CN116082269A - 一种含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物及其制备方法 - Google Patents
一种含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种含有三氟甲基季碳中心的1,3,4‑噁唑啉类化合物,属于有机合成技术领域。其制备方法为:将邻氨基三氟甲基苯乙酮与无机碱添加剂加入到有机溶剂中,搅拌均匀后再加入肼基氯化物进行环化反应,即得。本发明采用邻氨基三氟甲基苯乙酮和肼基氯化物,开发了一种1,3,4‑噁唑啉类化合物的合成新方法,底物邻氨基三氟甲基苯乙酮和肼基氯化物都可进行不同的取代基变换,同时可以在产物中引入一个三氟甲基季碳中心。与现有的1,3,4‑噁唑啉的合成方法相比,本发明方法操作简单、反应能耗低、底物范围广,且无需采用贵金属催化剂,合成成本低。本发明的合成产物具有抑制肿瘤细胞增殖的作用,可用于制备抑制肿瘤细胞增殖的药物。
Description
技术领域
本发明属于有机合成技术领域。具体涉及一种含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物及其制备方法。
背景技术
含有1,3,4-噁唑啉骨架的化合物表现出多种生物活性,如抗结核和抗肿瘤活性;同时,含有三氟甲基季碳中心的杂环骨架是当前医学和农药学中一类具有广泛应用价值和应用前景的活性结构单元,如HIV逆转录酶抑制剂Efavirenz(J.C.Adkins,S.Noble,Drugs,1998,56,1055;Plosker,G.L.;Perry,C.M.;Goa,K.L.Efavirenz.PharmacoEconomics.2001,19,421–436;J.W.Corbett,S.S.Ko,J.D.Rodgers,L.A.Gearhart,N.A.Magnus,L.T.Bacheler,S.Diamond,S.Jeffrey,R.M.Klabe,B.C.Cordova,S.Garber,K.Logue,G.L.Trainor,P.S.Anderson and S.K.Erickson-Viitanen,J.Med.Chem.,2000,43,2019.)、抗疟疾药物Fluoroartemisinin等(G.Magueur,B.Crousse,S.Charneau,P.Grellier,J.-P.Be′gue′and D.J.Bonnet-Delpon,Med.Chem.,2004,47,2694.)。在此背景下,高效构筑多取代的1,3,4-噁唑啉衍生物具有重要意义。
传统的1,3,4-噁唑啉合成方法是使用N-酰基腙为原料,在高温条件下与醋酸酐(P.C.Shyma,B.Kalluraya,S.K.Peethambar,S.Telkar and T.Arulmoli,Eur.J.Med.Chem.,2013,68,394.)或乙酰氯发生环化反应(L.Somogyi,Tetrahedron,1985,41,5187.);后来发展出一种在氧气存在的条件下,通过钯催化的酰基肼与叔丁基异氰的氧化环化反应来合成2-亚氨基-1,3,4-噁唑啉类化合物(T.Fang,Q.Tan,Z.Ding,B.Liu andBin Xu,Org.Lett.2014,16,2342.)。上述现有的1,3,4-噁唑啉合成方法,都需高温条件或加热回流,增加了反应能耗,且都只能对两个反应底物中的其中一个底物(N-酰基腙或酰基肼)的取代基进行变换、调节,另一个底物是单一、固定不变的,从而限制了合成方法的应用范围。另外,在最近发展的钯催化下酰基肼与叔丁基异氰的氧化环化这一合成方法中,不仅需要贵金属钯的参与,而且需要往体系中额外通入氧气才能顺利实现催化循环,合成成本较高;重金属钯在反应完成之后难以彻底去除,限制了产物在医药上的应用。
发明内容
本发明的目的是解决上述现有技术的不足,提供一种含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物及其制备方法。
技术方案
一种含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物,其结构式如式(I)所示:
其中,R1、R2为芳基;R3为氢、烷基、烷氧基、苄基、卤素、苯基、巯基或氨基;R4为磺酰基。
上述含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物的制备方法:将邻氨基三氟甲基苯乙酮与无机碱添加剂加入到有机溶剂中,搅拌均匀后再加入肼基氯化物进行环化反应,得到含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物。
进一步,所述邻氨基三氟甲基苯乙酮的结构式如式(II)所示:
式(II)中R3和R4同式(I)中R3和R4对应一致。
进一步,所述肼基氯化物的结构式如式(III)所示:
式(II)中R1和R2同式(I)中R1和R2对应一致。
进一步,所述无机碱添加剂为碳酸钾。
进一步,所述有机溶剂为二氯甲烷。
进一步,所述环化反应温度为35℃~45℃。
上述含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物在制备抑制肿瘤细胞增殖的药物中的应用。
本发明的有益效果:
(1)本发明公开了一种含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物,其具有抑制肿瘤细胞增殖的作用,可用于制备抑制肿瘤细胞增殖的药物。
(2)本发明采用邻氨基三氟甲基苯乙酮和肼基氯化物,开发了一种1,3,4-噁唑啉类化合物的合成新方法,邻氨基三氟甲基苯乙酮和肼基氯化物两底物都可进行不同的取代基变换,同时可以在产物中引入一个三氟甲基季碳中心。与现有技术中1,3,4-噁唑啉的合成方法相比,本发明方法操作简单、反应能耗低、底物范围广,且无需采用贵金属催化剂,合成成本低。
