Method for synthesizing hydroxypinacolone retinoate through solvent-free continuous flow

Abstract

The invention discloses a method for synthesizing hydroxypinacolone retinoate through solvent-free continuous flow, and belongs to the technical field of organic synthesis. Compared with the existing similar methods, the method has the advantages that no additional organic solvent is needed in the reaction process, the raw material is used as the reaction solvent, the reaction system is simplified, the process cost is reduced, the post-treatment is simpler, and the reaction time is shorter; 20 min), the yield is higher (gt; 90%). And compared with an intermittent reaction process, the continuous flow reaction process has higher mass and heat transfer efficiency, the reaction time can be greatly shortened, the yield and the conversion rate are improved, the time loss of shutdown, cleaning, loading and unloading and the like in the traditional batch treatment process is avoided, personal errors among batches are reduced, and more stable product quality is provided.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester. Background Art

[0002] Hydroxypinacolone retinoic acid ester is a retinol derivative that can directly bind to cellular retinoic acid receptors (RARs). It has the functions of anti-aging, acne prevention, whitening and freckle removal, and regulating epidermal metabolism. Compared with retinol, it has the advantages of stability, mildness, safety, low irritation, high activity, direct effect, and easier transdermal absorption. It is widely used in cosmetics, medicine, personal care and other fields.

[0003] There are three routes for synthesizing hydroxypinacolone retinoic acid ester in the prior art. Route 1 is to prepare hydroxypinacolone by hydrolysis of chloropinacolone under strong alkaline conditions, and then condense hydroxypinacolone with retinoic acid under the conditions of a condensing agent and a catalyst to generate hydroxypinacolone retinoic acid ester. Patent CN113149880A discloses a method for synthesizing hydroxypinacolone retinoic acid ester through route 1. The condensing agent and catalyst used in the process are DCC and DMAP. After the reaction, dicyclohexylurea (DCU) solid waste is generated, and DCU and DMAP are easily residual in the product and need to be removed by column chromatography or a large amount of acid washing. The cost of three waste treatment is high and the production efficiency is low.

[0004] Route 2 is the acyl chloride method, which includes the following reaction steps: (1) Retinoic acid reacts with an excess of an acyl chloride reagent to prepare tinoic acid chloride; (2) Chloropinacolone is hydrolyzed under strong alkaline conditions to prepare hydroxypinacolone; (3) Retinoic acid chloride reacts with hydroxypinacolone in the presence of an acid-binding agent to produce hydroxypinacolone retinoic acid ester. Patent CN114436924A discloses a synthesis process for synthesizing hydroxypinacolone retinoic acid ester by the acyl chloride method. The process uses phosphorus trichloride as an acyl chloride reagent, generates a large amount of phosphorus-containing waste liquid, and has a relatively complex reaction route and harsh reaction conditions.

[0005] Route 3 directly uses chloropinacolone and retinoic acid as raw materials, and reacts under alkaline conditions to generate hydroxypinacolone retinoic acid ester. Usually, the yield of this process is only about 50%, which leads to the easy residue of genotoxic impurity chloropinacolone in the product, and halogenated hydrocarbon substances are prohibited in cosmetics. Patent CN115260071A improves this method, with a reaction time of 6 to 30 hours and a product yield of about 80%. This route has simple steps, mild reaction conditions, and only produces inorganic salt solid waste, but the current yield is still low.

[0006] In addition to the above three main routes, patent CN112522331A reports a method for synthesizing hydroxypinacolone retinoic acid ester using biological enzyme catalysis, which uses retinoic acid ester and hydroxypinacolone as raw materials, acyltransferase as biological enzyme catalyst, and reacts in an aqueous buffer solution with a pH of 7.0 to 10.0 to prepare hydroxypinacolone retinoic acid ester. Biological enzymes are relatively expensive, have poor environmental adaptability, and have strict requirements on the production environment, resulting in relatively high production costs, which limits the large-scale industrial production of this process. Summary of the invention

[0007] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

[0008] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0009] Therefore, the purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for synthesizing hydroxypinacolone retinoic acid ester in a solvent-free continuous flow.

