CN111056889B - 一类n-烷基/n-芳基硫代酰胺衍生物及其合成方法和应用 - Google Patents
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Abstract
本发明公开了一类N‑烷基/N‑芳基硫代酰胺衍生物的合成方法,以式(1)所示的胺硫代甲酰氟和丙二酸酯作为原料,在无机碱的存在下,在有机溶剂中,温度为80℃的条件下,发生亲核取代反应得到所述的N‑烷基/N‑芳基硫代酰胺衍生物。本发明N‑烷基/N‑芳基硫代酰胺衍生物的合成方法通过条件控制,具有操作简单、原子经济、步骤经济、绿色高效、底物适用范围广等优点。本发明还公开了所述N‑烷基/N‑芳基硫代酰胺衍生物在生物制药和特殊制剂方面的应用。
Description
技术领域
本发明属于合成医药、化工领域,主要涉及一类N-烷基/N-芳基硫代酰胺衍生物及其合成方法和应用。
背景技术
硫代酰胺是一类非常重要的有机硫化物,该类物质具有很高的稳定性,且化学性质较酰胺更为活泼,可以发生一系列的转化反应。近几年的研究结果表明,硫代酰胺类化合物的生物活性较为广泛,可以用于抗炎、杀菌和抗结核,该类化合物还可以作为特殊的试剂或中间体。所以开发出一种简单、高效的合成硫代酰胺及其衍生物的方法很有研究价值。
发明内容
本发明的目的是针对现有技术的不足而提供的一类N-烷基/N-芳基硫代酰胺衍生物及其合成方法,该合成方法采用了容易制备的原料和绿色的无机碱,通过简单高效的亲核取代反应,原子经济、步骤经济地以良好至优秀的收率合成了N-烷基/N-芳基硫代酰胺衍生物。该方法具有操作简单、原子经济、步骤经济、绿色高效、底物适用范围广等优点。
本发明提出了N-烷基/N-芳基硫代酰胺衍生物的合成方法。
本发明提出的一类N-烷基/N-芳基硫代酰胺衍生物,其具下式(2)结构:
其中,R1为氢、烷基、苯基、酰基、酯基、卤素、烷氧基、磺酰胺基等;
R2为烷基、苄基、有取代的烷基等;
R3、R4独自为烷基或苄基等。
优选地,R1为氢、甲基、甲氧基、磺酰胺基、卤素、甲酸乙酯基、乙酰基、苯基等;
R2为甲基、乙基、异丙基、正己基、苄基、苯乙基、3-甲氧基丙基等;
R3、R4独自为甲基、乙基、异丙基、苄基等。
本发明提出的一种N-烷基/N-芳基硫代酰胺衍生物的合成方法,包括:将式(1)所示的胺硫代甲酰氟、丙二酸酯和无机碱于有机溶剂中,在80℃的温度条件下,进行亲核取代反应,得到所述N-烷基/N-芳基硫代酰胺衍生物。所述过程如反应式(Ⅰ)所示:
其中,R1为氢、烷基、苯基、酰基、酯基、卤素、烷氧基、磺酰胺基等;
R2为烷基、苄基、有取代的烷基等;
R3、R4独自为烷基或苄基等。
优选地,R1为氢、甲基、甲氧基、磺酰胺基、卤素、甲酸乙酯基、乙酰基、苯基等;
R2为甲基、乙基、异丙基、正己基、苄基、苯乙基、3-甲氧基丙基等;
R3、R4独自为甲基、乙基、异丙基、苄基等。
其中,所述式(1)所示的胺硫代甲酰氟与丙二酸酯的摩尔比为1:1.5;式(1)所示的胺硫代甲酰氟与无机碱的摩尔比为1:(1.5~3);优选地,为1:1.5、1:2、1:2.5、1:3;进一步优选地,为1:2.5。
其中,所述的无机碱为碳酸钾、磷酸钾、碳酸铯、叔丁醇钾、氢化钠;优选地为碳酸铯。
其中,所述的有机溶剂为四氢呋喃、乙腈;优选地为乙腈。
其中,所述反应的温度优选为80℃。
其中,所述的反应时间为8~12小时。
其中,本发明所述方法还包括后处理和柱色谱分离纯化步骤;其中,所述分离纯化是用乙酸乙酯/石油醚混合溶剂为洗脱剂进行柱层析分离,乙酸乙酯:石油醚混合溶剂的体积比为1:3~1:10。
在一个具体实施方式中,本发明所述方法包括:将式(1)所示的胺硫代甲酰氟、丙二酸酯和无机碱于有机溶剂中,在80℃下反应,TLC监测至原料反应完。过滤除去反应体系中的沉淀物,滤液在减压下浓缩,残余物采用石油醚/乙酸乙酯的混合溶剂进行柱色谱分离,得到如式(2)所示的N-烷基/N-芳基硫代酰胺衍生物。
本发明提出的合成N-烷基/N-芳基硫代酰胺衍生物的方法,是将胺硫代甲酰氟和丙二酸酯和无机碱在有机溶剂中,温度为80℃的条件下,通过简单高效的亲核取代反应后,得到所述N-烷基/N-芳基硫代酰胺衍生物;经过后处理和柱色谱分离纯化,得到纯化的N-烷基/N-芳基硫代酰胺衍生物。
本发明还提供了所述N-烷基/N-芳基硫代酰胺衍生物在生物制药和特殊制剂方面的应用。
本发明采用了易于制备的起始原料和绿色环保的无机碱,通过亲核取代反应,高效构建了一类N-烷基/N-芳基硫代酰胺衍生物。该方法具有操作简单、绿色高效、原子步骤经济,底物适用范围广等优点。本发明合成的N-烷基/N-芳基硫代酰胺衍生物均为新化合物,是首次合成,可以应用于生物制药和特殊制剂。
