A kind of preparation method of hydroxypinacolone retinoic acid ester

Abstract

The present invention belongs to the technical field of fine chemical synthesis, and specifically relates to a method for preparing hydroxypinacolone retinoic acid ester, comprising the following steps: (1) mixing retinoic acid, hydroxyacetone and acetone, adding an acidic catalyst to react; (2) after the reaction of step (1) is completed, adding an alkaline metal to carry out a reduction reaction, and then adding an acidic catalyst to carry out a molecular rearrangement reaction; (3) after the reaction of step (2) is completed, cooling and filtering to obtain a solution, adding an organic solvent to the solution, condensing and crystallizing to obtain a yellow solid; (4) washing the solid, evaporating and drying to obtain the hydroxypinacolone retinoic acid ester. The present invention realizes a one-pot synthesis of a hydroxypinacolone retinoic acid ester with low irritation without detection of retinoic acid or isotretinoin, and the preparation process is simple to operate, and the yield and purity of the hydroxypinacolone retinoic acid ester are high, and the hydroxypinacolone retinoic acid ester are high, and the hydroxypinacolone retinoic acid ester are suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemical synthesis, and particularly relates to a method for preparing hydroxypinacolone retinoic acid ester. Background Art

[0002] At present, the research on the efficacy of hydroxypinacolone retinoate (HPR) on the market is relatively mature. As a retinoic acid derivative, HPR can directly bind to the ATRA receptor on the cell surface without conversion, compared with the three-step conversion and degradation of retinol to alcohol, aldehyde and acid. At the same time, it has lower cytotoxicity than 10 times that of isotretinoin.

[0003] However, the HPR raw material itself still has the side effects of trans-retinoic acid, such as redness, photosensitivity, desquamation and other discomfort symptoms. Therefore, in the commonly used preparation process of HPR, the presence or absence of chlorinated alkanes and chloropinacolone impurities is often used as a measurement standard for preparation process optimization. However, the detection of retinoic acid and isotretinoin and biosafety toxicity should be used as key indicators in the preparation process to evaluate the safety of HPR raw materials. Therefore, a new HPR preparation method without the detection of retinoic acid and isotretinoin has better market application potential.

[0004] In the prior art, for example, the patent with publication number CN 114436924 A discloses a method for preparing hydroxypinacolone retinoic acid ester, which uses retinoic acid and 1-hydroxy-3,3-dimethylbutane-2-one as raw materials, undergoes acylation and esterification to obtain a crude product, and then undergoes refined crystallization to obtain a finished product, thereby preparing hydroxypinacolone retinoic acid ester. During the reaction, a large amount of genotoxic impurity chloropinacolone may be produced, and chlorinated alkane residues that are prohibited in cosmetics may also be introduced. A similar description is also provided in the Chinese patent with publication number CN 116283697 A.

[0005] The patent with publication number CN112522331A discloses a method for synthesizing hydroxypinacolone retinoic acid ester catalyzed by biological enzymes, wherein retinoic acid ester and 1-hydroxy-3,3-dimethylbutane-2-one are used as raw materials and reacted in an aqueous buffer solution with a pH of 7.0 to 10.0 containing an acyltransferase. However, there are some defects in the preparation method of hydroxypinacolone retinoic acid ester in this process, such as poor environmental adaptability of biological enzymes, stringent production environment requirements, and high enzyme prices, resulting in relatively high production costs, thereby limiting the large-scale industrial production of the above-mentioned products.

[0006] The patent with publication number CN113149880A discloses a method for preparing hydroxypinacolone retinoic acid ester, in which chloropinacolone is hydrolyzed under strong alkaline conditions to prepare the corresponding pinacolone, and then pinacolone and retinoic acid are subjected to a condensation reaction under the conditions of a condensation agent and a catalyst to obtain the product. The DCC dehydrating agent used in the condensation reaction generates DCU solid waste after the reaction is completed, and the cost of treating the three wastes is high and residues are present in the product, thereby leading to problems such as low production efficiency and high cost.

[0007] Therefore, none of the reactions described in the prior art have any detection or determination of retinoic acid or isotretinoin, and at the same time, none of the reaction raw materials currently involved have proposed a semi-natural degree, and therefore cannot guarantee the pure beauty needs of the existing market. Summary of the invention

[0008] The object of the present invention is to overcome the shortcomings and deficiencies of the prior art and to provide a method for preparing hydroxypinacolone retinoic acid ester.

