ammonia (NH3), ammonia (NH3) can be in the form of ammonia gas or in the form of ammonia water, and preferably in the form of ammonia water.

[0018] In the present invention, unless otherwise specified, when the alkaline substance is ammonia water; when considering the amount of water in solvent A, the amount of water in ammonia water is not included; that is, ammonia water is regarded as a whole, and the amount of water in ammonia water is included in the amount of the alkaline substance.

[0019] Recrystallization is a method to improve the purity of solids. The solubility of solids in a solvent generally increases with the increase of temperature; by selecting a suitable solvent, the solid (containing impurities) is dissolved in the hot solvent to form a hot saturated solution (or a hot high-concentration solution), and optionally insoluble impurities are removed while it is hot (for example, by filtration), and the temperature of the solution is lowered (optionally lowered below room temperature), so that the main component precipitates from the solution with decreasing temperature, and the soluble impurities remain in the solution; thereby improving the purity of the solid.

[0020] In a specific embodiment of the present invention, the method for separating solids from the solid-liquid mixture includes but is not limited to filtration and centrifugation. For example, when carried out on a laboratory scale, due to the small batch size, filtration is preferably used for the solid-liquid separation operation; in industrial production, due to the large batch size, centrifugation is preferably used for the solid-liquid separation operation.

[0021] In a specific embodiment of the present invention, the solvent C in step (b) is water. The mass ratio of the solvent C to the crude valdecoxib is (4-20):1, preferably (6-17):1, and most preferably (8-13):1. For example, it can be 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1. Increasing the amount of the solvent C can better remove inorganic salt impurities; at the same time, since the intermediate valdecoxib has poor solubility in the solvent C, increasing the amount of the solvent C has no significant impact on the reduction of the product yield; however, increasing the amount of the solvent C puts higher requirements on the volume of the production equipment and increases the workload of the subsequent wastewater treatment.

[0022] The stirring in step (b) is carried out at 15-35 °C, preferably at 20-30 °C; 20-30 °C is usually consistent with room temperature, and can also be regarded as preferably stirring at room temperature. The stirring duration is 15 min to 3 hours, preferably 30 min to 2 hours, and more preferably 45 min to 1.5 hours.

[0023] In a specific embodiment of the present invention, the drying can be carried out by a drying method with or without increasing the temperature, and can be carried out under normal pressure or reduced pressure; for example, normal pressure drying at room temperature, reduced pressure drying at room temperature, normal pressure drying above room temperature, reduced pressure drying above room temperature; preferably normal pressure drying above room temperature or reduced pressure drying above room temperature. Exemplarily, it can be drying at 50-60 °C for 6-24 hours, or drying at 60 °C for 12 hours.

[0024] In the second aspect of the present invention, there is provided a method for preparing parecoxib shown in formula (III), which includes obtaining a purified valdecoxib from crude valdecoxib according to the method described in the first aspect of the present invention, and then reacting the purified valdecoxib with propionic anhydride to obtain parecoxib. Further, the parecoxib can be made into parecoxib sodium shown in formula (IV).

[0025]

[0026] In the third aspect of the present invention, there is provided a method for directly preparing parecoxib sodium shown in formula (IV) from valdecoxib; without following the method described in the second aspect of the present invention, via the separated parecoxib and then further making it into parecoxib sodium.

[0027] In a specific embodiment of the present invention, a method for preparing parecoxib sodium shown in formula (IV) includes the steps:

[0028] (d) Mix valdecoxib, propionic anhydride, and solvent E, and stir to react;

[0029] (e) Add an alkaline solution containing sodium ions to the reaction solution in step (d), and stir to react;

[0030] (f) Heat the reaction solution in step (e) to reflux, filter the reaction solution while it is hot to obtain filtrate G;

[0031] (g) Heat and concentrate filtrate G, cool the concentrated solution to -5 to 10 °C, and precipitate parecoxib sodium.

[0032] In a specific embodiment of the present invention, the valdecoxib in step (d) is the purified valdecoxib obtained in step (c) of the method described in the first aspect of the present invention.

[0033] Preferably, the molar ratio of valdecoxib to propionic anhydride in step (d) is 1:(3-6); more preferably 1:(3-5).