附图说明
图1-37为本发明实施例1-37合成的N-烷基/N-芳基硫代酰胺衍生物的核磁共振1HNMR、13C NMR图谱。
具体实施方式
以下结合具体实施例及附图,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
实施例1
将甲基(苯基)氨基甲硫代氟化物(169.04mg,1mmol),丙二酸二甲酯(0.17mL,1.5mmol),碳酸铯(814.5mg,2.5mmol)加入到100mL反应瓶中,加入乙腈15mL,反应体系温度为80℃,反应12小时,TLC监测甲基(苯基)氨基甲硫代氟化物完全消耗,然后过滤除去不溶性固体,滤液在减压下浓缩,残留物通过硅胶柱层析纯化,得到纯产品280.6mg。其结构如式(2-1)所示。产率为87%。核磁共振1H NMR、13C NMR图谱如图1所示,产物:1H NMR(500MHz,CDCl3)δ7.51–7.41(m,3H),7.20(dd,J=5.3,3.3Hz,2H),4.67(s,1H),3.75(s,3H),3.71(s,6H).13C NMR(126MHz,CDCl3)δ192.42,165.52,144.76,130.32,129.31,125.70,63.85,53.07,45.71.
HRMS(EI)m/z calculated forC13H15NO4S[M]+281.0722,found281.0723.
实施例2
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(4-甲氧基苯基)(甲基)氨基甲硫基氟,80℃下反应时间18小时,所得到的产物如结构式(2-2)所示。产率为86%。核磁共振1H NMR、13C NMR图谱如图2所示,产物:1H NMR(500MHz,CDCl3)δ7.26(d,J=8.1Hz,2H),7.06(d,J=8.3Hz,2H),4.69(s,1H),3.73(s,3H),3.71(s,6H),2.40(s,3H).13CNMR(126MHz,CDCl3)δ192.48,165.58,142.25,139.44,130.85,125.32,63.80,53.06,45.76,21.16.
HRMS(EI)m/z calculated forC14H17NO5S[M]+311.0827,found311.0823.
实施例3
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为甲基(对甲苯基)氨基甲硫基氟,80℃下反应时间12小时,所得到的产物如结构式(2-3)所示。产率为78%。核磁共振1H NMR、13C NMR图谱如图3所示,产物:1H NMR(500MHz,CDCl3)δ7.26(d,J=8.1Hz,2H),7.06(d,J=8.3Hz,2H),4.69(s,1H),3.73(s,3H),3.72(s,6H),2.40(s,3H).13CNMR(126MHz,CDCl3)δ192.50,165.59,142.26,139.45,130.86,125.33,63.81,53.06,45.76,21.17.
HRMS(EI)m/z calculated forC14H17NO4S[M]+295.0878,found 295.0881.
实施例4
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(4-(N,4-二甲基苯基磺酰胺基)苯基)(甲基)氨基甲硫酰氟,80℃下反应时间8小时,所得到的产物如结构式(2-4)所示。产率为78%。核磁共振1H NMR、13C NMR图谱如图4所示,产物:1H NMR(500MHz,CDCl3)δ7.42(d,J=8.2Hz,2H),7.30–7.26(m,2H),7.23(d,J=8.7Hz,2H),7.14(d,J=8.7Hz,2H),4.63(s,1H),3.73(s,9H),3.17(s,3H),2.43(s,3H).13C NMR(126MHz,CDCl3)δ192.56,165.38,144.12,143.02,142.42,132.91,129.59,127.79,127.78,126.30,64.13,53.19,45.67,37.67,21.59.
HRMS(EI)m/z calculated forC21H24N2O6S2[M]+464.1076,found 464.1072.
