CN1344722A - Amino polyoligoglucosan with 1-6 connection and glucoside and their synthesis and application - Google Patents
Amino polyoligoglucosan with 1-6 connection and glucoside and their synthesis and application Download PDFInfo
- Publication number
- CN1344722A CN1344722A CN 01136484 CN01136484A CN1344722A CN 1344722 A CN1344722 A CN 1344722A CN 01136484 CN01136484 CN 01136484 CN 01136484 A CN01136484 A CN 01136484A CN 1344722 A CN1344722 A CN 1344722A
- Authority
- CN
- China
- Prior art keywords
- compound
- amino
- connects
- deoxidation
- ligoglucoside
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses the structure of beta-D-amino polyoligoglucosan or glucoside with 1-6 connection, its synthesis, and its application in anticancer medicine and its composite.
Description
Invention field
The present invention relates to amino ligoglucoside and the glucosides and the synthetic and application thereof of 1 → 6 connection, more specifically, the present invention relates to 1 → 6 amino ligoglucoside that connects and the glucosides and the synthetic and application thereof of formula (I).
Background technology
Carbohydrate chemistry and sugared pharmacology is through after nearly 20 years arduous groping, welcome finally " dreams come true for the Cinderella " the moment (science, 291 (2001), p2337).Just not saying Acarbose, carbohydrate medicines such as Swainsonin and AZT have become the new drug of treatment diabetes, cancer and AIDS, CM101 (treatment spinal cord injury and rheumatic arthritis) is more arranged, Globo-H (being used for the treatment of mammary cancer) Le
Y(being used for the treatment of cancer of the stomach), GM-1 many clinical carbohydrate medicines of each phase that entered such as (being used for the treatment of the cancer of the brain and neural the reparation).The whole world only be used for the treatment of the carbohydrate medicine of all kinds of cancers at present existing 10 enter I to the III phase clinical (science291 (2001), p2341).
Glucosamine is one of monose of nature amount maximum, and it and Fucose are called as the indispensable monose element of many physiological processs in the life entity together.Exist a large amount of N-acetylglucosamines that link to each other with lipid with protein in biological structure, they participate in a large amount of bioprocesss, immune closely bound up with cell.The most typical biological structure that the amino grape oligosaccharides of 1 → 6 2-position deoxidation that connects participates in is exactly cell membrane lipid Lipid A (Essentials of glycobiology, 1998,267268, Gold SpringHarbor laborotary press), it extensively is present on the cytolemma of Gram-negative bacteria, can evoke the immune response of host cell.As, Lipid A be attached to CD14 or huge have a liking on the cell can cause cytotoxic secretion, concerning Mammals, then cause a large amount of deleterious such as fever, the physiologic immunity reaction of inflammation and so on.In addition, be one step of key during malignant tumour shifts by the tumor cell adhesion of glycan or glycolipid mediation, thereby the cell-cell interaction that suppresses by glycan or glycolipid mediation is the most effective method that prevents the tumour diffusion.
Summary of the invention
The present invention can help to develop the medicine of anti metastasis or be used to prepare antibody by 1 → 6 relevant amino grape oligosaccharides of the 2-position deoxidation glucosides that connects of preparation, also can be used for developing the foodstuff additive with the immunity regulated and preventing cancer function.
The invention provides compound with following general formula (I),
R wherein
1Can be hydrogen, amino-acid residue, the alkyl of the aryl of replacement or 1 to 12 carbon, R
2To R
N+3Be hydrogen or acyl group, n=1-10.
R in the above-claimed cpd
1Be preferably octyl group; R
2To R
N+3Be ethanoyl; More preferably, R wherein
1Be octyl group, R
2To R
N+3Be ethanoyl, n=4; Perhaps R wherein
1Be octyl group, R
2To R
N+3Be hydrogen, n=4.
The present invention also provides several methods (reaction scheme of seeing below) that prepare general formula (I) compound, and one of method is characterised in that:
1) with 6-position protected silane, the 2-amino-beta--D-grape pyrans sulphur glycosides 6 of 3,4 acyl group protections is a glycosyl donor, with 6-position free hydroxyl group, 1,2-amino-beta--D-the glucopyanosyl 3 of 3,4 full acidylates can obtain the disaccharide derivative that 1 → 6 of high yield connects for the linked reaction of acceptor, as 7;
2) remove 6 silylation of 7, can make disaccharide 8, itself and 6 glycosylation make trisaccharide 9;
3) and the like can make the amino ligoglucoside derivative of 1 → 6 β that connects-D-;
4) remove all protecting groups in the methanol solution of the methanol solution of sodium methylate or ammonia, can get the amino ligoglucoside product 10 of 1 → 6 β that connects-D-;
5) 10 if can get the acetylizad product of N-with the diacetyl oxide processing, as 11 in methyl alcohol.
Two being characterised in that of method for preparing general formula (I) compound:
1) compound 5 and 3 is coupled, gets disaccharide, through further functional group's conversion, gets glycosyl
Sulphur glycosides 27 makes tetrose 28 with 8 glycosylation then;
2) remove 6 silylation of 28, again with 27 glycosylation, and the like can make
Getting the sugar unit number is the amino ligoglucoside derivative of β-D-that even 1 → 6 connects;
3) remove all protecting groups in the methanol solution of the methanol solution of sodium methylate or ammonia,
The amino ligoglucoside product of 1 → 6 β that connects-D-is as 30;
4) 30 if can get the acetylizad product of N-with the diacetyl oxide processing, as 31 in methyl alcohol.
The method of another kind of synthetic general formula (I) compound is characterized in that:
1) sulphur glycosides 6 carries out glycosylation with alkyl alcohol earlier and makes glucosides 16;
2) remove 6 silylation of 16, again with 6 glycosylations, disaccharide glucosides 18,
3) remove 6 silylation of 18 and get 19,19 and 6 glycosylations, the trisaccharide glucosides
20, and the like can make the amino ligoglucoside glycoside derivates of 1 → 6 β that connects-D-
4) remove all acyl group protections in the methanol solution of the methanol solution of sodium methylate or ammonia
Base gets the amino ligoglucoside glycoside product of 1 → 6 β that connects-D-.5) the said products if
Can get the acetylizad product of N-with the diacetyl oxide processing in the methyl alcohol.
The method that the third prepares general formula (I) compound is characterized in that: 1) trisaccharide 13 makes glycosyl sulphur glycosides 14,2 with the Helfrich reaction of mercaptan) trisaccharide glucosides 20 usefulness boron trifluoride diethyl etherate methods remove 6 silylation and get 21; 3) 14 and 21 glycosylation makes six glucosides 22; 4) remove protecting groups all in 22 in the methanol solution of the methanol solution of sodium methylate or ammonia, get the amino grape six sugared glucosides 23 of 1 → 6 β that connects-D-; 5) 23 if can get the acetylizad product 24 of N-with the diacetyl oxide processing in methyl alcohol.
In the aforesaid method, the catalyzer of glycosylation is the mixed catalyst of nitrogen-iodo succinimide (NIS) and Louis silk acid; Solvent is a methylene dichloride, ether, toluene etc.Wherein silk acid in Louis is selected from trifluoromethanesulfonic acid, trimethyl silicane triflate and silver trifluoromethanesulfonate.And the method that wherein removes 6-position silylation is selected from trifluoroacetic acid (TFA) method, tetrabutyl fluoride amine (TBAF) method and boron trifluoride diethyl etherate method; Boron trifluoride diethyl etherate method most preferably.
