Synthesis method of vitamin C ethyl ether

Abstract

The invention discloses a synthesis method of vitamin C ethyl ether, and belongs to the technical field of vitamin derivative synthesis. The synthesis method comprises the following steps: adding vitamin C, benzaldehyde and a catalyst into a first organic solvent, carrying out an aldolization reaction, adding an organic alkali after the aldolization reaction is finished, carrying out a neutralization reaction, adding an alkylation reagent, carrying out an alkylation reaction, and removing the first organic solvent after the alkylation reaction is finished, so as to obtain the vitamin C benzaldehyde. The preparation method comprises the following steps: adding a first organic solvent into a first organic solvent, pulping, filtering, collecting filter residues, washing and drying to obtain 5, 6-O-benzyl-3-O-ethyl-L-ascorbic acid, carrying out hydrogenation deprotection on the 5, 6-O-benzyl-3-O-ethyl-L-ascorbic acid, filtering after hydrogenation deprotection, collecting filtrate, crystallizing, collecting precipitate, washing and drying to obtain the 5, 6-O-benzyl-3-O-ethyl-L-ascorbic acid. The vitamin C ethyl ether is obtained. The synthesis method provided by the invention is simple to operate and high in production efficiency, and the obtained vitamin C ethyl ether is high in yield and purity.

Description

Technical Field

[0001] The invention belongs to the technical field of vitamin derivative synthesis, and in particular relates to a method for synthesizing vitamin C ethyl ether. Background Art

[0002] Vitamin C ethyl ether is a product in which the hydroxyl group at the 3rd position of vitamin C is replaced by an ethyl group. Compared with natural vitamin C, the molecular structure of vitamin C ethyl ether is more stable and is not easily damaged by external environments such as ultraviolet rays, high temperatures, and heavy metals. Its unique hydrophilic and lipophilic properties have greatly broadened its application areas. It can inhibit the activity of tyrosinase and block the formation of melanin; it has whitening and freckle removal effects (when added at 2%); it resists inflammation caused by sunlight and has strong antibacterial and anti-inflammatory effects; at the same time, it improves dull skin, gives the skin luster and elasticity, repairs skin cell activity, and promotes collagen production.

[0003] At present, there are two main synthetic ideas for vitamin C ethyl ether: one-step method and three-step method. Patent CN100586941C discloses a one-step synthetic method, which uses vitamin C as a raw material and directly reacts with halogenated alkane or diethyl sulfate under the catalysis of an acid-binding agent to obtain a synthetic method for vitamin C ethyl ether. Figure 1 As shown. Although the one-step method for synthesizing bio-C ethyl ether in the patent CN100586941C is simple, during the process of synthesizing bio-C ethyl ether by this method, not only the hydroxyl group at the C3 position is alkylated, but also the hydroxyl groups at other positions are alkylated, resulting in more by-products, making it difficult to separate the product and the yield is low. Subsequently, a large amount of organic solvent needs to be used, and the bio-C ethyl ether with higher purity can be obtained by purification by column chromatography, which makes it difficult to realize industrialization of the one-step method.

[0004] Patents CN101302207B and CN103113333B disclose a three-step synthesis route for preparing ethyl ether of vitamin C: first, the OH groups at positions 5 and 6 are protected, then alkylation is performed under alkaline conditions using DMF or DMSO as a solvent, and finally, the protective groups at positions 5 and 6 of OH are removed under acidic conditions using methanol or ethanol as a solvent to obtain the target product. Figure 2As shown. The advantage of the three-step method for synthesizing ethyl ether of biotin C is that it generates fewer impurities, which reduces the difficulty of product purification, but it still has some defects. For example, the first step of the reaction process in the patent requires the use of a large amount of acetone, which is easy to make drugs, as a reaction reagent and solvent, which increases the difficulty of production compliance; secondly, a large amount of acetyl chloride is used as an acid catalyst, and the hydrogen chloride generated during the reaction is highly corrosive to the production equipment, requiring special enamel reaction equipment, and the mother liquor after the reaction contains a lot of hydrogen chloride, acetic acid and water, which is difficult to remove, making it difficult to recycle and reuse the mother liquor, and some of the intermediates are still in the reaction solvent, and the product yield is low. The use of DMSO or DMF as a reaction solvent in the patent not only makes the post-reaction treatment more complicated, but also requires the use of a large amount of organic solvents for repeated extraction, and the organic phase after extraction needs to be repeatedly washed with water, which is very time-consuming, labor-intensive and occupies a large amount of production equipment; and the crude compound 3 has a large solubility in solvents such as DMSO or DMF, which makes the product yield low after subsequent extraction and crystallization treatment, so that the crude compound 3 yield is only about 50-60%. Finally, the total yield of the final product, vitamin C ethyl ether, is low, only about 30-40%. In addition, the alkylation reaction step in the patent takes a long time, about 16-20 hours; and because solvents such as DMSO or DMF are used, a large amount of mixed waste liquid of DMSO / DMF and water is generated during the post-treatment process, increasing the cost of waste liquid treatment. Summary of the invention

[0005] The object of the present invention is to overcome the deficiencies of the above-mentioned prior art and to provide a method for synthesizing vitamin C ethyl ether which is efficient, environmentally friendly, easy to operate and has a high yield and purity of the prepared vitamin C ethyl ether.