实施例5
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(4-氟苯基)(甲基)氨基甲硫基氟,80℃下反应时间8小时,所得到的产物如结构式(2-5)所示。产率为80%。核磁共振1H NMR、13C NMR图谱如图5所示,产物:1H NMR(500MHz,CDCl3)δ7.24–7.13(m,4H),4.64(s,1H),3.73(s,3H),3.72(s,6H).13C NMR(126MHz,CDCl3)δ192.82,165.41,163.38,161.38,140.73,140.70,127.82,127.75,117.42,117.24,63.87,53.14,45.84.
HRMS(EI)m/z calculated forC13H14NO4SF[M]+299.0628,found 299.0625.
实施例6
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(4-氯苯基)(甲基)氨基甲硫基氟,80℃下反应时间8小时,所得到的产物如结构式(2-6)所示。产率为85%。核磁共振1H NMR、13C NMR图谱如图6所示,产物:1H NMR(500MHz,CDCl3)δ7.45(d,J=8.6Hz,2H),7.16(d,J=8.6Hz,2H),4.64(s,1H),3.72(s,9H).13C NMR(126MHz,CDCl3)δ192.62,165.37,143.17,135.33,130.55,127.26,63.80,53.17,45.74.
HRMS(EI)m/z calculated forC13H14NO4SCl[M]+315.0322,found 315.0329.
实施例7
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(4-溴苯基)(甲基)氨基甲硫基氟,80℃下反应时间10小时,所得到的产物如结构式(2-7)所示。产率为88%。核磁共振1H NMR、13C NMR图谱如图7所示,产物:1H NMR(500MHz,CDCl3)δ7.61(d,J=8.6Hz,2H),7.10(d,J=8.6Hz,2H),4.64(s,1H),3.72(s,9H).13C NMR(126MHz,CDCl3)δ192.52,165.36,143.68,133.56,127.55,123.33,63.77,53.18,45.70.
HRMS(EI)m/z calculated forC13H14NO4SBr[M]+358.9827,found 358.9832.
实施例8
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(4-碘苯基)(甲基)氨基甲酸硫代氟,80℃下反应时间8小时,所得到的产物如结构式(2-8)所示。产率为97%。核磁共振1H NMR、13C NMR图谱如图8所示,产物:1H NMR(600MHz,CDCl3)δ7.76–7.72(m,2H),6.91–6.87(m,2H),4.58(s,1H),3.65(s,6H),3.64(s,3H).13C NMR(151MHz,CDCl3)δ192.43,165.36,144.39,139.55,127.69,94.87,63.75,53.20,45.68.
HRMS(EI)m/z calculated forC13H14INO4S[M]+406.9688,found406.9690.
实施例9
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为4-((氟代硫代甲酰基)(甲基)氨基)苯甲酸乙酯,80℃下反应时间8小时,所得到的产物如结构式(2-9)所示。产率为83%。核磁共振1H NMR、13C NMR图谱如图9所示,产物:1H NMR(500MHz,CDCl3)δ8.15(d,J=8.5Hz,2H),7.30(d,J=8.5Hz,2H),4.63(s,1H),4.42(q,J=7.1Hz,2H),3.75(s,3H),3.72(s,6H),1.42(t,J=7.1Hz,3H).13C NMR(126MHz,CDCl3)δ192.33,165.31,165.14,148.36,131.64,131.33,125.96,63.79,61.59,53.18,45.60,14.28.
HRMS(EI)m/z calculated forC16H19NO6S[M]+353.0933,found 353.0930.
实施例10
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(4-乙酰基苯基)(甲基)氨基甲硫基氟,80℃下反应时间8小时,所得到的产物如结构式(2-10)所示。产率为78%。核磁共振1H NMR、13C NMR图谱如图10所示,产物:1H NMR(500MHz,CDCl3)δ8.07(d,J=8.5Hz,2H),7.34(d,J=8.4Hz,2H),4.64(s,1H),3.75(s,3H),3.72(s,6H),2.65(s,3H).13C NMR(126MHz,CDCl3)δ196.44,192.29,165.27,148.48,137.39,130.34,126.24,63.76,53.19,45.59,26.73.
HRMS(EI)m/z calculated forC15H17NO5S[M]+323.0827,found 323.0833.
实施例11
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(2-甲氧基苯基)(甲基)氨基甲硫基氟(199.1mg,1mmol),丙二酸二甲酯(396.3mg,3mmol),碳酸铯(1629.0mg,5mmol)和乙腈(15mL),80℃下反应时间18小时,所得到的产物如结构式(2-11)所示。产率为64%。核磁共振1H NMR、13C NMR图谱如图11所示,产物:1H NMR(500MHz,CDCl3)δ7.40(t,J=7.9Hz,1H),7.11(d,J=7.7Hz,1H),7.01(dd,J=16.4,8.2Hz,2H),4.55(s,1H),3.88(s,3H),3.74(s,3H),3.66(s,6H).13C NMR(126MHz,CDCl3)δ193.20,165.70,165.45,153.22,132.85,130.87,127.26,121.24,112.45,63.85,55.77,53.00,52.95,44.58.
