Refining method of tretinoin

Abstract

The invention relates to the technical field of medicines, and discloses a refining method of tretinoin, which comprises the following steps: S1, dissolving a tretinoin crude product with a mixed solvent of dichloromethane and lower alcohol, adding activated carbon for decoloration, and filtering; and S2, distilling the filtrate obtained in the step S1, adding low alcohol in the distillation process for band removal, then cooling and crystallizing, washing crystals with low alcohol, filtering, and drying to obtain refined tretinoin. According to the refining method, the influence of impurities in the crude product can be avoided, a good technical effect is achieved, the purity of tretinoin reaches 99.9% or above, the single impurity content is not higher than 0.05%, the total impurity content is lower than 0.1%, the refining yield reaches 90% or above, and the refining method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a method for refining retinoic acid. Background Art

[0002] Retinoic acid (English name: Tretinoin), also known as all-trans retinoic acid, has a chemical structure as shown in Compound 1. It is used topically in different dosage forms such as cream, gel, or solution to treat acne and is approved for the treatment of acute promyelocytic leukemia.

[0003] It is now reported that the preparation method of retinoic acid mainly involves Wittig reaction and isomerization reaction of double bonds. Wittig reaction is used for molecular skeleton construction, and isomerization reaction is used to obtain all-trans polyene structure. Isomerization reaction is very important for the preparation of retinoic acid. This reaction is either catalyzed by metal or catalyzed by iodine: CN102775338A discloses a one-pot process of Wittig reaction and isomerization reaction. Phosphonate and β-formyl crotonic acid undergo Wittig reaction under the action of alkali, and the obtained mixture is adjusted to pH value and then added with palladium catalyst for isomerization, and water is added and neutralized to obtain crude retinoic acid, and ethyl acetate is refined to obtain retinoic acid. In CN101774954A, β-formyl crotonic acid butyl ester is used as raw material, and after the Wittig reaction product is hydrolyzed, a composite catalyst of palladium nitrate, triphenylphosphine and triethylamine is added to catalyze the preparation of retinoic acid, and retinoic acid is obtained by concentration and crystallization after the reaction. In CN102558007A, phosphonium salt and 5-hydroxy-4-methyl-2-furanone are used as raw materials, and the mixture obtained by Wittig reaction is isomerized in ethanol as solvent under the action of iodine to obtain retinoic acid.

[0004] In the above prior art, CN102775338A mentions ethyl acetate refining, and CN108689899A provides a process of ethyl acetate, methanol, and ethanol reflux dissolution and crystallization, and other processes involve very few purification and refining of retinoic acid. The retinoic acid obtained by catalytic isomerization reaction is actually a crude retinoic acid product, which cannot be used directly as a bulk drug, and needs to be refined to better control organic impurities, inorganic impurities, etc. The yield reported in CN108689899A is only 78%-85%, which is not conducive to cost control. Therefore, it is still a technical problem to be solved to develop a retinoic acid refining process that avoids the influence of metal residues or iodine residues in crude retinoic acid products and obtains high-purity retinoic acid with high yield. Summary of the invention

[0005] The present invention provides a method for refining retinoic acid, which can improve the purity of retinoic acid to more than 99.9%, and the refining yield to more than 90%. The refining method is suitable for scaled-up production.

[0006] The technical solution of the present invention is to provide a method for refining retinoic acid, comprising the following steps: S1. Dissolve the crude retinoic acid with dichloromethane and lower alcohol, add activated carbon for decolorization, and filter; The filtrate obtained from S2 and S1 is distilled, and a lower alcohol is added during the distillation process to remove the band, and then the temperature is lowered to crystallize. The crystals are washed with a lower alcohol, filtered, and then dried to obtain refined retinoic acid.

[0007] Furthermore, the lower alcohol is one or more of methanol, ethanol or isopropanol.

[0008] Furthermore, the volume ratio of dichloromethane to lower alcohol is 1-9:1.

[0009] Furthermore, in step S1, the ratio of the total volume of dichloromethane and lower alcohol used for dissolution to the volume (mL) and weight (g) of the crude retinoic acid is 10-25:1; and the dissolution temperature is 20-40°C.

[0010] Furthermore, the amount of activated carbon added is 0.01 to 0.2 times the quality of crude retinoic acid; and the decolorization mixing time is 5 to 30 minutes.

