CN116554219A - 一种有机合成催化剂、其合成方法、其用途和有机化合物合成方法 - Google Patents
一种有机合成催化剂、其合成方法、其用途和有机化合物合成方法 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体涉及一种有机合成催化剂、其合成方法、其用途和有机化合物合成方法。本发明提供式II所示化合物,或其盐,或其溶剂合物,或其晶型,其与贵金属盐构成金属/Lewis碱接力催化体系,从而制成了一系列新的双环戊烯基吡唑啉酮类化合物。这些双环戊烯基吡唑啉酮类化合物具有良好的磷酸二酯酶抑制活性,可用于制备磷酸二酯酶抑制剂,对炎性肺损伤和/或肺纤维化具有很好的治疗效果,应用前景良好。式II。
Description
技术领域
本发明属于医药技术领域,具体涉及一种有机合成催化剂、其合成方法、其用途和有机化合物合成方法。
背景技术
螺吡唑酮类化合物具有多种生物活性,如抗肿瘤、抗微生物和镇痛等,因而具有巨大的药物开发潜力。此外,由于具有特权结构,吡唑和吡唑酮类化合物与各种生物活性蛋白显示出良好的结合能力。例如,它们的衍生物对PDE1有很好的抑制作用。因此,构建新的螺吡唑酮化合物文库并研究其酶结合特性具有重要意义。
构建新的螺吡唑酮化合物文库首先需要开发高选择性、高效、经济的合成策略。近年来,多酶体系和小分子多催化因其优于传统的单一催化剂方法而受到广泛关注。一方面,它们可以通过应用不同类型的催化剂来统一不同的键活化方式。另一方面,这些工艺能够从简单的材料中生产复杂的产品,而不需要分离中间体。因此,开发新的多催化体系有望实现更高效、更环保的有机合成,具有时间短、成本低、操作简单等特点。
通过将过渡金属催化剂与有机催化剂相结合,在这一领域已经取得了重大进展。化学家们开发了过渡金属与Lewis碱的合作催化体系和接力催化体系,并展示了它们在不对称催化中的巨大潜力。在这些工艺中,叔胺、膦、N-杂环卡宾(NHCs)和异硫脲被成功地用作Lewis碱催化剂(如图1中的方案A)。4-氨基吡啶,如DMAP,代表了一类特殊的Lewis碱催化剂。由于其高度亲核的平面核心结构,它们通常表现出优异的催化活性和独特的选择性。此外,与其他Lewis碱催化剂相比,它们的氨基吡啶骨架更易于修饰,这有利于模块化设计和结构修饰。然而,与其他Lewis碱形成鲜明对比的是,4-氨基吡啶与过渡金属的双重催化体系仍未被开发(如图1中的方案B),可能是因为它能与金属中心强配位,使金属配合物失活。
炔-烯类化合物和烯酰亚胺的环异构化/(3+n)和(4+n)环化级联反应已成为构建不同稠合呋喃的重要方法(如图1中的方案C)。张、马、池、周、刘、邓等人成功地开发了新颖的催化体系和不同的环化反应。例如,池课题组报道了通过金/NHC催化剂接力催化环异构化/(4+2)环加成合成呋喃稠内酰胺。赵等人实现了金/钯接力催化环异构化/(4+5)环加成。在这些报道中,该过程倾向于通过级联(3+n)或(4+n)环化得到芳香呋喃产物。然而,环异构化/(2+n)反应尚未见报道(如图1中的方案D)。这一挑战可能是由于环加成步骤的空间位阻和芳香族产物更好的热力学稳定性造成的。
因此,如何实现环异构化/(2+n)反应,从而构建新的螺吡唑酮化合物文库,这是本领域中一个非常有意义的课题。
发明内容
针对现有技术的问题,本发明提供了一种新的手性吡咯烷基吡啶(PPY),其与贵金属盐构成金属/Lewis碱接力催化体系,从而制成了一系列新的双环戊烯基吡唑啉酮类化合物(一类螺吡唑酮化合物)。
式II所示化合物,或其盐,或其溶剂合物,或其晶型,式II所示化合物结构式如下:
式II
其中,
Ar1和Ar2分别独立选自被至少一个取代基取代的苯基,其中,取代基选自C1-C10烷基、C6-C10芳基;
R7选自H或TBDPS。
优选的,Ar1和Ar2分别独立选自被一至二个取代基取代的苯基,其中,取代基选自叔丁基或苯基。
优选的,Ar1和Ar2分别独立选自被一至二个取代基取代的苯基,其中,取代基选自苯基;
R7选自TBDPS。
优选的,式II所示化合物结构式如下:
、/>。
本发明还提供上述化合物,或其盐,或其溶剂合物,或其晶型的合成方法,包括如下步骤:
步骤a,将原料a与4-氯烟酸反应,得到中间物b;
步骤b,将中间物b与吡咯烷反应,即得。
优选的,步骤a中,所述反应在溶剂作用下进行,所述溶剂选自DCM或DMF;所述反应在缩合剂和催化剂的作用下进行,所述缩合剂选自草酰氯、DCC或EDCI中的至少一种,所述催化剂选自DMAP或DMF中的至少一种;反应温度为0-40 ℃,反应时间为0.5-10 h;
或,步骤b中,所述反应在溶剂甲苯或无溶剂条件下进行,反应温度为60-100 ℃,反应时间为0.5-10 h。
本发明还提供上述化合物,或其盐,或其溶剂合物,或其晶型用于作为有机合成催化剂的用途。
本发明还提供一种催化剂组合物,它包括如下摩尔份的组分:
有机物催化剂10-20份、贵金属盐5-10份;
其中,有机物催化剂选自上述化合物,或其盐,或其溶剂合物,或其晶型。
优选的,所述贵金属盐选自金盐或银盐中的至少一种,所述金盐选自PPh3AuCl,所述银盐选自AgSbF6、AgOTf、Ag2CO3或AgOAc中的至少一种。
优选的,它包括如下摩尔份的组分:有机物催化剂20 份、贵金属盐10 份。
本发明还提供一种有机化合物合成方法,所述合成方法包括如下反应:
将原料A和原料B在上述催化剂组合物的催化作用下进行反应,得到式I所示的化合物;
其中,
R1选自被至少一个取代基取代或未取代的C1-C10烷基、被至少一个取代基取代或未取代的C6-C10芳基,其中,取代基选自C1-C10烷氧基、C1-C10烷基、卤素;
R2选自C1-C10烷基;
R3选自被至少一个取代基取代或未取代的C1-C10烷基、被至少一个取代基取代或未取代的C6-C10芳基、被至少一个取代基取代或未取代的5-10元杂芳基,其中,取代基选自C1-C10烷氧基、C1-C10烷基、卤素;
R4选自磺酰基;
R5选自被至少一个取代基取代或未取代的C6-C10芳基,其中,取代基选自C1-C10烷氧基、C1-C10烷基、卤素;
R6选自C1-C10烷基。
优选的,R1选自C1-C4烷基、被一个取代基取代或未取代的苯基,其中,取代基选自甲基、甲氧基、Cl或Br。
优选的,R2选自甲基或乙基。
优选的,R3选自C1-C4烷基、被一个取代基取代或未取代的苯基、5元杂芳基,其中,取代基选自甲基、甲氧基、Cl或F。
优选的,R4选自对甲苯磺酰基、硝基苯磺酰基、甲磺酰基。
优选的,R5选自被一至二个取代基取代或未取代的C6-C10芳基,其中,取代基选自甲氧基、Cl或F。
优选的,R6选自甲基或乙基。
优选的,式I所示化合物结构式如下:
。
优选的,所述反应的溶剂选自CHCl3、DCM、THF、甲苯、1,4-二氧六环、DCE或DMF中的至少一种。
优选的,所述反应的溶剂选自CHCl3。
优选的,所述反应条件为0-80 ℃反应0.5-1h。
或,0-80 ℃搅拌24-72h, 然后0-80 ℃搅拌1-3h。
优选的,所述催化剂组合物的用量按照如下方式确定:有机物催化剂的用量为原料A的10-20 mol%。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适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它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀 Ca-Cb烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1-C4烷基”是指包含1-4个碳原子的烷基。
“烷基”是指具有指定数目的成员原子的饱和烃链。例如,C1-C6烷基是指具有1至6个成员原子,例如 1 至 4 个成员原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分,所述其他基团为例如C1-C6烷氧基。
“烷氧基”是指由饱和碳原子和至少一个氧原子共同作为分子链构成的基团。
“卤素”为氟、氯、溴或碘。
“杂芳基”指包含至少一个杂原子的芳香性不饱和环基;其中杂原子指氮原子、氧原子、硫原子;
本发明的化合物中的氢原子可以是氢的各种同位素,比如:氕(¹H)、氘(²H)或氚(3H)。
术语“取代”可以是指被一个基团取代,也可以是指被至少两个基团取代。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明中,基团缩写的含义如下:
Ac:乙酰基;Boc:叔丁氧羰基;Me:甲基;Et:乙基;tBu:叔丁基;Ph:苯基;Ts:对甲苯磺酰基;Ns:硝基苯磺酰基;Ms:甲磺酰基;TBDPS:叔丁基二苯基硅烷基;TMS:四甲基硅烷基。
对于取代苯基,本发明采用如下方式进行缩写:“n-XPh”或“n,m-XkPh”,其中,n或m表示取代基在苯基上的位置,X表示取代基的种类,k表示取代基的数量。例如:“2-MePh”表示基团“”,“4-OMePh”表示基团“/>”,“2,4-Cl2Ph”表示基团“/>”。
