CN106496288A - A kind of preparation method of 2 deoxidation D glucose - Google Patents
A kind of preparation method of 2 deoxidation D glucose Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of 2 deoxidation D glucose, the method is protected to amino with cheap and easily-available D Glucosamines as initiation material with P-methoxybenzal-dehyde, in 4 dimethylamino naphthyridines（DMAP）Under catalysis; solvent is made with pyridine; acetic anhydride carries out acetylation protection for reactant to all of hydroxyl on D Glucosamines; protection group on deaminizating obtains 1,3,4 in acid condition; 6 four oxygen acetyl group, 2 aminoglucose hydrochloride; amino is changed into isothiocyano with PhOC (=S) Cl further, initiator is done with AIBN then, with three (trimethyl silicon substrate) silane（TTMS‑H）With 1,3,4,6 four oxygen acetyl group, 2 isothiocyano glucose carries out radical reaction, and last deacetylate obtains 2 deoxyglucoses.The new synthetic route raw material is easy to get, simple to operate, is not related to any chromatographic column lock out operation, and gross production rate is high, and low cost is suitable for large-scale production；The preparation method of the present invention is simple to the aftertreatment technology of product, and product is easily isolated, it is easy to accomplish large-scale production.
Description
Technical field
The present invention relates to carbohydrate chemistry technical field, specifically a kind of preparation method of 2-deoxy-D-glucose.
Background technology
2-deoxy-D-glucose also known as 1,5-anhydroglucitol, are natural antimetabolic species antibiotic, with multiple physiology medicines
Reason effect, additionally, it is also a kind of important medicine intermediate, has a wide range of applications in the industry such as medicine and cosmetics, but
It is that current price on the market is higher, typically in 250 ~ 290g/ units, limits which and apply, this is mainly by preparation at this stage
Technique determines.
The preparation technology of 2-deoxy-D-glucose has two kinds at present：One be with glucose as raw material, through acetylation, bromination,
Reduction obtains 3,4,6- tri--acetyl group-D- glucals, then by changing protection group, addition, catalytic hydrogenation preparation 2- deoxidations Portugal
Grape sugar, above method are related to catalytic hydrogenation process, and complex process is high to equipment requirement, and the time used is long, low yield, thus raw
High cost is produced, is not suitable for industrial production；Two is to prepare 1,5-anhydroglucitol with D- Glucosamines as raw material, using sodium borohydride
Hydrotreating is carried out, and then 1,5-anhydroglucitol is obtained using natrium nitrosum, but the separation of target product is difficult, needs ion
Displacement chromatography post, and the inorganic salts removed in product are needed using anion-cation exchange resin chromatographic column or electrodialysis-film point
From device, high to equipment requirement, high cost, it is difficult to realize large-scale production.
Content of the invention
For solving complex process present in existing 2-deoxy-D-glucose synthetic technology, yield is relatively low, cost is high etc. asks
Topic, the invention provides a kind of preparation method of 2-deoxy-D-glucose.
The present invention for achieving the above object, is achieved through the following technical solutions：
A kind of preparation method of 2-deoxy-D-glucose, comprises the following steps：
1. aminoglucose hydrochloride is added to the water, stirring dissolves which, is then added thereto to NaOH, stirs
After obtain mixed liquor 1, in mixed liquor 1 be added dropwise p-anisaldehyde, during dropwise addition keep mixed liquor 1 temperature be 2 ~ 7 DEG C, and
Stirring reaction 10 ~ 15 hours, obtain reactant liquor 1 at this temperature, in reactant liquor 1 add methyl tertiary butyl ether(MTBE), stir 20 ~ 40 points
Clock, suction filtration, gained filter cake 1 are 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, standby；
The mass volume ratio of described aminoglucose hydrochloride, water, NaOH, p-anisaldehyde and methyl tertiary butyl ether(MTBE) is 20
~25g：120~150ml：4~4.5g：10~15g：180~200ml；
2. by step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose is added in pyridine and is dissolved, and is obtained
Mixed liquor 2 being arrived, acetic anhydride being added dropwise in mixed liquor 2, during keeping being added dropwise, the temperature of mixed liquor 2 is 0 ~ 5 DEG C, then 0 ~ 5
DMAP is added thereto at DEG C, and completion of dropping obtains reactant liquor 2, reactant liquor 2 reacts at 20 ~ 30 DEG C 10 ~
15 hours, then added water crystallization, suction filtration, and gained filter cake 2 is 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxies
Base benzylidene）Amino-D-Glucose, standby；
Described pyridine, step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, acetic anhydride, 4-
The mass volume ratio of dimethylamino naphthyridine and water is 65 ~ 75ml：20~25g：40~50g：0.15~0.25g：200~250ml；
3. by step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
Grape sugar is added in acetone and is dissolved, and hydrochloric acid solution is added dropwise thereto then, adjusts its pH value to 1 ~ 4, and completion of dropping is at 20 ~ 30 DEG C
Stirring 1 ~ 2 hour, suction filtration, gained filter cake are 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides；
Wherein step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
The mass volume ratio of grape SA is 20 ~ 25g：250~280ml；
4. by step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides are added in acetonitrile, at 0 ~ 5 DEG C
Stirring is added dropwise the sodium bicarbonate aqueous solution that mass fraction is for 10 ~ 15% thereto, and completion of dropping is stirred 30 ~ 40 minutes, dripped thereto
Plus mass fraction is the acetonitrile solution of 10 ~ 15% benzene oxygen thio-carbonyl chlorides, completion of dropping, at 20 ~ 30 DEG C, stirring reaction 1 ~ 2 is little
When, reactant liquor 4 being obtained, gained reactant liquor 4 is extracted with ethyl acetate and saturated aqueous common salt successively, is merged organic phase, gained has
Machine phase vacuum distillation obtains 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose；
Wherein step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, acetonitrile, sodium bicarbonate aqueous solution
Mass volume ratio with the acetonitrile solution of benzene oxygen thio-carbonyl chloride is 1.5 ~ 2g：15~20ml：35~40g：10~15g；
The volume ratio of reactant liquor 4, ethyl acetate and saturated aqueous common salt is 2 ~ 3：3：3；
5. under nitrogen protection, by step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyanos glucose add toluene
Middle dissolving, is added dropwise three (trimethyl silicon substrate) silane and azodiisobutyronitrile thereto successively, is warming up to 80 ~ 90 DEG C of reactions 3 ~ 5 little
When, reactant liquor 5 being obtained, reactant liquor 5 is cooled to 20 ~ 30 DEG C, it is 1 to use volume ratio after vacuum distillation：1 acetone and petroleum ether are mixed
Close liquation crystalline substance 2 ~ 3 hours, obtain 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol；
Wherein step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose, toluene, three (trimethyl silicon substrate) silicon
The mass volume ratio of alkane and azodiisobutyronitrile is 4 ~ 6g：100~200ml：1.5~2g：0.1~0.5g；
6. by step 5. gained 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol is dissolved in methyl alcohol, is cooled to 0 ~ 5 DEG C, so
After be added thereto to sodium methoxide, stirring reaction adds acetic acid after 1 ~ 2 hour, obtains reactant liquor 6, by 6 vacuum distillation of reactant liquor after
Dichloromethane crystallization is used, 2-deoxy-D-glucose is obtained；
Wherein 1, the mass body of 3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol, methyl alcohol, sodium methoxide, acetic acid and dichloromethane
Product is than being 1 ~ 2g：5~10ml：0.2~0.3g：2~4ml：5~8ml.