HRMS(EI)m/z calculated forC14H17NO5S[M]+311.0827,found 311.0823.
实施例12
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为甲基(邻甲苯基)氨基甲硫基氟(183.1mg,1mmol),丙二酸二甲酯(396.3mg,3mmol),碳酸铯(1629.0mg,5mmol)和乙腈(15mL),80℃下反应时间18小时,所得到的产物如结构式(2-12)所示。产率为76%。核磁共振1H NMR、13C NMR图谱如图12所示,产物:1H NMR(500MHz,CDCl3)δ7.34(d,J=4.4Hz,2H),7.27(ddd,J=8.6,6.3,2.7Hz,1H),7.07(d,J=7.7Hz,1H),4.47(s,1H),3.73(s,3H),3.69(s,3H),3.67(s,3H),2.27(s,3H).13C NMR(126MHz,CDCl3)δ192.56,165.42,165.38,143.57,133.87,132.04,129.66,127.70,125.98,77.36,77.11,76.85,63.61,53.09,53.02,44.14,17.28.
HRMS(EI)m/z calculated forC14H17NO4S[M]+295.0878,found 295.0882.
实施例13
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(3-甲氧基苯基)(甲基)氨基甲硫基氟,80℃下反应时间12小时,所得到的产物如结构式(2-13)所示。产率为86%。核磁共振1H NMR、13C NMR图谱如图13所示,产物:1H NMR(500MHz,CDCl3)δ7.36(t,J=8.1Hz,1H),6.95(dd,J=8.4,2.2Hz,1H),6.77(d,J=7.8Hz,1H),6.71(s,1H),4.72(s,1H),3.82(s,3H),3.74(s,3H),3.72(s,6H).13C NMR(126MHz,CDCl3)δ192.36,165.61,160.88,145.76,131.07,117.57,114.92,111.37,63.74,55.57,53.08,45.55.
HRMS(EI)m/z calculated forC14H17NO5S[M]+311.0827,found 311.0828.
实施例14
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为甲基(间甲苯基)氨基甲酰氟,80℃下反应时间12小时,所得到的产物如结构式(2-14)所示。产率为84%。核磁共振1H NMR、13C NMR图谱如图14所示,产物:1H NMR(500MHz,CDCl3)δ7.34(t,J=7.7Hz,1H),7.23(d,J=7.7Hz,1H),6.98(d,J=9.6Hz,2H),4.67(s,1H),3.73(s,3H),3.72(s,6H),2.39(s,3H).13C NMR(126MHz,CDCl3)δ192.32,165.60,144.72,140.65,130.05,130.00,126.09,122.52,63.90,53.04,45.64,21.26.
HRMS(EI)m/z calculated forC14H17NO4S[M]+295.0878,found 295.0875.
实施例15
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为[1,1'-联苯]-3-基(甲基)氨基甲硫基氟,80℃下反应时间10小时,所得到的产物如结构式(2-15)所示。产率为85%。核磁共振1H NMR、13C NMR图谱如图15所示,产物:1H NMR(500MHz,CDCl3)δ7.66(d,J=7.8Hz,1H),7.59–7.51(m,3H),7.47(t,J=7.6Hz,2H),7.43–7.38(m,2H),7.18(d,J=7.9Hz,1H),4.74(s,1H),3.80(s,3H),3.68(d,J=29.6Hz,6H).13C NMR(126MHz,CDCl3)δ192.47,165.59,145.26,143.58,139.07,130.72,129.11,128.33,127.78,126.98,124.39,124.18,63.96,53.10,45.73.
HRMS(EI)m/z calculated forC19H19NO4S[M]+357.1035,found 357.1031.
实施例16
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(3-氟苯基)(甲基)氨基甲酸硫代氟(3-氟苯基)(甲基)氨基甲酸硫代氟,80℃下反应时间8小时,所得到的产物如结构式(2-16)所示。产率为82%。核磁共振1H NMR、13C NMR图谱如图16所示,产物:1HNMR(500MHz,CDCl3)δ7.47(dd,J=14.4,8.1Hz,1H),7.17(td,J=8.3,2.2Hz,1H),7.03(d,J=8.0Hz,1H),6.98–6.93(m,1H),4.65(s,1H),3.73(d,J=3.6Hz,9H).13C NMR(126MHz,CDCl3)δ192.57,165.37,164.09,162.09,145.89(d,J=9.2Hz),131.69(d,J=9.1Hz),121.75(d,J=3.4Hz),116.61(d,J=20.9Hz),113.61(d,J=22.8Hz),63.83,53.16,45.56.
