CN110156735B - 芒柄花黄素衍生物及其制备方法和应用 - Google Patents
芒柄花黄素衍生物及其制备方法和应用 Download PDFInfo
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- CN110156735B CN110156735B CN201910329582.0A CN201910329582A CN110156735B CN 110156735 B CN110156735 B CN 110156735B CN 201910329582 A CN201910329582 A CN 201910329582A CN 110156735 B CN110156735 B CN 110156735B
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- formononetin
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 73
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 73
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- 229940125898 compound 5 Drugs 0.000 claims description 44
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 42
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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Abstract
Description
技术领域
本发明属于药物化合物技术领域,尤其是涉及芒柄花黄素衍生物及其制备方法和应用。
背景技术
芒柄花黄素作为一种具有生物活性的异黄酮,具有多种药理学益处。它通过增加AP-1DNA的结合活性上调活化T细胞中白细胞介素-4的产生,从而证明了代谢作用。它还通过显着抑制HT-29人结肠癌细胞中的花生四烯酸释放而具有抗炎活性。芒柄花黄素还可以降低血压和中心动脉僵硬度,从而降低心血管风险。在多种癌症方面有一定的药理活性,如结肠癌,卵巢癌等。但是芒柄花黄素抗肿瘤活性并不突出,这也制约着芒柄花黄素在抗肿瘤领域的进一步发展。因此合成系列的芒柄花黄素衍生物,以期得到抗肿瘤活性更好的化合物,对临床应用具有深远的意义。
发明内容
有鉴于此,本发明旨在提出一种芒柄花黄素衍生物及其制备方法和应用,以克服现有技术的不足。
为达到上述目的,本发明的技术方案是这样实现的:
芒柄花黄素衍生物,其特征在于,具有以下结构:
R1选自以下结构中的一种:
n=1-9;
R2选自以下结构中的一种:
一种制备如上所述的芒柄花黄素衍生物的方法,包括以下步骤:
将芒柄花黄素溶解于有机溶剂中,加入无水K2CO3,抽真空氩气保护;随后将溴代炔烃缓慢加入,室温反应8-12小时,反应完成;将反应体系旋干除去大部分有机溶剂;加入水,用二氯甲烷进行萃取;有机相用无水硫酸钠干燥,减压、抽滤、浓缩得到粗品,硅胶柱层析纯化,得到化合物;
所述溴代炔烃包括3-溴丙炔、1-溴-2-丁炔、1-溴-2-戊炔中的一种;
所述有机溶剂为DMF(N,N-二甲基甲酰胺)、甲醇、四氢呋喃、乙腈中的一种或两种以上;
优选的,芒柄花黄素与溴代炔烃的摩尔比为1:1-1:2;优选的,1:1;所述无水K2CO3与芒柄花黄素的摩尔比为3:1-3:3,优选的,3:2。
一种制备如上所述的芒柄花黄素衍生物的方法,包括以下步骤:
将芒柄花黄素溶解于有机溶剂中,抽真空氩气保护;将DIPEA缓慢滴加到反应中,室温搅拌10-30分钟后,将反应体系移入50-75℃油浴搅拌回流;随后将溴乙酸酯类缓慢加入,继续反应10-16小时,反应完成;降至室温后,将反应体系旋干除去大部分有机溶剂;加入水,用二氯甲烷进行萃取;有机相用无水硫酸钠干燥、减压、抽滤、浓缩得到粗品,硅胶柱层析纯化;
所述溴乙酸脂类包括溴乙酸苯酯、溴乙酸苄酯中的一种;
所述有机溶剂为DMF(N,N-二甲基甲酰胺)、甲醇、四氢呋喃、乙腈中的一种或两种以上;
优选的,芒柄花黄素与溴乙酸酯类的摩尔比为1:1-1:2,优选的,1:1;所述DIPEA与芒柄花黄素的摩尔比为3:1-3:3,优选的,3:2。
一种制备如上所述的芒柄花黄素衍生物的方法,包括以下步骤,
将化合物5溶解于有机溶剂中,加入无水K2CO3,抽真空氩气保护;随后将溴代炔烃缓慢加入,室温反应8-12小时,反应完成将反应体系旋干除去大部分有机溶剂;加入水,用二氯甲烷进行萃取,;有机相用无水硫酸钠干燥,减压、抽滤,浓缩得到粗品硅胶柱层析纯化,得到化合物;
所述溴代炔烃包括3-溴丙炔、1-溴-2-丁炔、1-溴-2-戊炔中的一种;且化合物5与溴代炔烃的摩尔比为1:0.8-1:1;优选的,1:1;
所述有机溶剂为DMF(N,N-二甲基甲酰胺)、甲醇、四氢呋喃、乙腈中的一种或两种以上;
一种制备如上所述的芒柄花黄素衍生物的方法,包括以下步骤,
将化合物5溶解于有机溶剂中,抽真空氩气保护;将DIPEA缓慢滴加到反应中,搅拌10-30分钟后将反应体系移入油浴中,50-75℃搅拌回流;随后将溴酸酯类缓慢加入,反应12-16小时,反应完成降至室温,将反应体系旋干除去大部分有机溶剂;加入水,用二氯甲烷进行萃取;有机相用无水硫酸钠干燥,减压、抽滤,浓缩得到粗品,硅胶柱层析纯化;
所述溴酸酯类包括溴乙酸苯酯、溴代乙酸叔丁酯、2-溴丙酸乙酯中的一种;
所述有机溶剂为DMF(N,N-二甲基甲酰胺)、甲醇、四氢呋喃、乙腈中的一种或两种以上;
一种制备如上所述的芒柄花黄素衍生物的方法,包括以下步骤,
将化合物5溶解于有机溶剂中,加入无水K2CO3,抽真空氩气保护;随后将卤代烃缓慢加入,室温反应8-12小时,反应完成将反应体系旋干除去大部分有机溶剂;加入水,用二氯甲烷进行萃取;有机相用无水硫酸钠干燥,减压、抽滤,浓缩得到粗品硅胶柱层析纯化,得到化合物;
所述卤代烃包括1-溴-2-丁炔、乙酰氯中的一种;且化合物5与卤代烃的摩尔比为1:1.5-1:3;优选的,1:1.5;
所述有机溶剂为DMF(N,N-二甲基甲酰胺)、甲醇、四氢呋喃、乙腈中的一种或两种以上;
一种制备如上所述的芒柄花黄素衍生物的方法,包括以下步骤,
