CN104177459A - 1,3,4-oxadiazole derivative containing glucosamine fragment as well as synthetic method and use of derivative - Google Patents
1,3,4-oxadiazole derivative containing glucosamine fragment as well as synthetic method and use of derivative Download PDFInfo
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- CN104177459A CN104177459A CN201410383355.3A CN201410383355A CN104177459A CN 104177459 A CN104177459 A CN 104177459A CN 201410383355 A CN201410383355 A CN 201410383355A CN 104177459 A CN104177459 A CN 104177459A
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Abstract
The invention discloses a 1,3,4-oxadiazole derivative containing a glucosamine fragment as well as a synthetic method of the 1,3,4-oxadiazole derivative containing the glucosamine fragment and a use of the derivative. The 1,3,4-oxadiazole derivative containing the glucosamine fragment is a novel compound, and has relatively high inhibitory activity on urease. The synthetic method disclosed by the invention is a convenient, high-yield and efficient method; paratoluensulfonyl chloride is taken as a cyclization reagent, the operation is simple and safe, the environmental pollution is small, the scope of application is wide and the yield is high.
Description
Technical field
The present invention relates to organic synthesis field, specifically relate to a kind of 1,3 of glucosamine fragment that contains, 4-oxadiazole derivative, the invention still further relates to its synthetic method and purposes.
Background technology
1,3,4-oxadiazole is owing to being easy in vivo the feature of metabolism and can associating with hydrogen bond form, thereby, be a kind of conventional drug activity group, also shown numerous biological activitys as: anti-inflammatory, antibacterial, anticancer, anticonvulsion, analgesia and diuresis etc.At present, the depressor of the marketization, as Han You oxadiazole active group (structural formula is as follows) all in tiodazosin (I) and nesapidil (II) and antibiolics Furamizole (III) molecular structure.Some compounds that contain 1,3,4-oxadiazole also can be used as the inhibitor of hiv integrase and revascularization.
D-glucosamine (2-amino-2-deoxy-D-Glucose) is obtained by degradation of chitin, is the important monose that forms higher animal glycoprotein chains, is extensively present in tissue and cell.In its molecule, contain four-OH and one-NH
2, it is carried out to chemically modified and can prepare miscellaneous derivative, be expected to obtain having multiple bioactive novel substance.Research shows, D-glucosamine and derivative thereof participate in building human body hyaluronic acid, heparin, have antiviral, antibacterial isoreactivity, can treatment of arthritis, and stimulatory protein(SP) polysaccharide synthetic, and can activate NK, LAK cell, there is immunoregulation effect.
Given this, will there is biocompatibility and bioactive glucosamine fragment and be incorporated in 1,3,4-oxadiazole molecule, to obtaining the glycosyl azole material that novel biological activity is good.It is reported, the synthetic method of 1,3,4-oxadiazole has following several conventionally: with polyphosphoric acid, as dewatering agent, cyclization makes as raw material one, to using aromatic acid and hydrazine hydrate; Two, take Isosorbide-5-Nitrae-disubstituted semicarbazide as substrate, (1), at POCl
3under effect, make; (2), at I
2under the catalysis of/NaOH system, prepare; (3), under fluoroborate (XtalFluor-E) existence condition, make; Three, take Isosorbide-5-Nitrae-disubstituted amido thiocarbamide is substrate, (1), under red precipitate exists, desulfurization cyclization makes; (2), to prepare under DCC/THF condition; (3), take iodoxy phenylformic acid (IBX) as catalyzer preparation; (4), take phenyl-iodide, potassium hydrogen persulfate makes etc. as the cyclization of desulfurization reagent.Although some is commonly used in aforesaid method, mostly there is one or more shortcoming, as: severe reaction conditions, cyclization time are long, by product is more, catalyzer is expensive, substrate use range is narrower and unfriendly etc. to environment.Therefore, seek a kind of easy, efficient, wide spectrum applicable 1,3, the synthetic method of 4-oxadiazole derivative is very necessary.
Summary of the invention
Technical problem to be solved by this invention is for the deficiencies in the prior art, provides a kind of new for 1,3 of glucosamine fragment, 4-oxadiazole derivative.
Another technical problem to be solved by this invention is to provide above-mentioned containing 1,3 of glucosamine fragment, the synthetic method of 4-oxadiazole derivative.
Another technical problem to be solved by this invention is to provide above-mentioned containing 1,3 of glucosamine fragment, the purposes of 4-oxadiazole derivative.
Technical problem to be solved by this invention is achieved through the following technical solutions.The present invention is that a kind of containing 1,3 of glucosamine fragment, 4-oxadiazole derivative, is characterized in, its molecular formula is as shown in the formula III:
Wherein, described R is selected from CH
3-, C
4h
9-, C
6h
5-, 4-CH
3c
6h
4-, 3-CH
3c
6h
4-, 2-CH
3c
6h
4-, 4-CH
3oC
6h
4-, 3,4-di-CH
3oC
6h
4-, 3-CH
3oC
6h
4-, 4-FC
6h
4-, 2,3-di-FC
6h
4-, 4-ClC
6h
4-, 2-ClC
6h
4-, 4-BrC
6h
4-, 4-IC
6h
4-, 3-IC
6h
4-, 4-OHC
6h
4-, 4-NO
2c
6h
4-,
3-NO
2C
6H
4-,?3-C
6H
4N-,?2-C
5H
3S-,5-Cl-2-C
5H
2S-,?4-(
N,?
N-di-CH
3)-C
6H
4-。
Technical problem to be solved by this invention can also further realize by following technical scheme.The invention also discloses a kind of as described in above technology containing glucosamine fragment 1,3, the synthetic method of 4-oxadiazole derivative, is characterized in, its step is as follows:
(1) by the compound shown in formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide, Tosyl chloride and organic bases are dissolved in tetrahydrofuran (THF) and at 20～65 ℃, react 3～10 hours, reaction solution underpressure distillation, silica gel chromatography, obtains shown in formula II
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; The mol ratio of the compound shown in formula I, Tosyl chloride and organic bases is 1:1～1.5:1～2.1; Described organic bases is pyridine or triethylamine;
R in formula I, formula II is identical with the R in formula III;
(2) by the compound shown in formula II sodium methylate with in methanol mixed solution, at 0～25 ℃, react 0.5～4 hour, reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, finally obtains the compound shown in formula III
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; Described alkali is selected from sodium methylate, hydrazine hydrate, sodium carbonate or salt of wormwood, and the mol ratio of the compound shown in formula II and alkali is 1:1～1.5; In alkali and methanol mixed solution, the two adopts any blending ratio to mix.
Of the present invention containing 1,3 of glucosamine fragment, the synthetic method of 4-oxadiazole derivative, the step of its most preferred technical scheme is as follows:
(1) by the compound shown in formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide, Tosyl chloride and organic bases are dissolved in tetrahydrofuran (THF) and at 30 ℃, react 6 hours, reaction solution underpressure distillation, silica gel chromatography, obtains shown in formula II
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; The mol ratio of the compound shown in formula I, Tosyl chloride and organic bases is 1:1.2:1.5; Described organic bases is pyridine or triethylamine;
(2) by the compound shown in formula II sodium methylate with in methanol mixed solution, at 10 ℃, react 2 hours, reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, finally obtains the compound shown in formula III
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; Described alkali is selected from sodium methylate, hydrazine hydrate, sodium carbonate or salt of wormwood, and the mol ratio of the compound shown in formula II and alkali is 1:1.2; In alkali and methanol mixed solution, the two adopts any blending ratio to mix.
