CN114437102A - 一种新型的冬凌草甲素去6位羟基衍生物、其制备方法及医药用途 - Google Patents
一种新型的冬凌草甲素去6位羟基衍生物、其制备方法及医药用途 Download PDFInfo
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- CN114437102A CN114437102A CN202210083405.0A CN202210083405A CN114437102A CN 114437102 A CN114437102 A CN 114437102A CN 202210083405 A CN202210083405 A CN 202210083405A CN 114437102 A CN114437102 A CN 114437102A
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Abstract
本发明公开一种新型的冬凌草甲素去6位羟基类似物及其衍生物、其制备方法及医药用途，新型的冬凌草甲素去6位羟基类似物及其14位羟基衍生物，结构如式I所示；本发明还公开了这些新型化合物的制备方法以及其在治疗肿瘤疾病领域的应用。
Description
技术领域
本发明涉及天然药物及药物化学领域，具体涉及一类新型的冬凌草甲素去6位羟基类似物及其14位羟基衍生物。本发明还公开了这些新型化合物的制备方法以及其在治疗肿瘤疾病领域的应用。
背景技术
三阴性乳腺癌(TNBC)是指雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体-2(HER-2)表达均为阴性的一类乳腺癌，占所有乳腺癌患者的15％-20％，这类乳腺癌的恶性程度高、肿瘤侵袭性强、预后较差、内分泌治疗及靶向治疗不敏感(见Fresia PareJaandJorge S.Reis-Filho.Nature Reviews Clinical Oncology，2018，15，6)。因此，目前缺乏合适的三阴性乳腺癌治疗方法，治疗药物以传统的蒽环类药物、紫杉烷、铂类等药物为主，但其疗效一般且具有毒副作用大的缺陷(见Kwang Ai Won Charles Spruck.IntJOncol,2020,57,1245-1261)。
冬凌草甲素是唇形科(Labtea)香茶菜属(Rabdosia)植物冬凌草的主要活性成分，具有抗炎、抗菌和抗肿瘤等活性(见Liu Z,Ouyang L,Peng H,et al.Cell Proliferat,2012,45,499)。研究发现天然产物冬凌草甲素具有潜在的抗TNBC治疗效果，但其活性较为中等，阻碍了其进一步的临床应用(见Hong Yao,Shengtao Xu,JinyiXu.J.Med.Chem.2020,63,15)。冬凌草甲素中具有多个羟基基团，羟基过多影响透膜性质，导致体内抗肿瘤活性不够强。因此，有必要对其羟基进行结构改造研究，发现活性更优、安全性更高的新型化合物。
发明内容
本发明通过去除冬凌草甲素6位羟基并对14位羟基进行结构修饰，提供一类具有抗肿瘤活性的新化合物。与已有的同类化合物相比，本发明的化合物具有更优的细胞透膜性，更强抑制三阴乳腺癌生长的活性，并具有良好的选择性。
本发明是通过以下技术方案实现的。
通式Ⅰ所示的冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐：
其中，A可以为氢、羟基、卤素；U-Y可以为碳碳单键或碳碳双键；M是下列基团中的任意一个：(1)氢或氘原子，当M为氢时，A不为羟基，(2)C1-16脂肪链酰基或C1-16脂肪链磺酰基，(3)C3-10环烷酰基或C3-10环烷基磺酰基，(4)C3-10杂环烷酰基或C3-10杂环烷基磺酰基，(5)C1-6卤代烷酰基或C1-6卤代烷磺酰基，(6)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基或未被取代或被1、2、3、4个取代基所取代的C6-10芳基磺酰基，(7)未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的杂芳酰基或未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的杂芳基磺酰基，(8)C2-6烯酰基或C2-6烯基磺酰基，(9)C2-6炔酰基或C2-6炔基磺酰基，(10)氨基酸，(11)磷酰基，(12)芳香环或杂芳香环上未取代的或被1、2、3、4个取代基所取代的通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-或-(CH2)m-Z-(CH2)m-；m等于1、2、3、4、5、6；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；Z指代3-6个原子组成的碳环或含杂原子环基。
在本发明的一些实施方案中，A优选为氢或羟基；U-Y优选为碳碳单键或碳碳双键；M优选为：(1)C2-16脂肪链酰基或C2-16脂肪链磺酰基，(2)C3-10环烷酰基，(3)C3-10杂环烷酰基或C3-10杂环烷基磺酰基，(4)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基，(5)未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的杂芳酰基，(6)C2-6烯酰基，(7)芳香环或杂芳香环上未取代的或被1、2、3、4个取代基所取代的通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-、-CH＝C(CH3)-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-或-(CH2)m-Z-(CH2)m-；m等于1、2、3、4、5、6；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；Z指代3-6个原子组成的碳环或含杂原子环基。
在本发明的一些实施方案中，M为：(1)C1-10脂肪链酰基或C1-6脂肪链磺酰基，(2)C3-6碳环酰基，(3)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基，(4)未被取代或被1、2、3、4个取代基所取代的具有1～3个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基，(5)C2-4烯酰基，(6)通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-、-CH＝C(CH3-、-CH2-O-CH2-或-CH2-S-CH2-；m等于1、2、3、4；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；或者Ar指代未被取代或被1、2、3、4个取代基所取代的具有1～3个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基。
在本发明的一些实施方案中，M为：(1)C1-8脂肪链酰基或C1-3脂肪链磺酰基，(2)C3-6碳环酰基，(3)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基，(4)未被取代或被1、2、3、4个取代基所取代的具有1～2个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基，(5)C2-4烯酰基，(6)通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-或-CH＝C(CH3)-；m等于1、2；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；或者Ar指代未被取代或被1、2、3、4个取代基所取代的具有1～2个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基。
本发明所述的取代基选自卤素、C1-3烷基、C1-3烷氧基、C1-3卤代烷基或C1-3烷基磺酰基，在一些实施例中，例如为Br、Cl、F、甲基、乙基、甲基磺酰基、乙基磺酰基、甲氧基、乙氧基、三氟甲基等。
在本发明的一些实施方案中，本发明所述的杂芳基可以选自：吡咯基、呋喃基、噻吩基、吡啶基、嘧啶基、吡嗪基、吲哚基、喹啉基、苯并氧五环、咪唑基、噁唑基、噻唑基、吡唑基、异喹啉基、嘌呤基、吖啶基、咔唑基、噌啉基、喹噁啉基、吲哚基、苯并三唑基、苯并噻吩基、苯并呋喃基、异噁唑基、吡嗪基、哒嗪基、四唑基、三嗪基和咔唑基等。
根据本发明，代表性的冬凌草甲素去6位羟基类似物及衍生物其部分具体化合物选自如下结构：
本发明冬凌草甲素衍生物可用下列方法制备得到，以下合成方案列出了制备本发明中公开化合物的实验步骤。
合成方案1
式1可以通过合成方案1所公开的方法合成。首先将化合物I-a溶于干燥的丙酮中，加入催化剂量对甲基苯磺酸，再滴加2,2-二甲氧基丙烷，室温反应2h得到产物I-b；将化合物I-b溶于甲醇中，冷却至0℃，加入过氧化氢水溶液和氢氧化钠水溶液，低温搅拌2h，得到化合物I-c；然后将化合物I-c溶于干燥的二氯甲烷中，冰浴搅拌，加入三乙胺，将异丁酰氯用干燥的二氯甲烷稀释，再将稀释液用恒压滴液漏斗缓慢加入至反应体系中，继续冰浴搅拌2h，得到化合物I-d；然后与咪唑溶解在四氢呋喃中，惰性气体保护下，冷却至0℃后分批加入钠氢，最后加入二硫化碳和碘甲烷，得到化合物I-e；溶解于甲苯，惰性气体保护下，加入催化剂量的AIBN和三正丁基氢化锡，回流反应2小时，得到化合物I-f；溶解于二氯甲烷，冰浴下加入1N氢氧化钠溶液，得到化合物I-g；溶解于无水二氯甲烷，在0℃条件下，缓慢滴加三乙胺，待体系混合均匀后，使用恒压滴液漏斗将无水二氯甲烷稀释过的甲磺酰氯缓慢滴入反应体系，继续冰浴搅拌2h，得到化合物I-h；溶于干燥的DMF中，加入碳酸锂和溴化锂，110℃反应1小时，得到化合物I-i；最后溶解于四氢呋喃中，冰浴搅拌，加入1N盐酸溶液，移至室温反应1小时，水洗，柱层析，得到化合物1。
合成方案2
式2可以通过合成方案2所公开的方法合成。将合成方案1中间体I-f溶解在干燥的二氯甲烷中，0℃下，缓慢滴加三乙胺，待体系混合均匀后，将甲基磺酰氯用干燥的二氯甲烷稀释后缓缓滴入反应液中，得到化合物II-a；然后溶解在干燥的DMF中，加入碳酸锂和溴化锂，加热至110℃，油浴搅拌1～2h，得到化合物II-b；溶解在四氢呋喃中，冰浴下加入1N盐酸溶液，得到化合物II-c；将化合物II-c溶解于二氯甲烷，冰浴下加入的1N氢氧化钠溶液，继续反应2h，水洗，柱层析，得到化合物2；
合成方案3
式III-g可以通过合成方案3所公开的方法合成。R1基团具有如本发明所述M基团包含的定义。将合成方案1中间体I-b溶解在甲醇中，在0-5℃的温度下，缓慢滴入NaOH溶液，搅拌均匀后再缓慢滴加过氧化氢水溶液，继续低温反应2h，得到化合物III-a；与咪唑溶于无水四氢呋喃，惰性气体保护下分批加入钠氢，最后加入二硫化碳及碘甲烷，得到化合物III-b；将化合物III-b溶解在干燥的甲苯中，加入偶氮二异丁腈做催化剂，加入三正丁基氢化锡，惰性气体保护，加热回流反应1～2h，得到化合物III-c；溶解在干燥的二氯甲烷中，0℃下，缓慢滴加三乙胺，待体系混合均匀后，将甲基磺酰氯用干燥的二氯甲烷稀释后缓缓滴入反应液中，得到化合物III-d；干燥的DMF溶解，加入碳酸锂和溴化锂，加热至110℃，油浴搅拌1～2h,得到化合物III-e；溶解在四氢呋喃中，冰浴下加入1N盐酸溶液，得到化合物III-f；将化合物III-f溶解于干燥的甲烷中，加入有机碱和DMAP和EDCI，过量相对应取代基团的酸，室温反应6～72h；水洗，柱层析，得到式III-g。
合成方案4
式IV-a可以通过合成方案4所公开的方法合成。将合成方案3中中间体III-f溶解于无水二氯甲烷中，加入三乙胺和甲磺酰氯，反应30min，水洗，柱层析得到化合物IV-a。
合成方案5
式V-a可以通过合成方案5所公开的方法合成。R2基团具有如本发明所述M基团包含的定义。将合成方案1中化合物1溶解于干燥的甲烷中，加入有机碱和DMAP和EDCI，过量相对应取代基团的酸，室温反应6～72h；水洗，柱层析，得到式V-a。
合成方案6
式VI-a可以通过合成方案6所公开的方法合成。R3基团具有如本发明所述M基团包含的定义。将合成方案2中化合物2溶解于干燥的甲烷中，加入有机碱和DMAP和EDCI，过量相对应取代基团的酸，室温反应6～72h；水洗，柱层析，得到式VI-a。
本发明还提供一种药物组合物，其包含本发明通式I所示的冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐，以及药学上可接受的辅料。
本发明还提供通式I所示的冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐或包含他们的药物组合物在制备抗肿瘤药物中的应用。
本发明所述的肿瘤是机体在各种致癌因素作用下，局部组织的某一个细胞在基因水平上失去对其生长的正常调控，导致其克隆性异常增生而形成的异常病变，包括但不限于乳腺癌。
关于本发明的使用术语的定义：除非另有说明，本文中的基团或者术语提供的初始定义用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予的含义。术语“取代”是指分子中的氢原子或分子所替换，包括一个取代基或多个取代基的情况。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)、碘(I)或砹(At)离子。
