A method for refining 8dm acetate

Abstract

The application belongs to the technical field of medicine, environment and chemical industry, and particularly relates to a refining method of 8DM acetate. The specific refining method steps are as follows: (1) stirring and dissolving; (2) esterification reaction; (3) water dripping and crystallization; (4) cooling and crystallization; (5) solid-liquid separation; and (6) vacuum drying. The yield of 8DM acetate refined by the method reaches more than 96%, the purity of 8DM acetate is more than 99%, and the single impurity is less than 0.2%. The application has the characteristics of high yield and good product quality, and the method is stable and easy to realize industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical, environmental and chemical technology, and specifically relates to a purification method for 8DM acetate. Background Technology

[0002] 8DM acetate, also known as dexamethasone epoxide hydrolysate acetate, has the chemical name 17α-21-dihydroxy-9β,11β-epoxy-16α-methylpregn-1,4-diene-3,20-dione-21-acetate, and its English name is 17α,21-dihydroxy-9β,11β-epoxy-16α-methylpregn-1,4-diene-3,20-dione-21-acetate. Its structural formula is as follows:

[0003]

[0004] 8DM acetate is a pale yellow to off-white crystalline powder. It is an intermediate for the synthesis of steroidal hormone drugs such as flumethasone, fluticasone propionate, and fluticasone furoate.

[0005] Currently, the existing technology for synthesizing 8DM acetate uses 8DM epoxide (SM1) as the starting material, which is obtained through methylation, epoxidation, and acid hydrolysis. The specific synthetic route is shown below:

[0006]

[0007] In the crude 8DM acetate, only impurities A and B are above 0.2%, while all other impurities are below 0.2%. During the conversion of IM2 to 8DM acetate, hydrochloric acid is used as the acidic reagent. During the reaction, the ester group at position 21 undergoes a small amount of hydrolysis, generating impurity A (8DM). In the process, impurity A ranges from 0.2% to 5%, and its structure is as follows:

[0008]

[0009] During the synthesis of 8DM acetate using this route, the siloxy groups in IM1 are sensitive to temperature, acid, and alkali, and are easily degraded into hydroxyl groups. The enol structure is unstable and transforms into a carbonyl group, generating impurity B. Impurity B accounts for 0.2%–0.5% of the total content during the process, and its structure is as follows:

[0010]

[0011] Impurity A has relatively low solubility in conventional solvents, making it difficult to control its concentration below 0.2% using conventional purification methods such as recrystallization and pulping. Since impurity A has a similar structure to 8DM acetate, a suitable crystallization solvent is required to keep it below 0.2%. Therefore, a reasonable purification method for 8DM acetate needs to be developed to address the current process requirements. Summary of the Invention

[0012] To address the problems existing in the prior art, the present invention aims to provide a method for refining 8DM acetate. Using this method, the yield of 8DM acetate reaches over 96%, the purity of 8DM acetate is over 99%, and the content of any single impurity is less than 0.2%. This invention features high yield and good product quality; the method is stable and easily scalable for industrial production.

[0013] The technical principle of this invention is as follows:

[0014] (1) Using acetone, DMF or DMSO as solvents, impurity A can be converted into 8DM acetate by reacting with acetic anhydride under the catalysis of DMAP. The reaction equation is as follows:

[0015]

[0016] (2) Compared with 8DM acetate, impurity B has a higher solubility in acetone, DMF or DMSO. By taking advantage of the difference in solubility, impurity B in 8DM acetate can be removed. However, in order to improve the purification yield, water crystallization needs to be introduced. Using this method, impurity B can be reduced from 0.2% to 0.5% to below 0.2%.

[0017] The technical solution of this invention is:

[0018] A method for purifying 8DM acetate, the method specifically comprising the following steps:

[0019] Step (1), stirring and dissolving: Add crude 8DM acetate to the reaction solvent, control the temperature at 30-60℃, stir and dissolve, and proceed to the next step;

[0020] Step (2), esterification reaction: Add catalyst to step (1), control the temperature at 30-60℃, stir the reaction for 0.5-3h, and detect by HPLC that impurity A is less than 0.2% and the material proceeds to the next step;

[0021] Step (3), water drop crystallization: The material obtained in step (2) is kept at a temperature of 45-65℃ and water is added. After the water drop is completed, the material proceeds to the next step.

