CN114230519A - 一类具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物及其合成方法和应用 - Google Patents
一类具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物及其合成方法和应用 Download PDFInfo
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- CN114230519A CN114230519A CN202111479806.XA CN202111479806A CN114230519A CN 114230519 A CN114230519 A CN 114230519A CN 202111479806 A CN202111479806 A CN 202111479806A CN 114230519 A CN114230519 A CN 114230519A
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- Prior art keywords
- pleuromutilin
- compound
- drug
- cinnamate
- nmr
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- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 title claims abstract description 78
- -1 Pleuromutilin cinnamate compounds Chemical class 0.000 title claims abstract description 64
- 239000003814 drug Substances 0.000 title claims abstract description 57
- 229940079593 drug Drugs 0.000 title claims abstract description 53
- 241000894006 Bacteria Species 0.000 title claims abstract description 41
- 230000000694 effects Effects 0.000 title claims abstract description 25
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical compound C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 claims abstract description 45
- 239000002608 ionic liquid Substances 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 229940114081 cinnamate Drugs 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 9
- 150000001851 cinnamic acid derivatives Chemical class 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 60
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 26
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 229930016911 cinnamic acid Natural products 0.000 claims description 15
- 235000013985 cinnamic acid Nutrition 0.000 claims description 15
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
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Abstract
本发明公开了一类具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物及其合成方法,属于医药化学领域。该类化合物以截短侧耳素、肉桂酸类化合物为原料,反应过程用N2保护,在离子液体中反应或者在催化剂作用下于有机溶剂中反应,合成了一类未见报道的截短侧耳素肉桂酸酯类化合物。该合成方法操作安全性高,反应条件温和,适用于工业化生产。经初步生物活性测试和安全性评价表明该类截短侧耳素肉桂酸酯化合物有较好的抗耐药菌活性和安全性,可应用于治疗感染性疾病,特别是耐药菌引起的感染性疾病,具有很好的医药开发价值。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一类截短侧耳素肉桂酸酯类衍生物及其合成方法和在治疗感染性疾病,特别是多重耐药菌引起的感染性疾病的药物中的应用。
背景技术
多年来,随着抗生素的滥用,多种具有耐药性的“超级细菌”开始在全球蔓延,对人类的健康构成新威胁。耐药菌的出现增加了感染性疾病治愈的难度,随着耐药细菌的增多,耐药范围和耐药程度也不断增大。目前革兰氏阳性菌和革兰氏阴性菌均有耐药趋向,革兰氏阳性菌的耐药问题更为严重。耐甲氧西林金黄色葡萄球菌(MRSA)是临床上常见的毒性较强的细菌,从发现至今感染几乎遍及全球,是临床抗感染治疗十分棘手的问题。开发新型抗菌药已迫在眉睫,目前世界许多制药公司都在积极寻找能对付多药耐药菌的新型药物,其中在构效关系研究指导下修饰现有抗菌药的化学结构是开发耐药菌新药的常用方法。
截短侧耳素是从两种天然担子菌(Pleurotus mutilus、Pleurotuspasseckerianus)中分离出来的一种带有刚性的5-6-8三环结构碳骨架的二萜类化合物。研究显示,它对革兰阳性菌和支原体具有良好的抑制作用。截短侧耳素及其衍生物的抗菌机制不同于目前主流抑制蛋白质合成的抗生素-氯霉素类、大环内酯类、恶唑烷酮类等,其能够通过与细菌核糖体肽酰转移中心(PTC)发生作用,干扰tRNA与P-位点和A-位点结合,从而抑制蛋白质的合成。由于PTC高度的保守性,使其耐药率较低。由于截短侧耳素及其衍生物特殊的抗菌机制和耐药缓慢,使其成为目前抗生素研究的热点之一。
肉桂酸又称桂皮酸、桂酸,是一种重要的精细化工合成中间体,由于其良好的防腐杀菌作用而广泛应用于果蔬防腐、食品添加剂以及医药工业中。肉桂酸及其衍生物被报道普遍具有良好的抗菌活性,可作为优势结构片段用于新型抗生素的开发。
目前,将截短侧耳素与肉桂酸类化合物作为原料合成短侧耳素肉桂酸酯类化合物还未见报道。
发明内容
为了克服上述现有技术的缺点,本发明的目的在于提供一类截短侧耳素肉桂酸酯衍生物及其制备方法和其在制备治疗感染性疾病,特别是耐药菌引起的感染性疾病的新型抗耐药菌药物中的应用。
为了达到上述目的,本发明采用以下技术方案予以实现:
本发明公开了一类具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物,所述截短侧耳素肉桂酸酯类化合物的结构式为:
其中:R1、R2、R3、R4和R5为任意取代的氢、卤素、硝基、氰基、甲氧基、三氟甲基、苄氧基、芳基或二甲基氨基。
优选地,所述化合物为下列化合物中的一种:
本发明还公开了制备上述具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物的方法,合成路线Ⅰ如下:
将肉桂酸类化合物、截短侧耳素和催化剂溶于离子液体中,通入氮气保护,反应完全后得到截短侧耳素肉桂酸酯类化合物。
优选地,肉桂酸类化合物和截短侧耳素的摩尔比为1:1~1:1.2,催化剂为硅钼酸,离子液体为1-丁基-3-甲基咪唑四氟硼酸盐,反应的温度为20℃~60℃,反应的时间为4~8小时。
本发明还公开了制备上述具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物的方法,合成路线Ⅱ如下:
1)肉桂酸类化合物在机溶剂中与酰氯化试剂作用,形成肉桂酰氯;
2)将步骤1)得到的肉桂酰氯与截短侧耳素溶于有机溶剂中,在催化剂的作用下反应得到截短侧耳素肉桂酸酯类化合物。
优选地,步骤1)中的酰氯化试剂为草酰氯、氯化亚砜或五氯化磷。
优选地,步骤1)中的肉桂酸类化合物和酰氯化试剂的摩尔比为1:1.2~1:3。
优选地,步骤2)中的肉桂酰氯和截短侧耳素的摩尔比为1:1~1:1.5,催化剂为三乙胺、吡啶或DMAP,反应时间为3~6小时。
本发明还公开了上述具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物在制备抗耐药菌药物中的应用。
优选地,所述抗耐药菌药物为治疗多重耐药菌引起的感染性疾病的药物。
优选地,所述耐药菌为革兰氏阳性菌和/或革兰氏阴性菌。
与现有技术相比,本发明具有以下有益效果:
本发明提供的一类具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物,利用肉桂酸及其衍生物作为优势结构片段对截短侧耳素进行结构改造,获得了具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物。该化合物结构新颖,具有显著的抗耐药菌活性,经初步生物活性测试和安全性评价,化合物1-21中大部分化合物都可以对大肠杆菌和鲍曼不动杆菌产生抑制作用,其中,化合物1、2、4、5、10、15的抑菌效果皆好于阳性药瑞他莫林、沃尼妙林和泰妙菌素,化合物10对细菌的抑菌效果远远好于进行测试的三种阳性药,实验表明该类截短侧耳素肉桂酸酯化合物有较好的抗耐药菌活性和安全性,可应用于治疗感染性疾病,特别是耐药菌引起的感染性疾病,具有很好的医药开发价值。
本发明还提供了制备截短侧耳素肉桂酸酯类化合物的方法,以截短侧耳素和肉桂酸类化合物为原料,反应过程用N2保护,在离子液体中反应或者在催化剂作用下于有机溶剂中反应,即可得到截短侧耳素肉桂酸酯类化合物。该合成方法操作安全性高,反应条件温和,制得的目标产物产率在82%~93.5%之间,适用于工业化生产。
附图说明
图1为本发明的化合物1的核磁共振氢谱图;
图2为本发明的化合物1的核磁共振碳谱图;
图3为本发明的化合物2的核磁共振氢谱图;
图4为本发明的化合物2的核磁共振碳谱图;
图5为本发明的化合物3的核磁共振氢谱图;
图6为本发明的化合物3的核磁共振碳谱图;
