CN105254620A - Pyrazole derivative, synthesis method and application of pyrazole derivative - Google Patents
Pyrazole derivative, synthesis method and application of pyrazole derivative Download PDFInfo
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- CN105254620A CN105254620A CN201510834893.4A CN201510834893A CN105254620A CN 105254620 A CN105254620 A CN 105254620A CN 201510834893 A CN201510834893 A CN 201510834893A CN 105254620 A CN105254620 A CN 105254620A
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- 0 **1C=CC(N(C(C2=C*)=O)NC2=O)=CC=C1 Chemical compound **1C=CC(N(C(C2=C*)=O)NC2=O)=CC=C1 0.000 description 4
- ZLLITWZGTRJWQY-UHFFFAOYSA-N Cc([s]1)ccc1[I]=O Chemical compound Cc([s]1)ccc1[I]=O ZLLITWZGTRJWQY-UHFFFAOYSA-N 0.000 description 1
- LEGSCVWPWMTRHF-UHFFFAOYSA-N Cc(ccc(CCC(CC(N)=[U])=O)c1)c1Br Chemical compound Cc(ccc(CCC(CC(N)=[U])=O)c1)c1Br LEGSCVWPWMTRHF-UHFFFAOYSA-N 0.000 description 1
- ZTGVAOCXYKEGOL-UHFFFAOYSA-N Cc(ccc(N(C(C1)=O)NC1=O)c1)c1Br Chemical compound Cc(ccc(N(C(C1)=O)NC1=O)c1)c1Br ZTGVAOCXYKEGOL-UHFFFAOYSA-N 0.000 description 1
- QAFHGMPFPKOKDN-UHFFFAOYSA-N Cc1ccc(CC(C(N)=O)C(Nc2ccc(C)c(Br)c2)=O)[s]1 Chemical compound Cc1ccc(CC(C(N)=O)C(Nc2ccc(C)c(Br)c2)=O)[s]1 QAFHGMPFPKOKDN-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/28—Two oxygen or sulfur atoms
- C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
- C07D231/32—Oxygen atoms
- C07D231/34—Oxygen atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/28—Two oxygen or sulfur atoms
- C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
- C07D231/32—Oxygen atoms
- C07D231/36—Oxygen atoms with hydrocarbon radicals, substituted by hetero atoms, attached in position 4
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- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a pyrazole derivative, a synthesis method and application of the pyrazole derivative. The pyrazole derivative is obtained by firstly, synthesizing a pyrazol ring diketone compound with the phenyl group at the first position substituted with substituted benzene hydrazine monohydrochloride as substrates under the effects of malonic acid and phosphorus trichloride; secondly, conducting condensation on methylene at the fourth position of the pyrazol ring diketone compound and aromatic aldehyde. The method is gentle in reaction condition, high in operation safety and suitable for industrialized production, and raw materials are low in price and easy to obtain. The preliminary bioactivity detection shows that the compound of the type has high antineoplastic activity.
Description
Technical field
The present invention relates to synthesis and the application thereof of pyrazoles small molecule, anti-tumor lead compound, belong to technical field of medical chemistry.
Background technology
The health of the tumour serious threat mankind, find safe and effective, that side effect is little antitumor drug is the target that tumour medicine development person pursues always.Pyrazole ring is the core texture unit of a lot of natural compounds and synthetic drugs, and as the important branch of heterogeneous ring compound, pyrazole compound is because it is efficient, low toxicity, and ring substituents can multi-faceted conversion and being widely used at pharmaceutical field.
In recent years, research for the pyrazole derivatives having anti-tumor activity becomes focus gradually, Pharmaceutical Chemist and biologist have carried out large quantity research, the antitumor pyrazole derivatives of various different base group modification has been screened in synthesis, has laid solid foundation for developing antitumor drug that is effective, low toxicity further.
Summary of the invention
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of pyrazole derivatives, synthetic method and application thereof.Production process of the present invention compares environmental protection, and production cost is low, and processing safety is high, and reaction conditions is gentle, simple to operate; The pyrazole derivatives obtained can be used for preparing antitumor drug.
Technical solution of the present invention is specific as follows.
A kind of pyrazole derivatives, its structure is as shown in logical formula I:
Wherein, R is selected from one or both in methyl, halogen or methyl halide; R
1be selected from thienyl, C
1-C
3alkylated substituted thiazoline fen base, phenyl, halogen substituted phenyl, pyridyl or C
1-C
3in alkyl substituted pyridines base any one.
