CN108586361A - Isolonglifolane base dihydro-pyrimidin thioketone and its preparation method and application - Google Patents

Isolonglifolane base dihydro-pyrimidin thioketone and its preparation method and application Download PDF

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CN108586361A
CN108586361A CN201810291217.0A CN201810291217A CN108586361A CN 108586361 A CN108586361 A CN 108586361A CN 201810291217 A CN201810291217 A CN 201810291217A CN 108586361 A CN108586361 A CN 108586361A
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pyrimidin
thioketone
isolonglifolane
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base dihydro
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CN108586361B (en
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杨益琴
马崇慧
王石发
单宇
黄真真
董阜豪
谷文
徐徐
王芸芸
吴陈亮
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Nanjing Forestry University
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Abstract

The invention discloses isolonglifolane base dihydro-pyrimidin thioketones and its preparation method and application.The present invention uses 7 aryl methylene isolonglifolane ketone compounds for raw material, and isolonglifolane base dihydro-pyrimidin thioketone is obtained with thiocarbamide cyclization.External antiproliferative activity of the compound to 231 cells of human breast carcinoma MDA MB, 2 cell of human cervical carcinoma Hela cell and human liver cancer HepG is tested using mtt assay, and cytotoxicity test has been carried out for mouse monokaryon macrophage Raw264.7.The result shows that compound 2l goes out strongest antitumor activity to 231 cells shows of MDA MB, compound 2i goes out strongest antitumor activity to HeLa cells shows, and compound 2g goes out strongest antitumor activity to 2 cells shows of HepG.It can be seen that isolonglifolane base dihydro-pyrimidin thioketone will have good application value as antitumor drug.

Description

Isolonglifolane base dihydro-pyrimidin thioketone and its preparation method and application
Technical field
The invention belongs to Minute Organic Synthesis technical field and technical field of medicine synthesis, and it is phonetic to be related to isolonglifolane base dihydro Pyridine thioketone and its preparation method and application.
Background technology
Pyrimidine heterocyclic structure is widely present in natural products, and such compound has important pharmacological activity, such as has Ca2+ overloading, decompression, α1aAntagonism and anticancer isoreactivity etc..In addition, some isolated are with bioactivity from marine organisms Guanidine alkaloid, also contain pyrimidine parent nucleus, wherein alkaloid in such as Crambine, Batzelladine and Ptilomycalin Batzelladine A and Batzelladine B be for the first time report can inhibit HIV gp-120 and with human immunocyte CD4 The small-molecular-weight natural products of cell combination is expected to become the drug for the treatment of AIDS (AIDS).In thiourea structure Since there are different substituted peptide bonds, not only the anti-microbial property with wide spectrum, also has such as anti-inflammatory, anti-mistake of fabulous bioactivity Quick, antiviral, antibacterial etc..Deracil class drug is the drug for clinically commonly treating hyperthyroidism simultaneously.
Dihydropyrimidinonesand is a kind of important Biginelli's reaction product, because it is with a variety of pharmacological activity, so in medicine Object finds that dihydropyrimidinonesand is also considered as a kind of advantage skeleton with design field.In recent years, dihydropyrimidinonesand receives people Extensive concern and research, the research about dihydropyrimidinone derivative report, and be found that many there is researching value Lead compound provides many important information for drug development.
Invention content
Goal of the invention：For the deficiencies in the prior art, the purpose of the present invention is to provide one kind with antitumor Active isolonglifolane base dihydro-pyrimidin thioketone.Another object of the present invention is to provide isolonglifolane base dihydro is phonetic The preparation method of pyridine thioketone.
Technical solution：In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is：
Isolonglifolane base dihydro-pyrimidin thioketone, structural formula are：
In formula：R is 4- chlorphenyls, 4- bromophenyls, 4- fluorophenyls, 4- aminomethyl phenyls, 4- methoxyphenyls, phenyl, 3- nitre Base phenyl, 4- nitrobenzophenones, 2- pyridyl groups, 2- chlorphenyls, 2- bromophenyls, 2- fluorophenyls, 2- aminomethyl phenyls, 2- methoxybenzenes Base.
