CN115677545B - 一种抗hbv磺胺苯甲酰胺类衍生物及其制备方法和应用 - Google Patents
一种抗hbv磺胺苯甲酰胺类衍生物及其制备方法和应用 Download PDFInfo
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- CN115677545B CN115677545B CN202211340256.8A CN202211340256A CN115677545B CN 115677545 B CN115677545 B CN 115677545B CN 202211340256 A CN202211340256 A CN 202211340256A CN 115677545 B CN115677545 B CN 115677545B
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- OHOVBSAWJQSRDD-UHFFFAOYSA-N thiophen-2-yloxyboronic acid Chemical compound OB(O)OC1=CC=CS1 OHOVBSAWJQSRDD-UHFFFAOYSA-N 0.000 claims 1
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Abstract
本发明公开了一种抗HBV磺胺苯甲酰胺类衍生物及其制备方法和应用,所述化合物具有通式I、II所示的结构。本发明还涉及含有通式I、II结构化合物的制备方法,药物组合物以及提供上述化合物在制备的抗HBV药物中的应用。
Description
技术领域
本发明属于医药化学领域,具体涉及一种具有抗乙型肝炎病毒(HBV)活性的磺胺苯甲酰胺类衍生物及其制备方法和应用。
背景技术
目前治疗慢性乙肝的常用药物主要有干扰素和核苷酸类似物,虽然这两类药物能够抑制HBV DNA的复制,但是这些疗法无法清除乙肝病毒表面抗原,从而使机体免疫系统受到影响,导致患者出现细胞坏死和炎症等症状,甚至引发肝硬化、肝癌等疾病。因此,大力研发针对不同靶点的抗乙肝新药,使慢性乙型肝炎的治疗具有更多选择,同时联合使用不同机制的治疗方案,在未来才有望实现慢性乙型肝炎的功能性治愈。
核心蛋白是HBV核壳体组成的主要结构蛋白,在病毒进化过程中相对保守,并且核心蛋白的组装在乙肝病毒生命周期中发挥着重要作用。然而,目前还没有相关靶点的药物上市。针对目前进入临床候选药物肝毒性强、水溶性差以及代谢稳定性差的缺点,通过核心蛋白与配体的晶体复合物结构,进行了基于靶点的合理药物设计,设计了一类新型的抗HBV磺胺苯甲酰胺化合物。
发明内容
为了克服上述现有技术所存在的缺陷,本发明提供了一种抗HBV磺胺苯甲酰胺类衍生物及其制备方法,本发明还提供了上述化合物作为非核苷类HBV抑制剂的活性筛选结果及其应用。
本发明的技术方案如下:
一、抗HBV磺胺苯甲酰胺类衍生物
一种抗HBV磺胺苯甲酰胺类衍生物,具有如下通式Ⅰ或Ⅱ所示的结构:
其中,R1为烷烃取代的氨基;
R2为Br、芳环、杂环、烷烃取代基,或烷烃取代的氨基;
R3为F、杂环、烷烃取代基,或烷烃取代的氨基;
R4为烷烃取代的氨基;
R5为Br、芳环、杂环取代基,丙烯酸酯基或丙烯酰胺基;
R6为F或烷烃取代的氨基;
所述的烷烃选自C1-8,杂环为五元或六元杂环。
根据本发明优选的,通式I或II中,R1为R2为Br、/> R3为F、/> R4为/>R5为Br、/> R6为F、/>
根据本发明进一步优选的,所述的抗HBV磺胺苯甲酰胺类衍生物,其特征在于,是具有下列结构的化合物之一:
二、抗HBV磺胺苯甲酰胺类衍生物的制备方法
抗HBV磺胺苯甲酰胺类衍生物的制备方法,以2-溴-4-氟苯甲酸和2-溴-6-氟苯甲酸为原料,经过磺化反应,酰化反应,磺酰化反应,铃木反应得到产物;
合成路线1如下:
合成路线2如下:
其中R1,R2,R3,R4,R5,R6如通式I或II所述。
试剂及其条件:(i)氯磺酸,0℃,6-12h,140-150℃;(ii)氯化亚砜,N,N-二甲基甲酰胺,3-5h,80℃;(iii)乙腈,3,4,5-三氟苯胺,8h,60℃;(iv)二氯甲烷,N,N-二异丙基乙胺,不同类型的胺,8h,45℃;(v)1,4-二氧六环,水,无机碱,不同类型的钯,不同类型的硼酸、酯、酰胺及胺,8h,100℃。
所述的不同类型的胺选自:对羟基环己胺、4-羟基哌啶、吗啡啉、环己胺、环戊胺。
所述的无机碱选自:磷酸钾,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠。
所述的不同类型的钯选自:醋酸钯、四(三苯基膦)钯、双(三苯基膦)二氯化钯。
所述的不同类型的硼酸、酯、酰胺及胺选自:苯硼酸、4-氰基苯硼酸、4-羟基苯硼酸、2-氟苯硼酸、4-(三氟甲基)苯硼酸、吡啶-3-硼酸、2-噻吩基硼酸、3-噻吩基硼酸、3,4-(亚甲基二氧基)苯硼酸、正己基硼酸、环丙基硼酸、丙烯酸-2-2羟乙基酯、丙烯酸甲酯、丙烯酸乙酯、N-异丙基丙烯酰胺、2-乙基己胺、吗啡啉、环戊胺。
本发明抗HBV磺胺苯甲酰胺类衍生物的制备方法,具体步骤如下:
(1)将277.54mmol氯磺酸并降温至0℃,低温下缓慢加入27.75mmol化合物1或2,升至室温,100℃回流反应6h;反应结束后冷却至室温,逐滴加入150mL冰水中,抽滤,水洗,干燥得化合物3或4;
(2)将3.58mmol中间体3或4溶于10mL氯化亚砜中,加入2滴N,N-二甲基甲酰胺,80℃回流反应,反应结束后冷却至室温,旋蒸得到中间体5或6;
(3)将中间体5或6溶于20mL乙腈中,加入不同类型的苯胺,60℃回流反应,反应结束后冷却至室温,浓缩,干法上样,快速制备硅胶色谱柱分离,二氯甲烷-正己烷混合溶剂重结晶,得到化合物7或8;
(4)将化合物7或8溶于二氯甲烷中,加入不同类型的胺,加入3倍量的N,N-二异丙基乙胺,45℃回流反应,反应结束后,冷却至室温,旋蒸除去二氯甲烷,加水,乙酸乙酯进行萃取,合并有机相,饱和食盐水洗三次,无水硫酸钠干燥,浓缩,干法上样,快速制备硅胶色谱柱分离,重结晶得到目标化合物9a-9d或10a-10c,所述的不同类型的胺选自对羟基环己胺、4-羟基哌啶、吗啡啉、环己胺、环戊胺;
(5)将9.51mmol 9a、9b、9c、10b或10c溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入19.02mmol不同的碱,加入14.27mmol不同类型的硼酸、酯、酰胺或胺,氩气置换三次,快速加入0.95mmol不同类型的钯及其配体,氩气置换三次,90℃加热反应,TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶,得到11a-11q或12a-12k。
三、抗HBV磺胺苯甲酰胺类衍生物的应用
本发明公开了抗HBV磺胺苯甲酰胺衍生物抗HBV活性筛选结果及其作为抗HBV抑制剂的应用。通过实验证明本发明的磺胺苯甲酰胺类化合物可作为经典的HBV非核苷类抑制剂应用。
如表1所示,对所合成的目标化合物9a-9d,10a-10c,11a-11q,12a-12k进行了体外抗HBV活性评价,通过CCK-8法测定了4μM药物浓度下细胞的死亡率;同时,通过定量PCR法测定了4μL药物浓度下抑制HBV DNA复制活性和体外细胞毒性,选择先导化合物NVR 3-778为阳性对照,其中9c,10a表现了较好的抑制HBV DNA复制活性,对其进行了靶点活性的研究。
