A method for synthesizing L-ascorbyl palmitate by acyl chloride method

Abstract

The application 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, adding SOCl2 dropwise, performing acyl chloride reaction, continuously adding L-ascorbic acid after the reaction is completed, heating and keeping the temperature to perform reaction, and obtaining a reaction product; (2) adding ethyl acetate and distilled water into the reaction product, placing the reaction product into a separating funnel, obtaining a water layer and an organic layer, re-extracting the water layer with ethyl acetate once, and combining the organic layers obtained twice; washing the organic layer with water three times, then drying the organic layer with anhydrous Na2SO4, removing the organic solvent by rotary evaporation, and obtaining a crude product; (3) purifying the crude product by using a silica gel chromatography column, collecting eluent within 60-150 min, and performing rotary evaporation on the eluent, and obtaining L-ascorbyl palmitate. The method has high yield and purity for preparing L-ascorbyl palmitate.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing L-ascorbate palmitate via an acyl chloride process. Background Technology

[0002] L-Ascorbyl palmitate is a derivative of vitamin C (ascorbic acid). It is a fat-soluble form of vitamin C with good stability and permeability, and is commonly used in food, cosmetics, and health products. Synthetic processes for L-Ascorbyl palmitate include enzymatic catalysis, direct exchange, transesterification, and palmitoyl chloride synthesis.

[0003] Chinese patent CN106883202B discloses a method for preparing L-ascorbic acid palmitate. L-ascorbic acid and palmitic acid undergo esterification under concentrated sulfuric acid catalysis. After the reaction is complete, ethyl acetate is added dropwise to the reaction system, followed by ice water. After filtration, crude L-ascorbic acid palmitate is obtained. This is then recrystallized from ethyl acetate to obtain the target product, L-ascorbic acid palmitate. This method requires concentrated strong acid as a catalyst and solvent, the product has a dark color, and separation and purification are difficult.

[0004] Chinese patent CN102304109B discloses a method for synthesizing L-ascorbic acid palmitate: Palmitic acid is pulverized into a fine powder; the palmitic acid powder is slowly added to pure sulfuric acid at 25℃-20℃ to dissolve; 0.95 times the molar amount of L-ascorbic acid is added to the reaction solution, followed by the addition of a dehydrating agent, and the reaction continues for 6-7 hours; the resulting reaction solution is poured into crushed ice, the crude product is filtered out, dried, and washed with water; the prepared crude L-ascorbic acid palmitate is heated and dissolved in ethyl acetate, and the solution is decolorized and purified by passing it through a granular activated carbon column; the resulting solution is distilled under reduced pressure and concentrated, and the solution is cooled to 0℃ to obtain a white powder of L-ascorbic acid palmitate. The product yield of this method is less than 90%.

[0005] The palmitoyl chloride process, with its low reaction temperature and few byproducts, has garnered increasing attention in recent years. In the preparation of L-ascorbic acid palmitate via the palmitoyl chloride process, achieving high yield and high purity has become crucial to meeting product quality requirements, reducing production costs, enhancing market competitiveness, and ensuring product safety in sensitive areas. With increasing consumer focus on health and safety and rising quality standards in the food industry, the purity of L-ascorbic acid palmitate, as a highly effective antioxidant, directly impacts its antioxidant efficacy. High-purity products better delay food oxidation and spoilage, extending shelf life. Furthermore, high-purity L-ascorbic acid palmitate exhibits greater chemical stability, making it less prone to decomposition or unpleasant odors during storage and use, thus ensuring food quality and taste.

[0006] Therefore, there is an urgent need for a method to synthesize L-ascorbate palmitate via the acyl chloride process. Summary of the Invention

[0007] The purpose of this invention is to provide a method for synthesizing L-ascorbate palmitate via an acyl chloride process.

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] A method for synthesizing L-ascorbate palmitate via an acyl chloride process includes the following steps:

[0010] (1) Add palmitic acid to a mixed solvent, dissolve it, add SOCl2, carry out acyl chloride reaction, after the reaction is completed, continue to add L-ascorbic acid, raise the temperature, keep the reaction at the temperature, and obtain the 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 two organic layers. Wash the organic layer with water three times, then dry it with anhydrous Na2SO4 and remove the organic solvent by rotary evaporation to obtain the crude product.

[0012] (3) The crude product was purified using a silica gel chromatography column. The eluent was collected within 60-150 min and then rotary evaporated to obtain L-ascorbate palmitate.

[0013] Furthermore, the dissolution method in step (1) is to dissolve by stirring at 25-30°C.

[0014] Furthermore, in step (1), SOCl2 is added dropwise under ice-water bath conditions.

[0015] Further, in step (1), the molar ratio of palmitic acid, SOCl2 and L-ascorbic acid is 1:(1.1-1.2):(1.3-1.4).