图7为本发明的化合物4的核磁共振氢谱图;
图8为本发明的化合物4的核磁共振碳谱图;
图9为本发明的化合物5的核磁共振氢谱图;
图10为本发明的化合物5的核磁共振碳谱图;
图11为本发明的化合物6的核磁共振氢谱图;
图12为本发明的化合物6的核磁共振碳谱图;
图13为本发明的化合物7的核磁共振氢谱图;
图14为本发明的化合物7的核磁共振碳谱图;
图15为本发明的化合物8的核磁共振氢谱图;
图16为本发明的化合物8的核磁共振碳谱图;
图17为本发明的化合物9的核磁共振氢谱图;
图18为本发明的化合物9的核磁共振碳谱图;
图19为本发明的化合物10的核磁共振氢谱图;
图20为本发明的化合物10的核磁共振碳谱图;
图21为本发明的化合物11的核磁共振氢谱图;
图22为本发明的化合物11的核磁共振碳谱图;
图23为本发明的化合物12的核磁共振氢谱图;
图24为本发明的化合物12的核磁共振碳谱图;
图25为本发明的化合物13的核磁共振氢谱图;
图26为本发明的化合物13的核磁共振碳谱图;
图27为本发明的化合物14的核磁共振氢谱图;
图28为本发明的化合物14的核磁共振碳谱图;
图29为本发明的化合物15的核磁共振氢谱图;
图30为本发明的化合物15的核磁共振碳谱图;
图31为本发明的化合物16的核磁共振氢谱图;
图32为本发明的化合物16的核磁共振碳谱图;
图33为本发明的化合物17的核磁共振氢谱图;
图34为本发明的化合物17的核磁共振碳谱图;
图35为本发明的化合物18的核磁共振氢谱图;
图36为本发明的化合物18的核磁共振碳谱图;
图37为本发明的化合物19的核磁共振氢谱图;
图38为本发明的化合物19的核磁共振碳谱图;
图39为本发明的化合物20的核磁共振氢谱图;
图40为本发明的化合物20的核磁共振碳谱图;
图41为本发明的化合物21的核磁共振氢谱图;
图42为本发明的化合物21的核磁共振碳谱图;
图43为本发明的化合物1对甲氧西林敏感表皮葡萄球菌(ATCC12228)的体外抗菌活性测定结果图;
图44为本发明的化合物1对金黄色葡萄球菌(ATCC29213)的体外抗菌活性测定结果图;
图45为本发明的化合物3对金黄色葡萄球菌(ATCC25923)的体外抗菌活性测定结果图;
图46为本发明的化合物4对甲氧西林敏感表皮葡萄球菌(ATCC12228)的体外抗菌活性测定结果图;
图47为本发明的化合物4对金黄色葡萄球菌(ATCC25923)的体外抗菌活性测定结果图;
图48为本发明的化合物5对金黄色葡萄球菌(ATCC25923)的体外抗菌活性测定结果图;
图49为本发明的化合物10对金黄色葡萄球菌(ATCC29213)的体外抗菌活性测定结果图;
图50为本发明中不同浓度的瑞他莫林对HepG2细胞、HEK293细胞和A549细胞的影响图;
图51为本发明中不同浓度的沃尼妙林对HepG2细胞、HEK293细胞和A549细胞的影响图;
图52为本发明中不同浓度的泰妙菌素对HepG2细胞、HEK293细胞和A549细胞的影响图;
图53为本发明中不同浓度的化合物1对HepG2细胞、HEK293细胞和A549细胞的影响图;
图54为本发明中不同浓度的化合物10对HepG2细胞、HEK293细胞和A549细胞的影响图;
图55为本发明中经不同浓度瑞塔莫林处理的HepG2细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图56为本发明中经不同浓度沃尼妙林处理的HepG2细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图57为本发明中经不同浓度泰妙菌素处理的HepG2细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图58为本发明中经不同浓度化合物10处理的HepG2细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图59为本发明中经不同浓度化合物5处理的HepG2细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图60为本发明中经不同浓度化合物4处理的HepG2细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图61为本发明中经不同浓度化合物1处理的HepG2细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图62为本发明中经不同浓度瑞他莫林处理的HEK293细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图63为本发明中经不同浓度沃尼妙林处理的HEK293细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图64为本发明中经不同浓度泰妙菌素处理的HEK293细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图65为本发明中经不同浓度化合物10处理的HEK293细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图66为本发明中经不同浓度化合物5处理的HEK293细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图67为本发明中经不同浓度化合物4处理的HEK293细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图68为本发明中经不同浓度化合物1处理的HEK293细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图69为本发明中经不同浓度瑞他莫林处理的A549细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图70为本发明中经不同浓度沃尼妙林处理的A549细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图71为本发明中经不同浓度泰妙菌素处理的A549细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图72为本发明中经不同浓度化合物10处理的A549细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图73为本发明中经不同浓度化合物5处理的A549细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图74为本发明中经不同浓度化合物4处理的A549细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM;
图75为本发明中经不同浓度化合物1处理的A549细胞显微图;其中,(A)0μM(B)0.78μM(C)1.56μM(D)3.125μM(E)6.25μM(F)12.5μM(G)25μM(H)50μM(I)100μM(J)200μM。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案,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,所描述的实施例仅仅是本发明一部分的实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都应当属于本发明保护的范围。
需要说明的是,本发明的说明书和权利要求书及上述附图中的术语“第一”、“第二”等是用于区别类似的对象,而不必用于描述特定的顺序或先后次序。应该理解这样使用的数据在适当情况下可以互换,以便这里描述的本发明的实施例能够以除了在这里图示或描述的那些以外的顺序实施。此外,术语“包括”和“具有”以及他们的任何变形,意图在于覆盖不排他的包含,例如,包含了一系列步骤或单元的过程、方法、系统、产品或设备不必限于清楚地列出的那些步骤或单元,而是可包括没有清楚地列出的或对于这些过程、方法、产品或设备固有的其它步骤或单元。
下面结合附图对本发明做进一步详细描述:
本发明提供的一类具抗耐药菌性的截短侧耳素肉桂酸酯衍生物的结构式如式Ⅰ所示:
其中:R1、R2、R3、R4、R5为任意取代的氢、卤素、硝基、氰基、甲氧基、三氟甲基、苄氧基、芳基或二甲基氨基。
本发明提供的合成上述具抗耐药菌性的截短侧耳素肉桂酸酯类衍生物的制备方法如下:
合成路线Ⅰ:将肉桂酸类化合物和截短侧耳素以及适量的催化剂硅钼酸溶于离子液体1-丁基-3-甲基咪唑四氟硼酸盐中,置于反应器中,同时通入N2保护,即可得到截短侧耳素肉桂酸酯类衍生物。
本发明提供的截短侧耳素肉桂酸酯类衍生物的合成路线Ⅰ如下所示:
其中:R1、R2、R3、R4、R5为任意取代的氢、卤素、硝基、氰基、甲氧基、三氟甲基、苄氧基、芳基或二甲基氨基。
为了实现上述合成路线Ⅰ,本发明的合成步骤如下:
(1)将一定量肉桂酸类化合物和一定量的截短侧耳素以及适量的催化剂硅钼酸溶于离子液体1-丁基-3-甲基咪唑四氟硼酸盐中,置于反应器中,通入N2保护,在20℃~60℃温度下,反应4-8小时。其中,肉桂酸类化合物和截短侧耳素的摩尔比优选为1:1~1:1.2,进一步优选为1:1.2;反应温度优选为30℃,反应时间优选为5小时。
(2)薄层色谱法跟踪反应至完全,将反应混合体系通过萃取和减压浓缩除去有机溶剂和离子液体,通过重结晶方法提纯,干燥得到目标产物。
合成路线Ⅱ:首先将肉桂酸类化合物在酰氯化试剂的作用下形成肉桂酰氯,然后与截短侧耳素在有机碱存在的情况下反应,即可得到截短侧耳素肉桂酸酯类衍生物。
本发明提供的截短侧耳素肉桂酸酯类衍生物的合成路线Ⅱ如下所示:
其中:R1、R2、R3、R4、R5为氢、卤素、硝基、氰基、甲氧基、三氟甲基、苄氧基、芳环或二甲基氨基。
为了实现上述合成路线Ⅱ,本发明的合成步骤如下:
(1)将一定量肉桂酸类化合物溶于有机溶剂,置于反应器中,同时通入N2保护,加入催化量的DMF,后加入一定量的酰氯化试剂于反应体系中,在20℃~60℃温度下,反应2~4小时。其中,酰氯化试剂优选草酰氯、氯化亚砜和五氯化磷,进一步优选为草酰氯;肉桂酸类化合物和酰氯化试剂的摩尔比优选为1:1.2~1:3,进一步优选为1:2;反应温度优选为30℃,反应时间优选为3小时。
(2)反应完全后,撤去保护装置,减压浓缩除去有机溶剂和过量的酰氯化试剂得到各种肉桂酰氯备用。将一定量截短侧耳素溶于有机溶剂,置于反应器中,加入催化剂,同时通入N2保护,再将一定量肉桂酰氯溶于有机溶剂中并滴加到反应器中,室温下反应3-6小时。其中,肉桂酰氯和截短侧耳素的摩尔比优选为1:1~1:1.5,进一步优选为1:1.1~1:1.3;催化剂优选为三乙胺、吡啶和DMAP,进一步优选为三乙胺;反应时间优选为5小时。
