CN106674128A - Licochalcone A thiouracil derivatives with antitumor activity and synthesis method thereof - Google Patents

Licochalcone A thiouracil derivatives with antitumor activity and synthesis method thereof Download PDF

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CN106674128A
CN106674128A CN201611265731.4A CN201611265731A CN106674128A CN 106674128 A CN106674128 A CN 106674128A CN 201611265731 A CN201611265731 A CN 201611265731A CN 106674128 A CN106674128 A CN 106674128A
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licochalcone
reaction
thiourea
dmso
toluene
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梁承远
田丹妮
贾敏
贾敏一
鞠伟会
裴少萌
田蕾
丁顺军
刘柯
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Shaanxi University of Science and Technology
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Shaanxi University of Science and Technology
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Priority to CN201611265731.4A priority Critical patent/CN106674128A/en
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Priority to CN201710650036.8A priority patent/CN107235916A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms

Abstract

The invention discloses licochalcone A thiouracil derivatives with antitumor activity and a synthesis method thereof. The licochalcone A thiouracil derivatives, compounds, are synthesized from licochalcone A and thiourea compounds by reacting with methylbenzene as a solvent. The synthesis method has the advantages of high safety and mild reaction conditions and is applicable to industrialized production. Preliminary biological activity tests show that the compounds are high in antitumor activity and can be used for studying antitumor lead compounds.

Description

The licochalcone A deracil analog derivative of one class tool anti-tumor activity and its conjunction Into method
Technical field
The present invention relates to the licochalcone A deracil analog derivative and its synthetic method of class tool anti-tumor activity, Belong to medicinal chemistry arts.
Background technology
Tumor has seriously threatened the health of the mankind, finds the little antitumor drug of effective and safe, toxic and side effects and is always The target that tumour medicine R＆D worker seek assiduously.With pharmaceutical chemical development, with pyrimidine ring as the chemical combination of structure parent nucleus Effect of the thing in oncotherapy causes extensive concern.
Licochalcone A is considered the species specificity composition of Glycyrrhiza inflata Bat., and its structure is as follows.
In recent years, research finds that licochalcone A has antiinflammatory, antibacterial, antioxidation, antitumor, lipid-loweringing, spasmolytic and malaria The multiple biological activities such as parasiticide, have very big Development volue in field of medicaments, but licochalcone A is that flatness is strong Molecule, poorly water-soluble.
The content of the invention
It is an object of the invention to provide a class tool anti-tumor activity licochalcone A deracil analog derivative and its Synthetic method, to improve the water solublity and anti-tumor activity of licochalcone A.
The present invention's realizes that process is as follows：
General structure（I）Shown compound,
Wherein：R for C1-C4 alkyl, the alkoxyl of C1-C4, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, Nitro；
Described being substituted by is monosubstituted or polysubstituted, and substituent group is：Halogen, the alkoxyl of C1-C4, cyano group, trifluoromethyl, benzene oxygen Base.
General structure（I）The synthetic method of shown compound, with licochalcone A, thiourea as raw material, with Organic base is catalyst, is synthesized under conditions of toluene or DMF are as reaction dissolvent,
。
Specifically, comprise the steps,
（1）It is in molar ratio 1 in reactor:1~1:1.5 add licochalcone A and thiourea, add organic molten Agent mix homogeneously, adds organic alkali catalyst, 80 DEG C ~ 120 DEG C back flow reaction 3 ~ 8 hours；
（2）By step（1）After the solidliquid mixture concentrating under reduced pressure of reaction system, column chromatography for separation purification is dried to obtain target product Thing.
Step（1）Described in the mol ratio of licochalcone A and thiourea be preferably 1:1 ~1:1.3, it is organic Solvent is toluene or DMF, and reaction temperature is preferably 105 DEG C ~ 115 DEG C, and organic base is preferably triethylamine.
It is an advantage of the current invention that：Raw material environmental protection, low production cost, processing safety is high, and reaction condition is gentle, is capable of achieving Reaction raw materials make full use of, it is adaptable to industrialized production, solve the problems, such as prior art low yield, while pyrimidine ring is drawn Enter in the chemical constitution of licochalcone A, the biological activity to probing into such compound has important with summary structure activity relationship Theory value and using value.