Isolonglifolane base dihydro-pyrimidin thioketone, specific name and structural formula are as follows：
Compound 2a：4- (4'- chlorphenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2b：4- (4'- bromophenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2c：4- (4'- fluorophenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2d：4- (4'- aminomethyl phenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2e：4- (4'- methoxyphenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros - 1H-6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2f：4- phenyl -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge are sub- Methylbenzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2g：4- (3'- nitrobenzophenones) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2h：4- (4'- nitrobenzophenones) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2i：4- (2'- pyridyl groups) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2j：4- (2'- chlorphenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2k：4- (2'- bromophenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2l：4- (2 '-fluorophenyl) -6,6,10,10- tetramethyls -3,4,5,6,8,9,10,10a- octahydro -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2m：4- (2 '-aminomethyl phenyl) -6,6,10,10- tetramethyls -3,4,5,6,8,9,10,10a- octahydro -1H- 6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
Compound 2n：4- (2 '-methoxyphenyl) -6,6,10,10- tetramethyls -3,4,5,6,8,9,10,10a- octahydros - 1H-6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones, structural formula are as follows：
The preparation method of isolonglifolane base dihydro-pyrimidin thioketone uses 7- aryl methylenes isolongitolanone to rise Beginning raw material is catalyst with potassium tert-butoxide using ethyl alcohol and the tert-butyl alcohol as solvent, and carrying out cyclization with thiocarbamide obtains isolonglifolane Base dihydro-pyrimidin thioketone.Its reaction equation is as follows：
R is：a：4- chlorphenyls b：4 bromophenyl c：4- fluorophenyls
d：4 aminomethyl phenyl e：4- methoxyphenyls f：Phenyl
g：3- nitrobenzophenones h：4 nitrobenzophenone i：2- pyridyl groups
j：2- chlorphenyls k：2 bromophenyls 1：2 fluorophenyls
m：2- aminomethyl phenyls n：2- methoxyphenyls
The preparation method of isolonglifolane base dihydro-pyrimidin thioketone, specific synthesis step are as follows：
(1) by 7- aryl methylene isolongitolanones, ethyl alcohol, tert-butyl alcohol mixed solvent, thiocarbamide, potassium tert-butoxide sequentially adds instead It answers in device, back flow reaction, it is 60% or more that GC tracing detections, which are reacted to feed stock conversion, and after solvent is steamed, acetic acid second is added Ester dissolves, and then uses distilled water and saturated common salt water washing to neutrality, organic layer uses anhydrous Na again2SO4After dry, filtering, concentration Obtain crude product；
(2) crude product is purified using preparative silica gel plate layer chromatography, obtains isolonglifolane base dihydro-pyrimidin thiones chemical combination Object.
In step (1), the volume ratio of in the mixed solvent ethyl alcohol and the tert-butyl alcohol is 1:3.
Isolonglifolane base dihydro-pyrimidin thioketone application in preparation of anti-tumor drugs.
The tumour cell includes human breast cancer cell MDA-MB-231, human cervical carcinoma cell HeLa and human liver cancer cell HepG-2。
Advantageous effect：Compared with prior art, advantages of the present invention is as follows：
(1) derivative of the isolongitolanone as renewable resource longifolene has resourceful, the low face of price, favorably In industrialized production.
(2) synthesis technology of isolonglifolane base dihydro-pyrimidin thioketone has easy to operate, the recyclable profit of solvent With the advantages that, meet the requirement of sustainable development.
(3) comprehensive utilization for synthesizing expansion China's turpentine oil resource of isolonglifolane base dihydro-pyrimidin thioketone Channel, the terebinthine utility value of raising are of great significance.
It, will since there is isolongitolanone itself preferable bioactivity, the present invention to use aldol condensation and cyclization Dihydro-pyrimidin thioketones active function groups are constructed on isolongitolanone skeleton, and biologically active isolonglifolane base dihydro is developed Pyrimidine thioketone class compound is of great significance.
Specific embodiment
The invention is further illustrated with reference to specific implementation case.