附图说明
图1为实施例1、3-5的含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物在CAL33细胞上抑制增殖活性测试结果。
具体实施方式
下面结合附图和具体实施例对本发明的技术方案作清楚、完整地说明。
实施例1
制备N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,反应方程式为:
具体操作步骤如下:室温(25℃)下,依次将103mg(0.30mmol)4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺、83mg(0.60mmol)碳酸钾和3.0mL二氯甲烷加入15mL的圆底烧瓶中,搅拌均匀后,在搅拌下加入104mg(0.45mmol)N-苯基苯肼酰氯,之后在40℃下反应8小时,通过TLC监测反应。反应完成后,通过硅胶柱进行柱层析分离(淋洗剂比例为石油醚:乙酸乙酯=5:1,体积比),得到N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺121mg,记为3aa,白色固体,收率75%。
产物数据表征如下:
熔点104-106℃;
1H NMR(400MHz,CDCl3)δ7.86(d,J=7.6Hz,2H),7.78(d,J=8.4Hz,1H),7.64(d,J=8.1Hz,1H),7.58–7.40(m,4H),7.36(d,J=8.0Hz,2H),7.23–7.07(m,3H),7.02–6.92(m,3H),6.86(d,J=8.0Hz,2H),2.23(s,3H);
13C NMR(101MHz,CDCl3)δ153.7,143.8,140.5,138.0,136.3,132.2,131.7,129.5,129.0,128.8,127.1,127.0,124.1,123.6,123.4,121.4,120.1,117.7,98.8(q,J=29.7Hz),21.5;
19F NMR(376MHz,CDCl3)δ-73.90(s,3F);
HRMS(ESI)m/z C28H23F3N3O3S([M+H]+):计算值:538.1407;实测值:538.1403。
实施例2
制备4-甲基-N-(2-(3-苯基-5-(对甲苯基)-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)苯基)苯磺酰胺,其结构式如下:
将原料N-苯基苯肼酰氯换为4-甲基-N-苯基苯肼酰氯,其余与实施例1相同,得到产物4-甲基-N-(2-(3-苯基-5-(对甲苯基)-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)苯基)苯磺酰胺,记为3ab,白色固体,收率84%。
产物数据表征如下:
熔点127-129℃;
1H NMR(400MHz,CDCl3)δ7.74–7.60(m,3H),7.53(d,J=8.0Hz,1H),7.29(t,J=9.5Hz,3H),7.17(d,J=7.9Hz,2H),7.13–6.93(m,4H),6.92–6.81(m,3H),6.77(d,J=8.0Hz,2H),2.31(s,3H),2.12(s,3H);
13C NMR(101MHz,CDCl3)δ153.9,143.8,142.2,140.7,138.0,136.3,132.1,129.5,129.5,129.0,127.2,127.0,124.0,123.2,121.3,120.7,120.2,117.6,98.7(q,J=29.8Hz),21.7,21.5;
19F NMR(376MHz,CDCl3)δ-73.93(s,3F);
HRMS(ESI)m/z C29H25F3N3O3S([M+H]+):计算值:552.1563;实测值:552.1560。
实施例3
制备N-(2-(5-(4-甲氧基苯基)-3-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料N-苯基苯肼酰氯换为4-甲氧基-N-苯基苯肼酰氯,其余与实施例1相同,得到产物N-(2-(5-(4-甲氧基苯基)-3-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,记为3ac,白色固体,收率68%。
产物数据表征如下:
熔点138-141℃;
1H NMR(400MHz,CDCl3)δ7.72(d,J=8.5Hz,2H),7.64(d,J=8.3Hz,1H),7.54(d,J=8.2Hz,1H),7.38–7.24(m,3H),7.10–6.99(m,3H),6.92–6.83(m,5H),6.80(d,J=8.0Hz,2H),3.75(s,3H),2.14(s,3H);
13C NMR(101MHz,CDCl3)δ161.3,152.6,142.7,139.7,136.9,135.3,131.0,128.4,127.8,127.7,126.1,122.8,122.0,120.1,119.1,116.5,114.8,113.2,97.5(q,J=29.7Hz),54.4,20.4;
19F NMR(376MHz,CDCl3)δ-73.93(s,3F);
HRMS(ESI)m/z C29H25F3N3O4S([M+H]+):计算值:568.1512;实测值:568.1506。
实施例4
制备N-(2-(5-(4-氯苯基)-3-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料N-苯基苯肼酰氯换为4-氯-N-苯基苯肼酰氯,其余与实施例1相同,得到产物N-(2-(5-(4-氯苯基)-3-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,记为3ad,白色固体,收率73%。