Preferably, step 3. middle hydrochloric acid solution concentration be 5mol/L, the pH value being adjusted to be 2.
Preferably, the ratio of step 4. middle material is：Step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucoses
The mass volume ratio of the acetonitrile solution of sugared hydrochloride, acetonitrile, sodium bicarbonate aqueous solution and benzene oxygen thio-carbonyl chloride is 1.5g：
18ml：38g：12g.
Preferably, step 4. middle reactant liquor 4, ethyl acetate and saturated aqueous common salt volume ratio be 2：3：3.
Further preferred preparation method, comprises the following steps：
1. aminoglucose hydrochloride is added to the water, stirring dissolves which, is then added thereto to NaOH, stirs
After obtain mixed liquor 1, in mixed liquor 1 be added dropwise p-anisaldehyde, during dropwise addition keep mixed liquor 1 temperature be 2 ~ 7 DEG C, and
Stirring reaction 12 hours, obtain reactant liquor 1 at this temperature, in reactant liquor 1 add methyl tertiary butyl ether(MTBE), stir 30 minutes, take out
Filter, gained filter cake 1 are 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, standby；
The mass volume ratio of described aminoglucose hydrochloride, water, NaOH, p-anisaldehyde and methyl tertiary butyl ether(MTBE) is
22g：130ml：4.8g：12g：200ml；
2. by step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose is added in pyridine and is dissolved, and is obtained
Mixed liquor 2 being arrived, acetic anhydride being added dropwise in mixed liquor 2, during keeping being added dropwise, the temperature of mixed liquor 2 is 5 DEG C, then at 5 DEG C
DMAP is added thereto to, completion of dropping obtains reactant liquor 2, reactant liquor 2 reacts at 25 DEG C 12 hours, then
Add water crystallization, suction filtration, and gained filter cake 2 is 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）
Amino-D-Glucose, standby；
Described pyridine, step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, acetic anhydride, 4-
The mass volume ratio of dimethylamino naphthyridine and water is 70ml：22g：45g：0.20g：220ml；
3. by step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
Grape sugar is added in acetone and is dissolved, and the hydrochloric acid solution that 5mol/L is then added dropwise thereto adjusts pH value to 2, and completion of dropping is at 25 DEG C
Stirring 2 hours, suction filtration, gained filter cake are 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides；
Wherein step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
The mass volume ratio of grape SA is 22g：260ml；
4. by step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides are added in acetonitrile, are stirred at 0 DEG C
The sodium bicarbonate aqueous solution for being added dropwise that mass fraction is 12% thereto is mixed, completion of dropping is stirred 35 minutes, and quality point is added dropwise thereto
Acetonitrile solution of the number for 15% benzene oxygen thio-carbonyl chloride, completion of dropping, stirring reaction 1 hour at 25 DEG C obtain reactant liquor 4, will
Gained reactant liquor 4 is extracted with ethyl acetate and saturated aqueous common salt successively, merges organic phase, and gained organic phase vacuum distillation obtains 1,
3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose；
Wherein step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, acetonitrile, sodium bicarbonate aqueous solution
Mass volume ratio with the acetonitrile solution of benzene oxygen thio-carbonyl chloride is 1.5g：18ml：38g：12g；
The volume ratio of reactant liquor 4, ethyl acetate and saturated aqueous common salt is 2：3：3；
5. under nitrogen protection, by step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyanos glucose add toluene
Middle dissolving, is added dropwise three (trimethyl silicon substrate) silane and azodiisobutyronitrile thereto successively, is warming up to 85 DEG C and reacts 4 hours, obtains
To reactant liquor 5, reactant liquor 5 is cooled to 25 DEG C, it is 1 that volume ratio is used after vacuum distillation：1 acetone and petroleum ether mixed liquor crystallization
2 ~ 3 hours, obtain 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol；
Wherein step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose, toluene, three (trimethyl silicon substrate) silicon
The mass volume ratio of alkane and azodiisobutyronitrile is 5g：150ml：1.7g：0.3g；
6. by step 5. gained 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol is dissolved in methyl alcohol, is cooled to 0 DEG C, then
Be added thereto to sodium methoxide, stirring reaction adds acetic acid after 1 hour, obtains reactant liquor 6, by after 6 vacuum distillation of reactant liquor with two
Chloromethanes crystallization, obtains 2-deoxy-D-glucose；
Wherein 1, the mass body of 3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol, methyl alcohol, sodium methoxide, acetic acid and dichloromethane
Product is than being 1g：6ml：0.25g：3ml：6ml.
