CN104725317B - A kind of pyrazole carboxylic acid class compound and its synthetic method for having antitumor activity - Google Patents
A kind of pyrazole carboxylic acid class compound and its synthetic method for having antitumor activity Download PDFInfo
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Abstract
The present invention relates to a kind of pyrazole carboxylic acid class compound and its synthetic method with antitumor activity.Such compound is using phenyl isocyanate, ethyl acetoacetate and its derivative, phenylhydrazine as raw material, in toluene as reaction synthesizing pyrazole carboxylic acid compound under solvent.The inventive method processing safety is high, and reaction condition is gentle, suitable for industrialized production.Show that the type compound has preferable antitumor activity through preliminary biological activity test, there are important medical applications to be worth.
Description
Technical field
The present invention relates to a kind of pyrazole carboxylic acid class compound and its synthetic method with antitumor activity, belong to medicalization
Field.
Background technology
Tumour is a kind of disease of serious threat human health, finds the small antineoplastic of effective and safe, toxic side effect
The target that always tumour medicine R＆D worker seek assiduously.It is female by structure of pyrazole carboxylic acid with pharmaceutical chemical development
Effect of the compound of core in oncotherapy causes extensive concern.
Pyrazole ring is the core texture unit in many native compounds and synthetic drug, as one in heterocyclic compound
Individual important branch, pyrazole compound because its have efficiently, low toxicity, and its ring substituents can with multi-faceted conversion and
It is used widely in drug field.Research find pyrazole compound have anti-inflammatory, analgesic, antibacterial, sterilization, antihyperglycemic,
The pharmacological activity such as anticancer, anticoagulant.Carboxyl is introduced into the chemical constitution of pyrazoles, its bioactivity can be strengthened, improves choosing
Selecting property, there is important theory value and actual application value.In recent years, for having the pyrazole derivatives of antitumor activity, medicine
Materialization scholar and biologist have carried out substantial amounts of research, and synthesis filters out the antitumor activity that has of various different genes modifications
Pyrazole derivatives, the antineoplastic for further exploitation effectively low toxicity have laid solid foundation.
The content of the invention
It is an object of the invention to provide a kind of novel pyrazole carboxylic acid class compound of structure with antitumor activity.
Another object of the present invention is to provide the synthetic method of above-mentioned pyrazole carboxylic acid class compound.
The implementation process of the present invention is as follows：
General structure（Ⅰ）Shown compound,
（Ⅰ）
Wherein, R1、R2Independently selected from hydrogen, nitro, alkoxy, halogen, phenyl, substituted-phenyl, lower alkyl-cycloalkyl,
Cycloalkyl-lower alkyl, substituted or unsubstituted low alkyl group or cycloalkyl；
Described lower paraffin hydrocarbon is C1~C10 alkane, the substituted substituent be C1~C10 alkane, alkoxy,
Nitro, halogen.
Most preferred mode is R1、R2Independently selected from hydrogen, methyl, nitro, halogen.
Above-claimed cpd（I）Synthetic method, comprise the following steps：
（1）Phenyl isocyanate is with ethyl acetoacetate, methyl acetoacetate or isopropyl acetoacetate at 80~120 DEG C
Reaction；
（2）To step（1）Phenylhydrazine is added in product, continues to react at 80~120 DEG C；
（3）By step（2）After reaction gained solidliquid mixture is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, adjust pH value
To neutrality, room temperature is cooled to, then filters to obtain compound（1）Crude product.
Above-mentioned phenyl isocyanate：Ethyl acetoacetate, methyl acetoacetate or isopropyl acetoacetate：Mole of phenylhydrazine
Than for 1:1:1~1:2.5:2.5, or be 1:1:1.5~1:1.5:2.
Above-mentioned steps（1）In reaction temperature be 105~115 DEG C, the reaction time be 2~3 hours.Used in course of reaction
Thin-layer chromatography is followed the trail of, the carry out degree of monitoring reaction in time.
Above-mentioned steps（3）The compound of preparation（1）Crude product is further purified with ethyl alcohol recrystallization.
