CN105218600B - A kind of synthetic method of 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates - Google Patents
A kind of synthetic method of 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates Download PDFInfo
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- CN105218600B CN105218600B CN201510669042.9A CN201510669042A CN105218600B CN 105218600 B CN105218600 B CN 105218600B CN 201510669042 A CN201510669042 A CN 201510669042A CN 105218600 B CN105218600 B CN 105218600B
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Abstract
The invention discloses one kind 2; 3; 4; the synthetic method of 6 O acetyl group α D mannopyranose tri- chloroacetimidates; this method include by D mannoses with pyridylacetic acid acid anhydride is agitated mixes; complete acylated mannopyranose is synthesized by catalyst of 4 dimethylamino naphthyridines; then complete acylated mannopyranose is selectively taken off into C1 acetyl group in organic solvent and obtains 2; 3,4,6 four O acetyl group D mannoses; it is finally reacted under base catalysis and is made 2; 3,4,6 O acetyl group α D mannopyranose tribromo-acetyl imines.The method simple and effective of the present invention, product yield are high.
Description
Technical field
The invention belongs to chemosynthesis technical fields, relate in particular to a kind of 2,3,4,6-O- acetyl group-α-D- pyrans
The preparation method of mannose tri- chloroacetimidate.
Background technology
Mannose, it is currently the only for saccharic nutrient clinically, it is distributed widely in body fluid and tissue, directly
Synthesis glycoprotein is utilized, participates in immunological regulation.Many diseases are led just because of the ferment lacked in mannose saccharification
It causes.Its physiological effect in human body is as follows：1）Adjust immune system 2）It is anti-that Macrophage Surface has 4 kinds of recipients that can capture
Original has mannose component 3）Increase wound healing 4）Anti-inflammatory effect 5）Inhibit tumour growth and transfer, increase cancer survival
Rate 6）It can be to avoid certain bacterium infections, such as urethral infection.
In chemical synthesis, Koenigs-Knorr methods are a kind of classics of common silver salt and mercury salt for catalyst
Stereoselective syntheses glucosides, but the stability there are glycosyl donor halogeno-sugar is poor, not easy to maintain, used catalyst is attached most importance to
Metal salt, expensive, the problems such as environmental pollution is serious.
The active good low temperature lower structure of 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates is stablized
Many advantages, such as stereoselectivity is good, available for synthesis sulphur glycosides, oxygen glycosides, carbon glycosides and nitrogen glycosides etc., in mannosan and glycosyl albumen
Deng synthesis in have important role.Therefore, 2,3,4,6-O- acetyl group-α-D- mannopyranoses tri- chloroacetimidates of research are made
To synthesize the important intermediate of sugar esters compounds, it has also become the another much-talked-about topic in life science field.
Invention content
Present invention aim to address problems and shortcomings exist in the prior art, provide a kind of synthesis 2,3,4,6-O- acetyl
The novel method of base-α-D- mannopyranose tribromo-acetyl imines, the stability for solving glycosyl donor halogeno-sugar is poor, is not easy to protect
The problem of depositing, being not easy to obtain reagent glycosylation with potential medical value.
Specifically, the present invention is achieved through the following technical solutions.
A kind of synthetic method of 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates, feature exist
In, D-MANNOSE with pyridylacetic acid acid anhydride is agitated mixes, synthesize complete acylated pyrans sweet dew by catalyst of 4-dimethylaminopyridine
Then complete acylated mannopyranose is selectively taken off C1 acetyl group and obtains 2,3,4,6- tetra--O- acetyl by sugar in organic solvent
Base-D-MANNOSE finally reacts under base catalysis and 2,3,4,6-O- acetyl group-α-D- mannopyranoses tribromo-acetyls Asia is made
Amine, synthesis step include：
The synthesis of (1) five acetyl mannopyranose
At 0 DEG C, D-MANNOSE is dissolved in pyridine, is slowly added to acetic anhydride, and mixture is placed in 0 DEG C of ice-water bath and stirs
0.5 ~ 1h adds in the 4-dimethylaminopyridine of catalytic amount, reacts 6h at room temperature, obtains five acetyl mannopyranose solution；
(2) synthesis of tetra--O- acetyl group of 2,3,4,6--D-MANNOSE
Five acetyl mannopyranoses and tetrahydrofuran are pressed into 1g:The mass volume ratio mixing of 15-20mL, in the condition of ice bath
Under benzylamine is added dropwise thereto, 0.5 ~ 1h is stirred after being added dropwise under ice bath, then reacts 30h at ambient temperature, reaction knot
Vacuum distillation removes tetrahydrofuran after beam, and residue is dissolved with dichloromethane, washed successively with 1M hydrochloric acid solution and water, dry,
Filtering and concentrating obtains water white transparency viscous product；
(3) synthesis of 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates
Tetra--O- acetyl group of 2,3,4,6--D-MANNOSE and dry methylene chloride are pressed into 1g:The mass volume ratio of 10-15mL
Mixing then adds in Tritox stirring 10min, adds in the basic catalyst stirring 30h of catalytic amount, mixes after reaction
Object is washed successively with the water and saturated salt solution of 50mL, dry, is filtered, and is concentrated in vacuo, is obtained colorless viscous product.