Specific embodiment：
With reference to specific embodiment, the present invention is further elaborated.These embodiments are only in order at purpose of explanation, And do not limit the scope of the invention and essence.
The synthetic method of one class licochalcone A deracil analog derivative comprises the steps：
（1）It is in molar ratio 1 in reactor:1~1:1.5, add licochalcone A, thiourea, plus toluene or DMF Mix homogeneously, wherein solvent volume add organic alkali catalyst triethylamine less than the 2/3 of reactor volume, are placed in magnetic agitation Stir on device, be heated to 80 DEG C ~ 120 DEG C, back flow reaction 3 ~ 8 hours；
（2）Thin layer chromatography is followed the trail of used in course of reaction, and what in time monitoring was reacted carries out degree, is stopped after raw material reaction is complete Heating, removes condensing units；
（3）By step（2）After the solidliquid mixture concentrating under reduced pressure of reaction system, column chromatography for separation purification is dried to obtain target product Thing.
Structural formula of compound in certain preferred embodiments of the present invention is as follows：
Embodiment 1
6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy phenyls）- 1- methyl -5, 6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (1).
200mg (1mmol) licochalcone As and 68.44mg (1.3mmol) 1- methylthioureas are added in the reactor, plus 50ml toluene and 5mLDMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, and electric jacket is heated to 100 DEG C, and magnetic force is stirred Mix back flow reaction 3 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography is de- dry to obtain brown ceramic powder （113mg）, total recovery 46.57%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J= 7.52Hz), 6.95 (1H,s), 6.85(2H,d,J=7.52Hz), 6.41(1H,s), 6.30(1H,q), 5.35 (2H, s), 5.00-4.98(2H,m), 3.9(1H,t), 3.83(3H,s), 3.04(3H,s), 1.76-1.51(2H,m), 1.69 (6H,s). 13C NMR(75MHz,DMSO-d6)δ(ppm): 182.2, 164.6, 160.8, 156.1, 155.0, 148.8, 133.2, 129,2, 125.2, 116.2, 111.1, 103.8, 61.8, 56.1, 40.2, 39.8, 28.6. HRMS(ESI)for (M+H)+: calcd: 411.17, found:411.78。
Embodiment 2
1- benzyl -6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy phenyls）-5,6- Dihydro-pyrimidin -2（1H）The preparation of-thioketone (2).
200mg (1mmol) licochalcone As and 127.73mg (1.3mmol) 1- benzylthioureas are added in the reactor, Plus 50ml toluene and 5mLDMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic force It is stirred at reflux reaction 5 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography is de- dry to obtain brown powder End（124.72mg）, total recovery 43.36%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J= 7.52Hz), 7.33 (2H,m),7.23(2H,m), 7.26(1H,m), 6.95(1H,s), 6.85(2H,d,J=7.52Hz), 6.41(1H,s), 6.30(1H,q), 5.35(2H,s), 5.00-4.98(2H,m), 3.9(1H,t), 3.83(3H,s), 3.81(2H,s), 1.76-1.51(2H,m), 1.69 (6H,s).13C NMR(75MHz,DMSO-d6)δ(ppm): 182.2, 164.6, 160.8, 156.1, 155.0, 148.8, 136.4, 133.2, 129.2, 128.5, 127.4, 125.2, 116.2, 111.1, 103.8, 59.2, 56.4, 40.5, 39.8, 28.6. HRMS(ESI)for(M+H)+: calcd: 487.20, found:487.63。
Embodiment 3
6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy phenyls）- 1- phenyl -5,6- Dihydro-pyrimidin -2（1H）The preparation of-thioketone (3).
