CN108586361B - Isolongifolane dihydro-pyrimidine thioketone compound and preparation method and application thereof - Google Patents

Isolongifolane dihydro-pyrimidine thioketone compound and preparation method and application thereof Download PDF

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CN108586361B
CN108586361B CN201810291217.0A CN201810291217A CN108586361B CN 108586361 B CN108586361 B CN 108586361B CN 201810291217 A CN201810291217 A CN 201810291217A CN 108586361 B CN108586361 B CN 108586361B
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isolongifolanyl
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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 isolongifolanyl dihydropyrimidinthione compounds, a preparation method and application thereof. The invention adopts 7-arylmethylene isolongifolanone compounds as raw materials, and the isolongifolanone compounds and thiourea undergo cyclization reaction to obtain the isolongifolanone dihydropyrimidinthethione compounds. The in vitro antiproliferative activity of the compound on human breast cancer MDA-MB-231 cells, human cervical carcinoma Hela cells and human liver cancer HepG-2 cells is tested by adopting an MTT method, and cytotoxicity test is carried out on mouse mononuclear macrophage Raw264.7. The results show that compound 2l shows the strongest antitumor activity against MDA-MB-231 cells, compound 2i shows the strongest antitumor activity against HeLa cells, and compound 2g shows the strongest antitumor activity against HepG-2 cells. Therefore, the isolongifolanyl dihydropyrimidinthione compound has good application value as an anti-tumor medicament.

Description

Isolongifolane dihydro-pyrimidine thioketone compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of fine organic synthesis and the technical field of drug synthesis, and relates to isolongifolanyl dihydropyrimidinthione compounds, and a preparation method and application thereof.
Background
Pyrimidine heterocyclic structures widely exist in natural products, and the compounds have important pharmacological activity, such as calcium antagonism, blood pressure reduction and alpha1aAntagonistic and anticancer activities, etc. In addition, some guanidine alkaloids with biological activity separated from marine organisms, such as Crambine, Batziladine and Ptilomycin, also contain pyrimidine parent nucleus, wherein the alkaloids Batziladine A and Batziladine B are natural products with small molecular weight and capable of inhibiting HIV gp-120 and combining with human immune cell CD4 cells for the first timeThe product is expected to be a medicine for treating AIDS. The thiourea compound has a structure with different substituted peptide bonds, so that the thiourea compound not only has broad-spectrum antibacterial performance, but also has excellent biological activity such as inflammation diminishing, antianaphylaxis, antivirus, antibiosis and the like. Meanwhile, the thiourea pyridine medicine is a clinically common medicine for treating hyperthyroidism.
Dihydropyrimidinones are an important class of products of the biginel reaction, and because of their various pharmacological activities, they are also considered as a dominant backbone in the field of drug discovery and design. In recent years, dihydropyrimidinone has received extensive attention and research, and research reports on dihydropyrimidinone derivatives have found many lead compounds with research value, and provide many important information for drug development.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the defects in the prior art, the invention aims to provide isolongifolyl dihydropyrimidinthione compounds with anti-tumor activity. The invention also aims to provide a preparation method of the isolongifolyl dihydropyrimidinthione compound.
The technical scheme is as follows: in order to achieve the purpose of the invention, the invention adopts the technical scheme that:
the isolongifolanyl dihydropyrimidinthione compound has a structural formula as follows:
Figure BDA0001617578120000011
in the formula: r is 4-chlorphenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, phenyl, 3-nitrophenyl, 4-nitrophenyl, 2-pyridyl, 2-chlorphenyl, 2-bromophenyl, 2-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl.