[0010] In order to solve the above technical problems, the present invention provides the following technical solutions, including:

[0011] Under light-proof conditions, retinoic acid and an acid-binding agent are mixed, heated and dissolved to form a reaction solution;

[0012] The reaction solution is mixed with monohalopinacolone for reaction, and after the reaction is completed, the solution is filtered. After the filtrate is concentrated, a recrystallization solvent is added to dissolve the solution by heating, and then the temperature is lowered for crystallization, thereby obtaining hydroxypinacolone retinoic acid ester.

[0013] As a preferred embodiment of the method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester of the present invention, the acid-binding agent comprises an organic tertiary amine.

[0014] As a preferred embodiment of the method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester of the present invention, the organic tertiary amine comprises one of triethylamine, tripropylamine, N,N-diisopropylethylamine, triisopropylamine and triethanolamine.

[0015] As a preferred embodiment of the method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester of the present invention, the molar ratio of retinoic acid to the acid-binding agent is 1:1-5.

[0016] As a preferred embodiment of the method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester of the present invention, the temperature of heating and dissolving is 40-60°C.

[0017] As a preferred embodiment of the method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester of the present invention, the monohalopinacolone comprises monochloropinacolone or monobromopinacolone.

[0018] As a preferred embodiment of the method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester of the present invention, the molar ratio of retinoic acid to monohalopinacolone is 1:1-2.

[0019] As a preferred embodiment of the method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester of the present invention, the reaction temperature of the mixed reaction is 80°C to 150°C.

[0020] As a preferred embodiment of the method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester of the present invention, the reaction time of the mixing reaction is 1 to 20 minutes.

[0021] As a preferred embodiment of the method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester of the present invention, the recrystallization solvent comprises one or more of ethanol, isopropanol and n-heptane.

[0022] As a preferred embodiment of the method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester of the present invention, the mass ratio of the recrystallization solvent to the crude product is 2 to 20:1.

[0023] Beneficial effects of the present invention:

[0024] (1) Compared with the existing similar methods, the reaction process of the present invention does not require the addition of additional organic solvents, and the raw materials themselves are used as the reaction solvent, which simplifies the reaction system, shortens the reaction time (<20min), reduces the process cost, makes post-treatment simpler, and has higher reaction efficiency and yield (>90%).

[0025] (2) Compared with intermittent reaction processes, continuous flow reaction processes have higher mass transfer and heat transfer efficiencies, can greatly shorten reaction time, improve yield and conversion rate, avoid time losses such as downtime, cleaning, and loading and unloading in traditional batch processes, reduce human errors between batches, and provide more stable product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work. Among them:

[0027] Figure 1 Flow chart of continuous flow synthesis process.

[0028] Figure 2 This is the H NMR spectrum of the hydroxypinacolone retinoic acid ester product.

[0029] Figure 3 This is the liquid chromatogram of the hydroxypinacolone retinoic acid ester product. DETAILED DESCRIPTION

[0030] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0031] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0032] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0033] The raw materials used in the present invention are all commercially available unless otherwise specified.

[0034] The retinoic acid ester reactor is a Hechen chip reactor purchased from Hechen Technology (Shanghai) Co., Ltd.; the model is L1, and the material is Schott BF33 special glass; the temperature range is -40℃~200℃. Customized channel size: 1000*1000μm, maximum pressure resistance 18Bar, liquid holding volume: 4~8ml, sandwich heat exchange channel clamping mixing channel.