Of the present invention containing 1,3 of glucosamine fragment, in the step of the synthetic method of 4-oxadiazole derivative (1), reaction can be carried out under the condition of traditional heating mode, traditional heating mode has gas burning lamp, electric mantle, water-bath, oil bath, water vapour is bathed, sand-bath, salt bath, metal bath etc.Reaction scheme of the present invention is as follows:
Of the present invention containing 1,3 of glucosamine fragment, in the synthetic method technical scheme of 4-oxadiazole derivative, the compound shown in described formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'the preparation method of-amido thiocarbamide is as follows:
(1) the formula I-I Compound D-glucosamine hydrochloride, triethylamine, the diacetyl oxide that by mol ratio, are 1:1～2:1.2～4 are dissolved in methyl alcohol, at room temperature stirring reaction is 2.5～8 hours, standing after reacting completely, filter, pump solvent, washing with acetone, obtains formula I-II compound acetylglucosamine; Then, formula I-II compound reacts 16～24 hours in Acetyl Chloride 98Min. under room temperature, and reaction is finished, and adds chloroform, washing, and ether recrystallization, obtains formula I-III compound chloro sugar; Finally, under 4-butyl ammonium hydrogen sulfate, molecular sieve exist, chloro sugar reacts 4～6 hours in acetonitrile solution with KSCN at 25～60 ℃; filter filtrate decompression distillation, silica gel chromatography; obtain intermediate product formula I-IV compound 2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose lsothiocyanates; The mol ratio of chloro sugar, 4-butyl ammonium hydrogen sulfate and potassium thiocyanate is 1:1～1.5:1～2;
(2) formula I-IV compound is dissolved in ethanolic soln, adds hydrazides at 25～70 ℃, to react 0.5～3 hour, the mol ratio of formula IV compound and hydrazides is 1:1～1.5; Reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, obtains target product formula I compound
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide.
Of the present invention containing 1,3 of glucosamine fragment, in the synthetic method of 4-oxadiazole derivative: the compound shown in formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'the most preferred preparation method of-amido thiocarbamide is as follows:
(1) the formula I-I Compound D-glucosamine hydrochloride, triethylamine, the diacetyl oxide that by mol ratio, are 1:1.5:2.5 are dissolved in methyl alcohol, and at room temperature stirring reaction is 5 hours, standing after reacting completely, filter, pump solvent, washing with acetone, obtains formula I-II compound acetylglucosamine; Then, formula I-II compound reacts 20 hours in Acetyl Chloride 98Min. under room temperature, and reaction is finished, and adds chloroform, washing, and ether recrystallization, obtains formula I-III compound chloro sugar; Finally, under 4-butyl ammonium hydrogen sulfate, molecular sieve exist, chloro sugar reacts 5 hours in acetonitrile solution with KSCN at 30 ℃; filter filtrate decompression distillation, silica gel chromatography; obtain intermediate product formula I-IV compound 2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose lsothiocyanates; The mol ratio of chloro sugar, 4-butyl ammonium hydrogen sulfate and potassium thiocyanate is 1:1.2:1.5;
(2) formula I-IV compound is dissolved in ethanolic soln, adds hydrazides at 30 ℃, to react 2 hours, the mol ratio of formula IV compound and hydrazides is 1:1.2; Reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, obtains target product formula I compound
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide.
Compound shown in described formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'in the preparation method of-amido thiocarbamide: described hydrazides is selected from acethydrazide, daminozide, benzoyl hydrazine, 4-toluyl hydrazine, 3-toluyl hydrazine, 2-toluyl hydrazine, 4-methoxybenzoyl hydrazine, 3, 4-veratroyl hydrazine, 3-methoxybenzoyl hydrazine, 4-fluorobenzoyl hydrazine, 3, 4-difluorobenzene formyl hydrazine, 4-chlorobenzoyl hydrazine, 2-chlorobenzoyl hydrazine, 4-bromobenzene formyl hydrazine, 4-iodobenzene formyl hydrazine, 3-iodobenzene formyl hydrazine, 4-hydroxybenzoyl hydrazine, 4-nitrobenzoyl hydrazides, 3-nitrobenzoyl hydrazides, 3-pyridine formyl hydrazine, 2-thenoyl hydrazine, the chloro-2-thenoyl of 5-hydrazine, N, N-dimethylamino benzoyl hydrazine.
It is below the compound shown in Chinese style I of the present invention
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'the synthetic route of-amido thiocarbamide is as follows:
Compound shown in Chinese style I of the present invention
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'in the step of the synthetic method of-amido thiocarbamide (1), in the process of synthesis type I-III compound, bibliographical information reacts formula I-II compound dissolution in the chloride solution that soaks completely saturated hydrogenchloride.In experiment, find, we take directly formula II compound dissolution to be reacted in Acetyl Chloride 98Min., have so not only avoided building the trouble that hydrogenchloride generating unit and device for absorbing tail gas bring, and have also guaranteed yield and environmental protection simultaneously.For formula I-III compound purge process, because it more easily decomposes when the comparatively high temps, especially under acidic conditions.After acetylize protects sugared chloro complete, while washing with water, can emit a large amount of heat, add now and in solution, to exist a large amount of HCl and make solution be acid, so chloro sugar is easy to decompose.Therefore,, in order to reduce the loss, when washing, add a large amount of trash ices to prevent that temperature from raising, and avoided the decomposition of chloro sugar.
Purifying for formula I-IV compound, bibliographical information, with ethyl acetate/normal hexane system silica gel column chromatography, yet we select conventional ethyl acetate/petroleum ether system as eluent in experimentation, with the sherwood oil of cheap low toxicity, substitute normal hexane more expensive and that toxicity is larger, this has not only saved cost but also environmental protection.For synthesizing of formula I compound of the present invention, it is known that TLC follows the tracks of reaction, R
f=0.75 left and right have an impure point and with product point R
f=0.60 distance is very near, and this gives the refining trouble of having brought of product.The present invention tests in the product of finding to utilize the method for recrystallization to obtain and still contains a small amount of impurity, but adopts ether washing to obtain highly purified formula V compound for 2～3 times.
Of the present invention containing 1,3 of glucosamine fragment, 4-oxadiazole derivative or synthetic method of the present invention make containing 1,3 of glucosamine fragment, and 4-oxadiazole derivative has the purposes in the composition that suppresses urease activity in preparation.
Compared with prior art, advantage of the present invention is:
(1), synthetic method of the present invention be a kind of easy, efficient, high yield method;
(2), the present invention take Tosyl chloride as cyclization reagent, it is cheap be easy to get and toxicity less;
(3), the present invention adopts traditional heating mode reaction, experimental implementation is simple, convenient post-treatment and environmentally safe;
(4), the present invention has widened the substrate use range of the method, is the applicable synthetic glycosyl 1,3 of a kind of wide spectrum, the method for 4-oxadiazole;
(5), the present invention is incorporated into glucosamine group in 1,3,4-oxadiazole, is expected to obtain the material that biological activity is higher.
