CN101121711A - Pyrazolcarbazone derivatives and application thereof - Google Patents
Pyrazolcarbazone derivatives and application thereof Download PDFInfo
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Abstract
The invention relates to a 1-aryl methyl-3-aryl-1H-pyrazole-5-carbon acylhydrazone derivative in the formula (I). Therein, R1 stands for hydrogen, C1 to 4 alkyl, alkoxy, halogen, and nitro; R2 stands for hydrogen, C1 to 4 alkyl, alkoxy, halogen, and nitro; R3 stands for hydrogen, C1 to 4 alkyl, and aromatic; X stands for carbon and nitrogen. The synthesis method of the compound is: under the condition of the potash as the acid-attaching regent, the aryl methyl chloride and 3-aryl-1H-pyrazole-5-ethyl formate react in the acetonitrile return to make the 1-aryl methyl-3-aryl-pyrazole-5-carboxylic acid ethyl ester derivative; then the derivative reacts with the hydrazine hydrate in the alcohol solution to get the 1-aryl methyl-3-aryl-1H-pyrazol-5-carbohydrazide derivative; the 1-aryl methyl-3-aryl-1H-pyrazol-5-carbohydrazide derivative reacts with the corresponding aromatic aldehyde in the ethanol return to make the 1-aryl methyl-3-aryl-1 H-pyrazole-5-carboacylhydrazone derivative. Based on the pharmacological experimental evaluation, the compound of the invention has the obvious anti-tumor effects of inhibiting the human lung cancer A549 cell proliferation.
Description
Invention field
The present invention relates to pyrazoles acyl hydrazone derivative and application thereof, relate in particular to and relate to 1-arylmethyl-3-aryl-1H-pyrazoles-5-phosphinylidyne hydrazone derivative and application thereof.
Background technology
The acylhydrazone compounds shows pharmacologically actives such as good anti-inflammatory, sterilization, anticonvulsion, antitumor, anti-diabetic, tuberculosis germ because of its special chemical structure-CONHN=CH-, get more and more people's extensive concerning for many years always, become one of emphasis problem that chemists further investigate.For example: the acyl hydrazone derivative of describing in patent JP52027775, US3513165, US3972905, US5122368, EP0398305 has anti-inflammatory, sterilization, anticonvulsion, antitumor, antiviral pharmacologically active; The related benzylidene benzoyl hydrazone derivative of patent WO02/070464 has the antimicrobial activity; The hydrazone compound that patent WO01/70213 is related can be used for treating infectation of bacteria; In patent CN1218933C, acyl hydrazone derivative can be used as guide's thing of antimycotic and antibacterials.In addition, acyl hydrazone derivative can also be as the inhibitor of cell kinase, as introduced the acyl hydrazone derivative that suppresses human body kinases H-SGK in patent WO00/62781; And the acyl hydrazone derivative that patent US2007/0060646A1 is introduced also is the inhibitor of SGK, can suppress the growth and the transfer of tumour cell, and can be used for treating SGK inductive diabetes, cardiovascular disorder and kidney disease etc.In other respects, described among the patent US4065565 treatment psychosis and the mentally deranged acyl hydrazone derivative that fine pharmacologically active is arranged; The related acyl hydrazone derivative of patent JP11/106371 is used for the treatment of diabetes and complication thereof; And the aromatics acyl hydrazone derivative can be used as calm toughener and brings high blood pressure down among the patent JP41/20699.In addition, weedicide (Dflufenzopyr) all has the acylhydrazone chemical structure behind commercial sterilant ferimzone (Ferimzone) and the corn field.
Aspect structural modification, often can obtain better biological activity by the reasonably combined of pharmacophoric group.Therefore have anti-inflammatory, pain relieving, bringing down a fever, introducing the acylhydrazone chemical structure in the pyrazole compound of pharmacologically actives such as antibacterial, sterilization, hyperglycemia, anticancer, anti-coagulant, with potential pharmacologically active of further exploration acyl hydrazone derivative and the new important meaning of the purposes person of having.
Summary of the invention
To the object of the present invention is to provide a kind of pyrazoles acyl hydrazone derivative be 1-arylmethyl-3-aryl-1H-pyrazoles-5-phosphinylidyne hydrazone derivative and suppress people's lung cancer A549 cell propagation medicine, i.e. application in the antitumor drug in preparation.
1-arylmethyl of the present invention-3-aryl-1 H-pyrazole-5-carbohydrazide derivative is represented with following general formula (I):
Wherein:
R
1Represent hydrogen, C
1~4One of alkyl, alkoxyl group, halogen, nitro;
R
2Represent hydrogen, C
1~4One of alkyl, alkoxyl group, halogen, nitro;
R
3Represent hydrogen, C
1~4One of alkyl, aromatic base;
X represents one of carbon, nitrogen.