The present invention has advantages below compared to existing technology：
The preparation technology of 1,5-anhydroglucitol is developed into the industrialized production stage by existing laboratory stage by the present invention, should
Method is protected to amino with cheap and easily-available D- Glucosamines as initiation material with P-methoxybenzal-dehyde, upper acetyl
Base, deprotection obtain 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, further use PhOC (=S) Cl by amino
It is changed into isothiocyano, initiator is done with AIBN then, with three (trimethyl silicon substrate) silane（TTMS-H）With 1,3,4,6- tetra--
Oxy-acetyl -2- isothiocyanos glucose carries out radical reaction, and last deacetylate obtains 1,5-anhydroglucitol.This is new
Synthetic route raw material cheap and easily-available, operating process is few, and last handling process is not related to any chromatographic column lock out operation, total produces
Rate is high, low cost, is suitable for large-scale production；
The raw material and solvent toxicity that the preparation method of the present invention is related to is little, and safety and environmental protection, postprocessing working procedures operating procedure are few, product
It is easy to purify, and purity is high, the first step is protected to the amino on D-Glucosamine Hydrochloride with P-methoxybenzal-dehyde
94 ~ 95%, second step carries out guarantor of the yield of acetylation protection on 88 ~ 90%, the 3rd step deaminizatings to the yield of shield to hydroxyl
Amino is converted to the yield of isothiocyano 87 ~ 90% in 92 ~ 94%, the 4th steps by the yield of shield base, and the 5th step carries out free radical
The yield of reaction 81 ~ 85%, the 6th step deacetylations yield 94 ~ 98%, as the yield of every step is higher, or even reach
To more than 95%, and yield stable.
Requirement of the preparation method of the present invention to equipment is low, can achieve industrial production using existing equipment, and each
The yield of step is high, the yield of each step more than 80%, even up to more than 90%, low cost；The preparation method pair of the present invention
The aftertreatment technology of product is simple, and product is easily isolated, it is easy to accomplish large-scale production.
Specific embodiment
It is an object of the invention to provide a kind of preparation method of 2-deoxy-D-glucose, is achieved through the following technical solutions：
A kind of preparation method of 2-deoxy-D-glucose, comprises the following steps：
1. aminoglucose hydrochloride is added to the water, stirring dissolves which, is then added thereto to NaOH, stirs
After obtain mixed liquor 1, in mixed liquor 1 be added dropwise p-anisaldehyde, during dropwise addition keep mixed liquor 1 temperature be 2 ~ 7 DEG C, and
Stirring reaction 10 ~ 15 hours, obtain reactant liquor 1 at this temperature, in reactant liquor 1 add methyl tertiary butyl ether(MTBE), stir 20 ~ 40 points
Clock, suction filtration, gained filter cake 1 are 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, standby；
The mass volume ratio of described aminoglucose hydrochloride, water, NaOH, p-anisaldehyde and methyl tertiary butyl ether(MTBE) is 20
~25g：120~150ml：4~4.5g：10~15g：180~200ml；
2. by step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose is added in pyridine and is dissolved, and is obtained
Mixed liquor 2 being arrived, acetic anhydride being added dropwise in mixed liquor 2, during keeping being added dropwise, the temperature of mixed liquor 2 is 0 ~ 5 DEG C, then 0 ~ 5
DMAP is added thereto at DEG C, and completion of dropping obtains reactant liquor 2, reactant liquor 2 reacts at 20 ~ 30 DEG C 10 ~
15 hours, then added water crystallization, suction filtration, and gained filter cake 2 is 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxies
Base benzylidene）Amino-D-Glucose, standby；
Described pyridine, step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, acetic anhydride, 4-
The mass volume ratio of dimethylamino naphthyridine and water is 65 ~ 75ml：20~25g：40~50g：0.15~0.25g：200~250ml；
3. by step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
Grape sugar is added in acetone and is dissolved, and hydrochloric acid solution is added dropwise thereto then, adjusts its pH value to 1 ~ 4, and completion of dropping is at 20 ~ 30 DEG C
Stirring 1 ~ 2 hour, suction filtration, gained filter cake are 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides；
Wherein step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
The mass volume ratio of grape SA is 20 ~ 25g：250~280ml；
4. by step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides are added in acetonitrile, at 0 ~ 5 DEG C
Stirring is added dropwise the sodium bicarbonate aqueous solution that mass fraction is for 10 ~ 15% thereto, and completion of dropping is stirred 30 ~ 40 minutes, dripped thereto
Plus mass fraction is the acetonitrile solution of 10 ~ 15% benzene oxygen thio-carbonyl chlorides, completion of dropping, at 20 ~ 30 DEG C, stirring reaction 1 ~ 2 is little
When, reactant liquor 4 being obtained, gained reactant liquor 4 is extracted with ethyl acetate and saturated aqueous common salt successively, is merged organic phase, gained has
Machine phase vacuum distillation obtains 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose；
Wherein step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, acetonitrile, sodium bicarbonate aqueous solution
Mass volume ratio with the acetonitrile solution of benzene oxygen thio-carbonyl chloride is 1.5 ~ 2g：15~20ml：35~40g：10~15g；
The volume ratio of reactant liquor 4, ethyl acetate and saturated aqueous common salt is 2 ~ 3：3：3；
5. under nitrogen protection, by step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyanos glucose add toluene
Middle dissolving, is added dropwise three (trimethyl silicon substrate) silane and azodiisobutyronitrile thereto successively, is warming up to 80 ~ 90 DEG C of reactions 3 ~ 5 little
When, reactant liquor 5 being obtained, reactant liquor 5 is cooled to 20 ~ 30 DEG C, it is 1 to use volume ratio after vacuum distillation：1 acetone and petroleum ether are mixed
Close liquation crystalline substance 2 ~ 3 hours, obtain 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol；
Wherein step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose, toluene, three (trimethyl silicon substrate) silicon
The mass volume ratio of alkane and azodiisobutyronitrile is 4 ~ 6g：100~200ml：1.5~2g：0.1~0.5g；
6. by step 5. gained 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol is dissolved in methyl alcohol, is cooled to 0 ~ 5 DEG C, so
After be added thereto to sodium methoxide, stirring reaction adds acetic acid after 1 ~ 2 hour, obtains reactant liquor 6, by 6 vacuum distillation of reactant liquor after
Dichloromethane crystallization is used, 2-deoxy-D-glucose is obtained；
Wherein 1, the mass body of 3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol, methyl alcohol, sodium methoxide, acetic acid and dichloromethane
Product is than being 1 ~ 2g：5~10ml：0.2~0.3g：2~4ml：5~8ml.
