CN105153143A - Thiouracil derivatives containing oxadiazole/thiadiazole and preparation method and application of thiouracil derivatives - Google Patents
Thiouracil derivatives containing oxadiazole/thiadiazole and preparation method and application of thiouracil derivatives Download PDFInfo
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- CN105153143A CN105153143A CN201510695853.6A CN201510695853A CN105153143A CN 105153143 A CN105153143 A CN 105153143A CN 201510695853 A CN201510695853 A CN 201510695853A CN 105153143 A CN105153143 A CN 105153143A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses thiouracil derivatives containing oxadiazole/thiadiazole, and further provides a method for synthesizing the thiouracil derivatives. The general chemical formula of the thiouracil derivatives is shown in figure I or figure II, wherein R1, R2 and R3 are hydrogen or halogen or aryl-. The method includes the steps of making aromatic aldehyde react with ethyl cyanoacetate and thiourea under the catalysis of piperidine to obtain a compound III, making aromatic aldehyde react with semicarbazide to obtain a compound IV, making the compound IV react with bromine to obtain a compound V, making the compound V react with benzoyl chloride to obtain a compound VI, making the compound VI and the compound III have a reflux reaction under the catalysis of potassium carbonate to obtain the general chemical formula I, making aromatic acid react with thiosemicarbazide to obtain a compound VII, making the compound VII react with benzoyl chloride to obtain a compound VIII, and making the compound VIII react with the compound III under the catalysis of potassium carbonate to obtain the general chemical formula II. The adopted method is simple, easy to operate and beneficial to large-scale production; it is verified that the prepared compound has high bacteriostatic activity and can be widely applied in bacteriostatic drug preparations.
Description
Technical field
The present invention relates to antimicrobial DP finish and preparation method thereof, specifically a kind of thiouracil derivative and its preparation method and application of Han oxadiazole/thiadiazoles.
Background technology
Bacterial infection is modal type in infectious diseases, and treat timely and effectively if lacked, the state of an illness can increase the weight of, and even causes death.Therefore, the world of medicine have studied various types of antimicrobial drug, in order to selection of clinical medication.But, along with antibacterials and antibiotic a large amount of use, make many microorganisms create resistance to antibacterials, and the problem of resistance has become one of most thorny issue on current anti-infective clinical treatment.Therefore, the research staff in industry needs constantly to develop new antiseptic-germicide, and especially those have the antiseptic-germicide of new drug targets, alleviates the puzzlement of pathogenic bacterium to the resistance of antiseptic-germicide.
In bacterial cell, the protein of 1/3rd is transported to tenuigenin in post synthesis just to play function outward.Wherein most of albumen carries out transmembrane movement by Sec approach (i.e. Secretory Pathway secretionpathway).SecA is a kind of ATPase, be called " power-driven pump " in Sec approach, this enzyme is Conversion of energy enzyme uniquely known in Sec approach, order about protein precursor through bacterial inner membrane by hydrolysis circulation, it is required to the existence of bacterium, and human body does not exist similar enzyme, therefore, suppress the compound of SecAATPase activity can not only the transhipment of arrestin and secretion specifically, thus produce anti-microbial effect, and probably can be very little to the toxic side effect of human body.In recent years, test the verified object that can reach bacteria growing inhibiting by suppressing the dynein SecA of hydrolysising ATP, but be that the anti-microbial type compound that target spot is developed is little with SecA.Therefore, taking SecA as the new drug that target development is more, anti-microbial activity is stronger, is the problem that current line is tried to explore in the industry to overcome the puzzlement of clinical resistance.
Summary of the invention
Object of the present invention is just to provide the thiouracil derivative of a class containing oxadiazole/thiadiazoles, there is provided the synthetic method of this analog derivative and this analog derivative preparing the application in antibiotic preparation simultaneously, solve existing antimicrobial drug clinical application and there is resistance and the relatively poor problem of anti-microbial activity, to providing more multiplex medicine to select for clinical treatment bacteriological infection.
The object of the invention is to be achieved through the following technical solutions: a kind of thiouracil derivative of Han oxadiazole/thiadiazoles, the chemical general formula of this derivative is as shown in I or II:
Wherein R
1, R
2, R
3be hydrogen, halogen or aromatic base.
R described in the present invention
1, R
2, R
3be hydrogen, chlorine, bromine, fluorine or phenyl.
R in chemical general formula I described in I in the present invention
1for hydrogen, R
2for chlorine or R
1, R
2be phenyl.
Derivative provided by the invention is the following two kinds chemical structure particularly preferably:
The anti-microbial activity of the compound of these two kinds of chemical structures is very strong, to separating the anti-microbial property that amylomyces, Salmonellas, intestinal bacteria and dysentery bacterium all have 100% in 24h, is significantly higher than the bacteriostasis rate of conventional antimicrobial drug in prior art.
The invention provides the preparation method of the thiouracil derivative of described Han oxadiazole/thiadiazoles, comprise the following steps:
A () takes aromatic aldehyde, ethyl cyanacetate and thiocarbamide for 1:1:1 in molar ratio, be dissolved in anhydrous ethanol solvent, take piperidines as catalyzer, and 90-95 DEG C of back flow reaction 10-12h, is cooled to room temperature, filters, obtains solid chemical compound III; The structural formula of compound III is:
R in its compound III
2for hydrogen, halogen or aromatic base;
B Urea,amino-is dissolved in the water by (), adjust solution to neutral, be warming up to 63-67 DEG C, dropwise add the ethanolic soln of aromatic aldehyde, 80 DEG C of back flow reaction 2h, are cooled to room temperature, filter, obtain solid chemical compound IV; The structural formula of compound IV is:
R in its compound IV
1for hydrogen, halogen or aromatic base;
C described compound IV is reacted with bromine by () in acetic acid/sodium acetate medium, reaction terminates rear cooling, filters, obtains solid chemical compound V; The structural formula of compound V is:
R in its compound V
1for hydrogen, halogen or aromatic base;
D () is 1:1 mixing by described compound V with to chloromethyl benzoic acid chlorides in molar ratio, be acid binding agent, react in tetrahydrofuran (THF) that cooling is filtered, obtained solid chemical compound VI with triethylamine; The structural formula of compound VI:
R in its compound V
1for hydrogen, halogen or aromatic base;
E described compound VI and described compound III are pressed 1:1 mixing by (), be catalyzer with salt of wormwood, in acetonitrile solvent, 90 DEG C of back flow reaction 10h, desolventize, purifying, obtain the thiouracil derivative of Han oxadiazole as shown in chemical general formula I;
R in its general formula
1, R
2for hydrogen, halogen or aromatic base;
F aromatic acid and thiosemicarbazide react by () in phosphorus oxychloride medium, 75-85 DEG C of hydrolysis reaction 1.5-2.5h, cools to obtain solid, by after solid heating for dissolving again at 110 DEG C of back flow reaction 4h, cooling, adjust ph is to 7.5-8.5, filter, obtain compound VI I; The chemical structure of its compound VI I is:
Wherein R
3for hydrogen, halogen or aromatic base;
G () is 1:1 mixing by described compound VI I with to chloromethyl benzoic acid chlorides in molar ratio, be acid binding agent, react in tetrahydrofuran (THF) under room temperature condition that cooling is filtered, obtained solid chemical compound VIII with triethylamine; The chemical structure of its compound VI II is:
Wherein R
3for hydrogen, halogen or aromatic base;
H described compound VI II and described compound III are pressed 1:1 mixing by (), be catalyzer with salt of wormwood, in acetonitrile, 90 DEG C of back flow reaction 10h, desolventize, purifying, obtain the thiouracil derivative containing thiadiazoles as shown in chemical general formula II; The chemical structure of its chemical general formula II is:
Wherein R
2, R
3for hydrogen, halogen or aromatic base.
