CN110563641A - 一种邻位卤代苯基吡啶甲酮类化合物及其制备方法 - Google Patents

一种邻位卤代苯基吡啶甲酮类化合物及其制备方法 Download PDF

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CN110563641A
CN110563641A CN201910936035.9A CN201910936035A CN110563641A CN 110563641 A CN110563641 A CN 110563641A CN 201910936035 A CN201910936035 A CN 201910936035A CN 110563641 A CN110563641 A CN 110563641A
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刘祈星
陈永盛
张银
陈淡宜
文思妙妙
赵蓉蓉
刘毅恒
周海峰
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China Three Gorges University CTGU
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    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

本发明涉及一种邻位卤代苯基吡啶甲酮类化合物及其制备方法。以二溴海因或二氯海因为卤代试剂,通过钯催化的选择性碳氢卤代反应,实现了二芳基甲酮化合物的邻位卤代,得到邻位卤代二芳基甲酮类化合物。本发明所使用的二溴海因和二氯海因与其它卤代试剂相比具有价廉、活性卤含量高、贮存稳定性好、使用经济等优点。本发明所提供的卤代二芳基甲酮化合物的选择性合成方法,成本低、对环境伤害较小,适合工业化生产,为乙型肝炎治疗药物洛那法尼的合成提供了新的方法。

Description

一种邻位卤代苯基吡啶甲酮类化合物及其制备方法
技术领域
本发明属于有机合成技术领域,具体涉及一种邻位卤代苯基吡啶甲酮类化合物及其制备方法。
背景技术
芳香卤代物是一类重要的有机合成中间体,被广泛应用于合成染料、农药、香料和药物等。目前芳香卤代物合成常用的卤代试剂主要有以下几类:(1)卤素单质,卤素单质为气体或挥发性大,毒性强,反应的选择性差,环境污染大;(2)N-卤代丁二酰亚胺,该类卤代试剂原子经济性差;(3)卤化铜,该卤代试剂用到了金属卤化物,毒性大,成本高;(4)卤化物/氧化剂(氧化卤代),该反应体系复杂,且需要用到氧化试剂;但以上卤代试剂仍存在各自的缺点。因此发展一种绿色的具有选择性的卤代试剂以及卤代方法具有重要的科学意义和应用价值。
发明内容
针对上述技术问题,本发明提供一种邻位卤代二芳基甲酮类化合物,以及相关的制备方法。所述的邻位卤代二芳基甲酮化合物,其结构式为:所述的R1、R2、R3、R4、R5、R6、R7、R8为氢、卤素、氨基、C1-C6烷基、C1-C6卤代烷基、C3-C8环烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6烷基磺酰基、C6-C12芳基、C6-C12芳基磺酰基、C5-C10杂芳基中的任意一种;X卤素。
该邻位卤代二芳基甲酮类化合物的定义中,所用术语不论单独使用还是用在复合词中,代表如下取代基:
卤素:指氟、氯、溴;
烷基:指直链或支链烷基;
卤代烷基:指直链或支链烷基,在这些烷基上的氢原子部分或全部被卤原子取代;环烷基:指饱和或不饱和的环烷基;
C6—C12芳基指苯基和由它派生出的一环芳基或多环芳基;
C5—C10杂芳基指一环杂芳基或多环杂芳基,环中含有1-5个下列中相同或不同的杂原子:N,O,S,P。
进一步优选为R1、R2、R3、R4、R5、R6、R7、R8为氢、卤素、C1-C2烷基氧基中的任意一种;X为Br或Cl。
所述的邻位卤代二芳基甲酮化合物的结构式包括
在上述优选方式下,本申请所述的邻位卤代二芳基甲酮化合物的结构式为
本发明的另一技术方案是提供一种邻位卤代二芳基甲酮衍生物的制备方法,包括如下步骤,
以苯基吡啶基甲酮(I)为原料,以二卤海因为卤代试剂,于适当的反应溶剂中,通过钯催化剂催化的碳氢氯卤化反应,在90-120℃下反应10-20h后(优选反应时间为10-12h)制得邻位卤代二芳基甲酮类化合物(II),具体合成通式如下:
所述的二卤海因包括二溴海因或二氯海因。所述的钯催化剂为Pd(OAc)2;所述的反应溶剂包括氯苯、醋酸、N,N-二甲基甲酰胺、乙腈、二氯乙烷中的一种或多种溶剂任意比例的混合溶液。卤海因的加入量为苯基吡啶基甲酮(I)质量的0.5-1.5倍;钯催化剂的加入量为原料总量的1-10mol%。
在反应过程中,卤海因的添加量不能过多,过多会造成卤代位点多,进而造成副产物多,卤代试剂原料成本高,过少会造成反应产率太低。
本发明中以二溴海因或二氯海因为卤代试剂,在Pd(OAc)2催化剂的作用下选择性活化邻位C-H键,通过碳氢活化卤代反应,实现多种二芳基甲酮化合物的邻位卤代,具体选择性邻位卤代的反应过程如下所示:
具体实施方式
以下实施例旨在说明本发明而不是对本发明的进一步限定。
实施例1