[0011] Furthermore, the lower alcohol added during distillation and washing in S2 is the same as the lower alcohol used in S1.

[0012] Furthermore, the amount of the lower alcohol added in step S2 is 1 to 2 times the volume of the dichloromethane in S1.

[0013] Further, in step S2, a lower alcohol is added to remove the band, and the mixture is distilled to a temperature of 50 to 70°C. Furthermore, the crystallization temperature is -10 to 20°C, preferably 0 to 10°C.

[0014] Furthermore, during washing with lower alcohol, the temperature of the alcohol is ≤10°C.

[0015] The present invention has the following beneficial effects: The retinoic acid obtained by the existing process, in different processes, inevitably has residual metal elements (such as palladium) or residual iodine. The presence of these active impurities can promote the epoxidation and allylic oxidation side reactions of retinoic acid with multiple conjugated double bonds, and the isomerization side reaction of retinoic acid can also occur, which will lead to the increase of oxidative impurities (including impurity G of epoxy structure and impurity F of allyl methoxy in European Pharmacopoeia) and isomer impurities in the refining process, especially higher temperature is more conducive to these side reactions. If ethyl acetate, methanol, ethanol and the like are used for refining, since retinoic acid has poor solubility (slightly soluble or even slightly soluble) in conventional solvents such as ethyl acetate, methanol, ethanol, isopropanol, and dichloromethane at room temperature, heating dissolution and crystallization are required. During the heating process, the residual metal impurities (such as palladium) or iodine in the crude retinoic acid promote oxidation, isomerization and other side reactions, which is not conducive to the quality control of retinoic acid raw materials. The increase of side reactions will also affect the refining yield.

[0016] When the crude retinoic acid product is refined, the dichloromethane and lower alcohol mixed solvent system introduced by the present invention greatly improves the problem of poor solubility of retinoic acid when a single solvent is used. The mixed solvent is first used to treat the crude product containing metal residues or iodine residues, and the crude product can be dissolved near room temperature. The conditions are mild, and the adverse effects of active impurities on the refining process are avoided, especially the increased side reactions under the heating process are avoided; then distillation and crystallization are adopted, and the boiling point difference of the solvent is cleverly used during distillation, and a certain amount of lower alcohol (methanol, ethanol, isopropanol) is added for debonding. In the process of removing dichloromethane, retinoic acid is gradually precipitated, and the crystallization process is stable. While the organic impurities in the crude retinoic acid product are well removed, the precipitation yield of the retinoic acid product can also be ensured.

[0017] The refining method provided by the present invention has good removal ability for organic impurities (including isomer impurities A, impurities D, etc.), and the oxidized impurities G and impurities F are low, both not higher than 0.05%. The purity of the obtained retinoic acid is greater than 99.9% by HPLC detection, the maximum single impurity is less than 0.05%, and the total impurities are less than 0.1%. The elemental impurities are also well controlled, and the refining yield is as high as more than 90%, which is beneficial to the cost control of the raw material drug. The refined retinoic acid has good stability, and the entire refining method adopts conventional operations, is easy to operate, and the parameters are easy to control, which is suitable for the industrial production of retinoic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the HPLC spectrum of retinoic acid obtained in Example 1.

[0019] Figure 2 This is the XRD comparison spectrum of retinoic acid obtained in Example 1 (the upper one is for 0 months, and the lower one is for 6 months).

[0020] Figure 3This is the HPLC spectrum of retinoic acid obtained in Comparative Example 1. DETAILED DESCRIPTION

[0021] The present invention is described in detail below in conjunction with specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and a specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0022] The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified.

[0023] When specifically detecting retinoic acid, a high performance liquid chromatography (HPLC) method was used: chromatographic column C18 alkyl silica gel column (150*4.6mm, 3um); mobile phase: methanol-water-glacial acetic acid solution (5:225:770); flow rate: 1.0 mL / min; wavelength: 355 nm.