(3)薄层色谱法跟踪反应至完全,将反应混合体系减压浓缩除去有机溶剂,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物。
本发明部分优选实施方案中化合物结构式及编号如下所示:
1.合成化合物1-21的具体实施例
实施例1
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydr o-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl3-(4-nitrophenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(4-硝基苯基)丙烯酸酯的制备
将193.2mg(1.0mmol)4-硝基肉桂酸置于反应器中,加入10ml CH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.13ml(1.5mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在25℃下反应4小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2和0.14ml(1.0mmol)的三乙胺,并通入N2保护,后将4-硝基肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物512.2mg,产率为92.5%。化合物1的核磁共振氢谱如图1所示,核磁共振碳谱如图2所示。
1H NMR(400MHz,CDCl3)δ8.30(d,J=8.2Hz,2H),7.83(d,J=16.0Hz,1H),7.73(d,J=8.4Hz,2H),6.67(d,J=16.1Hz,1H),6.52(dd,J=17.3,11.0Hz,1H),5.86(d,J=8.5Hz,1H),5.39(d,J=10.9Hz,1H),5.26(d,J=17.3Hz,1H),4.71(dd,J=16.0Hz,2H),3.41(d,J=6.4Hz,1H),2.36(t,J=7.0Hz,1H),2.27(q,J=10.1,9.3Hz,2H),2.17–2.07(m,2H),1.88–1.51(m,7H),1.49(s,3H),1.41(d,J=15.8Hz,2H),1.23(s,3H),0.92(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H).
13C NMR(101MHz,CDCl3)δ216.91,166.53,165.11,148.71,143.19,140.18,138.80,130.46,128.83,124.24,123.22,121.07,117.38,74.58,69.92,61.62,58.09,45.46,44.63,44.06,41.89,36.68,36.07,34.45,30.40,26.84,26.45,24.84,16.64,14.79,11.47.
实施例2
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydr o-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl3-(3-chlorophenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(3-氯苯基)丙烯酸酯的制备
将182.6mg(1.0mmol)3-氯肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.13ml(1.5mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在20℃下反应4小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2和0.14ml(1.0mmol)三乙胺,并通入N2保护,后将3-氯肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物494.2mg,产率91.0%。化合物2的核磁共振氢谱如图3所示,核磁共振碳谱如图4所示。
1H NMR(400MHz,CDCl3)δ(ppm):7.75(d,J=16.0Hz,1H),7.57(s,1H),7.42(m,3H),6.58(s,1H),6.54–6.50(m,1H),5.87(d,J=8.5Hz,1H),5.44–5.25(m,2H),4.73(dd,J=38.8,16.0Hz,2H),3.42(d,J=6.4Hz,1H),2.39(t,J=7.2Hz,1H),2.32–2.20(m,2H),2.18–2.12(m,2H),1.85–1.52(m,7H),1.51(s,3H),1.45–1.41(m,2H),1.24(s,3H),0.94(d,J=7.0Hz,3H),0.85(d,J=7.0Hz,3H).
13C-NMR(101MHz,CDCl3)δ(ppm):216.77,166.64,165.54,144.52,138.81,135.98,135.00,130.42,130.16,127.94,126.33,118.29,117.32,74.59,69.78,61.44,58.10,45.44,44.64,44.05,41.89,36.69,36.05,34.42,30.42,26.83,26.42,24.83,16.60,14.78,11.40.
实施例3
化合物2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethylcinnamate 2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧基-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基-2-氧乙基肉桂酸酯的制备
将148.2mg(1mmol)肉桂酸、454.2mg(1.2mmol)截短侧耳素与17.1mg(0.01mmol)硅钼酸依次置于250mL反应器中,加入142.9ml离子液体1-丁基-3-甲基咪唑四氟硼酸盐充分溶解后,通入N2保护,在20℃下反应4.5h。薄层色谱法跟踪反应至完全,撤去保护装置。将反应混合体系静止分层,至于分液漏斗中,将离子液体层与酯层分离,所得酯层为肉桂酸酯类衍生物粗品。用50mL甲醇进行重结晶干燥即得肉桂酸酯类衍生物475.4mg,总收率为93.5%。化合物3的核磁共振氢谱如图5所示,核磁共振碳谱如图6所示。
1H NMR(400MHz,CDCl3)δ7.81(d,J=16.0Hz,1H),7.59–7.56(m,2H),7.47–7.40(m,3H),6.62–6.47(m,2H),5.85(d,J=8.4Hz,1H),5.40(d,J=11.0Hz,1H),5.26(d,J=17.4Hz,1H),4.79–4.58(m,2H),3.40(s,1H),2.37(t,J=7.3Hz,1H),2.32–2.19(m,2H),2.16–2.06(m,2H),1.84–1.51(m,6H),1.49(s,3H),1.47–1.35(m,2H),1.22(s,3H),1.18–1.10(m,1H),0.92(d,J=6.9Hz,4H),0.84(d,J=6.8Hz,3H).
13C NMR(101MHz,CDCl3)δ216.98,166.84,166.02,146.28,138.77,134.14,130.62,128.95,128.24,117.41,116.72,74.57,69.67,61.36,58.10,45.45,44.58,44.03,41.88,36.71,36.02,34.46,30.42,26.83,26.38,24.83,16.67,14.80,11.48.
实施例4
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(4-methoxyphenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环五[8]环烯-5-基)氧基)-2-氧代乙基-3-(4-甲氧基苯基)丙烯酸酯的制备
将178.2mg(1.0mmol)4-甲氧基肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.17ml(2.0mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在25℃下反应4小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2和0.14ml(1.0mmol)三乙胺,并通入N2保护,后将4-甲氧基肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应4.5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物492.7mg,产率为88.5%。化合物4的核磁共振氢谱如图7所示,核磁共振碳谱如图8所示。
1H NMR(400MHz,CDCl3)δ7.76(d,J=15.8Hz,1H),7.52(d,J=8.3Hz,2H),6.95(d,J=8.3Hz,2H),6.53(dd,J=17.4,11.1Hz,1H),6.41(d,J=15.9Hz,1H),5.85(d,J=8.4Hz,1H),5.39(d,J=11.0Hz,1H),5.25(d,J=17.4Hz,1H),4.75–4.60(m,2H),3.88(s,3H),3.40(d,J=6.4Hz,1H),2.37(t,J=7.1Hz,1H),2.29–2.18(m,2H),2.14–2.09(m,2H),1.83–1.54(m,6H),1.49–1.39(m,6H),1.22(s,3H),0.91(d,J=6.9Hz,3H),0.84(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ216.98,166.99,166.34,161.67,145.94,138.82,129.96,126.94,117.39,114.40,114.16,74.60,69.62,61.27,58.13,55.41,45.47,44.61,44.05,41.90,36.74,36.04,34.47,30.44,26.85,26.39,24.85,16.67,14.82,11.48.
