CN117209426A - 类两面针碱-磺胺衍生物及其制备方法和应用 - Google Patents
类两面针碱-磺胺衍生物及其制备方法和应用 Download PDFInfo
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- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims description 119
- 229910052739 hydrogen Inorganic materials 0.000 claims description 119
- 150000002431 hydrogen Chemical class 0.000 claims description 77
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 239000000460 chlorine Substances 0.000 claims description 27
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 21
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 21
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Abstract
本发明公开了一种类两面针碱‑磺胺衍生物,该衍生物具有如通式为A或通式B的结构:本发明提供了一种类两面针碱‑磺胺衍生物,其结构新颖,且底物适用性广、操作简便、副产物少、便于分离提纯、可适用于较大规模的制备,具有可观的应用前景。
Description
技术领域
本发明涉及有机合成技术领域。更具体地说,本发明涉及一种类两面针碱-磺胺衍生物及其制备方法和应用。
背景技术
肿瘤是一种基因病,是指细胞在致瘤因素作用下,基因发生了改变,失去对其生长的正常调控,导致异常增生。目前临床上使用的抗癌药物都不同程度的存在靶向性较低、毒副作用明显、容易产生耐药性等缺点。而中药抗肿瘤具有多方位、多靶点、多效性、不易产生耐药性等优点,同时,多靶点性在其逆转肿瘤耐药的过程中发挥了独特的优势。
两面针富含多种生物碱类、黄酮类甾体类、酯类等活性成分,具有抗炎、抗氧化、抗癌、保护心血管系统等作用。氯化两面针碱(Nitidine Chloride,NC)是从植物两面针中提取分离到的苯菲啶类生物碱成分,具有广谱抗肿瘤作用。但大部分两面针碱类似物在研究过程中仍发现具有水溶性差,口服生物利用度低等缺陷,限制了它们在药物上的应用。因此,如何提高两面针碱类似物的水溶性以及如何提高两面针碱类似物的活性和降低其细胞毒性等问题仍然是需要解决的首要问题。
越来越多的研究表明,引入磺胺基团开发新一代的抗肿瘤药物是有希望的,如部分磺胺衍生物对人乳腺癌细胞、人恶性黑色素瘤细胞、人肝癌细胞、人肾癌细胞均具有显著的细胞毒性,并且抑制效果优于索拉菲尼,且部分磺胺衍生物对人乳腺癌细胞和人宫颈癌细胞的细胞毒性与对照药物五氟尿嘧啶相当。因此,若能采用减少脂溶性基团、引入极性基团等水溶性化学结构改造策略,并结合活性拼接的原理设计合成水溶性好、高效低毒的类两面针碱-磺胺衍生物,这不仅对扩大两面针碱类似物库具有重要价值,也为新型抗肿瘤化合物的发现奠定基础,还能促进两面针的进一步开发和利用。
发明内容
本发明的一个目的是解决至少上述问题,并提供至少后面将说明的优点。
为了实现根据本发明的这些目的和其它优点,提供了一种类两面针碱-磺胺衍生物,该衍生物具有如通式为A或通式B的结构:
式中,当R1为甲基,R2为氢时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1为氢,R2为甲基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1、R2为甲氧基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟。
本发明还提供一种类两面针碱-磺胺衍生物的制备方法,其包括以下步骤:
步骤一、以式1所示的酰氯化合物1和甲氧氨盐酸盐为原料,在碳酸钾的作用下和乙酸乙酯的溶剂中,合成式2所示的化合物2;
步骤二、将化合物2与碘苯、醋酸钯、氧化银溶解于醋酸中,在氮气保护下,反应合成如式3所示的化合物3;
步骤三、将化合物3溶解于无水甲醇中,在紫外灯照射下反应得如式4所示的化合物4;
步骤四、以化合物4和1,4-二溴丁烷或1,6-二溴己烷为原料,在氢化钠作用下和DMF溶剂中,合成得到如式5所示的化合物5或如式6所示的化合物6;
步骤五、将化合物5或化合物6与邻苯二甲酰亚胺,碘化钾和碳酸钾,在乙腈溶剂中,合成得如式7所示的化合物7或如式8所示的化合物8;
步骤六、将化合物7或化合物8溶于甲胺水溶液中,电磁搅拌,反应得到如式9所示的化合物9或如式10所示的化合物10;
步骤七、将化合物9或化合物10与式11所示的化合物11,在三乙胺的作用下和二氯甲烷的作用下,反应得到如式A所示的化合物12,或如式B所示的化合物13;
其中,当R1为甲基,R2为氢时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1为氢,R2为甲基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1、R2为甲氧基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟。
优选的是,所述的类两面针碱-磺胺衍生物的制备方法,步骤一中,甲氧胺盐酸盐、碳酸钾、化合物1的摩尔比为1:2:1。
优选的是,所述的类两面针碱-磺胺衍生物的制备方法,步骤二中,化合物2、碘苯、醋酸钯、氧化银的摩尔比为1:2:0.05:2。
优选的是,所述的类两面针碱-磺胺衍生物的制备方法,步骤三中,紫外灯选用175W紫外线高压汞灯。
优选的是,所述的类两面针碱-磺胺衍生物的制备方法,步骤四中,化合物4、氢化钠、1,4-二溴丁烷或1,6-二溴己烷的摩尔比为1:3.14:5。
优选的是,所述的类两面针碱-磺胺衍生物的制备方法,步骤五中,化合物5或化合物6、邻苯二甲酰亚胺、碘化钾、碳酸钾的摩尔比为1:1:0.1:3。
优选的是,所述的类两面针碱-磺胺衍生物的制备方法,步骤六中,化合物9或化合物10、三乙胺、化合物11的摩尔比为1:7.2:1。
本发明还提供一种类两面针碱-磺胺衍生物在制备治疗肿瘤药物中的应用,该衍生物具有如通式为A或通式B的结构:
式中,当R1为甲基,R2为氢时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1为氢,R2为甲基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1、R2为甲氧基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟。
本发明至少包括以下有益效果:
1、本发明提供了一种类两面针碱-磺胺衍生物,其结构新颖,且底物适用性广、操作简便、副产物少、便于分离提纯、可适用于较大规模的制备,具有可观的应用前景;
2、本发明提供的类两面针碱-磺胺衍生物具有优异的抗肿瘤活性,化合物12h和12n对Hepg2、H460和HeLa细胞均具有显著的抑制增殖活性,在40μmol/L浓度下对上述细胞的抑制率均大于50%,且化合物12h、12n和13h对于H460细胞抑制率分别为82.39%、86.62%和88.98%,不仅优于阳性对照5-氟尿嘧啶(45.08%),还与其母核结构氯化两面针碱(86.68%)相当。