[0006] To achieve the above object, the present invention provides a method for synthesizing vitamin C ethyl ether, which comprises the following steps:

[0007] (1) Synthesis of 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid: Vitamin C, benzaldehyde and a catalyst are added to a first organic solvent to carry out an acetalization reaction, an organic base is added after the acetalization reaction is completed to carry out a neutralization reaction, and then an alkylating agent is added to carry out an alkylation reaction. After the alkylation reaction is completed, the first organic solvent is removed, and a second organic solvent is added to carry out pulping, followed by filtering, collecting the filter residue, washing and drying, to obtain 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid;

[0008] (2) Synthesis of Vitamin C ethyl ether: 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid is subjected to hydrogenation deprotection. After the hydrogenation deprotection is completed, the solution is filtered, the filtrate is collected and crystallized, and the precipitate is collected, washed, and dried to obtain Vitamin C ethyl ether.

[0009] The synthetic method of a vitamin C ethyl ether provided by the present invention is simple to operate, the raw materials are environmentally friendly and the reaction is efficient, and the yield and purity of the obtained vitamin C ethyl ether are high, which has made significant progress compared with the prior art. Specifically, on the one hand, the present invention first selects vitamin C and benzaldehyde as raw materials, and performs acetalization reaction through the action of a catalyst. In the subsequent deprotection reaction, acid hydrolysis can be avoided in the traditional three-step synthesis, and the cumbersome operation of acid hydrolysis treatment, such as concentration and multiple recrystallization, can be avoided, and production efficiency can be significantly improved; and the use of difficult-to-remove solvents such as DMF and DMSO can be avoided, and production efficiency can be improved; At the same time, the use of easily made-drug solvents such as acetone can be avoided, and production safety and environmental protection can be improved. On the other hand, the present invention adds an organic base after the acetalization reaction is completed, and then adds an alkylating agent to the reaction system, and alkylation reaction can be carried out without material post-treatment and transfer processes, which can effectively improve reaction efficiency and save operating costs.

[0010] As a preferred embodiment of the synthesis method of the present invention, the molar ratio of vitamin C, benzaldehyde and catalyst is 1:(1-1.5):(0.01-0.05).

[0011] As a preferred embodiment of the synthesis method of the present invention, the molar ratio of vitamin C to organic base is 1:(1-3).

[0012] As a preferred embodiment of the synthesis method of the present invention, the molar ratio of vitamin C to the alkylating agent is 1:(1-2).

[0013] The present invention has found that when the molar ratio of vitamin C to benzaldehyde, catalyst, organic base and alkylating agent is further selected within the above range, the obtained product yield and purity are better.

[0014] As a preferred embodiment of the synthesis method of the present invention, the catalyst includes at least one of formic acid, acetic acid, sulfuric acid, and benzenesulfonic acid.

[0015] The present invention has been found that, in the present invention, vitamin C and benzaldehyde are used as raw materials, and the above-mentioned type of acid can be selected as a catalyst; on the one hand, the above-mentioned type of acid has an excellent catalytic effect and can effectively introduce a protecting group; on the other hand, the above-mentioned type of acid is not easy to volatilize, and compared with the acyl chloride conventionally used in the prior art, the acyl chloride can avoid corrosion of the reaction equipment.

[0016] As a preferred embodiment of the synthesis method of the present invention, the organic base includes at least one of triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0017] The present invention has found that the selection of the above-mentioned type of organic base can not only effectively neutralize the acid catalyst added in the acetalization reaction, but also promote the dissolution of the product of the acetalization reaction in the first organic solvent, thereby efficiently carrying out the subsequent alkylation reaction.

[0018] As a preferred embodiment of the synthesis method of the present invention, the alkylating agent includes at least one of ethyl benzenesulfonate and ethyl methanesulfonate.

[0019] The present invention has been found that the use of ethyl benzenesulfonate and / or ethyl methanesulfonate as an alkylation reaction reagent after the acetalization reaction can avoid the problems of low boiling point of conventional ethyl bromide, high price of ethyl iodide, low activity of diethyl carbonate and difficulty in removing diethyl sulfate; specifically, the alkylation reagent selected by the present invention can accurately control the dosage, and at the same time, can effectively reduce the byproduct of the hydroxyl group at the C4 position being replaced by the ethyl group, and can be simply removed by beating after the reaction is completed; that is, the alkylation reagent selected by the present invention is safe, environmentally friendly, easy to operate, easy to remove, and can also improve the yield of the product.

[0020] As a preferred embodiment of the synthesis method of the present invention, the first organic solvent includes at least one of 1,4-dioxane, 2-methyltetrahydrofuran and 2,5-dimethyltetrahydrofuran.

