CN107880080A - A kind of synthetic method of 2,3,4,6 tetrabenzyl D glucopyranoses - Google Patents
A kind of synthetic method of 2,3,4,6 tetrabenzyl D glucopyranoses Download PDFInfo
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- CN107880080A CN107880080A CN201711382656.4A CN201711382656A CN107880080A CN 107880080 A CN107880080 A CN 107880080A CN 201711382656 A CN201711382656 A CN 201711382656A CN 107880080 A CN107880080 A CN 107880080A
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Abstract
The invention discloses a kind of synthetic method of 2,3,4,6 tetrabenzyl D glucopyranoses, it is characterised in that step is：A. methyl glucoside is dissolved in organic solvent, it is passed through nitrogen, add metal hydride, stir 5 45min and be wholly absent to caused bubble, benzylic halides are slowly added dropwise system temperature control≤15 DEG C and into system, drop finishes be warming up to 20 40 DEG C after the 4h of stirring reaction 1, treat that TLC measure raw materials disappear and post-treated obtain tetra-O-benzyl glucopyranose first glycosides；B. tetra-O-benzyl glucopyranose first glycosides is added in acid/alcohol mixed liquor, 60 100 DEG C of 2 8h of reaction, separates out a large amount of white solids, treated that TLC measure raw material disappearances are post-treated and obtain product.Two step yields are up to 97.4%, 79.3% respectively, and operation is simpler, cost is low, raw material is easy to get, few to the more friendly pollution of environment, and there was only acid solution in waste liquid, can neutralize, be more suitable for the needs of large-scale industrial production with alkali lye.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, in particular to a kind of synthesis of 2,3,4,6- tetrabenzyl-D- glucopyranoses
Method.
Background technology
2,3,4,6- tetrabenzyl-D- glucopyranoses are a kind of very important medicine intermediates, can be used for treatment sugar
Urinate the synthesis of disease voglibose.The synthetic method of the compound, which has more document report to cross in general method, two kinds：The
A kind of method first step is methyl glucoside NaOH makees alkali, normal octane (bp=125.6 DEG C) is made to stir back under solvent condition
Flow in separatory funnel substantially again it is anhydrous start when being distilled out of benzyl chloride drop Bi Fanying 7~8h, TLC is added dropwise determine its raw material and disappear
Lose, start post processing and can obtain methyl tetra-O-benzyl glucopyranose glycosides HPLC to survey its content 40%, yield is 50%, it is necessary to refined
The next step can just be thrown；The refined rear and propionic acid of methyl tetra-O-benzyl glucopyranose glycosides that second step reacts to obtain above-mentioned reaction-
(aqueous 25%) and perchloric acid (70%~72%) add in reaction bulb after stirring is warming up to 80 DEG C of reaction 8h the aqueous solution together
HPLC survey its react liquid hold-up carried out within 5% in post processing NaOH with, steam solvent and add methyl-n-butyl ketone to be washed with water to neutrality
Filtration and recrystallization filtering drying obtains white solid yield as 50%；The second method first step is methyl glucoside in KOH
Make alkali, dioxane (bp=101.3 DEG C) make solvent condition be stirred vigorously below side add benzyl chloride and temperature rising reflux reaction 8h,
TLC determines the disappearance of its raw material and post-processed, and dichloromethane extraction is added, respectively with saturated sodium bicarbonate aqueous solution and water washing
Organic layer, finally cross post and obtain yellow oil yield as 80%；The methyl tetrabenzyl Portugal that second step reaction obtains above-mentioned reaction
Polyglycoside, glacial acetic acid, hydrochloric acid add back flow reaction 6h in reaction bulb, and TLC determines the disappearance of its raw material and post-processed to obtain white
Solid, yield 46%.More above-mentioned 2,3,4,6- tetrabenzyl-D- glucopyranoses obtain synthetic method it is seen that, the first
Method first step NaOH makees alkali and reacts very not thorough, and yield is low, and cost is high but also deposits what is easily lumpd during the course of the reaction
Situation brings very big trouble to post processing, and normal octane makees solvent in addition, and back flow reaction temperature is high, and energy consumption is big, reaction time length,
Cost is high；After this most strong inorganic acid of perchloric acid has been used during second step reacts and can make troubles and handle to post processing
Caused perchlorate easily pollutes environment.In addition the step reaction yield is low, causes cost too high, unsuitable industrialized production
Needs.The second method first step has used KOH to make alkali more thoroughly has big progress compared with NaOH reactions, but still has
The problem of reaction time is long especially becomes apparent in iodine industrialized production, makees solvent refluxing reaction with normal octane
There is also the big cost of temperature high energy consumption it is high the problem of, although yield has big raising compared to first method, because thick
Product content needed post purifying to cause cycle long cost high less than 70%, and second step has that reaction yield is too low, and cost is too high
Problem, it is unfavorable for large-scale industrial production.