本发明的磺胺苯甲酰胺衍生物是一类结构新型的非核苷类HBV抑制剂,可作为抗HBV的先导化合物。
本发明的磺胺苯甲酰胺类衍生物可作为非核苷类HBV抑制剂应用。具体地说作为HBV抑制剂用来制备抗乙肝药物。
一种抗HBV药物组合物,包括本发明的磺胺苯甲酰胺类衍生物和一种或多种药学上可接受载体或赋形剂。
本发明公开此类磺胺苯甲酰胺类衍生物、其制备方法、抗HBV活性筛选结果及其作为抗HBV抑制剂的首次应用,实验证明磺胺苯甲酰胺类衍生物可作为HBV抑制剂用于制备抗乙肝药物。
具体实施方式
通过下述实例有利于理解本发明,但是不能限制本发明的内容,在下列实例中所有目标化合物的编号与上文相同。
合成方案1
合成方案2
试剂及其条件:(i)氯磺酸,0℃,6-12h,140-150℃;(ii)氯化亚砜,N,N-二甲基甲酰胺,3-5h,80℃;(iii)乙腈,3,4,5-三氟苯胺,8h,60℃;(iv)二氯甲烷,N,N-二异丙基乙胺,不同类型的胺,8h,45℃;(v)1,4-二氧六环,水,无机碱,不同类型的钯,不同类型的硼酸、酯、酰胺及胺,8h,100℃。
实施例1:化合物3的制备,取50mL圆底烧瓶,加入277.54mmol氯磺酸并降温至0℃,低温下缓慢加入27.75mmol 2-溴-4-氟苯甲酸,升至室温,100℃回流反应6h。反应结束后冷却至室温,逐滴加入150mL冰水中,抽滤,水洗,干燥得棕黄色固体4.7356g,产率58%。
实施例2:化合物4的制备,操作同例1,将2-溴-4-氟苯甲酸换成2-溴-6-氟苯甲酸,得棕黄色固体5.0622g,产率62%。
实施例3:中间体5的制备,取25ml圆底烧瓶,将3.58mmol中间体3溶于10mL氯化亚砜中,加入2滴N,N-二甲基甲酰胺,80℃回流反应,反应结束后冷却至室温,旋蒸后得油状产物。
实施例4:中间体6的制备,操作同例3,将中间体3换成中间体4,产物为油状物。
实施例5:中间体7的制备,取100mL圆底烧瓶,将中间体5溶于20mL乙腈中,3,4,5-三氟苯胺,60℃回流反应,反应结束后冷却至室温,浓缩,干法上样,快速制备硅胶色谱柱分离,二氯甲烷-正己烷混合溶剂重结晶。
实施例6:中间体8的制备,操作同例5,将中间体5换成中间体6。
实施例7:化合物9a的制备
取25mL圆底烧瓶,将1.7mmol中间体7溶于10mL二氯甲烷中,加入1.7mmol 4-羟基环己醇、5.1mmol N,N-二异丙基乙胺,40℃回流反应。反应结束后冷却至室温,加入水(20mLx 3),合并有机相,饱和食盐水洗(20mL x 3),无水硫酸钠干燥,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷-正己烷混合溶剂重结晶,白色固体粉末,产率60%,熔点214.2-216.2℃。
化合物9a
化合物9a波谱数据
1H-NMR(400MHz,DMSO)δ10.98(s,1H),8.16(s,1H),8.04(d,J=9.7Hz,1H),7.95(d,J=7.5Hz,1H),7.59(dd,J=9.9,6.5Hz,2H),4.50(d,J=4.4Hz,1H),3.07(s,1H),1.88–1.57(m,4H),1.38–0.99(m,4H).13C-NMR(100MHz,DMSO)δ164.73,158.34(d,J=259Hz),151.43,149.45,136.93,135.27(d,J=4Hz),134.54,129.59(d,J=14Hz),125.23(d,J=9.6Hz),122.65(d,J=24.9Hz),104.65(d,J=24Hz),68.04,52.35,34.13,31.55.ESI-MS:calculated for C19H18BrF4N2O4S[M-H]+524.00285,found 524.99384.
实施例8:化合物9b的制备,操作同例7,所不同的是把4-羟基环己胺换成4-羟基哌啶,产物为白色固体,产率65%,熔点211.2-212.3℃。
化合物9b
化合物9b波谱数据
1H-NMR(400MHz,DMSO)δ10.96(s,1H),8.02(d,J=9.7Hz,1H),7.87(d,J=7.0Hz,1H),7.51(dd,J=9.4,6.6Hz,3H),4.78(d,J=3.7Hz,1H),2.91(s,1H),1.69(s,4H),1.43–1.12(m,4H).13C-NMR(100MHz,DMSO)δ164.03,160.63(d,J=258Hz)135.76(d,J=9.8Hz),131.41,130.96,125.60(d,J=15.8Hz),118.70,118.47,105.35(d,J=24.5Hz),64.38,43.34,39.35,33.62.ESI-MS:calculated for C18H15BrF4N2O4S[M-H]+509.98720,found510.96774.
实施例9:化合物9c的制备,操作同例7,所不同的是把4-羟基环己胺换成环戊胺,产物为白色固体,产率58%,熔点198.3-200.5℃。
化合物9c
化合物9c波谱数据
1H-NMR(400MHz,DMSO)δ10.99(s,1H),8.23(d,J=7.5Hz,1H),8.05(d,J=9.6Hz,1H),7.95(d,J=7.3Hz,1H),7.59(dd,J=9.8,6.5Hz,2H),3.56(dd,J=13.7,6.8Hz,1H),1.77–1.51(m,5H),1.39(dt,J=17.5,8.9Hz,4H).13C-NMR(100MHz,DMSO)δ164.74,158.27(d,J=273Hz),152.02,149.45,135.33,129.97,129.47(d,J=14.9Hz),125.38,125.28,122.77,122.52,104.67(d,J=24.5Hz),54.96,32.86,23.29.ESI-MS:calculated forC18H15BrF4N2O3S[M-H]-495.99024,found 494.97964.
实施例10:化合物9d的制备,操作同例7,所不同的是把4-羟基环己胺换成环己胺,产物为黄色固体,产率为38%,熔点178.2-183.1℃。
化合物9d
化合物9d波谱数据
1H-NMR(400MHz,DMSO)δ11.00(s,1H),8.21(d,J=7.8Hz,1H),8.03(d,J=9.6Hz,1H),7.94(d,J=7.4Hz,1H),7.59–7.46(m,2H),3.09(d,J=7.2Hz,1H),2.06(s,1H),1.55(dd,J=60.8,9.3Hz,5H),1.36–1.13(m,5H).13C-NMR(100MHz,DMSO)δ164.78,160.28(d,J=235Hz),151.96,149.38,136.36,130.40,129.73,125.71,122.75,108.78,104.80,62.96,58.02,56.62,33.73,25.21,24.93,18.95.ESI-MS:calculated for C19H17BrF4N2O3S[M-H]-510.00589,found 508.98071.