Embodiment 1
(1) preparation of isolonglifolane base dihydro-pyrimidin thioketone
0.01mol intermediate 7- aryl methylene isolongitolanones 1a~1n, 80mL (the 20mL ethyl alcohol+60mL tert-butyl alcohols) is molten Agent, 0.012mol thiocarbamides, 0.02mol potassium tert-butoxides sequentially add three mouthfuls of burnings of the 250mL with thermometer and reflux condensing tube In bottle.Back flow reaction 30h, GC monitoring reaction to feed stock conversion is 60% or more, and after solvent is steamed, it is molten that ethyl acetate is added Then solution uses distilled water and saturated common salt water washing to neutrality, organic layer uses anhydrous Na again2SO4It is obtained after dry, filtering, concentration Crude product.Crude product is purified using preparative silica gel plate layer chromatography, obtains isolonglifolane base dihydro-pyrimidin thioketone 2a ~2n.
(2) the structural characterization data of isolonglifolane base dihydro-pyrimidin thioketone 2a~2n are as follows：
4- (4'- chlorphenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge methylenes Base benzene [simultaneously] quinazoline -2- thioketones (2a)：White solid, yield 65.4%, purity 98.8%, m.p.208.4~209.1 DEG C；1H NMR(400MHz,CDCl3)δ(ppm)：7.32(s,1H),7.30(s,1H),7.27(s,1H),7.19(s,1H),7.17(s, 1H), 6.85 (s, 1H), 4.72 (s, 1H), 2.18 (s, 1H), 1.83 (s, 1H), 1.65 (t, J=10.08Hz, 1H), 1.51 (dd,J1=3.72Hz, J2=3.68Hz, 1H), 1.41 (d, J=9.32Hz, 1H), 1.35 (d, J=12.04Hz, 1H), 1.30 (s, 1H), 1.26~1.20 (m, 2H), 1.14 (s, 3H), 1.13 (s, 3H), 1.01 (d, J=11.84Hz, 1H), 0.89 (s, 3H),0.83(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)：172.96,140.43,134.30,129.26,128.42, 127.43,108.11,60.90,55.65,51.10,50.91,40.37,37.19,36.01,33.98,32.81,26.19, 24.55,24.44,24.05,22.82；HRMS(m/z)：[M+H]+calcd for C23H29ClN2S+H+,401.1818； found,401.1818.
4- (4'- bromophenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge methylenes Base benzene [simultaneously] quinazoline -2- thioketones (2b)：White solid, yield 66.7%, purity 99.0%, m.p.218.2~218.9 DEG C；1H NMR(400MHz,CDCl3)δ(ppm)：7.50(s,1H),7.48(s,1H),7.15(s,1H),7.13(s,1H),6.91(s, 1H),6.77(s,1H),4.72(s,1H),2.20(s,1H),1.85(s,1H),1.52(dd,J1=3.88Hz, J2=3.76Hz, 1H), 1.42 (d, J=9.28Hz, 1H), 1.38~1.32 (m, 2H), 1.26 (d, J=11.72Hz, 2H), 1.22 (s, 1H), 1.16 (s, 3H), 1.15 (s, 3H), 1.04 (d, J=10.32Hz, 1H), 0.91 (s, 3H), 0.84 (s, 3H)；13C NMR (100MHz,CDCl3)δ(ppm)：173.41,141.00,132.34,128.74,127.54,122.65,108.07,61.21, 55.71,51.17,50.99,40.46,37.28,36.07,34.05,32.89,26.25,24.60,24.49,24.11, 22.89；HRMS(m/z)：[M+H]+calcd for C23H29BrN2S+H+,445.1313；found,445.1317.