Compound shown in formula I of the present invention
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'the advantage of the synthetic method of-amido thiocarbamide is: synthetic method of the present invention be a kind of easy, efficient, high yield method; Present method is synthetic
n-acetylglucosamine base-
n'it is raw material that-amido thiocarbamide be take commercially available glucosamine hydrochloride, hydrazides class, and raw material is cheap to be easy to get, cost-saving; Reaction adopts traditional heating mode reaction, and experimental implementation is simple, and convenient post-treatment and environmentally safe have been widened the substrate use range of the method, are the methods of the applicable synthetic glycosyl amido thiocarbamide of a kind of wide spectrum; Glucosamine group is incorporated in amido thiocarbamide molecule, is expected to obtain having the more material of high biological activity.
Embodiment
By following examples of implementation, will contribute to understand the present invention below, but not limit content of the present invention.
Embodiment 1, a kind of glucosamine base 1,3, and 4-oxadiazole, its molecular formula is as shown in the formula III:
Wherein, described R is selected from as CH
3-, C
4h
9-, C
6h
5-, 4-CH
3c
6h
4-, 3-CH
3c
6h
4-, 2-CH
3c
6h
4-, 4-CH
3oC
6h
4-, 3,4-di-CH
3oC
6h
4-, 3-CH
3oC
6h
4-, 4-FC
6h
4-, 2,3-di-FC
6h
4-, 4-ClC
6h
4-, 2-ClC
6h
4-, 4-BrC
6h
4-, 4-IC
6h
4-, 3-IC
6h
4-, 4-OHC
6h
4-, 4-NO
2c
6h
4-,
3-NO
2C
6H
4-,?3-C
6H
4N-,?2-C
5H
3S-,5-Cl-2-C
5H
2S-,?4-(
N,?
N-di-CH
3)-C
6H
4-。
The present invention is containing 1,3 of glucosamine fragment, and 4-oxadiazole derivative derivative, as a class new compound, has higher inhibition active to urease.Below urease activity experimentation and result thereof.Urease activity testing method: method (the Tanaka T of urease activity detection employing Tanaka etc., Kawase M, Tani S. (2003). Urease inhibitory activity of simple α, β-unsaturated ketones. Life Sci, 73,2985-2990.) in 96 orifice plates, add under 25 microlitres (4 unit) sword bean urease and 25 microlitre testing compound room temperatures and hatch 2 hours.Then add the substrate solution containing 500 mM/ls of urea and 0.002% phenolsulfonphthalein of 100 mM/ls of phosphoric acid buffer preparations of pH value 6.8 for 200 microlitres.After mixing, at 37 ° of C, under 570nM wavelength, with microplate reader detection reaction liquid, from pH 6.8, be raised to pH 7.7 time used.
Active testing result shows, glucosamine and 1,3,4-oxadiazole does not all have Urease inhibitor active under 100 mM/ls of concentration, the present invention is containing 1 of glucosamine fragment, 3,4-oxadiazole derivative derivative has higher inhibition active to urease under this concentration, and inhibiting rate is 42%～87%.
Embodiment 2, a kind of as described in Example 1 containing 1,3 of glucosamine fragment, the synthetic method of 4-oxadiazole derivative, and its step is as follows:
(1) by the compound shown in formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide, Tosyl chloride and organic bases are dissolved in tetrahydrofuran (THF) and at 20 ℃, react 3 hours, reaction solution underpressure distillation, silica gel chromatography, obtains shown in formula II
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; The mol ratio of the compound shown in formula I, Tosyl chloride and organic bases is 1:1:1; Described organic bases is pyridine or triethylamine;
R in formula I, formula II is identical with the R in formula III;
(2) by the compound shown in formula II alkali with in methanol mixed solution, at 0 ℃, react 0.5 hour, reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, finally obtains the compound shown in formula III
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; Described alkali is selected from sodium methylate, hydrazine hydrate, sodium carbonate or salt of wormwood, and the mol ratio of the compound shown in formula II and alkali is 1:1; In alkali and methanol mixed solution, the two adopts any blending ratio to mix.
Embodiment 3, a kind of as described in Example 1 containing 1,3 of glucosamine fragment, the synthetic method of 4-oxadiazole derivative, and its step is as follows:
(1) by the compound shown in formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide, Tosyl chloride and organic bases are dissolved in tetrahydrofuran (THF) and at 65 ℃, react 10 hours, reaction solution underpressure distillation, silica gel chromatography, obtains shown in formula II
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; The mol ratio of the compound shown in formula I, Tosyl chloride and organic bases is 1:1.5:2.1; Described organic bases is pyridine or triethylamine;
R in formula I, formula II is identical with the R in formula III;
(2) by the compound shown in formula II alkali with in methanol mixed solution, at 25 ℃, react 4 hours, reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, finally obtains the compound shown in formula III
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; Described alkali is selected from sodium methylate, hydrazine hydrate, sodium carbonate or salt of wormwood, and the mol ratio of the compound shown in formula II and alkali is 1:1.5; In alkali and methanol mixed solution, the two adopts any blending ratio to mix.
Embodiment 4, a kind of as described in Example 1 containing 1,3 of glucosamine fragment, the synthetic method of 4-oxadiazole derivative, and its step is as follows:
(1) by the compound shown in formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide, Tosyl chloride and organic bases are dissolved in tetrahydrofuran (THF) and at 30 ℃, react 6 hours, reaction solution underpressure distillation, silica gel chromatography, obtains shown in formula II
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; The mol ratio of the compound shown in formula I, Tosyl chloride and organic bases is 1:1.2:1.5; Described organic bases is pyridine or triethylamine;
(2) by the compound shown in formula II sodium methylate with in methanol mixed solution, at 10 ℃, react 2 hours, reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, finally obtains the compound shown in formula III
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; Described alkali is selected from sodium methylate, hydrazine hydrate, sodium carbonate or salt of wormwood, and the mol ratio of the compound shown in formula II and alkali is 1:1.2; In alkali and methanol mixed solution, the two adopts any blending ratio to mix.
Embodiment 5, a kind of base of glucosamine as described in Example 11,3, and 4-oxadiazole synthetic method, its step is as follows:
(1) compound ii
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-methyl isophthalic acid, the preparation of 3,4-oxadiazole-2-amine: in tetrahydrofuran solution, formula I compound
n-glycosyl-
n'-kharophen thiocarbamide, Tosyl chloride and organic bases reaction obtain; Chemical compounds I, the mol ratio of Tosyl chloride and organic bases is 1:1:1.1, and temperature of reaction is 20 ℃, and the time is 10 hours, and described organic bases is triethylamine and pyridine.IR(KBr),?
v/cm
-1:?3328,?2928,?1749,?1662,?1040;?
1H?NMR(400?MHz,?DMSO)?
δ:?8.33(d,?
J?=?9.3?Hz,?1H),?8.05(d,?
