CN114634457A

CN114634457A - Refining method of valdecoxib

Info

Publication number: CN114634457A
Application number: CN202210437302.XA
Authority: CN
Inventors: 陈祝功
Original assignee: Jinan Lead Pharm Chemical Co ltd
Current assignee: Jinan Lead Pharm Chemical Co ltd
Priority date: 2022-04-21
Filing date: 2022-04-21
Publication date: 2022-06-17

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a refining method of valdecoxib. Adding a valdecoxib crude product into dichloromethane or trichloromethane, heating and stirring to form a suspension; stopping heating, stirring, cooling and crystallizing, continuing to keep the temperature, stirring and crystallizing, performing suction filtration, and drying under reduced pressure to obtain a valdecoxib refined product; not only can completely remove the impurity I and the impurity VI, but also can well remove other impurities in the valdecoxib, thereby obviously improving the liquid phase purity and the content of effective components of the product.

Description

Refining method of valdecoxib

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a refining method of valdecoxib.

Background

Valdecoxib, chemical name: 4- [ (5-methyl-3-phenyl) -isoxazolyl ] benzenesulfonamide, is a key intermediate of a novel selective cyclooxygenase-2 (COX-2) inhibitor parecoxib sodium, belongs to the class of coxib analgesics in antiarthritic drugs, and is mainly used for short-term treatment of postoperative pain.

The main reaction steps for preparing parecoxib at present are as follows:

the compound in the formula I is valdecoxib, and the compound in the formula II is parecoxib. The HPLC profile and data of valdecoxib prepared according to patent CN 1578774 are shown in FIG. 1 and Table 1.

TABLE 1 HPLC analysis of valdecoxib

The Applicant has found that impurities I and VI are of similar polarity to valdecoxib (very similar peaks by HPLC) and that complete purification by the methods described in the literature is difficult. If the two impurities are not completely removed, side reactions continue to occur in the next reaction, so that the impurities are more difficult to remove, and the quality of the valdecoxib directly influences the quality of the final parecoxib sodium, so that the refining of the valdecoxib is particularly important for preparing the parecoxib sodium.

In the prior art, many documents are concerned with the purification of valdecoxib, such as: patent CN 1578774 utilizes an aqueous solution of methanol for recrystallization; patent CN 103172583 utilizes a mixed solvent of isopropanol, water and butanone for recrystallization; patent IN 827/CHENP/2003 utilizes N, N-dimethylformamide and N, N-dimethylacetamide for recrystallization. However, in these methods, only a part of impurities with large polarity are actually removed, the purity data is inaccurate, impurities I and VI which are very similar to the peak of valdecoxib are not considered, and high-purity valdecoxib is not obtained finally, and some of the methods have high requirements on production equipment or have low yield, so that industrial production cannot be carried out at all, and the commercial value is low.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a refining method of valdecoxib, which can not only completely remove impurities I and VI, but also well remove other impurities in the valdecoxib, thereby obviously improving the liquid phase purity and the content of effective components of the product.

The invention relates to a refining method of valdecoxib, which comprises the following specific steps: adding the valdecoxib crude product into an organic solvent, heating and stirring to form a suspension; stopping heating, stirring, cooling and crystallizing, continuing to keep the temperature, stirring and crystallizing, performing suction filtration, and drying under reduced pressure to obtain a valdecoxib refined product; the organic solvent is dichloromethane or trichloromethane.

When dichloromethane is used as a solvent, the heating temperature is 35-40 ℃, and when chloroform is used as a solvent, the adding temperature is 60-65 ℃.

The weight volume ratio of the valdecoxib crude product to the organic solvent is 1 g: 4-6 mL.

The heating reflux and stirring time is 2-5h, preferably 2-3 h.

Stirring and cooling to 0-25 ℃ for crystallization, preferably 20-25 ℃.

The time for heat preservation, stirring and crystallization is 1-4h, preferably 1-2 h.

The temperature of reduced pressure drying is 40-45 ℃.

The method adopts dichloromethane or trichloromethane as a solvent to refine the valdecoxib, can not only completely remove impurities I and VI with lower polarity, but also well remove other impurities with higher polarity in the product, obviously improves the liquid phase purity and the effective component content of the product, and ensures that the purity of the refined product is more than 99.9 percent in the true sense, and the single impurity is less than 0.10 percent. Meanwhile, the refined solvent adopted by the invention is a single solvent, can be effectively recycled, is convenient for large-scale production of products and reduces the cost.

Drawings

Figure 1 is an HPLC profile of valdecoxib.

Detailed Description

Example 1

Adding 1kg of valdecoxib crude product into a reaction vessel containing 4L of dichloromethane, heating to 35 ℃ and stirring for 2 hours to form turbid liquid, stopping heating, stirring and cooling to 0 ℃ for crystallization, continuing to keep the temperature and stirring for crystallization for 1 hour, performing suction filtration, and drying at 40 ℃ under reduced pressure to obtain 950g of valdecoxib refined product, wherein the yield is as follows: 95%, purity: 99.9 percent, and no impurity I or impurity VI is detected, and the single impurity is less than 0.10 percent.

Example 2

Adding 1kg of valdecoxib crude product into a reaction vessel containing 5L of dichloromethane, heating to 35 ℃ and stirring for 3 hours to form turbid liquid, stopping heating, stirring and cooling to 20 ℃ for crystallization, continuing to keep the temperature and stirring for crystallization for 2 hours, performing suction filtration, and drying at 45 ℃ under reduced pressure to obtain 960g of valdecoxib refined product, wherein the yield is as follows: 96%, purity: 99.9 percent, and no impurity I or impurity VI is detected, and the single impurity is less than 0.10 percent.