4- (4'- fluorophenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge methylenes Base benzene [simultaneously] quinazoline -2- thioketones (2c)：White solid, yield 65.8%, purity 98.3%, m.p.168.2~169.0 DEG C；1H NMR(400MHz,CDCl3)δ(ppm)：7.25~7.22 (m, 2H), 7.06 (t, J=8.56Hz, 2H), 6.94 (s, 1H), 6.48 (s, 1H), 4.75 (s, 1H), 2.21 (s, 1H), 1.86 (s, 1H), 1.68 (t, J=11.28Hz, 1H), 1.50 (d, J= 4.0Hz, 1H), 1.44 (s, 1H), 1.37 (d, J=12.0Hz, 1H), 1.32 (s, 1H), 1.28~1.24 (m, 2H), 1.17 (s, 6H), 1.11 (d, J=19.2Hz, 1H), 0.92 (s, 3H), 0.85 (s, 3H)；13C NMR(100MHz,CDCl3)δ(ppm)： 173.23,162.81 (d, J=245.81Hz), 137.85,128.80 (d, J=8.17Hz), 127.39,116.11 (d, J= 21.61Hz),108.37,61.06,55.71,51.16,50.98,40.45,37.24,36.06,34.04,32.86,26.25, 24.60,24.48,24.10,22.87；HRMS(m/z)：[M+H]+calcd for C23H29FN2S+H+,385.2114；found, 385.2112.
4- (4'- aminomethyl phenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge are sub- Methylbenzene [simultaneously] quinazoline -2- thioketones (2d)：White solid, yield 65.4%, purity 97.5%, m.p.205.2~205.8 ℃；1H NMR(400MHz,CDCl3)δ(ppm)：7.14(s,4H),6.9(m,1H),6.86(s,1H),4.70(s,1H),2.32 (s, 3H), 2.19 (s, 1H), 1.83 (s, 1H), 1.66 (t, J=9.80Hz, 1H), 1.54 (dd, J1=3.64Hz, J2= 3.60Hz, 1H), 1.41 (d, J=9.16Hz, 1H), 1.32 (d, J=11.96Hz, 2H), 1.26~1.20 (m, 2H), 1.16 (s, 3H), 1.15 (s, 3H), 1.09 (d, J=9.48Hz, 1H), 0.89 (s, 3H), 0.82 (s, 3H)；13C NMR(100MHz, CDCl3)δ(ppm)：173.19,138.97,138.47,129.82,127.07,108.62,61.60,55.75,51.20, 51.01,40.46,37.23,36.07,34.07,32.87,26.28,24.60,24.49,24.11,22.87,21.32；HRMS (m/z)：[M+H]+calcd for C24H32N2S+H+,381.2364；found,381.2360.
4- (4'- methoxyphenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridges Methylene-benzene [simultaneously] quinazoline -2- thioketones (2e)：White solid, yield 62.5%, purity 98.4%, m.p.197.4~198.0 ℃；1H NMR(400MHz,CDCl3)δ(ppm)：7.17(s,1H),7.15(s,1H),6.92(s,1H),6.86(s,1H),6.84 (s, 2H), 4.69 (s, 1H), 3.78 (s, 3H), 2.18 (s, 1H), 1.83 (s, 1H), 1.66 (t, J=9.72Hz, 1H), 1.53 (dd,J1=3.68Hz, J2=3.68Hz, 1H), 1.41 (d, J=9.28Hz, 1H), 1.34~1.29 (m, 2H), 1.24-1.20 (m,2H),1.15(s,3H),1.14(s,3H),1.10(s,1H),0.89(s,3H),0.82(s,3H)；13C NMR(100MHz, CDCl3)δ(ppm)：172.70,159.67,134.09,128.32,126.95,114.34,108.67,61.03,55.67, 55.36,51.10,50.92,40.37,37.13,35.99,33.98,32.77,26.21,24.55,24.41,24.04, 22.81；HRMS(m/z)：[M+H]+calcd for C24H32N2OS+H+,397.2314；found,397.2310.