The present invention also provides a kind of pharmaceutical composition, it is characterized in that containing the compound and the pharmaceutical carrier of the claim 1 of significant quantity.Compound in the said composition is R wherein preferably
1Be octyl group, R
2To R
N+3Be hydrogen, the formula of n=4 (I) compound.From the formulation aspect, this pharmaceutical composition is preferably oral or injection type.
The present invention provides the purposes of compound in producing cancer therapy drug of general formula (I) on the other hand.Wherein the medicine of being produced preferably is used for the treatment of the medicine in cancer of the stomach, lung cancer and the intestinal cancer.More preferably, the medicine of being produced is oral or injection type.
The present invention also provides the application of general formula (I) compound in producing protective foods.
Embodiment:
General method: specific rotation gets with the automatic polarimeter side of Perkin-Elmer 241 MC in the time of 25 ℃.
1HNMR by BrukerARX400 at CDCl
3In record, be interior mark with tetramethylsilane.Mass spectrum is with VG PLATFORM mass spectrograph, with ESI technology sample introduction.Thin-layer chromatography (TLC) is by HF
254Sulfuric acid methanol solution or ultraviolet (UV) detector with 30% (v/v) on the silica-gel plate detect.Column chromatography adopts 100-200 purpose silica gel at 16 * 240mm, and 18 * 300mm uses ethyl acetate-sherwood oil (60-90 ℃) as leacheate, solution underpressure distillation less than 60 ℃ the time on the silicagel column of 35 * 400mm.
Embodiment 1
Synthesize 1,3,4,6-four-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl 4
2-deoxidation-2-amido-D-glucopyanosyl (commercially available) 30 grams are dissolved in methyl alcohol, add 1.2 normal sodium methylates, stir 20 minutes, and suction filtration falls sodium chloride salt; Add Tetra hydro Phthalic anhydride 12 grams in filtrate, reacted 15 minutes, first is gone into 16 gram triethylamines then, and restock 12 gram Tetra hydro Phthalic anhydrides continue reaction 30 minutes, and suction filtration gets compound 2-deoxidation-2-phthalimide-based D-glucopyanosyl 1.With 1 (18.6 grams; 60 mmoles) be dissolved in 160 milliliters of pyridines; add 40 ml acetic anhydride then, stirring at room 2 hours, adding toluene steams altogether and removes pyridine in the mixture; residuum dilutes with 150 milliliters of methylene dichloride; add frozen water then and wash twice to remove pyridinium salt, water is used 50 milliliters of dichloromethane extractions once again, merges organic phase; after concentrating; last silica gel chromatography is separated, and leacheate is petrol ether/ethyl acetate (4: 1), obtains product 1; 3; 4,6-four-oxy-acetyl-2-deoxidation-2-phthalimide-based-D-glucopyanosyl (23 grams, 48.2 mmoles; nucleus magnetic resonance shows that product/the β product is 1/3 to α), productive rate 80%.Get 15.5 gram β products 1,3,4,6-four-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside 4. nucleus magnetic resonance δ: 1.87,2.00,2.04,2.12 (4 COCH with petrol ether/ethyl acetate system recrystallization
3), 4.02 (ddd, 1H, H-5), 4.15 (dd, 1H, H-6a), 4.36 (dd, 1H, H-6b), 4.47 (dd, 1H, H-2), 5.21 (dd, 1H, H-4), 5.89 (dd, 1H, H-3), 6.52 (d, 1H, H-1), 7.73-7.88 (m, 4H, Ph).Fusing point: 96-97 ℃.
Embodiment 2
Synthetic iprotiazem base 3,4,6-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (5)
Compound 4 (9.53 grams, 20 mmoles) is dissolved in 50 milliliters of methylene dichloride, adds 1.3 normal isopropyl mercaptans (2.43 milliliters) and 1.3 normal boron trifluoride ether solutions then, stirring at room 2.5 hours.Add in the saturated sodium bicarbonate aqueous solution then and boron trifluoride diethyl etherate, dichloromethane extraction, evaporate to dryness, adding toluene steams altogether and removes unnecessary isopropyl mercaptan in the mixture, and residuum dissolves with a small amount of methylene dichloride, going up silica gel chromatography then separates, leacheate is petrol ether/ethyl acetate (2.5: 1), obtain draining behind the soup compound 5 (2.5 grams, 4.5 mmoles), productive rate 86%. nuclear-magnetism δ: 1.24 (2t, SCH (CH
3)
2), 1.87,2.05,2.11 (3s, COCH
3), 3.15 (m, 1H, SCH (CH
3)
2), 3.91 (m, 1H, H-5), 4.17 (dd, 1H, H-6a), 5.31 (dd, 1H, H-6a), 4.37 (t, 1H, H-2), 5.17 (t, 1H, H-4), 5.57 (d, 1H, H-1), 5.83 (t, 1H, H-3), 7.74-7.88 (m, 4H, Ph).
Embodiment 3
Synthetic iprotiazem base 3,4-two-oxy-acetyl-6-oxygen-tertiary butyl dimethylsilyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (6).
Compound 5 (15 gram, 29.4 mmoles) is dissolved in 100 ml methanol, and adding sodium methylate then, to make system pH be 9-10, stirring at room 1 hour.Add the neutralization of IR-120 positive ion acidic resins then and be 6-7 for the pH value, filter, the filtrate evaporate to dryness gets, iprotiazem base 2-deoxidation-2-phthalimide-based-β-D-glucopyranoside.This compound (8.611 grams, 23.46 mmole) be dissolved in 50 milliliters of dry pyridines, add 1.1 normal TERT-BUTYL DIMETHYL CHLORO SILANE (8.37 grams, 25.8 mmole) and the 4-dimethylamino pyridine of catalytic amount (be DMAP, 50 milligrams), reacted 20 hours, in reaction mixture, add 35 milliliters of acetic anhydride then, reacted 1 hour, toluene band dry mixture separates with silica gel chromatography, leacheate is petrol ether/ethyl acetate (4: 1), obtain decorating film 6 (10.35 grams, 18.3 mmoles, two step overall yields 78%). optically-active [α]
D 25(c1, CHCl
3); Nuclear-magnetism δ: 0.06,0.08 (2Si (CH
3)
2), 0.90 (s, 9H, t-Bu), 1.22,1.26 (2s, SCH (CH
3)
2), 1.85,2.03 (2s, COCH
3), 3.15 (m, 1H, SCH (CH
3)
2), 3.70 (dd, 1H, H-5), 4.34 (t, H-2), 5.09 (t, 1H, H-4), 5.53 (d, 1H, H-1), 5.82 (t, 1H, H-3), 7.72-7.87 (m, 4H, Ph).The molecular weight calculated value, 565; Measured value, 588.33 (M+Na, MALDI-TOF-MS).