本发明提供了一种新的PPY化合物,其与贵金属盐构成金属/Lewis碱接力催化体系。该催化体系成功地应用于烯胺类化合物的环异构化/(2+3)环加成反应,合成一系列新的双环戊烯基吡唑啉酮类化合物。采用双环戊烯基吡唑啉酮类化合物的合成具有立体选择性和经济性的特点(最高可达>19:1dr,99.5:0.5er)。产物的转化可以得到立体发散的非对映异构体和高度官能化的多环衍生物。在随后的生物实验中,这些新的含有特权类药物支架的产物在体外显示出异构体选择性磷酸二酯酶1(PDE1)抑制活性。优化后的先导化合物通过抑制PDE1在体内表现出良好的抗肺纤维化作用。因此,本发明具有很好的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为现有技术和本发明的合成路线示意图,其中,A为已知的金属/有机Lewis碱双催化体系示意图,B为尚未开发的金属/有机Lewis碱双催化体系示意图,C为炔烯酮和烯酰胺的级联环异构化/环化反应已建立的反应途径的示意图,D为炔烯酮和烯酰胺的级联环异构化/环化反应尚未建立的反应途径的示意图,E为本发明的合成路线示意图。
图2为实验例2中的PDE抑制实验结果图;其中,A为化合物3a-3ac对PDE1B的抑制率@0.1 μmol·L−1实验结果图;B为部分化合物对三种PDE1亚型的抑制作用的实验结果图;C为化合物3x对PDE家族蛋白的相对抑制作用@0.1 μmol·L−1实验结果图;
图3为实验例2中的肺纤维化治疗实验结果图;其中,A为蛋白质免疫印迹检测纤维连接蛋白, Ⅰ型胶原蛋白,α-SMA和GAPDH的表达水平实验结果图;B为纤维连接蛋白, Ⅰ型胶原蛋白和α-SMA相对表达水平的柱状图;C为α-SMA蛋白表达的免疫荧光染色分析实验结果图;D为免疫荧光染色分析纤维连接蛋白的表达实验结果图;E为不同组大鼠的肺呼吸功能柱形图;F为对照组、BLM处理组、BLM + PFD处理组和BLM + 3x处理组肺组织代表性苏木精-伊红(H&E)染色切片和Masson染色切片实验结果图。
具体实施方式
以下实施例和实验例中,所用的试剂和原料均为市售品。
基于现有技术中环化反应的现状(如图1A-D所示),本发明提供了一种新的催化体系,该催化体系成功地应用于烯胺类化合物的环异构化/(2+3)环加成反应,合成一系列新的双环戊烯基吡唑啉酮类化合物。具体实施例如下:
实施例1 PPY化合物C8
本实施例提供一种PPY催化剂,其结构式如下:
化合物C8的合成方法为:
步骤1:圆底烧瓶中加入搅拌子,称取L-羟基脯氨酸7.5 g,碳酸钾6.9 g,加入MeOH作为溶剂,冰浴下加入氯甲酸甲酯,完毕后移至常温,搅拌过夜。随后减压浓缩,再将残留固体混合物溶于DCM,加入水萃取分离各相,有机层用无水硫酸钠干燥,过滤后浓缩得到无色黏稠状液体9.3 g。
步骤2:圆底烧瓶中加入搅拌子,镁屑0.5 g,再加入一粒碘单质,在瓶口接入恒压滴液漏斗,用氩气充气装置向瓶内充满惰性气体,使用注射器向瓶内注入溶于无水THF的4.6 g 4-溴代联苯,打开恒压滴液漏斗活塞向烧瓶中滴入少量,关闭活塞,用吹风机对瓶身加热,直至烧瓶中溶液微沸并澄清,停止加热,打开活塞,缓慢滴入分液漏斗中的溶液,完毕后将烧瓶60 °C加热30分钟,随后冷却至室温。
步骤3:将步骤2的烧瓶移至冰浴,称取步骤1所得产物1.6 g溶于无水THF,并缓慢滴入烧瓶,随后移至常温反应过夜。加入饱和NH4Cl溶液淬灭反应,萃取分离各相,有机层用无水硫酸钠干燥,过滤后浓缩得粗产品1.7 g。
步骤4:圆底烧瓶中加入搅拌子,将步骤3所得粗产品溶于MeOH和1,4-二氧六环1:1混合的溶液中,加入氢氧化钾 3.0 g,置于80 °C下回流4小时。然后冷却至室温,加入淬灭反应,萃取分离各相,有机层用无水硫酸钠干燥,过滤后浓缩,使用硅胶柱纯化, PE : EA =2 : 1洗脱,得白色固体1.5 g。
步骤5:圆底烧瓶中加入搅拌子,将步骤4所得固体溶于DCM,冰浴下加入咪唑1.8 g和DMAP 91 mg,然后缓慢加入TBDPSCl 2.3 mL,常温搅拌2小时。加入水淬灭反应,萃取分离各相,有机层用无水硫酸钠干燥,过滤后浓缩,使用硅胶柱纯化分离, PE :EA = 15 : 1洗脱,得白色固体2.1 g。
步骤6:圆底烧瓶中加入搅拌子,将步骤5所得固体溶于DCM,再加入4-氯烟酸0.9g,EDCI 1.9 g和DMAP 1.2 g,常温反应2小时。加入水淬灭反应,萃取分离各相有机层用无水硫酸钠干燥,过滤后浓缩,使用硅胶柱纯化分离, PE : EA = 3 : 1洗脱,得白色固体2.2g。
步骤7:圆底烧瓶中加入搅拌子,将步骤6所得固体溶于甲苯,加入吡咯烷0.6 mL,80°C搅拌过夜。减压浓缩,使用硅胶柱纯化分离,PE : EA = 1 : 1洗脱,得白色固体C8 2.1g。
化合物C8的核磁共振氢谱和质谱表征数据如下:
1H NMR (600 MHz, CDCl3) δ 8.10 (d,J= 6.0 Hz, 1H), 7.63 – 7.60 (m, 3H),7.61 – 7.56 (m, 4H), 7.54 – 7.50 (m, 4H), 7.48 – 7.39 (m, 9H), 7.38 (t,J= 7.8Hz, 2H), 7.37 – 7.29 (m, 6H), 7.27 (t,J= 7.2 Hz, 2H), 6.45 (d,J= 6.0 Hz, 1H),5.48 (t,J= 9.0 Hz, 1H), 4.14 (d,J= 3.0 Hz, 1H), 3.54 (d,J= 12.0 Hz, 1H), 3.50(d,J= 7.8 Hz, 2H), 3.27 – 3.21 (m, 2H), 3.07 (dd,J= 12.0, 3.6 Hz, 1H), 2.06(dd,J= 9.0, 3.0 Hz, 2H), 1.91 – 1.87 (m, 2H), 1.71 – 1.68 (m, 2H), 1.01 (s,9H).13C NMR (151 MHz, CDCl3) δ 172.1, 150.0, 149.0, 149.0, 144.0, 141.5,140.8, 140.6, 140.6, 140.3, 135.6,135.5, 133.2, 133.0, 130.2, 130.2, 128.9,128.2, 128.1, 128.0, 128.0, 127.5, 127.5, 127.3, 127.2, 126.9, 126.6, 116.1,108.7, 81.6, 71.3, 68.0, 60.8, 49.3,40.3, 27.1, 25.8, 19.2. HRMS (ESI-TOF) m/z: [M+H]+Calcd for C55H56N3O3Si+834.4085, Found 834.4089.
实施例2 PPY化合物C9
本实施例提供一种PPY催化剂,其结构式如下:
化合物C9的合成方法为:
利用C8相同方法可以制得C9,根据C8与C9的取代基差异,选择对应的原料化合物即可。
化合物C9的核磁共振氢谱和质谱表征数据如下:
1H NMR (600 MHz, CDCl3) δ 8.06 (d,J= 6.0 Hz, 1H), 7.99 (s, 1H), 7.84(d,J= 1.8 Hz, 1H), 7.82 (d,J= 1.8 Hz, 2H), 7.73 (s, 3H), 7.61 – 7.57 (m, 8H),7.47 (d,J= 7.2 Hz, 2H), 7.45 – 7.41 (m, 6H), 7.40 – 7.37 (m, 6H), 7.36 – 7.34(m, 2H), 7.33 – 7.29 (m, 2H), 7.27 – 7.23(m, 2H), 7.10 (t,J= 7.2 Hz, 2H),6.98 (s, 1H), 6.43 (d,J= 6.6 Hz, 1H), 5.56 (t,J= 9.0 Hz, 1H), 4.16 (d,J= 3.0Hz, 1H), 3.58 (d,J= 12.0 Hz, 1H), 3.51 (d,J= 8.4 Hz, 2H), 3.24 (d,J= 7.8 Hz,2H), 3.18 (dd,J= 12.0, 3.6 Hz, 1H), 2.10 (dd,J= 9.0, 3.0 Hz, 2H), 1.93 (s,2H), 1.73 (d,J= 7.8 Hz, 2H), 0.98 (s, 9H).13C NMR (151 MHz, CDCl3) δ 172.1,149.9, 149.1, 148.7, 145.6, 143.3, 141.8, 141.3, 141.2, 135.5, 135.5,132.9,132.8, 130.3, 130.2, 129.0, 128.0, 128.0, 127.6, 127.6, 127.5, 126.1, 126.0,125.7, 125.1, 116.0, 108.7, 82.1, 71.1, 69.5, 61.3, 49.5, 41.0, 27.1,25.9,19.2. HRMS (ESI-TOF) m/z: [M+H]+Calcd for C67H64N3O3Si+986.4711, Found 986.4717.