实施例5
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydr o-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl3-(3-cyanophenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(3-氰基)丙烯酸酯的制备
将173.2mg(1.0mmol)3-氰基肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.10ml(1.2mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在30℃下反应3小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素567.8mg(1.5mmol)置于反应器中,依次加入10ml的CH2Cl2和0.08ml(1.0mmol)吡啶,并通入N2保护,后将3-氰基肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应5.5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物491.0mg,产率92.0%。化合物5的核磁共振氢谱如图9所示,核磁共振碳谱如图10所示。
1H NMR(400MHz,CDCl3)δ(ppm):7.78(s,1H),7.75–7.66(m,3H),7.52(t,J=7.8Hz,1H),6.54(d,J=16.1Hz,1H),6.46(dd,J=17.4,11.0Hz,1H),5.81(d,J=8.5Hz,1H),5.34(d,J=11.0Hz,1H),5.21(d,J=17.4Hz,1H),4.67(dd,J=36.4,16.0Hz,2H),3.36(d,J=6.2Hz,1H),2.32(t,J=6.8Hz,1H),2.25–2.16(m,2H),2.11–2.05(m,2H),1.79–1.60(m,4H),1.56–1.47(m,3H),1.44(s,3H),1.41–1.34(m,2H),1.18(s,3H),0.87(d,J=7.0Hz,3H),0.78(d,J=7.0Hz,3H).
13C-NMR(101MHz,CDCl3)δ(ppm):216.74,166.51,165.19,143.32,138.81,135.45,133.44,131.92,131.46,129.86,119.59,117.99,117.32,113.53,74.60,69.89,61.55,58.09,45.44,44.67,44.06,41.90,36.68,36.06,34.42,30.41,26.83,26.43,24.83,16.59,14.77,11.39.
实施例6
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(4-cyanophenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(4-氰基)丙烯酸酯的制备
将173.2mg(1.0mmol)4-氰基肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和氯化亚砜0.11ml(1.5mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在30℃下反应2小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的氯化亚砜得到肉桂酰氯备用。将截短侧耳素567.8mg(1.5mmol)置于反应器中,依次加入10ml的CH2Cl2和0.08ml(1.0mmol)吡啶,并通入N2保护,后将4-氰基肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应4.5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物437.6mg,产率82.0%。化合物6的核磁共振氢谱如图11所示,核磁共振碳谱如图12所示。
1H NMR(400MHz,CDCl3)δ7.78(d,J=16.1Hz,1H),7.73(d,J=8.3Hz,2H),7.66(d,J=8.4Hz,2H),6.62(d,J=16.0Hz,1H),6.51(dd,J=17.4,11.0Hz,1H),5.86(d,J=8.5Hz,1H),5.39(d,J=11.0,1H),5.26(d,J=17.4,1H),4.72(dd,J=37.2,16.0Hz,2H),3.41(d,J=6.5Hz,1H),2.37(t,J=6.8,1H),2.32–2.19(m,2H),2.18–2.09(m,2H),1.84–1.52(m,7H),1.49(s,3H),1.46–1.39(m,2H),1.23(s,3H),0.92(d,J=6.9Hz,3H),0.83(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ216.77,166.52,165.17,143.68,138.83,138.41,132.70,128.53,120.42,118.22,117.34,113.79,74.61,69.93,61.59,58.10,45.46,44.68,44.08,41.91,36.69,36.08,34.43,30.42,26.85,26.45,24.84,16.61,14.78,11.41.
实施例7
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(3,4-dimethoxyphenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环五[8]环烯-5-基)氧基)-2-氧代乙基3-(3,4-二甲氧基苯基)丙烯酸酯的制备
将208.2mg(1mmol)的3,4-二甲氧基肉桂酸、454.2mg(1.2mmol)截短侧耳素与17.1mg(0.01mmol)硅钼酸依次置于250mL反应器中,加入142.9ml离子液体1-丁基-3-甲基咪唑四氟硼酸盐充分溶解后,通入N2保护,在30℃下反应4h。薄层色谱法跟踪反应至完全,撤去保护装置。将反应混合体系静止分层,至于分液漏斗中,将离子液体层与酯层分离,所得酯层为肉桂酸酯类衍生物粗品。用50mL甲醇进行重结晶干燥即得肉桂酸酯类衍生物527.8mg,总收率为92.8%。化合物7的核磁共振氢谱如图13所示,核磁共振碳谱如图14所示。
1H NMR(400MHz,CDCl3)δ(ppm):7.75(d,J=15.9Hz,1H),7.18–7.07(m,2H),6.91(d,J=8.3Hz,1H),6.53(dd,J=17.3,11.0Hz,1H),6.42(d,J=15.9Hz,1H),5.85(d,J=8.5Hz,1H),5.39(d,J=10.9Hz,1H),5.23(t,J=17.0Hz,1H),4.68(dd,J=36.7,16.0Hz,2H),3.99–3.91(m,6H),3.40(s,1H),2.37(t,J=6.8Hz,1H),2.29–2.18(m,2H),2.14–2.09(m,2H),1.83–1.54(m,7H),1.49(s,3H),1.41(m,2H),1.22(s,3H),0.92(d,J=6.8Hz,3H),0.84(d,J=6.9Hz,3H).
13C-NMR(101MHz,CDCl3)δ(ppm):216.79,166.90,166.17,151.47,149.31,146.12,138.85,127.21,122.89,117.29,114.42,111.14,109.86,74.60,69.67,61.27,58.12,55.98,55.91,45.45,44.65,44.06,41.90,36.72,36.06,34.43,30.43,26.84,26.43,24.83,16.61,14.80,11.40.
实施例8
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(3-fluorophenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(3-氟苯基)丙烯酸酯的制备
将166.2mg(1.0mmol)反式-3-氟肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.17ml(2.0mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在25℃下反应4小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2和124.7mg(1.0mmol)DMAP,同时通入N2保护,后将反式-3-氟肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应6小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物475.6mg,产率90.3%。化合物8的核磁共振氢谱如图15所示,核磁共振碳谱如图16所示。
1H NMR(400MHz,CDCl3)δ7.76(d,J=16.0Hz,1H),7.45–7.31(m,2H),7.26(d,J=9.8Hz,1H),7.14(t,J=8.4Hz,1H),6.59–6.46(m,2H),5.85(d,J=8.4Hz,1H),5.40(d,J=11.0Hz,1H),5.26(d,J=17.4Hz,1H),4.69(d,J=16.0Hz,2H),3.40(d,J=6.4Hz,1H),2.37(t,J=7.2Hz,1H),2.32–2.18(m,2H),2.18–2.04(m,2H),1.88–1.51(m,6H),1.49(s,3H),1.46–1.31(m,2H),1.22(s,3H),1.19–1.09(m,1H),0.92(d,J=6.9Hz,3H),0.83(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ216.94,166.72,165.66,144.83,138.79,136.43,130.58,130.50,124.24,118.20,117.60,114.58,114.36,74.59,69.77,61.45,58.11,45.46,44.62,44.06,41.90,36.71,36.05,34.46,30.43,26.85,26.40,24.84,16.66,14.80,11.47.
