CN102285967A - 2-arylmethylmercapto-6-(tetrahydroquinoline-1-methyl)-4-pyrimidone derivatives, and preparation method and use thereof - Google Patents
2-arylmethylmercapto-6-(tetrahydroquinoline-1-methyl)-4-pyrimidone derivatives, and preparation method and use thereof Download PDFInfo
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Abstract
Description
技术领域 technical field
本发明涉及一种衍生物及其制备方法,具体涉及5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物及其制备方法和应用,属于有机化合物合成与医药应用技术领域。 The invention relates to a derivative and a preparation method thereof, in particular to 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl] The invention relates to 3H-pyrimidin-4-one derivatives and their preparation method and application, which belong to the technical field of organic compound synthesis and medical application. the
背景技术 Background technique
艾滋病(AIDS)是由人类免疫缺陷病毒(HIV)引起的传染病,严重影响着人类的生命健康。HIV是一种逆转录病毒,逆转录酶在病毒生命周期中的重要作用使其成为抗病毒治疗的重要靶点。逆转录酶抑制剂分为两类:核苷类逆转录酶抑制剂和非核苷类逆转录酶抑制剂。非核苷类逆转录酶抑制剂(NNRTIs)因具有高效、低毒、高选择性等特点而倍受关注。但是由于耐药毒株的蔓延使该类药物迅速丧失临床效价。因此新型、高效、低毒、广谱抗耐药的NNRTIs的研发是目前抗HIV药物研究的重要方向之一。 AIDS (AIDS) is an infectious disease caused by human immunodeficiency virus (HIV), which seriously affects human life and health. HIV is a retrovirus, and the important role of reverse transcriptase in the viral life cycle makes it an important target for antiviral therapy. There are two classes of reverse transcriptase inhibitors: nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have attracted much attention due to their high efficiency, low toxicity, and high selectivity. However, due to the spread of drug-resistant strains, such drugs rapidly lose their clinical efficacy. Therefore, the research and development of novel, efficient, low-toxicity, and broad-spectrum anti-drug-resistant NNRTIs is one of the important directions of anti-HIV drug research. the
据目前文献报道的有50多类NNRTIs,其中二氢烷氧苄基嘧啶酮(Dihydro-alkylthio-benzyl-oxopyrimidines,DABOs)衍生物是较为典型的一类。DABO类衍生物能够提高分子构象的柔性及在靶点中的位置可适应性,有利于化合物活性的提高。我们总结前人有关DABOs的研究成果,发现2-硫基DABO类似物使抗HIV-1RT活性有了显著提高,成为一类具有开发前景的NNRTIs。目前为止,以S-DABOs嘧啶母环为基本骨架,对其C2-,C3-,C4-,C5-,C6-进行了一系列的结构修饰,已经发现了许多高活性的S-DABOs衍生物,并对其进行了构效关系(SAR)研究。 According to the current literature reports, there are more than 50 types of NNRTIs, among which dihydro-alkylthio-benzyl-oxopyrimidines (DABOs) derivatives are a typical one. DABO derivatives can improve the flexibility of the molecular conformation and the adaptability of the position in the target, which is beneficial to the improvement of the activity of the compound. We summarized previous research results on DABOs and found that 2-thio DABO analogues have significantly improved anti-HIV-1RT activity, and have become a class of NNRTIs with development prospects. So far, with the S-DABOs pyrimidine parent ring as the basic skeleton, a series of structural modifications have been made to its C 2- , C 3- , C 4- , C 5- , and C 6- , and many highly active S-DABOs derivatives, and its structure-activity relationship (SAR) study.
因此,以S-DABOs嘧啶母环为基本骨架,利用先导化合物构效关系的有效信息,对其6位侧链进行结构改造,对发现广谱高效抗HIV药物具有重要意义。 Therefore, using the S-DABOs pyrimidine mother ring as the basic skeleton and using the effective information of the structure-activity relationship of the lead compound to modify the structure of its 6-position side chain is of great significance for the discovery of broad-spectrum and highly effective anti-HIV drugs. the
发明内容 Contents of the invention
本发明旨在提供5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物及其制备方法,本发明还提供上述化合物的用途。 The present invention aims to provide 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-ones Derivatives and preparation methods thereof, the present invention also provides the use of the above compounds. the
本发明的技术方案如下: Technical scheme of the present invention is as follows:
1.5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物 1.5-Alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives
本发明的5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物,结构通式I如下: 5-Alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives of the present invention , the general structural formula I is as follows:
其中, in,
R1为:H、甲基或乙基; R 1 is: H, methyl or ethyl;
R2为:2-溴代苯乙酮、对甲基-2-氯代苯乙酮、对氯-2-氯代苯乙酮、对硝基-2-氯代苯乙酮、对氰基-2-氯代苯乙酮、对甲氧基-2-氯代苯乙酮、对氟-2-氯代苯乙酮、溴苄、对甲基氯苄、对氯氯苄、对硝基氯苄、对氰基氯苄、对甲氧基氯苄或对氟氯苄。 R2 is: 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2-chloroacetophenone, p-cyano -2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, bromobenzyl, p-methylchlorobenzyl, p-chlorobenzyl, p-nitro Benzyl chloride, p-cyanobenzyl chloride, p-methoxybenzyl chloride or p-fluorobenzyl chloride.
优选的,上述通式I化合物是下列之一: Preferably, the above-mentioned general formula I compound is one of the following:
2.5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物的合成路线如下: 2. The synthetic route of 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives as follows:
试剂:(i)K2CO3,甲苯,回流24h,90℃;(ii)15%NaOH,15h;(iii)MgCl2,Et3N,CH3CN,R1CH(CO2Et)(CO2K),N,N-羰基二咪唑,室温搅拌过夜后回流2小时;(iv)硫脲,EtONa,回流6-12小时;(v)取代卤苄和取代α-卤代苯乙酮,碳酸钾(K2CO3),N,N-二甲基甲酰胺(DMF),室温12小时。 Reagents: (i) K 2 CO 3 , toluene, reflux for 24h, 90°C; (ii) 15% NaOH, 15h; (iii) MgCl 2 , Et 3 N, CH 3 CN, R 1 CH(CO 2 Et)( CO 2 K), N, N-carbonyldiimidazole, stirred overnight at room temperature and then refluxed for 2 hours; (iv) thiourea, EtONa, refluxed for 6-12 hours; (v) substituted benzyl halides and substituted α-halogenated acetophenones , potassium carbonate (K 2 CO 3 ), N,N-dimethylformamide (DMF), room temperature for 12 hours.
3.中间体1,2,3,4-四氢喹啉-1-乙酸的制备方法 3. The preparation method of intermediate 1,2,3,4-tetrahydroquinoline-1-acetic acid
将1,2,3,4-四氢喹啉30.37mmol和K2CO3 60.78mmol置于80mL甲苯中,在搅拌条件下滴入溴乙酸乙酯29.94mmol,90℃条件下反应24h,TLC检测反应进行;反应完毕后,将反应液冷却到室温,过滤,减压蒸馏,剩余液体用氯仿萃取三次,并用盐水洗涤;无水硫酸镁干燥后得到油状粗品,体积比为1∶4的乙酸乙酯-石油醚柱层析纯化,得褐色油状纯品。不用纯化直接加入1mol/L的NaOH水溶液中回流12h,冷却后滴入1mol/LHCl,出现褐色沉淀,过滤,干燥得粗品。 Put 30.37mmol of 1,2,3,4-tetrahydroquinoline and 60.78mmol of K 2 CO 3 in 80mL of toluene, add 29.94mmol of ethyl bromoacetate dropwise under stirring condition, react at 90°C for 24h, detect by TLC The reaction was carried out; after the reaction was completed, the reaction solution was cooled to room temperature, filtered, and distilled under reduced pressure, and the remaining liquid was extracted three times with chloroform, and washed with brine; after drying over anhydrous magnesium sulfate, the oily crude product was obtained, and the volume ratio was 1:4 ethyl acetate Purified by ester-petroleum ether column chromatography, the pure product was obtained as a brown oil. Add directly to 1mol/L NaOH aqueous solution without purification and reflux for 12h, drop in 1mol/L HCl after cooling, a brown precipitate appears, filter and dry to obtain the crude product.
1,2,3,4-四氢喹啉-1-乙酸(3),褐色固体,收率46.5%,mp:45-46℃(dec).MS(ESI):m/z192.31(M+1). 1,2,3,4-Tetrahydroquinoline-1-acetic acid (3), brown solid, yield 46.5%, mp: 45-46°C (dec). MS (ESI): m/z192.31 (M +1).
4.β-酮酸酯的制备(4a-c) 4. Preparation of β-ketoesters (4a-c)
将0.5mol的取代丙二酸二乙酯置于800mL无水乙腈中,依次加入0.595mol的无水MgCl2,0.717mol Et3N,室温搅拌2个小时;将0.25mol的1,2,3,4-四氢喹啉-1-乙酸和0.275mol的N,N-羰基二咪唑置于300mL乙腈中反应15分钟,然后将反应混合液倒入取代丙二酸二乙酯,无水MgCl2,Et3N的混合液中;室温搅拌过夜,加热回流2h,TLC跟踪至反应完全;冰浴环境下滴加质量浓度为13%HCl 150mL,滴毕搅拌10min.,分层取有机层蒸干,加入150ml乙酸乙酯;将乙酸乙酯的混合液先用NaHCO3洗三次,每次150ml,再用NaCl溶液洗三次,每次150ml,之后无水MgSO4干燥,减压蒸馏得β酮酸酯(4a-c)的粗品,不经纯化直接用于下一步。 Put 0.5 mol of substituted diethyl malonate in 800 mL of anhydrous acetonitrile, add 0.595 mol of anhydrous MgCl 2 , 0.717 mol of Et 3 N, and stir at room temperature for 2 hours; add 0.25 mol of 1, 2, 3 , 4-tetrahydroquinoline-1-acetic acid and 0.275mol of N,N-carbonyldiimidazole were placed in 300mL acetonitrile for 15 minutes, and then the reaction mixture was poured into substituted diethyl malonate, anhydrous MgCl 2 , Et 3 N mixture; stirred at room temperature overnight, heated to reflux for 2h, followed by TLC until the reaction was complete; 150mL of 13% HCl was added dropwise in an ice-bath environment, stirred for 10min after dropping, and the organic layer was separated and evaporated to dryness , add 150ml ethyl acetate; wash the ethyl acetate mixture three times with NaHCO 3 , 150ml each time, then wash three times with NaCl solution, 150ml each time, then dry with anhydrous MgSO 4 , and distill under reduced pressure to obtain β-keto acid Crude esters (4a-c) were used in the next step without purification.
3-氧-4-(1-(1,2,3,4-四氢喹啉))丁酸乙酯(4a):黄色透明油状物,收率:15.1%,MS(ESI):m/z 262.30(M+1).。 Ethyl 3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4a): yellow transparent oil, yield: 15.1%, MS (ESI): m/ z 262.30(M+1).. the
2-甲基-3-氧-4-(1-(1,2,3,4-四氢喹啉))丁酸乙酯(4b):黄色透明油状物,收率:12.1%,MS(ESI):m/z 276.41(M+1)。 Ethyl 2-methyl-3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4b): yellow transparent oil, yield: 12.1%, MS ( ESI): m/z 276.41 (M+1). the
2-乙基-3-氧-4-(1-(1,2,3,4-四氢喹啉))丁酸乙酯(4c):黄色透明油状物,收率:10.7%,MS(ESI):m/z 290.33(M+1)。 Ethyl 2-ethyl-3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4c): yellow transparent oil, yield: 10.7%, MS ( ESI): m/z 290.33 (M+1). the
5.5-烷基-6-芳基甲基-2-巯基-3H-嘧啶-4-酮的合成 5. Synthesis of 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one
在干燥的反应瓶中,将0.3mol钠分批加入100mL无水乙醇中,待钠溶解冷却,一次性加入硫脲0.225mol,然后加入0.15mol粗产品β-酮酸酯4a-c,将混合物加热回流,TLC跟踪至β-酮酸酯原料点消失后停止加热,冷却后减压蒸出溶剂,将残余物溶解于100mL水中,过滤,用1mol/L的盐酸、冰醋酸调PH=4,有白色沉淀产生;过滤,滤饼用冰乙醇、冰乙醚洗,可得5a-c白色固体;可不经纯化直接用于下一步(约含纯品90%以上)。 In a dry reaction flask, add 0.3 mol of sodium in batches to 100 mL of absolute ethanol, wait for the sodium to dissolve and cool, add 0.225 mol of thiourea at one time, then add 0.15 mol of the crude product β-ketoester 4a-c, and dissolve the mixture Heat to reflux, TLC traces until the β-keto ester raw material point disappears, then stop heating, evaporate the solvent under reduced pressure after cooling, dissolve the residue in 100mL water, filter, adjust the pH to 4 with 1mol/L hydrochloric acid and glacial acetic acid, A white precipitate is produced; filter and wash the filter cake with glacial ethanol and glacial ether to obtain 5a-c white solids; they can be directly used in the next step without purification (about 90% or more of the pure product). the
6-(1,2,3,4-四氢喹啉甲基)-2-巯基-4(3H)嘧啶酮(5a):白色固物,收率:67.1%,mp:238-240℃(dec).1H NMR(DMSO-d6,ppm)δ:12.41(s,1H,N3H),12.37(s,1H,N1H),6.35-6.95(m,4H,quinoline-H),5.41(s,1H,C5-H),4.19(s,2H,NCH2)3.31-3.33(m,2H,quinoline-H2),2.71-2.73(m,2H,quinoline-H4),1.89-1.90(m,2H,quinoline-H3);ESI-MS:m/z 274.09(M+1)。 6-(1,2,3,4-tetrahydroquinolinylmethyl)-2-mercapto-4(3H)pyrimidinone (5a): white solid, yield: 67.1%, mp: 238-240°C ( dec). 1 H NMR (DMSO-d 6 , ppm) δ: 12.41 (s, 1H, N 3 H), 12.37 (s, 1H, N 1 H), 6.35-6.95 (m, 4H, quinoline-H) , 5.41 (s, 1H, C 5 -H), 4.19 (s, 2H, NCH 2 ) 3.31-3.33 (m, 2H, quinoline-H 2 ), 2.71-2.73 (m, 2H, quinoline-H 4 ), 1.89-1.90 (m, 2H, quinoline- H3 ); ESI-MS: m/z 274.09 (M+1).
6-(1,2,3,4-四氢喹啉甲基)-2-巯基-5-甲基-4(3H)嘧啶酮(5b):白色固物,收率:70.3%,mp:227-228℃(dec).1H NMR(DMSO-d6,ppm)δ:12.01(s,1H,N3H),11.99(s,1H,N1H),6.57-6.99(m,4H,quinoline-H),5.41(s,1H,C5-H),4.21(s,2H,NCH2)3.15-3.17(m,2H,quinoline-H2),2.68-2.70(m,2H,quinoline-H4),1.86-1.88(m,2H,quinoline-H3),1.79(s,3H,C5-CH3).ESI-MS:m/z 288.11(M+1).C15H17N3OS(287.38)。 6-(1,2,3,4-tetrahydroquinolinylmethyl)-2-mercapto-5-methyl-4(3H)pyrimidinone (5b): white solid, yield: 70.3%, mp: 227-228°C (dec). 1 H NMR (DMSO-d 6 , ppm) δ: 12.01 (s, 1H, N 3 H), 11.99 (s, 1H, N 1 H), 6.57-6.99 (m, 4H , quinoline-H), 5.41 (s, 1H, C 5 -H), 4.21 (s, 2H, NCH 2 ) 3.15-3.17 (m, 2H, quinoline-H 2 ), 2.68-2.70 (m, 2H, quinoline -H 4 ), 1.86-1.88 (m, 2H, quinoline-H 3 ), 1.79 (s, 3H, C 5 -CH 3 ). ESI-MS: m/z 288.11 (M+1). C 15 H 17 N 3 OS (287.38).
