CN113214197B - Preparation method of vitamin C ethyl ether - Google Patents
Preparation method of vitamin C ethyl ether Download PDFInfo
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- CN113214197B CN113214197B CN202110371910.0A CN202110371910A CN113214197B CN 113214197 B CN113214197 B CN 113214197B CN 202110371910 A CN202110371910 A CN 202110371910A CN 113214197 B CN113214197 B CN 113214197B
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- ascorbic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/62—Three oxygen atoms, e.g. ascorbic acid
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a vitamin C derivative, in particular to a preparation method of vitamin C ethyl ether. The method takes vitamin C as a starting material, firstly reacts with cyclopentanone to generate ketal, then reacts with ethanol and thionyl chloride to generate ether, and finally hydrolyzes the ketal through hydrochloric acid to prepare the vitamin C ethyl ether. The method has the advantages of easily available raw materials, simple operation, environmental protection and low cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of vitamin C ethyl ether, belonging to the field of synthesis of cosmetic raw materials.
Background
Vitamin C is one of the strongest antioxidants in nature and can capture free radicals, protect cell tissues and resist damage caused by free radicals and reactive oxygen species. Vitamin C has limited applications due to its low lipophilicity, heat sensitivity, and autooxidative degradation. Therefore, many vitamin C derivatives that improve their properties have come into existence, such as magnesium ascorbyl phosphate, ascorbyl palmitate, etc., which have been widely used. The vitamin C ethyl ether is a new oleophilic hydrophilic amphoteric vitamin C derivative, can be used very conveniently in a formula, easily penetrates through the horny layer of the skin to enter the corium layer, and is easily decomposed by biological enzyme to exert the biological effect of the vitamin C after entering the skin, so that the bioavailability is improved, and the vitamin C ethyl ether can be used as an anti-aging agent and a whitening agent in cosmetics. The chemical structural formula is as follows:
at present, the synthesis method of vitamin C ethyl ether is divided into a one-step method and a three-step method. The one-step synthesis method is that vitamin C directly reacts with halogenated alkane or diethyl sulfate under the catalysis of an acid binding agent to prepare vitamin C ethyl ether. The three-step synthesis method is that vitamin C and acetone generate 5, 6-O-isopropylidene-ascorbic acid under the catalysis of acid, then the vitamin C and halogenated alkane or diethyl sulfate react to form ether, and finally ketal is hydrolyzed under the catalysis of acid to generate vitamin C ethyl ether.
The one-step method not only can alkylate the 3-position hydroxyl, but also can alkylate the 5-position hydroxyl and the 6-position hydroxyl, and has the disadvantages of more generated impurities, difficult separation and low yield. The three-step method can protect 5, 6-position hydroxyl from alkylation, and the reaction generates less impurities; however, the solvent of the alkylation reaction is DMSO or DMF, the product is highly dissolved in the solvent, the product yield is low, the post-treatment is difficult, and the toxicity and the pollution are large when the halogenated alkane or diethyl sulfate is used as the alkylation reagent.
Disclosure of Invention
The invention mainly aims at the defects of the prior art and provides a synthesis method of vitamin C ethyl ether suitable for industrial production. The method uses vitamin C as a raw material, the vitamin C reacts with cyclopentanone to form ketal under the catalysis of acetyl chloride, then the ketal is formed with ethanol and thionyl chloride under the catalysis of triethylamine, and finally the ketal is hydrolyzed under the catalysis of dilute hydrochloric acid to prepare the vitamin C ethyl ether. The preparation process is more suitable for industrial production, is more environment-friendly, and has simple post-treatment, high total yield and high purity.
A preparation method of vitamin C ethyl ether comprises the following steps:
step 1: using vitamin C as an initial raw material, using cyclopentanone as a reactant and a solvent, reacting for 4 hours at 20-30 ℃ under the catalysis of acetyl chloride, and filtering to obtain the 5, 6-O-cyclopentyl-ascorbic acid.
Step 2: dropwise adding thionyl chloride into ethanol, reacting for 1h at 0-5 ℃, adding 5, 6-O-cyclopentyl-ascorbic acid and triethylamine, refluxing and reacting for 12h, evaporating to dryness under reduced pressure, adding ethyl acetate and water, stirring, separating liquid, evaporating to remove ethyl acetate to obtain 1/4, crystallizing at 0-5 ℃ for 2h, and filtering to obtain 3-O-ethyl-5, 6-O-cyclopentyl-ascorbic acid ether.
And step 3: reacting 3-O-ethyl-5, 6-O-cyclopentyl-ascorbic acid ether with dilute hydrochloric acid at 50 ℃ for 2h, decompressing and evaporating to dryness, and recrystallizing the obtained product with ethanol to obtain the vitamin C ethyl ether.
The specific synthetic reaction route is as follows:
specifically, the mass ratio of cyclopentanone to vitamin C in step 1 is 5:1 to 10:1, preferably 7: 1; the molar ratio of acetyl chloride to vitamin C is from 0.5:1 to 1.5:1, with 1:1 being preferred.
The mass ratio of the ethanol to the intermediate 1 in the step 2 is 3:1 to 10:1, wherein 5:1 is preferred; the molar ratio of thionyl chloride to intermediate 1 is from 1.2:1 to 2:1, with 1.5:1 being preferred; the molar ratio of triethylamine to intermediate 1 is 1.2:1 to 2:1, with 1.5:1 being preferred; the mass ratio of ethyl acetate to intermediate 1 is 4:1 to 10:1, with 8:1 being preferred; the molar ratio of water to intermediate 1 is from 3:1 to 10:1, with 5:1 being preferred.
