CN101085758A - 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide derivative, preparation method and application thereof - Google Patents
1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide derivative, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to 1- aryl methyl- 3- arylamine - 1H- pyrazole- 5- carbonhydrazides derivant in general formula (I). R1 represents hydrogen, alkyl group of C1 to C4, alkoxy, halide or nitro; R2 represents hydrogen, alkyl group of C1 to C4, alkoxy, halide or nitro; X represents carbon or nitrogen. The invention aslo relates to a method for synthesizing, separating and purifying said compound. Said method comprises following steps: taking aryl chloride and 3- arylamine - 1H- pyrazole- 5- ethyl formate as raw material, refluxing it in polar solution with potash existence and preparing derivant of 1- aryl methyl- 3- arylamine - 1H- pyrazole- 5- carboxylate, mixing said derivant with hydrazine hydrate in polar solution for reaction and getting 1- aryl methyl- 3- arylamine - 1H- pyrazole- 5- carbonhydrazides derivant. The invention aslo relates to the application of said product for preparing medicine for promoting lung carcinoma A549 cell withering.
Description
Technical field
The present invention relates to pyrazoles carbohydrazide derivative and preparation method thereof and application, relate in particular to 1-arylmethyl-3-aryl-1 H-pyrazole-5-carbohydrazide derivative and synthetic, separation thereof, purification process and application.
Background technology
Pyrazole derivatives and carbohydrazide derivative are the very important compounds of two classes, are subjected to extensive concern in new drug development.
Pharmacologically actives such as pyrazole compound has anti-inflammatory, pain relieving, brings down a fever, antibacterial, sterilization, hyperglycemia, anticancer, anti-coagulant, for example: the pyrazole derivatives of describing in patent JP5017470, US5134142, WO96/03385 has anti-inflammatory, rheumatism, antibacterium, antiviral pharmacologically active; Patent US4000281 related 4, the pyrazoles that 5-aryl/heterocyclic aryl replaces has the activity of anti-RNA and for example glutinous virus of dna virus, adenovirus, rhinovirus and various simplexviruss; The patent No. is the related pyrazoles of the patent of US3984431-5-acetic acid compound, especially 1-tertiary butyl-3, and 4-phenylbenzene-1H pyrazoles-5-acetic acid has the anti-inflammatory pharmacologically active.In addition, pyrazole derivatives can also all have to relate in patent JP5345772, WO97/01551, US 5559137, EP115640 as the inhibitor of cell and enzyme.And in patent WO02076949, also relate to treatment psychosis and mentally deranged (4S)-4 that fine pharmacologically active is arranged the 5-dihydro-1 h-pyrazole derivatives.In other respects, the novel pyrazole derivative that the pyrazole compound that patent WO92/19615, EP515041 are related and pyrimidine replace has mycocidal pharmacologically active on agricultural, and the pyrazole carboxylic acid derivative can be used as weedicide and uses among the patent JP4145081.
Carbohydrazide is a kind of important chemical intermediate, can be used for industries such as medicine, weedicide, plant-growth regulator, dyestuff, as carbohydrazide compound related among patent US 4269717, US 4259717, EP0103400, the US5078966.And make part with carbohydrazide, and can prepare multiple compound, be widely used in the industry such as medicine, oil, national defence.Aspect biological medicine, the pharmacologically active of carbohydrazide derivative report is less.But in the past studies show that carbohydrazide derivative arrestin enzyme, be used for the treatment of osteoporosis, gum disease comprises gingivitis, periodontitis, sacroiliitis malignant tumour and bone metabolism disease etc., as the patent No. is US6284777, the carbohydrazide derivative that the patent of US2002077455 is related; Carbohydrazide derivative also has anti-tumor activity in addition, is US4166810 as the patent No., the carbohydrazide derivative that the patent of DK14083 is related.