本发明的其它优点、目标和特征将部分通过下面的说明体现,部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
附图说明
图1为本发明在一个实施例中所述的类两面针碱-磺胺衍生物的结构式;
图2为本发明在另一个实施例中所述的类两面针碱-磺胺衍生物的制备方法的流程图。
具体实施方式
下面结合附图及实施例对本发明做进一步的详细说明,以令本领域技术人员参照说明书文字能够据以实施。
应当理解,本文所使用的诸如“具有”、“包含”以及“包括”术语并不排除一个或多个其它元件或其组合的存在或添加。
需要说明的是,下述实施方案中所述实验方法,如无特殊说明,均为常规方法,所述试剂和材料,如无特殊说明,均可从商业途径获得。
在本发明的描述中,术语“横向”、“纵向”、“上”、“下”、“前”、“后”、“左”、“右”、“竖直”、“水平”、“顶”、“底”、“内”、“外”等指示的方位或位置关系为基于附图所示的方位或位置关系,仅是为了便于描述本发明和简化描述,并不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和操作,因此不能理解为对本发明的限制。
<实施例1>
如图1所示,本发明提供一种类两面针碱-磺胺衍生物,其具有如图1中通式A和通式B的结构式;
图1中当R1为甲基,R2为氢时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1为氢,R2为甲基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1、R2为甲氧基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟。
<实施例2>
如图2所示,本发明提供一种类两面针碱-磺胺衍生物的制备方法,具体包括以下步骤:
步骤一、取150mL圆底烧瓶,称量加入甲氧胺盐酸盐(CH3ONH2·HCl)(0.835g,10mmol)及K2CO3(2.76g,20mmol),以60mL乙酸乙酯溶解后,置于0℃冷井中搅拌,缓慢加入15mL水后,分别加入含有化合物1(如化合物1a-1c:间甲基苯甲酰氯、对甲基苯甲酰氯、3,4-二甲氧基苯甲酰氯)(10mmol)的15mL乙酸乙酯溶液,搅拌5min后,转至室温搅拌5h,TLC监测反应(石油醚:乙酸乙酯=1:1),反应结束后,收集乙酸乙酯层,水层用乙酸乙酯(3×20mL)萃取分液,合并有机层并用无水Na2SO4干燥,减压蒸馏得化合物2(如化合物2a-2c);
步骤二、在N2保护下,取100mL圆底烧瓶加入化合物2(2a-2c)(8mmol),碘苯(1.79mL,16mmol),醋酸钯(0.334g,0.4mmol),氧化银(3.708g,16mmol),以60mL的醋酸溶解,120℃下搅拌回流26h,TLC监测反应(石油醚:乙酸乙酯=2:1),反应结束后,加入100mL的乙酸乙酯溶液,抽滤除去褐色不溶物,将所得棕黑色滤液以适量饱和NaHCO3洗涤至pH为7左右后,再以水洗涤,分液萃取,有机相以无水Na2SO4干燥后浓缩,残余物通过层析柱分离纯化(石油醚:乙酸乙酯=4:1)得化合物3(3a-3c);
步骤三、取50mL的西林瓶,加入化合物3(3a-3c)(1.4mmol),以45mL的无水甲醇溶解后置于175W紫外线高压汞灯下照射8h,TLC监测反应(石油醚:乙酸乙酯=1:1),反应结束后,直接减压蒸馏得化合物4(4a-4c);
步骤四、取50mL的圆底烧瓶,加入化合物4(4a-4c)(0.86mmol)和氢化钠(60%,0.105g,2.7mmol),溶于20mLDMF,室温下搅拌1h,再加入1,4-二溴丁烷(0.516mL,4.3mmol)或1,6-二溴己烷(0.696mL,4.3mmol),室温搅拌6h,TLC监测反应(石油醚:乙酸乙酯=2:1),反应结束后,用冰水淬灭,乙酸乙酯(3×10mL)萃取,合并有机相并用饱和氯化钠溶液洗涤,无水Na2SO4干燥后浓缩,残余物通过层析柱分离纯化(洗脱剂为石油醚:乙酸乙酯=5:1)到化合物5(5a-5c)或6(6a-6c);
步骤五、在电磁搅拌下,将化合物5(5a-5c)或6(6a-6c)(2mmol)溶于20mL乙腈中,并加入邻苯二甲酰亚胺(0.294g,2mmol),碘化钾(0.0332g,0.2mmol)和碳酸钾(0.829g,6mmol)。将混合物在80℃下回流搅拌6h,TLC监测反应(石油醚:乙酸乙酯=2:1),反应结束后,加入30mL饱和NaHCO3溶液,然后用乙酸乙酯萃取(3×10mL),合并有机相用2N HCl酸化并用水洗涤,用4N NaOH溶液将pH调节至12,然后用二氯甲烷萃取,无水硫酸钠干燥,浓缩得化合物7(7a-7c)或8(8a-8c);
步骤六、在电磁搅拌下,将化合物7(7a-7c)或8(8a-8c)(3mmol)溶于30mL 40%的甲胺水溶液,室温下搅拌36h,TLC监测反应(二氯甲烷:甲醇=90:1),反应结束后,添加20mL、20%(质量浓度)NaOH溶液,室温搅拌搅拌1.5h。然后加入4g氯化钠,溶液用二氯甲烷(3×10mL)萃取,合并有机相并用水洗涤,无水硫酸钠干燥,浓缩得化合物9(9a-9c)或10(10a-10c);
步骤七、将化合物9(9a-9c)或10(10a-10c)(0.5mmol)和三乙胺(0.5mL,3.6mmol)溶于15mL二氯甲烷中,0℃下加入苯磺酰氯化合物11(11a-11e)(苯磺酰氯或对甲苯磺酰氯或2,4,6-三甲氧基苯磺酰氯或3,4-二氯苯磺酰氯或3-氟苯磺酰氯)(0.5mmol),移至室温搅拌3h,TLC监测反应(二氯甲烷:甲醇=90:1),反应结束后,减压蒸馏除去溶剂和三乙胺,然后将得到的沉淀物溶解在10mL的二氯甲烷中,随后用5%(质量浓度)NaHCO3溶液(10mL)和水(10mL)洗涤,有机水层经无水硫酸钠干燥,滤液浓缩;用二氯甲烷/甲醇重结晶得(通式A)化合物12(12a-12o)或(通式B)化合物(13a-13o)。
化合物12a~12o以及化合物13a~13o的具体结构式以及特性表征如下所示:
12a:白色针晶,产率68%,m.p.150.1-151.6℃;HRMS(ESI)m/z:calcd forC24H24N2O3S[M+H]+:421.1587,found:421.1586.1H NMR(500MHz,CDCl3)δ8.31(s,1H),8.26(d,J=7.8Hz,1H),8.17(d,J=8.3Hz,1H),7.88(d,J=7.3Hz,2H),7.58(d,J=7.3Hz,1H),7.54–7.50(m,2H),7.47(t,J=7.4Hz,2H),7.36(d,J=8.4Hz,1H),7.31(t,J=7.5Hz,1H),5.13(t,J=6.0Hz,1H,-NH),4.37(t,J=7.2Hz,2H,-NCH2),3.09(q,J=6.6Hz,2H,-SCH2),2.52(s,3H),1.86–1.80(m,2H),1.69–1.64(m,2H).13C NMR(126MHz,CDCl3)δ161.78,140.12,138.33,136.55,134.08,132.66,131.26,129.35,129.20,128.67,127.15,125.23,123.42,122.64,121.77,119.81,115.08,42.95,41.84,26.67,24.77,21.52.
