Method for preparing dexamethasone palmitate

Abstract

A method for preparing dexamethasone palmitate comprises the following steps: (1) adding an organic solvent into a dexamethasone palmitate crude product to dissolve the dexamethasone palmitate crude product; (2) adding aluminum oxide and strong base into the solution obtained in the step (1), and filtering after reaction; and (3) crystallizing the filtrate obtained in the step (2) to obtain dexamethasone palmitate. The method provided by the invention can effectively reduce the content of free fatty acid in the product, improve the quality of the product to reach the standard of pharmacopeia, reduce the use of toxic organic solvents and the like, and is economical and environment-friendly.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology. Specifically, the present invention relates to a method for preparing dexamethasone palmitate. Background Art

[0002] Dexamethasone palmitate, chemical name 9-fluoro-11β,17,21-trihydroxy-16a-methylpregnane-1,4-diene-3,20-dione-21-palmitate, molecular formula C 38 H 59 FO6, molecular weight 630.87, structural formula:

[0003]

[0004] Dexamethasone palmitate is a highly lipid-soluble nonspecific steroidal anti-inflammatory prodrug formed by esterifying the 21-hydroxy palmitate of dexamethasone in order to increase the lipid solubility of the drug. It has no pharmacological activity itself, but has a tendency to act on inflamed tissues after administration, is easily concentrated at the site of inflammation, and is hydrolyzed and deesterified under the action of esterase to form the biological metabolite dexamethasone. Dexamethasone palmitate has significant therapeutic effects, and its anti-inflammatory effect is 2-5 times that of dexamethasone. Clinically, dexamethasone palmitate is mainly used to treat diseases such as chronic rheumatoid arthritis, asthma, systemic infections and various malignant lymphomas. Dexamethasone palmitate injection (trade name: Limethason) developed by Mitsubshi Company of Japan was approved for marketing in Japan on June 1, 1988, and entered my country in 1996 under the trade name of Duolisheng.

[0005] Most of the existing preparation methods use dexamethasone as the starting material, and the starting material is subjected to an esterification reaction with palmitoyl chloride to obtain dexamethasone palmitate. In this process, free palmitic acid is produced due to the hydrolysis of palmitoyl chloride. Since palmitic acid is insoluble in water, has a melting point of 61-62.5°C, and has similar physical and chemical properties to dexamethasone palmitate, it is not easy to separate, which affects the quality of the product. The method of removing palmitic acid in industry is usually to convert it into a fatty acid salt or crystallize it at a low temperature. Since palmitic acid and dexamethasone palmitate have similar properties, in order to obtain qualified products, it is often necessary to increase the number of refining times and sacrifice the product yield to ensure that the free fatty acids in dexamethasone palmitate meet the standards (the JP Pharmacopoeia requires that the free fatty acids are not higher than 0.5%).

[0006] CN102391342B discloses a method for refining dexamethasone palmitate. The method achieves the purpose of purification by separation and purification through activated carbon adsorption, crystallization and macroporous resin adsorption, and finally obtains high-purity dexamethasone palmitate. The method includes two solvent dissolutions, which need to be dissolved, decolorized, precipitated, dissolved, adsorbed and eluted. There are defects such as cumbersome process operation, long purification time, need for a large amount of solvent for elution, and low product yield. Although the purity of the product after treatment can reach more than 99.5%, the content of free fatty acids therein is not paid attention to.

[0007] CN105732756A discloses a method for purifying a fat-soluble dexamethasone derivative, which comprises: using 200-300 mesh silica gel to wet-pack a column; loading a crude dexamethasone palmitate product, eluting with a first cyclohexane-ethyl acetate mixed solution with a specific gravity between 0.7900-0.8000 to remove impurities; then eluting with a second cyclohexane-ethyl acetate mixed solution with a specific gravity between 0.8100-0.8300, collecting a receiving solution of dexamethasone derivative spots, adding acetone after concentration, and precipitating dexamethasone palmitate crystals. This method also uses chromatographic separation, and the product purity is only 98.8%, and the content of free fatty acids is also not concerned.

