A kind of synthesis method of ascorbyl tetraisopalmitate

Abstract

The invention relates to the field of chemical synthesis, and specifically discloses a method for synthesizing ascorbic acid tetraisopalmitate. The method is a one-step synthesis, comprising: mixing an alkaline substance, a condensing agent and vitamin C with 2-hexyldecanoic acid in an organic solvent, and performing an esterification reaction to obtain ascorbic acid tetraisopalmitate. The synthesis method avoids the generation of by-products such as ascorbic acid palmitate (CAS No.: 137-66-6) and ascorbic acid dipalmitate (CAS No.: 28474-90-0), and avoids the use of a strong corrosive agent thionyl chloride, thereby extending the service life of equipment and reducing the pressure of daily maintenance and inspection of equipment. The reaction conditions are mild, the reaction process is controllable, the product is easy to separate and purify, the yield is high, the purity is high, and the method is suitable for industrial-scale production.

Description

Technical Field

[0001] The present application relates to the technical field of compound synthesis, and in particular to a method for synthesizing ascorbyl tetraisopalmitate. Background Art

[0002] Ascorbyl Tetraisopalmitate (English: Ascorbyl Tetraisopalmitate, alias: Ascorbyl Tetraisopalmitate, molecular formula is C 70 H 128 0 10 , molecular weight: 1129.76, CAS number: 183476-82-6), it is a fat-soluble antioxidant. Ascorbyl tetraisopalmitate can effectively inhibit tyrosinase, reduce skin pigmentation, promote the synthesis of collagen and amino acids, and has anti-inflammatory effects. The product has good skin absorption effect. According to literature reports, the whitening and anti-melanin absorption effect of the product is 16.5 times that of ordinary whitening agents. Oil-soluble vitamin C derivatives with excellent skin absorbability and stability have the effects of whitening, SOD activity, eliminating active oxygen, promoting collagen synthesis, etc., are easily soluble in oil, and have broad market prospects. However, there are few synthetic methods for ascorbyl tetraisopalmitate compounds, and the existing synthetic methods have many defects. If they need to be carried out step by step, strong acids or corrosive acyl chloride compounds are used, the pollution is large, and the purification and separation are more troublesome.

[0003] Patent application CN 108069926 A discloses a method for synthesizing ascorbic acid tetraisopalmitate, but the first step uses highly corrosive thionyl chloride, which causes great corrosion to the equipment and the generated corrosive gas is difficult to handle.

[0004] Therefore, there is an urgent need for a safe, environmentally friendly, few-step, simple-operation, mild-reaction, high-yield, high-purity chemical synthesis process route for ascorbic acid tetraisopalmitate. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0006] In a first aspect, the present invention provides a method for synthesizing ascorbyl tetraisopalmitate, comprising:

[0007] The alkaline substance, condensation agent and vitamin C are mixed with 2-hexyldecanoic acid in an organic solvent, and ascorbic acid tetraisopalmitate is obtained through esterification reaction.

[0008] In some embodiments, the synthesis method comprises: mixing a condensing agent with 2-hexyldecanoic acid in an organic solvent, and then mixing with an alkaline substance and vitamin C after 30 to 60 minutes, preferably mixing with an alkaline substance and vitamin C after 30 minutes.

[0009] In some embodiments, the reaction temperature is 30-40° C. In some preferred embodiments, the reaction temperature of the esterification reaction is 30-35° C. In some more preferred embodiments, the reaction temperature of the esterification reaction is 35° C.

[0010] In some embodiments, the vitamin C is one or more of levorotatory vitamin C and dextrorotatory vitamin C.

[0011] In some embodiments, the ascorbyl tetraisopalmitate exists in the form of stereoisomers or tautomers.

[0012] In some embodiments, the ascorbyl tetraisopalmitate comprises formula (I), formula (II), or formula (III);

[0013]

[0014] In some embodiments, the condensing agent is one or more of methyl silicate, ethyl silicate, and isopropyl silicate.

[0015] In some embodiments, the alkaline substance is one or more of sodium bicarbonate, dipotassium hydrogen phosphate, triethylamine and N,N-diisopropylethylamine.

[0016] In some embodiments, the molar ratio of the condensing agent to 2-hexyldecanoic acid is 1.1:1.0 to 1.5:1.0. In some preferred embodiments, the molar ratio of the condensing agent to 2-hexyldecanoic acid is 1.1:1.0 to 1.3:1.0. In some more preferred embodiments, the molar ratio of the condensing agent to 2-hexyldecanoic acid is 1.1:1.0 to 1.2:1.0.