实施例9
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(5-bromo-2-fluorophenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环五[8]环烯-5-基)氧基)-2-氧代乙基3-(5-溴-2-氟苯基)丙烯酸酯的制备
将245.1mg(1.0mmol)5-溴-2-氟肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.13ml(1.5mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在25℃下反应4小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素492.1mg(1.3mmol)置于反应器中,依次加入10ml的CH2Cl2和124.7mg(1.0mmol)DMAP,并通入N2保护,后将5-溴-2-氟肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物560.8mg,产率92.6%。化合物9的核磁共振氢谱如图17所示,核磁共振碳谱如图18所示。
1H NMR(400MHz,CDCl3)δ7.78(d,J=6.7Hz,1H),7.70(d,J=16.0Hz,1H),7.53–7.45(m,1H),7.19(t,J=8.4Hz,1H),6.58–6.44(m,2H),5.86(d,J=8.6Hz,1H),5.40(d,J=11.0Hz,1H),5.26(d,J=17.4Hz,1H),4.69(dd,J=40.0,16.0Hz,2H),3.41(d,J=6.4Hz,1H),2.37(t,J=8.0Hz,1H),2.32–2.21(m,2H),2.18–2.08(m,2H),1.86–1.50(m,6H),1.49(s,3H),1.41(d,J=15.9Hz,2H),1.23(s,3H),1.21–1.13(m,1H),0.92(d,J=6.8Hz,3H),0.83(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ216.78,166.62,165.43,143.37,138.80,133.17,128.87,128.79,117.95,117.33,117.14,116.92,74.59,69.80,61.45,58.10,45.44,44.64,44.05,41.89,36.69,36.05,34.43,30.41,26.83,26.42,24.83,16.61,14.78,11.41.
实施例10
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(4-(dimethylamino)phenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(4-(二甲氨基)苯基)丙烯酸酯的制备
将191.3mg(1mmol)4-二甲氨基肉桂酸、454.2mg(1.2mmol)截短侧耳素与17.1mg(0.01mmol)硅钼酸依次置于250mL反应器中,加入142.9ml离子液体1-丁基-3-甲基咪唑四氟硼酸盐充分溶解后,通入N2保护,在60℃下反应5h。薄层色谱法跟踪反应至完全,撤去保护装置。将反应混合体系静止分层,至于分液漏斗中,将离子液体层与酯层分离,所得酯层为肉桂酸酯类衍生物粗品。用50mL甲醇进行重结晶干燥即得肉桂酸酯类衍生物505.9mg,总收率为91.7%。化合物10的核磁共振氢谱如图19所示,核磁共振碳谱如图20所示。
1H NMR(400MHz,CDCl3)δ7.73(d,J=15.8Hz,1H),7.46(d,J=8.3Hz,2H),6.73(d,J=8.4Hz,2H),6.53(dd,J=17.5,11.0Hz,1H),6.32(d,J=15.9Hz,1H),5.84(d,J=8.6Hz,1H),5.39(d,J=10.9Hz,1H),5.25(d,J=17.4Hz,1H),4.66(dd,J=16.0Hz,2H),3.40(s,1H),3.07(s,6H),2.38(t,J=7.2Hz,1H),2.31–2.18(m,2H),2.17–2.02(m,2H),1.85–1.52(m,6H),1.49(s,3H),1.42(d,J=15.7Hz,2H),1.22(s,3H),1.11(d,J=18.5Hz,1H),0.92(d,J=7.0Hz,3H),0.84(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ217.04,167.21,166.83,146.72,138.83,130.01,117.39,111.99,111.00,74.60,69.48,61.12,58.13,45.46,44.57,44.04,41.89,40.26,36.75,36.03,34.48,30.44,26.84,26.36,24.84,16.68,14.82,11.49.
实施例11
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(4-fluorophenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(4-氟苯基)丙烯酸酯的制备
将166.2mg(1mmol)的4-氟肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.17ml(2mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在25℃下反应3.5小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2和0.14ml(1.0mmol)三乙胺,并通入N2保护,后将4-氟肉桂酸溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物498.4mg,产率为91.5%。化合物11的核磁共振氢谱如图21所示,核磁共振碳谱如图22所示。
1H NMR(400MHz,CDCl3)δ7.82(d,J=16.0Hz,1H),7.71–7.66(m,4H),6.62(d,J=15.9Hz,1H),6.56–6.48(m,1H),5.86(t,J=8.4Hz,1H),5.39(d,J=11.1Hz,1H),5.26(d,J=17.4Hz,1H),4.70(dd,J=23.4,2.7Hz,2H),3.40(s,1H),2.37(t,J=7.2Hz,1H),2.30–2.18(m,2H),2.16–2.10(m,3H),1.83–1.51(m,7H),1.49(s,3H),1.45–1.39(m,2H),1.22(s,3H),0.92(d,J=7.4Hz,3H),0.83(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ216.91,166.65,165.46,144.32,138.78,137.49,128.35,125.96,125.92,119.36,117.40,74.58,69.83,61.51,58.10,45.45,44.62,44.05,41.89,41.52,36.69,36.05,34.45,30.41,26.83,26.41,24.83,16.64,14.79,11.48.
实施例12
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(2,3,4-trifluorophenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(2,3,4-三氟苯基)丙烯酸酯的制备
将202.1mg(1.0mmol)3-(2,3,4-三氟苯基)丙烯酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.13ml(1.5mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在30℃下反应4小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素567.8mg(1.5mmol)置于反应器中,依次加入10ml的CH2Cl2和0.14ml(1.0mmol)三乙胺,并通入N2保护,后将3-(2,3,4-三氟苯基)丙烯酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴下反应5分钟后撤去冰浴装置,后在室温下反应6小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物506.3mg,产率90.0%。化合物12的核磁共振氢谱如图23所示,核磁共振碳谱如图24所示。
1H NMR(400MHz,CDCl3)δ7.72(d,J=16.0Hz,1H),7.40(t,J=9.3Hz,1H),7.28–7.21(m,1H),6.60–6.51(m,1H),6.48(d,J=16.6Hz,1H),5.86(d,J=8.5Hz,1H),5.41(d,J=11.0Hz,1H),5.27(d,J=17.4Hz,1H),4.70(dd,J=40.8,16.0Hz,2H),3.41(d,J=6.5Hz,1H),2.38(t,J=6.8Hz,1H),2.32–2.19(m,2H),2.18–2.08(m,2H),1.84–1.53(m,7H),1.50(s,3H),1.47–1.39(m,2H),1.23(s,3H),0.93(d,J=6.9Hz,3H),0.84(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ216.99,166.72,165.55,143.86,138.77,131.37,125.04,118.04,117.90,117.45,116.60,116.42,74.60,69.79,61.47,58.11,45.47,44.61,44.05,41.89,36.71,36.05,34.47,30.43,26.84,26.39,24.85,16.67,14.81,11.50.
实施例13
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(3-(benzyloxy)phenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(3-(苄氧基)苯基)丙烯酸酯的制备
将254.3mg(1mmol)3-氧基肉桂酸、454.2mg(1.2mmol)截短侧耳素与17.1mg(0.01mmol)硅钼酸依次置于250mL反应器中,加入142.9ml离子液体1-丁基-3-甲基咪唑四氟硼酸盐充分溶解后,通入N2保护,在30℃下反应6h。薄层色谱法跟踪反应至完全,撤去保护装置。将反应混合体系静止分层,至于分液漏斗中,将离子液体层与酯层分离,所得酯层为肉桂酸酯类衍生物粗品。用50mL甲醇进行重结晶干燥即得肉桂酸酯类衍生物557.0mg,总收率为90.6%。化合物13的核磁共振氢谱如图25所示,核磁共振碳谱如图26所示。
1H NMR(400MHz,CDCl3)δ7.76(d,J=16.0Hz,1H),7.56–7.32(m,5H),7.30(s,1H),7.17(d,J=2.5Hz,2H),7.06(d,J=8.8Hz,1H),6.55(d,J=11.0Hz,1H),6.51(d,J=9.9Hz,1H),5.86(d,J=8.6Hz,1H),5.40(d,J=11.0Hz,1H),5.26(d,J=17.5Hz,1H),5.13(s,2H),4.69(d,J=16.0Hz,2H),3.41(d,J=6.4Hz,1H),2.38(t,J=6.9Hz,1H),2.30–2.17(m,2H),2.17–2.07(m,2H),1.87–1.51(m,6H),1.49(s,3H),1.46–1.37(m,2H),1.23(s,3H),1.16(dd,J=14.2,4.5Hz,1H),0.93(d,J=7.0Hz,3H),0.84(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ216.73,166.81,166.02,159.17,146.12,138.82,136.65,135.61,129.99,128.67,128.12,127.47,121.20,117.40,117.13,114.21,74.62,70.65,70.17,61.39,58.13,45.45,44.79,44.03,41.96,41.50,36.70,36.06,34.43,30.42,26.85,26.39,24.85,16.73,14.80,11.46.