[0034] Preferably, the solvent E in step (d) is tetrahydrofuran, and the mass ratio of valdecoxib to solvent E is 1:(4-10), more preferably 1:(4-8), and most preferably 1:(4-6).

[0035] Preferably, the step (d) contains a catalyst, and the catalyst is 4-dimethylaminopyridine; more preferably, the molar ratio of the catalyst to valdecoxib is (0.05 - 0.2):1.

[0036] Preferably, the temperature of the stirring reaction in step (d) is 5 - 35°C; more preferably 5 - 30°C or 10 - 35°C; most preferably 10 - 30°C. The duration of the stirring reaction in step (d) is 2 - 10 hours; more preferably 3 - 7 hours; most preferably 3 - 5 hours.

[0037] Preferably, the alkaline solution containing sodium ions in step (e) means that a sodium-containing basic substance is dissolved in solvent F. The sodium-containing basic substance is selected from one or more of sodium hydroxide, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; preferably sodium hydroxide. The solvent F is selected from one or more of methanol, ethanol, and isopropanol, preferably ethanol. The molar ratio of the sodium-containing basic substance to propionic anhydride in step (d) is (1 - 3):1, preferably (1.5 - 2.5):1.

[0038] Preferably, the temperature of the stirring reaction in step (e) is 5 - 35°C; more preferably 10 - 30°C; most preferably 15 - 25°C. The duration of the stirring reaction in step (e) is 2 - 10 hours; more preferably 3 - 8 hours; most preferably 4 - 7 hours.

[0039] In step (f), filtering the reaction solution while it is hot can remove some impurities and salts.

[0040] In a specific embodiment of the present invention, optionally, the filter cake in step (f) is washed with solvent F, and the filtrate obtained from the washing is combined into filtrate G.

[0041] In a specific embodiment of the present invention, the parecoxib sodium precipitated in step (g) can be separated and further purified by recrystallization after separation; an exemplary recrystallization solution is ethanol. The method for separating the precipitated parecoxib sodium is filtration or centrifugation.

[0042] The refining method of valdecoxib provided by the present invention can significantly improve the purity of crude valdecoxib in a high-yield manner; for example, the purity of crude valdecoxib (purity 93.23%) can be increased to more than 99.9% (and the content reaches 99.5%), and the yield is 92% (if considering the actual content of valdecoxib in the crude product, the actual yield after correction is about 98%). The refining method of valdecoxib provided by the present invention also has the advantages of simple operation, easy control of parameter conditions, and low cost in large-scale production.

[0043] The method for preparing parecoxib sodium from valdecoxib by a one-pot method provided by the present invention does not require the separate isolation of parecoxib, and the production process is simpler, which is conducive to large-scale industrial production. Description of the Drawings

[0044] Figure 1 : HPLC chromatogram of crude valdecoxib

[0045] Figure 2 : Figure 1 In the HPLC chromatogram shown, the peak corresponding to the retention time of 36.982 min is valdecoxib (peak area 93.23%), the peak corresponding to the retention time of 34.399 min is the meta-impurity of valdecoxib (peak area 6.41%), and the chromatogram also shows 6 other related substances (total peak area 0.35%).

[0046] Figure 3 : HPLC chromatogram of the refined product (Example 1)

[0047] Figure 4 : Figure 3 In the HPLC chromatogram shown, the peak corresponding to the retention time of 36.735 min is valdecoxib (peak area 99.96%), the meta-impurity of valdecoxib is not detected, and the chromatogram also shows 1 other related substance (peak area 0.04%).

[0048] Figure 5 : HPLC chromatogram of the recrystallized product of parecoxib sodium obtained in Example 9.

[0049] Figure 6 : Figure 5 In the HPLC chromatogram shown, the peak corresponding to the retention time of 33.165 min is parecoxib (parecoxib sodium) (peak area 99.97%). Detailed Embodiments

[0050] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturers.