实施例11:化合物10a的制备,操作同例7,所不同的是把把原料换做8,产物白色固体,产率为35%,熔点217.2-221.4℃。
化合物10a
化合物10a的波谱数据
1H-NMR(400MHz,DMSO)δ11.32(d,J=14.0Hz,1H),8.20(d,J=7.7Hz,1H),7.81(dd,J=16.8,8.0Hz,2H),7.58(dd,J=9.7,6.4Hz,2H),3.20–2.92(m,2H),1.70(dd,J=36.7,10.5Hz,4H),1.26(dd,J=13.0,5.9Hz,5H).13C-NMR(100MHz,DMSO)δ161.04,151.98(d,J=249Hz),150.35,136.93,134.32,129.59,128.92,118.94,112.68,104.64(d,J=12Hz),76.68,68.10,68.01,62.39,34.17,31.65,18.83,17.20.ESI-MS:calculated forC19H18BrF4N2O4S[M-H]-524.00285,found 522.99280.
实施例12:化合物10b的制备,操作同例11,所不同的是把对氨基环己醇换做4-羟基哌啶,产物白色固体,产率为54%,熔点212.1-213.7℃。
化合物10b
化合物10b的核磁数据
1H NMR(400MHz,DMSO)δ11.26(s,1H),7.91(s,1H),7.83(s,1H),7.67(s,1H),7.34(d,J=5.1Hz,1H),3.66(d,J=4.1Hz,1H),1.87–1.74(m,2H),1.55–1.42(m,2H).13C NMR(100MHz,DMSO)δ162.68,137.65,132.63,132.54,132.00,131.97,131.90,129.30,129.18,128.20,127.72,126.29,126.13,123.78,104.64,104.40,64.22,43.28,33.58.ESI-MS:calculated for C18H15BrF4N2O4S[M-H]+509.98720,found 510.97794.
实施例13:化合物10c的制备,操作同例11,所不同的是把对氨基环己醇换做吗啡啉,产物白色固体,产率为46%,熔点213.5-216.8℃。
化合物10c
化合物10c的核磁数据
1H-NMR(400MHz,DMSO)δ11.32(d,J=16.4Hz,1H),δ8.20(dd,J=8.6,6.0Hz,1H),δ7.73–7.50(m,3H),δ3.65(s,4H),δ3.22(s,4H).13C-NMR(100MHz,DMSO)δ167.44,163.91–163.71(m),161.40,132.08(d,J=17.6Hz),129.13,128.76,125.77,124.47,119.56,116.15,104.44(d,J=24.7Hz),104.04–103.92(m),65.50,64.73,33.97,30.47.ESI-MS:calculated for C17H13BrF4N2O4S[M-H]+495.97155,found 496.96268.
实施例14:化合物11a的制备
将9.51mmol 9a溶于4mL 1,4-二氧六环、1mL水的混合溶剂中,加入19.02mmol碳酸钾,加入14.27mmol苯硼酸,氩气置换三次,快速加入0.95mmol双(三苯基膦)二氯化钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。产物为褐色固体,产率为33%,熔点180.5-183.3℃。
化合物11a
化合物11a波谱数据
1H-NMR(400MHz,DMSO)δ10.81(s,1H),8.16(s,1H),7.99(d,J=6.5Hz,1H),7.64(t,J=8.9Hz,4H),7.57(d,J=2.3Hz,1H),7.49(s,1H),7.42(s,2H),4.56(s,1H),3.33(s,1H),3.13(s,1H),1.91–1.56(m,4H),1.56–0.90(m,4H).13C-NMR(100MHz,DMSO)δ165.38,159.10(d,J=256Hz),148.93,144.68,135.58,133.98,131.68,129.46,129.31,128.75,120.94(d,J=23.3Hz),103.98(d,J=25.0Hz),68.10,60.22,52.34,34.18,31.94,31.39,14.53.ESI-MS:calculated for C25H22F4N2O4S[M-H]-522.12364,found 521.11664.
实施例15:化合物11b的制备,操作同例14,所不同的是把苯硼酸换成4-氰基苯硼酸,产物为淡黄色固体,产率为42%,熔点190.5-193.8℃。
化合物11b
化合物11b波谱数据
1H-NMR(400MHz,DMSO)δ10.84(d,J=43.5Hz,1H),8.19(d,J=6.9Hz,1H),8.04(d,J=7.1Hz,1H),7.92(d,J=8.0Hz,2H),7.69(dd,J=22.8,9.4Hz,3H),7.42(dd,J=9.8,6.5Hz,2H),4.52(dd,J=10.0,4.3Hz,1H),3.11(s,1H),1.98–1.44(m,4H),1.21(dq,J=23.1,10.8Hz,4H).13C-NMR(100MHz,DMSO)δ166.38,158.78(d,J=169Hz),142.99,132.93,131.95,129.87,119.07,118.72,113.68,111.81,107.90,104.57,97.31,68.06,52.37,34.15,31.68.ESI-MS:calculated for C26H21F4N3O4S[M-H]-547.11889,found 546.11102.
实施例16:化合物11c的制备,操作同例14,所不同的是把苯硼酸换成2-氟苯硼酸,产物为黄色固体,产率为42%,熔点205.5-207.3℃。
化合物11c
化合物11c波谱数据
1H-NMR(400MHz,DMSO)δ10.93(s,1H),8.33(d,J=7.8Hz,1H),8.24(d,J=7.7Hz,1H),8.12(d,J=7.1Hz,1H),7.69(dd,J=17.7,9.8Hz,2H),7.50(ddd,J=20.9,15.0,7.4Hz,3H),7.39–7.25(m,2H),4.61(dd,J=8.6,4.2Hz,1H),3.85–3.49(m,1H),3.19(d,J=7.4Hz,1H),1.86(dd,J=34.7,9.2Hz,4H),1.34(dd,J=19.8,10.6Hz,4H).13C-NMR(100MHz,DMSO)δ166.22,164.62(d,J=246Hz),161.60,160.90,153.66,141.35,137.04,131.76,131.03,130.36,125.90,120.43,119.60,115.11,68.30,52.61,48.92,34.36,31.40,30.09,21.10,14.56.ESI-MS:calculated for C25H21F5N2O4S[M-H]-540.11422,found539.10712.
实施例17:化合物11d的制备,操作同例14,所不同的是把苯硼酸换成4-(三氟甲基)苯硼酸,产物为白色固体,产率为39%,熔点213.2-215.9℃。
化合物11d
化合物11d波谱数据
1H-NMR(400MHz,DMSO)δ10.59(d,J=244.7Hz,1H),8.20(d,J=7.7Hz,1H),8.05(d,J=7.1Hz,1H),7.97(d,J=8.1Hz,1H),7.82(d,J=8.1Hz,1H),7.71(t,J=11.2Hz,2H),7.63–7.58(m,2H),7.41(dd,J=9.9,6.5Hz,2H),4.54(d,J=4.2Hz,1H),3.30(d,J=10.1Hz,1H),3.19–3.08(m,1H),1.82–1.60(m,4H),1.39–1.20(m,4H).13C-NMR(100MHz,DMSO)δ166.08,158.08(d,J=158Hz),143.08,132.69,132.49,131.96(d,J=9.8Hz),129.76,129.23(d,J=11.7Hz),128.46,126.44,126.15(d,J=50.7Hz),116.14,104.81,68.07,52.37,34.16,31.69.ESI-MS:calculated for C26H21F7N2O4S[M-H]-590.11103,found589.10327.