4- phenyl -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- endo-methylene group benzene [simultaneously] quinazoline -2- thioketones (2f)：White solid, yield 62.5%, purity 99.4%, m.p.114.8~115.4 DEG C；1H NMR(400MHz,CDCl3)δ(ppm)：7.35 (d, J=6.72Hz, 1H), 7.31 (t, J=6.84Hz, 2H), 7.26 (s, 1H), 7.24 (s, 1H), 6.96 (s, 1H), 6.86 (s, 1H), 4.74 (s, 1H), 2.20 (s, 1H), 1.84 (s, 1H), 1.66 (t, J= 9.80Hz,1H),1.54(dd,J1=3.92Hz, J2=3.92Hz, 1H), 1.41 (d, J=9.6Hz, 1H), 1.33-1.28 (m, 2H), 1.27~1.23 (m, 1H), 1.22-1.18 (m, 1H), 1.16 (s, 3H), 1.15 (s, 3H), 1.12 (d, J=9.6Hz, 1H),0.90(s,3H),0.82(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)：173.11,141.86,129.06, 128.52,127.20,127.11,108.42,61.71,55.71,51.17,50.97,40.44,37.19,36.03,34.01, 32.81,26.23,24.55,24.44,24.03,22.80；HRMS(m/z)：[M+H]+calcd for C23H30N2S+H+, 367.2208；found,367.2203.
4- (3'- nitrobenzophenones) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge are sub- Methylbenzene [simultaneously] quinazoline -2- thioketones (2g)：Yellow solid, yield 85.3%, purity 98.3%, m.p.132.4~133.1 ℃；1H NMR(400MHz,CDCl3)δ(ppm)：7.43 (s, 1H), 7.16 (t, J=7.84Hz, 1H), 6.87 (d, J= 7.72Hz,1H),6.76(s,1H),6.64(dd,J1=1.8Hz, J2=1.8Hz, 1H), 3.77 (s, 2H), 2.81 (dd, J1= 2.84Hz,J2=2.80Hz, 1H), 2.62 (d, J=18.44Hz, 1H), 1.96 (d, J=1.96Hz, 1H), 1.86-1.82 (m, 1H), 1.79 (d, J=11.44Hz, 1H), 1.75 (d, J=4.08Hz, 1H), 1.63 (td, J1=3.72Hz, J2=3.52Hz, 1H), 1.53~1.46 (m, 1H), 1.28 (d, J=9.84Hz, 1H), 1.23 (s, 3H), 1.09~1.05 (m, 1H), 1.04 (s, 3H),0.86(s,3H),0.83(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)：202.87,146.49,137.00, 136.90,135.24,129.21,120.89,117.00,115.54,63.00,55.59,48.10,44.76,41.65, 37.60,31.66,30.29,28.38,26.56,25.73,25.52,24.69,24.10.
4- (4'- nitrobenzophenones) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge are sub- Methylbenzene [simultaneously] quinazoline -2- thioketones (2h)：Yellow solid, yield 89.8%, purity 98.9%, m.p.158.1~158.7 ℃；1H NMR(400MHz,CDCl3)δ(ppm)：7.45(s,1H),7.37(s,1H),7.35(s,1H),6.69(s,1H),6.67 (s, 1H), 3.92 (s, 2H), 2.82 (d, J=16.76Hz, 1H), 2.60 (d, J=15.28Hz, 1H), 1.96 (s, 1H), 1.86 ~1.83 (m, 1H), 1.80~1.77 (m, 1H), 1.75 (d, J=4.12Hz, 1H), 1.63 (dd, J1=3.80Hz, J2= 3.64Hz, 1H), 1.54-1.45 (m, 1H), 1.29 (d, J=9.84Hz, 1H), 1.23 (s, 3H), 1.13-1.08 (m, 1H), 1.07(s,3H),0.86(s,6H)；13C NMR(100MHz,CDCl3)δ(ppm)：202.81,147.36,137.16,132.92, 131.94,126.43,114.72,63.03,55.66,48.26,44.78,42.29,37.69,31.77,30.36,28.54, 26.67,25.93,25.60,24.85,24.31.