J?=?9.0?Hz,?1H),?5.22-3.85(m,?7H),?1.98-1.74(4s,?12H
),?1.23(s,?3H);
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-methyl isophthalic acid, the preparation of 3,4-oxadiazole-2-amine: the methanol solution of alkali is dropwise added in the methanol solution of compound ii and react and obtain; The mol ratio of compound ii and alkali is 1:1, and temperature of reaction is 0 ℃, and the time is 1 hour, and described alkali is sodium methylate, hydrazine hydrate, sodium carbonate, salt of wormwood; IR (KBr),
v/ cm
-1: 3420,1628,1576,1420,1065;
1h NMR (400 MHz,
DMSO-D
2O)?
δ:?4.82(d,?
J?=?9.2?Hz,?1H),?3.70-3.20?(m,?6H),?1.86(s,?3H),?1.23(s,?3H);
Embodiment 6, a kind of base of glucosamine as described in Example 11,3, and 4-oxadiazole synthetic method, its step is as follows:
(1) compound ii
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-phenyl-1, the preparation of 3,4-oxadiazole-2-amine: in tetrahydrofuran solution,
n-glycosyl-
n'-benzoyl thiosemicarbazide (I), Tosyl chloride and organic bases reaction obtain; Chemical compounds I, the mol ratio of Tosyl chloride and organic bases is 1:1:1.2, and temperature of reaction is 30 ℃, and the time is 8 hours, and described organic bases is triethylamine and pyridine.IR(KBr),?
v/cm
-1:?3319,?2957,?1750,?1665,?1044;?
1H?NMR(400?MHz,?DMSO)?
δ:?8.86(d,?
J?=?9.6Hz,?1H),?8.08(d,?
J?=?9.0?Hz,?1H),?7.85(dd,?2H),?7.55(m,?3H),?5.24-3.97(m,?7H),?1.99-1.74(4s,?12H);
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-phenyl-1, the preparation of 3,4-oxadiazole-2-amine: the methanol solution of alkali is dropwise added in the methanol solution of compound ii and react and obtain; The mol ratio of compound ii and alkali is 1:1.1, and temperature of reaction is 0 ℃, and the time is 1 hour, and described alkali is sodium methylate, hydrazine hydrate, sodium carbonate, salt of wormwood; IR (KBr),
v/ cm
-1: 3418,1626,1578,1424,1060;
1h NMR (400 MHz, DMSO-D
2o)
δ: 7.87 (dd, 2H), 7.60 (m, 3H), 4.83 (d,
j=9.0 Hz, 1H), 3.71-3.19 (m, 6H), 1.89 (s, 3H);
Embodiment 7, a kind of base of glucosamine as described in Example 11,3, and 4-oxadiazole synthetic method, its step is as follows:
(1) compound ii
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-(4-aminomethyl phenyl)-1,3, the preparation of 4-oxadiazole-2-amine: in tetrahydrofuran solution,
n-glycosyl-
n'-(4-methylbenzene amido) thiocarbamide (I), Tosyl chloride and organic bases reaction obtain; Chemical compounds I, the mol ratio of Tosyl chloride and organic bases is 1:1.1:1, and temperature of reaction is 40 ℃, and the time is 7 hours, and described organic bases is triethylamine and pyridine.IR(KBr),?
v/cm
-1:?3315,?2926,?1749,?1667,?1043;?
1H?NMR(400?MHz,?DMSO)?
δ:?8.79(d,?
J?=?9.5Hz,?1H),?8.06(d,?
J?=?8.9?Hz,?1H),?7.73(d,?2H),?7.36(d,?2H),?5.20-3.94(m,?7H),?2.37(s,?3H),?1.98-1.74(4s,?12H);
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-(4-aminomethyl phenyl)-1,3, the preparation of 4-oxadiazole-2-amine: the methanol solution of alkali is dropwise added in the methanol solution of compound ii and react and obtain; The mol ratio of compound ii and alkali is 1:1.2, and temperature of reaction is 0 ℃, and the time is 2 hours, and described alkali is sodium methylate, hydrazine hydrate, sodium carbonate, salt of wormwood; IR (KBr),
v/ cm
-1: 3419,1629,1579,1413,1052;
1h NMR (400 MHz, DMSO-D
2o)
δ: 7.75 (d, 2H), 7.40 (d, 2H), 4.88 (d,
j=8.9 Hz, 1H), 3.69-3.24 (m, 6H), 2.37 (s, 3H), 1.90 (s, 3H);
Embodiment 8, a kind of base of glucosamine as described in Example 11,3, and 4-oxadiazole synthetic method, its step is as follows:
(1) compound ii
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-(3-p-methoxy-phenyl)-1,3, the preparation of 4-oxadiazole-2-amine: in tetrahydrofuran solution,
n-glycosyl-
n'-(3-anisole amido) thiocarbamide (I), Tosyl chloride and organic bases reaction obtain; Chemical compounds I, the mol ratio of Tosyl chloride and organic bases is 1:1.2:1, and temperature of reaction is 50 ℃, and the time is 6 hours, and described organic bases is triethylamine and pyridine.IR(KBr),?
v/cm
-1:?3316,?2946,?1746,?1666,?1044;?
1H?NMR(400?MHz,?DMSO)?
δ:?8.84(d,?
J?=?9.6?Hz,?1H),?8.06(d,?
J?=?8.9?Hz,?1H),?7.43(m,?2H),?7.31(s,?1H),?7.10(d,?1H),?5.18-3.92(m,?7H),?3.81(s,?3H),?1.96-1.72(4s,?12H);
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-(3-p-methoxy-phenyl)-1,3, the preparation of 4-oxadiazole-2-amine: the methanol solution of alkali is dropwise added in the methanol solution of compound ii and react and obtain; The mol ratio of compound ii and alkali is 1:1.3, and temperature of reaction is 25 ℃, and the time is 1 hour, and described alkali is sodium methylate, hydrazine hydrate, sodium carbonate, salt of wormwood; IR (KBr),
v/ cm
-1: 3416,1629,1581,1424,1042;
1h NMR (400 MHz, DMSO-D
2o)
δ: 7.44 (m, 2H), 7.34 (s, 1H), 7.20 (d, 1H), 4.84 (d,
j=9.2 Hz, 1H), 3.76-3.33 (m, 6H), 3.81 (s, 3H), 1.87 (s, 3H);
Embodiment 9, a kind of base of glucosamine as described in Example 11,3, and 4-oxadiazole synthetic method, its step is as follows:
(1) compound ii
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-(4-fluorophenyl)-1,3, the preparation of 4-oxadiazole-2-amine:: in tetrahydrofuran solution,
n-glycosyl-
n'-(4-fluorobenzene amido) thiocarbamide (I), Tosyl chloride and organic bases reaction obtain; Chemical compounds I, the mol ratio of Tosyl chloride and organic bases is 1:1.3:1, and temperature of reaction is 65 ℃, and the time is 4 hours, and described organic bases is triethylamine and pyridine.IR(KBr),?
v/cm
-1:?3383,?2957,?1749,?1668,?1045;?
1H?NMR(400?MHz,?DMSO)?
δ:?8.83(d,?
J?=?9.7?Hz,?1H),?8.06(d,?