[0009] To achieve the above objectives, the technical solutions adopted by the present invention include:

[0010] In a first aspect, the present invention provides a method for preparing hydroxypinacolone retinoic acid ester, comprising the following steps:

[0011] (1) mixing retinoic acid, hydroxyacetone and acetone, and adding an acidic catalyst to react;

[0012] (2) After the reaction in step (1) is completed, an alkaline metal is added to carry out a reduction reaction, and then an acidic catalyst is added to carry out a molecular rearrangement reaction;

[0013] (3) After the reaction in step (2) is completed, the solution is cooled and filtered to obtain a solution, an organic solvent is added to the solution, and condensed and crystallized to obtain a yellow solid;

[0014] (4) washing the solid, and evaporating to dryness to obtain the hydroxypinacolone retinoic acid ester.

[0015] The present invention realizes one-pot synthesis of low-irritation hydroxypinacolone retinoic acid ester without detection of retinoic acid or isotretinoic acid through the preparation method, thereby ensuring the existing market demand for pure beauty products using hydroxypinacolone retinoic acid ester as an active ingredient. In addition, the preparation process of the present invention is simple to operate, and the production efficiency of hydroxypinacolone retinoic acid ester is high, which is suitable for large-scale industrial production.

[0016] Preferably, the molar ratio of retinoic acid, hydroxyacetone and acetone is retinoic acid:hydroxyacetone:acetone=1:1.1:(1.2-1.5).

[0017] Preferably, the molar ratio of retinoic acid, hydroxyacetone and acetone is retinoic acid:hydroxyacetone:acetone=1:1.1:1.3.

[0018] Through experimental exploration, it was found that when the molar ratio of retinoic acid, hydroxyacetone and acetone is in the above preferred range of 1:1.1:(1.2-1.5), especially 1:1.1:1.3, the recovery rate of hydroxypinacolone retinoic acid ester can be effectively improved. However, when the dosage ratio exceeds the specified range of the present invention, it may cause competitive side reactions, resulting in a decrease in the yield of hydroxypinacolone retinoic acid ester and the residue of retinoic acid or isotretinoic acid in the product, resulting in safety issues of the product.

[0019] Preferably, the molar ratio of retinoic acid to alkaline metal is retinoic acid:alkaline metal=1:(2.5-3.0).

[0020] The present invention can effectively promote the generation of the target product of hydroxypinacolone retinoic acid ester by adding alkaline metal to carry out the reaction, and improve the selectivity of the reaction. It is found through experimental research that when the usage ratio of retinoic acid to alkaline metal is within the above preferred range, the reaction can be effectively improved, the reaction rate can be accelerated, and the yield of the hydroxypinacolone retinoic acid ester product can be improved to a certain extent.

[0021] Preferably, the molar ratio of retinoic acid to alkaline metal is retinoic acid:alkaline metal=1:3.

[0022] Preferably, in step (1), the acidic catalyst is 4-6 mol / L sulfuric acid; and in step (2), the acidic catalyst is 2-4 mol / L sulfuric acid.

[0023] The present invention adopts sulfuric acid as a reaction catalyst to provide an acidic environment to facilitate the esterification reaction between the hydroxyl group in hydroxyacetone and the carboxyl group in retinoic acid, thereby accelerating the generation of products. Meanwhile, an appropriate amount of sulfuric acid can help control the directionality of the reaction and inhibit the occurrence of side reactions, thereby improving the yield and purity of hydroxypinacolone retinoic acid ester.

[0024] Preferably, in step (1), the reaction time is 4-6 hours and the reaction temperature is 10-40°C.

[0025] More preferably, in step (1), the reaction time is 5 h and the reaction temperature is 25°C.

[0026] Preferably, in step (2), the reduction reaction time is 13-17 hours, and the reduction reaction temperature is 40-50°C.

[0027] More preferably, in step (2), the reduction reaction time is 15 h and the reduction reaction temperature is 45°C.

[0028] Preferably, in step (2), the time of the molecular rearrangement reaction is 1-3 hours, and the temperature of the molecular rearrangement reaction is 70-90°C.

[0029] More preferably, in the step (2), the time of the molecular rearrangement reaction is 2 hours, and the temperature of the molecular rearrangement reaction is 80°C.

[0030] It was found through experiments that the yield and purity of hydroxypinacolone retinoic acid ester can be significantly improved when the reaction conditions within the above preferred range are used to prepare hydroxypinacolone retinoic acid ester, and the detection of retinoic acid or isotretinoic acid can be avoided.

[0031] Preferably, the alkaline metal is zinc powder or magnesium powder, preferably, the alkaline metal is zinc powder.