产物数据表征如下:
熔点158-160℃;
1H NMR(400MHz,CDCl3)δ7.70(d,J=8.2Hz,2H),7.57(t,J=9.8Hz,2H),7.41–7.22(m,6H),7.19–6.99(m,3H),6.96–6.69(m,5H),2.16(s,3H);
13C NMR(101MHz,CDCl3)δ151.8,142.8,139.3,136.8,136.6,135.5,131.2,128.5,128.1,127.9,127.8(q,J=4.2Hz),127.1,126.0,123.2,122.4,121.0,120.8,119.4,116.5,97.9(q,J=29.8Hz),20.4;
19F NMR(376MHz,CDCl3)δ-74.11(s,3F);
HRMS(ESI)m/z C28H22ClF3N3O3S([M+H]+):计算值:572.1017;实测值:572.1011。
实施例5
制备N-(2-(5-(4-溴苯基)-3-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料N-苯基苯肼酰氯换为4-溴-N-苯基苯肼酰氯,其余与实施例1相同,得到产物N-(2-(5-(4-溴苯基)-3-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,记为3ae,白色固体,收率65%。
产物数据表征如下:
熔点129-131℃;
1H NMR(400MHz,CDCl3)δ7.78–7.62(m,4H),7.59(d,J=8.5Hz,2H),7.49–7.41(m,1H),7.39(d,J=8.0Hz,2H),7.22–7.17(m,1H),7.15(t,J=7.9Hz,2H),6.98(t,J=7.5Hz,1H),6.93(t,J=7.6Hz,4H),2.26(s,3H).
13C NMR(101MHz,CDCl3)δ152.9,143.9,140.4,138.0,136.6,132.3,132.1,129.6,129.0,128.8(t,J=4.3Hz),128.3,127.0,126.1,124.3,123.5,122.5,121.9,120.5,117.6,99.0(q,J=29.8Hz),21.6.
19F NMR(376MHz,CDCl3)δ-74.11(s,3F).
HRMS(ESI)m/z C28H22BrF3N3O3S([M+H]+):计算值:616.0512;实测值:616.0506。
实施例6
制备4-甲基-N-(2-(3-苯基-5-(间甲苯基)-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)苯磺酰胺,其结构式如下:
将原料N-苯基苯肼酰氯换为3-甲基-N-苯基苯肼酰氯,其余与实施例1相同,得到产物4-甲基-N-(2-(3-苯基-5-(间甲苯基)-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)苯磺酰胺,记为3af,白色固体,收率83%。
产物数据表征如下:
熔点112-114℃;
1H NMR(400MHz,CDCl3)δ7.70(d,J=8.3Hz,1H),7.65–7.48(m,3H),7.34(t,J=8.0Hz,1H),7.31–7.15(m,4H),7.12–7.00(m,3H),6.91–6.82(m,3H),6.78(d,J=7.9Hz,2H),2.33(s,3H),2.14(s,3H);
13C NMR(101MHz,CDCl3)δ153.8,143.8,140.6,138.7,138.0,136.3,132.5,132.1,129.5,129.0,129.0,128.8,128.7,127.5,127.2,124.2,124.0,123.4,123.3,121.2,120.0,117.7,98.7(q,J=29.5Hz),21.5,21.4;
19F NMR(376MHz,CDCl3)δ-73.88(s,3F);
HRMS(ESI)m/z C29H24F3N3O3S([M+H]+):计算值:552.1563;实测值:552.1557。
实施例7
制备N-(2-(5-(3-氯苯基)-3-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料N-苯基苯肼酰氯换为3-氯-N-苯基苯肼酰氯,其余与实施例1相同,得到产物N-(2-(5-(3-氯苯基)-3-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,记为3ag,白色固体,收率71%。
产物数据表征如下:
熔点118-121℃;
1H NMR(400MHz,CDCl3)δ7.85–7.73(m,3H),7.64(d,J=8.1Hz,1H),7.52–7.45(m,2H),7.43–7.33(m,3H),7.25–7.11(m,4H),7.00(t,J=7.5Hz,1H),6.94(t,J=7.7Hz,4H),2.27(s,3H);
13C NMR(101MHz,CDCl3)δ152.5,144.0,140.3,137.9,136.4,134.9,132.3,131.6,130.2,129.6,129.1,128.9(q,J=4.2Hz),127.1,126.8,125.3,125.1,124.3,123.6,121.8,120.2,117.7,99.1(q,J=29.8Hz),21.6;
19F NMR(376MHz,CDCl3)δ-73.99(s,3F);
HRMS(ESI)m/z C28H22ClF3N3O3S([M+H]+):计算值:572.1017;实测值:572.1012.