J?=?8.9?Hz,?1H),?7.90(dd,?2H),?7.41(t,?
J?=?8.9?Hz,?2H),?5.20-3.94(m,?7H),?1.99-?1.74(4s,?12H);
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-(4-fluorophenyl)-1,3, the preparation of 4-oxadiazole-2-amine: the methanol solution of alkali is dropwise added in the methanol solution of compound ii and react and obtain; The mol ratio of compound ii and alkali is 1:1.4, and temperature of reaction is 25 ℃, and the time is 1.5 hours, and described alkali is sodium methylate, hydrazine hydrate, sodium carbonate, salt of wormwood; IR (KBr),
v/ cm
-1: 3455,1622,1570,1438,1051;
1h NMR (400 MHz DMSO-D
2o)
δ: 7.91 (dd, 2H), 7.42 (d,
j=8.8 Hz, 2H), 4.87 (d,
j=9.5 Hz, 1H), 3.80-3.36 (m, 6H), 1.92 (s, 3H);
Embodiment 10, a kind of base of glucosamine as described in Example 11,3, and 4-oxadiazole synthetic method, its step is as follows:
(1) compound ii
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-(4-nitrophenyl)-1,3, the preparation of 4-oxadiazole-2-amine: in tetrahydrofuran solution,
n-glycosyl-
n'-(4-oil of mirbane amido) thiocarbamide (I), Tosyl chloride and organic bases react and obtain in tetrahydrofuran solution; Chemical compounds I, the mol ratio of Tosyl chloride and organic bases is 1:1.4:1, and temperature of reaction is 65 ℃, and the time is 3.5 hours, and described organic bases is triethylamine and pyridine.IR(KBr),?
v/cm
-1:?3334,?2956,?1746,?1665,?1046;?
1H?NMR(400?MHz,?DMSO)?
δ:?9.13(d,J?=?9.5?Hz,?1H),?8.39(d,?
J?=?8.8?Hz,?2H),?8.09(d,?
J?=?8.8?Hz,?3H),5.2-3.96(m,?7H),?1.99-1.74?(4s,?12H);
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-(4-nitrophenyl)-1,3, the preparation of 4-oxadiazole-2-amine: the methanol solution of alkali is dropwise added in the methanol solution of compound ii and react and obtain; The mol ratio of compound ii and alkali is 1:1.5, and temperature of reaction is 25 ℃, and the time is 2 hours, and described alkali is sodium methylate, hydrazine hydrate, sodium carbonate, salt of wormwood; IR (KBr),
v/ cm
-1: 3439,1620,1565,1444,1047;
1h NMR (400MHz, DMSO-D
2o)
δ: 8.40 (d,
j=8.8 Hz, 2H), 8.10 (d,
j=8.8 Hz, 2H), 4.89 (d,
j=9.7 Hz, 1H), 3.85-3.40 (m, 6H), 1.98 (s, 3H);
Embodiment 11, a kind of base of glucosamine as described in Example 11,3, and 4-oxadiazole synthetic method, its step is as follows:
(1) compound ii
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-(4-hydroxy phenyl)-1,3, the preparation of 4-oxadiazole-2-amine: in tetrahydrofuran solution,
n-glycosyl-
n'-(4-hydroxybenzene amido) thiocarbamide (I), Tosyl chloride and organic bases reaction obtain; Chemical compounds I, the mol ratio of Tosyl chloride and organic bases is 1:1.5:1, and temperature of reaction is 65 ℃, and the time is 2.5 hours, and described organic bases is triethylamine and pyridine.IR(KBr),?
v/cm
-1:?3392,?3054,?1752,?1630,?1045;?
1H?NMR(400?MHz,?DMSO)?
δ:?10.12(s,?1H),?8.65(d,?
J?=?9.6?Hz,?1H),?8.04(d,
J?=?8.9?Hz,?1H),?7.67(d,?
J?=?8.7?Hz,?2H),?6.90(d,?
J?=?8.8?Hz,?2H?),?5.18-3.93(m,?7H),?1.98-1.74(4s,?12H);
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-(4-hydroxy phenyl)-1,3, the preparation of 4-oxadiazole-2-amine: the methanol solution of alkali is dropwise added in the methanol solution of compound ii and react and obtain; The mol ratio of compound ii and alkali is 1:1, and temperature of reaction is 25 ℃, and the time is 1 hour, and described alkali is sodium methylate, hydrazine hydrate, sodium carbonate, salt of wormwood; IR (KBr),
v/ cm
-1: 3456,1629,1545,1454,1042;
1h NMR (400MHz, DMSO-D
2o)
δ: 7.72 (d,
j=8.8 Hz, 2H), 6.70 (d,
j=8.7 Hz, 2H), 4.81 (d,
j=9.4 Hz, 1H), 3.86-3.39 (m, 6H), 1.95 (s, 3H);
Embodiment 12, a kind of base of glucosamine as described in Example 11,3, and 4-oxadiazole synthetic method, its step is as follows:
(1) compound ii
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-(3-pyridyl)-1,3, the preparation of 4-oxadiazole-2-amine: in tetrahydrofuran solution,
n-glycosyl-
n'-(3-pyridine formamido group) thiocarbamide (I), Tosyl chloride and organic bases reaction obtain; Chemical compounds I, the mol ratio of Tosyl chloride and organic bases is 1:1:1.5, and temperature of reaction is 65 ℃, and the time is 4 hours, and described organic bases is triethylamine and pyridine.IR(KBr),?
v/cm
-1:?3393,?2926,?1750,?1665,?1049;?
1H?NMR(400?MHz,?DMSO)?
δ:?9.03(s,?1H),?8.95(d,?
J?=?9.6?Hz,?1H),?8.72(d,?1H),?8.21(ddd,?1H),?8.06(d,?
J?=?8.9?Hz,?1H?),?7.59(m,?1H),?5.22-3.98(m,?7H),1.99-1.74?(4s,?12H);
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-(3-pyridyl)-1,3, the preparation of 4-oxadiazole-2-amine: the methanol solution of alkali is dropwise added in the methanol solution of compound ii and react and obtain; The mol ratio of compound ii and alkali is 1:1.1, and temperature of reaction is 25 ℃, and the time is 2 hours, and described alkali is sodium methylate, hydrazine hydrate, sodium carbonate, salt of wormwood; IR (KBr),
v/ cm
-1: 3466,1634,1555,1450,1068;
1h NMR (400MHz, DMSO-D
2o)
δ: 9.05 (s, 1H), 8.76 (d, 1H), 8.21 (dd, 1H), 7.60 (m, 1H), 4.87 (d,
j=9.2 Hz, 1H), 3.86-3.40 (m, 6H), 1.92 (s, 3H);
Embodiment 13, a kind of base of glucosamine as described in Example 11,3, and 4-oxadiazole synthetic method, its step is as follows:
(1) compound ii
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-(4-(
n,
n-dimethylamino phenyl)-1,3, the preparation of 4-oxadiazole-2-amine:: in tetrahydrofuran solution,
n-glycosyl-
n'-(4-(
n,
n-dimethylamino) benzoyl is amino) thiocarbamide (I), Tosyl chloride and organic bases reaction obtain; Chemical compounds I, the mol ratio of Tosyl chloride and organic bases is 1:1:2.1, and temperature of reaction is 65 ℃, and the time is 5 hours, and described organic bases is triethylamine and pyridine.IR(KBr),?
v/cm
-1:?3421,?2924,?1748,?1663,?1046;?