12b:白色针晶,产率63%,m.p.161.5-163.8℃;HRMS(ESI)m/z:calcd forC25H26N2O3S[M+H]+:435.1747,found:435.1742.1HNMR(500MHz,CDCl3)δ8.33(d,J=10.6Hz,1H),8.30–8.25(m,1H),8.18(dd,J=11.1,8.4Hz,1H),7.77(dd,J=11.2,8.3Hz,2H),7.59(t,J=9.2Hz,1H),7.53(dd,J=18.1,7.9Hz,1H),7.41–7.35(m,1H),7.35–7.27(m,3H),5.09–4.94(m,1H,-NH),4.38(d,J=6.9Hz,2H,-NCH2),3.07(dq,J=13.0,6.6Hz,2H,-SCH2),2.53(d,J=11.3Hz,3H),2.40(d,J=11.3Hz,3H),1.89–1.80(m,2H),1.68–1.64(m,2H).13CNMR(126MHz,CDCl3)δ161.76,143.42,138.31,137.10,136.58,134.06,131.26,129.81,129.35,128.67,127.23,125.26,123.42,122.62,121.77,119.80,115.09,42.92,41.89,26.73,24.76,21.63,21.52.
12c:白色针晶,产率60%,m.p.160.1-161.1℃;HRMS(ESI)m/z:calcd forC27H30N2O3S[M+Na]+:485.1881,found:485.1875.1H NMR(500MHz,CDCl3)δ8.31(s,1H),8.27(d,J=7.4Hz,1H),8.17(d,J=8.3Hz,1H),7.60–7.56(m,1H),7.52(dd,J=11.5,4.2Hz,1H),7.35(d,J=8.4Hz,1H),7.31(t,J=7.5Hz,1H),6.91(s,2H),4.96(t,J=6.2Hz,1H,-NH),4.37(t,J=7.2Hz,2H,-NCH2),3.01(q,J=6.7Hz,2H,-SCH2),2.63(s,6H),2.52(s,3H),2.25(s,3H),1.84–1.78(m,2H),1.67–1.62(m,2H).13C NMR(126MHz,CDCl3)δ161.74,142.19,139.12,138.31,136.59,134.05,132.08,131.25,129.33,128.67,125.28,123.43,122.60,121.77,119.81,115.07,42.35,41.90,26.82,24.88,23.14,21.53,21.03.
12d:白色针晶,产率66%,m.p.167.8-168.8℃;HRMS(ESI)m/z:calcd forC24H22Cl2N2O3S[M+H]+:489.0810,found:489.0806.1H NMR(500MHz,CDCl3)δ8.32(s,1H),8.27(d,J=8.0Hz,1H),8.17(d,J=8.3Hz,1H),8.02(d,J=1.7Hz,1H),7.73(dd,J=8.4,1.8Hz,1H),7.59(d,J=8.3Hz,1H),7.55(d,J=8.4Hz,1H),7.52(t,J=7.8Hz,1H),7.37(d,J=8.4Hz,1H),7.32(t,J=7.6Hz,1H),5.77(t,J=5.9Hz,1H,-NH),4.38(t,J=6.9Hz,2H,-NCH2),3.12(q,J=6.3Hz,2H,-SCH2),2.52(s,3H),1.91–1.84(m,2H),1.68(dt,J=13.9,6.9Hz,2H).13C NMR(126MHz,CDCl3)δ161.96,140.27,138.42,137.35,136.49,134.19,133.79,131.30,131.23,129.36,129.26,128.68,126.32,125.15,123.50,122.77,121.81,119.90,115.04,43.04,41.79,26.34,24.91,21.51.
12e:白色针晶,产率64%,m.p.147.6-148.5℃;HRMS(ESI)m/z:calcd forC24H23FN2O3S[M+H]+:439.1498,found:439.1492.1H NMR(500MHz,CDCl3)δ8.31(s,1H),8.26(d,J=7.9Hz,1H),8.16(d,J=8.3Hz,1H),7.68(d,J=7.8Hz,1H),7.60(dd,J=16.7,7.8Hz,2H),7.52(t,J=7.6Hz,1H),7.46(td,J=8.0,5.4Hz,1H),7.36(d,J=8.4Hz,1H),7.31(t,J=7.5Hz,1H),7.22(td,J=8.3,2.1Hz,1H),5.49(t,J=5.9Hz,1H,-NH),4.38(t,J=7.2Hz,2H,-NCH2),3.12(q,J=6.5Hz,2H,-SCH2),2.52(s,3H),1.89–1.82(m,2H),1.71–1.65(m,2H).13C NMR(126MHz,CDCl3)δ163.56,161.87,161.56,142.35,138.38,136.48,134.14,131.26,131.02,130.95,129.35,128.67,125.16,123.45,122.93,122.91,122.71,121.78,119.91,119.84,119.74,115.05,114.69,114.50,43.01,41.79,26.47,24.83,21.51.
12f:白色固体,产率69%,m.p.179.3-182.2℃;HRMS(ESI)m/z:calcd forC24H24N2O3S[M+H]+:421.1590,found:421.1586.1H NMR(500MHz,CDCl3)δ8.40(d,J=8.1Hz,1H),8.29(d,J=8.0Hz,1H),8.06(s,1H),7.88(d,J=7.8Hz,2H),7.52(dd,J=14.3,6.9Hz,2H),7.47(t,J=7.4Hz,2H),7.40(d,J=8.1Hz,1H),7.36(d,J=8.3Hz,1H),7.31(t,J=7.6Hz,1H),5.17(d,J=5.5Hz,1H,-NH),4.35(t,J=7.1Hz,2H,-NCH2),3.08(dd,J=13.0,6.5Hz,2H,-SCH2),2.57(s,3H),1.86–1.79(m,2H),1.66(s,1H),1.40(t,J=7.3Hz,1H).13CNMR(126MHz,CDCl3)δ161.74,143.22,140.19,137.08,133.70,132.63,129.71,129.58,129.19,128.94,127.15,123.61,123.16,122.54,121.77,119.64,115.13,46.06,42.97,41.81,26.73,24.80,22.32.
12g:白色固体,产率63%,m.p.133.3-136.5℃;HRMS(ESI)m/z:calcd forC25H26N2O3S[M+H]+:435.1740,found:435.1742.1H NMR(500MHz,CDCl3)δ8.39(d,J=8.1Hz,1H),8.29(d,J=7.4Hz,1H),8.06(s,1H),7.75(d,J=8.2Hz,2H),7.56–7.51(m,1H),7.38(dd,J=17.1,8.2Hz,2H),7.31(t,J=7.5Hz,1H),7.27(s,1H),5.05(t,J=6.2Hz,1H,-NH),4.35(t,J=7.3Hz,2H,-NCH2),3.05(q,J=6.6Hz,2H,-SCH2),2.57(s,3H),2.38(s,3H),1.83(dt,J=15.1,7.4Hz,2H),1.68(d,J=7.0Hz,1H),1.63(d,J=6.9Hz,1H).13C NMR(126MHz,CDCl3)δ161.60,143.29,143.08,137.01,136.98,133.58,129.69,129.59,129.46,128.82,127.11,123.49,123.06,122.41,121.66,119.52,115.01,42.81,41.73,26.65,24.67,22.20,21.50.