实施例8
制备N-(2-(5-(2-氯苯基)-3-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料N-苯基苯肼酰氯换为2-氯-N-苯基苯肼酰氯,其余所需原料和制备方法与实施例1相同,得到产物N-(2-(5-(2-氯苯基)-3-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,记为3ah,白色固体,收率62%。
产物数据表征如下:
熔点105-107℃;
1H NMR(400MHz,CDCl3)δ7.64(dd,J=24.6,8.0Hz,2H),7.51(d,J=7.8Hz,1H),7.40(d,J=7.8Hz,1H),7.35–7.12(m,6H),7.14–6.93(m,3H),6.90–6.60(m,5H),2.07(s,3H).
13C NMR(101MHz,CDCl3)δ151.5,143.8,140.4,138.0,136.4,133.5,132.2,132.1,131.3,130.8,129.4,129.0,128.9(d,J=4.4Hz),127.0,126.9,124.2,123.5,122.6,121.9,120.3,117.7,98.3(q,J=29.8Hz),21.5.
19F NMR(376MHz,CDCl3)δ-73.83(s,3F).
HRMS(ESI)m/z C28H22ClF3N3O3S([M+H]+):计算值:572.1017;实测值:572.1012.
实施例9
制备4-甲基-N-(2-(3-苯基-5-(噻吩-2-基)-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)苯磺酰胺,其结构式如下:
将原料N-苯基苯肼酰氯换为N-苯基噻吩-2-甲酰肼氯化物,其余与实施例1相同,得到产物4-甲基-N-(2-(3-苯基-5-(噻吩-2-基)-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)苯磺酰胺,记为3ai,黄色油状物,收率69%。
产物数据表征如下:
1H NMR(400MHz,CDCl3)δ7.74(d,J=8.3Hz,1H),7.67–7.58(m,1H),7.59–7.33(m,5H),7.31–7.06(m,6H),7.04–6.69(m,5H),2.26(s,3H).
13C NMR(101MHz,CDCl3)δ150.1,143.8,140.4,138.0,136.4,132.2,130.2,130.1,129.5,129.0,128.9,127.9,127.1,124.9,124.1,123.5,121.5,120.0,117.8,98.9(q,J=30.1Hz),21.6.
19F NMR(376MHz,CDCl3)δ-73.88(s,3F).
HRMS(ESI)m/z C26H21F3N3O3S2([M+H]+):计算值:544.0971;实测值:544.0966.
实施例10
制备N-(2-(3-(4-溴苯基)-5-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料N-苯基苯肼酰氯换为N-(4-溴苯基)苯肼酰氯,其余与实施例1相同,得到产物N-(2-(3-(4-溴苯基)-5-苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2基)苯基)-4-甲基苯磺酰胺,记为3aj,白色固体,收率76%。
产物数据表征如下:
熔点146-148℃;
1H NMR(400MHz,CDCl3)δ7.77(d,J=7.6Hz,2H),7.70(d,J=8.4Hz,1H),7.54(d,J=8.1Hz,1H),7.42(d,J=7.2Hz,1H),7.37(t,J=6.8Hz,3H),7.27(d,J=7.8Hz,2H),7.20–7.06(m,4H),6.80(d,J=8.0Hz,2H),6.69(d,J=8.4Hz,2H),2.15(s,3H).