6-(1,2,3,4-四氢喹啉甲基)-2-巯基-5-乙基-4(3H)嘧啶酮(5c):白色固物,收率:69.7%,mp:210-211℃(dec).1H NMR(DMSO-d6,ppm)δ:12.03(s,1H,N3H),12.01(s,1H,N1H),6.45-6.97(m,4H,quinoline-H),4.20(s,2H,NCH2)3.30-3.37(m,2H,quinoline-H2),2.37-2.45(m,2H,quinoline-H4),2.28-2.31(q,2H,J=7.2Hz,C5-CH2CH3),1.68-1.79(m,2H,quinoline-H3),1.79(s,3H,C5-CH3),1.62-1.71(m,2H,quinolineH3),1.05(t,3H,J=7.2Hz,C5-CH2CH3).ESI-MS:m/z302.12(M+1)。 6-(1,2,3,4-tetrahydroquinolinylmethyl)-2-mercapto-5-ethyl-4(3H)pyrimidinone (5c): white solid, yield: 69.7%, mp: 210-211°C (dec). 1 H NMR (DMSO-d 6 , ppm) δ: 12.03 (s, 1H, N 3 H), 12.01 (s, 1H, N 1 H), 6.45-6.97 (m, 4H , quinoline-H), 4.20 (s, 2H, NCH 2 ) 3.30-3.37 (m, 2H, quinoline-H 2 ), 2.37-2.45 (m, 2H, quinoline-H 4 ), 2.28-2.31 (q, 2H , J=7.2Hz, C 5 -CH 2 CH 3 ), 1.68-1.79 (m, 2H, quinoline-H 3 ), 1.79 (s, 3H, C 5 -CH 3 ), 1.62-1.71 (m, 2H, quinolineH3 ), 1.05 (t, 3H, J=7.2Hz, C5 - CH2CH3 ). ESI-MS: m/z 302.12 (M+1).
6.5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物的制备方法 6. Preparation method of 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives
将上述中间体5-烷基-6-芳基甲基-2-巯基-3H-嘧啶-4-酮,与各个取代卤苄和取代α-卤代苯乙酮进行烃化反应,然后经重结晶纯化得到5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物的衍生物6,所述的取代基选自:2-溴代苯乙酮、对甲基-2-氯代苯乙酮、对氯-2-氯代苯乙酮、对硝基-2-氯代苯乙酮、对氰基-2-氯代苯乙酮、对甲氧基-2-氯代苯乙酮、对氟-2-氯代苯乙酮、溴苄、对甲基氯苄、对氯氯苄、对硝基氯苄、对氰基氯苄、对甲氧基氯苄或对氟氯苄,所得目标化合物6a1-6c14,结构见表1。 The above-mentioned intermediate 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one is subjected to an alkylation reaction with each substituted benzyl halide and substituted α-halogenated acetophenone, and then Purified by crystallization to obtain 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives The derivative 6, the substituent is selected from: 2-bromoacetophenone, p-methyl-2-chloroacetophenone, p-chloro-2-chloroacetophenone, p-nitro-2- Chloroacetophenone, p-cyano-2-chloroacetophenone, p-methoxy-2-chloroacetophenone, p-fluoro-2-chloroacetophenone, bromobenzyl, p-methylchlorobenzyl , p-chlorobenzyl chloride, p-nitrobenzyl chloride, p-cyanobenzyl chloride, p-methoxybenzyl chloride or p-fluorobenzyl chloride, the obtained target compounds 6a1-6c14, the structures are shown in Table 1. the
以下提供优选的操作步骤: The following provides the preferred operation steps:
将5-烷基-6-芳基甲基-2-巯基-3H-嘧啶-4-酮(5a-c)(2mmol)和K2CO3(2.2mmol)置于反应瓶中,加入无水二甲基甲酰胺(DMF),于室温搅拌30min后,加入2.0mmol取代基(取代氯乙酰苯胺或取代氯苄),室温搅拌,TLC跟踪至原料点消失,停止反应;加入冰水,有白色沉淀产生;过滤,用EtOH或EtOH-DMF混合溶剂重结晶得目标化合物;所得目标化合物6a1-6c14(见表1)。 Put 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one (5a-c) (2mmol) and K 2 CO 3 (2.2mmol) in a reaction flask, add anhydrous Dimethylformamide (DMF), after stirring at room temperature for 30min, add 2.0mmol substituents (substituted chloroacetanilide or substituted benzyl chloride), stir at room temperature, TLC tracking until the raw material point disappears, stop the reaction; add ice water, white Precipitation occurred; filtered and recrystallized with EtOH or EtOH-DMF mixed solvent to obtain the target compound; the obtained target compound 6a1-6c14 (see Table 1).
7.5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物药物组合物 7.5-Alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives pharmaceutical composition
一种抗HIV-1药物组合物,含有上述的5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物与药用辅料,制成不同剂型的药物。 An anti-HIV-1 pharmaceutical composition, containing the above-mentioned 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]- 3H-pyrimidin-4-one derivatives and pharmaceutical excipients are used to make medicines in different dosage forms. the
8.5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物应用 8. Application of 5-alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives
本发明的5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物可作为HIV-1非核苷类抑制剂应用。具体地说,作为HIV-1抑制剂用于制备抗艾滋病药物。 5-Alkyl-2-arylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives of the present invention It can be used as an HIV-1 non-nucleoside inhibitor. Specifically, it is used as an HIV-1 inhibitor for the preparation of anti-AIDS drugs. the
本发明在分子模拟的基础上,C2-采用活性基团取代卤苄和取代α-卤代苯乙酮,在C6-侧链引入柔性较强的1,2,3,4-四氢喹啉-1-甲基,以增加抑制剂分子与周围氨基酸残基的疏水和氢键作用,合成了一系列的5-烷基-2-芳基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮类衍生物。该系列化合物具有较高的抗HIV活性,且细胞毒性较低,具有进一步药用开发价值。 In the present invention, on the basis of molecular simulation, C2 - uses active groups to replace halobenzyl and α-halogenated acetophenone, and introduces more flexible 1,2,3,4-tetrahydro in the C6- side chain Quinoline-1-methyl, in order to increase the hydrophobicity and hydrogen bonding between the inhibitor molecule and the surrounding amino acid residues, a series of 5-alkyl-2-arylmethylthio-6-[(1,2 , 3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one derivatives. The series of compounds have high anti-HIV activity and low cytotoxicity, and have further medicinal development value.
具体实施方式: Detailed ways:
下面结合实施例对本发明做进一步说明,所有目标化合物的编号与表1相同。所述百分比数均为质量百分比。 The present invention will be further described below in conjunction with embodiment, and the numbering of all target compounds is identical with table 1. The percentages are all percentages by mass. the
实施例1中间体5-烷基-6-芳甲基-2-巯基-3H-嘧啶-4-酮的合成 The synthesis of embodiment 1 intermediate 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-ketone
中间体1,2,3,4-四氢喹啉-1-乙酸的制备 Preparation of intermediate 1,2,3,4-tetrahydroquinoline-1-acetic acid
将1,2,3,4-四氢喹啉30.37mmol和K2CO3 60.78mmol置于80mL甲苯中,在搅拌条件下滴入溴乙酸乙酯29.94mmol,90℃条件下反应24h,TLC检测反应进行;反应完毕后,将 反应液冷却到室温,过滤,减压蒸馏,剩余液体用氯仿萃取三次,并用盐水洗涤;无水硫酸镁干燥后得到油状粗品,体积比为1∶4的乙酸乙酯-石油醚柱层析纯化,得褐色油状纯品。不用纯化直接加入1mol/L的NaOH水溶液中回流12h,冷却后滴入1mol/LHCl,出现褐色沉淀,过滤,干燥得粗品。 Put 30.37mmol of 1,2,3,4-tetrahydroquinoline and 60.78mmol of K 2 CO 3 in 80mL of toluene, add 29.94mmol of ethyl bromoacetate dropwise under stirring condition, react at 90°C for 24h, detect by TLC The reaction was carried out; after the reaction was completed, the reaction solution was cooled to room temperature, filtered, and distilled under reduced pressure, and the remaining liquid was extracted three times with chloroform, and washed with brine; after drying over anhydrous magnesium sulfate, the oily crude product was obtained, and the volume ratio was 1:4 ethyl acetate Purified by ester-petroleum ether column chromatography, the pure product was obtained as a brown oil. Add directly to 1mol/L NaOH aqueous solution without purification and reflux for 12h, drop in 1mol/L HCl after cooling, a brown precipitate appears, filter and dry to obtain the crude product.
1,2,3,4-四氢喹啉-1-乙酸(3),褐色固体,收率46.5%,mp:45-46℃(dec).MS(ESI):m/z192.31(M+1). 1,2,3,4-Tetrahydroquinoline-1-acetic acid (3), brown solid, yield 46.5%, mp: 45-46°C (dec). MS (ESI): m/z192.31 (M +1).
β-酮酸酯的制备(4a-c) Preparation of β-ketoesters (4a-c)
将0.5mol的取代丙二酸二乙酯置于800mL无水乙腈中,依次加入0.595mol的无水MgCl2,0.717mol Et3N,室温搅拌2个小时;将0.25mol的1,2,3,4-四氢喹啉-1-乙酸和0.275mol的N,N-羰基二咪唑置于300mL乙腈中反应15分钟,然后将反应混合液倒入取代丙二酸二乙酯,无水MgCl2,Et3N的混合液中;室温搅拌过夜,加热回流2h,TLC跟踪至反应完全;冰浴环境下滴加质量浓度为13%HCl 150mL,滴毕搅拌10min.,分层取有机层蒸干,加入150ml乙酸乙酯;将乙酸乙酯的混合液先用NaHCO3洗三次,每次150ml,再用NaCl溶液洗三次,每次150ml,之后无水MgSO4干燥,减压蒸馏得β酮酸酯(4a-c)的粗品,不经纯化直接用于下一步。 Put 0.5 mol of substituted diethyl malonate in 800 mL of anhydrous acetonitrile, add 0.595 mol of anhydrous MgCl 2 , 0.717 mol of Et 3 N, and stir at room temperature for 2 hours; add 0.25 mol of 1, 2, 3 , 4-tetrahydroquinoline-1-acetic acid and 0.275mol of N,N-carbonyldiimidazole were placed in 300mL acetonitrile for 15 minutes, and then the reaction mixture was poured into substituted diethyl malonate, anhydrous MgCl 2 , Et 3 N mixture; stirred at room temperature overnight, heated to reflux for 2h, followed by TLC until the reaction was complete; 150mL of 13% HCl was added dropwise in an ice-bath environment, stirred for 10min after dropping, and the organic layer was separated and evaporated to dryness , add 150ml ethyl acetate; wash the ethyl acetate mixture three times with NaHCO 3 , 150ml each time, then wash three times with NaCl solution, 150ml each time, then dry with anhydrous MgSO 4 , and distill under reduced pressure to obtain β-keto acid Crude esters (4a-c) were used in the next step without purification.
3-氧-4-(1-(1,2,3,4-四氢喹啉))丁酸乙酯(4a):黄色透明油状物,收率:15.1%,MS(ESI):m/z 262.30(M+1)。 Ethyl 3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4a): yellow transparent oil, yield: 15.1%, MS (ESI): m/ z 262.30(M+1). the
2-甲基-3-氧-4-(1-(1,2,3,4-四氢喹啉))丁酸乙酯(4b):黄色透明油状物,收率:12.1%,MS(ESI):m/z 276.41(M+1)。 Ethyl 2-methyl-3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4b): yellow transparent oil, yield: 12.1%, MS ( ESI): m/z 276.41 (M+1). the
2-乙基-3-氧-4-(1-(1,2,3,4-四氢喹啉))丁酸乙酯(4c):黄色透明油状物,收率:10.7%,MS(ESI):m/z 290.33(M+1)。 Ethyl 2-ethyl-3-oxo-4-(1-(1,2,3,4-tetrahydroquinoline))butanoate (4c): yellow transparent oil, yield: 10.7%, MS ( ESI): m/z 290.33 (M+1). the
5-烷基-6-芳甲基-2-巯基-3H-嘧啶-4-酮的合成: Synthesis of 5-alkyl-6-arylmethyl-2-mercapto-3H-pyrimidin-4-one:
将钠(6.9g,0.3mol)分批加入100mL无水乙醇中,待钠溶解冷却,一次性加入硫脲(17.1g,0.225mol),然后加入粗产品β-酮酸酯4a-c(0.15mol),将混合物加热回流,TLC跟踪至β-酮酸酯原料点消失后停止加热,冷却后减压蒸出溶剂,将残余物溶解于水中(100mL),过滤,用1mol/L的盐酸,冰醋酸调PH=4,有白色沉淀产生。过滤,滤饼用冰乙醇、冰乙醚洗,,可得5a-c白色固体。可不经纯化直接用于下一步(约含纯品90%以上)。 Sodium (6.9g, 0.3mol) was added in 100mL of absolute ethanol in batches, and after the sodium was dissolved and cooled, thiourea (17.1g, 0.225mol) was added in one go, and then the crude product β-ketoester 4a-c (0.15 mol), the mixture was heated to reflux, followed by TLC until the β-ketoester raw material point disappeared, and the heating was stopped. After cooling, the solvent was evaporated under reduced pressure, and the residue was dissolved in water (100mL), filtered, and 1mol/L hydrochloric acid was used. Adjust the pH to 4 with glacial acetic acid, and a white precipitate occurs. Filter and wash the filter cake with glacial ethanol and glacial ether to obtain 5a-c white solids. It can be directly used in the next step without purification (about 90% pure product). the
6-[(1,2,3,4-四氢喹啉)-1-甲基]-2-巯基-4(3H)嘧啶酮(5a):白色固物,收率:67.1%,mp:238-240℃(dec).1H NMR(DMSO-d6,ppm)δ:12.41(s,1H,N3H),12.37(s,1H,N1H),6.35-6.95(m,4H,quinoline-H),5.41(s,1H,C5-H),4.19(s,2H,NCH2)3.31-3.33(m,2H,quinoline-H2),2.71-2.73(m,2H,quinoline-H4),1.89-1.90(m,2H,quinoline-H3);ESI-MS:m/z 274.09(M+1)。6-[(1,2,3,4-四氢喹啉)-1-甲基]-2-巯基-5-甲基-4(3H)嘧啶酮(5b):白色固物,收率:70.3%,mp:227-228℃(dec).1H NMR(DMSO-d6,ppm)δ:12.01(s,1H,N3H),11.99(s,1H,N1H),6.57-6.99(m,4H,quinoline-H),5.41(s,1H,C5-H),4.21(s,2H,NCH2)3.15-3.17(m,2H,quinoline-H2),2.68-2.70(m,2H,quinoline-H4),1.86-1.88(m,2H,quinoline-H3),1.79(s,3H,C5-CH3).ESI-MS:m/z 288.11(M+1).C15H17N3OS(287.38)。 6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-2-mercapto-4(3H)pyrimidinone (5a): white solid, yield: 67.1%, mp: 238-240°C (dec). 1 H NMR (DMSO-d 6 , ppm) δ: 12.41 (s, 1H, N 3 H), 12.37 (s, 1H, N 1 H), 6.35-6.95 (m, 4H , quinoline-H), 5.41 (s, 1H, C 5 -H), 4.19 (s, 2H, NCH 2 ) 3.31-3.33 (m, 2H, quinoline-H 2 ), 2.71-2.73 (m, 2H, quinoline -H 4 ), 1.89-1.90 (m, 2H, quinoline-H 3 ); ESI-MS: m/z 274.09 (M+1). 6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-2-mercapto-5-methyl-4(3H)pyrimidinone (5b): white solid, yield: 70.3%, mp: 227-228°C (dec). 1 H NMR (DMSO-d 6 , ppm) δ: 12.01 (s, 1H, N 3 H), 11.99 (s, 1H, N 1 H), 6.57- 6.99 (m, 4H, quinoline-H), 5.41 (s, 1H, C 5 -H), 4.21 (s, 2H, NCH 2 ) 3.15-3.17 (m, 2H, quinoline-H 2 ), 2.68-2.70 ( m, 2H, quinoline-H 4 ), 1.86-1.88 (m, 2H, quinoline-H 3 ), 1.79 (s, 3H, C 5 -CH 3 ). ESI-MS: m/z 288.11 (M+1) .C15H17N3OS ( 287.38 ) .
6-[(1,2,3,4-四氢喹啉)-1-甲基]-2-巯基-5-乙基-4(3H)嘧啶酮(5c):白色固物,收率:69.7%,mp:210-211℃(dec).1H NMR(DMSO-d6,ppm)δ:12.03(s,1H,N3H),12.01(s,1H,N1H),6.45-6.97(m,4H,quinoline-H),4.20(s,2H,NCH2)3.30-3.37(m,2H,quinoline-H2),2.37-2.45(m,2H, quinoline-H4),2.28-2.31(q,2H,J=7.2Hz,C5-CH2CH3),1.68-1.79(m,2H,quinoline-H3),1.79(s,3H,C5-CH3),1.62-1.71(m,2H,quinolineH3),1.05(t,3H,J=7.2Hz,C5-CH2CH3).ESI-MS:m/z302.12(M+1)。 6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-2-mercapto-5-ethyl-4(3H)pyrimidinone (5c): white solid, yield: 69.7%, mp: 210-211°C (dec). 1 H NMR (DMSO-d 6 , ppm) δ: 12.03 (s, 1H, N 3 H), 12.01 (s, 1H, N 1 H), 6.45- 6.97(m, 4H, quinoline-H), 4.20(s, 2H, NCH 2 ) 3.30-3.37(m, 2H, quinoline-H 2 ), 2.37-2.45(m, 2H, quinoline-H 4 ), 2.28- 2.31 (q, 2H, J=7.2Hz, C 5 -CH 2 CH 3 ), 1.68-1.79 (m, 2H, quinoline-H 3 ), 1.79 (s, 3H, C 5 -CH 3 ), 1.62-1.71 (m, 2H, quinolineH3 ), 1.05 (t, 3H, J=7.2Hz, C5 - CH2CH3 ). ESI-MS: m/z 302.12 (M+1).