实施例18:化合物11e的制备,操作同例14,所不同的是把苯硼酸换成吡啶-3-硼酸,产物为白色固体,产率为45%,熔点203.1-204.2℃。
化合物11e结构
化合物11e波谱数据
1H-NMR(400MHz,DMSO)δ10.92(s,1H),8.63(d,J=5.1Hz,2H),8.20(d,J=7.6Hz,1H),8.04(d,J=7.0Hz,1H),7.76–7.70(m,1H),7.60(dd,J=9.9,6.7Hz,1H),7.51–7.36(m,3H),4.53(d,J=4.2Hz,1H),3.44–3.37(m,1H),3.12(d,J=7.5Hz,1H),1.78–1.67(m,4H),1.34–1.21(m,4H).13C-NMR(100MHz,DMSO)δ166.27,161.26(d,J=269Hz),150.30,146.64,145.71,143.69,134.23,131.75,129.51,124.74,104.84,101.91,68.57,63.29,53.01,34.06,31.76,29.74.ESI-MS:calculated for C24H21F4N3O4S[M-H]-523.11889,found522.11206.
实施例19:化合物11f的制备,操作同例14,将苯硼酸换成2-噻吩基硼酸,产物为白色固体,产率为55%,熔点198.2-199.7℃。
化合物11f
化合物11f波谱数据
1H-NMR(400MHz,DMSO)δ11.05(s,1H),8.18(d,J=7.7Hz,1H),7.93(d,J=7.3Hz,1H),7.80(dd,J=21.9,8.1Hz,2H),7.59–7.47(m,3H),7.20(t,J=4.3Hz,1H),4.58(d,J=4.1Hz,1H),3.36(d,J=4.6Hz,1H),3.21–3.06(m,1H),1.81–1.66(m,4H),1.40–1.24(m,4H).13C-NMR(100MHz,DMSO)δ170.81,166.52,163.08(d,J=218Hz),159.97,157.39,149.54,146.36,138.38,129.94,129.56,129.08,128.69,104.73,68.06,60.23,52.37,34.16,31.66,21.22,14.55.ESI-MS:calculated for C23H20F4N2O4S2[M-H]-528.28006,found 527.07288.
实施例20:化合物11g的制备,操作同例14,将苯硼酸换成3-噻吩基硼酸,产物为白色固体,产率为50%,熔点197.5-198.4℃。
化合物11g
化合物11g波谱数据
1H-NMR(400MHz,DMSO)δ10.86(s,1H),8.12(d,J=7.7Hz,1H),7.90(d,J=7.2Hz,1H),7.83(d,J=1.1Hz,1H),7.73(d,J=11.2Hz,1H),7.66–7.60(m,1H),7.49(dd,J=9.9,6.5Hz,2H),7.30(d,J=5.0Hz,1H),4.53(d,J=4.2Hz,1H),3.30(dd,J=9.6,4.6Hz,1H),3.19–2.96(m,1H),1.72(dd,J=26.0,11.4Hz,4H),1.49–0.94(m,4H).13C-NMR(100MHz,DMSO)δ166.84,158.73(d,J=255Hz),149.32,140.51,137.90,135.36,132.24,129.51,128.66(d,J=15.2Hz),127.94,127.71,126.19,118.46(d,J=22.4Hz),104.66(d,J=24.4Hz),68.07,55.38,52.35,34.17,31.66.ESI-MS:calculated for C23H20F4N2O4S2[M-H]-528.28006,found 527.07281.
实施例21:化合物11h的制备,操作同例14,将苯硼酸换成3,4-(亚甲基二氧基)苯硼酸,产物为淡黄色固体,产率为33%,熔点203.2-204.6℃。
化合物11h
化合物11h波谱数据
1H-NMR(400MHz,DMSO)δ10.81(s,1H),8.11(d,J=7.7Hz,1H),7.92(d,J=7.3Hz,1H),7.60(d,J=11.1Hz,1H),7.45(dd,J=10.0,6.5Hz,2H),7.07(s,1H),6.95(q,J=8.3Hz,2H),6.06(s,2H),3.45–3.40(m,1H),3.17–3.06(m,1H),1.88–1.63(m,4H),1.37–1.16(m,4H).13C-NMR(100MHz,DMSO)δ166.70,158.66(d,J=262Hz),148.25,148.02,135.46,132.56(d,J=4Hz),131.58,129.55,128.57,122.84,109.16,108.92,104.63,104.38,101.94,68.07,52.34,34.16,31.69,14.49(d,J=12.5Hz).ESI-MS:calculatedfor C26H22F4N2O6S[M-H]-566.11347,found 565.10291.
实施例22:化合物11i的制备
将9.51mmol 9b溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入19.02mmol碳酸钾,加入14.27mmol 2-噻吩苯硼酸,氩气置换三次,快速加入0.95mmol醋酸钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。白色固体,产率:34%,熔点201.3-204.3℃。
化合物11i
化合物11i波谱数据
1H NMR(400MHz,DMSO)δ10.99(s,1H),8.19(d,J=7.7Hz,1H),8.05(d,J=9.6Hz,1H),7.95(d,J=7.4Hz,1H),4.52(d,J=4.2Hz,1H),3.19–2.93(m,1H),1.69(dd,J=40.5,11.0Hz,4H),1.18(dq,J=23.0,10.7Hz,5H).13C-NMR(101MHz,DMSO)δ164.74,158.47(d,J=230Hz),151.95,149.64,135.30,130.05,129.71,125.19,122.54,104.67(d,J=24.7Hz),68.03,52.35,34.13,31.58.ESI-MS:calculated for C22H18F4N2O4S2[M-H]-514.06441,found 513.1470.
实施例23:化合物11j的制备
将9.51mmol 9b溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入19.02mmol碳酸钾,加入14.27mmol环戊胺,氩气置换三次,快速加入0.95mmol醋酸钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。白色固体,产率:42%,熔点205.3-206.2℃。
化合物11j
化合物11j核磁数据
1H-NMR(400MHz,DMSO)δ10.94(s,1H),7.87(s,1H),7.69(dd,J=5.1,1.1Hz,1H),7.57(s,1H),7.39(dd,J=3.6,1.1Hz,1H),7.13(dd,J=5.0,3.7Hz,1H),4.73(dd,J=11.9,4.3Hz,2),3.61(dd,J=7.4,3.8Hz,2H),3.31–3.08(m,2H),3.00–2.65(m,4H),1.78(ddd,J=19.6,8.9,6.5Hz,4H),1.67–1.33(m,4H).13C-NMR(100MHz,DMSO)δ164.21,160.18(d,J=245Hz)138.97,131.52,129.81,128.85 122.51,14.66,104.60(d,J=4Hz),68.11,66.51,56.53,52.32,34.09,31.61,18.93,14.61.ESI-MS:calculated for C23H25F4N3O4S[M-H]-515.15019,found 514.13580.