13C NMR(101MHz,CDCl3)δ153.8,144.0,139.6,137.9,136.1,132.4,131.9,129.5,128.9,128.8(d,J=4.1Hz),127.1,127.0,124.2,123.2,121.4,119.6,118.8,115.7,98.5(q,J=30.1Hz),21.6.
19F NMR(376MHz,CDCl3)δ-74.13(s,3F).
HRMS(ESI)m/z C28H22BrF3N3O3S([M+H]+):计算值:616.0512;实测值:616.0506.
实施例11
制备N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)-4-甲氧基苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为N-(4-甲氧基-2-(2,2,2-三氟乙酰基)苯基)-4-甲基苯磺酰胺,其余与实施例1相同,得到产物N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)-4-甲氧基苯基)-4-甲基苯磺酰胺,记为3ba,白色固体,收率76%。
产物数据表征如下:
熔点138-141℃;
1H NMR(400MHz,CDCl3)δ7.74(d,J=7.5Hz,2H),7.53(d,J=9.0Hz,1H),7.49–7.30(m,3H),7.26(d,J=7.9Hz,2H),7.16–7.09(m,1H),7.05(t,J=7.8Hz,2H),6.94–6.82(m,4H),6.77(d,J=8.0Hz,2H),3.68(s,3H),2.13(s,3H).
13C NMR(101MHz,CDCl3)δ156.3,153.5,143.5,140.7,136.8,131.5,130.4,129.5,129.0,128.7,127.1,127.0,124.7,123.8,123.3,117.6,116.1,115.7(q,J=4.2Hz),98.6(q,J=29.5Hz),55.6,21.5.
19F NMR(376MHz,CDCl3)δ-74.10(s,3F).
HRMS(ESI)m/z C29H25F3N3O4S([M+H]+):计算值:568.1512;实测值:568.1508.
实施例12
制备N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)-4-乙基苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为N-(4-乙基-2-(2,2,2-三氟乙酰基)苯基)-4-甲基苯磺酰胺,其余与实施例1相同,得到产物N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)-4-乙基苯基)-4-甲基苯磺酰胺,记为3ca,白色固体,收率76%。
产物数据表征如下:
熔点138-141℃;
1H NMR(400MHz,CDCl3)δ7.93(d,J=7.4Hz,2H),7.74(d,J=8.4Hz,1H),7.71–7.48(m,4H),7.44(d,J=7.8Hz,2H),7.35(d,J=8.2Hz,1H),7.22(t,J=7.8Hz,2H),7.04(d,J=8.1Hz,3H),6.93(d,J=7.9Hz,2H),2.71(q,J=7.9Hz,2H),2.29(s,3H),1.29(t,J=7.8Hz,3H).
13C NMR(101MHz,CDCl3)δ153.6,143.7,140.7,140.2,136.6,135.5,131.6,131.5,129.5,129.0,128.8,128.2(q,J=4.1Hz),127.1,127.0,123.7,123.3,121.9,120.5,117.7,98.9(q,J=29.7Hz),28.3,21.5,15.3.
19F NMR(376MHz,CDCl3)δ-73.80(s,3F).
HRMS(ESI)m/z C30H27F3N3O3S([M+H]+):计算值:566.1720;实测值:566.1715.
实施例13
制备N-(4-叔丁基-2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为N-(4-(叔丁基)-2-(2,2,2-三氟乙酰基)苯基)-4-甲基苯磺酰胺,其余与实施例1相同,得到产物N-(4-叔丁基-2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,记为3da,白色固体,收率76%。
产物数据表征如下:
熔点140-142℃;
1H NMR(400MHz,CDCl3)δ7.94(d,J=7.3Hz,2H),7.79–7.64(m,2H),7.63–7.37(m,6H),7.20(t,J=7.4Hz,2H),7.11–6.84(m,5H),2.29(s,3H),1.37(s,9H).
13C NMR(101MHz,CDCl3)δ153.6,147.1,143.6,140.8,136.8,135.1,131.6,129.5,128.9,128.8,127.1,127.0,125.9(d,J=4.3Hz),123.7,123.3,121.4,120.0,117.8,99.1(q,J=29.8Hz),34.6,31.2,21.5.
19F NMR(376MHz,CDCl3)δ-74.06(s,3F).
HRMS(ESI)m/z C32H31F3N3O3S([M+H]+):计算值:594.2033;实测值:594.2028.