Above-mentioned compound, optimal way is:
R
1Represent hydrogen, 2-methyl, 2-ethyl, 2-propyl group, 2-sec.-propyl, the 2-butyl, 2-isobutyl-, the 2-tertiary butyl, 2-sec-butyl, the 4-methyl, 4-ethyl, 4-propyl group, 4-sec.-propyl, the 4-butyl, 4-isobutyl-, the 4-tertiary butyl, 4-sec-butyl, the 2-methoxyl group, 2-oxyethyl group, 4-methoxyl group, 4-oxyethyl group, 2-chlorine, 2-bromine, 4-chlorine, one of 4-bromine;
R
2Represent hydrogen, 2-methyl, 2-ethyl, 2-propyl group, 2-sec.-propyl, the 2-butyl, 2-isobutyl-, the 2-tertiary butyl, 2-sec-butyl, 4-methyl, the 4-ethyl, 4-propyl group, 4-sec.-propyl, 4-butyl, 4-isobutyl-, the 4-tertiary butyl, 4-sec-butyl, 2-methoxyl group, 2-oxyethyl group, the 4-methoxyl group, 4-oxyethyl group, 2-chlorine, 2-bromine, 4-chlorine, 4-bromine, 2-nitro, one of 4-nitro;
R
3Represent hydrogen, 2-aminomethyl phenyl, 2-ethylphenyl, 2-propyl group phenyl, 2-isopropyl phenyl, 2-butyl phenyl, the 2-isobutyl phenenyl, 2-tert-butyl-phenyl, 2-secondary butyl phenenyl, the 2-hydroxy phenyl, 4-aminomethyl phenyl, 4-ethylphenyl, 4-propyl group phenyl, 4-isopropyl phenyl, 4-butyl phenyl, the 4-isobutyl phenenyl, 4-tert-butyl-phenyl, 4-secondary butyl phenenyl, the 2-p-methoxy-phenyl, 2-ethoxyl phenenyl, 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, 2-chloro-phenyl-, 2-bromophenyl, the 4-chloro-phenyl-, 4-bromophenyl, 2-nitrophenyl, the 4-nitrophenyl, piperonyl, one of furfuryl;
X represents one of carbon, nitrogen.
Further preferred embodiment is:
R
1Represent one of H, 2-methoxyl group, 4-methoxyl group, 2-oxyethyl group, 4-oxyethyl group, 2-chlorine, 4-chlorine, 2-bromine, 4-bromine;
R
2Represent one of H, 2-isobutyl-, 4-isobutyl-, the 2-tertiary butyl, the 4-tertiary butyl, 2-chlorine, 4-chlorine;
R
3Represent one of 2-aminomethyl phenyl, 2-hydroxy phenyl, 4-aminomethyl phenyl, 2-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-chloro-phenyl-, 2-bromophenyl, 4-chloro-phenyl-, 4-nitrophenyl, piperonyl, furfuryl;
X represents carbon or nitrogen.
Most preferably mode is:
R
1Represent one of H, 2-methoxyl group, 4-methoxyl group, 2-chlorine, 4-chlorine;
R
2Represent one of H, 2-isobutyl-, 4-isobutyl-, the 2-tertiary butyl, 2-chlorine, 4-chlorine;
R
3Represent the 2-hydroxy phenyl, 4-p-methoxy-phenyl, piperonyl, one of furfuryl;
X represents carbon or nitrogen.
The preparation method of general formula of the present invention (I) expression compound comprises the steps:
Is that 1: 1~1.2 ratio joins in the polar solvent with arylmethyl chlorine and 3-aryl-1H-pyrazoles-5-ethyl formate with mole ratio, with etc. mol ratio be that the amount of pyrazole compound adds acid binding agent, under reflux temperature, reacted 2~10 hours; Concentrating under reduced pressure is removed solvent, adds ethyl acetate, filters, and filtrate concentrates.Enriched material separates with silica gel column chromatography, and used developping agent is a petrol ether/ethyl acetate, and its volume ratio is 2~2.2: 1, obtain the derivative of 1-arylmethyl-3-arylpyrazole-5-carboxylic acid, ethyl ester;
Is that 1: 20~22 ratio joins in the polar solvent back flow reaction 1~5 hour with the hydrazine hydrate of 1-arylmethyl-3-arylpyrazole-5-carboxylic acid, ethyl ester derivative of obtaining and 80% with its mole ratio; Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-arylmethyl-3-aryl-1 H-pyrazole-5-carbohydrazide derivative with ethyl alcohol recrystallization;
Is that 1: 1 ratio joins in the polar solvent back flow reaction 2~14 hours with 1-arylmethyl-3-aryl-1 H-pyrazole-5-carbohydrazide derivative of obtaining and corresponding aroma aldehyde with its mole ratio; Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-arylmethyl-3-aryl-1H-pyrazoles-5-phosphinylidyne hydrazone derivative with ethyl alcohol recrystallization.
In the preparation method of above-claimed cpd: described arylmethyl chlorine is preferably 1: 1 with the ratio of 3-aryl-1H-pyrazoles-5-ethyl formate mole number; Described 1-arylmethyl-3-arylpyrazole-5-carboxylic acid, ethyl ester derivative is preferably 1: 20 with the ratio of the mole number of hydrazine hydrate.
In the preparation method of above-claimed cpd: described polar solvent is a methyl alcohol, acetonitrile, one of ethanol.
In the preparation method of above-claimed cpd: described acid binding agent is a Strontium carbonate powder, yellow soda ash, one of salt of wormwood.
Wherein: the preferred salt of wormwood of acid binding agent.
In the preparation method of above-claimed cpd: the preferred volume ratio of described developping agent petrol ether/ethyl acetate is 2: 1.
The preparation feedback formula of compound is as follows shown in the above-mentioned general formula (I):
Compound 1-arylmethyl of the present invention-3-aryl-1H-pyrazoles-5-phosphinylidyne hydrazone derivative suppresses people's lung cancer A549 cell propagation in preparation, promptly prepares the application in anti-people's lung-cancer medicament.
Through experiment confirm: 1-arylmethyl of the present invention-3-aryl-1H-pyrazoles-5-phosphinylidyne hydrazone derivative has obvious effects in suppressing people's lung cancer A549 cell propagation, possess very big clinical application DEVELOPMENT PROSPECT.
