CN111518085B - 穿心莲内酯类化合物及其制备方法、药物组合物和其在抗肿瘤药物中的应用 - Google Patents
穿心莲内酯类化合物及其制备方法、药物组合物和其在抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明实施例公开了一种穿心莲内酯类化合物及其制备方法、药物组合物和其在抗肿瘤药物中的应用,本发明在对穿心莲内酯的结构改造的尝试中,在12位引入胺基,并使引入的胺基和17位的C重新成键,形成了新型的12,17‑氨基取代的三环穿心莲内酯类化合物,增强了化合物的生物活性,经实验验证,该类化合物对肿瘤细胞具有抑制作用。
Description
技术领域
本发明涉及化学制药领域,更具体地,涉及一种穿心莲内酯类化合物及其制备方法、药物组合物和其在抗肿瘤药物中的应用。
背景技术
天然产物对药物研究领域有着重要的意义,迄今为止,临床应用的药物中有三分之一以上直接来自天然产物或是以天然产物活性成分为先导化合物发展出来的衍生物。天然产物的多样性结构和易于与生物大分子结合的特点,决定了其在参与生命生理过程中所具有的无可比拟的优势,这些都赋予了天然产物在新药研发中不可替代的重要地位,是发现候选药物和药物先导结构的重要来源。
穿心莲内酯(Andrographo1ide)是从爵床科植物穿心莲中提取得到的主要二萜内酯成分之一,其结构如下式所示:
药理研究表明,穿心莲内酯及其衍生物具有消炎、抗菌、抗病毒感染、抗肿瘤、抗氧化、抗糖尿病、免疫调节、降血脂、保护心脏、肝以及神经等功效,被誉为天然抗生素药物。因其资源广泛,在动物体内吸收快且无明显的毒副作用,故具有较高的临床药用价值。比如,脱水穿心莲内酯琥珀酸半酯(穿琥宁注射液,炎琥宁注射液)、莲必治注射液、以及穿心莲内酯总酯磺化物(喜炎平注射液)被广泛的在临床使用,用于治疗上呼吸道感染等疾病。
近年来,国内外关于穿心莲内酯在抗肿瘤方面的研究已成为关注的热点。研究发现,穿心莲内酯及其衍生物通过各种不同的作用机制发挥抗肿瘤作用,其作用机制包括诱导肿瘤细胞凋亡、坏死和自噬、氧化应激诱导细胞死亡、阻滞肿瘤细胞周期、抑制肿瘤新生血管形成、抗炎和免疫系统介导的作用等多方面。穿心莲内酯在许多体内外模型上表现出中等强度的抗肿瘤作用,可以抑制白血病细胞、肝癌、乳腺癌、肺癌、前列腺癌、结肠癌、胰腺癌、脑癌、胃癌、骨癌、皮肤癌以及其它肿瘤细胞的生长,已经成为一类有前景、有潜力的抗肿瘤候选药物。尽管如此,由于穿心莲内酯具有生物利用度低,低水溶性(74μg/ml)以及相对较弱的稳定性,导致其抗肿瘤应用受到一定的限制,结构改造工作成为解决其生物利用度低、增强临床疗效的主要方法。
发明内容
本发明的目的之一为提供一种新型的穿心莲内酯类化合物,对穿心莲内酯的结构进行改造,提高穿心莲内酯的生物活性,增强穿心莲内酯的抗肿瘤药效。
为实现上述目的,本发明的技术方案如下:
一种穿心莲内酯类化合物,其结构如式(Ⅰ)所示:
其中,-R1选自-H、苄基、取代的苄基、芳基、杂环基、杂芳基、取代的C1~C10的直链烷基、取代的C3~C10的支链烷基和取代的环烷基中的任意一种;
-R2和-R3相同,所述-R2和所述-R3选自-H、甲基、乙基、丙基和-(O)CR4中的任意一种,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、取代的苯基、呋喃基、噻吩基和吡啶基中的任意一种;
本发明的目的之二为提供上述穿心莲内酯类化合物的制备方法,技术方案如下:
提供化合物A,所述化合物A的结构为:
其中,M1为烷基或-(O)CR4,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、取代的苯基、呋喃基、噻吩基和吡啶基中的任意一种;
-R2和-R3相同,所述-R2和所述-R3选自-H、甲基、乙基、丙基和-(O)CR4中的任意一种,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、取代的苯基、呋喃基、噻吩基和吡啶基中的任意一种;
或者-R2和-R3一起形成下列基团:-C(R5)(R6)-,-R5为-H、烷基或芳基,-R6为-H、烷基或芳基;
将所述化合物A、胺和碱性介质加入有机溶剂中,发生反应,得到化合物B,所述胺的化学式为R1-NH2,-R1选自选自-H、苄基、取代的苄基、芳基、杂环基、杂芳基、取代的C1~C10的直链烷基、取代的C3~C10的支链烷基和取代的环烷基中的任意一种,所述化合物B的结构为:
将所述化合物B、氢原子转移供体和光氧化还原催化剂加入有机溶剂中,在光的照射下发生反应,得到化合物C,所述化合物C的结构为:
本发明还公开了包括上述穿心莲内酯类化合物的药物组合物,以及公开了穿心莲内酯类化合物和包含其的药物组合物在制备抗肿瘤药物中的应用。
实施本发明实施例,将具有如下有益效果:
本发明在结构改造的尝试中,突破了现有的对3位、19位和14位的羟基的改造,在12位引入胺基,并使引入的胺基和17位的C重新成键,形成了新型的12,17-氨基取代的三环穿心莲内酯类化合物,增强了化合物的生物活性,经实验验证,该化合物对肿瘤细胞具有抑制作用。
具体实施方式
下面将结合具体实施例中对本发明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作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
对穿心莲内酯进行结构改造是发现新型抗肿瘤药物骨架的重要途径。目前,对穿心莲内酯的结构改造主要包括:对三个羟基不同程度的酯化、醚化以及氧化等;对端基烯烃的还原、环氧化以及环氧化开环等;对共轭烯烃的还原、加成以及[3+2]环加成等。本发明提出了新的改造思路和策略,利用一些新颖的合成方法和技术对穿心莲内酯的其他位置尝试改造,或以穿心莲内酯衍生物为底物进行进一步修饰改造,以期发现更多有价值的药物骨架。
下面简写词的使用贯穿本发明:
-Ac:CH3CO-,乙酰基
-Me:CH3,甲基
But:叔丁基
Et:CH3CH2-,乙基
AcOH:乙酸
THF:四氢呋喃
EtOH:CH3CH2OH,乙醇
本发明的穿心莲内酯类化合物,其结构如式(Ⅰ)所示:
所述式(Ⅰ)中,-R1选自-H、苄基、取代的苄基、芳基、杂环基、杂芳基、取代的C1~C10的直链烷基、取代的C3~C10的支链烷基和取代的环烷基中的任意一种;-R2和-R3相同,所述-R2和所述-R3选自-H、甲基、乙基、丙基和-(O)CR4中的任意一种,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、取代的苯基、呋喃基、噻吩基和吡啶基中的任意一种。
上述的“烷基”是指饱和烃基,只含有C和H两种原子,包括环烷基、直链烷基或支链烷基,其中,环烷基、直链烷基或支链烷基均可以是取代的也可以是非取代的。
在本发明的具体实施例中,C1~C10的直链烷基和C3~C10的支链烷基包括,但不限于,-CH2CH(CH3)2、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3或-CH2CH2CH(CH3)2等,取代的C1~C10的直链烷基和取代的C3~C10的支链烷基上的取代基任选。
上述的“环烷基”是指一价,非芳香族,饱和或部分不饱和环状烷基,可以是C3~C12的单环环烷基、C7~C12的双环环烷基或C7~C12的螺环环烷基,可以是取代的或非取代的,取代的环烷基包括一个、两个或两个以上取代基,取代基可以是,但不限于,羟基、胺基、-X、甲基、乙基、-CX3、-OCH3、-OCH2CH3、氰基、酯基、羧基和硝基等中的任意一种,其中,X为F、Cl、Br或I原子。在本发明的具体实施例中,环烷基可以是,但不限于,环丙基、环丁基、环戊基、环己基、环庚基、
上述的“苄基”是指甲苯分子中的甲基碳上去掉一个氢原子后剩下的一价基团。
上述的“取代的苄基”的苯环上含有一个、两个或两个以上的取代基,取代基可以是,但不限于,羟基、胺基、-X、甲基、乙基、-CX3、C3的环烷基、-OCH3、-OCH2CH3、苯基、吡啶基、嘧啶基、噻吩基、呋喃基、吡咯基、吡唑基、噻唑基、吲哚基、苯并噻吩基、苯并呋喃基、吗啉基、哌啶基、哌嗪基、四氢吡咯基、氰基、酯基、羧基、磺酰基、磺酰氨基、氨基磺酰基、酰胺基、氨基酰基、脲基、硫脲基、硝基、螺环基或螺环杂环基等中的任意一种,其中,X为F、Cl、Br或I原子。在本发明具体实施例中,取代的苄基包括,但不限于,、
上述的“芳基”是指芳烃分子的芳核碳上去掉一个氢原子后,剩下一价基团的总称,其可以为单环芳基或2~5环的稠环芳基,单环芳基和稠环芳基均可可以为取代或非取代的,取代的单环芳基或取代的稠环芳基的苯环上含有一个、两个或两个以上的取代基,取代基可以是,但不限于,羟基、胺基、-X、甲基、乙基、-CX3、-OCH3、-OCH2CH3和硝基等中的任意一种,其中,X为F、Cl、Br或I原子。在本发明的具体实施例中,芳基可以包括,但不限于,苯基、联苯基或萘基等。
上述的“杂环基”是指含有杂原子的环基,可以为3~12个原子的单环杂环基、7~12个原子的双环杂环基或7~12个原子的螺环杂环基,单环杂环基、双环杂环基或螺环杂环基的环上一个或多个原子可以独立任选地被杂原子所取代,杂原子可以是N、O、S或P等,环可以是完全饱和的或包含一个或多个不饱和度,一个或多个环上的氢原子可以被一个或多个取代基所取代,取代基可以是,但不限于,羟基、胺基、-X、甲基、乙基、-CX3、-OCH3、-OCH2CH3、氰基、酯基、羧基和硝基等中的任意一种,其中,X为F、Cl、Br或I原子。在本发明的具体实施例中,杂环基可以包括,但不限于,咪唑基、噻吩基或呋喃基、吡啶基、嘧啶基、噻吡咯基、吡唑基、噻唑基、吲哚基、苯并噻吩基、苯并呋喃基、吗啉基、哌啶基、哌嗪基、四氢吡咯基等。
上述的“杂芳基”是指含有1~3个苯环取代基的单环杂环基、含有1~3个苯环取代基的螺环杂环基、含有1~3个单环杂环取代基的苯基或含有1~3个单环杂环取代基的螺环杂环基,单环杂环基是指包含一个或多个杂原子的单环体系,苯环和/或单环杂环基上可以包括一个、两个或两个以上的取代基,取代基可以是,但不限于,羟基、胺基、-X、甲基、乙基、-CX3、C3的环烷基、-OCH3、-OCH2CH3、苯基、氰基、酯基、羧基和硝基等中的任意一种,其中,X为F、Cl、Br或I原子。在本发明的具体实施例中,杂芳基可以是,但不限于,苯并咪唑基、苯并噻吩基或苯并呋喃基、吲哚等。
优选地,-R1选自-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2CH(CH3)2、-CH(CH3)2、-CH2CH2CH(CH3)、环丙基、环丁基、环戊基、环己基、环庚基、
优选地,-R2和-R3为-H或-OAc;或者,-R2和-R3一起形成下列基团:-C(CH3)2-或-CH2-。
在本发明的具体实施例中,穿心莲内酯类化合物具体为下列式中之一的结构:
本发明的穿心莲内酯类化合物还可以是上述式(I)所示化合物的对映体、非对映体、互变体、盐、溶剂化物或各位置同位素取代形式的分子。
本发明还公开了上述穿心莲内酯类化合物的制备方法,包括以下步骤:
步骤1):提供化合物A,化合物A的结构为:
其中,M1为烷基或-(O)CR4,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、取代的苯基、呋喃基、噻吩基和吡啶基中的任意一种;
-R2和-R3相同,-R2和-R3选自-H、甲基、乙基、丙基和-(O)CR4中的任意一种,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、取代的苯基、呋喃基、噻吩基和吡啶基中的任意一种;
步骤2):将化合物A、胺和碱性介质加入有机溶剂中,发生反应,得到化合物B,胺的化学式为R1-NH2,-R1选自-H、环烷基、苄基、取代的苄基、芳基、杂环基、杂芳基、C1~C10的直链烷基和C3~C10的支链烷基中的任意一种,化合物B的结构为:
在本步骤中,胺对12位进行氨基化取代反应,具体的,胺可以为各种脂肪胺或芳香胺。-R1、-R2和-R3在前面段落中已详细介绍,在此不一一赘述。
在本步骤中,优选地,有机溶剂选自二氯甲烷、四氢呋喃、乙醚、1,4-二氧六环、甲苯、苯和氯仿中的一种、两种、三种或三种以上;碱性介质选自三乙胺、二异丙基乙基胺和吡啶中的一种、两种或三种,最优选三乙胺。
步骤3):将化合物B、氢原子转移供体和光氧化还原催化剂加入有机溶剂中,在光的照射下发生反应,得到化合物C,化合物C的结构为:
在本步骤中,发生分子内胺氢化反应,利用光氧化还原催化剂进行光催化反应。优选地,光氧化还原催化剂选自金属铱催化剂、金属铑催化剂和有机染料类催化剂中的任意一种;光氧化还原催化剂的当量为化合物B的当量的1%~10%,最优选2%。氢原子转移供体的当量为化合物B的当量的20%~100%,最优选50%;氢原子转移供体选自2,4,6-三异丙基苯硫酚、1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸二乙酯和1,4-环己二烯中的任意一种;光的波长范围为300nm~500nm,优选波长为460nm;有机溶剂可以为甲苯、苯、1,4-二氧六环、二氯甲烷、氯仿和四氢呋喃等中的至少一种,优选甲苯。
具体的,化合物A可以以穿心莲内酯为原料来制备,具体的制备方法可以有两种,分别如下:
第一种
将穿心莲内酯加入有机溶剂中,加入酰化剂或卤代烃,加入路易斯酸作为催化剂,酰化剂或卤代烃与穿心莲内酯的3位、19位和14位的-OH发生反应,得到化合物A。
在本步骤中,酰化剂与-OH发生酯化反应,酰化剂可以为酸酐或酰卤;酸酐和酰卤可以为取代或非取代,取代基可以为各种脂肪族或芳香族取代基。具体的,酸酐的化学式为:R4-C(O)-O-C(O)-R4,酰卤的化学式为R4-C(O)-卤素,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、取代的苯基、呋喃基、噻吩基和吡啶基中的任意一种;前面段落中对“卤素”的定义和解释同样适用本段落中的“卤素”。
上述酯化反应可以使用无水ZnCl2等路易斯酸进行催化。
有机溶剂可以为二氯甲烷、四氢呋喃、乙醚、1,4-二氧六环和甲苯等中的一种、两种或两种以上,优选二氯甲烷。
优选地,于25℃~100℃温度下反应(优选50℃),反应2h~5h。
如此,得到的化合物A中3位、19位和14位的取代基-M1=-R2=-R3=-(O)CR4。
上述过程中,酰化剂还可以用卤代烃代替,其余反应条件不变,卤代烃与-OH发生缩合反应,卤代烃的化学式为:烷基-卤素,前面段落中对“烷基”和“卤素”的定义和解释同样适用本段落中的“烷基”和“卤素”。得到的化合物A中的3位、19位和14位的取代基-M1=-R2=-R3=烷基。具体的,烷基可以为甲基、乙基、丙基、异丙基、丁基、异丁基等。
进一步的,通过上述步骤2)和步骤3)得到化合物C,具体的反应过程如下所示:
第二种
将穿心莲内酯、羰基化试剂和酸催化剂加入到反应介质中,在60℃~100℃(优选80℃)的反应温度下,羰基化试剂的羰基与穿心莲内酯的3位和19位的-OH发生缩合反应,得到化合物D。
在本步骤中,羰基化试剂对3位和19位的-OH进行缩酮或缩醛的改造,具体的,羰基化试剂的化学式为R5-C(OMe)2-R6或R5-CO-R6,-R5和-R6可以分别独立的选自以下基团:-H、烷基或芳基,前面段落中对“烷基”和“芳基”的定义和解释同样适用本段落中的“烷基”和“芳基”。如此,得到的化合物D的结构为:
优选地,该反应以甲苯和二甲亚砜的混合溶剂为反应介质,以对甲苯磺酸或浓硫酸作酸催化剂,酸催化剂的当量为穿心莲内酯的当量的10%~40%,最优选20%;羰基化试剂的当量为穿心莲内酯的当量的100%~600%,最优选400%。
进一步地,将化合物D加入有机溶剂中,加入酰化剂或卤代烃,加入碱性介质,酰化剂或卤代烃与化合物D的14位的-OH发生反应,得到化合物A。
在本步骤中,具体的,酰化剂为酸酐或酰卤;酸酐的化学式为:R4-C(O)-O-C(O)-R4,酰卤的化学式为R4-C(O)-卤素,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、取代的苯基、呋喃基、噻吩基和吡啶基中的任意一种,卤代烃的化学式为:烷基-卤素,前面段落中对“烷基”、“卤素”和“芳基”的定义和解释同样适用本段落中的“烷基”、“卤素”和“芳基”。具体的,烷基可以为甲基、乙基、丙基、异丙基、丁基、异丁基等。
如此,得到的化合物A中的-M1=烷基或-(O)CR4。
在本步骤中,优选地,酰化剂或卤代烃的当量为化合物D的当量的100%~600%;有机溶剂为二氯甲烷、四氢呋喃、乙醚、1,4-二氧六环和甲苯等中的一种、两种或两种以上,优选二氯甲烷;以三乙胺、二异丙基乙基胺、吡啶等中的一种、两种或两种以上作碱性介质,最优选三乙胺,碱性介质的当量为化合物D的当量的100%~600%。反应温度为室温到回流温度。
进一步的,通过上述步骤2)和步骤3)得到化合物C,具体的反应过程如下所示:
为了增加上述化合物C的水溶性或生物活性,还可以以化合物C为结构骨架,进一步拓展穿心莲内酯衍生物。
本发明还对3位和19位的-OH进行恢复,以化合物C-II为底物,加入反应溶剂,加入酸,发生水解反应,得到化合物E,化合物E的结构为:
在本步骤中,在酸性条件下进行水解反应,反应溶剂选自四氢呋喃、1,4-二氧六环和水中的一种、两种或两种以上;酸选自盐酸、对甲苯磺酸、硫酸和醋酸中的任意一种。更优地,反应溶剂为四氢呋喃和水,酸为醋酸,醋酸、四氢呋喃和水的体积比为(3.5~4.5):(0.5~1.5):(1.5~2.5)。
本发明还公开了一种药物组合物,包括上述的穿心莲内酯类化合物。
以及本发明进一步公开了上述的穿心莲内酯类化合物或上述的药物组合物在制备抗肿瘤药物中的应用。
优选地,抗肿瘤药物是抗鼻咽癌、宫颈癌、肝癌、乳腺癌、肺癌、前列腺癌、结肠癌、胰腺癌、脑癌、胃癌、骨癌、皮肤癌或白血病类类药物。
以下为具体实施例
实施例1
化合物I-a-1的制备:
在20ml的圆底烧瓶中,加入穿心莲内酯1(1.75g,5mmol)和20ml乙酸酐,搅拌5min之后,再称入催化量的无水ZnCl2(100mg,10mol%),升温至50℃,剧烈搅拌4h。悬浮液变得澄清时,降温至室温,加10ml EtOH和5ml水搅拌30min,抽滤得到白色固体II-1(1.9g,收率92%)。
在10ml的圆底烧瓶中,依次加入乙酰氧基保护的穿心连内酯II-1(190mg,0.4mmol),4-氟苄胺(0.72mmol,3当量),三乙胺(0.17ml,1.2mmol,1.2当量),再加入3ml二氯甲烷作为溶剂,室温搅拌3h。反应结束后,浓缩反应物,柱层析分离纯化得到产物III-1,收率28%。
在8ml的玻璃瓶中,依次加入氨基化的穿心莲内酯化合物III-1(0.05mmol,1当量),光氧化还原催化剂Ir(dF(Me)ppy)2(dtbbpy)]PF6(2mol%),2,4,6-三异丙基苯硫酚(6mg,0.025mmol,50mol%),然后再加入干燥过的甲苯(2ml),用油泵换氮气5次,用两盏40WKessil KSH150B blue LED lamp照射,室温搅拌18h,柱层析分离得到化合物I-a-1,收率53%。
化合物I-a-1的结构测定:1H NMR(500MHz,CDCl3)δ7.40(s,1H),7.22(dd,J=8.4,5.6Hz,2H),6.97(t,J=8.7Hz,2H),4.79(s,2H),4.56(dd,J=11.1,4.8Hz,1H),4.36(d,J=11.7Hz,1H),4.12–4.07(m,1H),3.77(d,J=13.8Hz,1H),3.14(d,J=9.3Hz,1H),2.92(d,J=13.8Hz,1H),2.77(dd,J=11.1,3.2Hz,1H),2.02(d,J=3.8Hz,6H),1.80–1.42(m,10H),1.16–1.04(m,2H),0.98(s,3H),0.85–0.76(m,5H);13C NMR(125MHz,CDCl3)δ173.26,170.87,170.42,162.85,160.90,145.78,137.22,134.71,134.68,129.78,129.72,115.15,114.98,80.02,70.30,64.96,60.18,59.24,58.51,55.22,53.77,41.18,36.63,35.93,34.90,32.97,31.82,23.78,22.58,21.74,21.12,21.02,14.43;HRMS(m/z)calc.forC31H41FNO6(+)542.2918,found 542.2918。
实施例2
化合物I-a-2的制备:
参照实施例1中的制备方法制备化合物III-2。在8ml的玻璃瓶中,依次加入氨基化的穿心莲内酯化合物III-2(0.05mmol,1当量),光氧化还原催化剂Ir(dFppy)2(dtbbpy)]PF6(2mol%),2,4,6-三异丙基苯硫酚(6mg,0.025mmol,50mol%),然后再加入干燥过的甲苯(2ml),用油泵换氮气5次,用两盏40WKessil KSH150B blue LED lamp照射,室温搅拌18h,柱层析分离得到化合物I-a-2,收率23%。
化合物I-a-2的结构测定:1H NMR(500MHz,CDCl3)δ7.39(s,1H),7.28–7.26(m,1H),7.22(t,J=7.8Hz,2H),7.17(d,J=7.0Hz,1H),4.79(s,2H),4.57(dd,J=11.1,4.6Hz,1H),4.37(d,J=11.7Hz,1H),4.11(d,J=11.8Hz,1H),3.78(d,J=14.0Hz,1H),3.15(d,J=9.6Hz,1H),2.93(d,J=14.0Hz,1H),2.76(dd,J=11.1,3.2Hz,1H),2.03(d,J=4.3Hz,6H),1.78–1.38(m,10H),1.17–1.03(m,2H),0.99(s,3H),0.85(s,5H);13C NMR(125MHz,CDCl3)δ173.36,170.99,170.53,145.91,137.17,132.59,129.65,129.07,128.48,128.26,125.33,80.05,77.33,77.07,76.82,70.40,65.02,60.27,59.25,58.61,55.22,53.74,41.19,36.64,35.96,34.91,32.99,31.82,23.80,22.63,21.76,21.21,21.11,14.47;HRMS(m/z)calc.for C31H41ClNO6(+)558.2622,found 558.2620。
实施例3
化合物I-a-3的制备:
参照实施例1中的制备方法制备化合物III-3。在8ml的玻璃瓶中,依次加入氨基化的穿心莲内酯化合物III-3(0.05mmol,1当量),光氧化还原催化剂Ir(ppy)2(dtbbpy)]PF6(2mol%),2,4,6-三异丙基苯硫酚(6mg,0.025mmol,50mol%),然后再加入干燥过的甲苯(2ml),用油泵换氮气5次,用两盏40W Kessil KSH150B blue LED lamp照射,室温搅拌18h,柱层析分离得到化合物I-a-3,收率50%。
化合物I-a-3的结构测定:1H NMR(300MHz,CDCl3)δ7.41(d,J=8.2Hz,3H),7.16(d,J=8.2Hz,2H),4.79(s,2H),4.57(dd,J=10.1,5.6Hz,1H),4.37(d,J=11.7Hz,1H),4.14–4.07(m,1H),3.76(d,J=14.0Hz,1H),3.15(d,J=10.1Hz,1H),2.92(d,J=14.0Hz,1H),2.76(d,J=8.3Hz,1H),2.03(d,J=2.8Hz,6H),1.82–1.36(m,10H),1.17–1.02(m,2H),0.98(s,3H),0.88–0.71(m,5H);13C NMR(75MHz,CDCl3)δ173.56,171.21,170.74,146.14,138.34,137.31,131.63,130.24,120.86,80.22,77.58,77.26,76.94,70.62,65.22,60.44,59.42,58.82,55.39,53.90,41.37,36.82,36.15,35.07,33.16,31.99,23.98,22.82,21.94,21.41,21.32,14.66;HRMS(m/z)calc.for C31H41BrNO6(+)602.2117,found602.2110。
实施例4
化合物I-a-4的制备:
参照实施例1中的制备方法制备化合物III-4。在8ml的玻璃瓶中,依次加入氨基化的穿心莲内酯化合物III-4(0.05mmol,1当量),光氧化还原催化剂Ir(dF(CF3)ppy)2(dtbbpy)]PF6(6mol%),2,4,6-三异丙基苯硫酚(6mg,0.025mmol,50mol%),然后再加入干燥过的甲苯(2ml),用油泵换氮气5次,用两盏40WKessil KSH150B blue LED lamp照射,室温搅拌18h,柱层析分离得到化合物I-a-4,收率52%。
化合物I-a-4的结构测定:1H NMR(300MHz,CDCl3)δ7.55(d,J=8.1Hz,2H),7.41(d,J=7.4Hz,3H),4.79(s,2H),4.57(dd,J=10.2,5.6Hz,1H),4.37(d,J=11.7Hz,1H),4.11(d,J=11.6Hz,1H),3.86(d,J=14.3Hz,1H),3.19(d,J=9.7Hz,1H),3.03(d,J=14.4Hz,1H),2.76(dd,J=10.7,2.5Hz,1H),2.03(d,J=2.2Hz,6H),1.87–1.34(m,10H),1.21–1.12(m,1H),1.12–1.04(m,1H),0.99(s,3H),0.91–0.75(m,5H);13C NMR(75MHz,CDCl3)δ173.53,171.21,170.75,146.17,143.71,137.31,129.64,129.26,128.63,128.45,125.50,125.46,80.22,77.58,77.26,76.94,70.60,65.22,60.61,59.44,59.03,55.40,53.90,41.37,36.82,36.16,35.10,33.15,31.98,23.98,22.82,21.94,21.41,21.31,14.66;HRMS(m/z)calc.for C32H41F3NO6(+)592.2886,found 592.2880。
实施例5
化合物I-a-5的制备:
参照实施例1中的制备方法制备化合物III-5。在8ml的玻璃瓶中,依次加入氨基化的穿心莲内酯化合物III-5(0.05mmol,1当量),光氧化还原催化剂9-均三甲基苯基-10-三甲基吖啶四氟硼酸盐(6mol%),2,4,6-三异丙基苯硫酚(6mg,0.025mmol,50mol%),然后再加入干燥过的甲苯(2ml),用油泵换氮气5次,用两盏40W Kessil KSH150B blue LED lamp照射,室温搅拌18h,柱层析分离得到化合物I-a-5,收率40%。
化合物I-a-5的结构测定:1H NMR(300MHz,CDCl3)δ8.16(d,J=8.6Hz,2H),7.48(d,J=8.5Hz,2H),7.40(s,1H),4.80(s,2H),4.57(dd,J=10.0,5.5Hz,1H),4.37(d,J=11.7Hz,1H),4.12(d,J=11.7Hz,1H),3.89(d,J=14.7Hz,1H),3.22(d,J=9.4Hz,1H),3.09(d,J=14.9Hz,1H),2.77–2.64(m,1H),2.03(d,J=1.9Hz,6H),1.74–1.57(m,10H),1.08(d,J=11.0Hz,2H),0.99(s,3H),0.87(s,5H);13C NMR(75MHz,CDCl3)δ173.41,171.23,170.78,147.51,147.33,146.34,137.22,129.01,123.87,80.22,77.59,77.27,76.95,70.60,65.23,60.78,59.50,58.92,55.41,53.92,41.39,36.84,36.19,35.14,33.07,31.98,23.99,22.84,21.94,21.44,21.34,14.69;HRMS(m/z)calc.for C31H41FN2O8(+)569.2863,found 569.2857。
实施例6
化合物I-a-6的制备:
参照实施例1中的制备方法制备化合物III-6。在8ml的玻璃瓶中,依次加入氨基化的穿心莲内酯化合物III-6(0.05mmol,1当量),9-均三甲基苯基-2,7,10-三甲基吖啶高氯酸盐(6mol%),2,4,6-三异丙基苯硫酚(6mg,0.025mmol,50mol%),然后再加入干燥过的甲苯(2ml),用油泵换氮气5次,用两盏40W Kessil KSH150B blue LED lamp照射,室温搅拌18h,柱层析分离得到化合物I-a-6,收率79%。
化合物I-a-6的结构测定:1H NMR(300MHz,CDCl3)δ7.42(s,1H),7.37–7.18(m,5H),4.78(s,2H),4.57(dd,J=10.2,5.6Hz,1H),4.36(d,J=11.7Hz,1H),4.10(d,J=12.0Hz,1H),3.82(s,1H),3.15(d,J=9.9Hz,1H),2.96(d,J=13.9Hz,1H),2.87–2.73(m,1H),2.02(d,J=2.3Hz,6H),1.60(qdd,J=26.7,12.8,2.8Hz,10H),1.11(dd,J=27.1,7.5Hz,2H),0.98(s,3H),0.88–0.74(m,5H);13C NMR(75MHz,CDCl3)δ173.65,171.15,170.68,146.01,139.28,137.42,130.11,128.50,127.09,80.21,77.58,77.26,76.94,70.59,65.18,60.47,59.48,59.41,55.37,53.89,41.34,36.79,36.11,35.06,33.23,31.99,29.96,29.88,29.51,27.40,23.97,22.79,21.92,21.38,21.28,21.24,14.63;HRMS(m/z)calc.forC31H42NO6(+)524.3012,found 524.3004。
实施例7
化合物I-a-7的制备:
参照实施例6中的制备方法制备化合物I-a-7,收率53%。化合物I-a-7的结构测定:1H NMR(500MHz,CDCl3)δ7.42(s,1H),7.15(d,J=7.9Hz,2H),7.10(d,J=7.8Hz,2H),4.79(s,2H),4.57(dd,J=11.2,4.8Hz,1H),4.37(d,J=11.7Hz,1H),4.11(d,J=11.7Hz,1H),3.80(d,J=13.7Hz,1H),3.14(d,J=10.3Hz,1H),2.94(d,J=13.8Hz,1H),2.83(dd,J=11.1,2.7Hz,1H),2.32(s,3H),2.02(d,J=3.7Hz,6H),1.80–1.40(m,10H),1.09(dd,J=21.0,19.2Hz,2H),0.98(s,3H),0.85–0.76(m,5H);13C NMR(125MHz,CDCl3)δ173.64,171.14,170.68,145.93,137.53,136.73,136.06,129.22,128.54,80.29,77.51,77.26,77.01,70.59,65.22,60.41,59.41,59.19,55.47,53.99,41.43,36.87,36.17,35.13,33.29,32.06,29.91,24.03,22.83,21.99,21.38,21.29,14.67,14.31;HRMS(m/z)calc.forC32H44NO6(+)538.3169,found 538.3159。
实施例8
化合物I-a-8的制备:
参照实施例6中的制备方法制备化合物I-a-8,收率53%。化合物I-a-8的结构测定:1H NMR(300MHz,CDCl3)δ7.44(s,1H),7.16(d,J=8.5Hz,2H),6.83(d,J=8.6Hz,2H),4.80(s,2H),4.56(dd,J=10.0,5.6Hz,1H),4.36(d,J=11.7Hz,1H),4.09(d,J=11.8Hz,1H),3.78(s,4H),3.12(d,J=9.7Hz,1H),2.92(d,J=13.6Hz,1H),2.81(d,J=8.3Hz,1H),2.02(d,J=2.5Hz,6H),1.80–1.37(m,10H),1.17–1.03(m,2H),0.97(s,3H),0.86–0.71(m,5H);13C NMR(75MHz,CDCl3)δ173.85,171.21,170.73,158.81,146.14,137.33,130.79,129.81,113.86,77.68,77.26,76.83,65.18,60.13,59.26,58.74,55.47,55.34,53.85,41.32,36.77,36.09,34.98,33.19,32.01,23.96,22.78,21.92,21.41,21.31,14.63;HRMS(m/z)calc.for C32H44FNO7(+)554.3118,found 554.3110。
实施例9
化合物I-a-9的制备:
参照实施例6中的制备方法制备化合物I-a-9,收率57%。化合物I-a-9的结构测定:1H NMR(300MHz,CDCl3)δ7.26(s,1H),7.11(d,J=8.1Hz,2H),6.75(d,J=8.4Hz,2H),4.84(s,2H),4.56(dd,J=10.0,5.8Hz,1H),4.36(d,J=11.7Hz,1H),4.13–4.07(m,1H),3.79(s,1H),3.00(m,4H),2.03(d,J=2.6Hz,6H),1.84–1.38(m,10H),1.15-1.02(m,2H),0.98(s,3H),0.86-0.76(m,5H).13C NMR(125MHz,CDCl3)δ172.92,171.04,170.59,152.64,135.92,125.06,124.16,115.29,105.83,80.05,67.11,66.68,65.03,60.41,59.10,58.54,55.18,41.18,36.62,35.96,33.63,31.85,29.73,23.78,22.62,21.74,21.21,21.11,14.43;HRMS(m/z)calc.for C31H43NO7(+)540.2961found 540.2956。
实施例10
化合物I-a-10的制备:
参照实施例6中的制备方法制备化合物I-a-10,收率44%。化合物I-a-10的结构测定:1H NMR(500MHz,CDCl3)δ7.42(s,1H),7.32(d,J=8.2Hz,2H),7.20(d,J=8.1Hz,2H),4.77(d,J=4.4Hz,2H),4.57(dd,J=11.3,4.7Hz,1H),4.37(d,J=11.7Hz,1H),4.12(d,J=11.7Hz,1H),3.81(d,J=13.9Hz,1H),3.15(d,J=10.1Hz,1H),2.96(d,J=13.9Hz,1H),2.87(dd,J=11.1,2.8Hz,1H),2.03(d,J=2.9Hz,6H),1.82–1.50(m,10H),1.31(s,9H),1.08(d,J=11.1Hz,2H),0.99(s,3H),0.86–0.78(m,5H);13C NMR(125MHz,CDCl3)δ173.66,171.14,170.68,150.08,145.91,137.60,136.19,128.21,125.44,77.52,77.26,77.01,60.56,59.43,59.13,55.50,54.00,41.46,36.90,36.21,35.18,34.70,33.34,32.10,31.64,24.06,22.86,22.02,21.39,21.28,14.69;HRMS(m/z)calc.for C35H50NO6(+)580.3638found 580.3629。
实施例11
化合物I-a-11的制备:
参照实施例6中的制备方法制备化合物I-a-11,收率47%。化合物I-a-11的结构测定:1H NMR(500MHz,CDCl3)δ7.43(d,J=7.1Hz,1H),7.36(s,1H),7.14(dt,J=16.7,7.1Hz,3H),4.75(d,J=8.5Hz,2H),4.59(dd,J=11.3,4.9Hz,1H),4.38(d,J=11.7Hz,1H),4.16–4.11(m,1H),3.68(d,J=14.5Hz,1H),3.19(d,J=10.3Hz,1H),3.07–2.98(m,1H),2.83(d,J=9.6Hz,1H),2.24(s,3H),2.03(d,J=3.5Hz,6H),1.79–1.58(m,10H),1.09(d,J=10.7Hz,2H),1.00(s,3H),0.91–0.85(m,5H);13C NMR(125MHz,CDCl3)δ173.83,171.22,170.75,145.98,137.46,136.64,130.35,128.41,126.82,126.07,77.58,77.26,76.94,70.61,65.28,60.82,59.83,57.26,55.44,54.00,41.39,36.85,36.17,35.18,33.42,32.04,24.02,22.84,21.98,21.43,21.33,19.60,14.68;HRMS(m/z)calc.for C32H44NO6(+)538.3169found 538.3176。
实施例12
化合物I-a-12的制备:
参照实施例6中的制备方法制备化合物I-a-12,收率57%。化合物I-a-12的结构测定:
1H NMR(300MHz,CDCl3)δ7.48(s,1H),7.34(t,J=7.4Hz,1H),7.24–7.15(m,1H),7.09(t,J=7.1Hz,1H),7.04–6.94(m,1H),4.83(s,2H),4.57(dd,J=10.3,5.4Hz,1H),4.36(d,J=11.7Hz,1H),4.10(d,J=11.8Hz,1H),3.81(d,J=13.8Hz,1H),3.12(dd,J=22.3,12.2Hz,2H),2.85(dd,J=11.0,2.8Hz,1H),2.02(d,J=1.8Hz,6H),1.83–1.37(m,10H),1.11(d,J=11.4Hz,2H),0.98(s,3H),0.86–0.75(m,5H);13C NMR(75MHz,CDCl3)δ173.59,171.11,170.65,162.54,160.58,146.14,137.15,131.26,128.88,124.12,115.61,115.44,80.25,77.51,77.26,77.01,70.63,65.20,60.37,59.58,55.44,53.86,52.68,41.42,36.85,36.16,35.06,33.31,32.07,24.02,22.83,21.97,21.37,21.27,14.65;HRMS(m/z)calc.for C31H41FNO6(+)542.2918found 542.2910。
实施例13
化合物I-a-13的制备:
参照实施例6中的制备方法制备化合物I-a-13,收率60%。化合物I-a-13的结构测定:1H NMR(400MHz,CDCl3)δ7.41(s,1H),7.21(t,J=8.1Hz,1H),6.86(d,J=7.0Hz,2H),6.77(d,J=7.5Hz,1H),4.78(s,2H),4.57(dd,J=10.8,5.0Hz,1H),4.37(d,J=11.7Hz,1H),4.12(d,J=11.6Hz,1H),3.81(s,3H),3.16(d,J=10.1Hz,1H),2.96(d,J=14.0Hz,1H),2.85(d,J=8.5Hz,1H),2.03(d,J=3.7Hz,6H),1.69–1.50(m,10H),1.16–1.03(m,2H),0.99(s,3H),0.85(s,5H);13C NMR(100MHz,CDCl3)δ173.41,171.21,170.73,159.94,145.97,141.17,137.48,129.54,120.82,114.31,112.09,80.27,77.58,77.46,77.26,76.94,70.63,65.26,60.64,59.36,55.47,53.94,41.40,36.85,36.17,35.13,33.31,32.05,29.70,24.02,22.84,21.99,21.42,21.33,14.68;HRMS(m/z)calc.for C32H44NO7(+)554.3118found 554.3118。
实施例14
化合物I-a-14的制备:
参照实施例6中的制备方法制备化合物I-a-14,收率57%。化合物I-a-14的结构测定:1H NMR(300MHz,CDCl3)δ7.42(s,1H),7.30(s,1H),7.21(d,J=5.7Hz,2H),7.17–7.10(m,1H),4.80(s,2H),4.58(d,J=9.6Hz,1H),4.37(d,J=11.7Hz,1H),4.11(d,J=11.6Hz,1H),3.80(d,J=14.1Hz,1H),3.16(d,J=10.1Hz,1H),2.93(d,J=14.1Hz,1H),2.78(d,J=8.2Hz,1H),2.03(d,J=3.0Hz,6H),1.84–1.34(m,10H),1.10(dd,J=17.6,16.0Hz,2H),0.99(s,3H),0.90–0.76(m,5H);13C NMR(75MHz,CDCl3)δ173.61,171.21,170.74,146.13,141.65,137.31,134.51,129.81,128.35,127.34,126.66,80.23,77.58,77.26,76.94,70.64,65.25,60.56,59.38,58.96,55.39,53.90,41.36,36.82,36.16,35.04,33.20,32.00,23.98,22.83,21.95,21.41,21.32,14.66;HRMS(m/z)calc.for C31H41ClNO6(+)558.2622found 558.2618。
实施例15
化合物I-a-15的制备:
参照实施例6中的制备方法制备化合物I-a-15,收率53%。化合物I-a-15的结构测定:1H NMR(400MHz,CDCl3)δ7.50(s,1H),7.35(d,J=1.1Hz,1H),6.28(dd,J=3.1,1.9Hz,1H),6.13(d,J=3.0Hz,1H),4.82(s,2H),4.57(s,1H),4.36(d,J=11.7Hz,1H),4.10(d,J=11.6Hz,1H),3.69(d,J=14.5Hz,1H),3.28(d,J=14.5Hz,1H),3.09(d,J=9.7Hz,1H),2.92(dd,J=11.3,3.4Hz,1H),2.02(d,J=6.3Hz,6H),1.77–1.38(m,10H),1.06(d,J=12.6Hz,2H),0.98(s,3H),0.83(s,3H),0.80–0.67(m,2H);13C NMR(100MHz,CDCl3)δ173.60,171.20,170.74,146.44,142.38,130.34,110.38,108.92,80.23,77.51,77.26,77.01,60.65,58.65,55.40,53.74,51.81,41.40,36.82,36.15,35.08,33.07,32.06,24.00,22.83,21.97,21.42,21.33,14.66;HRMS(m/z)calc.for C29H40NO7(+)514.2805found 514.2800。
实施例16
化合物I-a-16的制备:
参照实施例6中的制备方法制备化合物I-a-16,收率60%。化合物I-a-16的结构测定:1H NMR(300MHz,CDCl3)δ7.51(s,1H),7.20(d,J=4.9Hz,1H),6.93(dd,J=5.0,3.5Hz,1H),6.84(d,J=3.2Hz,1H),4.82(s,2H),4.56(dd,J=10.1,5.7Hz,1H),4.36(d,J=11.7Hz,1H),4.14–4.08(m,1H),3.89(d,J=14.5Hz,1H),3.36(d,J=14.5Hz,1H),3.17(d,J=9.6Hz,1H),2.95(dd,J=11.1,3.3Hz,1H),2.03(d,J=3.5Hz,6H),1.83–1.42(m,10H),1.09(s,2H),0.98(s,3H),0.87–0.73(m,5H);13C NMR(75MHz,CDCl3)δ173.65,171.21,170.73,146.09,142.71,137.10,126.91,125.65,124.84,80.23,77.58,77.47,77.26,76.94,70.74,65.23,60.42,58.72,55.39,53.93,53.82,41.38,36.82,36.15,35.13,33.33,32.02,23.99,22.83,21.95,21.42,21.32,14.65;HRMS(m/z)calc.for C29H40NO6S(+)530.2576found 530.2574。
实施例17
化合物I-a-17的制备:
参照实施例6中的制备方法制备化合物I-a-17,收率53%。化合物I-a-17的结构测定:.1H NMR(300MHz,CDCl3)δ8.14–8.06(m,1H),7.88–7.80(m,1H),7.74(d,J=8.1Hz,1H),7.61(d,J=6.9Hz,1H),7.52–7.39(m,3H),7.37(s,1H),4.64(dt,J=16.0,11.9Hz,3H),4.38(d,J=11.7Hz,1H),4.12(dd,J=13.3,5.6Hz,2H),3.55(d,J=14.6Hz,1H),3.28(d,J=9.9Hz,1H),2.87(dd,J=11.1,2.6Hz,1H),2.03(s,6H),1.86–1.42(m,10H),1.11(s,2H),0.99(s,3H),0.87(s,5H);13CNMR(75MHz,CDCl3)δ173.82,171.22,170.75,146.02,137.38,135.01,133.90,132.13,128.80,127.65,126.01,125.97,125.83,125.73,123.98,80.27,77.58,77.26,76.94,70.57,65.27,61.21,60.10,57.76,55.42,54.01,41.38,36.85,36.17,35.20,33.41,32.01,24.01,22.83,21.96,21.42,21.32,14.70;HRMS(m/z)calc.forC35H44NO6(+)574.3169found 574.3138。
实施例18
化合物I-a-18的制备:
参照实施例6中的制备方法制备化合物I-a-18,收率60%。化合物I-a-18的结构测定:1H NMR(300MHz,CDCl3)δ7.41(s,1H),7.34(d,J=6.7Hz,1H),7.09(dd,J=13.6,6.6Hz,2H),4.81(s,2H),4.58(d,J=9.2Hz,1H),4.37(d,J=11.6Hz,1H),4.11(d,J=11.5Hz,1H),3.75(d,J=13.9Hz,1H),3.15(d,J=10.1Hz,1H),2.89(d,J=14.0Hz,1H),2.74(d,J=9.0Hz,1H),2.03(s,6H),1.64(m,J=48.5,31.1,19.0Hz,10H),1.08(d,J=12.1Hz,2H),0.99(s,3H),0.86(s,5H);13C NMR(75MHz,CDCl3)δ173.52,171.21,170.75,158.51,156.05,146.15,137.29,136.50,130.26,128.10,128.03,121.12,120.95,116.65,116.44,80.22,77.58,77.27,76.95,70.62,65.23,60.42,59.39,58.34,55.39,53.92,41.36,36.82,36.16,35.05,33.14,32.00,23.98,22.83,21.94,21.41,21.32,14.66;HRMS(m/z)calc.forC31H40ClFNO6(+)576.2528found 576.2525。
实施例19
化合物I-a-19的制备:
参照实施例6中的制备方法制备化合物I-a-19,收率43%。化合物I-a-19的结构测定:1H NMR(400MHz,CDCl3)δ7.47(s,1H),4.87–4.78(m,2H),4.57(dd,J=10.8,5.3Hz,1H),4.37(d,J=11.7Hz,1H),4.12(d,J=11.7Hz,1H),3.16–3.02(m,2H),2.51(dd,J=11.6,5.4Hz,1H),2.03(d,J=8.3Hz,8H),1.71–1.42(m,10H),1.13–1.04(m,2H),0.99(s,3H),0.83(d,J=16.0Hz,10H);13C NMR(100MHz,CDCl3)δ173.66,171.18,170.73,139.16,114.38,80.20,77.51,77.26,77.00,70.71,65.20,59.95,59.12,57.07,55.38,53.79,41.38,36.79,36.15,34.80,32.73,32.11,23.97,22.82,21.99,21.41,21.33,19.26,14.61,12.04;HRMS(m/z)calc.for C27H42NO66(+)476.3012found 476.3005。
实施例20
化合物I-a-20的制备:
参照实施例6中的制备方法制备化合物I-a-20,收率30%。化合物I-a-20的结构测定:1H NMR(300MHz,CDCl3)δ7.66(s,1H),4.95–4.76(m,2H),4.65–4.48(m,1H),4.37(d,J=11.7Hz,1H),4.12(d,J=11.6Hz,1H),3.51(d,J=10.2Hz,1H),3.02(dd,J=39.3,8.4Hz,2H),2.04(d,J=6.4Hz,7H),1.71(ddd,J=16.5,10.0,4.6Hz,10H),1.16(d,J=6.6Hz,3H),1.10(s,2H),1.00(s,3H),0.98–0.93(m,3H),0.91–0.77(m,5H);13C NMR(75MHz,CDCl3)δ173.16,171.13,170.77,149.90,139.99,80.11,77.51,77.26,77.01,70.86,65.24,56.39,55.36,53.91,51.02,41.37,36.80,36.27,32.05,29.94,29.52,27.51,23.94,22.91,21.97,21.41,21.33,14.58;HRMS(m/z)calc.for C27H42NO6(+)476.3012found 476.3012。
实施例21
化合物I-a-21的制备:
参照实施例6中的制备方法制备化合物I-a-21,收率50%。化合物I-a-21的结构测定:1H NMR(300MHz,CDCl3)δ7.41(s,1H),4.93–4.78(m,2H),4.56(dd,J=10.1,5.9Hz,1H),4.37(d,J=11.7Hz,1H),4.11(dd,J=9.5,2.2Hz,1H),3.11–2.99(m,2H),2.59–2.46(m,1H),2.03(d,J=6.4Hz,8H),1.80–1.32(m,13H),1.14–1.04(m,2H),0.99(s,3H),0.86(d,J=7.3Hz,4H),0.85–0.74(m,5H);13CNMR(75MHz,CDCl3)δ173.70,171.19,170.73,146.57,136.77,77.58,77.26,76.94,70.64,65.18,60.12,59.24,55.39,55.06,53.85,41.38,36.79,36.13,35.01,32.93,32.15,28.53,23.98,22.81,22.00,21.41,21.33,20.87,14.62,14.21;HRMS(m/z)calc.for C28H44NO6(+)490.3169found 490.3164。
实施例22
化合物I-a-22的制备:
参照实施例6中的制备方法制备化合物I-a-22,收率47%。化合物I-a-22的结构测定:1H NMR(400MHz,CDCl3)δ7.32(s,1H),4.91–4.71(m,2H),4.57(dd,J=10.7,5.3Hz,1H),4.37(d,J=11.7Hz,1H),4.12(d,J=11.7Hz,1H),2.97(dd,J=18.2,8.9Hz,2H),2.10(t,J=12.0Hz,1H),2.03(d,J=7.6Hz,6H),1.81–1.43(m,12H),1.12–1.04(m,2H),0.99(s,3H),0.85(d,J=8.7Hz,8H),0.78(d,J=6.3Hz,4H);13C NMR(100MHz,CDCl3)δ173.92,171.22,170.73,146.18,137.79,80.28,77.58,77.26,76.94,70.54,65.24,63.57,60.65,59.84,55.43,53.81,41.40,36.80,36.11,35.10,33.46,32.24,25.92,24.00,22.83,22.03,21.51,21.43,21.34,20.80,14.66;HRMS(m/z)calc.for C28H44NO6(+)490.3169found490.3164。
实施例23
化合物I-a-23的制备:
参照实施例6中的制备方法制备化合物I-a-23,收率37%。化合物I-a-23的结构测定:1H NMR(400MHz,CDCl3)δ7.43(s,1H),4.91–4.75(m,2H),4.56(dd,J=10.7,5.4Hz,1H),4.36(d,J=11.7Hz,1H),4.17–4.09(m,1H),3.16–3.01(m,2H),2.62–2.52(m,1H),2.10–1.97(m,8H),1.77–1.39(m,11H),1.38–1.28(m,2H),1.16–1.05(m,2H),0.99(s,3H),0.88–0.72(m,11H);13C NMR(100MHz,CDCl3)δ173.55,171.07,170.64,146.42,136.39,80.24,77.51,77.26,77.01,70.62,65.17,60.56,60.11,59.27,55.46,53.90,53.55,41.45,36.85,36.18,35.21,34.99,32.83,32.15,29.90,26.72,24.01,23.06,22.83,22.59,22.03,21.35,21.27,14.63;HRMS(m/z)calc.for C29H46NO6(+)504.3325found 504.3323。
实施例24
化合物I-a-24的制备:
参照实施例1中的制备方法制备化合物I-a-24,收率47%。化合物I-a-24的结构测定:1H NMR(500MHz,MeOD)δ7.73(s,1H),4.94(dd,J=3.6,1.4Hz,2H),4.57(dd,J=11.6,4.6Hz,1H),4.46(d,J=11.7Hz,1H),4.14(d,J=11.7Hz,1H),3.55(d,J=10.5Hz,1H),3.44–3.33(m,1H),3.03(dd,J=11.5,3.4Hz,1H),2.27–2.10(m,1H),2.03(d,J=8.8Hz,6H),1.83–1.47(m,18H),1.21(d,J=13.8Hz,2H),1.03(s,3H),0.98–0.85(m,5H);13C NMR(125MHz,MeOD)δ173.83,171.37,170.93,151.14,139.40,80.12,71.09,64.53,62.01,58.10,54.80,53.11,51.59,48.11,47.94,47.77,47.60,47.43,47.26,47.09,41.01,36.10,35.61,34.02,31.32,28.22,24.27,23.96,23.36,22.18,21.55,21.47,19.68,19.59,13.28;HRMS(m/z)calc.for C29H44NO6(+)502.3169found 502.3163。
实施例25
化合物I-a-25的制备:
参照实施例1中的制备方法制备化合物I-a-25,收率37%。化合物I-a-25的结构测定:1H NMR(300MHz,CDCl3)δ7.39(s,1H),4.85(d,J=6.2Hz,2H),4.66–4.49(m,1H),4.38(d,J=11.7Hz,1H),4.11(d,J=11.7Hz,1H),3.47(d,J=9.5Hz,1H),2.88(d,J=10.3Hz,1H),2.42(s,1H),2.04(d,J=5.9Hz,6H),1.75–1.46(m,21H),1.11–1.05(m,2H),1.00(s,4H),0.86(s,5H);13C NMR(100MHz,CDCl3)δ171.54,171.10,170.79,146.49,133.32,80.01,77.56,77.25,76.93,75.48,65.32,63.69,55.26,54.67,54.01,52.72,41.29,36.79,36.28,34.40,32.17,31.88,29.93,29.55,24.40,23.86,22.93,21.92,21.41,21.32,14.53,14.30;HRMS(m/z)calc.for C30H46NO6(+)516.3325found 516.3326。
实施例26
化合物I-a-26的制备:
参照实施例1中的制备方法制备化合物I-a-26,收率43%。化合物I-a-26的结构测定:1H NMR(500MHz,MeOD)δ7.73(s,1H),5.01–4.90(m,2H),4.57(dd,J=11.6,4.6Hz,1H),4.46(d,J=11.7Hz,1H),4.14(d,J=11.7Hz,1H),3.66(s,1H),3.03(d,J=9.1Hz,1H),2.81(s,1H),2.31–2.09(m,1H),2.03(d,J=8.5Hz,6H),1.91–1.37(m,20H),1.28–1.08(m,4H),1.02(s,3H),0.98–0.82(m,5H);13C NMR(125MHz,MeOD)δ173.78,171.39,170.94,148.73,143.94,80.13,75.62,71.16,64.52,55.97,54.82,53.23,51.88,41.01,36.09,35.63,34.22,32.57,31.30,27.45,27.27,25.10,24.47,23.36,21.54,21.45,19.67,19.59,13.32;HRMS(m/z)calc.for C31H49NO6(+)530.3482found 530.3474。
实施例27
化合物I-b-1的制备:
将穿心莲内酯1(10.0g,28.54mmol)溶于甲苯(200ml)和二甲基亚砜(27ml)中,然后将2,2-二甲氧基丙烷(14ml)和对甲苯磺酸(催化当量)加入反应体系中。升温至80摄氏度搅拌反应2小时,然后将体系降至室温,加入7ml三乙胺淬灭反应。用150ml二氯甲烷萃取反应,水洗,分液,用无水硫酸钠干燥,减压蒸干,用乙醚打浆得到8.65g类白色固体化合物IV-1,收率78%。
将化合物IV-1(8.65g,22.17mmol)、乙酸酐(11.31g,110.86mmol)、三乙胺(11.22g,110.85mmol)和二氯甲烷(250ml)加入反应瓶中,升温到45摄氏度回流反应2小时。反应完后,降至室温,加入饱和碳酸氢钠水溶液淬灭反应直至没有气泡产生,然后用二氯甲烷萃取三次。有机相用水洗3次、盐水洗3次,分液后用无水硫酸钠干燥有机相。抽滤,减压浓缩后用柱层析(5~25%EA/PE)分离纯化,得到白色固体化合物V-1(8.52g,89%)。1H NMR(400MHz,CDCl3)δ7.03(dd,J=6.9,1.6Hz,1H),5.93(d,J=6.1Hz,1H),4.90(s,1H),4.64–4.46(m,2H),4.24(dd,J=11.2,1.9Hz,1H),3.96(d,J=11.6Hz,1H),3.50(dd,J=8.5,3.9Hz,1H),3.18(d,J=11.6Hz,1H),2.55–2.35(m,3H),2.12(s,3H),2.09–1.92(m,2H),1.92–1.67(m,4H),1.43(s,3H),1.37(s,3H),1.34–1.24(m,3H),1.20(s,3H),0.96(s,3H).