Preferably, step 3. middle hydrochloric acid solution concentration be 5mol/L, the pH value being adjusted to be 2.
Preferably, the ratio of step 4. middle material is：Step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucoses
The mass volume ratio of the acetonitrile solution of sugared hydrochloride, acetonitrile, sodium bicarbonate aqueous solution and benzene oxygen thio-carbonyl chloride is 1.5g：
18ml：38g：12g.
Preferably, step 4. middle reactant liquor 4, ethyl acetate and saturated aqueous common salt volume ratio be 2：3：3.
Further preferred preparation method, comprises the following steps：
1. aminoglucose hydrochloride is added to the water, stirring dissolves which, is then added thereto to NaOH, stirs
After obtain mixed liquor 1, in mixed liquor 1 be added dropwise p-anisaldehyde, during dropwise addition keep mixed liquor 1 temperature be 2 ~ 7 DEG C, and
Stirring reaction 12 hours, obtain reactant liquor 1 at this temperature, in reactant liquor 1 add methyl tertiary butyl ether(MTBE), stir 30 minutes, take out
Filter, gained filter cake 1 are 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, standby；
The mass volume ratio of described aminoglucose hydrochloride, water, NaOH, p-anisaldehyde and methyl tertiary butyl ether(MTBE) is
22g：130ml：4.8g：12g：200ml；
2. by step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose is added in pyridine and is dissolved, and is obtained
Mixed liquor 2 being arrived, acetic anhydride being added dropwise in mixed liquor 2, during keeping being added dropwise, the temperature of mixed liquor 2 is 5 DEG C, then at 5 DEG C
DMAP is added thereto to, completion of dropping obtains reactant liquor 2, reactant liquor 2 reacts at 25 DEG C 12 hours, then
Add water crystallization, suction filtration, and gained filter cake 2 is 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）
Amino-D-Glucose, standby；
Described pyridine, step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, acetic anhydride, 4-
The mass volume ratio of dimethylamino naphthyridine and water is 70ml：22g：45g：0.20g：220ml；
3. by step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
Grape sugar is added in acetone and is dissolved, and the hydrochloric acid solution that 5mol/L is then added dropwise thereto adjusts pH value to 2, and completion of dropping is at 25 DEG C
Stirring 2 hours, suction filtration, gained filter cake are 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides；
Wherein step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
The mass volume ratio of grape SA is 22g：260ml；
4. by step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides are added in acetonitrile, are stirred at 0 DEG C
The sodium bicarbonate aqueous solution for being added dropwise that mass fraction is 12% thereto is mixed, completion of dropping is stirred 35 minutes, and quality point is added dropwise thereto
Acetonitrile solution of the number for 15% benzene oxygen thio-carbonyl chloride, completion of dropping, stirring reaction 1 hour at 25 DEG C obtain reactant liquor 4, will
Gained reactant liquor 4 is extracted with ethyl acetate and saturated aqueous common salt successively, merges organic phase, and gained organic phase vacuum distillation obtains 1,
3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose；
Wherein step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, acetonitrile, sodium bicarbonate aqueous solution
Mass volume ratio with the acetonitrile solution of benzene oxygen thio-carbonyl chloride is 1.5g：18ml：38g：12g；
The volume ratio of reactant liquor 4, ethyl acetate and saturated aqueous common salt is 2：3：3；
5. under nitrogen protection, by step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyanos glucose add toluene
Middle dissolving, is added dropwise three (trimethyl silicon substrate) silane and azodiisobutyronitrile thereto successively, is warming up to 85 DEG C and reacts 4 hours, obtains
To reactant liquor 5, reactant liquor 5 is cooled to 25 DEG C, it is 1 that volume ratio is used after vacuum distillation：1 acetone and petroleum ether mixed liquor crystallization
2 ~ 3 hours, obtain 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol；
Wherein step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose, toluene, three (trimethyl silicon substrate) silicon
The mass volume ratio of alkane and azodiisobutyronitrile is 5g：150ml：1.7g：0.3g；
6. by step 5. gained 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol is dissolved in methyl alcohol, is cooled to 0 DEG C, then
Be added thereto to sodium methoxide, stirring reaction adds acetic acid after 1 hour, obtains reactant liquor 6, by after 6 vacuum distillation of reactant liquor with two
Chloromethanes crystallization, obtains 2-deoxy-D-glucose；
Wherein 1, the mass body of 3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol, methyl alcohol, sodium methoxide, acetic acid and dichloromethane
Product is than being 1g：6ml：0.25g：3ml：6ml.
The principle of the preparation method of 2-deoxy-D-glucose of the present invention is：
Step 1：With D-Glucosamine Hydrochloride as initiation material, amino is protected with P-methoxybenzal-dehyde.
Step 2：In DMAP（DMAP）Under catalysis, solvent is made with pyridine, acetic anhydride is reactant to D- ammonia
On base glucose, all of hydroxyl carries out acetylation protection.
Step 3：Protection group on deaminizating in acid condition.
Step 4：Amino is changed into isothiocyano with PhOC (=S) Cl.
Step 5：With AIBN as initiator, with three (trimethyl silicon substrate) silane（TTMS-H）With 1,3,4,6- tetra--oxygen-acetyl
Base -2- isothiocyanos glucose carries out radical reaction.
Step 6：Under alkalescence condition, deacetylation obtains target product 1,5-anhydroglucitol.
