CN107304189A - 一种三嗪化合物及其制备方法和应用 - Google Patents
一种三嗪化合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN107304189A CN107304189A CN201610239410.0A CN201610239410A CN107304189A CN 107304189 A CN107304189 A CN 107304189A CN 201610239410 A CN201610239410 A CN 201610239410A CN 107304189 A CN107304189 A CN 107304189A
- Authority
- CN
- China
- Prior art keywords
- compound
- halogen
- alkyl
- alkoxies
- triazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CC1*(C)C=CCC1 Chemical compound CC1*(C)C=CCC1 0.000 description 4
- RQQUFNIJIIZLPB-UHFFFAOYSA-N Cc(cc1)ccc1Sc1nc(CNc2cc(C)ccc2)nc(Sc2ccc(C)cc2)n1 Chemical compound Cc(cc1)ccc1Sc1nc(CNc2cc(C)ccc2)nc(Sc2ccc(C)cc2)n1 RQQUFNIJIIZLPB-UHFFFAOYSA-N 0.000 description 1
- JJYPMNFTHPTTDI-UHFFFAOYSA-N Cc1cc(N)ccc1 Chemical compound Cc1cc(N)ccc1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 1
- MGNCLNQXLYJVJD-UHFFFAOYSA-N Clc1nc(Cl)nc(Cl)n1 Chemical compound Clc1nc(Cl)nc(Cl)n1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N Nc(cc1)ccc1F Chemical compound Nc(cc1)ccc1F KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/42—One nitrogen atom
- C07D251/46—One nitrogen atom with oxygen or sulfur atoms attached to the two other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/48—Two nitrogen atoms
- C07D251/52—Two nitrogen atoms with an oxygen or sulfur atom attached to the third ring carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种如化学式(I)所示的三嗪化合物及其制备方法,以及其在制备治疗中枢神经系统疾病的药物中的应用,其中,R1选自氢、卤素、C1‑C4烷基、C1‑C4烷氧基、含卤素的C1‑C4烷基或含卤素的C1‑C4烷氧基,n=1‑2;R2选自C1‑C6烷基、苄基、苯基、吡啶、苯并噻唑、被卤素、C1‑C4烷基、C1‑C4烷氧基、C1‑C4烷硫基、C1‑C4烷酰胺基和羟基中的一个或多个取代的苯基;R3选自卤素、肼、C1‑C4烷酰肼基、芳酰肼基、苯并噻唑基硫基、苯硫基、苄硫基、被卤素、C1‑C4烷基和C1‑C4烷氧基中的一个或多个取代的苯硫基。
Description
技术领域
本发明属于药物化学领域,涉及一种三嗪化合物及其制备方法,以及其在制备治疗中枢神经系统疾病的药物中的应用。
背景技术
老年痴呆症,又名阿尔茨海默症,是一种进行性发展的致死性神经退行性疾病,临床表现为认知和记忆功能不断恶化,日常生活能力进行性减退,并有各种神经精神症状和行为障碍。很多研究明确表明AD患者脑中乙酰胆碱缺乏、烟碱型乙酰胆碱受体(nAChRs)表达减少是常见的现象。
根据文献报道,α7烟碱型乙酰胆碱受体正向变构调节剂(PAM)都有增加学习记忆的作用,实验表明缺乏α7nAChR亚基的小鼠与含有α7nAChR亚基小鼠的对照组相比,在水迷宫实验中学习记忆能力降低。α7尼古丁乙酰胆碱受体正向变构调节剂(nAChRPAMs)作用方式不同于激动剂,不易产生脱敏现象,潜在的毒副作用也会大大下降。通过调控α7尼古丁乙酰胆碱受体这一通路,有望发现一种新型疗法,用于治疗一系列中枢神经系统疾病如阿尔兹海默症和帕金森症等。
三嗪化合物是一种重要的含氮化合物,具有广泛的生物活性,包括抗菌、杀虫、抗肿瘤、除草等。因此,制备新颖的三嗪化合物具有重要的理论意义和实用价值。
发明内容
本发明提供了一种三嗪化合物,该化合物具有如化学式(I)所示的结构:
其中,R1选自氢、卤素、C1-C4烷基、C1-C4烷氧基、含卤素的C1-C4烷基或含卤素的C1-C4烷氧基,n=1-2;R2选自C1-C6烷基、苄基、苯基、吡啶、苯并噻唑、被卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷酰胺基和羟基中的一个或多个取代的苯基;R3选自卤素、肼、C1-C4烷酰肼基、芳酰肼基、苯并噻唑基硫基、苯硫基、苄硫基、被卤素、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫基。
本发明还提供了化学式(I)所示的三嗪化合物的制备方法,该方法包括:
(1)将2,4,6-三氯-1,3,5-三嗪与苯胺反应,或与被卤素、C1-C4烷基、C1-C4烷氧基、含卤素的C1-C4烷基和含卤素的C1-C4烷氧基中的一个或多个取代的苯胺反应,生成化合II;
(2)将化合物II与C1-C6硫醇、苄硫醇、苯硫酚、巯基吡啶或巯基苯并噻唑反应,或与被卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷酰胺基和羟基中的一个或多个取代的苯硫酚反应,生成化合物IV或V中的任意一个或两个化合物,化合物IV和V均为部分式(I)所示的化合物;
(3)将2,4,6-三氯-1,3,5-三嗪与C1-C6硫醇、苄硫醇、苯硫酚、巯基吡啶或巯基苯并噻唑反应,或与被卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷酰胺基和羟基中的一个或多个取代的苯硫酚反应,生成化合物III;
(4)将化合物III与苯胺反应,或与被卤素、C1-C4烷基、C1-C4烷氧基、含卤素的C1-C4烷基和含卤素的C1-C4烷氧基中的一个或多个取代的苯胺反应,生成化合物IV,为部分式I所示的化合物;
(5)将化合物IV与水合肼反应,生成化合物VI,为部分式(I)所示的化合物;
(6)将化合物VI与C1-C4烷酰氯反应,或与芳酰氯反应,生成化合物VII,为部分式(I)所示的化合物。
具体地,对于不同的式(I)化合物,其制备方法可以为以下三种合成路线中的一种。
合成路线一:
合成路线二:
合成路线三:
本发明还提供了化学式(I)所示的三嗪化合物在制备治疗中枢神经系统疾病的药物中的应用。
本发明提供的三嗪化合物具有一定的α7nAChR正向变构调节剂的活性,EC50值为1~100μM,且活性-浓度量效关系明显,为新药筛选和开发奠定了基础。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐明本发明,而不是为了限制本发明的范围。
实施例1:制备4-氯-N-苯基-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-00)
1、合成4,6-二氯-N-苯基-1,3,5-三嗪-2-胺(Ab1)
将化合物A(562mg,3mmol)置于4ml四氢呋喃中,冰浴下缓慢滴加溶有化合物b1(281mg,3mmol)与三乙胺(310mg,3mmol)的四氢呋喃溶液(2ml),缓慢升至室温,搅拌过夜。减压蒸馏除去四氢呋喃,加水,乙酸乙酯萃取3次,合并乙酸乙酯层,经饱和食盐水洗涤后旋干、拌样,硅胶柱色谱(石油醚:乙酸乙酯)分离,得白色固体410mg,记作Ab1,收率56.9%。
2、合成4-氯-N-苯基-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-00)
将化合物Ab1(247mg,1mmol)溶于4ml四氢呋喃中,冰浴下加入化合物c1(125mg,1mmol)、碳酸氢钠(84mg,1mmol)过饱和水溶液0.5ml,缓慢升至室温,搅拌过夜。后续操作同化合物Ab1,得白色固体176mg,记作PG-B-00,收率53.5%。1H NMR(400MHz,CDCl3)δ7.50(d,J=7.5Hz,2H),7.36(s,1H),7.30(d,J=7.5Hz,2H),7.04(s,5H),2.50(s,3H).13C NMR(101MHz,CDCl3)δ185.32,168.46,162.20,140.25,136.78,136.05,130.29,128.66,124.12,123.78,119.69,21.50.HRMS:m/z理论值C16H13ClN4S[M+H]+329.0622;实测值329.0630.