将化合物5溶解于有机溶剂中,抽真空氩气保护;用微量注射器将DIPEA缓慢滴加到反应中,搅拌10-30分钟后将反应体系移入油浴中,50-75℃搅拌回流;随后将溴酸酯类缓慢加入,反应12-16小时,反应完成降至室温,将反应体系旋干除去大部分有机溶剂;加入水,用二氯甲烷进行萃取,;有机相用无水硫酸钠干燥,减压、抽滤,浓缩得到粗品,硅胶柱层析纯化;
所述溴酸酯类包括溴代乙酸叔丁酯、2-溴丙酸乙酯、2-溴丙酸甲酯、溴乙酸甲酯中的一种;
所述有机溶剂为DMF(N,N-二甲基甲酰胺)、甲醇、四氢呋喃、乙腈中的一种或两种以上;
一种制备如上所述的芒柄花黄素衍生物的方法,包括如下步骤,
将化合物5溶解于有机溶剂中,将化合物13a-h,K2CO3,KI依次加入到反应体系中,抽真空氩气保护;室温搅拌10-30分钟后将反应体系移入油浴,50-75℃搅拌回流;加热反应1-2h,反应至完成;冷却至室温后将反应体系旋干除去大部分有机溶剂,加入适量蒸馏水和二氯甲烷进行萃取合并有机相;加入适量干燥的无水硫酸钠干燥,抽滤,浓缩得到粗品硅胶柱层析分离纯化,得到化合物;其中化合物5的结构式为化合物13a-h的结构式为其中,
本发明同时提供一种所述的芒柄花黄素衍生物或如上所述的制备方法制备的芒柄花黄素衍生物在抗肿瘤药物或药物制备中的应用。
优选的,所述的肿瘤为乳腺癌。
相对于现有技术,本发明所述的芒柄花黄素衍生物及其制备方法和应用,具有以下优势:
本发明所述的衍生物,能具有抗肿瘤的活性,对肿瘤细胞具有抑制作用。
附图说明
图1为化合物3a的1H NMR谱图;图2为化合物3a的13C NMR谱图;
图3为化合物3b的1H NMR谱图;图4为化合物3b的13C NMR谱图;
图5为化合物3c的1H NMR谱图;图6为化合物3c的13C NMR谱图;
图7为化合物3d的1H NMR谱图;图8为化合物3d的13C NMR谱图;
图9为化合物3e的1H NMR谱图;图10为化合物3e的13C NMR谱图;
图11为化合物6a的1H NMR谱图;图12为化合物6a的13C NMR谱图;
图13为化合物6b的1H NMR谱图;图14为化合物6b的13C NMR谱图;
图15为化合物6c的1H NMR谱图;图16为化合物6c的13C NMR谱图;
图17为化合物6d的1H NMR谱图;图18为化合物6d的13C NMR谱图;
图19为化合物6f的1H NMR谱图;图20为化合物6f的13C NMR谱图;
图21为化合物6g的1H NMR谱图;图22为化合物6g的13C NMR谱图;
图23为化合物7b的1H NMR谱图;图24为化合物7b的13C NMR谱图;
图25为化合物7f的1H NMR谱图;图26为化合物7f的13C NMR谱图;
图27为化合物7g的1H NMR谱图;图28为化合物7g的13C NMR谱图;
图29为化合物7h的1H NMR谱图;图30为化合物7h的13C NMR谱图;
图31为化合物7i的1H NMR谱图;图32为化合物7i的13C NMR谱图;
图33为化合物7J的1H NMR谱图;图34为化合物7J的13C NMR谱图;
图35为化合物14a的1H NMR谱图;图36为化合物14a的13C NMR谱图;
图37为化合物14b的1H NMR谱图;图38为化合物14b的13C NMR谱图;
图39为化合物14c的1H NMR谱图;图40为化合物14c的13C NMR谱图;
图41为化合物14d的1H NMR谱图;图42为化合物14d的13C NMR谱图;
图43为化合物14e的1H NMR谱图;图44为化合物14e的13C NMR谱图;
图45为化合物14f的1H NMR谱图;图46为化合物14f的13C NMR谱图;
图47为化合物14g的1H NMR谱图;图48为化合物14g的13C NMR谱图;
图49为化合物14h的1H NMR谱图;图50为化合物14h的13C NMR谱图;
图51为化合物3a-e对乳腺癌细胞MCF-7的抑制作用;
图52为化合物6a-d和6f-g对乳腺癌细胞MCF-7的抑制作用;
图53为化合物7b和7f-J对乳腺癌细胞MCF-7的抑制作用;
图54为化合物14a-d对乳腺癌细胞MCF-7的抑制作用;
图55为化合物7b和6f-J对乳腺癌细胞MCF-7的抑制作用;
图56为化合物3a-e对乳腺癌细胞SUM159的抑制作用;
图57为化合物6a-d和6f-g对乳腺癌细胞SUM159的抑制作用;
图58为化合物7b和7f-J对乳腺癌细胞SUM159的抑制作用;
图59为化合物14a-d对乳腺癌细胞SUM159的抑制作用;
图60为化合物7b和6f-J对乳腺癌细胞SUM159的抑制作用。
具体实施方式
除有定义外,以下实施例中所用的技术术语具有与本发明所属领域技术人员普遍理解的相同含义。以下实施例中所用的试验试剂,如无特殊说明,均为常规生化试剂;所述实验方法,如无特殊说明,均为常规方法。
下面结合实施例来详细说明本发明。
实施例一
合成路线为如下图所示,
1、化合物3a的合成
取干燥50mL单口烧瓶一个,将化合物1(400mg,1.5mmol)溶解于15mL无水DMF中,加入无水K2CO3(310mg,2.25mmol),抽真空氩气保护。随后将3-溴丙炔(120μL,1.5mmol)缓慢加入,室温反应12小时,TLC监测反应完成。将反应体系旋干除去大部分DMF。加入30mL水,用二氯甲烷(20mL×3)进行萃取,直到水相没有产物。将有机相加入适量干燥的无水硫酸钠干燥,减压抽滤,浓缩得到粗品硅胶柱层析纯化,洗脱剂纯DCM,得到化合物3a为白色粉末状固体(401mg),产率87.4%。
1H NMR(600MHz,Chloroform-d)δ8.22(d,J=8.9Hz,1H),7.92(s,1H),7.51–7.49(m,2H),7.04(dd,J=8.9,2.4Hz,1H),6.97(dd,J=5.6,3.1Hz,3H),4.78(s,2H),3.84(s,3H);13C NMR(151MHz,Chloroform-d)δ175.81,161.91,159.60,157.67,152.13,130.12,127.82,124.91,124.19,118.92,114.79,113.98,101.62,98.65,94.13,57.14,55.34;ESI-MS:calcd for C19H14NO4[M+H]+:307.32,found 307.36;mp:119.7-119.2℃.