Its total reaction general formula is as follows:
In its synthesis step, reaction conditions is respectively: a: piperidines, ethanol, backflow; B: backflow; C: bromine, acetic acid/sodium acetate, room temperature; D: tetrahydrofuran (THF), triethylamine, room temperature; E, acetonitrile, salt of wormwood, backflow; F, phosphorus oxychloride, backflow.
In preparation method of the present invention, step (a) and aromatic aldehyde described in step (b) to be in phenyl aldehyde, the phenyl aldehyde of halo or phenyl substituted benzaldehyde any one.
Aromatic aldehyde in preparation method of the present invention described in step (a) is preferably 2,4 dichloro benzene formaldehyde, 2,6-dichlorobenzaldehydes or to phenyl phenyl aldehyde; Aromatic aldehyde described in step (b) is preferably phenyl aldehyde, 2,6-dichlorobenzaldehydes or to phenyl phenyl aldehyde.
Aromatic aldehyde in preparation method of the present invention described in step (a): ethyl cyanacetate: thiocarbamide: dehydrated alcohol: the molecular volume of piperidines is than being 10mmol:10mmol:10mmol:100mL:2mL.
Described in preparation method of the present invention, step (a) after filtration, purifying can be carried out to filtering the solid obtained, its concrete purification step is: be dissolved in the NaOH solution of 1mmol/L by filtering the solid crude product obtained, wash three times by ethyl acetate, aqueous phase is collected in beaker, adjust its pH value to be 2.5-3.5 with the HCl solution of 1mmol/L, separate out solid, filter, solid is dried, obtains the sterling of compound III.
In preparation method of the present invention, the mol ratio of the described Urea,amino-of step (b) and aromatic aldehyde is 1:1.
The solid that in preparation method of the present invention, described filtration obtains by step (b) carries out recrystallization, that is: be dissolved in ethanol by filtering the solid obtained, recrystallization at 80 DEG C, obtains solid chemical compound IV sterling.
The molecular volume ratio of the compound IV described in step (c) of the present invention and bromine is: 3mmol:0.6mL, and described acetic acid/sodium acetate medium refers to by 14mL glacial acetic acid: the reaction medium that 6mL anhydrous sodium acetate forms; Described reaction is carried out at ambient temperature; Described cooling refers to reaction solution to pour in frozen water lowers the temperature; The solid ethyl alcohol recrystallization that described filtration obtains, described in the same step (b) of its re-crystallization step.
In preparation method of the present invention, step (d) is described to chloromethyl benzoic acid chlorides: compound V: triethylamine: the molecular volume ratio of tetrahydrofuran (THF) is: 1mmol:1mmol:1mL:7.5mL.
The described compound VI of step (e) in preparation method of the present invention: compound III: salt of wormwood: the molecular volume ratio of acetonitrile is: 1mmol:1mmol:3mmol:25mL.
In preparation method of the present invention, aromatic acid described in step (f) is phenylformic acid, halogenated benzoic acid or phenyl substituted benzoic acid; Preferably, described aromatic acid is for being phenylformic acid, 2-chloro-benzoic acid or 2,4 dichloro benzene formic acid.
Aromatic acid described in step (f) in preparation method of the present invention: thiosemicarbazide: phosphorus oxychloride mol ratio is: 1:1:1.2; Described hydrolysis reaction condition optimization 80 DEG C reaction 2h; Described cooling all refers to reaction solution to pour in frozen water lower the temperature.
In preparation method of the present invention, step (g) is described to chloromethyl benzoic acid chlorides: compound VI I: triethylamine: the molecular volume ratio of tetrahydrofuran (THF) is: 1mmol:1mmol:1mL:7.5mL.
The described compound VI II of step (h) in preparation method of the present invention: compound III: salt of wormwood: the molecular volume ratio of acetonitrile is: 1mmol:1mmol:3mmol:25mL.
The compound of the present invention's synthesis is active ingredient, can be prepared into oral liquid with the combination of components such as water, sucrose, Sionit, fructose; Tablet or capsule is prepared into the combination of components such as vehicle (lactose, glucose, sucrose, N.F,USP MANNITOL sugar), disintegrating agent (starch), lubricant (stearic acid, talcum powder), tackiness agent (gelatin, polyvinyl alcohol).
The mixed carrier that the compound of the present invention's synthesis also can form with physiological saline, glucose solution or salt solution and glucose as active ingredient is prepared into injection liquid.
Prove by experiment, derivative prepared by the present invention has the performance suppressing to separate amylomyces, Salmonellas, intestinal bacteria and dysentery bacterium, and part of compounds has the fungistatic effect of 100% in 24h.Therefore, compound provided by the invention and pharmacology allow the carrier Homogeneous phase mixing used, and formulation method conveniently can be prepared into the various forms of pharmaceutical preparations for antiseptic-germicide.Applicant this completes this compound and is preparing the invention of the purposes in antibacterial medicine preparation.
Simultaneously; the thiouracil derivative of above chemical general formula Han oxadiazole/thiadiazoles as shown in (I), (II) can be used as intermediate feed; for the synthesis of the compound with anti-microbial activity; then be applied, also within protection scope of the present invention preparing in antibacterial medicine preparation.
The present invention for can the effective dose of reference be 10 ~ 20mg/ people/day time clinical, every day 2 ~ 3 times.Doctor also according to patient individual difference, can draft taking dose.
The present invention take SecA as the target spot that antiseptic-germicide designs, adopt active group splicing principle, be incorporated into special groups oxadiazole/thiadiazoles among deracil structure, obtain a series of thiouracil derivative being replaced Han oxadiazole/thiadiazoles by special groups.The target compound Zhong oxadiazole/thiadiazoles of designed synthesis is connected with deracil by amido linkage, both splicing after in organism with target point protein in conjunction with time can produce more hydrogen bond action, this effect makes this compounds to be better combined with target point protein thus to produce stronger biological activity; Meanwhile, contriver finds unexpectedly in R&D process, and the part of compounds with the deracil of special groups oxadiazole/thiadiazoles has very outstanding fungistatic effect, has very high using value in antibiotic preparation.
Provided by the invention take SecA as the deracil analog derivative of target spot Han oxadiazole/thiadiazoles is reported first in industry as antiseptic-germicide, this bacteriostatic activity comparatively prior art is significantly increased, it is is successfully researched and developed, greatly extend the range of choice of antibacterial medicines, also effectively can overcome the drawback of bacterial drug resistance.
The preparation method of the thiouracil derivative of Han oxadiazole/thiadiazoles provided by the invention is simple to operate, processing ease, be easy to large-scale production; the compound of preparation is through verification experimental verification; it has stronger bacteriostatic activity, can widespread use in antibacterial medicines preparation.
