CN106397500B - A kind of synthetic method of L glucose - Google Patents

A kind of synthetic method of L glucose Download PDF

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CN106397500B
CN106397500B CN201610816858.4A CN201610816858A CN106397500B CN 106397500 B CN106397500 B CN 106397500B CN 201610816858 A CN201610816858 A CN 201610816858A CN 106397500 B CN106397500 B CN 106397500B
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petroleum ether
ethyl acetate
sodium
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CN106397500A (en
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李文举
唐鹏飞
贾元雪
李秀珍
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JINAN SAM BIOLOGICAL MEDICINE TECHNOLOGY Co.,Ltd.
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Ji'nan Biological Medicine Technology Co Ltd
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Abstract

The invention discloses a kind of synthetic method of L glucose, using sodium glucoheptonate as initiation material, is all protected hydroxyl with 2,2 dimethoxy propanes；Then in acid condition, selective Deprotection；Methyl esters is reduced into alcohol；Alcohol is oxidized to aldehyde；Take off whole protection groups and obtain target product L glucose；The invention provides a kind of preparation method for being adapted to industrial L glucose; this method is through overprotection, selective protection, reduction; oxidation and five steps of deprotection prepare L glucose; the post-processing operation often walked is simple, pertains only to be concentrated under reduced pressure, extraction; the techniques such as crystallization; any chromatographic column lock out operation it is not related to, the requirement to equipment is low, is adapted to large-scale production；Requirement of the preparation method of the present invention to equipment is low, and industrial production can be achieved using existing equipment, and the yield of each step is high, and the yield of each step is more than 70%, and even up to 100%, cost is low；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 industrial production.

Description

A kind of synthetic method of L- glucose
Technical field
The present invention relates to the synthetic method of carbohydrate chemistry technical field, specifically L- glucose.
Background technology
There is less sugar in nature in L- glucose, by L-configuration can not be urged by the catalysis glycometabolism enzyme in human body Change and decompose, thus L- glucose will not be digested, and be a kind of preferable for diabetes or the crowd that need to be gone on a diet Sweetener.Because of the unfermentable L sugar of oral microorganism, L- glucose will not cause carious tooth, and L- glucose is unlike artificial synthesized Sweetener there is rear bitter taste.In recent years, because its special biochemical characteristic, L- glucose are increasingly becoming a kind of more and more important Medicine intermediate, demand is larger, but expensive, and typically in 3210 yuan/5g, this mainly prepares work by its laboratory What skill determined.
Current preparation method has two kinds, when concentrated by L-arabinose in the presence of sodium methoxide with nitromethane, Target product L- glucose is obtained by Nef reaction again, the method makees solvent with nitromethane, and security risk is big, is unsuitable for putting Produce greatly and the method is not easy to purify；Second, prepared using D- gluconic acids -1,5- lactone as initiation material, D- glucose Acid -1,5- lactones obtain bromo- 2, the 6- dideoxies of 2,6- bis--D-MANNOSE acid-Isosorbide-5-Nitrae-lactone under hydrobromic acid effect, further To bromo- 6- deoxidations -2, the 3- dehydration-D- sweet dews-Isosorbide-5-Nitrae-lactones of 6-, final step by bromo- 6- deoxidations -2, the 3- dehydration-D- sweet dews of 6- - Isosorbide-5-Nitrae-lactone prepares L- glucose, is to need ion-exchange chromatography acid post, alkali post the shortcomings that the technique, purifying technique it is complicated and Cost is higher.
The content of the invention
To solve the above problems, it is an object of the invention to provide the synthetic method of L- glucose.
The present invention to achieve the above object, is achieved through the following technical solutions：
A kind of synthetic method of L- glucose, comprises the following steps：
1. sodium glucoheptonate is dissolved in into 2,2-dimethoxypropane and is cooled to 0 ~ 5 DEG C, under agitation, dripped into system Add methanol hydrochloride solution, rear return stirring is added dropwise and reacts 1 ~ 2 hour, is then cooled to 0 ~ 5 DEG C, pH value is adjusted with sodium carbonate To 6 ~ 8, filtering, filtrate is obtained, gained filtrate decompression is distilled, added petroleum ether thereto after removing solvent, then wash, closed And petroleum ether phase, gained petroleum ether is mutually evaporated under reduced pressure to obtain compound 1；
The wherein mass volume ratio of sodium glucoheptonate, 2,2-dimethoxypropane, methanol hydrochloride solution, petroleum ether and water For 1g：4~6ml：2~3ml：4~6ml：4~6ml；
The methanol hydrochloride solution is hydrochloric acid and methanol by mass fraction 37% according to volume ratio 1：1 mixing composition；
The structural formula I of the compound 1 is：
；
2. by step, 1. gained compound 1 is dissolved in methanol and is cooled to -10 ~ -5 DEG C, then under agitation to its dropwise addition pair Toluenesulfonic acid, reacted at such a temperature after being added dropwise 3 ~ 5 hours, obtain reaction solution 1, triethylamine regulation is added to reaction solution 1 PH value obtains mixed liquor to 8 ~ 9, and gained mixed liquor is evaporated under reduced pressure and removes solvent, then adds petroleum ether 1 thereto, washing, Merge aqueous phase, aqueous phase is extracted with ethyl acetate, combined ethyl acetate phase, then the ethyl acetate phase of merging is evaporated under reduced pressure and removed Ethyl acetate is removed, adds petroleum ether 2 thereto, crystallization, filtering, gained filter cake is compound 2；