2、化合物3b-c的合成
化合物3b-c的合成方法与3a相似。
化合物3b:白色固体,产率85.3%。1H NMR(600MHz,Chloroform-d)δ8.20(d,J=8.9Hz,1H),7.90(s,1H),7.49(d,J=6.7Hz,2H),7.02(dd,J=8.9,2.4Hz,1H),6.96–6.94(m,3H),4.74(q,J=2.2Hz,2H),3.82(s,3H),1.87(t,J=2.3Hz,3H);13C NMR(151MHz,Chloroform-d)δ175.85,162.11,159.66,157.78,152.17,130.18,127.85,124.94,124.30,118.86,114.95,114.03,101.53,84.99,73.05,57.04,55.40,3.76;mp:152.5-160.0℃;ESI-MS:calcd for C20H16NO4[M+H]+:321.34,found:321.66;mp:152.5-152.9℃.
化合物3c:白色固体,产率86.5%。1H NMR(600MHz,Chloroform-d)δ8.22(d,J=8.9Hz,1H),7.92(s,1H),7.51–7.48(m,2H),7.03(dd,J=8.9,2.4Hz,1H),6.98–6.95(m,3H),4.77(t,J=2.1Hz,2H),3.83(s,3H),2.25(dtd,J=7.5,5.4,2.1Hz,2H),1.15(t,J=7.5Hz,3H);13C NMR(151MHz,Chloroform-d)δ175.93,162.19,159.71,157.83,152.20,130.23,127.89,125.01,118.90,115.01,114.09,101.64,73.24,57.14,55.45,13.64,12.60;ESI-MS:calcd for C21H18NO4[M+H]+:335.37,found:335.42;mp:85.7-86.0℃.
3、化合物3d的合成
取干燥50mL三口烧瓶一个,将化合物1(400mg,1.5mmol)溶解于15mL无水DMF中,抽真空氩气保护。用微量注射器将DIPEA(391μL,2.25mmol)缓慢滴加到反应中,室温搅拌十分钟后将反应体系移入65℃油浴搅拌回流。随后将溴乙酸苯酯(322mg,1.5mmol)缓慢加入,反应16小时,TLC监测反应完成。降温至室温,将反应体系旋干除去大部分DMF。加入30mL水,用二氯甲烷(20mL×4)进行萃取,直到水相没有产物。将有机相加入适量干燥的无水硫酸钠干燥,减压抽滤,浓缩得到粗品硅胶柱层析纯化,洗脱剂PE:EA=10:1-5:1,得到化合物3d为乳白色粉末状固体(418mg),产率69.3%。
1H NMR(600MHz,Chloroform-d)δ8.28(d,J=8.9Hz,1H),7.94(s,1H),7.51(d,J=2.0Hz,1H),7.50(d,J=1.8Hz,1H),7.43–7.39(m,2H),7.28(d,J=7.4Hz,1H),7.15(d,J=1.1Hz,1H),7.13(s,1H),7.10(dd,J=8.9,2.4Hz,1H),6.98(d,J=2.0Hz,1H),6.97(s,1H),6.94(d,J=2.4Hz,1H),4.99(s,2H),3.85(s,3H);13C NMR(151MHz,Chloroform-d)δ175.88,166.57,161.90,159.80,157.80,152.32,150.08,130.28,129.79,128.49,126.59,125.22,124.18,121.30,119.58,114.46,114.15,101.72,65.61,55.50;ESI-MS:calcd forC24H18NO6[M+H]+:403.40,found:403.47;mp:153.1-153.7℃.
4、化合物3e的合成
化合物3e的合成方法与3d相似,白色固体,产率76.6%。
1H NMR(600MHz,Chloroform-d)δ8.23(d,J=8.9Hz,),7.91(s,1H),7.50(d,J=1.8Hz,1H),7.49(d,J=1.8Hz,1H),7.36(q,J=4.9Hz,5H),7.02(dd,J=8.9,2.4Hz,1H),6.98(s,1H),6.97(s,1H),6.81(d,J=2.4Hz,1H),5.26(s,2H),4.77(s,2H),3.84(s,3H);13C NMR(151MHz,Chloroform-d)δ175.88,167.92,161.99,159.78,157.76,152.27,135.00,130.26,128.84,128.71,128.58,128.33,125.15,124.20,119.38,114.51,114.14,101.56,67.52,65.59,55.49;ESI-MS:calcd for C25H20NO6[M+H]+:417.43,found:417.49;mp:132.8-133.3℃.
实施例二
合成路线为如下图所示,
1、化合物4的合成
在单口的1L圆底烧瓶中,室温下,将化合物1(26.8g,100mmol)溶解于500mL冰醋酸中。同时在25mL的单口的圆底烧瓶中,将6.1mL的浓硫酸缓慢滴加进入7mL浓硝酸中,并用玻璃棒搅拌均均,制成混酸。将混酸在常温下缓慢滴加进入反应中,搅拌均匀后,将反应体系移入50℃下在回流状态下搅拌12小时,TLC监测反应,原料大部分反应完全。将适量冰水倒入反应体系中将反应淬灭。将得到的沉淀化合物用砂芯漏斗过滤,用水洗涤,得到黄色固体。将粗品从EtOH中结晶,得到化合物4为黄色粉末(25g),产率79.9%。
1H NMR(600MHz,DMSO-d6)δ10.88(s,1H),8.51(s,1H),8.16(dd,J=15.3,2.0Hz,1H),7.98(d,J=8.7Hz,1H),7.91–7.85(m,1H),7.43(d,J=8.8Hz,1H),6.97–6.95(m,1H),6.90–6.88(m,1H),3.96(s,3H).