[0008] CN116396346A discloses a method for reducing the free fatty acid content in dexamethasone palmitate. Specifically, ethanol is added to the concentrated solution after the reaction to heat and dissolve, and then the temperature is lowered for crystallization and filtration after the solution is cleared. The filtrate is concentrated until there is no ethanol, and then acetonitrile is added to heat and dissolve, and then the temperature is lowered for crystallization and filtration after the solution is cleared, so as to obtain dexamethasone palmitate. Although the method controls the free fatty acid content to be less than 0.2%, since acetonitrile belongs to a medium-toxic solvent, the production process has high requirements on environmental conditions, and since acetonitrile has a high boiling point, if it is not completely dried, it is very easy to produce residues, which affects the quality of the drug.

[0009] Therefore, there is an urgent need for a method for preparing dexamethasone palmitate, which can effectively reduce the content of free fatty acids in the product, improve the quality of the product to meet the standards of the pharmacopoeia, and reduce the use of toxic organic solvents, which is economical and environmentally friendly. Summary of the invention

[0010] The object of the present invention is to provide a method for preparing dexamethasone palmitate, which can obtain dexamethasone palmitate with low free fatty acid content and high purity. More specifically, the method can effectively reduce the content of free fatty acids in the product, improve the quality of the product to meet the standards of the pharmacopoeia, and reduce the use of toxic organic solvents, which is economical and environmentally friendly.

[0011] The above-mentioned object of the present invention is achieved through the following technical solutions.

[0012] The present invention provides a method for preparing dexamethasone palmitate, which comprises the following steps:

[0013] (1) adding an organic solvent to the crude dexamethasone palmitate to dissolve it;

[0014] (2) adding aluminum oxide and a strong base to the solution obtained in step (1), and filtering after the reaction;

[0015] (3) crystallizing the filtrate obtained in step (2) to obtain dexamethasone palmitate.

[0016] The inventors of the present application unexpectedly found that when simply adding aluminum oxide or simply adding a strong base to a solution of crude dexamethasone palmitate, a good separation effect cannot be achieved, but when aluminum oxide and a strong base such as sodium hydroxide and / or potassium hydroxide are added at the same time for reaction, dexamethasone palmitate with low free fatty acid content and high purity can be obtained. By the method of the present invention, the content of free fatty acids can be controlled to be below 0.5% by weight, and in some embodiments, it can reach below 0.2% by weight, and the purity of the product can reach above 99.3%.

[0017] The crude dexamethasone palmitate is not particularly limited in the present invention, and can be commercially available or prepared by conventional techniques. For example, dexamethasone and palmitoyl chloride react in an organic solvent under alkaline conditions to obtain the crude dexamethasone palmitate.

[0018] In a specific embodiment, the crude dexamethasone palmitate of the present invention can be prepared by a method comprising the following steps:

[0019] Dissolve 500g of palmitoyl chloride in 650ml of acetone for later use, add 500g of dexamethasone, 5L of acetone and 1.25L of pyridine into the reaction vessel and stir to dissolve, then add palmitoyl chloride-acetone solution, control the reaction temperature to 10-20℃ and keep warm for 2h, and use TLC to control the endpoint. After the reaction is complete, add purified water for washing, combine the organic phases, and concentrate under reduced pressure to obtain crude dexamethasone palmitate.

[0020] According to some specific embodiments of the present invention, the method for preparing dexamethasone palmitate comprises the following steps:

[0021] (1) adding an organic solvent to the crude dexamethasone palmitate and heating to dissolve;

[0022] (2) adding aluminum oxide and a strong base to the solution obtained in step (1), and filtering after the reaction;

[0023] (3) Cooling and crystallizing the filtrate obtained in step (2), and centrifuging and drying to obtain dexamethasone palmitate.

[0024] Preferably, in the method of the present invention, the strong base is sodium hydroxide and / or potassium hydroxide.

[0025] Preferably, in the method of the present invention, the ratio of the crude dexamethasone palmitate to the organic solvent is 1 g:(3.5-8.0) ml, more preferably 1 g:(4.0-6.0) ml.

[0026] Preferably, in the method of the present invention, the organic solvent is selected from one or more of acetone, dichloromethane, methanol, ethanol and ethyl acetate.