HRMS(EI)m/z calculated forC13H14FNO4S[M]+299.0628,found 299.0631.
实施例17
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(3-氯苯基)(甲基)氨基甲硫基氟,80℃下反应时间10小时,所得到的产物如结构式(2-17)所示。产率为68%。核磁共振1HNMR、13C NMR图谱如图17所示,产物:1H NMR(500MHz,CDCl3)δ7.43(d,J=5.0Hz,2H),7.22(s,1H),7.15–7.10(m,1H),4.62(s,1H),3.73(d,J=2.9Hz,9H).13C NMR(126MHz,CDCl3)δ192.60,165.37,145.64,135.86,131.32,129.64,126.37,124.13,63.99,53.19,45.60.
HRMS(EI)m/z calculated forC13H14NO4S[M]+315.0332,found 315.0336.
实施例18
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(3,5-二甲氧基苯基)(甲基)氨基甲酸硫代氟,80℃下反应时间10小时,所得到的产物如结构式(2-18)所示。产率为85%。核磁共振1H NMR、13C NMR图谱如图18所示,产物:1H NMR(500MHz,CDCl3)δ6.40(t,J=2.2Hz,1H),6.24(d,J=2.2Hz,2H),4.70(s,1H),3.72(s,6H),3.66(s,6H),3.65(s,3H).13C NMR(126MHz,CDCl3)δ192.27,165.72,161.86,146.25,103.79,100.98,63.62,55.66,53.08,45.37.
HRMS(EI)m/z calculated forC15H19NO6S[M]+341.0933,found341.0938.
实施例19
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(3,5-二氟苯基)(甲基)氨基甲硫酰氟,80℃下反应时间8小时,所得到的产物如结构式(2-19)所示。产率为85%。核磁共振1H NMR、13C NMR图谱如图19所示,产物:1H NMR(500MHz,CDCl3)δ6.86(tt,J=8.6,2.2Hz,1H),6.78–6.68(m,2H),4.57(s,1H),3.67(s,6H),3.64(s,3H).13C NMR(126MHz,CDCl3)δ192.64(s),165.25(s),164.49(d,J=14.0Hz),162.47(d,J=14.0Hz),146.47(t,J=11.7Hz),110.12(d,J=7.1Hz),109.96(d,J=7.1Hz),105.36(t,J=25.1Hz),63.80(s),53.25(s),45.41(s).
HRMS(EI)m/z calculated forC13H13F2NO4S[M]+317.0533,found317.0527.
实施例20
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为甲基(萘-1-基)氨基甲硫基氟,80℃下反应时间16小时,所得到的产物如结构式(2-20)所示。产率为96%。核磁共振1H NMR、13C NMR图谱如图20所示,产物:1H NMR(500MHz,CDCl3)δ7.95(t,J=8.5Hz,2H),7.72(d,J=8.1Hz,1H),7.63(dt,J=13.9,6.7Hz,2H),7.50(t,J=7.8Hz,1H),7.34(d,J=7.2Hz,1H),4.48(s,1H),3.84(s,3H),3.68(s,3H),3.56(s,3H).13C NMR(126MHz,CDCl3)δ193.67,165.63,165.33,140.89,134.72,130.01,128.79,128.21,128.18,127.43,125.55,124.04,122.09,63.78,53.04,52.92,45.30.
HRMS(EI)m/z calculated forC17H17NO4S[M]+331.0878,found 331.0875.
实施例21
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为甲基(萘-2-基)氨基甲硫基氟,80℃下反应时间12小时,所得到的产物如结构式(2-21)所示。产率为63%。核磁共振1H NMR、13C NMR图谱如图21所示,产物:1H NMR(500MHz,CDCl3)δ7.95(d,J=8.7Hz,1H),7.93–7.88(m,1H),7.86–7.81(m,1H),7.67(d,J=1.4Hz,1H),7.59(p,J=6.1Hz,2H),7.31–7.26(m,1H),4.72(s,1H),3.83(s,3H),3.68(s,6H).13C NMR(126MHz,CDCl3)δ192.62,165.58,141.99,133.39,132.81,130.73,128.03,127.99,127.61,127.59,124.69,122.93,64.00,53.05,45.80.
HRMS(EI)m/z calculated forC17H17NO4S[M]+331.0878,found 331.0875.
实施例22
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为甲基(噻吩-2-基)氨基甲硫基氟,80℃下反应时间12小时,所得到的产物如结构式(2-22)所示。产率为72%。核磁共振1H NMR、13C NMR图谱如图22所示,产物:1H NMR(500MHz,CDCl3)δ7.43(dd,J=5.1,3.2Hz,1H),7.21(dd,J=3.1,1.3Hz,1H),6.94(dd,J=5.1,1.3Hz,1H),4.76(s,1H),3.73(s,6H),3.71(s,3H).13C NMR(126MHz,CDCl3)δ193.33,165.58,142.47,127.59,124.13,121.01,64.02,53.11,45.42.