[0021] By selecting benzaldehyde as the reaction raw material, the present invention can avoid the use of conventional acyl chlorides, and can also avoid the use of acetone, a solvent that is easy to make drugs, and DMF and DMSO, solvents that are difficult to post-process. By selecting the above-mentioned types of organic solvents, the yield can be improved and the operation difficulty can be reduced.

[0022] Preferably, after the alkylation reaction is completed, the first organic solvent is removed by vacuum concentration, and the vacuum concentration temperature is 50-60°C.

[0023] The first organic solvent removed by concentrated distillation under reduced pressure can be recovered and reused repeatedly.

[0024] As a preferred embodiment of the synthesis method of the present invention, the second organic solvent includes at least one of methyl tert-butyl ether, isopropyl ether and petroleum ether.

[0025] Preferably, the mass ratio of the second organic solvent to vitamin C is (4-6):1.

[0026] The present invention has been found that by selecting the alkylating agent of the present invention for reaction and then adding the above-mentioned second organic solvent for pulping after the alkylation reaction, purification can be carried out efficiently, and the obtained product has a high yield and purity.

[0027] As a preferred embodiment of the synthesis method of the present invention, the temperature of the acetalization reaction is 25-30° C. and the time is 4-6 hours.

[0028] As a preferred embodiment of the synthesis method of the present invention, the temperature of the alkylation reaction is 45-55° C. and the time is 8-10 h.

[0029] The present invention has been found that within the reaction temperature and reaction time range provided by the present invention, vitamin C ethyl ether can be efficiently synthesized with excellent yield and purity.

[0030] As a preferred embodiment of the synthesis method of the present invention, the hydrogenation deprotection process is: 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid is added to a third organic solvent to dissolve, and then palladium carbon is added to react at 25-30° C. for 1-3 hours.

[0031] In the early stage of the present invention, benzaldehyde is used as a raw material for hydroxyl protection, so the use of traditional acid hydrolysis can be effectively avoided in the deprotection process, and the palladium-carbon hydrogenolysis of the present invention can quickly remove the protecting group, which has the advantages of fast reaction rate, low reaction temperature and simple reaction operation, and significantly improves the production efficiency; and, by adopting the palladium-carbon hydrogenolysis of the present invention, the subsequent product can be directly precipitated without further separation and purification.

[0032] As a preferred embodiment of the synthesis method of the present invention, the mass ratio of palladium carbon to vitamin C is (0.01-0.05):1.

[0033] As a preferred embodiment of the synthesis method of the present invention, the third organic solvent includes ethyl acetate.

[0034] As a preferred embodiment of the synthesis method of the present invention, the crystallization is stirring crystallization, the crystallization temperature is (-5) ± 5°C, and the crystallization time is 2-4h.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] The synthesis method of vitamin C ethyl ether provided by the present invention has the advantages of simple process, green environmental protection, short reaction time and low production cost; which is specifically embodied in the following aspects:

[0037] First, the synthesis method uses benzaldehyde as a condensation agent, and in the subsequent deprotection reaction, the conventional acid hydrolysis of similar protective agents can be avoided, and only a hydrogenation reaction with the characteristics of fast reaction rate, low reaction temperature and high purity of the reaction product is required for removal, while avoiding the cumbersome operation, concentration and recrystallization after acid hydrolysis, thereby greatly improving the simplicity and efficiency of the operation; and after the acetal reaction is completed, no further separation and purification is required, and the subsequent alkylation reaction can be directly carried out; at the same time, it has been verified that the yield of the acetal reaction of the present invention is 100%;

[0038] In a second aspect, the alkylating agent of the present invention preferably includes ethyl benzenesulfonate and / or ethyl methanesulfonate, and the amount of the alkylating agent used can be accurately controlled in the reaction, thereby avoiding the problems of low boiling point of ethyl bromide, high price of ethyl iodide, low activity of diethyl carbonate, and difficulty in removing diethyl sulfate, and can effectively reduce the byproduct of the hydroxyl group at the C4 position being replaced by an ethyl group; and after the reaction, the byproduct can be removed by simple pulping and purification; the yield of the obtained 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid can be as high as 90.7%;

[0039] Thirdly, the hydrogenation reaction is selected in the deprotection reaction, which has the characteristics of fast reaction rate, low reaction temperature and high purity of the reaction product. The use of hydrogenation reaction instead of acid hydrolysis can greatly improve the reaction rate, reduce the formation of impurities and avoid tedious post-processing operations (such as concentration, especially the need for concentrated water); in addition, after the hydrogenation reaction, it is only necessary to filter and directly crystallize the reaction filtrate to obtain the final product, vitamin C ethyl ether; the final vitamin C ethyl ether has a yield of up to 87.52%, a purity of up to 99.7%, and its aqueous solution (mass percentage is 3%) has a conductivity as low as 16.54 μS / cm. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 A one-step synthesis route of vitamin C ethyl ether in the prior art;

[0041] Figure 2 The three-step synthesis route of vitamin C ethyl ether in the prior art is shown in FIG.