[0051] Example 1

[0052] Add 20 g of crude valdecoxib (purity 93.23%), 120 g of ethanol and 20 g of a water mixed solvent (i.e., solvent A), and 2 g of ammonia water into a 250 ml three-necked flask. Heat the mixture to 65 ± 5 °C, stir for 0.5 h, then cool it to 0 - 10 °C, and keep stirring at 0 - 10 °C for 1 h for crystal precipitation. Filter the mixture. Add the filter cake (i.e., solid B) to 200 g of water (i.e., solvent C), control the temperature at 20 - 30 °C and stir for 1 h, then filter again. Dry the filter cake (i.e., solid D) at 60 °C for 12 h to obtain 18.4 g of refined valdecoxib with a yield of 92.0%, a purity of 99.96%, and no detectable valdecoxib meta-impurity; the content is 99.5%.

[0053] Ammonia water: Commercially available ammonia water chemical reagent, with an ammonia content of about 25% - 28%.

[0054] Example 2

[0055] Add 20 g of crude valdecoxib (purity 93.23%), 126.3 g of 95% ethanol, 13.7 g of water, and 2 g of ammonia water into a 250 ml three-necked flask. Heat the mixture to 65 ± 5 °C, stir for 0.5 h, then cool it to 0 - 10 °C, and keep stirring at 0 - 10 °C for 1 h for crystal precipitation. Filter the mixture. Add the filter cake to 200 g of water, control the temperature at 20 - 30 °C and stir for 1 h, then filter again. Dry the product at 60 °C for 12 h to obtain 18.3 g of refined valdecoxib with a yield of 91.5%, a purity not less than 99.9%, a content not less than 99%; and no detectable valdecoxib meta-impurity.

[0056] Example 3

[0057] Add 20 g of crude valdecoxib (purity 93.23%), 120 g of methanol, 20 g of water, and 0.8 g of ammonia water into a 250 ml three-necked flask. Heat the mixture to 65 ± 5 °C, stir for 0.5 h, then cool it to 0 - 10 °C, and keep stirring at 0 - 10 °C for 1 h for crystal precipitation. Filter the mixture. Add the filter cake to 200 g of water, control the temperature at 20 - 30 °C and stir for 1 h, then filter again. Dry the product at 60 °C for 12 h to obtain 18.0 g of refined valdecoxib with a yield of 90.0%, a purity not less than 99.9%, a content not less than 99%; and no detectable valdecoxib meta-impurity.

[0058] Example 4

[0059] Referring to the method of Example 1, by changing ethanol to isopropanol or ethylene glycol, high-purity refined valdecoxib was also obtained.

[0060] Example 5

[0061] Referring to the method of Example 1, by changing ammonia water to triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide, high-purity refined valdecoxib was also obtained.

[0062] Example 6

[0063] Referring to the method of Example 1, the weight ratio of ethanol to water in the recrystallization solvent (120 g of ethanol and 20 g of water) was adjusted to 4:1, 5:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, and high-purity valdecoxib refined products were also obtained.

[0064] An increase in the proportion of alcohols will reduce the yield of the refined product; for example, when anhydrous ethanol is used to replace Solvent A, the yield of the refined product decreases significantly, but there is almost no need to improve the purity. If industrial economy is not considered, the recrystallization solvent can be alcohol without water.

[0065] Example 7

[0066] Referring to the method of Example 1, the total mass of the recrystallization solvent (120 g of ethanol and 20 g of water) was adjusted to 4 times, 5 times, 6 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times the mass of the crude valdecoxib, and high-purity valdecoxib refined products were also obtained.

[0067] However, with the increase in the total mass of the recrystallization solvent, the yield of the valdecoxib refined product will decrease; if industrial economy is not considered, the total mass of the recrystallization solvent can be more than 20 times the mass of the crude valdecoxib.

[0068] Example 8

[0069] Referring to the method of Example 1, the amount of ammonia water in the recrystallization solvent was adjusted from 2 g to 4 g, 3 g, 2 g, 1 g, 0.4 g, 0.2 g, and high-purity valdecoxib refined products were also obtained.

[0070] Control Example 1

[0071] Referring to the method of Example 1, the recrystallization step did not contain ammonia water. The obtained valdecoxib refined product had a purity of 98.9% and the valdecoxib meta-impurity was 0.55% (exceeding the limit of 0.5%).

[0072] Adding an alkaline substance (such as ammonia water) in the recrystallization step can react with the hydrolysis product of valdecoxib and the unreacted sulfonyl chloride (the intermediate product produced after adding chlorosulfonic acid) to form the corresponding salts, which are dissolved in the recrystallization solvent and the subsequent solvent water; it can improve the purity and content, and can also increase the dissolution of the valdecoxib meta-impurity in the refining solvent to completely remove the meta-impurity.

