CN115466195B - 一类联苯类酰胺化合物及其制备方法和应用 - Google Patents
一类联苯类酰胺化合物及其制备方法和应用 Download PDFInfo
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- CN115466195B CN115466195B CN202211119980.8A CN202211119980A CN115466195B CN 115466195 B CN115466195 B CN 115466195B CN 202211119980 A CN202211119980 A CN 202211119980A CN 115466195 B CN115466195 B CN 115466195B
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Abstract
本发明属于有机化合物领域，具体涉及一类联苯类酰胺化合物及其制备方法。具体技术方案为：一类新的联苯类酰胺化合物，具有明显的抑制IL‑1β的效果，具有相关药物制备潜力。合成方法为：采用一步合成策略，以联芳基高碘盐为原料，在金属催化下发生反应。本发明反应条件温和，具有专一的区域选择性，一方面减少了分离纯化的难度，另一方面也进一步提高了反应效率。合成过程具有反应步骤短、条件温和、产率高、选择性好、操作简单、活性高等优点。
Description
技术领域
本发明属于有机化合物领域，具体涉及一类联苯类酰胺化合物及其制备方法。
背景技术
痛风是因血尿酸增高及尿酸盐结晶在关节和组织沉积而引起的一组综合征，包括关节炎、痛风石、泌尿道尿酸性结石及痛风性肾病等(Nature ReviewsRheumatology.2020，16，380)。引起痛风的原因为体内嘌呤代谢的最终产物尿酸过剩。现有研究表明，尿酸过剩的原因包括：缺乏尿酸氧化酶(或尿酸酶)，导致尿酸不能被氧化；肾脏功能不全，尿酸排泄减少(Pediatric Nephrology.2014，29，999；International Journalof Cardiology.2016，213，8；Current Opinion in Nephrology and Hypertension.2020，29，423)。
针对痛风的不同临床阶段，抗痛风药可分为控制急性关节炎症状和抗高尿酸血症两大类药物(Seminars in Arthritis and Rheumatism.2020，50，S24)。控制痛风性关节炎症状的药物主要包括秋水仙碱、非甾体类抗炎药和糖皮质激素等；抗高尿酸血症类药物主要包括抑制尿酸生成药(如别嘌醇)和促进尿酸排出药(如苯溴马隆和丙磺舒等)(ExpertOpinion on Drug Discovery.2020，15，943；Annals of Internal Medicine.2017，166，58)。目前在抗炎症方面，主要都是生物类药物，而合成类化合物鲜有报道。生物类药物合成成本较高、提纯难度较大，在市场推广应用上弱于合成类化合物。IL-1β抑制剂能有效降低痛风相关的炎症，但相关合成类化合物较少。
发明内容
本发明的目的是提供一类联苯类酰胺化合物及其制备方法。
为实现上述发明目的，本发明所采用的技术方案是：一类联苯类酰胺化合物，所述化合物结构通式如式(1)或式(2)所示，
式(1)中，R1为烷基、卤素、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基、-O-烷基、-O-芳基、-O-杂芳基、-O-磺酰基中的任意一种；R2为烷基、卤素、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基、-O-烷基、-O-芳基、-O-杂芳基、-O-磺酰基中的任意一种；R3为氢、卤素、烷基、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基中的任意一种，其在A环上的取代个数为1、2或3；R4为氢、卤素、烷基、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基中的任意一种，其在B环上的取代个数为1、2或3；R5为烷基、芳基、腈基、烯基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基中的任意一种；
式(2)中，R1为烷基、卤素、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基、-O-烷基、-O-芳基、-O-杂芳基、-O-磺酰基中的任意一种；R2为烷基、卤素、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基、-O-烷基、-O-芳基、-O-杂芳基、-O-磺酰基中的任意一种；R3为氢、卤素、烷基、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基，其在A环上的取代个数为1、2或3中的任意一种；R4为氢、卤素、烷基、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基，其在B环上的取代个数为1、2或3中的任意一种；R5为芳基、杂芳基。
优选的，所述联苯类酰胺化合物结构式为下述结构式中任意一种，
相应的，所述化合物的制备方法合成通式为：
n＝1或2。
其中，L1的结构式为：
优选的，当L1为消旋体时，得到产物为消旋体；当L1为R构型时，得到产物为S构型；当L1为S构型时，得到产物为R构型。
优选的，S1的结构式为S1-1到S1-7中的任意一种，
优选的，S2的结构式具体为S2-1到S2-22中的任意一种，
优选的，所述制备方法包括如下步骤：向干燥的试管中加入Pd2dba3、L1和溶剂，搅拌后，加入S1和Na2CO3，使反应体系处于CO氛围中，添加S2进行反应。
优选的，所述反应在0℃下进行。
优选的，所述溶剂为：按体积比，CHCl3：C6H5Cl＝2:3的混合物。
相应的，所述联苯类酰胺化合物在制备抑制IL-1β药物中的应用。
本发明具有以下有益效果：本发明提供了一类新的联苯类酰胺化合物，具有明显的抑制IL-1β的效果，具有相关药物制备潜力。
本发明采用一步合成策略，以联芳基高碘盐为原料，在金属催化下，高效、高选择性合成了一系列联芳基轴手性酰胺类化合物。本发明反应条件温和，具有专一的区域选择性，一方面减少了分离纯化的难度，另一方面也进一步提高了反应效率。合成过程具有反应步骤短、条件温和、产率高、选择性好、操作简单、活性高等优点。
附图说明
图1为本发明的合成的一部分联苯类酰胺化合物结构式；
