Preparation method of hydroxyl pinacolone retinoate

Abstract

The invention provides a preparation method of hydroxyl pinacolone retinoate, which comprises the following steps: dissolving retinoic acid and trisubstituted organic amine in an organic solvent, dropwise adding pivaloyl chloride, and stirring for reaction to obtain retinoic acid pivaloyl anhydride; and dropwise adding hydroxyl pinacolone into the prepared retinoic acid pivaloic anhydride reaction liquid, carrying out a stirring reaction to prepare hydroxyl pinacolone retinoate, carrying out post-treatment, carrying out crystallization by using an alcohol solvent to separate out hydroxyl pinacolone retinoate crystals, and at least carrying out filtration and drying to obtain the hydroxyl pinacolone retinoate product. The preparation method has the advantages of simplicity in operation, cheap and easily available raw materials, convenience in purification and few three wastes.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing hydroxypinacolone retinoic acid ester. Background Art

[0002] Hydroxypinacolone Retinoate, chemical name: (3,3-dimethyl-2-oxo-butyl)(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)nonane-2,4,6,8-tetraenoate, is a structural derivative of retinol. Hydroxypinacolone Retinoate can directly bind to the cell retinoic acid receptor, has the function of regulating the metabolism of the epidermis and stratum corneum, can resist aging, reduce sebum secretion, lighten epidermal pigments, prevent skin aging, treat acne, whiten and lighten spots, etc. It is mainly used for anti-aging, wrinkle removal and prevention of acne recurrence.

[0003] At present, many methods have been reported for the preparation of hydroxypinacolone retinoic acid ester. Some methods use expensive condensation agents, produce a lot of three wastes, and are difficult to post-process; some methods use genotoxic starting materials, resulting in poor product quality, and the reaction yield is often not high, and the cost of industrial scale-up production is high.

[0004] Patent CN116283697A discloses a method for synthesizing hydroxypinacolone retinoic acid ester: retinoic acid and hydroxypinacolone are subjected to a condensation reaction in the presence of EDCI, HOBT and DMAP using a base as an acid-binding agent to obtain hydroxypinacolone retinoic acid ester. The EDCI and HOBT used in this preparation method are both relatively expensive raw materials, and after the reaction, a large amount of by-products that are difficult to handle are generated, the product purification is difficult, and the cost of scaled-up production is high.

[0005] Patent CN117720451A discloses a method for synthesizing hydroxypinacolone retinoic acid ester: using retinoic acid and 1-chloropinacolone as raw materials, the hydroxypinacolone retinoic acid ester is prepared by the following steps: (1) adding retinoic acid, sodium carbonate and a solvent into a reaction kettle, then introducing argon gas, and then adding 1-chloropinacolone; (2) raising the temperature of the reaction kettle to 35-45°C, stirring the reaction kettle for 4-8 hours, and then cooling the temperature to 20-30°C; then adding water to the reaction kettle for crystallization for 30-60 minutes; (3) after the crystallization is completed, filtering the reaction product to obtain a solid; (4) washing and drying the solid to obtain the hydroxypinacolone retinoic acid ester. The yield of this preparation process in most solvents is moderate, not exceeding 80%. Only when the volume ratio of tetrahydrofuran to 1-hydroxy-1-cyclohexylcarboxylic acid ethyl ester is 2.5:1, a yield of 96.8% can be obtained. However, the solvent used in this reaction system is relatively expensive, and in the subsequent processing process, the solvent is difficult to recover and reuse, and the production cost is high; and the raw material 1-chloropinacolone used is easy to remain in the product, and the raw material is prohibited from use in cosmetics, and the subsequent product purification cost is high.