实施例14
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-([1,1'-biphenyl]-3-yl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-([1,1'-联苯]-4-基)丙烯酸酯的制备
将224.3mg(1.0mmol)4-苯基肉桂酸、454.2mg(1.2mmol)截短侧耳素与17.1mg(0.01mmol)硅钼酸依次置于250mL反应器中,加入142.9ml离子液体1-丁基-3-甲基咪唑四氟硼酸盐充分溶解后,通入N2保护,在30℃下反应8h。薄层色谱法跟踪反应至完全,撤去保护装置。将反应混合体系静止分层,至于分液漏斗中,将离子液体层与酯层分离,所得酯层为肉桂酸酯类衍生物粗品。用50mL甲醇进行重结晶干燥即得肉桂酸酯类衍生物533.3mg,总收率为91.2%。化合物14的核磁共振氢谱如图27所示,核磁共振碳谱如图28所示。
1H NMR(400MHz,CDCl3)δ7.86(d,J=15.9Hz,1H),7.70–7.63(m,6H),7.51(t,J=7.5Hz,2H),7.42(t,J=7.4Hz,1H),6.64–6.49(m,2H),5.87(d,J=8.4Hz,1H),5.41(d,J=11.0Hz,1H),5.27(d,J=17.6Hz,1H),4.71(d,J=9.0Hz,2H),3.41(d,J=6.4Hz,1H),2.38(t,J=7.0Hz,1H),2.26(p,J=10.2,9.6Hz,2H),2.13(d,J=18.6Hz,2H),1.87–1.53(m,7H),1.51(s,3H),1.49–1.39(m,2H),1.23(s,3H),0.93(d,J=6.8Hz,3H),0.86(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ216.96,166.88,166.06,145.80,143.40,140.10,138.82,133.13,128.93,128.76,127.93,127.61,127.08,117.41,116.57,74.60,70.85,61.39,57.75,45.89,44.63,44.06,41.91,37.31,36.05,34.47,30.05,26.86,26.40,24.85,16.68,14.82,11.48.
实施例15
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(4-(trifluoromethyl)phenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(4-(三氟甲基)苯基)丙烯酸酯的制备
将216.2mg(1.0mmol)(E)-4-三氟甲基肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.13ml(1.5mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在45℃下反应4小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2和0.14ml(1.0mmol)三乙胺,并通入N2保护,后将2-氟肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应5.5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物528.3mg,产率91.6%。化合物15的核磁共振氢谱如图29所示,核磁共振碳谱如图30所示。
1H NMR(400MHz,CDCl3)δ7.82(d,J=16.0Hz,1H),7.68(d,J=3.2Hz,4H),6.62(d,J=15.9Hz,1H),6.57–6.48(m,1H),5.86(d,J=8.4Hz,1H),5.39(d,J=11.1Hz,1H),5.26(d,J=17.4Hz,1H),4.70(dd,J=23.4,2.7Hz,2H),3.40(s,1H),2.42–2.33(m,1H),2.30–2.18(m,2H),2.13(q,J=8.5,7.0Hz,2H),1.86–1.51(m,7H),1.49(s,3H),1.46–1.34(m,2H),1.22(s,3H),0.92(d,J=7.4Hz,3H),0.83(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ216.91,166.65,165.46,144.32,138.78,137.49,128.35,125.96,125.92,119.36,117.40,74.58,69.83,61.51,58.10,45.45,44.62,44.05,41.89,41.52,36.69,36.05,34.45,30.41,26.83,26.41,24.83,16.64,14.79,11.48.
实施例16
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(3-(trifluoromethyl)phenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(3-(三氟甲基)苯基)丙烯酸酯的制备
将216.2mg(1.0mmol)3-三氟甲基肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.10ml(1.2mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在35℃下反应3小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2和0.08ml(1.0mmol)吡啶,并通入N2保护,后将3-三氟甲基肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应4.5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物532.3mg,产率92.3%。化合物16的核磁共振氢谱如图31所示,核磁共振碳谱如图32所示。
1H NMR(400MHz,CDCl3)δ7.82(d,J=13.5Hz,2H),7.74(d,J=7.8Hz,1H),7.69(d,J=7.9Hz,1H),7.57(t,J=7.9Hz,1H),6.61(d,J=15.7Hz,1H),6.52(dd,J=17.6,11.2Hz,1H),5.86(d,J=8.3Hz,1H),5.39(d,J=10.8Hz,1H),5.26(d,J=17.6Hz,1H),4.77–4.64(m,2H),3.40(d,J=6.4Hz,1H),2.37(t,J=7.2Hz,1H),2.31–2.19(m,J=9.5Hz,2H),2.17–2.08(m,2H),1.87–1.51(m,6H),1.49(s,3H),1.47–1.37(m,2H),1.22(s,3H),1.20–1.12(m,1H),0.92(d,J=6.8Hz,3H),0.83(d,J=6.9Hz,3H).
13C-NMR(101MHz,CDCl3)δ(ppm):216.80,166.62,165.43,144.29,138.82,137.53,128.33,125.95,125.91,119.41,117.36,74.61,69.86,61.52,60.36,58.11,45.46,44.67,44.07,41.91,36.70,36.07,34.43,30.43,26.85,26.43,24.84,21.00,16.62,14.79,14.18,11.42.
实施例17
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(4-(1H-imidazol-1-yl)phenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(4-((1H-咪唑-1-基)甲基)苯基)丙烯酸酯的制备
将228.3mg(1.0mmol)(E)-3-[4-(1H-咪唑-1-基甲基)苯基]-2-丙烯酸、454.2mg(1.2mmol)截短侧耳素与17.1mg(0.01mmol)硅钼酸依次置于250mL反应器中,加入142.9ml离子液体1-丁基-3-甲基咪唑四氟硼酸盐充分溶解后,通入N2保护,在30℃下反应6.5h。薄层色谱法跟踪反应至完全,撤去保护装置。将反应混合体系静止分层,至于分液漏斗中,将离子液体层与酯层分离,所得酯层为肉桂酸酯类衍生物粗品。用50mL甲醇进行重结晶干燥即得肉桂酸酯类衍生物527.6mg,,总收率为89.6%。化合物17的核磁共振氢谱如图33所示,核磁共振碳谱如图34所示。
1H NMR(400MHz,CDCl3)δ7.78(d,J=16.0Hz,1H),7.66(s,1H),7.56(d,J=7.8Hz,2H),7.22(d,J=7.7Hz,2H),7.16(s,1H),6.96(s,1H),6.53(t,J=14.9Hz,2H),5.85(d,J=8.6Hz,1H),5.39(d,J=10.9Hz,1H),5.26(d,J=17.4Hz,1H),5.20(s,2H),4.69(d,J=16.0Hz,2H),3.41(d,J=6.3Hz,1H),2.37(t,J=7.5Hz,1H),2.32–2.17(m,2H),2.19–2.06(m,2H),1.88–1.50(m,6H),1.48(s,3H),1.46–1.34(m,2H),1.22(s,3H),1.20–1.12(m,1H),0.92(d,J=6.9Hz,3H),0.83(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ217.02,166.77,165.81,145.17,138.81,138.54,137.44,134.25,129.75,128.80,127.75,119.33,117.50,117.37,74.55,69.76,61.40,58.10,50.48,45.45,44.59,44.04,41.88,36.69,36.04,34.46,30.41,26.83,26.43,24.82,16.65,14.79,11.48.