One or both in the present invention, R is selected from ortho position, contraposition, position replace methyl, hydrogen, chlorine, bromine, iodine or trifluoromethyl; R
1for in 2-methyl substituted thiophene-5-base, 4-phenyl, 4-chloro-phenyl-or 2-picoline-5-base any one.
In the present invention, shown in logical formula I, compound is:
(E)-4-((5-thiotolene-2-base) methylene radical)-1-(bromophenyl) pyrazolidine-3,5-diketone;
(E)-4-((5-thiotolene-2-base) methylene radical)-1-((3-methyl)-phenyl) pyrazolidine-3,5-diketone;
(E)-4-((5-thiotolene-2-base) methylene radical)-1-(Chloro-O-Phenyl) pyrazolidine-3,5-diketone;
(E)-4-((5-thiotolene-2-base) methylene radical)-1-((2,4-dichloro)-phenyl) pyrazolidine-3,5-diketone;
(E)-4-((5-thiotolene-2-base) methylene radical)-1-phenylpyrazole alkane-3,5-diketone;
(E)-4-((5-thiotolene-2-base) methylene radical)-1-(4-iodophenyl) pyrazolidine-3,5-diketone;
(E)-1-(3-fluorophenyl)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone;
(E)-1-(3-fluorophenyl)-4-(4-chlorine benzylidene) pyrazolidine-3,5-diketone;
(E)-1-(3-fluorophenyl)-4-benzylidene pyrazolidine-3,5-diketone;
(E)-1-((3-methyl fluoride) phenyl)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone;
(E)-1-(the chloro-4--fluorophenyl of 2-)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone;
(E)-1-(2-bromophenyl)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone.
The present invention also provides a kind of synthetic method of above-mentioned pyrazole derivatives, and concrete steps are as follows:
(1) in reactor, add the hydrazinobenzene hydrochloride salt that mol ratio is the R replacement of 1:1 ~ 1:1.5
and propanedioic acid, add PCl
3, adding tetrahydrofuran (THF) reflux to reacting completely, obtaining pyrazolone intermediate;
(2) by pyrazolone intermediate and aromatic aldehyde R
1-CHO in molar ratio 1:1 ~ 1:1.5 adds reactor, and dehydrated alcohol is solvent, and heating reflux reaction is complete;
(3), after reaction terminates, cold filtration obtains pyrazole derivatives; Its reaction equation is as follows:
Wherein: R be selected from methyl, halogen or methyl halide one or both, R
1for thienyl, C
1-C
3alkylated substituted thiazoline fen base, phenyl, halogen substituted phenyl, pyridyl or C
1-C
3alkyl substituted pyridines base.
Further, the present invention also provides a kind of above-mentioned pyrazole derivatives preparing the application in antitumor drug.
Beneficial effect of the present invention is: production process compares environmental protection, and become to produce cost low, processing safety is high, and reaction conditions is gentle, simple to operate; The pyrazole derivatives obtained can be used for preparing antitumor drug.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.These embodiments are only be in purpose of explanation, and are not limited to scope of the present invention and essence.
The preparation of embodiment 1 (E)-4-((5-thiotolene-2-base) methylene radical)-1-(bromophenyl) pyrazolidine-3,5-diketone
Add bromophenyl-hydrazine hydrochloride and propanedioic acid 0.698g (6.711mmol) between 1g (4.474mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-(bromophenyl)-3,5-pyrazole ring diketone 0.585g.Get 1-(bromophenyl)-3,5-pyrazole ring diketone 0.15g (0.865mmol) and 5-methyl-2 thiophene aldehyde 0.088g (0.706mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain yellow product 0.206g, yield is 84.4%.
Product is yellow solid,
1h-NMR (501MHz, DMSO) δ 8.074-8.141 (m, 3H), 7.712-7.729 (d, 1H), 7.371-7.431 (m, 2H), 7.118 (d, 1H), 2.495 (s, 3H).MS(EI,m/z)363.8(+H)。
The preparation of embodiment 2 (E)-4-((5-thiotolene-2-base) methylene radical)-1-((3-methyl)-phenyl) pyrazolidine-3,5-diketone
Add 1g (6.303mmol) 3-hydrazinobenzoic acid hydrochloride and propanedioic acid 0.984g (9.460mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-(3-methyl)-phenyl)-3,5-pyrazole ring diketone 0.765g.Get 1-(3-methyl)-phenyl)-3,5-pyrazole ring diketone 0.15g (0.789mmol) and 5-methyl-2 thiophene aldehyde 0.119g (0.947mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain yellow product 0.210g, yield is 89%.
