CN103467420A - Preparation method for 3-O-alkyl ascorbic acid - Google Patents
Preparation method for 3-O-alkyl ascorbic acid Download PDFInfo
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- CN103467420A CN103467420A CN2013104491296A CN201310449129A CN103467420A CN 103467420 A CN103467420 A CN 103467420A CN 2013104491296 A CN2013104491296 A CN 2013104491296A CN 201310449129 A CN201310449129 A CN 201310449129A CN 103467420 A CN103467420 A CN 103467420A
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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 (being L-AA), the extremely concern of region of chemistry, medical circle and nutrition educational circles always since manually successfully synthesizing the thirties in 20th century.It has brought into play vital role in the fields such as makeup, foodstuff additive, medicines and health protection.Vitamins C can promote the synthetic of cell glue protoplasm, improves skin tension to reduce wrinkle.It offsets removing freckle and senile plaque also has good booster action.Unstable although vitamins C is active high, be subject to the destruction of light, heat, oxygen etc. and lose reducing power, this unstable has greatly reduced its utilising efficiency and in the commercial value of the industries such as makeup.
The 3-O-alkyl ascorbic acid is a kind of very useful vitamin C derivatives, it is not only highly stable on chemical property, is non-discoloring vitamin C derivatives, and is amphiphilic (hydrophilic and oleophilic) property material, this has expanded its range of application greatly, especially the application in detergents and cosmetic.The 3-O-alkyl ascorbic acid is easy to see through stratum corneum and enters corium, thereby after it enters human body, ascorbic biological effectiveness is brought into play in the interior biological enzyme decomposition of very easy body.At present, the preparation of 3-O-alkyl ascorbic acid is all the method by chemosynthesis, comprises single stage method and three-step approach.With respect to three-step approach, one-step technology is simpler, and facility investment is little, and European patent EP 086554 and Japanese Patent JP2005320310 all have report to single stage method.But the one-step technology product is comparatively complicated, and the aftertreatment complexity, be not suitable for scale operation.
Summary of the invention
The invention provides and a kind ofly take the KGA ester and prepare the novel method of 3-O-alkyl ascorbic acid as raw material through single step reaction, development purity is high, and aftertreatment is simple, the process environment close friend, 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; it comprises the steps: under 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 existence, and the esterification under sodium bicarbonate and Calcium Fluoride (Fluorspan) effect of gained intermediate obtains the 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, and 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: the KGA ester: sulfuric acid diester: triethylamine: sodium bicarbonate: the Calcium Fluoride (Fluorspan) mol ratio is 1.00: 1.00 ~ 1.30: 1.00 ~ 1.50: 0.50 ~ 2.00: 0.01 ~ 0.50.The KGA ester: the 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 to pass through fast 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, the cleaning product solvent for use is one or more in methylene dichloride, trichloromethane, 1,2 ethylene dichloride.
The present invention has effectively overcome the deficiency of existing 3-O-alkyl ascorbic acid synthetic technology.Experiment showed, that it compared with prior art has that synthetic route is simple novel, simple process is feasible, aftertreatment is simple, product yield and purity are high, process environment is friendly, production cost is low, be applicable to the advantage such as industrial production.It is the new synthetic method of 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 following synthetic route by a large amount of experiments, screening, optimization reaction conditions:
Embodiment 1
Under nitrogen protection, 10.1 grams (0.1mol) triethylamine is joined in 50 ml methanol, stirring lower 20.8 grams (0.1mol) 2-Me-KLG slowly adds in above-mentioned mixed solution, after dissolving, add 1 mol sieve, then drip 12.6 grams (0.1mol) methyl-sulfate, be heated to 60 degree reaction 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 while going out fully.Solvent evaporated obtains yellow product.Under nitrogen protection; the gained yellow product is dissolved in 80 ml methanol; add 9.25 grams (0.11mol) sodium bicarbonate and 1.5 grams (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 is fast through silicagel column (Flash column chromatography) under ethyl acetate rinse, and some plate monitoring 3-O-methyl xitix stops while going out fully.Steaming desolventizes, and resulting thick product obtains sterling 3-O-methyl xitix by re-crystallizing in ethyl acetate.Yield 36.0%, product purity reaches 98.1%.
Embodiment 2
Under nitrogen protection, 10.1 grams (0.1mol) triethylamine is joined in 50 milliliters of ethanol, stirring lower 22.2 grams (0.1mol) KGA ethyl ester slowly adds in above-mentioned mixed solution, after dissolving, add 1 mol sieve, then drip 15.4 grams (0.1mol) ethyl sulfate, be heated to 78 degree reaction 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 while going out fully.Solvent evaporated obtains yellow product.Under nitrogen protection; the gained yellow product is dissolved in 80 milliliters of ethanol; add 9.25 grams (0.11mol) sodium bicarbonate and 1.5 grams (0.02mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; ethanol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated is fast through silicagel column (Flash column chromatography) under ethyl acetate rinse, and some plate monitoring 3-O-ethyl xitix stops while going out fully.Steaming desolventizes, and resulting thick product obtains sterling 3-O-ethyl xitix by re-crystallizing in ethyl acetate.Yield 29.1%, product purity reaches 98.4%.