Embodiment
Embodiment 1:(E)-preparation of N-piperonyl-1-benzyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, add salt of wormwood (0.005 mole), 3-(4-chloro-phenyl-)-1H-pyrazoles-5-ethyl formate (0.005 mole), phenmethyl chlorine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 8 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-phenmethyl-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 83%.
2) in methyl alcohol (5 milliliters) solution of 0.340 gram (0.001 mole) 1-phenmethyl-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 4 hours, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-benzyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 89%;
0.327 gram (0.001 mole) 1-phenmethyl-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide and the 0.150 gram piperonylaldehyde (0.001 mole) that 3) will obtain join in 10 milliliters of ethanol, back flow reaction 14 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-piperonyl-1-benzyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 82%.
Structural formula is as follows:
Molecular formula: C
25H
19ClN
4O
3
Molecular weight: 458.90
Proterties: white solid
Fusing point: 233-236 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(300MHz,CDCl
3+DMSO)δ:5.85(s,2H,CH
2),6.02(s,2H,O-CH
2),6.82(d,J=8.1Hz,1H,ArH),7.09(d,J=8.1Hz,1H,ArH),7.17(s,1H,4-H),7.26-7.35(m,3H,ArH),7.39(d,J=8.4Hz,2H,ArH),7.42-7.46(m,3H,ArH),7.78(d,J=8.4Hz,2H,ArH),8.23(s,1H,=CH),11.18(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3211-2892(NH),1651(C=O)cm-1.
Mass-spectrometric data is as follows:
ESI-MS:459.5(M+H)+.
Embodiment 2:(E)-preparation of N-furfurylidene-1-benzyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, add salt of wormwood (0.005 mole), 3-(4-chloro-phenyl-)-1H-pyrazoles-5-ethyl formate (0.005 mole), phenmethyl chlorine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 8 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-phenmethyl-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 83%.
2) in methyl alcohol (5 milliliters) solution of 0.340 gram (0.001 mole) 1-phenmethyl-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 4 hours, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-benzyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 89%.
0.327 gram (0.001 mole) 1-phenmethyl-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide and the 0.096 gram furtural (0.001 mole) that 3) will obtain join in 10 milliliters of ethanol, back flow reaction 7 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-furfurylidene-1-benzyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 92%.
Structural formula is as follows:
Molecular formula: C
22H
17ClN
4O
2
Molecular weight: 404.85
Proterties: white solid
Fusing point: 249-251 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,CDCl
3+DMSO)δ:5.84(s,2H,CH
2),6.50-6.51(m,1H,FuH),6.84(d,J=2.1Hz,1H,FuH),7.20(s,1H,4-H),7.22-7.29(m,3H,ArH),7.35-7.42(m,4H,ArH),7.54(s,1H,FuH),7.77(d,J=8.4Hz,2H,ArH),8.29(s,1H,=CH),11.51(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3198-3062(NH),1651(C=O)cm-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?405.5(M+H)+.
Embodiment 3:(E)-preparation of N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds salt of wormwood (0.005 mole), 3-phenyl-1H-pyrazoles-5-ethyl formate (0.005 mole), 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 4 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, productive rate is 87%.
2) in methyl alcohol (5 milliliters) solution of 0.341 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
0.328 gram (0.001 mole) 1-phenmethyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and piperonylaldehyde 0.150 gram (0.001 mole) join in 10 milliliters of ethanol, back flow reaction 11 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 87%.
Structural formula is as follows:
Molecular formula: C
24H
18ClN
5O
3
Molecular weight: 459.88
Proterties: white solid
Fusing point: 213-215 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,DMSO)δ:5.81(s,2H,CH
2),6.10(s,2H,O-CH
2),7.01(d,J=8.0Hz,1H,ArH),7.20(d,J=8.0Hz,1H,ArH),7.30(s,1H,4-H),7.37-7.51(m,5H,ArH),7.73(dd,J=2.1Hz,8.4Hz,1H,PyH),7.81(d,J=7.6Hz,2H,ArH),8.33(s,1H,=CH),8.37(d,J=2.1Hz,1H,PyH),11.90(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3173-2952(NH),1662(C=O)cm-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?460.5(M+H)+.
Embodiment 4:(E)-preparation of N-(2-phenol methylene)-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds salt of wormwood (0.005 mole), 3-phenyl-1H-pyrazoles-5-ethyl formate (0.005 mole), 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 4 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, productive rate is 87%.
2) in methyl alcohol (5 milliliters) solution of 0.341 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
0.328 gram (0.001 mole) 1-phenmethyl-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.122 gram (0.001 mole) salicylic aldehyde join in 10 milliliters of ethanol, back flow reaction 3 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-(2-phenol methylene)-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 89%.
Structural formula is as follows:
Molecular formula: C
23H
18ClN
5O
2
Molecular weight: 431.87
Proterties: faint yellow solid
Fusing point: 99-100 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(300MHz,CDCl
3)δ:5.78(s,2H,CH
2),6.89-7.02(m,3H,4-H,ArH),7.19-7.43(m,7H,ArH),7.73-7.74(m,3H,ArH,PyH,NH),8.38(s,1H,=CH),8.43(s,1H,PyH),9.50(s,1H,OH).
Ir data is as follows:
IR(KBr)v:3429-2959(NH),1664(C=O)cm-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?432.5(M+H)
+.
Embodiment 5:(E)-preparation of N-(4-anisole methylene radical)-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds salt of wormwood (0.005 mole), 3-phenyl-1H-pyrazoles-5-ethyl formate (0.005 mole), 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 4 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, productive rate is 87%.