Synthetic route is as follows：
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
A kind of preparation method of 2-deoxy-D-glucose, comprises the following steps：
1. 40kg aminoglucose hydrochlorides are added in 300L water, stirring dissolves which, is then added thereto to 8kg hydroxides
Sodium, obtains mixed liquor 1 after stirring, 20kg p-anisaldehydes are added dropwise in mixed liquor 1, keeps mixed liquor 1 during dropwise addition
Temperature is 2 ~ 7 DEG C, and stirring reaction 10 hours at such a temperature, obtains reactant liquor 1, adds 360L methyl- terts in reactant liquor 1
Butyl ether, stirs 20 minutes, suction filtration, and gained filter cake 1 is 2-（4'- methoxybenzylidenes）Amino -2- deoxidation-D- grapes
Sugar, yield 94%；
2. 20kg steps 1. gained 2- is taken（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose is added in 65L pyridines
Dissolving, obtains mixed liquor 2, and 40kg acetic anhydrides are added dropwise in mixed liquor 2, and during keeping being added dropwise, the temperature of mixed liquor 2 is 0 ~ 5
DEG C, at 0 ~ 5 DEG C, 0.15kg4- dimethylamino naphthyridines are then added thereto to, completion of dropping obtains reactant liquor 2, by reactant liquor 2
Then plus 200L elutriations are brilliant, suction filtration 10 ~ 15 hours are reacted at 20 ~ 30 DEG C, gained filter cake 2 is 1,3,4,6- tetra--oxygen-second
Acyl group -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D-Glucose, yield 88%；
3. by 20kg steps 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-
D-Glucose is added in 250L acetone and is dissolved, and the hydrochloric acid solution of 6N is then added dropwise thereto, adjusts its pH value to 1, completion of dropping
Stir 1 ~ 2 hour at 20 ~ 30 DEG C, suction filtration, gained filter cake are 1,3,4,6- tetra--oxy-acetyl -2- glucosamine hydrochloric acids
Salt, yield 92%；
4. by 1.5kg steps 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides are added in 15L acetonitriles,
The sodium bicarbonate aqueous solution for being added dropwise that 35kg mass fractions are 10% thereto is stirred at 0 DEG C, and completion of dropping is stirred 30 ~ 40 minutes,
Acetonitrile solution that 10kg mass fraction be 10% benzene oxygen thio-carbonyl chloride is added dropwise thereto, and completion of dropping is stirred at 20 ~ 30 DEG C
Reaction 1 ~ 2 hour, obtains reactant liquor 4, gained reactant liquor 4 is extracted with 90L ethyl acetate and 90L saturated aqueous common salts successively, is closed
And organic phase, gained organic phase vacuum distillation obtains 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose, in oily,
Yield 87%；
5. under nitrogen protection, by 1kg steps 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyanos glucose are added
Dissolve in 25L toluene, tri- (trimethyl silicon substrate) silane of 375g and 25g azodiisobutyronitriles is added dropwise successively thereto, is warming up to 80
DEG C reaction 3 hours, obtain reactant liquor 5, reactant liquor 5 be cooled to 20 DEG C, after vacuum distillation with volume ratio be 1：1 acetone and stone
Oily ether mixed liquor crystallization 2 hours, obtains 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol, and yield is 81%；
6. by 0.5kg steps 5. gained 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol is dissolved in 2.5L methyl alcohol, is cooled to
0 ~ 5 DEG C, 0.1kg sodium methoxides are then added thereto to, stirring reaction added 1L acetic acid after 1 ~ 2 hour, obtain reactant liquor 6, will be anti-
2.5L dichloromethane crystallizations are used after answering 6 vacuum distillation of liquid, 2-deoxy-D-glucose, yield 94% is obtained, HPLC purity is
99.2%.
Embodiment 2
A kind of preparation method of 2-deoxy-D-glucose, comprises the following steps：
1. 100kg aminoglucose hydrochlorides are added in 480L water, stirring dissolves which, is then added thereto to 18kg hydrogen-oxygens
Change sodium, after stirring, obtain mixed liquor 1, in mixed liquor 1,60kg p-anisaldehydes are added dropwise, during dropwise addition, keep mixed liquor 1
Temperature be 2 ~ 7 DEG C, and stirring reaction 10 ~ 15 hours at such a temperature obtain reactant liquor 1, add 800L first in reactant liquor 1
Base tertbutyl ether, stirs 20 ~ 40 minutes, suction filtration, and gained filter cake 1 is 2-（4'- methoxybenzylidenes）Amino -2- deoxidations -
D-Glucose, yield 95%；
2. by 50kg steps 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose is added in 150L pyridines
Dissolving, obtains mixed liquor 2, and 100kg acetic anhydrides are added dropwise in mixed liquor 2, and during keeping being added dropwise, the temperature of mixed liquor 2 is 0 ~ 5
DEG C, at 0 ~ 5 DEG C, 0.5kg4- dimethylamino naphthyridines are then added thereto to, completion of dropping obtains reactant liquor 2, and reactant liquor 2 is existed
Then plus 400L elutriations are brilliant, suction filtration 10 ~ 15 hours are reacted at 20 ~ 30 DEG C, gained filter cake 2 is 1,3,4,6- tetra--oxygen-acetyl
Base -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D-Glucose, yield 89%；
3. by 25kg steps 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-
D-Glucose is added in 280L acetone and is dissolved, and 8M hydrochloric acid solutions is added dropwise thereto then, adjusts its pH value to 4, and completion of dropping exists
Stir 1 hour at 30 DEG C, suction filtration, gained filter cake are 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, yield
93%；
4. by 4kg steps 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides are added in 40L acetonitriles, 5
Stir at DEG C thereto be added dropwise 80kg mass fractions be 15% sodium bicarbonate aqueous solution, completion of dropping stir 30 minutes, thereto
Be added dropwise 30kg mass fractions be 15% benzene oxygen thio-carbonyl chloride acetonitrile solution, completion of dropping, stirring reaction 1 hour at 30 DEG C,
Reactant liquor 4 is obtained, gained reactant liquor 4 is extracted with 150L ethyl acetate and 150L saturated aqueous common salts successively, is merged organic phase, institute
Organic phase vacuum distillation obtains 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose, product is in oily, yield 88%；
5. under nitrogen protection, by 3kg steps 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyanos glucose are added
Dissolve in 100L toluene, tri- (trimethyl silicon substrate) silane of 1kg and 0.25kg azodiisobutyronitriles is added dropwise successively thereto, is warming up to
80 ~ 90 DEG C are reacted 3 ~ 5 hours, obtain reactant liquor 5, reactant liquor 5 is cooled to 20 ~ 30 DEG C, and it is 1 to use volume ratio after vacuum distillation：1
Acetone and petroleum ether mixed liquor crystallization 2 hours, obtain 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol, yield 82%；
6. by 2kg steps 5. gained 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol is dissolved in 10L methyl alcohol, is cooled to 0 ~ 5
DEG C, 0.3kg sodium methoxides are then added thereto to, stirring reaction adds 4L acetic acid after 1 ~ 2 hour, obtains reactant liquor 6, by reactant liquor
With 8L dichloromethane crystallizations after 6 vacuum distillations, 2-deoxy-D-glucose, yield 95% is obtained, HPLC purity is 99.1%.
