CN104195196B - Preparation method of 2-deoxy-D-glucose - Google Patents
Preparation method of 2-deoxy-D-glucose Download PDFInfo
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- CN104195196B CN104195196B CN201410351912.3A CN201410351912A CN104195196B CN 104195196 B CN104195196 B CN 104195196B CN 201410351912 A CN201410351912 A CN 201410351912A CN 104195196 B CN104195196 B CN 104195196B
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Abstract
The invention discloses a preparation method of 2-deoxy-D-glucose. The method includes following steps: adding D-glucal to an acetone-citric acid and phosphate buffer solution; carrying out a reaction with methanol to generate 2-deoxy-D-methylglucoside with catalysis of [beta]-glucosidase; processing the 2-deoxy-D-methylglucoside; adding an aqueous solution of sulfur acid to the processed 2-deoxy-D-methylglucoside; and performing a demethylation reaction to obtain a finished product of the 2-deoxy-D-glucose. A yield is more than 77.8%. The preparation method is simple in processes, is convenient to carry out, is high in product yield and is suitable in industrial production.
Description
Technical field
The present invention relates to a kind of 2- deoxygenates the preparation method of-d- glucose, belong to biomedicine technical field.
Background technology
It is natural rare monosaccharide that 2- deoxygenates-d- glucose, also can be by glucose, mannose, Arabic carbohydrates and their derivative
Preparation, 2- deoxygenates-d- glucose as non-metabolism class glucalogue, has delay body cell metabolism process, reduces machine
Somatic cell division, the glucose transport in suppression tumor cell and the glycolysiss of tumor cell, thus suppressing growth of tumour cell,
The physiologically actives such as inducing cancer cell death.2- deoxygenates-d- glucose and trail(tumor necrosis factor-related
Apoptosis inducing-ligand) albumen use in conjunction can strengthen melanoma cell to inducing cell apoptosis material
Sensitivity.Meanwhile, 2- deoxygenates the glycosylation that-d- glucose can suppress protein, causes high sugar to be acylated and make sp1 dependency base
Because losing activity.2- deoxygenates-d- glucose and has antiviral, anticancer, anti-ageing multiple physiological and pharmacological functions of waiting for a long time, in medicine, food
In product and cosmetic industry, application prospect is extensive.
At present, the preparation method of the 2- deoxidation-d- glucose of report is extremely many, but great majority reaction is complicated, and yield is low, is difficult to
Realize large-scale production.In187908 through ester exchange, is hydrated two-step reaction with 3,4,6- tri--acetyl-d- glucals for raw material
2- deoxygenate-d- glucose:
,
The method process is simple, cost is relatively low, but yield is not high, and uses the larger barium salt of toxicity, should not be used in human body,
And the first step can simplify.
The preparation method (pct int appl., 2004058786,15 jul 2004) of report in 2004 is with d- Fructus Vitis viniferae alkene
Sugar be raw material, through three-step reaction obtain 2- deoxygenate-d glucose:
,
However, this technological operation is loaded down with trivial details, relatively costly, its yield is not also significantly improved, unsuitable industrialized production.
The patent of invention of Application No. 200510122912.7 discloses a kind of preparation method of 2- deoxyglucose, this
Bright by 3,4,6- tri--acetyl-d- glucals and absolute methanol are generated d- glucal under the catalytic action of Feldalat NM,
After vacuum distillation is evaporated methanol, directly toward in reactor, adds aqueous sulfuric acid, obtain 2- deoxyglucose through hydrolysis thick
Product, then with conventional method, crude product recrystallization is become 2- deoxyglucose finished product, although the present invention simplifies technique and avoids
The harm of barium salt, but its yield is not high, uses a large amount of methanol, be unfavorable for environmental protection in only 71.4%, and course of reaction.
Content of the invention
For the problems referred to above, the invention provides a kind of 2- deoxygenates the preparation method of-d- glucose (2-dg), work of the present invention
Skill reactions steps are few, and selectivity is good, and product yield is high, is suitable for large-scale production.