Embodiment 4
Synthesize 1,3,4 three-oxy-acetyl-6-oxygen-tertiary butyl dimethylsilyl-2-deoxidation-2-phthalimide-based-D-glucopyranoside (2)
Compound 2-deoxidation-2-phthalimide-based-D-glucopyanosyl (2 grams, 6.5 mmole) be dissolved in 10 milliliters of pyridines, the DMAP (20 milligrams) that adds catalytic amount in the mixture, add 1.1 normal TERT-BUTYL DIMETHYL CHLORO SILANE (1.065 grams then, 7.1 mmole), stirring at room is 24 hours.The mixed solution that adds 8 milliliters and 8 milliliters pyridines of diacetyl oxide then, stirring at room 6 hours, adding toluene steams altogether and removes pyridine in the mixture, residuum dilutes with 150 milliliters of methylene dichloride, add frozen water then and wash twice to remove pyridinium salt, water is used 50 milliliters of dichloromethane extractions once again, merges organic phase, after concentrating, last silica gel chromatography is separated, leacheate is petrol ether/ethyl acetate (2.5: 1), and decompressing and extracting obtains steeping powder material 2 (α, β mixture, 1: 1,2.5 gram, 4.5 mmoles), overall yield 70%.
Embodiment 5
Synthesize 1,3,4-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-D-glucopyranoside (3)
Compound 2 (3.83 grams, 6.98 mmole) be dissolved in 20 milliliters the methylene dichloride, added 1 normal boron trifluoride ether solution (0.88 milliliter) stirring at room 75 minutes, reaction finishes, and adds in the saturated sodium bicarbonate aqueous solution then and boron trifluoride diethyl etherate, dichloromethane extraction, evaporate to dryness. separate with silica gel chromatography, leacheate is 1: 1 petrol ether/ethyl acetate, obtains steeping powder product 3 (2.9 grams, 6.7 mmoles).Productive rate 99.5%.
Embodiment 6
Synthetic 3,4-two-oxy-acetyl-6-oxygen-tertiary butyl dimethyl is silica-based-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-1,3, and 4-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-D-glucopyanosyl (7)
(620 milligrams of compounds 3,1.43 mmole) and (885 milligrams of 1.1 normal compound donators 6,1.57 mmole) be dissolved in 5 milliliters dry methylene chloride, add 1 normal nitrogen iodo succinimide (322 milligrams) then,＜-20 ℃ liquid nitrogen/ethanol cooling, in the nitrogen atmosphere, drip trimethyl silicon based trifluoromethanesulfonic acid fat (TMSOTf) catalyzed coupling reaction of 0.05 equivalent (12 microlitre), react half an hour, drip triethylamine (1) neutralization reaction system, the evaporate to dryness mixture separates with silica gel chromatography, leacheate is petrol ether/ethyl acetate (2: 1), obtain steeping powder thing disaccharides 7 (1.24 grams, 1.34 mmoles, 94%, α, β mixture 3: 2).Nuclear-magnetism δ: 0.08,0.09 (2s, 15H, Si (CH
3)
2), 0.91 (s, t-Bu), 1.77,1.82,1.84,1.88,2.02 (5s, β-COCH
3), 1.71,1.78,1.85,1.93,2.02 (5s, α-COCH
3), 3.59-3.78 (m, H-6a, b, H-6a ', b '), 3.83 (m, 1H, H
β-5), 3.90 (t, 2.5H, H-5 '), 4.13 (m, 1H, H
α-5), 4.30 (m, 3.5H, H-2 ', H
β-2), 5.54 (dd, 1.5H, H
α-2), 4.90 (t, 1.5H, H
α-4), 5.02 (t, 1H, H
β-4), 5.11 (t, 2.5H, H-4 '), 5.41 (d, 2.5H, H-1 '), 5.75 (t, 3.5H, H-3 ', H
β-3), 5.94 (d, 1.5H, H
α-1), 6.34 (d, 1H, H
β-1), 6.39 (dd, 1.5H, H
α-3), and 7.69-7.86 (m, 20H, Ph).
Embodiment 7
Synthesize 3,4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-1,3,4-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-D-glucopyanosyl (8)
Compound 7 (1.47 grams, 1.59 mmole) be dissolved in 20 milliliters the methylene dichloride, added 2 normal boron trifluoride ether solution stirring at room 35 minutes, reaction finishes, and adds in the saturated sodium bicarbonate aqueous solution then and boron trifluoride diethyl etherate, dichloromethane extraction, evaporate to dryness obtains powdery product 8 (1.09 grams, 1.35 mmoles 84.6%, α, β mixture 3: 2).Nuclear-magnetism δ: 1.80,1.85,1.93,1.94,2.05 (5s, β-COCH
3), 1.79,1.86,1.93,1.96,2.06 (5s, α-COCH
3), 3.64-3.92 (m, 10H, H-6a, H-6b, H
β-5, H-5 '), 4.15 (m, 1H, H
α-5), 4.31 (dd, 1.7H, H-2 '), 4.36 (dd, 0.7H, H
β-2), 5.58 (dd, 1H, H
α-2), 5.0 (t, 1H, H
α-4), 5.10 (t, 2.4H, H
β-4, H-4 '), 5.56 (d, 0.7H, H
β-1 '), 5.41 (d, 1.0H, H
α-1 '), 5.78 (t, 2.4H, H-3 ', H
β-3), 6.0 (d, 1H, H
α-1), 6.38 (d, 0.6H, H
β-1), 6.42 (dd, 1H, H
α-3), and 7.7-7.86 (m, 14H, Ph).Molecular weight: calculated value, 810; Measured value, 833.27 (M+Na, MALDI-TOF-MS).
Embodiment 8
Synthetic 2-deoxidation-2-acetamido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-acetamido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-acetamido-β-D-glucopyanosyl (11)
Compound 8 (1.4 grams, 0.95 mmole) and (785 milligrams of 1.1 normal compound donators 6,1.1 mmole) be dissolved in 5 milliliters dry methylene chloride, add 1 normal nitrogen iodo succinimide then,＜-20 ℃ liquid nitrogen/ethanol cooling, in the nitrogen atmosphere, drip trimethyl silicon based trifluoromethanesulfonic acid fat (TMSOTf) catalyzed coupling reaction of 0.05 equivalent (12 microlitre), react half an hour, drip triethylamine (1) neutralization reaction system, the evaporate to dryness mixture, separate with silica gel chromatography, leacheate is petrol ether/ethyl acetate (2: 1), obtains steeping powder thing trisaccharide 9 (1.04 grams, α, β mixture 3: 2).Compound 9 is dissolved in the saturated methanol solution of ammonia, leaves standstill 7 days, gets solid chemical compound 10 after the solvent evaporated.Productive rate 83%.Compound 10 is dissolved in the methyl alcohol, adds 6 normal diacetyl oxides, stirs 16 hours under the room temperature, gets powdered compounds 11 after the solvent evaporated.Productive rate 100%.