Preferably, in step (1), the molar ratio of D-MANNOSE and acetic anhydride is 1:10-20.
Preferably, the solvent of full acetylated reaction is pyridine, and the molar ratio of pyridine and D-MANNOSE is 25-45:1.
Preferably, it after five acetyl mannopyranoses of step (1) synthesize and obtain five acetyl mannopyranose solution, also wraps
The processing step to five acetyl mannopyranose solution is included, the treating step comprises：By the five acetyl mannopyranose solution
It pours into the ice water quickly stirred, after stirring 30min, is extracted with ethyl acetate, merge organic phase, wash, dry, vacuum is dense
Contracting, obtains colorless viscous shape product.
Further, after merging organic phase, further comprise that the toluene azeotropic by the organic phase drying of merging takes part out of
Pyridine is then washed successively with copper/saturated copper sulphate solution, saturated salt solution, saturated sodium bicarbonate solution.
Further, obtained colorless viscous product further includes is handled further below：It is dissolved with anhydrous ether, Ran Hou
Refrigerator overnight freezing and crystallizing obtains white five acetyl mannopyranoses.
Preferably, in step (2), the molar ratio of five acetyl mannopyranoses and benzylamine is 1:1.19-1.25.
Preferably, in step (3), the molar ratio of 2,3,4,6- tetra--O- acetyl group-D-MANNOSE and Tritox is 1:
1.5-2.0。
Preferably, in step (3), basic catalyst used is cesium carbonate.
Compared with prior art the invention has the advantages that：
The method of present invention synthesis 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates overcomes existing
There are some technological deficiencies present in technology, method simple and effective of the invention, product yield height.
Specific embodiment
The purpose of the present invention is to provide a kind of new three chloroethenes of synthesis 2,3,4,6-O- acetyl group-α-D- mannopyranoses
Imido method, including by D-MANNOSE with pyridylacetic acid acid anhydride is agitated mixes, with 4-dimethylaminopyridine（DMAP）To urge
The complete acylated mannopyranose of agent synthesis, then will be acylated mannopyranose and selectively take off C1 acetyl group in organic solvent entirely
2,3,4,6- tetra--O- acetyl group-D-MANNOSE is obtained, is finally reacted under base catalysis and 2,3,4,6-O- acetyl group-α-D- is made
Mannopyranose tribromo-acetyl imines.
Specifically, the step of synthetic method of 2,3,4,6-O- acetyl group-α-D- mannopyranose tribromo-acetyl imines
It is as follows：
(1) five acetyl mannopyranoses are synthesized
At 0 DEG C, D-MANNOSE is dissolved in pyridine, is slowly added to acetic anhydride, and mixture is placed in 0 DEG C of ice-water bath and stirs
0.5 ~ 1h adds in the 4-dimethylaminopyridine of catalytic amount（DMAP）, 6h is reacted at room temperature, obtains five acetyl mannopyranoses
Solution；
(2) tetra--O- acetyl group of synthesis 2,3,4,6--D-MANNOSE
Five acetyl mannopyranoses and tetrahydrofuran are pressed into 1g:15-20mL mass volume ratios mix, under conditions of ice bath
Benzylamine is added dropwise thereto, stirs 0.5 ~ 1h after being added dropwise under ice bath, then reacts 30h under room temperature, after reaction
Vacuum distillation removes tetrahydrofuran, and residue is dissolved with dichloromethane, washed successively with 1 M hydrochloric acid solution and water, dry, filtering
Concentration, obtains water white transparency viscous product；
(3) 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates are synthesized
Tetra--O- acetyl group of 2,3,4,6--D-MANNOSE and dry methylene chloride are pressed into 1g:10-15mL mass volume ratios mix
It closes, then adds in Tritox stirring 10min, the basic catalyst for adding in catalytic amount stirs 30 h, mixes after reaction
Object is washed successively with the water and saturated salt solution of 50mL, dry, and filtering vacuum concentration obtains colorless viscous product.