实施例22-苯羰基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a1) Example 22-Benzylcarbonylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a1)
将6-芳甲基-2-巯基-3H-嘧啶-4-酮(5a)(2mmol)和K2CO3(2.2mmol)置于反应瓶中,加入无水DMF,于室温搅拌30min后,加入取代基2-溴代苯乙酮(2.0mmol),室温搅拌,TLC跟踪至原料点消失,停止反应。加入冰水,有白色沉淀产生。过滤,用EtOH或EtOH-DMF混合溶剂重结晶得目标化合物产率:48.6%,mp:160-163℃(dec). Put 6-arylmethyl-2-mercapto-3H-pyrimidin-4-one (5a) (2mmol) and K 2 CO 3 (2.2mmol) in a reaction flask, add anhydrous DMF, and stir at room temperature for 30min, Substituent 2-bromoacetophenone (2.0 mmol) was added, stirred at room temperature, followed by TLC until the starting point disappeared, and the reaction was stopped. Ice water was added, and a white precipitate was formed. Filter and recrystallize with EtOH or EtOH-DMF mixed solvent to obtain the target compound. Yield: 48.6%, mp: 160-163°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.72(s,1H,NH),8.04(d,2H,J=7.8Hz,PhH),7.69(t,1H,J1=7.8Hz,J2=15.6Hz,PhH),7.58(t,2H,J1=7.8Hz,J2=15.6Hz,PhH),6.23-6.86(m,4H,quinoline-H),5.86(s,1H,C5-H),4.77(s,2H,SCH2),3.99(s,2H,NCH2),3.24-3.26(m,2H,quinoline-H2),2.61-2.63(m,2H,quinoline-H4),1.75-1.77(m,2H,quinoline-H3).IR(KBr,cm-1)v3315(NH),2945,2846(CH2),1703(C=O),1654(C=O),1598,1575,1541,1499(aryl),1239(C-N),1204(C-N).ESI-MS:m/z 392.47(M+1).C22H21N3O2S(391.49). 1 H NMR (DMSO-d 6 , ppm) δ: 12.72 (s, 1H, NH), 8.04 (d, 2H, J = 7.8 Hz, PhH), 7.69 (t, 1H, J1 = 7.8 Hz, J 2 = 15.6Hz, PhH), 7.58(t, 2H, J1 =7.8Hz, J2 =15.6Hz, PhH), 6.23-6.86(m, 4H, quinoline-H), 5.86(s, 1H, C5 -H ), 4.77 (s, 2H, SCH 2 ), 3.99 (s, 2H, NCH 2 ), 3.24-3.26 (m, 2H, quinoline-H 2 ), 2.61-2.63 (m, 2H, quinoline-H 4 ), 1.75-1.77 (m, 2H, quinoline-H 3 ).IR (KBr, cm -1 ) v3315 (NH), 2945, 2846 (CH 2 ), 1703 (C=O), 1654 (C=O), 1598 , 1575, 1541, 1499 (aryl), 1239 (CN), 1204 (CN). ESI-MS: m/z 392.47 (M+1). C 22 H 21 N 3 O 2 S (391.49).
实施例32-[(4-甲基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a2) Example 32-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a2)
制备方法同实施例2,所不同的是取代基为对甲基-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the substituent is p-methyl-2-chloroacetophenone. the
所得产品2-[(4-甲基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a2)产率54.1%,mp:165-166℃(dec). The resulting product 2-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a2) Yield 54.1%, mp: 165-166°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.68(s,1H,NH),7.93(d,2H,J=7.8Hz,PhH),7.36(d,2H,J=7.8Hz,PhH),6.24-6.87(m,4H,quinoline-H),5.87(s,1H,C5-H),4.74(s,2H,SCH2),4.02(s,2H,NCH2),3.26-3.31(m,2H,quinoline-H2),2.71-2.73(m,2H,quinoline-H4),2.39(s,3H,PhCH3),1.76-1.78(m,2H,quinoline-H3).IR(KBr,cm-1)v 3421(NH),2927,2841(CH3,CH2),1675(C=O),1655(C=O),1602,1538,1506,1459(aryl),1315(C-N),1200(C-N).ESI-MS:m/z 406.47(M+1).C23H23N3O2S(405.51). 1 H NMR (DMSO-d 6 , ppm) δ: 12.68 (s, 1H, NH), 7.93 (d, 2H, J=7.8Hz, PhH), 7.36 (d, 2H, J=7.8Hz, PhH), 6.24-6.87 (m, 4H, quinoline-H), 5.87 (s, 1H, C 5 -H), 4.74 (s, 2H, SCH 2 ), 4.02 (s, 2H, NCH 2 ), 3.26-3.31 (m , 2H, quinoline-H 2 ), 2.71-2.73 (m, 2H, quinoline-H 4 ), 2.39 (s, 3H, PhCH 3 ), 1.76-1.78 (m, 2H, quinoline-H 3 ).IR(KBr , cm -1 )v 3421(NH), 2927, 2841(CH 3 , CH 2 ), 1675(C=O), 1655(C=O), 1602, 1538, 1506, 1459(aryl), 1315(CN ), 1200 (CN). ESI-MS: m/z 406.47 (M+1). C 23 H 23 N 3 O 2 S (405.51).
实施例42-[(4-氯苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a3) Example 42-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a3)
制备方法同实施例2,所不同的是取代基为对氯-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the substituent is p-chloro-2-chloroacetophenone. the
所得产品2-[(4-氯苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a3)产率37.9%,mp:193-195℃(dec). The resulting product 2-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a3) Yield 37.9%, mp: 193-195°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.79(s,1H,NH),8.05(d,2H,J=8.4Hz,PhH),7.64(d,2H,J=8.4Hz,PhH),6.22-6.86(m,4H,quinoline-H),5.87(s,1H,C5-H),4.75(s,2H,SCH2),3.99(s,2H,NCH2),3.25-3.33(m,2H,quinoline-H2),2.62-2.64(m,2H,quinoline-H4),1.76-1.78(m,2H,quinoline-H3).IR(KBr,cm-1)v 3522(NH),2927,2843(CH2),1690(C=O),1656(C=O),1600,1587,1545,1503(aryl),1310(C-N),1195(C-N).ESI-MS:m/z 426.87(M+1).C22H20ClN3O2S(425.93). 1 H NMR (DMSO-d6, ppm) δ: 12.79 (s, 1H, NH), 8.05 (d, 2H, J=8.4Hz, PhH), 7.64 (d, 2H, J=8.4Hz, PhH), 6.22 -6.86(m, 4H, quinoline-H), 5.87(s, 1H, C 5 -H), 4.75(s, 2H, SCH 2 ), 3.99(s, 2H, NCH 2 ), 3.25-3.33(m, 2H, quinoline-H 2 ), 2.62-2.64 (m, 2H, quinoline-H 4 ), 1.76-1.78 (m, 2H, quinoline-H 3 ).IR (KBr, cm -1 ) v 3522 (NH), 2927, 2843 (CH2), 1690(C=O), 1656(C=O), 1600, 1587, 1545, 1503(aryl), 1310(CN), 1195(CN).ESI-MS: m/z 426.87(M+1).C 22 H 20 ClN 3 O 2 S(425.93).
实施例52-[(4-硝基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a4) Example 5 2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a4)
制备方法同实施例2,所不同的是取代基为对硝基-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the substituent is p-nitro-2-chloroacetophenone. the
所得产品2-[(4-硝基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a4)产率45.1%,mp:215-216℃(dec). The resulting product 2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a4) yield 45.1%, mp: 215-216°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.37(s,1H,NH),8.27(d,2H,J=8.4Hz,PhH),8.03(d,2H,J=8.4Hz,PhH),6.35-6.95(m,4H,quinoline-H),5.41(s,1H,C5-H),4.65(s,2H,SCH2),4.19(s,2H,NCH2),3.32-3.34(m,2H,quinoline-H2),2.71-2.73(m,2H,quinoline-H4),1.89-1.90(m,2H,quinoline-H3).IR(KBr,cm-1)v 3405(NH),2923,2856(CH2),1703(C=O),1640(C=O),1579,1508,1458(aryl),1308(C-N),1185(C-N).ESI-MS:m/z 437.51(M+1).C22H20N4O4S(436.48). 1 H NMR (DMSO-d 6 , ppm) δ: 12.37 (s, 1H, NH), 8.27 (d, 2H, J=8.4Hz, PhH), 8.03 (d, 2H, J=8.4Hz, PhH), 6.35-6.95 (m, 4H, quinoline-H), 5.41 (s, 1H, C 5 -H), 4.65 (s, 2H, SCH 2 ), 4.19 (s, 2H, NCH 2 ), 3.32-3.34 (m , 2H, quinoline-H 2 ), 2.71-2.73 (m, 2H, quinoline-H 4 ), 1.89-1.90 (m, 2H, quinoline-H 3 ).IR (KBr, cm -1 ) v 3405 (NH) , 2923, 2856(CH 2 ), 1703(C=O), 1640(C=O), 1579, 1508, 1458(aryl), 1308(CN), 1185(CN).ESI-MS: m/z 437.51 (M+1).C 22 H 20 N 4 O 4 S (436.48).
实施例62-[(4-氰基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a5) Example 62-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a5)
制备方法同实施例2,所不同的是取代基为对氰基-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the substituent is p-cyano-2-chloroacetophenone. the
所得产品2-[(4-氰基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a5)产率43.3%,mp:174-175℃(dec). The resulting product 2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a5) yield 43.3%, mp: 174-175°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.73(s,1H,NH),7.67-7.98(m,4H,PhH),6.73-7.01(m,4H,quinoline-H),5.41(s,1H,C5-H),4.66(s,2H,SCH2),4.12(s,2H,NCH2),3.27-3.31(m,2H,quinoline-H2),2.41-2.53(m,2H,quinoline-H4),1.79-1.90(m,2H,quinoline-H3).IR(KBr,cm-1)v3391(NH),2925,2848(CH2),2229(C≡N),1662(C=O),1601(C=O),1581,1504,1458(aryl),1272(C-N),1198(C-N).ESI-MS:m/z 417.52(M+1).C23H20N4O2S(416.50). 1 H NMR (DMSO-d 6 , ppm) δ: 12.73 (s, 1H, NH), 7.67-7.98 (m, 4H, PhH), 6.73-7.01 (m, 4H, quinoline-H), 5.41 (s, 1H, C 5 -H), 4.66 (s, 2H, SCH 2 ), 4.12 (s, 2H, NCH 2 ), 3.27-3.31 (m, 2H, quinoline-H 2 ), 2.41-2.53 (m, 2H, quinoline-H 4 ), 1.79-1.90 (m, 2H, quinoline-H 3 ). IR (KBr, cm -1 ) v3391 (NH), 2925, 2848 (CH 2 ), 2229 (C≡N), 1662 ( C=O), 1601(C=O), 1581, 1504, 1458(aryl), 1272(CN), 1198( CN ).ESI-MS: m/z 417.52(M+1) .C23H20N 4 O 2 S (416.50).
实施例72-[(4-氰基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a6) Example 72-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a6)
制备方法同实施例2,所不同的是取代基为对氰基-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the substituent is p-cyano-2-chloroacetophenone. the
所得产品2-[(4-氰基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a6)产率39.1%,mp:163-165℃(dec). The resulting product 2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a6) Yield 39.1%, mp: 163-165°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.72(s,1H,NH),8.02(d,2H,J=8.4Hz,PhH),7.07(d,2H,J=8.4Hz,PhH),6.28-6.87(m,4H,quinoline-H),5.82(s,1H,C5-H),4.69(s,2H,SCH2),4.03(s,2H,NCH2),3.85(s,3H,PhOCH3).3.28-3.38(m,2H,quinoline-H2),2.63-2.65(m,2H,quinoline-H4),1.78-1.80(m,2H,quinoline-H3).1R(KBr,cm-1)v 3416(NH),2931,2838(CH3,CH2),1656(C=O),1610(C=O),1599,1574,1535,1507(aryl),1259(C-N),1172(C-N).ESI-MS:m/z 422.54(M+1).C23H23N3O3S(421.51). 1 H NMR (DMSO-d 6 , ppm) δ: 12.72 (s, 1H, NH), 8.02 (d, 2H, J=8.4Hz, PhH), 7.07 (d, 2H, J=8.4Hz, PhH), 6.28-6.87 (m, 4H, quinoline-H), 5.82 (s, 1H, C 5 -H), 4.69 (s, 2H, SCH 2 ), 4.03 (s, 2H, NCH 2 ), 3.85 (s, 3H , PhOCH3).3.28-3.38(m, 2H, quinoline-H 2 ), 2.63-2.65(m, 2H, quinoline-H 4 ), 1.78-1.80(m, 2H, quinoline-H 3 ).1R(KBr, cm -1 )v 3416(NH), 2931, 2838(CH 3 , CH 2 ), 1656(C=O), 1610(C=O), 1599, 1574, 1535, 1507(aryl), 1259(CN) , 1172 (CN). ESI-MS: m/z 422.54 (M+1). C 23 H 23 N 3 O 3 S (421.51).
实施例82-[(4-氟苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a7) Example 8 2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a7)
制备方法同实施例2,所不同的是取代基为对氟-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the substituent is p-fluoro-2-chloroacetophenone. the
所得产品2-[(4-氟苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a7)产率47.1%,mp:180-181℃(dec). The resulting product 2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a7) Yield 47.1%, mp: 180-181°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.73(s,1H,NH),8.10-8.13(m,2H,PhH),7.37-7.40(m,2H,PhH),6.23-6.86(m,4H,quinoline-H),5.85(s,1H,C5-H),4.74(s,2H,SCH2),4.19(s,2H,NCH2)3.26-3.33(m,2H,quinoline-H2),2.62-2.64(m,2H,quinoline-H4),1.77-1.81(m,2H,quinoline-H3).IR(KBr,cm-1)v 3318(NH),2940,2852(CH2),1702(C=O),1655(C=O),1597,1575,1539,1502(aryl),1220(C-N),1154(C-N).ESI-MS:m/z 410.49(M+1).C22H20FN3O2S(409.48). 1 H NMR (DMSO-d 6 , ppm) δ: 12.73 (s, 1H, NH), 8.10-8.13 (m, 2H, PhH), 7.37-7.40 (m, 2H, PhH), 6.23-6.86 (m, 4H, quinoline-H), 5.85 (s, 1H, C 5 -H), 4.74 (s, 2H, SCH 2 ), 4.19 (s, 2H, NCH 2 ) 3.26-3.33 (m, 2H, quinoline-H 2 ), 2.62-2.64 (m, 2H, quinoline-H 4 ), 1.77-1.81 (m, 2H, quinoline-H 3 ). IR (KBr, cm -1 ) v 3318 (NH), 2940, 2852 (CH 2 ), 1702(C=O), 1655(C=O), 1597, 1575, 1539, 1502(aryl), 1220(CN), 1154(CN).ESI-MS: m/z 410.49(M+1) .C 22 H 20 FN 3 O 2 S (409.48).