Wherein step 1. gained compound 1, methanol, p-methyl benzenesulfonic acid, petroleum ether 1, water, ethyl acetate and petroleum ether 2 Mass volume ratio is 2 ~ 3g：15~25ml：1g：10~15ml：10~15ml：15~17ml：3~5ml；
The formula II of the compound 2 is：
；
3. by step, 2. gained compound 2 is dissolved in tetrahydrofuran and is cooled to 0 ~ 5 DEG C, and hydroboration is then added dropwise thereto Sodium, back flow reaction is added dropwise 5 ~ 6 hours, obtains reaction solution 2, gained reaction solution 2 is cooled into 0 ~ 5 DEG C is added dropwise chlorination thereto Ammonium saturated solution is 7 ~ 8 to pH, is evaporated under reduced pressure and removes solvent, then adds ethyl acetate thereto and stirs, filters, filtrate Vacuum distillation obtains compound 3；
Wherein 2. gained compound 2, tetrahydrofuran, sodium borohydride, the mass volume ratio of ethyl acetate are 2 ~ 5g to step：10 ~15ml：1g：10~15ml；
The formula II I of described compound 3 is：
；
4. by step, 3. gained compound 3 is dissolved in dichloromethane 1, then adds sodium metaperiodate/silica gel mixing thereto Oxidation system, stirring reaction 1 ~ 2 hour, add after magnesium sulfate is dried and filter, silica gel with methylene chloride 2 elutes 2 times, and filtrate merges After be evaporated under reduced pressure, obtain compound 4；
Wherein 3. gained compound 3, dichloromethane 1, magnesium sulfate, the mass volume ratio of dichloromethane 2 are 1g to step：15~ 20ml：5~10g：5~10ml；
3. gained compound 3 and the mass ratio of the sodium metaperiodate in sodium metaperiodate/silica gel mixed oxidization system are 1g to step： 0.7~0.8g；
The structural formula IV of the compound 4 is：
；
5. by step, 4. gained compound 4 is soluble in water, adds tween thereto, stirs 20 ~ 25 hours, filtering, will filter Liquid is evaporated under reduced pressure to obtain L- glucose；Wherein 4. gained compound 4, water, the mass volume ratio of tween are 1 ~ 2g to step：14~ 18ml：1g.
Preferably, step 1. middle sodium glucoheptonate, 2,2-dimethoxypropane, methanol hydrochloride solution, petroleum ether and water Mass volume ratio be 1g：5ml：2.5ml：5ml：5ml.
Preferably, step 1. gained compound 1, methanol, p-methyl benzenesulfonic acid, petroleum ether 1, water, ethyl acetate and petroleum ether 2 Mass volume ratio be 2.5g：20ml：1g：12ml：12ml：16ml：4ml.
Preferably, the quality of the step 3. sodium metaperiodate in gained compound 3 and sodium metaperiodate/silica gel mixed oxidization system Than for 1g：0.75g.
Further preferred synthetic method, comprises the following steps：
1. sodium glucoheptonate is dissolved in into 2,2-dimethoxypropane and is cooled to 0 DEG C, under agitation, it is added dropwise into system Methanol hydrochloride solution, rear return stirring is added dropwise and reacts 1 hour, is then cooled to 0 DEG C, with sodium carbonate regulation pH value to 7, mistake Filter, obtains filtrate, gained filtrate decompression is distilled, and adds petroleum ether thereto after removing solvent, then washes, and merges petroleum ether Phase, gained petroleum ether is mutually evaporated under reduced pressure to obtain compound 1；
The wherein mass volume ratio of sodium glucoheptonate, 2,2-dimethoxypropane, methanol hydrochloride solution, petroleum ether and water For 1g：5ml：2.5ml：5ml：5ml；
The methanol hydrochloride solution is hydrochloric acid and methanol by mass fraction 37% according to volume ratio 1：1 mixing composition；
The structural formula I of the compound 1 is：
；
2. by step, 1. gained compound 1 is dissolved in methanol and is cooled to -10 DEG C, then under agitation to its dropwise addition to toluene Sulfonic acid, reacted at such a temperature after being added dropwise 4 hours, obtain reaction solution 1, to reaction solution 1 add triethylamine adjust pH value to 8, mixed liquor is obtained, gained mixed liquor is evaporated under reduced pressure and removes solvent, petroleum ether 1 is then added thereto, washing, merges water Phase, aqueous phase is extracted with ethyl acetate, combined ethyl acetate phase, then the ethyl acetate phase of merging is evaporated under reduced pressure and removes acetic acid Ethyl ester, petroleum ether 2 is added thereto, crystallization, filtering, gained filter cake is compound 2；
Wherein step 1. gained compound 1, methanol, p-methyl benzenesulfonic acid, petroleum ether 1, water, ethyl acetate and petroleum ether 2 Mass volume ratio is 2.5g：20ml：1g：12ml：12ml：16ml：4ml；
The formula II of the compound 2 is：
；
3. by step, 2. gained compound 2 is dissolved in tetrahydrofuran and is cooled to 0 DEG C, and hydroboration is then added dropwise thereto Sodium, back flow reaction is added dropwise 5 hours, obtains reaction solution 2, by gained reaction solution 2 be cooled to 0 DEG C thereto be added dropwise ammonium chloride satisfy It is 7 with solution to pH, is evaporated under reduced pressure and removes solvent, then adds ethyl acetate thereto and stir, filter, filtrate decompression is steamed Evaporate to obtain compound 3；
Wherein 2. gained compound 2, tetrahydrofuran, sodium borohydride, the mass volume ratio of ethyl acetate are 3g to step： 12ml：1g：12ml；
The formula II I of described compound 3 is：
；
4. by step, 3. gained compound 3 is dissolved in dichloromethane 1, then adds sodium metaperiodate/silica gel mixing thereto Oxidation system, stirring reaction 1 hour, add after magnesium sulfate is dried and filter, silica gel with methylene chloride 2 elutes 2 times, after filtrate merges It is evaporated under reduced pressure, obtains compound 4；
Wherein 3. gained compound 3, dichloromethane 1, magnesium sulfate, the mass volume ratio of dichloromethane 2 are 1g to step： 16ml：8g：8ml；
3. gained compound 3 and the mass ratio of the sodium metaperiodate in sodium metaperiodate/silica gel mixed oxidization system are 1g to step： 0.75g；
The structural formula IV of the compound 4 is：
；
5. by step, 4. gained compound 4 is soluble in water, adds tween thereto, stirs 22 hours, filtering, filtrate is subtracted Pressure distillation obtains L- glucose；Wherein 4. gained compound 4, water, the mass volume ratio of tween are 1.5g to step：16ml：1g.