实施例3 催化剂组合物
本实施例的催化剂组合物由10 mmol有机物催化剂和20 mmol贵金属盐组成;其中,有机物催化剂选自实施例1的化合物C8或实施例2的化合物C9;贵金属盐为银盐,选自AgSbF6、AgOTf、AgO、AgF、AgOTf2、Ag2CO3或AgOAc。
实施例4 化合物3a
化合物3a的制备方法原理如图1E所示,具体反应式为:
取化合物1a(0.1 mmol)和AgOAc(0.01mmol)溶解在1.0 ml CHCl3中,40°C搅拌1小时,加入化合物2a(0.1 mmol)和实施例1的化合物C9(0.02 mmol),0℃搅拌48 h, 然后40℃搅拌3 h。得到化合物3a,产率为80%,对映选择性(>19:1dr,95:5er)。
化合物3a的核磁共振氢谱和质谱表征数据如下:
1H NMR (600 MHz, CDCl3) δ 7.81 (d,J= 7.8 Hz, 2H), 7.51 (d,J= 2.4 Hz,1H), 7.39 (d,J= 8.4 Hz, 2H), 7.33 (t,J= 7.8 Hz, 2H), 7.29 (t,J= 7.2 Hz, 1H),7.21 (t,J= 7.8 Hz, 3H), 7.17 – 7.11 (m, 5H), 7.08 (d,J= 7.2 Hz, 2H), 7.04 (d,J= 7.2 Hz, 2H), 5.85 (s, 1H), 5.27 (d,J= 1.8 Hz, 1H), 3.70 (s, 3H), 2.33 (s,3H), 2.18 (s, 3H).13C NMR (151 MHz, CDCl3) δ 171.0, 165.8, 162.7, 158.2,156.2, 150.4, 144.0, 137.9, 137.6, 134.3, 133.8, 131.0, 129.6, 129.3, 129.1,128.9, 128.9, 128.1, 127.7,126.1, 125.8, 125.7, 119.4, 100.0, 71.8, 71.3,56.0, 52.5, 21.8, 18.3. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C38H31N3NaO6S+680.1826, Found 680.1825.
实施例5 化合物3b-3ac
本实施例提供系列化合物,其合成方法与实施例4相同,区别在于反应原料不同,反应通式为:
其中,原料A(即实施例4中的化合物1a)和原料B(即实施例4中的化合物2a)的结构式可根据式I化合物(即化合物3b-3ac)的结构式中的官能团R1、R2、R3、R4、R5、R6进行推断得到。
其中,化合物3b-3ac的结构式、反应收率和对映选择性数据如下:
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可以看到,化合物3b-3ac的合成结果均有较高的收率和对映选择性,符合工业生产的需求。
化合物3b-3ac的核磁共振氢谱和质谱表征数据如下:
3b:1H NMR (600 MHz, CDCl3) δ 7.42 (d,J= 2.4 Hz, 1H), 7.36 (d,J= 8.4Hz, 2H), 7.32 (tt,J= 7.2, 1.8 Hz, 1H), 7.26 (t,J= 7.2 Hz, 2H), 7.20 – 7.15(m, 1H), 7.16 – 7.09 (m, 6H), 7.03 (d,J= 7.2 Hz, 2H), 5.90 (s, 1H), 5.18 (d,J= 2.4 Hz, 1H), 3.69 (s, 3H), 2.33 (s, 3H), 2.02 (s, 3H), 1.44 (s, 9H).13C NMR(151 MHz, CDCl3) δ 172.7, 166.1, 162.8, 155.5, 155.4, 149.9, 143.9, 138.0,134.6, 134.2, 130.8, 129.5, 129.2, 129.0, 128.8, 128.0, 127.6, 126.4, 125.4,100.8, 71.7, 70.7, 58.1, 55.8, 52.3, 28.3, 21.8, 18.1. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C36H35N3NaO6S+660.2139, Found 660.2140.
3c:1H NMR (600 MHz, CDCl3) δ 7.45 (d,J= 2.4 Hz, 1H), 7.38 (d,J= 8.4Hz, 2H), 7.32 (tt,J= 7.2, 1.8 Hz, 1H), 7.27 (t,J= 7.8 Hz, 2H), 7.17 (d,J= 7.2Hz, 1H), 7.17 – 7.12 (m, 4H), 7.14 – 7.10 (m, 2H), 7.02 (d,J= 7.2 Hz, 2H),5.84 (s, 1H), 5.22 (d,J= 1.8 Hz, 1H), 3.71 (s, 3H), 3.25 (s, 3H), 2.33 (s,3H), 2.06 (s, 3H).13C NMR (151 MHz, CDCl3) δ 172.6, 166.0, 162.7, 157.6,155.9,150.2, 144.0, 137.9, 134.4, 133.9, 131.0, 129.5, 129.2, 128.9, 128.8,128.1, 127.7, 126.3, 125.6, 100.4, 70.8, 70.1, 56.0, 52.4, 31.7, 21.8, 18.2.HRMS(ESI-TOF) m/z: [M+Na]+Calcd for C33H29N3NaO6S+618.1669, Found 618.1668.
3d:1H NMR (600 MHz, CDCl3) δ 7.67 (dt,J= 8.4, 2.4 Hz, 2H), 7.50 (d,J=2.4 Hz, 1H), 7.40 (d,J= 7.8 Hz, 2H), 7.29 (t,J= 7.2 Hz, 1H), 7.24 – 7.18 (m,3H), 7.17 – 7.11 (m, 6H), 7.08 (dd,J= 8.4, 1.2 Hz, 2H), 7.04 (dd,J= 7.2, 1.8Hz, 2H), 5.85 (s, 1H), 5.27 (d,J= 1.8 Hz, 1H), 3.70 (s, 3H), 2.34 (s, 3H),2.29 (s, 3H), 2.17 (s, 3H).13C NMR (151 MHz, CDCl3) δ 170.8, 165.9, 162.7,158.1, 156.1, 150.4, 144.0, 138.0, 135.6, 135.2, 134.4,133.9, 131.0, 129.7,129.6, 129.3, 128.9, 128.9, 128.1, 127.7, 126.2, 125.7, 119.5, 100.1, 71.7,71.4, 56.0, 52.5, 21.8, 21.2, 18.3. HRMS (ESI-TOF) m/z:[M+Na]+Calcd forC39H33N3NaO6S+694.1982, Found 694.1985.
3e:1H NMR (600 MHz, CDCl3) δ 7.63 (d,J= 1.8 Hz, 1H), 7.61 (dd,J= 7.8,1.8 Hz, 1H), 7.51 (d,J= 1.8 Hz, 1H), 7.40 (d,J= 8.4 Hz, 2H), 7.29 (t,J= 7.2Hz, 1H), 7.21 (ddd,J= 13.8, 7.2, 3.0 Hz, 4H), 7.14 (td,J= 7.2, 6.0 Hz, 4H),7.09 (d,J= 7.2 Hz, 2H), 7.04 (d,J= 7.2 Hz, 2H), 6.97 (d,J= 7.2 Hz, 1H), 5.85(s, 1H), 5.28 (d,J= 2.4 Hz, 1H), 3.70 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H),2.18 (s, 3H).13C NMR (151 MHz, CDCl3) δ 171.0, 165.8, 162.6, 158.1, 156.2,150.4, 144.0, 139.1, 137.9, 137.5, 134.4, 133.9, 131.0, 129.6, 129.3, 129.0,128.9, 128.9, 128.1,127.7, 126.7, 126.1, 125.7, 120.0, 116.6, 100.0, 71.8,71.4, 56.0, 52.5, 21.8, 21.8, 18.3. HRMS (ESI-TOF) m/z: [M+Na]+Calcd forC39H33N3NaO6S+694.1982, Found 694.1984.
3f:1H NMR (600 MHz, CDCl3) δ 7.51 (d,J= 1.8 Hz, 1H), 7.45 – 7.42 (m,2H), 7.39 (d,J= 8.4 Hz, 2H), 7.29 (t,J= 7.2 Hz, 1H), 7.26 – 7.18 (m, 4H),7.14(td,J= 7.8, 6.6 Hz, 4H), 7.08 (d,J= 7.2 Hz, 2H), 7.04 (d,J= 7.2 Hz, 2H), 6.71– 6.69 (m, 1H), 5.84 (s, 1H), 5.27 (d,J= 2.4 Hz, 1H), 3.75 (s, 3H), 3.70 (s,3H), 2.33 (s, 3H), 2.18 (s, 3H).13C NMR (151 MHz, CDCl3) δ 171.0, 165.8,162.6, 160.2, 158.1,156.2, 150.4, 144.1, 138.8, 137.9, 134.3, 133.8, 131.0,129.9, 129.6, 129.3, 128.9, 128.9, 128.1, 127.7, 126.1, 125.7, 112.1, 111.5,104.6, 99.9, 71.9,71.4, 56.0, 55.6, 52.5, 21.8, 18.3. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C39H33N3NaO7S+710.1931, Found 710.1928.