Embodiment
Embodiment is for further describing the present invention below, but does not limit the present invention in any form.
(1) in the present invention, the concrete synthesis step of chemical general formula I is:
(1) in 250mL flask, add 10mmol aromatic aldehyde, 10mmol ethyl cyanacetate, 10mmol thiocarbamide, then add 100mL dehydrated alcohol, add 2mL piperidines after dissolving again and make catalyzer, at 90-95 DEG C of back flow reaction 10-12 hour; Be cooled to room temperature, produce a large amount of solid, filter, obtain solid crude product, solid crude product is dissolved in the NaOH solution of 1mmol/L, washing three times by ethyl acetate, will collect aqueous phase in beaker, is 2.8-3.2 with the HCl solution adjust pH of 1mmol/L, separate out a large amount of solid, filter, dry (105 DEG C/4h), obtain intermediate compound III; Its chemical reaction process is:
Wherein R
2for hydrogen, halogen or aromatic base, the one in preferred hydrogen, chlorine, bromine, fluorine or phenyl;
(2) getting 250mL flask, to add 5mmol Urea,amino-molten, add suitable quantity of water (25mL) to dissolve, adjust solution for neutral (pH value is 7), be warming up to 65 DEG C, dropwise add the ethanolic soln 20mL containing 5mmol aromatic aldehyde, 80 DEG C of back flow reaction 2h, produce a large amount of solid, are cooled to room temperature after reaction terminates, filter the crude product obtaining compound IV, this crude product is dissolved in ethanol, recrystallization at 80 DEG C, obtains sterling compound IV; Its chemical reaction process is:
Wherein R
1for hydrogen, halogen or aromatic base, the one in preferred hydrogen, chlorine, bromine, fluorine or phenyl;
(3) get 100mL flask and add 3mmol compound IV and 6mmol anhydrous sodium acetate, add 12mL glacial acetic acid again, stirring and dissolving, separately get a flask and add 0.6mL bromine and 2mL glacial acetic acid, it is slowly added drop-wise in the solution of compound IV, at room temperature standing and reacting 10h, pours in 100mL frozen water by reaction solution after reaction terminates, and produces white precipitate, filter, obtaining solid is compound V crude product, with ethyl alcohol recrystallization (with step 2), obtains sterling compound V; Its chemical reaction process is:
Wherein R
1for hydrogen, halogen or aromatic base, the one in preferred hydrogen, chlorine, bromine, fluorine or phenyl;
(4) get 100mL flask and add 2mmol to chloromethyl benzoic acid chlorides, the tetrahydrofuran (THF) adding 15mL drying dissolves, then in flask, adds 2mmol compound V and 2mL triethylamine (as acid binding agent), standing and reacting 10h under room temperature condition, produce a large amount of solid, poured into by reaction solution in the beaker filling 150mL cold water after reaction terminates, tetrahydrofuran (THF) is soluble in water, produces a large amount of solid, filter, by solid drying (105 DEG C, 4h), obtain compound VI; Its chemical reaction process is:
Wherein R
1for hydrogen, halogen or aromatic base, the one in preferred hydrogen, chlorine, bromine, fluorine or phenyl;
(5) get 100mL flask and add 1mmol compound III and 1mmol compound VI and 3mmolK
2cO
3, then adding 25mL acetonitrile, induction stirring, 90 DEG C of back flow reaction 10h, TLC monitoring reactions, after reaction terminates, revolve steaming solvent afforded crude material, wash with water, filter, dry (105 DEG C, 4h), purification by column chromatography (V
ethyl acetate: V
methyl alcohol=15:1), obtain as the target product of chemical structure of general formula as shown in I, its chemical reaction process is:
Wherein R
1, R
2for hydrogen, halogen or aromatic base, the one in preferred hydrogen, chlorine, bromine, fluorine or phenyl;
(2) in the present invention, the concrete synthesis step of chemical general formula II is:
(1) in 250mL flask, add 10mmol aromatic aldehyde, 10mmol ethyl cyanacetate, 10mmol thiocarbamide, then add 100mL dehydrated alcohol, add 2mL piperidines after dissolving again and make catalyzer, at 90-95 DEG C of back flow reaction 10-12 hour; Be cooled to room temperature, produce a large amount of solid, filter, obtain solid crude product, solid crude product is dissolved in the NaOH solution of 1mmol/L, washs three times by ethyl acetate, aqueous phase will be collected in beaker, be 3 with the HCl solution adjust pH of 1mmol/L, separate out a large amount of solid, filter, dry (105 DEG C, 4h), intermediate compound III is obtained; Its chemical reaction process is:
Wherein R
2for hydrogen, halogen or aromatic base, the one in preferred hydrogen, chlorine, bromine, fluorine or phenyl;
(2) get 250mL flask and add 10mmol aromatic acid, 10mmol thiosemicarbazide and 12mmol phosphorus oxychloride, react 2 hours under 80 DEG C of conditions, 30mL frozen water is slowly added in ice-water bath downhill reaction liquid, produce solid, 80 DEG C of heating make dissolution of solid, 110 DEG C of back flow reaction 4h, after reaction terminates, being poured into by reaction solution in 80mL frozen water, is 7.5-8.5 with the NaOH regulator solution pH of 1mmol/L, produces and precipitates in a large number, filter, by solid drying (105 DEG C, 4h), obtain compound VI I; Its chemical reaction process is:
Wherein R
3for hydrogen, halogen or aromatic base, the one in preferred hydrogen, chlorine, bromine, fluorine or phenyl;
(3) get 100mL flask and add 2mmol to chloromethyl benzoic acid chlorides, the tetrahydrofuran (THF) adding 15mL drying dissolves, then in flask, add 2mmol compound VI I and 2mL triethylamine (as Fu's acid agent), reacts 10h under room temperature condition, produce a large amount of solid, poured into by reaction solution in the beaker filling 150mL cold water after reaction terminates, tetrahydrofuran (THF) is soluble in water, produces a large amount of solid, filter, by solid drying (105 DEG C, 4h), obtain compound VI II; Its chemical reaction process is:
Wherein R
3for hydrogen, halogen or aromatic base, the one in preferred hydrogen, chlorine, bromine, fluorine or phenyl;
(4) get 100mL flask and add 1mmol compound III and 1mmol compound VI II and 3mmolK
2cO
3, then adding 25mL acetonitrile, induction stirring, 90 DEG C of back flow reaction 10h, TLC monitoring reactions, after reaction terminates, revolve steaming solvent afforded crude material, wash with water, filter, dry, purification by column chromatography (V
ethyl acetate: V
methyl alcohol=15:1), obtain as the target product of chemical structure of general formula as shown in I; Its chemical reaction process is:
Wherein R
2, R
3for hydrogen, halogen or aromatic base, the one in preferred hydrogen, chlorine, bromine, fluorine or phenyl.
