A method for reducing free fatty acids in dexamethasone palmitate

Abstract

The present invention provides a method for reducing free fatty acids in dexamethasone palmitate. The method for reducing free fatty acids in dexamethasone palmitate according to the present invention comprises the following steps: S1: reacting dexamethasone with a palmitoyl chloride solution in a solvent system of dichloromethane and pyridine, adding an acid to terminate the reaction after the reaction, standing for liquid separation, collecting the organic layer, washing and concentrating; S2: adding ethanol to the concentrated organic layer to dissolve it clearly, then cooling for crystallization, filtering, collecting the filtrate and concentrating; S3: adding acetonitrile to the concentrated filtrate to dissolve it clearly, then cooling for crystallization, filtering and drying to obtain dexamethasone palmitate. The method of the present invention has simple process operation, low free fatty acid content in the dexamethasone palmitate product, and high purity and yield of the product.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical drug synthesis, and in particular to a method for reducing free fatty acids in dexamethasone palmitate. Background Art

[0002] The chemical name of dexamethasone palmitate is 16α-methyl-11β,17α,21-trihydroxy-9α-fluoropregna-1,4-diene-3,20-dione-21-palmitate. It is a non-specific steroid anti-inflammatory drug mainly used for the treatment of chronic rheumatoid arthritis. It has high lipid solubility, and its anti-inflammatory effect is 2-5 times that of dexamethasone. Compared with dexamethasone, dexamethasone palmitate has a smaller dosage and can exert a long-lasting anti-inflammatory effect. It can not only reduce the inherent adverse reactions of hormonal drugs but also more effectively inhibit the chemotaxis, phagocytic activity, and release of superoxide anions of macrophages.

[0003] Most of the existing preparation methods use dexamethasone as the starting material to carry out an esterification reaction with palmitoyl chloride to obtain dexamethasone palmitate. Inevitably, free fatty acids will be produced during the process. Since fatty acids are insoluble in water, with a melting point of 61-62.5°C, and their physical properties are similar to those of dexamethasone palmitate, they are not easily separated. Currently, most methods 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%) by increasing the number of purification times and sacrificing the product yield.

[0004] CN110041391A discloses a preparation method of a dexamethasone palmitate compound, including the following steps: 1) dissolving the crude dexamethasone palmitate in an organic solvent, adding activated carbon, keeping warm and stirring for 15-30 min, filtering to remove carbon, and collecting the filtrate; 2) cooling the above filtrate to room temperature, slowly adding purified water, stirring to generate a precipitate, standing for 1-4 h to crystallize, and filtering to collect the precipitate; 3) dissolving the above precipitate in an appropriate amount of 1:1 ethanol / ethyl acetate, mixing evenly with an appropriate amount of macroporous adsorption resin, adding it to the top of a pretreated macroporous adsorption resin column, and eluting successively with water, 10% ethanol, and 40% isopropanol eluents. The above method needs to achieve the purification purpose through chromatographic separation and purification, and has defects such as cumbersome process operation, long purification time, the need for a large amount of solvent for elution, difficulty in process amplification, and low product yield.

[0005] CN105732756A discloses a purification method for a fat-soluble dexamethasone derivative, comprising: using silica gel of 200-300 mesh to perform wet column packing; loading the crude dexamethasone derivative, eluting with a first cyclohexane-ethyl acetate mixture having a specific gravity between 0.7900 and 0.8000 to remove impurities; then eluting with a second cyclohexane-ethyl acetate mixture having a specific gravity between 0.8100 and 0.8300, collecting the receiving solution of the dexamethasone derivative spot, concentrating, adding acetone, and precipitating dexamethasone derivative crystals. The above method also uses chromatographic separation, and the product purity is only 98.8%.