[0042] Figure 3 The synthetic route of vitamin C ethyl ether of the present invention is ascorbic acid;

[0043] Figure 4 This is the H NMR spectrum of the vitamin C ethyl ether synthesized in Example 1 of the present invention;

[0044] Figure 5 This is a high performance liquid chromatogram of the vitamin C ethyl ether synthesized in Example 1 of the present invention;

[0045] Figure 6This is a high performance liquid chromatogram of the vitamin C ethyl ether synthesized in Example 2 of the present invention. DETAILED DESCRIPTION

[0046] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0047] Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0048] Example 1

[0049] The embodiment of the present invention provides a method for synthesizing vitamin C ethyl ether, wherein the synthetic route is as follows: Figure 3 Described, the synthesis method comprises the following steps:

[0050] (1) Vitamin C (10 kg, 56.78 mol, 1 eq., compound 0), 6.03 kg of benzaldehyde (6.03 kg, 56.78 mol, 1 eq.), formic acid (0.078 kg, 1.70 mol, 0.03 eq.) and 1,4-dioxane (50 kg) were added into a 100 L reactor and stirred at 26±1°C for 4 h; (the reaction yielded Figure 3 Compound 1 in the reaction mixture may be directly subjected to the next step of alkylation reaction without separation);

[0051] (2) After the stirring reaction in step (1) was completed, triethylamine (7.47 kg, 73.81 mol, 1.30 eq.) was added for neutralization reaction. After the reaction solution was clarified, ethyl benzenesulfonate (10.57 kg, 56.78 mol, 1 eq.) was added, and the mixture was kept at 50° C. for 8 h.

[0052] (3) After the heat preservation reaction in step (2) is completed, the reaction system solvent 1,4-dioxane is removed by reduced pressure distillation at 55°C; then methyl tert-butyl ether (26 kg) is added to the concentrate and mixed evenly, stirred and slurried at 26±1°C for 1 hour, then filtered, and the solid filter cake is rinsed with methyl tert-butyl ether (3.7 kg), drained, and finally dried in a vacuum drying oven at 50°C for 24 hours; 12.56 kg of 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid (compound 2, calculated based on the raw material vitamin C, the yield of 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid is 90.7%) is obtained;

[0053] (4) dissolving the solid product of 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid (12.56 kg) in ethyl acetate (41.6 kg), adding palladium carbon (373 g), and reacting at 25° C. in a hydrogen atmosphere for 3 hours; filtering and washing after the reaction, and collecting the filtrate;

[0054] (5) The filtrate of step (4) was slowly cooled to 0±5°C, kept warm at 0±5°C and slowly stirred for crystallization for 2h. After the crystallization was completed, it was filtered and the filter cake was rinsed with ethyl acetate (4.8kg) at a temperature of 0±5°C. The filter cake was then placed in a vacuum drying oven at 50°C and dried for 8h to obtain 9.49kg of vitamin C ethyl ether (compound 3, calculated as 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid, the yield was 96.5%; calculated as vitamin C, the total yield was 87.52%).

[0055] Example 2

[0056] The embodiment of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthesis method and embodiment 1 is that the alkylating agent added in step (2) is different. In the embodiment, step (2) is as follows: after the stirring reaction in step (1) is completed, triethylamine (7.47 kg, 73.81 mol, 1.30 eq.) is added for neutralization reaction, and after the reaction liquid is clarified, ethyl methanesulfonate (7.05 kg, 56.78 mol, 1.0 eq.) is added, and the reaction is kept at 50° C. for 8 hours.

[0057] Example 3

[0058] The embodiment of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthesis method and embodiment 1 is that the organic base added in step (2) is different. In this embodiment, step (2) is: after the stirring reaction in step (1) is completed, diisopropylethylamine (9.54 kg, 73.81 mol, 1.30 eq.) is added for neutralization reaction.

[0059] Example 4

[0060] The embodiment of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthesis method and embodiment 1 is that the organic base added in step (2) is different. In this embodiment, step (2) is as follows: after the stirring reaction in step (1) is completed, DBU (11.24 kg, 73.81 mol, 1.30 eq.) is added for neutralization reaction.

[0061] Example 5

[0062] The embodiment of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthesis method and embodiment 1 is that the molar ratio of vitamin C to benzaldehyde in step (1) is 1:1.5.

[0063] Example 6

[0064] The embodiment of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthesis method and embodiment 1 is that in step (1), the molar ratio of vitamin C to the catalyst is 1:0.05.

[0065] Example 7

[0066] The embodiment of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthesis method and embodiment 1 is that the molar ratio of the organic base to vitamin C in step (1) is 3:1.

[0067] Example 8

[0068] The embodiment of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthesis method and embodiment 1 is that in step (1), the molar ratio of vitamin C to ethyl benzenesulfonate is 1:2.

[0069] Comparative Example 1

[0070] The comparative example of the present invention provides a method for synthesizing vitamin C ethyl ether, which is a one-step method and comprises the following steps:

[0071] (1) 1.76 g of vitamin C, 15 mL of methanol and 1.2 g of triethylamine were mixed and stirred until completely dissolved, and then 1.3 g of ethyl benzenesulfonate was added and refluxed for 2 hours to synthesize 3-O-alkyl ascorbic acid ether; after the reflux reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in 4 mL of water to obtain an aqueous solution of the reaction product, which was set aside.