2) in methyl alcohol (5 milliliters) solution of 0.341 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
0.328 gram (0.001 mole) 1-phenmethyl-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.136 gram (0.001 mole) anisyl aldehyde join in 10 milliliters of ethanol, back flow reaction 3 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-(4-anisole methylene radical)-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 98%.
Structural formula is as follows:
Molecular formula: C
24H
20ClN
5O
2
Molecular weight: 445.90
Proterties: white solid
Fusing point: 213-215 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(300MHz,CDCl
3)δ:3.85(s,3H,OCH
3),5.83(s,2H,CH
2),6.94-7.02(m,3H,ArH),7.23(s,1H,4-H),7.35-7.42(m,3H,ArH,PyH),7.59-7.79(m,5H,ArH,PyH),8.14(s,1H,=CH),8.50(s,1H,PyH),9.21(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3441-2838(NH),1651(C=O)cm
-1..
Mass-spectrometric data is as follows:
MS(EI):m/z?446.5(M+H)
+.
Embodiment 6:(E)-preparation of N-furfurylidene-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds salt of wormwood (0.005 mole), 3-phenyl-1H-pyrazoles-5-ethyl formate (0.005 mole), 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 4 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, productive rate is 87%.
2) in methyl alcohol (5 milliliters) solution of 0.341 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
0.328 gram (0.001 mole) 1-phenmethyl-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.096 gram (0.001 mole) furtural join in 10 milliliters of ethanol, back flow reaction 8 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-furfurylidene-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 98%.
Structural formula is as follows:
Molecular formula: C
21H
16ClN
5O
2
Molecular weight: 405.84
Proterties: white solid
Fusing point: 210-212 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(300MHz,CDCl
3+DMSO)δ:5.86(s,2H,CH
2),6.51(s,1H,FuH),6.87(s,1H,FuH),7.24(s,1H,4-H),7.27-7.43(m,5H,ArH,PyH,FuH),7.55-7.83(m,3H,ArH,PyH),8.31(s,1H,=CH),8.50(s,1H,PyH),11.57(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3204-3049(NH),1649(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?406.6(M+H)
+.
Embodiment 7:(E)-preparation of N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.253 gram 3-(4-chloro-phenyl-)-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.810 gram 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 2 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 90%.
2) in methyl alcohol (5 milliliters) solution of 0.376 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 84%.
0.361 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.096 gram (0.001 mole) piperonylaldehyde join in 10 milliliters of ethanol, back flow reaction 7 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 94%.
Structural formula is as follows:
Molecular formula: C
24H
17Cl
2N
5O
3
Molecular weight: 494.33
Proterties: white solid
Fusing point: 256-258 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,DMSO)δ:5.80(s,2H,CH
2),6.10(s,2H,O-CH
2),7.01(d,J=8.0Hz,1H,ArH),7.20(d,J=8.0Hz,1H,ArH),7.30(s,1H,ArH),7.47(s,1H,4-H),7.50(d,J=8.4Hz,1H,PyH),7.54(d,J=8.4Hz,2H,ArH),7.74(dd,J=2.1Hz,8.4Hz,1H,PyH),7.82(d,J=8.4Hz,2H,ArH),8.32(s,1H,=CH),8.37(d,J=2.1Hz,1H,PyH),11.91(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3165-2955(NH),1660(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?494.3(M)
+.
Embodiment 8:(E)-preparation of N-(2-phenol methylene)-1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.253 gram 3-(4-chloro-phenyl-)-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.810 gram 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 2 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 90%.
2) in methyl alcohol (5 milliliters) solution of 0.376 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 84%.
0.361 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.122 gram (0.001 mole) salicylic aldehyde join in 10 milliliters of ethanol, back flow reaction 3 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-(2-phenol methylene)-1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 96%.
Structural formula is as follows:
Molecular formula: C
23H
17C
L2N
5O
2
Molecular weight: 466.32
Proterties: faint yellow look solid
Fusing point: 231-233 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,CDCl
3+DMSO)δ:5.79(s,2H,CH
2),6.82-6.88(m,2H,ArH),7.20-7.28(m,2H,ArH,),7.33-7.36(m,4H,ArH,PyH,4-H),7.71-7.73(m,3H,ArH,PyH),8.36(s,1H,=CH),8.49(s,1H,PyH),11.10(s,1H,OH),11.99(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3615(OH),3216-3059(NH),1677(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?466.4(M+H)
+.
Embodiment 9:(E)-preparation of N-(4-anisole methylene radical)-1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.253 gram 3-(4-chloro-phenyl-)-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.810 gram 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 2 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 90%.
2) in methyl alcohol (5 milliliters) solution of 0.376 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 84%.
0.361 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.136 gram (0.001 mole) anisyl aldehyde join in 10 milliliters of ethanol, back flow reaction 2 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-(2-phenol methylene)-1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 94%.
Structural formula is as follows:
Molecular formula: C
24H
19Cl
2N
5O
2
Molecular weight: 480.35
Proterties: talk yellow solid
Fusing point: 235-237 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,DMSO)δ:3.82(s,3H,OCH
3),5.81(s,2H,CH
2),7.04(d,J=8.4Hz,2H,ArH),7.47(s,1H,4-H),7.50(d,J=8.4Hz,1H,PyH),7.53(d,J=8.4Hz,2H,ArH),7.69(d,J=8.4Hz,2H,ArH),7.74(dd,J=2.2Hz,8.4Hz,1H,PyH),7.82(d,J=8.4Hz,2H,ArH),8.35(s,1H,=CH),8.38(d,J=2.2Hz,1H,PyH),11.88(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3173-2961(NH),1653(C=O),1267(O-C)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?480.4(M+H)
+.