12h:白色固体,产率64%,m.p.200.1-203.3℃;HRMS(ESI)m/z:calcd forC27H30N2O3S[M+H]+:463.2056,found:463.2055.1H NMR(500MHz,CDCl3)δ8.39(d,J=8.1Hz,1H),8.30(d,J=7.3Hz,1H),8.06(s,1H),7.53(t,J=7.2Hz,1H),7.45–7.37(m,2H),7.35(d,J=8.4Hz,1H),7.31(t,J=7.7Hz,1H),6.91(s,1H),5.01(t,J=6.3Hz,1H,-NH),4.36(t,J=7.2Hz,2H,-NCH2),3.01(q,J=6.7Hz,2H,-SCH2),2.63(s,6H),2.57(s,3H),2.25(s,3H),1.81(dt,J=15.1,7.5Hz,2H),1.65(d,J=7.2Hz,1H),1.61(d,J=7.1Hz,1H).13C NMR(126MHz,CDCl3)δ161.58,143.08,142.04,139.01,137.00,133.58,131.95,129.56,129.46,128.83,123.50,123.08,122.39,121.65,119.53,114.98,42.24,41.73,26.72,24.78,23.00,22.20,20.90.
12i:白色固体,产率68%,m.p.150.4-153.2℃;HRMS(ESI)m/z:calcd forC24H22Cl2N2O3S[M+H]+:489.0810,found:489.0806.1H NMR(500MHz,CDCl3)δ8.39(d,J=8.1Hz,1H),8.31–8.27(m,1H),8.06(s,1H),8.01(d,J=2.1Hz,1H),7.72(dd,J=8.4,2.1Hz,1H),7.56–7.54(m,1H),7.53(dd,J=8.5,1.3Hz,1H),7.40(d,J=7.5Hz,1H),7.37(d,J=8.4Hz,1H),7.32(t,J=7.6Hz,1H),5.82(t,J=6.0Hz,1H,-NH),4.37(t,J=7.2Hz,2H,-NCH2),3.11(dd,J=12.8,6.5Hz,2H,-SCH2),2.57(s,3H),1.90–1.84(m,2H),1.73–1.67(m,2H).13C NMR(126MHz,CDCl3)δ161.90,143.36,140.22,137.33,136.97,133.76,133.71,131.23,129.72,129.65,129.24,128.94,126.31,123.67,123.02,122.67,121.81,119.70,115.09,43.02,41.74,26.37,24.89,22.34.
12j:类白色固体,产率70%,m.p.173.2-175.6℃;HRMS(ESI)m/z:calcd forC24H23FN2O3S[M+H]+:439.1510,found:439.1508..1H NMR(500MHz,CDCl3)δ8.40(d,J=9.1Hz,1H),8.29(d,J=8.1Hz,1H),8.06(s,1H),7.68(d,J=7.8Hz,1H),7.61(dd,J=8.2,1.5Hz,1H),7.53(t,J=7.8Hz,1H),7.46(dd,J=13.8,6.2Hz,1H),7.40(d,J=8.1Hz,1H),7.36(d,J=8.5Hz,1H),7.31(t,J=7.6Hz,1H),7.22(t,J=8.3Hz,1H),5.47(t,J=5.5Hz,1H,-NH),4.36(t,J=7.0Hz,2H,-NCH2),3.13–3.09(m,2H,-SCH2),2.57(s,3H),1.88–1.82(m,2H),1.68–1.64(m,2H).13C NMR(126MHz,CDCl3)δ163.57,161.84,143.31,142.36,137.04,133.71,131.02,130.96,129.72,129.63,128.96,123.66,123.11,122.94,122.91,122.62,121.79,119.90,119.73,119.69,115.10,114.70,114.51,43.02,41.75,26.54,24.85,22.34.
12k:白色固体,产率70%,m.p.186.6-188.4℃;HRMS(ESI)m/z:calcd forC25H26N2O5S[M+H]+:467.1643,found:467.1641.1H NMR(500MHz,CDCl3)δ8.16(d,J=7.7Hz,1H),7.89(d,J=3.6Hz,2H),7.87(s,1H),7.59(s,1H),7.55–7.50(m,2H),7.47(t,J=7.4Hz,2H),7.37(d,J=8.4Hz,1H),7.31(t,J=7.5Hz,1H),5.15(t,J=6.1Hz,1H,-NH),4.37(t,J=7.2Hz,2H,-NCH2),4.09(s,3H,-OCH3),4.03(s,3H,-OCH3),3.09(q,J=6.6Hz,2H,-SCH2),1.87–1.80(m,2H),1.66(dd,J=14.3,7.0Hz,2H).13C NMR(126MHz,CDCl3)δ161.20,153.55,150.02,140.22,136.46,132.63,129.19,128.97,128.52,127.15,123.08,122.47,119.52,119.45,115.18,109.05,102.64,56.34,56.28,43.02,41.92,26.76,24.93.
12l:白色固体,产率73%,m.p.189.3-192.4℃;HRMS(ESI)m/z:calcd forC26H28N2O5S[M+H]+:481.1802,found:481.1797.1H NMR(500MHz,CDCl3)δ8.16(d,J=7.6Hz,1H),7.89(s,1H),7.75(d,J=8.2Hz,2H),7.59(s,1H),7.51(dd,J=11.4,4.1Hz,1H),7.37(d,J=8.4Hz,1H),7.31(t,J=7.6Hz,1H),7.27(s,1H),5.04(t,J=6.1Hz,1H,-NH),4.37(t,J=7.3Hz,2H,-NCH2),4.09(s,3H,-OCH3),4.03(s,3H,-OCH3),3.06(q,J=6.6Hz,2H,-SCH2),2.39(s,3H),1.86–1.80(m,2H),1.70–1.65(m,2H).13C NMR(126MHz,CDCl3)δ161.19,153.53,150.00,143.42,137.15,136.47,129.81,128.97,128.52,127.23,123.08,122.47,119.51,119.46,115.19,109.04,102.63,56.34,56.28,42.97,41.96,26.79,24.91,21.62.
