CN104829536B - A kind of Phenylpyrazole carboxylic acid compound and its synthetic method for having antitumor activity - Google Patents
A kind of Phenylpyrazole carboxylic acid compound and its synthetic method for having antitumor activity Download PDFInfo
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses general structure（I）Shown compound, wherein R1Independently selected from hydrogen, methyl, nitro, halogen.Such compound obtains, synthetic method processing safety is high, and reaction condition is gentle, suitable for industrialized production using phenyl isocyanate, ethyl benzoylacetate or its analog, hydrazine hydrate as raw material in toluene as reaction under solvent.Show that the type compound has preferable antitumor activity through preliminary biological activity test, the research available for antitumor lead compound.
Description
Technical field
The present invention relates to a kind of Phenylpyrazole carboxylic acid compound and its synthetic method with antitumor activity, belong to doctor
Medicine technical field.
Background technology
To the health of the mankind, find the small antineoplastic of effective and safe, toxic side effect is always serious threat tumour
The target that tumour medicine R＆D worker seek assiduously.With pharmaceutical chemical development, the change using pyrazole carboxylic acid as structure parent nucleus
Effect of the compound in oncotherapy causes extensive concern.Pyrazole ring is the core knot in many native compounds and synthetic drug
Structure unit, as an important branch in heterocyclic compound, pyrazole compound has efficient, low toxicity, and its ring because of it
Upper substituent can be used widely with multi-faceted conversion in drug field.Carboxyl is introduced to the chemical constitution of pyrazoles
In, its bioactivity can be strengthened, selectivity is improved, there is important theory value and actual application value.
In recent years, a series of pyrazole derivatives of different base group modifications of research synthesis enter has efficient bio-active to screen
Medicine turn into one of study hotspot, especially for the pyrazole derivatives for having antitumor activity, Pharmaceutical Chemist and biology
Family has carried out substantial amounts of research, and synthesis filters out the pyrazole derivatives for having antitumor activity of various different genes modifications, to enter
The antineoplastic of one step exploitation effectively, less toxic has laid solid foundation.
The content of the invention
An object of the present invention is to provide a kind of Phenylpyrazole carboxylic acid compound with antitumor activity；
Another object of the present invention is to provide it is a kind of with phenyl isocyanate class compound, ethyl benzoylacetate or its
Analog, the synthetic method that hydrazine hydrate is the Phenylpyrazole carboxylic acid compound that Material synthesis has antitumor activity.
The implementation process of the present invention is as follows：
General structure（I）Shown compound,
（I）
Wherein, R1Independently selected from hydrogen, methyl, nitro, halogen.
Preferably compound is、Or。
General structure（I）The synthetic method of shown compound,
Using phenyl isocyanate class compound, ethyl benzoylacetate, hydrazine hydrate as raw material, toluene is as reaction dissolvent.
Specifically, general structure（I）The synthetic method of shown compound is：
（1）It is 1 that mol ratio is added into reactor:1~1:2 phenyl isocyanate class compound and benzoyl acetic acid second
Ester, add toluene and be heated to reflux to reaction completely；
（2）It is 1 by phenyl isocyanate and hydrazine hydrate mol ratio:1~1:2.5 add hydrazine hydrate, back flow reaction；
（3）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, filtered after being cooled to room temperature, filter cake is washed with warm water, obtains Phenylpyrazole crude carboxylic acid；
（4）Phenylpyrazole crude carboxylic acid obtains target product with ethyl alcohol recrystallization.
Above-mentioned phenyl isocyanate：Ethyl benzoylacetate：The mol ratio of hydrazine hydrate is 1:1:1~1:1.5:2.
Above-mentioned steps（1）In ethyl benzoylacetate with methyl benzoylacetate or benzoyl acetic acid isopropyl ester replace into
Row reaction.
Above-mentioned steps（1）Reaction temperature be 90~120 DEG C.
The advantage of the invention is that：Production process is more environmentally friendly, and production cost is low, and processing safety is high, reaction condition temperature
With reaction raw materials can be achieved and make full use of, suitable for industrialized production, solve the deficiency of prior art low yield, simultaneously
Carboxyl is incorporated into the chemical constitution of pyrazoles, to probe into the bioactivity of such compound with summarize structure-activity relationship have it is important
Theory value and application value.