4- (2'- pyridyl groups) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge methylenes Base benzene [simultaneously] quinazoline -2- thioketones (2i)：Brown solid, yield 88.5%, purity 99.1%, m.p.75.1~75.9 DEG C；1H NMR(400MHz,CDCl3)δ(ppm)：8.48 (d, J=5.72Hz, 1H), 7.55 (t, J=7.64Hz, 1H), 7.27 (d, J= 7.84Hz, 1H), 7.07 (t, J=5.84Hz, 1H), 6.52 (s, 1H), 3.82 (d, J=13.16Hz, 1H), 3.52 (d, J= 14.28Hz, 1H), 1.92 (s, 1H), 1.83~1.78 (m, 1H), 1.69~1.65 (m, 2H), 1.59 (dd, J1=3.56Hz, J2 =3.48Hz, 1H), 1.50~1.41 (m, 1H), 1.26~1.18 (m, 2H), 1.16 (s, 3H), 1.12 (d, J=11.76Hz, 1H), 1.08 (s, 3H), 0.99 (s, 3H), 0.92 (d, J=26.16Hz, 1H), 0.55 (s, 3H)；13C NMR(100MHz, CDCl3)δ(ppm)：200.10,159.99,156.49,149.19,136.29,135.73,123.99,121.20,61.45, 55.49,48.38,44.58,38.81,38.74,35.05,29.97,28.67,27.16,26.20,25.04,24.59.
4- (2'- chlorphenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge methylenes Base benzene [simultaneously] quinazoline -2- thioketones (2j)：White solid, yield 50.2%, purity 99.5%, m.p.75.8~76.4 DEG C；1H NMR(400MHz,CDCl3)δ(ppm)：7.39-7.34 (m, 2H), 7.31 (t, J=7.52Hz, 1H), 7.26~7.22 (m, 1H), 6.91 (s, 1H), 6.82 (s, 1H), 5.35 (s, 1H), 2.24 (s, 1H), 1.86 (s, 1H), 1.71 (t, J=9.04Hz, 1H),1.62(dd,J1=4.0Hz, J2=3.92Hz, 1H), 1.44 (d, J=10.08Hz, 2H), 1.38 (d, J=16.08Hz, 1H), 1.29~1.23 (m, 2H), 1.18 (s, 3H), 1.17 (s, 3H), 1.14 (d, J=7.36Hz, 1H), 0.93 (s, 3H), 0.86(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)：202.65,137.45,135.09,134.73,133.84, 130.38,129.83,129.46,126.40,63.33,55.93,48.35,44.98,40.87,37.84,32.03,30.61, 28.49,25.79,25.73,24.82,24.19；HRMS(m/z)：[M+H]+calcd for C23H29ClN2S+H+, 401.1818；found,401.1811.
4- (2'- bromophenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge methylenes Base benzene [simultaneously] quinazoline -2- thioketones (2k)：White solid, yield 51.7%, purity 98.0%, m.p.211.3~211.8 DEG C；1H NMR(400MHz,CDCl3)δ(ppm)：7.54 (d, J=7.32Hz, 1H), 7.39 (dd, J1=2.28Hz, J2=2.08Hz, 1H), 7.35 (d, J=6.92Hz, 1H), 7.19~7.15 (m, 1H), 6.92 (s, 1H), 6.72 (s, 1H), 5.34 (s, 1H), 2.24(s,1H),1.87(s,1H),1.62(dd,J1=3.96Hz, J2=3.92Hz, 1H), 1.46~1.37 (m, 3H), 1.34 ~1.23 (m, 3H), 1.19 (s, 3H), 1.17 (s, 3H), 1.15 (s, 1H), 0.93 (s, 3H), 0.86 (s, 3H)；13C NMR (100MHz,CDCl3)δ(ppm)：173.49,139.79,133.32,130.16,129.63,128.78,128.72,123.00, 107.35,60.05,55.80,51.43,50.95,40.26,37.27,36.14,34.04,32.94,26.32,24.58, 24.48,24.18,23.12；HRMS(m/z)：[M+H]+calcd for C23H29BrN2S+H+,445.1313；found, 445.1319.
