CN104725447A - 3-S-tetrahydroxy-beta-D-glucoside-1,2,4-triazole compound - Google Patents

3-S-tetrahydroxy-beta-D-glucoside-1,2,4-triazole compound Download PDF

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CN104725447A
CN104725447A CN201510154077.9A CN201510154077A CN104725447A CN 104725447 A CN104725447 A CN 104725447A CN 201510154077 A CN201510154077 A CN 201510154077A CN 104725447 A CN104725447 A CN 104725447A
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alcohol
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tetrahydroxy
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卢俊瑞
张瑞波
刘金彪
王宏韫
杨旭云
穆江蓓
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Tianjin University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides a 3-S-tetrahydroxy-beta-D-glucoside-1,2,4-triazole compound. The preparation method of the compound comprises the following steps: generating a potassium salt from substituted benzoyl hydrazine and carbon disulfide, and then reacting the potassium salt with hydrazine hydrate to obtain a 3-sulfydryl-4-amino-5-substituted aryl-1,2,4 triazole compound; reacting the compound with bromoacetylated alpha-D-glucopyranose to synthesize a 3-S-2',3'.4',6-tetra-O-acetyl-beta-D-glucopyranosyl-4-amino-5-substituted phenyl-1,2,4-triazole compound; generating a 3-S-2',3',4',6-tetrahydroxy-beta-D-glucopyranosyl-4-amino-5-substituted phenyl-1,2,4-triazole compound under an alkaline condition. The compound shows good bacteriostatic activity on escherichia coli, staphylococcus aureus, bacillus subtilis, and candida albicans; and the preparation method is simple, low in generation cost and high in yield.

Description

A kind of 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds
Technical field
The present invention relates to a kind of 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds and its preparation method and application.
Background technology
1,2,4-triazole glucoside compound as antibacterial, anticancer, antiviral, anti-inflammatory etc., thus enjoys the concern of people see document: El, S, H.El, A. owing to having biological activity widely in recent years; El, S, H.El T.; Mohy, E, D, A, El, F.; Ahmed, T.A.B.; Heba M.A, El, N.Eur.J.Med.Chem.2013,66,106-113; Karim, A, D.; Fazel, N, Pur; Nima, H, J.; Asma, A.; Zahra, N.；Farrin，M.Phosphorus,Sulfur,and Silicon.2014,189,81-87。
2013, hide red grade with O-hydroxybenzoic acid fat as starting raw material, that synthesizes contains 1,2,4-triazole glucoside compound, biological activity test shows: have good anti-microbial activity to Candida albicans (M.a.) (ATCC10231), but to streptococcus aureus (S.a.) (ATCC 6538) and intestinal bacteria (E.c.) (8099) anti-microbial activity insensitive, see document: Ji, D, Lu J R, Lu B W, Xin C W, Peng C Y, Bao X R, Bioorg.Med.Chem.Lett, 2013,23,1997.
We are according to biological activity superposition theorem, " salicyl " Molecular fragments and " 1; 2,4-triazole ", " glycosyl " rationally assembled, a kind of 3-S-tetrahydroxy-β-D-Glucose glycosides-1 of design and synthesis, 2,4-triazole class compounds, anti-microbial activity is given prominence to, and shows stronger broad spectrum antibiotic activity, greatly improve solubility property simultaneously, reduce side effect.
At present, the low toxicity of development of new, wide spectrum, antibacterials that resistance is strong have become the problem being badly in need of research.Therefore the invention provides a kind of 3-S-tetrahydroxy-β-D-Glucose glycosides-1 with extremely strong anti-microbial activity, 2,4-triazole class compounds, show through biological activity test, this compounds has good anti-microbial activity to Gram-negative, the positive and fungi, show stronger broad spectrum antibiotic activity, great exploitation potential for its, there is good application prospect.
Summary of the invention
The object of the invention is to for above-mentioned technical Analysis, a kind of 3-S-tetrahydroxy-β-D-Glucose glycosides-1 is provided, 2,4-triazole class compounds, this compounds not only novel structure, synthesis step is simple, production cost is low, productive rate is high, and bacteriostatic activity is strong, side effect is low, it all has good application prospect against gram-negative bacteria, positive bacteria and fungi.
Technical scheme of the present invention
A kind of 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds, its chemical formula is 3-S-2 ', 3 ', 4 ', 6 '-four-hydroxy-beta-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole class compounds, and its structural formula is:
(III) in formula: R is benzene, halogeno-benzene, amino-benzene, hydroxybenzene or oil of mirbane.
