Method for refining tretinoin with high efficiency

Abstract

The application discloses a high-efficiency refining method of tretinoin, which comprises the following steps: S1: dissolving tretinoin crude product, deoxycholic acid and gardenoside in a first solvent, adding a poor solvent, performing temperature reduction and crystallization, and filtering to obtain a tretinoin-deoxycholic acid compound; S2: dissolving the tretinoin-deoxycholic acid compound in water, adding activated carbon to perform decolorization treatment, filtering, adjusting the pH to 5.0-5.5, and making tretinoin precipitate; S3: dissolving the precipitated tretinoin in a second solvent, adding a poor solvent, performing temperature reduction and crystallization, washing, and drying to obtain refined tretinoin; the tretinoin is refined by the method, and high yield and high purity can be simultaneously achieved.

Description

Technical Field

[0001] This application relates to the field of retinoic acid purification technology, and in particular to a highly efficient method for retinoic acid purification. Background Technology

[0002] Retinoic acid (all-trans retinoic acid) is an important active metabolite of vitamin A and is widely used in dermatology. Crude retinoic acid is usually synthesized from β-ionone through multiple steps. Because the all-trans retinoic acid molecule contains conjugated polyene side chains, it is sensitive to light, heat, and oxygen, and is prone to cis-trans isomerization during synthesis and storage, generating configurational impurities such as 13-cis retinoic acid and 9-cis retinoic acid. Simultaneously, the polyene side chains are easily oxidized to form degradation products such as epoxides and 4-oxoretinoic acid. Among these impurities, the cis isomer has the same molecular skeleton and very similar polarity as the all-trans retinoic acid molecule, constituting the core challenge of the refining process.

[0003] Current conventional purification methods mainly employ activated carbon decolorization combined with organic solvent recrystallization, utilizing solubility differences to remove some impurities with significant polarity differences. However, these methods cannot effectively separate cis isomers and structurally similar oxidation products. Single recrystallization typically yields limited purity, while multiple recrystallizations reduce yield and may trigger new degradation. Other reports have described salt formation purification, but both all-trans and cis retinoic acid can form salts, and their solubility differences are limited, thus failing to effectively achieve selective separation of configurational impurities.

[0004] Therefore, there is an urgent need to develop a purification method that can efficiently separate the cis isomer and oxidized impurities in all-trans retinoic acid while achieving both high yield and high purity. Summary of the Invention

[0005] To address the challenge of achieving both high purity and high yield in existing retinoic acid purification methods, a highly efficient retinoic acid purification method is proposed.

[0006] The above-mentioned objective of this invention is achieved through the following technical solutions: A highly efficient purification method for retinoic acid includes the following steps: S1: Dissolve crude retinoic acid, deoxycholic acid and geniposide in the first solvent, add a poor solvent, cool to crystallize, filter, and obtain retinoic acid-deoxycholic acid complex. S2: Dissolve the retinoic acid-deoxycholic acid complex in water, add activated carbon for decolorization, filter, and adjust the pH to 5.0-5.5 to precipitate retinoic acid; S3: Dissolve the precipitated retinoic acid in a second solvent, add a poor solvent, cool to allow crystallization, wash, and dry to obtain purified retinoic acid.

[0007] By adopting the above technical solution, deoxycholic acid can effectively combine with all-trans retinoic acid to form a retinoic acid-deoxycholic acid complex. When the cis isomer or other impurities are added to a poor solvent and cooled for precipitation, this retinoic acid-deoxycholic acid complex can preferentially precipitate crystals, while other impurities can remain in the solution and be filtered out, thus achieving effective screening of retinoic acid. Afterwards, the obtained retinoic acid-deoxycholic acid complex is dissolved in water, activated carbon is added for decolorization to remove residual color, and the pH is adjusted so that retinoic acid can precipitate in the form of a precipitate. The obtained retinoic acid is then dissolved again, a poor solvent is added for cooling and crystallization again, and finally washed and dried to further remove residual trace impurities. Deoxycholic acid has two hydroxyl groups, 3α-OH and 12α-OH, both located on the same face (α-face) of the steroid ring, while the other face (β-face) is hydrophobic, giving it a stereoamic amphiphilic structure. This allows it to form a spatial and energy match with the extended conformation, hydrophobic polyene side chain, and carboxyl position of all-trans retinoic acid, assembling into a stable complex. Due to intermolecular hydrogen bonding and hydrophobic interactions, this complex is stable and has a much lower solubility in poor solvents than isomers and other impurities. Upon cooling, it preferentially nucleates and precipitates high-purity retinoic acid-deoxycholic acid complex crystals. Isomers, due to changes in the geometry of the double bonds, cannot form effective multi-point recognition with the α-face hydroxyl groups of deoxycholic acid. Oxidized impurities and structural analogs are also difficult to co-crystallize due to spatial and polarity mismatches, and most are retained in the mother liquor. Thus, efficient and selective separation of all-trans retinoic acid from configurational and oxidized impurities is achieved in the first step.