The content of the invention
Present invention aim to solve the deficiency of above-mentioned background technology, there is provided a kind of high income is simple up to 90%, operation
The synthetic method of single, environment-friendly 2,3,4,6- tetrabenzyl-D- glucopyranoses.
The technical scheme is that：A kind of preparation method of the bromo- 2- chlorobenzaldehydes of 5-, it is characterised in that step is：
A. methyl glucoside is dissolved in organic solvent, is passed through nitrogen, add metal hydride, stirring 5-45min is extremely
Caused bubble is wholly absent, and benzylic halides is slowly added dropwise by system temperature control≤15 DEG C and into system, drop, which finishes, is warming up to 20-
Stirring reaction 1-4h after 40 DEG C, treat that TLC measure raw material disappearances are post-treated and obtain tetra-O-benzyl glucopyranose first glycosides；
B. tetra-O-benzyl glucopyranose first glycosides is added in acid/alcohol mixed liquor, 60-100 DEG C of reaction 2-8h, it is solid separates out a large amount of whites
Body, treat that TLC measure raw material disappearances are post-treated and obtain product.The product purity that this programme obtains the first step is up to 91.3-
95.0%, effective yield is up to 85.5-97.4%；The product purity of second step is up to 97.2-99.6%, and high income reaches 66.7-
79.3%.
Preferably, metal hydride is NaH, KH, LiH or CaH in step a2.More preferably NaH or CaH2。
Preferably, benzylic halides are benzyl chloride or cylite in step a.More preferably benzyl chloride.
Preferably, molar ratio methyl glucoside in step a：Metal hydride：Benzylic halides=1:1-2:4-
8.More preferably molar ratio methyl glucoside：Metal hydride：Benzylic halides=1:1-1.15:4.15-5.
Preferably, solvent is acetonitrile, dichloromethane, toluene, dioxane, chloroform, tetrachloromethane, third in step a
One kind in ketone, N,N-dimethylformamide DMF, tetrahydrofuran THF.More preferably DMF, THF.
Preferably, the acid that acid/alcohol mixed liquor is concentration 3-12mol/L in step b mixes with alcohol, wherein acid is salt
One kind in acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, acetic acid, alcohol are one kind in methanol, ethanol, isopropanol, n-butanol,
Wherein tetra-O-benzyl glucopyranose first glycosides and the acid in acid/alcohol mixed liquor, alcohol mol ratio are 1:9:50-100.More preferably tetrabenzyl grape
Sugared first glycosides is 1 with the acid in acid/alcohol mixed liquor, alcohol mol ratio:9:82-90.
Preferably, the acid concentration in step b in acid/alcohol mixed liquor is 9-12mol/L.
Preferably, tetra-O-benzyl glucopyranose first glycosides is added in acid/alcohol mixed liquor in step b, 75-95 DEG C of reaction 4-6h.
In such scheme, the post processing in step a is：It is complete to kish hydride reaction that water is slowly added in system
Entirely, organic phase is merged after extraction, through 1mol/L hydrochloric acid, 1mol/L NaOH solutions, saturated common salt water washing, anhydrous MgSO4Dry
After filter, recycling design obtains golden yellow sticky oil thing to dry.
In such scheme, the post processing in step b is：0- after liquid cooling to the room temperature of white solid will be mixed with after reaction
12h is stood at 5 DEG C, filtration and recrystallization, obtains white solid product；Through extraction, saturation NaHCO after acid/alcohol mixed liquor disposing mother liquor3
Washing, anhydrous MgSO4Dry, ethyl alcohol recrystallization obtains white solid, ethanol mother liquor decompression is spin-dried for rejoining absolute ethyl alcohol ties again
Crystalline substance filters to obtain white solid, collects all dry 6h of 60 DEG C of white solid vacuum, obtains target product.
