CN114957262A - 一种c-6位芳基化去氮嘌呤衍生物的制备方法 - Google Patents
一种c-6位芳基化去氮嘌呤衍生物的制备方法 Download PDFInfo
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Abstract
本发明建立一种温和的反应条件下钯催化C‑H直接活化、高区域选择性引入芳基化官能团的合成新方法,能快速、简便、高效地实现去氮嘌呤衍生物的官能团化修饰,具有反应操作简单、底物普适性强、反应选择性好等特点,进一步拓展了去氮嘌呤化合物的应用范围。且本发明的C‑6位芳基化去氮嘌呤衍生物具有良好的抗肿瘤效果。
Description
技术领域
本发明涉及一种吡咯并[2,3-d]嘧啶衍生物的区域选择性芳基化的合成方法,具体涉及钯催化C-H直接芳基化,吡咯邻位引入芳基官能团的合成方法。
背景技术
吡咯并[2,3-d]嘧啶(7-去氮嘌呤)是具有多种生物活性的生物嘌呤碱基的重要类似物。由于7-去氮嘌呤的骨架与嘌呤的骨架极为相似,因此它们经常用作DNA和RNA规范成分的替代品,并被用于核酸测序(L.M.De Coen,Chem.Rev.,2016,116,80-139;P.Perlikova,Med.Res.Rev.,2017,37,1429-1460;F.Musumeci,M.Sanna,ExpertOpin.Ther.Pat.,2017,27,1305-1318.)。此外,吡咯并[2,3-d]嘧啶是存在于许多不同蛋白激酶的ATP竞争性抑制剂中,例如JAK,BTK,TAM,IGF-1R,c-Kit,Ret,CHk1和许多其他丝氨酸-苏氨酸激酶(F.Musumeci,Curr Med Chem,2017,24,2059-2085;F.Musumeci,Curr MedChem,2019,26,1806-1832;F.Jiang,Bioorg Med Chem,2019,27,4089-4100;T.Gao,Eur JMed Chem,2019,178,329-340;G.Tang,Eur J Med Chem,2019,173,167-183.)。最近,吡咯[2,3-d]嘧啶结构已被证实可作为灭菌剂、受体拮抗剂、抗癌剂、酶抑制剂和抗病毒核苷类药物(J.Zhao,J Med Chem,2018,61,10242-10254;Y.M.Liu,Future Med Chem,2019,11,959-974.)。
近年来,已报道了许多金属催化的吡咯并[2,3-d]嘧啶衍生物的合成案例,例如铱催化的C-H硼酸酯化反应(M.Eur J Org Chem,2015,7943-7961.),铜催化的C-H亚磺酰化反应(M.MedChemComm,2015,6,576-580.),钯催化的苯环邻位直接C-H芳基化反应(J.Zhou,Org Chem Front,2020,7,324-328;M.Liu,Tetrahedron Lett,2022,96,153754.),钯/铜催化的C-H胺化反应(N.Sabat,RSC Adv.,2014,4,62140-62143.),铁催化的C-H酰胺化反应(N.Sabat,ACS Omega,2018,3,4674-4678.),钌催化的C-H磺酰化反应(Y.F.Jiang,Tetrahedron Lett,2022,88,153569.),锰促进的C-H磷酰化反应(N.Sabat,JOrg Chem,2016,81,9507-9514.)。尽管这些方法可以得到想要的产物,但大多数方法底物范围有限且收率低。而且,其中一些方法需要苛刻的反应条件和很长的反应时间。另外一些反应,伴随有副产物的出现,区域选择性较差。
引入不同取代芳基是制药、农药和聚合物中常见的结构单元。然而,迄今为止还未见报道N-苯基-7H-吡咯[2,3-d]嘧啶-4-胺底物C-6位直接芳基化反应。
综上所述,开发具有条件温和、高区域选择性直接芳基化合成去氮嘌呤衍生物的方法是非常重要。
发明内容