实施例2:制备4-氯-N-(2-氟苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-29)
1、合成4,6-二氯-N-(2-氟苯基)-1,3,5-三嗪-2-胺(Ab2)
合成方法同化合物Ab1。白色固体,记作Ab2,收率11%。
2、合成4-氯-N-(2-氟苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-29)
合成方法同化合物PG-B-00。白色固体,记作PG-B-29,收率52.8%。1H NMR(400MHz,CDCl3)δ7.50(d,J=7.7Hz,3H),7.38(t,J=8.1Hz,1H),7.30(d,J=7.5Hz,2H),7.08–6.91(m,2H),6.62(t,J=7.4Hz,1H),2.50(s,3H).13C NMR(101MHz,CDCl3)δ185.63,168.76,162.30,153.56,151.12,140.36,136.11,130.36,125.43,124.18,123.93,123.76,121.29,114.74,21.52.HRMS:m/z理论值C16H12ClFN4S[M+H]+347.0528;实测值347.0530.
实施例3:制备4-氯-N-(3-氟苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-40)
1、合成2,4-二氯-6-(4-甲基苯硫基)-1,3,5-三嗪(Ac1)
将化合物A(9.336g,50mmol)置于100ml四氢呋喃中,冰浴下加入化合物c1(6.231g,50mmol)、碳酸氢钠(6.312g,75mmol)过饱和水溶液10ml,缓慢升至室温,搅拌过夜。后续操作同化合物Ab1,得白色针状晶体6.420g,记作Ac1,收率47.4%。
2、合成4-氯-N-(3-氟苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-40)
将化合物Ac1(272mg,1mmol)溶于4ml四氢呋喃中,冰浴下缓慢滴加溶有化合物b3(131mg,1.2mmol)与三乙胺(110mg,1.1mmol)的四氢呋喃溶液(2ml),缓慢升至室温,搅拌约30分钟。后续操作同化合物Ab1,得白色固体171mg,记作PG-B-40,收率49.3%。1H NMR(400MHz,CDCl3)δ7.48(d,J=7.6Hz,2H),7.38(d,J=7.6Hz,1H),7.29(d,J=7.4Hz,2H),7.06(d,J=6.9Hz,1H),6.97(d,J=10.6Hz,1H),6.73(d,J=7.8Hz,2H),2.45(s,3H).13C NMR(101MHz,CDCl3)δ185.70,168.69,164.10,162.44,161.66,140.98,138.42,138.31,135.64,130.46,129.85,123.30,115.04,111.07,110.87,107.37,77.35,77.24,77.03,76.72,21.41.HRMS:m/z理论值C16H12ClFN4S[M+H]+347.0528;实测值347.0538.
实施例4:制备4-氯-N-(4-氟苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-30)
1、合成4,6-二氯-N-(4-氟苯基)-1,3,5-三嗪-2-胺(Ab4)
合成方法同化合物Ab1。白色固体,记作Ab4,收率25%。
2、合成4-氯-N-(4-氟苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-30)
合成方法同化合物PG-B-00。白色固体,记作PG-B-30,收率53.4%。1H NMR(400MHz,CDCl3)δ7.48(d,J=7.9Hz,2H),7.36(s,1H),7.29(d,J=7.8Hz,2H),7.02(dd,J=8.7,4.6Hz,2H),6.73(t,J=8.5Hz,2H),2.50(s,3H).13C NMR(101MHz,CDCl3)δ185.36,168.55,162.22,159.18,140.31,136.04,132.77,130.27,123.80,121.59,115.31,21.46.HRMS:m/z理论值C16H12ClFN4S[M+H]+347.0528;实测值347.0533.
实施例5:制备4-氯-N-(3-氯苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-31)
1、合成4,6-二氯-N-(3-氯苯基)-1,3,5-三嗪-2-胺(Ab5)
合成方法同化合物Ab1。白色固体,记作Ab5,收率47%。
2、合成4-氯-N-(3-氯苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-31)
合成方法同化合物PG-B-00。无色半固体,记作PG-B-31,收率92.7%。1H NMR(400MHz,CDCl3)δ7.47(d,J=7.5Hz,2H),7.39(s,1H),7.28(s,2H),7.16(s,1H),6.99(s,3H),2.44(s,3H).13C NMR(101MHz,CDCl3)δ185.54,168.67,162.48,140.51,137.94,135.58,134.50,130.46,129.76,124.40,123.36,119.76,118.09,21.55.HRMS:m/z理论值C16H12Cl2N4S[M+H]+363.0232;实测值363.0232.
实施例6:制备4-氯-N-(4-氯苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-41);
实施例7:制备N-(4-氯苯基)-4,6-双(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-45)
1、合成4,6-二氯-N-(4-氯苯基)-1,3,5-三嗪-2-胺(Ab6)
合成方法同化合物Ab1。白色固体,记作Ab6,收率20%。
2、合成4-氯-N-(4-氯苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-41)及N-(4-氯苯基)-4,6-双(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-45)
将化合物Ab6(160mg,0.58mmol)溶于4ml四氢呋喃中,冰浴下加入化合物c1(110mg,0.88mmol)、碳酸氢钠(80mg,0.95mmol)过饱和水溶液0.5ml,缓慢升至室温,搅拌过夜。后续操作同化合物Ab1,得2份白色固体,分别记作:(1)PG-B-41,收率35.6%。1H NMR(400MHz,CDCl3)δ7.74–7.64(m,1H),7.47(d,J=7.6Hz,2H),7.29(d,J=7.5Hz,2H),6.98(s,4H),2.51(s,3H).13C NMR(101MHz,CDCl3)δ185.44,168.50,162.20,140.46,136.08,135.38,130.38,129.21,128.62,123.69,121.32,21.51.HRMS:m/z理论值C16H12Cl2N4S[M+H]+363.0232;实测值363.0227.(2)PG-B-45,收率34.4%。
1H NMR(400MHz,CDCl3)δ7.51–7.02(m,9H),6.91(s,4H),2.42(d,J=48.6Hz,6H).HRMS:m/z理论值C23H19ClN4S2[M+H]+451.0812;实测值451.0815.