Preferably, step is：
A. methyl glucoside is dissolved in organic solvent, is passed through nitrogen, sodium hydride is added portionwise 5-10 times, stir 20-
30min is wholly absent to caused bubble, and ice salt bath is cooled down system temperature control≤15 DEG C, and cylite is slowly added dropwise into system,
Drop, which finishes, removes ice bath, to stirring reaction 1-2h after 20-30 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains four benzyls
Base methyl αDglucopyranoside, wherein molar ratio methyl glucoside：Metal hydride：Benzylic halides=1:1-1.15:4.15-
5；
B. tetra-O-benzyl glucopyranose first glycosides is added in acid/alcohol mixed liquor, 75-95 DEG C of reaction 4-6h, it is solid separates out a large amount of whites
Body, treat that TLC measure raw material disappearances are post-treated and obtain product, wherein acid/alcohol mixed liquor is hydrochloric acid, sulfuric acid one of which and first
The mixture of alcohol, ethanol one of which, tetra-O-benzyl glucopyranose first glycosides are 1 with the acid in acid/alcohol mixed liquor, alcohol mol ratio:9:82-
90.This programme uses preferred reaction condition and preferred reactant ratio, and the product purity for obtaining the first step is up to
93.8-95%, effective yield are up to 92.9-97.4%；The product purity of second step is up to 99-99.6%, and high income reaches 76.7-
79.3%.
Further, step is：
A. methyl glucoside is dissolved in DMF DMF, is passed through nitrogen, NaH is added portionwise 5-10 times,
Stirring 25min is wholly absent to caused bubble, and ice salt bath is cooled down system temperature control≤15 DEG C, and chlorination is slowly added dropwise into system
Benzyl, drop, which finishes, removes ice bath, to stirring reaction 1.5h after 25 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains four benzyls
Base methyl αDglucopyranoside, wherein molar ratio methyl glucoside：Metal hydride：Benzylic halides=1:1.1:4.74；
B. tetra-O-benzyl glucopyranose first glycosides is added in acid/alcohol mixed liquor, 90 DEG C of reaction 5h, separates out a large amount of white solids, treat
TLC measure raw materials disappear it is post-treated obtain product, wherein acid/alcohol mixed liquor is the mixture of hydrochloric acid and methanol, tetrabenzyl Portugal
Grape sugar first glycosides is 1 with the acid in acid/alcohol mixed liquor, alcohol mol ratio:9:85.This programme uses accurate reaction condition and reactant ratio
Example, the product purity for obtaining the first step are up to 95%, and effective yield is up to 97.4%；The product purity of second step is up to
99.6%, high income is up to 79.3%.
Shown in the following Scheme 1 of synthetic route of the present invention：
The reaction mechanism of above-mentioned reaction is (shown in following Scheme2)：
The active hydrogen that first step reacting metal hydride is easy to capture on alcoholic extract hydroxyl group in non-protonic solvent forms gold
Belong to oxonium salt and release hydrogen, then due to the X in BnX-(predominantly Cl-、Br-) nucleophilicity can make in this case in BnX
- Bn the alkylated reaction generation tetra-O-benzyl glucopyranose first glycosides of oxygen, metal halide salt (pole easily occur with above-mentioned middle metal oxonium salt
It is soluble in water, easily remove)；
Second step reacts tetra-O-benzyl glucopyranose first glycosides in the case where acid acts on, the methyl on Lewis base B attack methyl ethers,
Because there is by force the oxygen electronegativity on methyl ether the proton A in very strong nucleophilic attack acid to generate the benzyls of product 2,3,4,6- tetra-
Base-D- glucopyranoses (note above-mentioned AB by taking HCl as an example, Lewis acid A:H+, Lewis base B:Cl-) methyl ether
Cracking can regard Lewis Acids and Bases exchange reaction as.
Beneficial effects of the present invention are：
Two step yields are up to 97.4%, 79.3% respectively, and operation is simpler, cost is low, raw material is easy to get, more friendly to environment
Good pollution is few, and there was only acid solution in waste liquid, can neutralize, be more suitable for the needs of large-scale industrial production with alkali lye.
Brief description of the drawings
Fig. 1 is that the H-NMR spectrum that tetra-O-benzyl glucopyranose first glycosides obtains after tested is made in step a of the present invention
Fig. 2 is that the H-NMR that product 2,3,4,6- tetrabenzyl-D- glucopyranoses obtain after tested is made in step b of the present invention
Spectrogram
Embodiment
The present invention is described in further detail with specific embodiment below in conjunction with the accompanying drawings.