[0008] The polyhydroxy structure of geniposide can be embedded in the hydrogen bond network between retinoic acid and deoxycholic acid, playing a stabilizing role. It can also regulate the crystallization process of the complex, promoting the formation of larger, more uniform, and more complete crystal particles, effectively reducing the adsorption of impurities on the crystal surface and the inclusion of mother liquor inside. At the same time, its antioxidant and free radical scavenging capabilities can inhibit the oxidative degradation of retinoic acid during the crystallization process, further reducing the content of oxidative impurities. Through the synergistic effect of molecular recognition crystallization, complex dissociation and reprecipitation, and decolorization purification, the purity of retinoic acid can be improved while maintaining a high yield.

[0009] Preferably, arginine is added when adding the unsuitable solvent to S3.

[0010] By adopting the above technical solution, arginine acts as a crystallization regulator during the crystallization process. Its side-chain guanidinium and amino groups can form reversible salt bridges and hydrogen bond networks with the carboxyl groups of retinoic acid, which can moderately slow down the nucleation rate and allow retinoic acid molecules to be arranged into the crystal lattice in a more orderly manner, reducing the mother liquor inclusion inside the crystal and the adsorption of surface impurities. At the same time, the alkalinity of arginine can also neutralize residual trace acidic impurities, and with its multifunctional group recognition ability, it can competitively dissociate amphiphilic impurities such as deoxycholic acid that may remain, further improving the purity of refined retinoic acid.

[0011] Preferably, the amount of arginine added is 0.5-2% of the molar amount of retinoic acid added in step S1.

[0012] By adopting the above technical solution, within this range, the crystallization induction and purification functions of arginine can be fully utilized, while ensuring that retinoic acid is extracted in high yield, thus achieving a balance between purity and yield.

[0013] Preferably, the first solvent is isopropanol.

[0014] By adopting the above technical solution, isopropanol has good solubility for crude retinoic acid, deoxycholic acid and geniposide. Moreover, after being miscible with poor solvents such as n-hexane, it can form a crystallization medium with moderate polarity, so that the retinoic acid-deoxycholic acid complex can be stably precipitated with a suitable supersaturation during the cooling process, which is conducive to obtaining high-purity and easily filterable crystals.

[0015] Preferably, n-hexane is a poor solvent.

[0016] By adopting the above technical solution, hexane, as a low-polarity poor solvent, can reduce the solubility of retinoic acid-deoxycholic acid complex in the system, driving its preferential nucleation and precipitation; its non-polar nature contrasts with components with high polarity such as cis isomers and oxidative impurities, effectively inhibiting the co-precipitation of these impurities.

[0017] Preferably, the second solvent is ethyl formate.

[0018] By adopting the above technical solution, ethyl formate has a strong solubility for retinoic acid and a low boiling point, which can ensure that retinoic acid dissolves during the recrystallization stage and forms a steep solubility gradient after the addition of unsuitable solvents, so that retinoic acid precipitates out with a more regular crystal habit; at the same time, ethyl formate is easy to volatilize and remove during subsequent drying, which helps to avoid the impact of solvent residue on product purity.

[0019] Preferably, the mass ratio of crude retinoic acid, deoxycholic acid, and geniposide is 1:(0.5-2):(0.01-0.1).

[0020] By adopting the above technical solution, deoxycholic acid is fully compounded with all-trans retinoic acid in this ratio, thereby improving the selective separation efficiency. Gardenin can fully exert its crystal morphology regulation and antioxidant function within this range, promoting the formation of particles with large particle size and complete crystal form, inhibiting oxidative degradation and reducing impurity inclusion. The synergistic effect of the three is better in this ratio, thereby improving purity and yield.