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.6mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL氯苯,120℃下反应12h,薄层色谱法纯化得到2-溴苯基吡啶基甲酮26.5mg,产率50.6%,1H NMR(400MHz,CDCl3):δ=8.73(d,J=4.8Hz,1H),8.20(d,J=8.0Hz,1H),7.98-7.94(dt,J1=7.6Hz,J2=2.0Hz,1H),7.68(dd,J1=7.6Hz,J2=1.2Hz,1H),7.55-7.50(m,2H),7.47(dd,J1=7.6Hz,J2=1.2Hz,1H),7.43-7.39(m,1H)ppm;13C NMR(100MHz,CDCl3):δ=195.9,153.5,149.4,140.3,137.1,133.1,131.6,129.9,127.1,127.0,124.0,120.1ppm。
实施例2
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.5mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Pd(TFA)2(0.02mmol),加入2mL氯苯,120℃下反应12h,无产物生成。
实施例3
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.6mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Fe(OAc)2(0.02mmol),加入2mL氯苯,120℃下反应12h,无产物生成。
所述的催化剂Fe(OAc)2替换为Cu(OAc)2或不加任何催化剂的条件下,同样无产物生成。
实施例4
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.6mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL乙酸,110℃下反应12h,薄层色谱法纯化得到2-溴苯基吡啶基甲酮22.3mg,产率42.5%。
实施例5
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.6mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mLDMF,110℃下反应12h,薄层色谱法纯化得到2-溴苯基吡啶基甲酮5.2mg,产率9.9%。
实施例6
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.5mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL乙腈,110℃下反应12h,薄层色谱法纯化得到2-溴苯基吡啶基甲酮5.2mg,产率9.9%。
实施例7
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.5mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL甲苯,110℃下反应12h,无产物生成。
实施例8
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.5mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mLDMSO,110℃下反应12h,无产物生成。
实施例9
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.5mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL水,110℃下反应12h,无产物生成。
实施例10
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.5mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL异丙醇,90℃下反应12h,无产物生成。
实施例11
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.5mg,0.2mmol)、二溴海因(85.8mg,0.3mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-溴苯基吡啶基甲酮43.6mg,产率83.2%。
实施例12
2-溴苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.5mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-溴苯基吡啶基甲酮43.6mg,产率83.2%。
实施例13
2-溴-6-甲氧基苯基吡啶基甲酮的合成
2-甲氧基苯基吡啶基甲酮(42.6mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-溴-6-甲氧基苯基吡啶基甲酮35.6mg,产率61.0%。1H NMR(400MHz,CDCl3):δ=8.68(d,J=4.8Hz,1H),8.05(d,J=7.6Hz,1H),7.93-7.89(dt,J1=8.0Hz,J2=2.0Hz,1H),7.65(d,J=2.4Hz,1H),7.60(dd,J1=8.8Hz,J2=2.4Hz,1H),7.50-7.47(m,1H),6.90(d,J=8.8Hz,1H),3.67(s,3H)ppm;13C NMR(100MHz,CDCl3):δ=194.7,157.3,154.7,149.0,136.9,135.2,132.7,130.0,126.6,123.2,113.5,112.9,56.0ppm.