术语“烷基”表示具有所述数目之碳原子的直链或支链饱和烃基。术语“C1-C6烷基”是指具有1-6个碳原子的直链或支链饱和烃基。C1-C6烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、2,2-二甲基丁基和2,3-二甲基丁基等。术语“C1-C3烷基”是指具有1-3个碳原子的直链或支链饱和烃基。
术语“环烷基”表示全部为碳原子的饱和的单环或多环的环结构。术语“C3-C10环烷基”是指具有总共3至10个碳原子的饱和的单环或多环环结构。C3-C10环烷基包括但不限于环丙基、环丁基、环戊基、环己基。
术语“烯基”指直链、支链或环状的，主链含有2～6个碳原子及至少一个碳-碳双键的非芳香烃基。因此，“C2-C6烯基”指主链具有2～6个碳原子的烯基。烯基包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基等。烯基的直链、支链或环状部分可含有双键且如果指明了取代的烯基则此部分可被取代。
术语“炔基”指直链、支链或环状的，主链含有2～6个碳原子及至少一个碳碳三键的非芳香烃基。因此，“C2-C6炔基”指具有2～6个碳原子的炔基。炔基包括乙炔基、丙炔基、丁炔基、3-甲基丁炔基等。炔基的直链、支链或环状部分可含有三键且如果指明了取代的炔基则此部分可被取代。
术语“C3-C10杂环”表示3到10个环原子的饱和环状基团，其中一个或两个环原子是选自N、O或S(O)m(其中m是0至2的整数)的杂原子，其余环原子是C，其中一个或两个C原子可以可选地被羰基代替。杂环基的环可以可选地独立地被一个、两个或三个取代基取代。
术语“芳香环”、“芳基”表示6至10个碳原子的全碳单环或稠合多环基团，具有完全共轭的π电子系统。芳香环或芳基的非限制性实例有苯基、萘基和蒽基。
术语“杂芳香环”、“杂芳基”表示5至10个环原子的单环或稠合环基团，含有一个、两个、三个或四个选自N、O或S的环杂原子，其余环原子是C，另外具有完全共轭的π电子系统。未取代的杂芳基的非限制性实例有吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、吡啶、吡唑、嘧啶、喹啉、异喹啉、嘌呤、四唑、三嗪和咔唑。杂芳香环或杂芳基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个，更为优选为一个、两个或三个，进而更为优选一个或两个。
本发明通过将冬凌草甲素6位羟基去除后，同时对14位羟基进一步衍生化，获得了一种新型的冬凌草甲素类似物及其14位羟基衍生物。该发明一方面可以显著提升冬凌草甲素的抗三阴乳腺癌肿瘤活性，另一方面通过结构优化有望获得具有成药性优良的新型广谱抗肿瘤活性分子。
具体实施方式
以下的实施例便于更好地理解本发明，但并不限定本发明。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。
实施例1
(a)将冬凌草甲素(2g)溶于无水丙酮(用五氧化二磷处理)30mL中，加入催化量的对甲苯磺酸，冰浴下滴加2,2-二甲氧基丙烷4mL，室温反应约2h，反应完成后二氯甲烷萃取三次，每次50mL，饱和食盐水洗两次，无水硫酸钠干燥，过滤，浓缩，得白色固体2.10g(收率95％)，可直接用于下一步反应。1H NMR(CDCl3,300MHz)δ6.15(s,1H),5.78(d,J＝8.1Hz,1H),5.56(s,1H),4.80(d,J＝1.2Hz,1H),4.24,4.04(dd,JA＝JB＝10.2Hz,1H),3.90(m,1H),3.47(m,1H),3.06(d,J＝9.0Hz,1H),2.50(m,1H),2.08(m,1H),1.91(m,2H),1.73(m,3H),1.68(m,2H),1.67(s,3H),1.44(m,1H),1.37(s,3H),1.28(s,3H),1.14(s,3H)；
(b)将(a)的产物溶解于40mL甲醇中，冷却至0℃，加入2.5mL 30％过氧化氢水溶液和5mL 6N氢氧化钠水溶液，低温搅拌2h。往反应液中加入水稀释，并用乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，得非对映异构混合物I-2c 0.94g(收率45％)。无需纯化，直接用于下一步反应。1H NMR(300MHz,CDCl3)δ5.34(d,J＝11.8Hz,1H),4.93(d,J＝1.9Hz,1H),4.27(d,J＝9.9Hz,1H),4.09(dd,J＝16.7,8.6Hz,1H),3.89(dd,J＝11.7,7.6Hz,1H),3.48(dd,J＝11.2,5.5Hz,1H),3.16(d,J＝5.9Hz,1H),2.97(d,J＝5.9Hz,1H),2.60-2.39(m,1H),2.28(d,J＝9.8Hz,1H),1.97-1.59(m,10H),1.39-1.04(m,12H).
(c)将(b)的产物溶于30mL无水二氯甲烷中，加入1mL三乙胺，冰浴搅拌，20min内逐滴加入3mL二氯甲烷稀释过的1.07mL异丁酰氯，继续搅拌1小时，TLC检测原料消失，加入70mL二氯甲烷，水洗两次，饱和食盐水洗一次，每次20mL，无水硫酸钠干燥，浓缩，得固体1.88g(收率80％)。1H NMR(300MHz,CDCl3)δ4.68(d,J＝7.0Hz,1H),4.55(dd,J＝7.0,3.7Hz,1H),4.32(d,J＝7.7Hz,1H),4.05(d,J＝12.4Hz,1H),3.93(dd,J＝7.7,7.0Hz,1H),3.80(d,J＝12.4Hz,1H),3.63(d,J＝3.1Hz,2H),2.88(dd,J＝7.0,2.5Hz,1H),2.55(m,1H),2.40(t,J＝7.0Hz,1H),2.16(d,J＝6.9Hz,1H),1.92-1.59(m,6H),1.48(s,6H),1.52-1.41(m,2H),1.15(dd,J＝15.0,6.8Hz,6H),0.95(d,J＝8.5Hz,5H).
(d)将非对映异构混合物I-1c(1g)与83mg咪唑溶于无水四氢呋喃30mL，惰性气体保护下，冷却至0℃后分批加入钠氢(244mg)，最后加入184μL二硫化碳和380μL碘甲烷，反应液呈棕黄色。加入甲醇淬灭，真空浓缩，柱层析得浅黄色固体I-2b 0.75g(收率75％)。1HNMR(300MHz,CDCl3)δ5.31(d,J＝7.0Hz,1H),4.68(t,J＝7.0Hz,1H),4.58(dd,J＝7.0,3.8Hz,1H),4.05(d,J＝12.3Hz,1H),3.82(d,J＝12.4Hz,1H),3.64(d,J＝3.8Hz,2H),2.89-2.35(m,1H),2.56-2.34(m,1H),2.48-2.33(m,3H),2.28-2.12(m,1H),1.91-1.67(m,4H),1.72-1.56(m,2H),1.48(s,6H),1.48-1.40(m,1H),1.15(dd,J＝15.0,6.8Hz,6H),0.96(d,J＝8.6Hz,5H).
(e)将(d)的产物溶解于甲苯(50mL)，惰性气体保护下，加入催化剂量的AIBN(200mg)和1.04mL三正丁基氢化锡，回流反应2小时，真空浓缩后，柱层析纯化得到产物0.5g(收率80％)。1H NMR(300MHz,CDCl3)δ4.09-3.96(m,1H),3.89-3.72(m,1H),2.85-2.48(m,1H),2.38-2.23(m,1H),1.93-1.31(m,3H),1.47(s,2H),1.14(dd,J＝15.0,6.8Hz,2H),1.03(s,1H),0.91(s,1H).
(f)将(e)的产物(2g)溶解于二氯甲烷(40mL)，冰浴下加入4mL的1N氢氧化钠溶液，TLC监测原料消失，加入70mL二氯甲烷，水洗两次，饱和食盐水洗一次，每次20mL，无水硫酸钠干燥，浓缩，得白色固体1.46g(86％)。无须纯化，直接进行下一步反应。1H NMR(300MHz,CDCl3)δ4.41-4.21(m,1H),4.09-3.72(m,7H),2.79-2.23(m,1H),2.52-2.12(m,1H),2.40-2.22(m,2H),2.01(dd,J＝12.3,6.9Hz,1H),1.94-1.77(m,2H),1.82-1.70(m,1H),1.75-1.62(m,3H),1.67-1.53(m,1H),1.48(s,6H),1.57-1.32(m,2H),1.01(d,J＝7.6Hz,5H).
(g)将(f)产物溶解于无水二氯甲烷(40mL)，在0℃条件下，缓慢滴加600mL三乙胺，待体系混合均匀后，使用恒压滴液漏斗将无水二氯甲烷稀释过的2mL甲磺酰氯缓慢滴入反应体系；TCL监测原料反应完全，真空浓缩，加入乙酸乙酯，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥，浓缩后得淡黄色固体粗品1.82g(收率90％)。无须纯化，直接进行下一步反应。1H NMR(300MHz,CDCl3)δ4.56-4.23(m,1H),4.47-4.23(m,1H),4.13(dd,J＝12.3,7.0Hz,1H),4.10-3.96(m,2H),3.78(d,J＝12.4Hz,1H),3.04(d,J＝4.1Hz,6H),2.90-2.45(m,1H),2.80-2.54(m,1H),2.39-2.23(m,2H),2.02(dd,J＝12.4,7.0Hz,1H),1.97-1.82(m,2H),1.87-1.76(m,1H),1.81-1.69(m,2H),1.74-1.51(m,2H),1.47(s,6H),1.43(d,J＝7.1Hz,1H),1.02(s,2H),0.91(s,2H).
(h)将(f)的产物(2g)溶于20mL预干燥的DMF中，加入碳酸锂(3.08g)，溴化锂(3.62g)，110℃反应1小时，冷却至室温，砂蕊漏斗过滤除去碳酸锂、溴化锂，固体用乙酸乙酯洗涤三遍，合并有机层，补加二氯甲烷至100mL，水洗两次，饱和食盐水洗一次，浓缩得粗品1.2g，无需纯化直接用于下一步反应。1H NMR(300MHz,CDCl3)δ5.98-5.24(m,2H),5.72-5.23(m,1H),5.58(t,J＝10.9,Hz,1H),4.47(dd,J＝7.0,3.8Hz,1H),3.89(d,J＝12.4Hz,1H),3.65(d,J＝12.4Hz,1H),3.06-2.87(m,1H),2.79-2.66(m,1H),2.39(dd,J＝12.4,7.0Hz,1H),2.09(dd,J＝12.4,7.0Hz,1H),2.03-1.76(m,3H),1.81-1.58(m,4H),1.47(s,5H),0.97(d,J＝15.2Hz,5H).
(i)将1.2g的(h)溶解于40mL四氢呋喃中，冰浴搅拌，加入11.97mL1N盐酸溶液，移至室温反应1小时，TLC检测原料消失，反应液由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，柱层析得化合物0.82g(收率76％)。1H NMR(300MHz,CDCl3)δ5.97-5.65(m,2H),5.72-5.54(m,1H),5.58-5.23(m,1H),5.05(s,1H),4.51(d,J＝5.9Hz,1H),4.37(m,1H),3.89(d,J＝12.4Hz,1H),3.65(d,J＝12.4Hz,1H),3.04-2.87(m,1H),2.90-2.76(m,1H),2.26(dd,J＝12.3,6.9Hz,1H),2.13-1.93(m,2H),1.97-1.62(m,6H),0.96(d,J＝17.7Hz,5H)；13C NMR(75MHz,CDCl3)δ206.09,206.05,206.02,151.87,133.62,133.56,133.51,126.43,126.37,126.31,117.97,117.91,99.32,99.28,73.44,73.42,73.40,73.39,73.37,67.48,67.43,67.42,60.42,60.39,60.38,52.14,52.09,46.94,46.89,45.11,45.09,45.06,45.02,41.94,41.92,41.89,41.86,41.84,41.81,41.76,36.67,36.65,36.60,36.58,34.47,34.43,34.39,33.40,33.37,33.35,33.32,31.77,31.73,31.70,28.28,28.26,28.22,28.21,28.17,28.16,25.13,25.11,25.07,25.06,25.02,25.01,19.13,19.09,19.05；MS(ESI)m/z:331.2[M+H]+.
实施例2
(a)将实施例1中I-1e(2g)溶于40mL无水二氯甲烷中，冰浴搅拌，加入1.9mL三乙胺，20min内逐滴加入0.6mL甲磺酰氯，继续搅拌1小时，TLC检测原料消失，加入70mL二氯甲烷，水洗两次，饱和食盐水洗一次，每次20mL，无水硫酸钠干燥，浓缩，得淡黄色固体2.06g(收率88％)。无需纯化，直接进行下一步反应。1H NMR(300MHz,CDCl3)δ4.67(t,J＝7.0Hz,1H),4.44-4.21(m,1H),4.12(dd,J＝12.4,7.0Hz,1H),4.10-3.96(m,2H),3.79(d,J＝12.3Hz,1H),3.05(s,3H),2.90-2.56(m,1H),2.81-2.54(m,1H),2.56-2.32(m,1H),2.40-2.23(m,2H),2.03(dd,J＝12.3,6.9Hz,1H),1.91-1.67(m,5H),1.72-1.61(m,1H),1.67-1.52(m,1H),1.47(s,6H),1.56-1.29(m,2H),1.15(dd,J＝15.0,6.8Hz,6H),1.03(s,3H),0.91(s,3H).