[0032] Preferably, in step (3), the organic solvent comprises at least one of methanol, ethyl acetate, ethanol, acetone and butanone.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] The present invention adopts retinoic acid and hydroxyacetone as starting materials for reaction, realizes one-pot synthesis of low-irritation hydroxypinacolone retinoic acid ester without detection of retinoic acid or isotretinoic acid, ensures the existing market demand for pure beauty makeup using hydroxypinacolone retinoic acid ester as an active functional ingredient, and the preparation process of the present invention is simple to operate, and the production efficiency of hydroxypinacolone retinoic acid ester is high, which is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 HPLC chart of hydroxypinacolone retinoic acid ester prepared in Example 1;

[0036] Figure 2 HPLC chart of hydroxypinacolone retinoic acid ester prepared in Example 2;

[0037] Figure 3 HPLC chart of hydroxypinacolone retinoic acid ester prepared in Example 3;

[0038] Figure 4 Graphs 1 to 3 show the detection of retinoic acid and isotretinoic acid, wherein Graph A shows the HPLC graphs of retinoic acid and isotretinoic acid standard products, and Graphs B to D show the HPLC graphs of hydroxypinacolone retinoic acid ester prepared in Examples 1-3, respectively. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical scheme and effect of the present invention clearer and more specific, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0040] Unless otherwise specified, all raw materials used in the following examples are commercially available general raw materials.

[0041] The reaction mechanism involved in preparing hydroxypinacolone retinoic acid ester (HPR) in the examples is as follows, wherein R-COOH represents the structural formula of retinoic acid:

[0042]

[0043] Example 1

[0044] This embodiment provides a method for preparing hydroxypinacolone retinoic acid ester, comprising the following steps:

[0045] (1) Under light-proof conditions, weigh retinoic acid, hydroxyacetone and acetone and put them into a reaction pot, the molar ratio of retinoic acid to hydroxyacetone and acetone is 1:1.1:1.3, add 5 mol / L sulfuric acid as a reaction catalyst, control the temperature at 25°C, and react for 5 hours;

[0046] (2) After the reaction is completed, zinc powder is slowly added for reduction (the molar ratio of retinoic acid to zinc powder is 1:2.5), the temperature is controlled at 45°C, the reaction is carried out for 15 hours, and then 3 mol / L sulfuric acid catalyst is added to cause molecular rearrangement reaction, the temperature is controlled at 80°C, and the reaction time is 2 hours;

[0047] (3) After the above reaction is complete, cool and filter to remove zinc sulfate salt, add ethanol solution and directly condense and crystallize at 0°C to obtain a yellow solid;

[0048] (4) washing the solid and drying it by rotary evaporation to obtain the hydroxypinacolone retinoic acid ester.

[0049] Example 2

[0050] This embodiment provides a method for preparing hydroxypinacolone retinoic acid ester, comprising the following steps:

[0051] (1) Under light-proof conditions, weigh retinoic acid, hydroxyacetone and acetone and put them into a reaction pot, the molar ratio of retinoic acid to hydroxyacetone and acetone is 1:1.1:1.2, add 5 mol / L sulfuric acid as a reaction catalyst, control the temperature at 10°C, and react for 4 hours;

[0052] (2) After the reaction is completed, zinc powder is slowly added for reduction (the molar ratio of retinoic acid to zinc powder is 1:2.5), the temperature is controlled at 40°C, the reaction is carried out for 17 hours, and then 3 mol / L sulfuric acid catalyst is added to cause molecular rearrangement reaction, the temperature is controlled at 70°C, and the reaction time is 3 hours;

[0053] (3) After the above reaction is complete, cool and filter to remove zinc sulfate salt, add ethanol solution and directly condense and crystallize at 0°C to obtain a yellow solid;

[0054] (4) washing the solid and drying it by rotary evaporation to obtain the hydroxypinacolone retinoic acid ester.

[0055] Example 3

[0056] This embodiment provides a method for preparing hydroxypinacolone retinoic acid ester, comprising the following steps:

[0057] (1) Under light-proof conditions, weigh retinoic acid, hydroxyacetone and acetone and put them into a reaction pot, the molar ratio of retinoic acid to hydroxyacetone and acetone is 1:1.1:1.5, add 5 mol / L sulfuric acid as a reaction catalyst, control the temperature at 40°C, and react for 6 hours;

[0058] (2) After the reaction is completed, zinc powder is slowly added for reduction (the molar ratio of retinoic acid to zinc powder is 1:3), the temperature is controlled at 50°C, the reaction is carried out for 13 hours, and then 3 mol / L sulfuric acid catalyst is added to cause molecular rearrangement reaction, the temperature is controlled at 90°C, and the reaction time is 1 hour;

[0059] (3) After the above reaction is complete, cool and filter to remove zinc sulfate salt, add ethanol solution and directly condense and crystallize at 0°C to obtain a yellow solid;

[0060] (4) washing the solid and drying it by rotary evaporation to obtain the hydroxypinacolone retinoic acid ester.

[0061] Comparative Example 1

[0062] This comparative example provides a method for preparing hydroxypinacolone retinoic acid ester, which is different from Example 1 in that: in the step (1), the molar ratio of retinoic acid to hydroxyacetone and acetone is 1:1.1:2.