将化合物V-1(100mg,0.23ml)、苄胺(0.42mmol)、三乙胺(70mg,0.69mmol)和二氯甲烷(3ml)加入反应瓶中,在室温下搅拌反应3小时。反应完毕后,加入饱和碳酸氢钠水溶液淬灭反应,用二氯甲烷萃取3次,分液,有机相用水和盐水各洗一次。有机相用无水硫酸钠干燥,抽滤,减压浓缩后柱层析(5-30%EA/PE)纯化,得到42mg化合物VI-1,收率38%。
将化合物VI-1(30mg,1.0当量)、9-均三甲基-2,7,10-三甲基吖啶高氯酸盐(6mol%)和2,4,6-三异丙基苯-1-硫酚(0.5当量)加入透明的带特氟塞的8*16mm反应管中。将反应管密闭,加入2ml无水甲苯,用氮气置换3次以上,将反应管置于两个40W KessilKSH150B的蓝光灯照射下搅拌反应,体系逐渐变为深棕色,用TLC板监测反应,直至原料反应彻底。将反应体系减压浓缩,用制备级薄层色谱板分离得到20mg化合物I-b-1,收率67%。
化合物I-b-1的结构测定:1H NMR(300MHz,CDCl3)δ7.44(s,1H),7.7-7.32(m,5H),4.82(s,2H),3.99(d,J=11.7Hz,1H),3.84(d,J=13.8Hz,1H),3.44-3.50(m,1H),3.17-3.21(m,2H),3.95(d,J=14.1Hz,1H),2.83(d,J=8.4Hz,1H),1.93-2.02(m,2H),1.59-1.86(m,7H),1.43(s,3H),1.37(s,3H),1.17(s,3H),1.03(s,3H),0.76-1.03(m,4H);13CNMR(75MHz,CDCl3)δ173.52,145.67,137.22,130.10,128.31,126.90,98.91,70.44,63.94,60.40,59.36,59.26,53.63,52.34,37.53,35.21,34.09,33.24,31.37,29.29,27.32,26.10,25.49,24.73,20.39,15.93,14.10;HRMS(m/z)calc.for C30H42NO4(+)480.3108,found 480.3111。
实施例28
化合物I-b-2的制备:
参照实施例27中的制备方法制备化合物I-b-2,收率62%。化合物I-b-2的结构测定:1H NMR(400MHz,CDCl3)δ7.41(s,1H),7.22-7.26(m,2H),6.97-7.01(m,2H),4.82(s,2H),4.00(d,J=11.6Hz,1H),3.78(d,J=13.6Hz,1H),3.44-3.48(m,1H),3.13-3.20(m,2H),2.93(d,J=14.0Hz,1H),2.79(d,J=13.6Hz,1H),1.94-2.02(m,2H),1.80(d,J=12.8Hz,1H),1.70-1.74(m,1H),1.58-1.70(m,5H),1.43(s,3H),1.37(s,3H),1.17(s,3H),1.03(s,3H),0.81-1.01(m,4H);13CNMR(100MHz,CDCl3)δ173.44,145.67,137.18,134.51,129.84,115.19,114.98,98.92,70.40,63.94,60.28,59.36,58.50,53.65,52.33,37.53,35.20,34.08,33.18,31.37,29.66,27.30,26.10,25.49,24.72,20.38,15.92;HRMS(m/z)calc.forC30H41FNO4(+)498.3014,found498.3001.
实施例29
化合物I-b-3的制备:
参照实施例27中的制备方法制备化合物I-b-3,收率53%。化合物I-b-3的结构测定:H NMR(300MHz,CDCl3)δ7.27(s,1H),7.14(d,J=8.4Hz,2H),6.78(d,J=7.8Hz,2H),4.87(s,2H),4.00(d,J=11.7Hz,1H),3.82-3.92(m,1H),3.35-3.58(m,2H),3.22-3.32(m,1H),3.17(d,J=11.6Hz,2H),2.90(d,J=7.8Hz,1H),1.86-2.05(m,2H),1.83(d,J=13.2Hz,1H),1.79–1.47(m,7H),1.42(s,3H),1.37(s,3H),1.17(s,3H),1.04(s,3H),0.59-1.02(m,6H);13C NMR(100MHz,CDCl3)δ173.59,155.70,130.40,129.75,115.35,98.92,70.74,65.75,63.80,59.23,58.52,53.21,52.13,37.42,35.09,34.61,33.92,31.13,29.57,29.19,27.19,25.98,25.38,22.56,20.22,15.76,15.11,14.00;HRMS(m/z)calc.forC30H42NO5(+)496.3057,found 496.3058。
实施例30
化合物I-b-4的制备:
参照实施例27中的制备方法制备化合物I-b-4,收率40%。化合物I-b-4的结构测定:1H NMR(400MHz,CDCl3)δ7.50–7.35(m,3H),7.17(d,J=8.0Hz,2H),4.83(d,J=9.7Hz,2H),4.01(d,J=11.7Hz,1H),3.78(d,J=13.7Hz,1H),3.46(dd,J=9.0,4.1Hz,1H),3.30–3.04(m,1H),2.93(d,J=14.2Hz,1H),2.77(d,J=8.8Hz,1H),2.06–1.89(m,2H),1.82(d,J=13.0Hz,1H),1.70(dd,J=11.2,6.8Hz,3H),1.65–1.49(m,6H),1.43(s,3H),1.37(s,3H),1.17(s,3H),1.03(s,3H),0.97(dd,J=8.2,4.8Hz,2H),0.93–0.73(m,4H);13CNMR(100MHz,CDCl3)δ173.32,145.97,137.16,131.48,131.28,129.89,98.83,70.30,63.85,60.30,59.26,58.52,53.55,52.24,37.45,35.11,33.98,33.09,31.80,31.26,29.57,29.19,27.19,26.01,25.40,24.62,22.57,20.29,15.83,14.00;HRMS(m/z)calc.for C30H41BrNO4(+)558.2213,found 558.2213。
实施例31
化合物I-b-5的制备:
参照实施例27中的制备方法制备化合物I-b-5,收率66%。化合物I-b-5的结构测定:1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.21(d,J=4.8Hz,1H),6.97–6.89(m,1H),6.85(s,1H),4.84(s,2H),4.02(d,J=11.6Hz,1H),3.90(d,J=14.4Hz,1H),3.46(dd,J=9.1,4.1Hz,1H),3.37(d,J=14.5Hz,1H),3.18(t,J=9.7Hz,2H),2.96(dd,J=11.0,2.8Hz,1H),2.04–1.87(m,1H),1.84(d,J=12.8Hz,1H),1.78–1.51(m,7H),1.43(s,3H),1.37(s,3H),1.18(s,3H),1.02(s,3H),0.95–0.64(m,4H);13CNMR(100MHz,CDCl3)δ173.49,145.66,142.53,137.92,126.67,125.37,124.57,98.92,70.53,63.95,60.40,58.68,53.72,53.64,52.34,37.54,35.31,35.26,34.10,33.32,31.38,29.68,27.33,26.11,25.50,24.73,20.39,15.93;HRMS(m/z)calc.for C28H40NO4S(+)486.2673,found 486.2673。
实施例32
化合物I-b-6的制备:
参照实施例27中的制备方法制备化合物I-b-6,收率67%。化合物I-b-6的结构测定:1H NMR(400MHz,CDCl3)δ7.55(t,J=8.8Hz,2H),7.42(d,J=8.8Hz,3H),4.94–4.66(m,2H),4.01(d,J=11.6Hz,1H),3.88(d,J=14.4Hz,1H),3.47(dd,J=9.0,4.1Hz,1H),3.19(d,J=11.5Hz,1H),3.05(d,J=14.4Hz,1H),2.77(d,J=8.6Hz,1H),2.09–1.90(m,1H),1.84(d,J=12.8Hz,1H),1.78–1.49(m,6H),1.43(s,3H),1.37(s,3H),1.18(s,3H),1.04(s,3H),1.03–0.97(m,1H),0.96–0.70(m,3H);13CNMR(100MHz,CDCl3)δ177.47,173.39,145.73,144.06,137.14,128.39,125.22,98.95,70.39,63.96,60.58,59.38,58.82,53.64,52.32,37.56,35.29,35.22,34.07,33.20,31.34,29.77,27.27,26.11,25.50,24.71,20.38,15.94;HRMS(m/z)calc.for C31H41F3NO4(+)548.2982,found 548.2982。
实施例33
化合物I-b-7的制备:
参照实施例27中的制备方法制备化合物I-b-7,收率57%。化合物I-b-7的结构测定:1H NMR(400MHz,CDCl3)δ7.44(s,1H),7.19(d,J=8.3Hz,2H),6.85(d,J=8.6Hz,2H),4.83(s,2H),4.02(d,J=11.5Hz,1H),3.80(s,3H),3.77(s,1H),3.46(dd,J=9.1,4.1Hz,1H),3.19(d,J=11.6Hz,1H),3.13(d,J=11.7Hz,1H),2.93(d,J=14.5Hz,1H),2.83(d,J=9.5Hz,1H),2.10–1.88(m,2H),1.82(d,J=12.8Hz,1H),1.78–1.61(m,7H),1.43(s,3H),1.37(s,3H),1.18(s,3H),1.03(s,3H),0.98-1.01(m,1H),0.96–0.68(m,4H);13CNMR(100MHz,CDCl3)δ173.52,159.05,145.78,129.89,129.86,129.61,129.59,113.70,98.91,70.47,60.23,59.26,58.59,55.25,53.63,52.34,37.53,35.21,34.10,33.37,32.46,31.39,29.67,29.30,27.33,27.21,26.10,25.49,24.73,22.93,20.39,15.93,14.34;HRMS(m/z)calc.for C31H44NO5(+)510.3214,found 510.3209。
实施例34
化合物I-b-8的制备:
参照实施例27中的制备方法制备化合物I-b-8,收率63%。化合物I-b-8的结构测定:1H NMR(400MHz,CDCl3)δ7.44(s,1H),7.33(d,J=8.2Hz,2H),7.21(d,J=8.0Hz,2H),4.92–4.68(m,2H),4.02(d,J=11.6Hz,1H),3.82(d,J=13.9Hz,1H),3.46(dd,J=9.1,4.1Hz,1H),3.24–3.08(m,2H),2.97(d,J=14.0Hz,1H),2.88(d,J=8.2Hz,1H),2.11–1.91(m,2H),1.84(d,J=13.2Hz,1H),1.78–1.63(m,6H),1.43(s,3H),1.36(s,3H),1.32(s,9H),1.18(s,3H),1.03(s,3H),0.99(s,1H),0.95–0.65(m,4H);13CNMR(100MHz,CDCl3)δ173.92,145.84,137.54,136.08,127.97,125.20,98.91,70.43,63.96,60.42,59.29,58.92,55.57,53.63,52.36,37.54,35.22,34.44,34.10,33.37,31.36,29.68,29.39,27.34,26.11,25.50,24.74,22.74,20.40,15.94;HRMS(m/z)calc.for C34H50NO4(+)536.3734,found536.3735。
实施例35
化合物I-b-9的制备:
参照实施例27中的制备方法制备化合物I-b-9,收率70%。化合物I-b-9的结构测定:1H NMR(400MHz,CDCl3)δ8.17(d,J=8.7Hz,2H),7.49(d,J=8.6Hz,2H),7.41(s,1H),4.91–4.71(m,2H),4.02(d,J=11.6Hz,1H),3.90(d,J=14.9Hz,1H),3.47(dd,J=9.1,4.1Hz,1H),3.21(t,J=10.1Hz,1H),3.10(d,J=14.9Hz,1H),2.76–2.65(m,1H),2.07–1.89(m,2H),1.84(d,J=13.0Hz,1H),1.58-1.72(m,6H),1.43(s,3H),1.37(s,3H),1.18(s,3H),1.05(s,3H),1.01(d,J=10.9Hz,1H),0.95–0.74(m,4H);13CNMR(100MHz,CDCl3)δ173.34,147.31,147.02,145.95,137.03,128.77,123.62,114.06,98.98,70.43,63.96,60.73,59.42,58.71,53.65,53.46,52.30,37.57,35.31,35.23,34.07,33.12,31.32,29.70,27.30,26.12,25.51,24.71,20.37,15.97;HRMS(m/z)calc.for C30H41N2O6(+)525.2959,found 525.2951。
实施例36
化合物I-b-10的制备:
参照实施例27中的制备方法制备化合物I-b-10,收率70%。化合物I-b-10的结构测定:1H NMR(400MHz,CDCl3)δ7.41(s,1H),7.35(d,J=5.3Hz,1H),7.16–7.10(m,1H),7.07(t,J=8.6Hz,1H),4.95–4.73(m,2H),4.02(d,J=11.6Hz,1H),3.77(d,J=14.3Hz,1H),3.47(dd,J=9.0,4.0Hz,1H),3.24–3.12(m,2H),2.91(d,J=14.1Hz,1H),2.76(d,J=7.7Hz,1H),2.06–1.88(m,2H),1.82(d,J=12.8Hz,1H),1.57-1.72(m,6H),1.43(s,3H),1.37(s,3H),1.18(s,3H),1.04(s,3H),1.00(d,J=10.8Hz,1H),0.82-0.88(m,4H);13CNMR(100MHz,CDCl3)δ173.38,145.70,137.15,136.60,130.02,127.85,122.61,116.41,98.94,70.41,63.95,60.40,59.34,58.14,53.66,52.32,37.55,35.22,34.08,33.18,31.36,29.67,27.29,26.12,25.50,24.72,20.38,15.94;HRMS(m/z)calc.for C30H40ClFNO4(+)532.2624,found532.2624。
实施例37
化合物I-b-11的制备:
参照实施例27中的制备方法制备化合物I-b-11,收率67%。化合物I-b-11的结构测定:1H NMR(400MHz,CDCl3)δ7.44(s,1H),7.17(d,J=7.9Hz,2H),7.12(d,J=7.9Hz,2H),4.82(s,2H),4.02(d,J=11.6Hz,1H),3.82(d,J=13.6Hz,1H),3.46(dd,J=9.1,4.1Hz,1H),3.19(d,J=8.9Hz,1H),3.14(d,J=10.2Hz,1H),2.94(d,J=13.7Hz,1H),2.84(d,J=8.2Hz,1H),2.34(s,3H),2.08–1.90(m,2H),1.78–1.67(m,2H),1.66–1.60(m,5H),1.43(s,3H),1.37(s,3H),1.17(s,3H),1.02(s,3H),0.82-0.98(m,5H);13CNMR(100MHz,CDCl3)δ173.45,145.49,137.80,136.59,136.00,128.89,128.22,98.80,70.35,63.84,60.28,59.21,58.84,53.53,52.26,37.43,35.11,34.00,33.13,31.27,29.57,29.37,27.24,26.00,25.39,24.64,20.97,20.30,15.83;HRMS(m/z)calc.for C31H44NO4(+)494.3265,found 494.3270。
实施例38
化合物I-b-12的制备:
参照实施例27中的制备方法制备化合物I-b-12,收率70%。化合物I-b-12的结构测定:1H NMR(400MHz,CDCl3)δ7.52(d,J=6.7Hz,1H),7.35(s,1H),7.21–7.12(m,2H),7.03–6.96(m,1H),4.83–4.69(m,2H),4.03(d,J=11.7Hz,1H),3.82(d,J=14.8Hz,1H),3.47(dd,J=9.1,4.1Hz,1H),3.36(d,J=14.7Hz,1H),3.22(t,J=12.4Hz,2H),2.90–2.85(m,1H),2.08–1.81(m,3H),1.80–1.61(m,8H),1.44(s,3H),1.38(s,3H),1.19(s,3H),1.04(s,3H),1.02(d,J=12.8Hz,1H),0.93–0.78(m,6H),0.70–0.59(m,1H),0.57–0.47(m,1H);13CNMR(100MHz,CDCl3)δ173.67,145.42,141.00,138.73,137.35,127.64,126.54,125.79,125.62,98.89,70.41,63.95,60.94,59.85,56.37,53.75,52.44,37.54,35.36,35.25,34.16,33.39,31.40,29.68,27.38,26.14,25.54,24.80,20.42,15.93,12.69,7.44,6.60;HRMS(m/z)calc.for C33H46NO4(+)520.3421,found 520.3414.