Aspect structural modification, often can obtain better biological activity by the reasonably combined of pharmacophoric group, literature search shows, at present the pyrazoles carbohydrazide derivative rarely has report, especially do not see relevant for 1-arylmethyl-3-aryl-1 H-pyrazole-5-carbohydrazide derivative and application or with the report of its associated viscera.
Summary of the invention
The object of the present invention is to provide a kind of pyrazoles carbohydrazide derivative 1-arylmethyl-3-aryl-1 H-pyrazole-5-carbohydrazide derivative and synthetic, separation thereof, purification process and its application in inducing people's lung cancer A549 cell apoptosis.
1-arylmethyl of the present invention-3-aryl-1H-pyrazoles 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;
X represents one of carbon, nitrogen.
In the above-mentioned compound:
R
1Preferred hydrogen or C
1～4One of alkyl, alkoxyl group, halogen;
R
2Preferred hydrogen or C
1～4One of alkyl, alkoxyl group, halogen, nitro;
X represents carbon or nitrogen.
Specifically, in the compound mentioned above:
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;
X represents carbon or nitrogen.
Wherein:
R
1Preferred hydrogen, alkoxyl group, one of Cl, Br;
R
2Preferred hydrogen, the tertiary butyl, Cl, Br, NO
2One of;
X represents carbon or nitrogen.
Wherein:
R
1Further preferred H, OCH
3, one of Cl;
R
2Further preferred H, C (CH
3)
3, Cl, NO
2One of;
X represents carbon or nitrogen.
Wherein:
R
1Most preferably H, OCH
3, one of Cl;
R
2Most preferably H, C (CH
3)
3, one of Cl;
X represents carbon or nitrogen.
General formula of the present invention (I) compound 1-arylmethyl-3-aryl-1 H-pyrazole-5-carbohydrazide derivative preparation method comprises the steps:
Is that 1～3: 1 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 the acetic acid ethyl dissolution product, 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: 1, obtains the derivative of 1-arylmethyl-3-aryl-1H-pyrazoles-5-carboxylic acid, ethyl ester;
Is that 1: 5～25 ratio joins in the polar solvent back flow reaction 1～5 hour with the hydrazine hydrate of 1-arylmethyl-3-aryl-1H-pyrazoles-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.
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: described acid binding agent is a salt of wormwood.
The preparation feedback formula of compound is as follows shown in the above-mentioned general formula (I):
The application of compound 1-arylmethyl of the present invention-3-aryl-1 H-pyrazole-5-carbohydrazide derivative in preparation promotion people lung cancer A549 cell apoptosis medicine.
Through experiment confirm: 1-arylmethyl of the present invention-3-aryl-1 H-pyrazole-5-carbohydrazide derivative is being induced in people's lung cancer A549 cell apoptosis has vital role, possesses very big application and development prospect.
Specific embodiments
The preparation of embodiment 1:1-benzyl-3-phenyl-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.080 gram 3-phenyl-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.633 gram 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) lysate, 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-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%.
Structural formula is as follows:
Molecular formula: C
17H
16N
4O
Molecular weight: 292.34
Proterties: white solid
Fusing point: 132-133 ℃
Nuclear magnetic resonance data is as follows:
1H-NMR(300MHz，CDCl
3)δ：4.03(s，2H，NH
2)，5.80(s，2H，CH
2)，6.80(s，1H，4-H)，7.24-7.43(m，9H，ArH，NH)，7.79(d，J＝7.2Hz，2H，ArH)。
Ir data is as follows:
IR(KBr)v：3302-3031(NH)，1681(C＝0)cm
-1。
Mass-spectrometric data is as follows:
MS(EI)：m/z?293.5(M+H)
+。
The preparation of embodiment 2:1-(4-tertiary butyl benzyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.080 gram 3-phenyl-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.913 gram to tertiary butyl benzyl chloride (0.005 mole) and acetonitrile (25 milliliters), installs 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) lysate, 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%.