In following examples, the post processing in step a is：200ml water is slowly added in system and has been reacted to NaH is remained
Entirely, organic phase is merged after DCM (130ml × 3) extractions, successively through 1mol/L hydrochloric acid (130ml × 2), 1mol/L NaOH solutions
The washing of (130ml × 2), saturated aqueous common salt (130ml × 2), anhydrous MgSO4Filtered after drying, recycling design obtains golden yellow to doing
Color sticky oil thing.The nitrogen that is passed through in step a refers to metal hydride charging, benzylic halides charging, course of reaction in nitrogen
Completed in gas.Post processing in step b is：It will be mixed with after reaction quiet at 0~5 DEG C after liquid cooling to the room temperature of white solid
12h is put, filtration and recrystallization, obtains white solid product；Through DCM (60ml × 3) extractions, saturation after acid/alcohol mixed liquor disposing mother liquor
NaHCO3Washing, anhydrous MgSO4Dry, 60ml absolute ethyl alcohols recrystallize to obtain white solid, and ethanol mother liquor decompression is spin-dried for rejoining
50ml absolute ethyl alcohols recrystallization filters to obtain white solid, collects all dry 6h of 60 DEG C of white solid vacuum, obtains target product.
Embodiment 1
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml acetonitriles in reaction bulb, is passed through nitrogen, 5-10
Secondary that NaH (4.06g, 0.11mol) is added portionwise, it is to keep temperature stabilization in system, stirring 5min to generation to be added portionwise
Bubble be wholly absent, ice salt bath cooling by system temperature control≤15 DEG C, be slowly added dropwise into system benzyl chloride (60g,
0.474mol), drop, which finishes, removes ice bath, to stirring reaction 1h after 20 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains
Golden yellow sticky oil thing 54.01g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 92.5%, yield 90.2%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (30g, purity 92.5%, 0.05mol) is added into acid/alcohol to mix
In liquid, acid/alcohol mixed liquor is that 75mL concentration 6mol/L hydrochloric acid mixes with 2.5mol ethanol, 60 DEG C of reaction 2h, is separated out a large amount of
White solid, treat that post-treated the product 20.43g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 98.8%, yield is
74.7%.
Embodiment 2
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml dichloromethane in reaction bulb, is passed through nitrogen,
KH (0.2mol) is added portionwise 5-10 times, it is to keep temperature stabilization in system, stirring 15min to caused gas to be added portionwise
Bubble is wholly absent, and ice salt bath is cooled down system temperature control≤15 DEG C, and benzyl chloride (0.4mol) is slowly added dropwise into system, and drop, which finishes, to be removed
Ice bath, to stirring reaction 2h after 35 DEG C after heating, treat that TLC measure raw material disappearances are post-treated and obtain golden yellow sticky oil thing
52.8g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 91.5%, yield 87.2%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (30.3g, purity 91.5%, 0.05mol) addition acid/alcohol is mixed
Close in liquid, acid/alcohol mixed liquor is that 75mL concentration 6mol/L nitric acid mixes with 4.1mol isopropanols, 70 DEG C of reaction 8h, is separated out
A large amount of white solids, treat that post-treated the product 19.3g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 97.8%, yield is
69.9%.
Embodiment 3
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml toluene in reaction bulb, is passed through nitrogen, 5-10
It is secondary that CaH is added portionwise2(0.15mol), it is to keep temperature stabilization in system, stirring 10min to caused gas to be added portionwise
Bubble is wholly absent, and ice salt bath is cooled down system temperature control≤15 DEG C, and cylite (0.5mol) is slowly added dropwise into system, and drop, which finishes, to be removed
Ice bath, to stirring reaction 3h after 40 DEG C after heating, treat that TLC measure raw material disappearances are post-treated and obtain golden yellow sticky oil thing
53.6g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 93.5%, yield 90.5%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (29.6g, purity 93.5%, 0.05mol) addition acid/alcohol is mixed
Close in liquid, acid/alcohol mixed liquor is that 56.25mL concentration 8mol/L acetic acid mixes with 2.5mol n-butanols, 80 DEG C of reaction 3h, analysis
Go out a large amount of white solids, treat that post-treated the product 19.2g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 97.2%, yield
For 69.1%.