实施例24:化合物11k的制备
将9.51mmol 9c溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入19.02mmol碳酸钠,加入14.27mmol 2-噻吩硼酸,氩气置换三次,快速加入0.95mmol醋酸钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。产物为白色固体,产率为38%,熔点184.5-185.3℃。
化合物11k
化合物11k波谱数据
1H-NMR(400MHz,DMSO)δ10.80(s,1H),8.22(d,J=7.6Hz,1H),7.98(d,J=7.0Hz,1H),7.73(d,J=10.6Hz,1H),7.66–7.47(m,2H),7.33(dd,J=10.2,6.5Hz,2H),3.59(d,J=6.7Hz,1H),1.59(s,4H),1.38(d,J=20.8Hz,5H).13C-NMR(100MHz,DMSO)δ166.98,159.15(d,J=307Hz),138.28,135.29,132.42,129.72,128.70,128.37,119.34(d,J=5.0Hz),117.99,104.72,104.51,54.97,32.93,21.58.ESI-MS:calculated for C22H18F4N2O3S2[M-H]-498.0695,found 497.0615.
实施例25:化合物11l的制备,操作同例24,将2-噻吩硼酸换成3-噻吩硼酸,产物为白色固体,产率为42%,熔点186.2-187.6℃。
化合物11l
化合物11l波谱数据
1H NMR(400MHz,DMSO)δ10.86(s,1H),8.16(d,J=7.4Hz,1H),7.90(d,J=7.2Hz,1H),7.84(d,J=2.7Hz,1H),7.74(d,J=11.2Hz,1H),7.63(dt,J=4.7,2.0Hz,1H),7.51–7.47(m,2H),7.30(d,J=5.1Hz,1H),3.61–3.56(m,1H),1.65(d,J=40.0Hz,4H),1.42(s,4H).13C NMR(100MHz,DMSO)δ166.87,157.54,149.31(d,J=14.9Hz),140.67(d,J=9.0Hz),137.91,135.35,132.95,129.81,127.95,126.21,125.60,118.57,118.35,104.81,104.56,54.97,32.93,23.31.ESI-MS:calculated for C22H18F4N2O3S2[M-H]-498.0695,found497.062.
实施例26:化合物11m的制备
将9.51mmol 9c溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入19.02mmol磷酸钾,加入14.27mmol环丙基硼酸,氩气置换三次,快速加入0.95mmol醋酸钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。产物为白色固体,产率为40%,熔点193.6-194.2℃。
化合物11m
化合物11m波谱数据
1H NMR(400MHz,DMSO)δ10.92(s,1H),8.00(d,J=7.5Hz,1H),7.78(d,J=7.1Hz,1H),7.64(dd,J=10.3,6.5Hz,2H),7.06(d,J=11.8Hz,1H),3.51(q,J=6.9Hz,1H),2.20(dq,J=8.7,5.4,4.4Hz,1H),1.68–1.55(m,4H),1.39(p,J=7.9,6.3Hz,4H),1.06(dd,J=8.1,5.4Hz,2H),0.89(t,J=5.2Hz,2H).13C NMR(100MHz,DMSO)δ166.74,158.35,151.18,133.47,128.92,126.39,126.24,113.22,112.99,104.85,104.61,54.87,32.86,23.28,13.35,11.49.ESI-MS:calculated for C21H20F4N2O3S[M-H]-456.11038,found 455.10599.
实施例27:化合物11n的制备
将9.51mmol 9a溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入19.02mmol碳酸氢钠,加入14.27mmol正己基硼酸,氩气置换三次,快速加入0.95mmol四(三苯基膦)钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。产物为白色固体,产率为43%,熔点201.2-205.6℃。
化合物11n
化合物11n波谱数据
1H-NMR(400Hz,DMSO)δ10.45(s,1H),7.33(s,5H),2.38(s,1H),1.32(s,1H),1.26(dd,J=16.2,8.4Hz,14H),0.85(t,J=6.7Hz,5H),0.56(t,J=7.6Hz,3H).13C-NMR(100MHz,DMSO)δ132.58,32.26,31.73,24.64,22.58,21.76,14.47.ESI-MS:calculated forC25H30BrF3N2O4S[M-H]-590.10618,found 590.09888.
实施例28:化合物11o的制备
将9.51mmol 9a溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入19.02mmol碳酸铯,加入14.27mmol 2-乙基己胺,氩气置换三次,快速加入0.95mmol四(三苯基膦)钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。白色固体,产率:35%,熔点210.2-215.6℃。
化合物11o
化合物11o波谱数据
1H-NMR(400MHz,DMSO)δ10.69(s,1H),7.87(d,J=7.5Hz,1H),7.75(s,1H),7.60(dd,J=9.9,6.6Hz,2H),7.06(s,1H),6.28(t,J=5.2Hz,1H),4.52(d,J=4.1Hz,1H),3.17(t,J=5.5Hz,2H),2.89(s,2H),2.73(s,1H),1.67(dd,J=33.9,11.8Hz,6H),1.39–1.29(m,9H),1.25(d,J=14.4Hz,7H).13C-NMR(100MHz,DMSO)δ165.95,161.24,153.96,147.32,143.69,131.67,126.37,124.07,121.33,115.60,104.45,67.88,51.66,46.37,38.68,34.07,31.38,30.40,28.70,24.07,23.43,14.75,10.42.ESI-MS:calculated forC27H35BrF3N3O4S[M-H]+633.14837,found 634.13397.
实施例29:化合物11p的制备
将9.51mmol 9a溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入19.02mmol碳酸铯,加入14.27mmol吗啉,氩气置换三次,快速加入0.95mmol醋酸钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。白色固体,产率:41%,熔点215.3-216.2℃。
化合物11p
化合物11p波谱数据
1H-NMR(400MHz,DMSO)δ10.80(s,1H),7.97(s,1H),7.68(dd,J=9.9,6.5Hz,2H),7.00(s,1H),6.87(d,J=7.1Hz,1H),4.48(d,J=4.3Hz,1H),3.81(s,4H),3.65(s,5H),3.06(d,J=21.5Hz,9H),1.65(dd,J=46.2,10.6Hz,5H),1.14(dd,J=73.1,11.3Hz,5H).13C-NMR(101MHz,DMSO)δ168.32,154.74,132.79,128.91,122.71,113.02,97.08,68.06,66.55(d,J=19.4Hz),55.38,53.80,52.23,51.76,34.15,31.60.ESI-MS:calculated forC27H33BrF3N4O6S[M-H]-598.20729,found 597.18683.
实施例30:化合物11q的制备
将9.51mmol 9c溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入19.02mmol碳酸铯,加入14.27mmol 2-噻吩苯硼酸,氩气置换三次,快速加入0.95mmol醋酸钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。白色固体,产率:32%,熔点202.3-204.8℃。
化合物11q
化合物11q波谱数据
1H-NMR(400MHz,DMSO)δ11.01(s,1H),8.18(d,J=7.3Hz,1H),7.89(d,J=7.2Hz,1H),7.79(d,J=11.2Hz,1H),7.73(d,J=5.0Hz,1H),7.63(dd,J=12.1,7.2Hz,2H),7.58–7.49(m,3H),7.47(d,J=3.3Hz,1H),7.15(t,J=4.2Hz,1H),3.59(d,J=6.6Hz,1H),1.71(d,J=3.4Hz,2H),1.60(s,2H),1.42(s,4H).13C-NMR(100MHz,DMSO)δ166.52,159.85,138.39,132.49,132.44,132.20,132.14,131.80,129.90(d,J=9.0Hz),129.23,129.16,129.08,128.70,128.30,118.31,118.08,104.61(d,J=24.7Hz),54.98,32.93,23.31.ESI-MS:calculated for C26H21BrF3N2O3S3[M-H]-562.06664,found 560.96655.