A kind of preparation method of described 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds, its synthetic route is as follows:
Preparation process is as follows:
1) preparation of intermediate bromoacetyl glucose
In the reactor that thermometer and constant pressure funnel are housed, add diacetyl oxide, dripping concentration is the HClO of 70-72wt% 4solution, HClO 4the volume ratio of solution and diacetyl oxide is 1:90-120, then dextrose anhydrous is joined in reactor, and with ice-water bath control temperature at 30-200 DEG C, continue reaction to solution to clarify, add red phosphorus, control temperature of reaction below 20 DEG C, dropwise bromine is added after abundant stirring, react half an hour, dropwise add water and control temperature is no more than 20 DEG C, wherein diacetyl oxide, dextrose anhydrous, red phosphorus, the mol ratio of bromine and water is 7-10:1:0.2:2-4:4-6, after water droplet adds, remove ice bath and continue reaction two hours, then solvent orange 2 A is added, dextrose anhydrous and solvent orange 2 A mass ratio are 1:4-6, suction filtration, by filtrate down in frozen water, separate organic layer, washing, and then use saturated NaHCO 3solution is transferred to neutrality, the anhydrous MgSO of organic phase 4drying, suction filtration, vacuum rotary steam under pressure is 100-200Pa, obtains glassy yellow syrupy shape solid, with solvent B recrystallization, obtains white solid intermediate,
2) 3-S-2 ', the preparation of 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole (II)
In the reactor, add distilled water, solvent C and alkali, compound 3-sulfydryl-4-amino-5-substituted aryl-1 is added after stirring and dissolving, 2, 4 triazoles (I), wherein chemical compounds I, alkali, the mol ratio of distilled water and solvent C is 1:1-5:10-12:30-40, stir 30min, add bromoacetyl glucose, the mol ratio of chemical compounds I and bromoacetyl glucose is 1:1-2, react in stirred at ambient temperature, TLC tracks to the rear stopped reaction of raw material spot disappearance, developping agent is volume ratio is the ethyl acetate of 1:2 and the mixture of sherwood oil, under pressure is 100-200Pa, vacuum rotary steam removes solvent C, gained solid is dissolved in solvent D, wash 2 times, aqueous phase solvent D extracts 2 times, then organic phase is merged, organic phase is filtered after anhydrous magnesium sulfate drying, under pressure is 100-200Pa, vacuum rotary steam is except desolventizing D, obtain target compound (II),
3) 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds and 3-S-2 ', the preparation of 3 ', 4 ', 6 '-four-hydroxy-beta-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole (III)
Add solvent E and alkali in the reactor, add above-claimed cpd (II) again, wherein the mol ratio of compound ii, alkali and solvent E is 1:1-5:100-150, stirring and dissolving, stirred at ambient temperature reacts, and TLC tracks to the rear stopped reaction of raw material spot disappearance, developping agent is volume ratio is the methylene dichloride of 5:1 and the mixture of methyl alcohol, adding 732 type storng-acid cation exchange resins adjusts PH to neutral, and silica gel column chromatography is separated, and obtains target compound (III).
Described step 1) in solvent orange 2 A be the mixture of a kind of, two kinds or two or more arbitrary proportion in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, sec-butyl alcohol, butyleneglycol, Pentyl alcohol, primary isoamyl alcohol, n-hexyl alcohol, hexalin, n-Heptyl alcohol, n-Octanol, isooctyl alcohol, sec-octyl alcohol, acetonitrile, methylene dichloride, chloroform, acetone and ether; Solvent B is the mixture of one or more arbitrary proportions in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, sec-butyl alcohol, butyleneglycol, Pentyl alcohol, primary isoamyl alcohol, n-hexyl alcohol, hexalin, n-Heptyl alcohol, n-Octanol, isooctyl alcohol, sec-octyl alcohol, acetonitrile, methylene dichloride, chloroform, acetone and ether;
Described step 2) in alkali used be the mixture of a kind of, two kinds or two or more arbitrary proportion in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, Quilonum Retard, saleratus, sodium sulfate, potassium sulfate, Lithium Sulphate, sodium pyrosulfate, sal enixum, sodium phosphate, Sodium phosphate dibasic and SODIUM PHOSPHATE, MONOBASIC.
Described step 2) in solvent C be the mixture of a kind of, two kinds or two or more arbitrary proportion in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, sec-butyl alcohol, butyleneglycol, Pentyl alcohol, primary isoamyl alcohol, n-hexyl alcohol, hexalin, n-Heptyl alcohol, n-Octanol, isooctyl alcohol, sec-octyl alcohol, acetonitrile, methylene dichloride, chloroform, acetone and ether; Solvent D is the mixture of one or more arbitrary proportions in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, sec-butyl alcohol, butyleneglycol, Pentyl alcohol, primary isoamyl alcohol, n-hexyl alcohol, hexalin, n-Heptyl alcohol, n-Octanol, isooctyl alcohol, sec-octyl alcohol, acetonitrile, methylene dichloride, chloroform, acetone and ether.
Described step 3) in alkali used be the mixture of one or more arbitrary proportions in sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide, diethylamine, triethylamine, quadrol, methylamine, ethamine, trolamine, aniline, pyridine and DMAP.