[0006] Patent CN114436924A discloses a method for synthesizing hydroxypinacolone retinoic acid ester, which comprises the following steps: (1) adding an organic solvent to retinoic acid, then adding an amide catalyst, stirring evenly and then placing in an ice bath; (2) adding phosphorus trichloride to the material obtained in (1) under nitrogen protection, and reacting; (3) standing to separate the lower inorganic solution, adding 1-hydroxy-3,3-dimethylbutane-2-one under ice bath conditions, then adding an acid binding agent, keeping the temperature for reaction, filtering the inorganic salt under reduced pressure, and concentrating the liquid phase under reduced pressure; (4) adding a recrystallization solvent, cooling and crystallizing to obtain hydroxypinacolone retinoic acid ester. The phosphorus trichloride used in this method generates a large amount of phosphorous acid wastewater in post-treatment, which has high wastewater treatment costs, is not environmentally friendly, and is not economical for scaled-up production.

[0007] In summary, the existing preparation methods of hydroxypinacolone retinoic acid esters have the problems of unreasonable selection of raw materials and reaction reagents, high prices, low process yields, or outstanding three-waste problems in the process, high three-waste treatment costs, and low product quality, which affect the scale-up production of the products. The present invention aims at the defects of the above-mentioned preparation process and provides a preparation method of hydroxypinacolone retinoic acid esters, which solves the problems of low process yield, difficult product purification, and outstanding three-waste problems, and realizes green and industrialized production of products. Summary of the invention

[0008] In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a method for preparing hydroxypinacolone retinoic acid ester, which has the advantages of simple operation, cheap and readily available raw materials, convenient purification and less three wastes.

[0009] To solve the above problems, the technical solution adopted by the present invention is as follows:

[0010] A method for preparing hydroxypinacolone retinoic acid ester comprises the following steps:

[0011] After dissolving retinoic acid and a trisubstituted organic amine in an organic solvent, pivaloyl chloride is added dropwise and stirred for reaction to prepare retinoic acid pivalic anhydride;

[0012] Hydroxypinacolone is added dropwise to the reaction solution of the prepared retinoic acid pivalic anhydride and stirred for reaction to prepare hydroxypinacolone retinoic acid ester, followed by post-treatment, crystallization with an alcohol solvent to precipitate hydroxypinacolone retinoic acid ester crystals, and at least filtering and drying to obtain a hydroxypinacolone retinoic acid ester product.

[0013] In some possible embodiments, the ratio of the retinoic acid: the trisubstituted organic amine: the pivaloyl chloride is 1:1.0-2.0:1.0-1.5, calculated on a substance basis.

[0014] In some possible embodiments, the tri-substituted organic amine is at least one selected from triethylamine, N,N-diisopropylethylamine and N-methylmorpholine.

[0015] In some possible embodiments, the ratio of the hydroxypinacolone to the retinoic acid is 1:0.90-1.1, calculated on the basis of the amount of the substance.

[0016] In some possible embodiments, the alcohol solvent is selected from at least one of methanol, ethanol, isopropanol or n-butanol.

[0017] In some possible embodiments, the step of adding the pivaloyl chloride dropwise and stirring the reaction comprises:

[0018] After cooling the reaction solution containing retinoic acid and trisubstituted organic amine to 0-5°C, adding the pivaloyl chloride dropwise, and controlling the internal temperature of the reaction to be less than or equal to 10°C;

[0019] After the pivaloyl chloride is added dropwise, the reaction is stirred at a temperature ranging from room temperature to 40° C. until the reaction solution becomes clear.

[0020] In some possible embodiments, the steps of preparing the hydroxypinacolone retinoic acid ester include:

[0021] After the hydroxypinacolone is added dropwise, the internal temperature of the reaction is controlled to be less than or equal to 10° C.;

[0022] After the hydroxypinacolone is added, the reaction is stirred at a temperature ranging from room temperature to 40° C. until the reaction solution becomes clear.