200mg (1mmol) licochalcone As and 116.95mg (1.3mmol) 1- phenylthioureas are added in the reactor, Plus 50ml toluene and 5mLDMF make reaction dissolvent, add 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic force It is stirred at reflux reaction 8 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography is de- dry to obtain brown powder End（115.31mg）, total recovery 41.28%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J= 7.52Hz), 7.23(2H,t),6.95(1H,s), 6.85(2H,d,J=7.52Hz), 6.77(1H,m), 6.60(2H,m), 6.41(1H,s), 6.30(1H,q), 5.35(2H,s), 5.00-4.98(2H,m), 3.9 (1H,t), 3.83(3H,s), 1.88-1.63(2H,m), 1.69(6H,s). 13C NMR(75MHz,DMSO-d6)δ(ppm):177.7, 164.6, 160.8, 155.1, 154.7, 148.8, 140.3,133.3,129.1, 128.4, 125.2, 121.6, 116.0, 111.1, 103.8, 69.9, 56.1,40.1, 39.8, 28.6. HRMS(ESI)for(M+H)+: calcd: 473.18, found: 473.63。
Embodiment 4
6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy phenyls）-1-（Adjacent toluene Base）- 5,6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (4).
200mg (1mmol) licochalcone As and 127.73mg (1.3mmol) 1- are added in the reactor（O-tolyl） Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography takes off dry obtaining Brown ceramic powder（121.79mg）, total recovery 42.35%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J= 7.52Hz), 7.18(1H, d),7.04(1H,t), 6.95(1H,s), 6.85(2H,d,J=7.52Hz), 6.65(1H,t), 6.41(1H,s), 6.30(1H,q), 6.19(1H,d), 5.35(2H,s), 5.00-4.98(2H, m),3.9(1H,t), 3.83(3H,s), 2.12(3H,s), 1.88-1.63(2H,m), 1.69 (6H,s). 13C NMR(75MHz,DMSO-d6)δ (ppm):177.7, 164.6, 160.8, 155.1,154.7, 148.8, 139.2, 137.2, 133.2, 130.8, 129.4, 128.3, 126.0,125.2, 121.7, 116.0, 111.1, 103.8, 70.2, 56.1, 40.1, 39.8, 28.6, 18.2. HRMS(ESI)for(M+H)+: calcd:487.20, found:487.63。
Embodiment 5
1-（2- chlorphenyls）-6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy benzeness Base）- 5,6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (5).
200mg (1mmol) licochalcone As and 143.41mg (1.3mmol) 1- are added in the reactor（2- chlorphenyls） Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 4 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography takes off dry obtaining Brown ceramic powder（148.23mg）, total recovery 49.46%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J= 7.52Hz), 7.43(1H, d), 7.11(1H,t), 6.95(1H,s), 6.85(2H,d,J=7.52Hz), 6.71(1H, t), 6.54(1H,d), 6.41(1H,s), 6.30(1H,q), 5.35(2H,s), 5.00-4.98 (2H,m), 3.9(1H, t), 3.83(3H,s), 1.88-1.63(2H,m), 1.69(6H,s). 13C NMR(75MHz,DMSO-d6)δ(ppm): 177.7, 164.6, 160.8, 155.1, 154.7,148.8, 146.0, 138.8, 133.2, 131.4, 130.2, 129.1, 128.3, 127.5, 125.2, 121.6, 116.0, 111.1, 103.8, 69.4, 56.1, 40.1, 39.8, 28.6. HRMS(ESI)for(M+H)+: calcd: 507.14, found: 507.52。
Embodiment 6
6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy phenyls）-1-（2- methoxyl groups Phenyl）- 5,6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (6).
200mg (1mmol) licochalcone As and 140.02mg (1.3mmol) 1- are added in the reactor（2- methoxyl groups Phenyl）Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 80 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography takes off and does To brown ceramic powder（135.94mg）, total recovery 45.76%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J= 7.52Hz), 6.95(1H, s), 6.88(1H,m), 6.85(2H,d,J=7.52Hz), 6.79(1H,m), 6.66(1H, m), 6.41(1H,s), 6.30(1H,q), 5.35(2H,s), 5.00-4.98(2H,m), 3.9(1H, t), 3.83(3H, s), 1.88-1.63(2H,m), 1.69(6H,s). 13C NMR(75MHz, DMSO-d6)δ(ppm): 177.7, 166.9, 164.6, 160.8, 155.1, 154.7, 148.8, 133.2, 129.1, 128.4, 127.2, 125.2, 122.0, 121.4, 116.0, 112.9, 111.1, 103.8, 70.2, 56.1, 55.8, 40.1, 39.8, 28.6. HRMS (ESI)for(M+H)+: calcd: 503.19, found: 503.62。
Embodiment 7
1-（3- fluorophenyls）-6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy benzeness Base）- 5,6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (7).