HRMS(EI)m/z calculated forC11H13NO4S2[M]+287.0286,found 287.0289.
实施例23
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为甲基(苯基)氨基甲硫代氟化物和丙二酸二乙酯,80℃下反应时间12小时,所得到的产物如结构式(2-23)所示。产率为69%。核磁共振1H NMR、13C NMR图谱如图23所示,产物:1H NMR(500MHz,CDCl3)δ7.45(dq,J=14.4,7.1Hz,3H),7.21(d,J=7.4Hz,2H),4.62(s,1H),4.17(q,J=7.1Hz,4H),3.75(s,3H),1.22(t,J=7.1Hz,6H).13C NMR(126MHz,CDCl3)δ192.76,165.14,144.87,130.24,129.14,125.84,64.05,62.09,45.65,13.90.
HRMS(EI)m/z calculated forC15H19NO4S[M]+309.1035,found 309.1037.
实施例24
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为甲基(苯基)氨基甲硫代氟化物(169.0mg,1mmol),丙二酸二异丙酯(582.1mg,3mmol),碳酸铯(1629.0mg,5mmol)和乙腈(15mL),80℃下反应时间12小时,所得到的产物如结构式(2-24)所示。产率为76%。核磁共振1H NMR、13C NMR图谱如图24所示,产物:1H NMR(500MHz,CDCl3)δ7.43(dq,J=14.1,7.0Hz,3H),7.21(d,J=7.4Hz,2H),5.02(dt,J=12.5,6.2Hz,2H),4.54(s,1H),3.74(s,3H),1.23(d,J=6.2Hz,6H),1.16(d,J=6.2Hz,6H).13C NMR(126MHz,CDCl3)δ193.12,164.72,144.95,130.18,128.99,125.93,69.73,64.27,45.54,21.51,21.37.
HRMS(EI)m/z calculated forC17H23NO4S[M]+337.1348,found 337.1352.
实施例25
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为甲基(苯基)氨基甲硫代氟化物和丙二酸二苄酯,80℃下反应时间18小时,所得到的产物如结构式(2-25)所示。产率为88%。核磁共振1H NMR、13C NMR图谱如图25所示,产物:1H NMR(500MHz,CDCl3)δ7.35–7.24(m,14H),7.04(d,J=7.6Hz,2H),5.12(q,J=12.2Hz,4H),4.71(s,1H),3.70(s,3H).13C NMR(126MHz,CDCl3)δ192.26,164.90,144.71,135.07,130.25,129.09,128.53,128.49,128.39,125.72,67.83,64.08,45.65.
HRMS(EI)m/z calculated forC25H23NO4S[M]+433.1348,found 433.1345.
实施例26
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为甲基(苯基)氨基甲硫代氟化物和苄基丙二酸二甲酯,80℃下反应时间12小时,所得到的产物如结构式(2-26)所示。产率为95%。核磁共振1H NMR、13C NMR图谱如图26所示,产物:1H NMR(500MHz,CDCl3)δ7.47–7.27(m,8H),7.12(ddd,J=34.6,26.9,14.4Hz,2H),5.18–5.09(m,2H),4.69(s,1H),3.72(s,3H),3.69(s,3H).13C NMR(126MHz,CDCl3)δ192.36,165.52,164.89,144.75,135.08,130.29,129.19,128.55,128.51,128.44,125.71,67.78,63.98,53.06,45.68.
HRMS(EI)m/z calculated for C19H19NO4S[M]+357.1035,found 357.1039.
实施例27
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为乙基(苯基)氨基甲硫代氟化物,80℃下反应时间18小时,所得到的产物如结构式(2-27)所示。产率为83%。核磁共振1H NMR、13C NMR图谱如图27所示,产物:1H NMR(500MHz,CDCl3)δ7.51–7.42(m,3H),7.18–7.14(m,2H),4.58(s,1H),4.32(q,J=7.1Hz,2H),3.70(s,6H),1.28(t,J=7.2Hz,3H).13C NMR(126MHz,CDCl3)δ191.75,165.56,142.94,130.22,129.35,126.67,64.24,53.03,51.82,11.03.
HRMS(EI)m/z calculated for C14H17NO4S[M]+295.0878,found 295.0879.
实施例28
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为异丙基(苯基)氨基甲硫代氟化物,80℃下反应时间18小时,所得到的产物如结构式(2-28)所示。产率为58%。核磁共振1H NMR、13C NMR图谱如图28所示,产物:1H NMR(500MHz,CDCl3)δ7.51–7.43(m,3H),7.08(dd,J=6.4,2.8Hz,2H),5.91(hept,J=6.7Hz,1H),4.46(s,1H),3.69(s,6H),1.15(d,J=6.7Hz,6H).13C NMR(126MHz,CDCl3)δ192.02,165.67,138.92,129.69,129.53,128.41,64.73,53.41,52.99,19.99.