(b)将(a)的产物溶于25mL预干燥的DMF中，加入碳酸锂(2g)，溴化锂(1.7g)，110℃反应2小时，冷却至室温，砂蕊漏斗过滤除去碳酸锂、溴化锂，固体用乙酸乙酯洗涤三遍，合并有机层，饱和食盐水洗一次，浓缩得粗品1.2g(收率76％)，无需纯化直接用于下一步反应。1H NMR(300MHz,CDCl3)δ5.98-5.67(m,2H),4.70(t,J＝7.0Hz,1H),4.43(dd,J＝7.0,3.8Hz,1H),4.01(d,J＝12.4Hz,1H),3.77(d,J＝12.4Hz,1H),3.15-2.98(m,1H),2.79-2.54(m,1H),2.55-2.43(m,1H),2.31(dd,J＝12.3,7.0Hz,1H),2.12-1.90(m,2H),1.93-1.82(m,1H),1.87-1.67(m,5H),1.47(s,6H),1.56-1.37(m,1H),1.14(dd,J＝15.0,6.7Hz,6H),1.03(s,2H),0.91(s,2H).
(c)将(d)的产物(1.2g)溶解于5mL四氢呋喃中，冰浴搅拌，加入12.36mL1N盐酸溶液，移至室温反应1小时，TLC检测原料消失，反应液由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，柱层析得化合物0.82g(收率76％)。1H NMR(300MHz,CDCl3)δ5.98-5.73(m,2H),5.13(s,1H),4.71(t,J＝7.0,1H),4.56(d,J＝5.9Hz,1H),4.34-4.21(m,1H),4.04(d,J＝12.4Hz,1H),3.81(d,J＝12.4Hz,1H),3.05-2.93(m,1H),2.86-2.54(m,1H),2.55-2.21(m,1H),2.24-2.05(m,1H),2.11-1.93(m,2H),1.92-1.64(m,6H),1.51-1.40(m,2H),1.14(dd,J＝15.0,6.8Hz,6H),1.03(s,3H),0.90(s,3H).
(d)将(c)的产物(1g)溶解于二氯甲烷(40mL)，冰浴下加入2mL的1N氢氧化钠溶液，TLC监测原料消失，加入50mL二氯甲烷，水洗两次，饱和食盐水洗一次，每次20mL，无水硫酸钠干燥，浓缩，得白色固体0.63g(78％)。无须纯化，直接进行下一步反应。1H NMR(300MHz,CDCl3)δ5.98-5.56(m,2H),5.14(s,1H),4.55(d,J＝5.9Hz,1H),4.34(dd,J＝7.0,3.8Hz,1H),4.03(d,J＝12.4Hz,1H),3.96(d,J＝7.2Hz,1H),3.92-3.73(m,2H),3.03(t,J＝7.0Hz,1H),2.88(dd,J＝7.0,2.5Hz,1H),2.27-2.04(m,2H),1.98(dd,J＝12.1,6.9Hz,1H),1.89(dd,J＝6.9,2.4Hz,1H),1.89-1.73(m,2H),1.78-1.60(m,3H),1.56-1.32(m,2H),1.01(d,J＝8.5Hz,5H).
实施例3
(a)将实施例1中的中间体I-1a(2.8g)溶解于40mL甲醇中，冷却至0℃，加入2.5mL30％过氧化氢水溶液和5mL 6N氢氧化钠水溶液，低温搅拌2h。往反应液中加入水稀释，并用乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，得非对映异构混合物I-3a2.03g(收率70％)。无需纯化，直接用于下一步反应。1H NMR(300MHz,CDCl3)δ5.34(d,J＝11.8Hz,1H),4.93(d,J＝1.9Hz,1H),4.27(d,J＝9.9Hz,1H),4.09(dd,J＝16.7,8.6Hz,1H),3.89(dd,J＝11.7,7.6Hz,1H),3.48(dd,J＝11.2,5.5Hz,1H),3.16(d,J＝5.9Hz,1H),2.97(d,J＝5.9Hz,1H),2.60-2.39(m,1H),2.28(d,J＝9.8Hz,1H),1.97-1.59(m,10H),1.39-1.04(m,12H).
(b)将非对映异构混合物I-3a(2g)与200mg咪唑溶于无水四氢呋喃，惰性气体保护下，冷却至0℃后分批加入钠氢(1g)，最后加入1.12mL二硫化碳和980μL碘甲烷，反应液呈棕黄色。加入甲醇淬灭，真空浓缩，柱层析得浅黄色固体I-3b 1.91g(收率75％)。1H NMR(300MHz,CDCl3)δ5.30(d,J＝7.0Hz,1H),5.06(t,J＝7.0Hz,1H),4.52(d,J＝7.0Hz,1H),3.98(d,J＝12.4Hz,1H),3.83(d,J＝12.4Hz,1H),3.73-3.56(m,2H),3.27-3.17(m,1H),2.95(d,J＝7.1Hz,1H),2.45-2.32(m,1H),2.29(d,J＝1.2Hz,6H),1.91-1.53(m,6H),1.53-1.43(m,2H),1.48(s,6H),0.97(dd,J＝13.3,1.5Hz,6H).
(c)将非对映异构混合物I-3b(2g)溶于重蒸的甲苯(50mL)中，加入催化量的AIBN(200mg)和3.8mL的三正丁基氢化锡，惰性气体保护，回流反应2h。真空浓缩后，柱层析纯化得到非对映异构混合物I-3c 1.5g(收率85％)。1H NMR(300MHz,CDCl3)δ4.42(dd,J＝7.0,0.8Hz,1H),4.02(dd,J＝7.0,6.3Hz,1H),3.93(d,J＝12.3Hz,1H),3.90-3.80(m,1H),3.85-3.72(m,2H),2.95-2.81(m,1H),2.64(d,J＝7.0Hz,1H),2.39-2.18(m,2H),2.05(dd,J＝12.4,7.0Hz,1H),1.93-1.48(m,9H),1.48(s,6H),1.53-1.37(m,1H),1.37-1.24(m,1H),0.92(dd,J＝2.7,1.5Hz,6H).
(d)将非对映异构混合物I-3c(1.75g)溶于40mL无水二氯甲烷中，加入1.2mL三乙胺，冰浴搅拌，20min内逐滴加入0.4mL甲磺酰氯，继续搅拌1小时，TLC检测原料消失，加入70mL二氯甲烷，水洗两次，饱和食盐水洗一次，每次20mL，无水硫酸钠干燥，浓缩，得淡黄色固体。无需纯化，直接进行下一步反应。
(e)将(d)的产物溶于25mL预干燥的DMF中，加入碳酸锂(1g)，溴化锂(1.2g)，110℃反应2小时，冷却至室温，砂蕊漏斗过滤除去碳酸锂、溴化锂，固体用乙酸乙酯洗涤三遍，合并有机层，饱和食盐水洗一次，浓缩得粗品1.2g，无需纯化直接用于下一步反应。
(f)将(d)的产物(1.2g)溶解于5mL四氢呋喃中，冰浴搅拌，加入12.36mL1N盐酸溶液，移至室温反应1小时，TLC检测原料消失，反应液由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，柱层析得化合物0.82g(收率76％)。1H NMR(300MHz,CDCl3)δ5.97(dd,J＝15.2,1.0Hz,2H),5.01(s,1H),4.48(d,J＝5.9Hz,1H),4.34(dd,J＝7.0,5.9Hz,1H),3.95(d,J＝12.4Hz,1H),3.76(d,J＝12.4Hz,1H),3.06-2.93(m,2H),2.27-2.08(m,2H),2.00(dd,J＝12.2,6.9Hz,1H),1.90(t,J＝6.9Hz,1H),1.78-1.23(m,9H),0.91(dd,J＝3.0,1.4Hz,6H)；13C NMR(75MHz,CDCl3)δ206.81,151.95,117.97,100.48,73.34,68.74,61.82,54.28,47.68,46.05,45.98,41.13,41.10,38.36,35.00,34.89,33.92,33.85,33.31,31.22,27.31,20.28,20.23,18.81,18.77,18.74,18.69；MS(ESI)m/z:332.2[M+H]+.
(g)将I-3f(50mg)溶于15mL二氯甲烷中，加入乙酸，EDCI(1.5eq),DMAP(催化量)，室温搅拌12小时，反应结束后补加二氯甲烷至50mL,水洗两次，饱和食盐水洗一次，每次10mL，无水硫酸钠干燥，浓缩，柱层析得白色固体45mg(收率80％)。1H NMR(300MHz,CDCl3)δ5.99(dd,J＝6.7,1.0Hz,2H),5.05(s,1H),4.96(dd,J＝7.0,3.8Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.66(dd,J＝7.0,2.5Hz,1H),2.24(dd,J＝12.4,7.0Hz,1H),2.05(s,3H),2.11-1.91(m,2H),1.89-1.24(m,11H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ205.91,205.88,205.84,170.02,169.98,149.69,117.82,117.76,98.98,98.94,76.41,76.38,76.34,76.30,68.83,68.78,59.38,59.35,52.30,52.26,47.94,47.90,44.90,44.85,44.83,41.24,41.21,41.18,41.15,41.13,41.10,38.04,37.99,35.21,35.17,35.16,35.12,34.61,34.57,34.53,33.03,33.00,32.98,32.95,31.04,31.01,30.98,30.96,30.32,30.27,30.21,23.93,23.87,23.82,21.08,18.95,18.93,18.90,18.86,18.85,18.44,18.41,18.39,18.36.MS(ESI)m/z:375.2[M+H]+.
实施例4
将实施例3中的化合物I-3f(50mg)溶解于5mL无水二氯甲烷中，加入30μL三乙胺，将混合液冷却至0℃，滴加20μL甲磺酰氯，反应30min。加少量水淬灭反应，由乙酸乙酯萃取三次，饱和食盐水洗涤，干燥后过滤，真空浓缩，快速柱层析得化合物40mg(收率74％)。1HNMR(300MHz,CDCl3)δ5.98(dd,J＝10.0,1.0Hz,2H),4.99(s,1H),4.78(dd,J＝7.0,3.8Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.18(t,J＝6.9Hz,1H),3.01(s,3H),2.64(dd,J＝7.0,2.5Hz,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.07-1.23(m,14H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.19,206.15,206.11,150.51,150.48,118.84,118.78,99.07,99.02,81.24,81.22,81.19,68.96,68.91,58.09,58.06,52.42,52.38,47.95,47.91,45.56,45.53,45.51,45.49,41.22,41.19,41.17,41.14,41.12,41.08,38.63,37.53,37.48,35.25,35.22,35.20,35.17,34.57,34.53,34.49,33.02,32.99,32.97,32.94,31.02,30.97,30.92,30.90,23.48,23.42,23.37,18.93,18.91,18.88,18.85,18.83,18.39,18.36,18.35,18.32.MS(ESI)m/z:411.2[M+H]+.
实施例5
参照实施例6的合成方法。1H NMR(300MHz,CDCl3)δ5.99(dd,J＝7.5,1.0Hz,2H),5.75(t,J＝10.9Hz,1H),5.55(t,J＝10.9Hz,1H),5.02(s,1H),4.95(dd,J＝7.0,3.7Hz,1H),3.89(d,J＝12.4Hz,1H),3.64(d,J＝12.4Hz,1H),3.26(t,J＝6.9Hz,1H),2.85-2.72(m,1H),2.41(t,J＝7.0Hz,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.13-1.31(m,18H),0.97(d,J＝16.3Hz,5H).13C NMR(75MHz,CDCl3)δ206.42,173.90,150.16,132.40,126.74,118.83,98.20,77.15,69.91,58.19,51.99,46.11,45.02,42.79,42.25,34.94,34.89,34.05,30.30,29.63,28.31,25.83,25.46,25.32,20.10.MS(ESI)m/z:441.2[M+H]+.