12m:白色固体,产率69%,m.p.169.2-171.3℃;HRMS(ESI)m/z:calcd forC28H32N2O5S[M+H]+:509.2115,found:509.2110.1H NMR(500MHz,CDCl3)δ8.17(d,J=7.4Hz,1H),7.89(s,1H),7.60(s,1H),7.53–7.49(m,1H),7.36(d,J=8.4Hz,1H),7.32(t,J=7.6Hz,1H),6.91(s,2H),5.00(t,J=6.2Hz,1H,-NH),4.38(t,J=7.2Hz,2H,-NCH2),4.09(s,3H,-OCH3),4.03(s,3H,-OCH3),3.01(q,J=6.6Hz,2H,-SCH2),2.63(s,6H),2.26(s,3H),1.85–1.78(m,2H),1.68–1.63(m,2H).13C NMR(126MHz,CDCl3)δ161.19,153.54,150.00,142.18,139.13,136.49,133.85,132.07,128.95,128.52,123.10,122.45,119.52,119.48,115.17,109.05,102.64,56.31,56.29,42.38,41.95,26.87,25.02,23.13,21.02.
12n:白色固体,产率72%,m.p.172.8-174.6℃;HRMS(ESI)m/z:calcd forC25H24Cl2N2O5S[M+H]+:535.0864,found:535.0861.1H NMR(500MHz,CDCl3)δ8.08(d,J=7.9Hz,1H),7.91(s,1H),7.79(s,1H),7.62(d,J=8.4Hz,1H),7.49(s,1H),7.44(dd,J=20.5,8.3Hz,2H),7.29(d,J=8.4Hz,1H),7.23(t,J=7.5Hz,1H),5.70(s,1H,-NH),4.29(s,2H,-NCH2),4.01(s,3H,-OCH3),3.94(s,3H,-OCH3),3.03(d,J=6.0Hz,2H,-SCH2),1.83–1.73(m,2H),1.63–1.57(m,2H).13C NMR(126MHz,CDCl3)δ161.35,153.62,150.05,140.22,137.35,136.35,133.78,131.21,129.22,128.98,128.56,126.30,123.15,122.61,119.57,119.31,115.13,108.98,102.63,56.36,56.29,43.08,41.85,26.37,25.02.
12o:白色固体,产率75%,m.p.178.6-181.8℃;HRMS(ESI)m/z:calcd forC25H25FN2O5S[M+H]+:485.1544,found:485.1546.1H NMR(500MHz,CDCl3)δ8.16(d,J=7.9Hz,1H),7.88(s,1H),7.68(d,J=7.8Hz,1H),7.61(dd,J=8.2,2.1Hz,1H),7.58(s,1H),7.51(t,J=7.8Hz,1H),7.46(td,J=8.1,5.3Hz,1H),7.37(d,J=8.5Hz,1H),7.32(t,J=7.6Hz,1H),7.23(td,J=8.3,2.1Hz,1H),5.53(t,J=6.0Hz,1H,-NH),4.38(t,J=7.1Hz,2H,-NCH2),4.09(s,3H,-OCH3),4.03(s,3H,-OCH3),3.11(q,J=6.5Hz,2H,-SCH2),1.89–1.83(m,2H),1.69–1.65(m,2H).13C NMR(126MHz,CDCl3)δ163.57,161.57,161.29,153.58,150.02,142.41,142.36,136.38,130.99,130.93,128.97,128.53,123.11,122.93,122.90,122.55,119.89,119.72,119.54,119.36,115.15,114.68,114.49,109.00,102.61,56.34,56.28,43.09,41.88,26.52,25.00.
13a:白色固体,产率71%,m.p.163.3-164.5℃;HRMS(ESI)m/z:calcd forC26H28N2O3S[M+H]+:449.1900,found:449.1899.1H NMR(500MHz,CDCl3)δ8.36(s,1H),8.28(d,J=7.4Hz,1H),8.18(d,J=8.3Hz,1H),7.91–7.84(m,2H),7.58(dd,J=8.2,1.4Hz,1H),7.56–7.51(m,2H),7.51–7.47(m,2H),7.37(d,J=8.4Hz,1H),7.31(t,J=7.5Hz,1H),4.86(t,J=5.9Hz,1H,-NH),4.37(t,J=7.1Hz,2H,-NCH2),2.97(q,J=6.6Hz,2H,-SCH2),2.52(s,3H),1.80–1.73(m,2H),1.52–1.46(m,2H),1.44–1.38(m,4H).13C NMR(126MHz,CDCl3)δ161.75,140.33,138.35,136.70,134.00,132.62,131.23,129.22,129.19,128.77,127.14,125.37,123.40,122.49,121.74,119.84,115.18,42.97,42.22,29.41,27.32,26.14,25.94,21.53.
13b:白色固体,产率66%,m.p.105.3-107.2℃;HRMS(ESI)m/z:calcd forC27H30N2O3S[M+H]+:463.2060,found:463.2055.1H NMR(500MHz,CDCl3)δ8.36(s,1H),8.28(d,J=7.9Hz,1H),8.18(d,J=8.3Hz,1H),7.75(d,J=8.1Hz,2H),7.58(d,J=7.9Hz,1H),7.52(t,J=7.6Hz,1H),7.37(d,J=8.4Hz,1H),7.29(t,J=7.5Hz,3H),4.77(t,J=5.9Hz,1H,-NH),4.38(d,J=6.8Hz,2H,-NCH2),2.94(dd,J=13.1,6.6Hz,2H,-SCH2),2.52(s,3H),2.40(s,3H),1.76(s,2H),1.48(d,J=5.5Hz,2H),1.41(d,J=7.0Hz,4H).13C NMR(126MHz,CDCl3)δ161.71,143.35,138.32,137.29,136.72,133.98,131.23,129.79,129.22,128.75,127.21,125.38,123.39,122.48,121.74,119.83,115.17,45.98,42.99,42.29,29.44,27.33,26.22,26.04,21.63,21.52.
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13c:白色固体,产率72%,m.p.122.3-124.5℃;HRMS(ESI)m/z:calcd forC29H34N2O3S[M+H]+:491.2362,found:491.2368.1H NMR(500MHz,CDCl3)δ8.35(d,J=8.4Hz,1H),8.28(t,J=8.5Hz,1H),8.18(t,J=8.7Hz,1H),7.59(t,J=8.2Hz,1H),7.52(dd,J=16.0,7.7Hz,1H),7.37(t,J=8.7Hz,1H),7.31(dd,J=16.6,8.5Hz,1H),6.95(d,J=9.0Hz,2H),4.69(d,J=7.8Hz,1H,-NH),4.37(d,J=6.7Hz,2H,-NCH2),3.00–2.83(m,2H,-SCH2),2.65(d,J=9.1Hz,6H),2.53(d,J=9.1Hz,3H),2.28(d,J=9.1Hz,3H),1.76(d,J=6.8Hz,2H),1.48(d,J=6.0Hz,2H),1.40(d,J=5.0Hz,4H).13C NMR(126MHz,CDCl3)δ161.54,142.08,139.06,138.19,136.63,133.85,133.75,131.96,131.11,129.09,128.62,125.29,123.28,122.34,121.63,119.71,115.02,45.92,42.31,42.22,29.38,27.22,26.20,26.11,23.03,21.41,20.93.