HRMS(EI)m/z calculated for C15H19NO4S[M]+309.1035,found 309.1031.
实施例29
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为己基(苯基)氨基甲硫基氟,80℃下反应时间16小时,所得到的产物如结构式(2-29)所示。产率为83%。核磁共振1H NMR、13C NMR图谱如图29所示,产物:1H NMR(500MHz,CDCl3)δ7.50–7.40(m,3H),7.18–7.12(m,2H),4.57(s,1H),4.27–4.20(m,2H),3.70(s,6H),1.71(dt,J=15.6,7.6Hz,2H),1.33–1.25(m,6H),0.86(t,J=6.8Hz,3H).13C NMR(126MHz,CDCl3)δ191.99,165.58,143.32,130.18,129.27,126.62,64.27,56.92,53.03,31.43,26.34,25.78,22.52,13.97.
HRMS(EI)m/z calculated forC18H25NO4S[M]+351.1504,found 351.1507.
实施例30
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为苯乙基(苯基)氨基甲硫基氟(259.1mg,1mmol),丙二酸二甲酯(396.3mg,3mmol),碳酸铯(1629.0mg,5mmol)和乙腈(15mL),80℃下反应时间18小时,所得到的产物如结构式(2-30)所示。产率为54%。核磁共振1H NMR、13C NMR图谱如图30所示,产物:1H NMR(500MHz,CDCl3)δ7.47–7.41(m,3H),7.29–7.24(m,2H),7.24–7.18(m,3H),7.08(dd,J=7.7,1.8Hz,2H),4.59(s,1H),4.47–4.41(m,2H),3.71(s,6H),3.15–3.09(m,2H).13C NMR(126MHz,CDCl3)δ192.30,165.55,143.62,137.94,130.27,129.36,128.85,128.54,126.60,126.52,64.31,58.35,53.08,31.68.
HRMS(EI)m/z calculated for C20H21NO4S[M]+371.1191,found 371.1196.
实施例31
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(3-甲氧基丙基)(苯基)氨基甲硫基氟(226.1mg,1mmol),丙二酸二甲酯(396.3mg,3mmol),碳酸铯(1629.0mg,5mmol)和乙腈(15mL),80℃下反应时间12小时,所得到的产物如结构式(2-31)所示。产率为86%。核磁共振1H NMR、13C NMR图谱如图31所示,产物:1H NMR(500MHz,CDCl3)δ7.49–7.40(m,3H),7.18–7.14(m,2H),4.58(s,1H),4.37–4.32(m,2H),3.70(s,6H),3.46(t,J=6.1Hz,2H),3.28(s,3H),2.07–2.00(m,2H).13C NMR(126MHz,CDCl3)δ192.38,165.55,143.31,130.25,129.35,126.60,70.05,64.27,58.65,54.53,53.03,26.21.
HRMS(EI)m/z calculated forC16H21NO5S[M]+339.1140,found 339.1137.
实施例32
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为苄基(苯基)硫代氨基甲酸氟,80℃下反应时间18小时,所得到的产物如结构式(2-32)所示。产率为77%。核磁共振1H NMR、13C NMR图谱如图32所示,产物:1H NMR(600MHz,CDCl3)δ7.35(ddd,J=9.5,6.5,1.4Hz,5H),7.31–7.27(m,3H),6.97(dd,J=7.8,1.7Hz,2H),5.60(s,2H),4.65(s,1H),3.74(s,6H).13C NMR(151MHz,CDCl3)δ193.50,165.59,142.70,134.93,130.00,129.38,128.73,128.53,127.92,126.83,64.30,59.80,53.14.
HRMS(EI)m/z calculated forC19H19NO4S[M]+357.1035,found 357.1038.
实施例33
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为苄基(4-甲氧基苯基)硫代氨基甲酸氟,80℃下反应时间12小时,所得到的产物如结构式(2-33)所示。产率为94%。核磁共振1H NMR、13C NMR图谱如图33所示,产物:1H NMR(600MHz,CDCl3)δ7.21(d,J=23.8Hz,5H),6.75(dd,J=24.7,8.0Hz,4H),5.47(s,2H),4.59(s,1H),3.70(s,3H),3.64(s,6H).13C NMR(151MHz,CDCl3)δ193.97,165.68,159.78,135.24,135.08,128.77,128.51,127.89,114.96,64.27,59.90,55.52,53.12.
HRMS(EI)m/z calculated forC20H21NO5S[M]+387.1140,found 387.1143.