Embodiment 1
According to the concrete synthesis step of above-mentioned chemical general formula I, when in step (1), aromatic aldehyde is 2,4 dichloro benzene formaldehyde, i.e. R
2when being 2,4-dichloro, when the aromatic aldehyde in step (2) is phenyl aldehyde, i.e. R
1during for hydrogen, final product compound Ia is obtained according to above synthetic method, called after: 4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-oxadiazole-2-base) benzamide; Its chemical structure is:
After testing, Compound I a4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-oxadiazole-2-base) benzamide: faint yellow solid, yield 59.6%, m.p.219.2 ~ 222.3 DEG C; IR (KBr, cm
-1): 3393 (N-H) and1642,1687 (2C=O), 2364 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.01 (d, J=7.8Hz, 2H, ArH), 7.76 (d, J=7.2Hz, 2H, ArH), 7.69 (d, J=8.4Hz, 2H, ArH), 7.64 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.58 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.47 (d, J=3.6Hz, 1H, ArH), 7.38 (d, J=6.0Hz, 1H, ArH), 4.40 (s, 2H, CH
2);
13cNMR (CD
3oD, 150MHz) δ: 30.2,93.7,117.6,126.9,127.0,127.0,127.3,127.3,128.0,128.0,128.5,129.0,129.0,129.0,129.4,131.9,132.9,133.4,134.6,136.5,144.5,163.1,165.2,168.1,170.5; MS (ESI) m/z:574.5 ([M-H]
+).
Embodiment 2
According to the concrete synthesis step of above-mentioned chemical general formula I, when in step (1), aromatic aldehyde is 2,6-dichlorobenzaldehyde, i.e. R
2when being 2,6-dichloro, when the aromatic aldehyde in step (2) is phenyl aldehyde, i.e. R
1during for hydrogen, obtain final product compound Ib, called after: 4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-oxadiazole-2-base) benzamide.
After testing, compounds ib 4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-oxadiazole-2-base) benzamide: faint yellow solid, yield 56.1%, m.p.204.4 ~ 206.1 DEG C; IR (KBr, cm
-1): 3407 (N-H) and1632,1682 (2C=O), 2361 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 7.96 (d, J=7.8Hz, 2H, ArH), 7.78 (d, J=7.2Hz, 2H, ArH), 7.66 (d, J=8.4Hz, 2H, ArH), 7.60 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.53 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.44 (d, J=3.6Hz, 1H, ArH), 7.35 (d, J=6.0Hz, 1H, ArH), 4.40 (s, 2H, CH
2);
13cNMR (CD
3oD, 150MHz) δ: 30.2,93.6,117.6,126.8,126.8,127.0,127.0,127.3,127.3,128.0,128.0,128.5,129.0,129.0,129.9,130.6,131.8,132.9,132.9,135.9,136.6,144.4,163.0,165.3,168.2,170.5; MS (ESI) m/z:574.5 ([M-H]
+).
Embodiment 3
According to the concrete synthesis step of above-mentioned chemical general formula I, when in step (1), aromatic aldehyde is to phenyl phenyl aldehyde, i.e. R
2during for 4-phenyl, when the aromatic aldehyde in step (2) is phenyl aldehyde, i.e. R
1during for hydrogen, obtain final product compound Ic, called after: 4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-oxadiazole-2-base) benzamide.
After testing, Compound I c4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-oxadiazole-2-base) benzamide: faint yellow solid, yield 53.6%, m.p.260.2 ~ 262.8 DEG C; IR (KBr, cm
-1): 3409 (N-H) and1632,1689 (2C=O), 2361 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.33 (d, J=7.2Hz, 2H, ArH), 8.02 (d, J=8.4Hz, 2H, ArH), 7.89 (d, J=8.4Hz, 2H, ArH), 7.77 (d, J=7.8Hz, 2H, ArH), 7.74 (d, J=7.8Hz, 2H, ArH), 7.71 (d, J=8.4Hz, 2H, ArH), 7.64 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.59 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.50 (dd, J=7.2Hz, J=8.4Hz, 2H, ArH), 7.40 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 4.40 (s, 2H, CH
2);
13cNMR (CD
3oD, 150MHz) δ: 30.2,93.4,117.2,126.8,126.8,127.0,127.0,127.3,127.3,127.4,127.4,127.4,128.0,128.0,128.5,129.0,129.0,129.0,129.0,131.9,133.8,135.8,136.5,144.6,163.2,165.2,168.1,170.6; MS (ESI) m/z:581.6 ([M-H]
+).
Embodiment 4
According to the concrete synthesis step of above-mentioned chemical general formula I, when in step (1), aromatic aldehyde is 2,4 dichloro benzene formaldehyde, i.e. R
2when being 2,4-dichloro, when the aromatic aldehyde in step (2) is 2,6-dichlorobenzaldehyde, i.e. R
1be 2,6-dichloro, obtain final product compound Id, called after: 4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazole-2-base) benzamide.
After testing, Compound I d4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazole-2-bases) benzamide: faint yellow solid, yield 51.4%, m.p.199.1 ~ 202.4 DEG C; IR (KBr, cm
-1): 3409 (N-H) and1634,1685 (2C=O), 2361 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 7.96 (d, J=7.8Hz, 2H, ArH), 7.81 (d, J=7.2Hz, 2H, ArH), 7.66 (d, J=8.4Hz, 2H, ArH), 7.58 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.49 (d, J=3.6Hz, 1H, ArH), 7.36 (d, J=6.0Hz, 1H, ArH), 4.40 (s, 2H, CH
2);
13cNMR (CD
3oD, 150MHz) δ: 30.2,93.4,117.2,126.9,127.3,127.3,127.5,127.5,128.0,128.0,129.0,129.2,131.4,131.9,132.9,133.7,133.7,134.6,137.4,144.5,163.2,165.3,168.0,170.6; MS (ESI) m/z:643.3 ([M-H]
+).
Embodiment 5
According to the concrete synthesis step of above-mentioned chemical general formula I, when in step (1), aromatic aldehyde is 2,6-dichlorobenzaldehyde, i.e. R
2when being 2,6-dichloro, when the aromatic aldehyde in step (2) is 2,6-dichlorobenzaldehyde, i.e. R
1be 2, during 6-dichloro, obtain final product compound Ie, called after: 4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazole-2-base) benzamide.
After testing, Compound I e4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazole-2-bases) benzamide: faint yellow solid, yield 49.4%, m.p.187.7 ~ 189.4 DEG C; IR (KBr, cm
-1): 3402 (N-H) and1632,1680 (2C=O), 2365 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 7.98 (d, J=7.8Hz, 2H, ArH), 7.84 (d, J=7.2Hz, 2H, ArH), 7.68 (d, J=7.8Hz, 2H, ArH), 7.59 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.46 (d, J=3.6Hz, 1H, ArH), 7.38 (d, J=6.0Hz, 1H, ArH), 4.40 (s, 2H, CH
2);
13cNMR (CD
3oD, 150MHz) δ: 30.2,93.4,117.2,126.9,126.9,127.3,127.3,127.5,127.5,128.0,128.0,130.5,131.4,131.9,132.9,132.9,133.7,133.7,135.6,137.4,144.5,163.2,165.3,168.0,170.6; MS (ESI) m/z:643.3 ([M-H]
+).
Embodiment 6
According to the concrete synthesis step of above-mentioned chemical general formula I, when in step (1), aromatic aldehyde is to phenyl phenyl aldehyde, i.e. R
2during for 4-phenyl, when the aromatic aldehyde in step (2) is 2,6-dichlorobenzaldehyde, i.e. R
1be 2, during 6-dichloro, obtain final product compound If, called after: 4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazole-2-base) benzamide.