3g:1H NMR (600 MHz, CDCl3) δ 7.50 (d,J= 1.8 Hz, 1H), 7.39 (d,J= 8.4Hz, 2H), 7.37 – 7.31 (m, 1H), 7.28 (t,J= 7.8 Hz, 2H), 7.22 (d,J= 3.6 Hz, 2H),7.20 – 7.18 (m, 2H), 7.18 – 7.16 (m, 3H), 7.16 – 7.12 (m, 4H), 7.04 (d,J= 7.2Hz, 2H), 6.00 (s, 1H), 5.24 (d,J= 1.8 Hz, 1H), 3.75 (s, 3H), 2.34 (s, 3H),2.19 (s, 3H), 2.15 (s, 3H).13C NMR (151 MHz, CDCl3) δ 171.9, 165.9, 162.7,158.0, 155.9, 150.5, 144.0, 137.9, 135.5, 135.5, 134.3, 133.9, 131.4, 131.1,129.6, 129.3, 129.1, 129.0, 128.9,128.1, 127.7, 126.8, 126.8, 126.2, 125.5,101.7, 70.8, 70.6, 56.0, 52.5, 21.8, 18.4, 18.2. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C39H33N3NaO6S+6941.1982, Found 694.1985.
3h:1H NMR (600 MHz, CDCl3) δ 7.61 (dd,J= 8.4, 1.2 Hz, 1H), 7.50 (d,J=2.4 Hz, 1H), 7.39 (d,J= 7.8 Hz, 2H), 7.33 (dd, J = 7.8, 6.6 Hz, 2H), 7.30(dd,J= 7.8, 1.8 Hz, 1H), 7.27 (t,J= 7.8 Hz, 2H), 7.24 – 7.19 (m, 3H), 7.18 –7.12 (m, 5H), 7.06 (d,J= 7.2 Hz, 2H), 6.14 (s, 1H), 5.22 (d,J= 1.8 Hz, 1H),3.76 (s, 3H), 2.34 (s, 3H), 2.16 (s, 3H).13C NMR (151 MHz, CDCl3) δ 172.0,165.9, 162.7, 158.3, 155.7, 150.4, 144.0, 137.9, 136.0, 134.3, 133.8, 133.7,130.9,130.5, 129.5, 129.2, 129.2, 128.9, 128.8, 128.5, 128.1, 127.6, 126.2,125.6, 121.3, 101.0, 70.8, 70.3, 56.1, 52.5, 21.7, 18.3. HRMS (ESI-TOF) m/z:[M+Na]+Calcd for C38H30BrN3NaO6S+758.0931, Found 758.0931.
3i:1H NMR (600 MHz, CDCl3) δ 7.50 (d,J= 1.8 Hz, 1H), 7.45 – 7.41 (m,1H), 7.39 (d,J= 8.4 Hz, 2H), 7.35 – 7.30 (m, 2H), 7.31 – 7.24 (m, 4H), 7.23 –7.19 (m, 1H), 7.19 – 7.13 (m, 4H), 7.13 (d,J= 8.4 Hz, 2H), 7.06 (d,J= 6.6 Hz,2H), 6.11 (s, 1H), 5.22 (d,J= 1.8 Hz, 1H), 3.75 (s, 3H), 2.34 (s, 3H), 2.16(s, 3H).13C NMR (151 MHz, CDCl3) δ 171.9, 165.9, 162.8, 158.4, 155.8, 150.6,144.0, 138.0, 134.4, 134.2, 133.9, 131.6, 131.0, 130.6, 130.3, 129.6, 129.3,128.9, 128.9,128.9, 128.1, 127.9, 127.7, 126.3, 125.7, 100.9, 70.8, 70.4,56.0, 52.5, 21.8, 18.3. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C38H30ClN3NaO6S+714.1436, Found 714.1433.
3j:1H NMR (700 MHz, CDCl3) δ 7.83 (dd,J= 8.4, 1.4 Hz, 2H), 7.49 (d,J=2.1 Hz, 1H), 7.41 (d,J= 8.4 Hz, 2H), 7.34 (dd,J= 8.4, 7.7 Hz, 2H), 7.29 (tt,J= 7.0, 1.4 Hz, 1H), 7.22 (dd,J= 8.4, 7.0 Hz, 2H), 7.20 – 7.18 (m, 1H), 7.16 –7.13 (m, 5H), 7.10 (d,J= 7.0 Hz, 2H), 7.05 (d,J= 7.0, 2H), 5.86 (s, 1H), 5.28(d,J= 2.1 Hz, 1H), 3.68 (s, 3H), 2.50 (dq,J= 17.5, 7.0 Hz, 1H), 2.39 (dq,J=17.5, 7.0 Hz, 1H), 2.34 (s, 3H), 1.16 (t,J= 7.0 Hz, 3H).13C NMR (176 MHz,CDCl3) δ 171.1, 166.0, 162.8, 162.1, 156.1,150.1, 144.1, 137.9, 137.8, 134.7,133.9, 131.0, 129.6, 129.3, 129.1, 128.9, 128.9, 128.1, 127.7, 126.2, 125.8,125.7, 119.4, 100.1, 71.8, 71.4, 56.0, 52.5,25.6, 21.8, 10.7. HRMS (ESI-TOF)m/z: [M+Na]+Calcd for C39H33N3NaO6S+694.1982, Found 694.1983.
3k:1H NMR (600 MHz, CDCl3) δ 7.81 (dd,J= 9.0, 1.2 Hz, 2H), 7.50 (d,J=2.4 Hz, 1H), 7.39 (d,J= 8.4 Hz, 2H), 7.33 (dd,J= 8.4, 7.2 Hz, 2H), 7.30 –7.26 (m, 1H), 7.23 – 7.18 (m, 3H), 7.14 (td,J= 7.8, 6.0 Hz, 5H), 7.09 (d,J=7.2 Hz, 2H), 7.05 (d,J= 7.2 Hz, 2H), 5.87 (s, 1H), 5.27 (d,J= 2.4 Hz, 1H),4.19 – 4.07 (m, 2H), 2.33 (s, 3H), 2.18 (s, 3H), 1.18 (t,J= 7.2 Hz, 3H).13CNMR (151 MHz, CDCl3) δ 171.1, 165.8, 162.2, 158.3, 156.1, 150.2, 144.0,137.9, 137.6, 134.6, 133.9,131.0, 129.5, 129.3, 129.1, 128.9, 128.8, 128.1,127.6, 126.1, 125.8, 125.7, 119.4, 100.0, 71.8, 71.3, 61.7, 56.0, 21.8, 18.3,14.2. HRMS (ESI-TOF) m/z:[M+Na]+Calcd for C39H33N3NaO6S+694.1982, Found694.1986.
3l:1H NMR (600 MHz, CDCl3) δ 8.24 (d,J= 9.0 Hz, 2H), 7.88 (dd,J= 8.4,1.2 Hz, 2H), 7.73 (d,J= 9.0 Hz, 2H), 7.59 (d,J= 1.8 Hz, 1H), 7.45 – 7.37 (m,3H), 7.34 – 7.28 (m, 3H), 7.27 – 7.21(m, 3H), 7.17 (d,J= 7.8 Hz, 2H), 7.11(d,J= 7.2 Hz, 2H), 6.00 (s, 1H), 5.39 (d,J= 2.4 Hz, 1H), 3.78 (s, 3H), 2.27(s, 3H).13C NMR (151 MHz, CDCl3) δ 170.7, 168.1, 162.5, 157.6, 156.3, 150.4,150.0, 146.3, 137.5, 134.5, 134.0,131.4, 129.2, 129.1, 129.0, 129.0, 128.9,128.3, 126.0, 125.7, 125.6, 124.2, 119.4, 100.6, 71.7, 71.4, 55.8, 52.7,18.2. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C37H28N4NaO8S+711.1520, Found711.1521.
3m:1H NMR (600 MHz, CDCl3) δ 7.83 (dd,J= 8.4, 1.2 Hz, 2H), 7.56 (d,J=2.4 Hz, 1H), 7.38 (d,J= 7.2 Hz, 2H), 7.35 (dt,J= 9.0, 7.2 Hz, 3H), 7.29 (t,J=7.2 Hz, 2H), 7.27 – 7.20 (m, 3H), 7.16 (td,J= 8.4, 1.8 Hz, 3H), 5.95 (s, 1H),5.33 (d,J= 1.8 Hz, 1H), 3.71 (s, 3H), 2.66 (s, 3H), 2.20 (s, 3H).13C NMR (151MHz, CDCl3) δ 171.0, 167.8, 162.6, 157.9, 156.4, 150.0, 137.6, 134.7, 134.1,131.3, 129.2, 129.1, 128.9,128.5, 126.0, 125.9, 125.8, 119.4, 100.3, 71.6,71.1, 56.2, 52.6, 41.9, 18.4. HRMS (ESI-TOF) m/z: [M+Na]+Calcd forC32H27N3NaO6S+604.1513, Found 604.1519.