200mg (1mmol) licochalcone As and 130.77mg (1.3mmol) 1- are added in the reactor（3- fluorophenyls） Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 90 DEG C, Magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography is de- dry to obtain palm fibre Color powder（126.76mg）, total recovery 43.72%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J=7.52Hz), 7.21(1H, m),6.95(1H,s), 6.85(2H,d,J=7.52Hz), 6.56(1H,m), 6.54(1H,m), 6.41(1H, s), 6.37(1H,m), 6.30(1H,q), 5.35(2H,s), 5.00-4.98(2H, m), 3.9(1H,t), 3.83(3H, s), 1.88-1.63(2H,m), 1.69(6H,s).13C NMR(75MHz,DMSO-d6)δ(ppm): 177.7, 164.6, 163,2, 160.8, 155.1, 154.7, 148.8, 141.9, 133.2, 130.6, 129.1, 128.2, 125.2, 121.6, 116.2, 115.0, 111.1, 103.8, 69.9, 56.1, 40.1, 39.8,28.6. HRMS (ESI)for (M+H)+: calcd: 491.17, found: 491.59。
Embodiment 8
3-（6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy phenyls）- 2- is thio- 5,6- dihydro-pyrimidins 1（2H）- base）The preparation of benzonitrile (8).
200mg (1mmol) licochalcone As and 136.16mg (1.3mmol) 1- are added in the reactor（3- cyano group benzene Base）Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 105 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography takes off dry Obtain brown ceramic powder（117.83mg）, total recovery 40.06%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J=7.52Hz), 7.30(1H, m),7.24(1H,m), 6.95(1H,s), 6.88(1H,m), 6.85(2H,d,J=7.52Hz), 6.69(1H, m), 6.41(1H,s), 6.30(1H,q), 5.35(2H,s), 5.00-4.98(2H, m), 3.9(1H,t), 3.83(3H, s), 1.88-1.63(2H,m), 1.69(6H,s). 13C NMR(75MHz,DMSO-d6)δ(ppm): 177.7, 164.6, 160.8, 155.1, 154.7, 148.8, 141.0, 136.7, 133.5, 131.2, 129.4, 128.3, 125.2, 121.6, 118.6, 116.0, 112.9, 111.1, 103.8, 69.9, 56.1, 40.1, 39.8, 28.6. HRMS (ESI)for(M+H)+: calcd: 498.18, found: 498.61。
Embodiment 9
6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy phenyls）-1-（3-（Trifluoro Methyl）Phenyl）- 5,6- dihydro-pyrimidin -2（1H）The preparation of-thioketone (9).
200mg (1mmol) licochalcone As and 169.19mg (1.3mmol) 1- are added in the reactor（3-（Fluoroform Base）Phenyl）Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket adds Heat to 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography, It is de- dry to obtain brown ceramic powder（131.32mg）, total recovery 41.10%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J=7.52Hz), 7.16(1H, t), 6.95(1H,s), 6.94(1H,m), 6.91(1H,m), 6.85(2H,d,J=7.52), 6.60(1H, m), 6.41(1H,s), 6.30(1H,q), 5.35(2H,s), 5.00-4.98(2H, m), 3.9(1H,t), 3.83(3H, s), 1.88-1.63(2H,m), 1.69(6H,s).13C NMR(75MHz,DMSO-d6)δ(ppm): 177.7, 164.6, 160.8, 155.1, 154.7, 148.8, 140.6, 135.7, 133.2, 131.3, 129.2, 128.3, 125.2. 124.1, 122.3, 121.3, 116.0, 111.1, 103.8, 69.9, 56.1, 40.1, 39.8, 28.6. HRMS (ESI)for(M+H)+: calcd: 541.17, found: 541.60。
Embodiment 10
6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy phenyls）-1-（To toluene Base）- 5,6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (10).