Structural formula is as follows:
Molecular formula: C
21H
24N
4O
Molecular weight: 348.44
Proterties: white solid
Fusing point: 148-149 ℃
Nuclear magnetic resonance data is as follows:
1H?NMR(300MHz，CDCl
3)δ：1.27(s，9H，3CH
3)，4.0l(s，2H，NH
2)，5.77(s，2H，CH
2)，6.79(s，1H，4-H)，7.24-7.43(m，8H，ArH，NH)，7.79(d，J＝7.8Hz，2H，ArH)。
Ir data is as follows:
IR(KBr)v：3329-2865(NH)，1663(C＝0)cm
-1。
Mass-spectrometric data is as follows:
MS(EI)：m/z?349.4(M+H)
+。
The preparation of embodiment 3:1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.690 gram salt of wormwood (0.005 mole), 1.080 gram 3-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) lysate, 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-phenyl-1H-pyrazoles-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-phenyl-1H-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-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
Structural formula is as follows:
Molecular formula: C
16H
14ClN
5O
Molecular weight: 327.77
Proterties: white solid
Fusing point: 152-154 ℃
Nuclear magnetic resonance data is as follows:
1H?NMR(300MHz，CDCl
3)δ：4.03(s，2H，NH
2)，5.79(s，2H，CH
2)，6.82(s，1H，4-H)，7.26(d，J＝8.1Hz，1H，PyH)，7.33-7.44(m，4H，ArH，NH)，7.68(dd，J＝2.1，8.1Hz，1H，PyH)，7.77(d，J＝7.2Hz，2H，ArH)，8.45(d，J＝2.1Hz，1H，PyH)。
Ir data is as follows:
IR(KBr)v：3423-2944(NH)，1676(C＝0)cm
-1。
Mass-spectrometric data is as follows:
MS(EI)：m/z?328.5(M+H)
+。
The preparation of embodiment 4:1-benzyl-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), 0.633 gram 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) lysate, 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-)-1H-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-benzyl-3-(4-chloro-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-benzyl-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 89%.
Structural formula is as follows:
Molecular formula: C
17H
15ClN
4O
Molecular weight: 326.78
Proterties: white solid
Fusing point: 180-182 ℃
Nuclear magnetic resonance data is as follows:
1H?NMR(300MHz，CDCl
3)δ：3.98(s，2H，NH
2)，5.79(s，2H，CH
2)，6.77(s，1H，4-H)，7.28-7.29(m，6H，ArH，NH)，7.37(d，J＝8.7Hz，2H，ArH)，7.72(d，J＝8.4Hz，2H，ArH)。
Ir data is as follows:
IR(KBr)v：3266-2958(NH)，1630(C＝0)cm
-1。
Mass-spectrometric data is as follows:
MS(EI)：m/z?327.3(M+H)
+。
The preparation of embodiment 5:1-(4-tertiary butyl benzyl)-3-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide
1) in the round-bottomed flask of 100mL, 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), 0.913 gram is to tertiary butyl benzyl chloride (0.005 mole) and ethanol (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) lysate, 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-)-1H-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-)-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-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 79%.
Structural formula is as follows:
Molecular formula: C
21H
23ClN
4O
Molecular weight: 382.89
Proterties: white solid
Fusing point: 122-124 ℃
Nuclear magnetic resonance data is as follows:
1H?NMR(300MHz，CDCl
3)δ：1.28(s，9H，3CH
3)，4.02(s，2H，NH
2)，5.75(s，2H，CH
2)，6.76(s，1H，4-H)，7.24-7.31(m，3H，ArH，NH)，7.32(d，J＝8.4，2H，ArH)，7.37(d，J＝8.4，2H，ArH)，7.73(d，J＝8.4Hz，2H，ArH)。
Ir data is as follows:
IR(KBr)v：3319-2860(NH)，1654(C＝0)cm
-1。
Mass-spectrometric data is as follows:
MS(EI)：m/z?383.5(M+H)
+(M+H)
+。
The preparation of embodiment 6:1-(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) lysate, 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-)-1H-pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 90%.