The molar concentration of the dilute hydrochloric acid in the step 3 is 3mol/L, and the weight ratio of the dilute hydrochloric acid to the intermediate 2 is 5:1 to 10:1, wherein the preferred weight ratio is 8: 1; the weight ratio of ethanol to intermediate 2 is 3:1 to 8:1, with 5:1 being preferred.
Compared with the method reported in the literature, the process has the following advantages:
1. cyclopentanone is used as a ketal reaction reagent, so that the generated ketal has reduced solubility in a solvent and improved product yield; and the solvent recovery rate is high, and the solvent can be recycled.
2. In the step 2, halogenated alkane and diethyl sulfate with high toxicity are avoided, and the product yield and purity are high.
3. The solvent used in the process can be recycled, and the process has no harsh reaction conditions, is suitable for industrial production, and conforms to the green synthesis concept.
Detailed Description
Example 1:
synthesis of intermediate 1
Adding vitamin C (25kg, 142mol) and cyclopentanone (175kg) into a 500L reaction kettle, stirring at room temperature, slowly dropwise adding acetyl chloride (11.1kg, 142mol), and reacting at 25 ℃ for 4h after dropwise adding; and (5) performing suction filtration, and leaching a filter cake by cyclopentanone to obtain 31.6kg of white solid, wherein the yield is 92% and the purity is 98.34%.
Example 2
Synthesis of intermediate 2
Adding ethanol (150kg) into a 500L reaction kettle, cooling and stirring to 0-5 ℃, dropwise adding thionyl chloride (22.1kg, 186mol), stirring at 0-5 ℃ for 1h, adding the intermediate 1(30kg, 124mol) into a reaction bottle, dropwise adding triethylamine (18.8kg, 186mol) at 0-5 ℃, heating and stirring to reflux after dropwise adding, carrying out reflux reaction for 12h, and carrying out reduced pressure evaporation to remove the solvent until the solvent is dried to obtain the white-like solid. Adding ethyl acetate (240kg) and water (150kg) into the obtained solid, stirring for 0.5h at room temperature, separating, evaporating an organic phase to remove about 170kg of the solvent, cooling to 0-5 ℃, stirring for crystallization for 2h, performing suction filtration, leaching a filter cake with a small amount of ethyl acetate to obtain 28.9kg of off-white solid, wherein the yield is 86.3%, and the purity is 98.84%.
Example 3
Synthesis of vitamin C ethyl ether
Sequentially adding the intermediate 2(27kg, 100mol) and 3mol/L hydrochloric acid (216kg) into a 500L reaction kettle three-necked bottle, heating and stirring to 50-60 ℃, carrying out heat preservation reaction for 2 hours, and evaporating the solvent under reduced pressure until the solvent is dried to obtain a yellow oily substance; adding ethanol (135kg), heating and stirring until the oily matter is dissolved, adding active carbon (1.35kg), refluxing for 0.5h, carrying out hot filtration, cooling the filtrate to-5-0 ℃, stirring and crystallizing for 2h, carrying out suction filtration, and leaching the filter cake with cold ethanol to obtain 16.3kg of white solid, wherein the yield is 80.1%, and the purity is 99.15%. ESI-MS (C) 8 H 12 O 6 M/z) found 204.1(204.06) [ M-H] － 。 1 H-NMR(400MHz,MeOH-d 4 ):1.28(t,3H)，3.65(m,2H)，3.90～3.92(m,1H)，4.45(m,2H)，4.79(d,1H)。
Claims (2)
1. A preparation method of vitamin C ethyl ether comprises the following steps:
step 1: using vitamin C as an initial raw material, using cyclopentanone as a reactant and a solvent, reacting for 4 hours at 20-30 ℃ under the catalysis of acetyl chloride, and filtering to obtain 5, 6-O-cyclopentyl-ascorbic acid;
step 2: dropwise adding thionyl chloride into ethanol, reacting for 1h at 0-5 ℃, adding 5, 6-O-cyclopentyl-ascorbic acid and triethylamine, refluxing and reacting for 12h, evaporating to dryness under reduced pressure, adding ethyl acetate and water, separating liquid, evaporating to remove the ethyl acetate to obtain 1/4, crystallizing at 0-5 ℃ for 2h, and filtering to obtain 3-O-ethyl-5, 6-O-cyclopentyl-ascorbic acid ether;
and step 3: reacting 3-O-ethyl-5, 6-O-cyclopentyl-ascorbic acid ether with dilute hydrochloric acid at 50 ℃ for 2h, decompressing and evaporating to dryness, and recrystallizing the obtained product with ethanol to obtain the vitamin C ethyl ether.
2. The method for preparing vitamin C ethyl ether according to claim 1, wherein step 2 comprises chlorinating ethanol with thionyl chloride to obtain ethyl chloride, and reacting with 5, 6-O-cyclopentyl-ascorbic acid to obtain ether; the molar ratio of thionyl chloride and 5, 6-O-cyclopentyl-ascorbic acid is from 1.2:1 to 2: 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS6069079A (en) * | 1983-09-27 | 1985-04-19 | Takeda Chem Ind Ltd | Production of l-ascorbic acid and d-erythorbic acid ketal |
| WO2012173410A2 (en) * | 2011-06-14 | 2012-12-20 | Green Cross Corporation | Novel c-aryl ansa sglt2 inhibitors |
| CN105367524A (en) * | 2015-06-19 | 2016-03-02 | 上海珈叶实业有限公司 | Preparation method of 3-O-alkyl ascorbic acid |
| CN104945286A (en) * | 2015-06-25 | 2015-09-30 | 成都百事兴科技实业有限公司 | Method for compounding high-purity sulfuric acid esters |
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