实施例92-苯基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a8) Example 92-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a8)
制备方法同实施例2,所不同的是取代基为溴苄。 The preparation method is the same as in Example 2, except that the substituent is benzyl bromide. the
所得产品2-苯基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a8)产率49.6%,mp:200-203℃(dec). The resulting product 2-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a8) yield 49.6%, mp :200-203℃(dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.70(s,1H,NH),7.39(d,2H,J=7.2Hz,PhH),7.30(t,1H,J1=7.2Hz,J2=14.4Hz,PhH),7.26(t,2H,J1=7.2Hz,J2=14.4Hz,,PhH),6.35-6.90(m,4H,quinoline-H),5.84(s,1H,C5-H),4.38(s,2H,SCH2),4.29(s,2H,NCH2),3.42-3.44(m,2H,quinoline-H2),2.70-2.72(m,2H,quinoline-H4),1.90-1.92(m,2H,quinoline-H3).IR(KBr,cm-1)v3426(NH),2928,2844(CH2),1656(C=O),1602,1574,1547,1508(aryl),1310(C-N),1246(C-N).ESI-MS:m/z 364.57(M+1).C21H21N3OS(363.48). 1 H NMR (DMSO-d 6 , ppm) δ: 12.70 (s, 1H, NH), 7.39 (d, 2H, J = 7.2 Hz, PhH), 7.30 (t, 1H, J 1 = 7.2 Hz, J 2 =14.4Hz, PhH), 7.26(t, 2H, J 1 =7.2Hz, J 2 =14.4Hz, ,PhH), 6.35-6.90(m, 4H, quinoline-H), 5.84(s, 1H, C 5 -H), 4.38 (s, 2H, SCH 2 ), 4.29 (s, 2H, NCH 2 ), 3.42-3.44 (m, 2H, quinoline-H 2 ), 2.70-2.72 (m, 2H, quinoline-H 4 ), 1.90-1.92 (m, 2H, quinoline-H 3 ).IR (KBr, cm -1 ) v3426 (NH), 2928, 2844 (CH 2 ), 1656 (C=O), 1602, 1574, 1547, 1508(aryl), 1310(CN), 1246(CN). ESI-MS: m/z 364.57(M+1). C 21 H 21 N 3 OS (363.48).
实施例102-[(4-甲基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a9) Example 10 2-[(4-methylphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a9)
制备方法同实施例2,所不同的是取代基为对甲基氯苄。 The preparation method is the same as in Example 2, except that the substituent is p-methyl benzyl chloride. the
所得产品2-[(4-甲基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a9)产率53.2%,mp:185-186℃(dec). Gained product 2-[(4-methylphenyl) methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a9) Yield 53.2%, mp: 185-186°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.60(s,1H,NH),7.27(d,2H,J=7.8Hz,PhH),7.10(d,2H,J=7.8Hz,PhH),6.34-6.91(m,4H,quinoline-H),5.89(s,1H,C5-H),4.33(s,2H,SCH2),4.28(s,2H,NCH2),3.41-3.44(m,2H,quinoline-H2),2.70-2.73(m,2H,quinoline-H4),2.27(s,3H,PhCH3),1.90-1.91(m,2H,quinoline-H3).IR(KBr,cm-1)v 3418(NH),2921,2849(CH3,CH2),1651(C=O),1602,1579,1534,1508(aryl),1310(C-N),1194(C-N).ESI-MS:m/z 378.57(M+1).C22H23N3OS(377.50). 1 H NMR (DMSO-d 6 , ppm) δ: 12.60 (s, 1H, NH), 7.27 (d, 2H, J=7.8Hz, PhH), 7.10 (d, 2H, J=7.8Hz, PhH), 6.34-6.91 (m, 4H, quinoline-H), 5.89 (s, 1H, C 5 -H), 4.33 (s, 2H, SCH 2 ), 4.28 (s, 2H, NCH 2 ), 3.41-3.44 (m , 2H, quinoline-H 2 ), 2.70-2.73 (m, 2H, quinoline-H 4 ), 2.27 (s, 3H, PhCH 3 ), 1.90-1.91 (m, 2H, quinoline-H 3 ).IR(KBr , cm -1 )v 3418(NH), 2921, 2849(CH 3 , CH 2 ), 1651(C=O), 1602, 1579, 1534, 1508(aryl), 1310(CN), 1194(CN). ESI-MS: m/z 378.57 (M+1). C 22 H 23 N 3 OS (377.50).
实施例112-[(4-氯苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a10) Example 11 2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a10 )
制备方法同实施例2,所不同的是取代基为对氯氯苄。 The preparation method is the same as in Example 2, except that the substituent is p-chlorobenzyl chloride. the
所得产品2-[(4-氯苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a10)产率57.9%,mp:190-193℃(dec). The resulting product 2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a10 ) yield 57.9%, mp: 190-193°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.65(s,1H,NH),7.41(d,2H,J=8.4Hz,PhH),7.33(d,2H,J=8.4Hz,PhH),6.33-6.90(m,4H,quinoline-H),5.90(s,1H,C5-H),4.36(s,2H,SCH2),4.28(s,2H,NCH2),3.41-3.44(m,2H,quinoline-H2),2.70-2.72(m,2H,quinoline-H4),1.88-1.92(m,2H,quinoline-H3).IR(KBr,cm-1)v 3413(NH),2921,2850(CH2),1648(C=O),1602,1581,1535(aryl),1310(C-N),1194(C-N).ESI-MS:m/z 398.74(M+1).C21H20ClN3OS(397.92). 1 H NMR (DMSO-d 6 , ppm) δ: 12.65 (s, 1H, NH), 7.41 (d, 2H, J=8.4Hz, PhH), 7.33 (d, 2H, J=8.4Hz, PhH), 6.33-6.90 (m, 4H, quinoline-H), 5.90 (s, 1H, C 5 -H), 4.36 (s, 2H, SCH 2 ), 4.28 (s, 2H, NCH 2 ), 3.41-3.44 (m , 2H, quinoline-H 2 ), 2.70-2.72 (m, 2H, quinoline-H 4 ), 1.88-1.92 (m, 2H, quinoline-H 3 ).IR (KBr, cm -1 ) v 3413 (NH) , 2921, 2850 (CH 2 ), 1648 (C=O), 1602, 1581, 1535 (aryl), 1310 (CN), 1194 (CN). ESI-MS: m/z 398.74 (M+1).C 21 H 20 ClN 3 OS(397.92).
实施例122-[(4-硝基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a11) Example 12 2-[(4-nitrophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a11)
制备方法同实施例2,所不同的是取代基为对硝基氯苄。 The preparation method is the same as in Example 2, except that the substituent is p-nitrobenzyl chloride. the
所得产品2-[(4-硝基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a11)产率51.5%,mp:180-182℃(dec). The resulting product 2-[(4-nitrophenyl) methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a11) Yield 51.5%, mp: 180-182°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.70(s,1H,NH),8.13(d,2H,J=8.4Hz,PhH),7.66(d,2H,J=8.4Hz,PhH),6.30-6.89(m,4H,quinoline-H),5.90(s,1H,C5-H),4.47(s,2H,SCH2),4.28(s, 2H,NCH2),3.39-3.43(m,2H,quinoline-H2),2.68-2.71(m,2H,quinoline-H4),1.87-1.91(m,2H,quinoline-H3).IR(KBr,cm-1)v 3370(NH),2930,2841(CH2),1660(C=O),1600,1583,1518(aryl),1310(C-N),1240(C-N).ESI-MS:m/z 409.51(M+1).C21H20N4O3S(408.47). 1 H NMR (DMSO-d 6 , ppm) δ: 12.70 (s, 1H, NH), 8.13 (d, 2H, J=8.4Hz, PhH), 7.66 (d, 2H, J=8.4Hz, PhH), 6.30-6.89 (m, 4H, quinoline-H), 5.90 (s, 1H, C 5 -H), 4.47 (s, 2H, SCH 2 ), 4.28 (s, 2H, NCH 2 ), 3.39-3.43 (m , 2H, quinoline-H 2 ), 2.68-2.71 (m, 2H, quinoline-H 4 ), 1.87-1.91 (m, 2H, quinoline-H 3 ).IR (KBr, cm -1 ) v 3370 (NH) , 2930, 2841(CH 2 ), 1660(C=O), 1600, 1583, 1518(aryl), 1310(CN), 1240(CN).ESI-MS: m/z 409.51(M+1).C 21 H 20 N 4 O 3 S (408.47).
实施例132-[(4-氰基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a12) Example 13 2-[(4-cyanophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a12)
制备方法同实施例2,所不同的是取代基为对氰基氯苄。 The preparation method is the same as in Example 2, except that the substituent is p-cyanobenzyl chloride. the
所得产品2-[(4-氰基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a12)产率54.0%,mp:186-188℃(dec). Gained product 2-[(4-cyanophenyl) methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one ( 6a12) Yield 54.0%, mp: 186-188°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.71(s,1H,NH),7.73(d,2H,J=7.8Hz,PhH),7.59(d,2H,J=7.8Hz,PhH),6.30-6.90(m,4H,quinoline-H),5.90(s,1H,C5-H),4.43(s,2H,SCH2),4.27(s,2H,NCH2),3.38-3.40(m,2H,quinoline-H2),2.69-2.71(m,2H,quinoline-H4),1.87-1.91(m,2H,quinoline-H3).IR(KBr,cm-1)v 3419(NH),2927,2840(CH2),2227(C≡N),1656(C=O),1601,1581,1533,1504(aryl),1311(C-N),1235(C-N).ESI-MS:m/z 389.52(M+1).C22H20N4OS(388.49). 1 H NMR (DMSO-d 6 , ppm) δ: 12.71 (s, 1H, NH), 7.73 (d, 2H, J=7.8Hz, PhH), 7.59 (d, 2H, J=7.8Hz, PhH), 6.30-6.90 (m, 4H, quinoline-H), 5.90 (s, 1H, C 5 -H), 4.43 (s, 2H, SCH 2 ), 4.27 (s, 2H, NCH 2 ), 3.38-3.40 (m , 2H, quinoline-H 2 ), 2.69-2.71 (m, 2H, quinoline-H 4 ), 1.87-1.91 (m, 2H, quinoline-H 3 ).IR (KBr, cm -1 ) v 3419 (NH) , 2927, 2840 (CH 2 ), 2227 (C≡N), 1656 (C=O), 1601, 1581, 1533, 1504 (aryl), 1311 (CN), 1235 (CN).ESI-MS: m/ z 389.52(M+1).C 22 H 20 N 4 OS(388.49).
实施例142-[(4-甲氧基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a13) Example 142-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a13)
制备方法同实施例2,所不同的是取代基为对甲氧基氯苄。 The preparation method is the same as in Example 2, except that the substituent is p-methoxybenzyl chloride. the
所得产品2-[(4-甲氧基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a13)产率48.7%,mp:194-196℃(dec). The resulting product 2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a13) yield 48.7%, mp: 194-196°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.60(s,1H,NH),7.31(d,2H,J=9.0Hz,PhH),6.91(d,2H,J=9.0Hz,PhH),6.35-6.84(m,4H,quinoline-H),5.89(s,1H,C5-H),4.32(s,2H,SCH2),4.29(s,2H,NCH2),3.72(s,3H,PhOCH3),3.42-3.45(m,2H,quinoline-H2),2.70-2.73(m,2H,quinoline-H4),1.89-1.93(m,2H,quinoline-H3).1R(KBr,cm-1)v 3426(NH),2928,2835(CH3,CH2),1649(C=O),1603,1579,1534,1510(aryl),1311(C-N),1246(C-N).ESI-MS:m/z 394.53(M+1).C22H23N3O2S(393.50). 1 H NMR (DMSO-d 6 , ppm) δ: 12.60 (s, 1H, NH), 7.31 (d, 2H, J=9.0Hz, PhH), 6.91 (d, 2H, J=9.0Hz, PhH), 6.35-6.84 (m, 4H, quinoline-H), 5.89 (s, 1H, C 5 -H), 4.32 (s, 2H, SCH 2 ), 4.29 (s, 2H, NCH 2 ), 3.72 (s, 3H , PhOCH3), 3.42-3.45 (m, 2H, quinoline-H 2 ), 2.70-2.73 (m, 2H, quinoline-H 4 ), 1.89-1.93 (m, 2H, quinoline-H 3 ).1R (KBr, cm -1 )v 3426(NH), 2928, 2835(CH 3 , CH2), 1649(C=O), 1603, 1579, 1534, 1510(aryl), 1311(CN), 1246(CN).ESI- MS: m/z 394.53 (M+1). C 22 H 23 N 3 O 2 S (393.50).
实施例152-[(4-氟苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a14) Example 15 2-[(4-fluorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a14 )
制备方法同实施例2,所不同的是取代基为对氟氯苄。 The preparation method is the same as in Example 2, except that the substituent is p-fluorochlorobenzyl. the
所得产品2-[(4-氟苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6a14)产率53.9%,mp:203-205℃(dec). The resulting product 2-[(4-fluorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6a14 ) yield 53.9%, mp: 203-205°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.66(s,1H,NH),7.31(d,2H,J=9.0Hz,PhH),6.91(d,2H,J=9.0Hz,PhH),6.35-6.84(m,4H,quinoline-H),5.89(s,1H,C5-H),4.36(s,2H,SCH2),4.29(s,2H,NCH2),3.41-3.43(m,2H,quinoline-H2),2.70-2.72(m,2H,quinoline-H4),1.90-1.91(m,2H,quinoline-H3).IR(KBr,cm-1)v 3319(NH),2923,2844(CH2),1649(C=O),1600,1577,1545,1508(aryl),1313(C-N),1229(C-N).ESI-MS:m/z 382.49(M+1).C21H20FN3OS(381.47). 1 H NMR (DMSO-d 6 , ppm) δ: 12.66 (s, 1H, NH), 7.31 (d, 2H, J=9.0Hz, PhH), 6.91 (d, 2H, J=9.0Hz, PhH), 6.35-6.84 (m, 4H, quinoline-H), 5.89 (s, 1H, C 5 -H), 4.36 (s, 2H, SCH 2 ), 4.29 (s, 2H, NCH 2 ), 3.41-3.43 (m , 2H, quinoline-H 2 ), 2.70-2.72 (m, 2H, quinoline-H 4 ), 1.90-1.91 (m, 2H, quinoline-H 3 ).IR (KBr, cm -1 ) v 3319 (NH) , 2923, 2844 (CH 2 ), 1649 (C=O), 1600, 1577, 1545, 1508 (aryl), 1313 (CN), 1229 (CN). ESI-MS: m/z 382.49 (M+1) .C 21 H 20 FN 3 OS(381.47).
实施例165-甲基-2-苯羰基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b1) Example 16 5-methyl-2-phenylcarbonylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6b1)
制备方法同实施例2,所不同的是母核为5b,取代基为2-溴代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is 2-bromoacetophenone. the
所得产品5-甲基-2-苯羰基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b1)产率45.4%,mp:188-189℃(dec). The resulting product 5-methyl-2-phenylcarbonylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6b1) Rate 45.4%, mp: 188-189°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.77(s,1H,NH),7.86(d,2H,J=7.8Hz,PhH),7.69(t,1H,J1=7.8Hz,J2=15.6Hz,PhH),7.54(t,2H,J1=7.8Hz,J2=15.6Hz,,PhH),6.29-6.82(m,4H,quinoline-H),4.61(s,2H,SCH2),4.21(s,2H,NCH2),3.16-3.18(m,2H,quinoline-H2),2.43-2.45(m,2H,quinoline-H4),1.95(s,3H,C5CH3),1.60-1.61(m,2H,quinoline-H3).IR(KBr,cm-1)v3420(NH),2922,2842(CH3,CH2),1682(C=O),1637(C=O),1601,1572,1506,1449(aryl),1262(C-N),1194(C-N).ESI-MS:m/z 406.47(M+1).C23H23N3O2S(405.51). 1 H NMR (DMSO-d 6 , ppm) δ: 12.77 (s, 1H, NH), 7.86 (d, 2H, J = 7.8 Hz, PhH), 7.69 (t, 1H, J 1 = 7.8 Hz, J 2 =15.6Hz, PhH), 7.54(t, 2H, J 1 =7.8Hz, J 2 =15.6Hz,, PhH), 6.29-6.82(m, 4H, quinoline-H), 4.61(s, 2H, SCH 2 ), 4.21 (s, 2H, NCH 2 ), 3.16-3.18 (m, 2H, quinoline-H 2 ), 2.43-2.45 (m, 2H, quinoline-H 4 ), 1.95 (s, 3H, C 5 CH 3 ), 1.60-1.61 (m, 2H, quinoline-H 3 ). IR (KBr, cm -1 ) v3420 (NH), 2922, 2842 (CH 3 , CH 2 ), 1682 (C=O), 1637 (C =O), 1601, 1572, 1506, 1449(aryl), 1262(CN), 1194(CN).ESI-MS: m/z 406.47(M+1).C 23 H 23 N 3 O 2 S (405.51 ).