The present invention has advantages below compared with prior art：
The invention provides a kind of preparation method for being adapted to industrial L- glucose, this method is with cheap and easily-available Portugal Grape sugar enanthic acid sodium is raw material, and through overprotection, selective protection, reduction, oxidation and five steps of deprotection prepare L- glucose, and design is skilful Wonderful, the post-processing operation flow often walked is few, pertains only to be concentrated under reduced pressure, extraction, the technique such as crystallization, is not related to any chromatogram post separation Operation, the requirement to equipment is low, is adapted to large-scale production；
The first step of the present invention by the reaction yield that hydroxyl is all protected 85 ~ 90%, second step selectivity in acid condition Alcohol is oxidized to aldehyde by the yield that methyl esters is reduced into alcohol in 85 ~ 90%, the 3rd steps by the yield of deprotection in 93 ~ 95%, the 4th steps Yield is 100%, and the yield of the 5th step Deprotection is 100%, and the yield of each step is more than 85%, the production of two of which step Rate reaches 100%, process stabilizing, and cost is low；
Requirement of the preparation method of the present invention to equipment is low, and industrial production, and this hair can be achieved using existing equipment Bright preparation method is simple to the aftertreatment technology of product, and product is easily isolated, it is easy to accomplish large-scale industrial production.
Embodiment
It is an object of the invention to provide the synthetic method of L- glucose, it is achieved through the following technical solutions：
A kind of synthetic method of L- glucose, comprises the following steps：
1. sodium glucoheptonate is dissolved in into 2,2-dimethoxypropane and is cooled to 0 ~ 5 DEG C, under agitation, dripped into system Add methanol hydrochloride solution, rear return stirring is added dropwise and reacts 1 ~ 2 hour, is then cooled to 0 ~ 5 DEG C, pH value is adjusted with sodium carbonate To 6 ~ 8, filtering, filtrate is obtained, gained filtrate decompression is distilled, added petroleum ether thereto after removing solvent, then wash, closed And petroleum ether phase, gained petroleum ether is mutually evaporated under reduced pressure to obtain compound 1；
The wherein mass volume ratio of sodium glucoheptonate, 2,2-dimethoxypropane, methanol hydrochloride solution, petroleum ether and water For 1g：4~6ml：2~3ml：4~6ml：4~6ml；
The methanol hydrochloride solution is hydrochloric acid and methanol by mass fraction 37% according to volume ratio 1：1 mixing composition；
The structural formula I of the compound 1 is：
；
2. by step, 1. gained compound 1 is dissolved in methanol and is cooled to -10 ~ -5 DEG C, then under agitation to its dropwise addition pair Toluenesulfonic acid, reacted at such a temperature after being added dropwise 3 ~ 5 hours, obtain reaction solution 1, triethylamine regulation is added to reaction solution 1 PH value obtains mixed liquor to 8 ~ 9, and gained mixed liquor is evaporated under reduced pressure and removes solvent, then adds petroleum ether 1 thereto, washing, Merge aqueous phase, aqueous phase is extracted with ethyl acetate, combined ethyl acetate phase, then the ethyl acetate phase of merging is evaporated under reduced pressure and removed Ethyl acetate is removed, adds petroleum ether 2 thereto, crystallization, filtering, gained filter cake is compound 2；
Wherein step 1. gained compound 1, methanol, p-methyl benzenesulfonic acid, petroleum ether 1, water, ethyl acetate and petroleum ether 2 Mass volume ratio is 2 ~ 3g：15~25ml：1g：10~15ml：10~15ml：15~17ml：3~5ml；
The formula II of the compound 2 is：
；
3. by step, 2. gained compound 2 is dissolved in tetrahydrofuran and is cooled to 0 ~ 5 DEG C, and hydroboration is then added dropwise thereto Sodium, back flow reaction is added dropwise 5 ~ 6 hours, obtains reaction solution 2, gained reaction solution 2 is cooled into 0 ~ 5 DEG C is added dropwise chlorination thereto Ammonium saturated solution is 7 ~ 8 to pH, is evaporated under reduced pressure and removes solvent, then adds ethyl acetate thereto and stirs, filters, filtrate Vacuum distillation obtains compound 3；
Wherein 2. gained compound 2, tetrahydrofuran, sodium borohydride, the mass volume ratio of ethyl acetate are 2 ~ 5g to step：10 ~15ml：1g：10~15ml；
The formula II I of described compound 3 is：
；
4. by step, 3. gained compound 3 is dissolved in dichloromethane 1, then adds sodium metaperiodate/silica gel mixing thereto Oxidation system, stirring reaction 1 ~ 2 hour, add after magnesium sulfate is dried and filter, silica gel with methylene chloride 2 elutes 2 times, and filtrate merges After be evaporated under reduced pressure, obtain compound 4；
Wherein 3. gained compound 3, dichloromethane 1, magnesium sulfate, the mass volume ratio of dichloromethane 2 are 1g to step：15~ 20ml：5~10g：5~10ml；
3. gained compound 3 and the mass ratio of the sodium metaperiodate in sodium metaperiodate/silica gel mixed oxidization system are 1g to step： 0.7~0.8g；
The structural formula IV of the compound 4 is：
；
5. by step, 4. gained compound 4 is soluble in water, adds tween thereto, stirs 20 ~ 25 hours, filtering, will filter Liquid is evaporated under reduced pressure to obtain L- glucose；Wherein 4. gained compound 4, water, the mass volume ratio of tween are 1 ~ 2g to step：14~ 18ml：1g.