[0017] In some embodiments, the molar ratio of the alkaline substance to vitamin C is 6.70:1.00 to 4.52:1.00. In some preferred embodiments, the molar ratio of the alkaline substance to vitamin C is 6.52:1.00 to 4.52:1.00. In some more preferred embodiments, the molar ratio of the alkaline substance to vitamin C is 4.52:1.00.

[0018] In some embodiments, the organic solvent is one or more of toluene, dichloromethane, tetrahydrofuran and N-methylpyrrolidone.

[0019] In some embodiments, the amount of 2-hexyldecanoic acid added to 1L of the organic solvent is 1.73-2.60 mol. In some preferred embodiments, the amount of 2-hexyldecanoic acid added to 1L of the organic solvent is 1.73 mol-2.23 mol. In some more preferred embodiments, the amount of 2-hexyldecanoic acid added to 1L of the organic solvent is 1.95 mol.

[0020] In some embodiments, the reaction occurs in an inert gas atmosphere.

[0021] In some embodiments, the inert gas is selected from one or more of nitrogen and argon.

[0022] In some embodiments, the molar ratio of vitamin C to 2-hexyldecanoic acid is 1.00:4.33 to 1.00:4.11. In some preferred embodiments, the molar ratio of vitamin C to 2-hexyldecanoic acid is 1.00:4.11. In some more preferred embodiments, the molar ratio of vitamin C to 2-hexyldecanoic acid is 1.00:4.00.

[0023] In some embodiments, 1.91 mol to 4.02 mol of the alkaline substance is added per 1 L of the organic solvent. In some preferred embodiments, 1.91 mol of the alkaline substance is added per 1 L of the organic solvent.

[0024] In a second aspect, the present invention provides a method for purifying ascorbic acid tetraisopalmitate prepared in the first aspect, the purification method comprising:

[0025] S1: After cooling, add water and extract the layers.

[0026] S2: Dry the organic layer and remove the solvent.

[0027] In some embodiments, the cooling method of step S1 is to cool the temperature to 10-15°C.

[0028] In some embodiments, the water in step S1 is deionized water.

[0029] In some embodiments, the organic layer in step S2 is dried using anhydrous sodium sulfate.

[0030] In some embodiments, the method for removing the solvent from S2 is selected from pressure reduction distillation or rotary evaporation.

[0031] In the above text, regardless of whether the words "about" or "approximately" are used, all the numbers disclosed herein are approximate values. Based on the disclosed numbers, the value of each number may vary by less than ±10% or reasonable differences considered by those skilled in the art, such as ±1%, ±2%, ±3%, ±4% or ±5%.

[0032] The term "and / or" should be understood to mean any one of the optional items or a combination of any two or more of the optional items.

[0033] The term "wt%" means percent by mass.

[0034] The term "% vol" means volume percentage.

[0035] The term "°C" means degrees Celsius.

[0036] The term "plurality" means two or more, for example, 2, 3, 4 or 5.

[0037] The by-products in the following examples or comparative examples all contain their isomers.

[0038] The reagents used in the present invention were purchased from the open legal market and were not further purified or optimized.

[0039] Advantages of the present invention:

[0040] Compared with the prior art, at least one embodiment of the present invention includes at least one of the following beneficial effects:

[0041] (1) At 30-40° C., under the action of the condensation agent such as methyl silicate, ethyl silicate or isopropyl silicate, vitamin C and 2-hexyldecanoic acid can be condensed in one step, avoiding the decrease in yield caused by multiple steps of reaction, and the operation is simple.

[0042] (2) Compared with the prior art, the present invention does not need to use strong corrosive agents such as thionyl chloride, thus avoiding corrosion of equipment and reducing equipment maintenance pressure.

[0043] (3) Compared with the use of highly corrosive reagents (such as thionyl chloride), the present invention uses a condensation agent to avoid the generation of by-products and improve the yield.

[0044] (4) The present invention helps to avoid the production of by-products such as ascorbyl palmitate and ascorbyl dipalmitate, improve the conversion rate of ascorbyl tetraisopalmitate, and avoid the complicated purification process of the mixture with the same by-product by-products by pre-activating the condensing agent and 2-hexyldecanoic acid in an organic solvent for 30-60 minutes and then adding the alkaline substance and vitamin C, and maintaining the reaction temperature at 30-40°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The HPLC chart of the reaction process monitoring in Example 1 is shown.

[0046] Figure 2 The HPLC detection chart of L-ascorbyl tetraisopalmitate in Example 1 is shown.

[0047] Figure 3 The HPLC chart of the reaction process monitoring in Example 2 is shown.