[0023] In some possible embodiments, the post-processing step includes:

[0024] Adding water to the prepared hydroxypinacolone retinoic acid ester, stirring and standing to separate the liquids, separating a first organic phase, washing the first organic phase with saline, separating a second organic phase, and distilling the second organic phase under reduced pressure to recover the organic solvent to obtain a post-treated product;

[0025] The steps of crystallization with alcohol solvent include:

[0026] After adding the alcohol solvent, the temperature is raised to 50-60°C to dissolve the post-treatment product, then the temperature is lowered to 10-20°C, and after the crystals are precipitated, the temperature is further lowered to 5-10°C, and stirred for 25-35 minutes;

[0027] The step of obtaining the hydroxypinacolone retinoic acid ester product also includes:

[0028] Before drying, the filtered cake is rinsed with the alcohol solvent at 0-5°C.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The preparation method provided by the present application has the advantages of simple operation, cheap and readily available raw materials, convenient purification and less waste. In addition, through further coordination of reaction steps, reaction conditions and material ratios, the preparation method provided by the present application further has the advantages of mild reaction conditions and high product yield.

[0031] The present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 A reaction scheme provided for one embodiment of the present application.

[0033] Figure 2 is a chromatogram of retinoic acid pivalic anhydride in the second reaction solution;

[0034] Figure 3 is the mass spectrum of retinoic acid pivalic anhydride in the second reaction solution;

[0035] Figure 4 The chromatogram and mass spectrum of hydroxypinacolone retinoic acid ester. DETAILED DESCRIPTION

[0036] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0037] The terms "first", "second", etc. in the specification and claims of this application and the above drawings are used to distinguish different objects rather than to describe a specific order. In addition, the terms "include" and "have" and any variations thereof are intended to cover non-exclusive inclusions.

[0038] Unless otherwise specified, the raw materials, reagents or devices used in the following examples and comparative examples can be obtained from conventional commercial sources or by existing known methods.

[0039] An embodiment of the present application provides a method for preparing hydroxypinacolone retinoic acid ester, comprising the following steps.

[0040] Step 1: After dissolving retinoic acid and a trisubstituted organic amine in an organic solvent, pivaloyl chloride is added dropwise and stirred for reaction to prepare retinoic acid pivalic anhydride.

[0041] In some embodiments, the tri-substituted organic amine is selected from at least one of triethylamine, N,N-diisopropylethylamine and N-methylmorpholine.

[0042] In some embodiments, the organic solvent may be selected from at least one of ethyl acetate, toluene, dichloromethane, or 1,2-dichloroethane.

[0043] In some embodiments, the step of dissolving retinoic acid and a tri-substituted organic amine in an organic solvent comprises: adding the retinoic acid and the organic solvent to a reaction vessel, filling with nitrogen for protection, stirring evenly, and then adding the tri-substituted organic amine. Exemplarily, the reaction vessel may comprise a three-necked flask. Exemplarily, the retinoic acid and the organic solvent may be stirred to form a yellow turbid liquid.

[0044] In some embodiments, the ratio of the retinoic acid: the trisubstituted organic amine: the pivaloyl chloride is 1: 1.0-2.0: 1.0-1.5, calculated on a substance basis.

[0045] In some embodiments, the step of dripping the pivaloyl chloride and stirring the reaction comprises: cooling the reaction solution containing retinoic acid and trisubstituted organic amine to 0-5°C, dripping the pivaloyl chloride, and controlling the reaction temperature to be less than or equal to 10°C. After the pivaloyl chloride is dripped, the reaction is stirred at a temperature range of room temperature to 40°C until the reaction solution is dissolved. Exemplarily, the residual amount of retinoic acid in the reaction solution can be tested by high performance liquid chromatography (HPLC) after the reaction solution is dissolved. Exemplarily, the stirring reaction time can be at least three hours.

[0046] Step 2: Add hydroxypinacolone to the reaction solution of the obtained retinoic acid pivalic anhydride and stir to react to prepare hydroxypinacolone retinoic acid ester, post-treat, crystallize with an alcohol solvent to precipitate hydroxypinacolone retinoic acid ester crystals, and obtain the hydroxypinacolone retinoic acid ester product after at least filtering and drying. Exemplarily, it can be dried by a 40°C water pump vacuum for at least two hours. For the specific reaction route, refer to Figure 1 .

[0047] In some embodiments, the ratio of hydroxypinacolone to retinoic acid is 1:0.90-1.1, calculated on a substance basis.