3n:1H NMR (700 MHz, CDCl3) δ 7.40 (d,J= 2.1 Hz, 1H), 7.37 (d,J= 8.4Hz, 2H), 7.24 (d,J= 8.4 Hz, 2H), 7.18 (d,J= 7.7 Hz, 1H), 7.14 – 7.11 (m, 4H),7.07 (d,J= 9.1 Hz, 2H), 7.00 (d,J= 7.0 Hz, 2H), 5.89 (s, 1H), 5.17 (d,J= 2.1Hz, 1H), 3.69 (s, 3H), 2.34 (s, 3H), 2.01 (s, 3H), 1.43 (s, 9H).13C NMR (176MHz, CDCl3) δ 172.6, 165.8, 162.7, 155.4, 154.5, 149.7, 144.0, 138.0, 137.0,134.7, 134.1,129.5, 129.3, 129.2, 128.8, 128.1, 127.6, 126.7, 124.8, 101.3,71.6, 70.7, 58.1, 55.9, 52.3, 28.3, 21.8, 18.1. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C36H34ClN3NaO6S+694.1749, Found 694.1747.
3o:1H NMR (700 MHz, CDCl3) δ 7.48 (d,J= 2.1 Hz, 1H), 7.43 (d,J= 7.7Hz, 2H), 7.24 (t,J= 7.0 Hz, 1H), 7.22 – 7.16 (m, 4H), 7.14 (d,J= 8.4 Hz, 2H),7.09 (d,J= 7.0 Hz, 2H), 6.83 (d,J= 9.1 Hz, 2H), 5.80 (s, 1H), 5.22 (d,J= 2.1Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.40 (s, 3H), 2.08 (s, 3H), 1.51 (s,9H).13C NMR (151 MHz, CDCl3) δ 172.8, 166.5, 162.8, 161.6, 155.5, 155.4,149.9, 143.8, 138.1, 134.6, 134.3,129.5, 129.3, 128.8, 127.9, 127.6, 127.1,119.0, 114.4, 98.3, 71.7, 70.8, 58.1, 55.8, 55.6, 52.3, 28.3, 21.8, 18.1.HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C37H37N3NaO7S+690.2244, Found 690.2246.
3p:1H NMR (600 MHz, CDCl3) δ 7.81 (dd,J= 8.7, 1.1 Hz, 2H), 7.51 (d,J=2.4 Hz, 1H), 7.33 (dd,J= 15.0, 8.4 Hz, 4H), 7.26 – 7.21 (m, 2H), 7.20 (t,J=7.2 Hz, 2H), 7.18 – 7.11 (m,4H), 7.06 (d,J= 6.6 Hz, 2H), 7.02 (dt,J= 7.8, 1.2Hz, 1H), 6.83 (t,J= 1.8 Hz, 1H), 5.89 (s, 1H), 5.28 (d,J= 2.4 Hz, 1H), 3.70(s, 3H), 2.33 (s, 3H), 2.20 (s, 3H).13C NMR (151 MHz, CDCl3) δ 170.9, 164.8,162.6, 158.1, 154.7, 150.3, 144.2, 137.8, 137.6, 135.1, 134.4, 133.8, 131.0,130.2, 129.7, 129.3, 129.2, 129.0, 128.2, 127.7, 127.5, 125.9, 125.5, 123.8,119.4, 101.5, 71.8, 71.1, 56.1, 52.5, 21.8, 18.3. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C38H30ClN3NaO6S+714.1436, Found 714.1436.
3q:1H NMR (600 MHz, CDCl3) δ 7.80 (dd,J= 8.4, 1.2 Hz, 2H), 7.51 (d,J=2.4 Hz, 1H), 7.36 (d,J= 8.4 Hz, 2H), 7.32 (td,J= 7.2, 1.8 Hz, 2H), 7.19 (t,J=7.2 Hz, 1H), 7.15 (t,J= 7.2 Hz, 3H), 7.11 (dt,J= 8.4, 4.2 Hz, 3H), 7.04 (d,J=7.2 Hz, 2H), 6.81 (ddd,J= 8.4, 2.4, 1.2 Hz, 1H), 6.68 (dt,J= 7.8, 1.2 Hz,1H), 6.53 (dd,J= 2.4, 1.8 Hz, 1H), 5.84 (s, 1H), 5.26 (d,J= 1.8 Hz, 1H), 3.69(s, 3H), 3.65 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H).13C NMR (151 MHz, CDCl3) δ171.0, 165.6, 162.6, 159.9, 158.2, 156.0, 150.4, 144.1, 137.8, 137.6, 134.3,133.8, 130.0,129.6, 129.2, 129.1, 128.9, 128.1, 127.6, 127.3, 125.8, 119.4,118.1, 116.4, 111.3, 100.3, 71.8, 71.3, 55.9, 55.5, 52.5, 21.7, 18.3. HRMS(ESI-TOF) m/z:[M+Na]+Calcd for C39H33N3NaO7S+710.1931, Found 710.1931.
3r:1H NMR (600 MHz, Chloroform-d) δ 7.78 (dd,J= 8.4, 1.2 Hz, 2H),7.50 (d,J= 2.4 Hz, 1H), 7.42 (d,J= 8.4 Hz, 2H), 7.34 (dd,J= 8.4, 7.2 Hz, 2H),7.27 (dddd,J= 9.0, 7.8, 5.4, 1.8 Hz, 1H), 7.21 – 7.19 (m, 1H), 7.17 – 7.13(m, 5H), 7.05 (d,J= 7.2 Hz, 2H), 7.01 – 6.96 (m, 2H), 6.93 (td,J= 7.8, 1.8Hz, 1H), 6.13 (d,J= 2.4 Hz, 1H), 5.30 (d,J= 1.8 Hz, 1H), 3.70 (s, 3H), 2.34(s, 3H), 2.18 (s, 3H).13C NMR (151 MHz, CDCl3) δ 170.9, 165.2, 162.7, 160.6(d,1 J CF= 255.2 Hz), 159.8, 158.0, 150.5, 150.2 (d,3 J CF= 3.0 Hz), 144.1, 137.9,137.5, 134.3, 133.8, 132.2 (d,3 J CF= 9.1 Hz), 129.6, 129.3, 129.1, 128.9,128.2, 127.8, 127.6, 125.9, 124.5 (d,3 J CF= 3.0 Hz), 119.7, 116.3 (d,2 J CF= 21.1Hz), 114.8 (d,2 J CF= 10.6 Hz), 105.8 (d,4 J CF= 1.5 Hz), 71.7, 71.6, 56.0, 52.5,21.8, 18.3. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C38H30FN3NaO6S+698.1732, Found698.1736.
3s:1H NMR (600 MHz, CDCl3) δ 7.90 (d,J= 8.4 Hz, 2H), 7.60 (d,J= 2.4Hz, 1H), 7.45 (d,J= 8.4 Hz, 2H), 7.41 (t,J= 7.8 Hz, 2H), 7.30 (t,J= 7.2 Hz,1H), 7.27 (s, 1H), 7.26 – 7.17 (m, 5H), 7.14 (dd,J= 7.2, 2.4 Hz, 3H), 7.07(t,J= 7.8 Hz, 1H), 6.80 (dd,J= 7.8, 1.2 Hz, 1H), 5.74 (s, 1H), 5.35 (d,J= 2.4Hz, 1H), 3.78 (s, 3H), 2.42 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H).13C NMR (151MHz, CDCl3) δ 171.0, 166.0, 162.7, 158.3, 155.9, 150.6, 144.0, 137.9, 137.6,137.2, 134.2,133.9, 131.4, 130.7, 129.5, 129.3, 129.1, 128.9, 128.4, 128.2,127.7, 126.1, 125.9, 125.8, 119.2, 104.7, 72.0, 71.6, 55.6, 52.5, 21.8, 21.5,18.2. HRMS(ESI-TOF) m/z: [M+Na]+Calcd for C39H33N3NaO6S+694.1982, Found694.1984.
3t:1H NMR (700 MHz, CDCl3) δ 7.79 (d,J= 8.4 Hz, 2H), 7.49 (d,J= 2.1Hz, 1H), 7.41 (d,J= 7.7 Hz, 2H), 7.33 (t,J= 7.7 Hz, 2H), 7.27 (t,J= 3.5 Hz,1H), 7.19 – 7.16 (m, 1H), 7.16 – 7.13 (m, 3H), 7.12 (d,J= 7.7 Hz, 2H), 7.04(d,J= 7.0 Hz, 2H), 6.88 (d,J= 2.8 Hz, 2H), 5.68 (s, 1H), 5.24 (d,J= 2.1 Hz,1H), 3.69 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H).13C NMR (176 MHz, CDCl3) δ171.0, 165.5, 162.6, 158.1, 151.1, 150.4, 144.1, 137.6, 137.6, 134.2, 133.8,129.5, 129.2, 129.1, 128.9, 128.4, 128.2, 128.1, 128.0,127.8, 125.9, 119.5,98.8, 71.8, 71.4, 56.0, 52.5, 21.8, 18.3. HRMS (ESI-TOF) m/z: [M+Na]+Calcdfor C36H29N3NaO6S2 +686.1390, Found 686.1398.