实施例18
化合物(E)-2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(naphthalen-2-yl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基3-(萘-2-基)丙烯酸酯的制备
将198.2mg(1.0mmol)3-(2-萘基)丙烯酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.17ml(2.0mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在50℃下反应4小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2和124.7mg(1.0mmol)DMAP,并通入N2保护,后将3-(2-萘基)丙烯酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应4小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物515.7mg,产率92.3%。化合物18的核磁共振氢谱如图35所示,核磁共振碳谱如图36所示。
1H NMR(400MHz,CDCl3)δ8.65(d,J=15.7Hz,1H),8.22(d,J=8.3Hz,1H),7.93(dd,J=12.7,8.3Hz,2H),7.81(d,J=7.2Hz,1H),7.64–7.51(m,3H),6.64(d,J=15.8Hz,1H),6.55(dd,J=17.5,11.1Hz,1H),5.87(d,J=8.5Hz,1H),5.41(d,J=10.9Hz,1H),5.27(d,J=17.4Hz,1H),4.82–4.66(m,2H),3.40(d,J=6.3Hz,1H),2.38(t,J=7.1Hz,1H),2.29–2.20(m,2H),2.17–2.11(m,2H),1.83–1.55(m,6H),1.51–1.41(m,6H),1.23(s,3H),0.91(d,J=6.8Hz,4H),0.86(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ217.00,166.87,165.92,143.28,138.81,133.68,131.47,131.41,130.89,128.79,127.00,126.31,125.49,125.26,123.32,119.31,117.45,74.60,69.73,61.45,58.12,45.47,44.62,44.07,41.92,36.73,36.05,34.47,30.43,26.86,26.40,24.84,16.71,14.84,11.50.
实施例19
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(2-fluoro-4-(trifluoromethyl)phenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(2-氟-4-(三氟甲基)苯基)丙烯酸酯的制备
将234.1mg(1.0mmol)3-(2-氟-4-(三氟甲基)苯基)丙烯酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.17ml(2.0mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在60℃下反应3小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2和124.7mg(1.0mmol)DMAP,并通入N2保护,后将3-(2-氟-4-(三氟甲基)苯基)丙烯酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应4小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物542.3mg,产率91.2%。化合物19的核磁共振氢谱如图37所示,核磁共振碳谱如图38所示。
1H NMR(400MHz,CDCl3)δ7.91(d,J=16.2Hz,1H),7.70(t,J=7.6Hz,1H),7.49(d,J=8.2Hz,1H),7.42(d,J=10.4Hz,1H),6.72(d,J=16.2Hz,1H),6.51(dd,J=17.5,11.0Hz,1H),5.85(d,J=8.4Hz,1H),5.39(d,J=10.9Hz,1H),5.26(d,J=17.4Hz,1H),4.70(dd,J=16.0Hz,2H),3.41(d,J=6.4Hz,1H),2.37(t,J=7.0Hz,1H),2.26(q,J=9.8,9.4Hz,2H),2.21–2.05(m,2H),1.88–1.51(m,6H),1.49(s,3H),1.41(d,J=16.2Hz,2H),1.22(s,3H),1.16(d,J=16.4Hz,1H),0.92(d,J=6.9Hz,3H),0.83(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ216.93,166.57,165.30,162.09,159.55,138.76,137.08,129.79,125.76,121.87,121.80,121.41,117.41,113.99,74.57,69.85,61.57,58.08,45.45,44.60,44.04,41.88,36.68,36.04,34.45,30.40,26.83,26.39,24.83,16.64,14.78,11.47.
实施例20
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(3-chloro-4-fluorophenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基3-(3-氯-4-氟苯基)丙烯酸酯的制备
将200.6mg(1.0mmol)3-氯-4-氟肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和草酰氯0.17ml(2.0mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在50℃下反应3小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的草酰氯得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2和124.7mg(1.0mmol)DMAP,并通入N2保护,后将3-氯-4-氟肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应4.5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物517.9mg,产率92.3%。化合物20的核磁共振氢谱如图39所示,核磁共振碳谱如图40所示。
1H NMR(400MHz,CDCl3)δ7.70(d,J=16.0Hz,1H),7.62(d,J=6.9Hz,1H),7.45(t,J=6.9Hz,1H),7.22(t,J=8.6Hz,1H),6.58–6.44(m,2H),5.85(d,J=8.4Hz,1H),5.40(d,J=11.0Hz,1H),5.26(d,J=17.4Hz,1H),4.69(d,J=16.0Hz,2H),3.41(d,J=6.4Hz,1H),2.41–2.33(m,1H),2.32–2.17(m,2H),2.12(d,J=18.9Hz,2H),1.86–1.50(m,6H),1.49(s,3H),1.41(d,J=15.8Hz,2H),1.22(s,3H),1.16(dd,J=14.1,4.1Hz,1H),0.92(d,J=6.8Hz,3H),0.83(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ216.98,166.69,165.52,143.57,138.77,131.53,130.24,128.18,128.11,117.90,117.43,117.35,117.13,74.58,69.77,61.46,58.09,45.45,44.60,44.04,41.88,36.69,36.03,34.46,30.41,26.83,26.39,24.83,16.65,14.80,11.48.
实施例21
化合物(E)-2-(((3aR,4R,5R,8S,9R,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethyl 3-(2-fluorophenyl)acrylate(E)-2-((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-羟基-4,7,9,12-四甲基-3-氧代-7-乙烯基十氢-4,9a-丙环戊[8]环烯-5-基)氧基)-2-氧代乙基-3-(2-(三氟甲基)苯基)丙烯酸酯的制备
将216.2mg(1.0mmol)邻三氟甲基肉桂酸置于反应器中,加入10mlCH2Cl2,通入N2保护,然后依次加入催化量的DMF(0.1ml)和氯化亚砜0.11ml(1.5mmol)于反应体系中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在45℃下反应4小时,反应完全后,撤去保护装置,减压浓缩除去CH2Cl2和过量的氯化亚砜得到肉桂酰氯备用。将截短侧耳素454.2mg(1.2mmol)置于反应器中,依次加入10ml的CH2Cl2,和0.08ml(1.0mmol)吡啶,同时通入N2保护,后将邻三氟甲基肉桂酰氯溶于5ml CH2Cl2中用恒压滴定管逐滴滴加到反应器中,先在冰浴条件下反应5分钟后撤去冰浴装置,后在室温下反应5小时。反应结束后,将反应混合体系减压浓缩除去CH2Cl2,所得浓缩液经水洗涤,乙酸乙酯萃取,柱层析分离提纯,干燥得到目标产物化合物474.6mg,产率82.3%。化合物21的核磁共振氢谱如图41所示,核磁共振碳谱如图42所示。
1H NMR(400MHz,CDCl3)δ8.17(d,J=15.8Hz,1H),7.75(d,J=7.7Hz,2H),7.62(t,J=7.8Hz,1H),7.54(t,J=7.9Hz,1H),6.56–6.49(m,2H),5.85(d,J=8.5Hz,1H),5.40(d,J=11.0Hz,1H),5.26(d,J=17.4Hz,1H),4.79–4.62(m,2H),3.40(s,1H),2.37(t,J=7.2Hz,1H),2.29–2.20(m,2H),2.14–2.09(m,2H),1.83–1.52(m,7H),1.48(s,3H),1.41(d,J=16.1Hz,2H),1.22(s,3H),0.91(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H).
13C NMR(101MHz,CDCl3)δ216.99,166.65,165.14,141.66,138.76,133.08,132.18,129.89,127.99,126.26,126.20,125.22,121.12,117.43,74.59,69.78,61.54,58.10,45.45,44.56,44.04,41.88,36.70,36.03,34.46,30.42,26.84,26.36,24.83,16.64,14.75,11.48.