Embodiment
With reference to specific embodiment, the present invention is further elaborated.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：
Embodiment 1 5- phenyl -3- (p- Tolylamino) -1H- pyrazoles -4- carboxylic acids（1）Preparation
1.33g (10mmol) 4- methyl phenylisocyanate and 2.30g (12mmol) benzoyl acetic acid are added in the reactor
Ethyl ester, add 50ml toluene to make reaction dissolvent, be placed on magnetic stirring apparatus and be heated to 110 DEG C of stirrings with electric jacket, back flow reaction 2 is small
When.Then 0.75g (15mmol) hydrazine hydrate is 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 5- phenyl -3- (p- Tolylamino) -1H- pyrazoles -4- crude carboxylic acids.Will
The crude product is added in reactor, is added 25ml ethanol and is recrystallized, filters, be dried to obtain to obtain light yellow crystalline powder
（2.14 gram）, total recovery 73.1%.
Product is light yellow crystalline powder, M.P.187.5 DEG C.1H-NMR(300MHz,DMSO-d6)δ(ppm):12.64
(1H,s),11.0
(1H,s),7.8-7.2(9H,m),4.0(1H,s),2.36(3H,s);13C-NMR(75MHz,DMSO-d6)δ
(ppm):169.6,153.8,
138.0,133.1,129.4,128.9,127.7,125.5,120.6,96.5,21.0;HRMS(ESI)for(M+H
)+:calcd:293.1166,found 293.1170。
Embodiment 2 3-((4- chlorphenyls) amino)-5- phenyl-1H- pyrazoles-4- carboxylic acids（2）Preparation
1.53g (10 mmol) 4- chlorine isocyanates and 2.30g (12mmol) benzoyl acetic acid 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 1 is small
When.Then 0.75g (15mmol) hydrazine hydrate is added in the reaction system and continues back flow reaction 2 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 3-((4- chlorphenyls) amino)-5- phenyl-1H- pyrazoles-4- crude carboxylic acids.
The crude product is added in reactor, 25ml ethanol is added and is recrystallized, filter, be dried to obtain Light yellow crystals powder
（2.24 gram）, total recovery 71.6%.
Light yellow crystals powder, M.P.193.5 DEG C.1H-NMR(300MHz,DMSO-d 6 )δ(ppm):12.64(1H,s),
11.0(1H,
s),7.8-7.2(9H,m),5.3(1H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.6,153.8,
139.1,133.2,129.4,128.9,127.9,125.4,122.3,96.5;HRMS(ESI)for(M+H)+:calcd:
313.0620,found 313.0623。
Embodiment 3 5- phenyl -3- (m- Tolylamino) -1H- pyrazoles -4- carboxylic acids（3）Preparation
Toluene diisocyanate and 1.92g (10mmol) benzoyl acetic acid 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 0.5g (10mmol) hydrazine hydrate 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, obtains 5- phenyl -3- (m- Tolylamino) -1H- pyrazoles -4- crude carboxylic acids.
The crude product is added in reactor, 25ml ethanol is added and is recrystallized, filter, be dried to obtain to obtain light yellow crystalline powder
（2.10 gram）, total recovery 68.7%.
Light yellow crystalline powder, M.P.164.3 DEG C.1H-NMR(300MHz,DMSO-d 6)δ(ppm):12.64(1H,s),
11.0
(1H,s),7.8-6.5(9H,m),4.0(1H,s),2.36(3H,s);13C-NMR(75MHz,DMSO-d 6)δ
(ppm):169.5,153.9,
140.9,139.4,133.2,129.5,128.9,127.6,125.4,121.2,119.2,114.9,96.5,
21.5;HRMS(ESI)for(M+H)+:calcd:293.1166,found 293.1169。
Embodiment 4
3-((3- chlorphenyls) amino)-5- phenyl-1H- pyrazoles-4- carboxylic acids（4）Preparation.
1.53g (10 mmol) 3- chlorobenzenes isocyanates and 2.875g (15mmol) benzoyl acetic acid 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 115 DEG C with electric jacket, back flow reaction 2
Hour.Then 1.0g (20mmol) hydrazine hydrate is added in the reaction system and continues back flow reaction 5 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, and it is thick to obtain 3-((3- chlorphenyls) amino)-5- 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（1.23 gram）, total recovery 39.4%.