Described step 3) solvent E is the mixture of one or more arbitrary proportions in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, sec-butyl alcohol, butyleneglycol, Pentyl alcohol, primary isoamyl alcohol, n-hexyl alcohol, hexalin, n-Heptyl alcohol, n-Octanol, isooctyl alcohol, sec-octyl alcohol, acetonitrile, methylene dichloride, chloroform, acetone and ether.
A kind of application of described 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds, for the preparation of against gram-negative bacteria, positive bacteria and antifungal drug.
Advantage of the present invention and positively effect are:
Such compound structure is novel, synthesis step is simple, production cost is low, productive rate is high, from design, produces the requirement of applying and all meeting environmental friendliness and Green Chemistry; This compounds all shows good bacteriostatic activity to intestinal bacteria, streptococcus aureus, subtilis and Candida albicans, there is broad-spectrum antimicrobial Development volue and application prospect, lead compound, basic theory and technical support can be provided for safe and efficient antimicrobial new drug development.
Embodiment
In order to understand the present invention further, provide embodiment, it is of the present invention that specific material and condition used are intended to explanation, is not construed as limiting its rational scope.
Embodiment 1:
A kind of 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds, its chemical formula is 3-S-2 ', 3 ', 4 ', 6 '-four-hydroxy-beta-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole class compounds, and its structural formula is:
(III) in formula: R is 4-hydroxybenzene, and its synthetic route is as follows:
Preparation process is as follows:
1) preparation of intermediate bromoacetyl glucose
In the 100mL there-necked flask that thermometer and constant pressure funnel are housed, add 15mL diacetyl oxide, dripping concentration is the HClO of 70wt% 4solution, HClO 4the volume ratio of solution and diacetyl oxide is 1:100, then 5.0g dextrose anhydrous is joined in there-necked flask, and with ice-water bath control temperature between 30-40 DEG C, continue reaction to solution to clarify, add 0.75g red phosphorus, control temperature of reaction below 20 DEG C, after fully stirring, dropwise add 3.0mL bromine; Reaction half an hour, dropwise add 1.8mL water and control temperature is no more than 20 DEG C.After water droplet adds, remove ice bath and continue reaction two hours, then add 15mL methylene dichloride, suction filtration, by filtrate down in 50mL frozen water, separate organic layer, washing, and then use saturated NaHCO 3solution is adjusted to neutrality.Organic phase is dry with anhydrous MgSO4.Suction filtration, vacuum rotary steam, obtains glassy yellow syrupy shape solid, uses anhydrous diethyl ether heating for dissolving, places in refrigerator, separates out white solid, productive rate 90.0%, fusing point: 86-88 DEG C.
2) 3-S-2 ', the synthesis of 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-glucopyranosyl-4-amino-5-(4-hydroxy-pheny)-1,2,4-triazoles
In 50mL there-necked flask, add 0.12g (2.0mmol) KOH, 2mL distilled water, 10mL acetone soln, 2.0mmol compound 3-sulfydryl-4-amino-5-(4-hydroxy-pheny)-1, 2, 4-triazole, stir 30min, 0.98g (2.4mmo1) 2 ' is dissolved with 10mL acetone soln, 3 ', 4 ', 6 '-four-O-ethanoyl-α-D-acetylbromoglycose, add in reactor, in stirred at ambient temperature reaction 16h, TLC tracks to the rear stopped reaction of raw material spot disappearance, developping agent is volume ratio is the ethyl acetate of 1:2 and the mixture of sherwood oil, under pressure is 100-200Pa, vacuum rotary steam removes solvent C, gained solid is dissolved in 20mL methylene dichloride, wash 2 times (2 × 20mL), aqueous phase dichloromethane extraction 2 times, then organic phase is merged.Organic phase is filtered after anhydrous magnesium sulfate drying, and decompression is spin-dried for removing solvent afforded crude material, and silica gel column chromatography is separated to obtain product, white solid, productive rate: 68.7%, m.p.178.3 ~ 179.4 DEG C. 1h NMR (DMSO-d 6, 400MHz) and δ: 9.93 (s, 1H, OH), 7.89 (d, 2H, J=8.8Hz, ArH), 6.88 (d, 2H, J=8.4Hz, ArH), 6.00 (s, 2H, NH 2), 5.52 (d, 1H, J h-1 '-H-2 '=10.0Hz, H-1 '), 5.38 (t, 1H, J h-3 '-H-4 '=J h-3 '-H-2 '=9.6Hz, H-3 '), 5.02 (t, 1H, J h-2 '-H-1 '=J h-2 '-H-3 '=9.4Hz, H-2 '), 4.97 (t, 1H, J h-4 '-H-5 '=J h-4 '-H-3 '=9.6Hz, H-4 '), 4.12 (dd, 1H, J h-6 '-H-5 '=5.2Hz, J h-6 '-H-6 "=12.0Hz, H-6 '), 4.07 (dd, 1H, J h-6 "-H-5 '=5.2Hz, J h-6 "-H-6 '=12.0Hz, H-6 "), 4.03 ~ 3.99 (m, 1H, H-5 '), 2.08,1.99,1.96,1.89 (4s, 12H, CH 3cO); 13c NMR (DMSO-d 6, 400MHz) and δ: 170.43,169.96,169.72,169.61,159.44,154.87,148.38,130.00,117.96,115.69,83.13,75.14,73.30,70.38,68.22,62.23,20.88,20.82,20.78,20.73; IR (KBr) ν: 3442,3230,1751,1614,1467,1401,1223,1045,848cm -1; ESI-MS m/s:539.1461 [M+H] +, HRMS calcd for C 22h 27n 4o 10s [M+H] +this compound number of 539.1448, found 539.1461. is compound a..