Preferably, step 1. middle sodium glucoheptonate, 2,2-dimethoxypropane, methanol hydrochloride solution, petroleum ether and water Mass volume ratio be 1g：5ml：2.5ml：5ml：5ml.
Preferably, step 1. gained compound 1, methanol, p-methyl benzenesulfonic acid, petroleum ether 1, water, ethyl acetate and petroleum ether 2 Mass volume ratio be 2.5g：20ml：1g：12ml：12ml：16ml：4ml.
Preferably, the quality of the step 3. sodium metaperiodate in gained compound 3 and sodium metaperiodate/silica gel mixed oxidization system Than for 1g：0.75g.
Further preferred synthetic method, comprises the following steps：
1. sodium glucoheptonate is dissolved in into 2,2-dimethoxypropane and is cooled to 0 DEG C, under agitation, it is added dropwise into system Methanol hydrochloride solution, rear return stirring is added dropwise and reacts 1 hour, is then cooled to 0 DEG C, with sodium carbonate regulation pH value to 7, mistake Filter, obtains filtrate, gained filtrate decompression is distilled, and adds petroleum ether thereto after removing solvent, then washes, and merges petroleum ether Phase, gained petroleum ether is mutually evaporated under reduced pressure to obtain compound 1；
The wherein mass volume ratio of sodium glucoheptonate, 2,2-dimethoxypropane, methanol hydrochloride solution, petroleum ether and water For 1g：5ml：2.5ml：5ml：5ml；
The methanol hydrochloride solution is hydrochloric acid and methanol by mass fraction 37% according to volume ratio 1：1 mixing composition；
The structural formula I of the compound 1 is：
；
2. by step, 1. gained compound 1 is dissolved in methanol and is cooled to -10 DEG C, then under agitation to its dropwise addition to toluene Sulfonic acid, reacted at such a temperature after being added dropwise 4 hours, obtain reaction solution 1, to reaction solution 1 add triethylamine adjust pH value to 8, mixed liquor is obtained, gained mixed liquor is evaporated under reduced pressure and removes solvent, petroleum ether 1 is then added thereto, washing, merges water Phase, aqueous phase is extracted with ethyl acetate, combined ethyl acetate phase, then the ethyl acetate phase of merging is evaporated under reduced pressure and removes acetic acid Ethyl ester, petroleum ether 2 is added thereto, crystallization, filtering, gained filter cake is compound 2；
Wherein step 1. gained compound 1, methanol, p-methyl benzenesulfonic acid, petroleum ether 1, water, ethyl acetate and petroleum ether 2 Mass volume ratio is 2.5g：20ml：1g：12ml：12ml：16ml：4ml；
The formula II of the compound 2 is：
；
3. by step, 2. gained compound 2 is dissolved in tetrahydrofuran and is cooled to 0 DEG C, and hydroboration is then added dropwise thereto Sodium, back flow reaction is added dropwise 5 hours, obtains reaction solution 2, by gained reaction solution 2 be cooled to 0 DEG C thereto be added dropwise ammonium chloride satisfy It is 7 with solution to pH, is evaporated under reduced pressure and removes solvent, then adds ethyl acetate thereto and stir, filter, filtrate decompression is steamed Evaporate to obtain compound 3；
Wherein 2. gained compound 2, tetrahydrofuran, sodium borohydride, the mass volume ratio of ethyl acetate are 3g to step： 12ml：1g：12ml；
The formula II I of described compound 3 is：
；
4. by step, 3. gained compound 3 is dissolved in dichloromethane 1, then adds sodium metaperiodate/silica gel mixing thereto Oxidation system, stirring reaction 1 hour, add after magnesium sulfate is dried and filter, silica gel with methylene chloride 2 elutes 2 times, after filtrate merges It is evaporated under reduced pressure, obtains compound 4；
Wherein 3. gained compound 3, dichloromethane 1, magnesium sulfate, the mass volume ratio of dichloromethane 2 are 1g to step： 16ml：8g：8ml；
3. gained compound 3 and the mass ratio of the sodium metaperiodate in sodium metaperiodate/silica gel mixed oxidization system are 1g to step： 0.75g；
The structural formula IV of the compound 4 is：
；
5. by step, 4. gained compound 4 is soluble in water, adds tween thereto, stirs 22 hours, filtering, filtrate is subtracted Pressure distillation obtains L- glucose；Wherein 4. gained compound 4, water, the mass volume ratio of tween are 1.5g to step：16ml：1g.
Reaction principle of the present invention is：
Step 1：Using sodium glucoheptonate as initiation material, hydroxyl is all protected with 2,2-dimethoxypropane；
Step 2：In acid condition, selective Deprotection；
Step 3：Methyl esters is reduced into alcohol；
Step 4：Alcohol is oxidized to aldehyde；
Step 5：Whole protection groups, which are taken off, with acid resin obtains target product L- glucose.