[0021] Preferably, the cooling and crystallization temperature is 0℃-5℃, and the time is 2-4h.

[0022] By adopting the above technical solution, the temperature and time conditions provide sufficient crystal nucleation and growth driving force for the retinoic acid-deoxycholic acid complex, enabling the complex to precipitate with a high recovery rate, suitable crystal particle size, and high purity, thus balancing separation effect and process economy.

[0023] In summary, this application has at least the following beneficial effects: (1): Deoxycholic acid forms a complex with all-trans retinoic acid. When cooled in a poor solvent, crystals are preferentially precipitated, while the cis isomer and other impurities remain in the solution. Subsequently, through dissociation, decolorization, recrystallization and other steps, retinoic acid can be purified efficiently. (2): Deoxycholic acid molecules have a stereoamphiphilic structure. Its α-side hydroxyl group can form a multi-point recognition with the extended conformation of all-trans retinoic acid and assemble into a stable complex. Its solubility is reduced in poor solvents, and it preferentially nucleates and precipitates. Other configurations and oxidized impurities are difficult to co-crystallize due to spatial mismatch, thus achieving selective separation. (3): The multi-hydroxy structure of geniposide is embedded in the hydrogen bond network of the complex, which stabilizes the system and regulates the crystallization process, promotes the formation of particles with uniform particle size and complete crystal form, reduces the adsorption of impurities and the inclusion of mother liquor, and at the same time, its antioxidant properties inhibit the oxidative degradation of retinoic acid, thus synergistically improving the purity and yield of the product. Detailed Implementation

[0024] raw material The crude retinoic acid and all-trans retinoic acid content is 96.51%. The main impurities include cis retinoic acid isomers, oxidative degradation products, and other impurities. Deoxycholic acid (CAS No. 83-44-3), geniposide, activated carbon, arginine, triethylamine, cyclohexane, n-hexane, ethyl formate, n-heptane, ethyl acetate, methyl acetate, ethanol, acetone, and isopropanol are all commercially available.

[0025] Example 1 A highly efficient purification method for retinoic acid includes the following steps: S1: Take 10.0g crude retinoic acid, 10.0g deoxycholic acid and 0.5g geniposide (mass ratio 1:1:0.05), place them in a reaction flask, add 100mL isopropanol, and dissolve by stirring at 200 rpm for 5min in a 35℃ water bath. While stirring continuously at 200 rpm, add 200mL n-hexane dropwise to the solution at a rate of 2mL / min. After the addition is complete, cool the system to 0℃ at a cooling rate of 5℃ / min and crystallize at 0℃ for 3h. After crystallization, filter under vacuum using a Buchner funnel with a vacuum degree of -0.095MPa. Wash the filter cake with isopropanol and dry it to obtain a wet filter cake of retinoic acid-deoxycholic acid complex. S2: Transfer the wet filter cake of retinoic acid-deoxycholic acid complex obtained in S1 to a beaker, add 200 mL of purified water, stir at 200 rpm for 10 min, then add 0.2 g of activated carbon, stir and decolorize for 30 min under light-protected conditions. After decolorization, filter with a Buchner funnel to remove activated carbon, collect the filtrate, add 1 mol / L NaOH solution dropwise to the filtrate while stirring at 200 rpm to adjust the pH to 5.2, continue stirring for 1 h to allow retinoic acid to fully precipitate, filter under vacuum at a vacuum degree of -0.095 MPa, wash the filter cake three times with purified water to obtain retinoic acid precipitate filter cake.

[0026] S3: Add the retinoic acid filter cake obtained in S2 to 75 mL of ethyl formate, heat to 40 °C, and stir at 150 rpm for 15 min to dissolve. After filtering the solution through a 0.45 μm microporous membrane, transfer it to a crystallizer. Heat the filtrate to 45 °C, and add 225 mL of n-hexane and 0.058 g of arginine sequentially while stirring at 50 rpm. After the addition is complete, first cool to 30 °C at a rate of 8 °C / h, and then slowly cool to 2 °C at a rate of 2 °C / h. Let it stand at 2 °C for 3 h to crystallize. After crystallization, filter under vacuum at a vacuum degree of -0.095 MPa. Wash the filter cake twice with isopropanol to replace the residual solvent. Finally, place the filter cake in a vacuum drying oven and dry it at 30 °C and -0.095 MPa for 12 h to obtain high-purity refined retinoic acid.