3) 3-S-2 ', the synthesis of 3 ', 4 ', 6 '-tetrahydroxy-β-D-glucopyranosyl-4-amino-5-(4-hydroxy-pheny)-1,2,4-triazoles
In 50mL there-necked flask, add 10mL methyl alcohol, then add 0.092g (4.0mmol) sodium Metal 99.5 and dissolve, then add 10mL methylene dichloride, add 1.08g (2.0mmol) compound 5R 1stirring and dissolving, room temperature reaction, TLC tracks to the rear stopped reaction of raw material spot disappearance, developping agent is volume ratio is the methylene dichloride of 5:1 and the mixture of methyl alcohol, after question response terminates, add 732 type storng-acid cation exchange resins, stir and measure solution PH to neutral, silica gel column chromatography is separated to obtain product, yellow solid, productive rate: 73.9%, m.p.119.4 ~ 121.3 DEG C. 1H NMR(DMSO-d 6,400MHz)δ:9.93(s,1H,OH),7.89(d,2H,J＝8.8Hz,ArH),6.88(d,2H,J＝8.8Hz,ArH),6.04(s,2H,NH 2),5.55(d,1H,J＝6.4Hz,H-1’),5.18(d,1H,J＝12.0Hz,H-3’),5.04(d,1H,J＝4.8Hz,H-2’),4.75(d,1H,J＝10.0Hz,H-4’),4.63(t,1H,J＝5.2,10.4Hz,H-6’),3.88～3.58(m,2H,H-5’,H-6”),3.20～3.07(m,4H,OH)； 13C NMR(DMSO-d 6,400MHz)δ:159.30,154.73,149.11,130.06,118.34,115.63,87.68,81.52,78.24,73.37,70.12,61.39；IR(KBr)ν:3416,2921,2862,1620,1463,1276,1172,1054,830cm -1；ESI-MS m/s:371.1021[M+H] +,HMRS calcd forC 14H 19N 4O 6S[M+H] +371.1025,found 371.1021.。This compound number is compd A.
Embodiment 2:
A kind of 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds, its chemical formula is 3-S-2 ', 3 ', 4 ', 6 '-four-hydroxy-beta-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole class compounds, and its structural formula is:
(III) in formula: R is 2-chlorobenzene, and its synthetic route is as follows:
Preparation process is as follows:
1) preparation method of intermediate bromoacetyl glucose is identical with embodiment 1.
2) 3-S-2 ', 3 ', 4 '; the synthesis of 6 '-four-O-ethanoyl-β-D-glucopyranosyl-4-amino-5-(the chloro-phenyl of 2-)-1,2,4-triazoles is identical with embodiment 1; obtained 3-S-2 ', 3 ', 4 '; 6 '-four-O-ethanoyl-β-D-glucopyranosyl-4-amino-5-(the chloro-phenyl of 2-)-1; 2,4-triazole, yellow solid; productive rate: 63.2.0%, m.p.66.6 ~ 67.9 DEG C. 1hNMR (DMSO-d 6, 400MHz) and δ: 7.64 (dd, 1H, J=2.8,5.2Hz, ArH), 7.60 ~ 7.56 (m, 1H, ArH), 7.50 ~ 7.49 (m, 2H, ArH), 5.59 (d, 1H, J h-1 '-H-2 '=10.4Hz, H-1 '), 5.43 (t, 1H, J h-3 '-H-4 '=9.6Hz, J h-3 '-H-2 '=9.2Hz, H-3 '), 5.06 (t, 1H, J h-2 '-H-1 '=J h-2 '-H-3 '=9.6Hz, H-2 '), 4.96 (t, 1H, J h-4 '-H-5 '=9.6Hz, J h-4 '-H-3 '=10Hz, H-4 '), 4.15 (dd, 1H, J h-6 '-H-5 '=5.2Hz, J h-6 '-H-6 "=12.0Hz, H-6 '), 4.11 (dd, 1H, J h-6 "-H-5 '=5.2Hz, J h-6 "-H-6 '=12.0Hz, H-6 "), 4.04 ~ 3.96 (m, 1H, H-5 '), 2.10,2.03,1.99,1.98 (4s, 12H, CH 3cO); 13c NMR (DMSO-d 6, 400MHz) and δ: 170.41,169.95,169.72,169.58,149.21,133.66,132.82,132.45,130.26,127.72,126.45,83.07,75.24,73.32,70.49,68.22,62.17,20.90,20.86,20.79,20.71; IR (KBr) ν: 3446,2961,1752,1635,1441,1376,1226,1046,767cm -1; ESI-MS m/s:557.1107 [M+H] +, HRMS calcd for C 22h 26clN 4o 9s [M+H] +this compound number of 557.1109, found 557.1107. is compound b.