Embodiment 10:(E)-preparation of N-furfurylidene-1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.253 gram 3-(4-chloro-phenyl-)-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.810 gram 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 2 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 90%.
2) in methyl alcohol (5 milliliters) solution of 0.376 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-phenylpyrazole-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 84%.
0.361 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.096 gram (0.001 mole) furtural join in 10 milliliters of ethanol, back flow reaction 9 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-furfurylidene-1-(3-(6-chloropyridine) methyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 81%.
Structural formula is as follows:
Molecular formula: C
21H
15Cl
2N
5O
2
Molecular weight: 440.28
Proterties: white solid
Fusing point: 178-180 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,DMSO)δ:5.80(s,2H,CH
2),6.66(s,1H,FuH),6.99(d,J=3.1Hz,1H,FuH),7.45(s,1H,4-H),7.50(d,J=8.6Hz,1H,PyH),7.53(d,J=8.4Hz,2H,ArH),7.73(d,J=8.6Hz,1H,PyH),7.83(d,J=8.4Hz,2H,ArH),7.88(s,1H,FuH),8.28(s,1H,=CH),8.37(s,1H,PyH),11.95(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3419-3051(NH),1654(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?440.5(M+H)
+.
Embodiment 11:(E)-preparation of N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.230 gram 3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.810 gram 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 4 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 92%.
2) in methyl alcohol (5 milliliters) solution of 0.371 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl) pyrazoles-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-p-methoxy-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
0.361 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.096 gram (0.001 mole) piperonylaldehyde join in 10 milliliters of ethanol, back flow reaction 3 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 92%.
Structural formula is as follows:
Molecular formula: C
25H
20ClN
5O
4
Molecular weight: 489.91
Proterties: yellow solid
Fusing point: 208-209 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,DMSO)δ:3.79(s,3H,OCH
3),5.79(s,2H,CH
2),6.10(s,2H,O-CH
2),7.00(d,J=8.0Hz,1H,ArH),7.02(d,J=8.4Hz,2H,ArH),7.19(d,J=8.0Hz,1H,ArH),7.30(s,1H,4-H),7.37(s,1H,ArH),7.50(d,J=8.0Hz,1H,PyH),7.72(dd,J=2.2Hz,8.4Hz,1H,PyH),7.73(d,J=8.4Hz,2H,ArH),8.32(s,1H,=CH),8.36(d,J=2.2Hz,1H,PyH),11.87(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3176-2957(NH),1652(C=O),1260(O-C)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?490.4(M)
+.
Embodiment 12:(E)-preparation of N-(2-phenol methylene)-1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.230 gram 3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.810 gram 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 4 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 92%.
2) in methyl alcohol (5 milliliters) solution of 0.371 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl) pyrazoles-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-p-methoxy-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
0.361 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.122 gram (0.001 mole) salicylic aldehyde join in 10 milliliters of ethanol, back flow reaction 3 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-piperonyl-1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 98%.
Structural formula is as follows.
Molecular formula: C
24H
20ClN
5O
3
Molecular weight: 461.90
Proterties: yellow solid
Fusing point: 100-102 ℃ ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,CDCl
3+DMSO)δ:3.77(s,3H,OCH
3),5.76(s,2H,CH
2),6.81-6.92(m,5H,ArH,OH),7.20-7.22(m,4H,ArH,PyH,4-H),7.66(d,J=8.4Hz,2H,ArH),7.68(dd,J=2.2Hz,8.4Hz,1H,PyH),8.35(d,J=2.2Hz,1H,PyH),8.45(s,1H,=CH),11.85(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3560(OH),3209-2833(NH),1680(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?462.4(M+H)
+.
Embodiment 13:(E)-preparation of N-(4-anisole methylene radical)-1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.230 gram 3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.810 gram 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 4 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 92%.
2) in methyl alcohol (5 milliliters) solution of 0.371 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl) pyrazoles-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-p-methoxy-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
0.361 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.136 gram (0.001 mole) anisyl aldehyde join in 10 milliliters of ethanol, back flow reaction 3 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-(4-anisole methylene radical)-1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 91%.
Structural formula is as follows:
Molecular formula: C
25H
22ClN
5O
3
Molecular weight: 475.93
Proterties: yellow solid
Fusing point: 205-206 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,DMSO)δ:3.79(s,3H,OCH
3),3.82(s,3H,OCH
3),5.79(s,2H,CH
2),7.02(J=8.4Hz,2H,ArH),7.03(d,J=8.4Hz,2H,ArH),7.37(s,1H,4-H),7.49(d,J=8.4Hz,1H,PyH),7.68(d,J=8.4Hz,2H,ArH),7.71-7.75(m,3H,ArH,PyH),8.35(s,1H,=CH),8.37(s,1H,PyH),11.83(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3174-2837(NH),1654(C=O),1263(O-C)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?476.4(M+H)
+.
Embodiment 14:(E)-preparation of N-furfurylidene-1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.230 gram 3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.810 gram 2-chloro-5-chloromethylpyridine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 4 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 92%.
2) in methyl alcohol (5 milliliters) solution of 0.371 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl) pyrazoles-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 1 hour, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(3-(6-chloropyridine) methyl)-3-p-methoxy-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
0.361 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.096 gram (0.001 mole) furtural join in 10 milliliters of ethanol, back flow reaction 2 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make high purity (E)-N-furfurylidene-1-(3-(6-chloropyridine) methyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 91%.
