Method for synthesizing L-ascorbyl palmitate by acyl chloride method

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing L-ascorbyl palmitate by an acyl chloride method. The method comprises the following steps: (1) adding palmitic acid into a mixed solvent, dropwise adding SOCl2, carrying out an acylating chlorination reaction, continuously adding L-ascorbic acid after the reaction is finished, and carrying out heating and heat preservation reaction to obtain a reaction product; (2) adding ethyl acetate and distilled water into the reaction product, putting into a separating funnel to obtain a water layer and an organic layer, extracting the water layer once by using ethyl acetate, and combining the organic layers obtained by two times; washing an organic layer with water for 3 times, then drying with anhydrous Na2SO4, and carrying out rotary evaporation to remove the organic solvent to obtain a crude product; and (3) purifying the crude product by using a silica gel chromatographic column, collecting eluent within 60-150 minutes, and performing rotary evaporation on the eluent to obtain the L-ascorbyl palmitate. The L-ascorbyl palmitate prepared by the method disclosed by the invention is high in yield and purity.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing L-ascorbyl palmitate by an acyl chloride method. Background Art

[0002] L-ascorbyl palmitate is a derivative of vitamin C (ascorbic acid). L-ascorbyl palmitate is a fat-soluble form of vitamin C, which has good stability and permeability and is commonly used in foods, cosmetics, and health products. The synthesis processes of L-ascorbyl palmitate include an enzyme-catalyzed method, a direct exchange method, a transesterification method, and a palmitoyl chloride chemical synthesis method.

[0003] Chinese Patent CN106883202B discloses a method for preparing L-ascorbyl palmitate. L-ascorbic acid and palmitic acid are subjected to an esterification reaction under the catalysis of concentrated sulfuric acid. After the reaction is complete, ethyl acetate is first added dropwise to the reaction system, and then ice water is added dropwise. After filtration, the crude product of L-ascorbyl palmitate is obtained; and then through recrystallization with ethyl acetate, the target product L-ascorbyl palmitate is obtained. This method requires the use of strong concentrated acid as a catalyst and a solvent, the product has a deep color, and the separation and purification are difficult.

[0004] Chinese Patent CN102304109B discloses a method for synthesizing L-ascorbyl palmitate: palmitic acid is crushed into fine powder; at 25°C - 20°C, the above-mentioned palmitic acid fine powder is slowly added to pure sulfuric acid for dissolution; L-ascorbic acid with a molar number 0.95 times is added to the above reaction solution, and then a dehydrating agent is added to the reaction solution, and the reaction continues for 6 - 7 hours; the generated reaction solution is poured into crushed ice, the crude product is filtered out, dried, and washed with water; after heating the prepared crude product of L-ascorbyl palmitate, it is dissolved in ethyl acetate, and the dissolved solution is decolorized and purified through a granular activated carbon column; the obtained solution is distilled under reduced pressure and concentrated, and the feed liquid is cooled to 0°C for discharging to obtain white powder L-ascorbyl palmitate. The product yield of this method is lower than 90%.

[0005] The palmitoyl chloride method has a low reaction temperature and few by-products, and has received increasing attention in recent years. In the process of preparing L-ascorbyl palmitate by the palmitoyl chloride method, in order to meet the product quality requirements, reduce production costs, improve market competitiveness, and ensure the safety of the product in sensitive fields, pursuing high yield and high purity has become a very important topic. With the increasing attention of consumers to health and safety, the quality standards in the food industry are continuously improving. As an efficient antioxidant, the purity of L-ascorbyl palmitate directly affects the antioxidant effect. High-purity products can better delay the oxidation and deterioration of foods and extend the shelf life. At the same time, high-purity L-ascorbyl palmitate has more stable chemical properties and is not easily decomposed or produce bad odors during storage and use, thus ensuring the quality and taste of foods.

[0006] Therefore, there is an urgent need for a method for synthesizing L-ascorbyl palmitate by the acyl chloride method. Summary of the Invention

[0007] The object of the present invention is to provide a method for synthesizing L-ascorbyl palmitate by the acyl chloride method.