实施例175-甲基-2-[(4-甲基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b2) Example 17 5-methyl-2-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6b2)
制备方法同实施例2,所不同的是母核为5b,取代基为对甲基-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-methyl-2-chloroacetophenone. the
所得产品5-甲基-2-[(4-甲基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b2)产率52.3%,mp:203-204℃(dec). The resulting product 5-methyl-2-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6b2) is 52.3%, mp: 203-204°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.71(s,1H,NH),7.76(d,2H,J=8.4Hz,PhH),7.31(d,2H,J=8.4Hz,PhH),6.31-6.83(m,4H,quinoline-H),4.56(s,2H,SCH2),4.21(s,2H,NCH2),3.16-3.18(m,2H,quinoline-H2),2.39(s,3H,PhCH3),2.47-2.50(m,2H,quinoline-H4),1.95(s,3H,C5-CH3),1.62-1.66(m,2H,quinoline-H3).IR(KBr,cm-1)v 3428(NH),2940,2920,2832(CH3,CH2),1704(C=O),1633(C=O),1603,1571,1550,1505(aryl),1265(C-N),1198(C-N).ESI-MS:m/z 420.74(M+1).C24H25N3O2S(419.54). 1 H NMR (DMSO-d 6 , ppm) δ: 12.71 (s, 1H, NH), 7.76 (d, 2H, J=8.4Hz, PhH), 7.31 (d, 2H, J=8.4Hz, PhH), 6.31-6.83 (m, 4H, quinoline-H), 4.56 (s, 2H, SCH 2 ), 4.21 (s, 2H, NCH 2 ), 3.16-3.18 (m, 2H, quinoline-H 2 ), 2.39 (s , 3H, PhCH3), 2.47-2.50 (m, 2H, quinoline-H 4 ), 1.95 (s, 3H, C 5 -CH 3 ), 1.62-1.66 (m, 2H, quinoline-H 3 ).IR(KBr , cm -1 )v 3428(NH), 2940, 2920, 2832(CH 3 , CH 2 ), 1704(C=O), 1633(C=O), 1603, 1571, 1550, 1505(aryl), 1265 (CN), 1198(CN). ESI-MS: m/z 420.74 (M+1). C 24 H 25 N 3 O 2 S (419.54).
实施例185-甲基-2-[(4-氯苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b3) Example 18 5-methyl-2-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6b3)
制备方法同实施例2,所不同的是母核为5b,取代基为对氯-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-chloro-2-chloroacetophenone. the
所得产品5-甲基-2-[(4-氯苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3h-嘧啶-4-酮(6b3)产率36.7%,mp:187-188℃(dec). The resulting product 5-methyl-2-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3h-pyrimidine -4-ketone (6b3) yield 36.7%, mp: 187-188°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.79(s,1H,NH),7.85(d,2H,J=8.4Hz,PhH),7.58(d,2H,J=8.4Hz,PhH),6.28-6.81(m,4H,quinoline-H),4.58(s,2H,SCH2),4.20(s,2H,NCH2),3.15-3.17(m,2H,quinoline-H2),2.43-2.50(m,2H,quinoline-H4),1.95(s,3H,C5-CH3),1.62-1.68(m,2H,quinoline-H3).IR(KBr,cm-1)v 3434(NH),2929,2842(CH3,CH2),1681(C=O),1637(C=O),1600,1587,1550,1504(aryl),1256(C-N),1193(C-N).ESI-MS:m/z 440.87(M+1).C23H22ClN3O2S(439.96). 1 H NMR (DMSO-d 6 , ppm) δ: 12.79 (s, 1H, NH), 7.85 (d, 2H, J=8.4Hz, PhH), 7.58 (d, 2H, J=8.4Hz, PhH), 6.28-6.81 (m, 4H, quinoline-H), 4.58 (s, 2H, SCH 2 ), 4.20 (s, 2H, NCH 2 ), 3.15-3.17 (m, 2H, quinoline-H 2 ), 2.43-2.50 (m, 2H, quinoline-H 4 ), 1.95 (s, 3H, C 5 -CH 3 ), 1.62-1.68 (m, 2H, quinoline-H 3 ).IR (KBr, cm -1 ) v 3434 (NH ), 2929, 2842 (CH 3 , CH 2 ), 1681 (C=O), 1637 (C=O), 1600, 1587, 1550, 1504 (aryl), 1256 (CN), 1193 (CN).ESI- MS: m/z 440.87 (M+1). C 23 H 22 ClN 3 O 2 S (439.96).
实施例195-甲基-2-[(4-硝基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b4) Example 19 5-methyl-2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6b4)
制备方法同实施例2,所不同的是母核为5b,取代基为对硝基-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-nitro-2-chloroacetophenone. the
所得产品5-甲基-2-[(4-硝基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b4)产率39.1%,mp:189-190℃(dec) The resulting product 5-methyl-2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6b4) is 39.1%, mp: 189-190℃(dec)
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.81(s,1H,NH),8.27(d,2H,J=7.8Hz,PhH),8.09(d,2H,J=7.8Hz,PhH),6.28-6.79(m,4H,quinoline-H),4.65(s,2H,SCH2),4.18(s,2H,NCH2),3.40-3.43(m,2H,quinoline-H2),2.50-2.51(m,2H,quinoline-H4),1.89-1.94(m,2H,quinoline-H3),1.620(s, 3H,C5-CH3).IR(KBr,cm-1)v 3406(NH),2918,2842(CH3,CH2),1696(C=O),1641(C=O),1602,1524,1505,1458(aryl),1344(C-N),1189(C-N).ESI-MS:m/z 451.43(M+1).C23H22N4O4S(450.51). 1 H NMR (DMSO-d 6 , ppm) δ: 12.81 (s, 1H, NH), 8.27 (d, 2H, J=7.8Hz, PhH), 8.09 (d, 2H, J=7.8Hz, PhH), 6.28-6.79 (m, 4H, quinoline-H), 4.65 (s, 2H, SCH 2 ), 4.18 (s, 2H, NCH 2 ), 3.40-3.43 (m, 2H, quinoline-H 2 ), 2.50-2.51 (m, 2H, quinoline-H 4 ), 1.89-1.94 (m, 2H, quinoline-H 3 ), 1.620 (s, 3H, C 5 -CH 3 ).IR(KBr, cm -1 ) v 3406 (NH ), 2918, 2842 (CH 3 , CH 2 ), 1696 (C=O), 1641 (C=O), 1602, 1524, 1505, 1458 (aryl), 1344 (CN), 1189 (CN).ESI- MS : m/z 451.43 (M+1 ) . C23H22N4O4S ( 450.51 ).
实施例205-甲基-2-[(4-氰基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b5) Example 205-methyl-2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6b5)
制备方法同实施例2,所不同的是母核为5b,取代基为对氰基-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-cyano-2-chloroacetophenone. the
所得产品5-甲基-2-[(4-氰基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b5)产率36.6%,mp:179-180℃(dec). The resulting product 5-methyl-2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6b5) is 36.6%, mp: 179-180℃(dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.73(s,1H,NH),7.63-7.96(m,4H,PhH),6.30-6.80(m,4H,quinoline-H),4.62(s,2H,SCH2),4.19(s,2H,NCH2),3.14-3.23(m,2H,quinoline-H2),2.44-2.50(m,2H,quinoline-H4),1.94(s,3H,C5-CH3),1.62-1.78(m,2H,quinoline-H3).IR(KBr,cm-1)v3442(NH),2919,2840(CH3,CH2),2231(C≡N),1690(C=O),1643(C=O),1602,1544,1505(aryl),1267(C-N),1195(C-N).ESI-MS:m/z 431.59(M+1).C24H22N4O2S(430.52). 1 H NMR (DMSO-d 6 , ppm) δ: 12.73 (s, 1H, NH), 7.63-7.96 (m, 4H, PhH), 6.30-6.80 (m, 4H, quinoline-H), 4.62 (s, 2H, SCH 2 ), 4.19 (s, 2H, NCH 2 ), 3.14-3.23 (m, 2H, quinoline-H 2 ), 2.44-2.50 (m, 2H, quinoline-H 4 ), 1.94 (s, 3H, C 5 -CH 3 ), 1.62-1.78 (m, 2H, quinoline-H 3 ). IR (KBr, cm -1 ) v3442 (NH), 2919, 2840 (CH 3 , CH 2 ), 2231 (C≡N ), 1690(C=O), 1643(C=O), 1602, 1544, 1505(aryl), 1267(CN), 1195(CN).ESI-MS: m/z 431.59(M+1).C 24 H 22 N 4 O 2 S (430.52).
实施例215-甲基-2-[(4-甲氧基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b6) Example 215-methyl-2-[(4-methoxyphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H -pyrimidin-4-one (6b6)
制备方法同实施例2,所不同的是母核为5b,取代基为对甲氧基-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-methoxy-2-chloroacetophenone. the
所得产品5-甲基-2-[(4-甲氧基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b6)产率38.9%,mp:210-211℃(dec). The resulting product 5-methyl-2-[(4-methoxyphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H -Pyrimidin-4-one (6b6) yield 38.9%, mp: 210-211°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.72(s,1H,NH),7.83(d,2H,J=8.4Hz,PhH),7.03(d,2H,J=8.4Hz,PhH),6.31-6.83(m,4H,quinoline-H),4.54(s,2H,SCH2),4.23(s,2H,NCH2),3.86(s,3H,PhOCH3),3.20-3.22(m,2H,quinoline-H2),2.47-2.50(m,2H,quinoline-H4),1.95(s,3H,C5-CH3),1.64-1.66(m,2H,quinoline-H3).IR(KBr,cm-1)v 3225(NH),2932,2839(CH3,CH2),1667(C=O),1646(C=O),1599,1574,1546,1502(aryl),1266(C-N),1165(C-N).ESI-MS:m/z436.71(M+1).C24H25N3O3S(435.54). 1 H NMR (DMSO-d 6 , ppm) δ: 12.72 (s, 1H, NH), 7.83 (d, 2H, J=8.4Hz, PhH), 7.03 (d, 2H, J=8.4Hz, PhH), 6.31-6.83 (m, 4H, quinoline-H), 4.54 (s, 2H, SCH 2 ), 4.23 (s, 2H, NCH 2 ), 3.86 (s, 3H, PhOCH3), 3.20-3.22 (m, 2H, quinoline-H 2 ), 2.47-2.50 (m, 2H, quinoline-H 4 ), 1.95 (s, 3H, C 5 -CH 3 ), 1.64-1.66 (m, 2H, quinoline-H 3 ).IR(KBr , cm -1 )v 3225(NH), 2932, 2839(CH 3 , CH 2 ), 1667(C=O), 1646(C=O), 1599, 1574, 1546, 1502(aryl), 1266(CN ), 1165 (CN). ESI-MS: m/z 436.71 (M+1). C 24 H 25 N 3 O 3 S (435.54).
实施例225-甲基-2-[(4-氟苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b7) Example 225-Methyl-2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-keto(6b7)
制备方法同实施例2,所不同的是母核为5b,取代基为对氟-2-氯代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-fluoro-2-chloroacetophenone. the
所得产品5-甲基-2-[(4-氟苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b7)产率47.6%,mp:179-180℃(dec). The resulting product 5-methyl-2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6b7) yield 47.6%, mp: 179-180°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.73(s,1H,NH),7.90-7.93(m,2H,PhH),7.33-7.36(m,2H,PhH),6.29-6.81(m,4H,quinoline-H),4.58(s,2H,SCH2),4.21(s,2H,NCH2),3.16-3.18(m,2H,quinoline-H2),2.43-2.45(m,2H,quinoline-H4),1.95(s,3H,C5-CH3),1.61-1.63(m,2H,quinoline-H3).IR(KBr,cm-1)v 3467(NH),2951,2893,2845(CH3,CH2),1703(C=O),1654(C=O),1600,1575,1551,1508(aryl),1263(C-N),1195(C-N).ESI-MS:m/z 424.56(M+1).C23H22FN3O2S(423.50). 1 H NMR (DMSO-d 6 , ppm) δ: 12.73 (s, 1H, NH), 7.90-7.93 (m, 2H, PhH), 7.33-7.36 (m, 2H, PhH), 6.29-6.81 (m, 4H, quinoline-H), 4.58 (s, 2H, SCH 2 ), 4.21 (s, 2H, NCH 2 ), 3.16-3.18 (m, 2H, quinoline-H 2 ), 2.43-2.45 (m, 2H, quinoline -H 4 ), 1.95(s, 3H, C 5 -CH 3 ), 1.61-1.63(m, 2H, quinoline-H 3 ).IR(KBr, cm -1 )v 3467(NH), 2951, 2893, 2845(CH 3 , CH 2 ), 1703(C=O), 1654(C=O), 1600, 1575, 1551, 1508(aryl), 1263(CN), 1195(CN).ESI-MS: m/ z 424.56(M+1).C 23 H 22 FN 3 O 2 S(423.50).
实施例235-甲基-2-苯基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b8) Example 23 5-methyl-2-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6b8)
制备方法同实施例2,所不同的是母核为5b,取代基为溴苄。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is benzyl bromide. the
所得产品5-甲基-2-苯基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b8)产率51.7%,mp:224-225℃(dec). The resulting product 5-methyl-2-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6b8) Rate 51.7%, mp: 224-225°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.63(s,1H,NH),7.20(d,2H,J=7.2Hz,PhH),7.17(t,1H,J1=7.2Hz,J2=14.4Hz,PhH),7.14(t,2H,J1=7.2Hz,J2=14.4Hz,,PhH),6.42-6.90(m,4H,quinoline-H),4.39(s,2H,SCH2),4.15(s,2H,NCH2),3.43-3.45(m,2H,quinoline-H2),2.61-2.63(m,2H,quinoline-H4),1.98(s,3H,C5-CH3),1.84-1.86(m,2H,quinoline-H3).IR(KBr,cm-1)v3427(NH),2942,2838(CH3,CH2),1640(C=O),1602,1573,1554,1508(aryl),1264(C-N),1197(C-N).ESI-MS:m/z 378.56(M+1).C22H23N3OS(377.50). 1 H NMR (DMSO-d 6 , ppm) δ: 12.63 (s, 1H, NH), 7.20 (d, 2H, J = 7.2 Hz, PhH), 7.17 (t, 1H, J 1 = 7.2 Hz, J 2 =14.4Hz, PhH), 7.14(t, 2H, J 1 =7.2Hz, J 2 =14.4Hz,, PhH), 6.42-6.90(m, 4H, quinoline-H), 4.39(s, 2H, SCH 2 ), 4.15 (s, 2H, NCH 2 ), 3.43-3.45 (m, 2H, quinoline-H 2 ), 2.61-2.63 (m, 2H, quinoline-H 4 ), 1.98 (s, 3H, C 5 -CH 3 ), 1.84-1.86 (m, 2H, quinoline-H 3 ). IR (KBr, cm -1 ) v3427 (NH), 2942, 2838 (CH 3 , CH 2 ), 1640 (C=O), 1602, 1573, 1554, 1508 (aryl), 1264 (CN), 1197 (CN). ESI-MS: m/z 378.56 (M+1). C 22 H 23 N 3 OS (377.50).
实施例245-甲基-2-[(4-甲基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b9) Example 24 5-methyl-2-[(4-methylphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6b9)
制备方法同实施例2,所不同的是母核为5b,取代基为对甲基氯苄。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-methylbenzyl chloride. the
所得产品5-甲基-2-[(4-甲基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b9)产率35.0%,mp:223-225℃(dec). The resulting product 5-methyl-2-[(4-methylphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6b9) yield 35.0%, mp: 223-225°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.35(s,1H,NH),7.01(d,2H,J=7.8Hz,PhH),6.96(d,2H,J=7.8Hz,PhH),6.58-6.61(m,4H,quinoline-H),4.22(s,2H,SCH2),4.12(s,2H,NCH2),3.43-3.45(m,2H,quinolineH2),2.61-2.63(m,2H,quinoline-H4),2.24(s,3H,PhCH3),1.97(s,3H,C5-CH3),1.84-1.86(m,2H,quinoline-H3).IR(KBr,cm-1)v 3334(NH),2926,2853(CH3,CH2),1683(C=O),16001,1538,1497(aryl),1239(C-N),1190(C-N).ESI-MS:m/z 392.53(M+1).C23H25N3OS(391.53). 1 H NMR (DMSO-d 6 , ppm) δ: 12.35 (s, 1H, NH), 7.01 (d, 2H, J=7.8Hz, PhH), 6.96 (d, 2H, J=7.8Hz, PhH), 6.58-6.61 (m, 4H, quinoline-H), 4.22 (s, 2H, SCH 2 ), 4.12 (s, 2H, NCH 2 ), 3.43-3.45 (m, 2H, quinoline- H 2 ), 2.61-2.63 (m , 2H, quinoline-H 4 ), 2.24 (s, 3H, PhCH 3 ), 1.97 (s, 3H, C 5 -CH 3 ), 1.84-1.86 (m, 2H, quinoline-H 3 ).IR(KBr, cm -1 )v 3334(NH), 2926, 2853(CH 3 , CH 2 ), 1683(C=O), 16001, 1538, 1497(aryl), 1239(CN), 1190(CN).ESI-MS : m/z 392.53(M+1).C 23 H 25 N 3 OS(391.53).