2、化合物5的合成
在单口的1L圆底烧瓶中,在室温下,加入400mL乙醇溶液,再加入体积为乙醇四分之一的100mL水,搅拌均匀,制成混合溶剂。将化合物4(31.3g,100mmol))溶解于此混合溶剂里,向混合体系中加入Fe粉(56g,1mol),最后加入NH4Cl(2.68g,0.05mmol),将反应体系移入75℃油浴使用机械搅拌回流4个小时,TLC监测反应,反应完全。适量冰水倒入反应体系中进行淬灭。将得到的混合物倒入装有硅藻土的砂芯漏斗中进行过滤,除去铁粉。将得到的滤液用旋转蒸发仪旋转蒸发干,得到粗品30g。将粗品干法上样进行硅胶柱层析纯化得到化合物5为黄色粉末(17g),产率60.1%。
1H NMR(600MHz,DMSO-d6)δ10.78(s,1H),8.22(s,1H),7.96(d,J=8.8Hz,1H),6.93(dd,J=8.8,2.2Hz,1H),6.87(d,J=2.1Hz,1H),6.85(d,J=2.2Hz,1H),6.82(d,J=8.3Hz,1H),6.69(dd,J=8.2,2.1Hz,1H),4.73(s,2H),3.78(s,3H).
化合物4和5可以通过以上方法制备合成,也可以通过现有的其他方法制备,或者直接使用现有的化合物成品。
3、化合物6a的合成
取干燥25mL单口烧瓶一个,将化合物5(286mg,1mmol)溶解于10mL无水DMF中,加入无水K2CO3(207mg,1.5mmol),抽真空氩气保护。随后将3-溴丙炔(86.2μL,1mmol)缓慢加入,反应12小时,TLC(DCM:MeOH=30:1)监测反应完成。降温后,将反应体系旋干除去大部分DMF。
加入30mL水,用二氯甲烷(20mL×3)进行萃取,直到水相没有产物。将有机相加入适量干燥的无水硫酸钠干燥,减压抽滤,浓缩得到粗品硅胶柱层析纯化,洗脱剂PE:EA=9:1-6:1,得到化合物6a为棕红色粉末状固体(220mg),产率68.5%。
化合物6b-c的合成方法与6a相似。
化合物6a:棕红色固体,产率68.5%。1H NMR(600MHz,Chloroform-d)δ8.22(d,J=8.9Hz,1H),7.90(s,1H),7.06–7.00(m,1H),6.96(d,J=4.2Hz,2H),6.88(d,J=8.2Hz,1H),6.83(d,J=8.2Hz,1H),4.79(s,2H),3.87(s,3H),2.59(s,1H);13C NMR(600MHz,Chloroform-d)NMR(600MHz,Chloroform-3H),2.59(s,1H)1H),6.96(d,6(d,,125.34,124.70,119.19,119.08,115.81,114.80,110.47,101.62,77.51,76.67,56.34,55.68;ESI-MS:calcd for C19H15NO4[M+H]+:322.33,found:322.36;mp:130.2-130.8℃.
化合物6b:白色固体,产率47.8%。1H NMR(600MHz,Chloroform-d)δ8.22(d,J=9.1Hz,1H),7.91(s,1H),7.03(dd,J=9.1,1.8Hz,1H),6.98(s,1H),6.95(s,1H),6.89(d,J=8.4Hz,1H),6.84(d,J=8.5Hz,1H),4.76(s,2H),3.88(s,3H),1.88(s,3H);13C NMR(600MHz,Chloroform-d)δ176.02,162.10,157.80,152.27,147.60,136.25,127.98,125.35,124.81,119.14,118.98,115.89,114.95,110.51,101.56,85.04,73.09,57.08,55.72,3.85;ESI-MS:calcd for C20H17NO4[M+H]+:336.36,found:336.38;mp:197.2-197.6℃.
化合物6c:白色固体,产率67.8%。1H NMR(600MHz,Chloroform-d)δ8.19(d,J=8.9Hz,1H),7.88(s,1H),7.01(dd,J=8.9,2.3Hz,1H),6.95(d,J=1.9Hz,1H),6.93(d,J=2.2Hz,1H),6.87(dd,J=8.3,2.0Hz,1H),6.81(d,J=8.3Hz,1H),4.75(t,J=1.9Hz,2H),3.85(s,3H),2.24(dddd,J=9.5,7.5,4.8,2.1Hz,2H),1.14(t,J=7.5Hz,3H);13C NMR(600MHz,Chloroform-d)δ175.84,161.97,157.61,152.19,147.42,136.17,127.73,125.12,124.67,118.94,118.79,115.70,114.81,110.34,101.46,90.66,73.20,57.00,55.56,13.55,12.50;ESI-MS:calcd for C21H19NO4[M+H]+:350.39,found:350.44;mp:109.1-109.6℃.
4、化合物6d的合成
取干燥25mL三口烧瓶一个,将化合物5(283mg,1mmol)溶解于10mL无水DMF中,抽真空氩气保护。用微量注射器将DIPEA(261.3μL,1.5mmol)缓慢滴加到反应中,搅拌十分钟后将反应体系移入65℃油浴搅拌回流。随后将溴乙酸苯酯(143μL,1mmol)缓慢加入,反应16小时,TLC(DCM:MeOH=30:1)监测反应完成。降温后,将反应体系旋干除去大部分DMF。加入30mL水,用二氯甲烷(20mL×4)进行萃取,直到水相没有产物。将有机相加入适量干燥的无水硫酸钠干燥,减压抽滤,浓缩得到粗品硅胶柱层析纯化,洗脱剂PE:EA=10:1-8:1,得到化合物6d为棕红色粉末状固体(297mg),产率71.2%。
化合物6f-g的合成方法与6d相似。
化合物6d:棕红色固体,产率71.2%。1H NMR(600MHz,Chloroform-d)δ8.27(d,J=8.8Hz,1H),7.92(s,1H),7.41(t,J=7.6Hz,2H),7.11(dd,J=20.0,7.7Hz,3H),7.02–6.81(m,5H),4.98(s,2H),3.88(s,3H);13C NMR(600MHz,Chloroform-d)δ175.92,166.58,161.82,,157.72,152.38,150.08,147.66,136.24,129.77,128.46,126.56,125.49,124.61,121.29,119.57,119.16,115.86,114.39,110.51,101.66,65.58,55.71;ESI-MS:calcd for C24H19NO6[M+H]+:418.42,found:418.52;mp:129.1-129.5℃.