1H?NMR(400?MHz,?DMSO)?
δ:?8.58(d,?J?=?9.7?Hz,?1H),?8.05(d,?
J?=?9.0?Hz,?1H?),?7.63(d,?2H),?6.8(d,?2H),?5.18-3.9(m,?7H),?2.99(s,?6H),?1.98-1.74(4s,?12H);
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-(4-(
n,
n-dimethylamino phenyl)-1,3, the preparation of 4-oxadiazole-2-amine: the methanol solution of alkali is dropwise added in the methanol solution of compound ii and react and obtain; The mol ratio of compound ii and alkali is 1:1.2, and temperature of reaction is 25 ℃, and the time is 3 hours, and described alkali is sodium methylate, hydrazine hydrate, sodium carbonate, salt of wormwood; IR (KBr),
v/ cm
-1: 3447,1626,1578,1439,1082;
1h NMR (400MHz, DMSO-D
2o)
δ: 7.71 (d, 2H), 6.85 (d, 2H), 4.84 (d,
j=9.8 Hz, 1H), 3.72-3.24 (m, 6H), 3.02 (s, 6H), 1.90 (s, 3H);
Embodiment 14, a kind of base of glucosamine as described in Example 11,3, and 4-oxadiazole compound experiment, experimental technique is with reference to embodiment 8, shown in reaction conditions and productive rate see the following form:
The structure of the target compound of synthesized and title are shown in as follows:
Embodiment 15, and a kind of glucosamine base 1,3 as described in embodiment 2-14 is during 4-oxadiazole is synthetic, described
n-acetylglucosamine base-
n'the synthetic method of-amido thiocarbamide, its step is as follows:
(1) 2-acetylaminohydroxyphenylarsonic acid 3,4, and 6
-three-O-ethanoyl-2-deoxidation-
βthe preparation of-D-pyranose lsothiocyanates: formula I Compound D-glucosamine hydrochloride, triethylamine, diacetyl oxide are dissolved in methyl alcohol, and at room temperature stirring reaction is 2.5 hours, standing after reacting completely, filter, pump solvent, washing with acetone, obtains product formula II compound; Then, formula II compound reacts 16 hours in Acetyl Chloride 98Min. under room temperature, and reaction is finished, and adds chloroform, washing, and ether recrystallization, obtains product formula III compound; Finally, under 4-butyl ammonium hydrogen sulfate, molecular sieve exist, formula III compound reacts 6 hours in acetonitrile solution with KSCN at 25 ℃, filter, and filtrate decompression distillation, silica gel chromatography obtains IV compound; The mol ratio of formula I compound, triethylamine and diacetyl oxide is 1: 1:1.2; The mol ratio of formula III compound, 4-butyl ammonium hydrogen sulfate and potassium thiocyanate is 1: 1: 1;
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'the preparation of-kharophen thiocarbamide: in ethanolic soln, formula IV compound reacts and obtains with acethydrazide; The mol ratio of formula IV compound and acethydrazide is 1:1, and temperature of reaction is 25 ℃, and the time is 2 hours; IR (KBr),
v/ cm
-1: 3320,2972,1749,1667,1044;
1h NMR (400 MHz, DMSO)
δ: 9.79 (br, 1H), 9.72 (br, 1H), 8.21 (d,
j=8.9 Hz, 1H), 7.84 (d,
j=7.3 Hz, 1H), 5.32-3.81 (m, 7H), 1.99-1.77 (5s, 15H);
Embodiment 16, and a kind of glucosamine base 1,3 as described in embodiment 2-14 is during 4-oxadiazole is synthetic, described
n-acetylglucosamine base-
n'the synthetic method of-amido thiocarbamide, its step is as follows:
(1) 2-acetylaminohydroxyphenylarsonic acid 3,4, and 6
-three-O-ethanoyl-2-deoxidation-
βthe preparation of-D-pyranose lsothiocyanates: formula I Compound D-glucosamine hydrochloride, triethylamine, diacetyl oxide are dissolved in methyl alcohol, and at room temperature stirring reaction is 4 hours, standing after reacting completely, filter, pump solvent, washing with acetone, obtains product formula II compound; Then, formula II compound reacts 18 hours in Acetyl Chloride 98Min. under room temperature, and reaction is finished, and adds chloroform, washing, and ether recrystallization, obtains product formula III compound; Finally, under 4-butyl ammonium hydrogen sulfate, molecular sieve exist, formula III compound reacts 8 hours in acetonitrile solution with KSCN at 25 ℃, filter, and filtrate decompression distillation, silica gel chromatography obtains IV compound; The mol ratio of formula I compound, triethylamine and diacetyl oxide is 1: 1.2: 1.4; The mol ratio of formula III compound, 4-butyl ammonium hydrogen sulfate and potassium thiocyanate is 1: 1.1: 1.2;
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'the preparation of-benzoyl thiosemicarbazide: in ethanolic soln, formula IV compound reacts and obtains with benzoyl hydrazine; The mol ratio of formula IV compound and benzoyl hydrazine is 1:1.1, and temperature of reaction is 40 ℃, and the time is 1.5 hours; IR (KBr),
v/ cm
-1: 3374,2931,1751,1668,1043;
1h NMR (400 MHz, DMSO)
δ: 10.38 (br, 1H), 9.91 (br, 1H), 8.21 (d,
j=8.8 Hz, 1H), 8.03 (d,
j=7.2 Hz, 1H), 7.83-7.46 (m, 5H), 5.44-3.81 (m, 7H), 1.97-1.70 (4s, 12H);
Embodiment 17, and a kind of glucosamine base 1,3 as described in embodiment 2-14 is during 4-oxadiazole is synthetic, described
n-acetylglucosamine base-
n'the synthetic method of-amido thiocarbamide, its step is as follows:
(1) 2-acetylaminohydroxyphenylarsonic acid 3,4, and 6
-three-O-ethanoyl-2-deoxidation-
βthe preparation of-D-pyranose lsothiocyanates: formula I Compound D-glucosamine hydrochloride, triethylamine, diacetyl oxide are dissolved in methyl alcohol, and at room temperature stirring reaction is 6 hours, standing after reacting completely, filter, pump solvent, washing with acetone, obtains product formula II compound; Then, formula II compound reacts 20 hours in Acetyl Chloride 98Min. under room temperature, and reaction is finished, and adds chloroform, washing, and ether recrystallization, obtains product formula III compound; Finally, under 4-butyl ammonium hydrogen sulfate, molecular sieve exist, formula III compound reacts 4 hours in acetonitrile solution with KSCN at 40 ℃, filter, and filtrate decompression distillation, silica gel chromatography obtains IV compound; The mol ratio of formula I compound, triethylamine and diacetyl oxide is 1: 1.4: 1.8; The mol ratio of formula III compound, 4-butyl ammonium hydrogen sulfate and potassium thiocyanate is 1: 1.2: 1.4;
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-(4-methyl benzoyl ammonia
Base) preparation of thiocarbamide: in ethanolic soln, formula IV compound and 4-toluyl hydrazine reaction obtain; The mol ratio of formula IV compound and 4-toluyl hydrazine is 1:1.2, and temperature of reaction is 50 ℃, and the time is 2.6 hours; IR (KBr),
v/ cm
-1: 3381,2925,1747,1666,1045;
1h NMR (400 MHz, DMSO)
δ: 10.29
(br,?1H),?9.87?(br,?1H),?8.14?(d,?