图2为本发明合成的另一部分联苯类酰胺化合物结构式；
图3为本发明合成的部分联苯类酰胺化合物作用下细胞相对活力示意图；
图4为本发明合成的部分联苯类酰胺化合物作用下IL-1β相对释放率示意图。
具体实施方式
本发明提供了一类新的联苯类酰胺化合物，其结构通式如(1)或式(2)所示。
其中，R1为烷基、卤素、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基、-O-烷基、-O-芳基、-O-杂芳基、-O-磺酰基中的任意一种；R2为烷基、卤素、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基、-O-烷基、-O-芳基、-O-杂芳基、-O-磺酰基中的任意一种；R3为氢、卤素、烷基、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基中的任意一种，其在A环上的取代个数为1、2或3；R4为氢、卤素、烷基、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基中的任意一种，其在B环上的取代个数为1、2或3；R5为烷基、芳基、腈基、烯基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基中的任意一种。
其中，R1为烷基、卤素、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基、-O-烷基、-O-芳基、-O-杂芳基、-O-磺酰基中的任意一种；R2为烷基、卤素、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基、-O-烷基、-O-芳基、-O-杂芳基、-O-磺酰基中的任意一种；R3为氢、卤素、烷基、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基，其在A环上的取代个数为1、2或3中的任意一种；R4为氢、卤素、烷基、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基，其在B环上的取代个数为1、2或3中的任意一种；R5为芳基、杂芳基。
本发明还对应提供了这类化合物的合成方法，合成通式为：
其中，L1为配体，结构式为：当L1为消旋体时，得到产物为消旋体；当L1为R构型时，得到产物为S构型；当L1为S构型时，得到产物为R构型。
S1的结构式为S1-1到S1-7中的任意一种。
当S2为烷基胺(苄胺、取代丁胺等)时，产物为式(1)结构；当S2为芳基胺(各种取代苯胺)时，产物为式(2)结构。S2的结构式具体为S2-1到S2-22中的任意一种。
合成方法具体包括如下步骤：在手套箱中，相对于S1的摩尔量，向干燥的试管中加入5mol％的Pd2dba3、12mol％的配体L1和0.1M混合溶剂(CHCl3：C6H5Cl＝2:3，v/v)。将混合溶液搅拌30分钟，然后加入S1(1.0eq.)和Na2CO3(2.2eq.，相对于S1的摩尔量)。随后将反应瓶从手套箱中取出，并用真空泵抽出试管内空气，再插CO气球充入CO，如此反复操作3次，最后将CO气球保留插在试管上，以保证反应在CO氛围中进行。本领域技术人员也可以选择其他可保证CO氛围的方法进行操作。随后在0℃下进行搅拌，添加S2(1.2eq.)。若S2为固体，可在加入Na2CO3之后(在置换CO之前)随即加入。然后将混合物在0℃下搅拌24h。硅藻土过滤，浓缩。
通过柱色谱法纯化，使用石油醚/乙酸乙酯(10/1)作为洗脱剂,得到目标化合物。纯品用1H NMR，13C NMR和HRMS表征，并通过手性HPLC测定ee，测定条件为：Daicel手性柱AD-H,流动相正己烷：异丙醇＝9:1，v/v,流速1.0mL/min,检测波长λ＝254nm,保留时间：24.62min(主)、31.10min(次)。
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
实施例
本实施例按上述方法合成部分联苯类酰胺化合物，具体结构式如图1、2所示。图1、2中，结构式下方数据代表化合物编号；例如，数字1对应化合物为本实施例中的化合物1。本实施例具体其中部分化合物的合成参数及核磁共振数据。
1、合成化合物1。其中，S1为：S1-1；S2为：S2-1。
产物为白色固体，收率91％，99％ee。1H NMR(400MHz,Chloroform-d)δ8.09–8.02(m,1H),7.76(d,J＝7.9Hz,1H),7.57(d,J＝7.5Hz,1H),7.48(t,J＝7.7Hz,1H),7.38–7.23(m,6H),7.03(s,1H),6.98(t,J＝7.8Hz,1H),4.44(qd,J＝14.8,5.9Hz,2H),2.04(s,3H),2.01(s,3H).13C NMR(101MHz,CDCl3)δ189.77,161.26,143.85,143.17,138.18,137.00,136.97,136.36,135.00,132.65,129.63,129.59,129.04,128.77,127.92,127.78,127.49,100.40,43.59,21.71,19.62.HRMS(m/z,ESI):Calcd.for C23H20INO2[M+Na]+:492.0436,found:492.0428[α]D20＝+47.7(c＝0.61,CHCl3).
2、合成化合物2。其中，S1为：S1-4；S2为：S2-1。
产物为白色固体，收率89％，99％ee。1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝7.9Hz,1H),7.65(d,J＝8.0Hz,1H),7.38–7.23(m,6H),6.98(s,1H),6.89(d,J＝8.0Hz,1H),4.49–4.34(m,2H),2.43(s,3H),2.29(s,3H),1.94(s,3H),1.89(s,3H).13C NMR(101MHz,CDCl3)δ189.67,161.69,144.69,143.32,143.17,137.05,137.00,136.63,135.71,135.67,130.70,130.56,129.48,128.84,128.74,127.91,127.74,97.40,43.54,21.25,20.28,18.28,15.73.HRMS(m/z,ESI):Calcd.for C25H24INO2[M+Na]+:520.0749,found:520.0750.[α]D20＝+24.9(c＝0.42,CHCl3).