实施例8:制备N-(2-溴苯基)-4-氯-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-28)
1、合成N-(2-溴苯基)-4,6-二氯-1,3,5-三嗪-2-胺(Ab7)
合成方法同化合物Ab1。类白色固体,记作Ab7,收率39%。
2、合成N-(2-溴苯基)-4-氯-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-28)
合成方法同化合物PG-B-00。白色固体,记作PG-B-28,收率58.8%。1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.49(d,J=8.1Hz,4H),7.29(d,J=7.9Hz,2H),6.84(d,J=38.9Hz,2H),2.48(s,3H).13C NMR(101MHz,CDCl3)δ184.35,168.85,162.46,140.31,136.03,134.69,132.40,130.95,130.30,127.70,124.98,123.72,121.64,21.51.HRMS:m/z理论值C16H12BrClN4S[M+H]+406.9727;实测值406.9727.
实施例9:制备N-(3-溴苯基)-4-氯-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-A-00)
1、合成N-(3-溴苯基)-4,6-二氯-1,3,5-三嗪-2-胺(Ab8)
合成方法同化合物Ab1。白色固体,记作Ab8,收率73%。
2、合成N-(3-溴苯基)-4-氯-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-A-00)
合成方法同化合物PG-B-00。无色半固体,记作PG-A-00,收率83.8%。1H NMR(400MHz,DMSO-d6)δ10.72(d,J=54.0Hz,1H),7.52(d,J=8.0Hz,2H),7.49(s,1H),7.35(d,J=7.6Hz,2H),7.27(d,J=8.0Hz,1H),7.20(d,J=7.7Hz,1H),6.93(t,J=7.9Hz,1H),2.42(s,3H).13C NMR(101MHz,DMSO-d6)δ184.00,168.01,162.63,140.62,139.77,135.86,130.82,130.63,126.78,123.45,122.73,121.70,119.32,21.51.HRMS:m/z理论值C16H12BrClN4S[M+H]+406.9727;实测值406.9724.
实施例10:制备N-(4-溴苯基)-4-氯-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-01)
合成方法同化合物PG-B-40。白色固体,记作PG-B-01,收率34.3%。1H NMR(400MHz,CDCl3)δ7.53–7.45(m,3H),7.33(d,J=7.3Hz,2H),7.16(d,J=8.1Hz,2H),6.96(d,J=8.1Hz,2H),2.55(s,3H).13C NMR(101MHz,CDCl3)δ185.49,168.56,162.18,140.45,136.06,135.81,131.59,130.35,123.69,121.46,116.84,21.46.HRMS:m/z理论值C16H12BrClN4S[M+H]+406.9727;实测值406.9720.
实施例11:制备4-氯-N-(2-甲基苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-02)
合成方法同化合物PG-B-40。白色固体,记作PG-B-02,收率32.1%。1H NMR(400MHz,CDCl3)δ7.46(d,J=7.4Hz,2H),7.33(d,J=7.8Hz,1H),7.25(d,J=7.4Hz,2H),7.12(d,J=6.9Hz,2H),7.01(t,J=6.8Hz,1H),6.83(t,J=6.8Hz,1H),2.47(s,3H),2.23(s,3H).13CNMR(101MHz,CDCl3)δ185.13,168.62,162.68,140.10,135.77,134.83,130.38,130.12,128.27,126.33,124.74,123.73,121.90,21.47,17.90.HRMS:m/z理论值C17H15ClN4S[M+H]+343.0779;实测值343.0776.
实施例12:制备4-氯-N-(4-甲基苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-04)
合成方法同化合物PG-B-40。白色固体,记作PG-B-04,收率81.6%。1H NMR(400MHz,CDCl3)δ7.49(d,J=7.9Hz,2H),7.44(d,J=5.9Hz,1H),7.29(d,J=7.8Hz,2H),6.94(d,J=8.3Hz,2H),6.84(d,J=8.2Hz,2H),2.51(s,3H),2.29(s,3H).HRMS:m/z理论值C17H15ClN4S[M+H]+343.0779;实测值343.0772.
实施例13:制备4-氯-N-(2-甲氧基苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-05)
1、合成4,6-二氯-N-(2-甲氧基苯基)-1,3,5-三嗪-2-胺(Ab12)
合成方法同化合物Ab1。白色固体,记作Ab12,收率42%。
2、合成4,6-二氯-N-(2-甲氧基苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-05)
合成方法同化合物PG-B-00。白色固体,记作PG-B-05,收率70.2%。1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.54(d,J=7.9Hz,2H),7.39(d,J=8.1Hz,1H),7.34(d,J=7.8Hz,2H),6.98(t,J=7.4Hz,1H),6.83(d,J=8.0Hz,1H),6.47(t,J=7.7Hz,1H),3.86(s,3H),2.54(s,3H).13C NMR(101MHz,CDCl3)δ185.34,168.45,162.00,148.03,140.29,136.19,130.37,126.54,124.00,123.80,120.44,119.71,109.90,55.78,21.57.HRMS:m/z理论值C17H15ClN4OS[M+H]+359.0728;实测值359.0737.
实施例14:制备4-氯-N-(4-甲氧基苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-42)
合成方法同化合物PG-B-40。白色固体,记作PG-B-42,收率46.2%。1H NMR(400MHz,CDCl3)δ7.50(d,J=7.4Hz,2H),7.46(s,1H),7.31(d,J=7.6Hz,2H),6.99(d,J=8.6Hz,2H),6.60(d,J=8.6Hz,2H),3.79(s,3H),2.52(s,3H).杂峰太多HRMS:m/z理论值C17H15ClN4OS[M+H]+359.0728;实测值359.0717.
实施例15:制备4-氯-6-(4-甲基苯硫基)-N-(4-三氟甲基苯基)-1,3,5-三嗪-2-胺(编号:PG-B-36);实施例16:制备4,6-双(4-甲基苯硫基)-N-(4-三氟甲基苯基)-1,3,5-三嗪-2-胺(编号:PG-B-44)
1、合成4,6-二氯-N-(4-三氟甲基苯基)-1,3,5-三嗪-2-胺(Ab14)
合成方法同化合物Ab1。白色固体,记作Ab14,收率20%。
2、合成4-氯-6-(4-甲基苯硫基)-N-(4-三氟甲基苯基)-1,3,5-三嗪-2-胺(编号:PG-B-36)及4,6-双(4-甲基苯硫基)-N-(4-三氟甲基苯基)-1,3,5-三嗪-2-胺(编号:PG-B-44)
合成方法同化合物PG-B-41与PG-B-45。得2份白色固体,分别记作:(1)PG-B-36,收率55.6%。1H NMR(400MHz,CDCl3)δ7.58(s,1H),7.49(d,J=7.1Hz,2H),7.36–7.26(m,4H),7.16(s,2H),2.50(s,3H).13C NMR(101MHz,CDCl3)δ185.89,168.93,162.44,140.59,139.86,136.14,130.46,125.88,125.32,123.71,122.62,119.66,21.33.HRMS:m/z理论值C17H12ClF3N4S[M+H]+397.0496;实测值397.0507.(2)PG-B-44,收率31.7%。1H NMR(400MHz,CDCl3)δ7.60(s,1H),7.45(s,4H),7.35–7.03(m,8H),2.45(s,6H).HRMS:m/z理论值C24H19F3N4S2[M+H]+485.1076;实测值485.1082.