[0048] Figure 4 The HPLC detection chart of dextrorotatory ascorbic acid tetraisopalmitate in Example 2 is shown.

[0049] Figure 5 The HPLC chart of the reaction process monitoring in Example 3 is shown.

[0050] Figure 6 The HPLC detection chart of L-ascorbyl tetraisopalmitate in Example 3 is shown. DETAILED DESCRIPTION

[0051] Under the protection of inert gas, 2-hexyldecanoic acid is dissolved in a mixed solution of one or more organic solvents such as toluene, dichloromethane, tetrahydrofuran and N-methylpyrrolidone to prepare a 1.73 mol / L to 2.6 mol / L 2-hexyldecanoic acid solution, stirred and cooled to 15 to 20° C., at least one condensing agent such as methyl silicate, ethyl silicate, isopropyl silicate and the like is added, stirred for 25 to 35 minutes, at least one alkaline substance such as sodium bicarbonate, dipotassium hydrogen phosphate, triethylamine and N, N-diisopropylethylamine is added, and vitamin C is added, the temperature is raised to 30-40° C., the reaction is carried out for 14-16 hours, the temperature is lowered to 10-15° C., deionized water is added for washing, extraction and stratification are carried out, the organic layer is collected, the organic layer is dried, and then the organic layer is rotary evaporated to obtain a colorless oil.

[0052] The present invention will be further described below according to specific embodiments:

[0053] Example 1

[0054] Under nitrogen protection, 200.0 g (0.78 mol, 1.00 eq) of 2-hexyldecanoic acid was dissolved in 450 mL of dichloromethane, and the mixture was cooled to 15° C. with stirring, and 130.60 g (0.86 mol, 1.10 eq) of methyl silicate was added. After the addition, stirring was continued at this temperature for 30 minutes, and then 86.80 g (0.86 mol, 1.10 eq) of triethylamine was added, and then 33.50 g (0.19 mol, 0.24 eq) of L-vitamin C was added. The mixture was then heated to 30° C. and stirred for reaction. The reaction process was monitored by HPLC. After 14 hours, it was detected that the raw materials were completely reacted, as shown in FIG. Figure 1, terminate the reaction, cool to 10 ° C, add 750 mL of deionized water, extract and separate, collect the organic layer, dry the organic layer over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and beat to obtain 200.27 g of L-ascorbic acid tetraisopalmitate (colorless oil, yield 93.30%, HPLC test purity 98.62%, such as Figure 2 ), as in formula (I).

[0055]

[0056] Example 2

[0057] Under argon protection, 200.0 g (0.78 mol, 1.00 eq) of 2-hexyldecanoic acid was dissolved in 400 mL of tetrahydrofuran, and the mixture was cooled to 15°C with stirring. 171.90 g (0.86 mol, 1.10 eq) of ethyl silicate was added. After the addition, stirring was continued at this temperature for 30 minutes. Then 86.80 g (0.86 mol, 1.10 eq) of triethylamine was added, and then 33.50 g (0.19 mol, 0.24 eq) of dextrorotatory vitamin C was added. The mixture was heated to 40°C and stirred for reaction. The reaction process was monitored by HPLC. After 14 hours, it was detected that the raw materials were completely reacted, as shown in FIG. Figure 3 , terminate the reaction, cool to 10 ° C, add 750 mL of deionized water, extract and separate, collect the organic layer, dry the organic layer over anhydrous sodium sulfate, remove the solvent from the organic layer by rotary evaporation, and beat to obtain 198.55 g of dextrorotatory ascorbic acid tetraisopalmitate, as shown in formula (III) (colorless oil, yield 92.50%, HPLC test purity 98.54%, as shown Figure 4 ).

[0058]

[0059] Example 3

[0060] Under nitrogen protection, 200.0 g (0.78 mol, 1.00 eq) of 2-hexyldecanoic acid was dissolved in 350 mL of N-methylpyrrolidone, and the mixture was cooled to 15° C. with stirring, and 226.90 g (0.86 mol, 1.10 eq) of isopropyl silicate was added. After the addition, stirring was continued at this temperature for 30 minutes, and then 149.80 g (0.86 mol, 1.10 eq) of dipotassium hydrogen phosphate was added, and then 33.50 g (0.19 mol, 0.24 eq) of L-vitamin C was added. The mixture was then heated to 30° C. and stirred for reaction. The reaction process was monitored by HPLC. After 16 hours, it was detected that the raw materials were completely reacted, as shown in FIG. Figure 5, terminate the reaction, cool to 15 ° C, add 750 mL of deionized water, extract and separate, collect the organic layer, dry the organic layer over anhydrous sodium sulfate, remove the solvent from the organic layer by rotary evaporation, and slurry to obtain 202.42 g of L-ascorbic acid tetraisopalmitate, as shown in formula (I) (colorless oil, yield 94.30%, HPLC test purity 98.50%, as shown Figure 6 ).