A kind of 2- deoxygenates the preparation method of-d- glucose (2-dg), and its preparation process is as follows:
(1) d- glucal () and acetone-citrate phosphate buffer are added in No. 1 reactor, after stirring and dissolving,
Add absolute methanol and beta-glucosidase, generate 2- deoxidation-methyl αDglucopyranoside (), reaction under beta-glucosidase enzyme catalysiss
After liquid concentrating under reduced pressure, after 2- deoxidation-methyl αDglucopyranoside silica gel column chromatography separates and collects, distill and transfer to No. 1 reactor to dry
In standby；Its chemical equation is as follows:
；
(2) add water in No. 2 reactors, enriching sulphuric acid, stirs and lowers the temperature, the aqueous sulfuric acid in No. 2 reactors is taken out
Enter in No. 1 reactor, stirring reaction under room temperature, add neutralization reagent to be neutralized, filter, filtrate is distilled to syrupy shape, plus
Enter the dissolving of ethanol that equal-volume volume fraction is 95%, 80 DEG C of backflow 30min, cooled and filtered, crystallize under room temperature, obtain 2- deoxygenate-
D- glucose crude product ()；Its chemical equation is as follows:
；
(3) crude product 2- is deoxygenated-d- glucose to add in No. 3 reactors, add the ethanol that volume fraction is 90%, heating
After dissolving, filtered with activated carbon decolorizing, crystallisation by cooling under filtrate room temperature, washing, dry, obtain final product 2- and deoxygenate-d- glucose.
In step (1) of the present invention, acetone and citrate phosphate buffer in described acetone-citrate phosphate buffer
Volume ratio be 7:3, described beta-glucosidase enzyme activity concentration is 20-50u/ml, described d- glucal and acetone-Fructus Citri Limoniae
The mass volume ratio of acid phosphoric acid buffer is 1:10-20 it is preferred that mass volume ratio is 1:15.
In step (1) of the present invention, reaction temperature is 20-30 DEG C, and ph is 4.5-5.5, and the response time is 24-48h；Excellent
Choosing, reaction temperature is 25 DEG C, and ph is 5.0, and the response time is 30h.
In step (2) of the present invention, the molar concentration of described sulphuric acid is 0.005-0.05mol/l, and 2- deoxygenates-d- Fructus Vitis viniferae
Sugared first glycosides is 1:20-30 with the mass volume ratio of aqueous sulfuric acid；Preferably, mass volume ratio is 1:25.
In step (2) of the present invention, described neutralization reagent is selected from naoh, na2co3、nahco3、koh、k2co3Or
khco3, regulation ph is 6.8-7.0, and neutral temperature is less than reaction temperature or identical with reaction temperature；Preferably naoh.
Deoxygenate-d- glucose and its recrystallization obtaining crude product 2- all using conventional method, two-step crystallization is all at room temperature
Keep 24-48h it is preferred that two-step crystallization all keeps 30h at room temperature.
Have the technical effect that acquired by the present invention
The present invention passes through enzyme law catalysis d- glucal and reacts generation 2- deoxidation-d- methyl αDglucopyranoside, Hou Zhezai with methanol
Produce 2- through demethylating reaction and deoxygenate-d- glucose, be above by the yield that the present invention prepares 2- deoxidation-d- glucose
The mass ratio of the 2-dg that 77.8%(the actually obtains and 2-dg obtaining in theory).Preparation process is simple of the present invention, step are few, choosing
Selecting property is good, and product yield is high, is suitable for large-scale production.
Specific embodiment
To further describe the present invention with reference to specific embodiment, advantages of the present invention and feature will be with description and
Apparent.But embodiment is only exemplary, any restriction is not constituted to the scope of the present invention.Those skilled in the art should
It should be appreciated that, can be to repair to the details of technical solution of the present invention and form under without departing from the spirit and scope of the present invention
Change or replace, but these modifications and replacement each fall within protection scope of the present invention.
