CN103467420B - Preparation method for 3-O-alkyl ascorbic acid - Google Patents
Preparation method for 3-O-alkyl ascorbic acid Download PDFInfo
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- CN103467420B CN103467420B CN201310449129.6A CN201310449129A CN103467420B CN 103467420 B CN103467420 B CN 103467420B CN 201310449129 A CN201310449129 A CN 201310449129A CN 103467420 B CN103467420 B CN 103467420B
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- ascorbic acid
- alkyl ascorbic
- kga
- ester
- propyl
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Abstract
The invention discloses a preparation method for 3-O-alkyl ascorbic acid. The preparation method comprises the steps that under protection of nitrogen, 2-keto-L-gulonic acid ester reacts with sulfuric acid diester at the presence of catalyst molecular sieves, and an obtained intermediate under the action of sodium bicarbonate and calcium fluoride generates the 3-O-alkyl ascorbic acid. According to the preparation method, a synthetic route is simple, a synthetic method is novel, a process is easy and convenient to achieve, postprocessing is simple, the yield and purity of products are high, catalysts are low in price and easy to obtain, the environment is not affected, and the preparation method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of 3-O-alkyl ascorbic acid.
Background technology
Vitamins C (i.e. L-AA), since the manually successfully concern of extremely region of chemistry, medical circle and nutrition educational circles always since the synthesis thirties in 20th century.It has played vital role in the fields such as makeup, foodstuff additive, medicines and health protection.Vitamins C can promote the synthesis of cell glue protoplasm, improves skin tension to reduce wrinkle.It offsets removing freckle and senile plaque also has good booster action.But although Vitamin C activity is high unstable, the destruction of easy light, heat, oxygen etc. and lose reducing power, this unstable significantly reduces its utilising efficiency and the commercial value in industries such as makeup.
3-O-alkyl ascorbic acid is a kind of very useful vitamin C derivatives, it is not only highly stable in the chemically, is non-discoloring vitamin C derivatives, and is amphiphilic (hydrophilic and oleophilic) property material, this extends its range of application greatly, the application especially in detergents and cosmetic.3-O-alkyl ascorbic acid is easy to enter corium through stratum corneum, and the biological enzyme be very easy to after it enters human body in body decomposes thus plays ascorbic biological effectiveness.At present, the preparation of 3-O-alkyl ascorbic acid is all the method by chemosynthesis, comprises single stage method and three-step approach.Relative to three-step approach, one-step technology is comparatively simple, and facility investment is little, and European patent EP 086554 and Japanese Patent JP2005320310 all have report to single stage method.But one-step technology product is comparatively complicated, aftertreatment is complicated, is not suitable for scale operation.
Summary of the invention
The invention provides a kind of with KGA ester for the novel method of 3-O-alkyl ascorbic acid to be prepared by raw material through single step reaction, development purity is high, and aftertreatment is simple, and process environment is friendly, production cost is low, is applicable to the 3-O-alkyl ascorbic acid production line of scale operation.
The technical scheme adopted is: a kind of synthetic method of 3-O-alkyl ascorbic acid; it is characterized in that; under it comprises the steps: nitrogen protection; KGA ester (2-Me-KLG, KGA ethyl ester, KGA propyl ester) reacts with sulfuric acid diester (methyl-sulfate, ethyl sulfate, propyl sulfate) under catalyst molecule sieve and triethylamine exist, and the esterification under sodium bicarbonate and Calcium Fluoride (Fluorspan) effect of gained intermediate obtains 3-O-alkyl ascorbic acid.3-O-alkyl ascorbic acid crude product obtains 3-O-alkyl ascorbic acid sterling through washing, recrystallization.
The synthetic method of above-mentioned 3-O-alkyl ascorbic acid, it is characterized in that: KGA ester and sulfuric acid diester reaction solvent are one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, reaction intermediate and sodium bicarbonate and Calcium Fluoride (Fluorspan) effect solvent for use are one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols.