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

[0017] The mixed solvent of this invention is a compound of N,N-dimethylacetamide and N,N-dimethylformamide, with dichloromethane as a co-solvent. The reaction is carried out at a temperature of 5–7°C for a reaction time of 0.5–0.6 h, which improves the product yield. Analysis shows that at this temperature, the mixing of DMAc, DMF, and CH4Cl, due to solvation structural changes, allows the mixed solvent to maintain good solubility of palmitic acid, reducing the interference of solid precipitation on the reaction. Simultaneously, the lower temperature suppresses side reactions, resulting in a final yield of over 93%.

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

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

[0020] Furthermore, in step (3), the silica gel chromatography column has a size of 20mm × 600mm and the silica gel is 100-200 mesh.

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

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

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

[0024] Furthermore, the yield of L-ascorbate palmitate prepared by the method is ≥93.5%.

[0025] Furthermore, the purity of the L-ascorbate 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, which do not require pretreatment and can be used directly to reduce the cost of enterprises. The yield of L-ascorbate palmitate prepared by the present invention is ≥93.5% and the purity is ≥98%, which improves the problems of low yield and low purity of L-ascorbate palmitate synthesized by the current acyl chloride method.

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

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

[0030] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0031] All raw materials used in this invention are commercially available products:

[0032] Palmitic acid, Sigma-Aldrich, Darmstadt, Germany, catalog number 76119.

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

[0034] SOCl2, industrial grade, Shandong Langcheng Chemical Co., Ltd.

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

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

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

[0038] Example 1

[0039] This embodiment provides a method for synthesizing L-ascorbate palmitate via the acyl chloride method, comprising the following steps:

[0040] (1) Palmitic acid was added to a mixed solvent and dissolved by stirring at 27°C. SOCl2 was added dropwise under ice-water bath conditions to carry out an acyl chloride reaction at 5°C for 0.5 h. After the reaction was completed, L-ascorbic acid was added, the temperature was raised to 27°C, and the reaction was maintained for 7.5 h to obtain the reaction product. The mixed solvent consisted of N,N-dimethylacetamide, N,N-dimethylformamide, and dichloromethane in a volume ratio of 2:1.4:1; the molar ratio of palmitic acid, SOCl2, and L-ascorbic acid was 1:1.1:1.4. The amount of mixed solvent used was 20 mL per 10 mmol of palmitic acid.

[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 again with 70 mL of ethyl acetate and combine the two organic layers. Wash the organic layer with water three times, then dry it with anhydrous Na2SO4 and remove the organic solvent by rotary evaporation to obtain the crude product.

[0042] (3) The crude product was purified using a silica gel chromatography column. The eluent was collected within 60-150 min and then rotary evaporated. The silica gel chromatography column was 20 mm × 600 mm with 100-200 mesh silica gel. The eluent used in the silica gel chromatography column was n-hexane and ethyl acetate in a volume ratio of 4:1 to obtain L-ascorbic acid palmitate.

[0043] In this embodiment, the yield of L-ascorbate palmitate was 93.8%; the purity of the L-ascorbate palmitate was 98.4%.

[0044] Example 2

[0045] This embodiment provides a method for synthesizing L-ascorbate palmitate via the acyl chloride method, comprising the following steps:

[0046] (1) Palmitic acid was added to a mixed solvent and dissolved by stirring at 25°C. SOCl2 was added dropwise under ice-water bath conditions to carry out an acyl chloride reaction at 7°C for 0.5 h. After the reaction was completed, L-ascorbic acid was added, the temperature was raised to 30°C, and the reaction was maintained for 7 h to obtain the reaction product. The mixed solvent consisted of N,N-dimethylacetamide, N,N-dimethylformamide, and dichloromethane in a volume ratio of 2:1.2:1; the molar ratio of palmitic acid, SOCl2, and L-ascorbic acid was 1:1.2:1.3. The amount of mixed solvent used was 25 mL per 10 mmol of palmitic acid.

[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 again with 70 mL of ethyl acetate and combine the two organic layers. Wash the organic layer with water three times, then dry it with anhydrous Na2SO4 and remove the organic solvent by rotary evaporation to obtain the crude product.

[0048] (3) The crude product was purified using a silica gel chromatography column. The eluent was collected within 60-150 min and then rotary evaporated. The silica gel chromatography column was 20 mm × 600 mm with 100-200 mesh silica gel. The eluent used in the silica gel chromatography column was n-hexane and ethyl acetate in a volume ratio of 5:1 to obtain L-ascorbic acid palmitate.

[0049] In this embodiment, the yield of L-ascorbate palmitate was 93.5%; the purity of the L-ascorbate palmitate was 98.7%.