[0035] Example 1

[0036] This embodiment provides a method for preparing hydroxypinacolone retinoic acid ester, referring to Figure 1 , specifically:

[0037] 150 g of retinoic acid and 76 g of triethylamine (i.e., the molar ratio of retinoic acid to acid-binding agent is 1:1.5) are added into a reactor, and the mixture is heated to 50° C. and stirred to dissolve under light-proof conditions to prepare a reaction solution;

[0038] The reaction solution and monochloropinacolone were introduced into the microchannel reactor using a feed pump to ensure that the molar ratio of retinoic acid to monochloropinacolone was 1.0:1.05, the reaction temperature was 110°C, and the residence time was 2 min;

[0039] The reaction liquid was collected, filtered, and the filtrate was concentrated to obtain a crude product. Ethanol 5 times the mass of the crude product was added and heated to 60° C. to dissolve, and then cooled to 0° C. to crystallize to obtain a yellow crystalline product, hydroxypinacolone retinoic acid ester, with a yield of 90% and a purity of 99%.

[0040] The above target products were characterized, such as Figure 2 and 3 As shown. The result is: yellow crystal; 1 H NMR (400MHz, CDCl3): δ = 7.02 (dd, J = 15.0, 11.4Hz, 1H), 6.35-6.24 (m, 2H), 6.14 (dd, J = 13.9, 6.2Hz, 2H), 5.90 (s, 1H), 4.93 (s ,2H),2.35(d,J=1.1Hz,3H),2.06-1.97(m,5H),1.71(s,3H),1.65-1.59(m,2H),1.47-1.44(m,2H),1.22(s,9H),1.03(s,6H).

[0041] According to the characterization data, the obtained reaction product is hydroxypinacolone retinoic acid ester.

[0042] Example 2

[0043] The difference between this embodiment and embodiment 1 is that the molar ratio of retinoic acid to monochloropinacolone is adjusted to 1:1, and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0044] Example 3

[0045] The difference between this embodiment and embodiment 1 is that the molar ratio of retinoic acid to monochloropinacolone is adjusted to 1:1.2, and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0046] The products obtained in the above examples were tested, and the comparison results with those in Example 1 are shown in Table 1.

[0047] Table 1

[0048]

[0049]

[0050] As can be seen from the above table, adjusting the ratio of retinoic acid to monochloropinacolone has a significant effect on the yield and purity of the product of the method, because equal monochloropinacolone cannot completely react retinoic acid, and the residual retinoic acid raw material affects the purity of the recrystallized product; excessive monochloropinacolone cannot further improve the conversion rate of retinoic acid, but the residual monochloropinacolone also affects the purity of the recrystallized product. According to the results in the above table, the best technical effect can be obtained when the molar ratio of retinoic acid to monochloropinacolone in the present invention is 1:1.05.

[0051] Example 4

[0052] The difference between this embodiment and embodiment 1 is that the reaction temperature is adjusted to 80° C., and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0053] Example 5

[0054] The difference between this embodiment and embodiment 1 is that the reaction temperature is adjusted to 100° C., and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0055] Example 6

[0056] The difference between this embodiment and embodiment 1 is that the reaction temperature is adjusted to 150° C., and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0057] The products obtained in the above examples were tested, and the comparison results with those in Example 1 are shown in Table 2.

[0058] Table 2

[0059] Example 1 Example 4 Example 5 Example 6 Yield (%) 90 57 84 70 purity(%) 99 90 95 73

[0060] As can be seen from the above table, adjusting the reaction temperature has a significant effect on the yield and purity of the product of the method. This is because too low a reaction temperature reduces the reaction rate, the conversion rate of retinoic acid decreases in the same time, and the unreacted retinoic acid affects the purity of the recrystallized product; while too high a reaction temperature intensifies side reactions such as condensation, resulting in a significant decrease in the yield and purity of the hydroxypinacolone retinoic acid ester product. According to the results in the above table, the best technical effect can be obtained when the reaction temperature in the present invention is 110°C.

[0061] Example 7

[0062] The difference between this embodiment and embodiment 1 is that the reaction retention time is adjusted to 1.0 min, and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0063] Example 8

[0064] The difference between this embodiment and embodiment 1 is that the reaction retention time is adjusted to 5.0 min, and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0065] The products obtained in the above examples were tested, and the comparison results with those in Example 1 are shown in Table 3.