本发明的目的是提供一种钯催化去氮嘌呤衍生物的高度区域选择性C-H芳基化方法,该方法是钯催化、TEMPO氧化条件下,对去氮嘌呤衍生物C-6位直接芳基化,解决已有合成路线步骤繁琐、条件苛刻、底物范围有限且收率低等问题。
为了实现上述目的,本发明的技术方案如下:
一种C-6位芳基化去氮嘌呤衍生物的制备方法,所述方法为:
将式(Ⅰ)所示化合物、苯硼酸、TEMPO(氧化剂,2,2,6,6-四甲基哌啶氧化物)和钯催化剂溶解在三氟乙酸中,在20℃-35℃(优选25℃)下搅拌3-5小时进行反应,所得反应混合物经后处理,得式(Ⅱ)所示化合物;
所述式(Ⅰ)所示化合物、苯硼酸、TEMPO与钯催化剂的物质的量之比为1.0:1.2-1.5:1.0-2.0:0.05-0.1(优选1.0:1.2:1.5:0.1);所述钯催化剂为醋酸钯或三氟乙酸钯(优选醋酸钯);
式(Ⅰ)、(Ⅱ)中,
R为C1-C3烷基、对甲苯磺酰基(Ts)或苄基(Bn);优选为甲基、丙基、苄基或对甲苯磺酰基;
R1为H、C1-C4烷基、C1-C4烷氧基、CF3、F、Cl、Br、NO2或OCF3;优选为H、叔丁基、甲氧基、乙氧基、Br、Cl或CF3。
优选地,所述式(Ⅱ)所示化合物为下列之一:
进一步,所述后处理的方法为:反应结束后,向所述反应混合物中加水淬灭(淬灭所用水与所述三氟乙酸的体积比为10:1),用氢氧化钠水溶液(质量分数52%)调至pH=9-10,用乙酸乙酯萃取所述反应混合物,萃取液上层经饱和氯化钠水溶液洗涤、无水硫酸钠干燥,过滤,滤液浓缩后,以体积比为2:1的石油醚(沸程:60~90℃)与乙酸乙酯的混合溶剂为洗脱剂进行快速柱层析,收集含目标化合物的洗脱液,蒸除溶剂并干燥,得到式(II)所示化合物。
本发明还提供一种C-6位芳基化去氮嘌呤衍生物在制备抗肿瘤药物中的应用,所述C-6位芳基化去氮嘌呤衍生物为下列之一:
所述肿瘤细胞为JEKO-1(人套细胞淋巴瘤)、SU-DHL-4(人B细胞淋巴瘤)或MCF-7(乳腺癌),优选为JEKO-1(人套细胞淋巴瘤)或SU-DHL-4(人B细胞淋巴瘤)。
尤其优选所述C-6位芳基化去氮嘌呤衍生物为式2c或2j所示化合物之一。
与现有技术相比,本发明具有以下有益效果:建立一种温和的反应条件下钯催化C-H直接活化、高区域选择性引入芳基化官能团的合成新方法,能快速、简便、高效地实现去氮嘌呤衍生物的官能团化修饰,具有反应操作简单、底物普适性强、反应选择性好等特点,进一步拓展了去氮嘌呤化合物的应用范围。且本发明的C-6位芳基化去氮嘌呤衍生物具有良好的抗肿瘤效果。
具体实施方式
下面通过具体实施例对本发明作进一步说明,但本发明的保护范围并不仅限于此。
实施例1
将7-甲基-N-苯基-7H-吡咯[2,3-d]嘧啶-4-胺(89.7mg,0.4mmol),TEMPO(93.6mg,0.6mmol),苯硼酸(58.6mg,0.48mmol),Pd(OAc)2(9mg,0.04mmol),溶解在三氟乙酸(1.5mL),室温下反应5小时,加水(15mL)淬灭并用氢氧化钠水溶液(质量分数52%)调至PH=7~8,用乙酸乙酯萃取所述反应混合物,萃取液经饱和氯化钠溶.液洗涤、无水硫酸钠干燥,过滤,滤液浓缩后,以体积比为2:1的的石油醚(沸程:60~90℃)/乙酸乙酯的混合溶剂为洗脱剂进行快速柱层析,收集含目标化合物的洗脱液,蒸除溶剂并干燥得产物为93.6mg7-甲基-N,6-二苯基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为78%,HPLC纯度为98.2%,产物为黄色固体。
1H NMR(500MHz,CDCl3)δ8.55(s,1H),7.59–7.53(m,2H),7.46–7.36(m,7H),7.18(t,J=7.0Hz,1H),6.06(s,1H),3.80(s,3H).13CNMR(126MHz,CDCl3)δ153.8,152.2,151.0,139.8,138.8,131.7,129.1,129.0,128.7,128.4,124.6,122.8,103.7,98.2,30.1.