Pale white crystals powder, M.P.183.1 DEG C.1H-NMR(300MHz,DMSO-d 6)δ(ppm):12.64(1H,s),
11.0
(1H,s),7.8-6.7(9H,m),4.0(1H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.5,
153.9,142.9,135.3,
131.0,129.6,128.9,127.6,125.4,122.5,116.8,116.1,96.5;HRMS(ESI)for(M+
H)+:calcd:313.0616,found 313.0619。
The 3- of embodiment 5 ((4- nitrobenzophenones) amino) -5- phenyl -1H- pyrazoles -4- carboxylic acids（5）Preparation
1.64g (10 mmol) 4- nitrophenylisocynic acids esters and 2.30g (12mmol) benzoyl second are added in the reactor
Acetoacetic 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 hours.Then 0.75g (15mmol) hydrazine hydrate 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- nitrobenzophenones) amino) -5- 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 pale brown
Color crystalline powder（2.17 gram）, total recovery 67.1%.
Brown color crystalline powder, M.P.191.0 DEG C.1H-NMR(300MHz,DMSO-d 6)δ(ppm):12.64(1H,s),
11.0
(1H,s),8.2-6.7(9H,m ),4.0(1H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.5,
153.9,147.2,138.1,
125.4,129.4,128.8,127.7,125.4,124.8,119.4,96.5;HRMS(ESI)for(M+Na)+:
calcd:324.0858,found 324.0861。
The 3- of embodiment 6 ((4- bromophenyls) amino) -5- phenyl -1H- pyrazoles -4- carboxylic acids（6）Preparation
1.97g (10 mmol) 4- bromobenzenes isocyanates and 3.83g (20mmol) benzoyl acetic acid 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 105 DEG C with electric jacket, back flow reaction 2
Hour.Then 1.25g (25mmol) hydrazine hydrate 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, and it is thick to obtain 3- ((4- bromophenyls) amino) -5- phenyl -1H- pyrazoles -4- carboxylic acids
Product.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is added and is recrystallized, filter, be dried to obtain reddish brown
Color crystalline powder（1.91 gram）, total recovery 53.6%.
Bronzing crystalline powder, M.P.196.8 DEG C.1H-NMR(300MHz,DMSO-d6)δ(ppm):12.64(1H,s),
11.0
(1H,s),7.9-7.1(9H,m),4.0(1H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.5,
153.8,140.1,133.2,
132.6,129.3,128.9,127.125.4,118.6,116.9,96.5;HRMS(ESI)for(M+Na)+:
calcd:357.0115,found 357.0116。
The 3- of embodiment 7 ((4- fluorophenyls) amino) -5- phenyl -1H- pyrazoles -4- carboxylic acids（7）Preparation
1.37g (10 mmol) 4- fluorobenzene isocyanates and 2.30g (12mmol) benzoyl acetic acid 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 110 DEG C with electric jacket, back flow reaction 2
Hour.Then 0.75g (15mmol) hydrazine hydrate 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, and it is thick to obtain 3- ((4- fluorophenyls) amino) -5- phenyl -1H- pyrazoles -4- carboxylic acids
Product.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is then added and is recrystallized, filter, be dried to obtain
Red powder（1.92 gram）, total recovery 64.6%.
Red powder, M.P.178.5 DEG C.1H-NMR(300MHz,DMSO-d6)δ(ppm):12.64(1H,s),11.0
(1H,s),
7.9-7.4(9H,m),4.0(1H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.5,157.5,
153.8,136.7,133.2,129.4,128.9,127.6, 125.4,120.8, 116.5, 96.4;HRMS(ESI)for(M+
Na)+:calcd:297.0916,found 297.0918。
The 3- of embodiment 8 ((3,5- dichlorophenyls) amino) -5- phenyl -1H- pyrazoles -4- carboxylic acids（8）Preparation
1.87g (10 mmol) 3,5- dichloro-benzenes isocyanic acids and 2.30g (12mmol) benzoyl second are added in the reactor
Acetoacetic 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
Hour.Then 0.75g (15mmol) hydrazine hydrate 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, obtains 3- ((3,5- dichlorophenyl) amino) -5- phenyl -1H- pyrazoles -4- carboxylics
Acid crude.The pyrazole carboxylic acid crude product is added in reactor, 25mL ethanol is then added and is recrystallized, filtered, dry
To white crystalline powder（1.74 gram）, total recovery 50.2%.