Embodiment 9
Synthetic 3; 4; 6-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-1; 3; 4-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-D-glucopyanosyl (α, β mixture 3: 2) (13)
Compound 8 (1.07 grams, 1.32 mmoles) and 1.1 normal compound donators 5 (724 milligrams, 1.24 mmoles) are dissolved in 15 milliliters dry methylene chloride, add 1 normal nitrogen iodo succinimide then,＜-20 ℃ liquid nitrogen/ethanol cooling, in the nitrogen atmosphere, drip the TMSOTf catalyzed coupling reaction of 0.05 equivalent (12 microlitre), react half an hour, drip triethylamine (1) neutralization reaction system, the evaporate to dryness mixture, separate with silica gel chromatography, leacheate is petrol ether/ethyl acetate (2: 1), obtains steeping powder material trisaccharide 13 (1.52 grams, 86%). δ: 1.74,1.78,1.84,1.86,1.92,1.95,2.04,2.15 (8s, β-COCH
3), 1.77,1.78,1.85,1.85,1.92,2.02,2.06,2.15 (8s, α-COCH
3), 3.33 (dd, 1H), 3.50 (m, 3.5H), 3.71-4.00 (m, 19H), 4.15-4.42 (m, 15H), 4.54 (dd, 1.5H, H
α-2), 4.85-4.96 (m, 7H), 5.15-5.25 (m, 3H), 5.27 (t, 1H), 5.28 (d, 1H, H
α-1 '), 5.51 (t, 1H), 5.52 (d, 1.5H, H
α-1 "), 5.55 (d, 1H, H
β-1 '), 5.59-5.81 (m 12H), 5.77 (d, 1H, H
β-1 '), 5.91 (d, 1.5H, H
α-1), 6.32 (d, 1H, H
β-1), 6.39 (dd, 1.5H, H
a-3 "), and 7.70-7.88 (m, 40H, Ph).Molecular weight: calculated value, 1227; Measured value, 1250.23 (M+Na, MALDI-TOF-MS).
Embodiment 10
Synthetic iprotiazem base 3; 4; 6-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3,4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (14)
Compound 13 (1.52 grams, 1.24 mmole) be dissolved in 20 milliliters the methylene dichloride, add 2 normal isopropyl mercaptan (156 microlitres, 2.52 mmole) and 1.8 normal boron trifluoride ether solutions (0.3 milliliter) stirring at room 15 minutes, reaction finishes, add in the saturated sodium bicarbonate aqueous solution then and boron trifluoride diethyl etherate, dichloromethane extraction, evaporate to dryness separates with silica gel chromatography, leacheate is 1: 1 petrol ether/ethyl acetate, obtain steeping powder product 14 (815 milligrams, productive rate 53%). δ: 1.04,1.09 (2s, 6H, SCH (CH
3)
2), 1.78,1.80,1.86,1.93,1.95,2.04,2.16 (7s, 21H, COCH
3), 2.97 (m, 1H, SCH (CH
3)
2), 3.47 (dd, 1H, H-6a), 3.59 (m, 1H, H-5), and 5.37-5.85 (m, 3H, H-6a ', H-5 ', H-6b), 3.87-4.10 (m, 2H, H-5 ", H-6b '), 4.18-4.23 (m, 2H; H-2 ', H-6b ") 4.35 (dd, 1H, H-2 "), 3.36 (dd, 1H; H-6b "), 4.82 (t, 1H, H-4), 4.94 (t, 1H, H-4 '), 5.19 (t, 1H, H-4 "), 5.32 (d; 1H, H-1 '), 5.39 (d, 1H, H-1); 5.52 (d, 1H, H-1 "), 5.62 (dd, 1H, H-3 '), 5.68 (dd, 1H, H-3), 5.77 (dd, 1H, H-3 "), 7.71-7.93 (m, 12H, Ph).δ
C：53.78(C-2)，54.38(C-2’，C-2”)，61.97(C-6”)，67.84(C-6’)，68.21(C-6)，68.90(C-4”)，69.57(C-4’)，69.61(C-4)，70.69(C-3”)，70.80(C-3’)，71.40(C-3)，72.02(C-5”)，72.09(C-5’)，76.76(C-5)，80.20(C-1)，97.54(C-1’)，97.93(C-1”)。The molecular weight calculated value, 1243; Measured value, 1266.76 (M+Na, MALDI-TOF-MS).
Embodiment 11
Synthetic octyl group 3,4-two-oxy-acetyl-6-oxygen-tertiary butyl dimethylsilyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (16)
Compound 6 (4.16 grams, 7.36 mmole), be dissolved in 25 milliliters of dry methylene chloride, add (1.87 milliliters of 1.5 normal octanols, 11.5 mmole) and 2 normal nitrogen iodo succinimides (3.12 gram, 14.7 mmoles), in＜liquid nitrogen/ethanol cooling of-20 ℃, in the nitrogen atmosphere, drip the TMSOTf catalyzed coupling reaction of 0.05 equivalent (67 microlitre), reacted 55 minutes, drip triethylamine (2) neutralization reaction system, the evaporate to dryness mixture, separate with silica gel chromatography, leacheate is petrol ether/ethyl acetate (2: 1), obtains soup compound 16 (4.35 grams, 7.03 mmole, 95.5%).Nuclear-magnetism δ: 0.06,0.07 (2s, Si (CH
3)
2), 0.79 (t, CH
2CH
3), 0.89 (s, 9H, t-Bu), 0.98-1.40 (m, 12H, 6 CH
2), 1.84,2.01 (2s, COCH
3), 3.42 (m, 1H, OCH
aH
b), 3.67-3.75 (m, 3H, H-5, H-6a, H-6b), 3.80 (m, 1H, OCH
aH
b), 4.53 (dd, 1H, H-2), 5.09 (t, 1H, H-4), 5.31 (d, 1H, H-1), 5.79 (dd, 1H, H-3), 7.71-7.85 (m, 4H, Ph)
Embodiment 12
Synthetic octyl group 3,4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (17)
Compound 16 (4.35 gram, 7.03 mmoles) is dissolved in 25 milliliters the methylene dichloride, adds 2 normal boron trifluoride ether solution stirring at room 15 minutes, reaction finishes, and adds in the saturated sodium bicarbonate aqueous solution then and boron trifluoride diethyl etherate, dichloromethane extraction, evaporate to dryness, separate with silica gel chromatography, leacheate is 1: 1 petrol ether/ethyl acetate, obtains 17 (3.1 grams, 6.2 mmole, 89%). nuclear-magnetism δ: 0.81 (t, 3H, CH
2CH
3), 0.88-1.43 (m, 12H, 6CH
2), 1.88,2.01 (2s, 6H, COCH
3), 3.44 (m, 1H, OCH
aH
b), 3.64-3.82 (m, 3H, H-5, H-6a, H-6b), 3.84 (m, 1H, OCH
aH
b), 4.29 (dd, 1H, H-2), 5.12 (t, 1H, H-4), 5.39 (d, 1H, H-1), 5.84 (dd, 1H, H-3), 7.34-7.87 (m, 4H, Ph).