实施例6
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ(dd,J＝9.8,1.0Hz,2H),5.07(s,1H),4.94(d,J＝7.0Hz,1H),4.10-3.97(m,2H),3.92-3.72(m,2H),3.27-3.13(m,2H),2.24(dd,J＝12.2,6.8Hz,1H),2.05(s,3H),2.16-1.92(m,2H),1.92-1.83(m,1H),1.89-1.74(m,1H),1.79-1.69(m,1H),1.74-1.58(m,3H),1.57-1.33(m,2H),1.01(d,J＝8.1Hz,5H).13C NMR(75MHz,CDCl3)δ206.43,206.40,169.99,169.94,150.20,150.17,118.17,118.11,100.14,100.09,76.33,76.29,76.26,76.22,72.88,72.84,72.80,65.33,65.29,65.25,60.32,60.28,52.61,52.57,52.53,46.60,46.58,46.56,46.54,46.51,46.46,39.95,39.90,39.01,38.98,38.96,38.93,38.90,38.88,38.85,34.39,34.35,34.31,30.96,30.93,30.91,30.89,29.94,29.89,29.86,29.84,29.81,29.47,29.42,29.37,28.19,28.15,28.11,25.09,25.03,24.98,21.07,20.58,20.55,20.52,20.50,20.47.MS(ESI)m/z:413.2[M+Na]+.
实施例7
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ5.99(dd,J＝7.5,1.0Hz,2H),5.02(s,1H),4.95(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.25(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.31(t,J＝7.0Hz,2H),2.21(dd,J＝12.4,7.0Hz,1H),2.10-1.92(m,2H),1.90-1.19(m,19H),0.93(d,J＝21.4Hz,7H),0.92-0.82(m,2H).13C NMR(75MHz,CDCl3)δ206.42,173.36,150.16,118.83,98.20,76.66,69.37,57.76,53.61,49.06,45.02,41.80,37.30,36.56,35.15,34.32,34.15,31.51,30.12,29.24,29.11,25.19,24.74,22.64,19.75,18.81,14.09.MS(ESI)m/z:467.3[M+H]+.
实施例8
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ5.98(dd,J＝8.9,1.0Hz,2H),5.02-4.89(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.66(dd,J＝7.0,2.5Hz,1H),2.48(t,J＝7.0Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.10-1.90(m,2H),1.89-1.26(m,10H),1.29-1.14(m,1H),1.19-1.10(m,1H),1.14-0.87(m,8H).13C NMR(75MHz,CDCl3)δ206.50,206.46,206.42,173.72,173.68,150.29,150.26,118.76,118.70,99.02,98.97,77.59,77.56,77.53,77.51,77.48,68.70,68.65,58.54,58.51,52.20,52.16,47.94,47.90,44.93,44.90,44.88,44.86,41.22,41.20,41.17,41.14,41.12,37.42,37.37,35.25,35.22,35.20,35.17,34.61,34.57,34.53,33.03,33.00,32.98,32.95,30.77,30.73,30.68,30.62,23.59,23.53,23.48,18.95,18.93,18.90,18.86,18.85,18.39,18.36,18.35,18.32,14.10,14.07,14.04,8.84,8.81.MS(ESI)m/z:423.2[M+Na]+.
实施例9
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ5.98(dd,J＝8.9,1.0Hz,2H),5.68(t,J＝1.0Hz,1H),5.02-4.91(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.66(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.12-1.94(m,8H),1.90-1.37(m,9H),1.37-1.23(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.84,206.81,206.77,166.27,158.39,158.34,150.54,150.52,118.87,118.80,115.78,115.72,115.67,115.61,99.08,99.03,77.25,77.22,77.19,68.70,68.65,58.63,58.60,52.01,51.96,47.17,47.13,44.86,44.84,44.82,44.79,41.22,41.20,41.17,41.14,41.12,37.30,37.25,35.25,35.22,35.20,35.17,34.19,34.14,34.10,33.05,33.02,33.00,32.97,30.98,30.95,30.92,30.89,30.75,30.70,30.65,25.60,25.55,25.54,25.49,23.55,23.50,23.44,20.77,20.72,20.66,18.95,18.93,18.90,18.86,18.85,18.82,18.79,18.78,18.75.MS(ESI)m/z:415.2[M+H]+.
实施例10
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.99-7.88(m,2H),7.59-7.48(m,1H),7.48-7.37(m,2H),5.99(dd,J＝7.5,1.0Hz,2H),5.05-4.95(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.14-1.95(m,2H),1.90-1.23(m,11H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,165.67,150.16,132.82,130.06,129.46,128.69,118.40,98.20,76.98,69.17,58.12,53.55,48.74,45.16,41.83,37.30,37.14,35.15,34.15,30.27,29.24,24.73,19.75,18.78.MS(ESI)m/z:437.2[M+H]+.
实施例11
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.09-7.97(m,2H),7.35-7.22(m,2H),6.03-5.95(m,2H),5.05-4.95(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.28(t,J＝6.9Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.14-1.95(m,2H),1.90-1.67(m,3H),1.67(t,J＝6.9Hz,1H),1.66-1.55(m,1H),1.60-1.46(m,3H),1.51-1.36(m,1H),1.36-1.22(m,1H),0.97(s,3H),0.91(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.09,150.18,131.59,131.48,118.83,114.47,114.20,98.20,76.93,69.37,58.23,52.04,49.06,45.16,41.83,37.30,36.56,35.15,34.15,30.27,28.37,25.42,19.88,18.77.MS(ESI)m/z:477.2[M+Na]+.
实施例12
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.97-7.87(m,2H),7.48-7.38(m,2H),6.03-5.95(m,2H),5.07-4.97(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.28(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.3,7.0Hz,1H),2.13-1.94(m,2H),1.91-1.36(m,9H),1.36-1.22(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.11,150.18,138.79,131.13,129.10,126.83,118.83,98.20,76.93,69.37,58.23,52.04,49.06,45.16,41.83,36.88,36.46,35.15,34.15,30.27,29.84,24.62,19.88,18.77.MS(ESI)m/z:493.2[M+Na]+.
实施例13
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.99-7.89(m,2H),7.03-6.94(m,2H),6.03-5.95(m,2H),5.05-4.95(m,2H),3.98(d,J＝12.4Hz,1H),3.86(s,3H),3.73(d,J＝12.4Hz,1H),3.28(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.3,7.0Hz,1H),2.11-1.92(m,2H),1.91-1.36(m,10H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.03,163.90,150.02,132.03,122.50,119.01,113.86,98.20,76.93,69.37,58.56,55.46,51.86,49.06,45.16,41.83,37.30,36.46,35.15,34.15,30.23,27.91,25.16,20.18,18.60.MS(ESI)m/z:467.2[M+H]+.
实施例14
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.06-7.97(m,2H),7.93-7.84(m,2H),5.99(d,J＝2.0Hz,2H),5.02(dd,J＝7.0,3.8Hz,1H),5.01(s,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.28(t,J＝7.0Hz,1H),3.21(s,3H),2.67(dd,J＝7.0,2.5Hz,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.10-1.92(m,2H),1.96-1.35(m,10H),1.35-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.32,165.54,150.08,141.08,131.74,130.62,128.48,118.72,98.20,76.74,68.88,58.78,52.04,48.36,45.16,43.30,41.76,37.50,36.46,35.53,34.15,30.27,28.69,25.76,20.09,18.60.MS(ESI)m/z:537.2[M+Na]+.
实施例15
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.91-8.83(m,2H),7.99-7.90(m,2H),5.99(dd,J＝7.5,1.0Hz,2H),5.05-4.93(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.14-1.95(m,2H),1.90-1.23(m,11H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,165.86,150.16,142.48,132.99,123.29,118.83,98.20,76.98,69.17,58.12,53.61,48.74,45.16,41.83,37.30,37.14,35.15,34.15,30.27,29.24,24.73,19.75,18.78.MS(ESI)m/z:460.2[M+Na]+.
实施例16
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ9.12(d,J＝1.6Hz,1H),8.74(dd,J＝7.5,1.4Hz,1H),8.17(d,J＝7.5Hz,1H),7.43(t,J＝7.5Hz,1H),5.99(dd,J＝7.5,1.0Hz,2H),5.05-4.95(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.14-1.94(m,2H),1.90-1.37(m,10H),1.37-1.23(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,165.02,152.67,150.96,150.16,137.40,126.18,123.60,118.83,98.20,76.98,69.17,58.12,53.61,48.74,45.16,41.83,37.30,37.14,35.15,34.15,30.27,29.24,24.73,19.75,18.78.MS(ESI)m/z:438.2[M+H]+.
实施例17
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.85(dd,J＝7.5,1.5Hz,1H),8.14(dd,J＝7.5,1.5Hz,1H),7.91(t,J＝7.5Hz,1H),7.42(d,J＝7.5Hz,1H),5.99(dd,J＝7.5,1.0Hz,2H),5.07-4.97(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.67(dd,J＝7.1,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.13-1.94(m,2H),1.89-1.23(m,11H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,161.97,150.16,149.06,148.51,138.25,124.46,124.16,118.83,98.20,76.98,69.17,58.12,53.61,48.74,45.20,41.83,37.30,37.14,35.15,34.15,30.27,29.24,24.73,19.75,18.78.MS(ESI)m/z:460.2[M+Na]+.
实施例18
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ9.14(s,1H),8.75(d,J＝7.5Hz,1H),8.72-8.64(m,1H),5.99(dd,J＝7.5,1.0Hz,2H),5.03(dd,J＝7.0,3.8Hz,1H),5.02(s,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.67(dd,J＝7.1,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.12-1.94(m,2H),1.90-1.37(m,10H),1.37-1.23(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.91,206.88,206.84,163.13,150.53,147.17,147.06,147.04,146.93,146.13,146.11,146.00,145.99,144.71,144.70,144.60,144.59,142.52,118.77,118.71,99.13,99.08,77.31,77.28,77.25,68.78,68.72,58.70,58.67,52.39,52.35,48.12,48.07,44.86,44.84,41.26,41.23,41.21,41.18,41.15,41.13,37.30,37.25,35.25,35.22,35.20,35.17,34.57,34.53,34.49,33.05,33.02,33.00,32.97,30.98,30.95,30.93,30.90,30.46,30.41,30.36,24.03,23.98,23.93,19.04,19.03,18.99,18.96,18.95,18.91,18.88,18.86,18.83.MS(ESI)m/z:439.2[M+H]+.
实施例19
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ9.32-9.26(m,1H),8.89-8.80(m,1H),7.99(dd,J＝7.5,1.5Hz,1H),5.99(dd,J＝7.5,1.0Hz,2H),5.02(s,1H),5.01(dd,J＝7.0,3.8Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.67(dd,J＝7.1,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.13-1.93(m,2H),1.90-1.37(m,10H),1.37-1.23(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.91,206.88,206.84,163.22,160.94,160.92,160.81,160.79,158.47,158.37,158.34,158.24,152.18,150.53,119.91,119.90,119.81,119.79,118.77,118.71,99.13,99.08,77.06,77.03,77.00,68.78,68.72,58.70,58.67,52.39,52.35,48.12,48.07,44.88,44.86,44.84,41.26,41.23,41.21,41.18,41.15,41.13,37.30,37.25,35.25,35.22,35.20,35.17,34.57,34.53,34.49,33.05,33.02,33.00,32.97,30.98,30.95,30.93,30.90,30.46,30.41,30.36,24.03,23.98,23.93,19.04,19.03,18.99,18.96,18.95,18.91,18.88,18.86,18.83.MS(ESI)m/z:439.2[M+H]+.
实施例20
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.80(dd,J＝7.5,1.5Hz,1H),8.47-8.40(m,1H),8.35-8.23(m,2H),8.11-8.02(m,1H),7.53(d,J＝7.4Hz,1H),6.03-5.95(m,2H),5.07-4.97(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.28(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.3,7.0Hz,1H),2.12-1.93(m,2H),1.91-1.36(m,9H),1.36-1.21(m,1H),0.98(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.05,149.88,148.69,145.64,135.72,129.25,128.58,127.76,125.93,124.16,121.90,118.72,98.20,76.74,68.91,58.78,51.86,49.09,45.16,41.79,37.17,36.41,35.15,34.15,30.27,28.69,25.76,20.09,18.60.MS(ESI)m/z:510.2[M+Na]+.
实施例21
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.32-7.13(m,5H),6.03-5.95(m,2H),5.02(s,1H),4.94(dd,J＝7.0,3.8Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.89(T,J＝6.9Hz,2H),2.73-2.59(m,3H),2.23(dd,J＝12.4,7.0Hz,1H),2.09-1.90(m,2H),1.90-1.60(m,4H),1.65-1.51(m,2H),1.56-1.46(m,2H),1.51-1.36(m,1H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,172.59,150.02,140.60,128.63,128.46,126.33,119.01,98.20,76.76,69.37,58.38,51.86,49.06,45.02,41.83,37.30,36.46,36.03,35.15,34.15,30.56,30.05,27.91,25.16,20.18,18.60.MS(ESI)m/z:465.2[M+H]+.