实施例31:化合物12a的制备
将2.01mmol 10c溶于10mL 1,4-二氧六环中,加入6.03mmol三乙胺,加入4.02mmol丙烯酸甲酯,氩气置换三次,快速加入0.20mmol醋酸钯及0.20mmol三(苯基甲基)磷,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。白色固体,产率:48%,熔点211.5-213.2℃。
化合物12a
化合物12a的核磁数据
1H-NMR(400MHz,DMSO)δ8.12–8.05(m,1H),δ7.80(d,J=8.0Hz,1H),δ7.62(dd,J=9.4,6.5Hz,2H),δ5.84(t,J=4.9Hz,1H),δ3.65(d,J=4.2Hz,4H),δ3.44(s,3H),δ3.07(s,4H).13C-NMR(100MHz,DMSO)δ169.96,162.68,152.80,156.13,153.66,151.94,151.40,149.81,149.55,135.90,124.42,120.57,109.91,109.68,65.91,57.75,52.08,46.10,35.22.ESI-MS:calculated for C21H18F4N2O6S[M-H]-502.08217,found 501.07095.
实施例32:化合物12b的制备,操作同31,所不同的是将丙烯酸甲酯换做丙烯酸乙酯,得白色固体,产率:46%,熔点210.3-212.8℃。
化合物12b
化合物12b的核磁数据
1H-NMR(400MHz,DMSO)δ8.12(m,1H),δ7.94(d,J=8.0Hz,1H)δ7.65(dd,J=9.3,6.5Hz,2H)δ5.97(t,1H)δ4.25(t,1H)δ3.99(q,2H)δ0.98(dd,J=12.0,4.9Hz,3H).13C-NMR(100MHz,DMSO)δ169.27,162.71,152.76,135.88,132.08(d,J=16.9Hz),129.13,124.42,120.60,110.10–110.07(m),109.76(d,J=23.7Hz),65.92,65.51,60.73,57.83,46.09,35.45,30.47,19.12,14.21,14.00.ESI-MS:calculated for C22H20F4N2O6S[M-H]+516.09782,found 517.09558.
实施例33:化合物12c的制备,操作同31,所不同的是将丙烯酸甲酯换做丙烯酸-2-羟乙酯,得白色固体,产率:51%,熔点214.5-217.3℃。
化合物12c
化合物12c的核磁数据
1H-NMR(400MHz,DMSO)δ8.08(t,J=6.8Hz,1H),δ7.81(d,J=8.0Hz,1H),δ7.66(ddd,J=22.3,16.4,6.4Hz,3H),δ5.83(d,J=4.7Hz,1H),δ4.74(s,1H),δ4.23(t,J=6.5Hz,1H),δ3.87(t,J=4.7Hz,2H),δ3.66(s,4H),δ3.08(s,4H).13C-NMR(100MHz,DMSO)δ169.47,165.08(d,J=473Hz),156.64,135.82,132.20,132.16,124.31,124.41,124.29,120.58,110.01,109.78,66.53,66.51,65.92,59.13,57.78,46.06,35.39,30.45,19.11,14.00.ESI-MS:calculated for C22H20F4N2O7S[M-H]-532.09273,found 531.07397.
实施例34:化合物12d的制备,制备方法同实例31,将丙烯酸甲酯换做N-异丙基丙烯酰胺,得白色固体,产率:43%,熔点217.2-218.9℃。
化合物12d
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化合物12d的核磁数据
1H-NMR(400MHz,DMSO)δ11.02(s,1H),δ8.10–8.04(m,1H),δ7.75-7.64(m,3H),δ7.59(dd,J=9.3,6.6Hz,2H),δ5.81(t,J=5.0Hz,1H),δ4.03(q,J=7.1Hz,1H),δ3.65(d,J=4.2Hz,4H),δ3.07(s,4H),δ0.92(d,J=6.7Hz,3H),δ0.80(d,J=6.5Hz,3H).13C-NMR(100MHz,DMSO)δ166.97,162.70,157.32(d,J=135Hz),153.58,135.58,132.21,132.01,129.13,124.09,124.03,120.63,110.26–110.24(m),109.75(d,J=23.1Hz),65.93,60.25,58.56,46.06,30.33,37.11,22.49(d,J=4.3Hz),21.38,19.11,14.00.ESI-MS:calculatedfor C23H23F4N3O5S[M-H]-529.12945,found 528.11090.
实施例35:化合物12e的制备
将2.01mmol 10c溶于5mL 1,4-二氧六环、1mL水的混合溶剂中,加入4.02mmol碳酸氢钠,加入3.02mmol 2-噻吩硼酸,氩气置换三次,快速加入0.20mmol双(三苯基磷)二氯化钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。淡黄色固体,产率:52%,熔点211.7-212.3℃。
化合物12e
化合物12e的核磁数据
1H-NMR(400MHz,DMSO)δ11.45(s,1H),δ7.99(t,J=7.8Hz,1H),δ7.83(dd,J=14.0,9.1Hz,2H),δ7.61–7.53(m,3H),δ7.26(t,J=4.2Hz,1H),δ3.76(s,4H),δ3.18(s,4H).13C NMR(100MHz,DMSO)δ162.24,155.73(d,J=271Hz),151.92,138.68,138.16,134.85,134.73,133.57,132.47(d,J=19.0Hz),131.95(d,J=9.7Hz),130.31,129.16(dd,J=18.1,7.4Hz),125.97,122.51,122.71,104.50(d,J=24.6Hz),65.96,46.05,30.47,19.07,14.01.ESI-MS:calculated for C21H16F4N2O4S2[M-H]-500.04876,found 499.03201.
实施例36:化合物12f的制备,操作同35,所不同的是把原料换成10b。白色固体,产率:56%,熔点215.3-216.8℃。
化合物12f
化合物12f的核磁数据
1H-NMR(400MHz,DMSO)δ11.37(s,1H),7.90(t,J=7.8Hz,1H),7.74(dd,J=11.1,6.7Hz,2H),7.53(ddd,J=26.7,26.2,7.6Hz,5H),7.17(t,J=4.1Hz,1H),5.76(s,1H),3.64(s,1H),3.34(d,J=5.8Hz,5H),1.78(s,2H),1.47(d,J=8.4Hz,3H).13C NMR(100MHz,DMSO)δ192.33,138.24,132.15,130.23,129.03,128.98,125.87,104.62,104.53,64.22,43.30,33.60.ESI-MS:calculated for C22H18F4N2O4S2[M-H]-514.06441,found 513.058.
实施例37:化合物12g的制备,同实例36,把2-噻吩硼酸换成3-噻吩硼酸。白色固体,产率:48%,熔点216.2-217.5℃。
化合物12g
化合物12g的核磁数据
1H NMR(400MHz,DMSO)δ11.25(s,1H),7.91(t,J=7.7Hz,1H),7.84(s,1H),7.68(d,J=8.2Hz,2H),7.50(dd,J=9.2,6.7Hz,2H),7.34(d,J=5.0Hz,1H),5.76(s,1H),4.79(s,1H),3.35(s,2H),3.01(t,J=8.6Hz,2H),1.86–1.74(m,2H),1.49(d,J=8.4Hz,2H).13CNMR(100MHz,DMSO)δ162.69,156.81,154.29,140.71,140.66,137.68,131.99,128.20,127.73,126.30,126.14,126.11,125.87,125.67,123.81,123.65,104.65,104.41,64.22,43.29,33.59.ESI-MS:calculated for C22H18F4N2O4S2[M-H]-514.06441,found 513.058.