3、化合物3。其中，S1为：S1-2；S2为：S2-1。
产物为白色固体，收率82％，97％ee。1H NMR(400MHz,Chloroform-d)δ8.07(d,J＝7.7Hz,1H),7.77(d,J＝7.8Hz,1H),7.64(d,J＝7.7Hz,1H),7.54(t,J＝7.7Hz,1H),7.38–7.30(m,4H),7.29–7.25(m,2H),7.06(q,J＝9.2,7.8Hz,2H),4.54–4.39(m,2H),2.31(p,J＝7.5Hz,4H),1.16(t,J＝7.6Hz,3H),1.05(t,J＝7.6Hz,3H).13C NMR(101MHz,Chloroform-d)δ189.51,161.19,143.76,142.72,142.32,137.03,136.20,132.95,132.54,129.67,129.14,128.75,127.91,127.76,127.60,127.29,101.54,43.60,27.58,25.63,13.98,13.81.HRMS(m/z,ESI):Calcd.for C25H24INO2[M+Na]+:520.0749,found:520.0750.[α]D20＝+20.2(c＝0.43,CHCl3).
4、化合物4。其中，S1为：S1-3；S2为：S2-1。
产物为白色固体，收率83％，99％ee。1H NMR(400MHz,Chloroform-d)δ8.13(d,J＝7.6Hz,1H),7.77(d,J＝7.8Hz,1H),7.70(d,J＝7.9Hz,1H),7.57(t,J＝7.8Hz,1H),7.32(ddd,J＝20.8,11.4,6.8Hz,7H),7.09(t,J＝7.8Hz,1H),4.51(d,J＝5.9Hz,2H),2.57(dp,J＝20.6,6.8Hz,2H),1.23(d,J＝6.8Hz,3H),1.16(d,J＝6.8Hz,6H),0.96(d,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3)δ188.88,161.06,148.73,147.98,142.61,141.29,137.08,136.21,132.08,131.12,130.31,129.33,128.75,127.94,127.76,127.71,125.20,101.99,43.64,31.96,29.69,24.42,24.37,23.73,23.45.HRMS(m/z,ESI):Calcd.for C27H28INO2[M+Na]+:548.1062,found:548.1066.[α]D20＝+3.5(c＝0.18,CHCl3).
5、化合物5。其中，S1为：S1-5；S2为：S2-1。
产物为白色固体，收率93％，97％ee。1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝7.8Hz,1H),7.55(d,J＝7.5Hz,1H),7.47(d,J＝7.7Hz,1H),7.33(dd,J＝11.9,7.1Hz,3H),7.29–7.23(m,2H),7.04(s,2H),4.50–4.38(m,2H),2.47(s,3H),2.39(s,3H),1.98(d,J＝7.4Hz,6H).13C NMR(101MHz,CDCl3)δ189.85,161.34,145.41,141.48,137.40,137.17,137.01,135.99,134.93,134.69,132.72,131.49,129.51,128.76,127.92,127.77,127.14,108.67,43.60,26.15,21.96,21.31,19.71.HRMS(m/z,ESI):Calcd.for C25H24INO2[M+Na]+:520.0749,found:520.0747.[α]D20＝+41.7(c＝0.65,CHCl3).
6、化合物6。其中，S1为：S1-7；S2为：S2-1。
产物为白色固体，收率81％，99％ee。1H NMR(400MHz,Chloroform-d)δ8.18(d,J＝8.6Hz,1H),8.03(d,J＝8.6Hz,1H),7.98(d,J＝8.2Hz,1H),7.62(t,J＝7.5Hz,1H),7.48–7.43(m,1H),7.40–7.19(m,8H),7.01(d,J＝6.1Hz,1H),4.44(dd,J＝18.6,5.9Hz,2H),2.51(s,3H),1.94(s,3H).13C NMR(101MHz,CDCl3)δ190.34,161.51,144.91,142.24,139.48,136.96,136.48,135.54,131.15,130.44,129.33,129.06,128.78,128.38,128.28,127.94,127.81,127.59,127.19,126.66,126.47,107.93,99.99,43.58,29.36,21.53.HRMS(m/z,ESI):Calcd.for C27H22INO2[M+Na]+:542.0593,found:542.0592.[α]D20＝+48.6(c＝0.51,CHCl3).
7、化合物7。其中，S1为：S1-6；S2为：S2-1。
产物为白色固体，收率92％，96％ee。1H NMR(400MHz,Chloroform-d)δ8.05(d,J＝7.7Hz,1H),7.57(d,J＝7.6Hz,1H),7.47(t,J＝7.7Hz,1H),7.38–7.23(m,5H),7.15(s,2H),7.03(s,1H),4.44(t,J＝7.0Hz,2H),2.48(s,3H),1.99(d,J＝5.5Hz,6H).13C NMR(101MHz,CDCl3)δ189.75,161.30,144.92,143.71,139.45,137.01,136.99,135.00,134.95,132.61,129.61,129.37,128.76,128.53,127.92,127.77,127.28,107.15,43.59,29.36,21.40,19.61.HRMS(m/z,ESI):Calcd.for C24H22INO2[M+Na]+:506.0593,found:506.0584.[α]D20＝+42.6(c＝0.57,CHCl3).
8、化合物8。其中，S1为：S1-1；S2为：S2-17。
产物为无色油状物，收率73％，90％ee。1H NMR(400MHz,Chloroform-d)δ7.83(d,J＝8.0Hz,1H),7.72(dd,J＝5.6,3.5Hz,1H),7.47(q,J＝3.2,2.1Hz,3H),7.35–7.22(m,5H),7.07(t,J＝7.2Hz,1H),7.00(t,J＝7.8Hz,1H),2.09(s,3H),2.03(s,3H).13C NMR(101MHz,CDCl3)δ166.68,143.23,140.33,138.98,137.77,136.75,136.45,135.61,132.52,130.73,129.82,128.87,128.47,126.37,124.28,119.93,100.69,21.86,19.94.HRMS(m/z,ESI):Calcd.for C21H18INO[M+H]+:428.0511,found:428.0508.[α]D20＝-20.4(c＝0.46,CHCl3).