实施例14
2,6-二溴苯基吡啶基甲酮的合成
2-溴苯基吡啶基甲酮(52.4mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2,6-二溴苯基吡啶基甲酮48.4mg,产率71.0%。1H NMR(400MHz,CDCl3):δ=8.72(d,J=4.0Hz,1H),8.28(d,J=7.6Hz,1H),7.97(dt,J1=8.0Hz,J2=1.6Hz,1H),7.62(d,J=8.0Hz,2H),7.56-7.53(m,1H),7.23(t,J=8.0Hz,1H)ppm;13C NMR(100MHz,CDCl3):δ=194.5,151.8,149.8,141.9,137.2,131.4,131.2,127.6,123.7,119.7ppm.
实施例15
2-溴-6-氯苯基吡啶基甲酮的合成
2-氯苯基吡啶基甲酮(43.5mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-溴-6-氯苯基吡啶基甲酮43.9mg,产率74.0%。1H NMR(400MHz,CDCl3):δ=8.71(d,J=4.8Hz,1H),8.26(d,J=8.0Hz,1H),8.14(dt,J1=7.6Hz,J2=1.6Hz,1H),7.78-7.72(m,2H),7.62(dd,J1=8.0Hz,J2=1.2Hz,1H),7.48(t,J=8.0Hz,1H)ppm;13C NMR(100MHz,CDCl3):δ=194.2,151.6,150.4,140.2,138.6,132.3,131.6,130.9,129.2,129.0,123.5,119.5ppm.
实施例16
2-溴-4-氟苯基吡啶基甲酮的合成
4-氟苯基吡啶基甲酮(40.2mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-溴-4-氟苯基吡啶基甲酮32.5mg,产率58.0%。1H NMR(400MHz,DMSO):δ=8.72(d,J=4.8Hz,1H),8.20(d,J=7.6Hz,1H),7.96(t,J=7.6Hz,1H),7.56-7.52(m,2H),7.43(dd,J1=8.4Hz,J2=2.4Hz,1H),7.19(dt,J1=8.4Hz,J2=2.4Hz,1H)ppm;13C NMR(100MHz,DMSO):δ=194.8,164.6(d,JC-F=253.3Hz),153.4,149.3,137.2,131.8(d,JC-F=9.0Hz),127.1,124.0,121.2(d,JC-F=9.9Hz),120.7(d,JC-F=24.5Hz),114.5(d,JC-F=21.3Hz),100.0ppm.
实施例17
2-溴-4-氯苯基吡啶基甲酮的合成
4-氯苯基吡啶基甲酮(43.5mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-溴-4-氯苯基吡啶基甲酮30.2mg,产率50.9%。1H NMR(400MHz,CDCl3):δ=8.73(d,J=4.8Hz,1H),8.21(dt,J1=8.0Hz,J2=1.2Hz,1H),7.97(dt,J1=7.6Hz,J2=1.6Hz,1H),7.70(t,J=0.8Hz,1H),7.56-7.53(m,1H),7.46(d,J=1.2Hz,2H)ppm;13C NMR(100MHz,CDCl3):δ=194.9,153.2,149.3,138.6,137.2,137.0,132.9,130.9,127.5,127.2,124.0,120.9ppm.
实施例18
2,4-二溴苯基吡啶基甲酮的合成
4-溴苯基吡啶基甲酮(52.4mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2,4-二溴苯基吡啶基甲酮43.0mg,产率63.0%。1H NMR(400MHz,CDCl3):δ=8.71(d,J=4.8Hz,1H),8.21(d,J=8.0Hz,1H),7.96(dt,J1=7.6Hz,J2=1.6Hz,1H),7.84(d,J=1.6Hz,1H),7.61(dd,J1=8.0Hz,J2=1.6Hz,1H),7.55-7.52(m,1H),7.37(d,J=8.0Hz,1H)ppm;13C NMR(100MHz,CDCl3):δ=195.0,153.1,149.1,139.1,137.2,135.6,131.0,130.4,127.3,125.0,123.9,121.0ppm.