Embodiment 1 2- deoxygenates the preparation method of-d- glucose
Have in the round-bottomed flask of plug belt stirrer in 1l twoport and add 300ml acetone-citrate phosphate buffer, Ran Houjia
Enter the d- glucal of 20g, after stirring and dissolving, (enzyme than work is to add 200ml dehydrated alcohol and 100g beta-glucosidase
150u/g), 25 DEG C, 2- deoxidation-methyl αDglucopyranoside, after concentrating under reduced pressure, 2- deoxidation-Fructus Vitis viniferae after stirring reaction 30h under ph5.0, are generated
Sugared first glycosides is separated and collected, vacuum distillation to syrupy shape with silica gel column chromatography (300 mesh silica gel, 1l chromatographic column), adds 620ml
h2so4(0.03m), stirring reaction 1h, is neutralized to ph7.0 with naoh, plus activated carbon 10g, 70 DEG C of insulation 10min sucking filtration, filtrate
Vacuum distillation is to syrupy shape, plus the ethanol that equal-volume volume fraction is 95%, 80 DEG C of backflow 30min, cooled and filtered, filtrate chamber
Temperature crystallization 24h, obtains 2- and deoxygenates-d- glucose crude product；Crude product 2- deoxygenates the ethanol weight that-d- glucose is 90% with volume fraction again
Crystallization, washs, dries to obtain 18.20g 2- deoxidation-d- glucose finished product, calculating its yield is 79.9%.
Embodiment 2 2- deoxygenates the preparation method of-d- glucose
Have in the round-bottomed flask of plug belt stirrer in 1l twoport and add 300ml acetone-citrate phosphate buffer, Ran Houjia
Enter the d- glucal of 15g, after stirring and dissolving, (enzyme than work is to add 200ml dehydrated alcohol and 100g beta-glucosidase
150u/g), 20 DEG C, 2- deoxidation-methyl αDglucopyranoside, after concentrating under reduced pressure, 2- deoxidation-Fructus Vitis viniferae after stirring reaction 40h under ph4.5, are generated
Sugared first glycosides is separated and collected, vacuum distillation to syrupy shape with silica gel column chromatography (300 mesh silica gel, 1l chromatographic column), adds 465ml
h2so4(0.01m), stirring reaction 1h, is neutralized to ph6.9 with koh, plus activated carbon 10g, 70 DEG C of insulation 10min sucking filtration, and filtrate subtracts
Pressure distillation is to syrupy shape, plus the ethanol that equal-volume volume fraction is 95%, 80 DEG C of backflow 30min, cooled and filtered, filtrate room temperature
Crystallization 30h, obtains 2- and deoxygenates-d- glucose crude product；Crude product 2- deoxygenates-d- glucose and is tied with the ethanol that volume fraction is 90% more again
Crystalline substance, washs, dries to obtain 13.99g 2- deoxidation-d- glucose finished product, calculating its yield is 81.9%.
Embodiment 3 2- deoxygenates the preparation method of-d- glucose
Having in 1l twoport adds acetone-citric acid phosphoric acid that 300ml, ph are 5.5 to delay in the round-bottomed flask of plug belt stirrer
Rush liquid, be subsequently adding the d- glucal of 20g, after stirring and dissolving, add 200ml dehydrated alcohol and 100g beta-glucosidase
(enzyme is 150u/g than living), generates 2- deoxidation-methyl αDglucopyranoside, after concentrating under reduced pressure, 2- by 30 DEG C after stirring reaction 30h under ph5.5
Deoxidation-methyl αDglucopyranoside is separated and collected, vacuum distillation to syrupy shape with silica gel column chromatography (300 mesh silica gel, 1l chromatographic column), adds
740ml h2so4(0.1m), stirring reaction 1h, is neutralized to ph7.0 with naoh, plus activated carbon 10g, 70 DEG C of insulation 10min sucking filtration,
Filtrate decompression is distilled to syrupy shape, plus the ethanol that equal-volume volume fraction is 95%, 80 DEG C of backflow 30min, cooled and filtered, filter
Liquid crystallizing at room temperature 35h, obtains 2- and deoxygenates-d- glucose crude product；Crude product 2- deoxygenates the second that-d- glucose is 90% with volume fraction again
Alcohol recrystallization, washs, dries to obtain 17.86g 2- deoxidation-d- glucose finished product, calculating its yield is 78.4%.