The specific name and structural formula of the isolongifolanyl dihydropyrimidinthione compound are as follows:
compound 2 a: 4- (4' -chlorophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione having the following structural formula:
Figure BDA0001617578120000021
compound 2 b: 4- (4' -bromophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione, having the following structural formula:
Figure BDA0001617578120000022
compound 2 c: 4- (4' -fluorophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione having the following structural formula:
Figure BDA0001617578120000023
compound 2 d: 4- (4' -methylphenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione having the following structural formula:
Figure BDA0001617578120000024
compound 2 e: 4- (4' -methoxyphenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione, having the following structural formula:
Figure BDA0001617578120000025
compound 2 f: 4-phenyl-6, 6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione having the following structural formula:
Figure BDA0001617578120000031
compound 2 g: 4- (3' -nitrophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione, having the following structural formula:
Figure BDA0001617578120000032
compound 2 h: 4- (4' -nitrophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione, having the following structural formula:
Figure BDA0001617578120000033
compound 2 i: 4- (2' -pyridyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione having the following structural formula:
Figure BDA0001617578120000034
compound 2 j: 4- (2' -chlorophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione having the following structural formula:
Figure BDA0001617578120000035
compound 2 k: 4- (2' -bromophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione, having the following structural formula:
Figure BDA0001617578120000041
compound 2 l: 4- (2' -fluorophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione having the following structural formula:
Figure BDA0001617578120000042
compound 2 m: 4- (2' -methylphenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione having the following structural formula:
Figure BDA0001617578120000043
compound 2 n: 4- (2' -methoxyphenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methanobenz [ o ] quinazoline-2-thione, having the following structural formula:
Figure BDA0001617578120000044
the preparation method of the isolongifolane dihydropyrimidinthione compound adopts 7-arylmethylene isolongifolane ketone as a starting material, ethanol and tert-butyl alcohol as solvents, potassium tert-butoxide as a catalyst, and the isolongifolane dihydropyrimidinethione compound is obtained by cyclization reaction with thiourea. The reaction formula is as follows:
Figure BDA0001617578120000045
r is: a: 4-chlorophenyl b: 4 bromophenyl group c: 4-fluorophenyl group
d: 4-methylphenyl e: 4-methoxyphenyl f: phenyl radical
g: 3-nitrophenyl h: 4 nitrophenyl i: 2-pyridyl group
j: 2-chlorophenyl k: 2 bromophenyl group 1: 2 fluorophenyl group
m: 2-methylphenyl n: 2-methoxyphenyl radical
The preparation method of the isolongifolanyl dihydropyrimidinthione compound comprises the following specific synthetic steps:
(1) sequentially adding 7-arylmethylidene isolongifolanone, ethanol, tert-butyl alcohol mixed solvent, thiourea and potassium tert-butoxide into a reactor, carrying out reflux reaction, carrying out GC tracking detection reaction until the conversion rate of the raw material is over 60%, evaporating the solvent, adding ethyl acetate for dissolving, washing with distilled water and saturated salt water to neutrality, and then using anhydrous Na for an organic layer2SO4Drying, filtering and concentrating to obtain a crude product;
(2) and purifying the crude product by preparative silica gel plate chromatography to obtain the isolongifolanyl dihydropyrimidinthethione compound.
In the step (1), the volume ratio of ethanol to tert-butanol in the mixed solvent is 1: 3.
An application of isolongifolyl dihydropyrimidinthione compounds in preparing antitumor drugs.
The tumor cells comprise human breast cancer cells MDA-MB-231, human cervical cancer cells HeLa and human liver cancer cells HepG-2.
Has the advantages that: compared with the prior art, the invention has the following advantages:
(1) isolongifolanone as derivative of longifolene as renewable resource has rich resource, low cost and is favorable for industrial production.
(2) The synthesis process of the isolongifolanyl dihydropyrimidinthione compound has the advantages of simple operation, recyclable solvent and the like, and meets the requirement of sustainable development.
(3) The synthesis of the isolongifolane dihydropyrimidinthione compound has important significance for expanding the comprehensive utilization channel of turpentine resources in China and improving the utilization value of turpentine.