[0072] (2) Prepare a glass column with 50mL of anion resin 717, and pretreat the resin: wash with 200mL of 1N sodium hydroxide, 200mL of distilled water, 200mL of 1N hydrochloric acid or sulfuric acid, 200mL of distilled water, and 200mL of 1N sodium hydroxide for regeneration and finally wash with distilled water until neutral. Load the aqueous solution of the reaction product of step (1) onto the column, and wash the column with water until the pH of the effluent is ≤8. Use 1% acetic acid aqueous solution to wash the column, collect the effluent, and detect it by thin layer chromatography or liquid chromatography. Detect once every 10mL collected, combine the effluent containing the product, and stop eluting when there is no product 3-O-methyl ascorbic acid in the effluent. Concentrate the effluent containing the product under reduced pressure to dryness, crystallize it with ethyl acetate, and obtain 0.90g of product 3-O-methyl ascorbic acid. Detect it by liquid chromatography, and compare it with the standard sample. The purity is 92% and the yield is 47%.

[0073] Comparative Example 2

[0074] The comparative example of the present invention provides a method for synthesizing vitamin C ethyl ether, which is a three-step method, selecting a traditional protective agent acetone, acid hydrolysis, and comprising the following steps:

[0075] (1) Add 18 g (0.102 mol) of vitamin C and 89.1 g (1.53 mol) of acetone to a 250 mL three-necked flask, start heating in a water bath with stirring, raise the temperature to 30° C., and use a constant pressure dropping funnel to start dropping 9.6 g (0.122 mol) of acetyl chloride. The dropping speed should not be too fast, so that the system temperature is maintained at about 30° C. After the dropping is completed, keep the temperature for 8 hours, and use HPLC to detect the end point. During the reaction, the system gradually becomes viscous and the color turns to orange. After the reaction is completed, filter and rinse the filter cake with clean ice acetone until it becomes a white solid. Dry to obtain 17.8 g of 5,6-O-isopropyl-L-ascorbic acid, with a yield of 80.5% and a purity of 98.8%;

[0076] (2) 18 g (0.083 mol) of 5,6-O-isopropyl-L-ascorbic acid, 50 mL of DMF, and 13.9 g (0.165 mol) of sodium bicarbonate were added to a 250 mL three-necked flask, and the temperature was raised and stirred. The temperature was raised to 60° C. in a water bath, and 10.9 g (0.1 mol) of ethyl bromide was added dropwise using a constant pressure dropping funnel. The temperature was kept for 20 h, and the reaction end point was detected by HPLC. After the reaction was completed, an equal volume of water was added, and ethyl acetate was added for extraction three times. The organic phases were combined, washed with water twice, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The concentrate was crystallized with ethyl acetate and n-hexane (the volume ratio of ethyl acetate to n-hexane was 1:2). A white solid precipitated, and the product was filtered to obtain 10.8 g, with a yield of 53.2% and a purity of 97.2%.

[0077] (3) In a 250 mL three-necked flask, 12 g (0.049 mol) of 5,6-O-isopropyl-3-O-ethyl-L-ascorbic acid and 50 mL of methanol were added, and 20 mL of 2 M dilute hydrochloric acid solution was added. The temperature was raised to 60° C. in a water bath and the mixture was kept warm for 2 h. After the reaction, the methanol was removed under reduced pressure, and ethyl acetate was added for extraction three times. The mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue, which was frozen in a refrigerator. A white solid precipitated and was filtered to obtain 7.64 g of vitamin C ethyl ether with a yield of 76.4%, a purity of 99.0%, and a melting point of 114-116° C. The total yield of the three-step reaction was 32.7%.

[0078] Comparative Example 3

[0079] The comparative example of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthetic method and Example 1 is that the alkylating agent added in step (2) is different. In this comparative example, step (2) is as follows: after the stirring reaction in step (1) is completed, triethylamine (7.47 kg, 73.81 mol, 1.30 eq.) is added for neutralization reaction, and after the reaction liquid is clarified, ethyl bromide (6.19 kg, 56.78 mol, 1.0 eq.) is added, and the reaction is kept at 50° C. for 8 hours.

[0080] Comparative Example 4

[0081] The comparative example of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthetic method and Example 1 is that the alkylating agent added in step (2) is different. In this comparative example, step (2) is as follows: after the stirring reaction in step (1) is completed, triethylamine (7.47 kg, 73.81 mol, 1.30 eq.) is added for neutralization reaction, and after the reaction liquid is clarified, iodoethane (8.86 kg, 56.78 mol, 1.0 eq.) is added, and the reaction is kept at 50° C. for 8 hours.

[0082] Comparative Example 5

[0083] The comparative example of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthetic method and Example 1 is that the alkylating agent added in step (2) is different. In this comparative example, step (2) is as follows: after the stirring reaction in step (1) is completed, triethylamine (7.47 kg, 73.81 mol, 1.30 eq.) is added for neutralization reaction, and after the reaction liquid is clarified, diethyl carbonate (6.71 kg, 56.78 mol, 1.0 eq.) is added, and the reaction is kept at 50° C. for 8 hours.