Structural formula is as follows:
Molecular formula: C
22H
18ClN
5O
3
Molecular weight: 435.86
Proterties: yellow solid
Fusing point: 200-202 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,DMSO)δ:3.79(s,3H,OCH
3),5.78(s,2H,CH
2),6.64-6.66(m,1H,FuH),6.98(d,J=3.0Hz,1H,FuH),7.02(d,J=8.4Hz,2H,ArH),7.35(s,1H,4-H),7.50(d,J=8.4Hz,1H,PyH),7.72(dd,J=2.0,8.4Hz,1H,PyH),7.74(d,J=8.4Hz,2H,ArH),7.87(s,1H,FuH),8.29(s,1H,=CH),8.36(d,J=2.0Hz,1H,PyH),11.91(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3211-2927(NH),1655(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?436.5(M+H)
+.
Embodiment 15:(E)-and the preparation 1 of N-(2-phenol methylene)-1-benzyl-3-phenyl-1H-pyrazoles-5-carbohydrazide) in 100 milliliters round-bottomed flask, add salt of wormwood (0.005 mole), 3-phenyl-1H-pyrazoles-5-ethyl formate (0.005 mole), phenmethyl chlorine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 8 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure is removed solvent, adds ethyl acetate (30 milliliters), filter, filtrate concentrates, and makes the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separates residuum (100~200 order silica gel), obtain 1-benzyl-3-phenyl-1H-pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 79%.
2) add 1.2 milliliter 80% hydrazine hydrate in methyl alcohol (5 milliliters) solution of 0.336 gram (0.001 mole) 1-benzyl-3-phenyl-1H-pyrazoles-5-carboxylic acid, ethyl ester, stirring and refluxing reaction 4 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-benzyl-3-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 93%.
0.292 gram (0.001 mole) 1-benzyl-3-phenyl-1H-pyrazoles-5-carbohydrazide and 0.122 gram (0.001 mole) salicylic aldehyde that 3) will obtain join in 10 milliliters of ethanol, and back flow reaction 7 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make the preparation of high purity (E)-N-(2-phenol methylene)-1-benzyl-3-phenyl-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 82%.
Structural formula is as follows:
Molecular formula: C
24H
20N
4O
2
Molecular weight: 396.44
Proterties: white solid
Fusing point: 234-236 ℃ ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,CDCl
3+DMSO)δ:5.74(s,2H,CH
2),6.77(t,J=8.0Hz,1H,ArH),6.87(d,J=8.4Hz,1H,ArH),7.10-7.32(m,11H,4-H,ArH),7.72(d,J=8.0Hz,2H,ArH),8.34(s,1H,=CH),11.23(s,1H,OH),11.52(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3246-2931(NH),1660(C=O)cm
-1。
Mass-spectrometric data is as follows:
MS(EI):m/z 397.5(M+H)
+.
Embodiment 16:(E)-preparation of N-(2-phenol methylene)-1-(4-tertiary butyl benzyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, add salt of wormwood (0.005 mole), 3-phenyl-1H-pyrazoles-5-ethyl formate (0.005 mole), to tert.-butylbenzene methyl chloride (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 6 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(4-tertiary butyl benzyl)-3-phenyl-1H-pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 80%.
2) in methyl alcohol (5 milliliters) solution of 0.362 gram (0.001 mole) 1-(4-tertiary butyl benzyl)-3-phenyl-1H-pyrazoles-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 4 hours, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(4-tertiary butyl benzyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 76%.
0.348 gram (0.001 mole) 1-(4-tertiary butyl benzyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.122 gram (0.001 mole) salicylic aldehyde join in 10 milliliters of ethanol, back flow reaction 6 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make the preparation of high purity (E)-N-(2-phenol methylene)-1-(4-tertiary butyl benzyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 97%.
Structural formula is as follows:
Molecular formula: C
28H
28N
4O
2
Molecular weight: 452.55
Proterties: white solid
Fusing point: 106-108 ℃ ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,CDCl
3+DMSO)δ:1.19(s,9H,3CH
3),5.74(s,2H,CH
2),6.81-6.88(m,2H,ArH),7.18-7.29(m,9H,ArH,4-H,OH),7.34(t,J=7.6Hz,2H,ArH),7.75(d,J=7.6Hz,2H,ArH),8.45(s,1H,=CH),11.86(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3480-2957(NH),1664(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?453.6(M+H)
+.
Embodiment 17:(E)-preparation of N-(2-phenol methylene)-1-benzyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, add salt of wormwood (0.005 mole), 3-(4-chloro-phenyl-)-1H-pyrazoles-5-ethyl formate (0.005 mole), benzyl chloride (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 8 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-benzyl-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 83%.
2) add 1.2 milliliter 80% hydrazine hydrate in methyl alcohol (5 milliliters) solution of 0.340 gram (0.001 mole) 1-benzyl-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, stirring and refluxing reaction 4 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-benzyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 89%.
0.327 gram (0.001 mole) 1-benzyl-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.122 gram (0.001 mole) salicylic aldehyde join in 10 milliliters of ethanol, back flow reaction 5 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make the preparation of high purity (E)-N-(2-phenol methylene)-1-benzyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 98%.