Because the isolongifolanone has better biological activity, the invention adopts aldol condensation and cyclization reaction to construct the dihydropyrimidinthione active functional group on the isolongifolanone skeleton, and has important significance in developing isolongifolanone dihydropyrimidione compounds with biological activity.
Detailed description of the preferred embodiments
The invention is further described below with reference to specific embodiments.
Example 1
(1) Preparation of isolongifolanyl dihydropyrimidethiones compound
0.01mol of intermediate 7-arylmethylidene isolongifolanone 1a to 1n, 80mL (20mL of ethanol +60mL of tert-butyl alcohol) of solvent, 0.012mol of thiourea and 0.02mol of potassium tert-butoxide are added in turn into a 250mL three-necked flask with a thermometer and a reflux condenser. Refluxing for 30h, monitoring reaction by GC until the conversion rate of raw materials is over 60%, evaporating solvent, dissolving with ethyl acetate, washing with distilled water and saturated saline solution to neutrality, and adding anhydrous Na into organic layer2SO4Drying, filtering and concentrating to obtain a crude product. Purifying the crude product by preparative silica gel plate chromatography to obtain the isolongifolyl dihydropyrimidinthethione compounds 2 a-2 n.
(2) The structural characterization data of the isolongifolyl dihydropyrimidinthione compounds 2a to 2n are as follows:
4- (4' -chlorophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 a): white solid, yield 65.4%, purity 98.8%, m.p.208.4-209.1 ℃;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' -bromophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 b): white solid, yield 66.7%, purity 99.0%, m.p.218.2～218.9℃；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' -fluorophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 c): white solid, yield 65.8%, purity 98.3%, m.p.168.2-169.0 ℃;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' -methylphenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 d): 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' -methoxyphenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 e): 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, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 f): white solid, yield of 62.5%, purity of 99.4%, m.p.114.8-115.4 ℃;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' -Nitrophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -amide]Quinazoline-2-thione (2 g): 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' -Nitrophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -amide]Quinazoline-2-thione (2 h): 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) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 i): brown solid with yield of 88.5 percent, purity of 99.1 percent and m.p.75.1-75.9 percent℃；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' -chlorophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 j): white solid, yield 50.2%, purity 99.5%, m.p. 75.8-76.4 ℃;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' -bromophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 k): white solid, yield 51.7%, purity 98.0%, m.p.211.3-211.8 ℃;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' -fluorophenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 l): white solid, yield 50.5%, purity 98.7%, m.p.104.8-105.4 ℃;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' -methylphenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2 m): 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' -methoxyphenyl) -6,6,10, 10-tetramethyl-3, 4,5,6,8,9,10,10 a-octahydro-1H-6 a, 9-methano-benzo [ o ] -, derivatives thereof]Quinazoline-2-thione (2n) is white solid, the yield is 54.1 percent, the purity is 98.2 percent, and the 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.
example 2
The isolongifolane dihydro pyrimidine thioketone compounds 2a to 2n have anti-tumor activity experiments on human breast cancer cells MDA-MB-231, human cervical cancer cells HeLa and human liver cancer cells HepG-2.
(1) Preparing cell suspension from cells in logarithmic growth phase, inoculating to 96-well plate at cell density of 10000/5000/5000 cells/well, inoculating volume of 100 μ L/well, and culturing at 37 deg.C with 5% CO2The incubator is used for tending for 24 hours;
(2) the compound stock solution (10mM) was diluted to 50. mu.M, 25. mu.M, 12.5. mu.M, 6.25. mu.M, 3.125. mu.M, 1.5625. mu.M in a basal medium, and 100. mu.L of each well was added to each well and cultured for 72 hours. Setting a blank control group and a positive control group of etoposide;
(3) mu.L of MTT stain was added to each well, incubation was continued for 4 hours, the wavelength lambda of the microplate reader was set to 570nm, and then the absorbance value of the solution was measured. Using the light absorption value (OD value) of each well, cells were calculatedI (%) ═ 1-OD1/OD)×100％。
Wherein: i is the inhibition rate of the cells; OD1The absorbance value of the drug-added group cells is taken (the average value is taken in three parallel tests); OD is the absorbance value of the blank control group cells (the average value is obtained by three parallel tests), and finally the obtained proliferation inhibition rate is converted into IC50(concentration inducing apoptosis 50%).