[0048] In some embodiments, the alcohol solvent is selected from at least one of methanol, ethanol, isopropanol, or n-butanol.

[0049] In some embodiments, the step of preparing the hydroxypinacolone retinoic acid ester comprises: after the hydroxypinacolone is added dropwise, the temperature in the reaction is controlled to be less than or equal to 10°C. After the hydroxypinacolone is added dropwise, the reaction is stirred at a temperature range of room temperature to 40°C until the reaction solution is clarified. Exemplarily, the stirring reaction time can be at least two hours. The pre-treatment liquid can be a dark yellow clarified liquid. Exemplarily, the residual amount of retinoic acid pivalic anhydride can be detected by HPLC.

[0050] In some embodiments, the post-treatment step includes: adding water to the prepared hydroxypinacolone retinoic acid ester, stirring and standing to separate the liquid, and separating the first organic phase. Washing the first organic phase with saline to separate the second organic phase. Exemplarily, the mass fraction of saline can be 10%. The number of times of saline washing can be once. The second organic phase is distilled under reduced pressure to recover the organic solvent to obtain a post-treated product. The post-treated product can be a yellow viscous substance. The step of crystallizing with an alcohol solvent includes: heating to 50-60°C after adding an alcohol solvent to dissolve the post-treated product, then cooling to 10-20°C, continuing to cool to 5-10°C after crystals are precipitated, and stirring for 25-35 minutes. The step of obtaining a hydroxypinacolone retinoic acid ester product also includes: rinsing the filtered filter cake with the alcohol solvent at 0-5°C before drying.

[0051] The preparation method provided by the present application has the advantages of simple operation, cheap and readily available raw materials, convenient purification and less waste. In addition, through further coordination of reaction steps, reaction conditions and material ratios, the preparation method provided by the present application further has the advantages of mild reaction conditions and high product yield.

[0052] The intermediate products and final products synthesized in this application can be confirmed by chromatograms and mass spectra. Figure 2 - Figure 4 .

[0053] Example 1

[0054] In a 2000mL three-necked flask, add 100.0g of retinoic acid and 800mL of ethyl acetate, fill with nitrogen protection, stir evenly, and the reaction liquid is a yellow turbid liquid. Then add 50g of triethylamine, cool to 0-5℃ in an ice-water bath, drop 50g of pivaloyl chloride into the reaction bottle, control the internal temperature ≤10℃, and the solid in the reaction liquid gradually dissolves; after the drop is completed, stir and react at room temperature for 3h, the solid in the reaction liquid gradually dissolves until it is completely clear, and retinoic acid pivalic anhydride is prepared. HPLC detection of retinoic acid residue ≤2.5% (relative ratio of liquid phase peak area); slowly add 40.0g of hydroxypinacolone to the reaction bottle, control the internal temperature ≤10℃, after the drop is completed, stir and react at room temperature for 2h, the reaction liquid is a dark yellow clear liquid, and HPLC detection of retinoic acid pivalic anhydride ≤0.5% (relative ratio of liquid phase peak area); add 350mL of water, stir for 30min, The first organic phase was separated by standing and liquid separation; the second organic phase was separated by washing once with 350 mL of 10% (mass fraction) salt water, and the solvent was recovered under reduced pressure at 40°C to obtain a residual yellow viscous substance (post-treatment product, hydroxypinacolone retinoic acid ester); 750 mL of ethanol was added, the temperature was raised to 50°C to dissolve, the temperature was slowly lowered to 10-20°C in a water bath, a large number of yellow fine needle-shaped crystals were precipitated, the temperature was further lowered to 5-10°C, and stirred for 30 minutes; the filter was filtered, the filter cake was rinsed with 100 mL of cold (0-5°C) ethanol, and the filter cake was collected; the filter cake was vacuum dried at 40°C for 2 hours to obtain 120.3 g of yellow solid (hydroxypinacolone retinoic acid ester product), the purity was 99.3%, and the yield was 90.7%. According to the amount of substance, the retinoic acid: the trisubstituted organic amine: the pivaloyl chloride was 1:1.48:1.24. According to the amount of substance, the hydroxypinacolone: ​​the retinoic acid was 1:0.97.