[0008] To achieve the above object, the present invention provides the following technical solutions:

[0009] A method for synthesizing L-ascorbyl palmitate by the acyl chloride method, comprising the following steps:

[0010] (1) Add palmitic acid to a mixed solvent, dissolve it, add SOCl 2 , carry out an acyl chlorination reaction. After the reaction is completed, continue to add L-ascorbic acid, raise the temperature, and keep the reaction at a constant temperature to obtain a reaction product; the mixed solvent includes N,N-dimethylacetamide, N,N-dimethylformamide, and dichloromethane;

[0011] (2) Add ethyl acetate and distilled water to the reaction product, place it in a separatory funnel to obtain an aqueous layer and an organic layer. Extract the aqueous layer with ethyl acetate again, and combine the organic layers obtained twice. Wash the organic layer with water 3 times, and then dry it with anhydrous Na 2 SO 4 , and rotary evaporate to remove the organic solvent to obtain a crude product;

[0012] (3) Purify the crude product using a silica gel chromatography column, collect the eluate within 60 - 150 min, and rotary evaporate the eluate to obtain L-ascorbyl palmitate.

[0013] Further, in the step (1), the dissolving method is to stir and dissolve at 25 - 30 °C.

[0014] Further, in the step (1), the method of adding SOCl 2 is to dropwise add SOCl 2 under ice-water bath conditions.

[0015] Further, in the step (1), the molar ratio of palmitic acid, SOCl 2 and L-ascorbic acid is 1:(1.1 - 1.2):(1.3 - 1.4).

[0016] Further, in the step (1), the mixed solvent includes N,N-dimethylacetamide, N,N-dimethylformamide, and dichloromethane with a volume ratio of 2:(1.2 - 1.5):1.

[0017] The mixed solvent of the present invention is prepared by mixing N,N-dimethylacetamide and N,N-dimethylformamide, and using dichloromethane as a cosolvent. The reaction is carried out at a temperature of 5-7 °C for a reaction time of 0.5-0.6 h, which can improve the yield of the product. The analysis shows that at this temperature, due to factors such as changes in the solvation structure after the mixing of DMAc, DMF and CH₂Cl₂, the mixed solvent can maintain a good dissolution state of palmitic acid at this temperature, reducing the interference of solid precipitation on the reaction. At the same time, the lower temperature inhibits the occurrence of side reactions, resulting in a final yield of more than 93%.

[0018] Further, in the step (1), the amount of the mixed solvent used per 10 mmol of palmitic acid is 20-25 mL.

[0019] Further, in the step (1), the temperature of the acyl chlorination reaction is 5-7 °C and the reaction time is 0.5-0.6 h.

[0020] Further, in the step (3), the specifications of the silica gel chromatography column are 20 mm × 600 mm and the silica gel is 100-200 mesh.

[0021] Further, in the step (1), the eluent used for the silica gel chromatography column is n-hexane and ethyl acetate with a volume ratio of (5-3):1.

[0022] The present invention uses n-hexane and ethyl acetate with a specific ratio as the eluent, which can improve the purity of the product.

[0023] Further, in the step (1), L-ascorbic acid is further added, the temperature is raised to 25-30 °C, and the reaction is carried out for 7-8 h to obtain a reaction product.

[0024] Further, the yield of L-ascorbic acid palmitate prepared by the method is ≥93.5%.

[0025] Further, the purity of the L-ascorbic acid palmitate is ≥98%.

[0026] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

[0027] 1. The solvents used in the method of the present invention are all commercially available products, and no pretreatment is required. Direct use reduces the cost of the enterprise. The yield of L-ascorbic acid palmitate prepared by the present invention is ≥93.5% and the purity is ≥98%, which improves the problems of low yield and low purity in the current synthesis of L-ascorbic acid palmitate by the acyl chloride method.

[0028] 2. The mixed solvent of the present invention is prepared by mixing N,N-dimethylacetamide and N,N-dimethylformamide, and using dichloromethane as a cosolvent. The reaction is carried out at a temperature of 5-7 °C for a reaction time of 0.5-0.6 h, which can improve the yield of the product.

[0029] 3. The present invention uses n - hexane and ethyl acetate in a specific ratio as the eluent, which can improve the purity of the product. Detailed implementation manners

[0030] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0031] The raw materials used in the present invention are all commercially available products:

[0032] Palmitic acid, Merck KGaA, Darmstadt, Germany, Sigma - Aldrich, product number 76119.

[0033] L - Ascorbic acid, Merck KGaA, Darmstadt, Germany, Sigma - Aldrich, product number A92902.

[0034] SOCl 2 , industrial grade, Shandong Langcheng Chemical Co., Ltd.

[0035] N,N - Dimethylacetamide, analytical pure, Merck KGaA, Darmstadt, Germany, Sigma - Aldrich.