3) 3-S-2 ', the synthesis of 3 ', 4 ', 6 '-tetrahydroxy-β-D-glucopyranosyl-4-amino-5-(the chloro-phenyl of 2-)-1,2,4-triazoles
10mL methyl alcohol is added in 50mL there-necked flask, then add 0.092g (4.0mmol) sodium Metal 99.5 to dissolve, add 10mL methylene dichloride again, add 1.11g (2.0mmol) compound 3-S-2 ', 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-glucopyranosyl-4-amino-5-(the chloro-phenyl of 2-)-1, 2, 4-triazole, stirring and dissolving, room temperature reaction, TLC tracks to the rear stopped reaction of raw material spot disappearance, developping agent is volume ratio is the methylene dichloride of 5:1 and the mixture of methyl alcohol, after question response terminates, add 732 type storng-acid cation exchange resins, stir and measure solution PH to neutral, silica gel column chromatography is separated to obtain product, white solid, productive rate: 82.4%, m.p.108.8 ~ 110.2 DEG C, 1h NMR (DMSO-d 6, 400MHz) and δ: 7.63 (d, 1H, J=8.0Hz, ArH), 7.59 ~ 7.55 (m, 1H, ArH), 7.49 (d, 2H, J=4.0Hz, ArH), 5.54 (d, 1H, J=6.0Hz, H-1 '), 5.24 (d, 1H, J=4.8Hz, H-3 '), 5.05 (t, 2H, J=4.0,5.2Hz, H-2 ', H-4 '), 4.46 (t, 1H, J=5.6,11.2Hz, H-6 '), 3.64 ~ 3.60 (m, 1H, H-6 "), 3.45 ~ 3.41 (m, 1H, H-5 '), 3.22 ~ 3.16 (m, 4H, OH), 13cNMR (DMSO-d 6, 400MHz) and δ: 149.45,144.97,133.44,132.66,132.61,130.41,127.90,126.31,86.94,81.78,78.43,73.30,69.92,61.23, IR (KBr) ν: 3473,3416,1626,1423,1122,1053,769cm -1, ESI-MS m/s:389.0666 [M+H] +, HMRS calcd forC 14h 18clN 4o 5s [M+H] +this compound number of 389.0686, found 389.0666. is compd B.
Embodiment 3:
A kind of 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds, its chemical formula is 3-S-2 ', 3 ', 4 ', 6 '-four-hydroxy-beta-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole class compounds, and its structural formula is:
(III) in formula: R is 4-bromobenzene, and its synthetic route is as follows:
Preparation process is as follows:
1) preparation of intermediate bromoacetyl glucose is identical with embodiment 1.
2) 3-S-2 ', 3 ', 4 '; the synthesis of 6 '-four-O-ethanoyl-β-D-glucopyranosyl-4-amino-5-(the bromo-phenyl of 4-)-1,2,4-triazoles is identical with embodiment 1; obtain 3-S-2 ', 3 ', 4 '; 6 '-four-O-ethanoyl-β-D-glucopyranosyl-4-amino-5-(the bromo-phenyl of 4-)-1; 2,4-triazole, yellow solid; productive rate: 65.6%, m.p.152.7 ~ 153.8 DEG C. 1hNMR (DMSO-d 6, 400MHz) and δ: 8.03 (d, 2H, J=8.8Hz, ArH), 7.76 (d, 2H, J=8.4Hz, ArH), 6.10 (s, 2H, NH 2), 5.57 (d, 1H, J h-1 '-H-2 '=10.0Hz, H-1 '), 5.39 (t, 1H, J h-3 '-H-4 '=9.6Hz, J h-3 '-H-2 '=9.2Hz, H-3 '), 5.05 (t, 1H, J h-2 '-H-1 '=9.6Hz, J h-2 '-H-3 '=10.0Hz, H-2 '), 4.98 (t, 1H, J h-4 '-H-5 '=9.2Hz, J h-4 '-H-3 '=9.6Hz, H-4 '), 4.13 (dd, 1H, J h-6 '-H-5 '=5.2Hz, J h-6 '-H-6 "=11.6Hz, H-6 '), 4.08 (dd, 1H, J h-6 "-H-5 '=5.2Hz, J h-6 "-H-6 '=12.0Hz, H-6 "), 4.03 ~ 4.00 (m, 1H, H-5 '), 2.06,1.99,1.96,1.90 (4s, 12H, CH 3cO); 13c NMR (DMSO-d 6, 400MHz) and δ: 170.41,169.96,169.72,169.62,153.92,149.62,132.04,130.23,126.45,123.99,82.93,75.19,73.31,70.37,68.19,62.19,20.88,20.82,20.81,20.74; IR (KBr) ν: 3450,1751,1635,1454,1382,1226,1094,828cm -1; ESI-MS m/s:601.0608 [M+H] +, HRMS calcd for C 22h 26brN 4o 9s [M+H] +this compound number of 601.0604, found 601.0608. is c.