Product is yellow solid,
1h-NMR (501MHz, DMSO) δ 8.068-8.131 (m, 2H), 7.498 (d, 2H), 7.301 (t, 1H), 7.104 (d, 1H), 7.024 (d, 1H), 2.493-2.524 (m, 3H), 2.320 (t, 3H).MS(EI,m/z)299.7(+H)。
The preparation of embodiment 3 (E)-4-((5-thiotolene-2-base) methylene radical)-1-(Chloro-O-Phenyl) pyrazolidine-3,5-diketone
Add 1g (6.303mmol) adjacent chlorophenylhydxazine hydrochloride and propanedioic acid 0.589g (5.660mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-(2-chloro-phenyl-)-3,5-pyrazole ring diketone 0.526g.Get 1-(2-chloro-phenyl-)-3,5-pyrazole ring diketone 0.1g (0.475mmol) and 5-methyl-2 thiophene aldehyde 0.072g (0.70mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain product 0.101g, yield is 67%.Product is yellow solid,
1h-NMR (501MHz, DMSO) δ 8.089-8.129 (m, 2H), 7.613 (d, 1H), 7.613 (d, 1H), 7.590-7.603 (m, 1H), 7.458-7.484 (m, 2H), 7.091-7.115 (m, 1H), (2.494-2.613 m, 3H).MS(EI,m/z)318.0(+H)。
The preparation of embodiment 4 (E)-4-((5-thiotolene-2-base) methylene radical)-1-((2,4-dichloro)-phenyl) pyrazolidine-3,5-diketone
Add 1g (6.303mmol) 2 in the reactor, 4-dichloride phenyl hydrazine hydrochloric acid salt and propanedioic acid 0.731g (7.028mmol), add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-(2,4-dichloro)-phenyl-3,5-pyrazodione 0.476g.Get 1-(2,4-dichloro)-phenyl-3,5-pyrazodione 0.1g (0.408mmol) and 5-methyl-2 thiophene aldehyde 0.062g (0.492mmol) are placed in reactor, and adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, 75 DEG C of stirring and refluxing are heated in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dries at being placed in 50 DEG C, baking oven, obtain product 0.087g, yield is 60%.
Product is yellow solid,
1h-NMR (501MHz, DMSO) δ 8.094-8.132 (m, 2H), 7.830-7.836 (d, 1H), 7.626 (d, 1H), 7.550-7.577 (m, 1H), 7.096-7.118 (m, 1H), (2.494 s, 3H).MS(EI,m/z)393.3(+K)。
The preparation of embodiment 5 (E)-4-((5-thiotolene-2-base) methylene radical)-1-phenylpyrazole alkane-3,5-diketone
Add 1g (6.92mmol) hydrazinobenzene hydrochloride salt and propanedioic acid 1.08g (10.38mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-phenyl-3,5 pyrazole rings-diketone 0.493g.Get 1-phenyl-3,5 pyrazole rings-diketone 0.15g (0.852mmol) and 5-methyl-2 thiophene aldehyde 0.129g (1.022mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain product 0.206g, yield is 84.4%.
Product is yellow solid,
1h-NMR (501MHz, DMSO) δ 8.09 (m, 2H), 7.43-7.465 (d, 2H), 7.424 (d, 2H), 7.192 (s, 1H), 7.104 (d, 1H), 2.55 (s, 3H).MS(EI,m/z)284.0(+H)。
The preparation of embodiment 6 (E)-4-((5-thiotolene-2-base) methylene radical)-1-(4-iodophenyl) pyrazolidine-3,5-diketone
Add 1g (3.71mmol) 4-iodobenzene hydrazine hydrochloride and propanedioic acid 0.589g (5.66mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 4-iodophenyl-3,5-pyrazole ring diketone 0.526g.Get 4-iodophenyl-3,5-pyrazole ring diketone 0.1g (0.331mmol) and 5-methyl-2 thiophene aldehyde 0.052g (0.397mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain product 0.045g, yield is 34%.