Structural formula is as follows:
Molecular formula: C
24H
19ClN
4O
2
Molecular weight: 430.89
Proterties: white solid
Fusing point: 208-209 ℃ ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,CDCl
3+DMSO)δ:5.77(s,2H,CH
2),6.80-6.90(m,2H,ArH),7.14-7.28(m,8H,ArH,4-H,),7.32(d,J=8.4Hz,2H,ArH),7.72(d,J=8.4Hz,2H,ArH),8.43(s,1H,=CH),11.21(s,1H,OH),11.86(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3234-3019(NH),1649(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?431.5(M+H)
+.
Embodiment 18:(E)-preparation of N-(2-phenol methylene)-1-(4-tertiary butyl benzyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide
1) in the round-bottomed flask of 100mL, adds salt of wormwood (0.005 mole), 3-(4-chloro-phenyl-)-1H-pyrazoles-5-ethyl formate (0.005 mole), to tertiary butyl benzyl chloride (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 5 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(4-tertiary butyl benzyl)-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 80%.
2) in methyl alcohol (5 milliliters) solution of 0.396 gram (0.001 mole) 1-(4-tertiary butyl benzyl)-3-(4-chloro-phenyl-) pyrazoles-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 5 hours, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(4-tertiary butyl benzyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 79%.
0.383 gram (0.001 mole) 1-(4-tertiary butyl benzyl)-3-(4-the chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.122 gram (0.001 mole) salicylic aldehyde join in 10 milliliters of ethanol, back flow reaction 5 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make the preparation of high purity (E)-N-(2-phenol methylene)-1-(4-tertiary butyl benzyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 92%.
Structural formula is as follows:
Molecular formula: C
24H
19ClN
4O
2
Molecular weight: 486.99
Proterties: white solid
Fusing point: 206-208 ℃ ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,CDCl
3+DMSO)δ:1.19(s,9H,3CH
3),5.73(s,2H,CH
2),6.81-6.89(m,2H,ArH),7.18-7.29(m,7H,ArH,4-H),7.33(d,J=8.4Hz,2H,ArH),7.72(d,J=8.4Hz,2H,ArH),8.44(s,1H,=CH),11.20(s,1H,OH),11.89(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3173-2866(NH),1657(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?487.5(M+H)
+.
Embodiment 19:(E)-preparation of N-(2-phenol methylene)-1-benzyl-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds salt of wormwood (0.005 mole), 3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-ethyl formate (0.005 mole), phenmethyl chlorine (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 10 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-benzyl-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 87%.
2) in methyl alcohol (5 milliliters) solution of 0.392 gram (0.001 mole) 1-benzyl-3-(4-p-methoxy-phenyl) pyrazoles-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 4 hours, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-benzyl-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 75%.
0.322 gram (0.001 mole) 1-benzyl-3-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.122 gram (0.001 mole) salicylic aldehyde join in 10 milliliters of ethanol, back flow reaction 7 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out white solid, filters, and decompress filter gets crude product; Make the preparation of high purity (E)-N-(2-phenol methylene)-1-benzyl-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 90%.
Structural formula is as follows:
Molecular formula: C
25H
22N
4O
3
Molecular weight: 426.47
Proterties: white solid
Fusing point: 206-208 ℃ ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,CDCl
3+DMSO)δ:3.76(s,3H,OCH
3),5.76(s,2H,CH
2),6.81-6.89(m,4H,ArH),7.11-7.26(m,8H,ArH,4-H),7.58(s,1H,OH),7.67(d,J=8.4Hz,2H,ArH),8.44(s,1H,=CH),11.84(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3201-2828(NH),1657(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?427.5(M+H)
+.
Embodiment 20:(E)-preparation of N-(2-phenol methylene)-1-(4-tertiary butyl benzyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds salt of wormwood (0.005 mole), 3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-ethyl formate (0.005 mole), to tertiary butyl benzyl chloride (0.005 mole) and acetonitrile (25 milliliters), the device reflux exchanger, top connects drying tube.Reflux 5 hours is reacted to the raw material completely consumed, with TLC detection reaction terminal point.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make the eluent silica gel column chromatography with ethyl acetate-sherwood oil (V/V=1/2) and separate residuum (100~200 order silica gel), obtain 1-(4-tertiary butyl benzyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 80%.
2) in methyl alcohol (5 milliliters) solution of 0.392 gram (0.001 mole) 1-(4-tertiary butyl benzyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carboxylic acid, ethyl ester, add 1.2 milliliter 80% hydrazine hydrate, stirring and refluxing reaction 5 hours, react to the raw material completely consumed, with TLC detection reaction terminal point.Standing over night is separated out solid, filters, and decompress filter gets crude product; Make high purity 1-(4-tertiary butyl benzyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 72%.
0.378 gram (0.001 mole) 1-(4-tertiary butyl benzyl)-3-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide that 3) will obtain and 0.122 gram (0.001 mole) salicylic aldehyde join in 10 milliliters of ethanol, back flow reaction 7 hours, react to the raw material completely consumed, with TLC detection reaction terminal point; Standing over night is separated out yellow solid, filters, and decompress filter gets crude product; Make the preparation of high purity (E)-N-(2-phenol methylene)-1-(4-tertiary butyl benzyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 92%.
Structural formula is as follows:
Molecular formula: C
29H
30N
4O
3
Molecular weight: 482.57
Proterties: yellow solid
Fusing point: 158-160 ℃ ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(400MHz,CDCl
3+DMSO)δ:1.18(s,9H,3CH
3),3.76(s,3H,OCH
3),5.73(s,2H,CH
2),6.80-6.93(m,4H,ArH),7.09(s,1H,4-H),7.16-7.22(m,7H,ArH,OH),7.67(d,J=8.4Hz,2H,ArH),8.40(s,1H,=CH),11.67(s,1H,NH).