[0055] Example 2

[0056] In a 2000mL three-necked flask, add 100.0g of retinoic acid and 800mL of toluene, fill with nitrogen protection, stir evenly, and the reaction liquid is a yellow turbid liquid. Then add 50g of triethylamine, cool to 0-5℃ in an ice-water bath, drop 45g of pivaloyl chloride into the reaction bottle, control the internal temperature ≤10℃, and the solid in the reaction liquid gradually dissolves; after the drop is completed, stir and react at room temperature for 3h, the solid in the reaction liquid gradually dissolves until it is completely clear, and retinoic acid pivalic anhydride is prepared. HPLC detection of retinoic acid residue is ≤2.5% (relative ratio of liquid phase peak area); slowly add 40.0g of hydroxypinacolone to the reaction bottle, control the internal temperature ≤10℃, after the drop is completed, stir and react at room temperature for 2h, the reaction liquid is a dark yellow clear liquid, and HPLC detection of retinoic acid pivalic anhydride is ≤0.5% (relative ratio of liquid phase peak area); add 350mL of water, stir for 30min, stand and separate, and separate the first An organic phase; wash once with 350mL of 10% (mass fraction) salt water, separate the second organic phase, recover the solvent under reduced pressure at 40℃, and obtain the residual yellow viscous substance (post-treatment product, hydroxypinacolone retinoic acid ester); add 800mL of isopropanol, heat to 60℃ to dissolve, slowly cool to 10-20℃ in a water bath, precipitate a large number of yellow fine needle crystals (hydroxypinacolone retinoic acid ester crystals), continue to cool to 5-10℃, stir for 30min; filter, rinse the filter cake with 100mL of cold (0-5℃) isopropanol, collect the filter cake; dry at 40℃ water pump vacuum for 2h, and obtain 127.0g of yellow solid (hydroxypinacolone retinoic acid ester product), purity: 99.1%, yield 95.7%. In terms of the amount of substance, the retinoic acid: the trisubstituted organic amine: the pivaloyl chloride is 1:1.48:1.12. Calculated by the amount of substance, the ratio of the hydroxypinacolone to the retinoic acid is 1:1.03.

[0057] Example 3

[0058] In a 2000ml three-necked flask, add 100.0g of retinoic acid and 700mL of dichloromethane, fill with nitrogen protection, stir evenly, and the reaction liquid is a yellow turbid liquid. Then add 37g of N-methylmorpholine, cool to 0-5℃ in an ice-water bath, drop 45g of pivaloyl chloride into the reaction bottle, control the internal temperature to ≤5℃, and the solid in the reaction liquid gradually dissolves; after the drop is completed, keep it at 0-10℃ and stir to react for 3h, the solid in the reaction liquid gradually dissolves until it is completely clear, and retinoic acid pivalic anhydride is prepared. HPLC detection of retinoic acid residue is ≤2.5% (relative ratio of liquid phase peak area); slowly add 38.6g of hydroxypinacolone to the reaction bottle, control the internal temperature to ≤10℃, after the drop is completed, keep it at 0-10℃ and stir to react for 2h, the reaction liquid is a dark yellow clear liquid, and HPLC detection of retinoic acid pivalic anhydride is ≤0.5% (relative ratio of liquid phase peak area); add 350mL of water, stir for 3 0min, stand and separate the liquid, separate the first organic phase; wash once with 350mL of 10% (mass fraction) salt water, separate the second organic phase, recover the solvent under reduced pressure at 40℃, and obtain the residual yellow viscous substance (post-treatment product, hydroxypinacolone retinoic acid ester); add 750mL of anhydrous ethanol, heat to 50℃ to dissolve, slowly cool to 10-20℃ in a water bath, precipitate a large number of yellow fine needle-shaped crystals, continue to cool to 5-10℃, stir for 30min; filter, rinse the filter cake with 100mL of cold (0-5℃) ethanol, collect the filter cake; vacuum dry at 40℃ water pump for 2h, and obtain 126.4g of yellow solid (hydroxypinacolone retinoic acid ester product), purity: 99.6%, yield 95.3%. According to the amount of substance, the retinoic acid: the trisubstituted organic amine: the pivaloyl chloride is 1:1.12:1.12. Calculated by the amount of substance, the ratio of the hydroxypinacolone to the retinoic acid is 1:1.01.