The molar ratio of a preferred embodiment of the invention, D-MANNOSE and acetic anhydride is 1:10-20.
A preferred embodiment of the invention, the solvent of full acetylated reaction are pyridine, and pyridine and D- sweet dews
The molar ratio of sugar is 25-45:1.
A preferred embodiment of the invention also further locates the five acetyl mannopyranose solution obtained
Reason, processing step include pouring the five acetyl mannopyranose solution obtained in the ice water quickly stirred into, stir 30min
Afterwards, it is extracted with ethyl acetate, merges organic phase, wash, it is dry, it is concentrated in vacuo, obtains colorless viscous shape product.
A kind of more preferable embodiment according to the present invention, it is above-described merging organic phase step after, merging it is organic
Mutually dry toluene azeotropic takes moieties pyridine out of, then molten with copper/saturated copper sulphate solution, saturated salt solution, saturated sodium bicarbonate
Liquid washs successively.
The more preferable embodiment of another kind according to the present invention, the anhydrous second of colorless viscous product obtained by the above
Ether dissolves, and then in refrigerator overnight freezing and crystallizing, obtains white five acetyl mannopyranoses.
The molar ratio of a preferred embodiment of the invention, five acetyl mannopyranoses and benzylamine is 1:1.19-
1.25。
A preferred embodiment of the invention, 2,3,4,6- tetra--O- acetyl group-D-MANNOSE and Tritox
Molar ratio is 1:1.5-2.0.
A preferred embodiment of the invention, basic catalyst used in step (3) are cesium carbonate.
The present invention is described in more detail below.
The present invention relates to a kind of synthetic methods of 2,3,4,6-O- acetyl group-α-D- mannopyranose tribromo-acetyl imines.
The step of this method, is as follows：
The synthesis of (1) five acetyl mannopyranose
At 0 DEG C, D-MANNOSE is dissolved in pyridine, is slowly added to acetic anhydride, and mixture is placed in 0 DEG C of ice-water bath and stirs
0.5 ~ 1h adds in the 4-dimethylaminopyridine of catalytic amount（DMAP）, 6h is reacted at room temperature, obtains five acetyl mannopyranoses
Solution.
D-MANNOSE is current product obtainable on the market.Acetic anhydride is also referred to as acetic anhydride and at present in market
Upper obtainable product.
Preferably, the molar ratio of D-MANNOSE and acetic anhydride is 1:10-20.
It is highly preferred that the molar ratio of D-MANNOSE and acetic anhydride is 1:12.
After full acylation reaction, solution is poured into the ice water quickly stirred, after stirring 30min, extracted with ethyl acetate
It takes, merges organic phase.
After merging organic phase, moieties pyridine is taken out of with dry toluene azeotropic, is then eaten with copper/saturated copper sulphate solution, saturation
Brine, saturated sodium bicarbonate solution wash successively.
After extraction, colorless viscous product is dissolved with anhydrous ether, then in refrigerator overnight freezing and crystallizing, obtains white five
Acetyl mannopyranose.
Nmr analysis method may be used in the five acetyl mannopyranoses that the step obtains, and reflects to product
It is fixed.
The five acetyl mannopyranoses that the step obtains can be directly used in the reaction of subsequent step without processing.
(2) synthesis of tetra--O- acetyl group of 2,3,4,6--D-MANNOSE
The five acetyl mannopyranoses that above step obtains and tetrahydrofuran are pressed into 1g:15-20mL mass volume ratios mix,
Benzylamine is added dropwise thereto under conditions of ice bath, stirs 0.5 ~ 1h after being added dropwise under ice bath, then reacts under room temperature
30h, after reaction vacuum distillation remove tetrahydrofuran, and residue is dissolved with dichloromethane, successively with 1 M hydrochloric acid solution and water
Washing, dry, filtering and concentrating obtains water white transparency viscous product.
Preferably, the molar ratio of five acetyl mannopyranoses and benzylamine is 1:1.19-1.25.
It is highly preferred that the molar ratio of five acetyl mannopyranoses and benzylamine is 1:1.23.
(3) synthesis of 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates
Tetra--O- acetyl group of 2,3,4,6--D-MANNOSE achieved above and dry methylene chloride are pressed into 1g:10-15mL matter
Volume ratio mixing is measured, then adds in Tritox stirring 10min, the basic catalyst for adding in catalytic amount stirs 30 h, reaction
After mixture washed successively with the water and saturated salt solution of 50mL, dry, filtering vacuum concentration obtains colorless viscous production
Object.