[0022] Step (4), Cooling and Crystallization: Cool the material obtained in step (3) to -10 to 10°C and control the temperature for 1 to 5 hours. The material then proceeds to the next step.

[0023] Step (5), solid-liquid separation: the material obtained in step (4) is separated into solid and liquid components. The mother liquor is treated and the reaction solvent is recovered. The solid material enters the next step.

[0024] Step (6) Vacuum drying: The solid material obtained in step (5) is vacuum dried at 55-65°C to obtain 8DM acetate.

[0025] Furthermore, the content of impurity A in the crude 8DM acetate in step (1) is 0.2% to 5.0%, and the content of impurity B is 0.2% to 0.5%.

[0026] Further, in step (1), the reaction solvent is at least one of acetone, DMF, or DMSO;

[0027] The mass ratio of the crude 8DM acetate to the volume ratio of the reaction solvent is 1:2 to 8, wherein the mass of the crude 8DM acetate is in g and the volume of the reaction solvent is in mL.

[0028] Furthermore, the catalyst in step (2) is a combination of DMAP and acetic anhydride.

[0029] Furthermore, in step (2), the mass ratio of crude 8DM acetate to DMAP is 1:0.001 to 0.1; the mass ratio of crude 8DM acetate to acetic anhydride is 1:0.01 to 0.1.

[0030] Further, in step (3), the mass ratio of the crude 8DM acetate to water is 1:2 to 12.

[0031] Furthermore, in step (3), the water is added over a period of 0.5 to 5.0 hours.

[0032] Furthermore, the drying weight loss of the 8DM acetate product after vacuum drying in step (6) is less than 0.5%.

[0033] Compared with the prior art, the purification method of 8DM acetate provided by the present invention has the following advantages:

[0034] (1) The present invention makes full use of the structural features of impurity A (8DM) and 8DM acetate, and adopts the esterification reaction to convert impurity A (8DM) into 8DM acetate, thereby controlling the content of impurity A to below 0.2%.

[0035] (2) The present invention makes full use of the difference in solubility between impurity B and 8DM acetate in the crystallization solvent, so that the content of impurity B can be controlled below 0.2%.

[0036] (3) Using the refining method provided by this invention, crude 8DM acetate with impurity A (8DM) of 0.2% to 5.0% and impurity B of 0.2% to 0.5% is processed, achieving a yield of over 96%, a purity of over 99% for the 8DM acetate, and a single impurity of less than 0.2%. Furthermore, this invention features high yield and good product quality; the method is stable and easily scalable for industrial production. Attached Figure Description

[0037] Figure 1 This is a process flow diagram of the purification method for 8DM acetate according to an embodiment of the present invention. Detailed Implementation

[0038] The present invention will be further described below through specific embodiments, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not depart from the basic idea of ​​the present invention, they are all within the protection scope of the present invention.

[0039] Unless otherwise specified, the reagents used in the following examples and comparative examples are conventional reagents and can be purchased from conventional reagent manufacturers and distributors; the methods used are all prior art unless otherwise specified.

[0040] Example 1: A method for purifying 8DM acetate

[0041] The crude 8DM acetate to be purified contains 5.0% impurity A and 0.2% impurity B.

[0042] The purification method for the 8DM acetate includes the following steps:

[0043] Step (1), stirring and dissolving: Add 200g of crude 8DM acetate to 1600mL of acetone, control the temperature at 60℃, stir and dissolve, and proceed to the next step;

[0044] Step (2), esterification reaction: Add 20g DMAP and 20g acetic anhydride to step (1), control the temperature at 60℃, stir and react for 2h. HPLC detection shows that impurity A is less than 0.2%, and the material proceeds to the next step.

[0045] Step (3), water drop crystallization: The material obtained in step (2) is kept at a temperature of 55-65℃, and 1200mL of water is added dropwise over 3.0h. After the addition is complete, the material proceeds to the next step.