[0024] Example 1: Refining of retinoic acid Weigh 20 g of crude retinoic acid (obtained by palladium acetate-catalyzed isomerization, HPLC detected the purity of retinoic acid to be 97.52%, and ICP-MS detected the residual Pd to be 95.3 ppm), add dichloromethane (160 mL) and methanol (80 mL), control the temperature to 20-30 ° C and stir to dissolve, add activated carbon (1 g), stir for about 10 minutes, and filter. The filtrate was distilled and concentrated to about 1 / 3 of the volume, methanol (240 mL) was added, and the stripping distillation was continued to the temperature of 55-65 ° C, cooled to 0-10 ° C, and stirred for about 2 hours. Filter, wash the filter cake with an appropriate amount of cold methanol (0-10 ° C), and dry the obtained filter cake under reduced pressure to obtain 18.8 g of retinoic acid. The yield was 94%, the purity of retinoic acid was 99.95% by HPLC, and the content of oxidized impurity G was 0.03% ( Figure 1 ), ICP-MS detected Pd residues less than 2ppm (below the safety limit).

[0025] The obtained retinoic acid was stored for 6 months, and the impurities did not change significantly; XRD detection also showed that the crystal form had good stability ( Figure 2 ).

[0026] Example 2: Refining of retinoic acid Weigh 10 g of crude retinoic acid (obtained by iodine-catalyzed isomerization, 96.29% purity of retinoic acid by HPLC), add dichloromethane (180 mL) and methanol (20 mL), control the temperature to 25-35 ° C and stir to dissolve, add activated carbon (0.5 g), stir for about 10 minutes, and filter. The filtrate is distilled and concentrated to about half the volume, methanol (100 mL) is added, and the stripping distillation is about half the volume, methanol (80 mL) is added, and the stripping distillation is continued to the temperature of 55-65 ° C, cooled to 0-10 ° C, and stirred for about 2 hours. Filter, add an appropriate amount of cold methanol (0-10 ° C) to wash the filter cake, and the obtained filter cake is dried under reduced pressure to obtain 9.2 g of retinoic acid. The yield is 92%, and the purity of retinoic acid is 99.96% by HPLC.

[0027] Example 3: Refining of retinoic acid Weigh 5g of crude retinoic acid (crude product with higher content of isomeric impurities A and impurity D: impurity A 3.38%, impurity D 2.33%), add dichloromethane (60mL) and ethanol (15mL), control the temperature to 30~40°C and stir to dissolve, add activated carbon (0.3g), stir for about 20 minutes, and filter. The filtrate is distilled and concentrated to about half the volume, ethanol (90mL) is added, and the stripping distillation is continued to the temperature of 60~70°C, cooled to -5~5°C, and stirred for about 2 hours. Filter, wash the filter cake with appropriate amount of cold ethanol (-5~5°C), and dry the obtained filter cake under reduced pressure to obtain 4.55g of retinoic acid. The yield is 91%, and the purity of retinoic acid detected by HPLC is 99.92%.

[0028] The refining method has good removal ability for isomeric impurities Impurity A and Impurity D.

[0029] Example 4: Refining of retinoic acid Weigh 5g of crude retinoic acid (HPLC detected retinoic acid purity of 98.82%), add dichloromethane (90mL) and isopropanol (10mL), control the temperature at 25~35°C to stir and dissolve, add activated carbon (0.3g), stir for about 20 minutes, and filter. The filtrate is distilled and concentrated to about half the volume, isopropanol (135mL) is added, and the stripping distillation is continued to the temperature of 60~70°C, cooled to 0~5°C, and stirred for about 2 hours. Filter, wash the filter cake with an appropriate amount of cold isopropanol (0~5°C), and the obtained filter cake is dried under reduced pressure to obtain 4.75g of retinoic acid. The yield is 95%, and the purity of retinoic acid is 99.93% detected by HPLC.

[0030] Comparative Example 1: Refining of Retinoic Acid Weigh 5 g of crude retinoic acid (same as in Example 1), add ethyl acetate (130 mL), stir and heat to 50°C (26 times the solvent is required) to dissolve, add activated carbon (0.3 g), stir for about 10 minutes, filter quickly while hot, gradually cool the filtrate to 0-5°C, and stir for about 2 hours. Filter, wash the filter cake with an appropriate amount of ethyl acetate (0-5°C), and dry the obtained filter cake under reduced pressure to obtain 4.1 g of retinoic acid. The yield is 82%, and the purity of retinoic acid detected by HPLC is 99.29%. The main impurities, oxidized impurities G and impurities F, contain 0.16% and 0.14% respectively ( Figure 3 ).