9、化合物9。其中，S1为：S1-1；S2为：S2-12。
产物为无色油状物，收率50％，85％ee。1H NMR(400MHz,Chloroform-d)δ8.00(d,J＝7.7Hz,1H),7.76(d,J＝7.9Hz,1H),7.55(d,J＝7.6Hz,1H),7.46(t,J＝7.7Hz,1H),7.30–7.22(m,1H),6.98(t,J＝7.7Hz,1H),6.73(s,1H),3.33–3.17(m,2H),2.03(s,3H),2.00(s,3H),1.49(s,2H),1.41–1.24(m,4H),0.93(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ190.19,161.42,143.75,143.21,138.16,136.91,136.33,134.86,132.77,129.58,129.56,129.01,127.43,100.48,39.16,31.24,21.72,20.00,19.61,13.68.HRMS(m/z,ESI):Calcd.for C20H22INO2[M+Na]+:458.0593,found:458.0594.[α]D20＝+28.7(c＝0.17,CHCl3).
10、化合物10。其中，S1为：S1-1；S2为：S2-13。
产物为无色油状物，收率71％，98％ee。1H NMR(400MHz,Chloroform-d)δ8.02(d,J＝7.8Hz,1H),7.77(d,J＝8.0Hz,1H),7.56(d,J＝7.6Hz,1H),7.46(t,J＝7.8Hz,1H),7.26(d,J＝7.6Hz,1H),6.98(t,J＝7.8Hz,1H),6.87(s,1H),4.85(d,J＝9.8Hz,2H),3.81(dd,J＝14.6,6.2Hz,2H),2.03(s,3H),2.00(s,3H),1.74(s,3H).13C NMR(101MHz,CDCl3)δ189.83,161.35,143.82,143.18,140.84,138.15,136.97,136.36,134.94,132.64,129.58,129.03,127.43,111.82,100.35,44.98,21.69,20.39,19.61.HRMS(m/z,ESI):Calcd.forC20H20INO2[M+Na]+:456.0436,found:456.0439.[α]D20＝+60.6(c＝0.37,CHCl3).
11、化合物11。其中，S1为：S1-1；S2为：S2-2。
产物为白色固体，收率80％，98％ee。1H NMR(400MHz,Chloroform-d)δ8.05(d,J＝7.7Hz,1H),7.76(d,J＝7.9Hz,1H),7.56(d,J＝7.6Hz,1H),7.47(t,J＝7.7Hz,1H),7.30–7.24(m,1H),7.15(s,4H),7.02–6.94(m,2H),4.40(dd,J＝12.9,5.9Hz,2H),2.36(s,3H),2.02(d,J＝11.0Hz,6H).13C NMR(101MHz,CDCl3)δ189.82,161.23,143.83,143.19,138.17,137.50,136.97,136.36,134.96,133.94,132.69,129.63,129.58,129.42,129.02,127.90,127.47,100.42,43.35,21.71,21.12,19.62.HRMS(m/z,ESI):Calcd.for C24H22INO2[M+Na]+:506.0593,found:506.0603.[α]D20＝+42.8(c＝0.60,CHCl3).
12、化合物12。其中，S1为：S1-1；S2为：S2-10。
产物为白色固体，收率88％，98％ee。1H NMR(400MHz,Chloroform-d)δ8.06(d,J＝7.7Hz,1H),7.76(d,J＝7.9Hz,1H),7.57(d,J＝7.6Hz,1H),7.48(t,J＝7.7Hz,1H),7.30–7.14(m,5H),6.97(t,J＝7.7Hz,1H),6.92(s,1H),4.45(dd,J＝17.3,5.7Hz,2H),2.32(s,3H),2.02(d,J＝10.4Hz,6H).13C NMR(101MHz,CDCl3)δ189.67,161.03,143.87,143.19,138.14,137.01,136.46,136.36,135.00,134.74,132.61,130.59,129.63,129.58,129.03,128.74,128.07,127.47,126.29,100.35,41.70,21.71,19.62,19.07.HRMS(m/z,ESI):Calcd.for C24H22INO2[M+Na]+:506.0593,found:506.0589.[α]D20＝+41.6(c＝0.41,CHCl3).
13、化合物13。其中，S1为：S1-1；S2为：S2-11。
产物为白色固体，收率68％，96％ee。1H NMR(400MHz,Chloroform-d)δ7.99(d,J＝7.8Hz,1H),7.73(d,J＝7.9Hz,1H),7.54(d,J＝7.6Hz,1H),7.45(t,J＝7.7Hz,1H),7.32–7.19(m,4H),6.97–6.84(m,3H),4.44(t,J＝5.4Hz,2H),3.85(s,3H),2.00(d,J＝7.9Hz,6H).13C NMR(101MHz,CDCl3)δ190.11,161.20,157.62,143.75,143.17,138.04,136.90,136.27,134.82,132.79,129.95,129.59,129.55,129.20,128.96,127.39,125.16,120.61,110.27,100.48,55.34,39.40,21.70,19.60.HRMS(m/z,ESI):Calcd.for C24H22INO3[M+Na]+:522.0542,found:522.0542.[α]D20＝+51.8(c＝0.52,CHCl3).