实施例17:制备4-氯-6-(4-甲基苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-B-13)
合成方法同化合物PG-B-40。白色固体,记作PG-B-13,收率33.9%。1H NMR(400MHz,CDCl3)δ7.54(d,J=18.4Hz,3H),7.32(d,J=12.2Hz,2H),7.11(s,2H),6.91(s,2H),2.52(s,3H).13C NMR(101MHz,CDCl3)δ185.60,168.69,162.29,145.13,140.47,136.12,135.39,130.37,123.75,121.19,121.05,120.46,21.31.HRMS:m/z理论值C17H12ClF3N4OS[M+H]+413.0445;实测值413.0456.
实施例18:制备4-氯-N-(4-乙基苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-38)
合成方法同化合物PG-B-40。无色半固体,记作PG-B-38,收率61.6%。1H NMR(400MHz,CDCl3)δ7.65(s,1H),7.49(d,J=7.9Hz,2H),7.30(d,J=7.8Hz,2H),6.98(d,J=8.3Hz,2H),6.88(d,J=8.3Hz,2H),2.60(dd,J=15.0,7.5Hz,2H),2.52(s,3H),1.23(t,J=7.6Hz,3H).HRMS:m/z理论值C18H17ClN4S[M+H]+357.0935;实测值357.0944.
实施例19:制备4-氯-N-(3,4-二甲基苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-39)
合成方法同化合物PG-B-40。无色半固体,记作PG-B-39,收率30.0%。1H NMR(400MHz,CDCl3)δ7.47(d,J=7.8Hz,3H),7.28(d,J=7.5Hz,2H),6.90–6.70(m,3H),2.44(d,J=15.8Hz,3H),2.18(s,3H),2.09(s,3H).13C NMR(101MHz,CDCl3)δ184.98,168.38,162.30,140.10,137.05,135.80,134.45,132.66,130.23,129.78,123.91,120.92,117.51,21.44,19.71,19.16.HRMS:m/z理论值C18H17ClN4S[M+H]+357.0935;实测值357.0945.
实施例20:制备N-(3-甲基苯基)-4,6-双(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-03)
将化合物A(5.815g,31.6mmol)置于40ml四氢呋喃中,冰浴下缓慢滴加溶有化合物b18(3.330g,31.1mmol)与三乙胺(3.312g,32.8mmol)的四氢呋喃溶液(20ml),缓慢升至室温,搅拌。两夜后,冰浴下加入溶有化合物c1(3.741g,30.2mmol)的四氢呋喃10ml、碳酸氢钠(3.316g,39.5mmol)过饱和水溶液6ml,缓慢升至室温,搅拌过两夜。后续操作同化合物Ab1,得类白色固体,记作PG-B-03,未计算收率。1H NMR(400MHz,CDCl3)δ7.44(d,J=6.6Hz,5H),7.20(d,J=6.7Hz,4H),6.99–6.75(m,4H),2.42(s,6H),2.17(s,3H).HRMS:m/z理论值C24H22N4S2[M+H]+431.1358;实测值431.1359.
实施例21:制备N-(4-甲氧基苯基)-4,6-双(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-06)
合成方法同PG-B-03。白色发泡状固体,记作PG-B-06,收率未计算。1H NMR(400MHz,CDCl3)δ7.41(dd,J=31.0,6.6Hz,4H),7.19(dd,J=32.4,14.6Hz,5H),6.95–6.89(m,2H),6.56–6.51(m,2H),3.74(s,3H),2.47(s,3H),2.35(s,3H).HRMS:m/z理论值C24H22N4OS2[M+H]+447.1308;实测值447.1311.
实施例22:制备4,6-双(4-甲基苯硫基)-N-(3-三氟甲基苯基)-1,3,5-三嗪-2-胺(编号:PG-B-37)
1、合成4,6-二氯-N-(3-三氟甲基苯基)-1,3,5-三嗪-2-胺(Ab20)
合成方法同化合物Ab1。白色固体,记作Ab20,收率37%。
2、合成4,6-双(4-甲基苯硫基)-N-(3-三氟甲基苯基)-1,3,5-三嗪-2-胺(编号:PG-B-37)
合成方法同化合物PG-B-45。无色半固体,记作PG-B-37,收率22.5%。1H NMR(400MHz,CDCl3)δ7.42(d,J=7.2Hz,6H),7.24–7.14(m,6H),7.05(t,J=7.9Hz,1H),2.42(s,6H).HRMS:m/z理论值C24H19F3N4S2[M+H]+485.1076;实测值485.1098.
实施例23:制备4,6-双(4-甲基苯硫基)-N-(3-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-B-43)
1、合成4,6-二氯-N-(3-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(Ab21)
合成方法同化合物Ab1。白色固体,记作Ab21,收率42%。
2、合成4,6-双(4-甲基苯硫基)-N-(3-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-B-43)
合成方法同化合物PG-B-45。白色固体,记作PG-B-43,收率72.2%。1H NMR(400MHz,CDCl3)δ7.60(s,1H),7.54–7.35(m,5H),7.00(ddd,J=64.9,50.7,31.0Hz,7H),2.41(t,J=26.3Hz,6H).HRMS:m/z理论值C24H19F3N4OS2[M+H]+501.1025;实测值501.1016.
实施例24:制备4-肼基-N-苯基-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-07)
将化合物PG-B-00(150mg,0.46mmol)置于2ml乙腈中,加入约0.2ml四氢呋喃使其溶解,加入化合物d的水溶液(d含量约24mg,0.48mmol)、碳酸氢钠(78mg,0.93mmol),室温搅拌。TLC检测原料点基本不可见后,加入大量水稀释,体系液面漂浮大量白色固体,抽滤、干燥,得白色固体146mg,记作PG-B-07,收率98.0%。1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),9.40(s,1H),8.65(s,1H),7.49(d,J=5.9Hz,2H),7.31(d,J=7.4Hz,3H),7.02(s,2H),6.90(s,1H),4.29(s,2H),2.42(s,3H).HRMS:m/z理论值C16H16N6S[M+H]+325.1230;实测值325.1228.
实施例25:制备N-(2-氟苯基)-4-肼基-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-33)
合成方法同化合物PG-B-07。白色固体,记作PG-B-33,收率64.2%。1H NMR(400MHz,DMSO-d6)δ8.96(d,J=64.5Hz,1H),8.60(d,J=47.8Hz,1H),7.54–6.89(m,8H),4.23(s,2H),2.35(s,3H).HRMS:m/z理论值C16H15FN6S[M+H]+343.1136;实测值343.1128.