实施例39:化合物I-b-13的制备:
参照实施例27中的制备方法制备化合物I-b-13,收率60%。化合物I-b-13的结构测定:1H NMR(400MHz,CDCl3)δ8.16–8.06(m,1H),7.85(dd,J=6.0,3.4Hz,1H),7.75(d,J=8.2Hz,1H),7.63(d,J=6.9Hz,1H),7.55–7.40(m,3H),7.37(s,1H),4.71(dt,J=45.9,9.8Hz,2H),4.14(d,J=14.5Hz,1H),4.02(d,J=11.6Hz,1H),3.57(d,J=14.6Hz,1H),3.48(dd,J=9.0,4.1Hz,1H),3.29(d,J=9.2Hz,1H),3.19(d,J=11.5Hz,1H),2.89(dd,J=11.1,2.9Hz,1H),1.95-2.05(m,2H),1.87(d,J=12.8Hz,1H),1.78–1.68(m,2H),1.69–1.60(m,5H),1.44(s,3H),1.38(s,3H),1.18(s,3H),1.05(s,3H),1.02(d,J=11.3Hz,1H),0.94–0.79(m,4H);13CNMR(100MHz,CDCl3)δ173.68,145.57,137.22,134.84,133.65,131.87,128.56,127.36,125.75,125.66,125.57,125.50,123.70,98.91,70.35,63.96,61.23,60.06,57.55,53.75,52.42,37.54,35.39,35.25,34.16,33.45,31.38,29.68,27.36,26.13,25.54,24.80,20.40,15.95;HRMS(m/z)calc.for C34H44NO4(+)530.3265,found530.3269。
实施例40
化合物I-b-14的制备:
参照实施例27中的制备方法制备化合物I-b-14,收率58%。化合物I-b-14的结构测定:1H NMR(400MHz,CDCl3)δ7.63(d,J=8.2Hz,2H),7.39(s,1H),7.05(d,J=8.2Hz,2H),4.87–4.73(m,2H),4.01(d,J=11.6Hz,1H),3.77(d,J=14.2Hz,1H),3.46(dd,J=9.0,4.2Hz,1H),3.17(dd,J=16.1,10.7Hz,2H),2.92(d,J=14.1Hz,1H),2.77(d,J=8.1Hz,1H),2.09–1.89(m,2H),1.82(d,J=12.8Hz,1H),1.71(dd,J=13.3,5.0Hz,2H),1.67–1.61(m,6H),1.43(s,3H),1.37(s,3H),1.22(dd,J=11.6,4.4Hz,2H),1.18(s,3H),1.13(dd,J=8.5,5.4Hz,1H),1.03(s,3H),1.00(d,J=13.0Hz,1H),0.93–0.71(m,4H);13CNMR(100MHz,CDCl3)δ173.42,145.65,138.85,137.36,137.19,130.28,98.93,92.05,70.40,63.95,60.45,59.35,58.71,53.65,52.33,37.55,35.29,35.21,34.08,33.21,31.35,29.68,27.30,26.11,25.50,24.72,20.39,15.94;HRMS(m/z)calc.for C30H41INO4(+)606.2075,found 606.2076。
实施例41
化合物I-b-15的制备:
参照实施例27中的制备方法制备化合物I-b-15,收率40%。化合物I-b-15的结构测定:1H NMR(400MHz,CDCl3)δ7.42(s,1H),7.32(s,1H),7.23(d,J=6.1Hz,2H),7.15(d,J=6.2Hz,1H),4.88–4.72(m,2H),4.02(d,J=11.6Hz,1H),3.82(d,J=14.1Hz,1H),3.47(dd,J=9.0,4.1Hz,1H),3.18(t,J=12.1Hz,2H),2.94(d,J=14.1Hz,1H),2.79(d,J=7.9Hz,1H),1.95-2.05(m,2H),1.83(d,J=12.9Hz,1H),1.78–1.67(m,1H),1.67–1.60(m,6H),1.43(s,3H),1.37(s,3H),1.18(s,3H),1.04(s,3H),1.01(d,J=12.7Hz,1H),0.95–0.71(m,4H);13CNMR(100MHz,CDCl3)δ173.47,145.66,141.46,137.19,134.27,129.56,128.09,127.08,126.40,98.92,70.42,63.95,60.56,59.35,58.79,53.65,52.35,37.55,35.23,34.09,33.25,31.37,29.68,27.31,26.12,25.51,24.73,20.39,15.94;HRMS(m/z)calc.forC30H41ClNO4(+)514.2719,found 514.2724。
实施例42
化合物I-b-16的制备:
参照实施例27中的制备方法制备化合物I-b-16,收率57%。化合物I-b-16的结构测定:1H NMR(400MHz,CDCl3)δ7.50(s,1H),7.36(s,1H),6.29(s,1H),6.14(s,1H),4.85(s,2H),4.01(d,J=11.7Hz,1H),3.71(d,J=14.7Hz,1H),3.45(dd,J=8.8,4.1Hz,1H),3.27(d,J=14.2Hz,1H),3.18(d,J=11.6Hz,1H),3.09(d,J=11.4Hz,1H),2.92(d,J=10.3Hz,1H),2.12–1.98(m,1H),1.94(dd,J=13.8,5.1Hz,1H),1.86–1.75(m,2H),1.62-1.57(m,4H),1.42(s,3H),1.36(s,3H),1.17(s,3H),1.13-1.10(m,2H),1.01(s,3H),0.97–0.91(m,1H),0.91–0.82(m,2H),0.78(t,J=10.1Hz,1H);13CNMR(100MHz,CDCl3)δ173.44,145.99,142.15,129.89,110.12,108.98,98.93,70.54,63.94,60.55,58.60,53.46,52.27,51.53,37.55,35.18,34.03,33.02,31.40,29.68,27.29,26.08,25.43,24.66,20.41,15.97;HRMS(m/z)calc.for C28H40NO5(+)470.2901,found 470.2906。
实施例43
化合物I-b-17的制备:
参照实施例27中的制备方法制备化合物I-b-17,收率16%。化合物I-b-17的结构测定:1H NMR(400MHz,CDCl3)δ7.33(s,1H),4.91–4.76(m,2H),4.03(d,J=11.6Hz,1H),3.46(dd,J=8.9,4.0Hz,1H),3.20(d,J=11.6Hz,1H),2.98(dd,J=20.1,9.3Hz,2H),2.12(s,1H),2.06–1.89(m,3H),1.85–1.66(m,6H),1.65–1.47(m,4H),1.43(s,3H),1.37(s,3H),1.19(s,3H),1.15–1.08(m,2H),1.02(s,3H),0.99–0.93(m,2H),0.87(d,J=6.8Hz,6H),0.79(d,J=5.1Hz,4H).13CNMR(100MHz,CDCl3)δ173.74,145.82,129.86,98.90,70.34,63.95,63.42,60.61,59.78,53.70,52.96,37.54,35.55,34.09,31.90,31.59,29.67,29.30,27.28,26.12,25.57,24.76,21.98,20.53,15.91,14.10;HRMS(m/z)calc.forC27H44NO4(+)446.3265,found 446.3268。
实施例44
化合物I-b-18的制备:
参照实施例27中的制备方法制备化合物I-b-18,收率36%。化合物I-b-18的结构测定:H NMR(300MHz,MeOD)δ7.84(s,1H),5.00(s,2H),4.06(d,J=11.6Hz,1H),3.82(d,J=7.4Hz,1H),3.50(dd,J=8.6,3.9Hz,1H),3.22(d,J=11.7Hz,1H),2.94(d,J=12.3Hz,1H),2.68(t,J=12.1Hz,1H),2.58–2.29(m,2H),2.00(dd,J=13.1,5.1Hz,2H),1.94–1.75(m,5H),1.75–1.60(m,5H),1.58–1.48(m,3H),1.41(s,3H),1.33(s,3H),1.19(s,3H),1.13(s,3H),0.91(dd,J=12.4,5.8Hz,9H);13CNMR(100MHz,CDCl3)δ172.95,129.60,128.49,99.90,99.11,76.36,71.09,63.83,58.75,52.91,52.05,37.60,35.27,33.95,33.47,30.98,29.47,29.24,27.08,26.23,26.05,25.40,24.48,22.57,22.03,20.14,15.91;HRMS(m/z)calc.for C28H46NO4(+)460.3421,found 460.3422。
实施例45
化合物I-b-19的制备:
参照实施例27中的制备方法制备化合物I-b-19,收率50%。化合物I-b-19的结构测定:1H NMR(400MHz,CDCl3)δ7.26(s,1H),4.99–4.76(m,2H),4.01(d,J=11.6Hz,1H),3.47(dd,J=8.7,3.7Hz,2H),3.34–3.23(m,1H),3.20(d,J=11.6Hz,1H),2.89–2.65(m,1H),2.44(dd,J=27.2,7.9Hz,2H),2.12–1.91(m,4H),1.88–1.67(m,5H),1.65–1.49(m,4H),1.42(s,3H),1.37(s,3H),1.19(s,3H),1.09(s,3H),0.90(dd,J=14.3,7.1Hz,9H);13CNMR(100MHz,CDCl3)δ173.11,129.86,129.12,99.08,76.43,70.98,63.87,59.01,54.40,53.03,52.07,37.60,35.90,35.25,33.95,31.49,30.13,29.68,29.29,27.16,26.08,25.40,24.51,22.66,20.26,15.93,14.10,13.68;HRMS(m/z)calc.for C27H44NO4(+)446.3265,found 446.3269。
实施例46
化合物I-b-20的制备:
将穿心莲内酯1(10.0g,28.54mmol)溶于甲苯(200ml)和二甲基亚砜(27ml)中,然后将2,2-二甲氧基丙烷(14ml)和对甲苯磺酸(催化当量)加入反应体系中。升温至80摄氏度搅拌反应2小时,然后将体系降至室温,加入7ml三乙胺淬灭反应。用150ml二氯甲烷萃取反应,水洗,分液,用无水硫酸钠干燥,减压蒸干,用乙醚打浆得到8.65g类白色固体化合物IV-2,收率78%。
将化合物IV-2(8.65g,22.17mmol)、乙酸酐(11.31g,110.86mmol)、三乙胺(11.22g,110.85mmol)和二氯甲烷(250ml)加入反应瓶中,升温到45摄氏度回流反应2小时。反应完后,降至室温,加入饱和碳酸氢钠水溶液淬灭反应直至没有气泡产生,然后用二氯甲烷萃取三次。有机相用水洗3次、盐水洗3次,分液后用无水硫酸钠干燥有机相。抽滤,减压浓缩后用柱层析(5~25%EA/PE)分离纯化,得到白色固体化合物V-2(8.52g,89%)。
将化合物V-2(100mg,0.23ml)、苄胺(0.42mmol)、三乙胺(70mg,0.69mmol)和二氯甲烷(3ml)加入反应瓶中,在室温下搅拌反应3小时。反应完毕后,加入饱和碳酸氢钠水溶液淬灭反应,用二氯甲烷萃取3次,分液,有机相用水和盐水各洗一次。有机相用无水硫酸钠干燥,抽滤,减压浓缩后柱层析(5-30%EA/PE)纯化,得到42mg化合物VI-20,收率38%。
将化合物VI-10(30mg,1.0当量)、9-均三甲基-2,7,10-三甲基吖啶高氯酸盐(6mol%)和2,4,6-三异丙基苯-1-硫酚(0.5当量)加入透明的带特氟塞的8*16mm反应管中。将反应管密闭,加入2ml无水甲苯,用氮气置换3次以上,将反应管置于两个40W KessilKSH150B的蓝光灯照射下搅拌反应,体系逐渐变为深棕色,用TLC板监测反应,直至原料反应彻底。将反应体系减压浓缩,用制备级薄层色谱板分离得到17mg化合物I-b-20,收率56%。
化合物I-b-20的结构测定:1H NMR(400MHz,CDCl3)δ7.42(s,1H),7.31(dd,J=11.7,4.7Hz,4H),7.23(d,J=6.5Hz,1H),4.93(d,J=6.3Hz,1H),4.83(d,J=6.5Hz,1H),4.80(s,2H),4.03(d,J=11.4Hz,1H),3.86(d,J=13.9Hz,1H),3.51–3.36(m,2H),3.16(d,J=10.1Hz,1H),2.97(d,J=13.9Hz,1H),2.84(dd,J=10.7,2.7Hz,1H),2.30–2.17(m,1H),1.91–1.80(m,1H),1.79–1.72(m,1H),1.63(d,J=10.5Hz,4H),1.37(s,3H),1.22–1.14(m,2H),1.05(td,J=13.3,2.8Hz,1H),0.95(d,J=12.8Hz,1H),0.91(d,J=4.7Hz,3H),0.89–0.68(m,3H);13CNMR(100MHz,CDCl3)δ173.47,145.64,139.01,137.27,128.30,126.90,87.66,79.62,70.41,69.28,60.40,59.27,54.79,53.41,37.48,35.82,35.44,34.79,33.05,31.40,29.68,25.75,20.42,19.92,15.10;HRMS(m/z)calc.for C28H38NO4(+)452.2795,found 452.2792。
实施例47