[0036] N,N - Dimethylformamide, analytical pure, Merck KGaA, Darmstadt, Germany, Sigma - Aldrich.

[0037] Dichloromethane, analytical pure, Merck KGaA, Darmstadt, Germany, Sigma - Aldrich.

[0038] Example 1

[0039] This example provides a method for synthesizing L - ascorbyl palmitate by the acyl chloride method, including the following steps:

[0040] (1) Add palmitic acid to the mixed solvent, stir and dissolve at 27°C, and dropwise add SOCl 2 under ice - water bath conditions for the acyl chlorination reaction. The temperature of the acyl chlorination reaction is 5°C, and the reaction time is 0.5 h. After the reaction is completed, continue to add L - ascorbic acid, raise the temperature to 27°C, and keep the temperature for reaction for 7.5 h to obtain the reaction product. Among them, the mixed solvent includes N,N - dimethylacetamide, N,N - dimethylformamide and dichloromethane with a volume ratio of 2:1.4:1; the molar ratio of palmitic acid, SOCl 2 and L - ascorbic acid is 1:1.1:1.4. The dosage of the mixed solvent used for every 10 mmol of palmitic acid is 20 mL.

[0041] (2) Add 45 mL of ethyl acetate and 35 mL of distilled water to 20 mL of the reaction product, place it in a separatory funnel to obtain an aqueous layer and an organic layer. Extract the aqueous layer with 70 mL of ethyl acetate again, and combine the organic layers obtained twice. Wash the organic layer with water 3 times, and then use anhydrous Na 2 SO 4 to dry it. Rotavaporize to remove the organic solvent to obtain a crude product;

[0042] (3) Purify the crude product using a silica gel chromatography column. Collect the eluate within 60 - 150 min, and rotavaporize the eluate. The specifications of the silica gel chromatography column are 20 mm × 600 mm, and the silica gel is 100 - 200 mesh. The eluent used for the silica gel chromatography column is a mixture of n - hexane and ethyl acetate with a volume ratio of 4:1 to obtain L - ascorbyl palmitate.

[0043] In this example, the yield of L - ascorbyl palmitate prepared is 93.8%; the purity of the L - ascorbyl palmitate is 98.4%.

[0044] Example 2

[0045] This example provides a method for synthesizing L - ascorbyl palmitate by the acyl chloride method, including the following steps:

[0046] (1) Add palmitic acid to the mixed solvent, stir and dissolve it at 25°C, and dropwise add SOCl 2 under ice - water bath conditions for an acyl chlorination reaction. The temperature of the acyl chlorination reaction is 7°C, and the reaction time is 0.5 h. After the reaction is completed, continue to add L - ascorbic acid, raise the temperature to 30°C, and keep the temperature for 7 h to obtain a reaction product. Among them, the mixed solvent includes N,N - dimethylacetamide, N,N - dimethylformamide, and dichloromethane with a volume ratio of 2:1.2:1; the molar ratio of palmitic acid, SOCl 2 and L - ascorbic acid is 1:1.2:1.3. The dosage of the mixed solvent used for every 10 mmol of palmitic acid is 25 mL.

[0047] (2) Add 45 mL of ethyl acetate and 35 mL of distilled water to 20 mL of the reaction product, place it in a separatory funnel to obtain an aqueous layer and an organic layer. Extract the aqueous layer with 70 mL of ethyl acetate again, and combine the organic layers obtained twice. Wash the organic layer with water 3 times, and then use anhydrous Na 2 SO 4 to dry it. Rotavaporize to remove the organic solvent to obtain a crude product;

[0048] (3) Purify the crude product using a silica gel chromatography column, collect the eluate within 60 - 150 min, perform rotary evaporation on the eluate. The specifications of the silica gel chromatography column are 20 mm × 600 mm, and the silica gel is 100 - 200 mesh; the eluent used for the silica gel chromatography column is n - hexane and ethyl acetate with a volume ratio of 5:1 to obtain L - ascorbyl palmitate.

[0049] In this example, the yield of L - ascorbyl palmitate prepared is 93.5%; the purity of the L - ascorbyl palmitate is 98.7%.