实施例19
2-溴-4-三氟甲基苯基吡啶基甲酮的合成
4-三氟甲基苯基吡啶基甲酮(50.2mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-溴-4-三氟甲基苯基吡啶基甲酮30.3mg,产率45.9%。1H NMR(400MHz,DMSO):δ=8.69(d,J=4.8Hz,1H),8.24(d,J=7.6Hz,1H),8.17-8.12(m,2H),7.93(d,J=8.8Hz,1H),7.78-7.72(m,2H)ppm;13C NMR(100MHz,DMSO):δ=195.3,152.3,150.0,145.5,138.5,130.5,129.6(m),128.8,125.0(q,JC-F=4.0Hz),124.8,123.8,119.8ppm.
实施例20
2-溴-3,5-二甲基苯基吡啶基甲酮的合成
3,5-二甲基苯基吡啶基甲酮(42.2mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-溴-3,5-二氧基苯基吡啶基甲酮25.6mg,产率44.1%。1H NMR(400MHz,CDCl3):δ=8.73(d,J=4.4Hz,1H),8.19(d,J=8.0Hz,1H),7.94(dt,J1=7.6Hz,J2=1.6Hz,,1H),7.52-7.49(m,1H),7.22(s,1H),7.09(s,1H),2.45(s,3H),2.36(s,3H)ppm;13C NMR(100MHz,CDCl3):δ=196.7,153.7,149.5,141.0,138.4,137.1,137.0,133.3,127.4,126.9,123.9,118.5,22.9,20.8ppm.
实施例21
2-溴苯基-(5-甲基吡啶-2-基)甲酮的合成
苯基-(5-甲基吡啶-2-基)甲酮(39.4mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-溴苯基-(5-甲基吡啶-2-基)甲酮27.6mg,产率50.0%。1H NMR(400MHz,CDCl3):δ=8.54(s,1H),8.11(d,J=8.0Hz,1H),7.75(dd,J1=8.0Hz,J2=2.0Hz,1H),7.66(d,J=8.0Hz,1H),7.49-7.44(m,2H),7.41-7.37(m,1H),2.47(s,3H)ppm;13C NMR(100MHz,CDCl3):δ=195.7,151.1,150.0,140.6,137.7,137.4,133.0,131.4,129.7,127.1,123.8,120.0,18.9ppm.
实施例22
2-溴苯基-(4-甲基吡啶-2-基)甲酮的合成
苯基-(4-甲基吡啶-2-基)甲酮(39.4mg,0.2mmol)、二溴海因(57.2mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-溴苯基-(4-甲基吡啶-2-基)甲酮28.0mg,产率50.7%。1H NMR(400MHz,CDCl3):δ=8.58(d,J=4.8Hz,1H),8.03(s,1H),7.67(dd,J1=8.0Hz,J2=1.2Hz,1H),7.51-7.45(m,2H),7.42-7.38(m,1H),7.34(d,J=5.2Hz,1H),2.52(s,3H)ppm;13C NMR(100MHz,CDCl3):δ=196.1,153.4,149.2,148.5,140.5,133.1,131.5,129.8,127.9,127.1,124.8,120.1,21.2ppm.