实施例34
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为苄基(4-氯苯基)硫代氨基甲酸氟,80℃下反应时间8小时,所得到的产物如结构式(2-34)所示。产率为87%。核磁共振1H NMR、13C NMR图谱如图34所示,产物:1H NMR(600MHz,CDCl3)δ7.22(d,J=8.7Hz,7H),6.82(d,J=7.7Hz,2H),5.47(s,2H),4.52(s,1H),3.65(s,6H).13C NMR(151MHz,CDCl3)δ193.60,165.43,141.01,135.45,134.68,130.22,128.73,128.66,128.33,128.12,64.22,59.75,53.23.
HRMS(EI)m/z calculated forC19H18ClNO4S[M]+391.0645,found 391.0652.
实施例35
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为苄基(4-溴苯基)硫代氨基甲酸氟,80℃下反应时间10小时,所得到的产物如结构式(2-35)所示。产率为96%。核磁共振1H NMR、13C NMR图谱如图35所示,产物:1H NMR(600MHz,CDCl3)δ7.39(d,J=7.8Hz,2H),7.21(d,J=13.7Hz,5H),6.76(d,J=7.8Hz,2H),5.47(s,2H),4.52(s,1H),3.65(s,6H).13C NMR(151MHz,CDCl3)δ193.52,165.42,141.55,134.67,133.22,128.72,128.67,128.60,128.13,123.55,64.20,59.72,53.24.
HRMS(EI)m/z calculated forC19H18BrNO4S[M]+435.0140,found 435.0138.
实施例36
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为4-(苄基(氟碳硫羰基)氨基)苯甲酸乙酯,80℃下反应时间8小时,所得到的产物如结构式(2-36)所示。产率为72%。核磁共振1H NMR、13C NMR图谱如图36所示,产物:1H NMR(600MHz,CDCl3)δ7.94(d,J=8.5Hz,2H),7.21(q,J=6.0Hz,5H),6.96(d,J=8.5Hz,2H),5.51(s,2H),4.50(s,1H),4.30(q,J=7.1Hz,2H),3.65(s,6H),1.31(t,J=7.1Hz,3H).13C NMR(151MHz,CDCl3)δ193.24,165.38,165.20,146.32,134.60,131.35,131.26,128.73,128.65,128.13,127.08,64.22,61.58,59.69,53.25,14.28.
HRMS(EI)m/z calculated forC22H23NO6S[M]+429.1246,found 429.1243.
实施例37
本实施例实验方法基本与实施例1相同,本实施例中所采用的原料为(羰基双(4,1-亚苯基))双(甲基氨基甲硫基氟)(364.4mg,1mmol),丙二酸二甲酯(396.3mg,3mmol),碳酸铯(1629.0mg,5mmol)和乙腈(15mL),80℃下反应时间4小时,所得到的产物如结构式(2-37)所示。产率为79%。核磁共振1H NMR、13C NMR图谱如图37所示,产物:1H NMR(600MHz,CDCl3)δ7.84(d,J=8.4Hz,4H),7.32(d,J=8.3Hz,4H),4.62(s,2H),3.72(s,6H),3.66(s,12H).13C NMR(151MHz,CDCl3)δ193.43,192.36,165.28,148.42,137.30,131.90,126.32,63.89,53.28,45.67.
HRMS(EI)m/z calculated forC27H28N2O9S2[M]+588.1236,found588.1232.
Claims (7)
2.根据权利要求1所述的合成方法,其特征在于,所述式(1)所示的胺硫代甲酰氟与丙二酸酯的摩尔比为1:1.5;式(1)所示的胺硫代甲酰氟与无机碱的摩尔比为1:(1.5~3)。
3.根据权利要求1所述的合成方法,其特征在于,所述的无机碱为碳酸钾、磷酸钾、碳酸铯、氢化钠。
4.根据权利要求1所述的合成方法,其特征在于,所述的有机溶剂为四氢呋喃、乙腈。
5.根据权利要求1所述的合成方法,其特征在于,所述的反应时间为8~12小时。
6.根据权利要求1所述的合成方法,其特征在于,所述方法还包括后处理和柱色谱分离纯化步骤;其中,所述分离纯化是用乙酸乙酯/石油醚混合溶剂为洗脱剂进行柱层析分离,乙酸乙酯:石油醚混合溶剂的体积比为1:3~1:10。
7.根据权利要求1所述的合成方法,其特征在于,所述方法包括:将式(1)所示的胺硫代甲酰氟、丙二酸酯和无机碱于有机溶剂中,在80 ℃下反应,TLC监测至原料反应完;过滤除去反应体系中的沉淀物,滤液在减压下浓缩,残余物采用石油醚/乙酸乙酯的混合溶剂进行柱色谱分离,得到如式(2)所示的N-烷基/N-芳基硫代酰胺衍生物。
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