实施例14
制备N-(4-苄基-2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为N-(4-苄基-2-(2,2,2-三氟乙酰基)苯基)-4-甲基苯磺酰胺,其余所需原料和制备方法与实施例1相同,得到产物N-(4-苄基-2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)苯基)-4-甲基苯磺酰胺,记为3ea,白色固体,收率89%。
产物数据表征如下:
熔点118-120℃;
1H NMR(400MHz,CDCl3)δ7.97(dt,J=7.0,1.7Hz,2H),7.75(dt,J=8.5,2.1Hz,1H),7.65–7.51(m,4H),7.47(dt,J=8.4,1.8Hz,2H),7.40(t,J=7.5Hz,2H),7.38–7.30(m,2H),7.29–
7.18(m,4H),7.13–7.03(m,3H),6.97(d,J=8.0Hz,2H),4.07(s,2H),2.31(s,3H).
13C NMR(101MHz,CDCl3)δ153.6,143.8,140.7,140.1,137.3,136.6,136.0,132.5,131.7,129.6,129.4(q,J=4.0Hz),129.0,128.9,128.8,128.8,127.2,127.0,126.6,123.7,123.4,121.9,120.5,117.8,98.9(q,J=29.8Hz),41.3,21.6.
19F NMR(376MHz,CDCl3)δ-74.01(s,3F).
HRMS(ESI)m/z C35H29F3N3O3S([M+H]+):计算值:628.1876;实测值:628.1872.
实施例15
制备N-(4-氯-2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为N-(4-氯-2-(2,2,2-三氟乙酰基)苯基)-4-甲基苯磺酰胺,其余所需原料和制备方法与实施例1相同,得到产物N-(4-氯-2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)苯基)-4-甲基苯磺酰胺,记为3fa,白色固体,收率73%。
产物数据表征如下:
熔点104-106℃;
1H NMR(400MHz,CDCl3)δ7.86–7.82(m,2H),7.77(d,J=8.9Hz,1H),7.63–7.57(m,1H),7.56–7.51(m,1H),7.52–7.45(m,2H),7.43(dd,J=8.9,2.3Hz,1H),7.39–7.31(m,2H),7.23–7.15(m,2H),7.06–7.00(m,1H),6.95(dd,J=7.6,1.6Hz,2H),6.87(d,J=8.1Hz,2H),2.25(s,3H).
13C NMR(101MHz,CDCl3)δ153.7,145.8,144.0,140.3,136.7,136.0,132.1,131.8,129.6,129.5,129.4,129.1,128.8,127.1,127.0,123.8,123.3,122.6,121.8,118.0,98.3(q,J=29.9Hz),21.5.
19F NMR(376MHz,CDCl3)δ-73.96(s,3F).
HRMS(ESI)m/z C28H22ClF3N3O3S([M+H]+):计算值:572.1017;实测值:572.1016.
实施例16
制备N-(3-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)二苯基-4-基)-4-甲基苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为4-甲基-N-(3-(2,2,2-三氟乙酰基)-[1,1'-联苯]-4-基)苯磺酰胺,其余所需原料和制备方法与实施例1相同,得到产物N-(3-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)二苯基-4-基)-4-甲基苯磺酰胺,记为3ga,白色固体,收率72%。
产物数据表征如下:
熔点168-170℃;
1H NMR(400MHz,CDCl3)δ7.82–7.71(m,4H),7.57(d,J=8.6Hz,1H),7.48–7.27(m,9H),7.23(t,J=7.3Hz,1H),7.04(t,J=7.7Hz,2H),6.95–6.82(m,3H),6.75(d,J=7.9Hz,2H),2.10(s,3H).
13C NMR(101MHz,CDCl3)δ153.8,143.9,140.6,139.3,137.2,137.0,136.4,131.7,130.6,129.6,129.2,129.1,128.9,128.0,127.5(t,J=4.3Hz),127.2,127.1,126.9,123.6(d,J=4.3Hz),121.8,120.7,117.9,99.0(q,J=29.6Hz),21.6.
19F NMR(376MHz,CDCl3)δ-73.52(s,3F).
HRMS(ESI)m/z C34H27F3N3O3S([M+H]+):计算值:614.1720;实测值:614.1715.