实施例23
2-氯苯基吡啶基甲酮的合成
苯基吡啶基甲酮(36.5mg,0.2mmol)、二氯海因(39.4mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-氯苯基吡啶基甲酮21.7mg,产率50.0%,1H NMR(400MHz,CDCl3):δ=8.75(d,J=4.4Hz,1H),8.18(d,J=7.6Hz,1H),7.94(dt,J1=8.0Hz,J2=1.6Hz,1H),7.56-7.41(m,5H)ppm;13C NMR(100MHz,CDCl3):δ=195.3,153.7,149.4,138.2,137.1,132.0,131.6,130.0,127.0,126.6,123.8ppm。
实施例24
2-氯-6-甲氧基苯基吡啶基甲酮的合成
2-甲氧基苯基吡啶基甲酮(42.6mg,0.2mmol)、二氯海因(39.4mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-氯-6-甲氧基苯基吡啶基甲酮20.8mg,产率42.0%,1H NMR(400MHz,CDCl3):δ=8.74(d,J=5.2Hz,1H),8.17(d,J=7.6Hz,1H),7.95(dt,J1=8.0Hz,J2=1.6Hz,1H),7.55-7.51(m,1H),7.36(d,J=8.8Hz,1H),7.07(d,J=3.2Hz,1H),7.04(dt,J1=8.8Hz,J2=1.2Hz,1H),3.86(s,3H)ppm;13C NMR(100MHz,CDCl3):δ=195.3,158.1,153.8,149.4,138.9,137.1,130.8,127.0,123.8,123.2,117.8,114.8,55.7ppm。
实施例25
2-氯-6-乙基苯基吡啶基甲酮的合成
2-乙基苯基吡啶基甲酮(42.2mg,0.2mmol)、二氯海因(39.4mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-氯-6-乙基苯基吡啶基甲酮20.1mg,产率40.9%,1H NMR(400MHz,CDCl3):δ=8.75(s,1H),8.20(d,J=8.0Hz,1H),7.95(dt,J1=8.0Hz,J2=2.0Hz,1H),7.55-7.51(m,1H),7.36(t,J=8.0Hz,1H),7.31-7.26(m,2H),2.56(q,J=7.6Hz,1H),1.17(t,J=7.6Hz,1H)ppm;13C NMR(100MHz,CDCl3):δ=196.8,153.3,149.8,143.5,138.2,137.1,130.4,130.2,127.3,126.9,126.7,123.4,26.5,22.1ppm。
实施例26
2-氯-6-溴苯基吡啶基甲酮的合成
2-溴苯基吡啶基甲酮(52.4mg,0.2mmol)、二氯海因(39.4mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-氯-6-溴苯基吡啶基甲酮35.6mg,产率60.0%,1H NMR(400MHz,CDCl3):δ=8.72(d,J=4.8Hz,1H),8.20(d,J=8.0Hz,1H),7.97(t,J=8.0Hz,1H),7.59-7.53(m,2H),7.44(d,J=8.0Hz,1H),7.30(t,J=8.0Hz,1H),ppm;13C NMR(100MHz,CDCl3):δ=193.9,152.1,149.8,140.1,137.2,131.7,130.9,128.4,127.7,123.5,119.7ppm。
实施例27
2-氯-4-溴苯基吡啶基甲酮的合成
4-溴苯基吡啶基甲酮(52.4mg,0.2mmol)、二氯海因(39.4mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-氯-4-溴苯基吡啶基甲酮32.1mg,产率54.1%,1H NMR(400MHz,CDCl3):δ=8.71(d,J=4.8Hz,1H),8.20(d,J=8.0Hz,1H),7.95(t,J=8.0Hz,1H),7.66(s,1H),7.60-7.52(m,2H),7.40(d,J=8.0Hz,1H)ppm;13C NMR(100MHz,CDCl3):δ=194.2,153.2,149.4,137.3,136.9,133.1,132.7,131.1,129.9,127.3,125.1,123.9ppm。
实施例28
2,4-二氯苯基吡啶基甲酮的合成