[0084] Comparative Example 6

[0085] The comparative example of the present invention provides a method for synthesizing vitamin C ethyl ether. The only difference between the synthetic method and Example 1 is that the alkylating agent added in step (2) is different. In this comparative example, step (2) is as follows: after the stirring reaction in step (1) is completed, triethylamine (7.47 kg, 73.81 mol, 1.30 eq.) is added for neutralization reaction, and after the reaction liquid is clarified, diethyl sulfate (8.74 kg, 56.78 mol, 1.0 eq.) is added, and the reaction is kept at 50° C. for 8 hours.

[0086] Effect example

[0087] The effect examples of the present invention record the purity, yield, melting point and residual amount of alkylating agent of vitamin C ethyl ether obtained by different synthesis methods in Examples 1-8 and Comparative Examples 1-6, as well as the conductivity and pH value of the aqueous solution (mass fraction of 3%) of the above vitamin C ethyl ether.

[0088] 1. The purity is obtained by high performance liquid chromatography analysis. The analysis method of high performance liquid chromatography is:

[0089] Methanol and 0.1% trifluoroacetic acid aqueous solution (chromatographic column: YMC-Triart C 18 column (250 mm × 4.6 mm, 5.0 μm);

[0090] Mobile phase: A is trifluoroacetic acid aqueous solution (volume ratio of trifluoroacetic acid: water = 0.1:99.9), B is methanol, flow rate is 1.0 mL / min;

[0091] Gradient elution program: 0-5 min, 98% A; 5-10 min, 98% A-10% A; 10-12 min, 10% A; 12-18 min, 10% A-98% A;

[0092] Column temperature: 40°C;

[0093] Detection wavelength: 250nm;

[0094] Injection volume: 10 μL.

[0095] 2. The method for determining conductivity in the present invention refers to GB / T 6908-2018. Specifically, 3 parts of the samples of Examples 1-8 and Comparative Examples 1-6 were dissolved in 97 parts of water (using the secondary water specified in GB / T 6682), and stirred for 10 minutes until completely dissolved. The conductivity meter was calibrated according to the operating procedures of the conductivity meter (manufacturer: Shanghai Leici; model: DDS-308F). After the instrument was calibrated, the electrode was first rinsed with water and then dried with lens paper. Carefully insert the electrode into the above-mentioned aqueous solutions of the samples of Examples 1-8 and Comparative Examples 1-6 to immerse the electrode, and wait for the conductivity meter readings to stabilize and record the readings. Each group of samples was tested in parallel 3 times, and the average reading value was taken as the result.

[0096] 3. The melting point test of the present invention adopts a melting point apparatus (manufacturer: Shanghai Instrument and Electronics; model: WRS-1C) to measure the melting points of Examples 1-8 and Comparative Examples 1-6. Specifically, before the test, the samples of Examples 1-8 and Comparative Examples 1-6 are placed in a 50°C blast oven for drying for 24 hours (the samples are stable and do not decompose at this temperature), and then 0.2g of the sample is put into a dry melting point tube (outer diameter 1.4mm; inner diameter 1.0mm), which is placed upright on a glass plate, and the melting point tube containing the sample is dropped into it several times until the sample in the melting point tube is shrunk to about 3mm high. Finally, the melting point tube is placed in a melting point apparatus for melting point determination. Among them, the initial temperature of heating is 50°C, and the heating rate is stably maintained at 1.0±0.1°C / min.

[0097] 4. The residual amount of the alkylating agent in the present invention is obtained by analysis using high performance liquid chromatography or gas chromatography, wherein:

[0098] The residual amount of ethyl benzenesulfonate was determined by high performance liquid chromatography. The high performance liquid chromatography analysis method is as follows: chromatographic column: SHIZUMADU VP-ODS, 150mm×4.6mm, 5μm; mobile phase: 1% triethylamine solution (phosphoric acid adjusted to pH 3.0): acetonitrile = 65:35; flow rate is 1.0mL / min; detection wavelength: 220nm; column temperature is 25℃; injection volume is 20μL. (Reference: Research on the Detection Methodology of Ethyl Benzenesulfonate in Amlodipine Besylate, Chinese Modern Pharmaceutical Impurities, 2015, 17(1): 56-59);

[0099] The residual amount of ethyl methanesulfonate was determined by liquid chromatography-mass spectrometry. The high performance liquid chromatography analysis method is as follows: chromatographic column: Angilent PLUS-C18 (3.5μm, 4.6×100mm); mobile phase: 10mM ammonium acetate solution-acetonitrile (60:40); flow rate is 0.4mL / min; column temperature is 30℃; injection volume: 50μL. Mass spectrometry conditions: ESI voltage +5500V; vaporization auxiliary temperature is 400℃; declustering voltage (DP) is 10V; focusing voltage (FP) is 50V; entrance voltage (EP) is 3V; working mode: Q1 MS. (Reference: Study on the determination of ethyl methanesulfonate and isopropyl methanesulfonate in drugs by liquid chromatography-mass spectrometry (LC-MS), Pharmaceutical Preparations, 2015: 78);