Embodiment 4
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml dioxane in reaction bulb, is passed through nitrogen,
LiH (0.11mol) is added portionwise 5-10 times, it is to keep temperature stabilization in system to be added portionwise, and stirring 40min is to caused
Bubble is wholly absent, and ice salt bath is cooled down system temperature control≤15 DEG C, and benzyl chloride (0.55mol) is slowly added dropwise into system, and drop finishes
Ice bath is removed, to stirring reaction 4h after 35 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains golden yellow sticky oil
Thing 52.9g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 92.9%, yield 88.7%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (29.8g, purity 92.9%, 0.05mol) addition acid/alcohol is mixed
Close in liquid, acid/alcohol mixed liquor is that 150mL concentration 3mol/L hydrobromic acids mix with 5mol isopropanols, 90 DEG C of reaction 5h, is separated out
A large amount of white solids, treat that post-treated the product 18.9g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 98%, yield is
68.6%.
Embodiment 5
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 150ml DMF in reaction bulb, is passed through nitrogen, 5-10
Secondary that NaH (0.1mol) is added portionwise, it is to keep temperature stabilization in system, stirring 20min to caused bubble to be added portionwise
It is wholly absent, ice salt bath is cooled down system temperature control≤15 DEG C, and benzyl chloride (0.415mol) is slowly added dropwise into system, and drop, which finishes, to be removed
Ice bath, to stirring reaction 1h after 25 DEG C after heating, treat that TLC measure raw material disappearances are post-treated and obtain golden yellow sticky oil thing
55g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 94.5%, yield 93.8%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (29.3g, purity 94.5%, 0.05mol) addition acid/alcohol is mixed
Close in liquid, acid/alcohol mixed liquor is that 50mL concentration 9mol/L sulfuric acid mixes with 4.1mol methanol, 75 DEG C of reaction 4h, is separated out big
White solid is measured, treats that post-treated the product 21.1g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 99.2%, yield is
77.5%.
Embodiment 6
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 120mlTHF in reaction bulb, is passed through nitrogen, 5-10
Secondary that NaH (0.105mol) is added portionwise, it is to keep temperature stabilization in system, stirring 30min to caused gas to be added portionwise
Bubble is wholly absent, and ice salt bath is cooled down system temperature control≤15 DEG C, and benzyl chloride (0.45mol) is slowly added dropwise into system, and drop, which finishes, removes
Ice bath is removed, to stirring reaction 2h after 30 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains golden yellow sticky oil thing
56.1g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 93.8%, yield 95%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (29.5g, purity 93.8%, 0.05mol) addition acid/alcohol is mixed
Close in liquid, acid/alcohol mixed liquor is that 45mL concentration 10mol/L sulfuric acid mixes with 4.25mol ethanol, 80 DEG C of reaction 6h, is separated out
A large amount of white solids, treat that post-treated the product 20.8g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 99.5%, yield is
76.7%.
Embodiment 7
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml DMF in reaction bulb, is passed through nitrogen, 5-10
It is secondary that CaH is added portionwise2(0.11mol), it is to keep temperature stabilization in system, stirring 25min to caused gas to be added portionwise
Bubble is wholly absent, and ice salt bath is cooled down system temperature control≤15 DEG C, and benzyl chloride (0.474mol) is slowly added dropwise into system, and drop, which finishes, removes
Ice bath is removed, to stirring reaction 1.5h after 25 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains golden yellow sticky oil
Thing 56.8g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 95%, yield 97.4%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (29.2g, purity 95%, 0.05mol) is added into acid/alcohol to mix
In liquid, acid/alcohol mixed liquor is that 45mL concentration 10mol/L hydrochloric acid mixes with 4.25mol methanol, 90 DEG C of reaction 5h, is separated out big
White solid is measured, treats that post-treated the product 21.5g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 99.6%, yield is
79.3%.
Embodiment 8
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml THF in reaction bulb, is passed through nitrogen, 5-10
It is secondary that CaH is added portionwise2(0.115mol), it is to keep temperature stabilization in system, stirring 25min to caused gas to be added portionwise
Bubble is wholly absent, and ice salt bath is cooled down system temperature control≤15 DEG C, and benzyl chloride (0.5mol) is slowly added dropwise into system, and drop, which finishes, to be removed
Ice bath, to stirring reaction 2h after 30 DEG C after heating, treat that TLC measure raw material disappearances are post-treated and obtain golden yellow sticky oil thing
55.7g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 94.4%, yield 94.9%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (29.3g, purity 94.4%, 0.05mol) addition acid/alcohol is mixed
Close in liquid, acid/alcohol mixed liquor is that 37.5mL concentration 12mol/L hydrochloric acid mixes with 4.5mol ethanol, 95 DEG C of reaction 5h, is separated out
A large amount of white solids, treat that post-treated the product 21.4g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 99%, yield is
78.5%.