14、化合物14。其中，S1为：S1-1；S2为：S2-9。
产物为白色固体，收率75％，98％ee。1H NMR(400MHz,Chloroform-d)δ8.05(d,J＝7.7Hz,1H),7.76(d,J＝7.9Hz,1H),7.57(d,J＝7.6Hz,1H),7.47(t,J＝7.7Hz,1H),7.26(t,J＝7.6Hz,2H),7.05(d,J＝6.3Hz,1H),6.97(t,J＝7.7Hz,1H),6.88–6.78(m,3H),4.41(dd,J＝15.4,6.0Hz,2H),3.81(s,3H),2.02(d,J＝11.3Hz,6H).13C NMR(101MHz,CDCl3)δ189.73,161.28,159.91,143.86,143.16,138.52,138.18,137.00,136.36,135.00,132.65,129.82,129.62,129.59,129.05,127.48,120.11,113.41,113.35,100.38,55.28,43.56,21.71,19.62.HRMS(m/z,ESI):Calcd.for C24H22INO3[M+Na]+:522.0542,found:522.0549.[α]D20＝+32.7(c＝0.47,CHCl3).
15、化合物15。其中，S1为：S1-1；S2为：S2-18。
产物为无色油状物，收率63％，91％ee。1H NMR(400MHz,Chloroform-d)δ7.84(d,J＝7.9Hz,1H),7.73(dd,J＝7.2,2.1Hz,1H),7.62(s,1H),7.53–7.42(m,6H),7.32–7.28(m,1H),7.01(t,J＝7.8Hz,1H),2.07(s,3H),2.04(s,3H).13C NMR(101MHz,CDCl3)δ166.83,143.08,140.78,140.35,139.00,136.82,136.63,135.03,132.94,130.84,129.99,128.97,128.58,128.40,126.44,126.13,119.31,100.54,21.79,19.91.19FNMR(376MHz,CDCl3)δ-62.15.HRMS(m/z,ESI):Calcd.for C22H17F3INO[M+H]+:496.0385,found:496.0383.[α]D20＝-24.5(c＝0.56,CHCl3).
16、化合物16。其中，S1为：S1-1；S2为：S2-8。
产物为白色固体，收率77％，96％ee。1H NMR(400MHz,Chloroform-d)δ8.06(d,J＝7.9Hz,1H),7.76(d,J＝7.9Hz,1H),7.57(d,J＝7.6Hz,1H),7.48(t,J＝7.7Hz,1H),7.25(dt,J＝10.7,8.4Hz,2H),7.14–6.95(m,5H),4.40(qd,J＝14.7,5.9Hz,2H),2.36(s,3H),2.04(s,3H),2.01(s,3H).13CNMR(101MHz,CDCl3)δ189.77,161.21,143.85,143.18,138.50,138.17,136.99,136.86,136.35,134.98,132.65,129.64,129.58,129.03,128.66,128.64,128.52,127.47,124.95,100.40,43.58,21.72,21.37,19.63.HRMS(m/z,ESI):Calcd.forC24H22INO2[M+Na]+:506.0593,found:506.0594.[α]D20＝+35.8(c＝0.45,CHCl3).
17、化合物17。其中，S1为：S1-1；S2为：S2-3。
产物为无色油状物，收率78％，98％ee。1H NMR(400MHz,Chloroform-d)δ8.04(d,J＝7.8Hz,1H),7.75(d,J＝7.9Hz,1H),7.57(d,J＝7.6Hz,1H),7.47(t,J＝7.7Hz,1H),7.25(q,J＝10.0,7.9Hz,3H),7.00(dt,J＝20.2,8.1Hz,4H),4.40(dd,J＝13.1,6.0Hz,2H),2.03(s,3H),2.00(s,3H).13C NMR(101MHz,CDCl3)δ189.70,161.27,143.85,143.15,138.22,137.03,136.37,135.04,132.60,129.68,129.59,129.03,127.49,115.73,115.52,100.34,42.84,21.67,19.58.HRMS(m/z,ESI):Calcd.for C23H19FINO2[M+Na]+:510.0342,found:510.0335.[α]D20＝+36.9(c＝0.53,CHCl3).
18、化合物18。其中，S1为：S1-1；S2为：S2-5。
产物为黄色油状物，收率76％，97％ee。1H NMR(400MHz,Chloroform-d)δ8.03(d,J＝7.8Hz,1H),7.75(d,J＝8.0Hz,1H),7.57(d,J＝7.7Hz,1H),7.51–7.44(m,3H),7.29–7.23(m,1H),7.17–7.11(m,2H),7.07(s,1H),6.98(t,J＝7.7Hz,1H),4.38(qd,J＝15.0,6.1Hz,2H),2.03(s,3H),2.00(s,3H).13C NMR(101MHz,CDCl3)δ189.66,161.35,143.83,143.11,138.24,137.05,136.37,136.11,135.07,132.59,131.85,129.59,129.56,129.54,129.07,127.51,121.68,100.33,42.87,21.69,19.60.HRMS(m/z,ESI):Calcd.for C23H19BrINO2[M+H]+:547.9722,found:547.9728.[α]D20＝+43.2(c＝0.40,CHCl3).