[0027] Preferably, in the method described in the present invention, the weight ratio of the aluminum oxide to the crude dexamethasone palmitate is (0.1-1.0):1, more preferably (0.5-1.0):1.

[0028] Preferably, in the method of the present invention, the molar ratio of the strong base to the free fatty acids in the crude dexamethasone palmitate is (0.5-2):1; more preferably (0.8-1.2):1.

[0029] Preferably, in the method of the present invention, the reaction in step (2) is carried out for 2-3 hours.

[0030] Preferably, in the method described in the present invention, the cooling and crystallization in step (3) is carried out under the following conditions: the crystallization temperature is -10°C to 5°C, and the crystallization time is 4 to 8 hours.

[0031] Preferably, in the method of the present invention, the drying in step (3) is carried out under the following conditions: the drying temperature is 30-40° C., and the drying time is 7-12 h.

[0032] The product prepared by the method of the present invention can be applied to the preparation of dexamethasone palmitate fat emulsion injection. To this end, the present invention also provides a dexamethasone palmitate fat emulsion injection, which is prepared from the dexamethasone palmitate prepared by the above method of the present invention.

[0033] The technical solution provided by the present invention has the following beneficial effects:

[0034] (1) The method of the present invention can control the free fatty acid content of dexamethasone palmitate to less than 0.5% by weight, and in some embodiments it can reach less than 0.2% by weight, and the product purity is more than 99.3%;

[0035] (2) The method of the present invention can avoid the use of multiple organic solvents, reduce the residual organic solvents in the finished product, and the organic solvents in the method of the present invention can be recycled and reused, which is more environmentally friendly;

[0036] (3) Compared with the method of separation and impurity removal by chromatographic column, the whole process of the method of the present invention only takes 2-3 hours, which greatly saves time and improves efficiency;

[0037] (4) After the fatty acid is removed, the method of the present invention can obtain high-purity dexamethasone palmitate by simple cooling and crystallization, and the product yield is above 85%;

[0038] (5) The method of the present invention is simple to operate and easy to implement. It does not require complicated equipment and technology, can reduce production costs, improve production efficiency, is suitable for large-scale production, and has good industrial application value. DETAILED DESCRIPTION

[0039] The present invention is further described in detail below in conjunction with specific embodiments. The given examples are only for illustrating the present invention, but not for limiting the scope of the present invention.

[0040] The crude dexamethasone palmitate used in the following examples was prepared by a method comprising the following steps:

[0041] Dissolve 500g of palmitoyl chloride in 650ml of acetone for later use, add 500g of dexamethasone, 5L of acetone and 1.25L of pyridine into the reaction vessel and stir to dissolve, then add palmitoyl chloride-acetone solution, control the reaction temperature to 20℃ and keep warm for 2h, and use TLC to control the endpoint. After the reaction is complete, add purified water for washing, combine the organic phases, and concentrate under reduced pressure to obtain crude dexamethasone palmitate.

[0042] The amount of free fatty acids in the crude product was determined to be 9.1% by weight by colorimetric titration.

[0043] Examples 1 to 7

[0044] The crude dexamethasone palmitate is added to an organic solvent and heated to dissolve. Subsequently, aluminum oxide and a strong base are added to the obtained solution, stirred to make it fully react, and then filtered. The filtrate is cooled to the crystallization temperature for crystallization for 5 hours and centrifuged. The obtained solid material is dried at 35°C for 8 hours to obtain a fine dexamethasone palmitate.

[0045] The specific process parameters as well as the yield, purity and fatty acid content of the obtained dexamethasone palmitate are shown in Table 1.

[0046] Note: The number of operations in Examples 1-6 in Table 1 refers to the number of times the sample is dissolved, alumina and a strong base are added for reaction, and filtration is performed.

[0047] Comparative Example 1

[0048] No added aluminum oxide and sodium hydroxide

[0049] The crude dexamethasone palmitate was dissolved in acetone, heated and stirred until the solution became clear, cooled to 0°C for crystallization for 5 hours, and centrifuged to obtain a solid material. This step was repeated 3 times, and after drying at 35°C for 8 hours, a fine product of dexamethasone palmitate was obtained.

[0050] The specific process parameters as well as the yield, purity and fatty acid content of the obtained dexamethasone palmitate are shown in Table 1.