[0100] The residual amount of ethyl bromide was determined by gas chromatography. The gas chromatography analysis method is: chromatographic column: HP-FFAP (30m×320μm×0.25μm); column temperature is 60℃; vaporization chamber temperature is 180℃; detection temperature is 180℃; carrier gas type: nitrogen (≥99.99%); hydrogen flow rate: 40mL / min; air flow rate: 450mL / min; tail nitrogen flow rate: 25mL / min; flow rate 1.0mL / min; injection volume is 1mL. (Reference: Research on the determination of ethyl bromide by gas chromatography, China New Technologies and New Products, 2013, NO.12:1);

[0101] The determination method of iodoethane residue is determined by referring to the method in 0712 of Part IV of the Pharmacopoeia of the People's Republic of China (2020 edition). The gas chromatography analysis method is: 25% phenyl-75% methyl polysiloxane is used as the stationary liquid, and the filling column is coated with a concentration of 20%; the column starting temperature is 100°C, maintained for 8 minutes, and then heated to 230°C at a rate of 50°C / min, and maintained for 2 minutes; the injection port temperature is 200°C; the detection chamber temperature is 250°C; carrier gas: helium, constant flow mode, flow rate 1.0mL / min; injection volume: 1.0μL;

[0102] The residual amount of diethyl carbonate was determined by gas chromatography. The gas chromatography analysis method is as follows: chromatographic column: filled with 5% PEG-10000 / 301 glazed carrier (80-100 mesh), 2m×3μm×0.5μm stainless steel column; column temperature: 65℃; vaporization chamber temperature 200℃; detection chamber temperature 200℃; carrier: nitrogen, flow rate 7.1mL / min; hydrogen flow: 25mL / min; auxiliary gas (O2) flow: 100mL / min; injection volume: 0.2μL. (Reference: Determination of diethyl carbonate content by gas chromatography, Journal of Zhejiang Institute of Technology, 1993, 1: 85-91);

[0103] The determination method of ethyl bromide refers to HG / T 2506-2006. The gas chromatography analysis method is as follows: chromatographic column: polyethylene glycol-silanized white diatomaceous earth (2m×4mm, particle size 0.18mm~0.25mm); injection port 70℃; carrier gas: helium, flow rate 30~40mL / min; vaporization chamber temperature: 100℃; detector temperature: 100℃, injection volume: 0.4~2.0;

[0104] The determination method of diethyl sulfate refers to GB / T 35771-2017. The gas chromatography analysis method is as follows: chromatographic column: 35% phenyl-methyl polysiloxane quartz capillary column (30m×250μm×0.25μm); injection port temperature: 250℃; carrier gas: helium, constant flow mode, flow rate 1.0mL / min; heating program: initial temperature 50℃ for 2min, increase to 130℃ at 10℃ / min, then increase to 280℃ at 25℃ / min, and maintain for 2min; split ratio: 10:1; injection volume: 1.0μL.

[0105] 5. The pH value determination method in the present invention refers to GB / T 13531.1-2008. Specifically, 3 parts of the samples of Examples 1-8 and Comparative Examples 1-6 are dissolved in 97 parts of water (using the third-grade water in GB / T 6682, wherein the conductivity is less than 5μS / cm, and it needs to be boiled and then cooled before use), and stirred for 10 minutes until completely dissolved. The pH meter is calibrated according to the operating procedures of the FE28 pH meter. After the instrument is calibrated, the electrode is cleaned with water and then dried with a test paper. The electrode is carefully inserted into the above-mentioned aqueous solution of the samples of Examples 1-8 and Comparative Examples 1-6, so that the electrode is immersed, and the pH meter reading is recorded when it is stable. Each group of samples is tested in parallel 3 times, with an error range of ±0.1, and the average reading value is taken as the result.

[0106] The obtained results are shown in Table 1;

[0107] Table 1

[0108]

[0109]

[0110] Comparative Example 1, Example 2, Comparative Examples 3-6 show that the alkylating agents used in Example 1, Example 2, and Comparative Examples 3-6 are ethyl benzenesulfonate, ethyl methanesulfonate, ethyl bromide, ethyl iodide, diethyl carbonate, and diethyl sulfate, respectively. Compared to ethyl methanesulfonate (Example 2), ethyl bromide (Comparative Example 3), ethyl iodide (Comparative Example 4), diethyl carbonate (Comparative Example 5), and diethyl sulfate (Comparative Example 6), ethyl benzenesulfonate is selected as the alkylating agent, and the yield and purity of the final synthesized vitamin C ethyl ether are both higher. In addition, the alkylating agent residues in Example 1 and Comparative Examples 3-6 are respectively undetected, 45 mg / g, 52 mg / g, 69 mg / g, and 88 mg / g, indicating that the vitamin C ethyl ether synthesized by the method in Example 1 has no alkylating agent residue, and the product is greener and safer.