Synthetic route is：
Sodium metaperiodate/silica gel mixed oxidization system in the embodiment of the present invention is prepared by following steps：
Sodium metaperiodate is soluble in water, silica gel is poured into thereto, and vigorous mechanical agitation to silica gel becomes solid liquid shape, i.e., Sodium metaperiodate/silica gel mixed oxidization system is obtained, the wherein mass ratio of sodium metaperiodate and silica gel is 1：10~20.
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
A kind of synthetic method of L- glucose, comprises the following steps：
1. 100kg sodium glucoheptonates are dissolved in 400L 2,2-dimethoxypropanes and are cooled to 0 DEG C, under agitation, to Methanol hydrochloride solution 200L is added dropwise in system, rear return stirring is added dropwise and reacts 1 hour, is then cooled to 0 DEG C, uses sodium carbonate PH value is adjusted to 6, filtering, filtrate is obtained, gained filtrate decompression is distilled, 400L petroleum ethers are added thereto after removing solvent, Then 400L water washings are used, merges petroleum ether phase, gained petroleum ether is mutually evaporated under reduced pressure to obtain compound 1；Yield 85%；
The methanol hydrochloride solution is hydrochloric acid and methanol by mass fraction 37% according to volume ratio 1：1 mixing composition；
The structural formula I of the compound 1 is：
；
2. taking 80kg steps, 1. gained compound 1 is dissolved in 60L methanol and is cooled to -10 DEG C, then dripped under agitation to it Add 40kg p-methyl benzenesulfonic acid, reacted at such a temperature after being added dropwise 3 hours, obtain reaction solution 1, three second are added to reaction solution 1 Amine adjusts pH value to 8, obtains mixed liquor, gained mixed liquor is evaporated under reduced pressure and removes solvent, then add 400L oil thereto Ether, with 600L water washings, merge aqueous phase, aqueous phase is extracted with 600L ethyl acetate, combined ethyl acetate phase, then by merging Ethyl acetate phase, which is evaporated under reduced pressure, removes ethyl acetate, adds 120L petroleum ethers thereto, crystallization, filtering, gained filter cake is to change Compound 2, yield 85%；
The formula II of the compound 2 is：
；
3. taking 40kg steps, 2. gained compound 2 is dissolved in 200L tetrahydrofurans and is cooled to 0 DEG C, then it is added dropwise thereto 20kg sodium borohydrides, back flow reaction is added dropwise 5 ~ 6 hours, obtains reaction solution 2, gained reaction solution 2 is cooled to 0 DEG C thereto It is 7 that ammonium chloride saturated solution, which is added dropwise, to pH, is evaporated under reduced pressure and removes solvent, and it is equal then to add the stirring of 200L ethyl acetate thereto Even, filtering, filtrate decompression distills to obtain compound 3, yield 93%；
The formula II I of described compound 3 is：
；
4. taking 20kg steps, 3. gained compound 3 is dissolved in 300L dichloromethane, sodium metaperiodate/silicon is then added thereto Glue mixed oxidization system, stirring reaction 1 ~ 2 hour, add after 100kg magnesium sulfate is dried and filter, silica gel 100L dichloromethane 2 Elution 2 times, filtrate are evaporated under reduced pressure after merging, and obtain compound 4, yield 100%；
Wherein sodium metaperiodate/silica gel mixed oxidization system obtains according to following steps：14kg sodium metaperiodates are dissolved in 14kg In water, 140kg silica gel is added thereto under agitation to solid liquid shape；
The structural formula IV of the compound 4 is：
；
5. taking 10kg steps, 4. gained compound 4 is dissolved in 140L water, 10kg tweens are added thereto, are stirred 20 hours, Filtering, filtrate decompression is distilled to obtain L- glucose, yield 100%, HPLC purity is 99.1%.
Embodiment 2
A kind of synthetic method of L- glucose, comprises the following steps：
1. 100kg sodium glucoheptonates are dissolved in into 600L2,2- dimethoxy propanes are simultaneously cooled to 5 DEG C, under agitation, to 300L methanol hydrochloride solutions are added dropwise in system, rear return stirring is added dropwise and reacts 2 hours, is then cooled to 5 DEG C, uses sodium carbonate PH value is adjusted to 8, filtering, filtrate is obtained, gained filtrate decompression is distilled, 600L petroleum ethers are added thereto after removing solvent, Then 600L water washings are used, merges petroleum ether phase, gained petroleum ether is mutually evaporated under reduced pressure to obtain compound 1, yield 88%；
The methanol hydrochloride solution is hydrochloric acid and methanol by mass fraction 37% according to volume ratio 1：1 mixing composition；
The structural formula I of the compound 1 is：
；
2. taking 60kg steps, 1. gained compound 1 is dissolved in 500L methanol and is cooled to -5 DEG C, then dripped under agitation to it Add to 20kg toluenesulfonic acids, reacted at such a temperature after being added dropwise 5 hours, obtain reaction solution 1, three second are added to reaction solution 1 Amine adjusts pH value to 8 ~ 9, obtains mixed liquor, gained mixed liquor is evaporated under reduced pressure and removes solvent, then add 300L stones thereto Oily ether, with 300L water washings, merge aqueous phase, aqueous phase is extracted with 340L ethyl acetate, combined ethyl acetate phase, then will be merged Ethyl acetate phase be evaporated under reduced pressure and remove ethyl acetate, add 100L petroleum ethers 2 thereto, crystallization, filtering, gained filter cake is Compound 2, yield 86%；
The formula II of the compound 2 is：
；
3. taking 30kg steps, 2. gained compound 2 is dissolved in 90L tetrahydrofurans and is cooled to 5 DEG C, then it is added dropwise thereto 6kg sodium borohydrides, back flow reaction is added dropwise 6 hours, obtains reaction solution 2, gained reaction solution 2 is cooled into 5 DEG C drips thereto Add ammonium chloride saturated solution to pH be 8, be evaporated under reduced pressure remove solvent, then thereto add 90L ethyl acetate stir, mistake Filter, filtrate decompression distill to obtain compound 3, yield 94%；
The formula II I of described compound 3 is：
；
4. taking 20kg steps, 3. gained compound 3 is dissolved in 400L dichloromethane, sodium metaperiodate/silicon is then added thereto Glue mixed oxidization system, stirring reaction 2 hours, add after 200kg magnesium sulfate is dried and filter, silica gel 200L eluent methylene chlorides 2 times, filtrate is evaporated under reduced pressure after merging, and obtains compound 4, yield 100%；
Wherein sodium metaperiodate/silica gel mixed oxidization system obtains according to following steps：16kg sodium metaperiodates are dissolved in 18kg In water, 320kg silica gel is added thereto under agitation to solid liquid shape；
The structural formula IV of the compound 4 is：
；
5. taking 10kg steps, 4. gained compound 4 is dissolved in 90L water, 5kg tweens are added thereto, are stirred 25 hours, mistake Filter, filtrate decompression is distilled to obtain L- glucose, yield 100%, purity 99.2%.