实施例38:化合物12h的制备,操作同36,所不同的是把2-噻吩硼酸换成苯硼酸。白色固体,产率:51%,熔点213.4-214.6℃。
化合物12h
化合物12h的核磁数据
1H-NMR(400MHz,DMSO)δ11.18(s,1H),7.96(t,J=7.6Hz,1H),7.62(d,J=11.7Hz,1H),7.57(d,J=8.1Hz,2H),7.51(d,J=7.3Hz,3H),7.47(d,J=5.2Hz,2H),7.44(s,1H),7.40(s,1H),4.80(d,J=2.4Hz,1H),3.66(s,2H),3.03(t,J=9.2Hz,4H),1.80(d,J=3.5Hz,2H),1.52–1.47(m,2H).13C-NMR(100MHz,DMSO)δ162.33,146.50,137.58,134.54,132.06,130.20,129.40,129.26,128.96,128.64,126.85,126.60,124.34,104.47,104.23,64.20,43.28,33.62.ESI-MS:calculated for C24H20F4N2O4S[M-H]+508.10799,found509.1166.
实施例39:化合物12i的制备,操作同36,所不同的是把2-噻吩硼酸换成4-羟基苯硼酸。白色固体,产率:51%,熔点219.9-220.5℃。
化合物12i
化合物12i的核磁数据
1H-NMR(400MHz,DMSO)δ10.84(d,J=31.0Hz,1H),9.55(d,J=21.5Hz,1H),8.20–8.12(m,1H),7.75–7.57(m,2H),7.28–7.21(m,1H),7.12–7.06(m,2H),6.94–6.79(m,1H),6.71–6.66(m,2H),4.29–3.98(m,1H),3.61–3.48(m,1H),1.70–1.14(m,8H).13C-NMR(100MHz,DMSO)δ162.03,157.64,142.04,132.01,131.56,125.00,122.56,117.04,115.66,114.24,104.19,103.94,65.50,64.89,42.35,33.87,33.24,30.48,21.23,19.12,14.02.ESI-MS:calculated for C24H20F4N2O5S[M-H]-524.10291,found 523.096.
实施例40:化合物12j的制备,操作同36,所不同的是把2-噻吩硼酸换成4-氰基苯硼酸。白色固体,产率:51%,熔点218.4-219.3℃。
化合物12j
化合物12j的核磁数据
1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.49(s,1H),8.18(ddd,J=14.2,9.0,5.5Hz,2H),7.94(d,J=7.7Hz,1H),7.84(d,J=8.0Hz,4H),7.69(d,J=8.6Hz,1H),5.76(s,1H),3.56(s,4H),3.00–2.94(m,4H).13C NMR(100MHz,DMSO-d6)δ160.63,135.09,131.44,131.38,131.26,122.96,119.27,115.43,111.38,64.66,55.38,42.48,33.68,14.73.ESI-MS:calculated for C25H19F4N3O4S[M-H]+533.10324,found 534.1121.
实施例41:化合物12k的制备
将5.22mmol 10b溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入10.44mmol碳酸钾,加入6.26mmol异丙胺,氩气置换三次,快速加入0.52mmol醋酸钯,氩气置换三次,90℃加热反应。TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶。白色固体,产率:38%,熔点225.5-226.2℃
化合物12k
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化合物12k的核磁数据
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),7.70(d,J=5.5Hz,1H),7.63–7.53(m,2H),7.15(d,J=8.5Hz,1H),6.06(d,J=9.3Hz,1H),4.83–4.79(m,1H),3.66(d,J=7.5Hz,2H),2.94(t,J=9.8Hz,2H),1.79(d,J=13.1Hz,2H),1.54–1.43(m,2H),1.30(s,6H).13CNMR(100MHz,DMSO-d6)δ213.34,167.70,153.90,152.27,133.06,129.00,127.96,109.31,103.72,97.65,85.30,75.16,68.89,46.22,43.16,33.45,31.62,29.48,27.88,22.29,19.68.ESI-MS:calculated for C21H23BrF3N3O4S[M-H]+549.05447,found 550.0484.
实施例42:目标化合物体外抗HBV细胞活性实验
HBV细胞株及培养条件
将HepAD38复苏,待细胞状态良好,待长满后消化,计数,于培养基中加入Tetracycline(终浓度为300ng/mL)以及G418(终浓度为400μg/mL),Tetracycline存在下病毒不表达,用含10% FBS的DMEM/F-12K培养基(包含终浓度为300μg/mL的Tetracycline以及终浓度为400μg/ml的G418,1%双抗)稀释成浓度为2×105/mL细胞悬液,以每孔100μL的量接种于96孔板(整块板铺满),置于37℃、5% CO2恒温培养箱中孵育24h。24h后,弃去旧培养基,加入200μL新鲜的含2%FBS及1%双抗DMEM/F-12K培养基。
抗病毒实验中化合物配制和细胞处理:用DMSO溶解化合物至20mM,进一步用DMSO稀释化合物到800μM,然后进行8个稀释度的4倍稀释,最高浓度为800μM,2复孔。加系列稀释的化合物1μL每孔到上述细胞板中,实验最高终浓度为4μM(200倍稀释)。使用圣湘生物48人份(PCR-荧光探针法)一步法的乙型肝炎病毒核酸定量检测试剂盒进行QPCR,吸取2.5μL上清进行Q-PCR,使用前待试剂盒试剂融化后涡旋混匀,离心后将酶混合液放置冰上待用,并保证后续步骤在冰上完成。于Q-PCR板中每孔加入2.5μL样本释放剂,2.5μL测试样本上清(实验组,对照组,标准曲线组)。QPCR反应后得到各孔病毒DNA拷贝数。用Graphpad Prism 5软件对实验数据进行分析处理,服从正态分布的定量资料采用均数±标准误(Means±SEM)进行统计学描述。
(1)细胞毒性实验
将HepAD38复苏,待细胞状态良好长满后消化、计数,用含10% FBS及1%双抗的DMEM/F-12K培养基稀释成浓度为1×105/mL细胞悬液,以每孔100μL的量接种于96孔板(整块板铺满),置于37℃、5% CO2恒温培养箱中孵育24h。24h后,弃去旧培养基,加入200μL新鲜的含2%FBS及1%双抗DMEM/F-12K培养基。