[0050] Example 3

[0051] This embodiment provides a method for synthesizing L-ascorbate palmitate via the acyl chloride method, comprising the following steps:

[0052] (1) Palmitic acid was added to a mixed solvent and dissolved by stirring at 30°C. SOCl2 was added dropwise under ice-water bath conditions to carry out an acyl chloride reaction at 5°C for 0.6 h. After the reaction was completed, L-ascorbic acid was added, the temperature was raised to 25°C, and the reaction was maintained for 8 h to obtain the reaction product. The mixed solvent consisted of N,N-dimethylacetamide, N,N-dimethylformamide, and dichloromethane in a volume ratio of 2:1.2:1; the molar ratio of palmitic acid, SOCl2, and L-ascorbic acid was 1:1.2:1.3. The amount of mixed solvent used was 20 mL per 10 mmol of palmitic acid.

[0053] (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 again with 70 mL of ethyl acetate and combine the two organic layers. Wash the organic layer with water three times, then dry it with anhydrous Na2SO4 and remove the organic solvent by rotary evaporation to obtain the crude product.

[0054] (3) The crude product was purified using a silica gel chromatography column. The eluent was collected within 60-150 min and then rotary evaporated. The silica gel chromatography column was 20 mm × 600 mm with 100-200 mesh silica gel. The eluent used in the silica gel chromatography column was n-hexane and ethyl acetate in a volume ratio of 3:1 to obtain L-ascorbic acid palmitate.

[0055] In this embodiment, the yield of L-ascorbate palmitate was 93.6%; the purity of the L-ascorbate palmitate was 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 in a volume ratio of 2:1.

[0058] In this comparative example, the yield of L-ascorbate palmitate was 90.5%; the purity of the L-ascorbate palmitate was 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-ascorbate palmitate was 91.7%; the purity of the L-ascorbate palmitate was 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-ascorbate palmitate was 91.3%; the purity of the L-ascorbate palmitate was 96.0%.

[0065] Comparative Example 4

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

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

[0068] Comparative Example 5

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

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

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

[0072] Table 1. Results of yield and purity tests

[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] The results above show that the L-ascorbic acid palmitate prepared in Examples 1-3 has a high yield and high purity. The raw materials used are simple and readily available, and no pretreatment is required, which can reduce enterprise costs and increase profits.

[0075] In Comparative Example 1, the yield and purity of L-ascorbic acid palmitate decreased when different mixed solvents were used. Analysis of Example 1 shows that by combining N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), and dichloromethane in a specific ratio, the limitations of single solvents can be overcome, achieving a synergistic effect. The synergistic effect of DMAc and DMF helps absorb the byproduct HCl. DMAc and DMF form a polar gradient with CHCl, optimizing the solubility and selectivity of the reaction system and reducing the occurrence of side reactions.

[0076] Comparative Examples 2 and 3 show that the yield and purity of L-ascorbic acid palmitate decreased under the reaction conditions of 0℃ and 10℃ in this invention. Acyl chloride reaction is a process in which acid anhydrides or carboxylic acids react with chlorinating reagents to generate acyl chlorides. This reaction releases byproducts HCl and SO, and various side reactions may occur during the reaction. In this invention, using a mixed solvent ensures complete dissolution, and the low temperature of 5℃ provides a moderate reaction rate, ensuring sufficient reaction time while avoiding the formation of byproducts due to excessively rapid reaction. Temperatures that are too high or too low are detrimental to the reaction.

[0077] In Comparative Examples 4 and 5, the different eluent ratios resulted in decreased product yield and purity. However, the embodiments of this invention, by adjusting the polarity of the eluent and collecting the product within 60-150 minutes followed by rotary evaporation to remove the solvent, achieved the optimal yield and purity. The specific eluent ratio optimized the separation window between the target compound and impurities, allowing them to pass through the column at different speeds, thus achieving efficient separation.

[0078] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing L-ascorbate palmitate via an acyl chloride process, characterized in that, Includes the following steps: (1) Add palmitic acid to a mixed solvent, dissolve it, add SOCl2, carry out acyl chloride reaction, after the reaction is completed, continue to add L-ascorbic acid, raise the temperature to 25~30℃, keep the temperature for 7~8h, and obtain the reaction product; wherein, the molar ratio of palmitic acid, SOCl2 and L-ascorbic acid is 1:(1.1-1.2):(1.3-1.4), the mixed solvent is N,N-dimethylacetamide, N,N-dimethylformamide and dichloromethane with a volume ratio of 2:(1.2-1.5):1, the amount of mixed solvent used per 10 mmol palmitic acid is 20~25mL, the temperature of the acyl chloride reaction is 5~7℃, and the reaction time is 0.5~0.6h; (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 two organic layers. Wash the organic layer with water, then dry it with anhydrous Na2SO4, and remove the organic solvent by rotary evaporation to obtain the crude product. (3) The crude product was purified by silica gel chromatography column, and the eluent was collected within 60-150 min. The eluent was then rotary evaporated to obtain L-ascorbate palmitate. The eluent used in the silica gel chromatography column was hexane and acetate in a volume ratio of (5~3):

1. The purity of the L-ascorbate palmitate was ≥98%.

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

3. The method for synthesizing L-ascorbate palmitate via the acyl chloride method according to claim 1, characterized in that, The method yields L-ascorbate palmitate at a rate ≥93.5%.