4- (2'- fluorophenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge methylenes Base benzene [simultaneously] quinazoline -2- thioketones (2l)：White solid, yield 50.5%, purity 98.7%, m.p.104.8~105.4 DEG C；1H NMR(400MHz,CDCl3)δ(ppm)：7.33(dd,J1=1.60Hz, J2=1.52Hz, 1H), 7.30~7.28 (m, 1H), 7.16 (t, J=7.48Hz, 1H), 7.04 (t, J=9.64Hz, 1H), 6.97 (s, 1H), 6.91 (s, 1H), 5.16 (s, 1H), 2.22 (s, 1H), 1.85 (s, 1H), 1.62 (d, J=3.96Hz, 1H), 1.43 (d, J=12.68Hz, 2H), 1.38~1.33 (m, 2H), 1.29~1.22 (m, 2H), 1.16 (s, 6H), 1.10~1.04 (m, 1H), 0.93 (s, 3H), 0.86 (s, 3H)；13C NMR(100MHz,CDCl3)δ(ppm)：173.52,160.05,130.11,128.89,128.49,128.16,125.01, 115.82,106.97,55.71,54.33,51.22,50.92,40.13,37.19,36.03,33.98,32.79,26.22, 24.54,24.41,24.00,22.80；HRMS(m/z)：[M+H]+calcd for C23H29FN2S+H+,385.2114；found, 385.2115.
4- (2'- aminomethyl phenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridge are sub- Methylbenzene [simultaneously] quinazoline -2- thioketones (2m)：White solid, yield 57.4%, purity 99.2%, m.p.101.5~102.4 ℃；1H NMR(400MHz,CDCk3)δ(ppm)：7.25 (s, 1H), 7.21-7.19 (m, 2H), 7.14~7.12 (m, 1H), 6.85 (s, 1H), 6.71 (s, 1H), 5.10 (s, 1H), 2.40 (s, 3H), 2.20 (s, 1H), 1.85 (s, 1H), 1.69 (t, J= 8.60Hz,1H),1.51(dd,J1=3.84Hz, J2=3.80Hz, 1H), 1.42 (d, J=10.8Hz, 1H), 1.37~1.34 (m, 1H), 1.27~1.24 (m, 2H), 1.23 (s, 1H), 1.17 (s, 3H), 1.16 (s, 3H), 1.11 (d, J=6.92Hz, 1H),0.91(s,3H),0.82(s,3H)；13C NMR(100MHz,CDCl3)δ(ppm)：202.80,138.00,136.08, 135.91,135.30,130.26,128.90,128.38,125.52,63.31,55.90,48.35,44.93,40.74, 37.84,32.04,30.65,28.49,25.82,25.69,24.82,23.98,20.12；HRMS(m/z)：[M+H]+calcd for C24H32N2S+H+,381.2364；found,381.2367.
4- (2'- methoxyphenyls) -6,6,10,10- tetramethyl -3,4,5,6,8,9,10,10a- octahydros -1H-6a, 9- bridges Methylene-benzene [simultaneously] quinazoline -2- thioketones (2n):White solid, yield 54.1%, purity 98.2%, m.p.106.8~107.3 ℃；1H NMR(400MHz,CDCl3)δ(ppm)：7.30~7.28 (m, 1H), 7.19 (dd, J1=1.68Hz, J2=1.64Hz, 1H), 6.96 (t, J=7.48Hz, 1H), 6.89 (s, 1H), 6.87 (s, 1H), 6.67 (s, 1H), 5.20 (s, 1H), 3.84 (s, 3H), 2.25 (s, 1H), 1.87 (s, 1H), 1.81~1.72 (m, 3H), 1.51~1.45 (m, 2H), 1.35 (d, J=8.2Hz, 1H), 1.32~1.30 (m, 2H), 1.18 (s, 3H), 1.17 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H)；13C NMR (100MHz,CDCl3)δ(ppm)：173.51,156.96,129.69,129.04,128.52,127.94,121.12,110.83, 106.67,55.89,55.55,55.09,51.74,50.97,40.91,37.19,36.21,34.00,32.97,26.41, 24.64,24.48,24.02,23.29；HRMS(m/z)：[M+H]+calcd for C24H32N2OS+H+,397.2314；found, 397.2317.
Embodiment 2
Isolonglifolane base dihydro-pyrimidin thioketone 2a~2n is to human breast cancer cell MDA-MB-231, human cervical carcinoma The antitumor activity experiment of cell HeLa, human liver cancer cell HepG-2.