[0006] CN110041391A discloses a synthesis method for dexamethasone palmitate. Under the catalysis of a solid base and a phase transfer catalyst, dexamethasone and methyl palmitate are subjected to transesterification reaction to obtain the target product; the solid base is loaded with a basic active component on a porous material as a carrier, and the basic active component includes lithium oxide, sodium oxide, potassium oxide, rubidium oxide, cesium oxide, magnesium oxide or calcium oxide. The above method needs to improve the product purity through the high activity and high selectivity of the solid base catalyst. However, the preparation of the solid base catalyst is complex and the cost is high, which is not conducive to industrial production.

[0007] In view of this, the present invention is specifically proposed. Summary of the Invention

[0008] The purpose of the present invention is to provide a method for reducing free fatty acids in dexamethasone palmitate. The method has simple process operation, low content of free fatty acids in the dexamethasone palmitate product, and high product purity and yield.

[0009] The present invention provides a method for reducing free fatty acids in dexamethasone palmitate, comprising the following steps:

[0010] S1: React dexamethasone with a palmitoyl chloride solution in a solvent system of dichloromethane and pyridine. After the reaction, add an acid to terminate the reaction and let it stand for layering. Collect the organic layer, wash and concentrate it;

[0011] S2: Add ethanol to the concentrated organic layer to dissolve it clearly, then cool it for crystallization, filter, collect the filtrate and concentrate it;

[0012] S3: Add acetonitrile to the concentrated filtrate to dissolve it clearly, then cool it for crystallization, filter and dry to obtain dexamethasone palmitate.

[0013] In step S1, the mass content of palmitoyl chloride in the palmitoyl chloride solution is 50-60%; the palmitoyl chloride solution is prepared by dissolving palmitoyl chloride in dichloromethane; the dosage ratio of dexamethasone, dichloromethane, pyridine and the palmitoyl chloride solution is 1 g: 5-10 mL: 0.1-1.0 mL: 0.5-2.0 mL; preferably 1 g: 7-9 mL: 0.1-0.3 mL: 1-2 mL. The reaction temperature is controlled at 20-25 °C and the reaction time is 2-3 h; after the reaction, a hydrochloric acid solution is added, stirred, and then left to stand for liquid separation; wherein, the concentration of the hydrochloric acid solution is 4-6%, and the dosage ratio between dexamethasone and the hydrochloric acid solution is 1 g: 3-8 mL, preferably 1 g: 3-5 mL, and the stirring time is 4-6 min.

[0014] In step S2, the dosage ratio of dexamethasone to ethanol is 1 g: 3-10 mL, preferably 1 g: 5-7 mL; it is heated to 50-60 °C for dissolution to clarity, and then cooled to -5 °C to -10 °C for crystallization.

[0015] In step S3, the dosage ratio of dexamethasone to acetonitrile is 1 g: 5-10 mL, preferably 1 g: 5-7 mL; it is heated to 50-60 °C for dissolution to clarity, cooled to -5 °C to -10 °C for crystallization; the content of free fatty acids in dexamethasone palmitate ≤ 0.2%; the purity of dexamethasone palmitate ≥ 99.5%.

[0016] In one embodiment, the method for reducing free fatty acids in dexamethasone palmitate of the present invention includes the following steps: reacting dexamethasone with a palmitoyl chloride solution in a solvent system of dichloromethane and pyridine, adding hydrochloric acid to terminate the reaction after the reaction, standing for liquid separation, washing and concentrating the organic layer, then adding ethanol for heating to dissolution to clarity, cooling for crystallization after dissolution to clarity, filtering, concentrating the filtrate until there is no ethanol, adding acetonitrile for heating to dissolution to clarity, cooling for crystallization after dissolution to clarity, and filtering to obtain dexamethasone palmitate. Among them: the dosage ratio of dexamethasone, dichloromethane, pyridine, palmitoyl chloride solution, hydrochloric acid solution, ethanol and acetonitrile is 1 g: 5-10 mL: 0.1-1.0 mL: 0.5-2.0 mL: 3-8 mL: 3-10 mL: 5-10 mL, preferably 1 g: 7-9 mL: 0.1-0.3 mL: 1-2 mL: 3-5 mL: 5-7 mL: 5-7 mL.