[0027] Comparative Example 1 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: geniposide is not added in step S1; the rest of the steps are the same as in Example 1.

[0028] Comparative Example 2 A highly efficient purification method for retinoic acid, which differs from Example 1 in that it uses triethylamine in place of deoxycholic acid by mass. The specific steps are as follows: S1: Take 10.0g crude retinoic acid, 10.0g triethylamine and 0.5g geniposide, place them in a reaction flask, add 100mL isopropanol, and dissolve by stirring at 200 rpm for 5min in a 35℃ water bath. While stirring continuously at 200 rpm, add 200mL n-hexane dropwise to the solution at a rate of 2mL / min. After the addition is complete, cool the system to 0℃ at a cooling rate of 5℃ / min and crystallize at 0℃ for 3h. After crystallization, filter under vacuum using a Buchner funnel with a vacuum degree of -0.095MPa. Wash the filter cake with isopropanol and dry it to obtain a wet filter cake of triethylamine retinoic acid salt. S2: Transfer the wet filter cake of retinoic acid triethylamine salt obtained in S1 to a beaker, add 200 mL of purified water, stir at 200 rpm for 10 min, then add 0.2 g of activated carbon, stir and decolorize for 30 min under light-protected conditions. After decolorization, filter with a Buchner funnel to remove activated carbon, collect the filtrate, add 1 mol / L dilute hydrochloric acid dropwise to the filtrate while stirring at 200 rpm to adjust the pH to 5.2, continue stirring for 1 h to allow retinoic acid to fully precipitate, filter under vacuum at a vacuum degree of -0.095 MPa, wash the filter cake three times with purified water to obtain retinoic acid precipitate filter cake; S3: Add the retinoic acid filter cake obtained in S2 to 75 mL of ethyl formate, heat to 40 °C, and stir at 150 rpm for 15 min to dissolve. After filtering the solution through a 0.45 μm microporous membrane, transfer it to a crystallizer, heat the filtrate to 45 °C, and add 225 mL of n-hexane and 0.058 g of arginine sequentially while stirring at 50 rpm. After the addition is complete, first cool to 30 °C at a rate of 8 °C / h, then slowly cool to 2 °C at a rate of 2 °C / h, and let it stand at 2 °C for 3 h to crystallize. After crystallization, filter under vacuum at a vacuum degree of -0.095 MPa. Wash the filter cake twice with isopropanol to replace the residual solvent. Finally, place the filter cake in a vacuum drying oven and dry at 30 °C and -0.095 MPa for 12 h to obtain purified retinoic acid.

[0029] Comparative Example 3 A highly efficient purification method for retinoic acid includes the following steps: Take 10.0 g of crude retinoic acid, add 150 mL of isopropanol, and stir to dissolve in a 40 °C water bath. Add 0.5 g of activated carbon, and stir to decolorize for 30 min under light-protected conditions. Filter to remove the activated carbon. Transfer the filtrate to a crystallizer, heat to 45 °C, and slowly add 300 mL of n-hexane while stirring. After the addition is complete, cool to 0 °C at a rate of 5 °C / min, and allow to stand at 0 °C for 3 h to crystallize. After crystallization, filter under vacuum, wash the filter cake with a small amount of isopropanol, and dry under vacuum at 30 °C for 12 h to obtain purified retinoic acid.

[0030] Example 2 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: arginine is not added in step S3; the rest of the method is the same as in Example 1.

[0031] Example 3 A highly efficient purification method for retinoic acid, which differs from Example 1 in that the amount of arginine added is 0.01g; the rest is the same as in Example 1.

[0032] Example 4 A highly efficient purification method for retinoic acid, which differs from Example 1 in that the amount of arginine added is 0.029g; the rest is the same as in Example 1.

[0033] Example 5 A highly efficient purification method for retinoic acid, which differs from Example 1 in that the amount of arginine added is 0.116g; the rest is the same as in Example 1.

[0034] Example 6 A highly efficient purification method for retinoic acid, which differs from Example 1 in that the amount of arginine added is 0.15g; the rest is the same as in Example 1.

[0035] Example 7 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: ethanol is used in place of isopropanol by mass; the rest is the same as in Example 1.

[0036] Example 8 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: acetone is used in place of isopropanol by mass; the rest is the same as in Example 1.

[0037] Example 9 A highly efficient purification method for retinoic acid, which differs from Example 1 in that ethyl acetate is used in place of ethyl formate by mass; the rest is the same as in Example 1.