[0050] Example 3

[0051] This example provides a method for synthesizing L - ascorbyl palmitate by the acyl chloride method, which includes the following steps:

[0052] (1) Add palmitic acid to the mixed solvent, stir and dissolve it at 30 °C, and dropwise add SOCl 2 under ice - water bath conditions to carry out the acyl chlorination reaction. The temperature of the acyl chlorination reaction is 5 °C, and the reaction time is 0.6 h; after the reaction is completed, continue to add L - ascorbic acid, raise the temperature to 25 °C, and keep the temperature for reaction for 8 h to obtain the reaction product. Among them, the mixed solvent includes N,N - dimethylacetamide, N,N - dimethylformamide and dichloromethane with a volume ratio of 2:1.2:1; the molar ratio of palmitic acid, SOCl 2 and L - ascorbic acid is 1:1.2:1.3. The dosage of the mixed solvent used for every 10 mmol of palmitic acid is 20 mL.

[0053] (2) Add 45 mL of ethyl acetate and 35 mL of distilled water to 20 mL of the reaction product, put it into a separating funnel to obtain an aqueous layer and an organic layer. Extract the aqueous layer with 70 mL of ethyl acetate once again, and combine the organic layers obtained twice; wash the organic layer with water 3 times, and then dry it with anhydrous Na 2 SO 4 and perform rotary evaporation to remove the organic solvent to obtain the crude product;

[0054] (3) Purify the crude product using a silica gel chromatography column, collect the eluate within 60 - 150 min, perform rotary evaporation on the eluate. The specifications of the silica gel chromatography column are 20 mm × 600 mm, and the silica gel is 100 - 200 mesh; the eluent used for the silica gel chromatography column is n - hexane and ethyl acetate with a volume ratio of 3:1 to obtain L - ascorbyl palmitate.

[0055] In this example, the yield of L - ascorbyl palmitate prepared is 93.6%; the purity of the L - ascorbyl palmitate is 98.2%.

[0056] Comparative Example 1

[0057] The difference between this comparative example and Example 1 is that the mixed solvent includes N,N-dimethylacetamide and dichloromethane with a volume ratio of 2:1.

[0058] In this comparative example, the yield of L-ascorbyl palmitate prepared is 90.5%; the purity of the L-ascorbyl palmitate is 93.8%.

[0059] Comparative Example 2

[0060] The difference between this comparative example and Example 1 is that the temperature of the acyl chlorination reaction is 10 °C and the reaction time is 0.5 h.

[0061] In this comparative example, the yield of L-ascorbyl palmitate prepared is 91.7%; the purity of the L-ascorbyl palmitate is 95.9%.

[0062] Comparative Example 3

[0063] The difference between this comparative example and Example 1 is that the temperature of the acyl chlorination reaction is 0 °C and the reaction time is 0.5 h.

[0064] In this comparative example, the yield of L-ascorbyl palmitate prepared is 91.3%; the purity of the L-ascorbyl palmitate is 96.0%.

[0065] Comparative Example 4

[0066] The difference between this comparative example and Example 1 is that the eluent used in the gel chromatography column is n-hexane and ethyl acetate with a volume ratio of 1:1.

[0067] In this comparative example, the yield of L-ascorbyl palmitate prepared is 92.4%; the purity of the L-ascorbyl palmitate is 94.6%.

[0068] Comparative Example 5

[0069] The difference between this comparative example and Example 1 is that the eluent used in the silica gel chromatography column is n-hexane and ethyl acetate with a volume ratio of 1:4.

[0070] In this comparative example, the yield of L-ascorbyl palmitate prepared is 92.9%; the purity of the L-ascorbyl palmitate is 95.0%.

[0071] The results of Examples 1-3 and Comparative Examples 1-5 are shown in Table 1.

[0072] Table 1 Test results of yield and purity

[0073] Test Yield % Purity % Example 1 93.8 98.4 Example 2 93.5 98.7 Example 3 93.6 98.2 Comparative Example 1 90.5 93.8 Comparative Example 2 91.7 95.9 Comparative Example 3 91.3 96.0 Comparative Example 4 92.4 94.6 Comparative Example 5 92.9 95.0

[0074] From the above results, it can be seen that the L-ascorbyl palmitate prepared in Examples 1-3 has a high yield, high purity, the raw materials used are simple and easy to obtain, and no pretreatment is required, which can reduce the cost of enterprises and increase the benefits.

[0075] In Comparative Example 1, different mixed solvents were used, and both the yield and purity of L-ascorbyl palmitate decreased. It was analyzed that in Example 1, by compounding N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF) and dichloromethane in proportion, the defects of a single solvent could be overcome and a synergistic effect could be achieved. The synergy between DMAc and DMF helped to absorb the by-product HCl. DMAc, DMF and CHCl formed a polarity gradient, optimizing the solubility and selectivity of the reaction system and reducing the occurrence of side reactions.