13d:白色固体,产率70%,m.p.156.5-157.3℃;HRMS(ESI)m/z:calcd forC26H26Cl2N2O3S[M+H]+:517.1122,found:517.1119.1H NMR(500MHz,CDCl3)δ8.38(s,1H),8.29(d,J=7.8Hz,1H),8.19(d,J=8.3Hz,1H),7.99(d,J=2.0Hz,1H),7.72(dd,J=8.4,2.0Hz,1H),7.58(dd,J=11.7,8.4Hz,2H),7.52(t,J=7.4Hz,1H),7.39(d,J=8.4Hz,1H),7.32(t,J=7.5Hz,1H),5.36(t,J=5.9Hz,1H,-NH),4.41(t,J=6.6Hz,2H,-NCH2),3.00(q,J=6.2Hz,2H,-SCH2),2.53(s,3H),1.81(p,J=7.0Hz,2H),1.53–1.46(m,4H),1.40(dd,J=13.7,6.7Hz,2H).13C NMR(126MHz,CDCl3)δ161.96,140.56,138.47,137.26,136.61,134.12,133.74,131.27,131.21,129.24,129.16,128.80,126.27,125.26,123.43,122.60,121.77,119.91,115.23,42.81,41.96,29.20,27.26,25.73,25.52,21.54.
13e:白色固体,产率74%,m.p.158.6-160.3℃;HRMS(ESI)m/z:calcd forC26H27FN2O3S[M+H]+:467.1811,found:467.1805.1H NMR(500MHz,CDCl3)δ8.38(d,J=6.8Hz,1H),8.29(t,J=7.6Hz,1H),8.19(t,J=7.8Hz,1H),7.69(t,J=7.3Hz,1H),7.63–7.58(m,2H),7.54–7.46(m,2H),7.38(t,J=7.9Hz,1H),7.32(dd,J=15.2,7.8Hz,1H),7.27(s,1H),5.15(d,J=6.0Hz,1H,-NH),4.40(d,J=6.4Hz,2H,-NCH2),3.00(dd,J=13.2,6.6Hz,2H,-SCH2),2.53(d,J=7.4Hz,3H),1.79(dd,J=14.1,7.1Hz,2H),1.54–1.49(m,2H),1.48–1.39(m,4H).13C NMR(126MHz,CDCl3)δ163.56,161.86,161.57,142.60,139.07,138.41,136.65,134.05,131.25,131.00,130.94,129.23,128.79,125.32,123.41,122.90,122.55,121.75,119.88,119.69,119.08,115.20,114.64,114.45,42.90,42.07,29.31,27.28,25.92,25.70,21.52.
13f:白色固体,产率72%,m.p.156.5-157.3℃;HRMS(ESI)m/z:calcd forC26H28N2O3S[M+H]+:449.1898,found:449.1899.1H NMR(500MHz,CDCl3)δ8.43(d,J=8.1Hz,1H),8.30(d,J=8.0Hz,1H),8.07(s,1H),7.91–7.86(m,2H),7.54(d,J=7.3Hz,2H),7.50(d,J=7.6Hz,2H),7.40(d,J=8.2Hz,1H),7.36(d,J=8.5Hz,1H),7.31(t,J=7.6Hz,1H),4.87(d,J=5.6Hz,1H,-NH),4.37(d,J=6.5Hz,2H,-NCH2),2.97(dd,J=12.6,6.1Hz,2H,-SCH2),2.57(s,3H),1.79–1.73(m,2H),1.48(d,J=6.3Hz,2H),1.40(s,4H).13C NMR(126MHz,CDCl3)δ161.72,143.12,140.43,137.25,133.69,132.61,129.61,129.58,129.19,129.05,127.16,123.60,123.31,122.41,121.75,119.70,115.21,42.97,42.15,29.44,27.34,26.14,25.93,22.32.
13g:白色固体,产率70%,m.p.150.1-152.2℃;HRMS(ESI)m/z:calcd forC27H30N2O3S[M+H]+:463.2053,found:463.2055.1H NMR(500MHz,CDCl3)δ8.43(d,J=8.1Hz,1H),8.30(d,J=8.1Hz,1H),8.07(s,1H),7.75(d,J=7.9Hz,2H),7.53(t,J=7.8Hz,1H),7.40(d,J=8.2Hz,1H),7.36(d,J=8.5Hz,1H),7.29(t,J=7.2Hz,3H),4.74(t,J=6.0Hz,1H,-NH),4.36(t,J=7.0Hz,2H,-NCH2),2.95(q,J=6.5Hz,2H,-SCH2),2.57(s,3H),2.40(s,3H),1.79–1.73(m,2H),1.48(d,J=5.9Hz,2H),1.40(s,4H).13C NMR(126MHz,CDCl3)δ161.69,143.37,143.10,137.27,133.69,129.80,129.59,129.04,127.23,123.60,123.33,122.39,121.75,119.69,115.20,42.99,42.21,29.47,27.36,26.23,26.03,22.31,21.63.
13h:白色固体,产率77%,m.p.163.2-164.6℃;HRMS(ESI)m/z:calcd forC29H34N2O3S[M+H]+:491.2368,found:491.2368.1H NMR(500MHz,CDCl3)δ8.42(d,J=8.1Hz,1H),8.30(d,J=8.0Hz,1H),8.07(s,1H),7.53(t,J=7.7Hz,1H),7.40(d,J=8.1Hz,1H),7.36(d,J=8.5Hz,1H),7.31(t,J=7.5Hz,1H),6.94(s,2H),4.66(s,1H,-NH),4.40–4.29(m,2H,-NCH2),2.90(dd,J=12.8,6.3Hz,2H,-SCH2),2.64(s,6H),2.57(s,3H),2.27(s,3H),1.79–1.71(m,2H),1.49–1.45(m,2H),1.39(d,J=3.2Hz,4H).13C NMR(126MHz,CDCl3)δ161.62,143.07,142.18,139.19,137.30,133.68,132.07,129.58,129.02,123.60,122.36,121.75,119.68,115.17,42.45,42.27,29.52,27.35,26.34,26.23,23.12,22.31,21.03.
13i:白色固体,产率66%,m.p.128.6-129.3℃;HRMS(ESI)m/z:calcd forC26H26Cl2N2O3S[M+H]+:517.1124,found:517.1119.1H NMR(500MHz,CDCl3)δ8.44(d,J=8.1Hz,1H),8.31(d,J=7.3Hz,1H),8.08(s,1H),8.00(d,J=2.0Hz,1H),7.72(dd,J=8.4,2.1Hz,1H),7.57(d,J=8.4Hz,1H),7.55–7.52(m,1H),7.41(d,J=8.1Hz,1H),7.39(d,J=8.4Hz,1H),7.32(t,J=7.5Hz,1H),5.44(t,J=6.0Hz,1H,-NH),4.40(t,J=6.5Hz,2H,-NCH2),3.00(q,J=6.2Hz,2H,-SCH2),2.57(s,3H),1.80(p,J=7.0Hz,2H),1.54–1.46(m,4H),1.39(dd,J=14.1,7.0Hz,2H).13C NMR(126MHz,CDCl3)δ161.94,143.27,140.66,137.24,137.14,133.73,131.21,129.71,129.60,129.17,129.05,126.29,123.63,123.18,122.52,121.78,119.76,115.28,42.77,41.85,29.25,27.27,25.68,25.47,22.33.