实施例22
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.64(t,J＝15.0Hz,1H),7.56(dd,J＝6.2,1.5Hz,2H),7.39-7.26(m,3H),6.39(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.02(s,1H),4.94(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.10-1.92(m,2H),1.92-1.36(m,10H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.80,150.02,144.96,134.57,130.12,128.93,128.82,119.01,117.35,98.20,76.92,69.37,58.21,51.86,49.06,45.02,41.83,37.30,36.46,35.15,34.15,30.23,27.93,25.09,20.18,18.60.MS(ESI)m/z:463.2[M+H]+.
实施例23
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.60-7.47(m,2H),7.47-7.30(m,3H),6.10(t,J＝1.0Hz,1H),6.03-5.95(m,2H),5.02(s,1H),4.95(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(d,J＝7.0Hz,1H),2.52(d,J＝1.0Hz,3H),2.23(dd,J＝12.4,7.0Hz,1H),2.09-1.91(m,2H),1.91-1.36(m,9H),1.36-1.22(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.14,151.84,149.88,135.95,130.39,128.31,127.99,120.45,118.72,98.20,76.92,69.37,58.71,51.86,49.06,45.02,41.81,36.88,36.46,35.15,34.15,30.27,28.58,25.88,20.09,18.60,17.73.MS(ESI)m/z:477.2[M+H]+.
实施例24
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.68-7.54(m,3H),7.18-7.06(m,2H),6.38(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.02(s,1H),4.94(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.4,7.0Hz,1H),2.09-1.91(m,2H),1.91-1.64(m,4H),1.68-1.52(m,2H),1.57-1.45(m,2H),1.51-1.36(m,1H),1.36-1.22(m,1H),0.98(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.71,149.88,145.42,130.13,130.03,119.02,117.47,115.56,115.29,98.20,76.92,69.37,58.71,51.86,49.29,45.02,41.81,36.88,36.46,35.15,34.15,30.27,28.58,25.88,20.09,18.60.MS(ESI)m/z:481.2[M+H]+.
实施例25
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.90-7.80(m,2H),7.73-7.58(m,3H),6.37(d,J＝15.1Hz,1H),5.99(dd,J＝6.5,1.0Hz,2H),5.02(s,1H),4.94(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.24(dd,J＝12.4,7.0Hz,1H),2.09-1.91(m,2H),1.91-1.22(m,11H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.80,150.08,145.70,133.67,130.32,129.03,128.66,118.72,117.42,98.20,76.92,68.88,58.71,51.86,49.29,45.02,41.80,37.17,36.46,35.15,34.15,30.27,28.69,25.76,20.09,18.60.MS(ESI)m/z:495.1[M+H]+.
实施例26
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.68-7.54(m,3H),6.96-6.87(m,2H),6.35(d,J＝15.1Hz,1H),6.04-5.95(m,2H),5.05-4.91(m,2H),3.98(d,J＝12.4Hz,1H),3.82(s,3H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.3,7.0Hz,1H),2.12-1.93(m,2H),1.91-1.35(m,10H),1.35-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.80,161.01,149.88,146.31,131.59,127.57,118.72,117.10,114.22,98.20,77.03,68.88,58.71,55.37,51.86,49.09,45.02,41.79,37.17,36.46,35.35,34.15,30.27,28.69,25.76,20.09,18.60.MS(ESI)m/z:493.2[M+H]+.
实施例27
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.54(dd,J＝7.5,1.5Hz,1H),7.38(dd,J＝15.1,0.6Hz,1H),6.77(dd,J＝7.5,0.7Hz,1H),6.54(t,J＝7.5Hz,1H),6.35(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.05-4.91(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.12-1.93(m,2H),1.91-1.36(m,10H),1.36-1.22(m,1H),0.97(s,3H),0.91(s,3H).13C NMR(75MHz,CDCl3)δ206.42,167.29,152.08,150.18,143.31,130.25,118.83,115.52,111.58,108.80,98.20,77.01,69.37,58.21,52.04,49.06,45.02,41.83,37.30,36.56,35.15,34.15,30.27,28.37,25.42,20.09,18.77.MS(ESI)m/z:475.2[M+Na]+.
实施例28
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.85(dd,J＝15.1,0.6Hz,1H),7.74(dd,J＝7.5,1.5Hz,1H),7.57(dd,J＝7.5,0.7Hz,1H),7.15(t,J＝7.5Hz,1H),6.35(d,J＝15.1Hz,1H),6.01(dd,J＝2.0,1.0Hz,1H),5.94(dd,J＝2.0,1.0Hz,1H),4.91(dd,J＝7.0,3.8Hz,1H),4.33(d,J＝8.0Hz,1H),3.96-3.80(m,1H),3.45(d,J＝12.4Hz,1H),3.36(d,J＝12.4Hz,1H),3.22(s,3H),3.25-3.12(m,1H),2.49(dd,J＝10.8,2.5Hz,1H),2.09-1.92(m,1H),1.88-1.33(m,12H),1.33-1.20(m,1H),0.84(d,J＝10.1Hz,5H).13C NMR(75MHz,CDCl3)δ208.43,166.88,148.10,139.62,136.66,129.08,127.72,127.70,118.39,115.56,76.94,73.41,72.99,61.48,59.23,48.88,47.73,44.80,41.95,40.38,34.49,33.40,30.86,30.28,27.93,24.95,22.14,18.92.MS(ESI)m/z:485.2[M+H]+.
实施例29
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.05-7.85(m,4H),7.76(dd,J＝15.2,0.7Hz,1H),7.66(dd,J＝7.5,0.6Hz,1H),7.54-7.42(m,3H),6.33(d,J＝15.2Hz,1H),5.99(d,J＝2.0Hz,2H),5.04-4.90(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.3,7.0Hz,1H),2.10-1.90(m,2H),1.90-1.21(m,11H),0.97(s,3H),0.91(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.67,150.08,139.62,134.32,133.54,132.56,128.57,128.23,127.17,127.07,126.51,125.76,125.17,119.02,116.14,98.20,76.94,68.20,58.13,52.09,48.12,45.18,41.79,37.33,36.36,35.38,34.15,30.27,28.69,25.76,19.88,18.60.MS(ESI)m/z:535.2[M+Na]+.
实施例30
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ6.66(dd,J＝15.1,6.2Hz,1H),6.15(dd,J＝10.9,1.0Hz,1H),5.99(d,J＝2.0Hz,2H),5.95-5.80(m,2H),5.25(d,J＝7.6Hz,2H),5.04-4.91(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.90(t,J＝7.1Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.31-2.14(m,3H),2.10-1.92(m,2H),1.96-1.75(m,2H),1.80-1.66(m,2H),1.66-1.51(m,2H),1.56-1.44(m,2H),1.49-1.35(m,1H),1.35-1.21(m,1H),0.97(s,3H),0.91(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.41,154.60,150.08,146.05,143.26,130.04,119.70,119.02,117.64,98.20,98.15,77.20,68.46,58.13,52.09,48.36,45.81,45.00,41.79,37.50,36.41,35.43,34.15,30.72,30.27,28.69,25.76,20.09,18.60.MS(ESI)m/z:531.2[M+Na]+.
实施例31
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ7.78(dd,J＝15.2,0.7Hz,1H),7.74(d,J＝7.5Hz,1H),7.61(dd,J＝7.3,0.6Hz,1H),7.47(dd,J＝7.6,0.4Hz,1H),7.33(t,J＝7.5Hz,1H),6.98-6.89(m,1H),6.35(d,J＝15.1Hz,1H),6.04-5.95(m,2H),5.04-4.91(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.3,7.0Hz,1H),2.12-1.92(m,2H),1.90-1.35(m,9H),1.35-1.21(m,1H),0.97(s,3H),0.91(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.80,155.07,150.08,144.63,139.16,129.80,127.34,127.01,125.47,119.02,116.32,112.87,107.39,98.20,77.20,68.46,58.12,52.09,48.66,45.00,41.79,37.13,36.41,35.35,34.15,30.27,28.69,25.76,20.09,18.60.MS(ESI)m/z:525.2[M+Na]+.
实施例32
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.65-8.56(m,2H),7.56(t,J＝15.1Hz,1H),7.51-7.43(m,2H),6.59(d,J＝15.2Hz,1H),6.03-5.95(m,2H),5.02(s,1H),4.94(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.10-1.92(m,2H),1.92-1.36(m,10H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.80,150.02,149.71,145.82,136.83,123.38,119.01,116.30,98.20,76.92,69.37,58.21,51.86,49.06,45.02,41.83,37.30,36.46,35.15,34.15,30.23,27.91,25.16,20.18,18.60.MS(ESI)m/z:464.2[M+H]+.
实施例33
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.95(d,J＝1.8Hz,1H),8.63-8.54(m,1H),8.03(dd,J＝7.5,0.7Hz,1H),7.66(t,J＝15.0Hz,1H),7.57(t,J＝7.5Hz,1H),6.38(d,J＝15.2Hz,1H),5.22(dd,J＝1.7,1.0Hz,1H),5.09(dd,J＝1.8,1.0Hz,1H),5.07(s,2H),4.82(s,1H),4.82(dd,J＝7.0,3.7Hz,1H),3.96(d,J＝12.4Hz,1H),3.72(d,J＝12.4Hz,1H),3.08(t,J＝7.0Hz,1H),2.50(dd,J＝7.0,2.5Hz,1H),2.05-1.87(m,3H),1.92-1.36(m,10H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ166.71,148.90,147.43,147.37,145.93,140.21,132.15,130.44,123.36,115.70,115.18,114.86,100.64,77.03,69.13,60.50,51.93,49.32,45.77,41.83,37.30,36.46,35.10,33.98,29.93,27.93,25.09,20.18,18.66.MS(ESI)m/z:485.2[M+Na]+.
实施例34
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.50(dd,J＝7.5,1.5Hz,1H),7.88(dd,J＝15.1,0.7Hz,1H),7.81-7.72(m,1H),7.66(d,J＝7.5Hz,1H),7.17(d,J＝7.5Hz,1H),6.62(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.02(s,1H),4.94(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.21(dd,J＝12.4,7.0Hz,1H),2.10-1.92(m,2H),1.92-1.36(m,10H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.93,150.02,149.61,149.51,137.08,136.90,123.62,123.54,119.01,115.76,98.20,76.92,69.37,58.21,51.86,49.06,45.02,41.83,37.30,36.46,35.15,34.15,30.23,27.91,25.16,20.18,18.60.MS(ESI)m/z:462.2[M+H]+.
实施例35
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.76(s,1H),8.47-8.33(m,2H),7.78(dd,J＝15.2,0.5Hz,1H),6.57(d,J＝15.2Hz,1H),6.03-5.95(m,2H),5.02(s,1H),4.94(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.4,7.0Hz,1H),2.10-1.92(m,2H),1.92-1.36(m,10H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.93,150.02,145.28,143.06,142.79,142.57,136.23,119.01,116.31,98.20,76.92,69.37,58.21,51.86,49.06,45.02,41.83,37.30,36.46,35.15,34.15,30.23,27.91,25.16,20.18,18.60.MS(ESI)m/z:487.2[M+Na]+.
实施例36
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ9.16(d,J＝0.5Hz,2H),8.85(s,1H),7.77-7.66(m,1H),6.44(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.02(s,1H),4.94(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.4,7.0Hz,1H),2.10-1.92(m,2H),1.92-1.36(m,10H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.93,157.95,150.02,149.59,140.04,129.20,119.01,117.16,98.20,76.92,69.37,58.21,51.86,49.06,45.02,41.83,37.30,36.46,35.15,34.15,30.23,27.91,25.16,20.18,18.60.MS(ESI)m/z:465.2[M+H]+.
实施例37
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.53-8.44(m,2H),7.22-7.13(m,2H),6.03-5.95(m,2H),5.02(s,1H),4.94(dd,J＝7.0,3.8Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.97-2.82(m,2H),2.73-2.59(m,3H),2.23(dd,J＝12.4,7.0Hz,1H),2.09-1.90(m,2H),1.90-1.36(m,9H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,172.59,150.02,149.77,141.99,124.37,119.01,98.20,76.76,69.37,58.38,51.86,49.06,45.02,41.83,37.30,36.46,36.03,35.15,34.15,30.46,30.05,27.91,25.16,20.18,18.60.MS(ESI)m/z:466.2[M+H]+.