After testing, Compound I f4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,6-dichlorophenyl)-1,3,4-oxadiazole-2-bases) benzamide: faint yellow solid, yield 50.1%, m.p.201.2 ~ 203.8 DEG C; IR (KBr, cm
-1): 3403 (N-H) and1635,1681 (2C=O), 2367 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.30 (d, J=7.2Hz, 2H, ArH), 7.98 (d, J=7.8Hz, 2H, ArH), 7.86 (d, J=8.4Hz, 2H, ArH), 7.75 (d, J=7.8Hz, 2H, ArH), 7.70 (d, J=7.8Hz, 2H, ArH), 7.66 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.58 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.51 (dd, J=7.2Hz, J=8.4Hz, 2H, ArH), 7.42 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 4.40 (s, 2H, CH
2); MS (ESI) m/z:650.5 ([M-H]
+).
Embodiment 7
According to the concrete synthesis step of above-mentioned chemical general formula I, when in step (1), aromatic aldehyde is 2,4 dichloro benzene formaldehyde, i.e. R
2when being 2,4-dichloro, when the aromatic aldehyde in step (2) is to phenyl phenyl aldehyde, i.e. R
1during for 4-phenyl, obtain final product compound Ig, called after: 4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(1,1'-xenyl-4-base)-1,3,4-oxadiazole-2-bases) benzamide.
After testing, Compound Ig per 4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(1,1'-xenyl-4-base)-1,3,4-oxadiazole-2-bases) benzamide: faint yellow solid, yield 53.2%, m.p.190.7 ~ 193.3 DEG C; IR (KBr, cm
-1): 3401 (N-H) and1631,1688 (2C=O), 2362 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.22 (d, J=7.2Hz, 2H, ArH), 7.94 (d, J=7.8Hz, 2H, ArH), 7.84 (d, J=7.8Hz, 2H, ArH), 7.76 (d, J=7.8Hz, 2H, ArH), 7.71 (d, J=7.8Hz, 2H, ArH), 7.65 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.59 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.52 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.44 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 4.40 (s, 2H, CH
2); MS (ESI) m/z:650.5 ([M-H]
+).
Embodiment 8
According to the concrete synthesis step of above-mentioned chemical general formula I, when in step (1), aromatic aldehyde is 2,6-dichlorobenzaldehyde, i.e. R
2when being 2,6-dichloro, when the aromatic aldehyde in step (2) is to phenyl phenyl aldehyde, i.e. R
1during for 4-phenyl, obtain final product compound Ih, called after: 4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(1,1'-xenyl-4-base)-1,3,4-oxadiazole-2-bases) benzamide.
After testing, Compound I f4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(1,1'-xenyl-4-base)-1,3,4-oxadiazole-2-bases) benzamide: faint yellow solid, yield 49.1%, m.p.185.3 ~ 187.6 DEG C; IR (KBr, cm
-1): 3404 (N-H) and1631,1686 (2C=O), 2361 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.24 (d, J=7.2Hz, 2H, ArH), 7.99 (d, J=7.8Hz, 2H, ArH), 7.89 (d, J=8.4Hz, 2H, ArH), 7.77 (d, J=7.8Hz, 2H, ArH), 7.71 (d, J=7.8Hz, 2H, ArH), 7.68 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.57 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.50 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.46 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 4.40 (s, 2H, CH
2); MS (ESI) m/z:650.5 ([M-H]
+).
Embodiment 9
According to the concrete synthesis step of above-mentioned chemical general formula I, when in step (1), aromatic aldehyde is to phenyl phenyl aldehyde, i.e. R
2during for 4-phenyl, when the aromatic aldehyde in step (2) is to phenyl phenyl aldehyde, i.e. R
1during for 4-phenyl, obtain final product compound Ii, called after: 4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(1,1'-xenyl-4-base)-1,3,4-oxadiazole-2-bases) benzamide.
After testing, Compound I i4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(1,1'-xenyl-4-base)-1,3,4-oxadiazole-2-bases) benzamide: faint yellow solid, yield 47.6%, m.p.195.7 ~ 197.6 DEG C; IR (KBr, cm
-1): 3405 (N-H) and1630,1684 (2C=O), 2363 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.28 (d, J=7.2Hz, 2H, ArH), 7.98 (d, J=7.8Hz, 2H, ArH), 7.88 (d, J=7.8Hz, 2H, ArH), 7.78 (d, J=7.8Hz, 2H, ArH), 7.72 (d, J=7.8Hz, 2H, ArH), 7.66 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.58 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.51 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.45 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.38 (d, J=7.8Hz, 2H, ArH), 4.40 (s, 2H, CH
2); MS (ESI) m/z:657.7 ([M-H]
+).
Embodiment 10
According to the concrete synthesis step of above-mentioned chemical general formula II, when in step (1), aromatic aldehyde is 2,4 dichloro benzene formaldehyde, i.e. R
2when being 2,4-dichloro, when the aromatic acid in step (2) is phenylformic acid, i.e. R
3for hydrogen, final product compound IIa is obtained according to above preparation method, called after: 4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-thiadiazoles-2-base) benzamide;
After testing, Compound II per a4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-thiadiazoles-2-base) benzamide: faint yellow solid, yield 58.5%, m.p.225.2 ~ 226.7 DEG C; IR (KBr, cm
-1): 3408 (N-H) and1626,1684 (2C=O), 2356 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.24 (d, J=7.2Hz, 2H, ArH), 7.99 (d, J=7.8Hz, 2H, ArH), 7.89 (d, J=8.4Hz, 2H, ArH), 7.77 (d, J=7.8Hz, 2H, ArH), 7.71 (d, J=7.8Hz, 2H, ArH), 7.57 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.46 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 4.40 (s, 2H, CH
2);
13cNMR (CD
3oD, 150MHz) δ: 30.2,93.6,117.2,126.9,127.0,127.0,127.3,127.3,128.0,128.0,128.5,129.0,129.0,131.9,132.9,133.4,134.6,136.5,144.6,163.0,165.2,168.0,170.5; MS (ESI) m/z:590.4 ([M-H]
+).
Embodiment 11
According to the concrete synthesis step of above-mentioned chemical general formula II, when in step (1), aromatic aldehyde is 2,6-dichlorobenzaldehyde, i.e. R
2when being 2,6-dichloro, when the aromatic acid in step (2) is phenylformic acid, i.e. R
3for hydrogen, final product compound IIb is obtained according to above preparation method, called after: 4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-thiadiazoles-2-base) benzamide;
After testing, Compound II per b4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-thiadiazoles-2-base) benzamide: faint yellow solid, yield 54.7%, m.p.205.5 ~ 207.7 DEG C; IR (KBr, cm
-1): 3402 (N-H) and1631,1682 (2C=O), 2361 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.01 (d, J=7.2Hz, 2H, ArH), 7.91 (d, J=7.8Hz, 2H, ArH), 7.84 (d, J=8.4Hz, 2H, ArH), 7.74 (d, J=7.8Hz, 2H, ArH), 7.70 (d, J=7.8Hz, 2H, ArH), 7.54 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.42 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 4.39 (s, 2H, CH
2);
13cNMR (CD
3oD, 150MHz) δ: 30.2,93.6,117.2,126.9,126.9,127.0,127.0,127.3,127.3,128.0,128.0,128.5,129.0,129.0,130.5,131.9,132.9,132.9,135.6,136.5,144.2,163.0,165.2,168.0,170.5; MS (ESI) m/z:590.4 ([M-H]
+).