19、化合物19。其中，S1为：S1-1；S2为：S2-6。
产物为黄色固体，收率78％，98％ee。1H NMR(400MHz,Chloroform-d)δ8.02(dd,J＝7.8,1.2Hz,1H),7.75(d,J＝7.9Hz,1H),7.68–7.64(m,2H),7.57(d,J＝7.5Hz,1H),7.47(t,J＝7.7Hz,1H),7.25(d,J＝7.5Hz,1H),7.06(s,1H),7.02–6.95(m,3H),4.37(qd,J＝15.0,6.1Hz,2H),2.03(s,3H),2.00(s,3H).13C NMR(101MHz,CDCl3)δ189.64,161.33,143.83,143.10,138.24,137.82,137.04,136.76,136.37,135.08,132.57,129.76,129.59,129.56,129.07,127.51,100.33,93.19,42.96,21.70,19.61.HRMS(m/z,ESI):Calcd.forC23H19I2NO2[M+H]+:595.9583,found:595.9578.[α]D20＝+26.8(c＝0.47,CHCl3).
20、化合物20。其中，S1为：S1-1；S2为：S2-4。
产物为无色油状物，收率72％，96％ee。1H NMR(400MHz,Chloroform-d)δ8.05–8.00(m,1H),7.75(d,J＝7.9Hz,1H),7.57(d,J＝7.5Hz,1H),7.47(t,J＝7.7Hz,1H),7.30(t,J＝7.2Hz,2H),7.25(d,J＝7.5Hz,1H),7.19(d,J＝8.3Hz,2H),7.07(s,1H),6.98(t,J＝7.7Hz,1H),4.40(qd,J＝15.0,6.1Hz,2H),2.03(s,3H),2.00(s,3H).13CNMR(101MHz,CDCl3)δ189.66,161.33,143.84,143.11,138.23,137.05,136.37,135.57,135.09,133.60,132.56,129.59,129.57,129.23,129.07,128.89,127.51,100.34,42.83,21.70,19.61.HRMS(m/z,ESI):Calcd.for C23H19ClNIO2[M+Na]+:526.0047,found:526.0043.[α]D20＝+48.5(c＝0.41,CHCl3).
21、化合物21。其中，S1为：S1-1；S2为：S2-7。
产物为白色固体，收率67％，99％ee。1H NMR(400MHz,Chloroform-d)δ8.03(d,J＝7.7Hz,1H),7.75(d,J＝7.9Hz,1H),7.57(d,J＝7.6Hz,1H),7.47(t,J＝7.7Hz,1H),7.32–7.27(m,2H),7.25(d,J＝7.6Hz,1H),7.19(d,J＝8.3Hz,2H),7.10(s,1H),6.97(t,J＝7.7Hz,1H),4.43(qd,J＝15.0,6.1Hz,2H),2.03(s,3H),2.00(s,3H).13C NMR(101MHz,CDCl3)δ189.65,161.35,148.71,143.85,143.11,138.24,137.06,136.37,135.86,135.10,132.56,129.59,129.57,129.31,129.07,127.52,121.27,119.15,100.33,42.74,21.70,19.60.19F NMR(376MHz,CDCl3)δ-57.91.HRMS(m/z,ESI):Calcd.for C24H19F3INO3[M+H]+:554.0440,found:554.0443.[α]D20＝+40.9(c＝0.52,CHCl3).
22、化合物22。其中，S1为：S1-1；S2为：S2-14。
产物为黄色油状物，收率41％，95％ee。1H NMR(400MHz,Chloroform-d)δ8.57–8.49(m,1H),8.00(d,J＝7.7Hz,1H),7.79(s,1H),7.72(d,J＝7.9Hz,1H),7.68(td,J＝7.7,1.8Hz,1H),7.56(d,J＝7.6Hz,1H),7.46(t,J＝7.7Hz,1H),7.23(td,J＝8.0,5.0Hz,3H),6.93(t,J＝7.7Hz,1H),4.64–4.48(m,2H),2.04(s,3H),2.00(s,3H).13CNMR(101MHz,CDCl3)δ189.76,161.81,155.46,149.20,143.84,143.10,138.19,136.98,136.80,136.35,134.92,132.79,129.57,129.54,129.00,127.47,122.55,121.90,100.48,44.40,21.73,19.61.HRMS(m/z,ESI):Calcd.for C22H19IN2O2[M+H]+:471.0569,found:471.0571.[α]D20＝+23.7(c＝0.16,CHCl3).
23、化合物23。其中，S1为：S1-1；S2为：S2-15。
产物为无色油状物，收率93％，98％ee。1H NMR(400MHz,Chloroform-d)δ8.04(dd,J＝7.8,1.3Hz,1H),7.75(d,J＝7.9Hz,1H),7.56(d,J＝7.5Hz,1H),7.47(t,J＝7.7Hz,1H),7.36(d,J＝1.8Hz,1H),7.24(d,J＝7.5Hz,1H),7.06(s,1H),6.97(t,J＝7.7Hz,1H),6.33(dd,J＝3.3,1.9Hz,1H),6.25(d,J＝3.2Hz,1H),4.43(dd,J＝5.7,2.9Hz,2H),2.02(s,3H),2.00(s,3H).13C NMR(101MHz,CDCl3)δ189.42,161.08,150.00,143.93,143.13,142.48,138.08,137.02,136.35,135.09,132.45,129.71,129.58,129.03,127.48,110.49,108.00,100.41,36.45,21.71,19.62.HRMS(m/z,ESI):Calcd.for C21H18INO3[M+Na]+:482.0229,found:482.0275.[α]D20＝+42.4(c＝0.34,CHCl3).