[0031] Comparative Example 2: Refining of Retinoic Acid Weigh 5 g of crude retinoic acid (same as in Example 2), add ethyl acetate (90 mL), stir and heat under reflux to dissolve (18 times the solvent is required), cool naturally to room temperature, continue to cool to 0-5 ° C, and stir for about 1 hour. Filter, wash the filter cake with an appropriate amount of ethyl acetate (0-5 ° C), and dry the obtained filter cake under reduced pressure to obtain 4 g of retinoic acid. The yield is 80%, and the purity of retinoic acid is 99.53% by HPLC, and RRT0.46 contains 0.29% of oxidized impurities.

[0032] Comparative Example 3: Retinoic Acid Refining Weigh 2 g of crude retinoic acid (same as in Example 1), add methanol (100 mL), stir and heat under reflux to dissolve (50 times the solvent is required), cool naturally to room temperature, continue to cool to 0-5°C, and stir for about 1 hour. Filter, wash the filter cake with an appropriate amount of methanol (0-5°C), and dry the obtained filter cake under reduced pressure to obtain 1.6 g of retinoic acid. The yield is 80%, and the purity of retinoic acid is 99.40% by HPLC, and the impurity F is 0.18%.

[0033] Comparative Example 4: Refining of Retinoic Acid Weigh 2 g of crude retinoic acid (same as in Example 1), add dichloromethane (16 mL) and methanol (8 mL), control the temperature to 20-30 ° C and stir to dissolve, add activated carbon (0.01 g), stir for about 10 minutes, filter, and wash the filter cake with a small amount of cold methanol (0-10 ° C). Cool to -5-0 ° C and stir for about 2 hours. Filter, and dry the obtained filter cake under reduced pressure to obtain 1.1 g of retinoic acid, with a yield of 55%. The purity of retinoic acid detected by HPLC is 99.96%.

[0034] Comparative Example 5 Weigh 5 g of crude retinoic acid (same as Example 1), add dichloromethane (40 mL) and methanol (20 mL), control the temperature to 20-30 ° C and stir to dissolve, add activated carbon (0.01 g), stir for about 10 minutes, and filter. The filtrate is distilled to a temperature of 55-65 ° C, cooled to 0-10 ° C, stirred for about 2 hours, filtered, and the filter cake is washed with a small amount of cold methanol (0-10 ° C). Filter, the obtained filter cake is dried under reduced pressure to obtain 4.3 g of retinoic acid with a yield of 86%. HPLC detected that the purity of retinoic acid was 98.82%, impurity A was 0.62%, and impurity D was 0.22%. During the distillation process, retinoic acid was rapidly precipitated in large quantities, the system was viscous, and it was not conducive to operation.

[0035] The above embodiments describe the preferred implementation of the present invention, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for refining retinoic acid, characterized in that: The following steps are involved: S1. Dissolve the crude retinoic acid with dichloromethane and lower alcohol, add activated carbon for decolorization, and filter; The filtrate obtained from S2 and S1 is distilled, and a lower alcohol is added during the distillation process to remove the band, and then the temperature is lowered to crystallize. After the crystallization, the lower alcohol is used to wash, filter and dry to obtain refined retinoic acid.

2. The refining method according to claim 1, characterized in that: The lower alcohol is one or more of methanol, ethanol or isopropanol.

3. The refining method according to claim 2, characterized in that: In step S1, the volume ratio of dichloromethane to lower alcohol is 1-9:

1.

4. The refining method according to claim 3, characterized in that: The ratio of the total volume of dichloromethane and lower alcohol used for dissolution in step S1 to the volume (mL) weight (g) of the crude retinoic acid is 10-25:1; and the dissolution temperature is 20-40°C.

5. The refining method according to claim 1, characterized in that: The amount of activated carbon added is 0.01~0.2 times the quality of crude retinoic acid; the decolorization time is 5~30min.

6. The refining method according to claim 1, characterized in that: The lower alcohol added during distillation and washing in S2 is the same as the lower alcohol used in S1.

7. The refining method according to claim 1, characterized in that: The amount of the lower alcohol added in step S2 is 1 to 2 times the volume of the dichloromethane in S1.

8. The refining method according to claim 1, characterized in that: In step S2, a lower alcohol is added to remove the band and distilled to a temperature of 50-70°C.

9. The purification method according to any one of claims 1 to 8, characterized in that: The cooling crystallization temperature is -10~20℃.

10. The purification method according to any one of claims 1 to 8, characterized in that: When washing with lower alcohol, the temperature of the alcohol is ≤10℃.

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