Embodiment 12
According to the concrete synthesis step of above-mentioned chemical general formula II, when in step (1), aromatic aldehyde is to phenyl phenyl aldehyde, i.e. R
2during for 4-phenyl, when the aromatic acid in step (2) is phenylformic acid, i.e. R
3for hydrogen, final product compound IIc is obtained according to above preparation method, called after: 4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-thiadiazoles-2-base) benzamide;
After testing, Compound II per c4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-phenyl-1,3,4-thiadiazoles-2-base) benzamide: faint yellow solid, yield 51.8%, m.p.235.3 ~ 237.4 DEG C; IR (KBr, cm
-1): 3404 (N-H) and1634,1685 (2C=O), 2363 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.22 (d, J=7.2Hz, 2H, ArH), 7.98 (d, J=7.8Hz, 2H, ArH), 7.85 (d, J=8.4Hz, 2H, ArH), 7.74 (d, J=7.8Hz, 2H, ArH), 7.70 (d, J=7.8Hz, 2H, ArH), 7.67 (d, J=8.4Hz, 2H, ArH), 7.60 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.52 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.45 (dd, J=7.2Hz, J=8.4Hz, 2H, ArH), 7.35 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 4.38 (s, 2H, CH
2);
13cNMR (CD
3oD, 150MHz) δ: 30.2,93.6,117.2,126.7,126.7,127.0,127.0,127.3,127.3,127.3,127.3,127.4,127.4,128.0,128.0,128.5,129.0,129.0,129.0,129.0,131.9,133.9,135.6,136.5,144.2,163.0,165.2,168.0,170.5; MS (ESI) m/z:597.7 ([M-H]
+).
Embodiment 13
According to the concrete synthesis step of above-mentioned chemical general formula II, when in step (1), aromatic aldehyde is 2,4 dichloro benzene formaldehyde, i.e. R
2when being 2,4-dichloro, when the aromatic acid in step (2) is 2-chloro-benzoic acid, i.e. R
3for 2-chlorine, final product compound IId is obtained according to above preparation method, called after: 4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2-chloro-phenyl-)-1,3,4-thiadiazoles-2-base) benzamide;
After testing, Compound II per d4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2-chloro-phenyl-)-1,3,4-thiadiazoles-2-base) benzamide: faint yellow solid, yield 54.6%, m.p.232.8 ~ 235.1 DEG C; IR (KBr, cm
-1): 3391 (N-H) and1644,1685 (2C=O), 2361 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 7.98 (d, J=7.8Hz, 2H, ArH), 7.82 (d, J=7.2Hz, 2H, ArH), 7.70 (d, J=8.4Hz, 2H, ArH), 7.62 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.56 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.44 (d, J=6.0Hz, 1H, ArH), 7.36 (d, J=6.0Hz, 1H, ArH), 4.39 (s, 2H, CH
2);
13cNMR (CD
3oD, 150MHz) δ: 30.2,93.6,117.2,126.9,126.9,127.1,127.3,127.3,128.0,128.0,128.4,129.0,129.2,129.4,129.9,131.9,132.3,133.4,134.4,136.8,144.4,163.0,165.2,168.0,170.5; MS (ESI) m/z:524.9 ([M-H]
+)
Embodiment 14
According to the concrete synthesis step of above-mentioned chemical general formula II, when in step (1), aromatic aldehyde is 2,6-dichlorobenzaldehyde, i.e. R
2when being 2,6-dichloro, when the aromatic acid in step (2) is 2-chloro-benzoic acid, i.e. R
3for 2-chlorine, final product compound IIe is obtained according to above preparation method, called after: 4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2-chloro-phenyl-)-1,3,4-thiadiazoles-2-base) benzamide;
After testing, Compound II per e4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2-chloro-phenyl-)-1,3,4-thiadiazoles-2-base) benzamide: faint yellow solid, yield 51.5%, m.p.209.2 ~ 211.7 DEG C; IR (KBr, cm
-1): 3390 (N-H) and1642,1681 (2C=O), 2364 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 7.96 (d, J=7.8Hz, 2H, ArH), 7.81 (d, J=7.2Hz, 2H, ArH), 7.71 (d, J=8.4Hz, 2H, ArH), 7.63 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.54 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.42 (d, J=6.0Hz, 1H, ArH), 7.34 (d, J=6.0Hz, 1H, ArH), 4.39 (s, 2H, CH
2);
13cNMR (CD
3oD, 150MHz) δ: 30.2,93.6,117.2,126.9,126.9,127.1,127.3,127.3,128.0,128.0,128.4,129.4,129.9,130.5,131.9,132.3,132.9,132.9,135.8,136.8,144.4,163.0,165.2,168.0,170.5; MS (ESI) m/z:524.9 ([M-H]
+)
Embodiment 15
According to the concrete synthesis step of above-mentioned chemical general formula II, when in step (1), aromatic aldehyde is 2-chlorobenzaldehyde, i.e. R
2during for 4-phenyl, when the aromatic acid in step (2) is 2-chloro-benzoic acid, i.e. R
3for 2-chlorine, final product compound IIf is obtained according to above preparation method, called after: 4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2-chloro-phenyl-)-1,3,4-thiadiazoles-2-base) benzamide;
After testing, Compound II per f4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2-chloro-phenyl-)-1,3,4-thiadiazoles-2-base) benzamide: faint yellow solid, yield 49.6%, m.p.233.7.8 ~ 235.9 DEG C; IR (KBr, cm
-1): 3409 (N-H) and1631,1683 (2C=O), 2364 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 7.86 (d, J=8.4Hz, 2H, ArH), 7.65 (d, J=8.4Hz, 3H, ArH), 7.59 (d, J=7.2Hz, 3H, ArH), 7.44 (d, J=8.4Hz, 3H, ArH), 7.36 (t, J=7.8Hz, 3H, ArH), 7.27 (m, 1H, ArH), 7.21 (d, J=7.8Hz, 2H, ArH), 4.39 (s, 2H, CH
2); MS (ESI) m/z:632.1 ([M-H]
+).
Embodiment 16
According to the concrete synthesis step of above-mentioned chemical general formula II, when in step (1), aromatic aldehyde is 2,4 dichloro benzene formaldehyde, i.e. R
2when being 2,4-dichloro, when the aromatic acid in step (2) is 2,4 dichloro benzene formic acid, i.e. R
3be 2,4-dichloro, final product compound IIg is obtained according to above preparation method, called after: 4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,4 dichloro benzene base)-1,3,4-thiadiazoles-2-base) benzamide;
After testing, Compound II per g4-(((5-cyano group-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,4-dichlorophenyl)-1,3,4-thiadiazoles-2-bases) benzamide: faint yellow solid, yield 47.8%, m.p.229.8 ~ 232.2 DEG C; IR (KBr, cm
-1): 3407 (N-H) and1627,1682 (2C=O), 2361 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.01 (d, J=8.4Hz, 2H, ArH), 7.90 (d, J=7.8Hz, 2H, ArH), 7.62 (d, J=2.4Hz, 1H, ArH), 7.56 (d, J=7.8Hz, 2H, ArH), 7.50 (d, J=2.4Hz, 1H, ArH), 7.43 (d, J=8.4Hz, 1H, ArH), 7.36 (d, J=7.8Hz, 1H, ArH), 7.30 (d, J=8.4Hz, 1H, ArH), 4.36 (s, 2H, CH
2); MS (ESI) m/z:659.4 ([M-H]
+).