Embodiment 13
Synthetic octyl group 3; 4-two-oxy-acetyl-6-oxygen-tert-butyl diphenyl is silica-based-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3, and 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (18)
Compound 17 (1.44 grams, 2.85 mmole) and 1.1 normal compound donators 6 (1.7 the gram, 3 mmoles) be dissolved in 50 milliliters dry methylene chloride, add 1.3 normal nitrogen iodo succinimides (0.84 gram) then,＜liquid nitrogen/ethanol cooling of-20 ℃, in the nitrogen atmosphere, drip the TMSOTf catalyzed coupling reaction of 0.05 equivalent (20 microlitre), reacted 20 minutes, and dripped triethylamine (1) neutralization reaction system, the evaporate to dryness mixture, separate with silica gel chromatography, leacheate is petrol ether/ethyl acetate (2: 1), obtains Powdered thing disaccharides 18 (2.27 grams, 2.28 mmoles, 80%). nuclear-magnetism δ: 0.08,0.10 (2s, 6H, Si (CH
3)
2), 0.81 (t, 3H, CH
2CH
3), 0.92 (s, 9H, t-Bu), 0.88-1.30 (m, 12H, 6CH
2), 1.78,1.84,1.92,2.02 (4s, 12H, COCH
3), 3.14 (m, 1H, OCH
aH
b), 3.45 (m, 1H, OCH
aH
b), 3.63 (dd, 1H, H-6a), 3.66-3.84 (m, 3H, H-5, H-5 ', H-6a ', H-6b), 3.90 (dd, 1H, H-6b '), 4.16 (dd, 1H, H-2), 4.29 (dd, 1H, H-2 '), 4.88 (t, 1H, H-4), 5.14 (t, 1H, H-4 '), 5.17 (d, 1H, H-1), (5.44 d, 1H, H-1 '), 5.67 (dd, 1H, H-3), (5.77 dd, 1H, H-3 '), and 7.70-7.85 (m, 8H, Ph).δ
C：54.59(C-2’)，54.62(C-2)，62.29(C-6)，68.07(C-6’)，69.35(OCH
2)，69.35(C-4’)，69.72(C-4)，71.70(C-3)，71.07(C-3’)，73.03(C-5’)，74.66(C-5)，97.59，97.66(C-1’，C-1)。
Embodiment 14
Synthetic octyl group 3,4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3,4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (19)
Compound 18 (2.2 gram, 2.21 mmoles) is dissolved in 20 milliliters the methylene dichloride, adds 2 normal boron trifluoride ether solution stirring at room 15 minutes, reaction finishes, add in the saturated sodium bicarbonate aqueous solution then and boron trifluoride diethyl etherate, dichloromethane extraction, evaporate to dryness, separate with silica gel chromatography, leacheate is 1: 1 petrol ether/ethyl acetate, obtains steeping powder product (19). (1.53 grams, 1.74 mmoles, 78%). nuclear-magnetism δ: 0.81 (t, CH
2CH
3), 0.88-1.28 (m, 12H, 6CH
2), 1.82,1.86,1.98,2.06 (4s, 4COCH
3), 3.21 (m, 1H, OCH
aH
b), 3.52 (m, 1H, OCH
aH
b), 3.64-3.73 (m, 3H, H-5, H-5 ', H-6a ', H-6a), (3.83 dd, 1H, H-6b '), 3.91 (m, 1H, H-6b), 4.18 (dd, 1H, H-2), 4.29 (dd, 1H, H-2 '), 4.97 (t, 1H, H-4), 5.14 (t, 1H, H-4 '), 5.20 (d, 1H, H-1), (5.49 d, 1H, H-1 '), 5.69 (dd, 1H, H-3), (5.81 dd, 1H, H-3 '), 7.70-7.87 (m, 8H, Ph) .8
C: 54.48 (C-2 '), 54.62 (C-2), 62.20 (C-6), 68.46 (C-6 '), 69.23 (C-4 '), 69.64 (OCH
2), 70.26 (C-4), 70.64 (C-3), 70.68 (C-3 '), 72.62 (C-5 '), 74.19 (C-5), 97.64 (C-1 '), 97.78 (C-1).The molecular weight calculated value, 880; Measured value, 903.3465 (M+Na, MALDI-TOF-MS).
Embodiment 15
Synthetic octyl group 3; 4; 6-three-oxy-acetyl-6-oxygen-tert-butyl diphenyl is silica-based-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3,4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (20)
Compound 19 (2.65 grams, 3.01 mmole) and 1.1 normal compound donators 6 (1.87 the gram, 3.31 mmole) be dissolved in 20 milliliters dry methylene chloride, add (750 milligrams in 1.1 normal nitrogen-iodo succinimide then, 3.3 mmole),＜-20 ℃ liquid nitrogen/ethanol cooling, in the nitrogen atmosphere, drip the TMSOTf catalyzed coupling reaction of 0.05 equivalent (20 microlitre), react half an hour, drip triethylamine (1) neutralization reaction system, the evaporate to dryness mixture separates with silica gel chromatography, and leacheate is petrol ether/ethyl acetate (1.5: 1), obtain steeping powder trisaccharide 20 (3.8 grams, 2.776 mmole, 92%). nuclear-magnetism δ: 0.096,0.111 (2s, 6H, Si (CH
3)
2), 0.81 (t, 3H, CH
2CH
3), 0.93 (s, 9H, t-Bu), 0.85-1.28 (m, 12H, 6CH
2), 1.77,1.79,1.85,1.91,1.93,2.02 (6s, 6COCH
3), 3.20 (m, 1H, OCH
aH
b), 3.46 (dd, 1H, H-6a), 3.50 (m, 2H, OCH
aH
b, H-5), 3.66-3.84 (m, 6H), 3.91 (d, 1H, H-6b), 4.13 (dd, 1H, H-2), 4.20 (dd, 1H, H-2 '), 4.30 (dd, 1H, H-2 "); 4.79 (t, 1H, H-4), 4.92 (t, 1H, H-4 '), 5.13 (d; 1H, H-1), 5.15 (t, 1H, H-4 "), 5.30 (d, 1H, H-1 '), 5.45 (d, 1H, H-1 "), 5.62 (dd, 2H, H-3; H-3 '), 5.77 (dd, 1H, H-3 '), 7.77-7.92 (m, 12H, Ph). δ
C: 54.41 (C-2 "), 54.53 (C-2 '), 54.57 (C-2), 62.33 (C-6 "), 67.67C-6 '), 67.90C-6), 69.39 (C-4 "), 69.43 (OCH
2), 69.54 (C-4 '), 69.64 (C-4), 70.65 (C-3), 70.70 (C-3 '), 71.06 C-3), 72.72 (C-5 '), 73.11 (C-5), 74.64 (C-5 "), 97.54 (C-1 "), 97.62 (C-1), 97.71 (C-1 ').
Embodiment 16
Synthetic octyl group 3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3,4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (21)
Compound 20 (1.8 gram, 1.29 mmoles) is dissolved in 20 milliliters the methylene dichloride, adds 2 normal boron trifluoride ether solutions (0.4 milliliter) stirring at room 15 minutes, reaction finishes, add in the saturated sodium bicarbonate aqueous solution then and boron trifluoride diethyl etherate, dichloromethane extraction, evaporate to dryness.Separate with silica gel chromatography, leacheate is 1: 1 petrol ether/ethyl acetate, obtains steeping powder and produces 21 (1.4 grams, 1.14 mmoles, 86.5%). nuclear-magnetism δ: 0.81 (t, CH
2CH
3), 0.85-1.26 (m, 12H, 6 CH
2), 1.79,1.80,1.86,1.92,1.97,2.06 (6s, 6COCH
3), 3.21 (m, 1H, OCH
aH
b), 3.49 (m, 1H, OCH
aH
b), 3.53 (dd, 1H, H-6a), 3.62 (m, 1H, H-5), 3.66 (dd, 1H, H-6a "), 3.71-3.85 (m, 5H; H-5 ", H-5 ', H-6a ', H-6b, H-6b "), 3.96 (m; 1H, H-6b '), 4.15 (dd, 1H, H-2), 4.23 (dd; 1H, H-2 '), 4.31 (dd, 1H, H-2 "), 4.84 (t, 1H, H-4), 5.03 (t, 1H, H-4 '), 5.15 (t, 1H, H-4 "), 5.16 (d, 1H, H-1), 5.35 (d; 1H, H-1 '), 5.51 (d, 1H, H-1 "), (5.65 dd, 2H, H-3, H-3 '), 5.80 (dd, 1H, H-3 '), 7.71-7.90 (m, 12H, Ph). δ
C: 54.36 (C-2 ", C-2 '), 54.55 (C-2), 61.15 (C-6 "), 67.92 (C-6 '), 68.35 (C-6), 69.16 (C-4 "), 69.44OCH
2), 69.85 (C-4 '), 69.87 (C-4), 70.56 (C-3, C-3 '), 70.75 (C-3 "), 72.51 (C-5 '), 72.69 (C-5), 74.22 (C-5 "), 97.48 (C-1 "), 97.61 (C-1), 97.72 (C-1 ').The molecular weight calculated value, 1255; Measured value, 1278.92 (M+Na, MALDI-TOF-MS).