Above-claimed cpd can be used for preparing anti-tumor activity medicine.
Advantages of the present invention and good effect：Raw material environmental protection, production cost is low, and processing safety is high, and reaction condition is gentle,
Reaction raw materials, suitable for industrialized production, solve the problems, such as prior art low yield, while carboxyl is incorporated into using fully
In the chemical constitution of pyrazoles, to probe into the bioactivity of such compound with summarize structure-activity relationship have important theory value and
Application value.
Embodiment
With reference to specific embodiment, the present invention is further elaborated, and these embodiments are only in order at the mesh of explanation
, and do not limit the scope of the invention and essence.
Structural formula of compound in certain preferred embodiments of the present invention is as follows：
（1）（2）（3）
（4）（5）（6）
（7）（8）（9）
（10）（11）（12）
Embodiment 1
5- methyl isophthalic acids-phenyl -3- (p- Tolylamino) -1H- pyrazoles -4- carboxylic acids（1）Preparation.
1.33g (10mmol) 4- methyl phenylisocyanate and 1.3g (10mmol) acetoacetate second are added in the reactor
Ester, add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and be heated to 105 DEG C of stirrings with electric jacket, back flow reaction 3 is small
When.Then 1.1g (10mmol) phenylhydrazine is added in the reaction system and continues back flow reaction 4 hours., will be above-mentioned after reaction terminates
After the solidliquid mixture of reaction system is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, tune pH value to neutrality, is cooled to room temperature,
Then filter, filter cake is washed with warm water, and it is thick to obtain 5- methyl isophthalic acids-phenyl -3- (p- Tolylamino) -1H- pyrazoles -4- carboxylic acids
Product.The crude product is added in reactor, 25mL ethanol is added and is recrystallized, filter, be dried to obtain to obtain pale yellow crystals
Powder（2.11 gram）, total recovery 72.5%.Light yellow crystalline powder, M.P.185.5 DEG C.1H-NMR(300MHz,DMSO-d6)δ
(ppm):11.20(1H,s), 9.45(1H,s),7.70-7.50(4H,q),7.46(1H,t),7.4-7.2(4H,q),2.53
(3H,s),2.35(3H,s);13C-NMR(75MHz,DMSOd 6)δ(ppm):169.6,158.5,139.8,139.2,137.7,
131.4,130.0,129.5,126.5,120.3,107.7,21.5,11.4;HRMS(ESI)for(M+H)+:calcd:
307.1322,found 307.1325。
Embodiment 2
3-((4- chlorphenyls) amino)-5- methyl isophthalic acids-phenyl-1H- pyrazoles-4- carboxylic acids（2）Preparation
1.53g (10 mmol) 4- chlorine isocyanates and 1.56g (12mmol) ethyl acetoacetate are added in the reactor,
Add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 110 DEG C with electric jacket, back flow reaction 2 hours.