实施例17
制备N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)-4-(甲硫基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为4-甲基-N-(4-(甲硫基)-2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺,其余与实施例1相同,得到产物N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)-4-(甲硫基)苯基)-4-甲基苯磺酰胺,记为3ha,黄色固体,收率74%。
产物数据表征如下:
熔点107-109℃;
1H NMR(400MHz,CDCl3)δ7.97–7.85(m,2H),7.79(d,J=8.6Hz,1H),7.64–7.47(m,4H),7.44–7.34(m,3H),7.23(t,J=7.9Hz,2H),7.04(t,J=7.2Hz,3H),6.92(d,J=8.0Hz,2H),2.50(s,3H),2.28(s,3H).
13C NMR(101MHz,CDCl3)δ153.7,143.8,140.5,136.3,135.1,134.7,131.7,130.2,129.6,129.1,128.8,127.1,127.0,123.6,123.5,122.4,121.3,117.9,98.6(q,J=29.8Hz),21.5,16.2.
19F NMR(376MHz,CDCl3)δ-73.65(s,3F).
HRMS(ESI)m/z C29H25F3N3O3S2([M+H]+):计算值:584.1284;实测值:584.1280.
实施例18
制备N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)-4-((1R,2S,5R)-2-异丙基-5-甲基环己基氧基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为N-(4-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)-2-(2,2,2-三氟乙酰基)苯基)-4-甲基苯磺酰胺,其余与实施例1相同,得到产物N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)-4-((1R,2S,5R)-2-异丙基-5-甲基环己基氧基)苯基)-4-甲基苯磺酰胺,记为3ia,淡黄色固体,收率95%。
产物数据表征如下:
熔点154-156℃;
1H NMR(400MHz,CDCl3)δ7.92(s,2H),7.71–7.36(m,5H),7.24(d,J=32.6Hz,4H),7.13–6.79(m,7H),4.03(s,1H),2.29(s,3H),2.20–2.04(m,2H),1.78(d,J=12.2Hz,2H),1.54(d,J=31.7Hz,2H),1.24–0.91(m,9H),0.84(s,3H).
13C NMR(101MHz,CDCl3)δ155.2,153.4,143.5,140.8,137.0(d,J=4.3Hz),131.5,130.1(d,J=6.8Hz),129.5,128.9(d,J=2.3Hz),128.7,127.1,127.0,124.8(d,J=3.8Hz),123.8(d,J=2.3Hz),123.4(d,J=11.3Hz),123.2,118.4(d,J=22.5Hz),117.9(d,J=4.3Hz),117.7(d,J=4.0Hz),98.6(q,J=29.4Hz),79.0,78.9,48.1,40.2,34.4,31.4,26.1,23.6(d,J=2.4Hz),22.2,21.5,20.8(d,J=2.8Hz),16.5.
19F NMR(376MHz,CDCl3)δ-74.27(s,3F).
HRMS(ESI)m/z C38H41F3N3O4S([M+H]+):计算值:692.2764;实测值:692.2759.
实施例19
制备N-(4-(二甲基氨基)-2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为N-(4-(二甲基氨基)-2-(2,2,2-三氟乙酰基)苯基)-4-甲基苯磺酰胺,其余与实施例1相同,得到产物N-(4-(二甲基氨基)-2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)-4-甲基苯磺酰胺,记为3ja,黄色固体,收率84%。
产物数据表征如下:
熔点150-152℃;
1H NMR(400MHz,CDCl3)δ7.94–7.76(m,2H),7.56–7.40(m,4H),7.37(d,J=8.0Hz,2H),7.17–7.10(m,2H),6.99–6.92(m,4H),6.88(d,J=8.1Hz,2H),6.81(s,1H),6.73(dd,J=9.1,2.8Hz,1H),2.95(s,6H),2.24(s,3H).
13C NMR(101MHz,CDCl3)δ153.3,147.8,143.1,140.9,137.4,131.3,129.4,128.9,128.6,127.1,127.0,125.7,124.1,123.9,122.8,117.4,114.9,112.3(d,J=5.0Hz),98.9(q,J=29.8Hz),40.4,21.5.
19F NMR(376MHz,CDCl3)δ-74.08(s,3F).
HRMS(ESI)m/z C30H28F3N4O3S([M+H]+):计算值:581.1829;实测值:581.1824.
实施例20
制备N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺,其余与实施例1相同,得到产物N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-噁二唑-2-基)苯基)苯磺酰胺,记为3ka,白色固体,收率71%。
产物数据表征如下:
熔点106-108℃;
1H NMR(400MHz,CDCl3)δ8.01–7.90(m,2H),7.83(d,J=8.0Hz,1H),7.76–7.66(m,1H),7.62–7.45(m,5H),7.39(s,1H),7.30–6.94(m,7H).