化合物6f:黄色固体,产率64.2%。1H NMR(600MHz,Chloroform-d)δ8.21(d,J=8.9Hz,1H),7.88(s,1H),7.01–6.96(m,2H),6.88(dd,J=8.2,1.6Hz,1H),6.83–6.79(m,2H),4.61(s,2H),3.85(s,3H),1.50(s,9H);13C NMR(600MHz,Chloroform-d)δ175.88,167.08,162.11,157.67,152.30,147.61,136.01,128.13,125.29,124.66,119.21,119.17,115.93,114.36,110.46,101.39,83.07,65.90,55.65,28.14;ESI-MS:calcd forC22H23NO6[M+H]+:398.43,found:398.47;mp:135.2-135.6℃.
化合物6g:黄色固体,产率49.6%。1H NMR(600MHz,Chloroform-d)δ8.20(d,J=8.9Hz,1H),7.89(s,1H),7.00–6.96(m,2H),6.90(dd,J=8.2,2.1Hz,1H),6.83(d,J=8.3Hz,1H),6.79(d,J=2.4Hz,1H),4.85(q,J=6.8Hz,1H),4.24(qd,J=7.2,0.9Hz,2H),3.87(s,3H),1.68(d,J=6.8Hz,3H),1.27(t,J=7.1Hz,3H);13C NMR(600MHz,Chloroform-d)δ175.92,171.31,161.87,157.73,152.32,147.76,135.70,128.22,125.31,124.73,119.51,119.17,116.16,114.73,110.54,101.74,73.07,61.79,55.73,18.50,14.27;ESI-MS:calcd for C21H21NO6[M-H]-:382.40,found:382.44;mp:101.6-102.2℃.
5、化合物7b的合成
取干燥25mL单口烧瓶一个,将化合物5(283mg,1mmol)溶解于10mL无水DMF中,加入无水K2CO3(207mg,1.5mmol),抽真空氩气保护。随后将1-溴-2-丁炔(135.7μL,1.5mmol)缓慢加入,室温反应12小时,TLC监测反应完成。降温后,将反应体系旋干除去大部分DMF。加入30mL水,用二氯甲烷(20mL×3)进行萃取,直到水相没有产物。将有机相加入适量干燥的无水硫酸钠干燥,减压抽滤,浓缩得到粗品硅胶柱层析纯化,洗脱剂纯DCM,得到化合物7b为白色粉末状固体(185mg),产率47.8%。
1H NMR(600MHz,Chloroform-d)δ8.21(d,J=8.9Hz,1H),7.93(s,1H),7.01(dd,J=8.9,2.4Hz,1H),6.95–6.91(m,2H),6.86(d,J=2.0Hz,1H),6.82(d,J=8.2Hz,1H),4.74(q,J=2.2Hz,2H),3.93(q,J=2.3Hz,2H),3.86(s,3H),1.87(t,J=2.3Hz,3H),1.80(t,J=2.4Hz,3H);13CNMR(600MHz,Chloroform-d)δ175.93,162.00,157.71,152.29,147.71,137.05,127.88,125.63,124.83,118.94,118.40,114.83,111.46,109.53,101.50,84.94,79.19,76.10,73.08,57.01,55.66,33.91,3.75,3.67;ESI-MS:calcd for C24H21NO4[M+H]+:388.44,found:336.50;mp:107.6-108.1℃。
6、化合物7f的合成
取干燥25mL三口烧瓶一个,将化合物5(283mg,1mmol)溶解于10mL无水DMF中,抽真空氩气保护。用微量注射器将DIPEA(261.3μL,1.5mmol)缓慢滴加到反应中,室温搅拌十分钟后将反应体系移入65℃油浴搅拌回流。随后将溴代乙酸叔丁酯(225μL,1.5mmol)缓慢加入,继续反应16小时,TLC监测反应完成。降至常温后,将反应体系旋干除去大部分DMF。加入25mL水,用二氯甲烷(20mL×3)进行萃取,直到水相没有产物。将有机相加入适量干燥的无水硫酸钠干燥,减压抽滤,浓缩得到粗品硅胶柱层析纯化,洗脱剂PE:EA=10:1-8:1,得到化合物7f为乳黄色粉末状固体(200mg),产率39.1%。
1H NMR(600MHz,DMSO-d6)δ8.34(s,1H),8.04(d,J=8.8Hz,1H),7.16–7.04(m,2H),6.92–6.83(m,2H),6.67(d,J=1.9Hz,1H),5.16(s,1H),4.87(s,2H),3.84(d,J=8.2Hz,5H),1.44(s,9H),1.41(s,9H);MR(600MHz,DMSO-d6)δ,175.01,170.71,167.63,162.40,157.51,153.79,146.82,137.40,127.50,124.92,124.58,118.55,117.55,115.24,110.66,110.01,101.94,82.25,81.22,65.84,56.00,45.88,28.19,28.16;ESI-MS:calcd forC28H33NO8[M+H]+:512.57,found:512.56;mp:140.9-141.8℃.
7、化合物7g-i的合成
化合物7g-i的合成方法与化合物7f相似。
化合物7g:白色固体,产率41.0%。1H NMR(600MHz,Chloroform-d)δ8.21(d,J=8.9Hz,1H),7.88(s,1H),6.98(dd,J=8.9,2.2Hz,1H),6.86(d,J=8.1Hz,1H),6.82(d,J=8.2Hz,1H),6.80–6.75(m,2H),4.85(q,J=6.7Hz,1H),4.28–4.16(m,5H),3.88(s,3H),1.68(d,J=6.7Hz,3H),1.51(d,J=6.9Hz,3H),1.26(dt,J=16.5,7.1Hz,6H);13C NMR(151MHz,Chloroform-d)δ175.91,174.64,171.35,152.29,147.36,136.53,128.23,125.67,124.77,119.23,118.15,114.70,111.29,109.79,101.74,73.07,61.80,61.23,55.74,51.85,19.01,18.52,14.34,14.28;ESI-MS:calcd for C26H29NO8[M+H]+:484.52,found:484.57;mp:194.6-195.1℃.