3) 3-S-2 ', the synthesis of 3 ', 4 ', 6 '-tetrahydroxy-β-D-glucopyranosyl-4-amino-5-(the bromo-phenyl of 4-)-1,2,4-triazoles
10mL methyl alcohol is added in 50mL there-necked flask, then add 0.092g (4.0mmol) sodium Metal 99.5 to dissolve, add 10mL methylene dichloride again, add 1.20g (2.0mmol) compound 3-S-2 ', 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-glucopyranosyl-4-amino-5-(the bromo-phenyl of 4-)-1, 2, 4-triazole, stirring and dissolving, room temperature reaction, TLC tracks to the rear stopped reaction of raw material spot disappearance, developping agent is volume ratio is the methylene dichloride of 5:1 and the mixture of methyl alcohol, after question response terminates, add 732 type storng-acid cation exchange resins, stir and measure solution PH to neutral, yellow solid, productive rate: 75.1%, m.p.115.0 ~ 116.3 DEG C, 1h NMR (DMSO-d 6, 400MHz) and δ: 8.03 (d, 1H, J=8.4Hz, ArH), 7.75 (t, 2H, J=8.4,8.4Hz, ArH), 7.69 (d, 1H, J=8.4Hz, ArH), 6.15 (s, 2H, NH 2), 5.60 (d, 1H, J=5.6Hz, H-1 '), 5.22 (d, 1H, J=4.8Hz, H-3 '), 5.07 (d, 1H, J=5.2Hz, H-2 '), 4.96 (d, 1H, J=10.0Hz, H-4 '), 4.81 (d, 1H, J=9.6Hz, H-6 '), 4.65 (t, 1H, J=5.2,10.8Hz, H-6 "), 3.43 ~ 3.40 (m, 1H, H-5 '), 3.22 ~ 3.13 (m, 4H, OH), 13c NMR (DMSO-d 6, 400MHz) and δ: 153.74,150.38,132.57,131.97,130.33,129.51,87.58,81.56,78.34,73.39,70.12,61.39, IR (KBr) ν: 3475,3415,1626,1447,1257,1121,1063,834cm -1, ESI-MS m/s:433.0182 [M+H] +, HMRS calcd forC 14h 18brN 4o 5s [M+H] +this compound number of 433.0181, found 433.0182. is Compound C.
3-S-tetrahydroxy-β prepared by embodiment 1-3-D-Glucose glycosides-1,2,4-triazole class compounds is used for the preparation of against gram-negative bacteria, positive bacteria and antifungal drug.
Prepared 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds biological activity test:
With reference to the measuring method of National Committee of Clinical Laboratory Standards (NCCLS) minimal inhibitory concentration (MIC), with fluconazole and triclosan for reference to medicine, In Vitro Bacteriostatic test has been carried out to target compound, bacterial strain uses therefor is intestinal bacteria (E.c.) (8099), streptococcus aureus (S.a.) (ATCC 6538), subtilis (Bacillus subtilis, B.s.) (ATCC 6051) and Candida albicans (M.a.) (ATCC10231), Microbiological Lab of Medical University Of Tianjin provides.
Bacteriostatic experiment embodiment:
3-S-2 ', 3 ', 4 ', 6 '-tetrahydroxy-β-D-glucopyranosyl-4-amino-5-(4-hydroxy-pheny)-1,2,4-triazole biological activity test
Concrete operations are as follows:
1) antibacterials stock solution preparation
Compound concentration is 256 μ g.mL -1antibacterials stock solution 10mL, with analytical balance, Weigh Compound 3.4mg, medicine used is pulvis, and the effective force of its medicine is 750 μ gmL -1.Calculating thinner consumption is: 3.4mg × 750 μ gmL -1)/256 μ gmL -1=10.0mL, with 2mL DMF and 8mL distilled water dissolved substance.Less than 0 DEG C storage antibacterials stock solution.
2) substratum
Prepare corresponding substratum: culturing bacterium nutrient broth medium, cultivate fungi Sabouraud dextrose liquid nutrient medium.
3) preparation of antibacterials is diluted
10 sterile test tube (13 × 100mm) are arranged in a row, except the 1st pipe, all the other often pipe add 1.0mL substratum, add antibacterials stock solution (as 256 μ gmL at the 1st pipe -1) 2mL mixing, draw 1mL and be added to the 2nd pipe, draw 1mL after mixing again to the 3rd pipe, so continuous in the 9th pipe, and from the 9th pipe, draw 1mL discard, the negative control that the 10th pipe is not drug containing.1st pipe is respectively 256,128,64,32,16,8,4,2,1 μ gmL to the 9th pipe drug level -1.