[0073] Control Example 2

[0074] Referring to the method of Example 1, after recrystallization, the filter cake was directly dried without stirring in water (solvent C). The obtained product had a purity of about 99.90%; however, when the product content was detected, it was found that the valdecoxib content was less than 97%.

[0075] Example 9

[0076] Add 106 g of tetrahydrofuran and 20.0 g (63.6 mmol) of valdecoxib refined product to a 500 ml three-necked flask. While stirring, add 32 g (245.9 mmol) of propionic anhydride and 0.8 g (6.55 mmol) of 4-dimethylaminopyridine. Stir at 10 - 30 °C for 4 hours. Dropwise add an ethanol solution of sodium hydroxide (16.7 g of sodium hydroxide (417.5 mmol) dissolved in 164 g of ethanol). After dropping, a solid precipitated. React at 15 - 25 °C for 5 h. Monitor the reaction by TLC until completion (the developing agent is a mixed solution of ethyl acetate: n-hexane = 1:1, 4 ml, add 2 drops of thionyl chloride, and develop under a 254 nm ultraviolet lamp). Heat up to reflux (66 °C), filter while hot, wash the filter cake with 20 ml of ethanol, discard the filter cake, combine the filtrates into a 500 ml three-necked flask, heat up to 75 - 80 °C, distill off part of the tetrahydrofuran and ethanol at atmospheric pressure (the collected gas-phase fraction is about 106 - 116.5 g), cool down to 0 - 10 °C, filter, add 100 g of absolute ethanol to the filter cake, heat up to 70 °C and stir until clear, filter, and dry under reduced pressure at 50 ± 5 °C for 8 hours to obtain 18.75 g of white powder (parecoxib sodium), with a yield of 75.1% and a purity of 99.97%. ESI-MS m / z: 369.2 [M-Na] - 。

[0077] Example 10

[0078] Referring to the method of Example 9, replace sodium hydroxide in the ethanol solution of sodium hydroxide with sodium methoxide, sodium ethoxide, and sodium tert-butoxide, and high-purity parecoxib sodium was obtained with a high yield in the same way.

[0079] Example 11

[0080] Referring to the method of Example 9, replace ethanol in the ethanol solution of sodium hydroxide with methanol and isopropanol, and high-purity parecoxib sodium was obtained with a high yield in the same way.

Claims

1. A preparation method of parecoxib sodium represented by formula (IV), comprising the steps: (a) Mixing the crude product of the compound of formula (II), an alkaline substance and solvent A, performing recrystallization, and separating the precipitated solid B; (b) Mixing the solid B with solvent C and stirring, and separating to obtain solid D; (c) Drying the solid D to obtain the refined product of the compound of formula (II); (d) Mixing valdecoxib, propionic anhydride and solvent E, and stirring for reaction; (e) Adding an alkaline solution containing sodium ions to the reaction solution in step (d), and stirring for reaction; (f) Heating the reaction solution in step (e) to reflux, filtering the reaction solution while it is hot to obtain filtrate G; (g) Heating and concentrating the filtrate G, cooling the concentrated solution to -5 to 10 °C, and precipitating parecoxib sodium; The alkaline substance is ammonia water; the solvent A is a mixed solvent of ethanol and water; the solvent C is water; the solvent E is tetrahydrofuran; the alkaline solution containing sodium ions refers to a sodium-containing alkaline substance dissolved in solvent F; the sodium-containing alkaline substance is selected from one or more of sodium hydroxide, sodium methoxide, sodium ethoxide, and sodium tert-butoxide; the solvent F is selected from one or more of methanol, ethanol, and isopropanol; In step (a), the mass ratio of the alkaline substance to the crude product of the compound of formula (II) is (0.01 - 0.2):1; In the solvent A, the mass ratio of ethanol to water is (4 - 20):1; In step (d), the valdecoxib is the refined product of the compound of formula (II) in step (c).

2. The method according to claim 1, wherein Having one or more of the following characteristics: (1) The separation method of the precipitated solid B in step (a) is filtration or centrifugation; (2) The separation method of obtaining solid D in step (b) is filtration or centrifugation; (3) The drying method in step (c) is atmospheric drying at a temperature higher than room temperature or vacuum drying at a temperature higher than room temperature.