Example 3

Adding 1kg of valdecoxib crude product into a reaction container containing 6L of dichloromethane, heating to 40 ℃, stirring for 5 hours to form suspension, stopping heating, stirring and cooling to 25 ℃ for crystallization, continuing to keep the temperature and stirring for crystallization for 4 hours, performing suction filtration, and drying at 45 ℃ under reduced pressure to obtain 940g of valdecoxib refined product, wherein the yield is as follows: 94%, purity: 99.9 percent, and no impurity I or impurity VI is detected, and the single impurity is less than 0.10 percent.

Example 4

Adding 1kg of valdecoxib crude product into a reaction vessel containing 4L of chloroform, heating to 60 ℃, stirring for 2 hours to form turbid liquid, stopping heating, stirring and cooling to 0 ℃ for crystallization, continuing to keep the temperature and stirring for crystallization for 1 hour, performing suction filtration, and drying at 40 ℃ under reduced pressure to obtain 965g of valdecoxib refined product, wherein the yield is as follows: 96.5%, purity: 99.9 percent, and no impurity I or impurity VI is detected, and the single impurity is less than 0.10 percent.

Example 5

Adding 1kg of valdecoxib crude product into a reaction vessel containing 5L of chloroform, heating to 60 ℃, stirring for 3 hours to form turbid liquid, stopping heating, stirring and cooling to 20 ℃ for crystallization, continuing to keep the temperature and stirring for crystallization for 2 hours, performing suction filtration, and drying at 45 ℃ under reduced pressure to obtain 955g of valdecoxib refined product, wherein the yield is as follows: 95.5%, purity: 99.9 percent, and no impurity I or impurity VI is detected, and the single impurity is less than 0.10 percent.

Example 6

Adding 1kg of valdecoxib crude product into a reaction vessel containing 6L of chloroform, heating to 65 ℃, stirring for 5 hours to form a suspension, stopping heating, stirring and cooling to 25 ℃ for crystallization, continuing to keep the temperature and stirring for crystallization for 4 hours, performing suction filtration, and drying under reduced pressure at 45 ℃ to obtain 945g of valdecoxib refined product, wherein the yield is as follows: 94.5%, purity: 99.9 percent, and no impurity I or impurity VI is detected, and the single impurity is less than 0.10 percent.

In addition, the applicant also carried out a purification test of valdecoxib using acetone or ethyl acetate as solvent.

Comparative example 1

Adding 100g of valdecoxib crude product into a reaction container containing 500mL of acetone, heating to 55-60 ℃, stirring for 2 hours to form a suspension, stopping heating, stirring and cooling to 20 ℃ for crystallization, continuing to keep the temperature and stirring for crystallization for 1 hour, performing suction filtration, and drying under reduced pressure at 40 ℃ to obtain 92g of valdecoxib refined product, wherein impurities I and VI are not obviously reduced, and the yield is as follows: 92%, purity: 97 percent.

Comparative example 2

Adding 100g of valdecoxib crude product into a reaction container containing 500mL of ethyl acetate, heating to 75-80 ℃, stirring for 2 hours to form a suspension, stopping heating, stirring and cooling to 20 ℃ for crystallization, continuing to keep the temperature and stirring for crystallization for 1 hour, performing suction filtration, and drying under reduced pressure at 40 ℃ to obtain 88g of valdecoxib refined product, wherein the impurity I and the impurity VI are not obviously reduced, and the yield is as follows: 88%, purity: 97.5 percent.

As can be seen from the two comparative examples above, valdecoxib of very high purity cannot be obtained with these solvents, in particular without a significant reduction in the content of impurities I and VI.

The method adopts dichloromethane or trichloromethane as a solvent to refine the valdecoxib, so that impurities I and VI with lower polarity can be completely removed, other impurities with higher polarity in the product can be well removed, the liquid phase purity and the effective component content of the product are obviously improved, the purity of the refined product is more than 99.9% in a real sense, and the single impurities are less than 0.10%.

Claims

1. The refining method of valdecoxib is characterized by comprising the following specific steps: adding the valdecoxib crude product into an organic solvent, heating and stirring to form a suspension; stopping heating, stirring, cooling, crystallizing, keeping the temperature, stirring, crystallizing, filtering, and drying under reduced pressure to obtain valdecoxib refined product; the organic solvent is dichloromethane or trichloromethane.

2. The refining method of valdecoxib as claimed in claim 1, wherein the weight volume ratio of the crude valdecoxib to the organic solvent is 1 g: 4-6 mL.

3. The refining method of valdecoxib as claimed in claim 2, wherein the heating temperature is 35-40 ℃ when dichloromethane is used as the solvent, and the adding temperature is 60-65 ℃ when trichloromethane is used as the solvent.

4. The refining method of valdecoxib as claimed in claim 2, wherein the heating and stirring time is 2-5 h.

5. The refining method of valdecoxib as claimed in claim 2, wherein the valdecoxib is stirred and cooled to 0-25 ℃ for crystallization.

6. The refining method of valdecoxib as claimed in claim 2, wherein the crystallization time under stirring is 1-4 h.

7. The refining method of valdecoxib as claimed in claim 2, wherein the temperature for drying under reduced pressure is 40-45 ℃.