实施例2
按照实施例1所述的方法,不同的是所用底物为:7-丙基-N-苯基-7H-吡咯[2,3-d]嘧啶-4-胺(100.9mg,0.4mmol),得产物为91.9mg7-丙基-N,6-二苯基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为70%,HPLC纯度为98%,产物为白色固体。
1H NMR(400MHz,CDCl3)δ8.52(s,1H),7.61(d,J=7.2Hz,2H),7.52–7.34(m,8H),7.17(t,J=7.4Hz,1H),6.12(s,1H),4.26(t,J=7.6Hz,2H),1.74-1.64(m,2H),0.78(t,J=7.4Hz,3H).13C NMR(101MHz,CDCl3)δ153.99,152.13,151.20,139.07,138.51,132.33,129.14,129.06,128.65,128.37,124.31,122.47,103.79,98.36,44.46,23.38,11.05.
实施例3
按照实施例1所述的方法,不同的是所用底物为:N-苯基-7-对甲苯磺酰基-7H-吡咯[2,3-d]嘧啶-4-胺(145.8mg,0.4mmol),得产物为79.3mg N,6-二苯基-7-对甲苯磺酰基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为45%,HPLC纯度为98.5%,产物为黄色固体。
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.10(d,J=8.1Hz,2H),7.41(t,J=7.7Hz,4H),7.31(dd,J=16.0,7.7Hz,5H),7.25(d,J=8.3Hz,4H),4.97(d,J=4.1Hz,1H),2.43(s,3H).13C NMR(101MHz,CDCl3)δ156.72,153.27,152.15,145.55,144.26,135.10,129.77,129.59,128.34,127.49,126.66,122.18,107.64,104.75,21.75.
实施例4
按照实施例1所述的方法,不同的是所用底物为:7-苄基-N-苯基-7H-吡咯[2,3-d]嘧啶-4-胺(120.1mg,0.4mmol),得产物为93.4mg7-苄基-N,6-二苯基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为62%,HPLC纯度为97.8%,产物为黄色固体。
1H NMR(600MHz,CDCl3)δ8.46(s,1H),7.82(s,1H),7.54(dd,J=8.5,1.2Hz,2H),7.36–7.27(m,5H),7.27–7.22(m,2H),7.17–7.10(m,4H),6.92–6.88(m,2H),6.10(s,1H),5.43(s,2H).13C NMR(101MHz,CDCl3)δ154.3,152.5,151.7,139.0,138.7,137.9,131.8,129.3,129.2,128.6,128.6,128.5,127.3,126.6,124.6,122.8,103.8,99.0,46.2.
实施例5
按照实施例1所述的方法,不同的是所用底物为:N-(4-甲氧基苯基)-7-甲基-7H-吡咯[2,3-d]嘧啶-4-胺(101.7mg,0.4mmol),得产物为95.2mg N-(4-甲氧基苯基)-7-甲基-6-苯基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为72%,HPLC纯度为98.3%,产物为白色固体。
1H NMR(400MHz,CDCl3)δ8.44(s,1H),7.82(s,1H),7.48-7.40(m,7H),6.99–6.89(m,2H),5.93(s,1H),3.84(s,3H),3.79(s,3H).13C NMR(101MHz,CDCl3)δ157.29,155.12,152.40,151.52,138.17,131.84,131.78,129.06,128.66,128.25,125.94,114.31,103.16,98.63,55.54,30.06.
实施例6
按照实施例1所述的方法,不同的是所用底物为:N-(4-乙氧基苯基)-7-甲基-7H-吡咯[2,3-d]嘧啶-4-胺(107.3mg,0.4mmol),得产物为100.6mg N-(4-乙氧基苯基)-7-甲基-6-苯基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为73%,HPLC纯度为97.6%,产物为白色固体。
1H NMR(400MHz,CDCl3)δ8.45(s,1H),7.53–7.39(m,7H),7.02–6.87(m,2H),5.92(s,1H),4.07(q,J=7.0Hz,2H),3.80(s,3H),1.45(t,J=6.9Hz,3H).13C NMR(101MHz,CDCl3)δ156.73,154.99,152.39,151.49,138.25,131.83,131.50,129.08,128.66,128.28,125.95,114.91,103.15,98.47,63.74,30.06,14.88.
实施例7
按照实施例1所述的方法,不同的是所用底物为:N-(4-(叔丁基)苯基)-7-甲基-7H-吡咯[2,3-d]嘧啶-4-胺(112.2mg,0.4mmol),得产物为87mg N-(4-(叔丁基)苯基)-7-甲基-6-苯基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为61%,纯度为98.1%,产物为黄色固体。
1H NMR(600MHz,CDCl3)δ8.54(s,1H),7.50–7.46(m,2H),7.44(dd,J=6.9,1.5Hz,4H),7.42–7.39(m,3H),6.06(s,1H),3.79(s,3H),1.34(s,9H).13C NMR(151MHz,CDCl3)δ154.2,152.3,151.2,147.9,138.6,136.2,131.8,129.1,128.8,128.4,126.0,122.9,103.7,98.4,34.6,31.5,30.2.