[0066] Table 3

[0067] Example 1 Example 7 Example 8 Yield (%) 90 65 85 purity(%) 99 91 94

[0068] As can be seen from the above table, adjusting the reaction time has a significant impact on the yield and purity of the product of the method. This is because if the retention time is too short, the reaction cannot be fully carried out, and the unreacted retinoic acid affects the purity of the recrystallized product; while if the retention time is too long, the side reactions are aggravated. According to the results in the above table, the best technical effect can be obtained when the reaction time in the present invention is 2 minutes.

[0069] Example 9

[0070] The difference between this embodiment and embodiment 1 is that the acid-binding agent is adjusted to tripropylamine, and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0071] Example 10

[0072] The difference between this embodiment and embodiment 1 is that the acid binding agent is adjusted to N,N-diisopropylethylamine, and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0073] Embodiment 11

[0074] The difference between this embodiment and embodiment 1 is that the molar ratio of retinoic acid to the acid-binding agent is adjusted to 1:1, and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0075] Example 12

[0076] The difference between this embodiment and embodiment 1 is that the molar ratio of retinoic acid to the acid-binding agent is adjusted to 1:5, and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0077] The products obtained in the above examples were tested, and the comparison results with those in Example 1 are shown in Table 4.

[0078] Table 4

[0079] Example 1 Example 9 Example 10 Embodiment 11 Example 12 Yield (%) 90 52 41 78 85 purity(%) 99 86 79 88 99

[0080] As can be seen from the table above, adjusting the molar ratio of retinoic acid, retinoic acid and acid-binding agent has a significant effect on the yield of the method and the purity of the product, because different acid-binding agents have different chemical properties, namely, the reaction performance with HCl. If the acid-binding agent is not properly selected, it may affect the condensation reaction activity of retinoic acid and monochloropinacolone, resulting in incomplete reaction, the production of by-products, and reduced yield and purity. Some acid-binding agents may react with reactants or products to form undesirable by-products, thereby affecting the purity of the final product.

[0081] In addition, if the amount of the acid binding agent is insufficient, it may not be able to react completely with HCl, resulting in the inability to proceed in the forward direction of the reaction, thereby affecting the effect of the reaction and the purity of the product. Adding too much acid binding agent may also cause the acid binding agent itself to participate in side reactions, produce impurities, and affect the purity and yield of the product. According to the results in the above table, the acid binding agent in the present invention is preferably triethylamine, and the molar ratio of retinoic acid to the acid binding agent is preferably 1:1.5.

[0082] Example 13

[0083] The difference between this embodiment and embodiment 1 is that the recrystallization solvent is adjusted to isopropanol, and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0084] Embodiment 14

[0085] The difference between this embodiment and embodiment 1 is that the recrystallization solvent is adjusted to n-heptane, and the rest of the preparation process is the same as that of embodiment 1 to prepare hydroxypinacolone retinoic acid ester.

[0086] The products obtained in the above examples were tested, and the comparison results with those in Example 1 are shown in Table 5.

[0087] Table 5

[0088] Example 1 Embodiment 13 Embodiment 14 Yield (%) 90 89 80 purity(%) 99 99 95

[0089] As can be seen from the above table, adjusting the recrystallization solvent has a significant effect on the yield of the method and the purity of the product. When isopropanol is the recrystallization solvent, the yield is slightly lower, while the non-polar recrystallization solvent n-heptane cannot obtain a good product yield and purity. According to the results in the above table, the best technical effect can be obtained when the recrystallization solvent in the present invention is ethanol.

[0090] Comparative Example 1

[0091] 1.5 g of retinoic acid and 0.76 g of triethylamine were added to a kettle reactor, followed by dropwise addition of 0.74 g of monochloropinacolone;

[0092] After the addition was complete, the reaction temperature was set to 110°C and the reaction was continued for 24 hours;

[0093] After the reaction was completed, the mixture was filtered and the filtrate was concentrated. 5 mL of ethanol was added and the temperature was raised to 60° C. to dissolve the mixture. The mixture was then cooled to 0° C. to crystallize, thereby obtaining a yellow crystalline product with a yield of 82% and a purity of 95%.