[0051] Comparative Example 2

[0052] Only aluminum oxide is added

[0053] The crude dexamethasone palmitate was dissolved in acetone, heated to dissolve, and then alumina was added. After sufficient reaction, the filtrate was filtered by suction, and the filtrate was cooled to 0°C for crystallization for 5 hours and centrifuged. The obtained solid material was dried at 35°C for 8 hours to obtain the fine dexamethasone palmitate.

[0054] The specific process parameters as well as the yield, purity and fatty acid content of the obtained dexamethasone palmitate are shown in Table 1.

[0055] Comparative Example 3

[0056] Only sodium hydroxide is added

[0057] The crude dexamethasone palmitate was dissolved in acetone, heated to dissolve, and then sodium hydroxide was added. After sufficient reaction, the filtrate was filtered, and the filtrate was cooled to 0°C for crystallization for 5 hours and centrifuged. The obtained solid material was dried at 35°C for 8 hours to obtain the fine dexamethasone palmitate.

[0058] The specific process parameters as well as the yield, purity and fatty acid content of the obtained dexamethasone palmitate are shown in Table 1.

[0059] Table 1: Process parameters and technical effects

[0060]

[0061] Table 1 shows:

[0062] When aluminum oxide and sodium hydroxide are not added but the product is directly refined (such as in Comparative Example 1), the fatty acid content cannot meet the requirements even after multiple refinings, and other impurities are not removed satisfactorily and the yield is low.

[0063] When only aluminum oxide is added (such as comparative example 2), the fatty acid content is significantly reduced, but it is still far from the qualified standard. However, the yield is greatly improved compared with the method of comparative example 1.

[0064] When only sodium hydroxide is added (such as comparative example 3), the refining effect and yield are similar to those of the solution of adding only alumina (comparative example 2), and the product quality requirements are still not met. Compared with not adding alumina and sodium hydroxide (such as comparative example 1), the yield is greatly improved.

[0065] It can be seen that when aluminum oxide or sodium hydroxide is simply added to the solution of crude dexamethasone palmitate, a good separation effect cannot be achieved. However, when aluminum oxide and a strong base such as sodium hydroxide and / or potassium hydroxide are added at the same time for reaction, dexamethasone palmitate with low free fatty acid content and high purity can be obtained. By the method of the present invention, the content of free fatty acids can be controlled to be below 0.5% by weight, and in some embodiments, it can reach below 0.2% by weight, and the product purity can reach above 99.3%.

Claims

1. A method for preparing dexamethasone palmitate, comprising the following steps: (1) adding an organic solvent to the crude dexamethasone palmitate to dissolve it; (2) adding aluminum oxide and a strong base to the solution obtained in step (1), and filtering after the reaction; (3) crystallizing the filtrate obtained in step (2) to obtain dexamethasone palmitate.

2. The method according to claim 1, wherein: The strong base is sodium hydroxide and / or potassium hydroxide.

3. The method according to claim 1, wherein: The ratio of the crude dexamethasone palmitate to the organic solvent is 1 g:(3.5-8.0) ml, preferably 1 g:(4.0-6.0) ml.

4. The method according to claim 1, wherein: The organic solvent is selected from one or more of acetone, dichloromethane, methanol, ethanol and ethyl acetate.

5. The method according to claim 1, wherein: The weight ratio of the aluminum oxide to the crude dexamethasone palmitate is (0.1-1.0):1, preferably (0.5-1.0):

1.

6. The method according to claim 1, wherein: The molar ratio of the strong base to the free fatty acid in the crude dexamethasone palmitate is (0.5-2):1; preferably (0.8-1.2):

1.

7. The method according to claim 1, wherein: The reaction in step (2) is carried out for 2-3 hours.

8. The method according to claim 1, wherein: The crystallization in step (3) is carried out under the following conditions: the crystallization temperature is -10°C to 5°C, and the crystallization time is 4 to 8 hours.

9. The method according to claim 1, wherein: The method further comprises a drying step after the crystallization.

10. The method according to claim 9, wherein: The drying is carried out under the following conditions: drying temperature is 30-40° C., and drying time is 7-12 hours.

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