体外细胞毒性实验中化合物配制和细胞处理:用DMSO溶解化合物至20mM,然后进行8个稀释度的4倍稀释,最高浓度为20nM,2复孔。加系列稀释的化合物1μL每孔到上述细胞板中,实验最高终浓度为100μM(200倍稀释)。Staurosporine(星苞菌素,Selleck,CASNo.62996 -74 -1)作为阳性对照化合物,最高浓度为1μM。阴性对照孔加入1μL DMSO,终浓度为0.5%。
72h后,弃去旧培养基,加入含有10%CCK8溶液的培养基,孵育20-40min,于酶标仪中检测,得到OD值,导出数据计算抑制率,用Graphpad Prism 5软件对实验数据进行分析处理,服从正态分布的定量资料采用均数±标准误(Means±SEM)进行统计学描述。
(2)抑制HBV DNA活性实验(定量PCR方法)
将HepAD38复苏,待细胞状态良好,待长满后消化,计数,于培养基中加入Tetracycline(终浓度为300ng/mL)以及G418(终浓度为400μg/mL),Tetracycline存在下病毒不表达,用含10% FBS的DMEM/F-12K培养基(包含终浓度为300μg/mL的Tetracycline以及终浓度为400μg/ml的G418,1%双抗)稀释成浓度为2×105/mL细胞悬液,以每孔100μL的量接种于96孔板(整块板铺满),置于37℃、5% CO2恒温培养箱中孵育24h。24h后,弃去旧培养基,加入200μL新鲜的含2%FBS及1%双抗DMEM/F-12K培养基。
抗病毒实验中化合物配制和细胞处理:用DMSO溶解化合物至20mM,进一步用DMSO稀释化合物到800μM,然后进行8个稀释度的4倍稀释,最高浓度为800μM,2复孔。加系列稀释的化合物1μL每孔到上述细胞板中,实验最高终浓度为4μM(200倍稀释)。使用圣湘生物48人份(PCR-荧光探针法)一步法的乙型肝炎病毒核酸定量检测试剂盒进行QPCR,吸取2.5μL上清进行Q-PCR,使用前待试剂盒试剂融化后涡旋混匀,离心后将酶混合液放置冰上待用,并保证后续步骤在冰上完成。于Q-PCR板中每孔加入2.5μL样本释放剂,2.5μL测试样本上清(实验组,对照组,标准曲线组)。QPCR反应后得到各孔病毒DNA拷贝数。用Graphpad Prism 5软件对实验数据进行分析处理,服从正态分布的定量资料采用均数±标准误(Means±SEM)进行统计学描述。
表1定向合成化合物和先导化合物NVR 3-778的抗乙肝病毒活性
活性结果表明,目标化合物10a表现出较好的细胞活性,化合物其EC50=0.56±0.21μM,活性与NVR 3-778相当,毒性大大降低,目标化合物9c表现出较好的细胞活性,化合物其EC50=0.11±0.04μM,活性优于NVR 3-778,毒性略有降低。
实施例43:化合物9c、10a体外抗HBV靶点活性实验
将HBV核心蛋白与荧光染料4℃孵育过夜以标记C150蛋白,葡聚糖凝胶过滤除去多余的荧光染料,然后将荧光标记的HBV核心蛋白与不同浓度的化合物室温孵育15分钟,加入NaCl,然后室温孵育1小时后用酶标仪SpectraMax M2测定荧光信号值(Ex485/Em 535)。
化合物测试起始浓度为30μM,3倍系列稀释,共8个浓度,2复孔。化合物测试试验体系中荧光标记的HBV核心蛋白终浓度为1.5μM,NaCl终浓度为150mM,DMSO浓度为0.5%,同时设置0%组装对照孔(0M NaCl)和100%组装对照孔(1M NaCl)。
组装活性%=[1-(样品荧光–1M NaCl平均对照荧光值)/(0M NaCl平均对照荧光值-1M NaCl平均对照荧光值)]×100。用Prism软件对实验数据及图片进行分析处理,并进行统计学描述。
表2先导化合物及化合物9c和10a靶点活性测定结果
根据靶点活性结果表明,10a(IC50=4.6480μM)的靶点活性弱于先导化合物NVR 3-778(IC50=1.2490μM),而9c(IC50=0.7412μM)靶点活性优于先导化合物。
Claims (6)
1.一种抗HBV磺胺苯甲酰胺类衍生物,具有如下通式Ⅰ所示的结构:
其中,通式I中,R1为R2为/>R3为F或/>
2.根据权利要求1所述的抗HBV磺胺苯甲酰胺类衍生物,其特征在于,是具有下列结构的化合物之一:
3.如权利要求2所述的抗HBV磺胺苯甲酰胺类衍生物的制备方法,以2-溴-4-氟苯甲酸为原料,经过磺化反应,酰化反应,磺酰化反应,铃木反应得到产物;
合成路线如下:
其中R1,R2,R3如通式I所述;
试剂及其条件:(i)氯磺酸,0℃,6-12h,140-150℃;(ii)氯化亚砜,N,N-二甲基甲酰胺,3-5h,80℃;(iii)乙腈,3,4,5-三氟苯胺,8h,60℃;(iv)二氯甲烷,N,N-二异丙基乙胺,不同类型的胺,8h,45℃;(v)1,4-二氧六环,水,无机碱,不同类型的钯,不同类型的硼酸,8h,100℃;
所述的不同类型的胺选自:对羟基环己胺、环戊胺;
所述的无机碱选自:磷酸钾,碳酸铯,碳酸钾,碳酸钠;
所述的不同类型的钯选自:醋酸钯、四(三苯基膦)钯、双(三苯基膦)二氯化钯;
所述的不同类型硼酸选自:2-噻吩基硼酸、3-噻吩基硼酸、环丙基硼酸。
4.权利要求3所述的抗HBV磺胺苯甲酰胺类衍生物的制备方法,具体步骤如下:
(1)将277.54mmol氯磺酸并降温至0℃,低温下缓慢加入27.75mmol化合物1,升至室温,100℃回流反应6h;反应结束后冷却至室温,逐滴加入150mL冰水中,抽滤,水洗,干燥得化合物3;
(2)将3.58mmol中间体3溶于10mL氯化亚砜中,加入2滴N,N-二甲基甲酰胺,80℃回流反应,反应结束后冷却至室温,旋蒸得到中间体5;
(3)将中间体5溶于20mL乙腈中,加入不同类型的苯胺,60℃回流反应,反应结束后冷却至室温,浓缩,干法上样,快速制备硅胶色谱柱分离,二氯甲烷-正己烷混合溶剂重结晶,得到化合物7;
(4)将化合物7溶于二氯甲烷中,加入不同类型的胺,加入3倍量的N,N-二异丙基乙胺,45℃回流反应,反应结束后,冷却至室温,旋蒸除去二氯甲烷,加水,乙酸乙酯进行萃取,合并有机相,饱和食盐水洗三次,无水硫酸钠干燥,浓缩,干法上样,快速制备硅胶色谱柱分离,重结晶得到目标化合物9a-9b,所述的不同类型的胺选自对羟基环己胺、环戊胺;
(5)将9.51mmol 9a或9b溶于4mL 1,4-二氧六环,1mL水的混合溶剂中,加入19.02mmol无机碱,加入14.27mmol不同类型的硼酸,氩气置换三次,快速加入0.95mmol不同类型的钯及其配体,氩气置换三次,90℃加热反应,TLC监测反应,反应完全后,冷却至室温,抽滤除去催化剂,浓缩,干法上样,快速制备色谱硅胶柱分离,二氯甲烷溶剂重结晶,得到11a-11e。
5.如权利要求1-2任一项所述的抗HBV磺胺苯甲酰胺类衍生物作为HBV抑制剂用来制备抗乙肝药物。
6.一种抗HBV药物组合物,包括权利要求1-2所述的抗HBV磺胺苯甲酰胺类衍生物和一种或多种药学上可接受载体。
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