The synthetic method of above-mentioned 3-O-alkyl ascorbic acid, is characterized in that: KGA ester: sulfuric acid diester: triethylamine: sodium bicarbonate: Calcium Fluoride (Fluorspan) mol ratio is 1.00: 1.00 ~ 1.30: 1.00 ~ 1.50: 0.50 ~ 2.00: 0.01 ~ 0.50.KGA ester: molecular sieve mass ratio is 1.00: 0.01 ~ 1.00.
The synthetic method of above-mentioned 3-O-alkyl ascorbic acid, is characterized in that: reaction intermediate and product preliminary purification method used are fast through silicagel column (Flash column chromatography).
The synthetic method of above-mentioned 3-O-alkyl ascorbic acid, is characterized in that: 3-O-alkyl ascorbic acid recrystallization solvent for use is one or more in methyl-formiate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate, propyl propionate.
The synthetic method of above-mentioned 3-O-alkyl ascorbic acid, is characterized in that: before 3-O-alkyl ascorbic acid recrystallization, cleaning product solvent for use is methylene dichloride, trichloromethane, 1, one or more in 2 ethylene dichloride.
The present invention effectively overcomes the deficiency of existing 3-O-alkyl ascorbic acid synthetic technology.Experiment proves, it compared with prior art has, and synthetic route is simple novel, simple process is feasible, aftertreatment is simple, product yield and purity is high, process environment is friendly, production cost is low, be applicable to the advantages such as industrial production.It is the new synthetic method producing 3-O-alkyl ascorbic acid product.Made 3-O-alkyl ascorbic acid can be widely used in the aspects such as household chemicals, makeup, foodstuff additive, Medicines and Health Product, is ascorbic ideal substitute.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
The present invention optimizes synthetic route below by a large amount of experiments, screening, Optimal reaction conditions:
Embodiment 1
Under nitrogen protection, 10.1 grams of (0.1mol) triethylamines are joined in 50 ml methanol, stirring lower 20.8 grams of (0.1mol) 2-Me-KLGs slowly adds in above-mentioned mixed solution, after dissolving, add 1 mol sieve, then 12.6 grams of (0.1mol) methyl-sulfates are dripped, be heated to 60 degree and react 3 hours, methyl alcohol underpressure distillation from reaction solution is gone out, thickness reaction solution after concentrated is quick through silicagel column (Flash column chromatography) under ethyl acetate rinse, point plate monitoring 2-ketone group-3-O-methyl-L-methyl 2-keto-L-gulonate stops when going out completely.Solvent evaporated obtains yellow product.Under nitrogen protection; gained yellow product is dissolved in 80 ml methanol; add 9.25 grams of (0.11mol) sodium bicarbonates and 1.5 grams of (0.02mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; methyl alcohol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated fast through silicagel column (Flash column chromatography), stops when point plate monitoring 3-O-methyl xitix is gone out completely under ethyl acetate rinse.Steaming desolventizes, and the thick product re-crystallizing in ethyl acetate obtained obtains sterling 3-O-methyl xitix.Yield 36.0%, product purity reaches 98.1%.
Embodiment 2
Under nitrogen protection, 10.1 grams of (0.1mol) triethylamines are joined in 50 milliliters of ethanol, stirring lower 22.2 grams of (0.1mol) KGA ethyl esters slowly adds in above-mentioned mixed solution, after dissolving, add 1 mol sieve, then 15.4 grams of (0.1mol) ethyl sulfates are dripped, be heated to 78 degree and react 3 hours, ethanol underpressure distillation from reaction solution is gone out, thickness reaction solution after concentrated is quick through silicagel column (Flash column chromatography) under ethyl acetate rinse, point plate monitoring 2-ketone group-3-O-ethyl-L-2-KLG ethyl ester stops when going out completely.Solvent evaporated obtains yellow product.Under nitrogen protection; gained yellow product is dissolved in 80 milliliters of ethanol; add 9.25 grams of (0.11mol) sodium bicarbonates and 1.5 grams of (0.02mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; ethanol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated fast through silicagel column (Flash column chromatography), stops when point plate monitoring 3-O-ethylascorbyl is gone out completely under ethyl acetate rinse.Steaming desolventizes, and the thick product re-crystallizing in ethyl acetate obtained obtains sterling 3-O-ethylascorbyl.Yield 29.1%, product purity reaches 98.4%.