Embodiment 3
Under nitrogen protection, 10.1 grams (0.1mol) triethylamine is joined in 50 milliliters of ethanol, stirring lower 20.8 grams (0.1mol) 2-Me-KLG slowly adds in above-mentioned mixed solution, after dissolving, add 1 mol sieve, then drip 22.2 grams (0.1mol) ethyl sulfate, be heated to 78 degree reaction 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 while going out fully.Solvent evaporated obtains yellow product.Under nitrogen protection; the gained yellow product is dissolved in 80 milliliters of ethanol; add 9.25 grams (0.11mol) sodium bicarbonate and 1.5 grams (0.02mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; ethanol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated is fast through silicagel column (Flash column chromatography) under ethyl acetate rinse, and some plate monitoring 3-O-ethyl xitix stops while going out fully.Steaming desolventizes, and resulting thick product obtains sterling 3-O-ethyl xitix by re-crystallizing in ethyl acetate.Yield 32.0%, product purity reaches 98.3%.
Embodiment 4
Under nitrogen protection, 10.1 grams (0.1mol) triethylamine is joined in 50 milliliters of ethanol, stirring lower 22.2 grams (0.1mol) KGA ethyl ester slowly adds in above-mentioned mixed solution, after dissolving, add 3 mol sieves, then drip 15.4 grams (0.1mol) ethyl sulfate, be heated to 78 degree reaction 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 while going out fully.Solvent evaporated obtains yellow product.Under nitrogen protection; the gained yellow product is dissolved in 80 milliliters of ethanol; add 9.25 grams (0.11mol) sodium bicarbonate and 1.5 grams (0.02mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; ethanol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated is fast through silicagel column (Flash column chromatography) under ethyl acetate rinse, and some plate monitoring 3-O-ethyl xitix stops while going out fully.Steaming desolventizes, and resulting thick product obtains sterling 3-O-ethyl xitix by re-crystallizing in ethyl acetate.Yield 32.1%, product purity reaches 98.5%.
Embodiment 5
Under nitrogen protection, 10.1 grams (0.1mol) triethylamine is joined in 50 milliliters of ethanol, stirring lower 22.2 grams (0.1mol) KGA ethyl ester slowly adds in above-mentioned mixed solution, after dissolving, add 1 mol sieve, then drip 15.4 grams (0.1mol) ethyl sulfate, be heated to 78 degree reaction 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 while going out fully.Solvent evaporated obtains yellow product.Under nitrogen protection; the gained yellow product is dissolved in 80 milliliters of ethanol; add 16.8 grams (0.20mol) sodium bicarbonate and 3.0 grams (0.04mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; ethanol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated is fast through silicagel column (Flash column chromatography) under ethyl acetate rinse, and some plate monitoring 3-O-ethyl xitix stops while going out fully.Steaming desolventizes, and resulting thick product obtains sterling 3-O-ethyl xitix by re-crystallizing in ethyl acetate.Yield 35.0%, product purity reaches 98.3%.
Embodiment 6
Under nitrogen protection, 10.1 grams (0.1mol) triethylamine is joined in 50 milliliters of ethanol, stirring lower 22.2 grams (0.1mol) KGA ethyl ester slowly adds in above-mentioned mixed solution, after dissolving, add 1 mol sieve, then drip 15.4 grams (0.1mol) ethyl sulfate, be heated to 78 degree reaction 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 while going out fully.Solvent evaporated obtains yellow product.Under nitrogen protection; the gained yellow product is dissolved in 80 milliliters of ethanol; add 9.25 grams (0.11mol) sodium bicarbonate and 1.5 grams (0.02mol) Calcium Fluoride (Fluorspan); back flow reaction 5 hours; ethanol underpressure distillation from reaction solution is gone out; thickness reaction solution after concentrated is fast through silicagel column (Flash column chromatography) under ethyl acetate rinse, and some plate monitoring 3-O-ethyl xitix stops while going out fully.Steaming desolventizes, and adds 60 milliliters of trichloromethanes, and ice bath stirs 2 hours, filters to obtain the off-white color solid crude product, and resulting thick product obtains sterling 3-O-ethyl xitix by re-crystallizing in ethyl acetate.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, it comprises the steps: under nitrogen protection, KGA ester (2-Me-KLG, the KGA ethyl ester, the KGA propyl ester) under catalyst molecule sieve and triethylamine exist with sulfuric acid diester (methyl-sulfate, ethyl sulfate, propyl sulfate) reaction, the esterification under sodium bicarbonate and Calcium Fluoride (Fluorspan) effect of gained intermediate obtains the 3-O-alkyl ascorbic acid, 3-O-alkyl ascorbic acid crude product is through washing, recrystallization obtains 3-O-alkyl ascorbic acid sterling.
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, and 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: the KGA ester: sulfuric acid diester: triethylamine: sodium bicarbonate: the Calcium Fluoride (Fluorspan) mol ratio is 1.00: 1.00 ~ 1.30: 1.00 ~ 1.50: 0.50 ~ 2.00: 0.01 ~ 0.50, the KGA ester: the 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, it is characterized in that: reaction intermediate and product preliminary purification method used are to pass through fast silicagel column (Flash column chromatography).
5. the synthetic method of 3-O-alkyl ascorbic acid according to claim 1, it 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, the cleaning product solvent for use is one or more in methylene dichloride, trichloromethane, 1,2 ethylene dichloride.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108997277A (en) * | 2018-06-29 | 2018-12-14 | 浙江拓普药业股份有限公司 | A kind of Vc ethylether production method |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108997277A (en) * | 2018-06-29 | 2018-12-14 | 浙江拓普药业股份有限公司 | A kind of Vc ethylether production method |
| 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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