200mg (1mmol) licochalcone As and 127.73mg (1.3mmol) 1- are added in the reactor（P- toluene Base）Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 115 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography takes off dry Obtain brown ceramic powder（139.51mg）, total recovery 48.51%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J=7.52Hz), 7.01(2H,d, J=7.34Hz), 6.95(1H,s), 6.85(2H,d,J=7.52Hz), 6.41(1H,s), 6.30 (1H, q), 6.13(2H,d,J=7.34Hz), 5.35(2H,s), 5.00-4.98(2H,m), 3.9 (1H,t), 3.83(3H,s), 2.34(3H,s), 1.88-1.63(2H,m), 1.69(6H,s). 13C NMR(75MHz,DMSO-d6)δ(ppm): 177.7, 164.6, 160.8, 155.1, 154.7, 148.8, 138.3, 137.3, 133.2, 129.2, 128.3, 125.2, 121.6, 116.0, 111.1, 103.8, 69.9, 56.1, 40.1, 39.8, 28.6, 21.3. HRMS (ESI)for (M+H)+: calcd: 487.20,found: 487.63。
Embodiment 11
1-（4- fluorophenyls）-6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy benzeness Base）- 5,6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (11).
200mg (1mmol) licochalcone As and 130.77mg (1.3mmol) 1- are added in the reactor（4- fluorophenyls） Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 120 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography takes off dry obtaining Brown ceramic powder（136.21mg）, total recovery 46.98%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J=7.52Hz), 7.02(2H, t), 6.95(1H,s), 6.85(2H,d,J=7.52Hz), 6.58(2H,m), 6.41(1H,s), 6.30 (1H,q), 5.35(2H,s), 5.00-4.98(2H,m), 3.9(1H,t), 3.83(3H, s), 1.88-1.63(2H,m), 1.69(6H,s). 13C NMR(75MHz,DMSO-d6)δ(ppm): 177.7, 164.6, 163.3, 160.8, 155.1, 154.7, 148.8, 135.9, 133.2, 129.1, 128.2, 125.2, 121.6, 116.0, 115.8, 111.1, 103.8, 69.9, 56.1, 40.1, 39.8, 28.6. HRMS(ESI)for(M+H)+: calcd: 491.17, found: 491.59。
Embodiment 12
6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxy phenyls）-1-（4- phenoxy groups Phenyl）- 5,6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (12).
200mg (1mmol) licochalcone As and 187.71mg (1.3mmol) 1- are added in the reactor（4- phenoxy group benzene Base）Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography takes off dry Obtain brown ceramic powder（147.08mg）, total recovery 44.07%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J= 7.52Hz), 7.41(2H, t),7.17(1H,m), 7.14(2H,m), 6.95(1H,s), 6.85(2H,d,J=7.52Hz), 6.79(2H,m), 6.78(2H,m), 6.41(1H,s), 6.30(1H,q), 5.35(2H,s), 5.00-4.98(2H,m), 3.9(1H,t), 3.83(3H,s), 1.88-1.63(2H,m), 1.69 (6H,s). 13C NMR(75MHz,DMSO-d6)δ (ppm): 177.7, 164.6, 160.8, 157.0, 155.1, 154.7, 150.2, 148.8, 133.3, 129.1, 128.3, 126.2, 125.2, 121.7,118.9, 116.0, 115.7, 111.1, 103.8, 69.9, 56.1, 40.1, 39.8, 28.6. HRMS(ESI)for(M+H)+: calcd: 565.21, found: 565.69。
Embodiment 13
1-（3,5- Dichlorobenzene base）-6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- hydroxyls Phenyl）- 5,6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (13).
200mg (1mmol) licochalcone As and 169.87mg (1.3mmol) 1- are added in the reactor（3,5- dichloro-benzenes Base）Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket is heated to 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography takes off dry Obtain brown ceramic powder（134.25mg）, total recovery 41.95%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J= 7.52Hz), 7.01(1H, m), 6.95(1H,s), 6.85(2H,d,J=7.52Hz), 6.66(2H,s), 6.41(1H, s), 6.30(1H,q), 5.35(2H,s), 5.00-4.98(2H,m), 3.9(1H,t), 3.83(3H, s), 1.88- 1.63(2H,m), 1.69(6H,s). 13C NMR(75MHz,DMSO-d6)δ(ppm): 177.7, 164.6, 160.8, 155.1, 154.7, 148.8, 143.1, 138.8, 133.2, 129.2, 128.3, 125.2, 121.6, 116.0, 111.1, 103.8, 69.9, 56.1, 40.1, 39.8, 28.6. HRMS(ESI)for(M+H)+: calcd: 541.10, found: 541.49。
Embodiment 14
1-（3,5- is double（Trifluoromethyl）Phenyl）-6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）- 4-（4- hydroxy phenyls）- 5,6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (14).