实施例255-甲基-2-[(4-氯苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b10) Example 255-Methyl-2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- 4-keto (6b10)
制备方法同实施例2,所不同的是母核为5b,取代基为对氯氯苄。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-chlorobenzyl. the
所得产品5-甲基-2-[(4-氯苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b10)产率56.3%,mp:220-222℃(dec). The resulting product 5-methyl-2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- 4-keto (6b10) yield 56.3%, mp: 220-222°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.64(s,1H,NH),7.15(d,2H,J=7.8Hz,PhH),7.11(d,2H,J=7.8Hz,PhH),6.40-6.91(m,4H,quinolineH),4.38(s,2H,SCH2),4.17(s,2H,NCH2),3.41-3.43(m,2H,quinolineH2),2.60-2.62(m,2H,quinolineH4),1.98(s,3H,C5CH3),1.82-1.86(m,2H,quinolineH3).IR(KBr,cm-1)v 3426(NH),2941,2840(CH3,CH2),1641(C=O),1601,1573,1554,1507(aryl),1265(C-N),1197(C-N).ESI-MS:m/z 412.56(M+1).C22H22ClN3OS(411.95). 1 H NMR (DMSO-d 6 , ppm) δ: 12.64 (s, 1H, NH), 7.15 (d, 2H, J=7.8Hz, PhH), 7.11 (d, 2H, J=7.8Hz, PhH), 6.40-6.91(m, 4H, quinolineH), 4.38(s, 2H, SCH 2 ), 4.17(s, 2H, NCH 2 ), 3.41-3.43(m, 2H, quinolineH 2 ), 2.60-2.62(m, 2H , quinolineH 4 ), 1.98(s, 3H, C 5 CH 3 ), 1.82-1.86(m, 2H, quinolineH 3 ).IR(KBr, cm -1 )v 3426(NH), 2941, 2840(CH 3 , CH 2 ), 1641 (C=O), 1601, 1573, 1554, 1507 (aryl), 1265 (CN), 1197 (CN). ESI-MS: m/z 412.56 (M+1). C 22 H 22 ClN 3 OS(411.95).
实施例265-甲基-2-[(4-硝基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b11) Example 26 5-methyl-2-[(4-nitrophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6b11)
制备方法同实施例2,所不同的是母核为5b,取代基为对硝基氯苄。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-nitrobenzyl chloride. the
所得产品5-甲基-2-[(4-硝基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b11)产率52.9%,mp:209-210℃(dec). The resulting product 5-methyl-2-[(4-nitrophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6b11) yield 52.9%, mp: 209-210°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.69(s,1H,NH),7.93(d,2H,J=8.4Hz,PhH),7.34(d,2H,J=8.4Hz,PhH),6.39-6.91(m,4H,quinoline-H),4.39(s,2H,SCH2),4.32(s,2H,NCH2),3.39-3.40(m,2H,quinoline-H2),2.57-2.59(m,2H,quinoline-H4),1.98(s,3H,C5-CH3),1.80-1.84(m,2H,quinoline-H3).IR(KBr,cm-1)v 3334(NH),2936,2842(CH3,CH2),1643(C=O),1599,1573,1516 (aryl),1344(C-N),1263(C-N).ESI-MS:m/z 423.57(M+1).C22H22N4O3S(422.50). 1 H NMR (DMSO-d 6 , ppm) δ: 12.69 (s, 1H, NH), 7.93 (d, 2H, J=8.4Hz, PhH), 7.34 (d, 2H, J=8.4Hz, PhH), 6.39-6.91 (m, 4H, quinoline-H), 4.39 (s, 2H, SCH 2 ), 4.32 (s, 2H, NCH 2 ), 3.39-3.40 (m, 2H, quinoline-H 2 ), 2.57-2.59 (m, 2H, quinoline-H 4 ), 1.98 (s, 3H, C 5 -CH 3 ), 1.80-1.84 (m, 2H, quinoline-H 3 ).IR(KBr, cm -1 ) v 3334 (NH ), 2936, 2842 (CH 3 , CH 2 ), 1643 (C=O), 1599, 1573, 1516 (aryl), 1344 (CN), 1263 (CN). ESI-MS: m/z 423.57 (M+ 1). C 22 H 22 N 4 O 3 S (422.50).
实施例275-甲基-2-[(4-氰基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b12) Example 27 5-methyl-2-[(4-cyanophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6b12)
制备方法同实施例2,所不同的是母核为5b,取代基为对氰基氯苄。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-cyanobenzyl chloride. the
所得产品5-甲基-2-[(4-氰基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b12)产率50.4%,mp:195-197℃(dec). The resulting product 5-methyl-2-[(4-cyanophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6b12) yield 50.4%, mp: 195-197°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.70(s,1H,NH),7.54(d,2H,J=7.8Hz,PhH),7.27(d,2H,J=7.8Hz,PhH),6.40-6.90(m,4H,quinoline-H),4.38(s,2H,SCH2),4.25(s,2H,NCH2),3.37-3.39(m,2H,quinoline-H2),2.57-2.59(m,2H,quinoline-H4),1.98(s,3H,C5-CH3),1.80-1.84(m,2H,quinoline-H3).IR(KBr,cm-1)v 3433(NH),2935,2842(CH3,CH2),2225(C≡N),1642(C=O),1601,1572,1541,1505(aryl),1260(C-N),1196(C-N).ESI-MS:m/z 403.57(M+1).C23H22N4OS(402.51). 1 H NMR (DMSO-d 6 , ppm) δ: 12.70 (s, 1H, NH), 7.54 (d, 2H, J=7.8Hz, PhH), 7.27 (d, 2H, J=7.8Hz, PhH), 6.40-6.90 (m, 4H, quinoline-H), 4.38 (s, 2H, SCH 2 ), 4.25 (s, 2H, NCH 2 ), 3.37-3.39 (m, 2H, quinoline-H 2 ), 2.57-2.59 (m, 2H, quinoline-H 4 ), 1.98 (s, 3H, C 5 -CH 3 ), 1.80-1.84 (m, 2H, quinoline-H 3 ).IR(KBr, cm -1 ) v 3433 (NH ), 2935, 2842 (CH 3 , CH 2 ), 2225 (C≡N), 1642 (C=O), 1601, 1572, 1541, 1505 (aryl), 1260 (CN), 1196 (CN).ESI- MS : m / z 403.57 (M+1). C23H22N4OS (402.51).
实施例285-甲基-2-[(4-甲氧基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b13) Example 28 5-methyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6b13)
制备方法同实施例2,所不同的是母核为5b,取代基为对甲氧基氯苄。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-methoxybenzyl chloride. the
所得产品5-甲基-2-[(4-甲氧基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b13)产率39.8%,mp:180-182℃(dec). The resulting product 5-methyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6b13) is 39.8%, mp: 180-182°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.59(s,1H,NH),7.05(d,2H,J=8.4Hz,PhH),6.91(d,2H,J=8.4Hz,PhH),6.41-6.84(m,4H,quinoline-H),4.38(s,2H,SCH2),4.10(s,2H,NCH2),3.68(s,3H,PhOCH3),3.44-3.47(m,2H,quinoline-H2),2.62-2.64(m,2H,quinoline-H4),1.98(s,3H,C5-CH3),1.85-1.89(m,2H,quinoline-H3).IR(KBr,cm-1)v 3413(NH),2928,2833(CH3,CH2),1641(C=O),1601,1571,1545,1511(aryl),1253(C-N),1198(C-N).ESI-MS:m/z 408.57(M+1).C23H25N3O2S(407.53). 1 H NMR (DMSO-d 6 , ppm) δ: 12.59 (s, 1H, NH), 7.05 (d, 2H, J=8.4Hz, PhH), 6.91 (d, 2H, J=8.4Hz, PhH), 6.41-6.84 (m, 4H, quinoline-H), 4.38 (s, 2H, SCH 2 ), 4.10 (s, 2H, NCH 2 ), 3.68 (s, 3H, PhOCH3), 3.44-3.47 (m, 2H, quinoline-H 2 ), 2.62-2.64 (m, 2H, quinoline-H 4 ), 1.98 (s, 3H, C 5 -CH 3 ), 1.85-1.89 (m, 2H, quinoline-H 3 ).IR(KBr , cm -1 )v 3413(NH), 2928, 2833(CH 3 , CH 2 ), 1641(C=O), 1601, 1571, 1545, 1511(aryl), 1253(CN), 1198(CN). ESI-MS: m/z 408.57 (M+1). C 23 H 25 N 3 O 2 S (407.53).
实施例295-甲基-2-[(4-甲氧基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b14) Example 29 5-methyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6b14)
制备方法同实施例2,所不同的是母核为5b,取代基为对甲氧基氯苄。 The preparation method is the same as in Example 2, except that the core is 5b, and the substituent is p-methoxybenzyl chloride. the
所得产品5-甲基-2-[(4-甲氧基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6b14)产率55.8%,mp:215-217℃(dec). The resulting product 5-methyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6b14) is 55.8%, mp: 215-217℃(dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.63(s,1H,NH),7.14(m,2H,PhH),6.93(m,2H,PhH),6.41-6.90(m,4H,quinoline-H),4.38(s,2H,SCH2),4.16(s,2H,NCH2),3.42-3.44(m,2H,quinoline-H2),2.61-2.63(m,2H,quinoline-H4),1.98(s,3H,C5-CH3),1.83-1.87(m,2H,quinoline-H3).IR(KBr,cm-1)v 3459(NH),2939,2840(CH3,CH2),1641(C=O),1601,1573,1554,1508(aryl),1265(C-N),1222(C-N).ESI-MS:m/z 396.53(M+1).C22H22FN3OS(395.49). 1 H NMR (DMSO-d 6 , ppm) δ: 12.63 (s, 1H, NH), 7.14 (m, 2H, PhH), 6.93 (m, 2H, PhH), 6.41-6.90 (m, 4H, quinoline- H), 4.38 (s, 2H, SCH 2 ), 4.16 (s, 2H, NCH 2 ), 3.42-3.44 (m, 2H, quinoline-H 2 ), 2.61-2.63 (m, 2H, quinoline-H 4 ) , 1.98 (s, 3H, C 5 -CH 3 ), 1.83-1.87 (m, 2H, quinoline-H 3 ). IR (KBr, cm -1 ) v 3459 (NH), 2939, 2840 (CH 3 , CH 2 ), 1641(C=O), 1601, 1573, 1554, 1508(aryl), 1265(CN), 1222(CN).ESI-MS: m/z 396.53(M+1).C 22 H 22 FN 3 OS(395.49).
实施例305-乙基-2-苯羰基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c1) Example 305-Ethyl-2-phenylcarbonylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6c1)
制备方法同实施例2,所不同的是母核为5c,取代基为2-溴代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is 2-bromoacetophenone. the
所得产品5-乙基-2-苯羰基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c1)产率47.5%,mp:193-194℃(dec). The resulting product 5-ethyl-2-phenylcarbonylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6c1) Rate 47.5%, mp: 193-194°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.77(s,1H,NH),7.85(d,2H,J=7.8Hz,PhH),7.68(t,1H,J1=7.8Hz,J2=15.6Hz,PhH),7.53(t,2H,J1=7.8Hz,J2=15.6Hz,PhH),6.32-6.82(m,4H,quinoline-H),4.60(s,2H,SCH2),4.24(s,2H,NCH2),3.16-3.18(m,2H,quinoline-H2),2.45-2.50(m,2H,quinoline-H4),2.43(q,2H,J=7.8Hz,C5-CH2CH3),1.60-1.63(m,2H,quinoline-H3),1.05(t,3H,J=7.8Hz,C5-CH2CH3).IR(KBr,cm-1)v 3462(NH),2931,2840(CH3,CH2),1682(C=O),1633(C=O),1599,1573,1507,1448(aryl),1254(C-N),1195(C-N).ESI-MS:m/z 420.21(M+1).C24H25N3O2S(419.54). 1 H NMR (DMSO-d 6 , ppm) δ: 12.77 (s, 1H, NH), 7.85 (d, 2H, J = 7.8 Hz, PhH), 7.68 (t, 1H, J 1 = 7.8 Hz, J 2 =15.6Hz, PhH), 7.53(t, 2H, J 1 =7.8Hz, J 2 =15.6Hz, PhH), 6.32-6.82(m, 4H, quinoline-H), 4.60(s, 2H, SCH 2 ) , 4.24(s, 2H, NCH 2 ), 3.16-3.18(m, 2H, quinoline-H 2 ), 2.45-2.50(m, 2H, quinoline-H 4 ), 2.43(q, 2H, J=7.8Hz, C 5 -CH 2 CH 3 ), 1.60-1.63 (m, 2H, quinoline-H 3 ), 1.05 (t, 3H, J=7.8Hz, C 5 -CH 2 CH 3 ).IR(KBr, cm -1 )v 3462 (NH), 2931, 2840 (CH 3 , CH 2 ), 1682 (C=O), 1633 (C=O), 1599, 1573, 1507, 1448 (aryl), 1254 (CN), 1195 ( CN). ESI-MS: m/z 420.21 (M+1). C 24 H 25 N 3 O 2 S (419.54).