Then 1.63g (15mmol) phenylhydrazine is added in the reaction system and continues back flow reaction 3 hours., will be above-mentioned anti-after reaction terminates
After answering the solidliquid mixture of system to be concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, adjusts pH value to be cooled to room temperature, so to neutrality
After filter, filter cake is washed with warm water, and it is thick to obtain 3-((4- chlorphenyls) amino)-5- methyl isophthalic acids-phenyl-1H- pyrazoles-4- carboxylic acids
Product.The crude product is added in reactor, 25mL ethanol is added and is recrystallized, filter, be dried to obtain Light yellow crystals powder
End（2.20 gram）, total recovery 70.9%.Light yellow crystals powder, M.P.192.7 DEG C.1H-NMR(300MHz,DMSO-d 6 )δ
(ppm):11.20(1H,s), 9.55(1H,br),7.70-7.50(6H,m),7.46(1H,t),7.25(2H,d),2.53(3H,
s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.6,158.5,139.8,139.0,129.9,129.3,127.9,
126.4,124.9,121.3,107.7,11.4;HRMS(ESI)for(M+H)+:calcd:327.0775,found
327.0779。
Embodiment 3
5- methyl isophthalic acids-phenyl -3- (m- Tolylamino) -1H- pyrazoles -4- carboxylic acids（3）Preparation
Toluene diisocyanate and 3.12g (24mmol) acetoacetate second between addition 1.33g (10 mmol) in the reactor
Ester, add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 115 DEG C with electric jacket, back flow reaction 2 is small
When.Then 2.72g (25mmol) phenylhydrazine is added in the reaction system and continues back flow reaction 3 hours., will be above-mentioned after reaction terminates
After the solidliquid mixture of reaction system is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, tune pH value to neutrality, is cooled to room temperature,
Then filter, filter cake is washed with warm water, and it is thick to obtain 5- methyl isophthalic acids-phenyl -3- (m- Tolylamino) -1H- pyrazoles -4- carboxylic acids
Product.The crude product is added in reactor, 25mL ethanol is added and is recrystallized, filter, be dried to obtain to obtain pale yellow crystals
Powder（2.03 gram）, total recovery 69.5%.Light yellow crystalline powder, M.P.163.0 DEG C.1H-NMR(300MHz,DMSO-d 6)δ
(ppm):11.25(1H,s), 9.50(1H,br),7.7-7.5(4H,q),7.5-7.4(2H,d),7.10(1H,t),6.58
(1H,d),2.56(3H,s),2.35(3H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.6,158.5,140.7,
139.8,139.2,129.5,126.4,124.7,121.3,119.2,114.9,107.8,21.5,11.4;HRMS(ESI)for
(M+H)+:calcd:307.1320,found 307.1324。
Embodiment 4
The preparation of 3-((3- chlorphenyls) amino)-5- methyl isophthalic acids-phenyl-1H- pyrazoles-4- carboxylic acids
1.53g (10 mmol) 3- chlorobenzenes isocyanates and 1.56g (12mmol) acetoacetate second are added in the reactor
Ester, add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 100 DEG C with electric jacket, back flow reaction 2 is small
When.Then 1.63g (15mmol) phenylhydrazine is added in the reaction system and continues back flow reaction 4 hours., will be above-mentioned after reaction terminates
After the solidliquid mixture of reaction system is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, tune pH value to neutrality, is cooled to room temperature,
Then filter, filter cake is washed with warm water, and it is thick to obtain 3-((3- chlorphenyls) amino)-5- methyl isophthalic acids-phenyl-1H- pyrazoles-4- carboxylic acids
Product.The crude product is added in reactor, 25mL ethanol is added and is recrystallized, filter, be dried to obtain to obtain pale white crystals
Powder（1.24 gram）, total recovery 39.7%.Pale white crystals powder, M.P.181.1 DEG C.1H-NMR(300MHz,DMSO-d 6)δ
(ppm):11.2(1H,s), 9.5(1H,br), 7.7-7.4(5H,m),7.16(1H,d),6.8-6.9(2H,m),2.53(3H,
s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.6,158.5,142.7,139.8,139.2,135.3,130.9,