[0017] The method of the present invention is simple to operate, has few refining times, low process cost, is easy to industrialize, can effectively separate and remove free fatty acids, the content of free fatty acids in the product is below 0.2%, far lower than the standard of not more than 0.5% of free fatty acids required in the JP Pharmacopoeia, the UPLC content reaches more than 99.5%, and the mass yield is more than 120%. Description of the Drawings

[0018] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0019] Figure 1 Process flow chart of Embodiment 1 of the present invention;

[0020] Figure 2 Liquid chromatography detection result of the product of Embodiment 1 of the present invention. Specific embodiments

[0021] It should be noted that the following detailed description is illustrative and aims to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present application belongs.

[0022] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form also includes the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or their combinations.

[0023] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are some embodiments of the present invention, rather than all embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0024] Embodiment 1

[0025] As Figure 1 shown, the method for reducing free fatty acids in dexamethasone palmitate in this embodiment is as follows:

[0026] S1: Reaction

[0027] Add 50 g of dexamethasone, 400 mL of dichloromethane, and 10 mL of pyridine into a reaction flask. Control the temperature at 25 °C, and then add 100 mL of a 50 wt% palmitoyl chloride - dichloromethane solution. Keep the temperature constant for reaction for 2 h. When the raw materials are completely reacted as detected by TLC, add 200 mL of a 5 wt% hydrochloric acid solution, stir for 5 min, let it stand for layer separation. The aqueous layer is handed over to environmental protection, and the organic layer is washed twice with 200 mL of drinking water. Let it stand to separate the aqueous layer, concentrate to remove dichloromethane, and obtain the crude product of dexamethasone palmitate.

[0028] S2: One-step refinement

[0029] Add 300 mL of ethanol to the crude product of dexamethasone palmitate obtained in step S1. After heating to 55 °C until it becomes clear, cool it down to -10 °C. A large amount of crystals will precipitate. Filter, and the filter cake is free fatty acid. Concentrate the filtrate under reduced pressure until there is no ethanol left to obtain the product of one-step refinement.

[0030] S3: Two-step refinement

[0031] Add 300 mL of acetonitrile to the product of one-step refinement obtained in step S2. After heating to 55 °C until it becomes clear, cool it down to -10 °C. A large amount of crystals will precipitate. Filter, and dry the filter cake under vacuum at 45 °C for 48 h to obtain 60.5 g of the refined product of dexamethasone palmitate. The total yield is 121%, the UPLC content is 99.6%, the free fatty acid content is 0.15%, and the liquid chromatography detection results are shown in Figure 2 .

[0032] Example 2

[0033] The method for reducing free fatty acids in dexamethasone palmitate in this example is as follows:

[0034] S1: Reaction

[0035] Add 50 g of dexamethasone, 350 mL of dichloromethane, and 5 mL of pyridine into a reaction flask. Control the temperature at 20 °C, and then add 50 mL of a 60 wt% palmitoyl chloride - dichloromethane solution. Keep the temperature constant for reaction for 3 h. When the raw materials are completely reacted as detected by TLC, add 150 mL of a 6 wt% hydrochloric acid solution, stir for 5 min, let it stand for layer separation. The aqueous layer is handed over to environmental protection, and the organic layer is washed twice with 200 mL of drinking water. Let it stand to separate the aqueous layer, concentrate to remove dichloromethane, and obtain the crude product of dexamethasone palmitate.

[0036] S2: One-step refinement

[0037] Add 250 mL of ethanol to the crude product of dexamethasone palmitate obtained in step S1. After heating to 50 °C until it becomes clear, cool it down to -5 °C. A large amount of crystals will precipitate. Filter, and the filter cake is free fatty acid. Concentrate the filtrate under reduced pressure until there is no ethanol left to obtain the product of one-step refinement.