Embodiment 3
A kind of synthetic method of L- glucose, comprises the following steps：
1. 100kg sodium glucoheptonates are dissolved in 500L 2,2-dimethoxypropanes and are cooled to 2 DEG C, under agitation, to 250L methanol hydrochloride solutions are added dropwise in system, rear return stirring is added dropwise and reacts 1.5 hours, is then cooled to 2 DEG C, uses carbonic acid Sodium adjusts pH value to 7, filtering, obtains filtrate, gained filtrate decompression is distilled, 500L oil is added thereto after removing solvent Ether, then 500L water washings, merge petroleum ether phase, gained petroleum ether are mutually evaporated under reduced pressure to obtain compound 1, yield 89%；
The methanol hydrochloride solution is hydrochloric acid and methanol by mass fraction 37% according to volume ratio 1：1 mixing composition；
The structural formula I of the compound 1 is：
；
2. taking 75kg steps, 1. gained compound 1 is dissolved in 600L methanol and is cooled to -8 DEG C, then dripped under agitation to it Add 30kg p-methyl benzenesulfonic acid, reacted at such a temperature after being added dropwise 4 hours, obtain reaction solution 1, three second are added to reaction solution 1 Amine adjusts pH value to 8, obtains mixed liquor, gained mixed liquor is evaporated under reduced pressure and removes solvent, then add 360L oil thereto Ether, with 380L water washings, merge aqueous phase, aqueous phase is extracted with 480L ethyl acetate, combined ethyl acetate phase, then by merging Ethyl acetate phase, which is evaporated under reduced pressure, removes ethyl acetate, adds 120L petroleum ethers thereto, crystallization, filtering, gained filter cake is to change Compound 2, yield 88%；
The formula II of the compound 2 is：
；
3. taking 30kg steps, 2. gained compound 2 is dissolved in 390L tetrahydrofurans and is cooled to 4 DEG C, then it is added dropwise thereto 10kg sodium borohydrides, back flow reaction is added dropwise 5.5 hours, obtains reaction solution 2, gained reaction solution 2 is cooled to 3 DEG C thereto It is 8 that ammonium chloride saturated solution, which is added dropwise, to pH, is evaporated under reduced pressure and removes solvent, and it is equal then to add the stirring of 110L ethyl acetate thereto Even, filtering, filtrate decompression distills to obtain compound 3, yield 95%；
The formula II I of described compound 3 is：
；
4. taking 10kg steps, 3. gained compound 3 is dissolved in 160L dichloromethane, sodium metaperiodate/silicon is then added thereto Glue mixed oxidization system, stirring reaction 1 ~ 2 hour, add after 60kg magnesium sulfate is dried and filter, silica gel 80L eluent methylene chlorides 2 times, filtrate is evaporated under reduced pressure after merging, and obtains compound 4, yield 100%；
Wherein sodium metaperiodate/silica gel mixed oxidization system obtains according to following steps：7.6kg sodium metaperiodates are dissolved in 10kg In water, 92kg silica gel is added thereto under agitation to solid liquid shape；
The structural formula IV of the compound 4 is：
；
5. taking 7.5kg steps, 4. gained compound 4 is dissolved in 80L water, 5kg tweens are added thereto, stirring 20 ~ 25 is small When, filtering, filtrate decompression is distilled to obtain L- glucose, yield 100%, HPLC purity 99.4%.