J?=?8.8?Hz,?1H),?8.03?(s,?1H),?7.81?(d,?2H),?7.29?(d,?2H),?5.45-3.81?(m,?7H),?2.37?(s,?3H),?1.99-1.71?(4s,?12H);
Embodiment 18, and a kind of glucosamine base 1,3 as described in embodiment 2-14 is during 4-oxadiazole is synthetic, described
n-acetylglucosamine base-
n'the synthetic method of-amido thiocarbamide, its step is as follows:
(1) 2-acetylaminohydroxyphenylarsonic acid 3,4, and 6
-three-O-ethanoyl-2-deoxidation-
βthe preparation of-D-pyranose lsothiocyanates: formula I Compound D-glucosamine hydrochloride, triethylamine, diacetyl oxide are dissolved in methyl alcohol, and at room temperature stirring reaction is 8 hours, standing after reacting completely, filter, pump solvent, washing with acetone, obtains product formula II compound; Then, formula II compound reacts 22 hours in Acetyl Chloride 98Min. under room temperature, and reaction is finished, and adds chloroform, washing, and ether recrystallization, obtains product formula III compound; Finally, under 4-butyl ammonium hydrogen sulfate, molecular sieve exist, formula III compound reacts 2.5 hours in acetonitrile solution with KSCN at 60 ℃, filter, and filtrate decompression distillation, silica gel chromatography obtains IV compound; The mol ratio of formula I compound, triethylamine and diacetyl oxide is 1: 1.6: 2.0; The mol ratio of formula III compound, 4-butyl ammonium hydrogen sulfate and potassium thiocyanate is 1: 1.3: 1.6;
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'synthesizing of-(4-fluorobenzene amido) thiocarbamide: in ethanolic soln, formula IV compound and 4-fluorobenzoyl hydrazine reaction obtain; The mol ratio of formula IV compound and 4-fluorobenzoyl hydrazine is 1:1.4, and temperature of reaction is 60 ℃, and the time is 1.2 hours; IR (KBr),
v/ cm
-1: 3377,2927,1753,1670,1044;
1h NMR (400 MHz, DMSO)
δ: 10.39 (br, 1H),
9.88?(br,?1H),?8.13?(d,?
J?=?8.7?Hz,?1H),?8.07?(d,?
J?=?7.5?Hz?1H),?7.98?(m,?2H),?7.34(t,?2H?),?5.45-3.78?(m,?7H),?1.99-1.70?(4s,?12H);
Embodiment 19, and a kind of glucosamine base 1,3 as described in embodiment 2-14 is during 4-oxadiazole is synthetic, described
n-acetylglucosamine base-
n'the synthetic method of-amido thiocarbamide, its step is as follows:
(1) 2-acetylaminohydroxyphenylarsonic acid 3,4, and 6
-three-O-ethanoyl-2-deoxidation-
βthe preparation of-D-pyranose lsothiocyanates: formula I Compound D-glucosamine hydrochloride, triethylamine, diacetyl oxide are dissolved in methyl alcohol, and at room temperature stirring reaction is 6 hours, standing after reacting completely, filter, pump solvent, washing with acetone, obtains product formula II compound; Then, formula II compound reacts 24 hours in Acetyl Chloride 98Min. under room temperature, and reaction is finished, and adds chloroform, washing, and ether recrystallization, obtains product formula III compound; Finally, under 4-butyl ammonium hydrogen sulfate, molecular sieve exist, formula III compound reacts 3.5 hours in acetonitrile solution with KSCN at 60 ℃, filter, and filtrate decompression distillation, silica gel chromatography obtains IV compound; The mol ratio of formula I compound, triethylamine and diacetyl oxide is 1: 2.0: 4.0; The mol ratio of formula III compound, 4-butyl ammonium hydrogen sulfate and potassium thiocyanate is 1: 1.5: 2.0;
(2)
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-(3-pyridine formyl ammonia
Base) thiocarbamide is synthetic: Glycosyl Isothiocyanates is reacted and obtained with 3-pyridine formyl hydrazine; The mol ratio of formula IV compound and 3-pyridine formyl hydrazine is 1:1.5, and temperature of reaction is 70 ℃, and the time is 1.5 hours; IR (KBr),
v/ cm
-1: 3303,2929,1747,1667,1042;
1h NMR (400 MHz, DMSO)
δ: 10.59 (br, 1H), 9.96 (br; 1H), 9.06 (s, 1H); 8.75 (d, J=3.9 Hz 1H), 8.23-8.13 (m; 3H), 7.54 (m, 1H); 5.46-3.81 (m; 7H), 1.99-1.71 (4s, 12H);
The step of the synthetic method described in embodiment (2), reaction is carried out under the condition of traditional heating mode.
1, experimental technique: with reference to embodiment 16;
2, shown in reaction raw materials, reaction conditions and productive rate see the following form.
Claims (7)
1. one kind containing 1,3 of glucosamine fragment, and 4-oxadiazole derivative, is characterized in that, its molecular formula is as shown in the formula III:
Wherein, described R is selected from CH
3-, C
4h
9-, C
6h
5-, 4-CH
3c
6h
4-, 3-CH
3c
6h
4-, 2-CH
3c
6h
4-, 4-CH
3oC
6h
4-, 3,4-di-CH
3oC
6h
4-, 3-CH
3oC
6h
4-, 4-FC
6h
4-, 2,3-di-FC
6h
4-, 4-ClC
6h
4-, 2-ClC
6h
4-, 4-BrC
6h
4-, 4-IC
6h
4-, 3-IC
6h
4-, 4-OHC
6h
4-, 4-NO
2c
6h
4-,
3-NO
2C
6H
4-,?3-C
6H
4N-,?2-C
5H
3S-,?5-Cl-2-C
5H
2S-,?4-(
N,?
N-di-CH
3)-C
6H
4-。
One kind as claimed in claim 1 containing glucosamine fragment 1,3, the synthetic method of 4-oxadiazole derivative, is characterized in that, its step is as follows:
(1) by the compound shown in formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide, Tosyl chloride and organic bases are dissolved in tetrahydrofuran (THF) and at 20～65 ℃, react 3～10 hours, reaction solution underpressure distillation, silica gel chromatography, obtains shown in formula II
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; The mol ratio of the compound shown in formula I, Tosyl chloride and organic bases is 1:1～1.5:1～2.1; Described organic bases is pyridine or triethylamine;
R in formula I, formula II is identical with the R in formula III;
(2) by the compound shown in formula II alkali with in methanol mixed solution, at 0～25 ℃, react 0.5～4 hour, reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, finally obtains the compound shown in formula III
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; Described alkali is selected from sodium methylate, hydrazine hydrate, sodium carbonate or salt of wormwood, and the mol ratio of the compound shown in formula II and alkali is 1:1～1.5; In alkali and methanol mixed solution, the two adopts any blending ratio to mix.