Product is yellow solid,
1h-NMR (501MHz, DMSO) δ 8.093 (d, 2H), 7.763-7.794 (m, 2H), 7.547 (s, 2H), 7.110 (s, 1H), 2.50 (s, 3H).MS(EI,m/z)434.1(+H+Na)。
The preparation of embodiment 7 (E)-1-(3-fluorophenyl)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone
Add 1g (6.14mmol) 3-fluorophenyl hydrazine hydrochloride and propanedioic acid 0.963g (9.259mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-(3-fluorophenyl)-3,5-pyrazole ring diketone 0.550g.Get 1-(3-fluorophenyl)-3,5-pyrazole ring diketone 0.1g (0.515mmol) and p-tolyl aldehyde 0.074g (0.617mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain product 0.113g, yield is 73.6%.
1H-NMR(501MHz,DMSO)δ8.52(d,2H),7.92(s,1H),7.61(s,2H),7.53-7.46(m,1H),7.40(d,2H),7.04(s,1H),2.42(s,3H)。MS(EI,m/z)297.1(+H)。
The preparation of embodiment 8 (E)-1-(3-fluorophenyl)-4-(4-chlorine benzylidene) pyrazolidine-3,5-diketone
Add 1g (6.14mmol) 3-fluorophenyl hydrazine hydrochloride and propanedioic acid 0.963g (9.259mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-(3-fluorophenyl)-3,5-pyrazole ring diketone 0.550g.Get 1-(3-fluorophenyl)-3,5-pyrazole ring diketone 0.1g (0.515mmol) and 4-chloro-benzaldehyde 0.086g (0.617mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain product 0.103g, yield is 67%.
1H-NMR(501MHz,DMSO)δ8.62(d,2H),7.97(s,1H),7.66(s,2H),7.63-7.56(m,1H),7.51(d,2H),7.06(s,1H)。MS(EI,m/z)339.03(+Na)。
The preparation of embodiment 9 (E)-1-(3-fluorophenyl)-4-benzylidene pyrazolidine-3,5-diketone
Add 1g (6.14mmol) 3-fluorophenyl hydrazine hydrochloride and propanedioic acid 0.963g (9.259mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-(3-fluorophenyl)-3,5-pyrazole ring diketone 0.550g.Get 1-(3-fluorophenyl)-3,5-pyrazole ring diketone 0.1g (0.515mmol) and phenyl aldehyde 0.065g (0.617mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain product 0.071g, yield is 52.6%.
1H-NMR(501MHz,DMSO)δ8.62(d,2H),7.96(s,1H),7.92-7.79(m,1H),7.66(d,3H),7.61(s,1H),7.51(d,1H),7.05(s,1H)。MS(EI,m/z)329.07(+2Na+H)。
The preparation of embodiment 10 (E)-1-((3-methyl fluoride) phenyl)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone
Add 1g (5.68mmol) 3-trifluoromethylbenzene hydrazine hydrochloride and propanedioic acid 0.886g (8.518mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-(3-methyl fluoride) phenyl-3,5-pyrazole ring diketone 0.590g.Get 1-(3-methyl fluoride) phenyl-3,5-pyrazole ring diketone 0.1g (0.410mmol) and p-tolyl aldehyde 0.059g (0.492mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain product 0.058g, yield is 42%.
1H-NMR(501MHz,DMSO)δ8.53(d,2H),7.97(s,3H),7.82(t,2H),7.40(d,2H),2.43(s,3H)。MS(EI,m/z)347.11(+H)。
The preparation of embodiment 11 (E)-1-(the chloro-4--fluorophenyl of 2-)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone
Add the chloro-4-fluorophenyl hydrazine hydrochloride of 1g (5.13mmol) 2-and propanedioic acid 0.816g (7.845mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-(the chloro-4--fluorophenyl of 2-)-3,5-pyrazole ring diketone 0.460g.Get 1-(the chloro-4--fluorophenyl of 2-)-3,5-pyrazole ring diketone 0.1g (0.438mmol) and p-tolyl aldehyde 0.059g (0.526mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain product 0.063g, yield is 45.5%.