13C NMR(101MHz,CDCl3)δ153.8,140.5,139.3,137.9,133.0,132.2,131.7,129.1,128.9,128.9,127.1,127.1,124.2,123.6,123.5,121.4,120.3,117.7,98.8(q,J=29.7Hz).
19F NMR(376MHz,CDCl3)δ-73.91(s,3F).
HRMS(ESI)m/z C27H21F3N3O3S([M+H]+):计算值:524.1250;实测值:524.1245.
实施例21
制备N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)苯基)-4-甲氧苯磺酰胺,其结构式如下:
将原料4-甲基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺换为4-甲氧基-N-(2-(2,2,2-三氟乙酰基)苯基)苯磺酰胺,其余与实施例1相同,得到产物N-(2-(3,5-二苯基-2-(三氟甲基)-2,3-二氢-1,3,4-恶二唑-2-基)苯基)-4-甲氧苯磺酰胺,记为3la,白色固体,收率81%。
产物数据表征如下:
熔点124-126℃;
1H NMR(400MHz,CDCl3)δ7.87(d,J=7.5Hz,1H),7.80(d,J=8.4Hz,0H),7.64(d,J=8.0Hz,1H),7.57–7.33(m,3H),7.23–7.07(m,2H),7.05–6.84(m,1H),6.53(d,J=8.5Hz,1H),3.68(s,1H).
13C NMR(101MHz,CDCl3)δ163.0,153.6,140.5,138.1,132.2,131.7,130.7,129.4,129.0,128.9,127.0,124.0,123.5,123.3,121.3,120.0,117.6,114.0,98.8(q,J=29.7Hz),55.5.
19F NMR(376MHz,CDCl3)δ-73.89(s,3F).
HRMS(ESI)m/z C28H23F3N3O4S([M+H]+):计算值:554.1356;实测值:554.1353.
测试部分实施例化合物在若干肿瘤细胞株上的抑制增殖活性,实验方法如下:
实验所用肿瘤细胞(CAL33细胞)来源于中国科学院上海生命科学研究院细胞资源中心。利用MTT细胞增殖抑制实验检测化合物对CAL33细胞活性的影响。取对数期生长的3种细胞,用胰酶消化CAL33得到细胞悬液,计数并调整至细胞密度2×104个/mL。每孔200μL细胞接种于96孔板中,于37℃、5% CO2的孵箱内培养24h后加入浓度为50μM的不同实施例化合物(3aa、3ac、3ad、3ae),每种化合物3个复孔,空白对照组只加入相应体积的溶剂(DMSO),不加化合物。然后继续置于37℃,5% CO2的孵箱内培养48h。之后加入终浓度为5mg/mL的3-(4,5-二甲基-2-噻唑)-2,5-二苯基溴化四氮唑噻唑蓝即(MTT)20μL培养4h。用Bio-Rad酶标仪检测各孔在490nm波长下吸光度值。
细胞数(%空白组)=100×(化合物处理组吸光度值-空白组吸光度值)/(对照组吸光度值-空白组吸光度值)
每组实验重复3次,以化合物编号为横坐标,细胞存活率为纵坐标,用GraphPadPrism软件作图。测试结果见图1,统计数据见表1。
图1为实施例1、3-5的含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物在CAL33细胞上抑制增殖活性测试结果。统计数据见表1:
表1
化合物编号 | CAL33细胞毒性(细胞存活率) |
3aa | 58.41 |
3ac | 69.96 |
3ad | 46.47 |
3ae | 73.23 |
空白对照组 | 100 |
由图1和表1可以看出,化合物3aa、3ac、3ad、3ae在CAL33细胞上显示出明显的抑制增殖效果,可能是治疗头颈癌的潜在药物。
Claims (8)
2.权利要求1所述含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物的制备方法,其特征在于,将邻氨基三氟甲基苯乙酮与无机碱添加剂加入到有机溶剂中,搅拌均匀后再加入肼基氯化物进行环化反应,得到含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物。
5.如权利要求2所述含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物的制备方法,其特征在于,所述无机碱添加剂为碳酸钾。
6.如权利要求2所述含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物的制备方法,其特征在于,所述有机溶剂为二氯甲烷。
7.如权利要求2至6任一项所述含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物的制备方法,其特征在于,所述环化反应温度为35℃~45℃。
8.权利要求1所述含有三氟甲基季碳中心的1,3,4-噁唑啉类化合物在制备抑制肿瘤细胞增殖的药物中的应用。
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