24、化合物24。其中，S1为：S1-1；S2为：S2-19。
产物为白色固体，收率93％，96％ee。1H NMR(400MHz,Chloroform-d)δ8.13(dt,J＝9.4,2.5Hz,2H),7.84(d,J＝7.9Hz,2H),7.76–7.68(m,1H),7.50(dd,J＝10.7,8.1Hz,4H),7.31(d,J＝7.6Hz,1H),7.01(t,J＝7.8Hz,1H),2.06(s,3H),2.04(s,3H).13C NMR(101MHz,CDCl3)δ166.91,143.56,143.46,142.95,140.48,138.99,136.89,136.81,134.58,133.30,130.91,130.12,128.66,126.49,125.00,118.98,100.45,21.79,19.92.HRMS(m/z,ESI):Calcd.for C21H17IN2O3[M+H]+:473.0362,found:473.0365.[α]D20＝-40.4(c＝0.71,CHCl3).
25、化合物25。其中，S1为：S1-1；S2为：S2-22。
产物为白色固体，收率32％，99％ee。1H NMR(400MHz,Chloroform-d)δ8.33(d,J＝35.6Hz,2H),8.17(d,J＝8.2Hz,1H),8.07(s,1H),7.82(d,J＝7.9Hz,1H),7.78–7.70(m,1H),7.52–7.44(m,2H),7.29(d,J＝7.6Hz,2H),7.00(t,J＝7.8Hz,1H),2.07(s,3H),2.03(s,3H).13C NMR(101MHz,CDCl3)δ167.04,145.27,143.09,141.16,140.41,138.94,136.93,136.62,134.76,134.59,133.00,130.84,130.07,128.57,127.18,126.53,123.61,100.57,21.79,19.93.HRMS(m/z,ESI):Calcd.for C20H17IN2O[M+H]+:429.0464,found:429.0467.[α]D20＝-18.8(c＝0.29,CHCl3).
26、化合物26。其中，S1为：S1-1；S2为：S2-21。
产物为白色固体，收率96％，93％ee。1H NMR(400MHz,Chloroform-d)δ7.86(t,J＝8.4Hz,2H),7.78–7.67(m,3H),7.54–7.45(m,2H),7.33(d,J＝7.6Hz,1H),7.23(dd,J＝8.9,2.3Hz,1H),7.04(t,J＝7.8Hz,1H),2.06(s,3H),2.04(s,3H).13C NMR(101MHz,CDCl3)δ166.89,142.88,142.72,142.23,140.48,139.01,136.93,136.87,134.26,133.47,130.96,130.22,128.84,128.71,127.08,126.51,121.55,117.31,100.40,21.79,19.90.HRMS(m/z,ESI):Calcd.for C21H16ClIN2O3[M+H]+:506.9972,found:506.9980.[α]D20＝-32.5(c＝0.91,CHCl3).
27、化合物27。其中，S1为：S1-1；S2为：S2-20。
产物为白色固体，收率87％，93％ee。1H NMR(400MHz,Chloroform-d)δ8.13(q,J＝2.4Hz,1H),7.91(dd,J＝8.2,2.2Hz,1H),7.87(d,J＝7.9Hz,1H),7.74(dd,J＝6.9,2.0Hz,1H),7.72–7.64(m,2H),7.54–7.46(m,2H),7.42(t,J＝8.2Hz,1H),7.32(d,J＝7.6Hz,1H),7.04(t,J＝7.7Hz,1H),2.07(s,3H),2.05(s,3H).13C NMR(101MHz,CDCl3)δ166.89,148.51,143.06,140.44,139.03,138.78,136.90,136.70,134.64,133.14,130.90,130.10,129.70,128.64,126.51,125.46,118.88,114.61,100.54,21.81,19.92.HRMS(m/z,ESI):Calcd.forC21H17IN2O3[M+H]+:473.0362,found:473.0364.[α]D20＝-38.5(c＝0.53,CHCl3).
28、化合物28。其中，S1为：S1-1；S2为：S2-16。
产物为无色油状物，收率80％，97％ee。1H NMR(400MHz,Chloroform-d)δ7.95(d,J＝7.7Hz,1H),7.77(d,J＝7.9Hz,1H),7.57(d,J＝7.6Hz,1H),7.47(t,J＝7.7Hz,1H),7.30–7.24(m,1H),7.14(s,1H),7.00(t,J＝7.8Hz,1H),3.52(qd,J＝6.7,2.2Hz,2H),2.57(t,J＝6.6Hz,2H),2.04(s,3H),2.00(s,3H).13C NMR(101MHz,CDCl3)δ189.23,161.89,143.77,142.90,138.40,137.12,136.48,135.21,132.52,129.63,129.40,129.20,127.61,117.45,100.41,35.61,21.69,19.59,18.11.HRMS(m/z,ESI):Calcd.for C19H17IN2O2[M+Na]+:455.0232,found:455.0234.[α]D20＝+58.4(c＝0.37,CHCl3).
29、化合物29。其中，S1为：S1-4；S2为：S2-19。
产物为白色固体，收率84％，97％ee。1H NMR(400MHz,Chloroform-d)δ8.12(d,J＝8.8Hz,2H),7.79–7.71(m,2H),7.68(d,J＝7.9Hz,1H),7.43(d,J＝8.8Hz,2H),7.36(d,J＝7.9Hz,1H),6.94(d,J＝8.1Hz,1H),2.42(s,3H),2.26(s,3H),1.94(d,J＝16.6Hz,6H).13CNMR(101MHz,Chloroform-d)δ166.98,143.75,143.30,143.18,141.14,141.07,138.41,137.79,136.33,135.24,132.23,131.64,129.98,126.47,124.98,118.86,97.37,21.02,20.38,18.31.HRMS(m/z,ESI):Calcd.for C23H21IN2O3[M+H]+:501.0675,found:501.0680.[α]D20＝-77.3(c＝0.45,CHCl3).