[0063] Comparative Example 2

[0064] This comparative example provides a method for preparing hydroxypinacolone retinoic acid ester, which is different from Example 1 in that: in the step (1), the molar ratio of retinoic acid to hydroxyacetone and acetone is 1:1.1:1.

[0065] Comparative Example 3

[0066] This comparative example provides a method for preparing hydroxypinacolone retinoic acid ester, which is different from Example 1 in that: in the step (2), the molar ratio of retinoic acid to the added zinc powder is 1:1.

[0067] Comparative Example 4

[0068] This comparative example provides a method for preparing hydroxypinacolone retinoic acid ester, which is different from Example 1 in that: in the step (2), the molar ratio of retinoic acid to the added zinc powder is 1:4.

[0069] Comparative Example 5

[0070] This comparative example provides a method for preparing hydroxypinacolone retinoic acid ester, which is different from Example 1 in that: in the step (1), the reaction temperature is controlled at 5° C. and the reaction time is 7 h.

[0071] Comparative Example 6

[0072] This comparative example provides a method for preparing hydroxypinacolone retinoic acid ester, which is different from Example 1 in that: in the step (1), the reaction temperature is controlled at 50° C. and the reaction time is 3 h.

[0073] Effect example

[0074] This effect example investigates the yield of hydroxypinacolone retinoic acid ester prepared in Examples 1-3 and Comparative Examples 1-6 and its purity by HPLC. The results are shown in Table 1.

[0075] Table 1

[0076] Sample source HPR yield (%) HPR purity (%) Example 1 85 99.9 Example 2 84 99.9 Example 3 86 99.6 Comparative Example 1 65 95.5 Comparative Example 2 67 94.5 Comparative Example 3 50 80.9 Comparative Example 4 68 87.6 Comparative Example 5 54 72.4 Comparative Example 6 46 68.2

[0077] HPLC liquid chromatography Figure 1-3 The hydroxypinacolone retinoic acid ester samples obtained in Examples 1-3 of the present invention are respectively corresponding to the hydroxypinacolone retinoic acid ester samples obtained in Examples 1-3 of the present invention. Figure 1-3 It is shown that the purity of the hydroxypinacolone retinoic acid ester prepared by the preparation process of the present invention reaches more than 99%, and the detection results of retinoic acid and isotretinoic acid in the samples of Examples 1-3 show that the retention times of retinoic acid and isotretinoic acid in the HPLC liquid chromatogram are 11.701 and 13.651 ( Figure 4 A), while the hydroxypinacolone retinoic acid ester sample prepared in Example 1-3 basically did not produce peaks within the above two retention times ( Figure 4 BD), indicating that no retinoic acid and isotretinoic acid were detected in the sample. The preparation process of the present invention not only ensures the synthesis of hydroxypinacolone retinoic acid ester with high yield and high purity, but also realizes the low irritation of hydroxypinacolone retinoic acid ester synthesized by one-pot method without the detection of retinoic acid or isotretinoic acid, thus ensuring the existing market demand for pure beauty products using hydroxypinacolone retinoic acid ester.

[0078] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing hydroxypinacolone retinoic acid ester, characterized in that: The following steps are involved: (1) mixing retinoic acid, hydroxyacetone and acetone, and adding an acidic catalyst to react; (2) After the reaction in step (1) is completed, an alkaline metal is added to carry out a reduction reaction, and then an acidic catalyst is added to carry out a molecular rearrangement reaction; (3) After the reaction in step (2) is completed, the solution is cooled and filtered to obtain a solution, an organic solvent is added to the solution, and condensed and crystallized to obtain a yellow solid; (4) washing the solid, evaporating and drying to obtain the hydroxypinacolone retinoic acid ester; The molar ratio of retinoic acid, hydroxyacetone and acetone is retinoic acid:hydroxyacetone:acetone=1:1.1:(1.2-1.5); The molar ratio of retinoic acid to alkaline metal is retinoic acid:alkaline metal=1:(2.5-3.0); In the step (1), the reaction time is 4-6 hours and the reaction temperature is 10-40°C; The alkaline metal is zinc powder or magnesium powder.

2. The method for preparing hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: The molar ratio of retinoic acid, hydroxyacetone and acetone is retinoic acid:hydroxyacetone:acetone=1:1.1:1.

3.

3. The method for preparing hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: In the step (1), the acidic catalyst is 4-6 mol / L sulfuric acid; In the step (2), the acidic catalyst is 2-4 mol / L sulfuric acid.

4. The method for preparing hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: In the step (2), the reduction reaction time is 13-17 hours, and the reduction reaction temperature is 40-50°C.

5. The method for preparing hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: In the step (2), the time of the molecular rearrangement reaction is 1-3 hours, and the temperature of the molecular rearrangement reaction is 70-90°C.

6. The method for preparing hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: In the step (3), the organic solvent includes at least one of methanol, ethyl acetate, ethanol, acetone and butanone.

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