实施例8
按照实施例1所述的方法,不同的是所用底物为:N-(3-氯苯基)-7-甲基-7H-吡咯[2,3-d]嘧啶-4-胺(103.5mg,0.4mmol),得产物为103.1mg N-(3-氯苯基)-7-甲基-6-苯基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为77%,纯度为97.5%,产物为黄色固体。
1H NMR(400MHz,CDCl3)δ8.40(s,1H),7.63(s,1H),7.49-7.38(m,7H),7.31(t,J=8.0Hz,1H),7.20(d,J=8.6Hz,1H),6.03(s,1H),3.82(s,3H).13C NMR(101MHz,CDCl3)δ151.80,151.42,147.09,139.96,139.09,134.76,130.83,130.17,129.09,128.92,128.86,125.65,123.54,121.54,102.97,99.58,30.35.
实施例9
按照实施例1所述的方法,不同的是所用底物为:N-(3-溴苯基)-7-甲基-7H-吡咯[2,3-d]嘧啶-4-胺(121.3mg,0.4mmol),得产物为113.8mg N-(3-溴苯基)-7-甲基-6-苯基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为75%,纯度为98.2%,产物为黄色固体。
1H NMR(400MHz,CDCl3)δ8.53(s,1H),7.91(s,1H),7.57–7.39(m,7H),7.27–7.17(m,2H),6.26(s,1H),3.81(s,3H).13C NMR(101MHz,CDCl3)δ153.27,153.24,152.27,151.11,140.61,140.59,139.27,139.25,131.56,130.23,129.07,128.76,128.53,126.65,124.36,124.34,122.58,120.00,119.98,104.15,97.51,30.15.
实施例10
按照实施例1所述的方法,不同的是所用底物为:N-(3-三氟甲基苯基)-7-甲基-7H-吡咯[2,3-d]嘧啶-4-胺(116.9mg,0.4mmol),得产物为106.1mg N-(3-三氟甲基苯基)-7-甲基-6-苯基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为72%,纯度为98.3%,产物为黄色固体。
1H NMR(400MHz,CDCl3)δ8.61(s,1H),7.94(s,1H),7.84(d,J=10.2Hz,1H),7.51-7.38(m,8H),6.23(s,1H),3.83(s,3H).13C NMR(101MHz,CDCl3)δ153.05,152.24,150.77,139.71,139.53,131.43,131.38(q,JC-F=33.3Hz),129.56,129.06,128.78,128.63,127.81(q,JC-F=249.5Hz),124.66,120.37(q,JC-F=3Hz),118.26(q,JC-F=4Hz),104.08,97.63,30.16.
对比例1:三氟乙酸钯代替醋酸钯作为催化剂
将7-甲基-N-苯基-7H-吡咯[2,3-d]嘧啶-4-胺(89.7mg,0.4mmol),TEMPO(93.6mg,0.6mmol),苯硼酸(58.6mg,0.48mmol),Pd(TFA)2(13mg,0.04mmol),溶解在三氟乙酸(1.5mL),室温下反应5小时,加水(15mL)淬灭并用氢氧化钠水溶液(52%)调至PH=7~8,用乙酸乙酯萃取所述反应混合物,萃取液经饱和氯化钠溶液洗涤、无水硫酸钠干燥,过滤,滤液浓缩后,以体积比为2:1的的石油醚(沸程:60~90℃)/乙酸乙酯的混合溶剂为洗脱剂进行快速柱层析,收集含目标化合物的洗脱液,蒸除溶剂并干燥得产物为78.1mg 7-甲基-N,6-二苯基-7H-吡咯[2,3-d]嘧啶-4-胺,收率为65%,纯度为98.2%,产物为黄色固体。
对比例2:不加氧化剂TEMPO的对照
将7-甲基-N-苯基-7H-吡咯[2,3-d]嘧啶-4-胺(89.7mg,0.4mmol),苯硼酸(58.6mg,0.48mmol),Pd(OAc)2(9mg,0.04mmol),溶解在三氟乙酸(1.5mL),室温下反应5小时,没有得到目标化合物。
对比例3