Embodiment 3
Under nitrogen protection, 10.1 grams of (0.1mol) triethylamines are joined in 50 milliliters of ethanol, stirring lower 20.8 grams of (0.1mol) 2-Me-KLGs slowly adds in above-mentioned mixed solution, after dissolving, add 1 mol sieve, then 22.2 grams of (0.1mol) ethyl sulfates are dripped, be heated to 78 degree and react 3 hours, ethanol underpressure distillation from reaction solution is gone out, thickness reaction solution after concentrated is quick through silicagel column (Flash column chromatography) under ethyl acetate rinse, point plate monitoring 2-ketone group-3-O-ethyl-L-methyl 2-keto-L-gulonate stops when going out completely.Solvent evaporated obtains yellow product.Under nitrogen protection; gained yellow product is dissolved in 80 milliliters of ethanol; add 9.25 grams of (0.11mol) sodium bicarbonates and 1.5 grams of (0.02mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; ethanol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated fast through silicagel column (Flash column chromatography), stops when point plate monitoring 3-O-ethylascorbyl is gone out completely under ethyl acetate rinse.Steaming desolventizes, and the thick product re-crystallizing in ethyl acetate obtained obtains sterling 3-O-ethylascorbyl.Yield 32.0%, product purity reaches 98.3%.
Embodiment 4
Under nitrogen protection, 10.1 grams of (0.1mol) triethylamines are joined in 50 milliliters of ethanol, stirring lower 22.2 grams of (0.1mol) KGA ethyl esters slowly adds in above-mentioned mixed solution, after dissolving, add 3 mol sieves, then 15.4 grams of (0.1mol) ethyl sulfates are dripped, be heated to 78 degree and react 3 hours, ethanol underpressure distillation from reaction solution is gone out, thickness reaction solution after concentrated is quick through silicagel column (Flash column chromatography) under ethyl acetate rinse, point plate monitoring 2-ketone group-3-O-ethyl-L-2-KLG ethyl ester stops when going out completely.Solvent evaporated obtains yellow product.Under nitrogen protection; gained yellow product is dissolved in 80 milliliters of ethanol; add 9.25 grams of (0.11mol) sodium bicarbonates and 1.5 grams of (0.02mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; ethanol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated fast through silicagel column (Flash column chromatography), stops when point plate monitoring 3-O-ethylascorbyl is gone out completely under ethyl acetate rinse.Steaming desolventizes, and the thick product re-crystallizing in ethyl acetate obtained obtains sterling 3-O-ethylascorbyl.Yield 32.1%, product purity reaches 98.5%.
Embodiment 5
Under nitrogen protection, 10.1 grams of (0.1mol) triethylamines are joined in 50 milliliters of ethanol, stirring lower 22.2 grams of (0.1mol) KGA ethyl esters slowly adds in above-mentioned mixed solution, after dissolving, add 1 mol sieve, then 15.4 grams of (0.1mol) ethyl sulfates are dripped, be heated to 78 degree and react 3 hours, ethanol underpressure distillation from reaction solution is gone out, thickness reaction solution after concentrated is quick through silicagel column (Flash column chromatography) under ethyl acetate rinse, point plate monitoring 2-ketone group-3-O-ethyl-L-2-KLG ethyl ester stops when going out completely.Solvent evaporated obtains yellow product.Under nitrogen protection; gained yellow product is dissolved in 80 milliliters of ethanol; add 16.8 grams of (0.20mol) sodium bicarbonates and 3.0 grams of (0.04mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; ethanol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated fast through silicagel column (Flash column chromatography), stops when point plate monitoring 3-O-ethylascorbyl is gone out completely under ethyl acetate rinse.Steaming desolventizes, and the thick product re-crystallizing in ethyl acetate obtained obtains sterling 3-O-ethylascorbyl.Yield 35.0%, product purity reaches 98.3%.