实施例38
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.48-8.37(m,2H),7.48(t,J＝7.6Hz,1H),7.24(t,J＝7.5Hz,1H),5.22(dd,J＝1.7,1.0Hz,1H),5.09(dd,J＝1.8,1.0Hz,1H),5.07(s,2H),4.82(s,1H),4.81(dd,J＝7.0,3.8Hz,1H),3.96(d,J＝12.4Hz,1H),3.72(d,J＝12.4Hz,1H),3.14-3.02(m,1H),3.08-2.97(m,2H),2.79-2.64(m,2H),2.50(dd,J＝7.1,2.5Hz,1H),2.04-1.87(m,3H),1.92-1.36(m,9H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ172.84,149.71,148.09,147.43,145.93,136.13,135.09,124.99,115.18,114.86,100.64,77.04,69.13,60.50,51.93,49.32,45.77,41.83,37.30,36.46,36.02,35.10,33.98,30.61,29.93,27.91,25.16,20.18,18.66.MS(ESI)m/z:488.2[M+Na]+.
实施例39
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.49(dd,J＝7.5,1.5Hz,1H),7.68(d,J＝7.5Hz,1H),7.49(d,J＝7.5Hz,1H),7.10(dd,J＝7.5,1.6Hz,1H),6.03-5.95(m,2H),5.02(s,1H),4.94(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),3.08(d,J＝7.1Hz,2H),2.84-2.71(m,2H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.4,7.0Hz,1H),2.09-1.90(m,2H),1.90-1.36(m,9H),1.36-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,172.73,161.78,151.11,150.02,136.78,123.39,122.95,119.01,98.20,76.76,69.37,58.38,51.86,49.06,45.02,41.83,37.30,36.46,35.15,34.15,30.35,30.17,30.05,27.91,25.16,20.18,18.60.MS(ESI)m/z:488.2[M+Na]+.
实施例40
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.43(d,J＝7.5Hz,1H),7.58(dd,J＝15.1,0.7Hz,1H),7.46-7.34(m,2H),6.51(d,J＝15.2Hz,1H),6.03-5.95(m,2H),5.05-4.91(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.4,7.0Hz,1H),2.09-1.91(m,2H),1.91-1.22(m,11H),0.98(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.71,149.88,146.95,146.76,146.59,146.55,120.01,119.97,119.02,115.13,104.09,103.83,98.20,77.03,69.37,58.71,51.65,47.43,45.02,41.80,36.88,36.46,34.65,34.15,30.27,28.58,25.88,20.09,19.38.MS(ESI)m/z:482.2[M+H]+.
实施例41
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.47(dd,J＝7.8,1.1Hz,2H),7.71(dd,J＝15.2,0.7Hz,1H),7.54(dd,J＝7.5,0.7Hz,1H),6.48(d,J＝15.2Hz,1H),6.03-5.95(m,2H),5.05-4.91(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.4,7.0Hz,1H),2.09-1.91(m,2H),1.91-1.22(m,11H),0.98(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.82,149.88,148.69,148.62,139.19,139.08,137.88,137.61,123.11,123.01,119.02,117.25,117.21,98.20,77.03,69.37,58.71,51.86,49.29,45.02,41.80,36.88,36.46,35.15,34.15,30.27,28.58,25.88,20.09,18.60.MS(ESI)m/z:448.2[M+H]+.
实施例42
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.33(d,J＝7.5Hz,1H),7.57(dd,J＝15.4,0.7Hz,1H),7.42(d,J＝1.5Hz,1H),7.31(dd,J＝7.5,0.6Hz,1H),6.52(d,J＝15.1Hz,1H),5.99(dd,J＝6.5,1.0Hz,2H),5.05-4.91(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.24(dd,J＝12.4,7.0Hz,1H),2.09-1.91(m,2H),1.91-1.22(m,11H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.80,150.29,150.08,146.97,146.41,134.64,121.71,121.20,118.72,115.20,98.20,77.07,68.88,58.71,51.65,47.43,45.02,41.80,37.17,36.46,34.65,34.15,30.27,28.69,25.76,20.09,19.38.MS(ESI)m/z:498.2[M+H]+.
实施例43
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.09(d,J＝7.5Hz,1H),7.58(dd,J＝14.9,0.7Hz,1H),7.39(dd,J＝7.6,0.7Hz,1H),6.90(d,J＝1.4Hz,1H),6.57(d,J＝15.2Hz,1H),6.04-5.95(m,2H),5.02(s,1H),4.94(dd,J＝7.0,3.7Hz,1H),3.98(d,J＝12.4Hz,1H),3.91(s,3H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.23(dd,J＝12.3,7.0Hz,1H),2.12-1.93(m,2H),1.91-1.43(m,9H),1.48-1.35(m,1H),1.35-1.21(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.71,163.20,149.88,146.57,145.17,135.03,118.97,118.72,115.17,107.24,98.20,76.94,68.88,58.71,53.70,51.86,49.09,45.02,41.79,37.17,36.46,35.35,34.15,30.27,28.69,25.76,20.09,18.60.MS(ESI)m/z:494.2[M+H]+.
实施例44
参照实施例3的合成方法。1H NMR(300MHz,CDCl3)δ8.71(s,1H),8.53(dd,J＝7.5,0.4Hz,1H),7.72(dd,J＝15.1,0.7Hz,1H),7.52(dd,J＝7.4,0.6Hz,1H),6.48(d,J＝15.1Hz,1H),5.99(dd,J＝6.5,1.0Hz,2H),5.05-4.91(m,2H),3.98(d,J＝12.4Hz,1H),3.73(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.67(dd,J＝7.0,2.5Hz,1H),2.24(dd,J＝12.4,7.0Hz,1H),2.09-1.91(m,2H),1.91-1.36(m,10H),1.36-1.22(m,1H),0.97(s,3H),0.90(s,3H).13C NMR(75MHz,CDCl3)δ206.42,166.82,150.08,148.30,148.27,139.54,131.55,128.09,123.38,118.72,117.29,98.20,77.07,68.88,58.71,51.86,49.29,45.02,41.80,37.17,36.46,35.15,34.15,30.27,28.69,25.76,20.09,18.60.MS(ESI)m/z:498.2[M+Na]+.
实施例45
将实施例1中化合物(50mg)溶于15mL二氯甲烷中，加入2-甲酸吡嗪，EDCI(1.5eq),DMAP(催化量)，室温搅拌12小时，反应结束后补加二氯甲烷至50mL,水洗两次，饱和食盐水洗一次，每次10mL，无水硫酸钠干燥，浓缩，柱层析得白色固体46mg(收率82％)。1H NMR(300MHz,CDCl3)δ9.14(s,1H),8.75(d,J＝7.5Hz,1H),8.72-8.64(m,1H),5.99(dd,J＝7.5,1.0Hz,2H),5.75(t,J＝10.9Hz,1H),5.55(t,J＝10.9Hz,1H),5.03(dd,J＝7.0,3.8Hz,1H),5.02(s,1H),3.89(d,J＝12.4Hz,1H),3.64(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.79(dd,J＝7.0,1.8Hz,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.14-1.61(m,8H),0.97(d,J＝16.3Hz,5H).13C NMR(75MHz,CDCl3)δ206.84,206.80,206.77,163.15,150.50,147.17,147.06,147.04,146.93,146.13,146.11,146.00,145.99,144.72,144.70,144.60,144.59,142.52,133.29,133.23,133.17,126.27,126.21,126.15,118.40,118.34,99.12,99.08,77.43,77.40,77.37,68.87,68.86,68.81,68.80,58.75,58.71,58.70,51.62,51.57,46.62,46.56,44.91,44.88,44.86,44.84,44.81,41.88,41.84,41.82,41.74,36.43,36.41,36.36,36.34,34.41,34.37,34.33,32.32,32.29,32.27,32.24,30.96,30.93,30.91,30.88,28.53,28.51,28.47,28.46,28.42,28.41,24.99,24.98,24.94,24.93,24.89,24.88,19.49,19.47,19.45,19.44,19.42.MS(ESI)m/z:459.2[M+Na]+.
实施例46
参照实施例47的合成方法。1H NMR(300MHz,CDCl3)δ9.32-9.26(m,1H),8.89-8.80(m,1H),7.98(dd,J＝7.5,1.5Hz,1H),5.99(dd,J＝7.5,1.0Hz,2H),5.75(t,J＝10.9Hz,1H),5.55(t,J＝10.9Hz,1H),5.02(s,1H),5.01(dd,J＝7.0,3.8Hz,1H),3.89(d,J＝12.4Hz,1H),3.64(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.79(dd,J＝7.0,1.8Hz,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.14-1.61(m,8H),0.97(d,J＝16.3Hz,5H).13C NMR(75MHz,CDCl3)δ206.84,206.80,206.77,163.23,160.93,160.92,160.81,160.79,158.47,158.37,158.34,158.24,152.18,150.50,133.29,133.23,133.17,126.27,126.21,126.15,119.91,119.90,119.81,119.79,118.40,118.34,99.12,99.08,77.43,77.40,77.37,68.87,68.86,68.81,68.80,58.75,58.71,58.70,51.62,51.57,46.62,46.56,44.91,44.88,44.86,44.84,44.81,41.88,41.84,41.82,41.74,36.43,36.41,36.36,36.34,34.41,34.37,34.33,32.32,32.29,32.27,32.24,30.96,30.93,30.91,30.88,28.53,28.51,28.47,28.46,28.42,28.41,24.99,24.98,24.94,24.93,24.89,24.88,19.49,19.47,19.45,19.44,19.42.MS(ESI)m/z:459.2[M+Na]+.
实施例47
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ8.65-8.56(m,2H),7.56(d,J＝15.2Hz,1H),7.51-7.43(m,2H),6.59(d,J＝15.2Hz,1H),6.03-5.95(m,2H),5.75(t,J＝10.9Hz,1H),5.55(t,J＝10.9Hz,1H),5.02(s,1H),4.95(dd,J＝7.0,3.8Hz,1H),3.89(d,J＝12.4Hz,1H),3.64(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.85-2.72(m,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.11-1.62(m,8H),0.96(d,J＝17.7Hz,5H).13C NMR(75MHz,CDCl3)δ206.42,166.80,150.02,149.71,145.82,136.83,132.51,126.07,123.38,119.01,116.30,98.20,76.92,69.91,58.36,51.90,46.11,45.02,42.25,34.96,34.89,34.23,30.28,28.62,23.93,20.10.MS(ESI)m/z:484.2[M+Na]+.
实施例48
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ8.95(d,J＝1.8Hz,1H),8.63-8.54(m,1H),8.03(dd,J＝7.5,0.7Hz,1H),7.64(t,J＝15.0Hz,1H),7.57(t,J＝7.5Hz,1H),6.38(d,J＝15.2Hz,1H),5.76(t,J＝10.9Hz,1H),5.54(t,J＝10.9Hz,1H),5.22(dd,J＝1.7,1.0Hz,1H),5.09(dd,J＝1.8,1.0Hz,1H),5.07(s,2H),4.87-4.77(m,2H),3.88(d,J＝12.4Hz,1H),3.64(d,J＝12.4Hz,1H),3.08(t,J＝7.0Hz,1H),2.66(dd,J＝7.0,1.8Hz,1H),2.06-1.91(m,3H),1.97-1.83(m,2H),1.88-1.77(m,1H),1.83-1.70(m,1H),1.75-1.60(m,2H),0.96(d,J＝17.7Hz,5H).13C NMR(75MHz,CDCl3)δ166.71,148.90,147.43,147.37,145.93,140.64,132.29,132.15,130.44,126.07,123.36,115.70,115.18,114.86,100.47,77.05,69.91,61.19,50.36,45.90,45.77,42.03,34.96,34.63,34.09,30.06,28.62,23.93,20.38.MS(ESI)m/z:484.2[M+Na]+.
实施例49
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ8.50(dd,J＝7.5,1.5Hz,1H),7.88(dd,J＝15.1,0.7Hz,1H),7.76(dd,J＝7.5,0.7Hz,1H),7.66(d,J＝7.5Hz,1H),7.17(d,J＝7.5Hz,1H),6.62(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.75(t,J＝10.9Hz,1H),5.55(t,J＝10.9Hz,1H),5.02(s,1H),4.95(dd,J＝7.0,3.8Hz,1H),3.89(d,J＝12.4Hz,1H),3.64(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.85-2.72(m,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.11-1.62(m,8H),0.96(d,J＝17.7Hz,5H).13C NMR(75MHz,CDCl3)δ206.42,166.93,150.02,149.61,149.51,137.08,136.90,132.51,126.07,123.62,123.54,119.01,115.76,98.20,76.92,69.91,58.36,51.90,46.11,45.02,42.25,34.96,34.89,34.23,30.28,28.62,23.93,20.10.MS(ESI)m/z:462.2[M+H]+.