1H-NMR(501MHz,DMSO)δ8.51(t,2H),7.91(s,1H),7.70(d,2H),7.38(dd,3H),2.42(d,3H)。MS(EI,m/z)331.06(+H)。
The preparation of embodiment 12 (E)-1-(2-bromophenyl)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone
Add the adjacent bromophenyl-hydrazine hydrochloride of 1g (4.474mmol) and propanedioic acid 0.698g (6.711mmol) in the reactor, add 6mL tetrahydrofuran (THF) and make solvent, 1mL phosphorus trichloride, be placed on magnetic stirring apparatus and be heated to 85 DEG C of stirring and refluxing, reaction terminates column chromatography and obtains off-white color solid 1-(o-bromophenyl)-3,5-pyrazole ring diketone 0.540g.Get 1-(o-bromophenyl)-3,5-pyrazole ring diketone 0.1g (0.393mmol) and p-tolyl aldehyde 0.057g (0.472mmol) are placed in reactor, adding 6mL dehydrated alcohol is solvent, drip 3 pyridines, be heated to 75 DEG C of stirring and refluxing in magnetic stirring apparatus, reaction terminates rear filtration, filter cake dehydrated alcohol and washed with diethylether two to three times, dry at being placed in 50 DEG C, baking oven, obtain yellow product 0.073g, yield is 54.6%.
1H-NMR(501MHz,DMSO)δ8.52(t,2H),7.91(s,1H),7.81(d,1H),7.63(d,1H),7.54(t,1H),7.44-7.34(m,3H),2.42(d,3H)。MS(EI,m/z)357.02(+H)。
The anti-tumor activity test of embodiment 13 the compounds of this invention
Carried out Cytostatic to tumor cell test to compound of the present invention, test method adopts conventional mtt assay.Cell strain is selected: colon cancer cell (HCT116), human cervical carcinoma cell (Hela), human liver cancer cell (MHCC97L).Nutrient solution adopts DMEM+10%FBS.
Mtt assay detects cytoactive and IC
50be worth measuring
Experimental principle: the succinodehydrogenase in viable cell plastosome can make exogenous MTT be reduced to water-insoluble bluish voilet crystallization first a ceremonial jade-ladle, used in libation (MTTFormazan) and be deposited in cell, and dead cell is without this function.First a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, measures its absorbance value with enzyme-linked immunosorbent assay instrument in 540 or 720nm wavelength place, can indirectly reflect viable cell quantity.Within the scope of certain cell count, the amount that MTT crystallization is formed is directly proportional to cell count.
Test method: cell is inoculated in 96 orifice plates, inoculum size is 1500 every/holes, 190 μ L/ holes, the CO of 37 DEG C 5%
2incubator overnight incubation.Next day, every hole added 10 μ L different pharmaceuticals, and drug level is 10-5 ~ 10-10M, if three parallel holes; The CO of 37 DEG C 5%
2incubator hatches 72h.Every hole adds the MTT of 20 μ L5mg/ml, the CO of 37 DEG C 5%
2incubator hatches 4h.Abandon supernatant, every hole adds the DMSO of 100 μ L, vibration.Measure absorbance by microplate reader at 570nm, adopt IC50 value computation software to obtain half-inhibition concentration (IC
50).
Experimental result refers to table 1, and wherein, sample is the pyrazole ring dione compounds prepared in embodiment, and in the corresponding embodiment of sample number into spectrum, compound is specifically numbered.
Table 1 compound is to the half-inhibition concentration IC of different tumour cell
50(μm ol/L)
Above-mentioned 12 samples all have restraining effect to three kinds of tumour cells.Wherein, except sample 5 and 6 two compounds are to except three kinds of inhibiting tumour cells DeGrains, all the other samples all have good restraining effect to three kinds of tumour cells.Comparatively speaking, better containing the sample inhibit activities that fluorine replaces and chlorine replaces.
Claims (5)
1. a pyrazole derivatives, is characterized in that, its structure is as shown in logical formula I:
Wherein, R is selected from one or both in methyl, halogen or methyl halide; R
1be selected from thienyl, C
1-C
3alkylated substituted thiazoline fen base, phenyl, halogen substituted phenyl, pyridyl or C
1-C
3in alkyl substituted pyridines base any one.
2. pyrazole derivatives according to claim 1, is characterized in that: one or both in R is selected from ortho position, contraposition, position replace methyl, hydrogen, chlorine, bromine, iodine or trifluoromethyl; R
1for 2-methyl substituted thiophene-5-base, 4-phenyl, 4-chloro-phenyl-or 2-picoline-5-base.