[0076] From Comparative Examples 2 and 3, it can be seen that when the reaction was carried out under the conditions of 0 °C and 10 °C in the present invention, both the yield and purity of L-ascorbyl palmitate decreased. The acyl chlorination reaction is a process of generating acyl chloride by reacting an acid anhydride or carboxylic acid with a chlorinating reagent. This reaction releases by-products HCl and SO, and there may be various side reactions during the reaction process. Under the condition that the mixed solvent used in the present invention can ensure complete dissolution, the low temperature condition of 5 °C makes the reaction rate moderate, ensuring both sufficient reaction time and avoiding the generation of by-products due to too fast reaction. Too high or too low temperature is not conducive to the progress of the reaction.

[0077] In Comparative Examples 4 and 5, the ratios of the eluents were different, and the yield and purity of the product decreased. However, in the examples of the present invention, by adjusting the polarity of the eluent, collecting and rotary evaporating to remove the solvent within 60 - 150 min, the best yield and purity were obtained. The proportion of a specific eluent optimized the separation window between the target compound and the impurities, enabling the two to pass through the chromatographic column at different speeds, thus achieving efficient separation.

[0078] The above are the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle described in the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing L-ascorbyl palmitate by an acyl chloride method, characterized in that: The following steps are involved: (1) adding palmitic acid to a mixed solvent, dissolving it, adding SOCl2, and carrying out an acyl chlorination reaction. After the reaction is completed, continuing to add L-ascorbic acid, raising the temperature, and keeping the temperature to react to obtain a reaction product; the mixed solvent includes N,N-dimethylacetamide, N,N-dimethylformamide, and dichloromethane; (2) adding ethyl acetate and distilled water to the reaction product, placing it in a separatory funnel to obtain an aqueous layer and an organic layer, extracting the aqueous layer once more with ethyl acetate, and combining the organic layers obtained twice; washing the organic layer with water, and then drying it with anhydrous Na2SO4, and removing the organic solvent by rotary evaporation to obtain a crude product; (3) The crude product was purified by silica gel chromatography, the eluate within 60-150 min was collected, and the eluate was rotary evaporated to obtain L-ascorbyl palmitate.

2. The method for synthesizing L-ascorbyl palmitate by the acyl chloride method according to claim 1, characterized in that: The molar ratio of palmitic acid, SOCl2 and L-ascorbic acid in step (1) is 1:(1.1-1.2):(1.3-1.4).

3. The method for synthesizing L-ascorbyl palmitate by the acyl chloride method according to claim 1, characterized in that, The mixed solvent in step (1) comprises N,N-dimethylacetamide, N,N-dimethylformamide and dichloromethane in a volume ratio of 2:(1.2-1.5):

1.

4. The method for synthesizing L-ascorbyl palmitate by the acyl chloride method according to claim 1, characterized in that: In the step (1), the amount of the mixed solvent used is 20 to 25 mL per 10 mmol of palmitic acid.

5. The method for synthesizing L-ascorbyl palmitate by the acyl chloride method according to claim 1, characterized in that, The temperature of the acyl chlorination reaction in step (1) is 5-7° C., and the reaction time is 0.5-0.6 h.

6. The method for synthesizing L-ascorbyl palmitate by the acyl chloride method according to claim 1, characterized in that: The size of the silica gel chromatography column in step (3) is 20 mm×600 mm, and the silica gel has a mesh size of 100 to 200.

7. The method for synthesizing L-ascorbyl palmitate by the acyl chloride method according to claim 1, characterized in that: The eluent used in the silica gel chromatography column in the step (1) is n-hexane and ethyl acetate in a volume ratio of (5-3):

1.

8. The method for synthesizing L-ascorbyl palmitate by the acyl chloride method according to claim 1, characterized in that: In the step (1), L-ascorbic acid is continuously added, the temperature is raised to 25-30° C., and the mixture is kept warm for 7-8 hours to obtain a reaction product.

9. The method for synthesizing L-ascorbyl palmitate by the acyl chloride method according to claim 1, characterized in that: The yield of L-ascorbyl palmitate prepared by the method is ≥93.5%.

10. The method for synthesizing L-ascorbyl palmitate by the acyl chloride method according to claim 1, characterized in that: The purity of the L-ascorbyl palmitate is ≥98%.