4-氯苯基吡啶基甲酮(43.5mg,0.2mmol)、二氯海因(39.4mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2,4-二氯苯基吡啶基甲酮25.2mg,产率50.0%,1H NMR(400MHz,CDCl3):δ=8.71(d,J=4.8Hz,1H),8.20(d,J=7.6Hz,1H),7.95(dt,J1=8.0Hz,J2=1.6Hz,1H),7.56-7.50(m,3H),7.40(dd,J1=8.0Hz,J2=1.6Hz,1H)ppm;13C NMR(100MHz,CDCl3):δ=194.3,153.6,149.3,137.2,137.1,136.6,133.1,131.0,129.9,127.2,127.0,123.7ppm。
实施例29
2-氯-4氟苯基吡啶基甲酮的合成
4-氟苯基吡啶基甲酮(43.5mg,0.2mmol)、二氯海因(39.4mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-氯-4氟苯基吡啶基甲酮21.2mg,产率45.0%,1H NMR(400MHz,CDCl3):δ=8.71(d,J=4.4Hz,1H),8.20(d,J=7.6Hz,1H),7.95(dt,J1=8.0Hz,J2=1.6Hz,1H),7.61-7.52(m,2H),7.23(dd,J1=8.4Hz,J2=2.4Hz,1H),7.13(dt,J1=8.4Hz,J2=2.4Hz,1H)ppm;13C NMR(100MHz,CDCl3):δ=194.1,164.8(d,JC-F=256.4Hz),153.8,149.2,137.1,133.7(d,JC-F=9.6Hz),131.9(d,JC-F=9.2Hz),130.9,127.1,123.8,117.5(d,JC-F=24.8Hz),114.0(d,JC-F=21.5Hz)ppm。
实施例30
2-氯-3,5-二甲氧基苯基吡啶基甲酮的合成
3,5-二甲氧基苯基吡啶基甲酮(48.6mg,0.2mmol)、二氯海因(39.4mg,0.2mmol)和Pd(OAc)2(4.5mg,0.02mmol),加入2mL二氯乙烷,90℃下反应12h,薄层色谱法纯化得到2-氯-3,5-二甲氧基苯基吡啶基甲酮25.0mg,产率45.0%,1H NMR(400MHz,CDCl3):δ=8.73(d,J=4.0Hz,1H),8.16(d,J=8.0Hz,1H),7.94(t,J=8.0Hz,1H),7.53-7.50(m,1H),6.68-6.64(m,2H),3.94(s,3H),3.86(s,3H)ppm;13C NMR(100MHz,CDCl3):δ=195.5,159.1,155.7,149.5,140.0,137.1,127.0,123.7,104.6,101.9,56.3,55.7ppm。

Claims (9)

1.一种邻位卤代二芳基甲酮衍生物,其特征在于,卤代二芳基甲酮化合物的结构式为:
所述的R1、R2、R3、R4、R5、R6、R7、R8为氢、卤素、氨基、C1-C6烷基、C1-C6卤代烷基、C3-C8环烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6烷基磺酰基、C6-C12芳基、C6-C12芳基磺酰基、C5-C10杂芳基中的任意一种;X卤素。
2.根据权利要求1所述的邻位卤代二芳基甲酮衍生物,其特征在于,所述的卤素为F、Cl或Br。
3.根据权利要求2所述的邻位卤代二芳基甲酮衍生物,其特征在于,R1、R2、R3、R4、R5、R6、R7、R8为氢、C1-C2烷基氧基、卤素中的任意一种;X为Br或Cl。
4.根据权利要求3所述的邻位卤代二芳基甲酮衍生物,其特征在于,所述的邻位卤代二芳基甲酮化合物的结构式包括
5.根据权利要求4所述的邻位卤代二芳基甲酮衍生物,其特征在于,所述的邻位卤代二芳基甲酮化合物的结构式为
6.根据权利要求1-5任一项所述的邻位卤代二芳基甲酮衍生物的制备方法,其特征在于,包括如下步骤,
以苯基吡啶基甲酮为原料,以二卤海因为卤代试剂,于适当的反应溶剂中,通过钯催化剂催化的碳氢溴化或氯化反应,在90-120℃下反应10-20h后制得邻位卤代二芳基甲酮类化合物,具体合成通式包括如下:
所述的R1、R2、R3、R4、R5、R6、R7、R8为氢、卤素、氨基、C1-C6烷基、C1-C6卤代烷基、C3-C8环烷基、C1-C6烷基氧基、C1-C6烷基氨基、C1-C6烷基磺酰基、C6-C12芳基、C6-C12芳基磺酰基、C5-C10杂芳基中的任意一种;X卤素。
7.根据权利要求6所述的邻位卤代二芳基甲酮衍生物的制备方法,其特征在于,所述的二卤海因包括二溴海因或二氯海因。
8.根据权利要求6所述的邻位卤代二芳基甲酮衍生物的制备方法,其特征在于,所述的钯催化剂为Pd(OAc)2;所述的反应溶剂包括氯苯、醋酸、N,N-二甲基甲酰胺、乙腈、二氯乙烷中的一种或多种溶剂任意比例的混合溶液。
9.根据权利要求6所述的邻位卤代二芳基甲酮衍生物的制备方法,其特征在于,卤海因的加入量为苯基吡啶基甲酮(I)质量的0.5-1.5倍;钯催化剂的加入量为原料总量的1-10mol%。
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