2.化合物体外抗耐药菌活性测定
采用微量肉汤稀释法,以瑞他莫林、沃尼妙林和泰妙菌素为阳性对照品,测试截短侧耳素肉桂酸酯类化合物衍生物及其原料截短侧耳素的最低抑菌浓度(Minimuminhibitory concentration,MIC)。
实验菌株包括革兰氏阳性菌:甲氧西林敏感表皮葡萄球菌ATCC12228、金黄色葡萄球菌ATCC29213、ATCC25923和耐甲氧西林金黄色葡萄球菌ATCC33591;革兰氏阴性菌:鲍曼不动杆菌ATCC19606和大肠杆菌ATCC25922(所用菌株来源于美国模式培养物集存库(American type culture collection,ATCC))。
具体操作步骤如下:
(1)MHB培养基配制:称取MHB培养基(购于上海吉至生化科技有限公司)20.0g,加入到1L蒸馏水中,加热煮沸至完全溶解,分装于锥形瓶中,121℃高压灭菌15min,备用;
(2)实验菌株培养至对数生长期:无菌条件下,将实验菌株接种到100mL MHB培养基中,置于37℃恒温恒湿培养箱中培养20-22h,备用;
(3)贮存液制备:称取待测样品,用1%DMSO溶液溶解,配置成浓度为5120μg/mL的贮存液;称取阳性对照品,用无菌蒸馏水溶解,配置成浓度为5120μg/mL的贮存液;
(4)菌悬液制备:无菌条件下,将培养至对数生长期的实验菌株用MHB培养基校正到0.5麦氏单位浊度标准后按1:200的比例进行稀释,备用;
(5)贮存液稀释和接种实验菌株:取无菌96孔板一个,无菌条件下在第4-11孔加入10μL MHB培养基;第2孔中加入10μL阳性对照品液,第3、4孔中加入10μL化合物样品液;第4孔中样品液与培养基混匀,然后吸取10μL至第5孔,混匀后再吸取10μL至第6孔,如此连续倍比稀释至第10孔,并从第10孔中吸取10μL弃去,第11孔为溶剂对照;然后,在每孔中加入上述制备好的菌悬液190μL,使每孔最终的菌液浓度为5×105CFU/mL;至此,阳性对照品浓度为256μg/mL,样品液浓度依次为256、128、64、32、16、8、4、2μg/mL。
(6)孵育:将已接种实验菌株的96孔板盖好盖子,置37℃恒温恒湿箱中培育20-22h;
(7)MIC终点判读:黑色背景下肉眼观察96孔板中所见能完全抑制细菌生长的浓度为该样品对该种细菌的最低抑菌浓度,记录结果见表1,活性图见图43-图49(其中,小孔自左向右依次对应为阳性、256、128、64、32、16、8、4、2、阴性)。
表1受试药物和已上市药的最低抑菌浓度(μg·mL-1)
由表1可知,合成的化合物1至21均可以对甲氧西林敏感表皮葡萄球菌ATCC25923产生抑制作用,与测试的三种阳性药进行对比,化合物1、2、4、5、10、15的抑菌效果皆好于阳性药;合成的化合物1至21均可以对金黄色葡萄球菌ATCC25293、金黄色葡萄球菌ATCC29213和耐甲氧西林金黄色葡萄球菌ATCC33591产生抑制作用,尤其化合物10对细菌的抑菌效果最好,并且要远远好于进行测试的三种阳性药;合成的化合物1至21中大部分化合物都可以对大肠杆菌和鲍曼不动杆菌产生抑制作用,其中化合物10对大肠杆菌的抑制程度与三种阳性药中沃尼妙林的抑菌程度相当,虽然合成化合物对鲍曼不动杆菌的抑制程度均比不上三种阳性药中效果最好的沃尼妙林,但是化合物1、10、13对鲍曼不动杆菌的抑制程度可以达到泰妙菌素的抑制程度。结合表1中的数据可以看出尤以化合物10对测试的不同细菌的抑制程度均好于或等同于所测试的三种阳性药,可以进一步做临床研究。
3.化合物对细胞毒性的测定:
采用CCK-8法测定截短侧耳素衍生物体外细胞毒性(所用试剂盒购于上海西格生物科技有限公司)。取健康HepG2、HEK293和A549细胞培养液(所用细胞来源于美国模式培养物集存库(American type culture collection,ATCC),所用细胞培养液购于赛默飞世尔科技(中国)有限公司),接种于无菌96孔细胞培养板,180μL/孔,保证细胞个数为1*104个/孔,置37℃体积分数为5%的CO2培养箱孵育,培养24h,至细胞完全贴壁。加入浓度梯度药液,每孔20μL,平行设6个复孔,置37℃体积分数为5%的CO2培养箱37℃孵育24h,显微镜下观察细胞情况。每孔加入5g/L CCK-8溶液20μL,继续培养4h。终止培养,轻轻吸去孔内培养液,每孔加入二甲基亚砜100μL,置摇床上低速振荡10min,使结晶物充分溶解后,于酶联免疫检测仪OD490nm处测量各孔的吸光值。同时设置调零孔即空白对照组(培养基、CCK-8、二甲基亚砜),正常对照组(不含药物组)。根据半抑制浓度(IC50)来评价药物对HepG2、HEK293和A549细胞的细胞毒性,部分记录结果见表2及图50-图75。
表2受试药物和阳性药的半数抑制浓度(IC50)(μM)
表2显示了不同试验药物的半数抑制浓度(IC50),其中化合物1的毒性最小,对三种细胞的IC50值都大于200μM,显著高于瑞他莫林、沃尼妙林和泰妙菌素。此外,化合物4对HepG2细胞的细胞毒性为83.7μM,是泰妙菌素(IC50=27.12μM)的3.1倍;对HEK293细胞的细胞毒性为90.24μM,是沃尼妙林(IC50=31.1μM)的2.9倍。
由图50-图54可以得知化合物1在浓度为100μM、200μM时对HepG2、HEK293、A549细胞的抑制率均远远低于三种测试的阳性药;化合物10在浓度为100μM、200μM时对HepG2、A549细胞的抑制率均远远低于三种测试的阳性药,而且其在200μM时对HEK293细胞的抑制率远低于瑞他莫林和沃尼妙林。由以上结果可知,合成的化合物1和10在高浓度(>100μM)时对HepG2、HEK293、A549细胞的毒性较小,可以进一步做临床研究。
以上内容仅为说明本发明的技术思想,不能以此限定本发明的保护范围,凡是按照本发明提出的技术思想,在技术方案基础上所做的任何改动,均落入本发明权利要求书的保护范围之内。
Claims (10)
3.制备权利要求1所述的具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物的方法,其特征在于,合成路线Ⅰ如下:
将肉桂酸类化合物、截短侧耳素和催化剂溶于离子液体中,通入氮气保护,反应完全后得到截短侧耳素肉桂酸酯类化合物。
4.如权利要求3所述的方法,其特征在于,肉桂酸类化合物和截短侧耳素的摩尔比为1:1~1:1.2,催化剂为硅钼酸,离子液体为1-丁基-3-甲基咪唑四氟硼酸盐,反应的温度为20℃~60℃,反应的时间为4~8小时。
5.制备权利要求1所述的具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物的方法,其特征在于,合成路线Ⅱ如下:
1)肉桂酸类化合物在机溶剂中与酰氯化试剂作用,形成肉桂酰氯;
2)将步骤1)得到的肉桂酰氯与截短侧耳素溶于有机溶剂中,在催化剂的作用下反应得到截短侧耳素肉桂酸酯类化合物。
6.如权利要求5所述的方法,其特征在于,步骤1)中的酰氯化试剂为草酰氯、氯化亚砜或五氯化磷。
7.如权利要求5所述的方法,其特征在于,步骤1)中的肉桂酸类化合物和酰氯化试剂的摩尔比为1:1.2~1:3。
8.如权利要求5所述的方法,其特征在于,步骤2)中的肉桂酰氯和截短侧耳素的摩尔比为1:1~1:1.5,催化剂为三乙胺、吡啶或DMAP,反应时间为3~6小时。
9.权利要求1所述的具有抗耐药菌活性的截短侧耳素肉桂酸酯类化合物在制备抗耐药菌药物中的应用。
10.如权利要求9所述的应用,其特征在于,所述抗耐药菌药物为治疗多重耐药菌引起的感染性疾病的药物。
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