实施例50
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ8.88-8.78(m,3H),7.76-7.65(m,1H),6.44(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.75(t,J＝10.9Hz,1H),5.55(t,J＝10.9Hz,1H),5.02(s,1H),4.95(dd,J＝7.0,3.8Hz,1H),3.89(d,J＝12.4Hz,1H),3.64(d,J＝12.4Hz,1H),3.26(t,J＝7.0Hz,1H),2.85-2.72(m,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.11-1.62(m,8H),0.96(d,J＝17.7Hz,5H).13C NMR(75MHz,CDCl3)δ206.42,166.93,157.95,150.02,149.59,140.04,132.51,129.20,126.07,119.01,117.16,98.20,76.92,69.91,58.36,51.90,46.11,45.02,42.25,34.96,34.89,34.23,30.28,28.62,23.93,20.10.MS(ESI)m/z:463.2[M+H]+.
实施例51
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ8.53-8.44(m,2H),7.22-7.13(m,2H),6.03-5.95(m,2H),5.72(dd,J＝10.9,1.7Hz,1H),5.58(t,J＝10.9Hz,1H),5.03(s,1H),4.92(d,J＝6.9Hz,1H),3.91(d,J＝12.4Hz,1H),3.62(d,J＝12.4Hz,1H),3.27-3.10(m,2H),2.97-2.82(m,2H),2.64(t,J＝7.0Hz,2H),2.22(dd,J＝12.4,7.0Hz,1H),2.14-1.57(m,8H),0.96(d,J＝17.7Hz,5H).13C NMR(75MHz,CDCl3)δ206.59,172.59,149.99,149.77,141.99,132.45,127.05,124.37,119.01,102.02,76.54,69.54,60.16,52.97,46.35,44.18,41.38,36.04,35.28,34.88,33.15,30.46,28.49,25.87,19.91.MS(ESI)m/z:486.2[M+Na]+.
实施例52
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ8.48-8.37(m,2H),7.48(t,J＝7.6Hz,1H),7.25(t,J＝7.5Hz,1H),6.03-5.95(m,2H),5.72(dd,J＝10.9,1.7Hz,1H),5.58(t,J＝10.9Hz,1H),5.03(s,1H),4.92(d,J＝6.9Hz,1H),3.91(d,J＝12.4Hz,1H),3.62(d,J＝12.4Hz,1H),3.27-3.10(m,2H),3.03(t,J＝7.0Hz,2H),2.79-2.64(m,2H),2.22(dd,J＝12.4,7.0Hz,1H),2.14-1.57(m,8H),0.96(d,J＝17.7Hz,5H).13C NMR(75MHz,CDCl3)δ206.59,172.59,149.99,149.71,148.09,136.13,135.09,132.45,127.05,124.99,119.01,102.02,76.54,69.54,60.16,52.97,46.35,44.18,41.38,36.02,35.28,34.88,33.15,30.61,28.49,25.87,19.91.MS(ESI)m/z:486.2[M+Na]+.
实施例53
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ8.49(dd,J＝7.5,1.5Hz,1H),7.68(d,J＝7.5Hz,1H),7.49(d,J＝7.5Hz,1H),7.10(dd,J＝7.5,1.6Hz,1H),6.03-5.95(m,2H),5.72(dd,J＝10.9,1.7Hz,1H),5.58(t,J＝10.9Hz,1H),5.03(s,1H),4.92(d,J＝6.9Hz,1H),3.91(d,J＝12.4Hz,1H),3.62(d,J＝12.4Hz,1H),3.27-3.10(m,2H),3.14-3.03(m,2H),2.84-2.66(m,2H),2.22(dd,J＝12.4,7.0Hz,1H),2.14-1.57(m,8H),0.96(d,J＝17.7Hz,5H).13C NMR(75MHz,CDCl3)δ206.59,172.73,161.78,151.11,149.99,136.78,132.45,127.05,123.39,122.95,119.01,102.02,76.54,69.54,60.16,52.97,46.35,44.18,41.38,35.28,34.88,33.15,30.35,30.17,28.49,25.87,19.91.MS(ESI)m/z:486.2[M+Na]+.
实施例54
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ8.90(s,1H),8.48(s,2H),6.03-5.95(m,2H),5.72(dd,J＝10.9,1.7Hz,1H),5.58(t,J＝10.9Hz,1H),5.03(s,1H),4.92(d,J＝6.9Hz,1H),3.91(d,J＝12.4Hz,1H),3.62(d,J＝12.4Hz,1H),3.18(t,J＝20.5Hz,4H),2.79(t,J＝7.1Hz,2H),2.24(dd,J＝12.4,7.0Hz,1H),2.14-1.57(m,8H),0.96(d,J＝17.7Hz,5H).13C NMR(75MHz,CDCl3)δ206.59,172.59,156.29,149.99,149.46,133.21,132.45,127.05,119.01,102.02,76.54,69.54,60.16,52.97,46.35,44.18,41.38,36.12,35.28,34.88,33.15,30.44,28.49,25.98,19.91.MS(ESI)m/z:465.2[M+H]+.
实施例55
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ8.85(dd,J＝7.5,1.5Hz,1H),8.14(dd,J＝7.5,1.6Hz,1H),7.91(t,J＝7.5Hz,1H),7.42(t,J＝7.5Hz,1H),5.99(dd,J＝7.5,1.0Hz,2H),5.75(d,J＝10.9Hz,1H),5.55(t,J＝10.9Hz,1H),5.03(dd,J＝7.0,3.8Hz,1H),5.02(s,1H),3.89(d,J＝12.4Hz,1H),3.64(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.79(dd,J＝7.0,1.8Hz,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.12-1.60(m,8H),0.97(d,J＝16.3Hz,5H).13C NMR(75MHz,CDCl3)δ206.42,161.97,150.16,149.06,148.51,138.27,132.40,126.74,124.46,124.16,118.40,98.20,76.98,69.73,58.56,51.99,46.11,45.20,42.25,34.89,34.81,34.23,30.29,28.45,24.66,20.10.MS(ESI)m/z:458.2[M+Na]+.
实施例56
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ9.12(d,J＝1.4Hz,1H),8.74(dd,J＝7.5,1.4Hz,1H),8.16(d,J＝7.5Hz,1H),7.43(t,J＝7.5Hz,1H),5.99(dd,J＝7.5,1.0Hz,2H),5.75(t,J＝10.9Hz,1H),5.55(t,J＝10.9Hz,1H),5.02(s,1H),5.00(dd,J＝7.0,3.7Hz,1H),3.89(d,J＝12.4Hz,1H),3.64(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.85-2.72(m,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.11-1.61(m,8H),0.97(d,J＝16.3Hz,5H).13C NMR(75MHz,CDCl3)δ206.42,165.02,152.67,150.96,150.16,137.40,132.40,126.74,126.18,123.60,118.40,98.20,76.98,69.73,58.56,51.99,46.11,45.20,42.25,34.89,34.81,34.23,30.30,28.45,24.66,20.10.MS(ESI)m/z:458.2[M+Na]+.
实施例57
参照实施例45的合成方法。1H NMR(300MHz,CDCl3)δ8.85(dd,J＝7.5,1.5Hz,1H),8.14(dd,J＝7.5,1.6Hz,1H),7.91(t,J＝7.5Hz,1H),7.42(d,J＝7.5Hz,1H),5.99(dd,J＝7.5,1.0Hz,2H),5.75(t,J＝10.9Hz,1H),5.55(t,J＝10.9Hz,1H),5.03(dd,J＝7.0,3.8Hz,1H),5.02(s,1H),3.89(d,J＝12.4Hz,1H),3.64(d,J＝12.4Hz,1H),3.27(t,J＝7.0Hz,1H),2.79(d,J＝7.0Hz,1H),2.22(dd,J＝12.4,7.0Hz,1H),2.12-1.60(m,8H),0.97(d,J＝16.3Hz,5H).13C NMR(75MHz,CDCl3)δ206.42,161.97,150.16,149.06,148.51,138.27,132.40,126.74,124.46,124.16,118.40,98.20,76.98,69.73,58.56,51.99,46.11,45.20,42.25,34.89,34.81,34.23,30.29,28.45,24.66,20.10.MS(ESI)m/z:458.2[M+Na]+.
实施例58
将实施例2中化合物(50mg)溶于15mL二氯甲烷中，加入对甲苯甲酸，EDCI(1.5eq),DMAP(催化量)，室温搅拌12小时，反应结束后补加二氯甲烷至50mL,水洗两次，饱和食盐水洗一次，每次10mL，无水硫酸钠干燥，浓缩，柱层析得白色固体40mg(收率79％)1H NMR(300MHz,CDCl3)δ7.84-7.74(m,2H),7.27(d,J＝7.6Hz,2H),6.03-5.95(m,2H),5.06-4.97(m,2H),4.04(d,J＝12.3Hz,1H),3.95(d,J＝7.3Hz,1H),3.76(d,J＝12.4Hz,1H),3.58(d,J＝7.0Hz,1H),3.22(t,J＝7.0Hz,1H),3.14(t,J＝6.9Hz,1H),2.43(t,J＝0.7Hz,3H),2.22(dd,J＝12.3,6.9Hz,1H),2.16-1.96(m,2H),1.94-1.77(m,2H),1.82-1.70(m,1H),1.75-1.56(m,3H),1.55-1.30(m,2H),1.01(d,J＝8.1Hz,5H).13C NMR(75MHz,CDCl3)δ206.59,165.86,149.99,140.79,129.45,129.33,129.19,119.01,102.02,76.65,72.49,67.16,60.35,53.67,47.34,46.73,38.65,38.03,34.40,33.60,29.55,28.58,26.62,21.53,20.21.MS(ESI)m/z:467.2[M+H]+.
实施例59
参照实施例58的合成方法。1H NMR(300MHz,CDCl3)δ7.53(t,J＝14.9Hz,1H),7.47-7.35(m,2H),7.27(dd,J＝7.5,0.7Hz,1H),6.37(d,J＝15.2Hz,1H),6.03-5.95(m,2H),5.01-4.89(m,2H),4.00(d,J＝12.4Hz,1H),3.87(d,J＝7.2Hz,1H),3.81(d,J＝12.3Hz,1H),3.59(t,J＝7.0Hz,1H),3.27-3.07(m,2H),2.25(dd,J＝11.8,6.5Hz,1H),2.15-1.81(m,4H),1.76-1.55(m,4H),1.54-1.31(m,2H),0.97(dd,J＝7.7,1.4Hz,6H).13C NMR(75MHz,CDCl3)δ206.59,166.64,149.99,141.82,137.46,129.49,128.32,127.96,119.02,115.63,102.02,76.68,72.50,67.16,60.04,53.67,46.49,46.35,38.79,38.08,34.40,33.60,29.50,28.58,26.66,20.21.MS(ESI)m/z:485.2[M+H]+.
实施例60
参照实施例58的合成方法。1H NMR(300MHz,CDCl3)δ7.84(d,J＝1.6Hz,1H),7.56(t,J＝15.0Hz,1H),7.40(dd,J＝7.5,1.4Hz,1H),6.78(dd,J＝7.5,0.6Hz,1H),6.42(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.03(s,1H),4.93(d,J＝6.9Hz,1H),4.04(d,J＝12.3Hz,1H),3.95(d,J＝7.3Hz,1H),3.76(d,J＝12.4Hz,1H),3.58(d,J＝7.0Hz,1H),3.27-3.08(m,2H),2.22(dd,J＝12.3,6.9Hz,1H),2.15-1.96(m,2H),1.94-1.56(m,6H),1.55-1.30(m,2H),1.01(d,J＝8.1Hz,5H).13C NMR(75MHz,CDCl3)δ206.59,166.77,149.99,143.26,142.27,139.79,127.74,119.01,115.75,108.22,102.02,76.68,72.49,67.16,59.75,53.67,46.73,46.35,38.65,38.03,34.40,33.60,29.55,28.58,26.62,20.21.MS(ESI)m/z:469.2[M+H]+.
实施例61
参照实施例58的合成方法。1H NMR(300MHz,CDCl3)δ9.16(d,J＝0.5Hz,2H),8.85(s,1H),7.78-7.66(m,1H),6.43(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.01-4.89(m,2H),4.00(d,J＝12.4Hz,1H),3.87(d,J＝7.2Hz,1H),3.81(d,J＝12.3Hz,1H),3.61(t,J＝7.0Hz,1H),3.27-3.07(m,2H),2.27-2.14(m,1H),2.14-1.81(m,4H),1.76-1.55(m,4H),1.43(dd,J＝12.3,6.7Hz,2H),0.97(dd,J＝7.8,1.4Hz,6H).13C NMR(75MHz,CDCl3)δ206.59,166.82,157.95,149.84,149.59,140.32,129.20,119.02,117.16,102.02,76.68,72.52,67.16,60.44,53.67,46.49,46.35,38.79,38.08,34.40,33.60,29.50,28.58,26.67,20.21.MS(ESI)m/z:481.2[M+H]+.