Preferably, the molar ratio of 2,3,4,6- tetra--O- acetyl group-D-MANNOSE and Tritox is 1:1.5-2.0.
It is highly preferred that the molar ratio of 2,3,4,6- tetra--O- acetyl group-D-MANNOSE and Tritox is 1:1.74.
Preferably, basic catalyst is cesium carbonate.
The present invention is illustrated by specific embodiment further below, but the present invention is not merely defined in these embodiments.
Embodiment 1
(1) five acetyl mannopyranoses are synthesized
At 0 DEG C, in the round-bottomed flask of 100mL, 3g D-MANNOSEs are dissolved in 33mL purifying pyridines, are slowly added to
The acetic anhydride of 31.5mL dryings, mixture stir 1h at 0 DEG C, add in the 4-dimethylaminopyridine of catalytic amount（DMAP）,
6h is reacted at room temperature.After reaction, mixture is poured into the ice water quickly stirred, after stirring 30min, with 100mL acetic acid second
Ester extracts, and concentrates organic phase, moieties pyridine is taken out of with dry toluene azeotropic, then with copper/saturated copper sulphate solution, saturated common salt
Water, saturated sodium bicarbonate solution wash the organic phase after washing by anhydrous sodium sulfate drying, filtering and concentrating, from obtaining nothing successively
The thick product of color, yield 96%.
(2) tetra--O- acetyl group of synthesis 2,3,4,6--D-MANNOSE
In the round-bottomed flask of 100mL, five acetyl mannopyranoses（1.6g）It is dissolved in 30mL tetrahydrofurans（THF）In,
0.55mL benzylamines are added dropwise under conditions of ice bath thereto, stir 30min after being added dropwise under ice bath, it is then anti-under room temperature
Answer 30h.Vacuum distillation removes tetrahydrofuran after reaction, and residue 30mL dichloromethane dissolves, molten with 1M hydrochloric acid successively
Liquid and water washing, the organic phase after having washed are dried with anhydrous magnesium sulfate, filtering and concentrating organic phase, obtain the sticky production of water white transparency
Object, yield 88%.
(3) 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates are synthesized
In the round-bottomed flask of 100mL, 2,3,4,6- tetra--O- acetyl group-D-MANNOSE（3g）It is dissolved in 30mL drying dichloros
In methane, the Tritox stirring 10min of 1.5mL is then added in, adds in the cesium carbonate stirring 30h of catalytic amount.Reaction terminates
Mixture is washed successively with the water and saturated salt solution of 50mL afterwards, and the organic phase after washing is dried with anhydrous sodium sulfate, and filtering is true
Sky concentration, obtains white solid, yield 90%.
1H NMR (400 MHz, CDCl3): δ 8.78 (s, 1H; NH), 6.27 (d, J = 5.3 Hz, 1H;
H-1), 5.46–5.47 (d, J = 5.3 Hz, 1H; H-4), 5.40 (dd, J = 5.3 and 18 Hz, 1H; H-
3), 5.38-5.39 (dd, J = 5.5 and 18 Hz, 1H; H-2), 4.25–4.28 (t, J = 10.7 Hz,
1H; H-5), 4.17–4.19 (m, 1H; H-6a), 4.09–4.14 (m, 1H; H-6b), 2.19 (s,3H;OAc),
2.07(s,3H ;OAc), 2.06 (s, 3H; OAc), 2.00(s, 3H; OAc)。
Application Example 1
The synthesis of four-O- acetyl group of p-methoxyphenyl -2,3,4,6--D-MANNOSE glycosides
8.00 g are added in into 100 mL round-bottomed flasks（16.29 mmol）2,3,4,6-O- acetyl group-α-D- pyrans is sweet
The sugared tri- chloroacetimidate of dew, 6.07g (48.88mmol) p methoxy phenols and 50mL CH2Cl2, after stirring and dissolving,
Under condition of ice bath, 2.10mL (16.29 mmol) boron trifluoride ether solution is added dropwise, is placed in 0 DEG C of ice bath after cooling and stirring 4h,
The reaction was complete for TLC monitorings, and decompression filters, and filtrate concentration, column chromatography for separation obtains white solid 5.69g, yield 76.9%.105~
107℃。
Embodiments of the present invention are described in detail above in conjunction with specific embodiment, but the present invention is not limited to upper
Embodiment is stated, in the knowledge having in technical field those of ordinary skill, the present invention can also not departed from
It is made a variety of changes under the premise of objective.