化合物7h:黄色固体,产率38.5%。1H NMR(600MHz,Chloroform-d)δ8.08(d,J=8.8Hz,1H),7.85(s,1H),6.91(dd,J=8.8,2.2Hz,1H),6.83(d,J=2.2Hz,1H),6.81(d,J=1.7Hz,1H),6.79(d,J=8.2Hz,1H),6.71(d,J=1.5Hz,2H),4.20(q,J=6.9Hz,1H),3.86(s,3H),3.72(s,3H),2.01,(s,3H)1.50(d,J=6.9Hz,3H),1.24(s,3H);13C NMR(151MHz,Chloroform-d)δ176.40,175.13,173.13,162.33,158.03,152.33,147.11,136.28,127.79,125.16,124.88,118.19,117.57,115.29,111.21,109.66,102.62,55.59,52.27,51.61,31.92,29.69,22.57,18.89;ESI-MS:calcd for C24H25NO6[M+H]+:424.47,found:424.57;mp:160.6-161.1℃.
化合物7i:黄色固体,产率59%。1HNMR(600MHz,Chloroform-d)δ8.21(d,J=8.9Hz,1H),7.89(s,1H),7.00(dd,J=8.9,2.5Hz,1H),6.84(dd,J=8.2,1.9Hz,1H),6.82–6.79(m,2H),6.72(d,J=1.8Hz,1H),4.72(s,2H),3.98(s,2H),3.87(s,3H),3.82(s,3H),3.76(s,3H);13C NMR(600MHz,Chloroform-d)δ175.85,171.62,168.45,161.84,157.61,152.33,147.28,136.96,128.19,125.56,124.69,119.30,118.02,114.35,110.83,109.58,101.37,65.36,55.66,52.56,52.28,45.56;ESI-MS:calcd for C22H21NO8[M+H]+:428.41,found:428.50;mp:108.1-108.6℃.
8、化合物7J的合成与7b相似
化合物7J:白色固体,产率57.7%。1H NMR(600MHz,Chloroform-d)δ8.44(d,J=1.9Hz,1H),8.30(d,J=8.7Hz,1H),8.03(s,1H),7.81(s,1H),7.39(dd,J=8.4,2.0Hz,1H),7.29(d,J=2.1Hz,1H),7.15(dd,J=8.7,2.1Hz,1H),3.89(s,3H),2.35(s,3H),2.20(s,3H);13C NMR(151MHz,Chloroform-d)δ175.67,168.54,168.28,156.61,154.36,153.18,147.79,127.81,127.78,125.06,124.98,124.18,122.30,119.86,119.38,110.92,109.92,55.84,24.93,21.19;ESI-MS:calcd for C20H17NO4[M+H]+:368.36,found:368.42;mp:195.4-195.9℃.
实施例三
合成路线为如下图所示,
1、化合物13a的合成
取一个干燥的25mL单口圆底烧瓶,将化合物12a(143mg,0.5mmol)溶解于5mL无水DCM中,搅拌均匀后加入化合物NBS(178mg,1mmol)。然后在冰水浴条件下分批加入化合物P(Ph)3(262.30mg,1mmol),加料完毕反应半个小时,TLC监测反应完成。加入适量碳酸氢钠水溶液进行萃取,直至水相没有产物。合并有机相,加入适量干燥的无水硫酸钠干燥,抽滤,浓缩得到粗品硅胶柱层析分离纯化,得到化合物13a为白色固体150mg,产率85.7%。
化合物13b-h的合成方法与13a相似,均为白色固体,产率65%-81%。
2、化合物14a的合成
取干燥50mL三口烧瓶一个,将化合物5(142mg,0.5mmol)溶解于10mL无水DMF中,将化合物13a(175mg,0.5mmol),K2CO3(103.6mg,0.75mmol),KI(16.6mg,0.01mmol)依次加入到反应体系中,抽真空氩气保护。室温搅拌十分钟后将反应体系移入65℃油浴搅拌回流。加热反应1h,TLC监测反应至完成。冷却至室温后将反应体系旋干除去大部分DMF,加入适量蒸馏水和二氯甲烷进行萃取,直至水相没有产物,合并有机相。加入适量干燥的无水硫酸钠干燥,抽滤,浓缩得到粗品硅胶柱层析分离纯化,得到化合物14a为黄色固体(155mg),产率56.2%。
1H NMR(600MHz,Chloroform-d)δ8.26(d,J=8.9Hz,1H),8.01(d,J=7.4Hz,2H),7.93(s,1H),7.71(t,J=7.5Hz,1H),7.54(t,J=7.9Hz,2H),7.01(dd,J=8.9,2.3Hz,1H),6.98(d,J=1.9Hz,1H),6.91–6.88(m,2H),6.84(d,J=8.3Hz,1H),4.84–4.81(m,2H),4.51–4.47(m,2H),3.88(s,3H);13C NMR(151MHz,Chloroform-d)δ175.95,162.41,158.84,157.87,152.38,147.67,138.17,136.30,135.81,129.80,129.75,128.67,128.34,125.50,124.63,119.26,119.14,115.84,114.64,110.53,101.25,69.22,65.89,55.73;ESI-MS:calcd for C26H21N3O9S[M+H]+:552.53,found:552.91;mp:168.8-169.4℃.
3、化合物14b-h的合成
化合物14b-h的合成方法与化合物14a相似。
化合物14b:黄色固体,产率62.0%。1H NMR(600MHz,Chloroform-d)δ8.23(d,J=8.9Hz,1H),8.02–7.98(m,2H),7.92(s,1H),7.71(d,J=7.5Hz,1H),7.54(t,J=7.9Hz,2H),6.99(dd,J=8.4,2.1Hz,2H),6.90(dt,J=4.4,2.7Hz,2H),6.84(d,J=8.3Hz,1H),4.67(t,J=6.0Hz,2H),4.29(t,J=5.9Hz,2H),3.88(s,3H),2.45–2.41(m,2H);13C NMR(151MHz,Chloroform-d)δ176.02,162.92,158.97,157.97,152.33,147.64,138.09,136.23,135.81,129.78,128.62,128.13,125.40,124.72,119.18,118.88,115.90,114.76,110.61,110.52,100.91,67.88,64.24,55.72,29.84;ESI-MS:calcd for C27H23N3O9S[M-H]-:564.55,found:564.19;mp:145.0-145.5℃.