Ir data is as follows:
IR(KBr)v:3523-2962(NH),1659(C=O)cm
-1.
Mass-spectrometric data is as follows:
MS(EI):m/z?483.5(M+H)
+.
Embodiment 21:1-arylmethyl-3-aryl-1H-pyrazoles-5-phosphinylidyne hydrazone derivative suppresses people's lung cancer A549 cell propagation in preparation, promptly prepares the application in anti-people's lung-cancer medicament.
With ordinary method cultivator lung cancer A549 cell, it is good and be in people's lung cancer A549 cell of exponential phase of growth to choose growth conditions, standby.
Application Pyrazolcarbazone derivatives 1-arylmethyl-3-aryl-1H-pyrazoles-5-phosphinylidyne hydrazone derivative carries out pharmacological evaluation to people's lung cancer A549 cell its application in suppressing people's lung cancer A549 cell propagation is described.
Experiment confirm: 1-arylmethyl of the present invention-3-aryl-1H-pyrazoles-5-phosphinylidyne hydrazone derivative has positive effect to suppressing people's lung cancer A549 cell propagation, has development and application values.
Claims (5)
2. according to the described compound of claim 1, it is characterized in that:
R
1Represent hydrogen, 2-methyl, 2-ethyl, 2-propyl group, 2-sec.-propyl, the 2-butyl, 2-isobutyl-, the 2-tertiary butyl, 2-sec-butyl, the 4-methyl, 4-ethyl, 4-propyl group, 4-sec.-propyl, the 4-butyl, 4-isobutyl-, the 4-tertiary butyl, 4-sec-butyl, the 2-methoxyl group, 2-oxyethyl group, 4-methoxyl group, 4-oxyethyl group, 2-chlorine, 2-bromine, 4-chlorine, one of 4-bromine;
R
2Represent hydrogen, 2-methyl, 2-ethyl, 2-propyl group, 2-sec.-propyl, the 2-butyl, 2-isobutyl-, the 2-tertiary butyl, 2-sec-butyl, 4-methyl, the 4-ethyl, 4-propyl group, 4-sec.-propyl, 4-butyl, 4-isobutyl-, the 4-tertiary butyl, 4-sec-butyl, 2-methoxyl group, 2-oxyethyl group, the 4-methoxyl group, 4-oxyethyl group, 2-chlorine, 2-bromine, 4-chlorine, 4-bromine, 2-nitro, one of 4-nitro;
R
3Represent hydrogen, 2-aminomethyl phenyl, 2-ethylphenyl, 2-propyl group phenyl, 2-isopropyl phenyl, 2-butyl phenyl, the 2-isobutyl phenenyl, 2-tert-butyl-phenyl, 2-secondary butyl phenenyl, the 2-hydroxy phenyl, 4-aminomethyl phenyl, 4-ethylphenyl, 4-propyl group phenyl, 4-isopropyl phenyl, 4-butyl phenyl, the 4-isobutyl phenenyl, 4-tert-butyl-phenyl, 4-secondary butyl phenenyl, the 2-p-methoxy-phenyl, 2-ethoxyl phenenyl, 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, 2-chloro-phenyl-, 2-bromophenyl, the 4-chloro-phenyl-, 4-bromophenyl, 2-nitrophenyl, the 4-nitrophenyl, piperonyl, one of furfuryl;
X represents one of carbon, nitrogen.
3. according to the described compound of claim 2, it is characterized in that:
R
1Represent one of H, 2-methoxyl group, 4-methoxyl group, 2-oxyethyl group, 4-oxyethyl group, 2-chlorine, 4-chlorine, 2-bromine, 4-bromine;
R
2Represent one of H, 2-isobutyl-, 4-isobutyl-, the 2-tertiary butyl, the 4-tertiary butyl, 2-chlorine, 4-chlorine;
R
3Represent one of 2-aminomethyl phenyl, 2-hydroxy phenyl, 4-aminomethyl phenyl, 2-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-chloro-phenyl-, 2-bromophenyl, 4-chloro-phenyl-, 4-nitrophenyl, piperonyl, furfuryl;
X represents carbon or nitrogen.
4. according to the described compound of claim 3, it is characterized in that:
R
1Represent one of H, 2-methoxyl group, 4-methoxyl group, 2-chlorine, 4-chlorine;
R
2Represent one of H, 2-isobutyl-, 4-isobutyl-, the 2-tertiary butyl, 2-chlorine, 4-chlorine;
R
3Represent the 2-hydroxy phenyl, 4-p-methoxy-phenyl, piperonyl, one of furfuryl;
X represents carbon or nitrogen.
5. the application of any described compound in preparation inhibition people lung cancer A549 cell propagation medicine in the claim 1~4.
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CN104546843A (en) * | 2015-01-28 | 2015-04-29 | 山东大学齐鲁医院 | Application of pyrazole hydrazone derivative in preparation of anti-breast cancer drug |
CN104606191A (en) * | 2015-01-28 | 2015-05-13 | 山东大学齐鲁医院 | Application of carbohydrazide in preparing brain cancer preventing medicine |
CN104688735A (en) * | 2015-01-28 | 2015-06-10 | 山东大学齐鲁医院 | Application of (E)-N-piperonyl-1-(3-(6-chloropyridine)methyl)-3-phenyl-1H-pyrazole-5-carbohydrazide in medicament pharmacy |
CN104945388A (en) * | 2015-07-09 | 2015-09-30 | 南京大学 | Preparing method for 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate and application to anti-cancer drugs |
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