13j:白色固体,产率71%,m.p.120.3-121.9℃;HRMS(ESI)m/z:calcd forC26H27FN2O3S[M+H]+:467.1802,found:467.1805.1H NMR(500MHz,CDCl3)δ8.44(d,J=8.1Hz,1H),8.30(d,J=8.0Hz,1H),8.07(s,1H),7.68(d,J=7.8Hz,1H),7.61(d,J=8.2Hz,1H),7.53(t,J=7.8Hz,1H),7.48(td,J=8.0,5.5Hz,1H),7.41(d,J=8.2Hz,1H),7.37(d,J=8.5Hz,1H),7.31(t,J=7.6Hz,1H),7.24(dd,J=8.3,1.7Hz,1H),5.16(t,J=5.9Hz,1H,-NH),4.39(d,J=6.6Hz,2H,-NCH2),3.00(q,J=6.3Hz,2H,-SCH2),2.57(s,3H),1.78(dt,J=13.9,7.1Hz,2H),1.50(dd,J=13.3,6.8Hz,2H),1.47–1.37(m,4H).13C NMR(126MHz,CDCl3)δ163.58,161.83,161.59,143.20,137.19,133.71,131.00,130.94,129.66,129.59,129.06,123.62,123.25,122.92,122.46,121.76,119.85,119.73,119.68,115.25,114.66,114.47,42.88,41.98,29.35,27.30,25.89,25.68,22.33.
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13k:白色固体,产率75%,m.p.144.4-146.5℃;HRMS(ESI)m/z:calcd forC27H30N2O5S[M+H]+:495.1951,found:495.1954.1H NMR(500MHz,CDCl3)δ8.19(d,J=7.5Hz,1H),8.00(s,1H),7.91–7.87(m,2H),7.61(s,1H),7.56–7.51(m,2H),7.49(d,J=7.8Hz,2H),7.39(d,J=8.4Hz,1H),7.32(t,J=7.5Hz,1H),5.12(t,J=6.1Hz,1H,-NH),4.40(t,J=6.8Hz,2H,-NCH2),4.10(s,3H,-OCH3),4.04(s,3H,-OCH3),2.98(q,J=6.2Hz,2H,-SCH2),1.82–1.75(m,2H),1.50–1.42(m,4H),1.38(d,J=6.7Hz,2H).13C NMR(126MHz,CDCl3)δ161.36,153.56,150.13,140.52,136.59,132.57,129.17,128.83,128.48,127.15,123.08,122.38,119.62,115.30,109.30,102.61,56.47,56.29,42.78,42.12,29.23,27.46,25.93,25.73.
13l:白色固体,产率81%,m.p.150.1-152.2℃;HRMS(ESI)m/z:calcd forC28H32N2O5S[M+H]+:509.2114,found:509.2110.1H NMR(500MHz,CDCl3)δ8.19(d,J=7.9Hz,1H),8.00(s,1H),7.76(d,J=8.2Hz,2H),7.61(s,1H),7.51(t,J=7.8Hz,1H),7.39(d,J=8.4Hz,1H),7.32(t,J=7.6Hz,1H),7.28(d,J=8.1Hz,2H),4.96(t,J=6.1Hz,1H,-NH),4.40(t,J=6.9Hz,2H,-NCH2),4.10(s,3H,-OCH3),4.04(s,3H,-OCH3),2.95(q,J=6.3Hz,2H,-SCH2),2.40(s,3H),1.81–1.75(m,2H),1.50–1.43(m,4H),1.42–1.38(m,2H).13C NMR(126MHz,CDCl3)δ161.31,153.53,150.10,143.31,137.44,136.60,129.78,128.83,128.47,127.21,123.07,122.36,119.60,115.28,109.27,102.61,56.45,56.29,42.81,42.18,29.28,27.47,26.02,25.84,21.63.
13m:白色固体,产率80%,m.p.162.3-163.4℃;HRMS(ESI)m/z:calcd forC30H36N2O5S[M+H]+:537.2422,found:537.2423.1H NMR(500MHz,CDCl3)δ8.18(d,J=7.6Hz,1H),7.96(s,1H),7.61(s,1H),7.51(t,J=7.3Hz,1H),7.37(d,J=8.4Hz,1H),7.31(t,J=7.5Hz,1H),6.94(s,2H),4.38(t,J=7.1Hz,2H,-NCH2),4.10(s,3H,-OCH3),4.05(s,3H,-OCH3),2.90(t,J=6.5Hz,2H,-SCH2),2.64(s,6H),2.27(s,3H),1.79–1.74(m,2H),1.46(d,J=6.3Hz,2H),1.40(s,4H).13C NMR(126MHz,CDCl3)δ161.19,153.50,150.06,142.15,139.19,136.62,133.96,132.06,128.81,128.46,123.07,122.33,119.58,115.25,109.21,102.61,56.41,56.28,42.31,42.28,29.43,27.45,26.20,26.12,23.12,21.03.
13n:白色固体,产率76%,m.p.141.2-143.3℃;HRMS(ESI)m/z:calcd forC27H28Cl2N2O5S[M+H]+:563.1172,found:563.1174.1H NMR(500MHz,CDCl3)δ8.20(d,J=8.0Hz,1H),8.04(s,1H),8.00(d,J=2.1Hz,1H),7.74(dd,J=8.4,2.1Hz,1H),7.62(s,1H),7.56(d,J=8.4Hz,1H),7.52(t,J=7.8Hz,1H),7.41(d,J=8.4Hz,1H),7.33(t,J=7.5Hz,1H),5.72(t,J=6.1Hz,1H,-NH),4.44(s,2H,-NCH2),4.10(s,3H,-OCH3),4.05(s,3H,-OCH3),3.01(q,J=5.9Hz,2H,-SCH2),1.86–1.80(m,2H),1.52–1.47(m,4H),1.39–1.33(m,2H).13C NMR(126MHz,CDCl3)δ161.62,153.68,150.25,140.80,137.20,136.48,133.71,131.19,129.20,128.84,128.55,126.28,123.12,122.51,119.71,119.49,115.37,109.36,102.62,56.55,56.31,42.56,41.81,28.92,27.41,25.44,25.25.
13o:白色固体,产率79%,m.p.152.6-153.8℃;HRMS(ESI)m/z:calcd forC27H29FN2O5S8.02(s,1H),7.69(d,J=7.8Hz,1H),7.63–7.60(m,2H),7.51(t,J=7.8Hz,1H),7.47(td,J=8.1,5.3Hz,1H),7.40(d,J=8.4Hz,1H),7.32(t,J=7.6Hz,1H),7.23(dd,J=8.0,2.1Hz,1H),5.43(t,J=6.0Hz,1H,-NH),4.42(t,J=6.5Hz,2H,-NCH2),4.10(s,3H,-OCH3),4.05(s,3H,-OCH3),3.00(q,J=5.9Hz,2H,-SCH2),1.81(p,J=7.0Hz,2H),1.48(s,4H),1.41–1.36(m,2H).13C NMR(126MHz,CDCl3)δ163.56,161.56,161.46,153.60,150.17,142.80,136.52,130.97,130.91,128.83,128.50,123.09,122.90,122.88,122.44,119.79,119.65,119.62,119.53,115.33,114.65,114.46,109.30,102.60,56.49,56.29,42.70,41.96,29.07,27.41,25.68,25.48.