3u:1H NMR (600 MHz, CDCl3) δ 7.77 (dd,J= 9.0, 1.2 Hz, 2H), 7.50 (d,J=1.8 Hz, 1H), 7.34 (dd,J= 8.4, 7.2 Hz, 2H), 7.27 (d,J= 8.4 Hz, 2H), 7.23 –7.20 (m, 3H), 7.15 (tt,J= 7.2, 1.2 Hz, 1H), 7.06 – 7.04 (m, 4H),5.15 (s, 1H),5.14 (d,J= 1.8 Hz, 1H), 3.70 (s, 3H), 2.29 (s, 3H), 2.15 (s, 3H), 0.74 (s,9H).13C NMR (151 MHz, CDCl3) δ 171.0, 168.1, 166.8, 162.7, 158.3, 150.5,143.8, 137.9, 137.6, 134.2, 134.1, 129.4, 129.2, 129.1, 128.7, 128.0, 127.7,125.9, 119.5,98.8, 71.6, 70.5, 55.0, 52.5, 32.4, 26.9, 21.7, 18.1. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C36H35N3NaO6S+660.2139, Found 660.2145.
3v:1H NMR (600 MHz, CDCl3) δ 7.82 (d,J= 7.2 Hz, 2H), 7.46 (d,J= 2.4Hz, 1H), 7.38 (d,J= 8.4 Hz, 2H), 7.34 (dd,J= 8.4, 7.2 Hz, 2H), 7.24 – 7.18(m, 1H), 7.20 – 7.15 (m, 2H), 7.15 (t,J= 6.6 Hz, 1H), 7.09 (d,J= 7.8 Hz, 2H),7.02 (d,J= 6.6 Hz, 2H), 5.23 (s, 1H), 5.14 (d,J= 1.8 Hz, 1H), 3.68 (s, 3H),2.33 (s, 3H), 2.15 (s, 3H), 2.05 – 1.99 (m, 2H), 1.12 – 1.00(m, 4H), 0.70 (t,J= 7.2 Hz, 3H).13C NMR (151 MHz, CDCl3) δ 171.0, 167.3, 162.7, 160.2, 158.2,150.7, 143.9, 137.7, 137.7, 134.2, 133.9, 129.4, 129.3, 129.1, 128.7, 128.1,127.8, 125.7, 119.2, 101.9, 71.5, 70.8, 55.2, 52.5, 27.7, 27.1, 21.8, 21.7,18.2, 13.6. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C36H35N3NaO6S+660.2139, Found660.2147.
3w:1H NMR (600 MHz, CDCl3) δ 7.85 – 7.79 (m, 3H), 7.73 – 7.67 (m, 2H),7.50 (d,J= 2.4 Hz, 1H), 7.47 (d,J= 8.4 Hz, 2H), 7.45 (dd,J= 7.2, 1.2 Hz, 1H),7.35 (dd,J= 8.4, 7.2 Hz, 2H), 7.30 (dd,J= 8.4, 7.2 Hz, 1H), 7.29 – 7.24 (m,2H), 7.23 – 7.18 (m, 1H), 7.16 (t,J= 7.2 Hz, 1H), 7.14 – 7.10 (m, 4H), 6.98(d,J= 7.2 Hz, 2H), 6.16 (d,J= 2.4 Hz, 1H), 6.01 (s, 1H), 3.72 (s, 3H), 2.32(s, 3H), 2.18 (s, 3H).13C NMR (151 MHz, CDCl3) δ 171.4, 165.6, 162.7, 158.2,155.7, 152.1, 144.2, 137.9, 137.6, 134.2, 133.8,131.8, 130.8, 130.1, 129.6,129.3, 129.2, 129.2, 129.0, 128.7, 127.7, 126.1, 126.1, 125.9, 125.8, 125.6,125.5, 123.4, 119.6, 100.7, 71.9, 71.5, 52.6, 52.6,21.8, 18.4. HRMS (ESI-TOF)m/z: [M+Na]+Calcd for C42H33N3NaO6S+730.1982, Found 730.1981.
3x:1H NMR (600 MHz, CDCl3) δ 7.80 (dd,J= 8.4, 1.2 Hz, 2H), 7.46 (d,J=8.4 Hz, 2H), 7.43 (d,J= 1.8 Hz, 1H), 7.32 (dd,J= 8.4, 7.2 Hz, 2H), 7.32 –7.28 (m, 1H), 7.23 (t,J= 7.8 Hz, 2H), 7.17 – 7.12 (m, 5H), 7.01 (d,J= 8.4 Hz,2H), 6.93 (d,J= 8.4 Hz, 2H), 5.84 (s, 1H), 5.22 (d,J= 2.4 Hz, 1H), 3.69 (s,3H), 2.35 (s, 3H), 2.21 (s, 3H).13C NMR (151 MHz, CDCl3) δ 170.8, 165.9,162.5, 158.0, 156.4, 149.5, 144.5, 137.5, 137.4, 134.7, 134.2, 132.4, 131.2,130.4, 129.6, 129.1, 129.0, 128.9, 127.8, 125.9, 125.8, 125.7, 119.4, 99.7,71.8, 71.3, 55.2, 52.5, 21.8, 18.3. HRMS (ESI-TOF) m/z: [M+Na]+Calcd forC38H30ClN3NaO6S+714.1436, Found 714.1436.
3y:1H NMR (600 MHz, CDCl3) δ 7.80 (dd,J= 8.4, 1.2 Hz, 2H), 7.52 (d,J=8.4 Hz, 2H), 7.42 (d,J= 1.8 Hz, 1H), 7.33 (dd,J= 8.4, 7.2 Hz, 2H), 7.30 (d,J=7.2 Hz, 1H), 7.24 (dd,J= 8.4, 7.2 Hz, 2H), 7.23 – 7.18 (m, 2H), 7.18 (s, 1H),7.16 (s,1H), 7.14 (t,J= 8.4 Hz, 1H), 7.08 (td,J= 7.8, 6.0 Hz, 1H), 6.85 (td,J= 8.4, 2.4 Hz, 1H), 6.80 (d,J= 7.8 Hz, 1H), 6.74 (dt,J= 9.6, 2.4 Hz, 1H),5.85 (s, 1H), 5.24 (d,J= 1.8 Hz, 1H), 3.68 (s, 3H), 2.34 (s, 3H), 2.18 (s,3H).13C NMR (151 MHz, CDCl3) δ 170.8, 166.0, 162.5, 162.2 (d,1 J CF= 247.6 Hz),157.9, 156.5, 149.5, 144.3, 137.6, 137.6, 136.3 (d,3 J CF= 7.6 Hz), 134.7,131.2, 130.4 (d,3 J CF= 7.6 Hz), 129.6, 129.1, 129.0, 127.7, 126.0, 125.9,125.8, 124.7 (d,4 J CF= 3.0 Hz), 119.4, 116.3 (d,2 J CF= 22.7 Hz), 115.2 (d,2 J CF=21.1 Hz), 99.6, 71.7, 71.2, 55.4, 52.5, 21.8, 18.2. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C38H30FN3NaO6S+698.1732, Found 698.1732.
3z:1H NMR (600 MHz, CDCl3) δ 7.88 (dd,J= 8.4, 1.2 Hz, 2H), 7.60 (d,J=8.4 Hz, 2H), 7.52 (d,J= 2.4 Hz, 1H), 7.41 (dd,J= 8.4, 7.2 Hz, 2H), 7.39 –7.37 (m, 1H), 7.32 (td,J= 7.2, 1.8 Hz, 2H), 7.28 – 7.26 (m, 2H),7.26 – 7.24(m, 2H), 7.24 – 7.21 (m, 2H), 7.14 (t,J= 1.8 Hz, 1H), 7.12 (t,J= 7.8 Hz, 1H),6.98 (d,J= 7.8 Hz, 1H), 5.92 (s, 1H), 5.31 (d,J= 1.8 Hz, 1H), 3.76 (s, 3H),2.42 (s, 3H), 2.25 (s, 3H).13C NMR (151 MHz, CDCl3) δ 170.8, 166.0, 162.5,157.9, 156.6, 149.3, 144.2, 137.7, 137.6, 136.0, 134.7, 131.2, 130.1,129.7,129.3, 129.1, 129.0, 128.5, 127.7, 127.1, 126.0, 125.9, 125.8, 119.4, 99.7,71.7, 71.1, 55.4, 52.6, 21.8, 18.2. HRMS (ESI-TOF) m/z: [M+Na]+Calcd forC38H30ClN3NaO6S+714.1436, Found 714.1437.
3aa:1H NMR (600 MHz, CDCl3) δ 7.79 (dd,J= 9.0, 1.2 Hz, 2H), 7.56 (d,J=8.4 Hz, 2H), 7.34 (dd,J= 7.2, 2.4 Hz, 1H), 7.34 – 7.29 (m, 3H), 7.30 – 7.24(m, 1H), 7.21 (t,J= 7.8 Hz, 2H), 7.18 (d,J= 1.2 Hz, 1H), 7.17 – 7.08 (m, 7H),5.94 (s, 1H), 5.83 (d,J= 2.4 Hz, 1H), 3.68 (s, 3H), 2.33 (s, 3H), 2.14 (s,3H).13C NMR (151 MHz, CDCl3) δ 170.9, 165.9, 162.5, 157.7, 154.7, 150.8,144.3, 137.9, 137.6, 134.6, 134.5, 133.4, 131.6,130.8, 129.8, 129.8, 129.7,129.1, 128.8, 127.7, 127.0, 126.3, 125.8, 125.7, 119.4, 101.5, 71.7, 71.6,53.2, 52.5, 21.8, 18.3. HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C38H30FN3NaO6S+714.1436, Found 714.1436.