Claims (6)
1. the synthetic method of 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates of one kind, feature exist
In, D-MANNOSE with pyridylacetic acid acid anhydride is agitated mixes, synthesize complete acylated pyrans sweet dew by catalyst of 4-dimethylaminopyridine
Then complete acylated mannopyranose is selectively taken off C1 acetyl group and obtains 2,3,4,6- tetra--O- acetyl by sugar in organic solvent
Base-D-MANNOSE finally reacts under base catalysis and 2,3,4,6-O- acetyl group-α-D- mannopyranoses tribromo-acetyls Asia is made
Amine, synthesis step include：
The synthesis of (1) five acetyl mannopyranose
At 0 DEG C, D-MANNOSE is dissolved in pyridine, is slowly added to acetic anhydride, mixture be placed in stirring 0.5 in 0 DEG C of ice-water bath ~
1h adds in the 4-dimethylaminopyridine of catalytic amount, reacts 6h at room temperature, obtains five acetyl mannopyranose solution, wherein
The molar ratio of D-MANNOSE and acetic anhydride is 1:10-20, and the molar ratio of pyridine and D-MANNOSE is 25-45:1；
(2) synthesis of tetra--O- acetyl group of 2,3,4,6--D-MANNOSE
Five acetyl mannopyranoses and tetrahydrofuran are pressed into 1g:15-20mL mass volume ratio mixing, under conditions of ice bath to
Benzylamine is wherein added dropwise, stirs 0.5 ~ 1h after being added dropwise under ice bath, then reacts 30h at ambient temperature, after reaction
Vacuum distillation removes tetrahydrofuran, and residue is dissolved with dichloromethane, washed successively with 1M hydrochloric acid solution and water, dry, filtering
Concentration, obtains water white transparency viscous product；
(3) synthesis of 2,3,4,6-O- acetyl group-α-D- mannopyranose tri- chloroacetimidates
Tetra--O- acetyl group of 2,3,4,6--D-MANNOSE and dry methylene chloride are pressed into 1g:The mass volume ratio mixing of 10-15mL,
Tritox stirring 10min is then added in, the basic catalyst cesium carbonate stirring 30h of catalytic amount is added in, mixes after reaction
Object is closed to be washed successively with the water and saturated salt solution of 50mL, it is dry, it filters, is concentrated in vacuo, obtains colorless viscous product.
2. according to the method described in claim 1, it is characterized in that, the five acetyl mannopyranoses in step (1) synthesize acquisition
After five acetyl mannopyranose solution, the processing step to five acetyl mannopyranose solution, the processing step packet are further included
It includes：The five acetyl mannopyranose solution is poured into the ice water quickly stirred, after stirring 30min, is extracted with ethyl acetate, is closed
And organic phase, it washs, it is dry, it is concentrated in vacuo, obtains colorless viscous shape product.
3. according to the method described in claim 2, it is characterized in that, after merging organic phase, further comprise the organic of merging
Mutually dry toluene azeotropic takes moieties pyridine out of, then molten with copper/saturated copper sulphate solution, saturated salt solution, saturated sodium bicarbonate
Liquid washs successively.
4. according to the method described in claim 2, it is characterized in that, still further comprise following steps：It is colourless viscous by what is obtained
Thick product is dissolved with anhydrous ether, then in refrigerator overnight freezing and crystallizing, obtains white five acetyl mannopyranoses.
5. according to the method described in claim 1, it is characterized in that, in step (2), five acetyl mannopyranoses and benzylamine
Molar ratio is 1:1.19-1.25.
6. according to the method described in claim 1, it is characterized in that, in step (3), 2,3,4,6- tetra--O- acetyl group-D- are sweet
The molar ratio of dew sugar and Tritox is 1:1.5-2.0.
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Non-Patent Citations (3)
| Title |
|---|
| 《Monovalent mannose-based DC-SIGN antagonists: Targeting the hydrophobic groove of the receptor》;Tihomir Tomasic et al.;《European Journal of Medicinal Chemistry》;20140131;第75卷;第308-326页 * |
| 《Synthesis and Anticoagulant Activity of Polyureas Containing Sulfated Carbohydrates》;Yongshun Huang et al.;《Biomacromolecules》;20141021;第15卷;第4455-4466页 * |
| 《Unique tetrameric and hexameric mannoside clusters prepared by click chemistry》;Hussein Al-Mughaid et al.;《Carbohydrate Research》;20150730;第417卷;第27-33页 * |
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