其它操作同实施例1,采用乙酸、特戊酸、三氟乙醇或六氟异丙醇(1.5mL)作为溶剂来代替三氟乙酸,均无法得到目标产物。
实施例12:体外抗肿瘤实验
选取上述实施例合成的取代芳基吡咯并[2,3-d]嘧啶衍生物进行体外抗肿瘤活性实验,分别对3种细胞系进行了筛选,JEKO-1(人套细胞淋巴瘤),SU-DHL-4(人B细胞淋巴瘤),MCF-7(乳腺癌)的细胞株,采用MTT还原测定吡咯并[2,3-d]嘧啶衍生物对多种人癌细胞株的抑制活性,并计算出抑制率达到50%时的药物浓度,即IC50。
选用上述对数生长期细胞,用胰酶进行消化后,L-15培养基配成6×104/mL的细胞悬液,然后将细胞悬液加入到96孔板中,每孔细胞数为15000个,37℃下,无CO2培养24小时,将事先配置好的不同浓度的药物分别加入到96孔板中,浓度梯度为100μM、75μM、50μM、25μM、10μM,每个浓度梯度设置4个副孔,37℃下,无CO2培养72小时,每孔加入10μL MTT,37℃下,无CO2培养3小时,弃去上清液,加入150μL DMSO,振荡均价后,酶标仪在490nm处测定光密度(OD值)
抑制率计算:
生长抑制率=(OD对照组-OD实验组)/(OD对照组-OD空白组)
根据药物浓度-生长抑制率曲线,计算IC50,结果如下表1所示:
表1
由表1可知,本发明所提供化合物均具有一定的抗癌作用,特别是化合物2c和2j表现出了较好的生物活性,该类化合物在抗肿瘤药物化学领域拥有较好的发展前景。
需要指出的是,上述实验实例仅为说明本发明的构思及特点,其目的是让熟悉本发明的人了解本实验并据以实施,并不能限制本发明的保护范围。凡根据本发明精神实质做出的等效变化或修饰,都应涵盖在本发明的保护范围内。
Claims (10)
2.如权利要求1所述的C-6位芳基化去氮嘌呤衍生物的制备方法,其特征在于:R为甲基、丙基、苄基或对甲苯磺酰基。
3.如权利要求1所述的C-6位芳基化去氮嘌呤衍生物的制备方法,其特征在于:R1为H、叔丁基、甲氧基、乙氧基、Br、Cl或CF3。
5.如权利要求1所述的C-6位芳基化去氮嘌呤衍生物的制备方法,其特征在于:所述反应的温度为25℃。
6.如权利要求1所述的C-6位芳基化去氮嘌呤衍生物的制备方法,其特征在于:所述式(Ⅰ)所示化合物、苯硼酸、TEMPO与钯催化剂的物质的量之比为1.0:1.2:1.5:0.1。
7.如权利要求1所述的C-6位芳基化去氮嘌呤衍生物的制备方法,其特征在于:所述钯催化剂为醋酸钯。
8.如权利要求1所述的C-6位芳基化去氮嘌呤衍生物的制备方法,其特征在于所述后处理的方法为:反应结束后,向所述反应混合物中加水淬灭,用氢氧化钠水溶液调至pH=9-10,用乙酸乙酯萃取所述反应混合物,萃取液上层经饱和氯化钠水溶液洗涤、无水硫酸钠干燥,过滤,滤液浓缩后,以体积比为2:1的石油醚与乙酸乙酯的混合溶剂为洗脱剂进行快速柱层析,收集含目标化合物的洗脱液,蒸除溶剂并干燥,得到式(II)所示化合物。
9.如权利要求8所述的C-6位芳基化去氮嘌呤衍生物的制备方法,其特征在于:淬灭所用水与所述三氟乙酸的体积比为10:1。
10.如权利要求8所述的C-6位芳基化去氮嘌呤衍生物的制备方法,其特征在于:氢氧化钠水溶液的质量分数为52%。
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WO2006004703A2 (en) * | 2004-06-29 | 2006-01-12 | Amgen Inc. | PYRROLO[2,3-d]PYRIMIDINES THAT MODULATE ACK1 AND LCK ACTIVITY |
WO2011149827A1 (en) * | 2010-05-24 | 2011-12-01 | Glaxosmithkline Llc | Compounds and methods |
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CN116143840A (zh) * | 2022-12-31 | 2023-05-23 | 浙江工业大学 | 一种膦酰基去氮嘌呤衍生物及其制备方法与应用 |
CN117865965A (zh) * | 2024-01-08 | 2024-04-12 | 贵州省天然产物研究中心 | 吡咯并嘧啶-4-胺和吡唑并嘧啶-4-胺衍生物及制备方法和应用 |
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