4) inoculum preparation
Picking colony prepares the bacteria suspension of 0.5 Maxwell than turbid standard, (about containing 1 ~ 2 × 10 after liquid nutrient medium 1: 1000 dilutes 8cFU.mL -1), add 100 μ L to every pipe, seal in rearmounted 37 DEG C of constant incubators, microbial culture 16 ~ 20h, fungus culture 72h judged result.
5) result judges
Treat microbial culture 16 ~ 20h, after fungus culture 72h, check result record data.First check that whether the bacterial strain of negative control pipe is all right, and ensure not contaminated.Then visual inspection, minimum concentration pipe, without strain growth person, is the minimal inhibitory concentration (MIC) of test strain.
By the method for bacteriostatic experiment embodiment 1, antibacterial biological activity test is carried out to the compound in above-described embodiment and fluconazole and triclosan, 3 compounds in above-described embodiment and the test result of fluconazole and triclosan as follows:
External minimal inhibitory concentration (the μ gmL of compound -1) the results are shown in following table:
Antibacterial test shows, 3-S-2 ', 3 ', 4 ', 6 '-tetrahydroxy-β-D-glucopyranosyl-4-amino-5-(4-hydroxy-pheny)-1,2,4-triazole to the MIC=16 μ g/mL of intestinal bacteria, streptococcus aureus and Candida albicans, to the MIC=64 μ g/mL of subtilis; 3-S-2 ', 3 ', 4 ', 6 '-tetrahydroxy-β-D-glucopyranosyl-4-amino-5-(the chloro-phenyl of 2-)-1,2,4-triazoles to the MIC=16 μ g/mL of intestinal bacteria, streptococcus aureus, to the MIC=8 μ g/mL of Candida albicans; 3-S-2 ', 3 ', 4 ', 6 '-tetrahydroxy-β-D-glucopyranosyl-4-amino-5-(the bromo-phenyl of 4-)-1, the MIC of 2,4-triazole to intestinal bacteria, streptococcus aureus, subtilis and Candida albicans is respectively 2,8,32 and 8 μ g/mL.This compounds all shows good bacteriostatic activity to intestinal bacteria, streptococcus aureus, subtilis and Candida albicans, has broad-spectrum antimicrobial Development volue and application prospect.
Above-mentioned reference embodiment is to the 3-S-2 ' of this formula III, 3 ', 4 ', 6 '-tetrahydroxy-β-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole class compounds and preparation method thereof and the detailed description of carrying out in the application of antibiosis are illustrative instead of determinate; Therefore in the change do not departed under general plotting of the present invention and amendment, should belong within protection scope of the present invention.

Claims (8)

1. 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds, is characterized in that chemical formula is 3-S-2 ', 3 ', 4 ', 6 '-four-hydroxy-beta-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole class compounds, its structural formula is:
(III) in formula: R is benzene, halogeno-benzene, amino-benzene, hydroxybenzene or oil of mirbane.
2. the preparation method of 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds as claimed in claim 1, is characterized in that synthetic route is as follows:
Preparation process is as follows:
1) preparation of intermediate bromoacetyl glucose
In the reactor that thermometer and constant pressure funnel are housed, add diacetyl oxide, dripping concentration is the HClO of 70-72wt% 4solution, HClO 4the volume ratio of solution and diacetyl oxide is 1:90-120, then dextrose anhydrous is joined in reactor, and with ice-water bath control temperature at 30-200 DEG C, continue reaction to solution to clarify, add red phosphorus, control temperature of reaction below 20 DEG C, dropwise bromine is added after abundant stirring, react half an hour, dropwise add water and control temperature is no more than 20 DEG C, wherein diacetyl oxide, dextrose anhydrous, red phosphorus, the mol ratio of bromine and water is 7-10:1:0.2:2-4:4-6, after water droplet adds, remove ice bath and continue reaction two hours, then solvent orange 2 A is added, dextrose anhydrous and solvent orange 2 A mass ratio are 1:4-6, suction filtration, by filtrate down in frozen water, separate organic layer, washing, and then use saturated NaHCO 3solution is transferred to neutrality, the anhydrous MgSO of organic phase 4drying, suction filtration, vacuum rotary steam under pressure is 100-200Pa, obtains glassy yellow syrupy shape solid, with solvent B recrystallization, obtains white solid intermediate,
2) 3-S-2 ', the preparation of 3 ', 4 ', 6 '-four-O-ethanoyl-β-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole (II)
In the reactor, add distilled water, solvent C and alkali, compound 3-sulfydryl-4-amino-5-substituted aryl-1 is added after stirring and dissolving, 2, 4 triazoles (I), wherein chemical compounds I, alkali, the mol ratio of distilled water and solvent C is 1:1-5:10-12:30-40, stir 30min, add bromoacetyl glucose, the mol ratio of chemical compounds I and bromoacetyl glucose is 1:1-2, react in stirred at ambient temperature, TLC tracks to the rear stopped reaction of raw material spot disappearance, developping agent is volume ratio is the ethyl acetate of 1:2 and the mixture of sherwood oil, under pressure is 100-200Pa, vacuum rotary steam removes solvent C, gained solid is dissolved in solvent D, wash 2 times, aqueous phase solvent D extracts 2 times, then organic phase is merged, organic phase is filtered after anhydrous magnesium sulfate drying, under pressure is 100-200Pa, vacuum rotary steam is except desolventizing D, obtain target compound (II),
3) 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds and 3-S-2 ', the preparation of 3 ', 4 ', 6 '-four-hydroxy-beta-D-glucopyranosyl-4-amino-5-substituted-phenyl-1,2,4-triazole (III)
Add solvent E and alkali in the reactor, add above-claimed cpd (II) again, wherein the mol ratio of compound ii, alkali and solvent E is 1:1-5:100-150, stirring and dissolving, stirred at ambient temperature reacts, and TLC tracks to the rear stopped reaction of raw material spot disappearance, developping agent is volume ratio is the methylene dichloride of 5:1 and the mixture of methyl alcohol, adding 732 type storng-acid cation exchange resins adjusts PH to neutral, and silica gel column chromatography is separated, and obtains target compound (III).