[0038] Example 10 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: methyl acetate is used in place of ethyl formate by mass; the rest is the same as in Example 1.

[0039] Example 11 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: cyclohexane is used in place of n-hexane by mass; the rest of the method is the same as in Example 1.

[0040] Example 12 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: n-heptane is used in place of n-hexane by mass; the rest of the method is the same as in Example 1.

[0041] Example 13 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: deoxycholic acid is 0.5g and geniposide is 0.01g; the rest of the ingredients are the same as in Example 1.

[0042] Example 14 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: deoxycholic acid is 2g and geniposide is 0.1g; the rest of the method is the same as in Example 1.

[0043] Example 15 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: deoxycholic acid is 2g and geniposide is 0.01g; the rest of the method is the same as in Example 1.

[0044] Example 16 A highly efficient purification method for retinoic acid, which differs from Example 1 in that: deoxycholic acid is 0.5g and geniposide is 0.1g; the rest of the ingredients are the same as in Example 1.

[0045] Example 17 A highly efficient purification method for retinoic acid differs from Example 1 in that the final temperature for cooling and crystallization in steps S1 and S3 is 0°C, and crystallization is carried out for 2 hours; the rest of the process is the same as in Example 1.

[0046] Example 18 A highly efficient purification method for retinoic acid differs from Example 1 in that the final temperature for cooling and crystallization in steps S1 and S3 is 5°C, and crystallization is carried out for 4 hours; the rest of the process is the same as in Example 1.

[0047] Example 19 A highly efficient purification method for retinoic acid, which differs from Example 1 in that the pH is adjusted to 5.0 in step S2; the rest of the steps are the same as in Example 1.

[0048] Example 20 A highly efficient purification method for retinoic acid, which differs from Example 1 in that the pH is adjusted to 5.5 in step S2; the rest of the steps are the same as in Example 1.

[0049] The following tests were conducted on Comparative Examples 1-2 and Examples 1-20: Record the amount of purified retinoic acid m1, the original amount of crude retinoic acid added m0, the yield = m1 / m0×100%, and the test results are shown in Table 1; The purity of retinoic acid was determined by high performance liquid chromatography (HPLC), and the results are shown in Table 1.

[0050] Table 1. Detection results of Examples 1-20 and Comparative Examples 1-2

[0051] Based on Table 1, the analysis is as follows: Compared with Comparative Example 1, the yield and purity of Example 1 were higher than those of Comparative Example 1. Comparative Example 1 did not add geniposide. Although step S1 could form a retinoic acid-deoxycholic acid complex, it could not effectively control the crystal morphology and particle size of the complex during crystallization, resulting in uneven crystal size, easy adsorption of impurities on the surface, and severe mother liquor inclusion inside. Furthermore, lacking the antioxidant protection of geniposide, some retinoic acid underwent oxidative degradation during crystallization, leading to an artificially high yield and decreased purity. In contrast, this invention introduces geniposide, whose multi-hydroxyl structure not only plays a stabilizing role by embedding itself in the hydrogen bond network of the complex but also regulates the crystallization process to form large, well-formed particles, effectively reducing impurity adsorption and inclusion. Moreover, its antioxidant capacity inhibits the generation of oxidative impurities, thereby improving product purity while maintaining a high yield.

[0052] Compared with Comparative Example 1 and Comparative Example 2, the yield and purity of Example 1 were higher than those of Comparative Example 2. Comparative Example 2 used triethylamine instead of deoxycholic acid. Triethylamine can only form a salt with retinoic acid and cannot perform specific molecular recognition based on its stereoamphiphilic structure. When cooling, it cannot preferentially and selectively precipitate the all-trans retinoic acid-deoxycholic acid complex, resulting in a large number of cis isomers and oxidized impurities co-crystallizing with the product, leading to low purification efficiency and a decrease in both yield and purity. Deoxycholic acid is used because the hydroxyl group on the α-side of its molecule is highly matched with the extended conformation of all-trans retinoic acid, forming a stable complex. This complex has extremely low solubility in poor solvents and can preferentially nucleate and precipitate, while configurational and oxidized impurities are difficult to co-crystallize due to spatial mismatch. This innovatively achieves highly efficient and selective separation in the first crystallization step, ensuring high product yield and high purity.