Embodiment 9
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml THF in reaction bulb, is passed through nitrogen, 5-10
Secondary that NaH (0.11mol) is added portionwise, it is to keep temperature stabilization in system, stirring 25min to caused bubble to be added portionwise
It is wholly absent, ice salt bath is cooled down system temperature control≤15 DEG C, and benzyl chloride (0.48mol) is slowly added dropwise into system, and drop, which finishes, to be removed
Ice bath, to stirring reaction 1.5h after 20 DEG C after heating, treat that TLC measure raw material disappearances are post-treated and obtain golden yellow sticky oil thing
54.8g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 93.9%, yield 92.9%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (29.5g, purity 93.9%, 0.05mol) addition acid/alcohol is mixed
Close in liquid, acid/alcohol mixed liquor is that 37.5mL concentration 12mol/L sulfuric acid mixes with 4.5mol methanol, 80 DEG C of reaction 6h, is separated out
A large amount of white solids, treat that post-treated the product 21g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 99.2%, yield is
77.2%.
Embodiment 10
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml chloroforms in reaction bulb, is passed through nitrogen,
NaH (0.12mol) is added portionwise 5-10 times, it is to keep temperature stabilization in system to be added portionwise, and stirring 45min is to caused
Bubble is wholly absent, and ice salt bath is cooled down system temperature control≤15 DEG C, and cylite (0.6mol) is slowly added dropwise into system, and drop, which finishes, removes
Ice bath is removed, to stirring reaction 1h after 35 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains golden yellow sticky oil thing
53.8g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 92.5%, yield 89.8%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (30g, purity 92.5%, 0.05mol) is added into acid/alcohol to mix
In liquid, acid/alcohol mixed liquor is that 150mL concentration 3mol/L hydroiodic acids mix with 3mol n-butanols, 100 DEG C of reaction 2h, is separated out
A large amount of white solids, treat that post-treated the product 18.9g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 98.8%, yield is
69.2%.
Embodiment 11
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml tetrachloromethanes in reaction bulb, is passed through nitrogen,
KH (0.15mol) is added portionwise 5-10 times, it is to keep temperature stabilization in system to be added portionwise, and stirring 15min is to caused
Bubble is wholly absent, and ice salt bath is cooled down system temperature control≤15 DEG C, and cylite (0.7mol) is slowly added dropwise into system, and drop, which finishes, removes
Ice bath is removed, to stirring reaction 2h after 40 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains golden yellow sticky oil thing
52.6g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 92.7%, yield 88%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (30g, purity 92.7%, 0.05mol) is added into acid/alcohol to mix
In liquid, acid/alcohol mixed liquor is that 50mL concentration 9mol/L sulfuric acid mixes with 3.5mol isopropanols, 95 DEG C of reaction 8h, is separated out big
White solid is measured, treats that post-treated the product 18.4g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 97.9%, yield is
66.7%.
Embodiment 12
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml acetone in reaction bulb, is passed through nitrogen, 5-10
It is secondary that CaH is added portionwise2(0.2mol), it is to keep temperature stabilization in system, stirring 10min to caused bubble to be added portionwise
It is wholly absent, ice salt bath is cooled down system temperature control≤15 DEG C, and cylite (0.8mol) is slowly added dropwise into system, and drop, which finishes, removes deicing
Bath, to stirring reaction 3h after 30 DEG C after heating, treat that TLC measure raw material disappearances are post-treated and obtain golden yellow sticky oil thing
51.9g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 91.3%, yield 85.5%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (30.3g, purity 91.3%, 0.05mol) addition acid/alcohol is mixed
Close in liquid, acid/alcohol mixed liquor is that 45mL concentration 10mol/L nitric acid mixes with 4mol methanol, 80 DEG C of reaction 3h, is separated out a large amount of
White solid, treat that post-treated the product 18.6g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 98.4%, yield is
67.8%.