[0059] Example 4

[0060] In a 2000mL three-necked flask, add 100.0g of retinoic acid and 700mL of 1,2-dichloroethane, fill with nitrogen protection, stir evenly, and the reaction liquid is a yellow turbid liquid. Then add 50g of N,N-diisopropylethylamine, cool to 0-5℃ in an ice-water bath, drop 45g of pivaloyl chloride into the reaction bottle, control the internal temperature to ≤5℃, and the solid in the reaction liquid gradually dissolves; after the drop is completed, keep it at 0-10℃ and stir to react for 3h, the solid in the reaction liquid gradually dissolves until it is completely clear, and retinoic acid pivalic anhydride is prepared. HPLC detection of retinoic acid residue is ≤2.5% (relative ratio of liquid phase peak area); slowly add 38.6g of hydroxypinacolone into the reaction bottle, control the internal temperature to ≤10℃, after the drop is completed, keep it at 0-10℃ and stir to react for 2h, the reaction liquid is a dark yellow clear liquid, and HPLC detection of retinoic acid pivalic anhydride is ≤0.5% (relative ratio of liquid phase peak area); add 350mL of water, stir Stir for 30 minutes, stand and separate the liquid, separate the first organic phase; wash once with 350mL of 10% (mass fraction) salt water, separate the second organic phase, recover the solvent under reduced pressure at 40℃, and obtain the residual yellow viscous substance (post-treatment product, hydroxypinacolone retinoic acid ester); add 750mL of anhydrous ethanol, heat to 50℃ to dissolve, slowly cool to 10-20℃ in a water bath, precipitate a large number of yellow fine needle-shaped crystals, continue to cool to 5-10℃, stir for 30 minutes; filter, rinse the filter cake with 100mL of cold (0-5℃) ethanol, collect the filter cake; dry under vacuum at 40℃ for 2h, and obtain 123.5g of yellow solid (hydroxypinacolone retinoic acid ester product), purity: 99.3%, yield 93.1%. According to the amount of substance, the retinoic acid: the trisubstituted organic amine: the pivaloyl chloride is 1:1.18:1.12. Calculated by the amount of substance, the ratio of the hydroxypinacolone to the retinoic acid is 1:1.

[0061] Example 5

[0062] In a 2000mL three-necked flask, add 100.0g of retinoic acid and 800mL of dichloromethane, fill with nitrogen protection, stir evenly, and the reaction liquid is a yellow turbid liquid. Then add 37g of triethylamine, cool to 0-5℃ in an ice-water bath, drop 41g of pivaloyl chloride into the reaction flask, control the internal temperature ≤10℃, and the solid in the reaction liquid gradually dissolves; after the drop is completed, stir and react at room temperature for 3h, the solid in the reaction liquid gradually dissolves until it is completely clear, and retinoic acid pivalic anhydride is prepared. HPLC detection of retinoic acid residue ≤2.5% (relative ratio of liquid phase peak area); slowly add 39.2g of hydroxypinacolone to the reaction flask, control the internal temperature ≤10℃, after the drop is completed, stir and react at room temperature for 2h, the reaction liquid is a dark yellow clear liquid, and HPLC detection of retinoic acid pivalic anhydride ≤0.5% (relative ratio of liquid phase peak area); add 350mL of water, stir for 30min, and stand The first organic phase was separated; the second organic phase was separated after washing with 350 mL of 10% (mass fraction) salt water; the solvent was recovered under reduced pressure at 40°C to obtain a residual yellow viscous substance (post-treatment product, hydroxypinacolone retinoic acid ester); 750 mL of n-butanol was added, the temperature was raised to 50°C to dissolve, the temperature was slowly lowered to 10-20°C in a water bath, a large number of yellow fine needle-shaped crystals were precipitated, the temperature was further lowered to 5-10°C, and the mixture was stirred for 30 minutes; the mixture was filtered, the filter cake was rinsed with 100 mL of cold (0-5°C) n-butanol, and the filter cake was collected; the mixture was vacuum dried at 40°C for 2 hours to obtain 129.2 g of a yellow solid (hydroxypinacolone retinoic acid ester product), the purity was 99.6%, and the yield was 97.4%. In terms of the amount of substance, the ratio of retinoic acid: the trisubstituted organic amine: the pivaloyl chloride was 1:12:1.03. In terms of the amount of substance, the ratio of hydroxypinacolone: ​​the retinoic acid was 1:1.03.