30、化合物30。其中，S1为：S1-7；S2为：S2-19。
产物为白色固体，收率48％，93％ee。1H NMR(400MHz,Chloroform-d)δ8.19–8.12(m,2H),8.08(d,J＝8.6Hz,1H),8.04–7.98(m,2H),7.92(s,1H),7.64(d,J＝1.3Hz,1H),7.53–7.43(m,3H),7.34–7.28(m,3H),2.58(s,3H),1.96(s,3H).13C NMR(101MHz,Chloroform-d)δ166.76,143.57,140.66,140.17,136.88,134.90,131.09,130.88,130.76,130.06,129.08,128.40,127.89,127.51,126.19,125.36,125.06,118.78,29.38,21.39.HRMS(m/z,ESI):Calcd.for C25H19IN2O3[M+H]+:523.0519,found:523.0521.[α]D20＝-49.3(c＝0.36,CHCl3).
31、测定上述各新合成的化合物抑制IL-1β的情况。方法为：将J774A.1细胞按1×10-6/mL密度铺在24孔板中，培养24h后更换无血清的opti-MEM培养液。用LPS(1ug/mL)刺激3h后，用VX765(500nmol/L)和不同浓度的待测化合物处理0.5h，对照组使用等量DMSO替代待测化合物，再用ATP(5mmol/L)刺激0.5h。收集细胞培养液，然后根据ELISA试剂盒说明书测定IL-1β的释放情况(Mouse IL-1βHigh Sensitivity ELISA Kit；货号：EK201BHS-96)。结果如图3、4所示。其中a表示对应化合物的消旋体，b表示化合物的S手性构型，c表示化合物的R手性构型，如：1a表示化合物1的消旋体,1b表示化合物1的S构型,1c表示化合物1的R构型。
细胞活力检测方法：将J774A.1细胞按1×10-6/mL密度铺在96孔板中，培养24h后，更换新鲜完全DMEM培养基,分别加入待测化合物，対照组加入等量DMSO，待化合物作用24h后，参照CCK8检测试剂盒(Cell Counting Kit-8，货号：B34304)说明书进行细胞活力测定。
细胞活力计算公式：细胞活力(％)＝[A(药物+)-A(空白)]/[A(药物-)-A(空白)]×100％。
其中，A(药物+)为具有细胞、CCK-8溶液和药物溶液的孔的吸光度；A(药物-)为具有细胞、CCK-8溶液而没有药物溶液的孔的吸光度；A(空白)为具有培养基和CCK-8溶液而没有细胞的孔的吸光度。
IL-1β释放率检测方法：参照ELISA试剂盒说明书进行数据处理(Mouse IL-1βHighSensitivity ELISA Kit；货号：EK201BHS-96)。将测试的吸光度值和对应标准品的浓度采用ELISA Calc回归/拟合计算程序–v0.1进行标曲的拟合，然后将实验组吸光度值输入计算程序，得出实验组IL-1β的浓度，再将其进行标准化，即得IL-1β释放率。
结果显示：如图3所示，待测化合物在作用浓度下对细胞活力均无显著影响；如图4所示，与刺激组(LPS+ATP)和阳性对照组(VX765)相比，大部分所测化合物均能抑制IL-1β的释放，其中以编号1a、1b、8a、8b、15a、15b、22a、26c等化合物的抑制效果尤其明显。
以上所述的实施例仅是对本发明的优选方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案做出的各种变形、变型、修改、替换，均应落入本发明权利要求书确定的保护范围内。
Claims (9)
1.一类联苯类酰胺化合物，其特征在于：所述联苯类酰胺化合物的结构式为下述结构式中的任意一种：
的消旋体、/>的消旋体、的R构型、/>的消旋体和S构型、/>的消旋体和S构型、/>的消旋体和S构型、/>的消旋体和S构型、/>的消旋体、/>
2.权利要求1所述联苯类酰胺化合物的制备方法，其特征在于：所述制备方法的合成通式为：
其中，L1的结构式为：n＝1或2；R1～R5的结构如权利要求1所示。
3.根据权利要求2所述的制备方法，其特征在于：向干燥的试管中加入Pd2(dba)3、L1和溶剂，搅拌后，加入S1和Na2CO3，使反应体系处于CO氛围中，添加S2进行反应。
4.一种联苯酰胺类化合物的制备方法，其特征在于：所述制备方法的合成通式为：
R1为烷基、卤素、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基、-O-烷基、-O-芳基、-O-杂芳基中的任意一种；R2为烷基、卤素、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基、-O-烷基、-O-芳基、-O-杂芳基中的任意一种；R3为氢、卤素、烷基、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基，其在A环上的取代个数为1、2或3中的任意一种；R4为氢、卤素、烷基、芳基、杂芳基、环烷基、杂环烷基、芳烷基、杂烷基，其在B环上的取代个数为1、2或3中的任意一种；R5为芳基、杂芳基，其中，L1的结构式为：n＝1。
5.根据权利要求4所述制备方法，其特征在于：向干燥的试管中加入Pd2(dba)3、L1和溶剂，搅拌后，加入S1和Na2CO3，使反应体系处于CO氛围中，添加S2进行反应。
6.根据权利要求2～5任意一项所述制备方法，其特征在于：当L1为消旋体时，得到产物为消旋体；当L1为R构型时，得到产物为S构型；当L1为S构型时，得到产物为R构型。
7.根据权利要求2～5任意一项所述制备方法，其特征在于：所述反应在0℃下进行。
8.根据权利要求2～5任意一项所述制备方法，其特征在于：所述溶剂为：按体积比，CHCl3：C6H5Cl＝2:3的混合物。
9.权利要求1所述联苯类酰胺化合物在制备抑制IL-1β药物中的应用。
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