Embodiment 13
A. methyl glucoside (19.4g, 0.1mol) is dissolved in 100ml dichloromethane in reaction bulb, is passed through nitrogen,
LiH (0.18mol) is added portionwise 5-10 times, it is to keep temperature stabilization in system to be added portionwise, and stirring 40min is to caused
Bubble is wholly absent, and ice salt bath is cooled down system temperature control≤15 DEG C, and cylite (0.55mol) is slowly added dropwise into system, and drop finishes
Ice bath is removed, to stirring reaction 4h after 40 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains golden yellow sticky oil
Thing 54.9g (tetra-O-benzyl glucopyranose first glycosides), HPLC determine its content 92.5%, yield 91.7%；
B. tetra-O-benzyl glucopyranose first glycosides made from step a (30g, purity 92.5%, 0.05mol) is added into acid/alcohol to mix
In liquid, acid/alcohol mixed liquor is that 37.5mL concentration 12mol/L hydrochloric acid mixes with 4.75mol ethanol, 100 DEG C of reaction 5h, is separated out
A large amount of white solids, treat that post-treated the product 17.4g, HPLC of obtaining of TLC measure raw material disappearances surveys its content 97.8%, yield is
63.0%.
Golden yellow sticky oil thing obtained by above-described embodiment step a tested to obtain H-NMR spectrum as shown in figure 1,1H
NMR(400MHz,CDCl3) δ 7.57-7.35 (m, 18H), 7.32 (d, J=7.4Hz, 2H), 5.10 (dd, J=57.2,7.9Hz,
2H), 4.89 (ddd, J=26.0,21.4,9.8Hz, 4H), 4.76-4.58 (m, 3H), 4.34-3.67 (m, 6H), 3.51 (d, J
=22.8Hz, 3H) for it will be seen from figure 1 that being identical with standard diagram, characteristic peak is corresponding, and it is really four benzyls to show the product
Base methyl αDglucopyranoside (methyl tetra-O-benzyl glucopyranose glycosides), and purity is higher.
Snow-white solid obtained by above-described embodiment step b tested to obtain H-NMR spectrum as shown in Fig. 21H NMR
(400MHz,CDCl3)δ7.30–7.08(m,18H),7.08–6.95(m,2H),5.15–4.78(m,2H),4.77–4.51(m,
4H), 4.51-4.29 (m, 3H), 3.99-3.35 (m, 6H), 3.31 (s, 1H) with standard diagram figure it is seen that highly kiss
Close, characteristic peak is corresponding, and it is really 2,3,4,6- tetrabenzyl-D- glucopyranoses to show the product, and purity is higher.
Claims (10)
1. the synthetic method of the tetrabenzyl-D- glucopyranoses of one kind 2,3,4,6-, it is characterised in that step is：
A. methyl glucoside is dissolved in organic solvent, is passed through nitrogen, add metal hydride, stirring 5-45min to generation
Bubble be wholly absent, benzylic halides are slowly added dropwise system temperature control≤15 DEG C and into system, drop, which finishes, is warming up to 20-40 DEG C
Stirring reaction 1-4h afterwards, treat that TLC measure raw material disappearances are post-treated and obtain tetra-O-benzyl glucopyranose first glycosides；
B. tetra-O-benzyl glucopyranose first glycosides is added in acid/alcohol mixed liquor, 60-100 DEG C of reaction 2-8h, separates out a large amount of white solids,
Treat that TLC measure raw material disappearances are post-treated and obtain product.
2. the synthetic method of as claimed in claim 12,3,4,6- tetrabenzyl-D- glucopyranoses, it is characterised in that step a
Middle metal hydride is NaH, KH, LiH or CaH2。
3. the synthetic method of as claimed in claim 12,3,4,6- tetrabenzyl-D- glucopyranoses, it is characterised in that step a
Middle benzylic halides are benzyl chloride or cylite.
4. the synthetic method of as claimed in claim 12,3,4,6- tetrabenzyl-D- glucopyranoses, it is characterised in that step a
Middle molar ratio methyl glucoside：Metal hydride：Benzylic halides=1:1-2:4-8.
5. the synthetic method of as claimed in claim 12,3,4,6- tetrabenzyl-D- glucopyranoses, it is characterised in that step a
Middle solvent is acetonitrile, dichloromethane, toluene, dioxane, chloroform, tetrachloromethane, acetone, N,N-dimethylformamide
One kind in DMF, tetrahydrofuran THF.
6. the synthetic method of as claimed in claim 12,3,4,6- tetrabenzyl-D- glucopyranoses, it is characterised in that step b
The acid that middle acid/alcohol mixed liquor is concentration 3-12mol/L mixes with alcohol, wherein acid is hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrogen
One kind in acid iodide, acetic acid, alcohol are methanol, ethanol, isopropanol, one kind in n-butanol, wherein tetra-O-benzyl glucopyranose first glycosides with
Acid, alcohol mol ratio in acid/alcohol mixed liquor are 1:9:50-100.