3. 3-S-tetrahydroxy-β-D-Glucose glycosides-1 according to claim 2,2, the preparation method of 4-triazole class compounds, is characterized in that: described step 1) in solvent orange 2 A be the mixture of a kind of, two kinds or two or more arbitrary proportion in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, sec-butyl alcohol, butyleneglycol, Pentyl alcohol, primary isoamyl alcohol, n-hexyl alcohol, hexalin, n-Heptyl alcohol, n-Octanol, isooctyl alcohol, sec-octyl alcohol, acetonitrile, methylene dichloride, chloroform, acetone and ether; Solvent B is the mixture of one or more arbitrary proportions in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, sec-butyl alcohol, butyleneglycol, Pentyl alcohol, primary isoamyl alcohol, n-hexyl alcohol, hexalin, n-Heptyl alcohol, n-Octanol, isooctyl alcohol, sec-octyl alcohol, acetonitrile, methylene dichloride, chloroform, acetone and ether.
4. 3-S-tetrahydroxy-β-D-Glucose glycosides-1 according to claim 2,2, the preparation method of 4-triazole class compounds, is characterized in that: described step 2) in alkali used be the mixture of a kind of, two kinds or two or more arbitrary proportion in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, Quilonum Retard, saleratus, sodium sulfate, potassium sulfate, Lithium Sulphate, sodium pyrosulfate, sal enixum, sodium phosphate, Sodium phosphate dibasic and SODIUM PHOSPHATE, MONOBASIC.
5. 3-S-tetrahydroxy-β-D-Glucose glycosides-1 according to claim 2,2, the preparation method of 4-triazole class compounds, is characterized in that: described step 2) in solvent C be the mixture of a kind of, two kinds or two or more arbitrary proportion in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, sec-butyl alcohol, butyleneglycol, Pentyl alcohol, primary isoamyl alcohol, n-hexyl alcohol, hexalin, n-Heptyl alcohol, n-Octanol, isooctyl alcohol, sec-octyl alcohol, acetonitrile, methylene dichloride, chloroform, acetone and ether; Solvent D is the mixture of one or more arbitrary proportions in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, sec-butyl alcohol, butyleneglycol, Pentyl alcohol, primary isoamyl alcohol, n-hexyl alcohol, hexalin, n-Heptyl alcohol, n-Octanol, isooctyl alcohol, sec-octyl alcohol, acetonitrile, methylene dichloride, chloroform, acetone and ether.
6. 3-S-tetrahydroxy-β-D-Glucose glycosides-1 according to claim 2,2, the preparation method of 4-triazole class compounds, is characterized in that: described step 3) in alkali used be the mixture of one or more arbitrary proportions in sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide, diethylamine, triethylamine, quadrol, methylamine, ethamine, trolamine, aniline, pyridine and DMAP.
7. 3-S-tetrahydroxy-β-D-Glucose glycosides-1 according to claim 2,2, the preparation method of 4-triazole class compounds, is characterized in that: described step 3) solvent E is the mixture of one or more arbitrary proportions in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, sec-butyl alcohol, butyleneglycol, Pentyl alcohol, primary isoamyl alcohol, n-hexyl alcohol, hexalin, n-Heptyl alcohol, n-Octanol, isooctyl alcohol, sec-octyl alcohol, acetonitrile, methylene dichloride, chloroform, acetone and ether.
8. the application of 3-S-tetrahydroxy-β-D-Glucose glycosides-1,2,4-triazole class compounds as claimed in claim 1, is characterized in that: for the preparation of against gram-negative bacteria, positive bacteria and antifungal drug.
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