实施例315-乙基-2-[(4-甲基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c2) Example 315-Ethyl-2-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6c2)
制备方法同实施例2,所不同的是母核为5c,取代基为对甲基-2-溴代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-methyl-2-bromoacetophenone. the
所得产品5-乙基-2-[(4-甲基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c2)产率57.1%,mp:185-187℃(dec). The resulting product 5-ethyl-2-[(4-methylphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6c2) is 57.1%, mp: 185-187°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.76(s,1H,NH),7.74(d,2H,J=8.4Hz,PhH),7.32(d,2H,J=8.4Hz,PhH),6.33-6.83(m,4H,quinoline-H),4.56(s,2H,SCH2),4.24(s,2H,NCH2),3.16-3.18(m,2H,quinoline-H2),2.45-2.50(m,2H,quinoline-H4),2.42(q,2H,J=7.2Hz,C5-CH2CH3),2.39(s,3H,PhCH3),1.62-1.65(m,2H,quinoline-H3),1.02(t,3H,J=7.2Hz,C5-CH2CH3).IR(KBr,cm-1)v 3437(NH),2929,2842(CH3,CH2),1677(C=O),1639(C=O),1602,1572,1505,1456(aryl),1254(C-N),1193(C-N).ESI-MS:m/z 434.57(M+1).C25H27N3O2S(433.18) 1 H NMR (DMSO-d 6 , ppm) δ: 12.76 (s, 1H, NH), 7.74 (d, 2H, J=8.4Hz, PhH), 7.32 (d, 2H, J=8.4Hz, PhH), 6.33-6.83 (m, 4H, quinoline-H), 4.56 (s, 2H, SCH 2 ), 4.24 (s, 2H, NCH 2 ), 3.16-3.18 (m, 2H, quinoline-H 2 ), 2.45-2.50 (m, 2H, quinoline-H 4 ), 2.42 (q, 2H, J=7.2Hz, C 5 -CH 2 CH 3 ), 2.39 (s, 3H, PhCH 3 ), 1.62-1.65 (m, 2H, quinoline -H 3 ), 1.02 (t, 3H, J=7.2Hz, C 5 -CH 2 CH 3 ).IR (KBr, cm -1 ) v 3437 (NH), 2929, 2842 (CH 3 , CH 2 ), 1677(C=O), 1639(C=O), 1602, 1572, 1505, 1456(aryl), 1254(CN), 1193(CN).ESI-MS: m/z 434.57(M+1).C 25 H 27 N 3 O 2 S (433.18)
实施例325-乙基-2-[(4-氯苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c3) Example 325-Ethyl-2-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6c3)
制备方法同实施例2,所不同的是母核为5c,取代基为对氯-2-溴代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-chloro-2-bromoacetophenone. the
所得产品5-乙基-2-[(4-氯苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c3)产率39.2%,mp:190-192℃(dec). The resulting product 5-ethyl-2-[(4-chlorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6c3) yield 39.2%, mp: 190-192°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.48(s,1H,NH),7.84(d,2H,J=8.4Hz,PhH),7.57(d,2H,J=8.4Hz,PhH),6.31-7.01(m,4H,quinoline-H),4.57(s,2H,SCH2),4.24(s,2H,NCH2),3.24-3.33(m,2H,quinoline-H2),2.67-2.71(m,2H,quinoline-H4),2.31(q,2H,J=7.2Hz,C5-CH2CH3),1.87-1.91(m,2H,quinoline-H3),1.06(t,3H,J=7.2Hz,C5-CH2CH3).IR(KBr,cm-1)v 3566(NH),2962,2930,2868(CH3,CH2),1686(C=O),1640(C=O),1601,1571,1536,1506(aryl),1254(C-N),1191(C-N).ESI-MS:m/z 454.43(M+1).C24H24ClN3O2S(454.13) 1 H NMR (DMSO-d6, ppm) δ: 12.48 (s, 1H, NH), 7.84 (d, 2H, J=8.4Hz, PhH), 7.57 (d, 2H, J=8.4Hz, PhH), 6.31 -7.01 (m, 4H, quinoline-H), 4.57 (s, 2H, SCH 2 ), 4.24 (s, 2H, NCH 2 ), 3.24-3.33 (m, 2H, quinoline-H 2 ), 2.67-2.71 ( m, 2H, quinoline-H 4 ), 2.31 (q, 2H, J=7.2Hz, C 5 -CH 2 CH 3 ), 1.87-1.91 (m, 2H, quinoline-H 3 ), 1.06 (t, 3H, J=7.2Hz, C 5 -CH 2 CH 3 ). IR (KBr, cm -1 ) v 3566 (NH), 2962, 2930, 2868 (CH 3 , CH 2 ), 1686 (C=O), 1640 ( C=O), 1601, 1571, 1536, 1506 (aryl), 1254 (CN), 1191 (CN). ESI-MS: m/z 454.43 (M+1). C 24 H 24 ClN 3 O 2 S ( 454.13)
实施例335-乙基-2-[(4-硝基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c4) Example 335-Ethyl-2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6c4)
制备方法同实施例2,所不同的是母核为5c,取代基为对硝基-2-溴代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-nitro-2-bromoacetophenone. the
所得产品5-乙基-2-[(4-硝基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c4)产率43.7%,mp:191-192℃(dec). The resulting product 5-ethyl-2-[(4-nitrophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6c4) is 43.7%, mp: 191-192°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.78(s,1H,NH),8.27(d,2H,J=7.8Hz,PhH),8.04(d,2H,J=7.8Hz,PhH),6.32-7.01(m,4H,quinoline-H),4.64(s,2H,SCH2),4.23(s,2H,NCH2),3.32-3.34 (m,2H,quinoline-H2),2.71-2.73(m,2H,quinoline-H4),2.43(q,2H,J=7.8Hz,C5-CH2CH3),1.89-1.90(m,2H,quinoline-H3),1.07(t,3H,J=7.8Hz,C5-CH2CH3).IR(KBr,cm-1)v 3467(NH),2930,2869(CH3,CH2),1693(C=O),1640(C=O),1601,1571,1536,1506(aryl),1344(C-N),1189(C-N).ESI-MS:m/z 465.55(M+1).C24H24N4O4S(464.15) 1 H NMR (DMSO-d 6 , ppm) δ: 12.78 (s, 1H, NH), 8.27 (d, 2H, J=7.8Hz, PhH), 8.04 (d, 2H, J=7.8Hz, PhH), 6.32-7.01 (m, 4H, quinoline-H), 4.64 (s, 2H, SCH 2 ), 4.23 (s, 2H, NCH 2 ), 3.32-3.34 (m, 2H, quinoline-H 2 ), 2.71-2.73 (m, 2H, quinoline-H 4 ), 2.43 (q, 2H, J=7.8Hz, C 5 -CH 2 CH 3 ), 1.89-1.90 (m, 2H, quinoline-H 3 ), 1.07 (t, 3H , J=7.8Hz, C 5 -CH 2 CH 3 ).IR(KBr, cm -1 ) v 3467(NH), 2930, 2869(CH 3 , CH 2 ), 1693(C=O), 1640(C =O), 1601, 1571, 1536, 1506 (aryl), 1344 (CN), 1189 (CN). ESI-MS: m/z 465.55 (M+1). C 24 H 24 N 4 O 4 S (464.15 )
实施例345-乙基-2-[(4-氰基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c5) Example 34 5-ethyl-2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6c5)
制备方法同实施例2,所不同的是母核为5c,取代基为对氰基-2-溴代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-cyano-2-bromoacetophenone. the
所得产品5-乙基-2-[(4-氰基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c5)产率49.6%,mp:192-194℃(dec). The resulting product 5-ethyl-2-[(4-cyanophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6c5) is 49.6%, mp: 192-194°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.80(s,1H,NH),7.60-7.96(m,4H,PhH),6.36-6.80(m,4H,quinoline-H),4.61(s,2H,SCH2),4.31(s,2H,NCH2),3.33-3.42(m,2H,quinoline-H2),2.43-2.51(m,2H,quinoline-H4),2.39(q,2H,J=7.2Hz,C5-CH2CH3),1.60-1.61(m,2H,quinoline-H3),1.02(t,3H,J=7.2Hz,C5-CH2CH3).IR(KBr,cm-1)v 3343(NH),2937,2869(CH3,CH2),2230(C≡N),1688(C=O),1640(C=O),1601,1542,1506(aryl),1251(C-N),1195(C-N).ESI-MS:m/z 445.54(M+1).C25H24N4O2S(444.16) 1 H NMR (DMSO-d 6 , ppm) δ: 12.80 (s, 1H, NH), 7.60-7.96 (m, 4H, PhH), 6.36-6.80 (m, 4H, quinoline-H), 4.61 (s, 2H, SCH 2 ), 4.31(s, 2H, NCH 2 ), 3.33-3.42(m, 2H, quinoline-H 2 ), 2.43-2.51(m, 2H, quinoline-H 4 ), 2.39(q, 2H, J=7.2Hz, C 5 -CH 2 CH 3 ), 1.60-1.61(m, 2H, quinoline-H 3 ), 1.02(t, 3H, J=7.2Hz, C 5 -CH 2 CH 3 ).IR( KBr, cm -1 ) v 3343 (NH), 2937, 2869 (CH 3 , CH 2 ), 2230 (C≡N), 1688 (C=O), 1640 (C=O), 1601, 1542, 1506 ( aryl), 1251 (CN), 1195 (CN). ESI-MS: m/z 445.54 (M+1). C 25 H 24 N 4 O 2 S (444.16)
实施例355-乙基-2-[(4-甲氧基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c6) Example 355-Ethyl-2-[(4-methoxyphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H -pyrimidin-4-one (6c6)
制备方法同实施例2,所不同的是母核为5c,取代基为对甲氧基-2-溴代苯乙酮。所得产品5-乙基-2-[(4-甲氧基苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c6)产率39.1%,mp:196-198℃(dec). The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-methoxy-2-bromoacetophenone. The resulting product 5-ethyl-2-[(4-methoxyphenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H -Pyrimidin-4-one (6c6) yield 39.1%, mp: 196-198°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.75(s,1H,NH),7.82(d,2H,J=8.4Hz,PhH),7.02(d,2H,J=8.4Hz,PhH),6.33-6.83(m,4H,quinoline-H),4.53(s,2H,SCH2),4.24(s,2H,NCH2),3.86(s,3H,PhOCH3).3.14-3.19(m,2H,quinoline-H2),2.45-2.50(m,2H,quinoline-H4),2.27-2.31(q,2H,J=7.2Hz,C5-CH2CH3),1.88-1.90(m,2H,quinoline-H3),1.05(t,3H,J=7.2Hz,C5-CH2CH3).IR(KBr,cm-1)v 3476(NH),2932,2839(CH3,CH2),1667(C=O),1642(C=O),1599,1564,1541,1504(aryl),1264(C-N),1166(C-N).ESI-MS:m/z 450.34(M+1).C25H27N3O3S(449.18). 1 H NMR (DMSO-d 6 , ppm) δ: 12.75 (s, 1H, NH), 7.82 (d, 2H, J=8.4Hz, PhH), 7.02 (d, 2H, J=8.4Hz, PhH), 6.33-6.83 (m, 4H, quinoline-H), 4.53 (s, 2H, SCH 2 ), 4.24 (s, 2H, NCH 2 ), 3.86 (s, 3H, PhOCH3). 3.14-3.19 (m, 2H, quinoline-H 2 ), 2.45-2.50 (m, 2H, quinoline-H 4 ), 2.27-2.31 (q, 2H, J=7.2Hz, C 5 -CH 2 CH 3 ), 1.88-1.90 (m, 2H, quinoline-H 3 ), 1.05 (t, 3H, J=7.2Hz, C 5 -CH 2 CH 3 ).IR (KBr, cm -1 ) v 3476 (NH), 2932, 2839 (CH 3 , CH 2 ) , 1667(C=O), 1642(C=O), 1599, 1564, 1541, 1504(aryl), 1264(CN), 1166(CN).ESI-MS: m/z 450.34(M+1). C 25 H 27 N 3 O 3 S (449.18).
实施例365-乙基-2-[(4-氟苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c7) Example 36 5-ethyl-2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-keto(6c7)
制备方法同实施例2,所不同的是母核为5c,取代基为对氟-2-溴代苯乙酮。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-fluoro-2-bromoacetophenone. the
所得产品5-乙基-2-[(4-氟苯基)羰基甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c7)产率49.3%,mp:192-193℃(dec). The resulting product 5-ethyl-2-[(4-fluorophenyl)carbonylmethylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6c7) yield 49.3%, mp: 192-193°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.84(s,1H,NH),7.90-7.92(m,2H,PhH),7.32-7.35(m,2H,PhH),6.32-6.82(m,4H,quinoline-H),4.58(s,2H,SCH2),4.24(s,2H,NCH2),3.33-3.44(m,2H,quinoline-H2),2.39-2.50(m,2H,quinoline-H4),2.28-2.31(q,2H,J=7.2Hz,C5-CH2CH3),1.62-1.71(m,2H,quinoline-H3),1.05(t,3H,J=7.2Hz,C5-CH2CH3).IR(KBr,cm-1)v 3466(NH),2933,2840(CH3,CH2),1680(C=O),1638(C=O),1598,1574,1547,1506(aryl),1253(C-N),1196(C-N).ESI-MS:m/z 438.56(M+1).C24H24FN3O2S(437.16). 1 H NMR (DMSO-d 6 , ppm) δ: 12.84 (s, 1H, NH), 7.90-7.92 (m, 2H, PhH), 7.32-7.35 (m, 2H, PhH), 6.32-6.82 (m, 4H, quinoline-H), 4.58 (s, 2H, SCH 2 ), 4.24 (s, 2H, NCH 2 ), 3.33-3.44 (m, 2H, quinoline-H 2 ), 2.39-2.50 (m, 2H, quinoline -H 4 ), 2.28-2.31(q, 2H, J=7.2Hz, C 5 -CH 2 CH 3 ), 1.62-1.71(m, 2H, quinoline-H 3 ), 1.05(t, 3H, J=7.2 Hz, C 5 -CH 2 CH 3 ). IR (KBr, cm -1 ) v 3466 (NH), 2933, 2840 (CH 3 , CH 2 ), 1680 (C=O), 1638 (C=O), 1598, 1574, 1547, 1506 (aryl), 1253 (CN), 1196 (CN). ESI-MS: m/z 438.56 (M+1). C 24 H 24 FN 3 O 2 S (437.16).
实施例375-乙基-2-苯基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c8) Example 37 5-ethyl-2-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6c8)
制备方法同实施例2,所不同的是母核为5c,取代基为溴苄。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is benzyl bromide. the
所得产品5-乙基-2-苯基甲硫基-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c8)产率46.9%,mp:224-226℃(dec). The resulting product 5-ethyl-2-phenylmethylthio-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidin-4-one (6c8) Rate 46.9%, mp: 224-226°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.62(s,1H,NH),7.20(d,2H,J=7.2Hz,PhH),7.18(t,1H,J1=7.2Hz,J2=14.4Hz,PhH),7.14(t,2H,J1=7.2Hz,J2=14.4Hz,PhH),6.34-6.91(m,4H,quinoline-H),4.42(s,2H,SCH2),4.14(s,2H,NCH2),3.42-3.44(m,2H,quinoline-H2),2.61-2.63(m,2H,quinoline-H4),2.46-2.51(q,2H,J=7.8Hz,C5-CH2CH3),1.84-1.86(m,2H,quinoline-H3),1.06(t,3H,J=7.8Hz,C5-CH2CH3).IR(KBr,cm-1)v 3361(NH),2932,2840(CH3,CH2),1635(C=O),1600,1570,1549,1508(aryl),1252(C-N),1197(C-N).ESI-MS:m/z 392.37(M+1).C23H25N3OS(391.53). 1 H NMR (DMSO-d 6 , ppm) δ: 12.62 (s, 1H, NH), 7.20 (d, 2H, J = 7.2 Hz, PhH), 7.18 (t, 1H, J 1 = 7.2 Hz, J 2 =14.4Hz, PhH), 7.14(t, 2H, J 1 =7.2Hz, J 2 =14.4Hz, PhH), 6.34-6.91(m, 4H, quinoline-H), 4.42(s, 2H, SCH 2 ) , 4.14 (s, 2H, NCH 2 ), 3.42-3.44 (m, 2H, quinoline-H 2 ), 2.61-2.63 (m, 2H, quinoline-H 4 ), 2.46-2.51 (q, 2H, J=7.8 Hz, C 5 -CH 2 CH 3 ), 1.84-1.86 (m, 2H, quinoline-H 3 ), 1.06 (t, 3H, J=7.8Hz, C 5 -CH 2 CH 3 ).IR(KBr, cm -1 )v 3361(NH), 2932, 2840(CH 3 , CH 2 ), 1635(C=O), 1600, 1570, 1549, 1508(aryl), 1252(CN), 1197(CN).ESI- MS: m/z 392.37 (M+1). C 23 H 25 N 3 OS (391.53).
实施例385-乙基-2-[(4-甲基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c9) Example 38 5-ethyl-2-[(4-methylphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6c9)
制备方法同实施例2,所不同的是母核为5c,取代基为对甲基氯苄。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-methylbenzyl chloride. the
所得产品5-乙基-2-[(4-甲基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c9)产率47.2%,mp:218-221℃(dec). The resulting product 5-ethyl-2-[(4-methylphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6c9) yield 47.2%, mp: 218-221°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.60(s,1H,NH),7.00(d,2H,J=8.4Hz,PhH),6.97(d,2H,J=8.4Hz,PhH),6.43-6.90(m,4H,quinoline-H),4.41(s,2H,SCH2),4.09(s,2H,NCH2),3.42-3.44(m,2H,quinoline-H2),2.61-2.64(m,2H,quinoline-H4),2.46-2.51(q,2H,J=7.8Hz,C5-CH2CH3),2.22(s,3H,PhCH3),1.84-1.88(m,2H,quinoline-H3),1.07(t,3H,J=7.8Hz,C5-CH2CH3).IR(KBr,cm-1)v 3422(NH),2930,2838,2796(CH3,CH2),1634(C=O),1600,1569,1546,1507(aryl),1251(C-N),1197(C-N).ESI-MS:m/z 406.59(M+1).C24H27N3OS(405.56). 1 H NMR (DMSO-d 6 , ppm) δ: 12.60 (s, 1H, NH), 7.00 (d, 2H, J=8.4Hz, PhH), 6.97 (d, 2H, J=8.4Hz, PhH), 6.43-6.90 (m, 4H, quinoline-H), 4.41 (s, 2H, SCH 2 ), 4.09 (s, 2H, NCH 2 ), 3.42-3.44 (m, 2H, quinoline-H 2 ), 2.61-2.64 (m, 2H, quinoline-H 4 ), 2.46-2.51 (q, 2H, J=7.8Hz, C 5 -CH 2 CH 3 ), 2.22 (s, 3H, PhCH3), 1.84-1.88 (m, 2H, quinoline-H 3 ), 1.07 (t, 3H, J=7.8Hz, C 5 -CH 2 CH 3 ).IR (KBr, cm -1 ) v 3422 (NH), 2930, 2838, 2796 (CH 3 , CH 2 ), 1634(C=O), 1600, 1569, 1546, 1507(aryl), 1251(CN), 1197(CN).ESI-MS: m/z 406.59(M+1).C 24 H 27 N 3 OS(405.56).