[0061]

[0062] Example 4

[0063] Under argon protection, 600.0 g (2.34 mol, 1.00 eq) of 2-hexyldecanoic acid was dissolved in 900 mL of N-methylpyrrolidone, and the mixture was cooled to 20°C with stirring, and 534.30 g (3.51 mol, 1.50 eq) of methyl silicate was added. After the addition, stirring was continued at this temperature for 30 minutes, and then 467.85 g (3.62 mol, 1.50 eq) of N, N-diisopropylethylamine was added, and then 95.80 g (0.54 mol, 1.50 eq) of dextrorotatory vitamin C was added. ol, 0.24eq) was then heated to 40°C and stirred for reaction. The reaction progress was monitored by HPLC. After 16 hours, it was detected that the raw material reaction was complete, the reaction was terminated, and the temperature was lowered to 10°C. 900mL of deionized water was added, and the layers were extracted and separated. The organic layer was collected and dried over anhydrous sodium sulfate. The organic layer was evaporated to remove the solvent and slurried to obtain 583.23g of dextrorotatory ascorbic acid tetraisopalmitate (colorless oil, yield 95.6%, HPLC test purity 98.54%).

[0064] Example 5

[0065] Under argon protection, 600.0 g (2.34 mol, 1.00 eq) of 2-hexyldecanoic acid was dissolved in 900 mL of toluene, and the mixture was cooled to 20°C with stirring. 928.10 g (3.51 mol, 1.50 eq) of isopropyl silicate was added, and the mixture was stirred for 30 minutes at this temperature. Then 294.90 g (3.51 mol, 1.50 eq) of sodium bicarbonate was added, and then 95.80 g (0.54 mol, 0.24 eq) of dextrorotatory vitamin C was added. q), then the temperature was raised to 40°C and stirred for reaction, and the reaction progress was monitored by HPLC. After 16 hours, it was detected that the raw material reaction was complete, and the reaction was terminated. After cooling to 10°C, 900 mL of deionized water was added, and the layers were extracted and separated. The organic layer was collected and dried over anhydrous sodium sulfate. The organic layer was evaporated to remove the solvent, and the mixture was slurried to obtain 586.28 g of dextrorotatory ascorbic acid tetraisopalmitate (colorless oil, yield 96.10%, HPLC test purity 98.62%).

[0066] Comparative Example 1

[0067] Under nitrogen protection, 200.0 g (0.78 mol, 1.00 eq) of 2-hexyldecanoic acid was dissolved in 400 mL of dichloromethane. After adding the condensing agents described in Table 1, 86.80 g (0.86 mol, 1.10 eq) of triethylamine was immediately added, and then 33.50 g (0.19 mol, 0.24 eq) of L-vitamin C was added. The mixture was then heated to 40° C. and stirred for reaction. The reaction process was monitored by HPLC. After 14 hours, the reaction of the raw materials was detected to be complete, and the reaction was terminated. After cooling to 10° C., 750 mL of deionized water was added, and the mixture was extracted and layered. The organic layer was collected and dried over anhydrous sodium sulfate. The organic layer was evaporated to remove the solvent, and the mixture was slurried to obtain a colorless oil. The results of HPLC detection were as shown in Table 1 of the reaction product.

[0068] The byproduct 1 is L-ascorbyl palmitate (molecular formula C 22 H 38 O7); byproduct 2 is L-ascorbyl dipalmitate (molecular formula C 38 H 68 O8); byproduct 3 is L-Ascorbic acid, 2,5,6-tris(2-hexyldecanoate) (molecular formula: C 54 H 98 O9);

[0069] Table 1 Reaction product table

[0070]

[0071] Comparative Example 2

[0072] This comparative example is the same as Example 3 except that the reaction temperature of the condensation reaction between 200 g (0.78 mol, 1 eq) of 2-hexyldecanoic acid and L-vitamin C under the action of a condensing agent is different.

[0073] The results are shown in Table 2.

[0074] The byproduct 1 is L-ascorbyl palmitate (molecular formula C 22 H 38 O7);

[0075] Byproduct 2 is L-ascorbyl dipalmitate (molecular formula C 38 H 68 O8, alias: L-ascorbic acid dipalmitate);

[0076] Byproduct 3 is L-Ascorbic acid, 2,5,6-tris(2-hexyldecanoate) (molecular formula: C 54 H 98 O9).