200mg (1mmol) licochalcone As and 221.44mg (1.3mmol) 1- are added in the reactor（3,5- is double（Three Methyl fluoride）Phenyl）Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric heating Set is heated to 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, post layer Analysis, it is de- dry to obtain brown ceramic powder（153.09mg）, total recovery 42.56%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J= 7.52Hz), 7.33(1H, m), 6.95(1H,s), 6.91(2H,s), 6.85(2H,d,J=7.52Hz), 6.41(1H, s), 6.30(1H,q), 5.35(2H,s), 5.00-4.98(2H,m), 3.9(1H,t), 3.83(3H, s), 1.88- 1.63(2H,m), 1.69(6H,s). 13C NMR(75MHz,DMSO-d6)δ(ppm): 177.7, 164.6, 160.8, 155.1, 154.7, 148.8, 140.9, 133.2, 131.6, 129.1, 128.3, 125.4, 121.6, 119.1, 116.0, 111.1, 103.8, 69.9, 56.1, 40.1, 39.8, 28.6. HRMS(ESI)for(M+H)+: calcd: 609.16, found: 609.59。
Embodiment 15
1-（2,4- Dimethoxyphenyls）-6-（4- hydroxyl -2- methoxyl group -5-（2- methyl butyl- 3- alkene -2- bases）Phenyl）-4-（4- Hydroxy phenyl）- 5,6- dihydro-pyrimidins -2（1H）The preparation of-thioketone (15).
200mg (1mmol) licochalcone As and 163.09mg (1.3mmol) 1- are added in the reactor（2,4- diformazans Base phenyl）Thiourea, plus 50ml toluene and 5mLDMF make reaction dissolvent, adds 0.5mL triethylamines as catalyst, electric jacket heating To 100 DEG C, magnetic agitation back flow reaction 6 hours.Thin layer chromatography following response, after reaction terminates, concentrating under reduced pressure, column chromatography takes off It is dry to obtain brown ceramic powder（135.70mg）, total recovery 43.11%.
Brown color crystalline powder solid.1H NMR(400MHz,DMSO-d6,300K):d 7.85(2H,d,J= 7.52Hz), 6.95(1H, s), 6.85(2H,d,J=7.52Hz), 6.41(1H,s), 6.38(1H,m), 6.36(1H, m), 6.33(1H,m), 6.30(1H,q), 5.35(2H,s), 5.00-4.98(2H,m), 3.9(1H, t), 3.83(3H, s), 1.88-1.63(2H,m), 1.69(6H,s). 13C NMR(75MHz, DMSO-d6 ) δ(ppm): 177.7, 170.0, 164.6, 160.8, 158.6, 155.1, 154.7, 148.8, 133.2, 129.1, 128.4, 125.2, 121.6, 119.5, 116.0, 111.1, 106.9, 103.8, 100.7, 70.2, 56.1, 55.8, 40.1, 39.8, 28.6. HRMS(ESI)for(M+H)+: calcd: 533.20, found: 533.65。
Embodiment 16
The anti-tumor activity test of the compounds of this invention
Cytostatic to tumor cell test is carried out to the compound of the present invention, test method is using conventional mtt assay.
Cell strain is selected：Human liver cancer cell (HepG2), human lung carcinoma cell (A-549), gastric carcinoma cells (SGC-7901).Culture Liquid is that DMEM+15%NBS+ is dual anti-.
The preparation of sample liquid：After with DMSO (Merck) dissolvings, add the solution of 100 μm of ol/L that PBS (-) is made into or Uniform suspension, then with PBS (-) dilution of DMSO, ultimate density is respectively 0.1,1,10,20,40,60,80,100 μ mol/L。
The antitumor drug cytosine arabinoside (Ara-C) of listing is made into into reference substance solution with same condition.