3ab:1H NMR (600 MHz, CDCl3) δ 7.67 (dd,J= 8.4, 1.2 Hz, 2H), 7.44 (d,J=8.4 Hz, 2H), 7.39 (d,J= 2.4 Hz, 1H), 7.32 (dd,J= 7.8, 1.8 Hz, 2H), 7.30 –7.26 (m, 5H), 7.24 (td,J= 7.8, 1.8 Hz,1H), 7.10 (tt,J= 7.8, 1.2 Hz, 2H), 7.05(d,J= 7.8 Hz, 2H), 6.85 (td,J= 7.8, 1.2 Hz, 1H), 6.75 (dd,J= 8.4, 1.2 Hz,1H), 6.16 (s, 1H), 5.22 (d,J= 2.4 Hz, 1H), 3.68 (s, 3H), 3.56 (s, 3H), 2.26(s, 3H), 1.93 (s, 3H).13C NMR (151 MHz, CDCl3) δ 171.1, 167.3, 162.5, 158.6,157.4, 152.6, 150.1, 143.8, 138.0, 137.8, 134.3, 130.6, 130.4, 129.8, 129.4,129.0, 128.9, 127.5, 126.9,125.6, 125.4, 122.8, 120.5, 119.7, 110.4, 105.5,71.6, 69.1, 55.3, 53.9, 52.6, 21.7, 18.5. HRMS (ESI-TOF) m/z: [M+Na]+Calcdfor C39H33N3NaO7S+710.1931,Found 710.1933.
3ac:1H NMR (600 MHz, CDCl3) δ 7.79 (dd,J= 8.4, 1.2 Hz, 2H), 7.61 (d,J=8.4 Hz, 2H), 7.32 (td,J= 7.2, 1.2 Hz, 2H), 7.32 – 7.27 (m, 1H), 7.28 – 7.19(m, 8H), 7.16 – 7.13 (m, 2H), 6.94 (dd,J= 8.4, 2.4 Hz, 1H), 5.91 (s, 1H),5.77 (d,J= 2.4 Hz, 1H), 3.70 (s, 3H), 2.37 (s, 3H), 2.17 (s, 3H).13C NMR (151MHz, CDCl3) δ 170.8, 166.0, 162.4, 157.6, 155.0, 150.1, 144.8, 137.5, 137.5,135.1, 135.0, 134.0, 131.0, 130.2, 129.8, 129.5, 129.1, 129.0, 127.9,127.2,126.2, 125.9, 125.8, 119.5, 101.2, 71.7, 71.7, 52.6, 52.6, 21.9, 18.4. HRMS(ESI-TOF) m/z: [M+Na]+Calcd for C38H29Cl2N3NaO6S+748.1046, Found 748.1046.
下面通过实验对本发明的技术方案做进一步的说明。
实验例1 催化剂组成与合成条件优化实验
一、实验方法
本实验例对实施例4的合成反应进行催化剂组成与合成条件的优化。
其中,包括两种反应条件:
a条件:1a (0.1 mmol)和M在 CHCl3(1.0 mL)中 40°C搅拌1小时,然后加入2a(0.1 mmol)和C (20 mol%),继续搅拌8 h。
b条件:加入2a和C后,0℃搅拌48 h, 然后40℃搅拌3 h。
其中,M为贵金属盐,选自PPh3AuCl(5mol%)+AgSbF6(10mol%)、AgOTf(10mol%)、Ag2CO3(10mol%)或AgOAc(10mol%);
C为有机物催化剂,选自化合物C1-C9,化合物C1-C9的结构式如下:
二、实验结果
不同合成条件和催化剂进行反应,得到的化合物3a的产率和对映选择性数据如下表所示:
实验组 | M | C | 收率 (%) | 对映选择性Er |
1 | PPh3AuCl, AgSbF6 | PPh3 | N.R. | - |
2 | PPh3AuCl, AgSbF6 | DABCO | N.R. | - |
3 | PPh3AuCl, AgSbF6 | C1 | 49 | 76:24 |
4 | AgOTf | C1 | 66 | 79:21 |
5 | Ag2CO3 | C1 | 56 | 72:28 |
6 | AgOAc | C1 | 58 | 80:20 |
7 | AgOAc | C2 | 26 | 74:26 |
8 | AgOAc | C3 | 42 | 70:30 |
9 | AgOAc | C4 | 37 | 56:43 |
10 | AgOAc | C5 | 66 | 74:26 |
11 | AgOAc | C6 | 22 | 83:17 |
12 | AgOAc | C7 | 52 | 85:15 |
13 | AgOAc | C8 | 86 | 86:14 |
14 | AgOAc | C9 | 82 | 89:11 |
15 | AgOAc | C9 | 80 | 95:5 |
以上各实验组中,实验组1-14的合成条件为“a条件”,实验组15的合成条件为“b条件”。
从上表的实验结果可以看到,采用化合物C1-C9与贵金属盐的组合作为催化剂,都能够催化反应,得到化合物1a,而选择化合物C8或化合物C9与AgOAc进行组合时,反应具有最佳的收率和对映选择性。
此外,对比实验组14和实验组15可知,在相同的催化剂组合下,采用“b条件”(即在40℃条件下反应前先在0℃条件下搅拌)能够进一步提高对映选择性。
实验例2 化合物3a-3ac的磷酸二酯酶抑制活性
一、实验方法
1、临近闪烁分析
通过使用固定量的酶和底物浓度的临近闪烁分析(SPA,ScintillationProximity Assay)测量相关PDEs亚型PDE1A、1B、1C、3A1、4D2、7A2、8A2和10A1的H3-cAMP或PDE2A、5A1、6C、9A2和11A4的H3-cGMP的转化,来测定对PDEs的抑制活性。圆球微粒(SPAbead)选择性地与H3-AMP或H3-GMP结合,其放射性计数的大小与PDE酶活性直接相关。简而言之,将待测化合物溶解于DMSO,配置成0.1 μmol.L−1浓度的样品溶液。在细胞培养板中每孔加入溶于DMSO中的试验化合物1 μL及含有Brij 35(0.01%(v/v))的缓冲液(Trizma和MgCl2),然后将相应酶溶液加入其中。对于PDE1亚型的检测,缓冲液还包括CaCl2(30 mM)和钙调蛋白(25 U.mL−1)。随后,在每个孔中加入20 μL的H3-cGMP(或20 μL的H3-cAMP)以开始反应,并在25 °C下孵育30分钟,通过MicroBeta微孔板计数器读取计数。
2、细胞培养
HLF细胞在含有10%胎牛血清(FBS)和1%青-链霉素的FI2K培养基中孵育。所有细胞系在37 °C含5%二氧化碳的恒温培养箱中培养。
3、免疫印迹(Western blotting)分析
收集细胞并用RIPA裂解液进行裂解。根据制造商指南,使用Pierce™Rapid GoldBCA蛋白检测试剂盒测量每个样品的蛋白质浓度。用12.5% SDS-PAGE分离总蛋白,转移到PVDF膜上,在室温下用5%脱脂牛奶封闭2小时,接着在摇床上4 °C孵育过夜。然后用含有0.1%吐温-20的TBS缓冲液洗涤三次,并与酶标二抗(1:10000稀释)在室温下放置1小时。使用Immobilon ECL Ultra Western HRP底物观察印迹蛋白,使用Chemi-Doc系统扫描,并使用ImageJ软件(https://imagej.net.)进行分析。
4、免疫荧光(IF)分析
总共约1×105个转染TGFβ1和/或化合物3x的HLF细胞被镀在盖玻片上,在37 °C下培养过夜,盖玻片用4%预冷的多聚甲醛在室温下固定20分钟,这些细胞固定在3.7%的福尔马林中,用0.25%的Triton X-100渗透,并用10%山羊血清阻断1小时。用10%山羊血清稀释的一抗孵育过夜后,加入250 μL荧光二抗溶液(1:100,10%山羊血清稀释),在室温下黑暗中孵育1小时,然后用DAPI在室温下黑暗中放置5分钟。最后,用中性树胶密封载玻片,用共聚焦荧光显微镜观察。
5、博来霉素致大鼠肺损伤模型的建立