2) in ethanol (5 milliliters) solution of 0.376 gram (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-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-(4-chloro-phenyl-)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 84%.
Structural formula is as follows:
Molecular formula: C
16H
13Cl
2N
5O
Molecular weight: 361.05
Proterties: white solid
Fusing point: 192-193 ℃
Nuclear magnetic resonance data is as follows:
1H?NMR(300MHz，CDCl
3)δ：4.11(s，2H，NH
2)，5.78(s，2H，CH
2)，6.78(s，1H，4-H)，7.26-7.30(m，2H，ArH，NH)，7.39(d，J＝8.7Hz，2H，ArH)，7.70-7.72(m，3H，ArH，PyH)，8.45(s，1H，PyH)。
Ir data is as follows:
IR(KBr) v：3299-2936(NH)，1675(C＝0)cm
-1。
Mass-spectrometric data is as follows:
MS(EI)：m/z?362.3(M+H)
+。
The preparation of embodiment 7:1-benzyl-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.53 gram anhydrous sodium carbonate (0.005 mole), 1.230 gram 3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.633 gram benzyl chloride (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) lysate, 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-)-1H-pyrazoles-5-carboxylic acid, ethyl ester, productive rate is 87%.2) in methyl alcohol (5 milliliters) solution of 0.336 gram (0.001 mole) 1-benzyl-3-(4-p-methoxy-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-benzyl-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 75%.
Structural formula is as follows:
Molecular formula: C
18H
18N
4O
2
Molecular weight: 322.36
Proterties: white solid
Fusing point: 142-144 ℃
Nuclear magnetic resonance data is as follows:
1H?NMR(300MHz，CDCl
3)δ：3.84(s，3H，OCH
3)，4.01(s，2H，NH
2)，5.78(s，2H，CH
2)，6.72(s，1H，4-H)，6.94(d，J＝8.4Hz，2H，ArH)，7.23-7.28(m，6H，ArH，NH)，7.72(d，J＝8.4Hz，2H，ArH)。
Ir data is as follows:
IR(KBr)v：3306-2835(NH)，1673(C＝0)cm
-1。
Mass-spectrometric data is as follows:
MS(EI)：m/z?323.4(M+H)
+。
The preparation of embodiment 8:1-(4-tertiary butyl benzyl)-3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-carbohydrazide
1) in 100 milliliters round-bottomed flask, adds 0.738 gram Strontium carbonate powder (0.005 mole), 1.230 gram 3-(4-p-methoxy-phenyl)-1H-pyrazoles-5-ethyl formate (0.005 mole), 0.913 gram is 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) lysate, 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-)-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%.
Structural formula is as follows:
Molecular formula: C
22H
26N
4O
2
Molecular weight: 378.47
Proterties: white solid
Fusing point: 142-144 ℃
Nuclear magnetic resonance data is as follows:
1H?NMR(300MHz，CDCl
3)δ：1.27(s，9H，3CH
3)，3.84(s，3H，OCH
3)，4.01(s，2H，NH
2)，5.75(s，2H，CH
2)，6.71(s，1H，4-H)，6.93(d，J＝8.4Hz，2H，ArH)，7.26-7.32(m，5H，ArH，NH)，7.72(d，J＝8.1Hz，2H，ArH)。
Ir data is as follows:
IR(KBr)v：3325-2867(NH)，1656(C＝0)cm
-1。
Mass-spectrometric data is as follows:
MS(EI)：m/z?379.6(M+H)
+(M+H)
+。
The preparation of embodiment 9:1-(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) lysate, 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)-1H-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)-1H-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%.