129.3,126.4,124.7,122.3,116.9,115.8,107.7,11.4;HRMS(ESI)for(M+H)+:calcd:
327.0776,found 327.0779。
Embodiment 5
The preparation of 5- methyl -3- ((4- nitrobenzophenones) amino) -1- phenyl -1H- pyrazoles -4- carboxylic acids
1.64g (10 mmol) 4- nitrophenylisocynic acids esters and 1.3g (10mmol) acetoacetate second are added in the reactor
Ester, add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 110 DEG C with electric jacket, back flow reaction 2 is small
When.Then 1.63g (15mmol) phenylhydrazine is added in the reaction system and continues back flow reaction 4 hours., will be above-mentioned after reaction terminates
After the solidliquid mixture of reaction system is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, tune pH value to neutrality, is cooled to room temperature,
Then filter, filter cake is washed with warm water, obtains 5- methyl -3- ((4- nitrobenzophenones) amino) -1- phenyl -1H- pyrazoles -4- carboxylics
Acid crude.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is added and is recrystallized, filter, be dried to obtain palm fibre
Yellow crystalline powder（2.20 gram）, total recovery 68.7%.Brown color crystalline powder, M.P.193.0 DEG C.1H-NMR(300MHz,
DMSO-d 6)δ(ppm):11.2(1H,s), 9.5(1H,br), 8.01(2H,d),7.7-7.5(4H,q),7.46(1H,t),
6.89(2H,d),2.55(3H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.6,158.5,147.2,139.8,
139.2,137.8,129.5,126.3,124.8,124.6,119.3,107.8,11.5;HRMS(ESI)for(M+Na)+:
calcd:361.1414,found 361.1409。
Embodiment 6
3- ((4- bromophenyls) amino) -5- methyl isophthalic acids-phenyl -1H- pyrazoles -4- carboxylic acids（6）Preparation
1.97g (10 mmol) 4- bromobenzenes isocyanates and 1.95g (15mmol) acetoacetate second are added in the reactor
Ester, add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 120 DEG C with electric jacket, back flow reaction 1 is small
When.Then 2.17g (20mmol) phenylhydrazine is added in the reaction system and continues back flow reaction 2 hours., will be above-mentioned after reaction terminates
After the solidliquid mixture of reaction system is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, tune pH value to neutrality, is cooled to room temperature,
Then filter, filter cake is washed with warm water, obtains 3- ((4- bromophenyls) amino) -5- methyl isophthalic acids-phenyl -1H- pyrazoles -4- carboxylic acids
Crude product.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is added and is recrystallized, filter, be dried to obtain red
Brown crystalline powder（1.99 gram）, total recovery 56.3%.Bronzing crystalline powder, M.P.198.7 DEG C.1H-NMR(300MHz,
DMSO-d6)δ(ppm):11.2 (1H, s), 9.6 (1H, br), 7.7-7.5 (4H, q), 7.46 (1H, t), 7.34 (2H, d),
7.03(2H,d),2.54(3H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.5,158.5,139.8,139.2,
132.5,129.5,124.8,118.6,116.8,107.7,11.4;HRMS(ESI)for(M+Na)+:calcd:394.1368,
found 394.1373。
Embodiment 7
The preparation of 3- ((4- fluorophenyls) amino) -5- methyl isophthalic acids-(4- nitrobenzophenones) pyrazoles -4- carboxylic acids
1.37g (10 mmol) 4 fluoro- phenylisocyanate and 1.95g (15mmol) acetoacetate second is added in the reactor
Ester, add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 110 DEG C with electric jacket, back flow reaction 2 is small
When.Then 2.30g (15mmol) paranitrophenylhydrazine is added in the reaction system and continues back flow reaction 3 hours.After reaction terminates,
After the solidliquid mixture of above-mentioned reaction system is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, adjusts pH value to neutrality, cooling
To room temperature, then filter, filter cake is washed with warm water, obtains 3- ((4- fluorophenyls) amino) -5- methyl isophthalic acids-(4- nitrobenzophenones) pyrrole