[0046] Step (4), Cooling and Crystallization: Cool the material obtained in step (3) to -10℃ and control the temperature for 3 hours. The material will then proceed to the next step.

[0047] Step (5), solid-liquid separation: the material obtained in step (4) is separated into solid and liquid components. The mother liquor is treated to recover acetone, and the solid material enters the next step.

[0048] Step (6) Vacuum drying: The solid material obtained in step (5) is vacuum dried at 55°C, and the limit of drying weight loss is 0.15%, to obtain 8DM acetate.

[0049] Testing revealed that 192.8 g of refined 8DM acetate was obtained using the purification method of Example 1, with a purification yield of 96.4%. The purity of the refined 8DM acetate was 99.3%, with impurity A at 0.07% and impurity B at 0.16%.

[0050] Example 2: A method for purifying 8DM acetate

[0051] The crude 8DM acetate to be purified contains 0.2% impurity A and 0.5% impurity B.

[0052] The purification method for the 8DM acetate includes the following steps:

[0053] Step (1), stirring and dissolving: Add 200g of crude 8DM acetate to 400mL of DMF, control the temperature at 30℃, stir and dissolve, and proceed to the next step;

[0054] Step (2), esterification reaction: Add 0.2g DMAP and 10g acetic anhydride to step (1), control the temperature at 30℃, stir and react for 3h. HPLC detection shows that impurity A is less than 0.2%, and the material proceeds to the next step.

[0055] Step (3), water drop crystallization: The material obtained in step (2) is kept at a temperature of 45-55℃, and 400mL of water is added dropwise over 0.5h. After the addition is complete, the material proceeds to the next step.

[0056] Step (4), Cooling and Crystallization: Cool the material obtained in step (3) to 10°C and control the temperature for 5 hours. The material will then proceed to the next step.

[0057] Step (5), solid-liquid separation: the material obtained in step (4) is separated into solid and liquid components. The mother liquor is treated and DMF is recovered. The solid material is then used in the next step.

[0058] Step (6) Vacuum drying: The solid material obtained in step (5) is vacuum dried at 65°C, and the limit of drying weight loss is 0.35%, to obtain 8DM acetate.

[0059] Testing revealed that 192.0 g of refined 8DM acetate was obtained using the purification method of Example 2, with a purification yield of 96.0%. The purity of the refined 8DM acetate was 99.1%, with impurity A at 0.12% and impurity B at 0.14%.

[0060] Example 3: A method for purifying 8DM acetate

[0061] The crude 8DM acetate to be purified contains 2.5% impurity A and 0.4% impurity B.

[0062] The purification method for the 8DM acetate includes the following steps:

[0063] Step (1), stirring and dissolving: Add 200g of crude 8DM acetate to 1000mL of DMSO, control the temperature at 45℃, stir and dissolve, and proceed to the next step;

[0064] Step (2), esterification reaction: Add 2g DMAP and 2g acetic anhydride to step (1), control the temperature at 45℃, stir and react for 0.5h. HPLC detection shows that impurity A is less than 0.2%, and the material proceeds to the next step.

[0065] Step (3), water drop crystallization: The material obtained in step (2) is kept at a temperature of 50-60℃, and 2400mL of water is added dropwise over 5.0h. After the addition is completed, the material proceeds to the next step.

[0066] Step (4), Cooling and Crystallization: Cool the material obtained in step (3) to 0°C and control the temperature for 1 hour. The material then proceeds to the next step.

[0067] Step (5), solid-liquid separation: the material obtained in step (4) is separated into solid and liquid components. The mother liquor is treated and DMSO is recovered. The solid material enters the next step.

[0068] Step (6) Vacuum drying: The solid material obtained in step (5) is vacuum dried at 60°C, and the limit of drying weight loss is 0.45%, to obtain 8DM acetate.

[0069] Testing revealed that 193.0 g of refined 8DM acetate was obtained using the purification method described in Example 3, with a purification yield of 96.5%. The purity of the refined 8DM acetate was 99.4%, with impurity A at 0.06% and impurity B at 0.17%.