Embodiment 6
Under nitrogen protection, 10.1 grams of (0.1mol) triethylamines are joined in 50 milliliters of ethanol, stirring lower 22.2 grams of (0.1mol) KGA ethyl esters slowly adds in above-mentioned mixed solution, after dissolving, add 1 mol sieve, then 15.4 grams of (0.1mol) ethyl sulfates are dripped, be heated to 78 degree and react 3 hours, ethanol underpressure distillation from reaction solution is gone out, thickness reaction solution after concentrated is quick through silicagel column (Flash column chromatography) under ethyl acetate rinse, point plate monitoring 2-ketone group-3-O-ethyl-L-2-KLG ethyl ester stops when going out completely.Solvent evaporated obtains yellow product.Under nitrogen protection; gained yellow product is dissolved in 80 milliliters of ethanol; add 9.25 grams of (0.11mol) sodium bicarbonates and 1.5 grams of (0.02mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; ethanol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated fast through silicagel column (Flash column chromatography), stops when point plate monitoring 3-O-ethylascorbyl is gone out completely under ethyl acetate rinse.Steaming desolventizes, and add 60 milliliters of trichloromethanes, ice bath stirs 2 hours, filters to obtain off-white color solid crude product, and the thick product re-crystallizing in ethyl acetate obtained obtains sterling 3-O-ethylascorbyl.Yield 23.4%, product purity reaches 99.0%.
Claims (6)
1. the synthetic method of a 3-O-alkyl ascorbic acid, it is characterized in that, under it comprises the steps: nitrogen protection, KGA ester reacts with sulfuric acid diester under catalyst molecule sieve and triethylamine exist, the esterification under sodium bicarbonate and Calcium Fluoride (Fluorspan) effect of gained intermediate obtains 3-O-alkyl ascorbic acid, and 3-O-alkyl ascorbic acid crude product obtains 3-O-alkyl ascorbic acid sterling through washing, recrystallization; Wherein KGA ester is one or more in 2-Me-KLG, KGA ethyl ester, KGA propyl ester, and wherein sulfuric acid diester is the one in methyl-sulfate, ethyl sulfate, propyl sulfate.
2. the synthetic method of 3-O-alkyl ascorbic acid according to claim 1, it is characterized in that: KGA ester and sulfuric acid diester reaction solvent are one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, reaction intermediate and sodium bicarbonate and Calcium Fluoride (Fluorspan) effect solvent for use are one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, butanols.
3. the synthetic method of 3-O-alkyl ascorbic acid according to claim 1, it is characterized in that: KGA ester: sulfuric acid diester: triethylamine: sodium bicarbonate: Calcium Fluoride (Fluorspan) mol ratio is 1.00:1.00 ~ 1.30:1.00 ~ 1.50:0.50 ~ 2.00:0.01 ~ 0.50, KGA ester: molecular sieve mass ratio is 1.00:0.01 ~ 1.00.
4. the synthetic method of 3-O-alkyl ascorbic acid according to claim 1, is characterized in that: reaction intermediate and product preliminary purification method used are fast through silicagel column.
5. the synthetic method of 3-O-alkyl ascorbic acid according to claim 1, is characterized in that: 3-O-alkyl ascorbic acid recrystallization solvent for use is one or more in methyl-formiate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate, propyl propionate.
6. the synthetic method of 3-O-alkyl ascorbic acid according to claim 1, is characterized in that: before 3-O-alkyl ascorbic acid recrystallization, cleaning product solvent for use is methylene dichloride, trichloromethane, 1, one or more in 2 ethylene dichloride.
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| CN110642816A (en) * | 2019-09-25 | 2020-01-03 | 旖肽(上海)生物科技有限公司 | Crystalline 3-O-ethyl vitamin C and preparation method and application thereof |
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| CN101824011A (en) * | 2010-01-06 | 2010-09-08 | 广东医学院 | Method for preparing 3-O-alkyl ascorbic acid |
| CN102140086A (en) * | 2011-03-07 | 2011-08-03 | 山东润鑫精细化工有限公司 | Method for synthesizing vitamin C crude product by adopting L-gulonic acid |
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| CN101824011A (en) * | 2010-01-06 | 2010-09-08 | 广东医学院 | Method for preparing 3-O-alkyl ascorbic acid |
| CN102140086A (en) * | 2011-03-07 | 2011-08-03 | 山东润鑫精细化工有限公司 | Method for synthesizing vitamin C crude product by adopting L-gulonic acid |
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