[0063] The above-mentioned embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by technicians in this field on the basis of the present invention shall fall within the scope of protection required by the present invention.

Claims

1. A method for preparing hydroxypinacolone retinoic acid ester, characterized in that: The steps include: After dissolving retinoic acid and a trisubstituted organic amine in an organic solvent, pivaloyl chloride is added dropwise and stirred for reaction to prepare retinoic acid pivalic anhydride; Hydroxypinacolone is added dropwise to the reaction solution of the prepared retinoic acid pivalic anhydride and stirred for reaction to prepare hydroxypinacolone retinoic acid ester, followed by post-treatment, crystallization with an alcohol solvent to precipitate hydroxypinacolone retinoic acid ester crystals, and at least filtering and drying to obtain a hydroxypinacolone retinoic acid ester product.

2. The preparation method according to claim 1, characterized in that Calculated by the amount of substance, the ratio of the retinoic acid: the trisubstituted organic amine: the pivaloyl chloride is 1:1.0-2.0:1.0-1.

5.

3. The preparation method according to claim 1, characterized in that: The trisubstituted organic amine is selected from at least one of triethylamine, N,N-diisopropylethylamine and N-methylmorpholine.

4. The preparation method according to claim 1, characterized in that: Calculated by the amount of substance, the ratio of the hydroxypinacolone to the retinoic acid is 1:0.90-1.

1.

5. The preparation method according to claim 1, characterized in that: The alcohol solvent is selected from at least one of methanol, ethanol, isopropanol or n-butanol.

6. The preparation method according to claim 1, characterized in that: The step of dropwise adding the pivaloyl chloride and stirring the reaction comprises: After cooling the reaction solution containing retinoic acid and trisubstituted organic amine to 0-5°C, adding the pivaloyl chloride dropwise, and controlling the internal temperature of the reaction to be less than or equal to 10°C; After the pivaloyl chloride is added dropwise, the reaction is stirred at a temperature ranging from room temperature to 40° C. until the reaction solution becomes clear.

7. The preparation method according to claim 1, characterized in that: The steps of preparing the hydroxypinacolone retinoic acid ester include: After the hydroxypinacolone is added dropwise, the internal temperature of the reaction is controlled to be less than or equal to 10° C.; After the hydroxypinacolone is added, the reaction is stirred at a temperature ranging from room temperature to 40° C. until the reaction solution becomes clear.

8. The preparation method according to claim 1, characterized in that: The post-processing steps include: Adding water to the prepared hydroxypinacolone retinoic acid ester, stirring and standing to separate the liquids, separating a first organic phase, washing the first organic phase with saline, separating a second organic phase, and distilling the second organic phase under reduced pressure to recover the organic solvent to obtain a post-treated product; The steps of crystallization with alcohol solvent include: After adding the alcohol solvent, the temperature is raised to 50-60°C to dissolve the post-treatment product, then the temperature is lowered to 10-20°C, and after the crystals are precipitated, the temperature is further lowered to 5-10°C, and stirred for 25-35 minutes; The step of obtaining the hydroxypinacolone retinoic acid ester product also includes: Before drying, the filtered cake is rinsed with the alcohol solvent at 0-5°C.

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