Embodiment 4
A kind of synthetic method of L- glucose, comprises the following steps：
1. 10kg sodium glucoheptonates are dissolved in 50L 2,2-dimethoxypropanes and are cooled to 0 DEG C, under agitation, Xiang Ti 25L methanol hydrochloride solutions are added dropwise in system, rear return stirring is added dropwise and reacts 1 hour, is then cooled to 0 DEG C, is adjusted with sodium carbonate PH value is saved to 7, filtering, filtrate is obtained, gained filtrate decompression is distilled, add 50L petroleum ethers thereto after removing solvent, then With 50L water washings, merge petroleum ether phase, gained petroleum ether is mutually evaporated under reduced pressure to obtain compound 1, yield 90%；
The methanol hydrochloride solution is hydrochloric acid and methanol by mass fraction 37% according to volume ratio 1：1 mixing composition；
The structural formula I of the compound 1 is：
；
2. by 5kg steps, 1. gained compound 1 is dissolved in 40L methanol and is cooled to -10 DEG C, is then added dropwise under agitation to it 2kg p-methyl benzenesulfonic acid, reacted at such a temperature after being added dropwise 4 hours, obtain reaction solution 1, adding triethylamine to reaction solution 1 adjusts PH value is saved to 8, mixed liquor is obtained, gained mixed liquor is evaporated under reduced pressure and removes solvent, then add 24L petroleum ethers thereto, use 24L water washings, merge aqueous phase, aqueous phase is extracted with 32kg ethyl acetate, combined ethyl acetate phase, then by the acetic acid second of merging Ester, which mutually depressurizes, is distilled off ethyl acetate, adds 8L petroleum ethers thereto, and crystallization, filtering, gained filter cake is compound 2, production Rate 90%；
The formula II of the compound 2 is：
；
3. taking 3kg steps, 2. gained compound 2 is dissolved in 12L tetrahydrofurans and is cooled to 0 DEG C, then it is added dropwise thereto 1kg sodium borohydrides, back flow reaction is added dropwise 5 hours, obtains reaction solution 2, gained reaction solution 2 is cooled into 0 DEG C drips thereto Add ammonium chloride saturated solution to pH be 7, be evaporated under reduced pressure remove solvent, then thereto add 12L ethyl acetate stir, mistake Filter, filtrate decompression distill to obtain compound 3, yield 95%；
The formula II I of described compound 3 is：
；
4. taking 1kg steps, 3. gained compound 3 is dissolved in 16L dichloromethane, sodium metaperiodate/silica gel is then added thereto Mixed oxidization system, stirring reaction 1 hour, add after 8kg magnesium sulfate is dried and filter, silica gel 8L eluent methylene chlorides 2 times, filter Liquid is evaporated under reduced pressure after merging, and obtains compound 4, yield 100%；
Wherein sodium metaperiodate/silica gel mixed oxidization system obtains according to following steps：0.75kg sodium metaperiodates are dissolved in 1kg In water, 7.5kg silica gel is added thereto under agitation to solid liquid shape；
The structural formula IV of the compound 4 is：
；
5. taking 0.75kg steps, 4. gained compound 4 is dissolved in 8L water, 0.5kg tweens are added thereto, are stirred 22 hours, Filtering, filtrate decompression is distilled to obtain L- glucose, yield 100%, HPLC purity 99.5%.

Claims (4)

  1. A kind of 1. synthetic method of L- glucose, it is characterised in that：Comprise the following steps：
    1. sodium glucoheptonate is dissolved in into 2,2-dimethoxypropane and is cooled to 0 ~ 5 DEG C, under agitation, salt is added dropwise into system Sour methanol solution, rear return stirring is added dropwise and reacts 1 ~ 2 hour, is then cooled to 0 ~ 5 DEG C, with sodium carbonate adjust pH value to 6 ~ 8, filtering, filtrate is obtained, gained filtrate decompression is distilled, added petroleum ether thereto after removing solvent, then wash, merge stone Oily ether phase, gained petroleum ether is mutually evaporated under reduced pressure to obtain compound 1；
    The mass volume ratio of wherein sodium glucoheptonate, 2,2-dimethoxypropane, methanol hydrochloride solution, petroleum ether and water is 1g：5ml：2.5ml：5ml：5ml；
    The methanol hydrochloride solution is hydrochloric acid and methanol by mass fraction 37% according to volume ratio 1：1 mixing composition；
    The structural formula I of the compound 1 is：
    2-1；
    2. by step, 1. gained compound 1 is dissolved in methanol and is cooled to -10 ~ -5 DEG C, then under agitation to its dropwise addition to toluene Sulfonic acid, reacted at such a temperature after being added dropwise 3 ~ 5 hours, obtain reaction solution 1, triethylamine regulation pH value is added to reaction solution 1 To 8 ~ 9, mixed liquor is obtained, gained mixed liquor is evaporated under reduced pressure and removes solvent, then adds petroleum ether 1 thereto, is washed, is merged Aqueous phase, aqueous phase is extracted with ethyl acetate, combined ethyl acetate phase, then the ethyl acetate phase of merging is evaporated under reduced pressure and removes second Acetoacetic ester, petroleum ether 2 is added thereto, crystallization, filtering, gained filter cake is compound 2；
    Wherein step 1. gained compound 1, methanol, p-methyl benzenesulfonic acid, petroleum ether 1, water, the quality of ethyl acetate and petroleum ether 2 Volume ratio is 2 ~ 3g：15~25ml：1g：10~15ml：10~15ml：15~17ml：3~5ml；
    The formula II of the compound 2 is：
    2-2；
    3. by step, 2. gained compound 2 is dissolved in tetrahydrofuran and is cooled to 0 ~ 5 DEG C, and sodium borohydride is then added dropwise thereto, Back flow reaction is added dropwise 5 ~ 6 hours, obtains reaction solution 2, gained reaction solution 2 is cooled into 0 ~ 5 DEG C is added dropwise ammonium chloride thereto Saturated solution is 7 ~ 8 to pH, is evaporated under reduced pressure and removes solvent, then adds ethyl acetate thereto and stirs, filters, filtrate subtracts Pressure distillation obtains compound 3；
    Wherein 2. gained compound 2, tetrahydrofuran, sodium borohydride, the mass volume ratio of ethyl acetate are 2 ~ 5g to step：10~ 15ml：1g：10~15ml；
    The formula II I of described compound 3 is：
    2-3；
    4. by step, 3. gained compound 3 is dissolved in dichloromethane 1, then adds sodium metaperiodate/silica gel mixed oxidization thereto System, stirring reaction 1 ~ 2 hour, add after magnesium sulfate is dried and filter, silica gel with methylene chloride 2 elutes 2 times, and filtrate subtracts after merging Pressure distillation, obtains compound 4；
    Wherein 3. gained compound 3, dichloromethane 1, magnesium sulfate, the mass volume ratio of dichloromethane 2 are 1g to step：15~20ml： 5~10g：5~10ml；
    3. gained compound 3 and the mass ratio of the sodium metaperiodate in sodium metaperiodate/silica gel mixed oxidization system are 1g to step：0.7~ 0.8g；
    The structural formula IV of the compound 4 is：
    2-4；
    5. by step, 4. gained compound 4 is soluble in water, adds tween thereto, stirs 20 ~ 25 hours, filtering, filtrate is subtracted Pressure distillation obtains L- glucose；Wherein 4. gained compound 4, water, the mass volume ratio of tween are 1 ~ 2g to step：14~18ml： 1g。
  2. 2. the synthetic method of L- glucose according to claim 1, it is characterised in that：Step 1. gained compound 1, first Alcohol, p-methyl benzenesulfonic acid, petroleum ether 1, water, the mass volume ratio of ethyl acetate and petroleum ether 2 are 2.5g：20ml：1g：12ml： 12ml：16ml：4ml.