化合物I-b-21的制备:
参照实施例46中的制备方法制备化合物I-b-21,收率53%。化合物I-b-21的结构测定:1H NMR(400MHz,CDCl3)δ7.51(s,1H),7.21(d,J=4.9Hz,1H),6.94(dd,J=5.0,3.5Hz,1H),6.84(d,J=3.2Hz,1H),4.93(d,J=6.3Hz,1H),4.84(s,2H),4.81(d,J=6.4Hz,1H),4.03(d,J=11.4Hz,1H),3.90(d,J=14.4Hz,1H),3.47–3.40(m,2H),3.36(d,J=14.5Hz,1H),3.17(d,J=9.4Hz,1H),2.96(dd,J=11.2,3.4Hz,1H),2.29–2.19(m,1H),1.88–1.80(m,1H),1.78–1.70(m,2H),1.69–1.63(m,3H),1.58-1.54(m,1H),1.37(s,3H),1.21–1.08(m,3H),1.04(td,J=13.4,3.0Hz,1H),0.97–0.93(m,1H),0.91(s,3H),0.90–0.73(m,3H);13CNMR(100MHz,CDCl3)δ173.43,145.65,142.52,136.95,126.66,125.35,124.55,87.66,79.61,70.51,69.28,60.34,58.53,54.78,53.73,53.32,37.48,35.82,35.44,34.84,33.11,31.40,29.68,25.75,20.40,19.91,15.09;HRMS(m/z)calc.for C26H36NO4S(+)458.2360,found 458.2357。
实施例48
化合物I-b-22的制备:
参照实施例46中的制备方法制备化合物I-b-22,收率60%。化合物I-b-22的结构测定:1H NMR(400MHz,CDCl3)δ7.49(s,1H),7.36(d,J=1.1Hz,1H),6.30(dd,J=3.0,1.9Hz,1H),6.14(d,J=2.9Hz,1H),4.93(d,J=6.3Hz,1H),4.85(s,2H),4.80(d,J=6.1Hz,1H),4.02(d,J=11.4Hz,1H),3.71(d,J=14.5Hz,1H),3.44(dd,J=12.2,5.5Hz,2H),3.26(d,J=14.5Hz,1H),3.09(d,J=10.2Hz,1H),2.92(dd,J=11.1,3.2Hz,1H),2.28–2.20(m,1H),2.07–1.92(m,1H),1.80(dd,J=12.8,3.0Hz,1H),1.77–1.69(m,3H),1.61–1.52(m,2H),1.37(s,3H),1.23–1.08(m,3H),1.04(dd,J=13.6,2.8Hz,1H),1.00–0.91(m,2H),0.89(s,3H),0.81–0.65(m,2H);13CNMR(100MHz,CDCl3)δ151.46,145.91,142.10,136.51,110.10,87.66,79.61,70.51,69.26,60.54,58.46,54.76,53.22,51.59,37.47,35.80,35.43,34.78,32.83,31.42,29.67,25.75,20.39,19.93,15.06;HRMS(m/z)calc.for C26H36NO5(+)442.2588,found 442.2590。
实施例49
化合物I-b-23的制备:
参照实施例46中的制备方法制备化合物I-b-23,收率60%。化合物I-b-23的结构测定:1H NMR(400MHz,CDCl3)δ7.41(s,1H),7.24(dd,J=8.3,5.6Hz,2H),6.99(t,J=8.7Hz,2H),4.93(d,J=6.3Hz,1H),4.82(s,2H),4.80(s,1H),4.03(d,J=11.4Hz,1H),3.79(d,J=13.8Hz,1H),3.49–3.39(m,2H),3.15(d,J=9.4Hz,1H),2.94(d,J=13.8Hz,1H),2.78(dd,J=10.6,2.4Hz,1H),2.28–2.19(m,1H),1.85–1.77(m,1H),1.74(dt,J=13.3,3.4Hz,1H),1.62(t,J=15.0Hz,7H),1.37(s,3H),1.23–1.10(m,3H),1.08–1.02(m,1H),0.95(d,J=11.0Hz,1H),0.91(d,J=4.7Hz,3H),0.89–0.67(m,3H);13CNMR(100MHz,CDCl3)δ173.37,160.63,145.70,137.20,134.54,129.76,115.19,114.98,87.65,79.60,70.38,69.26,60.23,59.23,58.50,54.79,53.42,37.47,35.81,35.44,34.77,32.97,31.40,29.67,25.74,20.41,19.91,15.08;HRMS(m/z)calc.for C28H37FNO4(+)470.2701,found 470.2701。
实施例50
化合物I-c-1的制备:
将I-b-1(0.03mmol,1.0当量),AcOH、THF和H2O(AcOH:THF:H2O=4:1:2(v/v))的混合溶剂2毫升加入反应管内,在45摄氏度搅拌反应2小时。降至室温,减压浓缩溶剂后用制备级薄层色谱板分离纯化得到7mg淡黄色固体化合物I-c-1,收率53%。1H NMR(400MHz,CDCl3)δ7.42(s,1H),7.37–7.28(m,4H),7.25-7.24(m,1H),4.80(s,2H),4.21(d,J=11.1Hz,1H),3.85(d,J=14.0Hz,1H),3.45(dd,J=11.8,3.9Hz,1H),3.32(d,J=10.7Hz,1H),3.15(d,J=11.0Hz,1H),2.97(d,J=13.4Hz,1H),2.84(d,J=11.2Hz,2H),2.02(d,J=5.3Hz,1H),1.86–1.76(m,2H),1.76–1.64(m,4H),1.21(s,3H),1.19–1.01(m,3H),0.96(d,J=10.9Hz,1H),0.87(dt,J=7.3,5.2Hz,3H),0.78(s,3H);13C NMR(100MHz,CDCl3)δ173.54,131.49,129.91,128.55,128.38,128.30,80.76,70.53,64.22,59.22,55.05,53.59,42.77,36.53,35.79,31.57,29.68,29.30,27.69,27.19,22.67,22.51,20.84,14.99,14.10.HRMS(m/z)calc.for C27H38NO4(+)440.2795,found 440.2796。
实施例51
化合物I-c-2的制备:
参照实施例50中的制备方法制备化合物I-c-2,收率53%。化合物I-c-2的结构测定:1H NMR(300MHz,CDCl3)δ7.26(s,1H),7.23(d,J=8.1Hz,2H),6.87(d,J=8.4Hz,2H),4.89(s,2H),4.19(d,J=11.0Hz,1H),4.10–3.83(m,1H),3.81(d,J=3.6Hz,3H),3.7–3.55(m,1H),3.47–3.25(m,3H),2.93(s,1H),2.16–1.94(m,2H),1.88–1.68(m,6H),1.62(s,2H),1.20(s,3H),1.11–1.02(m,2H),0.97(d,J=6.8Hz,2H),0.89(t,J=8.9Hz,4H),0.80(s,3H);13C NMR(100MHz,CDCl3)δ173.40,129.94,114.22,114.17,114.07,114.00,80.60,70.82,64.15,58.99,55.28,54.98,53.41,42.70,36.50,35.80,31.90,31.41,29.67,27.61,22.53,20.73,14.97,14.10;HRMS(m/z)calc.for C28H40NO5(+)470.2901,found470.2903。
实施例52
化合物I-c-3的制备:
参照实施例50中的制备方法制备化合物I-c-3,收率93%。化合物I-c-3的结构测定:1H NMR(400MHz,CDCl3)δ7.40(s,1H),7.34(d,J=7.3Hz,1H),7.17–7.10(m,1H),7.06(t,J=8.6Hz,1H),4.82(s,2H),4.21(d,J=11.1Hz,1H),3.76(d,J=14.1Hz,1H),3.45(dd,J=11.1,4.6Hz,1H),3.32(d,J=11.1Hz,1H),3.14(d,J=10.2Hz,1H),2.90(d,J=14.0Hz,1H),2.75(d,J=8.2Hz,1H),2.07(d,J=16.1Hz,1H),1.87–1.76(m,2H),1.76–1.62(m,8H),1.22(s,3H),1.19–1.00(m,3H),0.97(d,J=10.6Hz,1H),0.92–0.82(m,2H),0.79(s,3H);13CNMR(100MHz,CDCl3)δ173.37,155.72,145.77,136.93,129.96,127.79,120.79,116.32,116.11,80.57,70.38,65.73,64.12,60.15,59.05,57.97,54.95,53.54,42.61,36.41,35.68,34.57,32.94,31.47,29.57,27.54,22.45,20.73,15.13,14.90.HRMS(m/z)calc.forC27H36ClFNO4(+)492.2311,found 492.2321.
实施例53
化合物I-c-4的制备:
参照实施例50中的制备方法制备化合物I-c-4,收率94%。化合物I-c-4的结构测定:1H NMR(400MHz,CDCl3)δ7.52(s,1H),7.21(t,J=5.6Hz,1H),6.97–6.91(m,1H),6.85(s,1H),4.84(s,2H),4.21(d,J=11.1Hz,1H),3.90(d,J=13.1Hz,1H),3.48–3.42(m,1H),3.38(d,J=14.2Hz,1H),3.32(d,J=11.1Hz,1H),3.16(d,J=10.5Hz,1H),2.96(d,J=8.4Hz,1H),2.01(d,J=5.7Hz,1H),1.80(dd,J=16.0,6.5Hz,4H),1.75–1.62(m,7H),1.21(s,3H),1.14–1.00(m,3H),0.96(d,J=12.4Hz,1H),0.91–0.83(m,2H),0.78(s,3H).13C NMR(100MHz,CDCl3)δ173.51,145.76,136.64,126.65,125.54,124.45,80.71,70.48,64.17,60.12,58.33,54.96,53.45,42.59,36.36,35.67,34.55,33.07,31.42,29.57,27.56,22.44,20.75,14.89.HRMS(m/z)calc.for C25H36NO4S(+)446.2360,found 446.2351。
实施例54
化合物I-c-5的制备:
参照实施例50中的制备方法制备化合物I-c-5,收率66%。化合物I-c-5的结构测定:1H NMR(400MHz,CDCl3)δ7.50(s,1H),7.36(s,1H),6.30(s,1H),6.15(s,1H),4.91–4.75(m,2H),4.20(d,J=11.1Hz,1H),3.71(d,J=14.9Hz,1H),3.44(dd,J=11.3,4.4Hz,1H),3.30(t,J=14.8Hz,2H),3.08(d,J=10.0Hz,1H),2.93(d,J=11.5Hz,1H),2.06–1.98(m,1H),1.81–1.64(m,9H),1.22(s,3H),1.05(ddd,J=13.0,10.2,6.2Hz,3H),0.96(d,J=10.6Hz,1H),0.91–0.83(m,3H),0.76(s,3H),0.73(d,J=7.6Hz,1H).13C NMR(125MHz,CDCl3)δ173.52,142.19,129.93,110.16,100.82,80.81,70.61,64.25,60.50,58.45,55.06,53.47,51.57,42.80,36.53,35.79,34.73,31.65,29.72,29.34,27.71,22.63,20.89,15.01,14.15;HRMS(m/z)calc.for C25H36NO5(+)430.2588,found 430.2591。
实施例55
化合物I-d-1的制备:
在25ml的圆底烧瓶中加入穿心莲内酯衍生物I-a-5(300mg,0.53mmol,1eq,见实施例5),锌粉(540mg,8.4mmol,16eq),溶剂氯仿10ml,滴加1ml醋酸,室温搅拌反应30min,TLC检测反应,待反应结束,垫硅藻土抽滤,滤液用饱和碳酸氢钠溶液洗涤,二氯甲烷萃取,合并有机相,无水硫酸钠干燥后浓缩,柱层析(hexane/ethyl acetate 1:3)分离得到120mg化合物I-d-1,收率43%。
实施例56
化合物I-d-2的制备:
在8ml的圆底烧瓶中,加入化合物I-d-1(20mg,0.04mmol,1eq),三乙胺(30μl,0.2mmol,5eq),1ml二氯甲烷,降温至0℃,加入丙烯酰氯(9μl,0.6mmol,1.5eq),在该条件下反应30min。柱层析分离得到化合物I-d-2,收率53%。
化合物I-d-2的结构测定:1H NMR(300MHz,CDCl3)δ7.71(s,1H),7.52(s,4H),6.44(d,J=16.8Hz,1H),6.26(dd,J=16.5,10.1Hz,1H),5.78(d,J=9.9Hz,1H),4.83(s,2H),4.57(d,J=8.9Hz,1H),4.49–4.23(m,1H),4.11(d,J=11.6Hz,1H),3.85(s,1H),3.19(s,1H),3.02(s,1H),2.84(s,1H),2.34(s,2H),2.03(d,J=2.0Hz,6H),1.81–1.56(m,6H),1.44(d,J=8.1Hz,2H),1.06(d,J=12.2Hz,2H),0.98(s,3H),0.86(s,5H);HRMS(m/z)calc.forC34H45N2O7(+)593.3227,found593.3223.