3. according to claim 2 containing 1,3 of glucosamine fragment, the synthetic method of 4-oxadiazole derivative, is characterized in that, its step is as follows:
(1) by the compound shown in formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide, Tosyl chloride and organic bases are dissolved in tetrahydrofuran (THF) and at 30 ℃, react 6 hours, reaction solution underpressure distillation, silica gel chromatography, obtains shown in formula II
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; The mol ratio of the compound shown in formula I, Tosyl chloride and organic bases is 1:1.2:1.5; Described organic bases is pyridine or triethylamine;
(2) by the compound shown in formula II sodium methylate with in methanol mixed solution, at 10 ℃, react 2 hours, reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, finally obtains the compound shown in formula III
n-(2-acetylaminohydroxyphenylarsonic acid 2-deoxidation-
β-D-pyranose)-5-replaces-1,3,4-oxadiazole-2-amine; Described alkali is selected from sodium methylate, hydrazine hydrate, sodium carbonate or salt of wormwood, and the mol ratio of the compound shown in formula II and alkali is 1:1.2; In alkali and methanol mixed solution, the two adopts any blending ratio to mix.
According to described in claim 2 or 3 containing glucosamine fragment 1,3, the synthetic method of 4-oxadiazole derivative, is characterized in that, the compound shown in formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'the preparation method of-amido thiocarbamide is as follows:
(1) the formula I-I Compound D-glucosamine hydrochloride, triethylamine, the diacetyl oxide that by mol ratio, are 1:1～2:1.2～4 are dissolved in methyl alcohol, at room temperature stirring reaction is 2.5～8 hours, standing after reacting completely, filter, pump solvent, washing with acetone, obtains formula I-II compound acetylglucosamine; Then, formula I-II compound reacts 16～24 hours in Acetyl Chloride 98Min. under room temperature, and reaction is finished, and adds chloroform, washing, and ether recrystallization, obtains formula I-III compound chloro sugar; Finally, under 4-butyl ammonium hydrogen sulfate, molecular sieve exist, chloro sugar reacts 4～6 hours in acetonitrile solution with KSCN at 25～60 ℃; filter filtrate decompression distillation, silica gel chromatography; obtain intermediate product formula I-IV compound 2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose lsothiocyanates; The mol ratio of chloro sugar, 4-butyl ammonium hydrogen sulfate and potassium thiocyanate is 1:1～1.5:1～2;
(2) formula I-IV compound is dissolved in ethanolic soln, adds hydrazides at 25～70 ℃, to react 0.5～3 hour, the mol ratio of formula IV compound and hydrazides is 1:1～1.5; Reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, obtains target product formula I compound
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide.
5. according to claim 4 containing 1,3 of glucosamine fragment, the synthetic method of 4-oxadiazole derivative, is characterized in that, the compound shown in formula I
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6
-three-O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'the preparation method of-amido thiocarbamide is as follows:
(1) the formula I-I Compound D-glucosamine hydrochloride, triethylamine, the diacetyl oxide that by mol ratio, are 1:1.5:2.5 are dissolved in methyl alcohol, and at room temperature stirring reaction is 5 hours, standing after reacting completely, filter, pump solvent, washing with acetone, obtains formula I-II compound acetylglucosamine; Then, formula I-II compound reacts 20 hours in Acetyl Chloride 98Min. under room temperature, and reaction is finished, and adds chloroform, washing, and ether recrystallization, obtains formula I-III compound chloro sugar; Finally, under 4-butyl ammonium hydrogen sulfate, molecular sieve exist, chloro sugar reacts 5 hours in acetonitrile solution with KSCN at 30 ℃; filter filtrate decompression distillation, silica gel chromatography; obtain intermediate product formula I-IV compound 2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose lsothiocyanates; The mol ratio of chloro sugar, 4-butyl ammonium hydrogen sulfate and potassium thiocyanate is 1:1.2:1.5;
(2) formula I-IV compound is dissolved in ethanolic soln, adds hydrazides at 30 ℃, to react 2 hours, the mol ratio of formula IV compound and hydrazides is 1:1.2; Reaction solution underpressure distillation, aqueous ethanolic solution recrystallization, obtains target product formula I compound
n-(2-acetylaminohydroxyphenylarsonic acid 3,4,6-tri--O-ethanoyl-2-deoxidation-
β-D-pyranose)-
n'-amido thiocarbamide.
6. according to claim 4 containing 1 of glucosamine fragment, 3, the synthetic method of 4-oxadiazole derivative, it is characterized in that, described hydrazides is selected from acethydrazide, daminozide, benzoyl hydrazine, 4-toluyl hydrazine, 3-toluyl hydrazine, 2-toluyl hydrazine, 4-methoxybenzoyl hydrazine, 3, 4-veratroyl hydrazine, 3-methoxybenzoyl hydrazine, 4-fluorobenzoyl hydrazine, 3, 4-difluorobenzene formyl hydrazine, 4-chlorobenzoyl hydrazine, 2-chlorobenzoyl hydrazine, 4-bromobenzene formyl hydrazine, 4-iodobenzene formyl hydrazine, 3-iodobenzene formyl hydrazine, 4-hydroxybenzoyl hydrazine, 4-nitrobenzoyl hydrazides, 3-nitrobenzoyl hydrazides, 3-pyridine formyl hydrazine, 2-thenoyl hydrazine, the chloro-2-thenoyl of 5-hydrazine, N, N-dimethylamino benzoyl hydrazine.
7. claimed in claim 1 containing 1 of glucosamine fragment, 3, described in 4-oxadiazole derivative or claim 2 or 3, synthetic method makes containing 1,3 of glucosamine fragment, and 4-oxadiazole derivative has the purposes in the composition that suppresses urease activity in preparation.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105111260A (en) * | 2015-09-07 | 2015-12-02 | 淮海工学院 | Glucosamine-containing 1,3,4-thiadiazole derivative, and preparation method and application thereof |
| CN105503977A (en) * | 2016-01-27 | 2016-04-20 | 淮海工学院 | 1,3,4-oxadiazole derivative containing glucosamine molecules and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153604A (en) * | 2011-02-22 | 2011-08-17 | 淮海工学院 | Glucosamine enamine ketone derivative and synthetic method thereof |
-
2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153604A (en) * | 2011-02-22 | 2011-08-17 | 淮海工学院 | Glucosamine enamine ketone derivative and synthetic method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105111260A (en) * | 2015-09-07 | 2015-12-02 | 淮海工学院 | Glucosamine-containing 1,3,4-thiadiazole derivative, and preparation method and application thereof |
| CN105111260B (en) * | 2015-09-07 | 2018-08-24 | 淮海工学院 | Thiadiazoles derivatives of 1,3,4- containing Glucosamine and preparation method thereof and purposes |
| CN105503977A (en) * | 2016-01-27 | 2016-04-20 | 淮海工学院 | 1,3,4-oxadiazole derivative containing glucosamine molecules and preparation method and application thereof |
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