[0111] Comparing Example 1 and Examples 3-8, it can be seen that the yield and purity of the vitamin C ethyl ether product synthesized are different depending on the type of organic base and the raw material feed ratio. The yield and purity of the vitamin C ethyl ether synthesized by the method in Example 1 are the highest, indicating that the synthesis method in Example 1 is the best.

[0112] By comparing Example 1 and Comparative Example 1, it can be seen that compared with the one-step reaction (Comparative Example 1), the method in Example 1 of the present invention is used to synthesize vitamin C ethyl ether, and the yield and purity of the final product are higher, and the conductivity of its aqueous solution (3%) is lower, that is, the quality of the product synthesized by the method of Example 1 is better.

[0113] By comparing Examples 1-8 and Comparative Examples 1-2, it can be seen that the pH of Example 1-8 is higher than 4.0; while the pH of Comparative Example 1-2 is lower than 3.5, which is medium-strong acidity and more irritating to the skin. The low pH of Comparative Examples 1-2 is mainly because compound 3 is obtained by hydrolyzing compound 2 with a traditional acid during the synthesis process, and there is acid residue in the reaction product. In the embodiment of the present invention, hydrogenation reaction is used instead of acid hydrolysis, and the yield and purity of the final product are higher, there is no acid residue, and the conductivity of its aqueous solution (3%) is lower, that is, the quality of the product synthesized by the method of Example 1 is better.

[0114] In summary, the vitamin C ethyl ether obtained by the technical solution provided by the present invention, especially the synthesis method in Example 1, has the advantages of high yield, high purity, greenness, safety, and simple process.

[0115] Furthermore, the vitamin C ethyl ether synthesized in Example 1 was subjected to hydrogen spectrum detection, and the hydrogen spectrum obtained was as follows: Figure 4 As shown, the data is: 1H NMR (400 MHz, DMSO-d6): δ 1.24 (m, 3H, J = 7.0 Hz), 3.43-3.35 (m, 2H), 3.60 (d, 1H, J = 6.4 Hz), 4.38 (dddd, 2H, J = 17.3, 10.3, 7.0, 3.2 Hz), 4.70 (d, 1H, J = 1.2 Hz). The obtained HPLC chromatogram is shown in FIG. Figure 5 As shown; The HPLC chromatogram of the vitamin C ethyl ether synthesized in Example 2 is as shown Figure 6 shown.

[0116] Finally, it should be noted that the above embodiments are intended to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention may be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing vitamin C ethyl ether, characterized in that: The synthesis method comprises the following steps: (1) Synthesis of 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid: Vitamin C, benzaldehyde and a catalyst are added to a first organic solvent to carry out an acetalization reaction, an organic base is added after the acetalization reaction is completed to carry out a neutralization reaction, and then an alkylating agent is added to carry out an alkylation reaction. After the alkylation reaction is completed, the first organic solvent is removed, and a second organic solvent is added to carry out pulping, followed by filtering, collecting the filter residue, washing and drying, to obtain 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid; (2) Synthesis of Vitamin C ethyl ether: 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid is subjected to hydrogenation deprotection. After the hydrogenation deprotection is completed, the solution is filtered, the filtrate is collected and crystallized, and the precipitate is collected, washed, and dried to obtain Vitamin C ethyl ether.

2. The synthesis method according to claim 1, characterized in that The molar ratio of vitamin C, benzaldehyde and catalyst is 1:(1-1.5):(0.01-0.05); And / or, the molar ratio of vitamin C to the organic base is 1:(1-3); And / or, the molar ratio of vitamin C to the alkylating agent is 1:(1-2).

3. The synthesis method according to claim 1, characterized in that The catalyst comprises at least one of formic acid, acetic acid, sulfuric acid and benzenesulfonic acid; and / or, the organic base comprises at least one of triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene; And / or, the alkylating agent comprises at least one of ethyl benzenesulfonate and ethyl methanesulfonate.

4. The synthesis method according to claim 1, characterized in that The first organic solvent includes at least one of 1,4-dioxane, 2-methyltetrahydrofuran, and 2,5-dimethyltetrahydrofuran; And / or, the second organic solvent includes at least one of methyl tert-butyl ether, isopropyl ether and petroleum ether.

5. The synthesis method according to claim 1, characterized in that The acetalization reaction is carried out at a temperature of 25-30° C. and for a time of 4-6 hours.

6. The synthesis method according to claim 1, characterized in that The alkylation reaction is carried out at a temperature of 45-55° C. and for a time of 8-10 h.

7. The synthesis method according to claim 1, characterized in that The hydrogenation deprotection process is as follows: 5,6-O-benzyl-3-O-ethyl-L-ascorbic acid is added to a third organic solvent to dissolve, palladium carbon is added, and the mixture is reacted in a hydrogen environment at 25-30° C. for 1-3 hours.

8. The synthesis method according to claim 7, characterized in that The mass ratio of palladium carbon to vitamin C is (0.01-0.05):1; And / or, the third organic solvent comprises ethyl acetate.

9. The synthesis method according to claim 1, characterized in that The crystallization is stirred crystallization, the crystallization temperature is (-5) ± 5°C, and the crystallization time is 2-4h.

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