实施例26:制备N-(4-氟苯基)-4-肼基-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-34)
合成方法同化合物PG-B-07。白色固体,记作PG-B-34,收率93.4%。1H NMR(400MHz,DMSO-d6)δ9.53(d,J=76.5Hz,1H),8.65(s,1H),7.87–6.70(m,8H),4.27(s,2H),2.39(s,3H).HRMS:m/z理论值C16H15FN6S[M+H]+343.1136;实测值343.1144.
实施例27:制备N-(2-溴苯基)-4-肼基-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-32)
合成方法同化合物PG-B-07。白色固体,记作PG-B-32,收率82.4%。1H NMR(400MHz,DMSO-d6)δ8.76–8.65(m,1H),8.64–8.53(m,1H),7.59(d,J=7.9Hz,1H),7.43(s,3H),7.21(d,J=7.4Hz,3H),7.10–7.00(m,1H),4.30(s,2H),2.35(s,3H).HRMS:m/z理论值C16H15BrN6S[M+H]+403.0335;实测值403.0343.
实施例28:制备N-(3-溴苯基)-4-肼基-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-A-01)
将化合物PG-A-00(50mg,0.12mmol)置于2ml乙腈中,加入化合物d的水溶液(d含量约13mg,0.26mmol)、碳酸氢钠(21mg,0.25mmol),室温搅拌。后续操作同化合物PG-B-07,得白色固体32mg,记作PG-A-01,收率66.2%。1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.57(s,1H),8.74(s,1H),7.48(d,J=7.2Hz,3H),7.29(d,J=7.8Hz,2H),7.09(d,J=6.0Hz,1H),7.04–6.84(m,1H),4.31(s,2H),2.39(s,3H).13C NMR(101MHz,DMSO-d6)δ166.22,163.16,162.52,141.75,139.47,135.80,130.52,130.35,125.23,124.97,122.05,121.64,118.78,21.42.HRMS:m/z理论值C16H15BrN6S[M+H]+403.0335;实测值403.0330.
实施例29:制备N-(4-溴苯基)-4-肼基-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-08)
合成方法同化合物PG-B-07。白色固体,记作PG-B-08,收率97.2%。1H NMR(400MHz,DMSO-d6)δ9.64(d,J=74.5Hz,1H),8.71(s,1H),7.54–7.05(m,8H),4.33(s,2H),2.41(s,3H).HRMS:m/z理论值C16H15BrN6S[M+H]+403.0335;实测值403.0342.
实施例30:制备4-肼基-N-(2-甲基苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-09)
合成方法同化合物PG-B-07。白色固体,记作PG-B-09,收率78.6%。1H NMR(400MHz,DMSO-d6)δ8.76(d,J=50.2Hz,1H),8.48(d,J=27.1Hz,1H),7.42(s,2H),7.20(s,3H),7.14(s,1H),7.03(s,2H),4.17(s,2H),2.34(s,3H),2.15(s,3H).HRMS:m/z理论值C17H18N6S[M+H]+339.1386;实测值339.1389.
实施例31:制备4-肼基-N-(4-甲基苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-10)
合成方法同化合物PG-B-07。白色固体,记作PG-B-10,收率86.1%。1H NMR(400MHz,DMSO-d6)δ9.39(d,J=71.2Hz,1H),8.60(s,1H),7.76–6.69(m,8H),4.30(s,2H),2.41(s,3H),2.20(s,3H).HRMS:m/z理论值C17H18N6S[M+H]+339.1386;实测值339.1387.
实施例32:制备4-肼基-N-(2-甲氧基苯基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-胺(编号:PG-B-11)
合成方法同化合物PG-B-07。白色固体,记作PG-B-11,收率81.6%。1H NMR(400MHz,DMSO-d6)δ8.65(d,J=29.0Hz,1H),7.78(d,J=38.2Hz,1H),7.48(d,J=6.1Hz,3H),7.29(d,J=7.7Hz,2H),6.97(s,2H),6.62(s,1H),4.30(s,2H),3.81(s,3H),2.41(s,3H).HRMS:m/z理论值C17H18N6OS[M+H]+355.1336;实测值355.1340.
实施例33:制备4-肼基-6-(4-甲基苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-B-15)
合成方法同化合物PG-B-07。白色固体,记作PG-B-15,收率85.8%。1H NMR(400MHz,DMSO-d6)δ9.69(d,J=74.6Hz,1H),8.72(s,1H),7.26(t,J=103.4Hz,8H),4.33(s,2H),2.40(s,3H).HRMS:m/z理论值C17H15F3N6OS[M+H]+409.1053;实测值409.1059.
实施例34:制备N'-(4-苯氨基-6-(4-甲基苯硫基)-1,3,5-三嗪-2-基)乙酰肼(编号:PG-B-12)
将化合物PG-B-07(86mg,0.27mmol)置于1ml二氯甲烷中,加入三乙胺(50mg,0.5mmol),冰浴下滴加含化合物e1(39mg,0.5mmol)的二氯甲烷,缓慢升至室温,搅拌过夜。饱和碳酸氢钠水溶液洗涤体系,静置片刻,体系中出现白色固体,抽滤、洗涤、干燥,得白色固体50mg,记作PG-B-12,收率54.7%。HRMS:m/z理论值C18H18N6OS[M+H]+367.1336;实测值367.1346.
实施例35:制备N'-(4-(3-溴苯氨基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-基)乙酰肼(编号:PG-A-02)
合成方法同化合物PG-B-12。白色固体,记作PG-A-02,收率11.2%。1H NMR(400MHz,DMSO-d6)δ9.60(d,J=166.5Hz,3H),8.22(d,J=84.1Hz,1H),7.50(d,J=7.6Hz,2H),7.46(d,J=8.0Hz,1H),7.30(d,J=6.0Hz,2H),7.13(s,2H),2.38(s,3H),2.02–1.70(m,3H).13C NMR(101MHz,DMSO-d6)δ168.92,166.25,163.05,141.49,139.66,135.87,130.43,130.24,125.32,124.87,122.28,121.80,118.92,79.65,21.39,21.21.HRMS:m/z理论值C18H17BrN6OS[M+H]+445.0441;实测值445.0441.
实施例36:制备N'-(4-(3-溴苯氨基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-基)苯甲酰肼(编号:PG-A-03)
合成方法同化合物PG-B-12。白色固体,记作PG-A-03,收率13.4%。HRMS:m/z理论值C23H19BrN6OS[M+H]+507.0597;实测值507.0598.
实施例37:制备N'-(4-(3-溴苯氨基)-6-(4-甲基苯硫基)-1,3,5-三嗪-2-基)-4-甲氧基苯甲酰肼(编号:PG-A-04)
将化合物PG-A-01(410mg,1mmol)置于3ml二氯甲烷中,加入三乙胺(210mg,2mmol),冰浴下滴加含化合物e3(340mg,2mmol)的二氯甲烷溶液2ml,缓慢升至室温,搅拌过夜。乙酸乙酯稀释,饱和碳酸钾水溶液洗涤体系,乙酸乙酯层浓缩后出现白色固体,抽滤、洗涤、干燥,得白色固体180mg,记作PG-A-04,收率33.5%。HRMS:m/z理论值C24H21BrN6O2S[M+H]+537.0703;实测值537.0696.