<实施例3>
类两面针碱-磺胺衍生物抗肿瘤活性实验
采用CCK-8法研究类两面针碱-磺胺衍生物对于人肝癌细胞(Hep G2)、人宫颈癌细胞(HeLa)、人肺癌细胞(H460)和人正常肝细胞(LO2)在40μmol/L浓度的抑制率,以5-氟尿嘧啶和氯化两面针碱作为阳性对照组。
(1)细胞培养:将冻存细胞取出,在37℃水浴锅中解冻完全,酒精消毒后放入超净台内,取洁净离心管,加入解冻细胞和适量含10%胎牛血清的培养液,离心,再加入适量10%培养液重悬成细胞悬液后移入培养瓶中培养,待12h后观察细胞状态。
(2)种板:待细胞密集生长在瓶底(约80%)时,去除培养基,以PBS缓冲液洗涤1-2次。用0.25%胰蛋白酶消化1-2min,加培养基终止消化后离心,去除上清,加入培养基制成细胞悬浮液。细胞计数板计数,以50000/mL细胞数,每孔100μL接种于96孔板中。
(3)加药:将上述合成的化合物12a~12o、13a~13o及阳性对照药品(5-氟尿嘧啶-5-Fu)和氯化两面针碱(NC),分别以DMSO充分溶解并配制成浓度为40μmol/L的样品,每个浓度设3个复孔,每孔100μL。空白对照组每孔100μL的1%DMEM培养基。细胞继续培养24h。
(4)测试:取出加药培养24h的96孔板,每孔加入10μLCCK-8试剂,避光孵育2h后,酶标仪450nm测定,抑制率公式见下:
细胞生长抑制率(%)=[(Ac-As)]/(Ac-Ab)]×100%
As:实验孔吸光度Ac:对照孔吸光度Ab:空白孔吸光度
经计算后,类两面针碱-磺胺衍生物对细胞的抑制率如表1所述:
表1类两面针碱-磺胺衍生物在40μmol/L浓度下对细胞的抑制率
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本发明提供的类两面针碱-磺胺衍生物经抗肿瘤实验得出表1数据,可以看出类两面针碱-磺胺衍生物具有一定的抗肿瘤作用,其中,化合物12h和12n对Hepg2、H460和HeLa细胞均具有显著的抑制增殖活性,在40μmol/L浓度下对上述细胞的抑制率均大于50%,且化合物12h、12n和13h对于H460细胞抑制率分别为82.39%、86.62%和88.98%,不仅优于阳性对照5-氟尿嘧啶(45.08%),还与氯化两面针碱(NC)(86.68%)相当。
这里说明的设备数量和处理规模是用来简化本发明的说明的。对本发明的应用、修改和变化对本领域的技术人员来说是显而易见的。
尽管本发明的实施方案已公开如上,但其并不仅仅限于说明书和实施方式中所列运用,它完全可以被适用于各种适合本发明的领域,对于熟悉本领域的人员而言,可容易地实现另外的修改,因此在不背离权利要求及等同范围所限定的一般概念下,本发明并不限于特定的细节和这里示出与描述的图例。
Claims (9)
1.类两面针碱-磺胺衍生物,其特征在于,该衍生物具有如通式为A或通式B的结构:
式中,当R1为甲基,R2为氢时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1为氢,R2为甲基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1、R2为甲氧基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟。
2.类两面针碱-磺胺衍生物的制备方法,其特征在于,包括以下步骤:
步骤一、以式1所示的酰氯化合物1和甲氧氨盐酸盐为原料,在碳酸钾的作用下和乙酸乙酯的溶剂中,合成式2所示的化合物2;
步骤二、将化合物2与碘苯、醋酸钯、氧化银溶解于醋酸中,在氮气保护下,反应合成如式3所示的化合物3;
步骤三、将化合物3溶解于无水甲醇中,在紫外灯照射下反应得如式4所示的化合物4;
步骤四、以化合物4和1,4-二溴丁烷或1,6-二溴己烷为原料,在氢化钠作用下和DMF溶剂中,合成得到如式5所示的化合物5或如式6所示的化合物6;
步骤五、将化合物5或化合物6与邻苯二甲酰亚胺,碘化钾和碳酸钾,在乙腈溶剂中,合成得如式7所示的化合物7或如式8所示的化合物8;
步骤六、将化合物7或化合物8溶于甲胺水溶液中,电磁搅拌,反应得到如式9所示的化合物9或如式10所示的化合物10;
步骤七、将化合物9或化合物10与式11所示的化合物11,在三乙胺的作用下和二氯甲烷的作用下,反应得到如式A所示的化合物12,或如式B所示的化合物13;
其中,当R1为甲基,R2为氢时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1为氢,R2为甲基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1、R2为甲氧基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟。
3.如权利要求2所述的类两面针碱-磺胺衍生物的制备方法,其特征在于,步骤一中,甲氧胺盐酸盐、碳酸钾、化合物1的摩尔比为1:2:1。
4.如权利要求2所述的类两面针碱-磺胺衍生物的制备方法,其特征在于,步骤二中,化合物2、碘苯、醋酸钯、氧化银的摩尔比为1:2:0.05:2。
5.如权利要求2所述的类两面针碱-磺胺衍生物的制备方法,其特征在于,步骤三中紫外灯选用175W紫外线高压汞灯。
6.如权利要求2所述的类两面针碱-磺胺衍生物的制备方法,其特征在于,步骤四中,化合物4、氢化钠、1,4-二溴丁烷或1,6-二溴己烷的摩尔比为1:3.14:5。
7.如权利要求2所述的类两面针碱-磺胺衍生物的制备方法,其特征在于,步骤五中,化合物5或化合物6、邻苯二甲酰亚胺、碘化钾、碳酸钾的摩尔比为1:1:0.1:3。
8.如权利要求2所述的类两面针碱-磺胺衍生物的制备方法,其特征在于,步骤六中,化合物9或化合物10、三乙胺、化合物11的摩尔比为1:7.2:1。
9.类两面针碱-磺胺衍生物在制备治疗肿瘤药物中的应用,其特征在于,该衍生物具有如通式为A或通式B的结构:
式中,当R1为甲基,R2为氢时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1为氢,R2为甲基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟;
当R1、R2为甲氧基时,R3、R4、R5、R6均为氢或R3、R5、R6为氢、R4为甲基或R3、R4、R6为甲氧基、R5为氢或R3、R6为氢、R4、R5为氯或R3、R4、R6为氢、R5为氟。
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