[0094] Comparative Example 2

[0095] 1.5 g of retinoic acid and 10 mL of ethyl acetate were added into a reactor, heated to 50° C. under light-proof conditions, and stirred to dissolve to prepare a reaction solution;

[0096] Use a feed pump to pass the reaction solution and monochloropinacolone into the microchannel reactor, ensuring that the molar ratio of retinoic acid to monochloropinacolone is 1:1.05, the reaction temperature is 110°C, and the residence time is 2 minutes;

[0097] The reaction liquid was collected and filtered. The filtrate was concentrated to obtain a crude product. Ethanol 5 times the mass of the crude product was added and heated to 60°C to dissolve. The temperature was then lowered to 0°C for crystallization to obtain a yellow crystalline product, hydroxypinacolone retinoic acid ester, with a yield of 5% and a purity of 71%.

[0098] Comparative Example 3

[0099] 150 g of retinoic acid and 76 g of triethylamine were added into a reactor, and the temperature was raised to 50° C. under light-proof conditions, and stirred to dissolve to prepare a reaction solution;

[0100] Use a feed pump to pass the reaction solution and monochloropinacolone into the reactor, ensuring that the molar ratio of retinoic acid to monochloropinacolone is 1.0:1.05, the reaction temperature is 110°C, and the residence time is 2 minutes;

[0101] The reaction solution was collected, filtered, and the filtrate was concentrated to obtain a crude product with a crude yield of 93% and a purity of 90%.

[0102] The product obtained in the above comparative example was tested, and the comparison results with those of Example 1 are shown in Table 6.

[0103] Table 6

[0104] Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Yield (%) 90 82 5 93 purity(%) 99 95 71 90

[0105] It can be seen from the above table that the continuous flow synthesis of hydroxypinacolone retinoic acid ester has higher yield and product purity than the batch synthesis; the acid binding agent is the key to promoting the reaction; and the recrystallization process is a necessary step to obtain high-purity pinacolone retinoic acid ester products.

[0106] In summary, compared with existing similar methods, the reaction process of the present invention does not require the addition of additional organic solvents, and the raw materials themselves are used as reaction solvents, which simplifies the reaction system, reduces process costs, makes post-processing simpler, and shortens the reaction time (<20min) and increases the yield (>90%). In addition, compared with intermittent reaction processes, continuous flow reaction processes have higher mass transfer and heat transfer efficiency, which can greatly shorten the reaction time, increase the yield and conversion rate, avoid the time loss of downtime, cleaning, loading and unloading in traditional batch processes, reduce human errors between batches, and provide more stable product quality.

[0107] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester, characterized in that: include, Under light-proof conditions, retinoic acid and an acid-binding agent are mixed, heated and dissolved to form a reaction solution; The reaction solution is mixed with monohalopinacolone for reaction, and after the reaction is completed, the solution is filtered. After the filtrate is concentrated, a recrystallization solvent is added to dissolve the solution by heating, and then the temperature is lowered for crystallization, thereby obtaining hydroxypinacolone retinoic acid ester.

2. The method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: The molar ratio of the retinoic acid to the acid-binding agent is 1:1-5.

3. The method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: The acid binding agent includes an organic tertiary amine.

4. The method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: The organic tertiary amine includes one of triethylamine, tripropylamine, N,N-diisopropylethylamine, triisopropylamine and triethanolamine.

5. The method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: The monohalopinacolone includes monochloropinacolone or monobromopinacolone.

6. The method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: The molar ratio of retinoic acid to monohalopinacolone is 1:1-2.

7. The method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: The reaction temperature of the mixed reaction is 80°C to 150°C.

8. The method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: The reaction time of the mixing reaction is 1 to 20 minutes.

9. The method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: The recrystallization solvent includes one or more of ethanol, isopropanol, and n-heptane.

10. The method for solvent-free continuous flow synthesis of hydroxypinacolone retinoic acid ester according to claim 1, characterized in that: The mass ratio of the recrystallization solvent to the crude product is 2-20:1.

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