实施例38:制备4-氯-6-环己硫基-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-1)1、合成4,6-二氯-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(Ab15)
合成方法同化合物Ab1。白色固体,记作Ab15,收率57%。
2、合成4-氯-6-环己硫基-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-1)
将化合物Ab15(327mg,1mmol)溶于1.5ml四氢呋喃,冰浴下加入溶有化合物c2(182mg,1.57mmol)和三乙胺(140mg,1.4mmol)的四氢呋喃溶液1ml,缓慢升至室温,搅拌过夜。后续操作同化合物Ab1,得白色固体360mg,记作PG-C-1,收率88.9%。1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.59(d,J=8.1Hz,2H),7.23(d,J=8.4Hz,2H),3.72(s,1H),2.08(d,J=11.9Hz,2H),1.78(d,J=7.2Hz,2H),1.69–1.26(m,6H).13C NMR(101MHz,CDCl3)δ184.51,168.48,162.56,145.81,135.43,122.58,121.78,120.46,43.85,32.64,26.00,25.49.HRMS:m/z理论值C16H16ClF3N4OS[M+H]+405.0758;实测值405.0764.
实施例39:制备4-苄硫基-6-氯-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-17)
将化合物Ab15(332mg,1mmol)溶于2ml四氢呋喃,冰浴下加入溶有化合物c3(135mg,1.1mmol)和三乙胺(151mg,1.5mmol)的四氢呋喃溶液1ml,室温搅拌4小时。后续操作同化合物Ab1,得类白色固体125mg,记作PG-C-17,收率30.3%。1H NMR(400MHz,CDCl3)δ7.70–7.27(m,8H),7.21(s,2H),4.37(s,2H).13C NMR(101MHz,CDCl3)δ183.78,168.68,162.70,145.93,136.00,135.20,128.92,128.67,127.63,122.78,121.74,120.50,34.90.HRMS:m/z理论值C17H12ClF3N4OS[M+H]+413.0445;实测值413.0447.
实施例40:制备4-氯-6-(吡啶-2-基硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-5)
合成方法同化合物PG-C-1。白色固体,记作PG-C-5,收率63.8%。HRMS:m/z理论值C15H9ClF3N5OS[M+H]+400.0241;实测值400.0249.
实施例41:制备4-氯-6-(3-氟苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-6)
合成方法同化合物PG-C-17。白色固体,记作PG-C-6,收率64.7%。1H NMR(400MHz,CDCl3)δ7.62–7.28(m,6H),7.12(d,J=8.0Hz,2H),6.97(d,J=7.7Hz,2H).13C NMR(101MHz,CDCl3)δ184.36,168.86,163.94,162.47,161.46,145.53,135.11,131.71,130.77,128.93,123.02,121.48,120.45,117.26.HRMS:m/z理论值C16H9ClF4N4OS[M+H]+417.0194;实测值417.0189.
实施例42:制备4-氯-6-(4-氟苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-8)
合成方法,除室温搅拌过夜之外,其他项同化合物PG-C-17。白色固体,记作PG-C-8,收率86.3%。1H NMR(400MHz,CDCl3)δ7.58(d,J=4.6Hz,2H),7.32(s,1H),7.18(t,J=8.0Hz,2H),7.08(d,J=6.9Hz,2H),6.97(d,J=7.9Hz,2H).13C NMR(101MHz,CDCl3)δ184.95,168.81,164.07,162.39,145.47,138.37,135.19,122.61,121.35,120.90,120.45,116.79.HRMS:m/z理论值C16H9ClF4N4OS[M+H]+417.0194;实测值417.0191.
实施例43:制备4-(4-溴苯硫基)-6-氯-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-12);实施例44:制备4,6-双(4-溴苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-19)
合成方法同化合物PG-C-1。得两份白色固体,分别记作:(1)PG-C-12,收率22.0%。1H NMR(400MHz,CDCl3)δ7.63(d,J=8.1Hz,2H),7.47(d,J=8.1Hz,2H),7.38(s,1H),7.05(d,J=8.9Hz,2H),7.01(d,J=8.7Hz,2H).13C NMR(101MHz,CDCl3)δ184.56,168.80,162.24,145.42,137.74,135.12,132.85,126.23,125.02,121.54,120.96,120.41.HRMS:m/z理论值C16H9BrClF3N4OS[M+H]+476.9394;实测值476.9390.(2)PG-C-19,收率36.5%。1HNMR(400MHz,CDCl3)δ7.53(s,4H),7.39(d,J=6.7Hz,4H),7.09(d,J=9.1Hz,3H),6.99(d,J=8.9Hz,2H).HRMS:m/z理论值C22H13Br2F3N4OS2[M+H]+628.8922;实测值628.8908.
实施例45:制备4-氯-6-(4-甲氧基苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-10);实施例46:制备4,6-双(4-甲氧基苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-20)
合成方法同化合物PG-C-1。得两份白色固体,分别记作:(1)PG-C-10,收率54.8%。1H NMR(400MHz,CDCl3)δ7.51(d,J=8.5Hz,3H),7.07(d,J=8.3Hz,2H),7.01(d,J=8.0Hz,2H),6.91(d,J=7.9Hz,2H),3.89(s,3H).13C NMR(101MHz,CDCl3)δ185.93,168.63,162.19,161.32,145.12,137.82,135.43,121.26,120.90,120.42,117.84,115.11,55.35.HRMS:m/z理论值C17H12ClF3N4O2S[M+H]+429.0394;实测值429.0392.(2)PG-C-20,收率41.5%。1H NMR(400MHz,CDCl3)δ7.38(d,J=55.5Hz,5H),7.08–6.75(m,8H),3.85(s,6H).HRMS:m/z理论值C24H19F3N4O3S2[M+H]+533.0923;实测值533.0926.
实施例47:制备4-氯-6-(4-乙基苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-11);实施例48:制备4,6-双(4-乙基苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-18)
合成方法同化合物PG-C-1。得两份白色固体,分别记作:(1)PG-C-11,收率58.5%。1HNMR(400MHz,CDCl3)δ7.52(d,J=7.6Hz,2H),7.36(s,1H),7.33(d,J=7.6Hz,2H),7.10(d,J=8.4Hz,2H),6.89(d,J=8.1Hz,2H),2.79(q,J=7.2Hz,2H),1.33(t,J=7.4Hz,3H).13C NMR(101MHz,CDCl3)δ185.57,168.63,162.28,146.68,145.14,136.12,135.43,129.14,123.84,121.29,120.96,120.44,28.65,15.19.HRMS:m/z理论值C18H14ClF3N4OS[M+H]+427.0602;实测值427.0608.(2)PG-C-18,收率27.5%。1H NMR(400MHz,CDCl3)δ7.54–7.12(m,9H),7.00(dd,J=8.6,4.9Hz,2H),6.82(d,J=8.8Hz,2H),2.71(d,J=37.7Hz,4H),1.23(dd,J=37.4,13.0Hz,6H).HRMS:m/z理论值C26H23F3N4OS2[M+H]+529.1348;实测值529.1338.