3. The method according to claim 1, wherein In the solvent A, the mass ratio of ethanol to water is (4 - 16):

1.

4. The method according to claim 3, characterized in that, In the solvent A, the mass ratio of ethanol to water is (4 - 12):

1.

5. The method according to claim 3, wherein In the solvent A, the mass ratio of ethanol to water is (4 - 8):

1.

6. The method according to claim 1, characterized in that, The mass ratio of the solvent A to the crude product of the compound of formula (II) is (4 - 20):

1.

7. The method according to claim 6, wherein The mass ratio of the solvent A to the crude product of the compound of formula (II) is (4 - 16):

1.

8. The method according to claim 6, wherein The mass ratio of the solvent A to the crude product of the compound of formula (II) is (4 - 13):

1.

9. The method according to claim 6, wherein The mass ratio of the solvent A to the crude product of the compound of formula (II) is (4 - 10):

1.

10. The method according to claim 1, wherein In step (a), the mass ratio of the alkaline substance to the crude product of the compound of formula (II) is (0.02 - 0.2):

1.

11. The method according to claim 10, wherein, In step (a), the mass ratio of the alkaline substance to the crude product of the compound of formula (II) is (0.05 - 0.2):

1.

12. The method according to claim 10, wherein In step (a), the mass ratio of the alkaline substance to the crude product of the compound of formula (II) is (0.05 - 0.15):

1.

13. The method according to claim 1, wherein In step (b), the mass ratio of the solvent C to the crude product of the compound of formula (II) is (4 - 20):

1.

14. The method according to claim 13, wherein In step (b), the mass ratio of the solvent C to the crude product of the compound of formula (II) is (6 - 17):

1.

15. The method according to claim 13, wherein In step (b), the mass ratio of the solvent C to the crude product of the compound of formula (II) is (8 - 13):

1.

16. The method according to claim 1, characterized in that: In step (d), the molar ratio of valdecoxib to propionic anhydride is 1:(3 - 6); In step (d), the mass ratio of valdecoxib to solvent E is 1:(4 - 10); In step (d), the temperature of the stirring reaction is 5 - 35 °C; In step (d), the duration of the stirring reaction is 2 - 10 hours.

17. The method according to claim 16, characterized in that: In step (d), the molar ratio of valdecoxib to propionic anhydride is 1:(3 - 5); In step (d), the mass ratio of valdecoxib to solvent E is 1:(4 - 8); In step (d), the temperature of the stirring reaction is 5 - 30 °C or 10 - 35 °C; In step (d), the duration of the stirring reaction is 3 - 7 hours.

18. The method according to claim 16, characterized in that: In step (d), the mass ratio of valdecoxib to solvent E is 1:(4 - 6); In step (d), the temperature of the stirring reaction is 10 - 30 °C; In step (d), the duration of the stirring reaction is 3 - 5 hours.

19. The method according to claim 1, characterized in that: In step (e), the sodium-containing basic substance is sodium hydroxide; In step (e), the solvent F is ethanol; In step (e), the molar ratio of the sodium-containing basic substance to propionic anhydride in step (d) is (1 - 3):1; In step (e), the temperature of the stirring reaction is 5 - 35 °C; In step (e), the duration of the stirring reaction is 2 - 10 hours.

20. The method according to claim 19, characterized in that: In step (e), the molar ratio of the sodium-containing basic substance to propionic anhydride in step (d) is (1.5 - 2.5):1; In step (e), the temperature of the stirring reaction is 10 - 30 °C; In step (e), the duration of the stirring reaction is 3 - 8 hours.

21. The method according to claim 19, characterized in that: In step (e), the temperature of the stirring reaction is 15 - 25 °C; In step (e), the duration of the stirring reaction is 4 - 7 hours.

22. The method according to claim 1, wherein Having one or more of the following characteristics: (1) In step (d), a catalyst is contained, and the catalyst is 4-dimethylaminopyridine; (2) In step (f), the filter cake is washed with solvent F, and the filtrate obtained from the washing is combined into filtrate G; (3) After the parecoxib sodium precipitated in step (g) is separated, it is refined by recrystallization.

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