[0077] Table 2 Reaction product table

[0078]

[0079] Conclusion Analysis

[0080] By controlling the order of adding materials, after 2-hexyldecanoic acid is dissolved in one or more organic solvents such as toluene, dichloromethane, tetrahydrofuran and N-methylpyrrolidone, and the condensation agent is added, it must be left for 30 to 60 minutes to allow the acid to react with the condensation agent to produce active esters, and then alkaline substances such as triethylamine are added to allow vitamin C to undergo condensation. The condensation should be controlled at a temperature of 30 to 40°C.

[0081] By controlling the order of addition and the polycondensation temperature, it is helpful to avoid ascorbyl palmitate (molecular formula C 22 H 38 O7), ascorbyl dipalmitate (molecular formula C 38 H 68 O8) can make all hydroxyl groups undergo condensation reaction, thus avoiding ring-opening by-products.

[0082] At the same time, the widely used production process currently requires a two-step synthesis. In the first step, 2-hexyldecanoic acid is chlorinated with thionyl chloride to generate 2-hexyldecanoyl chloride, and 2-hexyldecanoyl chloride then undergoes a condensation reaction with vitamin C to generate ascorbyl tetraisopalmitate. Since the thionyl chloride used in the preparation process of 2-hexyldecanoyl chloride is highly corrosive, decomposes and releases irritating toxic fumes such as sulfur dioxide and hydrogen chloride when it encounters water or moisture, and can also produce toxic substances when it is decomposed by heat, this step requires dropwise addition under vigorous stirring to prepare 2-hexyldecanoyl chloride. The reaction process is long and prone to safety accidents. The reaction formula is as follows:

[0083]

[0084] The multi-step reaction must first prepare 2-hexyldecanoyl chloride, which is cumbersome to operate and prone to accidents, resulting in a decrease in yield.

[0085] The synthesis method of ascorbic acid tetraisopalmitate provided in the present application uses cheap and easily available raw materials in the preparation process, has a reasonable process design, simple operation, mild reaction conditions, and a controllable reaction process, which can effectively avoid potential safety hazards in the production process. The total reaction yield is not less than 92%, the product purity is not less than 98%, and the color is good; the production cost is low, and it can be widely used in industrial production.

[0086] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for synthesizing ascorbyl tetraisopalmitate, characterized in that: The method comprises mixing an alkaline substance, a condensing agent and vitamin C with 2-hexyldecanoic acid in an organic solvent, and esterifying the mixture at 30 to 40° C. to obtain ascorbic acid tetraisopalmitate; Wherein, the alkaline substance is selected from one or more of sodium bicarbonate, dipotassium hydrogen phosphate, triethylamine and N,N-diisopropylethylamine; The condensing agent is selected from one or more of methyl silicate, ethyl silicate and isopropyl silicate; The molar ratio of the condensing agent to 2-hexyldecanoic acid is (1.1-1.5):1.0; The molar ratio of the alkaline substance to vitamin C is (6.70-4.52):1.

00.

2. The method according to claim 1, characterized in that: The condensation agent and 2-hexyldecanoic acid are mixed in an organic solvent, and then mixed with an alkaline substance and vitamin C after 30 to 60 minutes.

3. The method according to claim 1, characterized in that: The vitamin C is selected from levorotatory vitamin C and dextrorotatory vitamin C.

4. The method according to claim 1, characterized in that: The ascorbyl tetraisopalmitate includes stereoisomers or tautomers, such as formula (I) to (III), 5. The method according to claim 1, characterized in that: The organic solvent is one or more of toluene, dichloromethane, tetrahydrofuran and N-methylpyrrolidone; and / or, The amount of 2-hexyldecanoic acid added to 1L of the organic solvent is 1.73 mol to 2.60 mol, and / or, The reaction occurs in an inert gas atmosphere; and / or, The inert gas is at least one of nitrogen and argon; and / or, 1.91 mol to 4.02 mol of the alkaline substance is added into every 1 L of the organic solvent.

6. The method according to claim 1, further comprising a method for purifying the ascorbic acid tetraisopalmitate, the method comprising: S1: After cooling, add water and extract the layers. S2: Dry the organic layer and remove the solvent. The cooling method of step S1 is to cool the temperature to 10-15°C; and / or, The water in step S1 is deionized water; and / or, The drying method of the organic layer in step S2 is drying with anhydrous sodium sulfate; and / or, The method of removing the solvent from S2 is selected from rotary evaporation or reduced pressure distillation.

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