Embodiment 3
A kind of preparation method of 2-deoxy-D-glucose, comprises the following steps：
1. 88kg aminoglucose hydrochlorides are added in 500L water, stirring dissolves which, is then added thereto to 16.4kg hydrogen
Sodium oxide molybdena, obtains mixed liquor 1 after stirring, 52kg p-anisaldehydes are added dropwise in mixed liquor 1, keeps mixed liquor during dropwise addition
1 temperature is 2 ~ 7 DEG C, and stirring reaction 12 hours at such a temperature, obtains reactant liquor 1, adds 740L methyl in reactant liquor 1
Tertbutyl ether, stirs 25 minutes, suction filtration, and gained filter cake 1 is 2-（4'- methoxybenzylidenes）Amino -2- deoxidation-D- grapes
Sugar, yield 94%；
2. by 66kg steps 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose is added in 213L pyridines
Dissolving, obtains mixed liquor 2, and 126kg acetic anhydrides are added dropwise in mixed liquor 2, and during keeping being added dropwise, the temperature of mixed liquor 2 is 0 ~ 5
DEG C, at 0 ~ 5 DEG C, 0.5kg4- dimethylamino naphthyridines are then added thereto to, completion of dropping obtains reactant liquor 2, and reactant liquor 2 is existed
Then plus 630L elutriations are brilliant, suction filtration 10 ~ 15 hours are reacted at 20 ~ 30 DEG C, gained filter cake 2 is 1,3,4,6- tetra--oxygen-acetyl
Base -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D-Glucose, yield 89%；
3. by 42kg steps 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-
D-Glucose is added in 520L acetone and is dissolved, and 5N hydrochloric acid solutions is added dropwise thereto then, adjusts its pH value to 2, and completion of dropping exists
Stir 1.5 hours at 24 DEG C, suction filtration, gained filter cake are 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, produce
Rate 93%；
4. by 18kg steps 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides are added in 160L acetonitriles,
The sodium bicarbonate aqueous solution for being added dropwise that 38kg mass fractions are 13% thereto is stirred at 0 ~ 5 DEG C, and completion of dropping is stirred 34 minutes,
Acetonitrile solution that 13kg mass fraction be 13% benzene oxygen thio-carbonyl chloride, completion of dropping, 22 DEG C at stirring reaction are added dropwise thereto
1.5 hours, reactant liquor 4 is obtained, gained reactant liquor 4 is extracted with ethyl acetate and saturated aqueous common salt successively, merges organic phase, institute
Organic phase vacuum distillation obtains 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose, product is in oily, yield 89%；
The volume ratio of wherein reactant liquor 4, ethyl acetate and saturated aqueous common salt is 2：3：3；
5. under nitrogen protection, by 5kg steps 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyanos glucose are added
Dissolve in 120L toluene, tri- (trimethyl silicon substrate) silane of 1.8kg and 0.2kg azodiisobutyronitriles is added dropwise successively thereto, heat up
Reacting 4 hours to 82 DEG C, obtaining reactant liquor 5, reactant liquor 5 is cooled to 24 DEG C, it is 1 that volume ratio is used after vacuum distillation：1 acetone
With petroleum ether mixed liquor crystallization 2 ~ 3 hours, 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol, yield 83% is obtained；
6. by 1.5kg steps 5. gained 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol is dissolved in 6L methyl alcohol, it is cooled to 0 ~
5 DEG C, 0.24kg sodium methoxides are then added thereto to, stirring reaction adds 3L acetic acid after 1 ~ 2 hour, obtains reactant liquor 6, will reaction
With 6L dichloromethane crystallizations after 6 vacuum distillation of liquid, 2-deoxy-D-glucose, yield 96% is obtained, HPLC purity is 99.4%.