Embodiment 4 2- deoxygenates the preparation method of-d- glucose
Having in 1l twoport adds acetone-citric acid phosphoric acid that 300ml, ph are 5.0 to delay in the round-bottomed flask of plug belt stirrer
Rush liquid, be subsequently adding the d- glucal of 20g, after stirring and dissolving, add 200ml dehydrated alcohol and 100g beta-glucosidase
(enzyme is 150u/g than living), generates 2- deoxidation-methyl αDglucopyranoside, after concentrating under reduced pressure, 2- by 25 DEG C after stirring reaction 30h under ph5.0
Deoxidation-methyl αDglucopyranoside is separated and collected, vacuum distillation to syrupy shape with silica gel column chromatography (300 mesh silica gel, 1l chromatographic column), adds
740ml h2so4(0.1m), stirring reaction 1h, uses nahco3It is neutralized to ph7.0, plus activated carbon 10g, 70 DEG C are incubated 10min and take out
Filter, filtrate decompression is distilled to syrupy shape, plus the ethanol that equal-volume volume fraction is 95%, 80 DEG C of backflow 30min, cooled and filtered,
Filtrate crystallizing at room temperature 48h, obtains 2- and deoxygenates-d- glucose crude product；It is 90% with volume fraction again that crude product 2- deoxygenates-d- glucose
Ethyl alcohol recrystallization, washs, dries to obtain 17.72g 2- deoxidation-d- glucose finished product, calculating its yield is 77.8%.
Claims (11)
1. a kind of 2- deoxygenates the preparation method of-d- glucose (2-dg), and its preparation process is as follows:
(1) add d- glucal () and acetone-citrate phosphate buffer in No. 1 reactor, after stirring and dissolving, add
Absolute methanol and beta-glucosidase, generate 2- deoxidation-methyl αDglucopyranoside () under beta-glucosidase enzyme catalysiss, and reactant liquor subtracts
After pressure concentrates, after 2- deoxidation-methyl αDglucopyranoside silica gel column chromatography separates and collects, distill to dry, transfer to standby in No. 1 reactor
With；
(2) add water in No. 2 reactors, enriching sulphuric acid, stirs and lowers the temperature, make aqueous sulfuric acid, by the sulfur in No. 2 reactors
In No. 1 reactor of aqueous acid suction, stirring reaction under room temperature, add neutralization reagent be neutralized, filter, by filtrate distill to
Syrupy shape, adds the ethanol dissolving that equal-volume volume fraction is 95%, 80 DEG C of backflow 30min, cooled and filtered, crystallizes under room temperature,
Obtain 2- and deoxygenate-d- glucose crude product ()；
(3) crude product 2- is deoxygenated-d- glucose to add in No. 3 reactors, add the ethanol that volume fraction is 90%, heating for dissolving
Afterwards, filtered with activated carbon decolorizing, crystallisation by cooling under filtrate room temperature, washing, dry, obtain final product 2- and deoxygenate-d- glucose.
2. preparation method according to claim 1 is it is characterised in that in described step (1), described acetone-citric acid phosphorus
In acid buffer, acetone and the volume ratio of citrate phosphate buffer are 7:3, and described beta-glucosidase enzyme activity concentration is 20-
50u/ml, described d- glucal is 1:10-20 with the mass volume ratio of acetone-citrate phosphate buffer.
3. preparation method according to claim 2 is it is characterised in that described d- glucal and acetone-citric acid phosphoric acid
Buffer mass volume ratio is 1:15.
4. it is characterised in that in described step (1), reaction temperature is 20-30 DEG C to preparation method according to claim 1,
Ph is 4.5-5.5, and the response time is 24-48h.
5. preparation method according to claim 4 is it is characterised in that in described step (1), reaction temperature is 25 DEG C, ph
For 5.0, the response time is 30h.
6. preparation method according to claim 1 is it is characterised in that in described step (2), the rubbing of described aqueous sulfuric acid
Your concentration is 0.005-0.05mol/l, and it is 1:20-30 that 2- deoxygenates-d- methyl αDglucopyranoside with the mass volume ratio of aqueous sulfuric acid.
7. preparation method according to claim 6 is it is characterised in that the molar concentration of described aqueous sulfuric acid is
It is 1:25 that 0.02mol/l, described 2- deoxygenate-d- methyl αDglucopyranoside with the mass volume ratio of aqueous sulfuric acid.
8. preparation method according to claim 1 is it is characterised in that in described step (2), described neutralization reagent is selected from
naoh、na2co3、nahco3、koh、k2co3Or khco3, regulation ph be 6.8-7.0, neutral temperature be less than reaction temperature or with
Reaction temperature is identical.
9. preparation method according to claim 8 is it is characterised in that described neutralization reagent is naoh.
10. preparation method according to claim 1 is it is characterised in that described two-step crystallization all keeps 24- at room temperature
48h.
11. preparation methoies according to claim 10 are it is characterised in that described two-step crystallization all keeps 30h at room temperature.
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