化合物14c:黄色固体,产率55.3%。1H NMR(600MHz,Chloroform-d)δ8.21(d,J=8.9Hz,1H),8.05(dd,J=8.4,1.1Hz,2H),7.90(s,1H),7.75(t,J=7.5Hz,1H),7.60(t,J=7.9Hz,2H),6.98(dd,J=8.5,2.2Hz,2H),6.88(dd,J=8.2,2.1Hz,1H),6.87(d,J=2.3Hz,1H),6.83(d,J=8.3Hz,1H),4.54(t,J=6.1Hz,2H),4.17(t,J=6.0Hz,2H),3.88(s,3H),2.13(dd,J=8.2,5.8Hz,2H),2.06(dd,J=8.2,5.8Hz,2H);13C NMR(151MHz,Chloroform-d)δ176.03,163.18,159.09,157.99,152.27,147.60,138.14,136.23,135.78,129.79,128.66,128.01,125.32,124.78,119.14,118.68,115.89,114.81,110.63,110.49,100.80,71.28,67.92,55.71,25.68,25.49;ESI-MS:calcd for C28H25N3O9S[M+H]+:580.58,found:580.81;mp:141.4-141.9℃.
化合物14d:黄色固体,产率59.0%。1H NMR(600MHz,Chloroform-d)δ8.19(d,J=8.9Hz,1H),8.05(d,J=7.4Hz,2H),7.89(s,1H),7.75(d,J=7.5Hz,1H),7.60(t,J=7.9Hz,2H),6.98–6.96(m,2H),6.88(dd,J=8.2,2.0Hz,1H),6.84–6.82(m,2H),4.45(t,J=6.4Hz,2H),4.08(t,J=6.3Hz,2H),3.87(s,3H),1.95–1.91(m,2H),1.91–1.87(m,2H),1.59(p,J=5.8,5.2Hz,4H);13C NMR(151MHz,Chloroform-d)δ176.02,163.43,159.16,157.99,152.21,147.56,138.21,136.22,135.71,129.74,128.64,127.89,125.26,124.82,119.12,118.49,115.88,114.86,110.61,110.47,100.70,71.55,68.45,55.69,28.96,28.47,25.70,25.50;ESI-MS:calcd for C30H29N3O9S[M+H]+:608.63,found:608.80mp:129.8-130.4℃
化合物14e:黄色固体,产率92.5%。1H NMR(600MHz,Chloroform-d)δ8.18(d,J=8.9Hz,1H),8.05(dd,J=8.5,1.2Hz,2H),7.89(s,1H),7.75–7.73(m,1H),7.62–7.59(m,2H),6.98–6.96(m,2H),6.88(dd,J=8.2,2.0Hz,1H),6.84–6.82(m,2H),4.42(t,J=6.5Hz,2H),4.06(t,J=6.4Hz,2H),3.87(s,3H),2.95(s,3H),2.88(s,3H),1.45–1.41(m,6H);13CNMR(151MHz,Chloroform-d)δ176.05,163.53,162.71,159.19,158.01,152.21,147.57,138.25,136.20,135.69,129.74,128.66,127.86,125.26,124.85,119.14,118.44,115.91,114.89,110.48,100.68,71.73,68.71,55.70,36.62,29.82,29.29,28.53,26.02,25.66;ESI-MS:calcd for C32H33N3O9S[M+H]+:636.69,found:636.92;mp:113.6-114.3℃
化合物14f:黄色固体,产率75.3%。1H NMR(600MHz,Chloroform-d)δ8.18(d,J=8.9Hz,1H),8.06(d,J=1.1Hz,1H),8.05(s,1H),7.89(s,1H),7.76–7.72(m,1H),7.61(td,J=7.6,1.7Hz,2H),6.98–6.95(m,2H),6.88(dd,J=8.2,2.1Hz,1H),6.84–6.81(m,2H),4.41(t,J=6.6Hz,2H),4.05(t,J=6.5Hz,2H),3.87(s,3H),1.89–1.82(m,4H),1.51–1.35(m,12H);13C NMR(151MHz,Chloroform-d)δ176.03,163.56,159.19,158.01,152.20,147.55,138.27,136.22,135.68,129.73,128.65,127.83,125.25,124.86,119.12,118.41,115.89,114.90,110.61,110.48,100.66,71.78,68.78,55.69,29.54,29.51,29.42,29.21,29.10,28.55,26.10,25.70;ESI-MS:calcd for C34H37N3O9S[M+H]+:664.74,found:664.86;mp:97.1-97.5℃.
化合物14g:黄色固体,产率59.2%。1H NMR(400MHz,Chloroform-d)δ8.20(d,J=8.9Hz,1H),8.07–8.04(m,2H),7.89(s,1H),7.71(t,J=7.5Hz,1H),7.57(t,J=7.9Hz,2H),7.02–6.97(m,2H),6.89(dd,J=8.0,2.1Hz,2H),6.83(d,J=8.3Hz,1H),4.63–4.60(m,2H),4.28–4.25(m,2H),4.03–4.01(m,4H),3.88(s,3H);13C NMR(101MHz,Chloroform-d)δ176.00,163.03,159.06,157.89,152.28,147.60,138.12,136.25,135.74,129.75,128.71,128.05,125.35,124.77,119.14,118.85,115.88,114.81,110.65,110.50,101.07,70.78,69.95,68.91,68.28,29.84;ESI-MS:calcd for C28H25N3O10S[M+H]+:596.58,found:596.74;mp:84.2-85.4℃.