实施例49:制备4-氯-6-(4-甲硫基苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-13)
合成方法同化合物PG-C-17。白色固体,记作PG-C-13,收率60.7%。1H NMR(400MHz,CDCl3)δ7.50(d,J=7.9Hz,3H),7.31(d,J=8.0Hz,2H),7.06(d,J=8.8Hz,2H),6.98(d,J=8.6Hz,2H),2.54(s,3Hz).13C NMR(101MHz,CDCl3)δ185.48,168.66,162.17,145.24,142.49,136.49,135.38,126.20,122.49,121.47,120.81,120.42,14.65.HRMS:m/z理论值C17H12ClF3N4OS2[M+H]+445.0166;实测值445.0168.
实施例50:制备4-(4-叔丁基苯硫基)-6-氯-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-15)
合成方法同化合物PG-C-17。白色固体,记作PG-C-15,收率48.4%。1H NMR(400MHz,CDCl3)δ7.57–7.49(m,5H),7.19(d,J=8.5Hz,2H),6.93(d,J=8.3Hz,2H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ185.40,168.54,162.28,153.68,145.11,135.58,135.45,126.57,123.55,121.44,120.86,120.40,34.91,31.24.HRMS:m/z理论值C20H18ClF3N4OS[M+H]+455.0915;实测值455.0912.
实施例51:制备N-(4-(4-氯-6-(4-三氟甲氧基苯基)氨基-1,3,5-三嗪-2-基)硫基苯基)乙酰胺(编号:PG-C-14)
合成方法同化合物PG-C-17。白色固体,记作PG-C-14,收率65.8%。1H NMR(400MHz,CDCl3)δ7.67(d,J=7.8Hz,2H),7.53(d,J=8.1Hz,2H),7.45(s,1H),7.33(s,1H),7.09(d,J=8.6Hz,2H),6.93(d,J=8.2Hz,2H),2.25(s,4H).13C NMR(101MHz,DMSO-d6)δ183.92,168.64,167.45,161.88,143.63,141.25,136.77,121.17,120.91,119.54,119.48,118.67,23.80.少OCF3HRMS:m/z理论值C18H13ClF3N5O2S[M+H]+456.0503;实测值456.0502.
实施例52:制备4-(4-氯-6-(4-三氟甲氧基苯基)氨基-1,3,5-三嗪-2-基)硫基苯酚(编号:PG-C-16)
合成方法同化合物PG-C-17。白色固体,记作PG-C-16,收率53.0%。1H NMR(400MHz,CDCl3)δ7.48(d,J=7.9Hz,2H),7.34(s,1H),7.10(d,J=8.4Hz,2H),6.97(t,J=7.6Hz,4H),5.14(s,1H).13C NMR(101MHz,DMSO-d6)δ184.90,167.98,162.44,160.12,144.14,138.29,137.49,121.66,121.48,117.15,115.49.少OCF3HRMS:m/z理论值C16H10ClF3N4O2S[M+H]+415.0238;实测值415.0239.
实施例53:制备4,6-双苄硫基-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-2)
合成方法同化合物PG-C-1。白色固体,记作PG-C-2,收率73.0%。1H NMR(400MHz,CDCl3)δ7.50(d,J=9.0Hz,2H),7.38–7.21(m,11H),7.13(d,J=8.6Hz,2H),4.35(s,4H).13CNMR(101MHz,CDCl3)δ180.17,160.99,145.24,136.69,136.03,128.87,128.62,127.42,121.97,121.65,120.47,34.51.HRMS:m/z理论值C24H19F3N4OS2[M+H]+501.1025;实测值501.1028.
实施例54:制备4,6-双(苯并[d]噻唑-2-基硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-4)
合成方法同化合物PG-C-1。白色固体,记作PG-C-4,收率10.2%。1H NMR(400MHz,CDCl3)δ8.09(d,J=27.9Hz,2H),7.75(s,2H),7.51(t,J=31.0Hz,4H),7.31(s,1H),7.15(d,J=6.2Hz,2H),6.61(d,J=6.8Hz,2H).HRMS:m/z理论值C24H13F3N6OS4[M+H]+587.0058;实测值587.0068.
实施例55:制备4,6-双(3-氟苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-7)
合成方法同化合物PG-C-1。浅黄半固体,记作PG-C-7,收率55.7%。1H NMR(400MHz,CDCl3)δ7.43–7.27(m,7H),7.17(d,J=9.0Hz,4H),6.98(d,J=8.7Hz,2H).HRMS:m/z理论值C22H13F5N4OS2[M+H]+509.0524;实测值509.0531.
实施例56:制备4,6-双(4-氟苯硫基)-N-(4-三氟甲氧基苯基)-1,3,5-三嗪-2-胺(编号:PG-C-9)
合成方法同化合物PG-C-1。白色固体,记作PG-C-9,收率50.4%。1H NMR(400MHz,CDCl3)δ7.43–7.27(m,7H),7.17(d,J=9.0Hz,4H),6.98(d,J=8.7Hz,2H).HRMS:m/z理论值C22H13F5N4OS2[M+H]+509.0524;实测值509.0532.