[0053] Compared with Example 1 and Comparative Example 3, Example 1 showed higher yield and purity than Comparative Example 3. Comparative Example 3 used a conventional purification method of dissolution, decolorization, and single crystallization, which relied solely on the difference in solubility of retinoic acid and impurities in a single solvent system for separation. This method could not distinguish between all-trans retinoic acid and its cis isomers and structurally similar oxidizing impurities. These impurities precipitated along with the product during cooling, resulting in a failure to effectively improve purity. At the same time, a large amount of product remained in the mother liquor, leading to a loss in single crystallization yield. In contrast, the multi-step synergistic purification strategy, which involved the specific recognition of all-trans retinoic acid by deoxycholic acid to form a complex for preferential precipitation, the regulation of crystallization morphology and inhibition of oxidation by geniposide, the dissociation and reprecipitation of the complex for decolorization, and the assisted ordered recrystallization by arginine, gradually and efficiently separated the configurational impurities and oxidizing impurities from the product, achieving a double improvement in purity and yield.

[0054] Comparing Example 1 and Example 2, Example 1 has a higher purity than Example 2, while the yields are similar. In Example 2, arginine was not added in step S3, which resulted in an excessively fast nucleation rate of retinoic acid molecules during cooling and recrystallization, leading to disordered crystal lattice arrangement. This made it easy for trace amounts of mother liquor and residual amphiphilic impurities such as deoxycholic acid to be trapped inside the crystal, thus failing to achieve a high purity level. In Example 1, by adding trace amounts of arginine, the nucleation rate can be slowed down, guiding retinoic acid molecules to arrange themselves into the crystal lattice with a more regular crystal habit. This effectively reduces lattice defects and mother liquor trapping. At the same time, its multifunctional groups can competitively dissociate residual impurities, thereby obtaining higher product purity.

[0055] Compared with Examples 1 and 3-6, Examples 1, 4, and 5 showed better purity and yield than Examples 3 and 6. In Example 3, the amount of arginine was too low, failing to fully utilize its functions of delaying nucleation, inducing ordered crystallization, and dissociating impurities, resulting in limited improvement in purity. In Example 6, the amount of arginine was too high, excessively inhibiting the nucleation and growth of retinoic acid, leading to insufficient product elution and a decreased yield. Examples 1, 4, and 5, by controlling the amount of arginine added within the range of 0.5-2% of the molar amount of retinoic acid added in S1, achieved a precise balance between the crystallization nucleation rate and the growth process, effectively improving purity while ensuring a high product yield, achieving a superior synergy between purity and yield.

[0056] This specific embodiment is merely an explanation of the present invention and is not intended to limit the present invention. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but as long as they are within the scope of protection claimed by the present invention, they are protected by patent law.

Claims

1. A highly efficient purification method for retinoic acid, characterized in that, Includes the following steps: S1: Dissolve crude retinoic acid, deoxycholic acid and geniposide in the first solvent, add a poor solvent, cool to crystallize, filter, and obtain retinoic acid-deoxycholic acid complex. S2: Dissolve the retinoic acid-deoxycholic acid complex in water, add activated carbon for decolorization, filter, and adjust the pH to 5.0-5.5 to precipitate retinoic acid; S3: Dissolve the precipitated retinoic acid in a second solvent, add a poor solvent, cool to allow crystallization, wash, and dry to obtain purified retinoic acid.

2. The method for efficient purification of retinoic acid according to claim 1, characterized in that, Arginine was also added when adding the unsuitable solvent in step S3.

3. The method for highly efficient purification of retinoic acid according to claim 2, characterized in that, The amount of arginine added is 0.5-2% of the molar amount of retinoic acid added in step S1.

4. The method for efficient purification of retinoic acid according to claim 1, characterized in that, The first solvent is isopropanol.

5. The method for highly efficient purification of retinoic acid according to claim 1, characterized in that, The unsuitable solvent is n-hexane.

6. The method for efficient purification of retinoic acid according to claim 1, characterized in that, The second solvent is ethyl formate.

7. The method for highly efficient purification of retinoic acid according to claim 1, characterized in that, The mass ratio of crude retinoic acid, deoxycholic acid, and geniposide is 1:(0.5-2):(0.01-0.1).

8. The method for highly efficient purification of retinoic acid according to claim 1, characterized in that, The cooling and crystallization temperature is 0℃-5℃, and the time is 2-4h.

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