Embodiment 17
According to the concrete synthesis step of above-mentioned chemical general formula II, when in step (1), aromatic aldehyde is 2,6-dichlorobenzaldehyde, i.e. R
2when being 2,6-dichloro, when the aromatic acid in step (2) is 2,4 dichloro benzene formic acid, i.e. R
3be 2,4-dichloro, final product compound IIj is obtained according to above preparation method, called after: 4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,4 dichloro benzene base)-1,3,4-thiadiazoles-2-base) benzamide;
After testing, Compound II per j4-(((5-cyano group-4-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,4-dichlorophenyl)-1,3,4-thiadiazoles-2-bases) benzamide: faint yellow solid, yield 49.4%, m.p.206.3 ~ 209.2 DEG C; IR (KBr, cm
-1): 3402 (N-H) and1632,1684 (2C=O), 2364 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.21 (d, J=7.8Hz, 2H, ArH), 7.91 (d, J=7.8Hz, 2H, ArH), 7.66 (d, J=2.4Hz, 1H, ArH), 7.58 (d, J=7.8Hz, 2H, ArH), 7.51 (d, J=2.4Hz, 1H, ArH), 7.43 (d, J=8.4Hz, 1H, ArH), 7.34 (d, J=7.8Hz, 1H, ArH), 4.39 (s, 2H, CH
2); MS (ESI) m/z:659.4 ([M-H]
+).
Embodiment 18
According to the concrete synthesis step of above-mentioned chemical general formula II, when in step (1), aromatic aldehyde is to phenyl phenyl aldehyde, i.e. R
2during for 4-phenyl, when the aromatic acid in step (2) is 2,4 dichloro benzene formic acid, i.e. R
3be 2,4-dichloro, final product compound IIk is obtained according to above preparation method, called after: 4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,4 dichloro benzene base)-1,3,4-thiadiazoles-2-base) benzamide;
After testing, Compound I k4-(((5-cyano group-4-(1,1'-xenyl-4-base)-6-oxo-1,6-dihydro-pyrimidin-2-base) sulfo-) methyl)-N-(5-(2,4-dichlorophenyl)-1,3,4-thiadiazoles-2-bases) benzamide: faint yellow solid, yield 47.2%, m.p.213.3 ~ 216.1 DEG C; IR (KBr, cm
-1): 3406 (N-H) and1634,1686 (2C=O), 2364 (-CN);
1hNMR (DMSO-d
6, 600MHz) and δ: 8.20 (d, J=7.2Hz, 2H, ArH), 7.96 (d, J=7.8Hz, 2H, ArH), 7.82 (d, J=7.8Hz, 2H, ArH), 7.75 (d, J=7.8Hz, 2H, ArH), 7.70 (d, J=7.8Hz, 2H, ArH), 7.64 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.58 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 7.52 (dd, J=7.2Hz, J=7.8Hz, 2H, ArH), 7.44 (dd, J=7.2Hz, J=7.8Hz, 1H, ArH), 4.39 (s, 2H, CH
2); MS (ESI) m/z:665 ([M-H]
+).
Embodiment 19
Compound I i5mg prepared by Example 9, lactose 50mg, potato powder 20mg, polyvinyl alcohol 2mg, Magnesium Stearate 1mg, is prepared into oral tablet.
In like manner, the compound that any one is prepared with embodiment 1-18 and pharmacology allow the carrier Homogeneous phase mixing used, and formulation method conveniently can be prepared into the various forms of pharmaceutical preparations for antiseptic-germicide.
Derivative bacteriostatic activity prepared by embodiment 20 the present invention detects
Experimental technique:
(1) for examination pathogenic bacterium: 2 strain gram-positive microorganisms: Salmonella, solution amylomyces; 2 strain Gram-negative bacterias: dysentery bacterium, intestinal bacteria
(2) preparation of sample and substratum: the preparation (50 μ g/mL) of test sample: get 0.1mg medicine, add 300 μ LDMSO and dissolve, add 1.7mL distilled water subsequently, shake up.
NA substratum: extractum carnis 3g, peptone 1g, agar 20g, NaCl5g, distilled water 1000mL;
NB substratum: the liquid form of NA substratum, namely removes agar in NA substratum;
PDA substratum: potato decortication 200g, is placed in 900mL water and boils 20-30min, four layers of filter-cloth filtering.Add glucose 10-20g in filtrate, agar 20g, stir fusing, be settled to 1000mL, adjust pH to be 6.7, packing, sterilizing.
(3) bacterium bacteriostasis rate measures (the method for plate culture count)
1. the preparation of Drug plates: accurately take compound prepared by embodiment 1-18, with etc. the norfloxicin of quality for contrast, after dissolving with a small amount of DMSO, adding in different substratum to medicine final concentration is be down flat plate after 50 μ g/mL mix, and solidifies rear for subsequent use;
2. the preparation of pathogenic bacteria bacteria suspension: in Bechtop, gets one, pathogenic bacteria inclined-plane, adds 10mL sterilized water, and with the lawn of sterilizing bamboo let scraping media surface gently, break up, vortex oscillator shaken well, makes bacteria suspension;
3. the gradient dilution of pathogenic bacteria bacteria suspension: get bacteria suspension 1mL and join in 9mL sterilized water, concussion evenly makes 10
-1diluent.Draw 1mL10 again
-1diluent joins in 9mL sterilized water, and concussion evenly makes 10
-2diluent; By that analogy, graded series bacteria suspension is prepared;
4. enumeration: respectively draw 10
-6or 10
-7gradient bacteria suspension 70 μ L, joins on the NA culture medium flat plate (contrast) of Drug plates and not dosing respectively, scrapes coating evenly, carry out mark, be placed in 37 DEG C of constant incubators and cultivate 24h with sterilizing triangle; After 24h, carry out enumeration.Often group arranges three parallel tests.