实施例62
参照实施例58的合成方法。1H NMR(300MHz,CDCl3)δ8.64-8.55(m,2H),7.55(t,J＝15.1Hz,1H),7.51-7.43(m,2H),6.56(d,J＝15.2Hz,1H),6.03-5.95(m,2H),5.01-4.89(m,2H),4.00(d,J＝12.4Hz,1H),3.87(d,J＝7.2Hz,1H),3.81(d,J＝12.3Hz,1H),3.61(t,J＝7.0Hz,1H),3.27-3.08(m,2H),2.29-2.14(m,1H),2.14-1.81(m,4H),1.76-1.55(m,4H),1.43(dd,J＝12.3,6.7Hz,2H),0.97(dd,J＝7.8,1.4Hz,5H).13C NMR(75MHz,CDCl3)δ206.59,166.80,149.84,149.69,145.82,136.83,123.00,119.02,116.30,102.02,76.68,72.52,67.16,60.44,53.67,46.49,46.35,38.79,38.08,34.40,33.60,29.50,28.58,26.67,20.21.MS(ESI)m/z:480.2[M+H]+.
实施例63
参照实施例58的合成方法。1H NMR(300MHz,CDCl3)δ8.95(d,J＝1.8Hz,1H),8.58(dd,J＝7.6,0.4Hz,1H),8.03(dd,J＝7.5,0.7Hz,1H),7.64(d,J＝15.1Hz,1H),7.57(t,J＝7.5Hz,1H),6.39(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.03(s,1H),4.93(d,J＝6.9Hz,1H),4.04(d,J＝12.3Hz,1H),3.95(d,J＝7.3Hz,1H),3.76(d,J＝12.4Hz,1H),3.60(d,J＝7.0Hz,1H),3.27-3.08(m,2H),2.22(dd,J＝12.3,6.9Hz,1H),2.15-1.96(m,2H),1.94-1.56(m,7H),1.55-1.30(m,2H),1.01(d,J＝7.6Hz,6H).13C NMR(75MHz,CDCl3)δ206.59,166.82,149.84,148.90,147.44,140.64,132.15,130.44,123.54,119.02,115.61,102.02,76.68,72.52,67.16,60.44,53.67,46.79,46.35,38.79,38.08,34.40,33.60,29.50,28.58,26.67,20.21.MS(ESI)m/z:502.2[M+Na]+.
实施例64
参照实施例58的合成方法。1HNMR(300MHz,CDCl3)δ8.49(dd,J＝7.5,1.5Hz,1H),7.86(dd,J＝15.1,0.7Hz,1H),7.76-7.43(m,1H),7.66-7.23(m,1H),7.17-6.89(m,1H),6.77(d,J＝15.1Hz,1H),6.03-5.95(m,2H),5.03(s,1H),4.93(d,J＝7.0Hz,1H),4.04(d,J＝12.3Hz,1H),3.95(d,J＝7.3Hz,1H),3.76(d,J＝12.4Hz,1H),3.60(d,J＝7.0Hz,1H),3.27-3.08(m,2H),2.22(dd,J＝12.3,6.9Hz,1H),2.15-1.96(m,2H),1.94-1.56(m,6H),1.55-1.30(m,2H),1.01(d,J＝7.6Hz,6H).13C NMR(75MHz,CDCl3)δ206.59,166.93,149.84,149.59,149.51,137.08,136.90,123.62,123.15,119.02,115.76,102.02,76.68,72.52,67.16,60.44,53.67,46.79,46.35,38.79,38.08,34.40,33.60,29.50,28.58,26.67,20.21.MS(ESI)m/z:502.2[M+Na]+.
实施例65【片剂】
取上述配方，用常规方法制备成片剂。
【药理活性】
药理试验证明，本发明的新型冬凌草甲素类似物及衍生物具有抗三阴性乳腺癌作用，并具有良好的选择性，可以用于制备抗肿瘤药物，选用细胞株人乳腺癌细胞MDA-MB-468及正常乳腺细胞MCF-10A进行药理实验。
下面是本发明部分化合物的药理实验结果：
1、部分化合物对三阴乳腺癌细胞生长的影响
实验设备与试剂
仪器超净工作台(苏州艾可林净化设备有限公司)
恒温CO2培养箱(日本SANYO)
酶联免疫检测仪(美国BIO-RAD)
倒置生物显微镜(日本OLYMPUS)
试剂青、链霉素混合液(南京凯基生物科技发展有限公司)
胰蛋白酶消化液(南京凯基生物科技发展有限公司)
PBS(南京凯基生物科技发展有限公司)
MTT(BIOSHARP)
DMSO(SIGMA)
细胞株人乳腺癌细胞MDA-MB-468
正常乳腺细胞MCF-10A
实验方法
1.细胞消化、计数、制成浓度为5×104个/mL的细胞悬液，96孔板中每孔加入100μL细胞悬液(每孔5×103个细胞)；
2.96孔板置于37℃，5％CO2培养箱中培养24小时；
3.用完全培养基稀释药物至所需浓度，每孔加入100μL相应的含药培养基，同时设立阴性对照组，溶媒对照组，阳性对照组；
4.96孔板置于37℃，5％CO2培养箱中培养72小时；
5.将96孔板进行MTT染色，λ＝490nm，测定OD值。
1)每孔加入20μL MTT(5mg/mL)，在培养箱继续培养4小时；
2)弃去培养基，每孔加入150μL DMSO溶解，摇床10分钟轻轻混匀；λ＝490nm，酶标仪读出每孔的OD值，计算抑制率。
细胞抑制率％＝100％×(阴性对照组OD值-化合物组OD值)/阴性对照组OD值
化合物对三阴乳腺癌细胞及正常乳腺细胞生长影响的实验结果
表1.部分化合物对体外细胞生长的影响(IC50：单位μmol/mL)
2、部分化合物对体内肿瘤生长的影响：
选取体重为18-22g并成功接种MDA-MB-468三阴乳腺癌肿瘤细胞的雌性ICR小鼠(来自上海思捷实验动物中心)，随机分组，每组8只。其中一组为空白对照，注射同样给药体积的生理盐水溶液；另一组为阳性药对照组，给予25mg/kg的环磷酰胺；剩余的组别分别给予一定剂量的化合物。环磷酰胺及上述化合物的溶解溶剂为DMF:吐温80:5％生理盐水＝10:2:88(V:V:V)，给药方式为1天给药一次，连续给药21天。实验结束后，处死老鼠并手术剥离肿瘤称重。得到的数据用SPSS 17.0进行统计分析。
部分化合物体内抑制肿瘤生长的结果：
| 组别 | 药物 | 剂量 | 抑瘤率 |
| 1 | 生理盐水 | - | - |
| 2 | 环磷酰胺 | 25mg/kg | 55.4％ |
| 3 | 化合物1 | 25mg/kg | 56.7％ |
| 4 | 化合物2 | 25mg/kg | 57.1％ |
| 5 | 化合物3 | 25mg/kg | 60.4％ |
| 6 | 化合物4 | 25mg/kg | 64.2％ |
| 7 | 化合物5 | 25mg/kg | 59.5％ |
| 8 | 化合物15 | 12.5mg/kg | 65.3％ |
| 9 | 化合物15 | 25mg/kg | 77.1％ |
| 10 | 化合物32 | 25mg/kg | 76.0％ |
| 11 | 化合物38 | 25mg/kg | 72.4％ |
| 12 | 化合物46 | 25mg/kg | 70.7％ |
| 13 | 化合物50 | 25mg/kg | 64.6％ |
| 14 | 化合物62 | 25mg/kg | 72.5％ |
| 15 | 冬凌草甲素 | 25mg/kg | 51.2％ |
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应该指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (10)
1.通式Ⅰ所示的冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐：
其中，A可以为氢、羟基、卤素；U-Y可以为碳碳单键或碳碳双键；M是下列基团中的任意一个：(1)氢或氘原子，当M为氢时，A不为羟基，(2)C1-16脂肪链酰基或C1-16脂肪链磺酰基，(3)C3-10环烷酰基或C3-10环烷基磺酰基，(4)C3-10杂环烷酰基或C3-10杂环烷基磺酰基，(5)C1-6卤代烷酰基或C1-6卤代烷磺酰基，(6)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基或未被取代或被1、2、3、4个取代基所取代的C6-10芳基磺酰基，(7)未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的杂芳酰基或未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的杂芳基磺酰基，(8)C2-6烯酰基或C2-6烯基磺酰基，(9)C2-6炔酰基或C2-6炔基磺酰基，(10)氨基酸，(11)磷酰基，(12)芳香环或杂芳香环上未取代的或被1、2、3、4个取代基所取代的通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-或-(CH2)m-Z-(CH2)m-；m等于1、2、3、4、5、6；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；Z指代3-6个原子组成的碳环或含杂原子环基；取代基选自卤素、C1-3烷基、C1-3烷氧基、C1-3卤代烷基或C1-3烷基磺酰基，优选的取代基选自Br、Cl、F、甲基、乙基、甲基磺酰基、乙基磺酰基、甲氧基、乙氧基、三氟甲基。
2.根据权利要求1所述的通式Ⅰ的冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐，其特征在于，M为：(1)C2-16脂肪链酰基或C2-16脂肪链磺酰基，(2)C3-10环烷酰基，(3)C3-10杂环烷酰基或C3-10杂环烷基磺酰基，(4)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基，(5)未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的杂芳酰基，(6)C2-6烯酰基，(7)芳香环或杂芳香环上未取代的或被1、2、3、4个取代基所取代的通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-、-CH＝C(CH3)-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-或-(CH2)m-Z-(CH2)m-；m等于1、2、3、4、5、6；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；Z指代3-6个原子组成的碳环或含杂原子环基。
3.根据权利要求1所述的通式Ⅰ的冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐，其特征在于，M为：(1)C1-10脂肪链酰基或C1-6脂肪链磺酰基，(2)C3-6碳环酰基，(3)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基，(4)未被取代或被1、2、3、4个取代基所取代的具有1～3个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基，(5)C2-4烯酰基，(6)通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-、-CH＝C(CH3)-、-CH2-O-CH2-或-CH2-S-CH2-；m等于1、2、3、4；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；或者Ar指代未被取代或被1、2、3、4个取代基所取代的具有1～3个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基。
4.根据权利要求1所述的通式Ⅰ的冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐，其特征在于，M为：(1)C1-8脂肪链酰基或C1-3脂肪链磺酰基，(2)C3-6碳环酰基，(3)未被取代或被1、2、3、4个取代基所取代的C6-10芳酰基，(4)未被取代或被1、2、3、4个取代基所取代的具有1～2个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基，(5)C2-4烯酰基，(6)通式为-(O)C-L-Ar的酰基；L指代以下基团的任意一个：-(CH2)m-、-C≡C-、-CH＝CH-、或-CH＝C(CH3)-；m等于1、2；Ar指代未被取代或被1、2、3、4个取代基所取代的5-10个原子组成的芳香基团；或者Ar指代未被取代或被1、2、3、4个取代基所取代的具有1～2个选自N、O或S杂原子的5-10个原子组成的杂芳基酰基。
5.根据权利要求1所述的通式Ⅰ的冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐，其特征在于，所述的杂芳基选自：吡咯基、呋喃基、噻吩基、吡啶基、嘧啶基、吡嗪基、吲哚基、喹啉基、苯并氧五环、咪唑基、噁唑基、噻唑基、吡唑基、异喹啉基、嘌呤基、吖啶基、咔唑基、噌啉基、喹噁啉基、吲哚基、苯并三唑基、苯并噻吩基、苯并呋喃基、异噁唑基、吡嗪基、哒嗪基、四唑基、三嗪基或咔唑基。
6.如下结构式所示的冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐：
7.一种药物组合物，其包含权利要求1～6任一项所述的冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐，以及药学上可接受的辅料。
8.权利要求1～6任一项所述冬凌草甲素类似物及衍生物，及其光学活性体或消旋体、非对映异构体混合物，或其可药用盐在用于制备治疗抗肿瘤药物中的应用。
9.权利要求7所述的组合物在用于制备治疗抗肿瘤药物中的应用。
10.根据权利要求8或9所述的应用，其特征在于，所述的肿瘤为三阴性乳腺癌。
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