White crystalline powder, M.P.210.6 DEG C.1H-NMR(300MHz,DMSO-d6)δ(ppm):12.64(1H,s),
11.0
(1H,s),7.9-6.7(8H,m),4.0(1H,s);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.5,
153.9,145.4,133.1,
129.9,129.4,128.9,127.6,125.5,119.4,115.0,115.0,96.5;HRMS(ESI)for(M+
H)+:calcd:347.0229,found 347.0231。
Embodiment 9 5- phenyl -3 (phenyl amino) -1H- pyrazoles -4- carboxylic acids（9）Preparation
1.19g (10 mmol) phenyl isocyanates and 2.30g (12mmol) ethyl benzoylacetate are added in the reactor, are added
50ml toluene makees reaction dissolvent, is placed on magnetic stirring apparatus and stirs, and is heated to 120 DEG C with electric jacket, back flow reaction 2 hours.So
0.75g (15mmol) hydrazine hydrate is added in the reaction system afterwards and continues back flow reaction 4 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, obtains 5- phenyl -3 (phenyl amino) -1H- pyrazoles -4- crude carboxylic acids.By the pyrazole carboxylic acid
Crude product is added in reactor, is then added 25mL ethanol and is recrystallized, filters, be dried to obtain to obtain white crystalline powder
（1.42 gram）, total recovery 50.9%.
White crystalline powder, M.P.204.5 DEG C.1H-NMR(300MHz,DMSO-d6)δ(ppm):12.64(1H,s),
11.0
(1H,s),7.9-6.9(10H,m),4.0(1Hs);13C-NMR(75MHz,DMSO-d 6)δ(ppm):169.5,
153.8,141.0,133.2,
129.7, 129.4,128.8,127.7, 125.4,122.5,117.9,96.5;HRMS(ESI)for(M+H)+:
calcd:
279.1004,found 279.1008。
The antitumor activity test of the compounds of this invention of embodiment 10
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).Training
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 IC50Measure：
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 Phenylpyrazole carboxylic acid compound prepared in corresponding embodiment,
Sample number into spectrum correspondingly prepares the specific numbering of compound resulting in embodiment.
Half-inhibition concentration IC of the compound of table 1 to different tumour cells50（Unit：μmol/L）
Compound 8 shows good antitumor activity in the 5 kinds of cell lines tested, compound 6 and 2 times
It, also shows good antitumor activity in different cell lines.Above test result indicates that, compound of the invention
Activity with good antitumor activity, particularly part Phenylpyrazole carboxylic acid compound is antitumor in specific cells strain
Activity is better than or is equal to cytarabine, can be studied as antitumor lead compound.
Claims (4)
1. general structure（I）The synthetic method of shown compound, it is characterised in that：
（I）
Wherein, R1Independently selected from hydrogen, methyl, nitro, halogen；
（1）It is 1 that mol ratio is added into reactor:1~1:2 phenyl isocyanate class compound and ethyl benzoylacetate,
Toluene is added to be heated to reflux to reaction completely；
（2）It is 1 by phenyl isocyanate and hydrazine hydrate mol ratio:1~1:2.5 add hydrazine hydrate, back flow reaction；
（3）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 into
Property, filtered after being cooled to room temperature, filter cake is washed with warm water, obtains Phenylpyrazole crude carboxylic acid；
（4）Phenylpyrazole crude carboxylic acid obtains target product with ethyl alcohol recrystallization.
2. the synthetic method of compound according to claim 1, it is characterised in that：Phenyl isocyanate：Benzoyl acetic acid second
Ester：The mol ratio of hydrazine hydrate is 1:1:1~1:1.5:2.
3. the synthetic method of compound according to claim 1, it is characterised in that：Step（1）In ethyl benzoylacetate
Replaced and reacted with methyl benzoylacetate or benzoyl acetic acid isopropyl ester.
4. the synthetic method of compound according to claim 1, it is characterised in that：Step（1）Reaction temperature be 90~120
℃。
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