Bacteriostasis rate=(control group colony number-Drug plates colony number)/control group colony number * 100%
The bacteriostasis rate of each compound under table 150 μ g/mL concentration
| Separate amylomyces | Salmonellas | Intestinal bacteria | Dysentery bacterium | |
| Ia | 100.00％ | 100.00％ | 100.00％ | 100.00％ |
| Ib | 44.90％ | 82.19％ | 90.77％ | 52.82％ |
| Ic | 30.61％ | 90.41％ | 99.62％ | 17.61％ |
| Id | 77.55％ | 91.78％ | 99.62％ | 35.21％ |
| Ie | 34.69％ | 43.84％ | 62.31％ | 38.73％ |
| If | 76.53％ | 95.21％ | 100.00％ | 41.55％ |
| Ig | 19.13％ | 69.18％ | 93.46％ | 38.73％ |
| Ih | 10.02％ | 64.38％ | 51.92％ | 12.68％ |
| Ii | 100.00％ | 100.00％ | 100.00％ | 100.00％ |
| IIa | 13.78％ | 45.21％ | 10.15％ | 64.79％ |
| IIb | 35.20％ | 73.29％ | 32.31％ | 0％ |
| IIc | 0％ | 89.73％ | 55.00％ | 10.41％ |
| IId | 2.55％ | 67.21％ | 56.15％ | 12.38％ |
| IIe | 29.08％ | 95.21％ | 59.23％ | 23.24％ |
| IIf | 6.63％ | 72.60％ | 98.85％ | 45.05％ |
| IIg | 55.61％ | 41.10％ | 5.03％ | 42.25％ |
| IIh | 31.12％ | 66.64％ | 45.77％ | 61.97％ |
| IIi | 19.90％ | 76.03％ | 100.00％ | 63.38％ |
| Norfloxicin | 88.24％ | 84.67％ | 85.23％ | 89.23％ |
The present invention has synthesized a series of thiouracil derivative being replaced Han oxadiazole (thiadiazoles) by special groups, and its anti-microbial activity is tested, from test result (see table 1), synthesized compound has stronger inhibit activities to for examination bacterium (separating amylomyces, Salmonellas, dysentery bacterium, intestinal bacteria), and the bacteriostatic activity of some compound is significantly better than the bacteriostatic activity of contrast norfloxicin.From structure activity relationship, the anti-microbial activity of chemical general formula I is generally higher than chemical general formula II, and this may be because the Sauerstoffatom on chemical general formula I Jie Gou Zhong oxadiazole rings is more suitable for generating with target point protein caused by hydrogen bond action and easier and targeted integration than the sulphur atom on Thiadiazole in chemical general formula II structure; Chemical general formula I is obviously better than other three kinds of bacteriums for colibacillary inhibition, Compound I a containing special groups and Compound I i has extremely strong restraining effect to four kinds for try bacterium (does 24 hours bacteriostatic tests and find that two compounds try bacterium bacteriostasis rate to four kinds of confessions and all reach 100%, do 48 hours bacteriostatic tests and find that Compound I i are 100%, Compound I a be respectively 74.76%, 99.11%, 100.00%, 95.54% to solution amylomyces, Salmonellas, dysentery bacterium, colibacillary bacteriostasis rate to four kinds of bacteriostasis rates for examination bacteriums.Visual compounds Ii has more lasting fungistatic effect).In chemical general formula II Compound II per e to Salmonellas, IAnd if IIi to colibacillary bacteriostasis rate also all more than 95%.The compound that the chemical general formula I of Han oxadiazole structure protects has stronger bacteriostatic activity, R in Compound I i
1with R
2for phenyl, have the strongest anti-microbial activity, this shows, in the specific replacement of end position phenyl ring (putting forward high molecular lipotropy), to be conducive to the anti-microbial activity improving this type of thiouracil derivative.
The embodiment 1-19 that the present invention enumerates is intended to illustrate containing the preparation method of the thiouracil derivative of oxadiazole/thiadiazoles and this compounds to the inhibit activities of bacterium, embodiment is not singly synthetic method and the anti-microbial activity of the concrete compound illustrated described in itself, also can be used for illustrating kind and the quantity of feed change simultaneously, synthesize its homologue and analogue, and any restriction is not formed to scope of the present invention.
Claims (9)
1., containing a thiouracil derivative for oxadiazole/thiadiazoles, it is characterized in that, the chemical general formula of this derivative is as shown in I or II:
Wherein R
1, R
2, R
3be hydrogen, halogen or aromatic base.
2. the thiouracil derivative of Han oxadiazole/thiadiazoles according to claim 1, is characterized in that, described R
1, R
2, R
3be hydrogen, chlorine, bromine, fluorine or phenyl.
3. the thiouracil derivative of Han oxadiazole/thiadiazoles according to claim 2, is characterized in that, R in described chemical general formula I
1for hydrogen, R
2for chlorine or R
1, R
2be phenyl.
4. the thiouracil derivative of Han oxadiazole/thiadiazoles according to claim 1 or 3, it is characterized in that, described chemical formula is:
5. the thiouracil derivative of Han oxadiazole/thiadiazoles according to claim 1 or 3, it is characterized in that, described chemical formula is:
6., containing a thiouracil derivative for oxadiazole/thiadiazoles, it is characterized in that, comprise the following steps:
A (), with aromatic aldehyde, ethyl cyanacetate and thiocarbamide for raw material, piperidines is catalyzer, in alcohol solvent, and back flow reaction, cooling, filters, obtains solid chemical compound III;
B Urea,amino-is dissolved in the water by (), regulator solution, to neutral, be warming up to 63-67 DEG C, dropwise add the alcoholic solution of aromatic aldehyde, back flow reaction, obtain solid chemical compound IV;
(c) by described compound IV in acetic acid/sodium acetate medium with bromine reaction, cooling, filter, obtain solid chemical compound V;
D () is 1:1 mixing by described compound V with to chloromethyl benzoic acid chlorides in molar ratio, be acid binding agent, react in tetrahydrofuran (THF) that cooling is filtered, obtained solid chemical compound VI with triethylamine;
E described compound VI and described compound III are pressed 1:1 mixing by (), be catalyzer with salt of wormwood, back flow reaction in acetonitrile solvent, desolventizes, and obtains the thiouracil derivative of Han oxadiazole as shown in chemical general formula I;
F aromatic acid and thiosemicarbazide are dissolved in phosphorus oxychloride medium by (), 75-85 DEG C of hydrolysis reaction 1.5-2.5h, cools to obtain solid, by back flow reaction after dissolution of solid, and cooling, adjust ph, to 7.5-8.5, is filtered, is obtained solid chemical compound VII;
G () is 1:1 mixing by described compound VI I with to chloromethyl benzoic acid chlorides in molar ratio, be acid binding agent, react in tetrahydrofuran (THF) that cooling is filtered, obtained solid chemical compound VIII with triethylamine;
H described compound VI II and described compound III are pressed 1:1 mixing by (), be catalyzer with salt of wormwood, back flow reaction in acetonitrile, desolventizes, and obtain the thiouracil derivative containing thiadiazoles as shown in chemical general formula II.
7. the preparation method of thiouracil derivative according to claim 6, is characterized in that, step (a) is any one in phenyl aldehyde, halogenated benzaldehyde, phenyl substituted benzaldehyde with the aromatic aldehyde described in step (b).
8. the preparation method of thiouracil derivative according to claim 6, is characterized in that, aromatic acid described in step (f) is any one in phenylformic acid, halogenated benzoic acid or phenyl substituted benzoic acid.
9. the thiouracil derivative of Han oxadiazole/thiadiazoles according to claim 1 is preparing the application in antibacterial medicine preparation.
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| CN111518104A (en) * | 2020-06-17 | 2020-08-11 | 河北农业大学 | 1,2, 4-triazolo [1,5-a ] pyrimidine compound containing thiourea pyrimidine and preparation method and application thereof |
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