Azoles -4- crude carboxylic acids.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is then added and is recrystallized, filtered,
It is dried to obtain to obtain red powder（2.23 gram）, total recovery 65.5%.Red powder, M.P.182.6 DEG C.1H-NMR(300MHz,
DMSO-d6)δ(ppm):11.2 (1H, s), 9.4 (1H, s), 8.43 (2H, d), 8.13 (2H, d), 7.41 (2H, t), 7.33
(2H,t),2.53(3H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.5,158.4,157.5,145.9,139.2,
136.7,124.5,124.6,120.7,116.5,107.3,11.4;HRMS(ESI)for(M+Na)+:calcd:379.1020,
found 379.1024。
Embodiment 8
The preparation of 3- ((3,5- dichlorophenyls) amino) -5- methyl isophthalic acids-phenyl -1H- pyrazoles -4- carboxylic acids
1.87g (10 mmol) 3,5- dichloro-benzenes isocyanic acids and 1.56g (12mmol) acetoacetate are added in the reactor
Ethyl ester, add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 80 DEG C with electric jacket, back flow reaction 3 is small
When.Then 1.63g (15mmol) phenylhydrazine is added in the reaction system and continues back flow reaction 6 hours., will be above-mentioned after reaction terminates
After the solidliquid mixture of reaction system is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, tune pH value to neutrality, is cooled to room temperature,
Then filter, filter cake is washed with warm water, obtains 3- ((3,5- dichlorophenyl) amino) -5- methyl isophthalic acids-phenyl -1H- pyrazoles -4-
Crude carboxylic acid.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is then added and is recrystallized, filtered, dried
Obtain obtaining white crystalline powder（1.87 gram）, total recovery 51.0%.White crystalline powder, M.P.209.1 DEG C.1H-NMR
(300MHz,DMSO-d6)δ(ppm):11.2 (1H, s), 9.5 (1H, br), 7.7-7.5 (4H, q), 7.46 (1H, t), 7.07
(1H,s),6.70(2H,s),2.53(3H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.5,158.4,145.4,
140.1,129.9,129.5,126.3,124.8,119.4,114.9,107.5,11.4;HRMS(ESI)for(M+H)+:
calcd:361.0383,found 361.0380。
Embodiment 9
The preparation of 3- ((3- chlorphenyls) amino) -1- (4- fluorophenyls) -5- methyl isophthalic acid H- pyrazoles -4- carboxylic acids
1.53g (10 mmol) 3- chlorobenzenes isocyanates and 1.3g (10mmol) acetoacetate second are added in the reactor
Ester, add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 110 DEG C with electric jacket, back flow reaction 2 is small
When.Then 1.89g (15mmol) 4- fluorine phenylhydrazines are added in the reaction system and continues back flow reaction 3 hours.After reaction terminates,
After the solidliquid mixture of above-mentioned reaction system is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, adjusts pH value to neutrality, cooling
To room temperature, then filter, filter cake is washed with warm water, obtain 3- ((3- chlorphenyls) amino) -1- (4- fluorophenyls) -5- methyl -
1H- pyrazoles -4- crude carboxylic acids.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is then added and is recrystallized,
Filtering, is dried to obtain to obtain salmon pink crystalline powder（1.42 gram）, total recovery 43.6%.Salmon pink crystalline powder, M.P.203.5
℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):11.2 (1H, s), 9.5 (1H, br), 7.61 (2H, d), 7.53 (1H, d),
7.25(2H,t),7.15(1H,t),6.90-6.80(2H,t),2.55(3H,s);13C-NMR(75MHz,DMSOd 6)δ(ppm):
169.5,160.6,158.5,142.8,139.1,135.5,130.8,122.4,116.8,115.9,115.7,107.8,11.4;
HRMS(ESI)for(M+Na)+:calcd:367.1681,found 367.1679.
Embodiment 10
The preparation of 1- (4- chlorphenyls) -5- methyl -3 (phenyl amino) -1H- pyrazoles -4- carboxylic acids
1.19g (10 mmol) phenyl isocyanates and 1.56g (12mmol) ethyl acetoacetate are added in the reactor,
Add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 110 DEG C with electric jacket, back flow reaction 2 hours.