实施例57:α7nAChR正向变构调节活性测试
利用双电极电压钳实验测试前述实施例中制备的化合物对蛙卵细胞中α7nAChR的正向变构调节活性。以单独加入100μM ACh引起的α7nAChR特征性电流作为对照,发现只加入10μM化合物不会诱发α7nAChR特征性电流,但10μM化合物孵育1min后再同时加入10μM化合物和100μM ACh,发现100μM ACh所引发的电流幅度与对照组相比有所变化。具有α7nAChR正向变构调节活性的化合物对电流幅度的调节程度见表1。其中部分化合物在100μM ACh条件下的EC50见表2。
表1化合物对100μM ACh电流幅度的调节程度(实验组与对照组电流峰值的比值)
续表1化合物对100μM ACh电流幅度的调节程度(实验组与对照组电流峰值的比值)
表2部分化合物在100μMACh条件下的EC50
Claims (4)
1.一种三嗪化合物,该化合物具有如化学式(I)所示的结构:
其中,R1选自氢、卤素、C1-C4烷基、C1-C4烷氧基、含卤素的C1-C4烷基或含卤素的C1-C4烷氧基,n=1-2;R2选自C1-C6烷基、苄基、苯基、吡啶、苯并噻唑、被卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷酰胺基和羟基中的一个或多个取代的苯基;R3选自卤素、肼、C1-C4烷酰肼基、芳酰肼基、苯并噻唑基硫基、苯硫基、苄硫基、被卤素、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫基。
2.权利要求1所述的三嗪化合物的制备方法,该方法包括以下步骤:
(1)将2,4,6-三氯-1,3,5-三嗪与苯胺反应,或与被卤素、C1-C4烷基、C1-C4烷氧基、含卤素的C1-C4烷基和含卤素的C1-C4烷氧基中的一个或多个取代的苯胺反应,生成化合II;
(2)将化合物II与C1-C6硫醇、苄硫醇、苯硫酚、巯基吡啶或巯基苯并噻唑反应,或与被卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷酰胺基和羟基中的一个或多个取代的苯硫酚反应,生成化合物IV或V中的任意一个或两个化合物,化合物IV和V均为部分式(I)所示的化合物;
(3)将2,4,6-三氯-1,3,5-三嗪与C1-C6硫醇、苄硫醇、苯硫酚、巯基吡啶或巯基苯并噻唑反应,或与被卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷酰胺基和羟基中的一个或多个取代的苯硫酚反应,生成化合物III;
(4)将化合物III与苯胺反应,或与被卤素、C1-C4烷基、C1-C4烷氧基、含卤素的C1-C4烷基和含卤素的C1-C4烷氧基中的一个或多个取代的苯胺反应,生成化合物IV,为部分式I所示的化合物;
(5)将化合物IV与水合肼反应,生成化合物VI,为部分式(I)所示的化合物;
(6)将化合物VI与C1-C4烷酰氯反应,或与芳酰氯反应,生成化合物VII,为部分式(I)所示的化合物。
3.根据权利要求2所述的制备方法,其中,所述制备方法包括以下三种合成路线:
合成路线一:
合成路线二:
合成路线三:
4.权利要求1所述的三嗪化合物或按照权利要求2或3所述制备方法制得的三嗪化合物在制备治疗中枢神经系统疾病的药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610239410.0A CN107304189A (zh) | 2016-04-18 | 2016-04-18 | 一种三嗪化合物及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610239410.0A CN107304189A (zh) | 2016-04-18 | 2016-04-18 | 一种三嗪化合物及其制备方法和应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN107304189A true CN107304189A (zh) | 2017-10-31 |
Family
ID=60151363
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610239410.0A Pending CN107304189A (zh) | 2016-04-18 | 2016-04-18 | 一种三嗪化合物及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107304189A (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114560819A (zh) * | 2020-11-27 | 2022-05-31 | 中国海洋大学 | 取代三嗪化合物、其制备方法及在氨基酸、肽、蛋白、细胞标记中的应用 |
CN115335058A (zh) * | 2020-03-27 | 2022-11-11 | 国立大学法人京都大学 | 神经细胞变性抑制剂 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3270018A (en) * | 1964-02-13 | 1966-08-30 | Upjohn Co | 1, 3, 5-triazine ethers |
WO2005003103A2 (en) * | 2003-06-30 | 2005-01-13 | Astrazeneca Ab | 2, 4, 6-tri-substituted 6-membered heterocycles and their use in the treatment of neurodegenerative diseases |
CN101583365A (zh) * | 2006-12-15 | 2009-11-18 | 阿布拉西斯生物科学公司 | 三嗪衍生物及其治疗应用 |
-
2016
- 2016-04-18 CN CN201610239410.0A patent/CN107304189A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3270018A (en) * | 1964-02-13 | 1966-08-30 | Upjohn Co | 1, 3, 5-triazine ethers |
WO2005003103A2 (en) * | 2003-06-30 | 2005-01-13 | Astrazeneca Ab | 2, 4, 6-tri-substituted 6-membered heterocycles and their use in the treatment of neurodegenerative diseases |
CN101583365A (zh) * | 2006-12-15 | 2009-11-18 | 阿布拉西斯生物科学公司 | 三嗪衍生物及其治疗应用 |
Non-Patent Citations (1)
Title |
---|
CAS: "127016-31-3、127016-30-2、127016-29-9、127016-28-8、30357-96-1、32998-30-4", 《REGISTER》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115335058A (zh) * | 2020-03-27 | 2022-11-11 | 国立大学法人京都大学 | 神经细胞变性抑制剂 |
CN114560819A (zh) * | 2020-11-27 | 2022-05-31 | 中国海洋大学 | 取代三嗪化合物、其制备方法及在氨基酸、肽、蛋白、细胞标记中的应用 |
CN114560819B (zh) * | 2020-11-27 | 2023-09-19 | 中国海洋大学 | 取代三嗪化合物、其制备方法及在氨基酸、肽、蛋白、细胞标记中的应用 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2814556T3 (es) | Amidas heterocíclicas como inhibidores de quinasa | |
CN103153968B (zh) | 三唑衍生物及含有其的具有镇痛作用的药物组合物 | |
CN103097359B (zh) | 作为微粒体前列腺素e2合酶-1抑制剂的化合物 | |
CN101902911B (zh) | 杂芳基化合物和其用途 | |
CN103274961B (zh) | 治疗细胞增殖紊乱的化合物和方法 | |
ES2678899T3 (es) | 6-Amino-nicotinamidas sustituidas como moduladores de KCNQ2/3 | |
CN103153955A (zh) | 吡啶化合物及其用途 | |
AU2011205485B2 (en) | Compounds and methods | |
AU2010223512B2 (en) | Substituted 2-mercapto-3-aminopyridines as KCNQ2/3 modulators | |
BRPI0718162A2 (pt) | Composição e métodos para modulara os receptores c-kit e pdgfr | |
ES2564952T3 (es) | Nuevos derivados de N-(4-(azetidina-1-carbonil)fenil)-(hetero-)arilsulfonamida como moduladores de piruvato quinasa M2 (PKM2) | |
CN103097382A (zh) | 2-(芳基氨基)-3H-咪唑并[4,5-b]吡啶-6-甲酰胺衍生物及其作为MPGES-1抑制剂的用途 | |
CN103402987A (zh) | 6-氨基-2-苯基氨基-1h-苯并咪唑-5-甲酰胺衍生物及其作为微粒体前列腺素e2合酶-1抑制剂的用途 | |
WO2007142323A1 (ja) | 側鎖にスピロ環構造を有する新規インダゾール誘導体 | |
CN105503827A (zh) | Egfr抑制剂及其制备方法和用途 | |
AU2010223556B2 (en) | Substituted 3-amino-2-mercaptoquinolines as KCNQ2/3 modulators | |
CN109369654A (zh) | 1,3-二取代-4-氨基吡唑并嘧啶类化合物及其制备方法和应用 | |
KR20170082632A (ko) | 소마토스타틴 수용체 아형 4 (sstr4) 작용제로서의 모르폴린 및 1,4-옥사제판 아미드 | |
CN102036972A (zh) | 杜兴氏肌营养不良的治疗 | |
CN107304189A (zh) | 一种三嗪化合物及其制备方法和应用 | |
CN110143925B (zh) | 乙内酰脲异羟肟酸类组蛋白去乙酰化酶6亚型选择性抑制剂及制备方法和应用 | |
AU2016367510A1 (en) | Substituted benzazinones as antibacterial compounds | |
CN108017633A (zh) | N-[5-(嘧啶-2-氨基)-2,4-二取代苯基]-2-氟代丙烯酰胺衍生物及应用 | |
CN105377837A (zh) | 用作s100-抑制剂的n-(杂芳基)磺酰胺衍生物 | |
WO2005082001A2 (en) | Advanced isothiazole based protein kinase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20171031 |
|
WD01 | Invention patent application deemed withdrawn after publication |