[0070] Comparative Example 1: A method for purifying 8DM acetate

[0071] Compared with Example 1, the difference of Comparative Example 1 is that step (2) esterification reaction was not performed, while other parameters and operations were the same as in Example 1.

[0072] Testing revealed that 193.6 g of refined 8DM acetate was obtained using the purification method described in Comparative Example 1, with a purification yield of 96.8%, a purity of 94.2%, impurity A of 4.5%, and impurity B of 0.13%.

[0073] Compared with Example 1, impurity A was reduced from 5.0% to 4.5%, far exceeding the impurity limit of 0.2%. Under the premise of ensuring yield, impurity A cannot be reduced to 0.2% by solvent crystallization.

[0074] Comparative Example 2: A method for purifying 8DM acetate

[0075] Compared with Example 3, the difference in Comparative Example 2 is that the dripping time in step (3) is 15 minutes, while other parameters and operations are the same as in Example 3.

[0076] According to the testing, 194.0g of 8DM acetate was obtained by the purification method of Comparative Example 2, with a purification yield of 97.0%, a purity of 99.1%, impurity A of 0.15%, and impurity B of 0.22%.

[0077] Compared with Example 3, the contents of impurity A and impurity B in Comparative Example 2 are both higher, especially impurity B, which exceeds 0.2%. The specific reason is that the water droplets are added too quickly, crystallization is fast, and impurities are encapsulated.

[0078] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A method for purifying 8DM acetate, characterized in that, The method specifically includes the following steps: Step (1), stirring and dissolving: Add crude 8DM acetate to the reaction solvent, control the temperature at 30~60℃, stir and dissolve, then proceed to the next step; Step (2), esterification reaction: Add catalyst to step (1), control the temperature at 30~60℃, stir the reaction for 0.5~3 h, and detect by HPLC that impurity A is less than 0.2% and the material proceeds to the next step; Step (3), water drop crystallization: The material obtained in step (2) is kept at a temperature of 45~65℃ and water is added. After the water drop is completed, the material proceeds to the next step. Step (4), Cooling and Crystallization: Cool the material obtained in step (3) to -10~10℃, control the temperature for 1~5 h, and the material will proceed to the next step; Step (5), solid-liquid separation: the material obtained in step (4) is separated into solid and liquid. The mother liquor is treated and the reaction solvent is recovered. The solid material enters the next step. Step (6), vacuum drying: The solid material obtained in step (5) is vacuum dried at 55~65℃ to obtain 8DM acetate. The synthetic route for the crude 8DM acetate is shown below: The crude 8DM acetate contains 0.2% to 5.0% impurity A and 0.2% to 0.5% impurity B. The structural formula of impurity A is as follows: The structural formula of impurity B is as follows: In step (1), the reaction solvent is at least one of acetone, DMF or DMSO.

2. The method for purifying 8DM acetate according to claim 1, characterized in that, The reaction equation for the conversion of impurity A in the crude 8DM acetate to 8DM acetate in step (2) esterification is as follows: 。 3. The method for purifying 8DM acetate according to claim 1, characterized in that, In step (1), the mass ratio of the crude 8DM acetate to the volume ratio of the reaction solvent is 1:2~8, where the mass of the crude 8DM acetate is in g and the volume of the reaction solvent is in mL.

4. The method for purifying 8DM acetate according to claim 1, characterized in that, The catalyst in step (2) is a combination of DMAP and acetic anhydride.

5. The method for purifying 8DM acetate according to claim 4, characterized in that, In step (2), the mass ratio of crude 8DM acetate to DMAP is 1:0.001~0.1; the mass ratio of crude 8DM acetate to acetic anhydride is 1:0.01~0.

1.

6. The method for purifying 8DM acetate according to claim 1, characterized in that, In step (3), the mass ratio of crude 8DM acetate to water is 1:2~12.

7. The method for purifying 8DM acetate according to claim 1, characterized in that, In step (3), the water is added over a period of 0.5 to 5.0 hours.

8. The method for purifying 8DM acetate according to claim 1, characterized in that, The drying loss of the 8DM acetate product after vacuum drying in step (6) is less than 0.5%.

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