Embodiment 17
Synthetic octyl group 3; 4; 6-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3; 4-dioxy-ethanoyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3,4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (22)
(797 milligrams of compounds 21,0.636 mmole) and (780 milligrams of 1 normal compound donators 14,0.636 mmole) be dissolved in 10 milliliters dry methylene chloride, add 1 normal nitrogen-iodo succinimide (150 milligrams) then,＜-20 ℃ liquid nitrogen/ethanol cooling, in the nitrogen atmosphere, drip the TMSOTf catalyzed coupling reaction of 0.10 equivalent (15 microlitre), react half an hour, drip triethylamine (1) neutralization reaction system, the evaporate to dryness mixture, separate with silica gel chromatography, leacheate is petrol ether/ethyl acetate (1: 1.5), obtains steeping powder six sugar 22 (0.984 milligram, productive rate 64%).Nuclear-magnetism δ: 0.81 (t, 3H, CH
2CH
3), 0.85-1.28 (m, 12H, 6 CH
2), 1.77,1.776,1.778,1.788,1.794 (5s, 15H, COCH
3), 1.87,1.936,1.937,1.942,1.945,1.950,2.052,2.164 (8s, 24H, COCH
3), 3.20 (m, 1H, OCH
aH
b), 3.46 (dd, 1H, H-6a), 3.16 (m, 1H, OCH
aH
b), 3.40-3.60 (m, 8H), 3.61-3.80 (m, 6H), 3.90-3.96 (m, 2H, H-6b
E, H-5
F), 4.11-4.24 (m, 6H), 4.36-4.41 (dd, 2H, H-6b
F, H-2
F), 4.70-4.82 (m, 3H, 3xH-4), 4.93 (t, 1H, H-4
E), 5.13 (d, 1H, H-1
A), 5.21 (t, 1H, H-4
F), 5.25 (d, 1H, H-1
B), 5.27 (d, 2H, H-1
c, H-1
d), 5.33 (d, 1H, H-1
E), 5.51 (d, 1H, H-1
F), 5.57-5.67 (m, 5H), 6.07 (dd, 1H, H-3
F), 7.71-7.92 (m, 24H, Ph) .8C:54.37 (5C, 5xC-2), 54.59 (1C, C-2), 61.94 (1C, C-6
F), 67.22,67.56,67.70,67.87,68.13 (5C, 5xC-6), 68.93,69.30,69.50,69.50,69.57,69.62 (6C, 6xC-6), 69.57 (1C, OCH
2), 70.55 (4 C, 4xC-3), 70.65,70.73 (2C, 2xC-3), 71.99 (1C, C-5
F), 72.60,72.65 (4C, 4xC-5), 72.95 (1C, C-5), 97.51,97.56 (2C, 2xC-1), 97.60 (2C, 2xC-1), 97.66 (1C, C-1), 98.00 (1C, C-1
F).The molecular weight calculated value, 2422; Measured value, 2444.0 (M+Na, MALDI-TOF-MS).
Embodiment 18
Synthetic octyl group 2-deoxidation-2-amido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-amido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-amido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-amido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-amido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-amido-β-D-glucopyranoside (23)
Compound 22 is dissolved in the saturated methanol solution of ammonia, leaves standstill 7-10 days, gets powdered compounds 23 after the solvent evaporated.Productive rate 80%.
13C?NMR：103.05，103.51，103.59，103.63，103.67，103.7(6C-1)。The molecular weight calculated value, 1096.55; Measured value, 1120.2 (M+Na, MALDI-TOF-MS).
Embodiment 19
Synthetic octyl group 2-deoxidation-2-acetamido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-acetamido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-acetamido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-acetamido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-acetamido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-acetamido-β-D-glucopyranoside (24)
Compound 23 is dissolved in the methyl alcohol, adds the normal diacetyl oxide of 6-8, stirs 16 hours under the room temperature, gets powdered compounds 24 after the solvent evaporated.Productive rate 100%.
Embodiment 20
Synthesize 3,4,6-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-1,3,4-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-D-glucopyanosyl (25)
(620 milligrams of compounds 3,1.43 mmole) and (850 milligrams of 1.1 normal compound donators 5,1.61 mmole) be dissolved in 10 milliliters dry methylene chloride, add 1 normal nitrogen iodo succinimide (322 milligrams) then,＜-20 ℃ liquid nitrogen/ethanol cooling, in the nitrogen atmosphere, drip trimethyl silicon based trifluoromethanesulfonic acid fat (TMSOTf) catalyzed coupling reaction of 0.05 equivalent (12 microlitre), react half an hour, drip triethylamine (1) neutralization reaction system, the evaporate to dryness mixture, separate with silica gel chromatography, leacheate is petrol ether/ethyl acetate (2: 1), obtains disaccharides 25 (1.01 gram). nuclear-magnetism δ: 1.60,1.80,1.84,1.88,2.00,2.02 (6s, β-COCH
3), 3.59-3.83 (m, 4H, H
β-5), and 3.90-4.13 (m, 1H, H-5), 4.30-4.90 (m, 3H), 7.69-7.86 (m, 20H, Ph).
Embodiment 21
Synthetic iprotiazem base 3,4,6-three-oxygen-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3,4--oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (26)
Compound 25 (1.24 mmole) is dissolved in 20 milliliters the methylene dichloride, added 2 normal isopropyl mercaptans and 1.8 normal boron trifluoride ether solution stirring at room 15 minutes, reaction finishes, and adds in the saturated sodium bicarbonate aqueous solution then and boron trifluoride diethyl etherate, dichloromethane extraction, evaporate to dryness.Separate with silica gel chromatography, leacheate is 1: 1 petrol ether/ethyl acetate, obtains steeping powder product 26 (productive rate 55%).
Embodiment 22
Synthetic iprotiazem base 3; 4-two-oxygen-acetyl-6-oxygen-tert-butyl diphenyl is silica-based-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3, and 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyranoside (27)
Compound 26 (1 mmole) is dissolved in 40 milliliters the methyl alcohol, added 0.2 equivalent sodium methylate stirring at room 10 hours, the acidic resins neutralization, be dissolved in behind the evaporate to dryness in the diacetyl oxide of 15 milliliters of pyridines and 7 milliliters, react evaporate to dryness after 5 hours, separate with silica gel chromatography, leacheate is 1: 1 petrol ether/ethyl acetate, gets compound 27 (productive rate 45%).