[0038] S3: Two-step refinement

[0039] Add 250 mL of acetonitrile to the one-step refined product in step S2. After heating to 50 °C until it becomes clear, cool it to -5 °C. A large amount of crystals precipitate. Filter, and vacuum dry the filter cake at 40 °C for 48 h to obtain 60.1 g of dexamethasone palmitate fine product. The total yield is 120.2%, the UPLC content is 99.4%, and the free fatty acid content is 0.10%.

[0040] Example 3

[0041] The method for reducing free fatty acids in dexamethasone palmitate in this example is as follows:

[0042] S1: Reaction

[0043] Add 50 g of dexamethasone, 450 mL of dichloromethane, and 15 mL of pyridine to a reaction flask. Control the temperature at 25 °C. Then add 75 mL of a 55 wt% palmitoyl chloride - dichloromethane solution. Keep the temperature for reaction for 2.5 h. Detect by TLC that the raw materials have completely reacted. Add 250 mL of a 4 wt% hydrochloric acid solution, stir for 5 min, let it stand for layer separation. The aqueous layer is handed over to environmental protection. The organic layer is washed twice with 200 mL of drinking water, let it stand to separate the aqueous layer, and concentrate to remove dichloromethane to obtain the crude dexamethasone palmitate.

[0044] S2: One-step refinement

[0045] Add 350 mL of ethanol to the crude dexamethasone palmitate in step S1. After heating to 50 °C until it becomes clear, cool it to -10 °C. A large amount of crystals precipitate. Filter. The filter cake is free fatty acids. The filtrate is concentrated under reduced pressure until there is no ethanol left to obtain the one-step refined product.

[0046] S3: Two-step refinement

[0047] Add 350 mL of acetonitrile to the one-step refined product in step S2. After heating to 50 °C until it becomes clear, cool it to -10 °C. A large amount of crystals precipitate. Filter, and vacuum dry the filter cake at 45 °C for 48 h to obtain 60.4 g of dexamethasone palmitate fine product. The total yield is 120.8%, the UPLC content is 99.5%, and the free fatty acid content is 0.18%.

[0048] Example 4

[0049] The method for reducing free fatty acids in dexamethasone palmitate in this example is as follows:

[0050] S1: Reaction

[0051] Add 500 g of dexamethasone, 4000 mL of dichloromethane, and 100 mL of pyridine into a reaction flask, control the temperature at 25 °C, then add 1000 mL of a 50 wt% palmitoyl chloride - dichloromethane solution, keep the temperature for reaction for 2 h, detect by TLC that the raw materials have completely reacted, add 2000 mL of a 5 wt% hydrochloric acid solution, stir for 5 min, let it stand for layering, hand over the aqueous layer to environmental protection, wash the organic layer with 2000 mL of drinking water twice, let it stand and separate the aqueous layer, concentrate to remove dichloromethane, and obtain the crude product of dexamethasone palmitate.

[0052] S2: One-step refining

[0053] Add 3000 mL of ethanol to the crude product of dexamethasone palmitate in step S1, heat up to 55 °C until it dissolves clearly, then cool down to -10 °C, a large amount of crystals precipitate, filter, the filter cake is free fatty acid, concentrate the filtrate under reduced pressure until there is no ethanol left, and obtain the product of one-step refining.

[0054] S3: Two-step refining

[0055] Add 3000 mL of acetonitrile to the product of one-step refining in step S2, heat up to 55 °C until it dissolves clearly, then cool down to -10 °C, a large amount of crystals precipitate, filter, dry the filter cake in vacuum at 45 °C for 48 h, obtain 610 g of the refined product of dexamethasone palmitate, the total yield is 122%, the UPLC content is 99.7%, and the free fatty acid content is 0.20%.

[0056] Control Examples 1 - 3

[0057] Except that the solvents used in one-step refining and two-step refining are different, the rest are the same as in Example 1.

[0058] The solvents used in Control Examples 1 - 3 and the product quality test results are shown in Table 1.