  3. 3. the synthetic method of L- glucose according to claim 1, it is characterised in that：Step 3. gained compound 3 with it is high The mass ratio of sodium metaperiodate in sodium iodate/silica gel mixed oxidization system is 1g：0.75g.
  4. 4. the synthetic method of L- glucose according to claim 1, it is characterised in that：Comprise the following steps：
    1. sodium glucoheptonate is dissolved in into 2,2-dimethoxypropane and is cooled to 0 DEG C, under agitation, hydrochloric acid is added dropwise into system Methanol solution, rear return stirring is added dropwise and reacts 1 hour, is then cooled to 0 DEG C, with sodium carbonate regulation pH value to 7, filter, Filtrate is obtained, gained filtrate decompression is distilled, petroleum ether is added thereto after removing solvent, then washes, merges petroleum ether phase, Gained petroleum ether is mutually evaporated under reduced pressure to obtain compound 1；
    The mass volume ratio of wherein sodium glucoheptonate, 2,2-dimethoxypropane, methanol hydrochloride solution, petroleum ether and water is 1g：5ml：2.5ml：5ml：5ml；
    The methanol hydrochloride solution is hydrochloric acid and methanol by mass fraction 37% according to volume ratio 1：1 mixing composition；
    The structural formula I of the compound 1 is：
    2-1；
    2. by step, 1. gained compound 1 is dissolved in methanol and is cooled to -10 DEG C, then under agitation to its dropwise addition to toluene sulphur Acid, reacted at such a temperature after being added dropwise 4 hours, obtain reaction solution 1, adding triethylamine to reaction solution 1 adjusts pH value to 8, Mixed liquor is obtained, gained mixed liquor is evaporated under reduced pressure and removes solvent, petroleum ether 1 is then added thereto, washing, merges aqueous phase, Aqueous phase is extracted with ethyl acetate, combined ethyl acetate phase, then the ethyl acetate phase of merging is evaporated under reduced pressure and removes acetic acid second Ester, petroleum ether 2 is added thereto, crystallization, filtering, gained filter cake is compound 2；
    Wherein step 1. gained compound 1, methanol, p-methyl benzenesulfonic acid, petroleum ether 1, water, the quality of ethyl acetate and petroleum ether 2 Volume ratio is 2.5g：20ml：1g：12ml：12ml：16ml：4ml；
    The formula II of the compound 2 is：
    2-2；
    3. by step, 2. gained compound 2 is dissolved in tetrahydrofuran and is cooled to 0 DEG C, and sodium borohydride is then added dropwise thereto, drips Add complete back flow reaction 5 hours, obtain reaction solution 2, by gained reaction solution 2 be cooled to 0 DEG C thereto be added dropwise ammonium chloride saturation it is molten Liquid is 7 to pH, is evaporated under reduced pressure and removes solvent, then adds ethyl acetate thereto and stirs, filters, filtrate decompression is distilled To compound 3；
    Wherein 2. gained compound 2, tetrahydrofuran, sodium borohydride, the mass volume ratio of ethyl acetate are 3g to step：12ml：1g： 12ml；
    The formula II I of described compound 3 is：
    2-3；
    4. by step, 3. gained compound 3 is dissolved in dichloromethane 1, then adds sodium metaperiodate/silica gel mixed oxidization thereto System, stirring reaction 1 hour, add after magnesium sulfate is dried and filter, silica gel with methylene chloride 2 elutes 2 times, and filtrate is depressurized after merging Distillation, obtains compound 4；
    Wherein 3. gained compound 3, dichloromethane 1, magnesium sulfate, the mass volume ratio of dichloromethane 2 are 1g to step：16ml：8g： 8ml；
    3. gained compound 3 and the mass ratio of the sodium metaperiodate in sodium metaperiodate/silica gel mixed oxidization system are 1g to step： 0.75g；
    The structural formula IV of the compound 4 is：
    2-4；
    5. by step, 4. gained compound 4 is soluble in water, adds tween thereto, stirs 22 hours, filtering, filtrate decompression is steamed Evaporate to obtain L- glucose；Wherein 4. gained compound 4, water, the mass volume ratio of tween are 1.5g to step：16ml：1g.
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