Embodiment 23
Synthetic 3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-β-D-glucopyanosyl base-(1 → 6)-3; 4-two-oxy-acetyl-2-deoxidation-2-phthalimide-based-D-glucopyanosyl-1; 3,4-three-oxy-acetyl-2-deoxidation-2-phthalimide-based-D-glucopyanosyl (29)
Compound 8 (1 mmole) and 1.1 normal compound donators 27 are dissolved in 5 milliliters dry methylene chloride, add 1 normal nitrogen iodo succinimide then,＜-20 ℃ liquid nitrogen/ethanol cooling, in the nitrogen atmosphere, drip 0.05 normal trimethyl silicon based trifluoromethanesulfonic acid fat (TMSOTf) catalyzed coupling reaction, react half an hour, drip triethylamine neutralization reaction system, the evaporate to dryness mixture, separate with silica gel chromatography, leacheate is a petrol ether/ethyl acetate, obtains tetrose 28 (84%, α, the β mixture).This mixture adds 2 normal boron trifluoride ether solutions in 15 milliliters methylene dichloride, stirring at room 15 minutes, and reaction finishes, and adds in the saturated sodium bicarbonate aqueous solution then and boron trifluoride diethyl etherate, dichloromethane extraction, evaporate to dryness.Separate with silica gel chromatography, obtain steeping powder product 29 (79%).
Embodiment 24
Synthetic 2-deoxidation-2-amido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-amido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-amido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-amido-β-D-glucopyanosyl (30).With 2-deoxidation-2-acetamido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-acetamido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-acetamido-β-D-glucopyanosyl base-(1 → 6)-2-deoxidation-2-acetamido-β-D-glucopyanosyl (31)
Compound 29 is dissolved in the saturated methanol solution of ammonia, leaves standstill 7 days, gets powdered compounds 30 after the solvent evaporated.Productive rate 89%.
13C?NMR：103.55，103.61，103.63，103.70(4C-1)。Compound 30 is dissolved in the methyl alcohol, adds the normal diacetyl oxide of 4-6, stirs 16 hours under the room temperature, gets powdered compounds 31 after the solvent evaporated.Productive rate 100%.
Pharmacodynamics test:
120 (about 20g) are healthy anosis through quarantining for Male Kunming strain mice, are divided into 10 groups at random.Except that control group, all inoculate the S180 cancer cells for all the other 9 groups in every mouse right fore oxter.Carrying out administration after 24 hours from inoculation handles.Pressed ip, 2mg, three dosage successive administrations of 5mg, 15mg/Kg 14 days, and handled the back in the last administration and put to death mouse, claim that knurl is heavy and calculate tumour inhibiting rate.This zooperal result proves: the compound with structure I has antitumous effect.Reaction scheme:
Reaction scheme 1
Reaction scheme 2
Reaction scheme 3
Claims (20)
1. the compound that has following general formula (I),
R wherein
1Can be hydrogen, amino-acid residue, the alkyl of the aryl of replacement or 1 to 12 carbon, R
2To R
N+3Be hydrogen or acyl group, n=1-10.
2. the compound of claim 1, wherein R
1Be octyl group.
3. the compound of claim 1, wherein R
2To R
N+3Be ethanoyl.
4. the compound of claim 1, wherein R
1Be octyl group, R
2To R
N+3Be ethanoyl, n=4.
5. the compound of claim 1, wherein R
1Be octyl group, R
2To R
N+3Be hydrogen, n=4.
6. prepare the method for general formula (I) compound of claim 1, it is characterized in that:
1) with 6-position protected silane, the 2-amino-beta--D-grape pyrans sulphur glycosides 6 of 3,4 acyl group protections is a glycosyl donor, with 6-position free hydroxyl group, 1,2-amino-beta--D-the glucopyanosyl 3 of 3,4 full acidylates can obtain the disaccharide derivative that 1 → 6 of high yield connects for the linked reaction of acceptor, as 7;
2) remove 6 silylation of 7, can make disaccharide 8, itself and 6 glycosylation make trisaccharide 9;
3) and the like can make the amino ligoglucoside derivative of 1 → 6 β that connects-D-;
4) remove all protecting groups in the methanol solution of the methanol solution of sodium methylate or ammonia, can get the amino ligoglucoside product 10 of 1 → 6 β that connects-D-;
5) 10 if can get the acetylizad product of N-with the diacetyl oxide processing, as 11 in methyl alcohol.
7. synthesize the method two of the amino ligoglucoside of 1 → 6 β that connects-D-, it is characterized in that:
1) compound in the claim 15 and 3 is coupled, gets disaccharide, through further sense
Group conversion, glycosyl sulphur glycosides 27, make tetrose 28 with 8 glycosylation then;
2) remove 6 silylation of 28, again with 27 glycosylation, and the like can make
Getting the sugar unit number is the amino ligoglucoside derivative of β-D-that even 1 → 6 connects;
3) remove all protecting groups in the methanol solution of the methanol solution of sodium methylate or ammonia,
The amino ligoglucoside product of 1 → 6 β that connects-D-is as 30;
4) 30 if can get the acetylizad product of N-with the diacetyl oxide processing, as 31 in methyl alcohol.
8. the method for one kind synthetic 1 → 6 amino ligoglucoside glycosides of the β that connects-D-, its feature exists
In:
1) sulphur glycosides 6 carries out glycosylation with alkyl alcohol earlier and makes glucosides 16;
2) remove 6 silylation of 16, again with 6 glycosylations, disaccharide glucosides 18,
3) remove 6 silylation of 18 and get 19,19 and 6 glycosylations, trisaccharide sugar
Glycosides 20, and the like can make the amino ligoglucoside glycosides of 1 → 6 β that connects-D-and derive
Thing
4) removing all acyl groups in the methanol solution of the methanol solution of sodium methylate or ammonia protects
Protect base, get the amino ligoglucoside glycoside product of 1 → 6 β that connects-D-.5) the said products
If in methyl alcohol, can get the acetylizad product of N-with the diacetyl oxide processing.
9. the synthetic method of poly-six glucosides in the amino Portugal of the β that connects for a kind 1 → 6-D-, its feature exists
In: 1) trisaccharide 13 makes glycosyl sulphur glycosides 14,2 with the Helfrich reaction of mercaptan) trisaccharide glucosides 20 usefulness boron trifluoride diethyl etherate methods remove 6 silylation and get 21; 3) 14 and 21 glycosylation makes six glucosides 22; 4) remove protecting groups all in 22 in the methanol solution of the methanol solution of sodium methylate or ammonia, get the amino grape six sugared glucosides 23 of 1 → 6 β that connects-D-; 5) 23 if can get the acetylizad product 24 of N-with the diacetyl oxide processing in methyl alcohol.
10. each method of claim 6-9, wherein the catalyzer of glycosylation is nitrogen-iodine
For the mixed catalyst of succinimide (NIS) with Louis silk acid; Solvent is a methylene dichloride,
Ether, toluene etc.
11. as the method for claim 10, wherein silk acid in Louis is selected from trifluoromethanesulfonic acid, trimethylammonium
Silicon triflate and silver trifluoromethanesulfonate.