[0059] Table 1 Different refining solvents and product quality test results

[0060] Primary refined solvent Secondary refined solvent UPLC content Free fatty acid content Example 1 Ethanol Acetonitrile 99.5％ 0.15％ Control Example 1 Methanol Acetonitrile 99.5％ 0.85％ Control Example 2 Isopropanol Acetone 99.1％ 1.56％ Control Example 3 Isopropanol Ethyl acetate 99.2％ 1.87％

[0061] Control Example 4

[0062] Refine the crude product of dexamethasone palmitate in step S1 of Example 1 by using chromatographic separation and purification method. The steps of the chromatographic separation and purification method in this control example are as follows:

[0063] A chromatographic column of 6.5×100 cm was filled with 1000 g of silica gel with 200 - 300 mesh. The silica gel was infiltrated with the mobile phase and packed into the column. The crude product of dexamethasone palmitate was directly loaded. The mobile phase was a cyclohexane - ethyl acetate mixture with a specific gravity of 0.80. Then, elution was carried out with this mobile phase, and a total of 7.2 L was used; then, the elution was changed to a cyclohexane - ethyl acetate mixture with a specific gravity of 0.83, and 7.0 L was used. The chromatographic process was tracked by TLC, and the receiving solution with a single spot (Rf was about 0.6, and the developing agent was a cyclohexane - ethyl acetate mixture with a specific gravity of 0.83) was collected, concentrated under reduced pressure to a viscous state. 250 mL of acetonitrile was poured into the system, and after dissolving clearly by heating to 55 °C, it was cooled to -10 °C, and a large amount of crystals precipitated. After filtration, the filter cake was dried in vacuo at 45 °C for 48 h to obtain the high - quality product of dexamethasone palmitate. The total yield was 110%, the UPLC content was 99.1%, and the free fatty acid content was 0.93%.

[0064] Finally, it should be noted that the above - mentioned embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for reducing free fatty acids in dexamethasone palmitate, characterized in that, It includes the following steps: S1: React dexamethasone with palmitoyl chloride solution in a solvent system of dichloromethane and pyridine. After the reaction, add acid to terminate the reaction and let it stand for liquid separation. Collect the organic layer, wash it, and concentrate it; S2: Add ethanol to the concentrated organic layer to dissolve it clearly, then cool it for crystallization, filter, collect the filtrate, and concentrate it; S3: Add acetonitrile to the concentrated filtrate to dissolve it clearly, then cool it for crystallization, filter, and dry to obtain dexamethasone palmitate; In step S1, the mass content of palmitoyl chloride in the palmitoyl chloride solution is 50 - 60%; the dosage ratio among dexamethasone, dichloromethane, pyridine, and palmitoyl chloride solution is 1 g: 5 - 10 mL: 0.1 - 1.0 mL: 0.5 - 2.0 mL; control the reaction temperature at 20 - 25°C and the reaction time at 2 - 3 h; In step S2, heat it to 50 - 60°C to dissolve it clearly, then cool it to -5°C to -10°C for crystallization; In step S3, heat it to 50 - 60°C to dissolve it clearly, and cool it to -5°C to -10°C for crystallization.

2. The method according to claim 1, characterized in that, In step S1, the palmitoyl chloride solution is prepared by dissolving palmitoyl chloride in dichloromethane.

3. The method according to claim 1, wherein In step S1, after the reaction, add hydrochloric acid solution, stir, and then let it stand for liquid separation; among them, the concentration of the hydrochloric acid solution is 4 - 6%, the dosage ratio between dexamethasone and hydrochloric acid solution is 1 g: 3 - 8 mL, and the stirring time is 4 - 6 min.

4. The method according to claim 1, characterized in that, In step S2, the dosage ratio between dexamethasone and ethanol is 1 g: 3 - 10 mL.

5. The method according to claim 1, wherein In step S3, the dosage ratio between dexamethasone and acetonitrile is 1 g: 5 - 10 mL.

6. The method according to claim 1, characterized in that, In step S3, the free fatty acid content in dexamethasone palmitate ≤ 0.2%.

7. The method according to claim 1, wherein In step S3, the purity of dexamethasone palmitate ≥ 99.6%.

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