实施例57
化合物I-d-3的制备:
在8ml的圆底烧瓶中,加入化合物I-d-1(20mg,0.04mmol,1eq),三乙胺(30μl,0.2mmol,5eq),1ml二氯甲烷,降温至0℃,滴加甲磺酰氯(8μl,0.6mmol,1.5eq),在该条件下反应30min。柱层析分离得到化合物I-d-3,收率47%。
化合物I-d-3的结构测定:1H NMR(300MHz,CDCl3)δ7.43(d,J=7.8Hz,2H),7.31(s,1H),7.22(d,J=8.2Hz,2H),4.81(s,2H),4.67–4.50(m,1H),4.37(d,J=11.7Hz,1H),4.10(d,J=12.1Hz,1H),3.79(d,J=13.7Hz,1H),3.14(d,J=8.1Hz,1H),2.94(d,J=13.1Hz,1H),2.81(d,J=9.0Hz,1H),2.17(s,1H),2.03(d,J=3.0Hz,7H),1.83–1.50(m,6H),1.50–1.36(m,2H),1.11(d,J=16.0Hz,2H),0.98(s,3H),0.85(s,5H);HRMS(m/z)calc.for C32H45N2O8S(+)617.2897,found617.2892。
实施例58
化合物I-d-4的制备:
在8ml的圆底烧瓶中,加入化合物I-d-1(20mg,0.04mmol,1eq),加1ml二氯甲烷,滴加正丁基异氰酸酯(10μl,0.6mmol,1.5eq),在该条件下反应30min,柱层析分离得到化合物I-d-4,收率52%。
化合物I-d-4的结构测定:1H NMR(300MHz,CDCl3)δ7.21(d,J=7.0Hz,4H),7.18(s,1H),6.82(s,1H),4.82(s,2H),4.66–4.48(m,1H),4.46–4.23(m,2H),4.10(d,J=11.7Hz,1H),3.78(s,1H),3.23(dd,J=12.7,6.8Hz,3H),3.02(s,1H),2.84(d,J=9.0Hz,1H),2.41–2.15(m,1H),2.03(d,J=3.3Hz,6H),1.68(m,,6H),1.57–1.42(m,4H),1.41–1.25(m,2H),1.16–1.00(m,2H),0.98(s,3H),0.91(t,J=7.2Hz,3H),0.85(m,5H);HRMS(m/z)calc.for C36H52N3O7(+)638.3805,found638.3802。
实施例59
化合物I-d-5的制备:
在室温条件下,在8ml的烧瓶中,加入化合物I-d-1(30mg,0.055mmol、1eq),化合物6(20mg,0.07mmol,1.2eq),HATU(25mg,0.07mmol,1.2eq),DIPEA(21mg,0.17mmol,3eq),DMF(1ml),搅拌过夜,反应结束之后,用5ml乙酸乙酯稀释,用饱和食盐水3ml洗三遍,旋干。薄层色谱制备板分离得到化合物I-d-5,收率32%。
化合物I-d-5的结构测定:1H NMR(300MHz,CDCl3)δ7.54(d,J=8.4Hz,2H),7.48(s,1H),7.23(d,J=8.4Hz,2H),4.82(s,2H),4.56(dd,J=10.1,5.5Hz,1H),4.36(d,J=11.7Hz,1H),4.17(d,J=2.4Hz,2H),4.12(s,2H),4.08(s,1H),3.82(d,J=13.7Hz,1H),3.77–3.62(m,12H),3.20(s,1H),2.88(s,1H),2.86(d,J=10.5Hz,2H),2.43(t,J=2.4Hz,1H),2.03(d,J=3.1Hz,6H),1.84–1.58(m,6H),1.50–1.37(m,2H),1.17–1.01(m,2H),0.98(s,2H),0.85(s,3H),0.85(m,5H);HRMS(m/z)calc.for C42H59N2O11(+)767.4119,found767.4113。
对照例60
穿心莲内酯衍生物对肿瘤细胞系的抗增殖活性
选取鼻咽癌、宫颈癌、肝癌以及白血病等细胞作为研究对象,以穿心莲内酯为阳性对照,筛选穿心莲内酯衍生物的抗肿瘤活性。选取的的细胞系分别为:人EBV阳性鼻咽癌细胞C666-1和HONE1-ebv、人宫颈癌细胞HeLa、人早幼粒白血病细胞HL-60和人肝癌细胞Huh7。
Resazurin实验方法的要点如下:采用对数生长期的肿瘤细胞,接种于96孔细胞培养板中,每孔100μL,每孔加入C666-1为7000个,HONE1-ebv、HeLa、Huh 7为2000个,HL-60为20000个,每个实验组设置2个复孔。培养24h后,每孔加入0.5μL化合物的DMSO溶液使其终浓度为50μM。此外,设置加0.5μLDMSO的孔为阳性对照,只加培养基的孔为阴性对照。化合物孵育72h后,加入10μL Resazurin的PBS溶液使其终浓度为100μM,37℃孵育3h,在摇床上震荡均匀后,用酶标仪检测荧光强度,激发光为560nm,发射光为590nm,抑制率计算公式为Inhition%=100%-(F-Fblank)/(FCtrl-Fblank)×100%,其中F为加化合物孔的荧光强度,Fblank为阴性对照孔读数,FCtrl为阳性孔荧光数值。测试结果见表1,从初步的筛选结果来看,氮杂三环穿心莲内酯衍生物中不少化合物表现出优良的抗肿瘤活性,部分化合物活性明显高于阳性对照穿心莲内酯。
表1:穿心莲内酯衍生物对肿瘤细胞系的抗增殖活性
肿瘤细胞抑制活性:肿瘤抑制率>70%=++++;70%>肿瘤抑制率>50%=+++;50%>肿瘤抑制率>30%=++;肿瘤抑制率<30%=+;ND表示没有测试该细胞系。
以上所揭露的仅为本发明较佳实施例而已,当然不能以此来限定本发明之权利范围,因此依本发明权利要求所作的等同变化,仍属本发明所涵盖的范围。
Claims (13)
1.一种穿心莲内酯类化合物,其特征在于,其结构如式(Ⅰ)所示:
其中,-R1选自-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2CH(CH3)2、-CH(CH3)2、-CH2CH2CH(CH3)、环丙基、环丁基、环戊基、环己基、环庚基、
-R2和-R3相同,所述-R2和所述-R3选自-H、甲基、乙基、丙基和-(O)CR4中的任意一种,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、呋喃基、噻吩基和吡啶基中的任意一种;
2.根据权利要求1所述的穿心莲内酯类化合物,其特征在于,
所述-R2和所述-R3为-H或-OAc;
或者,所述-R2和所述-R3一起形成下列基团:-C(CH3)2-或-CH2-。
4.一种如权利要求1~3任意一种所述的穿心莲内酯类化合物的制备方法,其特征在于,包括以下步骤:
提供化合物A,所述化合物A的结构为:
其中,M1为烷基或-(O)CR4,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、呋喃基、噻吩基和吡啶基中的任意一种;其中,所述烷基为环烷基、C1~C10的直链烷基或C3~C10的支链烷基,所述环烷基为C3~C12的单环环烷基、C7~C12的双环环烷基或C7~C12的螺环环烷基;
-R2和-R3相同,所述-R2和所述-R3选自-H、甲基、乙基、丙基和-(O)CR4中的任意一种,-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、呋喃基、噻吩基和吡啶基中的任意一种;
或者-R2和-R3一起形成下列基团:-R5为-H、烷基或芳基,-R6为-H、烷基或芳基;其中,所述烷基为环烷基、C1~C10的直链烷基或C3~C10的支链烷基,所述环烷基为C3~C12的单环环烷基、C7~C12的双环环烷基或C7~C12的螺环环烷基;所述芳基为单环芳基或2~5环的稠环芳基;
将所述化合物A、胺和碱性介质加入有机溶剂中,发生反应,得到化合物B,所述胺的化学式为R1-NH2,-R1选自-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3、-CH2CH(CH3)2、-CH(CH3)2、-CH2CH2CH(CH3)、环丙基、环丁基、环戊基、环己基、环庚基、
将所述化合物B、氢原子转移供体和光氧化还原催化剂加入有机溶剂中,在光的照射下发生反应,得到化合物C,所述化合物C的结构为:
5.根据权利要求4所述的制备方法,其特征在于,
得到所述化合物B和得到所述化合物C的过程中的所述有机溶剂分别独立选自二氯甲烷、四氢呋喃、乙醚、1,4-二氧六环、甲苯、苯和氯仿中的一种、两种、三种或三种以上;
所述碱性介质选自三乙胺、二异丙基乙基胺和吡啶中的一种、两种或三种;
所述氢原子转移供体的当量为所述化合物B的当量的20%~100%;所述氢原子转移供体选自2,4,6-三异丙基苯硫酚、1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸二乙酯和1,4-环己二烯中的任意一种;
所述光氧化还原催化剂的当量为所述化合物B的当量的1%~10%;所述光氧化还原催化剂选自金属铱催化剂、金属铑催化剂和有机染料类催化剂中的任意一种;
所述光的波长范围为300nm~500nm。
6.根据权利要求4或5所述的制备方法,其特征在于,所述化合物A的制备方法包括以下步骤:
将穿心莲内酯加入有机溶剂中,加入酰化剂或卤代烃,加入路易斯酸作为催化剂,所述酰化剂或卤代烃与所述穿心莲内酯的3位、19位和14位的-OH发生反应,得到所述化合物A;
所述酰化剂为酸酐或酰卤;所述酸酐的化学式为:R4-C(O)-O-C(O)-R4,所述酰卤的化学式为R4-C(O)-卤素,所述-R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、呋喃基、噻吩基和吡啶基中的任意一种;所述卤代烃的化学式为:烷基-卤素,所述烷基为环烷基、C1~C10的直链烷基或C3~C10的支链烷基,所述环烷基为C3~C12的单环环烷基、C7~C12的双环环烷基或C7~C12的螺环环烷基。
7.根据权利要求4或5所述的制备方法,其特征在于,所述化合物A的制备方法包括以下步骤:
将穿心莲内酯、羰基化试剂和酸催化剂加入到反应介质中,在60℃~100℃的反应温度下,所述羰基化试剂的羰基与所述穿心莲内酯的3位和19位的-OH发生缩合反应,得到化合物D,所述羰基化试剂的化学式为R5-C(OMe)2-R6或R5-CO-R6,其中,-R5为-H、烷基或芳基;-R6为-H、烷基或芳基,所述烷基为环烷基、C1~C10的直链烷基或C3~C10的支链烷基,所述环烷基为C3~C12的单环环烷基、C7~C12的双环环烷基或C7~C12的螺环环烷基;所述芳基为单环芳基或2~5环的稠环芳基;所述化合物D的结构为:
将所述化合物D加入有机溶剂中,加入酰化剂或卤代烃,加入碱性介质,所述酰化剂或卤代烃与所述化合物D的14位的-OH发生反应,得到所述化合物A,所述酰化剂为酸酐或酰卤;所述酸酐的化学式为:R4-C(O)-O-C(O)-R4,所述酰卤的化学式为R4-C(O)-卤素,所述R4选自甲基、乙基、丙基、异丙基、丁基、异丁基、呋喃基、噻吩基和吡啶基中的任意一种;所述卤代烃的化学式为:烷基-卤素,所述烷基为环烷基、C1~C10的直链烷基或C3~C10的支链烷基,所述环烷基为C3~C12的单环环烷基、C7~C12的双环环烷基或C7~C12的螺环环烷基。
8.根据权利要求7所述的制备方法,其特征在于,
所述反应介质为甲苯和二甲亚砜的混合溶剂;
所述酸催化剂为对甲苯磺酸或浓硫酸;
所述化合物A的制备方法中,所述酸催化剂的当量为所述穿心莲内酯的当量的10%~40%;所述羰基化试剂的当量为所述穿心莲内酯的当量的100%~600%;所述酰化剂或卤代烃的当量为所述化合物D的当量的100%~600%;所述碱性介质的当量为所述化合物D的当量的100%~600%。
10.根据权利要求9所述的制备方法,其特征在于,所述反应溶剂选自四氢呋喃、1,4-二氧六环和水中的一种、两种或两种以上;
所述酸选自盐酸、对甲苯磺酸、硫酸和醋酸中的任意一种。
11.一种药物组合物,其特征在于,包括权利要求1~3任意一项所述的穿心莲内酯类化合物。
12.权利要求1~3任意一项所述的穿心莲内酯类化合物或权利要求11所述的药物组合物在制备抗肿瘤药物中的应用。
13.根据权利要求12所述的应用,其特征在于,所述抗肿瘤药物是抗鼻咽癌、宫颈癌、肝癌、乳腺癌、肺癌、前列腺癌、结肠癌、胰腺癌、脑癌、胃癌、骨癌、皮肤癌或白血病类药物。
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