Embodiment 4
A kind of preparation method of 2-deoxy-D-glucose, comprises the following steps：
1. 44kg aminoglucose hydrochlorides are added in 260L water, stirring dissolves which, is then added thereto to 9.6kg hydrogen-oxygens
Change sodium, after stirring, obtain mixed liquor 1, in mixed liquor 1,24kg p-anisaldehydes are added dropwise, during dropwise addition, keep mixed liquor 1
Temperature be 2 ~ 7 DEG C, and stirring reaction 12 hours at such a temperature obtain reactant liquor 1, add 400L methyl in reactant liquor 1
Tertbutyl ether, stirs 30 minutes, suction filtration, and gained filter cake 1 is 2-（4'- methoxybenzylidenes）Amino -2- deoxidation-D- grapes
Sugar, yield 95%；
2. by 33kg steps 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose is added in 105L pyridines
Dissolving, obtains mixed liquor 2, and 67.5kg acetic anhydrides are added dropwise in mixed liquor 2, and during keeping being added dropwise, the temperature of mixed liquor 2 is 5
DEG C, at 5 DEG C, 0.3kg4- dimethylamino naphthyridines are then added thereto to, completion of dropping obtains reactant liquor 2, by reactant liquor 2 25
Then plus 330L elutriations are brilliant, suction filtration 12 hours are reacted at DEG C, gained filter cake 2 is 1,3,4,6- tetra--oxy-acetyl -2- and takes off
Oxygen -2-（4'- methoxybenzylidenes）Amino-D-Glucose, yield 90%；
3. by 22kg steps 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-
D-Glucose is added in 260L acetone and is dissolved, and the hydrochloric acid solution that 5mol/L is then added dropwise thereto adjusts pH value to 2, completion of dropping
Stir 2 hours at 25 DEG C, suction filtration, gained filter cake are 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, produce
Rate 94%；
4. by 6kg steps 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides are added in 72L acetonitriles, 0
Stir at DEG C thereto be added dropwise 152L mass fractions be 12% sodium bicarbonate aqueous solution, completion of dropping stir 35 minutes, thereto
Be added dropwise 48L mass fractions be 15% benzene oxygen thio-carbonyl chloride acetonitrile solution, completion of dropping, stirring reaction 1 hour at 25 DEG C,
Reactant liquor 4 is obtained, gained reactant liquor 4 is extracted with 408L ethyl acetate and 408L saturated aqueous common salts successively, is merged organic phase, institute
Organic phase vacuum distillation obtains 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose, product is in oily, yield 90%；
5. under nitrogen protection, by 5kg steps 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyanos glucose are added
Dissolve in 150L toluene, tri- (trimethyl silicon substrate) silane of 1.7kg and 0.3kg azodiisobutyronitriles is added dropwise successively thereto, heat up
Reacting 4 hours to 85 DEG C, obtaining reactant liquor 5, reactant liquor 5 is cooled to 25 DEG C, it is 1 that volume ratio is used after vacuum distillation：1 acetone
With petroleum ether mixed liquor crystallization 2 ~ 3 hours, 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol, yield 85% is obtained；
6. by 1kg steps 5. gained 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol is dissolved in 6L methyl alcohol, is cooled to 0 DEG C,
Then 0.25kg sodium methoxides are added thereto to, and stirring reaction adds 3L acetic acid after 1 hour, obtains reactant liquor 6, reactant liquor 6 is subtracted
With 6L dichloromethane crystallizations after pressure distillation, 2-deoxy-D-glucose, yield 98% is obtained, HPLC purity is 99.6%.
Claims (5)
1. a kind of preparation method of 2-deoxy-D-glucose, it is characterised in that：Comprise the following steps：
1. aminoglucose hydrochloride is added to the water, stirring dissolves which, is then added thereto to NaOH, stirs
After obtain mixed liquor 1, in mixed liquor 1 be added dropwise p-anisaldehyde, during dropwise addition keep mixed liquor 1 temperature be 2 ~ 7 DEG C, and
Stirring reaction 10 ~ 15 hours, obtain reactant liquor 1 at this temperature, in reactant liquor 1 add methyl tertiary butyl ether(MTBE), stir 20 ~ 40 points
Clock, suction filtration, gained filter cake 1 are 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, standby；
The mass volume ratio of described aminoglucose hydrochloride, water, NaOH, p-anisaldehyde and methyl tertiary butyl ether(MTBE) is 20
~25g：120~150ml：4~4.5g：10~15g：180~200ml；
2. by step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose is added in pyridine and is dissolved, and is obtained
Mixed liquor 2 being arrived, acetic anhydride being added dropwise in mixed liquor 2, during keeping being added dropwise, the temperature of mixed liquor 2 is 0 ~ 5 DEG C, then 0 ~ 5
DMAP is added thereto at DEG C, and completion of dropping obtains reactant liquor 2, reactant liquor 2 reacts at 20 ~ 30 DEG C 10 ~
15 hours, then added water crystallization, suction filtration, and gained filter cake 2 is 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxies
Base benzylidene）Amino-D-Glucose, standby；
Described pyridine, step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, acetic anhydride, 4-
The mass volume ratio of dimethylamino naphthyridine and water is 65 ~ 75ml：20~25g：40~50g：0.15~0.25g：200~250ml；
3. by step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
Grape sugar is added in acetone and is dissolved, and hydrochloric acid solution is added dropwise thereto then, adjusts its pH value to 1 ~ 4, and completion of dropping is at 20 ~ 30 DEG C
Stirring 1 ~ 2 hour, suction filtration, gained filter cake are 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides；
Wherein step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
The mass volume ratio of grape SA is 20 ~ 25g：250~280ml；
4. by step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides are added in acetonitrile, at 0 ~ 5 DEG C
Stirring is added dropwise the sodium bicarbonate aqueous solution that mass fraction is for 10 ~ 15% thereto, and completion of dropping is stirred 30 ~ 40 minutes, dripped thereto
Plus mass fraction is the acetonitrile solution of 10 ~ 15% benzene oxygen thio-carbonyl chlorides, completion of dropping, at 20 ~ 30 DEG C, stirring reaction 1 ~ 2 is little
When, reactant liquor 4 being obtained, gained reactant liquor 4 is extracted with ethyl acetate and saturated aqueous common salt successively, is merged organic phase, gained has
Machine phase vacuum distillation obtains 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose；
Wherein step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, acetonitrile, sodium bicarbonate aqueous solution
Mass volume ratio with the acetonitrile solution of benzene oxygen thio-carbonyl chloride is 1.5 ~ 2g：15~20ml：35~40g：10~15g；
The volume ratio of reactant liquor 4, ethyl acetate and saturated aqueous common salt is 2 ~ 3：3：3；
5. under nitrogen protection, by step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyanos glucose add toluene
Middle dissolving, is added dropwise three (trimethyl silicon substrate) silane and azodiisobutyronitrile thereto successively, is warming up to 80 ~ 90 DEG C of reactions 3 ~ 5 little
When, reactant liquor 5 being obtained, reactant liquor 5 is cooled to 20 ~ 30 DEG C, it is 1 to use volume ratio after vacuum distillation：1 acetone and petroleum ether are mixed
Close liquation crystalline substance 2 ~ 3 hours, obtain 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol；
Wherein step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose, toluene, three (trimethyl silicon substrate) silicon
The mass volume ratio of alkane and azodiisobutyronitrile is 4 ~ 6g：100~200ml：1.5~2g：0.1~0.5g；
6. by step 5. gained 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol is dissolved in methyl alcohol, is cooled to 0 ~ 5 DEG C, so
After be added thereto to sodium methoxide, stirring reaction adds acetic acid after 1 ~ 2 hour, obtains reactant liquor 6, by 6 vacuum distillation of reactant liquor after
Dichloromethane crystallization is used, 2-deoxy-D-glucose is obtained；
Wherein 1, the mass body of 3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol, methyl alcohol, sodium methoxide, acetic acid and dichloromethane
Product is than being 1 ~ 2g：5~10ml：0.2~0.3g：2~4ml：5~8ml.