实施例395-乙基-2-[(4-氯苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c10) Example 39 5-ethyl-2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- 4-keto (6c10)
制备方法同实施例2,所不同的是母核为5c,取代基为对氯氯苄。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-chlorobenzyl chloride. the
所得产品5-乙基-2-[(4-氯苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c10)产率49.7%,mp:227-229℃(dec). The resulting product 5-ethyl-2-[(4-chlorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- The yield of 4-ketone (6c10) is 49.7%, mp: 227-229°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.65(s,1H,NH),7.15(d,2H,J=8.4Hz,PhH),7.11(d,2H,J=8.4Hz,PhH),6.42-6.91(m,4H,quinoline-H),4.41(s,2H,SCH2),4.16(s,2H,NCH2),3.40-3.42(m,2H,quinoline-H2),2.60-2.62(m,2H,quinoline-H4),2.47-2.50(q,2H,J=7.8Hz,C5-CH2CH3),1.83-1.85(m,2H,quinoline-H3),1.06(t,3H,J=7.8Hz,C5-CH2CH3).IR(KBr,cm-1)v 3326(NH),2932,2840(CH3,CH2),1636(C=O),1600,1570,1546,1507(aryl),1251(C-N),1197(C-N).ESI-MS:m/z 426.74(M+1).C23H24ClN3OS(425.97). 1 H NMR (DMSO-d 6 , ppm) δ: 12.65 (s, 1H, NH), 7.15 (d, 2H, J=8.4Hz, PhH), 7.11 (d, 2H, J=8.4Hz, PhH), 6.42-6.91 (m, 4H, quinoline-H), 4.41 (s, 2H, SCH 2 ), 4.16 (s, 2H, NCH 2 ), 3.40-3.42 (m, 2H, quinoline-H 2 ), 2.60-2.62 (m, 2H, quinoline-H 4 ), 2.47-2.50 (q, 2H, J=7.8Hz, C 5 -CH 2 CH 3 ), 1.83-1.85 (m, 2H, quinoline-H 3 ), 1.06(t , 3H, J=7.8Hz, C 5 -CH 2 CH 3 ).IR (KBr, cm -1 ) v 3326(NH), 2932, 2840(CH 3 , CH 2 ), 1636(C=O), 1600 , 1570, 1546, 1507 (aryl), 1251 (CN), 1197 (CN). ESI-MS: m/z 426.74 (M+1). C 23 H 24 ClN 3 OS (425.97).
实施例405-乙基-2-[(4-硝基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c11) Example 40 5-ethyl-2-[(4-nitrophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-keto (6c11)
制备方法同实施例2,所不同的是母核为5c,取代基为对硝基氯苄。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-nitrobenzyl chloride. the
所得产品5-乙基-2-[(4-硝基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c11)产率45.1%,mp:195-197℃(dec). The resulting product 5-ethyl-2-[(4-nitrophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6c11) yield 45.1%, mp: 195-197°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.71(s,1H,NH),7.93(d,2H,J=8.4Hz,PhH),7.34(d,2H,J=8.4Hz,PhH),6.42-6.91(m,4H,quinoline-H),4.42(s,2H,SCH2),4.31(s,2H,NCH2),3.37-3.39(m,2H,quinoline-H2),2.56-2.58(m,2H,quinoline-H4),2.50(q,2H,J=7.2Hz,C5-CH2CH3),1.80-1.82(m,2H,quinoline-H3),1.07(t,3H,J=7.2Hz,C5-CH2CH3).IR(KBr,cm-1)v 3434(NH),2931,2840(CH3,CH2),1641(C=O),1600,1571,1519(aryl),1250(C-N),1196(C-N).ESI-MS:m/z 437.47(M+1).C23H24ClN4O3S(436.53). 1 H NMR (DMSO-d 6 , ppm) δ: 12.71 (s, 1H, NH), 7.93 (d, 2H, J=8.4Hz, PhH), 7.34 (d, 2H, J=8.4Hz, PhH), 6.42-6.91 (m, 4H, quinoline-H), 4.42 (s, 2H, SCH 2 ), 4.31 (s, 2H, NCH 2 ), 3.37-3.39 (m, 2H, quinoline-H 2 ), 2.56-2.58 (m, 2H, quinoline-H 4 ), 2.50 (q, 2H, J=7.2Hz, C 5 -CH 2 CH 3 ), 1.80-1.82 (m, 2H, quinoline-H 3 ), 1.07 (t, 3H , J=7.2Hz, C 5 -CH 2 CH 3 ).IR(KBr, cm -1 ) v 3434(NH), 2931, 2840(CH 3 , CH 2 ), 1641(C=O), 1600, 1571 , 1519(aryl), 1250(CN), 1196(CN).ESI-MS: m/z 437.47(M+1).C 23 H 24 ClN 4 O 3 S (436.53).
实施例415-乙基-2-[(4-氰基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c12) Example 41 5-ethyl-2-[(4-cyanophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-one (6c12)
制备方法同实施例2,所不同的是母核为5c,取代基为对氰基氯苄。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-cyanobenzyl chloride. the
所得产品5-乙基-2-[(4-氰基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c12)产率45.2%,mp:195-196℃(dec). The resulting product 5-ethyl-2-[(4-cyanophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine -4-ketone (6c12) yield 45.2%, mp: 195-196°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.70(s,1H,NH),7.54(d,2H,J=8.4Hz,PhH),7.27(d,2H,J=8.4Hz,PhH),6.42-6.91(m,4H,quinoline-H),4.41(s,2H,SCH2),4.24(s,2H,NCH2),3.36-3.38(m,2H,quinoline-H2),2.57-2.59(m,2H,quinoline-H4),2.50(q,2H,J=7.8Hz,C5-CH2CH3),1.80-1.83(m,2H,quinoline-H3),1.07(t,3H,J=7.8Hz,C5-CH2CH3).IR(KBr,cm-1)v 3411(NH),2932,2840(CH3,CH2),2227(C≡N),1640(C=O),1601,1571,1542,1503(aryl),1251(C-N),1195(C-N).ESI-MS:m/z 417.62(M+1).C24H24N4OS(416.54). 1 H NMR (DMSO-d 6 , ppm) δ: 12.70 (s, 1H, NH), 7.54 (d, 2H, J=8.4Hz, PhH), 7.27 (d, 2H, J=8.4Hz, PhH), 6.42-6.91 (m, 4H, quinoline-H), 4.41 (s, 2H, SCH 2 ), 4.24 (s, 2H, NCH 2 ), 3.36-3.38 (m, 2H, quinoline-H 2 ), 2.57-2.59 (m, 2H, quinoline-H 4 ), 2.50 (q, 2H, J=7.8Hz, C 5 -CH 2 CH 3 ), 1.80-1.83 (m, 2H, quinoline-H 3 ), 1.07 (t, 3H , J=7.8Hz, C 5 -CH 2 CH 3 ).IR(KBr, cm -1 ) v 3411(NH), 2932, 2840(CH 3 , CH 2 ), 2227(C≡N), 1640(C =O), 1601, 1571, 1542, 1503 (aryl), 1251 (CN), 1195 (CN). ESI-MS: m/z 417.62 (M+1). C 24 H 24 N 4 OS (416.54).
实施例425-乙基-2-[(4-甲氧基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c13) Example 42 5-ethyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- Pyrimidin-4-one (6c13)
制备方法同实施例2,所不同的是母核为5c,取代基为对甲氧基氯苄。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-methoxybenzyl chloride. the
所得产品5-乙基-2-[(4-甲氧基苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c13)产率48.7%,mp:187-188℃(dec). The resulting product 5-ethyl-2-[(4-methoxyphenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H- The yield of pyrimidin-4-one (6c13) is 48.7%, mp: 187-188°C (dec).
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.58(s,1H,NH),7.04(d,2H,J=8.4Hz,PhH),6.91(d,2H,J=8.4Hz,PhH),6.43-6.84(m,4H,quinoline-H),4.32(s,2H,SCH2),4.41(s,2H,NCH2),3.68(s,3H,PhOCH3),3.45-3.47(m,2H,quinoline-H2),2.62-2.64(m,2H,quinoline-H4),2.50(q,2H,J=8.4Hz,C5-CH2CH3),1.86-1.88(m,2H,quinoline-H3),1.06(t,3H,J=8.4Hz,C5-CH2CH3).IR(KBr,cm-1)v 3434(NH),2930,2833,2763(CH3,CH2),1637(C=O),1600,1569,1544,1509(aryl),1251(C-N),1197(C-N).ESI-MS:m/z 422.34(M+1).C24H27N3O2S(421.56). 1 H NMR (DMSO-d 6 , ppm) δ: 12.58 (s, 1H, NH), 7.04 (d, 2H, J=8.4Hz, PhH), 6.91 (d, 2H, J=8.4Hz, PhH), 6.43-6.84 (m, 4H, quinoline-H), 4.32 (s, 2H, SCH 2 ), 4.41 (s, 2H, NCH 2 ), 3.68 (s, 3H, PhOCH3), 3.45-3.47 (m, 2H, quinoline-H 2 ), 2.62-2.64 (m, 2H, quinoline-H 4 ), 2.50 (q, 2H, J=8.4Hz, C 5 -CH 2 CH 3 ), 1.86-1.88 (m, 2H, quinoline- H 3 ), 1.06 (t, 3H, J=8.4Hz, C 5 -CH 2 CH 3 ).IR (KBr, cm -1 ) v 3434 (NH), 2930, 2833, 2763 (CH 3 , CH 2 ) , 1637(C=O), 1600, 1569, 1544, 1509(aryl), 1251(CN), 1197(CN).ESI-MS: m/z 422.34(M+1).C 24 H 27 N 3 O 2 S(421.56).
实施例435-乙基-2-[(4-氟苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c14) Example 435-Ethyl-2-[(4-fluorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- 4-keto (6c14)
制备方法同实施例2,所不同的是母核为5c,取代基为对氟氯苄。 The preparation method is the same as in Example 2, except that the core is 5c, and the substituent is p-fluorochlorobenzyl. the
所得产品5-乙基-2-[(4-氟苯基)甲硫基]-6-[(1,2,3,4-四氢喹啉)-1-甲基]-3H-嘧啶-4-酮(6c14)产率59.7%,mp:224-227℃(dec) The resulting product 5-ethyl-2-[(4-fluorophenyl)methylthio]-6-[(1,2,3,4-tetrahydroquinoline)-1-methyl]-3H-pyrimidine- 4-keto (6c14) yield 59.7%, mp: 224-227°C (dec)
产物光谱分析数据: Product spectral analysis data:
1H NMR(DMSO-d6,ppm)δ:12.63(s,1H,NH),7.12(d,2H,J=8.4Hz,PhH),6.93(d,2H,J=8.4Hz,PhH),6.43-6.90(m,4H,quinoline-H),4.42(s,2H,SCH2),4.15(s,2H,NCH2),3.42-3.44(m,2H,quinoline-H2),2.60-2.63(m,2H,quinoline-H4),2.51(q,2H,J=7.2Hz,C5-CH2CH3),1.84-1.86(m,2H,quinoline-H3),1.07(t,3H,J=7.2Hz,C5-CH2CH3).IR(KBr,cm-1)v 3359(NH),2932,2841(CH3,CH2),1636(C=O),1600,1570,1547,1508(aryl),1251(C-N),1221(C-N). ESI-MS:m/z 410.29(M+1).C23H24FN3OS(409.52). 1 H NMR (DMSO-d 6 , ppm) δ: 12.63 (s, 1H, NH), 7.12 (d, 2H, J=8.4Hz, PhH), 6.93 (d, 2H, J=8.4Hz, PhH), 6.43-6.90 (m, 4H, quinoline-H), 4.42 (s, 2H, SCH 2 ), 4.15 (s, 2H, NCH 2 ), 3.42-3.44 (m, 2H, quinoline-H 2 ), 2.60-2.63 (m, 2H, quinoline-H 4 ), 2.51 (q, 2H, J=7.2Hz, C 5 -CH 2 CH 3 ), 1.84-1.86 (m, 2H, quinoline-H 3 ), 1.07 (t, 3H , J=7.2Hz, C 5 -CH 2 CH 3 ).IR(KBr, cm -1 ) v 3359(NH), 2932, 2841(CH 3 , CH 2 ), 1636(C=O), 1600, 1570 , 1547, 1508(aryl), 1251(CN), 1221(CN). ESI-MS: m/z 410.29(M+1).C 23 H 24 FN 3 OS (409.52).
实施例44:抗HIV细胞活性筛选试验 Embodiment 44: Anti-HIV cell activity screening test
术语说明: Glossary of terms:
MTT法:噻唑蓝法; MTT method: thiazolium blue method;
MT-4:人急性淋巴母细胞; MT-4: human acute lymphoblastic cells;
CCID50:细胞培养半数感染量; CCID50: Cell Culture Half Infection Dose;
DMSO:二甲基亚砜; DMSO: dimethyl sulfoxide;
EC50:保护50%感染HIV-1的MT-4细胞免于细胞病变的化合物浓度; EC 50 : the concentration of the compound that protects 50% of HIV-1-infected MT-4 cells from cytopathic changes;
CC50:使50%未感染HIV-1的细胞发生病变的化合物浓度; CC 50 : the concentration of the compound that makes 50% of the cells not infected with HIV-1 pathological;
SI:选择性系数,即CC50/EC50(HIV-1IIIB)的比值; SI: selectivity coefficient, that is, the ratio of CC 50 /EC 50 (HIV-1III B );
HIV-1(IIIB):HIV-1病毒株IIIB亚型; HIV-1 (III B ): HIV-1 virus strain III B subtype;
HIV-2(ROD):HIV-2病毒株ROD亚型。 HIV-2 (ROD): HIV-2 strain ROD subtype. the
化合物抗HIV活性试验,采用噻唑蓝法(MTT法):在96孔细胞培养板上,加入50uL含1×104MT-4细胞(人急性淋巴母细胞)培养液,再分别加入20uL感染HIV-1(IIIB)或HIV-2(ROD)的MT-4细胞混悬液(每毫升含100倍细胞培养半数感染量CCID50),然后加入不同浓度的待测化合物溶液,每个浓度3个孔,经过在37℃一定时间(5天)的培养后,向每个孔中加入20uL(5mg/ml)MTT溶液,继续培养2小时,然后加入溶解液二甲基亚砜(DMSO),与酶标仪上,在540nm测定吸收度,计算化合物不同浓度下的细胞增值率P%。同时设空白组,由此计算化合物保护50%的细胞免于HIV诱导的细胞病变所需浓度(EC50)。 Compound anti-HIV activity test, using the thiazolium blue method (MTT method): on a 96-well cell culture plate, add 50uL of culture medium containing 1× 104 MT-4 cells (human acute lymphoblastic cells), and then add 20uL respectively to infect HIV -1 (III B ) or HIV-2 (ROD) MT-4 cell suspension (per milliliter containing 100 times cell culture half infection dose CCID50), then add different concentrations of test compound solution, each concentration 3 Well, after culturing at 37°C for a certain period of time (5 days), add 20uL (5mg/ml) MTT solution to each well, continue to cultivate for 2 hours, then add the dissolving solution dimethyl sulfoxide (DMSO), and mix with On a microplate reader, the absorbance was measured at 540nm, and the cell proliferation rate P% at different concentrations of the compound was calculated. At the same time, a blank group was set up, from which the concentration required for the compound to protect 50% of the cells from HIV-induced cytopathy (EC 50 ) was calculated.
化合物毒性测定:在未感染的MT-4细胞中,与化合物抗HIV活性试验平行操作,用MTT法测定化合物使50%未感染细胞发生细胞病变的浓度,即毒性浓度(CC50)。 Determination of compound toxicity: in uninfected MT-4 cells, in parallel with the anti-HIV activity test of the compound, the MTT method was used to determine the concentration of the compound that caused 50% of the uninfected cells to undergo cytopathic changes, that is, the toxic concentration (CC 50 ).
选择指数的计算:SI=CC50/EC50。 Calculation of selection index: SI=CC 50 /EC 50 .
对上述合成的42个化合物6a1-6c14进行了抗HIV-1(IIIB)及HIV-2(ROD)活性筛选,它们的活性和毒性数据列于表2中,其中临床应用的核苷类逆转录酶抑制剂奈韦拉平(NVP)、地拉韦啶(DLV)、依法韦仑(EFV)和齐多夫定(AZT)作为阳性对照。由表可以看出,该类化合物对HIV-2(ROD)无抑制作用,但对HIV-1(IIIB)表现出了一定的抑制活性,其中活性最好的两个化合物6c1(EC50=0.24±0.05μM,CC50>297.95,SI>1218)和6c6(EC50=0.38+0.13μM,CC50>61.84μM,SI>164)。可作为抗HIV的先导化合物加以利用。 The 42 compounds 6a1-6c14 synthesized above were screened for anti-HIV-1 (III B ) and HIV-2 (ROD) activity, and their activity and toxicity data are listed in Table 2, wherein the nucleosides of clinical application reverse The transcriptase inhibitors nevirapine (NVP), delavirdine (DLV), efavirenz (EFV) and zidovudine (AZT) were used as positive controls. As can be seen from the table, these compounds have no inhibitory effect on HIV-2 (ROD), but have shown certain inhibitory activity on HIV-1 (III B ), among which the two compounds 6c1 with the best activity (EC 50 = 0.24±0.05 μM, CC 50 >297.95, SI >1218) and 6c6 (EC 50 =0.38+0.13 μM, CC 50 >61.84 μM, SI >164). It can be used as a lead compound against HIV.
表2化合物6a1-6c14的抗HIV-1(IIIB)及HIV-2(ROD)的活性和毒性(MT-4细胞) Anti-HIV-1 (III B ) and HIV-2 (ROD) activity and toxicity (MT-4 cell) of table 2 compound 6a1-6c14
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