7. the synthetic method of as claimed in claim 62,3,4,6- tetrabenzyl-D- glucopyranoses, it is characterised in that step b
Acid concentration in middle acid/alcohol mixed liquor is 9-12mol/L, and acid is hydrochloric acid or sulfuric acid, and alcohol is methanol or ethanol.
8. the synthetic method of as claimed in claim 12,3,4,6- tetrabenzyl-D- glucopyranoses, it is characterised in that step b
It is middle to add tetra-O-benzyl glucopyranose first glycosides in acid/alcohol mixed liquor, 75-95 DEG C of reaction 4-6h.
9. the synthetic method of as claimed in claim 12,3,4,6- tetrabenzyl-D- glucopyranoses, it is characterised in that step
For：
A. methyl glucoside is dissolved in organic solvent, is passed through nitrogen, sodium hydride is added portionwise 5-10 times, stir 20-30min
It is wholly absent to caused bubble, ice salt bath is cooled down system temperature control≤15 DEG C, and cylite is slowly added dropwise into system, and drop, which finishes, removes
Ice bath is removed, to stirring reaction 1-2h after 20-30 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains tetrabenzyl grape
Sugared first glycosides, wherein molar ratio methyl glucoside：Metal hydride：Benzylic halides=1:1-1.15:4.15-5；
B. tetra-O-benzyl glucopyranose first glycosides is added in acid/alcohol mixed liquor, 75-95 DEG C of reaction 4-6h, separates out a large amount of white solids, treat
TLC measure raw material disappearances are post-treated to obtain product, and wherein acid/alcohol mixed liquor is hydrochloric acid, sulfuric acid one of which and methanol, ethanol
The mixture of one of which, tetra-O-benzyl glucopyranose first glycosides are 1 with the acid in acid/alcohol mixed liquor, alcohol mol ratio:9:82-90.
10. the synthetic method of as claimed in claim 92,3,4,6- tetrabenzyl-D- glucopyranoses, it is characterised in that step
For：
A. methyl glucoside is dissolved in DMF DMF, is passed through nitrogen, NaH is added portionwise 5-10 times, stirred
25min is wholly absent to caused bubble, and ice salt bath is cooled down system temperature control≤15 DEG C, and benzyl chloride is slowly added dropwise into system,
Drop, which finishes, removes ice bath, to stirring reaction 1.5h after 25 DEG C after heating, treats that TLC measure raw material disappearances are post-treated and obtains tetrabenzyl Portugal
Grape sugar first glycosides, wherein molar ratio methyl glucoside：Metal hydride：Benzylic halides=1:1.1:4.74；
B. tetra-O-benzyl glucopyranose first glycosides is added in acid/alcohol mixed liquor, 90 DEG C of reaction 5h, separates out a large amount of white solids, treat that TLC is surveyed
Determine raw material disappear it is post-treated obtain product, wherein acid/alcohol mixed liquor is the mixture of hydrochloric acid and methanol, tetra-O-benzyl glucopyranose first
Glycosides is 1 with the acid in acid/alcohol mixed liquor, alcohol mol ratio:9:85.
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| CN115073408A (en) * | 2022-08-09 | 2022-09-20 | 江苏法安德医药科技有限公司 | Synthetic method of 2,3,4, 6-tetrabenzyl-D-glucopyranose |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013132470A2 (en) * | 2012-03-09 | 2013-09-12 | Universidade De Lisboa | New c-glycosylpolyphenol antidiabetic agents, effect on glucose tolerance and interaction with beta-amyloid. therapeutic applications of the synthesized agent(s) and of genista tenera ethyl acetate extracts containing some of those agents |
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2017
- 2017-12-20 CN CN201711382656.4A patent/CN107880080A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013132470A2 (en) * | 2012-03-09 | 2013-09-12 | Universidade De Lisboa | New c-glycosylpolyphenol antidiabetic agents, effect on glucose tolerance and interaction with beta-amyloid. therapeutic applications of the synthesized agent(s) and of genista tenera ethyl acetate extracts containing some of those agents |
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| XUAN PAN ET AL.: "Synthesis and biological evaluation of novel tetrahydroisoquinoline-C-aryl glucosides as SGLT2 inhibitors for the treatment of type 2 diabetes", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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| CN115073408A (en) * | 2022-08-09 | 2022-09-20 | 江苏法安德医药科技有限公司 | Synthetic method of 2,3,4, 6-tetrabenzyl-D-glucopyranose |
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