所有动物护理和实验方案均符合《实验动物护理和使用指南》(美国国立卫生研究院出版物,1996年修订本,第86-23期,马里兰州贝塞斯达),并经成都中医药大学动物研究机构伦理委员会批准(第2022-37号)。经过1周环境适应期后,将动物随机分为4组:对照组、模型组、3x组(20 mg.kg−1)和阳性对照组(吡非尼酮,PFD,150 mg.kg−1)。模型组、3x组和阳性对照组采用4%戊巴比妥钠(10mL.kg−1)腹腔注射麻醉后,无菌切开下颈,钝性解剖,充分暴露,然后注射博莱霉素5 mg.kg−1约0.2 mL,即刻将大鼠直立旋转多次,使药液均匀分布。缝合创面,观察大鼠康复后的状态。同时,向对照组大鼠气管内注入等量的生理盐水。给药28天后,测量各组大鼠的呼吸水平。然后,用4%戊巴比妥钠腹腔注射麻醉大鼠,安乐死后取左肺下叶,在室温下用4%缓冲多聚甲醛浸泡过夜,石蜡包埋。肺标本采用H&E或Masson三色染色。用Olympus FV-3000显微镜观察染色后的肺切片。
二、实验结果
如图2A所示,考察了化合物3a-3ac在0.1μmol.L−1浓度下对PDE1B的抑制能力。化合物3a表现出良好的抑制率。有趣的是,化合物3b和化合物3c对吡唑酮片段的抑制活性随着N-烷基取代而降低。在不同位置含有不同N-苯基的给电子和吸电子取代基的产物,对PDE1B的抑制率没有显著影响(化合物3d−3i)。用乙基取代吡唑酮环上的甲基会导致抑制活性的丧失,可能是由于空间位阻(化合物3j)所致。环戊烯环上的甲酯转变为乙酯对活性(化合物3k)的影响很小。对于不同烯胺类化合物作为底物制成的双环戊烯吡唑酮类化合物,甲磺酰胺或4-硝基苯磺酰胺取代显著减弱了抑制作用(化合物3l和化合物3m)。含有邻位取代苯基、烷基和噻吩基的双环戊烯吡唑酮类化合物的活性降低(化合物3n−3s)。值得注意的是,烯基上含有不同取代芳基的烯胺类化合物作为底物可以为双环戊烯吡唑酮类化合物提供更强的抑制活性(化合物3x-3ac),尤其是具有4-氯苯基的化合物3x。
筛选在0.1μM时对PDE1B的抑制率超过60%的化合物对三种PDE1亚型的IC50值(图2B)。这些化合物总体上对PDE1B有很好的抑制作用,但在三种PDE1亚型之间没有明显的特异性。测定了化合物3x在PDE家族中的亚型选择性,它对PDE1具有较强的抑制活性,而对其他PDE 抑制较弱(图2C)。
根据PDEs在炎性肺损伤和纤维化中的重要作用,对化合物3x的体内外治疗作用和初步机制进行了评价(图3)。纤维连接蛋白、I型胶原和α-SMA等纤维化标志物的表达水平被转化生长因子-β1刺激,化合物3x作用后被抑制(图3A-B)。纤维连接蛋白和α-SMA的免疫荧光染色在体外也观察到类似的结果(图3C-D)。在博莱霉素(BLM)诱导的特发性肺纤维化(IPF)大鼠模型上,化合物3x显示出与临床批准的药物吡非尼酮(PFD)类似的抗纤维化作用,图3E-F。BLM诱导的IPF大鼠经化合物3x或PFD治疗后,吸气末停顿(EIP)、呼气末停顿(EEP)、呼气中期流量(EF50)、最大吸气流量(PIF)、最大呼气流量(PEF)等肺通气性指标均明显减轻,提示化合物3x对IPF相关呼吸功能障碍有一定的治疗作用。通过苏木精-伊红(H&E)染色或马氏胶原三色染色观察肺组织的形态变化,与对照组相比,BLM组大鼠肺泡内可见明显的形态改变和胶原沉积,而PFD或化合物3x治疗组上述病理改变明显减轻。体外和体内实验结果表明,化合物3x可通过抑制PDE1而减轻博莱霉素诱导的肺纤维化。
通过上述实施例和实验例可以看到,本发明建立了一种金属/Lewis碱接力催化体系,该催化体系以醋酸银和基于手性4-羟基二芳基脯氨醇的新型手性PPY为基础。该催化体系已成功地应用于烯胺类化合物的环异构化/(2+3)环加成反应,这是以前未见过的。利用该催化体系进行双环戊烯基吡唑啉酮类化合物的合成具有较高的收率和立体选择性。
在随后的生物检测中,上述双环戊烯基吡唑啉酮类化合物在体外显示出特异的PDE1抑制活性。其中,化合物3x通过抑制PDE1对博莱霉素诱导的肺纤维化有较好的治疗作用。这为肺纤维化的治疗提供了很好的临床选择。
因此,本发明具有很好的应用前景。
Claims (22)
1.式II所示化合物,或其盐,或其溶剂合物,或其晶型,其特征在于,式II所示化合物结构式如下:
式II
其中,
Ar1和Ar2分别独立选自被至少一个取代基取代的苯基,其中,取代基选自C1-C10烷基、C6-C10芳基;
R7选自H或TBDPS。
2.按照权利要求1所述的化合物,或其盐,或其溶剂合物,或其晶型,其特征在于:Ar1和Ar2分别独立选自被一至二个取代基取代的苯基,其中,取代基选自叔丁基或苯基。
3.按照权利要求2所述的化合物,或其盐,或其溶剂合物,或其晶型,其特征在于:Ar1和Ar2分别独立选自被一至二个取代基取代的苯基,其中,取代基选自苯基;
R7选自TBDPS。
4.按照权利要求1-3任一项所述的化合物,或其盐,或其溶剂合物,或其晶型,其特征在于,式II所示化合物结构式如下:
、/>。
5.权利要求1-4任一项所述的化合物,或其盐,或其溶剂合物,或其晶型的合成方法,其特征在于,包括如下步骤:
步骤a,将原料a与4-氯烟酸反应,得到中间物b;
步骤b,将中间物b与吡咯烷反应,即得。
6.权利要求5所述的合成方法,其特征在于,步骤a中,所述反应在溶剂作用下进行,所述溶剂选自DCM或DMF;所述反应在缩合剂和催化剂的作用下进行,所述缩合剂选自草酰氯、DCC或EDCI中的至少一种,所述催化剂选自DMAP或DMF中的至少一种;反应温度为0-40 ℃,反应时间为0.5-10 h;
或,步骤b中,所述反应在溶剂甲苯或无溶剂条件下进行,反应温度为60-100 ℃,反应时间为0.5-10 h。
7.权利要求1-4任一项所述的化合物,或其盐,或其溶剂合物,或其晶型用于作为有机合成催化剂的用途。
8.一种催化剂组合物,其特征在于,它包括如下摩尔份的组分:
有机物催化剂10-20份、贵金属盐5-10份;
其中,有机物催化剂选自权利要求1-3任一项所述的化合物,或其盐,或其溶剂合物,或其晶型。
9.权利要求8所述的催化剂组合物,其特征在于:所述贵金属盐选自金盐或银盐中的至少一种,所述金盐选自PPh3AuCl,所述银盐选自AgSbF6、AgOTf、Ag2CO3或AgOAc中的至少一种。
10.权利要求8所述的催化剂组合物,其特征在于:它包括如下摩尔份的组分:有机物催化剂20 份、贵金属盐10 份。
11.一种有机化合物合成方法,其特征在于,所述合成方法包括如下反应:
将原料A和原料B在权利要求8-10任一项所述的催化剂组合物的催化作用下进行反应,得到式I所示的化合物;
其中,
R1选自被至少一个取代基取代或未取代的C1-C10烷基、被至少一个取代基取代或未取代的C6-C10芳基,其中,取代基选自C1-C10烷氧基、C1-C10烷基、卤素;
R2选自C1-C10烷基;
R3选自被至少一个取代基取代或未取代的C1-C10烷基、被至少一个取代基取代或未取代的C6-C10芳基、被至少一个取代基取代或未取代的5-10元杂芳基,其中,取代基选自C1-C10烷氧基、C1-C10烷基、卤素;
R4选自磺酰基;
R5选自被至少一个取代基取代或未取代的C6-C10芳基,其中,取代基选自C1-C10烷氧基、C1-C10烷基、卤素;
R6选自C1-C10烷基。
12.按照权利要求11所述的合成方法,其特征在于:R1选自C1-C4烷基、被一个取代基取代或未取代的苯基,其中,取代基选自甲基、甲氧基、Cl或Br。
13.按照权利要求11所述的合成方法,其特征在于:R2选自甲基或乙基。
14.按照权利要求11所述的合成方法,其特征在于:R3选自C1-C4烷基、被一个取代基取代或未取代的苯基、5元杂芳基,其中,取代基选自甲基、甲氧基、Cl或F。
15.按照权利要求11所述的合成方法,其特征在于:R4选自对甲苯磺酰基、硝基苯磺酰基、甲磺酰基。
16.按照权利要求11所述的合成方法,其特征在于:R5选自被一至二个取代基取代或未取代的C6-C10芳基,其中,取代基选自甲氧基、Cl或F。
17.按照权利要求11所述的合成方法,其特征在于:R6选自甲基或乙基。
18.按照权利要求11所述的合成方法,其特征在于,式I所示化合物结构式如下:
。
19.按照权利要求11所述的合成方法,其特征在于:所述反应的溶剂选自CHCl3、DCM、THF、甲苯、1,4-二氧六环、DCE或DMF中的至少一种。
20.按照权利要求19所述的合成方法,其特征在于:所述反应的溶剂选自CHCl3。
21.按照权利要求11所述的合成方法,其特征在于:所述反应条件为0-80 ℃反应0.5-1h;
或,0-80 ℃搅拌24-72h, 然后0-80 ℃搅拌1-3h。
22.按照权利要求11所述的合成方法,其特征在于:所述催化剂组合物的用量按照如下方式确定:有机物催化剂的用量为原料A的10-20 mol%。
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