Cell culture：Adherent growth tumor cell is incubated at containing 10% inactivation new-born calf serum and penicillin, strepto- Element（Each 1,000,000 U/L）RPMI-1640 in, be placed in 37 DEG C, 5% CO2, cultivate in the CO2 gas incubator of saturated humidity. Cell attachment grows, and passes on per 2~3 days 1 time, pours out culture fluid when passing on first, and PBS is washed 2 times, after pancreatin digestion, adds Fresh culture fluid piping and druming is uniform, adjusts cell to debita spissitudo and moves in new culture bottle, and addition culture fluid is to appropriate.It is right to take Number trophophase cell is used to test.
Mtt assay detects cytoactive and IC50Measure：
Experimental principle：The MTT of yellow can be reduced into water-fast bluish violet Chan Wu formazans by dehydrogenase in living cells mitochondria (MTT formazan), and be deposited in cell, the amount of generation is directly proportional to number of viable cells, and dead cell does not have this work( Energy.DMSO can dissolve bluish violet crystal, and shade is directly proportional to contained amount, therefore the absorbance value determined with microplate reader Cell survival rate can be reflected.
Half-inhibition concentration IC of the compound of table 1 to different tumor cells50（Unit：μmol/L）
Experimental technique：Take the logarithm trophophase cell, digestion, count, the culture of 96 holes is inoculated in the density of 2 × 104/mL 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 is dense Degree processes cell.Experimental group each concentration sets 5 multiple holes, is compared with the culture fluid containing 0.4% DMSO.Medicine effect 48 is little Shi Hou, removes supernatant, and 100 μ l MTT are added per hole（2- (4,5- dimethyl -2- thiazolyls) -3,5- diphenyl -2H- tetrazolium hydrogen bromines Hydrochlorate）(1mg/mL), continue to cultivate 4 hours, abandon supernatant, 100 μ l DMSO are added per hole, vibration is mixed, with microplate reader 570 Mensuration absorbance value at nm, using IC50Software for calculation obtains half-inhibition concentration (IC50)。
Result of the test refers to table 1, wherein, sample refers to the licochalcone A deracil class prepared in corresponding embodiment Derivant, sample number into spectrum correspondence prepares the concrete numbering of compound resulting in embodiment.
Compound 7 and compound 2 show good anti-tumor activity, chemical combination in the 3 kinds of cell strains tested Thing 1 and 11 takes second place, and good anti-tumor activity is also shown in different cell strains.Above test result indicate that, this The activity that bright compound has good anti-tumor activity, particularly part licochalcone A deracil analog derivative exists Anti-tumor activity is better than or is equal to cytosine arabinoside in specific cells strain, can be used for the research of antitumor drug.

Claims (7)

1. general structure（I）Shown compound,
Wherein：R for C1-C4 alkyl, the alkoxyl of C1-C4, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, Nitro；The substituent group is selected from halogen, the alkoxyl of C1-C4, cyano group, trifluoromethyl, phenoxy group.
2. general structure（I）The synthetic method of shown compound, it is characterised in that：It is with licochalcone A, thiourea Raw material, with organic base as catalyst, is synthesized under conditions of toluene or DMF are as reaction dissolvent,
。
3. synthetic method according to claim 2, it is characterised in that comprise the steps,
（1）It is in molar ratio 1 in reactor:1~1:1.5 add licochalcone As and thiourea, add toluene or DMF mix homogeneously, adds organic alkali catalyst triethylamine, 80 DEG C ~ 120 DEG C back flow reaction 3 ~ 8 hours；
（2）By step（1）After the solidliquid mixture concentrating under reduced pressure of reaction system, column chromatography for separation purification is dried to obtain target product Thing.
4. synthetic method according to claim 3, it is characterised in that：Step（1）Described in licochalcone A and thiourea The mol ratio of class compound is 1:1 ~1:1.3.
5. synthetic method according to claim 3, it is characterised in that：Step（1）The reaction temperature is 105 DEG C ~ 115 ℃。
6. application of the compound described in claim 1 in treatment antitumor drug is prepared.
7. apply according to claim 6, it is characterised in that：The tumor is hepatocarcinoma, pulmonary carcinoma or gastric cancer.
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