Structural formula is as follows:
Molecular formula: C
17H
16ClN
5O
2
Molecular weight: 357.79
Proterties: yellow solid
Fusing point: 157-159 ℃
Nuclear magnetic resonance data is as follows:
1H?NMR(300MHz，CDCl
3)δ：3.84(s，3H，OCH
3)，4.01(s，2H，NH
2)，5.76(s，2H，CH
2)，6.74(s，1H，4-H)，6.94(d，J＝8.4Hz，2H，ArH)，7.25(d，J＝7.8Hz，1H，PyH)，7.42(s，1H，NH)，7.66-7.70(m，3H，ArH，PyH)，8.44(s，1H，PyH)。
Ir data is as follows:
IR(KBr)v：3410-2834(NH)，1669(C＝0)cm
-1。
Mass-spectrometric data is as follows:
MS(EI)：m/z?358.5(M+H)
+。
The application of embodiment 10:1-arylmethyl-3-aryl-1 H-pyrazole-5-carbohydrazide derivative in preparation promotion people lung cancer A549 cell apoptosis medicine.
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.
Using pyrazoles carbohydrazide derivative 1-arylmethyl-3-aryl-1 H-pyrazole-5-carbohydrazide derivative carries out pharmacological evaluation to people's lung cancer A549 cell its application in people's lung cancer A549 cell apoptosis is described.
Experiment confirm: 1-arylmethyl of the present invention-3-aryl-1 H-pyrazole-5-carbohydrazide derivative has obvious promoter action to people's lung cancer A549 cell apoptosis.
Claims (9)
1. the compound of 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;
X represents one of carbon, nitrogen.
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;
X represents carbon or nitrogen.
3. according to the described compound of claim 2, it is characterized in that:
R
1Represent H, OCH
3, one of Cl;
R
2Represent H, C (CH
3)
3, one of Cl;
X represents carbon or nitrogen.
4. the preparation method of the described compound of one of claim 1～3 comprises the steps:
Is that 1～3: 1 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 the acetic acid ethyl dissolution product, 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: 1, obtains the derivative of 1-arylmethyl-3-aryl-1H-pyrazoles-5-carboxylic acid, ethyl ester;
Is that 1: 5～25 ratio joins in the polar solvent back flow reaction 1～5 hour with the hydrazine hydrate of 1-arylmethyl-3-aryl-1H-pyrazoles-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.
5. the preparation method of compound as claimed in claim 4, it is characterized in that: 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.
6. the preparation method of compound as claimed in claim 4, it is characterized in that: described polar solvent is a methyl alcohol, acetonitrile, one of ethanol.
7. the preparation method of compound as claimed in claim 4, it is characterized in that: described acid binding agent is a Strontium carbonate powder, yellow soda ash, one of salt of wormwood.
8. the preparation method of compound as claimed in claim 7, it is characterized in that: described acid binding agent is a salt of wormwood.
9. the application of any described compound in preparation promotion people lung cancer A549 cell apoptosis medicine in the claim 1～3.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101870676A (en) * | 2010-06-24 | 2010-10-27 | 山东大学 | 1-(2-oximido-2-phenylethyl)-3-phenyl-1H-pyrazol-5-ethyl formate derivative as well as preparation method and application thereof |
| CN102274226A (en) * | 2011-06-18 | 2011-12-14 | 山东大学 | Pharmaceutical use of 1-(3-(6-chloropyridine)methyl)-3-phenyl-1H-pyrazol-5-carbohydrazide |
-
2007
- 2007-07-03 CN CN 200710016661 patent/CN101085758A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101870676A (en) * | 2010-06-24 | 2010-10-27 | 山东大学 | 1-(2-oximido-2-phenylethyl)-3-phenyl-1H-pyrazol-5-ethyl formate derivative as well as preparation method and application thereof |
| CN102274226A (en) * | 2011-06-18 | 2011-12-14 | 山东大学 | Pharmaceutical use of 1-(3-(6-chloropyridine)methyl)-3-phenyl-1H-pyrazol-5-carbohydrazide |
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