Then 2.13g (15mmol) 4- chlorophenyl hydrazines are added in the reaction system and continues back flow reaction 3 hours., will be upper after reaction terminates
State reaction system solidliquid mixture be concentrated under reduced pressure after, be diluted with water, be acidified with watery hydrochloric acid, adjust pH value to neutrality, be cooled to room
Temperature, then filter, filter cake is washed with warm water, obtains 1- (4- chlorphenyls) -5- methyl -3 (phenyl amino) -1H- pyrazoles -4- carboxylic acids
Crude product.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is then added and is recrystallized, filter, be dried to obtain
Obtain white crystalline powder（1.61 gram）, total recovery 51.9%.White crystalline powder, M.P.206.6 DEG C.1H-NMR(300MHz,
DMSO-d6)δ(ppm):11.2 (1H, s), 9.8 (1H, br), 7.7-7.4 (6H, m), 7.21 (2H, t), 6.83 (1H, s), 2.56
(3H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.5,158.4,140.8,139.1,137.9,131.9,129.7,
129.3,122.5,119.7,117.9,107.7,11.4;HRMS(ESI)for(M+H)+:calcd:327.0774,found
327.0778。
Embodiment 11
The preparation of 5- methyl isophthalic acids-(tolyl) -3- (Tolylamino) -1H- pyrazoles -4- carboxylic acids
Tolyl isocyanate and 1.56g (12mmol) acetoacetate between addition 1.33g (10 mmol) in the reactor
Ethyl ester, add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 110 DEG C with electric jacket, back flow reaction 2
Hour.Then 1.83g (15mmol) 3- procarbazines are added in the reaction system and continues back flow reaction 3 hours.Reaction terminates
Afterwards, after the solidliquid mixture of above-mentioned reaction system is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, adjusts pH value to neutrality, it is cold
But to room temperature, then filter, filter cake is washed with warm water, obtain 5- methyl isophthalic acids-(tolyl) -3- (m- Tolylamino) -
1H- pyrazoles -4- crude carboxylic acids.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is then added and is recrystallized,
Filtering, is dried to obtain to obtain white crystalline powder（2.19 gram）, total recovery 64.9%.White crystalline powder, M.P.211.2 DEG C.1H-NMR(300MHz,DMSO-d6)δ(ppm):11.2 (1H, s), 9.7 (1H, br), 7.56 (1H, s), 7.5-7.2 (5H, m),
7.10(1H,t),6.58(1H,t),2.53(3H,s),2.33(3H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):
169.5,158.4,140.8,139.7,139.4,138.9,129.5,129.3,126.6,121.1,119.2,116.8,
114.9,107.5,21.5,11.4;HRMS(ESI)for(M+H)+:calcd:321.1476,found 321.1479。
Embodiment 12
The preparation of 5- methyl isophthalic acids-(4- nitrobenzophenones) -3- (phenyl amino) -1H- pyrazoles -4- carboxylic acids
1.19g (10 mmol) phenyl isocyanates and 1.56g (12mmol) ethyl acetoacetate are added in the reactor,
Add 50mL toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and stir, be heated to 110 DEG C with electric jacket, back flow reaction 2 hours.
Then 2.30g (15mmol) paranitrophenylhydrazine is added in the reaction system and continues back flow reaction 3 hours., will after reaction terminates
After the solidliquid mixture of above-mentioned reaction system is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, adjusts pH value to be cooled to neutrality
Room temperature, then filter, filter cake is washed with warm water, obtain 5- methyl isophthalic acids-(4- nitrobenzophenones) -3- (phenyl amino) -1H- pyrazoles -
4- crude carboxylic acids.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is added and is recrystallized, filtered, dry
To brown crystalline powder（1.32 gram）, total recovery 38.5%.Brown crystalline powder, M.P.195.0 DEG C.1H-NMR
(300MHz,DMSO-d6)δ(ppm):11.2(1H,s),9.7(1H,br), 8.45(2H,d),8.13(2H,d),7.65(2H,
d),7.21(2H,t),6.83(1H,t),2.53(3H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm): 169.5,158.5,
145.9,145.0,140.8,139.1,129.6,124.8,124.6,122.5,117.9,107.5,11.4;
HRMS(ESI)for(M+H)+:calcd:338.1016,found 338.1020。
Embodiment 13
The antitumor activity test of the compounds of this invention
Cytostatic to tumor cell experiment is carried out to the compound of the present invention, test method is using conventional mtt assay.
Cell line is selected：Human liver cancer cell (HepG2), human lung carcinoma cell (A-549), human cervical carcinoma cell (Hela), people
Stomach cancer cell (SGC-7901), human colon cancer cell (HCT-8).Nutrient solution is that DMEM+15%NBS+ is dual anti-.
The preparation of sample liquid：After being dissolved with DMSO (Merck), add 100 μm of ol/L solution that PBS (-) is made into or
Uniform suspension, then with DMSO PBS (-) dilution, ultimate density is respectively 0.1,1,10,20,40,60,80,100 μ
mol/L。
The antineoplastic cytarabine (Ara-C) of listing is made into reference substance solution with same condition.