(1) cell suspension is made in the cell of logarithmic growth phase, presses the thin of 10000/5000/5000 cells/well respectively Born of the same parents' density is inoculated into 96 orifice plates, and inoculation volume is 100 holes μ L/, at 37 DEG C, 5% CO2Incubator in foster for 24 hours；
(2) compound stock solutions (10mM) are diluted to 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μ with basal medium M, 1.5625 μM, the administration culture solution of 100 μ L various concentrations is added per hole, cultivates 72h.Separately set blank control group and positive control Group Etoposide；
(3) 10 μ L MTT coloring agents are added per hole, continues to cultivate 4h, the wavelength X of microplate reader is set as 570nm, then Measure the absorbance value of solution.Using the absorbance value (OD values) in each hole, the proliferation inhibition rate of cell is calculated:I (%)= (1-OD1/ OD) × 100%.
Wherein：I is the inhibiting rate of cell；OD1For dosing group cell absorbance value (parallel test is averaged three times)；OD For blank control group cell absorbance value (parallel test is averaged three times), finally the proliferation inhibition rate of gained is converted into IC50(concentration of inducing cell apoptosis 50%).
Table 1 is isolonglifolane base dihydro-pyrimidin thioketone 2a~2n to human breast cancer cell MDA-MB-231, people The IC of cervical cancer cell HeLa, human liver cancer cell HepG-2 and mouse monokaryon macrophage Raw264.750。
The antiproliferative activity and cytotoxicity of 1 isolonglifolane base dihydro-pyrimidin three kinds of cancer cells of thioketone pair of table
From table 1 it follows that isolongitolanone dihydro-pyrimidin thione compounds have centainly above-mentioned three kinds of cancer cells Antiproliferative activity, compound 2l goes out strongest antitumor activity, IC to MDA-MB-231 cells shows50Value is 3.12 μM； Compound 3i goes out strongest antitumor activity, IC to HeLa cells shows50Value is 4.04 μM；Compound 2g is to HepG-2 cells Show strongest antitumor activity, IC50Value is 3.65 μM.

Claims (6)

1. isolonglifolane base dihydro-pyrimidin thioketone, which is characterized in that structural formula is：
In formula：R is 4- chlorphenyls, 4- bromophenyls, 4- fluorophenyls, 4- aminomethyl phenyls, 4- methoxyphenyls, phenyl, 3- nitrobenzenes Base, 4- nitrobenzophenones, 2- pyridyl groups, 2- chlorphenyls, 2- bromophenyls, 2- fluorophenyls, 2- aminomethyl phenyls, 2- methoxyphenyls.
2. the preparation method of isolonglifolane base dihydro-pyrimidin thioketone described in claim 1, it is characterised in that：Using 7- aryl methylene isolongitolanones are catalyst with potassium tert-butoxide using ethyl alcohol and the tert-butyl alcohol as solvent for starting material, with thiocarbamide It carries out cyclization and obtains isolonglifolane base dihydro-pyrimidin thioketone.
3. the preparation method of isolonglifolane base dihydro-pyrimidin thioketone according to claim 2, which is characterized in that Include the following steps：
(1) by 7- aryl methylene isolongitolanones, ethyl alcohol, tert-butyl alcohol mixed solvent, thiocarbamide, potassium tert-butoxide sequentially adds reactor In, back flow reaction, it is 60% or more that GC tracing detections, which are reacted to feed stock conversion,；
(2) after steaming solvent, ethyl acetate dissolving is added, then uses distilled water and saturated common salt water washing to neutrality, it is organic Layer uses anhydrous Na again2SO4Crude product is obtained after dry, filtering, concentration；
(3) crude product is purified using preparative silica gel plate layer chromatography, obtains isolonglifolane base dihydro-pyrimidin thioketone.
4. the preparation method of isolonglifolane base dihydro-pyrimidin thioketone according to claim 3, which is characterized in that In step (1), the volume ratio of in the mixed solvent ethyl alcohol and the tert-butyl alcohol is 1:3.
5. isolonglifolane base dihydro-pyrimidin thioketone application in preparation of anti-tumor drugs described in claim 1.
6. application according to claim 5, the tumour cell includes human breast cancer cell MDA-MB-231, people's uterine neck Cancer cell HeLa and human liver cancer cell HepG-2.
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