2. the preparation method of 2-deoxy-D-glucose according to claim 1, it is characterised in that：3. middle hydrochloric acid is molten for step
The concentration of liquid is 5mol/L, and the pH value being adjusted to is 2.
3. the preparation method of 2-deoxy-D-glucose according to claim 1, it is characterised in that：Step 4. middle material
Ratio is：Step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, acetonitrile, sodium bicarbonate aqueous solution
Mass volume ratio with the acetonitrile solution of benzene oxygen thio-carbonyl chloride is 1.5g：18ml：38g：12g.
4. the preparation method of 2-deoxy-D-glucose according to claim 1, it is characterised in that：Step 4. middle reactant liquor
4th, the volume ratio of ethyl acetate and saturated aqueous common salt is 2：3：3.
5. the preparation method of 2-deoxy-D-glucose according to claim 1, it is characterised in that：Comprise the following steps：
1. aminoglucose hydrochloride is added to the water, stirring dissolves which, is then added thereto to NaOH, stirs
After obtain mixed liquor 1, in mixed liquor 1 be added dropwise p-anisaldehyde, during dropwise addition keep mixed liquor 1 temperature be 2 ~ 7 DEG C, and
Stirring reaction 12 hours, obtain reactant liquor 1 at this temperature, in reactant liquor 1 add methyl tertiary butyl ether(MTBE), stir 30 minutes, take out
Filter, gained filter cake 1 are 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, standby；
The mass volume ratio of described aminoglucose hydrochloride, water, NaOH, p-anisaldehyde and methyl tertiary butyl ether(MTBE) is
22g：130ml：4.8g：12g：200ml；
2. by step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose is added in pyridine and is dissolved, and is obtained
Mixed liquor 2 being arrived, acetic anhydride being added dropwise in mixed liquor 2, during keeping being added dropwise, the temperature of mixed liquor 2 is 5 DEG C, then at 5 DEG C
DMAP is added thereto to, completion of dropping obtains reactant liquor 2, reactant liquor 2 reacts at 25 DEG C 12 hours, then
Add water crystallization, suction filtration, and gained filter cake 2 is 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）
Amino-D-Glucose, standby；
Described pyridine, step 1. gained 2-（4'- methoxybenzylidenes）Amino-2-deoxy-D-glucose, acetic anhydride, 4-
The mass volume ratio of dimethylamino naphthyridine and water is 70ml：22g：45g：0.20g：220ml；
3. by step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
Grape sugar is added in acetone and is dissolved, and the hydrochloric acid solution that 5mol/L is then added dropwise thereto adjusts pH value to 2, and completion of dropping is at 25 DEG C
Stirring 2 hours, suction filtration, gained filter cake are 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides；
Wherein step 2. gained 1,3,4,6- tetra--oxy-acetyl -2- deoxidation -2-（4'- methoxybenzylidenes）Amino-D- Portugals
The mass volume ratio of grape SA is 22g：260ml；
4. by step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides are added in acetonitrile, are stirred at 0 DEG C
The sodium bicarbonate aqueous solution for being added dropwise that mass fraction is 12% thereto is mixed, completion of dropping is stirred 35 minutes, and quality point is added dropwise thereto
Acetonitrile solution of the number for 15% benzene oxygen thio-carbonyl chloride, completion of dropping, stirring reaction 1 hour at 25 DEG C obtain reactant liquor 4, will
Gained reactant liquor 4 is extracted with ethyl acetate and saturated aqueous common salt successively, merges organic phase, and gained organic phase vacuum distillation obtains 1,
3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose；
Wherein step 3. gained 1,3,4,6- tetra--oxy-acetyl -2- aminoglucose hydrochlorides, acetonitrile, sodium bicarbonate aqueous solution
Mass volume ratio with the acetonitrile solution of benzene oxygen thio-carbonyl chloride is 1.5g：18ml：38g：12g；
The volume ratio of reactant liquor 4, ethyl acetate and saturated aqueous common salt is 2：3：3；
5. under nitrogen protection, by step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyanos glucose add toluene
Middle dissolving, is added dropwise three (trimethyl silicon substrate) silane and azodiisobutyronitrile thereto successively, is warming up to 85 DEG C and reacts 4 hours, obtains
To reactant liquor 5, reactant liquor 5 is cooled to 25 DEG C, it is 1 that volume ratio is used after vacuum distillation：1 acetone and petroleum ether mixed liquor crystallization
2 ~ 3 hours, obtain 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol；
Wherein step 4. gained 1,3,4,6- tetra--oxy-acetyl -2- isothiocyano glucose, toluene, three (trimethyl silicon substrate) silicon
The mass volume ratio of alkane and azodiisobutyronitrile is 5g：150ml：1.7g：0.3g；
6. by step 5. gained 1,3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol is dissolved in methyl alcohol, is cooled to 0 DEG C, then
Be added thereto to sodium methoxide, stirring reaction adds acetic acid after 1 hour, obtains reactant liquor 6, by after 6 vacuum distillation of reactant liquor with two
Chloromethanes crystallization, obtains 2-deoxy-D-glucose；
Wherein 1, the mass body of 3,4,6- tetra--oxy-acetyls -1,5-anhydroglucitol, methyl alcohol, sodium methoxide, acetic acid and dichloromethane
Product is than being 1g：6ml：0.25g：3ml：6ml.
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| CN110511257A (en) * | 2019-09-23 | 2019-11-29 | 济南山目生物医药科技有限公司 | A kind of preparation method of four-O- acetyl group -2- phthaloyl imino-beta- glucose |
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| CN110511257B (en) * | 2019-09-23 | 2023-08-04 | 济南山目生物医药科技有限公司 | Preparation method of tetra-O-acetyl-2-phthalimido-beta-glucose |
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