3. pyrazole derivatives according to claim 1, is characterized in that: shown in logical formula I, compound is:
(E)-4-((5-thiotolene-2-base) methylene radical)-1-(bromophenyl) pyrazolidine-3,5-diketone;
(E)-4-((5-thiotolene-2-base) methylene radical)-1-((3-methyl)-phenyl) pyrazolidine-3,5-diketone;
(E)-4-((5-thiotolene-2-base) methylene radical)-1-(Chloro-O-Phenyl) pyrazolidine-3,5-diketone;
(E)-4-((5-thiotolene-2-base) methylene radical)-1-((2,4-dichloro)-phenyl) pyrazolidine-3,5-diketone;
(E)-4-((5-thiotolene-2-base) methylene radical)-1-phenylpyrazole alkane-3,5-diketone;
(E)-4-((5-thiotolene-2-base) methylene radical)-1-(4-iodophenyl) pyrazolidine-3,5-diketone;
(E)-1-(3-fluorophenyl)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone;
(E)-1-(3-fluorophenyl)-4-(4-chlorine benzylidene) pyrazolidine-3,5-diketone;
(E)-1-(3-fluorophenyl)-4-benzylidene pyrazolidine-3,5-diketone;
(E)-1-((3-methyl fluoride) phenyl)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone;
(E)-1-(the chloro-4--fluorophenyl of 2-)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone;
(E)-1-(2-bromophenyl)-4-(4-methylbenzilidene) pyrazolidine-3,5-diketone.
4. according to the synthetic method of the pyrazole derivatives one of claim 1-3 Suo Shu, it is characterized in that, concrete steps are as follows:
(1) in reactor, add the hydrazinobenzene hydrochloride salt that mol ratio is the R replacement of 1:1 ~ 1:1.5
and propanedioic acid, add PCl
3, adding tetrahydrofuran (THF) reflux to reacting completely, obtaining pyrazolone intermediate;
(2) by pyrazolone intermediate and aromatic aldehyde R
1-CHO in molar ratio 1:1 ~ 1:1.5 adds reactor, and dehydrated alcohol is solvent, and heating reflux reaction is complete;
(3), after reaction terminates, cold filtration obtains pyrazole derivatives; Its reaction equation is as follows:
Wherein: R be selected from methyl, halogen or methyl halide one or both, R
1be selected from thienyl, C
1-C
3alkylated substituted thiazoline fen base, phenyl, halogen substituted phenyl, pyridyl or C
1-C
3in alkyl substituted pyridines base any one.
5. preparing the application in antitumor drug according to the described pyrazole derivatives of one of claim 1-3.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002102359A2 (en) * | 2001-06-18 | 2002-12-27 | Applied Research Systems Ars Holding N.V. | Alkylidene pyrazolidinedione derivatives and use for treating diabetes and obesity |
WO2003074550A2 (en) * | 2002-03-01 | 2003-09-12 | Pintex Pharmaceuticals, Inc. | Pin1-modulating compounds and methods of use thereof |
US20070203236A1 (en) * | 2006-01-11 | 2007-08-30 | Smith Jeffrey W | Novel antagonists of the human fatty acid synthase thioesterase |
CN101961331A (en) * | 2010-08-19 | 2011-02-02 | 西安杰诺瓦生物科技有限公司 | Ubiquitin E1 inhibitor and preparation method thereof |
-
2015
- 2015-11-26 CN CN201510834893.4A patent/CN105254620A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002102359A2 (en) * | 2001-06-18 | 2002-12-27 | Applied Research Systems Ars Holding N.V. | Alkylidene pyrazolidinedione derivatives and use for treating diabetes and obesity |
WO2003074550A2 (en) * | 2002-03-01 | 2003-09-12 | Pintex Pharmaceuticals, Inc. | Pin1-modulating compounds and methods of use thereof |
US20070203236A1 (en) * | 2006-01-11 | 2007-08-30 | Smith Jeffrey W | Novel antagonists of the human fatty acid synthase thioesterase |
CN101961331A (en) * | 2010-08-19 | 2011-02-02 | 西安杰诺瓦生物科技有限公司 | Ubiquitin E1 inhibitor and preparation method thereof |
Non-Patent Citations (3)
Title |
---|
FABRIZIO MANETTI ET AL.: "A Combination of Docking/Dynamics Simulation and Pharmacophoric Modeling To Discover New Dual c-Src/Ab1 Kinase Inhibitors", 《J. MED. CHEM.》 * |
S.A.M.METWALLY ET AL.: "Novel synthesis of highly functionalized pyrazolone systems via rearrangement of 5-phenyl-1-oxa-5,6-diazaspiro[2.4]heptane-4,7-diones", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
STN: "stn", 《STN ON THE WEB》 * |
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