Cell culture：Adherent growth tumor cell is incubated at containing 10% inactivation NBCS and penicillin, strepto-
Element（Each 1,000,000 U/L）1640 culture medium in, be placed in 37 DEG C, 5% CO2, cultivate in the CO2gas incubator of saturated humidity.
Cell attachment is grown, and passes on 1 time within every 2~3 days, pours out nutrient solution first during passage, and PBS is washed 2 times, after pancreatin digestion, is added
Fresh nutrient solution piping and druming is uniform, and adjustment cell to debita spissitudo is moved into new blake bottle, and addition nutrient solution is to appropriate.Take pair
Number growth period cell is used to test.
Mtt assay detects cytoactive and IC50 measure：
Experimental principle：The MTT of yellow can be reduced into bluish violet product not soluble in water by dehydrogenase in living cells mitochondria
Formazan (MTT formazan), and be deposited in cell, the amount of generation is directly proportional to number of viable cells, and dead cell is without this
Kind function.DMSO can dissolve bluish violet crystal, and shade is directly proportional to contained amount, therefore the light determined with ELIASA is inhaled
Receipts value can reflect cell survival rate.
Experimental method：Take the logarithm growth period cell, digestion, count, the training of 96 holes is inoculated in 2 × 104/mL density
Support in plate, per the μ l of hole 100.After culture 24 hours, by testing compound with 0.1,1,10,20,40,60,80,100 μm of ol/L
Concentration handles cell.The each concentration of experimental group sets 5 multiple holes, is compared with the nutrient solution containing 0.4% DMSO.Medicine effect 48
After hour, supernatant is removed, 100 μ l MTT are added per hole（2- (4,5- dimethyl -2- thiazolyls) -3,5- diphenyl -2H- tetrazolium hydrogen
Bromate）(1mg/mL), continue culture 4 hours, abandon supernatant, 100 μ l DMSO are added per hole, vibration is mixed, existed with ELIASA
Absorbance is determined at 570 nm, using IC50Software for calculation obtains half-inhibition concentration (IC50).
Result of the test refers to table 1, wherein, sample refers to the pyrazole carboxylic acid class compound prepared in corresponding embodiment, sample
The corresponding specific numbering for preparing compound resulting in embodiment of numbering.Compound 8 is equal in the 5 kinds of cell lines tested
Good antitumor activity is shown, compound 2,7 and 9 is taken second place, and good resist also is shown in different cell lines
Tumor promotion.Test result indicates that, compound of the invention has good antitumor activity, particularly part pyrazoles carboxylic above
The activity of acid compounds antitumor activity in specific cells strain is better than or is equal to cytarabine.
Claims (5)
1. general structure（Ⅰ）Shown compound,
（Ⅰ）
Wherein, R1、R2Independently selected from hydrogen, nitro, halogen.
2. the synthetic method of compound described in claim 1, it is characterised in that comprise the following steps：
（1）Structural formula（2）Shown phenyl isocyanate is with ethyl acetoacetate in 80~120 DEG C of reactions；
（2）To step（1）Structural formula is added in product（3）Shown phenylhydrazine, continue to react at 80~120 DEG C；
（3）By step（2）After reaction gained solidliquid mixture is concentrated under reduced pressure, it is diluted with water, is acidified with watery hydrochloric acid, adjusts pH value into
Property, room temperature is cooled to, then filters to obtain compound（I）Crude product.
3. the synthetic method of compound according to claim 2, it is characterised in that：Step（1）In reaction temperature for 105~
115 DEG C, the reaction time is 2~3 hours.
4. the synthetic method of compound according to claim 2, it is characterised in that：Compound（I）Crude product ethyl alcohol recrystallization
Further purification.
5. application of the compound described in claim 1 in anti-tumor activity medicine is prepared, the tumour is liver cancer, lung cancer, palace
Neck cancer, stomach cancer or colon cancer.
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