化合物14h:黄色固体,产率42.6%。1H NMR(600MHz,Chloroform-d)δ8.21(d,J=8.9Hz,1H),7.91(d,J=1.6Hz,1H),7.67(dd,J=12.0,7.3Hz,2H),7.55(q,J=8.6,7.9Hz,1H),7.49–7.40(m,2H),6.98(t,J=5.9Hz,2H),6.89(dd,J=8.2,1.7Hz,1H),6.84(d,J=8.3Hz,2H),5.30–5.17(m,2H),4.26(t,J=6.6Hz,2H),3.88(s,3H),3.04–2.90(m,4H),2.41–2.17(m,4H);13C NMR(151MHz,Chloroform-d)δ175.81,162.51,152.08,136.01,132.07,132.01,131.24,128.50,128.42,127.94,118.95,118.67,115.69,114.49,112.32,112.02,110.28,100.74,68.49,67.18,55.50,50.18,49.76,40.94,40.59;ESI-MS:calcdfor C30H29N3O9S3[M+H]+:672.11,found:671.67;mp:102.2-102.7℃。
活性测试
以MCF-7细胞的测试方法为例,SUM159细胞的测试方法与MCF-7细胞的方法一致):
(1)选取处于对数生长期的MCF-7细胞,按每孔3×103接种于96孔板,5%CO2,37℃孵育培养过夜。
(2)加药,本实验中设置了多个浓度梯度,根据需要采用不同的浓度梯度,每个浓度5个复孔,同时设置对照组(不加药仅接种细胞)及空白孔(未接种细胞仅加培养基),5%CO2,37℃培养箱孵育48小时。
(3)每孔再加入20μL MTT溶液(5mg/ml,即0.5%MTT),继续培养4小时。若药物与MTT能够反应,可先离心后弃去培养液,小心用PBS冲洗2-3遍后,再加入含MTT的培养液。
(4)4小时后终止培养,小心地吸去孔内的液体。并向每孔加入150μL的二甲基亚砜。然后置于摇床上低速振荡15min左右,使结晶物充分溶解。采用酶联免疫检测仪MULTISKAN FC(Thermo scientific)测定490nm处及570nm各孔的吸光度值,测量时以空白孔作为调零孔。
(5)处理数据。以药物浓度为横坐标,细胞数为纵坐标,用数据处理软件Graphpad软件进行几率单位加权回归法(Bliss法)进行数据处理,计算抑制率或者IC50值(见表1和表2)。
表1芒柄花黄素衍生物3a-e、6a-d、6f-g、7b和7f-J对乳腺癌细胞MCF-7和SUM159的抑制作用
表2芒柄花黄素衍生物14a-14h对乳腺癌细胞MCF-7和SUM159的抑制作用
由表1和表2数据可知,合成的化合物对乳腺癌细胞SUM159、MCF-7均具有抑制活性,尤其是化合物14a-h的抑制活性更好,高达0.36μM,可以应用于治疗乳腺癌。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (15)
2.一种制备如权利要求1所述的芒柄花黄素衍生物的方法,其特征在于,包括以下步骤:
将芒柄花黄素溶解于有机溶剂中,加入无水K2CO3,抽真空氩气保护;随后将溴代炔烃缓慢加入,室温反应8-12小时,反应完成;将反应体系旋干除去大部分有机溶剂;加入水,用二氯甲烷进行萃取;有机相用无水硫酸钠干燥,减压、抽滤、浓缩得到粗品,硅胶柱层析纯化,得到化合物;
所述溴代炔烃选自3-溴丙炔、1-溴-2-丁炔、1-溴-2-戊炔中的一种;
所述有机溶剂为DMF、甲醇、四氢呋喃、乙腈中的一种或两种以上;
芒柄花黄素与溴代炔烃的摩尔比为1:1-1:2,所述无水K2CO3与芒柄花黄素的摩尔比为3:1-3:3。
3.根据权利要求2所述的方法,其特征在于,芒柄花黄素与溴代炔烃的摩尔比为1:1;所述无水K2CO3与芒柄花黄素的摩尔比为3:2。
4.一种制备如权利要求1所述的芒柄花黄素衍生物的方法,其特征在于,包括以下步骤:
将芒柄花黄素溶解于有机溶剂中,抽真空氩气保护;将DIPEA缓慢滴加到反应中,室温搅拌10-30分钟后,将反应体系移入50-75℃油浴搅拌回流;随后将溴乙酸酯类缓慢加入,继续反应10-16小时,反应完成;降至室温后,将反应体系旋干除去大部分有机溶剂;加入水,用二氯甲烷进行萃取;有机相用无水硫酸钠干燥、减压、抽滤、浓缩得到粗品,硅胶柱层析纯化;
所述溴乙酸酯类选自溴乙酸苯酯、溴乙酸苄酯中的一种;
所述有机溶剂为DMF、甲醇、四氢呋喃、乙腈中的一种或两种以上;
芒柄花黄素与溴乙酸酯类的摩尔比为1:1-1:2;所述DIPEA与芒柄花黄素的摩尔比为3:1-3:3。
5.根据权利要求4所述的方法,其特征在于,芒柄花黄素与溴乙酸酯类的摩尔比为1:1,DIPEA与芒柄花黄素的摩尔比为3:2。
7.根据权利要求6所述的方法,其特征在于,化合物5与溴代炔烃的摩尔比为1:1。
8.一种制备如权利要求1所述的芒柄花黄素衍生物的方法,其特征在于,包括以下步骤,
将化合物5溶解于有机溶剂中,抽真空氩气保护;将DIPEA缓慢滴加到反应中,搅拌10-30分钟后将反应体系移入油浴中,50-75℃搅拌回流;随后将溴酸酯类缓慢加入,反应12-16小时,反应完成降至室温,将反应体系旋干除去大部分有机溶剂;加入水,用二氯甲烷进行萃取;有机相用无水硫酸钠干燥,减压、抽滤,浓缩得到粗品,硅胶柱层析纯化;
所述溴酸酯类选自溴乙酸苯酯、溴代乙酸叔丁酯、2-溴丙酸乙酯中的一种;
所述有机溶剂为DMF、甲醇、四氢呋喃、乙腈中的一种或两种以上;
9.根据权利要求8所述的方法,其特征在于,化合物5与溴酸酯类的摩尔比为1:1,DIPEA与化合物5的摩尔比为3:2。
11.根据权利要求10所述的方法,其特征在于,化合物5与1-溴-2-丁炔或乙酰氯的摩尔比为1:1.5。
12.一种制备如权利要求1所述的芒柄花黄素衍生物的方法,其特征在于,包括以下步骤,
将化合物5溶解于有机溶剂中,抽真空氩气保护;将DIPEA缓慢滴加到反应中,搅拌10-30分钟后将反应体系移入油浴中,50-75℃搅拌回流;随后将溴酸酯类缓慢加入,反应12-16小时,反应完成降至室温,将反应体系旋干除去大部分有机溶剂;加入水,用二氯甲烷进行萃取,;有机相用无水硫酸钠干燥,减压、抽滤,浓缩得到粗品,硅胶柱层析纯化;
所述溴酸酯类选自溴代乙酸叔丁酯、2-溴丙酸乙酯、2-溴丙酸甲酯、溴乙酸甲酯中的一种;
所述有机溶剂为DMF、甲醇、四氢呋喃、乙腈中的一种或两种以上;
13.根据权利要求12所述的方法,其特征在于:化合物5与溴酸酯类的摩尔比为1:1.5,所述DIPEA与化合物5的摩尔比为3:2。
15.如权利要求1所述的芒柄花黄素衍生物或如权利要求2~14任一项所述的制备方法制备的芒柄花黄素衍生物在抗肿瘤药物制备中的应用,其特征在于,所述肿瘤为乳腺癌。
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