Table 1 shows the IC of isolongifolane dihydropyrimidin thione compounds 2 a-2 n for human breast cancer cells MDA-MB-231, human cervical cancer cells HeLa, human liver cancer cells HepG-2 and mouse mononuclear macrophage Raw264.750。
TABLE 1 antiproliferative activity and cytotoxicity of Isolongifolanyl dihydropyrimidethiones on three cancer cells
Figure BDA0001617578120000111
Figure BDA0001617578120000121
As can be seen from Table 1, the isolongifolanone dihydropyrimidinethione compound has certain antiproliferative activity on the three cancer cells, and the compound 2l shows the strongest antitumor activity on MDA-MB-231 cells, and the IC thereof is50The value was 3.12. mu.M; compound 3i showed the strongest antitumor activity against HeLa cells, IC thereof50The value was 4.04. mu.M; compound 2g showed the strongest antitumor activity against HepG-2 cells, IC thereof50The value was 3.65. mu.M.

Claims (5)

1. The isolongifolane dihydro-pyrimidine thioketone compound is characterized in that the structural formula is as follows:
Figure FDA0002911603130000011
in the formula: r is 4-chlorphenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, phenyl, 3-nitrophenyl, 4-nitrophenyl, 2-pyridyl, 2-chlorphenyl, 2-bromophenyl, 2-fluorophenyl, 2-methylphenyl, 2-methoxyphenyl.
2. The method for producing an isolongifolanyl dihydropyrimidinethione compound according to claim 1, wherein: adopting 7-arylmethylene isolongifolanone 1a-1n as a starting material, taking ethanol and tert-butyl alcohol as solvents, taking potassium tert-butoxide as a catalyst, and carrying out cyclization reaction with thiourea to obtain an isolongifolane dihydropyrimidinthione compound; the reaction formula is as follows:
Figure FDA0002911603130000012
r is: a: 4-chlorophenyl b: 4-bromophenyl c: 4-fluorophenyl group
d: 4-methylphenyl e: 4-methoxyphenyl f: phenyl radical
g: 3-nitrophenyl h: 4-nitrophenyl i: 2-pyridyl group
j: 2-chlorophenyl k: 2-bromophenyl l: 2-fluorophenyl group
m: 2-methylphenyl n: 2-methoxyphenyl group.
3. The method for producing an isolongifolanyl dihydropyrimidinethione compound according to claim 2, comprising the steps of:
(1) adding 7-arylmethylidene isolongifolanone 1a-1n, ethanol and tert-butyl alcohol mixed solvent, thiourea and potassium tert-butoxide into a reactor in sequence, carrying out reflux reaction, and carrying out GC tracking detection reaction until the conversion rate of the raw materials is over 60%;
(2) evaporating solvent, dissolving in ethyl acetate, washing with distilled water and saturated saline solution to neutrality, and adding anhydrous Na to organic layer2SO4Drying, filtering and concentrating to obtain a crude product;
(3) and purifying the crude product by preparative silica gel plate chromatography to obtain the isolongifolanyl dihydropyrimidinthethione compound.
4. The method for producing an isolongifolanyl dihydropyrimidinthione compound according to claim 3, wherein in step (1), the volume ratio of ethanol to t-butanol in the mixed solvent is 1: 3.
5. Use of isolongifolanyl dihydropyrimidinethiones according to claim 1 in the manufacture of an anti-tumour medicament; wherein, the tumor cells are human breast cancer cells MDA-MB-231, human cervical cancer cells HeLa and human liver cancer cells HepG-2.
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