12. each method of claim 6-9, the method that wherein removes 6-position silylation is selected from
Trifluoroacetic acid (TFA) method, tetrabutyl fluoride amine (TBAF) method and boron trifluoride second
The ether method.
13. the method for claim 12, the method that wherein removes 6-position silylation is a boron trifluoride second
The ether method.
14. a pharmaceutical composition is characterized in that containing the chemical combination of the claim 1 of significant quantity
Thing and pharmaceutical carrier.
15. the pharmaceutical composition of claim 14, compound wherein is R
1Be octyl group, R
2Extremely
R
N+3Be hydrogen, the formula of n=4 (I) compound.
16. the pharmaceutical composition of claim 14 is oral or injection type.
17. the purposes of the compound of claim 1 in producing cancer therapy drug.
18. the purposes of claim 17, wherein the medicine of being produced is to be used for the treatment of cancer of the stomach, lung cancer
With in the intestinal cancer.
19. the purposes of claim 18, wherein the medicine of being produced is oral or injection type.
20. the application of the compound of claim 1-5 in producing protective foods.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01136484 CN1344722A (en) | 2001-10-19 | 2001-10-19 | Amino polyoligoglucosan with 1-6 connection and glucoside and their synthesis and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01136484 CN1344722A (en) | 2001-10-19 | 2001-10-19 | Amino polyoligoglucosan with 1-6 connection and glucoside and their synthesis and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1344722A true CN1344722A (en) | 2002-04-17 |
Family
ID=4673695
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 01136484 Pending CN1344722A (en) | 2001-10-19 | 2001-10-19 | Amino polyoligoglucosan with 1-6 connection and glucoside and their synthesis and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1344722A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8492364B2 (en) | 2008-07-21 | 2013-07-23 | The Brigham And Women's Hospital, Inc. | Methods and compositions relating to synthetic β-1,6 glucosamine oligosaccharides |
| CN111793143A (en) * | 2019-04-01 | 2020-10-20 | 阿蒂娜自然资产工业贸易有限公司 | Method for extracting oligosaccharide from babassu pericarp powder of babassu palm, oligosaccharide extracted by method and application thereof |
| US10919956B2 (en) | 2002-11-12 | 2021-02-16 | The Brigham And Women's Hospital, Inc. | Polysaccharide vaccine for staphylococcal infections |
-
2001
- 2001-10-19 CN CN 01136484 patent/CN1344722A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10919956B2 (en) | 2002-11-12 | 2021-02-16 | The Brigham And Women's Hospital, Inc. | Polysaccharide vaccine for staphylococcal infections |
| US8492364B2 (en) | 2008-07-21 | 2013-07-23 | The Brigham And Women's Hospital, Inc. | Methods and compositions relating to synthetic β-1,6 glucosamine oligosaccharides |
| US9474806B2 (en) | 2008-07-21 | 2016-10-25 | The Brigham And Women's Hospital, Inc. | Methods and compositions relating to synthetic beta-1,6 glucosamine oligosaccharides |
| US10034927B2 (en) | 2008-07-21 | 2018-07-31 | The Brigham And Women's Hospital, Inc. | Methods and compositions relating to synthetic beta-1,6 glucosamine oligosaccharides |
| US11123416B2 (en) | 2008-07-21 | 2021-09-21 | The Brigham And Women's Hospital, Inc. | Methods and compositions relating to synthetic beta-1,6 glucosamine oligosaccharides |
| CN111793143A (en) * | 2019-04-01 | 2020-10-20 | 阿蒂娜自然资产工业贸易有限公司 | Method for extracting oligosaccharide from babassu pericarp powder of babassu palm, oligosaccharide extracted by method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Chen et al. | The total synthesis of eleutherobin: a surprise ending | |
| Ning et al. | Synthesis of β-(1→ 6)-branched β-(1→ 3) glucohexaose and its analogues containing an α-(1→ 3) linked bond with antitumor activity | |
| Hanee et al. | Synthesis, PASS, In Silico ADMET and thermodynamic studies of some galactopyranoside esters | |
| Ustyuzhanina et al. | Synthesis, NMR and Conformational Studies of Fucoidan Fragments, 8: Convergent Synthesis of Branched and Linear Oligosaccharides | |
| CN105541933A (en) | Method for improving beta-glucosidic bond stereoselectivity through bis(trifluoromethane sulfonimide) reagent activation glycosylation reaction | |
| Sau et al. | Stereoselective glycosylations by nitrosyl tetrafluoroborate-catalyzed activation of glycosyl trichloroacetimidate derivatives | |
| CN1344722A (en) | Amino polyoligoglucosan with 1-6 connection and glucoside and their synthesis and application | |
| CN1358730A (en) | Oligose capable of being used as medicine and its surfated products and preparation process thereof, and medicinal composition having same | |
| Yasutomi et al. | Transition-Metal-Free β-Selective C-Glycosylation of β-Glycosyl Boronates via Stereoretentive 1, 2-Migration | |
| Xia et al. | Roles of 3′ and 4′ hydroxyls in α-galactosylceramide stimulation of invariant natural killer T cells | |
| Comber et al. | α-(1→ 2)-, α-(1→ 3)-, and α-(1→ 6)-Linked thioglycosidic disaccharides: syntheses and anti-HIV testing of thiokojibiose octaacetate, thionigerose, and thioisomaltose | |
| CN102212087A (en) | A method for preparing 3,6-position branched glucotriose | |
| Pfister et al. | Zwitterionic Polysaccharides of Shigella sonnei: Synthetic Study toward a Ready-for-Oligomerization Building Block Made of Two Rare Amino Sugars | |
| Yang et al. | Synthesis of a glucoheptaose-the repeating unit of lentinan | |
| US20130178616A1 (en) | Use of modified oligo-b-(1,3)-glucanes for treating diseases of the immune system oligo-b-(1,3v-glucane-(1,3)-mannose, oligo-b-(1,3)-glucane-(1,3)-mannitol and derivatives thereof, methods for preparing the same and drugs containing them | |
| CN110128491B (en) | Antrodia camphorata galactomannoside derivative and preparation method and application thereof | |
| Tsvetkov et al. | Enhanced sialylating activity of O-chloroacetylated 2-thioethyl sialosides | |
| Xue et al. | A Concise Synthesis of N-Trichloroethoxycarbonyl Lactosamine Trichloroacetimidate Donor and its Application in the Synthesis of Gal (β1-4) GlcNAc (β1-3) L-Fuc (α-OAll) | |
| WO2008032817A1 (en) | Sugar chain having activity against helicobacter pylori | |
| Kartha et al. | Simple and efficient strategy for making β-(1→ 6)-linked galactooligosaccharides using ‘naked’galactopyranosides as acceptors | |
| Sawada et al. | The first synthesis of glycan parts of lactoganglio-and neolactoganglio-series gangliosides | |
| Zong et al. | Synthesis of a mannose hexasaccharide related to the cell wall mannan of Candida dubliniensis and Trychophyton mentagrophytes | |
| CN1300158C (en) | Non-natural active oligosaccharide compounds, preparing process and application | |
| CN1163500C (en) | A method for synthesizing saponins with 2,4-O-disubstituted glucosyl sugar chains | |
| Ma et al. | Synthesis of two oligosaccharides, the GPI anchor glycans from S. cerevesiae and A. fumigatus |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |