CN110317179B - 类赤霉素化合物、其制备方法、药物组合物及应用及其中间体 - Google Patents

类赤霉素化合物、其制备方法、药物组合物及应用及其中间体 Download PDF

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CN110317179B
CN110317179B CN201810273045.4A CN201810273045A CN110317179B CN 110317179 B CN110317179 B CN 110317179B CN 201810273045 A CN201810273045 A CN 201810273045A CN 110317179 B CN110317179 B CN 110317179B
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张洪彬
吴明江
李艳
何严萍
陈静波
羊晓东
陈文�
龚雅潇
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Kunming Institute of Botany of CAS
Yunnan University YNU
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Abstract

本发明公开了一种类赤霉素化合物、其制备方法、药物组合物、应用及其中间体，所述如式I所示的类赤霉素化合物具有较好的体外抗肿癌细胞毒活性，尤其对于乳腺癌细胞或结肠癌细胞具有显著的体外细胞毒活性。

Description

类赤霉素化合物、其制备方法、药物组合物及应用及其中间体
技术领域
本发明涉及类赤霉素化合物、其制备方法、药物组合物及应用及其中间体。
背景技术
癌症通常也叫恶性肿瘤，是严重威胁人类健康和生命的主要疾病之一，已成为危害人类健康的“第二杀手”(仅次于心血管疾病)。癌症作为一种全身性疾病，药物治疗是一种非常重要的治疗方法，但是目前常用的化疗药物多数具有大的副作用，抗瘤谱狭窄，从而限制了其应用。
例如，赤霉素是一类具有多种生物活性的四环二萜类化合物，广泛存在于微生物和植物体内，作为具有生物活性的基团表现出很强的抗癌活性。但是，目前还没有发现赤霉素类抗癌药物。
因此，寻找特异性高、毒副作用低甚至无毒的抗癌药物已成为药物研究中十分重要的课题。
发明内容
本发明所要解决的技术问题是为了克服现有技术中目前治疗癌症的药物多数具有副作用、抗瘤谱狭窄、从而限制其应用的问题，因而提供了一种类赤霉素化合物、其制备方法、药物组合物、应用及其中间体。本发明提供的类赤霉素化合物具有较好的体外抗肿癌细胞毒活性，尤其对于乳腺癌细胞或结肠癌即系具有显著的体外细胞毒活性。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物：
Figure BDA0001613015610000011
其中，R1为H或卤素；
R2为H、OH或OTs(Ts为对甲苯磺酰基)；
R3为甲基；
Figure BDA0001613015610000021
代表单键或双键；
R6为H或O；
当
Figure BDA0001613015610000022
中
Figure BDA0001613015610000023
代表单键时，R6为H；
当
Figure BDA0001613015610000024
中
Figure BDA0001613015610000025
代表双键时，R6为O；
当
Figure BDA0001613015610000026
中
Figure BDA0001613015610000027
代表单键时，R4为H；R5为取代或未取代的C6-C20的芳基，或取代或未取代的C2-C20的杂芳基；所述取代或未取代的C6-C20的芳基，或取代或未取代的C2-C20的杂芳基中的取代基为
Figure BDA0001613015610000028
其中X选自C，N，S或O(例如C或N)；R为H、卤素、C1-C6的烷基、卤素取代的C1-C6的烷基，或C1-C6的烷氧基；n为1-5的整数；
当
Figure BDA0001613015610000029
中
Figure BDA00016130156100000210
代表双键，R4为O，
Figure BDA00016130156100000211
中
Figure BDA00016130156100000212
代表单键，R6为H时，R5为C2-C6的烷氧基或苄氧基；
当
Figure BDA00016130156100000213
中
Figure BDA00016130156100000214
代表双键，R4为O，
Figure BDA00016130156100000215
中
Figure BDA00016130156100000216
代表双键，R6为O时，R5为C1-C6的烷氧基或苄氧基；
R7为CH2或O；
R8为OH、C1-C6的烷基或C1-C6的烷氧基；
且所述是式I所示的化合物不为如下任一结构所示的化合物：
Figure BDA00016130156100000217
本发明中，所述取代或未取代的C6-C20的芳基可为取代或未取代的C6-C10的芳基，例如取代或未取代的苯基，或取代或未取代的萘基。
本发明中，所述取代或未取代的C2-C20的杂芳基可为含有一个或多个(例如两个)芳杂环，杂原子为N、S或O(例如N)；所述杂原子的个数为1个或多个(例如2或3)的杂芳基，例如所述取代或未取代的C2-C20的杂芳基为含有一个芳杂环，杂原子为氮，所述杂原子的个数为1-3个的取代或未取代的C2-C10的杂芳基(例如为取代或未取代的吡咯，取代或未取代的呋喃，取代或未取代的噻吩，取代或未取代的吡唑，取代或未取代的咪唑，取代或未取代的噁唑，取代或未取代的噻唑，取代或未取代的异噁唑，取代或未取代的吡啶，取代或未取代的哒嗪，取代或未取代的嘧啶，取代或未取代的吡嗪、取代或未取代的1,2,4三氮唑
Figure BDA0001613015610000031
或者取代或未取代的1,2,3三氮唑
Figure BDA0001613015610000032
再例如所述取代或未取代的C2-C20的杂芳基为含有2个环的稠合芳杂基(例如取代或未取代的苯并吲哚，取代或未取代的苯并咪唑，取代或未取代的喹啉，取代或未取代的异喹啉。)
本发明中，所述卤素可为氟、氯、溴或碘，例如溴。
本发明中，所述C1-C6的烷基可为C1-C4的烷基，例如甲基，乙基，丙基，异丙基和正丁基。
本发明中，所述卤素取代的C1-C6的烷基中的卤素取代基的个数可为一个或多个(2个或三个)；所述卤素可为氟。
本发明中，所述C1-C6的烷氧基可为C1-C4的烷氧基，例如甲氧基，乙氧基和丙氧基。
本发明中，当
Figure BDA0001613015610000033
中
Figure BDA0001613015610000034
代表双键，所述R4为O，
Figure BDA0001613015610000035
中
Figure BDA0001613015610000036
代表单键，所述R6为H时，所述R5可为C2-C6的烷氧基；
当
Figure BDA0001613015610000037
中
Figure BDA0001613015610000038
代表双键，所述R4为O，
Figure BDA0001613015610000039
中
Figure BDA00016130156100000310
代表双键，所述R6为O时，所述R5可为C1-C6的烷氧基。
本发明中，所述
Figure BDA00016130156100000311
中，所述n可为1；例如，所述
Figure BDA00016130156100000312
为
Figure BDA00016130156100000313
本发明中，所述R8为OH或C1-C6的烷氧基时，所述
Figure BDA00016130156100000314
可为
Figure BDA00016130156100000315
所述R8为C1-C6的烷基时，所述
Figure BDA00016130156100000316
可为
Figure BDA00016130156100000317
本发明中，所述
Figure BDA00016130156100000318
可为
Figure BDA00016130156100000319
例如，所述
Figure BDA00016130156100000320
为
Figure BDA00016130156100000321
所述
Figure BDA00016130156100000322
为
Figure BDA00016130156100000323
所述
Figure BDA0001613015610000041
为
Figure BDA0001613015610000042
本发明中，所述式I所示的化合物可选自如下式II、式III、式IV或式V所示的化合物中的任一种：
Figure BDA0001613015610000043
其中，R9、R10和R11各自独立地为
Figure BDA0001613015610000044
Figure BDA0001613015610000045
R13、R14、R15、R16、R17、R18和R19各自独立地为H或
Figure BDA0001613015610000046
R20和R21各自独立地为H、
Figure BDA0001613015610000047
或甲基。
R12为C1-C6的烷基；
R1、R2、X、R和C1-C6的烷基的定义均如前所述。
所述R9、R10和R11可各自独立地为
Figure BDA0001613015610000048
Figure BDA0001613015610000049
例如，所述
Figure BDA00016130156100000410
为
Figure BDA00016130156100000411
较佳地，所述式II所示化合物中：
当所述R1为卤素时，所述R为卤素，或者卤素取代的C1-C6的烷基(例如-CF3)；
当所述R1为H，所述R为卤素取代的C1-C6的烷基(例如-CF3)。
较佳地，所述式II所示的化合物中，所述R2为OH。
所述式II所示的化合物的结构可为：
Figure BDA0001613015610000051
各取代基定义如前所述。
所述式III所示化合物中，所述R1可为氢或卤素，例如氢。
所述式III所示化合物中，所述R2可OH或OTs，优选OH。
在本发明一优选实施方式中，所述式III所示的化合物中，所述R2为OH或OTs；所述R1氢；所述R10为
Figure BDA0001613015610000052
例如，所述
Figure BDA0001613015610000053
为
Figure BDA0001613015610000054
所述式III所示的化合物的结构可为：
Figure BDA0001613015610000055
各取代基定义如前所述。
所述式IV所示的化合物中，所述R1可为氢。
所述式IV所示的化合物中，所述R2可为OH或OTs。
在本发明一优选实施方式中，所述式IV所示的化合物中，所述R2为OH或OTs；所述R1氢；所述R11为
Figure BDA0001613015610000056
所述式IV所示的化合物的结构可为：
Figure BDA0001613015610000061
各取代基定义如前所述。
所述式V所示的化合物中，所述R1可为卤素，例如氟。
所述式V所示的化合物中，所述R1可为OH或OTs。
所述式V所示的化合物中，所述R12可为甲基。
在本发明一优选实施方式中，所述式II、式III、式IV或式V所示的化合物中，所述R9、R10和R11各自独立地为
Figure BDA0001613015610000062
R13、R14、R15、R16、R17、R18和R19、R20和R21各自独立地为H或
Figure BDA0001613015610000063
R20和R21各自独立地为甲基；其余各取代基定义如前所述。
在本发明一优选实施方式中，所述式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物中，
所述R1为H或卤素；
所述R2为H、OH或OTs；
所述R3为甲基；
Figure BDA0001613015610000064
代表单键或双键；
当所述
Figure BDA0001613015610000065
中
Figure BDA0001613015610000066
代表单键时，所述R6为H；
当所述
Figure BDA0001613015610000067
中
Figure BDA0001613015610000068
代表双键时，R6为O；
当所述
Figure BDA0001613015610000069
中
Figure BDA00016130156100000610
代表单键时，R4为H；R5为取代或未取代的C6-C20的芳基，或取代或未取代的C2-C20的杂芳基；所述取代或未取代的C6-C20的芳基，和取代或未取代的C2-C20的杂芳基中的取代基为
Figure BDA00016130156100000611
其中X选自C，N，S或O(例如C或N)；R选自H、卤素、C1-C6的烷基、卤素取代的C1-C6的烷基或C1-C6的烷氧基；n为1；
当
Figure BDA0001613015610000071
中
Figure BDA0001613015610000072
代表双键，R4为O，
Figure BDA0001613015610000073
中
Figure BDA0001613015610000074
代表单键，R6为H时，R5为C2-C6的烷氧基或苄氧基；
当
Figure BDA0001613015610000075
中
Figure BDA0001613015610000076
代表双键，R4为O，
Figure BDA0001613015610000077
中
Figure BDA0001613015610000078
代表双键，R6为O时，R5为C1-C6的烷氧基或苄氧基；
R7为CH2或O；
所述R8为OH或C1-C6的烷氧基时，所述
Figure BDA0001613015610000079
为
Figure BDA00016130156100000710
所述R8为C1-C6的烷基时，所述
Figure BDA00016130156100000711
为
Figure BDA00016130156100000712
在本发明一优选实施方式中，所述式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物中，所述取代或未取代的C6-C20的芳基为取代或未取代的C6-C10的芳基；所述取代或未取代的C2-C20的杂芳基为含有一个芳杂环，杂原子为氮，所述杂原子的个数为1-3个的取代或未取代的C2-C10的杂芳基，或者所述取代或未取代的C2-C20的杂芳基为含有2个环的稠合芳杂基；所述
Figure BDA00016130156100000713
为
Figure BDA00016130156100000714
Figure BDA00016130156100000715
其他各基团及取代基定义如前所述。
在本发明一优选实施方式中，所述式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物中，所述取代或未取代的C6-C20的芳基为取代或未取代的C6-C10的芳基；所述取代或未取代的C2-C20的杂芳基为含有一个芳杂环，杂原子为氮，所述杂原子的个数为1-3个的取代或未取代的C2-C10的杂芳基，或者所述取代或未取代的C2-C20的杂芳基为含有2个环的稠合芳杂基；所述
Figure BDA0001613015610000081
为
Figure BDA0001613015610000082
Figure BDA0001613015610000083
所述
Figure BDA0001613015610000084
为
Figure BDA0001613015610000085
所述
Figure BDA0001613015610000086
为
Figure BDA0001613015610000087
所述
Figure BDA0001613015610000088
为
Figure BDA0001613015610000089
其他各基团定义如前所述。
在本发明一优选实施方式中，所述式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物中，所述取代或未取代的C6-C20的芳基为取代或未取代的苯基，或取代或未取代的萘基；所述取代或未取代的C2-C20的杂芳基为取代或未取代的吡咯，取代或未取代的呋喃，取代或未取代的噻吩，取代或未取代的吡唑，取代或未取代的咪唑，取代或未取代的噁唑，取代或未取代的噻唑，取代或未取代的异噁唑，取代或未取代的吡啶，取代或未取代的哒嗪，取代或未取代的嘧啶，取代或未取代的吡嗪、取代或未取代的1,2,4三氮唑
Figure BDA00016130156100000810
取代或未取代的1,2,3三氮唑
Figure BDA00016130156100000811
取代或未取代的苯并吲哚，取代或未取代的苯并咪唑，取代或未取代的喹啉，或取代或未取代的异喹啉；所述R8为OH或C1-C6的烷氧基时，所述
Figure BDA00016130156100000812
为
Figure BDA00016130156100000813
所述R8为C1-C6的烷基时，所述
Figure BDA00016130156100000814
为
Figure BDA00016130156100000815
其他各基团定义如前所述。
在本发明一优选实施方式中，所述式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物中，所述取代或未取代的C6-C20的芳基为取代或未取代的苯基，或取代或未取代的萘基；所述取代或未取代的C2-C20的杂芳基为取代或未取代的吡咯，取代或未取代的呋喃，取代或未取代的噻吩，取代或未取代的吡唑，取代或未取代的咪唑，取代或未取代的噁唑，取代或未取代的噻唑，取代或未取代的异噁唑，取代或未取代的吡啶，取代或未取代的哒嗪，取代或未取代的嘧啶，取代或未取代的吡嗪、取代或未取代的1,2,4三氮唑
Figure BDA0001613015610000091
取代或未取代的1,2,3三氮唑
Figure BDA0001613015610000092
取代或未取代的苯并吲哚，取代或未取代的苯并咪唑，取代或未取代的喹啉，或取代或未取代的异喹啉；所述
Figure BDA0001613015610000093
为
Figure BDA0001613015610000094
所述
Figure BDA0001613015610000095
为
Figure BDA0001613015610000096
所述
Figure BDA0001613015610000097
为
Figure BDA0001613015610000098
所述
Figure BDA0001613015610000099
为
Figure BDA00016130156100000910
其他各基团定义如前所述。
本发明中，所述式II所示的化合物可选自下列任一化合物：
Figure BDA0001613015610000101
Figure BDA0001613015610000111
本发明中，所述式III所示的化合物可选自下列任一化合物：
Figure BDA0001613015610000121
本发明中，所述式IV所示的化合物可选自下列任一化合物：
Figure BDA0001613015610000131
本发明中，所述式V所示的化合物可选自下列任一化合物：
Figure BDA0001613015610000132
本发明还提供了一种如式I所示的赤霉素衍生物制备方法，其包括以下步骤：
方法1：在铜的催化作用下，将式VI所示的化合物式VII所示的化合物进行环加成反应，得到式I所示化合物即可；
Figure BDA0001613015610000141
或方法2：
Figure BDA0001613015610000142
各取代基定义如前所述。
所述方法1中，所述环加成反应的操作及方法可参考本领域的常规操作及方法；例如参照V.V.Rostovtsev,L.G.Green,V.V.Fokin and K.B.Sharpless,Angewandte Chemie,2002,41,2596-2599记载的操作及方法。
例如，制备路线1：
Figure BDA0001613015610000151
本发明一优选实施方式中，以赤霉素(GA3)为原料，与硫酸二甲酯、碳酸钾和丙酮反应合成赤霉素(GA3)甲酯，经过戴斯-马丁氧化得到羰基赤霉素甲酯，(具体操作可参考J.Chen,Z.Sun,Y.Zhang,X.Zeng,C.Qing,J.Liu,L.Li and H.Zhang,Bioorganic&medicinal chemistry letters,2009,19,5496-5499)；然后与四三苯基膦钯、蒽醌-2-磺酸钠、二甲亚砜和水，在80℃反应12h得到芳构化产物，(具体操作可参考J.R.Annand,P.A.Bruno,A.K.Mapp and C.S.Schindler,Chemical communications,2015,51,8990-8993)，四氢铝锂还原芳构化产物并用对甲苯磺酰氯保护伯羟基得到磺酸酯化合物，用叠氮化钠和N，N-二甲基甲酰胺在80℃下反应3h得到叠氮化合物，最后在抗坏血酸钠、醋酸铜、四氢呋喃和水的作用下，发生铜催化的叠氮-炔基Husigen环加成反应制备化合物C1-C8。例如，制备路线2：
Figure BDA0001613015610000161
本发明一优选实施方式中，以赤霉素(GA3)为原料，与1.2M盐酸，在65℃下反应2.5h得到芳构化产物，在硫酸二甲酯、碳酸钾和丙酮的作用下得到芳构化的赤霉素(GA3)甲酯化合物，通过四氢铝锂还原酯基和对甲苯磺酰氯保护伯羟基得到磺酸酯化合物，用叠氮化钠将磺酸酯叠氮化，最后经过铜催化的叠氮-炔基Husigen环加成反应制备化合物C9-C16。(具体操作可参考R.W.Huigens,3rd,K.C.Morrison,R.W.Hicklin,T.A.Flood,Jr.,M.F.Richter and P.J.Hergenrother,Nature chemistry,2013,5,195-202；和V.V.Rostovtsev,L.G.Green,V.V.Fokin and K.B.Sharpless,Angewandte Chemie,2002,41,2596-2599。)
例如，制备路线3：
Figure BDA0001613015610000171
本发明一优选实施方式中，合合成的芳构化产物8，用叔丁基二甲基氯硅烷保护酚羟基，四氢铝锂还原酯基，对甲苯磺酰氯保护伯羟基，四正丁基氟化胺脱去叔丁基二甲基硅醚保护，叠氮化钠将磺酸酯叠氮化，最后经过铜催化的叠氮-炔基Husigen环加成反应制备化合物C17-C24。
例如，制备路线4：
Figure BDA0001613015610000172
本发明一优选实施方式中，合成的叠氮化合物21与N-溴代丁二酰亚胺、二异丙基胺和二氯甲烷反应得到溴代化合物，再经过铜催化的叠氮-炔基Husigen环加成反应制备化合物C25-C31。
例如，制备路线5：
Figure BDA0001613015610000181
本发明一优选实施方式中，合成的磺酸酯化合物10与二氧化硒、过氧叔丁醇和二氯甲烷反应得到烯丙醇化合物23和含酮化合物24；烯丙醇化合物经叠氮化反应得到叠氮化合物25，再经过铜催化的叠氮-炔基Husigen环加成反应和戴斯-马丁氧化制备化合物C32-C39；同样，化合物24经过叠氮化反应和铜催化的叠氮-炔基Husigen环加成反应制备C48-C55。
例如，制备路线6：
Figure BDA0001613015610000191
本发明一优选实施方式中，合成硅醚保护的化合物17与过氧叔丁醇、二氧化硒和二氯甲烷反应得到烯丙醇化合物29，用四氢铝锂还原甲酯，对甲苯磺酰氯活化伯羟基，叠氮化钠将磺酸酯转化为叠氮化合物32；叠氮化合物经过铜催化的叠氮-炔基Husigen环加成反应，戴斯-马丁氧化和四正丁基氟化胺脱去叔丁基二甲基硅醚保护得到化合物C40-C47。
例如，制备路线7：
Figure BDA0001613015610000192
本发明一优选实施方式中，合成的酚类化合物20与二氧化硒、过氧叔丁醇和二氯甲烷反应得到酮化合物27，经过叠氮化反应和铜催化的叠氮-炔基Husigen环加成反应制备C56-C62。
根据本发明公开的上述制备方法，本领域技术人员可采用与之相同的原理和方法，制得本发明的通式化合物II、III、IV或V中涉及的各具体化合物。
本发明还提供了一种药物组合物，其包括治疗有效量的如式I所示的类赤霉素衍生物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，和一种或多种药学上可接受的载体或赋形剂。
本发明还提供了如式I所示的类赤霉素衍生物在制备治疗和/或预防抗肿瘤药物中的应用。
所述抗肿瘤药物可为抗乳腺癌药物和/或抗肠癌药物。
本发明还提供了如下所示的式I所示类赤霉素衍生物的中间体：
Figure BDA0001613015610000201
本发明中，所述的确定了碳数范围的“Cx1-Cy1”的取代基(x1和y1为整数)、如“Cx1-Cy1”烷基、“Cx1-Cy1”的烷氧基、“Cx1-Cy1”芳基或“Cx1-Cy1”杂芳基，均表示未包含取代基的碳数，例如C1-C10烷基表示未包含取代基的C1-C10烷基。
关于任一基团包含一个或多个取代基，本领域一般技术人员均可理解，但不包括不切实际的高位阻、合成上不可行的和/或内在不稳定的取代基。
本发明中，所用的术语“药学上可接受的盐”指药学上可接受的与酸或与碱形成的盐和溶剂化物。这类药学上可接受的盐包括但不限于与无机酸形成的盐，如盐酸盐、磷酸盐、二磷酸盐、氢溴酸盐、硫酸盐、亚磺酸盐、硝酸盐、及其类似盐；也包括与有机酸形成的盐，如苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、醋酸盐、乳酸盐、磺酸盐、对甲苯磺酸盐、2-羟基乙基磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和链烷酸盐如醋酸盐，HOOC-(CH2)n-COOH其中n为0-4的盐，及其类似盐。类似地，药学上可接受的阳离子包括但不限于钠、钾、钙、铝、锂和铵。本领域的成熟技术人员可识别各种可能用来制备无毒的药学上可接受的盐的合成方法。
本发明中，所述的“溶剂化物”如“水合物”，是由溶剂和化合物互相作用形成。术语“化合物”，应该包括了化合物的溶剂化物(包括化合物的水合物)。同样，“盐”也包括了盐的溶剂化物(如盐的水合物)。合适的溶剂化物是药学上可接受的，例如水合物，它包括了单水合物和半水合物。
本发明中，所述的“预防和/或治疗有效剂量”表示(i)预防和/或治疗本申请所述的具体疾病或病症的本发明化合物的量，(ii)削弱、改善或消除本申请所述的具体疾病或病症的一种或多种症状的本发明化合物的量，或(iii)预防或延迟本申请所述的具体疾病或病症的一种或多种症状的发作的本发明化合物的量。
在不违背本领域常识的基础上，上述各优选条件，可任意组合在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的类赤霉素衍生物具有较好的抗肿瘤活性。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
C1-C8的制备反应式如下：
Figure BDA0001613015610000221
上述制备方法步骤如下：
化合物5的合成：
将赤霉酸(GA3)(5.19g,15mmol)溶于丙酮(80mL)中，在0℃下加入硫酸二甲酯(1.80g,14.3mmol)和无水碳酸钾(4.14g,30mmol)，加完后移除冰水浴，室温反应10h，TLC监测反应完毕后，减压蒸出反应液，加入50mL水，水相用乙酸乙酯(3×100mL)萃取，合并有机相，依次用水(40mL)、饱和食盐水(2×40mL)洗，用无水硫酸钠干燥有机相，减压蒸干得白色固体，即化合物5，5.31g，粗产物未经柱层析直接做下一步反应。
化合物6的合成：
将化合物5(5.31g,14.75mmol)溶于二氯甲烷(140mL)中，缓慢的加入戴斯-马丁氧化剂(6.88g,16.23mmol)，室温反应8h,反应完毕后，加入80mL水，碳酸氢钠(4eq)，硫代硫酸钠(4eq)，搅拌至溶液澄清。用二氯甲烷(3×100mL)萃取，合并有机相，依次用水(2×40mL)和饱和食盐水(2×40mL)洗，用无水硫酸钠干燥有机相，减压蒸干得白色固体即化合物6，4.14g。粗产物未经柱层析直接做下一步反应。
化合物8的合成：
在氮气保护下，将化合物6(4.14g,11.56mmol)、四三苯基膦钯(535mg,0.46mmol)、蒽醌-2-磺酸钠(538mg,1.73mmol)、二甲亚砜(60ml)和水(20ml)混合，在80℃下反应16h，反应毕后，加入60mL水，水相用乙酸乙酯(3×120mL)萃取，合并有机相，依次用水(3×40mL)、饱和食盐水(3×40mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体2.31g。从赤霉酸(GA3)为原料合成化合物8的三步总收率为49％。
1H NMR(400MHz,CDCl3)δ:6.77(d,J＝7.9Hz,1H),6.62(d,J＝7.9Hz,1H),6.16(s,1H),5.17(t,J＝2.4Hz,1H),5.02(t,J＝1.9Hz,1H),3.66(s,3H),3.62(s,1H),3.33(dd,J＝8.4,2.5Hz,1H),2.73(dt,J＝16.3,3.0Hz,1H),2.54-2.22(m,2H),2.09(s,3H),2.04(dt,J＝6.4,4.1Hz,1H),1.92(ddt,J＝15.0,10.3,8.0Hz,1H),1.75(dtd,J＝20.0,10.5,9.3,6.5Hz,2H),1.60(dd,J＝10.7,2.6Hz,1H),1.56-1.45(m,1H).13C NMR(100MHz,CDCl3)δ:173.08,155.19,152.92,140.97,138.19,121.84,120.09,114.30,106.89,78.78,56.53,54.04,51.95,48.64,47.53,38.57,38.35,21.16,12.27.
化合物9的合成：
在氮气保护下，将化合物8(4.14g，13.18mmol)溶于无水的四氢呋喃(100mL)中，在冰水浴的条件下分批加入四氢铝锂(1.00g，26.36mmol)，加完后撤去冰水浴，在室温反应4h，反应结束，缓慢加入40mL冰水，水相用乙酸乙酯(3×110mL)萃取，合并有机相，依次用水(2×30mL)、饱和食盐水(2×30mL)洗，用无水硫酸钠干燥有机相，减压蒸干得白色固体3.53g，粗产物未经柱层析直接做下一步反应。
化合物10的合成：
将化合物9(3.53g，12.34mmol)溶于无水的二氯甲烷(100mL)中，分别加入二异丙基乙胺(3.98g，30.85mmol)、对甲苯磺酰氯(4.92g，25.91mmol)、4-二甲氨基吡啶(301mg，2.47)，在室温反应8h，反应结束，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物10，5.25g。两步的总收率为67％。
1H NMR(300MHz,CDCl3)δ:7.77-7.65(m,2H),7.66-7.57(m,2H),7.31(dd,J＝10.9,8.1Hz,4H),6.84(s,2H),5.14(d,J＝2.4Hz,1H),5.00(s,1H),4.22-3.85(m,2H),3.04(d,J＝7.9Hz,1H),2.97(dd,J＝7.4,4.5Hz,1H),2.75(dt,J＝16.5,2.9Hz,1H),2.43(d,J＝8.6Hz,7H),2.21(s,1H),2.14-2.03(m,1H),1.84(s,3H),1.70-1.57(m,2H),1.46(d,J＝10.8Hz,1H),1.33(dd,J＝10.7,2.6Hz,1H),0.85(dq,J＝7.0,3.5,3.0Hz,1H).13C NMR(75MHz,CDCl3)δ:154.76,146.96,145.48,145.00,144.47,142.20,132.84,132.29,129.85,129.76,128.89,128.22,127.65,121.44,120.11,106.90,77.79,67.85,52.98,49.70,48.59,46.73,38.19,37.62,21.64,21.55,20.55,12.65.
化合物11的合成：
将化合物10(5.25g，8.82mmol)和叠氮化钠(1.72g，26.46mmol)溶于无水的N,N-二甲基甲酰胺(80mL)。在氮气保护下，80℃反应4h，反应毕后，加入50mL水，水相用乙酸乙酯(3×130mL)萃取，合并有机相，依次用水(3×40mL)、饱和食盐水(4×40mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物11，3.08g。产率为75％。
1H NMR(400MHz,CDCl3)δ:7.70(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,2H),6.86(t,J＝5.6Hz,2H),5.16(t,J＝2.3Hz,1H),5.06(s,1H),3.42(dd,J＝12.7,7.3Hz,1H),3.35(dd,J＝12.6,5.1Hz,1H),3.15(d,J＝8.1Hz,1H),2.86(dd,J＝7.2,5.2Hz,1H),2.79(dt,J＝16.3,3.0Hz,1H),2.51(d,J＝2.5Hz,1H),2.44(s,3H),2.17-2.06(m,1H),2.00(s,3H),1.97-1.83(m,2H),1.66(dd,J＝10.3,4.5Hz,2H),1.47(d,J＝10.8Hz,1H),1.38(dd,J＝10.8,2.7Hz,1H).13C NMR(100MHz,CDCl3)δ155.02,147.16,145.41,144.34,144.16,133.00,129.79,128.78,128.46,121.49,120.19,107.06,78.14,53.43,50.60,50.11,48.96,46.84,38.34,37.83,21.78,20.73,12.99。
化合物C1的制备：
将化合物11(50mg，0.11mmol)、苯乙炔(22.4mg，0.22mmol)、醋酸铜(33.0mg，0.17mmol)、抗坏血酸钠(43.6mg，0.22mmol)、四氢呋喃(8mL)和水(2mL)混合，反应5h，反应结束，加入10mL水，水相用乙酸乙酯(3×20mL)萃取，合并有机相，依次用水(2×8mL)、饱和食盐水(2×8mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C1，38.4mg，收率61％。熔点:109-111℃。
IRνmax(cm-1):3418,2928,2859,1733,1597,1467,1369,1171,1093,814.87,715,553.HRMS(ESI)m/z calculated for C33H34O4N3S[M+H]+:568.2265,found:568.2264.1H NMR(400MHz,CDCl3)δ:7.75(d,J＝7.4Hz,2H),7.69(d,J＝8.1Hz,2H),7.38(t,J＝7.5Hz,2H),7.31(d,J＝7.3Hz,1H),7.27-7.24(m,2H),7.23(s,1H),6.83(d,J＝8.1Hz,1H),6.77(d,J＝8.1Hz,1H),5.16(d,J＝2.5Hz,1H),5.06(s,1H),4.62(dd,J＝14.2,6.0Hz,1H),4.51(dd,J＝14.2,5.8Hz,1H),3.34(t,J＝5.9Hz,1H),2.80-2.67(m,2H),2.66-2.56(m,1H),2.43(s,3H),2.05(dt,J＝15.2,4.4Hz,2H),1.95-1.81(m,4H),1.64(dt,J＝12.7,6.1Hz,2H),1.55(d,J＝10.8Hz,1H),1.41(dd,J＝10.8,2.6Hz,1H).13C NMR(100MHz,CDCl3)δ:154.54,147.77,147.24,145.42,144.65,143.74,133.23,130.35,129.82,129.21,128.81,128.27,128.18,125.73,121.48,120.61,120.51,107.37,78.06,53.70,50.99,49.49,49.29,46.55,38.23,37.39,21.71,20.71,12.78.
化合物C2的制备：
制备方法同化合物C1，将苯乙炔改成4-溴苯乙炔，得白色固体即化合物C2，41.3mg，收率58％，熔点:118-121℃。
IRνmax(cm-1):3416,2928,2861,1597,1468,1367,1195,1171,1045,834,554.HRMS(ESI)m/z calculated for C33H33O4N3Br S[M+H]+:646.1370,found:[M+H]+646.1372,[M+2+H]+648.1336.1H NMR(400MHz,CDCl3)δ:7.68(d,J＝8.2Hz,2H),7.67–7.57(m,2H),7.53–7.43(m,2H),7.31–7.27(m,3H),6.84(d,J＝8.1Hz,1H),6.76(d,J＝8.1Hz,1H),5.17(t,J＝2.3Hz,1H),5.05(d,J＝2.4Hz,1H),4.62(dd,J＝14.1,5.9Hz,1H),4.48(dd,J＝14.2,6.1Hz,1H),3.33(t,J＝6.0Hz,1H),2.71(dd,J＝18.9,5.1Hz,2H),2.61(dt,J＝16.1,2.9Hz,1H),2.44(s,3H),2.24(d,J＝3.5Hz,1H),2.07(dd,J＝9.2,5.8Hz,1H),1.99–1.87(m,1H),1.87(s,3H),1.64(dd,J＝10.8,4.8Hz,2H),1.56(d,J＝10.8Hz,1H),1.40(dd,J＝10.8,2.6Hz,1H).13C NMR(100MHz,CDCl3)δ:154.48,147.13,146.69,145.56,144.67,143.76,133.14,131.92,129.89,129.34,129.27,128.21,127.30,122.01,121.46,120.92,120.54,107.41,77.98,53.70,50.95,49.55,49.15,46.53,38.27,37.40,21.77,20.69,12.78.
化合物C3的制备：
制备方法同化合物C1，将苯乙炔改成4-甲氧基苯乙炔，得白色固体即化合物C3，42.1mg，收率64％，熔点:112-113℃。
IRνmax(cm-1):3417,2929,1618,1500,1467,1368,1249,1171,1093,836,554.HRMS(ESI)m/z calculated for C34H36O5N3S[M+H]+:598.2370,found:598.2368.1H NMR(400MHz,CDCl3)δ:7.68(ddd,J＝8.5,5.2,2.4Hz,4H),7.28(d,J＝1.5Hz,2H),7.18(s,1H),6.96–6.86(m,2H),6.84(d,J＝8.2Hz,1H),6.78(d,J＝8.1Hz,1H),5.16(t,J＝2.4Hz,1H),5.04(d,J＝2.5Hz,1H),4.59(dd,J＝14.1,6.0Hz,1H),4.45(dd,J＝14.1,5.9Hz,1H),3.80(s,3H),3.33(t,J＝6.0Hz,1H),2.73(d,J＝8.5Hz,1H),2.70–2.64(m,1H),2.61(t,J＝2.9Hz,1H),2.43(s,3H),2.19(d,J＝4.6Hz,1H),2.05(dt,J＝9.0,4.2Hz,1H),1.96–1.87(m,1H),1.86(s,3H),1.70–1.60(m,2H),1.55(d,J＝10.9Hz,1H),1.39(dd,J＝11.1,2.6Hz,1H).13CNMR(100MHz,CDCl3)δ:159.63,154.63,147.62,147.19,145.49,144.69,143.91,133.20,129.87,129.22,128.29,127.06,123.14,121.45,120.50,119.88,114.26,107.34,78.01,55.38,53.73,51.00,49.42,49.22,46.54,38.28,37.39,21.76,20.71,12.75.
化合物C4的制备：
制备方法同化合物C1，将苯乙炔改成2-乙炔基吡啶，经柱层析(石油醚/乙酸乙酯＝1:2)得白色固体即化合物C4，33.8mg，收率：54％，熔点:108-122℃。
IRνmax(cm-1):3416,2927,2857,1598,1470,1369,1195,1172,1044,836,784,554.HRMS(ESI)m/z calculated for C32H33O4N4S[M+H]+:569.2217,found:569.2215.1H NMR(400MHz,CDCl3)δ:8.53(dt,J＝4.8,1.3Hz,1H),8.14(d,J＝7.9Hz,1H),7.83(s,1H),7.80–7.70(m,3H),7.35–7.28(m,2H),7.22(ddd,J＝7.6,4.8,1.2Hz,1H),6.87(d,J＝8.2Hz,1H),6.82(d,J＝8.1Hz,1H),5.13(d,J＝2.6Hz,1H),5.01(d,J＝2.1Hz,1H),4.60(dd,J＝14.2,7.4Hz,1H),4.41(dd,J＝14.2,5.4Hz,1H),3.38(dd,J＝7.4,5.3Hz,1H),2.91(d,J＝8.0Hz,1H),2.63(dd,J＝16.2,2.7Hz,1H),2.48–2.38(m,4H),2.34(s,1H),2.10(dd,J＝14.8,4.4Hz,1H),1.97–1.77(m,4H),1.70–1.61(m,2H),1.53(d,J＝10.8Hz,1H),1.38(dd,J＝10.7,2.8Hz,1H).13C NMR(100MHz,CDCl3)δ:154.59,150.02,149.40,148.42,147.26,145.45,144.27,143.63,136.99,133.05,129.84,128.97,128.50,123.00,122.77,121.76,120.45,120.31,107.36,77.89,53.75,50.91,49.25,49.20,46.46,38.25,37.22,21.78,20.65,12.62.
化合物C5的制备：
制备方法同化合物C1，将苯乙炔改成4-三氟甲基苯乙炔，得白色固体即化合物C5，39.3mg，收率56％，熔点:114-116℃。
IRνmax(cm-1):3420,2930,2862,1622,1468,1326,1171,1123,1064,850,554.HRMS(ESI)m/z calculated for C34H33O4N3F3S[M+H]+:636.2138,found:636.2138.1H NMR(400MHz,CDCl3)δ:7.89(d,J＝8.1Hz,2H),7.75–7.67(m,2H),7.64(d,J＝8.2Hz,2H),7.40–7.18(m,3H),6.84(d,J＝8.1Hz,1H),6.77(d,J＝8.1Hz,1H),5.19(t,J＝2.5Hz,1H),5.10(s,1H),4.68(dd,J＝14.2,5.7Hz,1H),4.57(dd,J＝14.2,5.8Hz,1H),3.37(t,J＝5.8Hz,1H),2.83–2.74(m,1H),2.73–2.63(m,2H),2.45(s,3H),2.15–2.02(m,1H),1.94(s,3H),1.87(q,J＝7.1,5.7Hz,1H),1.66(dd,J＝10.6,4.6Hz,2H),1.58(d,J＝10.9Hz,1H),1.45(dd,J＝10.8,2.6Hz,1H).13C NMR(100MHz,CDCl3)δ:154.46,147.20,146.42,145.55,144.74,143.61,133.80,133.20,130.10,129.85,129.78,129.45,129.35,128.20,125.87,125.83,125.80,125.76,125.72,125.44,122.73,121.55,120.60,107.47,78.07,53.69,51.01,49.66,49.31,46.59,38.25,37.45,21.70,20.73,12.88.
化合物C6的制备：
制备方法同化合物C1，将苯乙炔改成4-甲基苯乙炔，得白色固体即化合物C6，37.8mg，收率59％，熔点:194-196℃。
IRνmax(cm-1):3423,2920,1654,1378,1325,1171,1126,891,839,813,769,551.HRMS(ESI)m/z calculated for C34H36O4N3S[M+H]+:582.2421,found:582.2418.1H NMR(400MHz,CDCl3)δ:7.85–7.74(m,2H),7.73–7.64(m,2H),7.42–7.29(m,2H),7.26(t,J＝4.0Hz,3H),6.90(d,J＝8.2Hz,1H),6.85(d,J＝8.1Hz,1H),5.23(t,J＝2.4Hz,1H),5.12(d,J＝2.2Hz,1H),4.67(dd,J＝14.2,6.1Hz,1H),4.55(dd,J＝14.2,5.8Hz,1H),3.40(t,J＝5.9Hz,1H),2.87–2.72(m,2H),2.67(dt,J＝16.2,2.9Hz,1H),2.50(s,3H),2.42(s,3H),2.12(dt,J＝15.0,4.4Hz,1H),2.00(d,J＝13.5Hz,1H),1.95(s,3H),1.96–1.80(m,1H),1.78–1.66(m,2H),1.61(d,J＝10.9Hz,1H),1.47(dd,J＝10.7,2.7Hz,1H).
13C NMR(100MHz,CDCl3)δ:154.67,147.91,147.29,145.50,144.72,143.88,138.10,133.29,129.90,129.56,129.26,128.37,127.64,125.71,121.56,120.56,120.30,107.43,78.11,53.78,51.06,49.50,49.37,46.60,38.31,37.45,21.81,21.36,20.78,12.82.
化合物C7的制备：
制备方法同化合物C1，将苯乙炔改成4-氯苯乙炔，得白色固体即化合物C7，36.4mg，收率55％，熔点:112-115℃。
IRνmax(cm-1):3416,2927,2862,1597,1467,1369,1195,1171,1093,1045,836,554.HRMS(ESI)m/z calculated for C33H33O4N3ClS[M+H]+:602.1875,found:602.1877.1HNMR(400MHz,CDCl3)δ:7.82–7.60(m,4H),7.39–7.32(m,2H),7.29(d,J＝8.1Hz,2H),7.23(s,1H),6.85(d,J＝8.1Hz,1H),6.77(d,J＝8.1Hz,1H),5.18(t,J＝2.5Hz,1H),5.07(d,J＝2.2Hz,1H),4.64(dd,J＝14.1,5.9Hz,1H),4.51(dd,J＝14.2,5.9Hz,1H),3.35(t,J＝5.9Hz,1H),2.79–2.69(m,2H),2.68–2.59(m,1H),2.45(s,3H),2.11–2.02(m,1H),1.98–1.82(m,5H),1.72–1.61(m,2H),1.56(d,J＝10.9Hz,1H),1.43(dd,J＝10.9,2.6Hz,1H).
13C NMR(100MHz,CDCl3)δ:154.57,147.26,146.82,145.60,144.75,143.79,133.95,133.28,129.94,129.37,129.06,128.97,128.30,127.08,121.58,120.88,120.62,107.50,78.12,53.79,51.06,49.63,49.34,46.64,38.33,37.50,21.82,20.80,12.89.
化合物C8的制备：
制备方法同化合物C1，将苯乙炔改成4-氟苯乙炔，得白色固体即化合物C8，36.7mg，收率57％，熔点:109-112℃。
IRνmax(cm-1):3424,2929,2862,1597,1561,1497,1467,1368,1224,1171,1094,1045,841,554.HRMS(ESI)m/z calculated for C33H33O4N3FS[M+H]+:586.2170,found:586.2168.1H NMR(400MHz,CDCl3)δ:7.82–7.60(m,4H),7.28(d,J＝8.2Hz,2H),7.19(s,1H),7.12–6.97(m,2H),6.84(d,J＝8.1Hz,1H),6.76(d,J＝8.1Hz,1H),5.17(t,J＝2.4Hz,1H),5.07(d,J＝2.1Hz,1H),4.63(dd,J＝14.2,5.9Hz,1H),4.50(dd,J＝14.1,5.9Hz,1H),3.34(t,J＝5.9Hz,1H),2.80–2.68(m,2H),2.68–2.56(m,1H),2.44(s,3H),2.06(dt,J＝14.7,4.3Hz,1H),2.02–1.73(m,5H),1.65(dd,J＝10.6,4.5Hz,2H),1.56(d,J＝10.8Hz,1H),1.42(dd,J＝10.7,2.7Hz,1H).13C NMR(100MHz,CDCl3)δ:163.87,161.42,154.52,147.18,146.93,145.51,144.67,143.74,133.20,129.85,129.30,128.23,127.52,127.44,126.61,121.48,120.53,120.45,115.86,115.64,107.42,78.05,53.71,50.99,49.52,49.29,46.56,38.25,37.42,21.73,20.71,12.81.
C9-C16的制备反应式如下：
Figure BDA0001613015610000281
上述制备方法步骤如下：
化合物12的合成：
将赤霉酸(GA3)(5.19g,15mmol)和1.2M的盐酸(30mL)混合，在氮气保护下，65℃反应3h，反应结束后，，加入20mL冰水冷却，抽滤，水洗，干燥得到白色固体，即化合物12，2.81g，收率66％，未经进一步处理直接做下一步反应。
化合物13的合成：
将化合物12(2.81g，9.89mmol)溶于丙酮(75mL)中，在冰水浴下加入硫酸二甲酯(1.18g,9.40mmol)和碳酸钾(2.73g,19.78mmol)，加完后撤去冰水浴，室温反应10h，反应完毕后，减压蒸出反应液，加入40mL水，水相用乙酸乙酯(3×80mL)萃取，合并有机相，依次用水(30mL)、饱和食盐水(2×40mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物13，2.42g，收率82％。
1H NMR(400MHz,CDCl3)δ:7.14(t,J＝7.5Hz,1H),7.02(d,J＝7.6Hz,1H),6.94(d,J＝7.3Hz,1H),5.01(d,J＝2.6Hz,1H),4.78(d,J＝2.2Hz,1H),3.98(s,1H),3.78(s,3H),2.82(dd,J＝12.5,5.0Hz,1H),2.31–2.10(m,7H),2.05–1.87(m,3H),1.73(ddd,J＝11.9,4.8,2.3Hz,1H),1.60(qd,J＝12.8,5.2Hz,1H).13C NMR(100MHz,CDCl3)δ:171.94,154.42,144.47,138.36,135.06,129.04,127.52,119.79,103.37,80.61,77.47,77.16,76.84,54.83,53.47,52.14,51.89,48.83,39.46,34.28,22.08,19.80.
化合物14的合成：
在氮气保护下，将化合物13(2.41g，8.12mmol)溶于无水的四氢呋喃(65mL)中，在冰水浴的条件下，分批加入四氢铝锂(617mg，16.24mmol)，加完后移除冰水浴，在室温反应3.5h，反应结束，缓慢加入30mL冰水，水相用乙酸乙酯(3×90mL)萃取，合并有机相，依次用水(2×30mL)、饱和食盐水(2×30mL)洗，用无水硫酸钠干燥有机相，减压蒸干，得粗产物1.78g，粗产物未经柱层析直接做下一步反应。
化合物15的合成：
将化合物14(1.78g，6.59mmol)溶于无水的二氯甲烷(50mL)中，分别加入二异丙基乙胺(1.28g，12.75mmol)、对甲苯磺酰氯(1.50g，7.91mmol)、4-二甲氨基吡啶(160.8mg，1.32)，在室温反应7.5h，反应结束，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝3:1)得白色粉末即化合物15，2.31g。两步的总收率为67％。
1H NMR(400MHz,CDCl3)δ:7.91–7.77(m,2H),7.35(d,J＝8.1Hz,2H),7.04(t,J＝7.4Hz,1H),6.87(dd,J＝7.5,4.5Hz,2H),5.04(d,J＝2.5Hz,1H),4.81(dd,J＝10.1,5.3Hz,1H),4.69(d,J＝1.9Hz,1H),4.22(dd,J＝10.1,8.7Hz,1H),3.36(dd,J＝8.6,5.3Hz,1H),2.64(dd,J＝12.5,5.0Hz,1H),2.49(d,J＝27.9Hz,1H),2.43(s,3H),2.30–2.10(m,5H),2.00–1.85(m,2H),1.84–1.74(m,2H),1.70(ddd,J＝12.0,5.2,2.6Hz,1H),1.46(qd,J＝12.7,5.3Hz,1H).
13C NMR(100MHz,CDCl3)δ:154.24,145.02,144.96,138.77,133.60,132.43,129.91,129.35,127.90,127.01,120.00,103.51,79.78,68.84,53.08,51.30,49.02,47.68,39.19,31.30,21.80,21.57,20.64.
化合物16的合成：
将化合物15(2.31g，5.44mmol)和叠氮化钠(1.06g，16.32mmol)溶于无水的N,N-二甲基甲酰胺(40mL)。在氮气保护下，80℃反应3.8h，反应结束后，加入25mL水，水相用乙酸乙酯(3×75mL)萃取，合并有机相，依次用水(3×20mL)、饱和食盐水(4×20mL)洗，有机相用无水硫酸钠干燥，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物16，1.24g。产率为77％。
1H NMR(400MHz,CDCl3)δ:7.11(t,J＝7.4Hz,1H),6.95(t,J＝8.4Hz,2H),5.06(d,J＝2.5Hz,1H),4.83(s,1H),4.22(dd,J＝12.7,5.3Hz,1H),3.63(dd,J＝12.6,8.8Hz,1H),3.31(dd,J＝8.8,5.5Hz,1H),2.72(dd,J＝12.6,5.0Hz,1H),2.41–2.30(m,5H),2.29–2.20(m,2H),2.05(s,1H),2.02–1.85(m,3H),1.80–1.71(m,1H),1.55(qd,J＝12.8,5.2Hz,1H).13C NMR(100MHz,CDCl3)δ:154.76,145.16,140.19,133.90,129.61,127.02,120.12,103.66,80.18,53.47,51.51,50.73,49.13,47.94,39.44,31.58,22.07,20.95.
化合物C9的制备：
将化合物16(50mg，0.10mmol)、苯乙炔(20.4mg，0.22mmol)、醋酸铜(30.0mg，0.15mmol)、抗坏血酸钠(39.6mg，0.20mmol)、水(2mL)和四氢呋喃(8mL)混合，反应6h，反应结束，加入9mL水，水相用乙酸乙酯(3×18mL)萃取，合并有机相，依次用水(2×7mL)、饱和食盐水(2×7mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C9，25.0mg，收率63％，熔点:203-205℃。
IRνmax(cm-1):3507,2924,2865,1658,1463,1327,1219,1156,1083,899,762,693.HRMS(ESI)m/z calculated for C26H28ON3[M+H]+:398.2227,found:398.2226.1H NMR(400MHz,CDCl3)δ:7.90(s,1H),7.83(d,J＝7.7Hz,2H),7.42(t,J＝7.5Hz,2H),7.33(t,J＝7.4Hz,1H),7.14(t,J＝7.5Hz,1H),6.98(t,J＝7.6Hz,2H),5.32(dd,J＝14.1,5.2Hz,1H),4.99(s,1H),4.86–4.67(m,2H),3.91(dd,J＝11.1,5.0Hz,1H),2.68(dt,J＝12.9,6.4Hz,2H),2.39(s,3H),2.20(dt,J＝12.0,5.3Hz,1H),1.96(d,J＝17.2Hz,1H),1.92–1.75(m,2H),1.66(dd,J＝12.4,4.9Hz,1H),1.53(dq,J＝9.0,5.6Hz,2H),0.76(d,J＝10.2Hz,1H).
13C NMR(100MHz,CDCl3)δ:154.00,148.26,145.31,139.40,133.52,130.49,130.03,128.98,128.41,127.40,125.88,120.58,119.72,104.20,79.87,53.53,51.67,49.50,49.40,48.19,38.92,31.08,22.07,21.50.
化合物C10的制备：
制备方法同化合物C9，将苯乙炔改成4-溴苯乙炔，得白色固体即化合物C10，28.6mg，收率60％，熔点:233-236℃。
IRνmax(cm-1):3509,2932,2850,1657,1452,1328,1083,971,897,793,508.
HRMS(ESI)m/z calculated for C26H27ON3Br[M+H]+:476.1332,found:[M+H]+476.1329,[M+2+H]+478.1298.1H NMR(400MHz,CDCl3)δ:7.89(s,1H),7.71(d,J＝8.2Hz,2H),7.55(d,J＝8.5Hz,2H),7.14(t,J＝7.5Hz,1H),6.98(t,J＝6.9Hz,2H),5.41–5.24(m,1H),4.99(d,J＝2.7Hz,1H),4.85–4.68(m,2H),3.91(dd,J＝11.1,5.0Hz,1H),2.78–2.62(m,2H),2.39(s,3H),2.21(dt,J＝12.0,5.2Hz,1H),2.01–1.93(m,1H),1.85(dt,J＝12.2,6.2Hz,1H),1.66(d,J＝12.6Hz,2H),1.54(tq,J＝12.4,7.1,6.4Hz,2H),0.73(dd,J＝10.3,2.4Hz,1H).13C NMR(100MHz,CDCl3)δ:153.97,147.30,145.27,139.29,133.52,132.17,130.10,129.46,127.51,127.41,127.37,122.36,120.65,119.77,104.27,79.91,53.55,51.72,49.61,49.44,48.28,38.97,31.11,22.10,21.53.
化合物C11的制备：
制备方法同化合物C9，将苯乙炔改成4-甲氧基苯乙炔，得白色固体即化合物C11，29.1mg，收率68％，熔点:199-200℃。
IRνmax(cm-1):3406,2927,2859,1723,1657,1462,1332,1223,1055,894,764,694.513.HRMS(ESI)m/z calculated for C27H30O2N3[M+H]+:428.2333,found:428.2337.1HNMR(400MHz,CDCl3)δ:7.81(s,1H),7.75(d,J＝8.3Hz,2H),7.13(t,J＝7.6Hz,1H),7.04–6.79(m,4H),5.40–5.24(m,1H),4.99(s,1H),4.79(s,1H),4.77–4.61(m,1H),3.97–3.73(m,4H),2.67(d,J＝15.4Hz,2H),2.39(s,3H),2.19(dt,J＝12.0,5.3Hz,1H),1.99–1.79(m,3H),1.73–1.61(m,1H),1.53(d,J＝11.2Hz,2H),0.75(d,J＝10.3Hz,1H).13C NMR(100MHz,CDCl3)δ:159.80,154.05,148.12,145.32,139.44,133.52,130.00,127.36,127.17,123.21,120.55,118.94,114.38,104.15,79.85,55.45,53.51,51.65,49.44,49.38,48.14,38.92,31.05,22.07,21.48.
化合物C12的制备：
制备方法同化合物C9，将苯乙炔改成2-乙炔基吡啶，经柱层析(石油醚/乙酸乙酯＝1:2)得白色固体即化合物C12，23.5mg，收率59％，熔点:107-110℃。
IRνmax(cm-1):3415,2930,2865,1734,1603,1461,1421,1248,1202,1088,1046,783,742,542.HRMS(ESI)m/z calculated for C25H27ON4[M+H]+:399.2179,found:399.2177.1H NMR(400MHz,CDCl3)δ:8.44(s,1H),8.43–8.37(m,1H),7.88(d,J＝7.9Hz,1H),7.75(td,J＝7.7,1.8Hz,1H),7.27(ddd,J＝7.6,4.7,1.3Hz,1H),7.15(t,J＝7.5Hz,1H),6.99(dd,J＝7.4,5.2Hz,2H),5.40–5.26(m,1H),5.12(d,J＝2.6Hz,1H),4.90(s,1H),4.78(dd,J＝14.0,12.1Hz,1H),3.89(dd,J＝12.2,4.8Hz,1H),2.88–2.64(m,2H),2.41(s,3H),2.29–2.16(m,1H),2.13–1.98(m,2H),1.89(td,J＝12.3,5.1Hz,1H),1.77–1.67(m,1H),1.67–1.51(m,2H),0.86(dd,J＝10.2,2.2Hz,1H).13C NMR(100MHz,CDCl3)δ:154.73,149.30,148.90,147.93,145.21,139.21,137.09,133.55,130.01,127.36,123.14,122.04,120.58,120.43,103.97,79.53,53.29,52.04,49.54,49.07,48.54,39.25,30.99,21.94,21.56.
化合物C13的制备：
制备方法同化合物C9，将苯乙炔改成4-三氟甲基苯乙炔，得白色固体即化合物C13，28.4mg，收率62％，熔点:224-226℃。
IRνmax(cm-1):3512,2939,1620,1456,1326,1165,1127,1062,797.HRMS(ESI)m/zcalculated for C27H27ON3F3[M+H]+:466.2101,found:466.2095.1H NMR(400MHz,DMSO-d6)δ:8.97(s,1H),8.09(d,J＝8.1Hz,2H),7.85(d,J＝8.1Hz,2H),7.10(t,J＝7.4Hz,1H),6.96(t,J＝8.1Hz,2H),5.38(dd,J＝14.2,5.1Hz,1H),4.91–4.62(m,4H),4.03–3.85(m,1H),2.74–2.55(m,2H),2.36(s,3H),2.23–2.06(m,1H),1.71(t,J＝15.5Hz,2H),1.54–1.41(m,1H),1.39–1.15(m,2H),0.61(d,J＝10.1Hz,1H).13C NMR(100MHz,DMSO-d6)δ:154.73,145.18,145.08,139.76,134.82,133.50,129.63,126.89,126.06,125.70,122.87,120.04,103.05,78.37,53.20,51.00,48.77,48.55,46.97,30.82,21.84,20.86.
化合物C14的制备：
制备方法同化合物C9，将苯乙炔改成4-甲基苯乙炔，得白色固体即化合物C14，26.8mg，收率65％，熔点:200-204℃。
IRνmax(cm-1):3494,2928,2863,1739,1660,1500,1460,1326,1236,1090,1073,977,885,814,738,511.HRMS(ESI)m/z calculated for C27H30ON3[M+H]+:412.2383,found:412.2388.1H NMR(400MHz,CDCl3)δ:7.86(s,1H),7.72(d,J＝7.8Hz,2H),7.21(d,J＝7.8Hz,2H),7.13(t,J＝7.5Hz,1H),6.97(t,J＝8.2Hz,2H),5.30(dd,J＝14.1,5.2Hz,1H),4.99(d,J＝2.6Hz,1H),4.79(d,J＝2.1Hz,1H),4.72(dd,J＝14.1,11.0Hz,1H),3.88(dd,J＝11.1,5.1Hz,1H),2.78–2.57(m,2H),2.37(d,J＝8.8Hz,6H),2.18(dtd,J＝10.5,5.4,2.8Hz,1H),2.05–1.90(m,2H),1.84(td,J＝12.2,5.1Hz,1H),1.71–1.59(m,1H),1.59–1.39(m,2H),0.75(dd,J＝10.2,2.3Hz,1H).13C NMR(100MHz,CDCl3)δ:154.02,148.29,145.31,139.43,138.26,133.50,129.98,129.62,127.66,127.34,125.77,120.53,119.42,104.15,79.83,53.50,51.62,49.43,49.36,48.11,38.90,31.04,22.05,21.47,21.38.
化合物C15的制备：
制备方法同化合物C9，将苯乙炔改成4-氯苯乙炔，得白色固体即化合物C15，25.1mg，收率58％，熔点:235-237℃。
IRνmax(cm-1):3507,2936,2856,1657,1456,1326,1218,1156,1084,970,898,792,510.HRMS(ESI)m/z calculated for C26H27ON3Cl[M+H]+:432.1837,found:432.1834.1HNMR(400MHz,CDCl3)δ:7.88(s,1H),7.82–7.67(m,2H),7.45–7.34(m,2H),7.14(t,J＝7.5Hz,1H),6.98(t,J＝6.9Hz,2H),5.39–5.30(m,1H),4.99(t,J＝2.6Hz,1H),4.84–4.68(m,2H),3.91(dd,J＝11.1,5.1Hz,1H),2.76–2.61(m,2H),2.39(s,3H),2.28–2.14(m,1H),1.97(dq,J＝17.2,2.3Hz,1H),1.86(td,J＝12.2,5.1Hz,1H),1.67(d,J＝12.7Hz,2H),1.61–1.44(m,2H),0.74(dd,J＝10.2,2.3Hz,1H).13C NMR(100MHz,CDCl3)δ:153.97,147.29,145.28,139.30,134.23,133.52,130.10,129.22,129.01,127.50,127.13,127.09,120.65,119.74,104.26,79.91,53.56,51.72,49.60,49.44,48.28,38.97,31.11,22.10,21.53.
化合物C16的制备：
制备方法同化合物C9，将苯乙炔改成4-氟苯乙炔，得白色固体即化合物C16，24.9mg，收率60％，熔点:211-213℃。
IRνmax(cm-1):3506,2934,2855,1658,1558,1498,1459,1326,1223,1157,1083,899,843,791,521.HRMS(ESI)m/z calculated for C26H27ON3F[M+H]+:416.2133,found:416.2137.1H NMR(400MHz,DMSO-d6)δ:8.77(s,1H),7.98–7.76(m,2H),7.40–7.24(m,2H),7.09(t,J＝7.4Hz,1H),6.95(t,J＝8.4Hz,2H),5.34(dd,J＝14.1,5.2Hz,1H),4.84(d,J＝10.4Hz,2H),4.79–4.66(m,2H),3.93(dd,J＝11.2,5.0Hz,1H),2.75–2.56(m,2H),2.36(s,3H),2.13(dt,J＝11.6,5.1Hz,1H),1.70(td,J＝14.2,12.6,3.8Hz,2H),1.55–1.42(m,1H),1.41–1.25(m,2H),0.72–0.52(m,1H).13C NMR(101MHz,DMSO)δ163.06,160.63,154.75,145.72,145.11,139.81,133.50,129.63,127.47,127.44,127.25,127.17,126.87,121.47,120.03,116.05,115.84,103.03,78.39,53.21,51.00,48.67,48.57,46.96,40.05,30.81,21.86,20.88.
C17-C24的制备反应式如下：
Figure BDA0001613015610000341
上述制备方法步骤如下：
化合物17的合成：
将化合物8(1.1g，3.50mmol)溶于二氯甲烷(30mL)中，依次加入咪唑(357.3mg，5.25mmol)和叔丁基二甲基氯硅烷(739.9mg，4.90mmol)，室温反应4h，反应结束，加入20mL水，水相用二氯甲烷(3×40mL)萃取，合并有机相，依次用水(20mL)、饱和食盐水(2×15mL)洗，有机相用无水硫酸钠干燥，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝6:1)得1.40g产物即化合物17。收率93％。
1H NMR(400MHz,CDCl3)δ:6.82(d,J＝8.0Hz,1H),6.67(d,J＝8.0Hz,1H),5.16(t,J＝2.4Hz,1H),5.02(d,J＝2.1Hz,1H),3.63(d,J＝10.3Hz,4H),3.36(dd,J＝8.5,2.5Hz,1H),2.73(dt,J＝16.4,2.9Hz,1H),2.56–2.39(m,1H),2.10(s,5H),1.94(ddt,J＝15.0,10.3,7.9Hz,1H),1.83–1.65(m,2H),1.60(dd,J＝10.6,2.6Hz,1H),1.54(dd,J＝10.7,2.3Hz,1H),1.01(s,9H),0.21(d,J＝2.5Hz,6H).13C NMR(100MHz,CDCl3)δ:172.65,155.50,152.41,141.11,138.84,126.08,119.78,117.54,106.65,78.46,56.68,53.92,51.70,48.74,47.60,38.61,38.43,25.85,21.15,18.30,13.09,-4.15,-4.17.
化合物18的合成：
在氮气保护下，将化合物17(1.40g，3.26mmol)溶于无水的四氢呋喃(30mL)中，在冰水浴的条件下，加入四氢铝锂(248.8mg，6.52mmol)，加完后移除冰水浴，在室温反应5h，反应完毕后，缓慢加入20mL冰水，水相用乙酸乙酯(3×80mL)萃取，合并有机相，依次用水(20mL)、饱和食盐水(2×15mL)洗，用无水硫酸钠干燥有机相，减压蒸干，得粗产物1.03g，未经柱层析直接做下一步反应。
化合物19的合成：
将化合物18(1.03g，2.57mmol)溶于无水的二氯甲烷(30mL)中，分别加入二异丙基乙胺(464.1mg，3.60mmol)、对甲苯磺酰氯(512.7mg，2.70mmol)、4-二甲氨基吡啶(62.7mg，0.514mmol)，在室温反应9h，反应结束，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝2:1)得白色粉末即化合物19，1.10g。两步的总收率为61％。
1H NMR(400MHz,CDCl3)δ:7.66(d,J＝8.1Hz,2H),7.29(d,J＝8.0Hz,2H),6.75(d,J＝8.0Hz,1H),6.62(d,J＝8.0Hz,1H),5.12(d,J＝2.3Hz,1H),5.00(s,1H),4.03(qd,J＝10.2,6.3Hz,2H),3.10–2.92(m,2H),2.80(dt,J＝16.4,2.9Hz,1H),2.42-2.37(m,4H),2.14–2.01(m,2H),1.98(s,3H),1.87(ddt,J＝15.4,11.8,8.3Hz,1H),1.72–1.55(m,2H),1.48–1.34(m,2H),1.00(s,9H),0.19(d,J＝4.0Hz,6H).13C NMR(100MHz,CDCl3)δ:155.44,152.54,144.79,141.42,137.80,132.66,129.80,127.83,126.14,119.59,117.23,106.65,78.03,68.19,53.03,49.92,48.82,46.41,38.33,37.88,25.80,21.64,20.76,18.23,12.86,-4.18,-4.24.
化合物20的合成：
将化合物19(1.10g，1.98mmol)溶于无水的四氢呋喃，然后加入四正丁基氟化铵(517.3mg，1.98mmol)，室温反应1h,反应结束，加入25mL水，用乙酸乙酯(3×50mL)萃取，合并有机相，依次用水(18mL)、饱和食盐水(2×18mL)洗，有机相用无水硫酸钠干燥，减压蒸干，经柱层析(石油醚/乙酸乙酯＝2:1-1:1)得白色粉末即化合物20，750.9mg产物。收率86％。
1H NMR(400MHz,CDCl3)δ:7.66(d,J＝8.0Hz,2H),7.29(d,J＝8.1Hz,2H),6.74(d,J＝7.9Hz,1H),6.61(d,J＝7.9Hz,1H),5.14(t,J＝2.3Hz,1H),5.03(d,J＝2.4Hz,1H),4.03(qd,J＝10.3,6.3Hz,2H),3.09–2.94(m,2H),2.81(dt,J＝16.5,3.0Hz,1H),2.40-2.45(m,4H),2.16–2.02(m,1H),1.97(s,3H),1.88(tt,J＝15.1,8.6Hz,1H),1.67(qd,J＝13.1,12.4,8.0Hz,2H),1.51–1.39(m,2H).13C NMR(100MHz,CDCl3)δ:155.32,153.03,145.04,141.49,137.31,132.53,129.93,127.92,121.75,120.02,113.86,106.95,78.46,68.39,53.20,49.86,48.92,46.48,38.36,37.95,21.75,20.91,12.04.
化合物21的合成：
将化合物20(750.9mg，1.70mmol)和叠氮化钠(331.5mg，5.10mmol)溶于无水的N,N-二甲基甲酰胺(18mL)。在氮气保护下，80℃反应3h，反应结束后，加入20mL水，用乙酸乙酯(3×50mL)萃取，合并有机相，依次用水(3×15mL)、饱和食盐水(4×18mL)洗，有机相用无水硫酸钠干燥，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物21，423.0mg，产率为80％。
1H NMR(400MHz,CDCl3)δ:6.79(d,J＝7.9Hz,1H),6.64(d,J＝7.9Hz,1H),5.87(s,1H),5.18(t,J＝2.1Hz,1H),5.09(s,1H),3.41(d,J＝6.4Hz,2H),3.10(d,J＝8.1Hz,1H),2.92(t,J＝6.4Hz,1H),2.83(dt,J＝16.2,3.0Hz,1H),2.51(d,J＝16.2Hz,1H),2.20(s,3H),2.17–2.08(m,2H),1.93(ddt,J＝15.3,11.4,8.2Hz,1H),1.80–1.62(m,2H),1.50(t,J＝2.7Hz,2H).13C NMR(100MHz,CDCl3)δ:155.29,153.00,143.58,137.12,121.63,119.95,113.70,107.04,78.73,53.52,50.87,50.09,49.03,46.49,38.40,38.02,20.95,12.29.
化合物C17的制备：
将化合物21(44mg，0.14mmol)、苯乙炔(28.6mg，0.28mmol)、醋酸铜(42.0mg，0.21mmol)、抗坏血酸钠(55.4mg，0.28mmol)、水(2mL)和四氢呋喃(8mL)混合，反应8h，反应结束，加入9mL水，水相用乙酸乙酯(3×18mL)萃取，合并有机相，依次用水(2×6mL)、饱和食盐水(2×6mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C17，34.3mg，收率59％，熔点:141-142℃。
IRνmax(cm-1):3385,2929,2861,1639,1600,1465,1446,1356,1333,1262,1159,1054,895,822,764,695.HRMS(ESI)m/z calculated for C26H28O2N3[M+H]+:414.2176,found:414.2177.1H NMR(400MHz,CDCl3)δ:7.78–7.56(m,2H),7.33(dd,J＝8.3,6.6Hz,2H),7.28(s,1H),7.23(s,1H),6.72(q,J＝8.1Hz,3H),5.11(s,1H),4.98(s,1H),4.57(dd,J＝14.0,6.3Hz,1H),4.34(dd,J＝14.0,6.9Hz,1H),3.31(t,J＝6.7Hz,1H),2.80(d,J＝7.8Hz,1H),2.61–2.41(m,2H),2.29(s,1H),2.13–1.97(m,1H),1.92–1.68(m,1H),1.78(s,3H),1.62(dd,J＝10.9,7.0Hz,2H),1.49(d,J＝10.9Hz,1H),1.45–1.34(m,1H).
13C NMR(100MHz,CDCl3)δ:154.85,153.48,147.83,143.22,136.85,130.31,128.98,128.37,125.88,122.12,120.78,120.30,114.11,107.33,78.37,53.94,50.99,50.02,49.18,46.31,38.38,37.49,20.95,11.79.
化合物C18的制备：
制备方法同化合物C17，将苯乙炔改成4-溴苯乙炔，得白色固体即化合物C1839.3mg，收率57％，熔点:151-153℃。
IRνmax(cm-1):3424,2927,2859,1638,1601,1451,1264,1120,1069,1011,823,514.HRMS(ESI)m/z calculated for C26H27O2N3Br[M+H]+:492.1281,found:[M+H]+492.1280,[M+2+H]+494.1256.1H NMR(400MHz,CDCl3)δ:
7.58(d,J＝8.5Hz,2H),7.52–7.44(m,2H),7.28(s,1H),6.80(d,J＝8.0Hz,1H),6.72(d,J＝7.9Hz,1H),6.31(s,1H),5.16(d,J＝2.5Hz,1H),5.04(s,1H),4.63(dd,J＝13.9,6.2Hz,1H),4.39(dd,J＝14.0,7.0Hz,1H),3.35(t,J＝6.7Hz,1H),2.83(d,J＝8.0Hz,1H),2.67–2.47(m,2H),2.10(q,J＝6.5,5.9Hz,2H),1.90(d,J＝8.9Hz,2H),1.80(s,3H),1.66(t,J＝17.1Hz,1H),1.53(d,J＝10.9Hz,1H),1.46(dd,J＝10.7,2.2Hz,1H).13C NMR(100MHz,CDCl3)δ:154.83,153.36,146.85,143.22,137.03,132.13,129.34,127.38,122.26,122.03,120.82,120.40,114.10,107.40,78.37,53.99,51.01,50.10,49.25,46.36,38.41,37.54,20.99,11.75.
化合物C19的制备：
制备方法同化合物C17，将苯乙炔改成4-甲氧基苯乙炔，得白色固体即化合物C19，37.9mg，收率61％，熔点:150-154℃。
IRνmax(cm-1):3415,2929,1658,1618,1500,1460,1249,1176,1054,1031,835,605,533.HRMS(ESI)m/z calculated for C27H30O3N3[M+H]+:444.2282,found:444.2285.1H NMR(400MHz,CDCl3)δ:7.61(d,J＝8.3Hz,2H),7.40(s,1H),7.24(s,1H),6.87(d,J＝8.4Hz,2H),6.73(s,2H),5.12(s,1H),4.98(s,1H),4.55(dd,J＝14.1,6.2Hz,1H),4.32(dd,J＝14.1,6.8Hz,1H),3.77(s,3H),3.38–3.24(m,1H),2.81(d,J＝7.5Hz,1H),2.50(q,J＝16.5Hz,3H),2.14–1.99(m,1H),1.85(s,1H),1.79(s,3H),1.61(d,J＝8.4Hz,2H),1.50(d,J＝10.8Hz,1H),1.42(d,J＝10.7Hz,1H).13C NMR(100MHz,CDCl3)δ:159.68,154.87,153.63,147.60,143.21,136.62,127.17,122.99,122.20,120.17,120.09,114.38,114.04,107.24,78.30,55.41,53.88,50.95,49.95,49.07,46.25,38.38,37.45,20.90,11.80.
化合物C20的制备：
制备方法同化合物C17，将苯乙炔改成2-乙炔基吡啶，粗产品经柱层析(石油醚/乙酸乙酯＝1:2)得白色固体化合物C20，28.5mg，收率49％，熔点:144-147℃。
IRνmax(cm-1):3405,2927,2856,1734,1686,1601,1496,1422,1251,1121,1053,894,823,784.HRMS(ESI)m/z calculated for C25H27O2N4[M+H]+:415.2129,found:415.2128.1H NMR(400MHz,CDCl3)δ:8.50(d,J＝5.0Hz,1H),8.19(d,J＝7.9Hz,1H),8.00(s,1H),7.78(td,J＝7.7,1.8Hz,1H),7.22(dd,J＝7.5,5.0Hz,1H),6.74(d,J＝7.9Hz,1H),6.66(d,J＝7.9Hz,1H),5.12(t,J＝2.4Hz,1H),4.98(s,1H),4.61(dd,J＝14.1,7.2Hz,1H),4.36(dd,J＝14.1,6.0Hz,1H),3.34(t,J＝6.7Hz,1H),3.03–2.83(m,2H),2.56(d,J＝16.3Hz,1H),2.39(dt,J＝16.2,3.0Hz,1H),2.08(dd,J＝13.4,4.9Hz,1H),1.95–1.73(m,4H),1.63(dd,J＝11.0,6.5Hz,2H),1.55–1.36(m,2H).13C NMR(101MHz,CDCl3)δ154.96,153.81,149.91,149.10,147.86,143.02,137.53,136.44,123.20,123.15,122.28,120.73,120.14,114.14,107.22,78.20,53.87,51.09,49.91,49.26,46.26,38.44,37.44,20.89,11.95.
化合物C21的制备：
制备方法同化合物C17，将苯乙炔改成4-三氟甲基苯乙炔，得白色固体化合物C21，35.1mg，收率52％，熔点:148-150℃。
IRνmax(cm-1):3387,2929,2862,1623,1451,1326,1167,1123,1065,849,822,598.HRMS(ESI)m/z calculated for C27H27O2N3F3[M+H]+:482.2050,found:482.2047.1HNMR(400MHz,CDCl3)δ:7.80(d,J＝8.1Hz,2H),7.60(d,J＝8.1Hz,2H),7.36(s,1H),6.78(d,J＝8.0Hz,1H),6.75–6.57(m,2H),5.15(t,J＝2.4Hz,1H),5.02(s,1H),4.63(dd,J＝14.0,6.1Hz,1H),4.40(dd,J＝14.0,7.0Hz,1H),3.35(t,J＝6.6Hz,1H),2.81(d,J＝7.8Hz,1H),2.66–2.46(m,2H),2.36(s,1H),2.21–1.99(m,1H),1.95–1.82(m,1H),1.78(s,3H),1.65(dd,J＝10.7,6.3Hz,2H),1.53(d,J＝10.9Hz,1H),1.48–1.38(m,1H).13C NMR(100MHz,CDCl3)δ:154.69,153.44,146.48,143.13,136.93,133.73,130.65,130.33,130.00,129.68,125.98,125.94,125.49,122.79,122.10,121.57,120.37,114.11,107.44,78.40,53.97,50.97,50.17,49.16,46.33,38.38,37.51,20.95,11.75.
化合物C22的制备：
制备方法同化合物C17，将苯乙炔改成4-甲基苯乙炔，得白色固体化合物C22，31.1mg，收率52％，熔点:143-147℃。
IRνmax(cm-1):3406,2927,2861,1685,1600,1499,1450,1359,1263,1120,1054,895,822,517.HRMS(ESI)m/z calculated for C27H30O2N3[M+H]+:428.2333,found:428.2329.1H NMR(400MHz,CDCl3)δ:7.59(d,J＝7.8Hz,2H),7.28(s,1H),7.16(d,J＝7.8Hz,2H),7.12–6.86(m,1H),6.81–6.61(m,2H),5.13(s,1H),4.99(s,1H),4.56(dd,J＝14.1,6.3Hz,1H),4.33(dd,J＝14.0,6.8Hz,1H),3.31(t,J＝6.6Hz,1H),2.81(d,J＝7.7Hz,1H),2.64–2.13(m,3H),2.33(s,3H),2.14–1.97(m,1H),1.97–1.72(m,4H),1.74–1.55(m,2H),1.50(d,J＝11.0Hz,1H),1.43(d,J＝10.8Hz,1H).13C NMR(100MHz,CDCl3)δ154.86,153.55,147.87,143.20,138.22,136.73,129.64,127.45,125.78,122.15,120.47,120.23,114.10,107.28,78.36,53.91,50.98,49.98,49.13,46.28,38.37,37.46,21.36,20.93,11.79.
化合物C23的制备：
制备方法同化合物C17，将苯乙炔改成4-氯苯乙炔，得白色固体即化合物C23，33.3mg，收率53％，熔点:139-142℃。
IRνmax(cm-1):3387,2928,2860,1660,1600,1485,1452,1358,1333,1264,1253,1093,1054,974,895,822,517.HRMS(ESI)m/z calculated for C26H27O2N3Cl[M+H]+:448.1786,found:448.1786.1H NMR(400MHz,CDCl3)δ:7.62(d,J＝8.1Hz,2H),7.38–7.28(m,3H),6.90(s,1H),6.83–6.60(m,2H),5.15(s,1H),5.02(s,1H),4.61(dd,J＝14.0,6.2Hz,1H),4.38(dd,J＝14.0,7.0Hz,1H),3.33(t,J＝6.6Hz,1H),2.82(d,J＝7.9Hz,1H),2.63–2.46(m,2H),2.44–2.22(m,1H),2.08(dd,J＝13.8,5.2Hz,1H),1.87(dd,J＝17.5,7.9Hz,1H),1.79(s,3H),1.65(dd,J＝10.7,6.6Hz,2H),1.52(d,J＝10.9Hz,1H),1.45(d,J＝10.9Hz,1H).13C NMR(100MHz,CDCl3)δ:154.79,153.52,146.78,143.15,136.81,134.07,129.15,128.84,127.10,122.11,120.87,120.31,114.08,107.36,78.35,53.94,50.98,50.08,49.15,46.32,38.40,37.51,20.95,11.77.
化合物C24的制备：
制备方法同化合物C17，将苯乙炔改成4-氟苯乙炔，得白色固体即化合物C24，29.0mg，收率48％。熔点:125-128℃。
IRνmax(cm-1):3386,2929,2861,1773,1659,1600,1561,1498,1500,1229,1157,1054,841,599,526.HRMS(ESI)m/z calculated for C26H27O2N3F[M+H]+:432.2082,found:432.2085.1H NMR(400MHz,CDCl3)δ:7.66(dd,J＝8.6,5.4Hz,2H),7.28(s,1H),7.04(t,J＝8.6Hz,2H),6.86(s,1H),6.78(d,J＝8.1Hz,1H),6.73(d,J＝8.0Hz,1H),5.14(d,J＝2.5Hz,1H),5.02(s,1H),4.61(dd,J＝14.1,6.2Hz,1H),4.37(dd,J＝15.3,5.7Hz,1H),3.34(t,J＝6.7Hz,1H),2.84(d,J＝8.0Hz,1H),2.62–2.49(m,2H),2.40(s,1H),2.08(dq,J＝12.2,6.7,5.2Hz,1H),1.95–1.82(m,1H),1.79(s,3H),1.65(dd,J＝10.7,6.8Hz,2H),1.53(d,J＝11.0Hz,1H),1.49–1.40(m,1H).13C NMR(101MHz,CDCl3)δ164.01,161.55,154.78,153.50,146.99,143.19,136.81,127.68,127.60,126.49,122.14,120.62,120.30,116.07,115.85,114.07,107.36,78.37,53.96,50.98,50.07,49.14,46.32,38.40,37.51,20.95,11.76.
C25-C31的制备反应式如下：
Figure BDA0001613015610000391
上述制备方法步骤如下：
化合物22的合成：
将化合物21(700.0mg，2.25mmol)和二异丙基胺(23mg，0.23mmol)溶于无水的二氯甲烷(15mL)，在冰水浴下，缓慢加入N-溴代琥珀酰亚胺(400.5mg，2.25mmol)的二氯甲烷(5mL)溶液，在该温度下反应1h，反应结束后，直接减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物22，570.3mg，收率65％。
1H NMR(400MHz,CDCl3)δ:7.05(s,1H),5.55(s,1H),5.18(dd,J＝3.2,1.7Hz,1H),5.09(s,1H),3.68–3.30(m,2H),3.13(d,J＝8.1Hz,1H),2.91(t,J＝6.4Hz,1H),2.82(dt,J＝16.2,3.1Hz,1H),2.56–2.46(m,1H),2.27(s,3H),2.09(dd,J＝14.9,6.1Hz,1H),1.94(ddt,J＝15.4,11.4,8.2Hz,1H),1.86–1.60(m,4H),1.55–1.41(m,2H).13C NMR(100MHz,CDCl3)δ:155.18,149.20,143.37,138.45,123.23,122.76,108.92,107.13,78.30,53.48,50.82,50.02,49.18,46.56,38.38,37.95,20.97,13.32.
化合物C25的制备：
将化合物22(45mg，0.12mmol)、苯乙炔(24.5mg，0.24mmol)、醋酸铜(36.0mg，0.18mmol)、抗坏血酸钠(47.5mg，0.24mmol)、水(2mL)和四氢呋喃(8mL)混合，反应10h，反应毕后，加入10mL水，水相用乙酸乙酯(3×18mL)萃取，合并有机相，依次用水(6mL)、饱和食盐水(2×7mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C25，36.6mg，收率62％。
IRνmax(cm-1):3504,2938,2846,1658,1617,1558,1498,1454,1327,1241,1178,1083,1036,899,843,792,640,525.HRMS(ESI)m/z calculated for C26H27O2N3Br[M+H]+:492.1281,found:[M+H]+492.1280，[M+2+H]+494.1247.
1H NMR(400MHz,CDCl3)δ:7.88–7.60(m,2H),7.37(td,J＝15.9,15.5,7.5Hz,4H),7.07(s,1H),5.68(s,1H),5.16(t,J＝2.4Hz,1H),5.04(d,J＝2.1Hz,1H),4.62(dd,J＝14.0,6.4Hz,1H),4.36(dd,J＝14.0,7.2Hz,1H),3.37(t,J＝6.8Hz,1H),2.92(d,J＝7.9Hz,1H),2.66–2.44(m,2H),2.14–1.98(m,2H),1.98–1.87(m,1H),1.87(s,3H),1.67(dd,J＝11.7,6.7Hz,2H),1.55(d,J＝10.9Hz,1H),1.44(dd,J＝10.9,2.4Hz,1H).13C NMR(100MHz,CDCl3)δ:154.56,149.32,147.96,143.12,138.34,130.44,128.96,128.34,125.85,123.71,123.11,120.46,109.20,107.51,78.09,53.94,50.90,49.66,49.18,46.26,38.24,37.39,20.91,12.68.
化合物C26的制备：
制备方法同化合物C25，将苯乙炔改成4-甲氧基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C26，32.6mg，收率52％。熔点:152-154℃。
IRνmax(cm-1):3423,2928,2859,1774,1617,1561,1499,1459,1335,1250,1177,896,837,532.HRMS(ESI)m/z calculated for C27H29O3N3Br[M+H]+:522.1387,found:[M+H]+522.1386,[M+2+H]+524.1353.1H NMR(400MHz,CDCl3)δ:7.75–7.59(m,2H),7.28(s,1H),7.08(s,1H),6.97–6.87(m,2H),5.64(s,1H),5.16(t,J＝2.4Hz,1H),5.05(s,1H),4.61(dd,J＝14.0,6.4Hz,1H),4.35(dd,J＝14.1,7.3Hz,1H),3.83(s,3H),3.37(t,J＝6.8Hz,1H),2.93(d,J＝8.0Hz,1H),2.64–2.45(m,2H),2.08(dd,J＝15.2,5.6Hz,1H),1.99–1.88(m,2H),1.86(s,3H),1.68(dd,J＝11.7,6.7Hz,2H),1.55(d,J＝10.9Hz,1H),1.45(dd,J＝10.7,2.3Hz,1H).13C NMR(101MHz,CDCl3)δ159.81,154.59,149.31,147.87,143.17,138.35,127.18,123.72,123.11,119.72,114.42,109.18,107.52,78.13,55.47,53.97,50.91,49.65,49.20,46.28,38.25,37.40,20.93,12.67.
化合物C27的制备：
制备方法同化合物C25，将苯乙炔改成2-乙炔基吡啶，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C27，24.8mg，收率42％。熔点:149-153℃。
IRνmax(cm-1):3422,2927,2860,1732,1603,1461,1422,1331,1225,1121,1046,894,784.HRMS(ESI)m/z calculated for C25H26O2N4Br[M+H]+:493.1234,found:[M+H]+493.1233,[M+2+H]+495.1199.1H NMR(400MHz,CDCl3)δ:
8.58–8.46(m,1H),8.17(d,J＝8.0Hz,1H),7.94(s,1H),7.77(td,J＝7.8,1.8Hz,1H),7.22(ddd,J＝7.7,4.9,1.2Hz,1H),7.08(s,1H),5.82–5.63(m,1H),5.14(d,J＝2.5Hz,1H),5.02(d,J＝2.4Hz,1H),4.65(dd,J＝14.0,7.2Hz,1H),4.34(dd,J＝14.0,6.7Hz,1H),3.40(t,J＝7.0Hz,1H),3.05(d,J＝8.0Hz,1H),2.65–2.51(m,1H),2.43(dt,J＝16.3,3.0Hz,1H),2.11(dd,J＝14.7,5.7Hz,1H),2.05–1.79(m,4H),1.75–1.58(m,2H),1.58–1.49(m,1H),1.45(dd,J＝10.7,2.7Hz,1H),1.25(s,1H).13C NMR(100MHz,CDCl3)δ:154.64,150.12,149.44,149.40,148.52,142.99,138.13,137.16,123.70,123.11,122.81,120.49,109.35,107.51,78.07,53.99,50.95,49.63,49.26,46.27,38.28,37.35,20.90,12.74。
化合物C28的制备：
制备方法同化合物C25，将苯乙炔改成4-三氟甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C28，30.9mg，收率46％。熔点:119-122℃。
IRνmax(cm-1):3405,2929,2861,1622,1461,1325,1190,1123,1064,849,798,597.HRMS(ESI)m/z calculated for C27H26O2N3BrF3[M+H]+:560.1155,found:[M+H]+560.1160,[M+2+H]+562.1141.1H NMR(400MHz,CDCl3)δ:7.86(d,J＝8.0Hz,2H),7.66(d,J＝8.1Hz,2H),7.41(s,1H),7.09(s,1H),5.61(s,1H),5.18(t,J＝2.4Hz,1H),5.07(s,1H),4.67(dd,J＝14.0,6.2Hz,1H),4.41(dd,J＝14.0,7.2Hz,1H),3.40(t,J＝6.7Hz,1H),2.92(d,J＝8.0Hz,1H),2.69–2.50(m,2H),2.09(dd,J＝14.5,5.2Hz,1H),2.00–1.88(m,1H),1.86(s,3H),1.78(s,1H),1.69(dd,J＝11.5,6.7Hz,2H),1.57(d,J＝10.9Hz,1H),1.47(dd,J＝10.8,2.2Hz,1H).13C NMR(100MHz,CDCl3)δ:154.36,149.24,146.53,142.88,138.24,133.78,130.26,129.93,125.89,125.85,125.40,123.53,123.08,122.70,121.08,109.16,107.51,78.00,53.87,50.80,49.73,49.13,46.20,38.16,37.32,20.84,12.56.
化合物C29的制备：
制备方法同化合物C25，将苯乙炔改成4-甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C29，29.1mg，收率48％。熔点:169-171℃。
IRνmax(cm-1):3432,2929,2863,1719,1642,1561,1497,1452,1334,1223,1157,1052,912,865,796,765,527.HRMS(ESI)m/z calculated for C27H29O2N3Br[M+H]+:506.1438,found:[M+H]+506.1436,[M+2+H]+508.1403.
1H NMR(400MHz,CDCl3)δ:7.64(d,J＝7.9Hz,2H),7.30(s,1H),7.22(d,J＝7.8Hz,2H),7.08(s,1H),5.57(s,1H),5.16(t,J＝2.4Hz,1H),5.05(d,J＝2.6Hz,1H),4.63(dd,J＝14.0,6.4Hz,1H),4.37(dd,J＝14.0,7.1Hz,1H),3.38(t,J＝6.7Hz,1H),2.92(d,J＝8.0Hz,1H),2.69–2.49(m,2H),2.37(s,3H),2.09(dd,J＝14.9,5.5Hz,1H),2.00–1.81(m,4H),1.80–1.60(m,3H),1.60–1.51(m,1H),1.46(dd,J＝10.8,2.4Hz,1H).13C NMR(100MHz,CDCl3)δ:154.53,149.19,147.97,143.07,138.25,138.11,129.53,127.57,125.65,123.57,122.98,119.93,109.06,107.39,78.02,53.85,50.82,49.52,49.17,46.18,38.14,37.29,21.27,20.84,12.57.
化合物C30的制备：
制备方法同化合物C25，将苯乙炔改成4-氯苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C30，27.2mg，收率43％。熔点:166-169℃。
IRνmax(cm-1):3416,2927,2858,1726,1656,1485,1452,1333,1223,1092,1054,975,891,835,517.HRMS(ESI)m/z calculated for C26H26O2N3BrCl[M+H]+:526.0891,found:[M+H]+526.0896,[M+2+H]+528.0861.1H NMR(400MHz,CDCl3)δ:7.68(d,J＝8.3Hz,2H),7.38(d,J＝8.1Hz,2H),7.27(s,1H),7.09(s,1H),5.59(s,1H),5.17(t,J＝2.4Hz,1H),5.06(d,J＝2.6Hz,1H),4.65(dd,J＝14.0,6.3Hz,1H),4.38(dd,J＝14.0,7.1Hz,1H),3.38(t,J＝6.7Hz,1H),2.92(d,J＝8.0Hz,1H),2.72–2.45(m,2H),2.09(dd,J＝14.6,5.2Hz,1H),1.93(dq,J＝11.6,8.0,7.4Hz,1H),1.86(s,3H),1.79–1.62(m,3H),1.56(d,J＝10.8Hz,1H),1.46(dd,J＝10.8,2.3Hz,1H).13C NMR(100MHz,CDCl3)δ:154.42,149.22,146.86,142.95,138.24,134.01,129.07,128.87,126.97,123.53,123.03,120.35,109.12,107.47,78.01,53.86,50.81,49.63,49.15,46.19,38.15,37.31,20.84,12.56.
化合物C31的制备：
制备方法同化合物C25，将苯乙炔改成4-氟苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C31，27.5mg，收率45％。熔点:151-154℃。
IRνmax(cm-1):3415,2927,2861,1726,1655,1499,1459,1334,1222,1120,1054,889,820,793,517.HRMS(ESI)m/z calculated for C26H26O2N3BrF[M+H]+:510.1187,found:[M+H]+510.1189,[M+2+H]+512.1156.1H NMR(400MHz,CDCl3)δ:7.87–7.56(m,2H),7.31(s,1H),7.16–7.00(m,3H),5.64(s,1H),5.17(d,J＝2.5Hz,1H),5.05(d,J＝2.2Hz,1H),4.64(dd,J＝14.0,6.4Hz,1H),4.37(dd,J＝14.0,7.2Hz,1H),3.38(t,J＝6.8Hz,1H),2.93(d,J＝8.0Hz,1H),2.70–2.47(m,2H),2.09(dd,J＝14.4,5.2Hz,1H),1.99–1.77(m,5H),1.73–1.62(m,2H),1.56(dd,J＝11.0,2.3Hz,1H),1.46(dd,J＝10.9,2.4Hz,1H).13C NMR(100MHz,CDCl3)δ:163.93,161.47,154.44,149.22,147.04,142.99,138.24,127.53,127.45,126.59,126.56,123.57,123.02,120.10,115.96,115.74,109.11,107.44,78.00,53.86,50.81,49.60,49.11,46.18,38.16,37.31,20.83,12.56。
C32-C39和C48-C55的制备反应式如下：
Figure BDA0001613015610000431
上述制备方法步骤如下：
化合物23和24的合成：
将化合物10(3.00g，5.04mmol)溶于二氯甲烷(35mL)中，依次加入二氧化硒(279.7mg，2.52mmol)和70％的过氧化叔丁醇水溶液(1.94g，15.12mmol)，室温反应4h，反应结束，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得化合物24，1.35g，收率45％。经柱层析(石油醚/乙酸乙酯＝1:2)得化合物23，1.20g，收率39％。
化合物23的核磁数据：
1H NMR(400MHz,CDCl3)δ:7.70(dd,J＝8.3,1.9Hz,2H),7.46(dd,J＝8.3,1.8Hz,2H),7.36–7.27(m,2H),7.24–7.11(m,2H),6.89–6.72(m,2H),5.38(s,1H),5.31(s,1H),4.36(s,1H),4.32(ddd,J＝10.0,5.3,1.6Hz,1H),4.28–4.16(m,1H),3.07(dd,J＝7.3,4.0Hz,2H),2.95(s,2H),2.42(d,J＝1.7Hz,3H),2.36(d,J＝1.6Hz,3H),2.09–1.99(m,1H),1.92(d,J＝11.0Hz,1H),1.76(d,J＝1.8Hz,3H),1.69(dd,J＝14.5,7.5Hz,1H),1.58(dd,J＝11.4,5.0Hz,2H),1.21–1.13(m,1H).13C NMR(100MHz,CDCl3)δ:159.09,147.06,145.55,145.04,144.02,142.37,132.96,131.98,129.88,128.99,128.27,127.64,121.39,120.25,112.34,77.20,75.47,68.61,57.99,47.85,44.68,44.58,37.94,21.73,21.60,20.73,12.84。
化合物24的核磁数据：
1H NMR(400MHz,CDCl3)δ:7.67(dd,J＝16.2,8.0Hz,4H),7.30(dd,J＝8.0,5.1Hz,4H),6.79(s,2H),4.12(dd,J＝10.4,8.3Hz,1H),4.01(dd,J＝10.4,4.0Hz,1H),3.20–3.05(m,2H),2.43(d,J＝7.5Hz,6H),2.16(dt,J＝13.7,5.0Hz,1H),2.08–1.97(m,2H),1.93–1.79(m,5H),1.62(dd,J＝12.9,5.1Hz,1H),1.53(td,J＝12.8,5.0Hz,1H),1.34(qd,J＝12.9,5.3Hz,1H),1.04(s,3H).13C NMR(101MHz,CDCl3)δ218.78,147.38,145.59,145.22,143.46,141.28,132.93,132.44,130.00,129.86,128.91,128.36,127.83,122.02,120.95,67.32,50.57,50.42,50.15,48.44,48.34,44.09,36.53,22.27,21.78,21.70,19.78,12.76.
化合物25的合成：
将化合物23(1.20g，1.96mmol)和叠氮化钠(383.0mg，5.89mmol)溶于无水的N,N-二甲基甲酰胺(20mL)。在氮气保护下，80℃反应3h，反应结束后，加入20mL水，水相用乙酸乙酯(3×65mL)萃取，合并有机相，依次用水(3×15mL)、饱和食盐水(4×15mL)洗，有机相用无水硫酸钠干燥，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1-1:1)得白色固体即化合物25，670.8mg。产率为71％。
1H NMR(400MHz,CDCl3)δ:7.73(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),7.00–6.72(m,2H),5.50(s,1H),5.43(s,1H),4.51(s,1H),3.65(dd,J＝12.6,8.5Hz,1H),3.51(dd,J＝12.6,4.5Hz,1H),3.16(t,J＝9.3Hz,2H),3.08(dd,J＝8.6,4.5Hz,1H),2.46(s,3H),2.13(dt,J＝15.0,4.0Hz,1H),2.04(s,3H),1.99(d,J＝10.9Hz,2H),1.87–1.75(m,1H),1.73–1.51(m,2H),1.23(d,J＝11.4Hz,1H).13C NMR(100MHz,CDCl3)δ:158.91,147.37,145.51,143.83,143.54,133.18,129.89,128.84,128.57,121.75,120.50,112.45,77.57,75.63,59.00,49.96,48.43,45.07,44.06,37.84,21.88,20.88,13.00.
化合物26的合成：
将化合物24(1.35g，2.27mmol)和叠氮化钠(442.4mg，6.81mmol)溶于无水的N,N-二甲基甲酰胺(22mL)。在氮气保护下，80℃反应3h，反应完毕后，加入22mL水，水相用乙酸乙酯(3×70mL)萃取，合并有机相，依次用水(3×15mL)、饱和食盐水(4×18mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物26，730.0mg。产率为69％。
1H NMR(400MHz,CDCl3)δ:7.70(d,J＝8.3Hz,2H),7.30(d,J＝8.1Hz,2H),6.83(s,2H),3.50(dd,J＝12.7,8.0Hz,1H),3.42(dd,J＝12.7,4.7Hz,1H),3.25(dd,J＝12.3,5.1Hz,1H),2.99(dd,J＝7.9,4.7Hz,1H),2.44(s,3H),2.24–2.15(m,1H),2.09–1.96(m,6H),1.93–1.85(m,1H),1.68–1.55(m,2H),1.44–1.32(m,1H),1.08(s,3H).13C NMR(100MHz,CDCl3)δ:218.97,147.48,145.47,143.31,133.04,129.82,128.63,128.47,121.94,120.95,50.88,50.54,50.44,50.25,48.57,48.50,44.26,36.70,22.36,21.77,19.85,12.97.
化合物C32的制备：
将化合物25(70mg，0.15mmol)、苯乙炔(30.6mg，0.30mmol)、醋酸铜(36.0mg，0.23mmol)、抗坏血酸钠(59.4mg，0.30mmol)、水(2.5mL)和四氢呋喃(10mL)混合，反应10h，反应结束，加入12mL水，水相用乙酸乙酯(3×20mL)萃取，合并有机相，依次用水(6mL)、饱和食盐水(2×9mL)洗，用无水硫酸钠干燥有机相，减压蒸干，未经进一步纯化，粗产品溶于无水的二氯甲烷(8mL)，加入戴斯-马丁氧化剂(127.2mg，0.30mmol)，室温反应4h，反应完毕后，加入10mL水，水相用二氯甲烷(3×18mL)萃取，合并有机相，依次用水(8mL)、饱和食盐水(2×10mL)洗，用无水硫酸钠干燥，减压蒸干，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C32，33.2mg，两步收率38％。熔点:116-118℃。
IRνmax(cm-1):3428,2933,2868,1725,1643,1622,1468,1372,1326,1168,1123,1064,849,814,547.HRMS(ESI)m/z calculated for C33H32O5N3S[M+H]+:582.2057,found:582.2055.1H NMR(400MHz,CDCl3)δ:7.93(d,J＝8.0Hz,2H),7.78(s,1H),7.70(d,J＝7.7Hz,2H),7.65(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,3H),6.97(s,2H),6.21(s,1H),5.65(s,1H),5.53(dd,J＝14.2,6.0Hz,1H),4.55(dd,J＝14.2,6.6Hz,1H),3.70(t,J＝6.2Hz,1H),3.42(d,J＝7.4Hz,1H),2.51(s,1H),2.45(s,3H),2.27(d,J＝12.7Hz,1H),1.96-1.74(m,5H),1.70(s,3H).13C NMR(100MHz,CDCl3)δ203.16,152.35,147.74,146.13,145.66,143.78,141.18,134.12,133.23,129.98,128.34,128.32,126.05,125.90,125.86,125.83,122.47,122.42,122.26,120.98,118.80,75.10,63.21,50.36,48.49,47.00,45.38,37.12,21.83,21.19,12.57,12.54.
化合物C33的制备：
制备方法同化合物C32，将苯乙炔改成4-溴苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C33，34.7mg，两步收率35％。熔点:139-141℃。
IRνmax(cm-1):3425,2932,2865,1724,1642,1597,1467,1454,1370,1194,1169,1094,1046,814,726,692,547.HRMS(ESI)m/z calculated for C33H31O5N3BrS[M+H]+:660.1162,found:660.1163,[M+2+H]+662.1144.
1H NMR(400MHz,CDCl3)δ:7.80–7.59(m,5H),7.52(dd,J＝8.4,1.4Hz,2H),7.30(d,J＝7.9Hz,2H),6.97(d,J＝1.4Hz,2H),6.20(s,1H),5.64(s,1H),5.58–5.38(m,1H),4.65–4.35(m,1H),3.67(t,J＝6.4Hz,1H),3.42(d,J＝7.4Hz,1H),2.59(s,1H),2.45(s,3H),2.30–2.21(m,1H),2.06–1.78(m,4H),1.75(d,J＝11.7Hz,1H),1.67(d,J＝1.4Hz,3H).13CNMR(100MHz,CDCl3)δ:203.15,152.33,147.69,146.45,145.63,143.82,141.14,133.19,132.02,129.99,129.95,129.59,128.32,127.45,122.20,122.04,121.75,120.94,118.78,75.06,63.20,50.35,48.42,46.96,45.32,37.07,21.86,21.16,12.48.
化合物C34的制备：
制备方法同化合物C32，将苯乙炔改成4-甲氧基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C34，36.7mg，两步收率40％。熔点:141-144℃。
IRνmax(cm-1):3426,2931,2863,1724,1643,1618,1499,1467,1370,1249,1171,1093,1046,834,814,719,547.HRMS(ESI)m/z calculated for C34H34O6N3S[M+H]+:612.2163,found:612.2163.1H NMR(400MHz,CDCl3)δ:7.80-7.61(m,4H),7.55(d,J＝1.2Hz,1H),7.24(d,J＝2.2Hz,2H),6.94(d,J＝1.9Hz,2H),6.92-6.83(m,2H),6.14(s,1H),5.60(s,1H),5.48(dd,J＝14.1,5.7Hz,1H),4.44(dd,J＝14.2,7.1Hz,1H),3.78(d,J＝1.2Hz,3H),3.61(t,J＝6.5Hz,1H),3.39(d,J＝7.2Hz,1H),3.18(s,1H),2.40(s,3H),2.32-2.14(m,1H),2.06-1.76(m,4H),1.68(d,J＝11.3Hz,1H),1.56(s,3H).13C NMR(100MHz,CDCl3)δ:203.21,159.61,152.41,147.61,147.27,145.54,143.98,141.18,133.15,129.93,129.86,128.28,127.18,123.25,122.04,120.86,120.82,118.63,114.29,74.91,63.20,55.41,50.37,48.34,46.91,45.15,37.04,21.80,21.10,12.34.
化合物C35的制备：
制备方法同化合物C32，将苯乙炔改成2-乙炔吡啶，经柱层析(石油醚/乙酸乙酯＝1:2)得白色固体即化合物C35，28.0mg，两步收率32％。熔点:127-128℃。
IRνmax(cm-1):3425,2930,2865,1723,1642,1598,1470,1421,1370,1222,1169,1093,1047,784,723,547.HRMS(ESI)m/z calculated for C32H31O5N4S[M+H]+:583.2010,found:583.2009.1H NMR(400MHz,CDCl3)δ:8.52(ddd,J＝4.9,1.8,0.9Hz,1H),8.08(d,J＝6.9Hz,2H),7.74(td,J＝7.7,1.8Hz,1H),7.71-7.65(m,2H),7.28(d,J＝8.0Hz,2H),7.19(ddd,J＝7.6,4.8,1.2Hz,1H),6.93(d,J＝1.5Hz,2H),6.16(s,1H),5.60(s,1H),5.50(dd,J＝14.2,6.1Hz,1H),4.50(dd,J＝14.1,6.6Hz,1H),3.67(t,J＝6.3Hz,1H),3.42(d,J＝7.4Hz,1H),3.13(s,1H),2.41(s,3H),2.23(ddd,J＝14.2,6.9,3.8Hz,1H),1.96-1.77(m,4H),1.72(d,J＝11.2Hz,1H),1.62(s,3H).13C NMR(100MHz,CDCl3)δ:203.05,152.38,150.22,149.40,147.90,147.74,145.52,143.75,141.11,136.99,133.12,129.92,129.77,128.38,123.82,122.91,122.18,120.83,120.38,118.67,74.96,63.11,50.19,48.38,46.92,45.23,37.11,21.82,21.16,12.41.
化合物C36的制备：
制备方法同化合物C32，将苯乙炔改成4-三氟甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C36，35.1mg，两步收率36％。熔点119-121℃。
IRνmax(cm-1):3416,2933,2866,1724,1643,1597,1467,1371,1194,1168,1093,1046,815,765,695,547.HRMS(ESI)m/z calculated for C34H31O5N3F3S[M+H]+:650.1931,found:650.1934.1H NMR(400MHz,CDCl3)δ:7.84-7.76(m,2H),7.69(q,J＝5.2,4.0Hz,3H),7.40(t,J＝7.6Hz,2H),7.34-7.28(m,2H),6.99(q,J＝8.1Hz,2H),6.20(s,1H),5.63(s,1H),5.52(dd,J＝14.1,5.9Hz,1H),4.51(dd,J＝14.1,6.8Hz,1H),3.67(t,J＝6.3Hz,1H),3.42(d,J＝7.3Hz,1H),2.66(s,1H),2.43(s,3H),2.30-2.22(m,1H),1.96-1.71(m,5H),1.64(s,3H).13C NMR(101MHz,CDCl3)δ:203.16,152.43,147.74,147.47,145.55,143.92,141.16,133.26,130.65,129.96,129.90,128.91,128.35,128.33,128.20,125.91,122.20,121.59,120.91,118.66,75.07,63.21,50.44,48.38,47.00,45.33,37.09,21.83,21.20,12.44.
化合物C37的制备：
制备方法同化合物C32，将苯乙炔改成4-甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C37，4.0mg，两步收率38％。熔点:171-174℃。
IRνmax(cm-1):3424,2929,2865,1724,1643,1467,1195,1169,1093,1046,814,782,720,546.HRMS(ESI)m/z calculated for C34H34O5N3S[M+H]+:596.2214,found:596.2214.1HNMR(400MHz,CDCl3)δ:7.69(d,J＝2.6Hz,2H),7.67(d,J＝2.4Hz,2H),7.63(s,1H),7.27(d,J＝8.1Hz,2H),7.20(d,J＝7.9Hz,2H),6.98(q,J＝8.2Hz,2H),6.18(s,1H),5.62(s,1H),5.51(dd,J＝14.1,5.8Hz,1H),4.48(dd,J＝14.2,7.0Hz,1H),3.65(t,J＝6.4Hz,1H),3.42(d,J＝7.3Hz,1H),2.94(s,1H),2.42(s,3H),2.36(s,3H),2.30-2.22(m,1H),2.09-1.77(m,4H),1.72(d,J＝11.1Hz,1H),1.60(s,3H).13C NMR(100MHz,CDCl3)δ:203.20,152.40,147.67,147.50,145.54,143.96,141.15,138.02,133.20,129.94,129.87,129.56,128.31,127.75,125.80,122.12,121.24,120.88,118.65,74.99,63.21,50.41,48.35,46.95,45.23,37.05,21.82,21.37,21.15,12.36.
化合物C38的制备：
制备方法同化合物C32，将苯乙炔改成4-氯苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C38，32.3mg，两步收率35％。熔点:135-136℃。
IRνmax(cm-1):3424,2932,2865,1723,1642,1597,1484,1467,1370,1194,1169,1093,1046,833,814,718,547.HRMS(ESI)m/z calculated for C34H31O5N3ClS[M+H]+:616.1667,found:616.1667.1H NMR(400MHz,CDCl3)δ:7.92-7.57(m,5H),7.43-7.33(m,2H),7.29(d,J＝8.1Hz,2H),6.96(s,2H),6.19(s,1H),5.63(s,1H),5.51(dd,J＝14.2,6.0Hz,1H),4.49(dd,J＝14.2,6.7Hz,1H),3.67(t,J＝6.3Hz,1H),3.48-3.29(m,1H),2.61(s,1H),2.44(s,3H),2.33-2.15(m,1H),2.08-1.77(m,4H),1.74(d,J＝11.2Hz,1H),1.66(s,3H).13CNMR(100MHz,CDCl3)δ:203.16,152.33,147.69,146.43,145.63,143.83,141.15,133.89,133.19,129.98,129.96,129.14,129.08,128.32,127.17,122.20,121.73,120.94,118.77,75.06,63.21,50.36,48.42,46.97,45.32,37.08,21.86,21.16,12.48.
化合物C39的制备：
制备方法同化合物C32，将苯乙炔改成4-氟苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C39，32.4mg，两步收率36％。熔点:184-186℃。
IRνmax(cm-1):3416,2933,2868,1723,1645,1598,1498,1468,1454,1373,1220,1170,1043,842,830,754,662,529.HRMS(ESI)m/z calculated for C33H31O5N3FS[M+H]+:600.1963,found:600.1962.1H NMR(400MHz,CDCl3)δ:7.86-7.72(m,2H),7.70(d,J＝8.3Hz,2H),7.64(s,1H),7.30(d,J＝8.1Hz,2H),7.09(t,J＝8.7Hz,2H),6.98(s,2H),6.21(s,1H),5.64(s,1H),5.53(dd,J＝14.1,5.9Hz,1H),4.50(dd,J＝14.2,6.8Hz,1H),3.68(t,J＝6.4Hz,1H),3.49-3.34(m,1H),2.44(s,4H),2.35-2.17(m,1H),2.10-1.80(m,4H),1.75(d,J＝11.2Hz,1H),1.66(s,3H).13C NMR(100MHz,CDCl3)δ:203.15,163.96,161.50,152.36,147.70,146.64,145.62,143.89,141.15,133.21,129.98,128.37,128.33,127.70,127.62,126.87,122.19,121.40,120.93,118.75,115.96,115.74,75.09,63.23,50.39,48.41,46.98,45.33,37.08,21.86,21.18,12.47.
化合物C48的制备：
将化合物26(50mg，0.11mmol)、苯乙炔(22.4mg，0.22mmol)、醋酸铜(33.0mg，0.17mmol)、抗坏血酸钠(43.6mg，0.22mmol)、水(2.5mL)和四氢呋喃(10mL)混合，反应10h，反应结束，加入12mL水，用乙酸乙酯(3×20mL)萃取，合并有机相，依次用水(6mL)、饱和食盐水(2×10mL)洗，用无水硫酸钠干燥，减压蒸干，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C48，36.2mg，收率58％。熔点:223-226℃。
IRνmax(cm-1):2957,2931,1739,1598,1469,1404,1364,1164,1095,1050,890,854,829,751,694,663,593,538.HRMS(ESI)m/z calculated for C33H34O4N3S[M+H]+:568.2265,found:568.2264.1H NMR(400MHz,CDCl3)δ:7.82-7.76(m,2H),7.73-7.66(m,2H),7.51-7.36(m,2H),7.35-7.31(m,1H),7.30(s,1H),7.28(s,1H),7.26(s,1H),6.77(q,J＝8.1Hz,2H),4.71(dd,J＝14.2,6.4Hz,1H),4.60(dd,J＝14.2,5.3Hz,1H),3.51(t,J＝5.9Hz,1H),2.83(dd,J＝12.3,5.1Hz,1H),2.44(s,3H),2.27(dd,J＝11.4,3.5Hz,1H),2.20-2.04(m,2H),1.99(s,1H),1.96(s,3H),1.91-1.84(m,1H),1.71-1.52(m,2H),1.35(qd,J＝12.6,5.9Hz,1H),1.07(s,3H).13C NMR(100MHz,CDCl3)δ:218.52,147.91,147.60,145.59,143.71,143.04,133.19,130.42,129.93,129.15,128.92,128.36,128.32,125.79,122.01,121.34,120.68,51.28,51.07,50.67,49.30,48.76,48.33,43.50,36.58,22.39,21.82,19.82,12.94.
化合物C49的制备：
制备方法同化合物C48，将苯乙炔改成4-溴苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C49，37.7mg，收率53％。熔点:119-123℃。
IRνmax(cm-1):2925,2868,1739,1597,1456,1370,1197,1177,1093,1046,839,814,728,552.HRMS(ESI)m/z calculated for C33H33O4N3BrS[M+H]+:646.1370,found:[M+H]+646.1374,[M+2+H]+648.1379.1H NMR(400MHz,CDCl3)δ:7.77-7.62(m,4H),7.55-7.45(m,2H),7.29(dd,J＝8.7,2.8Hz,3H),6.90-6.71(m,2H),4.72(dd,J＝14.2,6.3Hz,1H),4.59(dd,J＝14.2,5.5Hz,1H),3.51(t,J＝5.9Hz,1H),2.84(dd,J＝12.3,5.2Hz,1H),2.46(s,3H),2.26(dd,J＝11.3,3.5Hz,1H),2.17-2.06(m,2H),2.00(s,1H),1.95(s,3H),1.92-1.83(m,1H),1.74-1.51(m,2H),1.36(qd,J＝12.7,5.9Hz,1H),1.08(s,3H).13C NMR(100MHz,CDCl3)δ:218.38,147.52,146.87,145.66,143.68,142.99,133.16,132.01,129.95,129.36,129.20,128.29,127.34,122.14,122.01,121.36,120.89,51.27,51.04,50.65,49.36,48.69,48.33,43.50,36.56,22.37,21.82,19.80,12.94。
化合物C50的制备：
制备方法同化合物C48，将苯乙炔改成4-甲氧基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C50，40.1mg，收率61％。熔点:179-180℃。
IRνmax(cm-1):2924,2848,1736,1618,1597,1561,1500,1457,1367,1248,1198,1093,1032,888,838,721,664,551.HRMS(ESI)m/z calculated for C34H36O5N3S[M+H]+:598.2370,found:598.2372.1H NMR(400MHz,CDCl3)δ:7.68(dd,J＝8.6,3.2Hz,4H),7.27(s,1H),7.25(s,1H),7.21(s,1H),7.01-6.85(m,2H),6.84-6.66(m,2H),4.66(dd,J＝14.2,6.5Hz,1H),4.52(dd,J＝14.2,5.5Hz,1H),3.79(s,3H),3.48(t,J＝6.0Hz,1H),2.84(dd,J＝12.2,5.1Hz,1H),2.42(s,3H),2.22(dd,J＝11.4,3.5Hz,1H),2.16-1.97(m,2H),1.96(s,1H),1.91(s,3H),1.88-1.75(m,1H),1.66-1.47(m,2H),1.46-1.26(m,1H),1.04(s,3H).
13C NMR(100MHz,CDCl3)δ:218.51,159.70,147.73,147.52,145.57,143.66,143.11,133.15,129.90,129.09,128.32,127.06,123.11,121.94,121.28,119.85,114.28,55.39,51.25,51.02,50.60,49.19,48.67,48.25,43.44,36.55,22.36,21.79,19.78,12.85.
化合物C51的制备：
制备方法同化合物C48，将苯乙炔改成2-乙炔吡啶，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C51，30.7mg，收率49％。熔点:238-240℃。
IRνmax(cm-1):2955,2927,1739,1601,1473,1367,1165,1095,1046,853,811,751,664,538.HRMS(ESI)m/z calculated for C32H33O4N4S[M+H]+:569.2217,found:569.2218.1HNMR(400MHz,CDCl3)δ:8.53(ddd,J＝4.9,1.7,0.9Hz,1H),8.13(dt,J＝7.9,1.1Hz,1H),7.85(s,1H),7.77(dd,J＝7.7,1.8Hz,1H),7.75-7.68(m,2H),7.28(d,J＝8.0Hz,2H),7.22(ddd,J＝7.6,4.8,1.2Hz,1H),6.80(d,J＝2.0Hz,2H),4.69(dd,J＝14.2,8.0Hz,1H),4.45(dd,J＝14.2,4.9Hz,1H),3.56(dd,J＝8.0,4.9Hz,1H),3.02(dd,J＝12.2,5.2Hz,1H),2.42(s,3H),2.26-1.98(m,3H),1.95(s,1H),1.91(s,3H),1.73-1.49(m,3H),1.36(qd,J＝12.6,5.8Hz,1H),1.00(s,3H).13C NMR(100MHz,CDCl3)δ:218.47,150.02,149.50,148.62,147.60,145.55,143.33,142.79,137.01,133.03,129.88,128.82,128.54,123.08,122.65,122.30,121.30,120.32,51.23,50.99,50.54,49.07,48.63,48.17,43.40,36.60,22.40,21.82,19.78,12.72.
化合物C52的制备：
制备方法同化合物C48，将苯乙炔改成4-三氟甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C52，40.1mg，收率58％。熔点:139-141℃。
IRνmax(cm-1):2928,1741,1622,1469,1372,1326,1166,1124,1064,888,849,719,552.HRMS(ESI)m/z calculated for C34H33O4N3F3S[M+H]+:636.2138,found:636.2136.1HNMR(400MHz,CDCl3)δ:7.89(d,J＝8.1Hz,2H),7.70-7.65(m,2H),7.62(d,J＝8.2Hz,2H),7.37(s,1H),7.27(d,J＝6.4Hz,2H),6.78(d,J＝8.1Hz,1H),6.74(s,1H),4.74(dd,J＝14.2,6.2Hz,1H),4.62(dd,J＝14.2,5.5Hz,1H),3.51(t,J＝5.8Hz,1H),2.81(dd,J＝12.3,5.1Hz,1H),2.43(s,3H),2.27(dd,J＝11.3,3.6Hz,1H),2.11(dt,J＝18.8,3.5Hz,2H),1.99(s,1H),1.96(s,3H),1.90(dd,J＝11.3,1.5Hz,1H),1.71-1.50(m,2H),1.34(qd,J＝12.6,6.0Hz,1H),1.07(s,3H).13C NMR(100MHz,CDCl3)δ:218.33,147.55,146.54,145.71,143.73,142.95,133.86,133.16,130.19,129.94,129.87,129.26,128.27,128.21,125.95,125.92,125.88,125.84,125.80,125.50,122.80,122.05,121.66,121.40,51.29,51.05,50.68,49.45,48.72,48.38,43.52,36.56,22.36,21.78,19.79,12.99.
化合物C53的制备：
制备方法同化合物C48，将苯乙炔改成4-甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C53，41.0mg，收率64％。熔点:141-143℃。
IRνmax(cm-1):2925,2868,1740,1597,1467,1370,1177,1093,1047,841,814,720,552.HRMS(ESI)m/z calculated for C34H36O4N3S[M+H]+:582.2421,found:582.2420.1H NMR(400MHz,CDCl3)δ:7.68(dd,J＝10.9,8.0Hz,4H),7.30-7.27(m,3H),7.21(d,J＝7.9Hz,2H),6.93-6.54(m,2H),4.69(dd,J＝14.2,6.5Hz,1H),4.56(ddd,J＝14.0,5.5,1.6Hz,1H),3.51(t,J＝5.9Hz,1H),2.85(dd,J＝12.3,5.1Hz,1H),2.44(s,3H),2.36(s,3H),2.31-2.19(m,1H),2.11(ddd,J＝18.6,11.9,4.2Hz,2H),1.98(s,1H),1.93(d,J＝1.6Hz,3H),1.85(d,J＝11.3Hz,1H),1.69-1.51(m,2H),1.46-1.28(m,1H),1.06(s,3H).13C NMR(100MHz,CDCl3)δ:218.53,147.95,147.55,145.56,143.66,143.08,138.15,133.17,129.90,129.56,129.08,128.35,127.58,125.68,121.98,121.29,120.29,51.26,51.04,50.62,49.22,48.70,48.27,43.45,36.56,22.38,21.80,21.35,19.79,12.86.
化合物C54的制备：
制备方法同化合物C48，将苯乙炔改成4-氯苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C54，41.1mg，收率62％。熔点:117-119℃。
IRνmax(cm-1):2926,2868,1740,1597,1456,1370,1178,1093,1047,839,814,663,552.HRMS(ESI)m/z calculated for C33H33O4N3ClS[M+H]+:602.1875,found:602.1873.1HNMR(400MHz,CDCl3)δ:7.82-7.57(m,4H),7.35(d,J＝8.5Hz,2H),7.29(dd,J＝7.8,3.2Hz,3H),6.80(d,J＝8.1Hz,1H),6.75(d,J＝8.1Hz,1H),4.72(dd,J＝14.2,6.4Hz,1H),4.59(dd,J＝14.2,5.6Hz,1H),3.51(t,J＝5.9Hz,1H),2.85(dd,J＝12.3,5.2Hz,1H),2.45(s,3H),2.26(dd,J＝11.3,3.6Hz,1H),2.20-2.06(m,2H),2.00(s,1H),1.95(s,3H),1.89(dd,J＝11.4,1.5Hz,1H),1.74-1.53(m,2H),1.36(qd,J＝12.7,5.9Hz,1H),1.08(s,3H).13C NMR(100MHz,CDCl3)δ:218.39,147.52,146.85,145.66,143.68,143.00,133.98,133.16,129.94,129.20,129.06,128.92,128.28,127.05,122.00,121.35,120.86,51.27,51.03,50.65,49.35,48.69,48.33,43.49,36.56,22.36,21.81,19.80,12.93。
化合物C55的制备：
制备方法同化合物C48，将苯乙炔改成4-氟苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C55，40.6mg，收率63％。熔点:180-182℃。
IRνmax(cm-1):2926,2868,1740,1597,1561,1497,1467,1370,1223,1178,1094,1046,888,841,771,716,813,552.HRMS(ESI)m/z calculated for C33H33O4N3FS[M+H]+:586.2170,found:586.2169.1H NMR(400MHz,CDCl3)δ:7.98-7.73(m,2H),7.69(d,J＝8.2Hz,2H),7.30(d,J＝7.8Hz,3H),7.08(t,J＝8.7Hz,2H),6.80(d,J＝8.1Hz,1H),6.75(d,J＝8.1Hz,1H),4.72(dd,J＝14.2,6.4Hz,1H),4.58(dd,J＝14.2,5.5Hz,1H),3.52(t,J＝6.0Hz,1H),2.86(dd,J＝12.2,5.1Hz,1H),2.45(s,3H),2.26(dd,J＝11.4,3.5Hz,1H),2.19-2.05(m,2H),2.00(s,1H),1.95(s,3H),1.91-1.84(m,1H),1.72-1.54(m,2H),1.36(qd,J＝12.7,6.0Hz,1H),1.07(s,3H).13C NMR(101MHz,CDCl3)δ:218.41,163.92,161.46,147.50,147.01,145.64,143.66,143.03,133.13,129.92,129.17,128.27,127.55,127.47,126.64,126.61,121.95,121.31,120.51,115.92,115.71,51.25,51.01,50.62,49.28,48.66,48.29,43.46,36.54,22.34,21.78,19.77,12.89.
C40-C47的制备反应式如下：
Figure BDA0001613015610000521
上述制备步骤如下：
化合物29的合成：
将化合物17(3.50g，8.16mmol)溶于二氯甲烷(45mL)中，依次加入二氧化硒(452.9mg，4.08mmol)和70％的过氧化叔丁醇水溶液(3.15g，24.48mmol)，室温反应4h，反应结束，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物29，2.83g，收率78％。
1H NMR(400MHz,CDCl3)δ:6.81(d,J＝8.0Hz,1H),6.67(d,J＝8.0Hz,1H),5.45(s,1H),5.41(d,J＝1.3Hz,1H),4.53(s,1H),3.76(s,1H),3.63(s,4H),3.35(d,J＝7.7Hz,1H),3.06(s,1H),2.14(s,3H),2.11–2.03(m,1H),2.03–1.97(m,1H),1.85–1.60(m,3H),1.44–1.33(m,1H),1.01(s,9H),0.21(d,J＝1.4Hz,6H).13C NMR(100MHz,CDCl3)δ:173.56,159.06,152.58,140.52,138.05,126.69,119.84,117.57,112.34,77.64,76.32,59.79,54.16,52.12,45.22,44.42,37.81,25.88,21.06,18.35,13.21,-4.13.
化合物30的合成：
在氮气保护下，将化合物29(2.83g，6.36mmol)溶于无水的四氢呋喃(45mL)中，在冰水浴的条件下分批加入四氢铝锂(483.3mg，12.72mmol)，加完后移除冰水浴，在室温反应4h，反应结束，缓慢加入30mL冰水，水相用乙酸乙酯(3×60mL)萃取，合并有机相，依次用水(2×20mL)、饱和食盐水(2×20mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物30，2.33g，收率88％。
1H NMR(400MHz,CDCl3)δ:6.77(d,J＝8.0Hz,1H),6.61(d,J＝7.9Hz,1H),5.80(s,1H),5.46(s,1H),5.38(d,J＝16.8Hz,2H),4.56(s,1H),4.05(s,1H),3.70(t,J＝10.8Hz,1H),3.56(d,J＝10.7Hz,1H),3.16(dd,J＝10.6,2.8Hz,1H),3.07(d,J＝7.5Hz,1H),2.15(s,3H),2.13–2.06(m,1H),2.02–1.88(m,1H),1.82–1.57(m,3H),1.33(d,J＝10.8Hz,1H),1.02(s,9H),0.21(d,J＝3.6Hz,6H).13C NMR(100MHz,CDCl3)δ:158.10,152.70,142.71,136.65,125.96,119.57,116.85,112.69,77.80,76.20,59.81,58.83,51.94,45.14,44.02,37.79,25.91,20.68,18.35,12.87,-4.09,-4.11.
化合物31的合成：
将化合物30(2.33g，5.59mmol)溶于无水的二氯甲烷(40mL)中，分别加入二异丙基乙胺(1.08g，8.39mmol)、对甲苯磺酰氯(1.06g，5.59mmol)、4-二甲氨基吡啶(136.4mg，1.12)，在室温反应10h，反应结束，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物31，2.68g。收率为84％。
1H NMR(400MHz,CDCl3)δ:7.58–7.52(m,2H),7.23(dd,J＝8.5,2.3Hz,2H),6.76(d,J＝8.0Hz,1H),6.62(d,J＝8.0Hz,1H),5.41(d,J＝2.0Hz,1H),5.34(s,1H),4.41(d,J＝1.8Hz,1H),4.29(qd,J＝9.9,5.7Hz,2H),3.14(dd,J＝11.2,5.4Hz,3H),3.04(d,J＝7.8Hz,1H),2.40(d,J＝2.0Hz,3H),2.10–2.00(m,1H),1.96(d,J＝11.2Hz,1H),1.92(s,3H),1.78–1.53(m,3H),1.26(dd,J＝10.7,1.9Hz,1H),1.01(s,9H),0.20(d,J＝11.2Hz,6H).13C NMR(100MHz,CDCl3)δ:159.21,152.61,144.83,141.49,137.28,132.28,129.80,127.82,126.31,119.76,117.23,112.26,77.36,75.71,68.90,58.21,47.90,44.80,44.17,37.99,25.86,21.68,20.91,18.29,13.04,-4.08,-4.23.
化合物32的合成：
将化合物31(2.68g，4.69mmol)和叠氮化钠(914.6mg，14.07mmol)溶于无水的N,N-二甲基甲酰胺(50mL)。在氮气保护下，80℃反应3h，反应结束后，加入50mL水，水相用乙酸乙酯(3×90mL)萃取，合并有机相，依次用水(3×18mL)、饱和食盐水(4×25mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物32，1.49g。产率为72％。
1H NMR(400MHz,CDCl3)δ:6.80(d,J＝8.0Hz,1H),6.65(d,J＝8.0Hz,1H),5.45(s,1H),5.39(s,1H),4.47(s,1H),3.77(d,J＝2.9Hz,1H),3.66(dd,J＝12.5,8.4Hz,1H),3.52(dd,J＝12.5,4.6Hz,1H),3.33(s,1H),3.17–2.99(m,2H),2.18(s,3H),2.15–2.04(m,1H),2.03–1.95(m,1H),1.86–1.55(m,3H),1.27(dd,J＝10.8,1.8Hz,1H),1.02(s,9H),0.21(d,J＝5.2Hz,6H).13C NMR(100MHz,CDCl3)δ:158.60,152.75,143.09,136.89,125.86,119.82,117.22,112.43,77.40,75.75,58.81,50.27,48.46,44.81,43.75,37.91,25.86,20.88,18.30,13.07,-4.11,-4.20.
化合物C40的制备：
将化合物32(70mg，0.16mmol)、苯乙炔(32.6mg，0.32mmol)、醋酸铜(48.0mg，0.24mmol)、抗坏血酸钠(63.4mg，0.32mmol)、水(2mL)和四氢呋喃(10mL)混合，室温反应11h，反应结束，加入14mL水，水相用乙酸乙酯(3×24mL)萃取，合并有机相，依次用水(8mL)、饱和食盐水(2×12mL)洗，用无水硫酸钠干燥，减压蒸干，未经进一步纯化，粗产品溶于无水的二氯甲烷(10mL)，加入戴斯-马丁氧化剂(135.7mg，0.32mmol)，室温反应4.5h，反应完毕后，加入11mL水，用二氯甲烷(3×24mL)萃取，合并有机相，依次用水(10mL)、饱和食盐水(2×10mL)洗，用无水硫酸钠干燥，减压蒸干，未经进一步纯化，溶于无水的四氢呋喃(10mL)中，加入三水合四丁基氟化铵(55.6mg，0.18mmol)，室温反应1h，反应结束，加入10mL水，用乙酸乙酯(3×25mL)萃取，合并有机相，依次用水(8mL)、饱和食盐水(3×12mL)洗，用无水硫酸钠干燥，减压蒸干，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C40，2.0mg，三步总收率45％。熔点:165-167℃。
IRνmax(cm-1):3387,2932,2864,1722,1642,1601,1464,1264,1081,1054,821,765,694.HRMS(ESI)m/z calculated for C26H26O3N3[M+H]+:428.1969,found:428.1969.1H NMR(400MHz,MeOD)δ:7.95(d,J＝2.4Hz,1H),7.72(d,J＝7.5Hz,2H),7.39(td,J＝7.6,1.7Hz,2H),7.35–7.19(m,1H),6.90(d,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),6.17(s,1H),5.58(s,1H),5.54(d,J＝5.5Hz,1H),4.62(ddd,J＝14.5,8.9,2.2Hz,1H),3.68(dd,J＝8.9,5.4Hz,1H),3.48(d,J＝6.8Hz,1H),2.45–2.23(m,1H),1.88–1.76(m,4H),1.67(d,J＝11.1Hz,1H),1.50(s,3H).13C NMR(100MHz,MeOD)δ:205.02,155.80,154.52,148.54,144.27,134.05,131.60,129.93,129.27,126.63,124.06,123.65,121.52,118.09,114.59,75.63,65.21,51.06,50.05,47.76,45.76,38.26,21.96,11.64.
化合物C41的制备：
制备方法同化合物C40，将苯乙炔改成4-溴苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C41，34.8mg，三步总收率43％。熔点:157-160℃。
IRνmax(cm-1):3405,2931,2864,1722,1642,1602,1454,1336,1263,1179,1070,1010,972,821,652,514.HRMS(ESI)m/z calculated for C26H25O3N3Br[M+H]+:506.1074,found:[M+H]+506.1072,[M+2+H]+508.1059.1H NMR(400MHz,MeOD)δ:8.00(s,1H),7.65(d,J＝8.4Hz,2H),7.55(d,J＝8.3Hz,2H),6.90(d,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),6.17(s,1H),5.68–5.50(m,2H),4.62(dd,J＝14.1,8.8Hz,1H),3.68(dd,J＝8.7,5.5Hz,1H),3.48(d,J＝7.1Hz,1H),2.32(dd,J＝11.5,3.9Hz,1H),1.83(tt,J＝9.4,4.1Hz,4H),1.67(d,J＝11.1Hz,1H),1.51(s,3H).13C NMR(100MHz,MeOD)δ:205.03,155.82,154.54,147.42,144.23,134.06,133.08,130.84,128.32,124.02,123.90,122.92,121.54,118.10,114.62,75.64,65.21,51.04,50.10,47.78,45.77,38.28,21.97,11.65.
化合物C42的制备：
制备方法同化合物C40，将苯乙炔改成4-甲氧基苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C42，34.4mg，三步总收率47％。熔点：157-158℃。
IRνmax(cm-1):3394,2933,2864,1722,1642,1618,1500,1457,1249,1176,836,732,534.HRMS(ESI)m/z calculated for C27H28O4N3[M+H]+:458.2074,found:458.2076.1H NMR(400MHz,CDCl3)δ:7.65(d,J＝8.7Hz,2H),7.59(s,1H),6.97–6.85(m,2H),6.81(d,J＝8.0Hz,1H),6.77–6.70(m,2H),6.16(s,1H),5.61(s,1H),5.53(dd,J＝14.0,5.7Hz,1H),4.44(dd,J＝14.1,7.5Hz,1H),3.80(s,3H),3.60(t,J＝6.7Hz,1H),3.39(d,J＝5.7Hz,1H),2.21(d,J＝7.8Hz,1H),1.96–1.71(m,6H),1.63(s,3H).13C NMR(100MHz,CDCl3)δ:203.99,159.67,154.02,152.67,147.24,143.12,133.47,127.24,123.12,122.83,121.07,120.64,118.44,114.50,114.40,75.27,63.76,55.46,50.36,48.94,46.88,45.29,37.13,21.28,11.56.
化合物C43的制备：
制备方法同化合物C40，将苯乙炔改成2-乙炔吡啶，经柱层析(石油醚/乙酸乙酯＝1:2)得白色固体即化合物C43，27.8mg，三步总收率38％。熔点:164-166℃。
IRνmax(cm-1):3404,2932,2864,1722,1642,1602,1473,1422,1264,1054,997,822,784,742.HRMS(ESI)m/z calculated for C25H25O3N4[M+H]+:429.1921,found:429.1922.
1H NMR(400MHz,MeOD)δ:8.53(d,J＝4.9Hz,1H),8.21(s,1H),8.05(d,J＝7.9Hz,1H),7.90(td,J＝7.8,1.7Hz,1H),7.40–7.28(m,1H),6.90(d,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),6.18(s,1H),5.64–5.53(m,2H),4.71(dd,J＝14.1,8.4Hz,1H),3.72(dd,J＝8.4,5.6Hz,1H),3.50(d,J＝6.9Hz,1H),3.36(s,1H),2.38–2.26(m,1H),1.91–1.79(m,4H),1.69(d,J＝11.1Hz,1H),1.57(s,3H).13C NMR(100MHz,MeOD)δ:205.01,155.84,154.55,150.95,150.32,148.24,144.13,138.89,134.06,125.57,124.42,123.94,121.51,121.45,118.07,114.63,75.64,65.13,51.05,50.14,47.80,45.81,38.29,21.96,11.70.
化合物C44的制备：
制备方法同化合物C40，将苯乙炔改成4-三氟甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C44，29.4mg，三步总收率37％。熔点：160-161℃。
IRνmax(cm-1):3397,2934,2866,1724,1663,1325,1265,1167,1123,1065,849,822,733.HRMS(ESI)m/z calculated for C27H25O3N3F3[M+H]+:496.1843,found:496.1847.1HNMR(400MHz,MeOD)δ:8.13(s,1H),7.92(d,J＝8.0Hz,2H),7.70(d,J＝8.1Hz,2H),6.91(d,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),6.17(s,1H),5.57(q,J＝6.5,5.5Hz,2H),4.66(dd,J＝9.2,5.1Hz,1H),3.70(dd,J＝8.7,5.7Hz,1H),3.49(d,J＝7.0Hz,1H),2.42–2.24(m,1H),2.00–1.73(m,5H),1.67(d,J＝11.0Hz,1H),1.52(s,3H).13C NMR(101MHz,MeOD)δ:205.03,155.85,154.53,147.03,144.21,135.54,134.07,131.35,131.02,130.70,130.38,126.96,126.91,126.87,126.83,124.70,124.25,124.01,121.57,118.13,114.64,75.66,65.22,51.02,50.15,47.79,45.77,38.28,21.96,11.66.
化合物C45的制备：
制备方法同化合物C40，将苯乙炔改成4-甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C45，29.7mg，三步总收率42％。熔点:154-156℃。
IRνmax(cm-1):3404,2931,2865,1723,1642,1601,1453,1264,1183,1081,1054,820,519.HRMS(ESI)m/z calculated for C27H28O3N3[M+H]+:442.2125,found:442.2126.1HNMR(400MHz,MeOD)δ:7.90(s,1H),7.60(d,J＝8.0Hz,2H),7.21(d,J＝7.9Hz,2H),6.90(d,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),6.17(s,1H),5.67–5.49(m,2H),4.60(dd,J＝14.1,8.9Hz,1H),3.67(dd,J＝8.9,5.4Hz,1H),3.48(d,J＝7.0Hz,1H),2.30-2.35(s,4H),1.85(ddt,J＝25.4,9.6,5.8Hz,4H),1.66(d,J＝11.1Hz,1H),1.49(s,3H).13C NMR(100MHz,MeOD)δ:205.04,155.81,154.57,148.65,144.31,139.31,134.05,130.53,128.79,126.59,124.09,123.30,121.51,118.06,114.58,75.64,65.24,51.09,50.04,47.78,45.78,38.28,21.97,21.30,11.62.
化合物C46的制备：
制备方法同化合物C40，将苯乙炔改成4-氯苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C46，28.8mg，三步总收率39％。熔点:162-165℃。
IRνmax(cm-1):3374,2931,2863,1722,1642,1601,1455,1336,1263,1092,1054,820,653,517.HRMS(ESI)m/z calculated for C26H25O3N3Cl[M+H]+:462.1579,found:462.1581.1H NMR(400MHz,MeOD)δ:7.98(s,1H),7.70(d,J＝8.4Hz,2H),7.39(d,J＝8.3Hz,2H),6.90(d,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),6.16(s,1H),5.65–5.48(m,2H),4.61(dd,J＝14.1,8.7Hz,1H),3.68(dd,J＝8.7,5.5Hz,1H),3.47(d,J＝7.0Hz,1H),2.32(dt,J＝12.0,2.7Hz,1H),1.96–1.73(m,4H),1.67(d,J＝11.0Hz,1H),1.51(s,3H).13C NMR(100MHz,MeOD)δ:205.02,155.81,154.52,147.39,144.22,134.90,134.05,130.41,130.07,128.05,124.02,123.87,121.54,118.10,114.61,79.42,65.19,51.02,50.08,47.77,45.75,38.26,21.96,11.65.
化合物C47的制备：
制备方法同化合物C40，将苯乙炔改成4-氟苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C47，25.6mg，三步总收率36％。熔点:161-163℃。
IRνmax(cm-1):3405,2933,2865,1723,1643,1602,1498,1458,1337,1264,1226,1157,1055,841,815,526.HRMS(ESI)m/z calculated for C26H25O3N3F[M+H]+:446.1874,found:446.1873.1H NMR(400MHz,MeOD)δ:7.85(s,1H),7.70–7.56(m,2H),7.03(t,J＝8.7Hz,2H),6.80(d,J＝8.0Hz,1H),6.58(d,J＝8.0Hz,1H),6.06(s,1H),5.67–5.33(m,2H),4.51(dd,J＝14.0,8.7Hz,1H),3.57(dd,J＝8.8,5.5Hz,1H),3.38(d,J＝7.0Hz,1H),3.20(p,J＝1.6Hz,1H),2.22(dt,J＝12.4,2.7Hz,1H),1.82–1.64(m,4H),1.56(d,J＝11.1Hz,1H),1.39(s,3H).13C NMR(100MHz,MeOD)δ:205.04,165.27,162.82,155.83,154.56,147.65,144.28,134.07,128.63,128.55,128.11,128.08,124.07,123.57,121.54,118.09,116.86,116.64,114.61,75.65,65.24,51.07,50.08,47.78,45.78,38.29,21.97,11.62.
C56-C62的制备反应式如下：
Figure BDA0001613015610000581
上述制备方法步骤如下：
化合物27的合成：
将化合物20(2.00g，4.54mmol)溶于二氯甲烷(35mL)中，依次加入二氧化硒(252.0mg，2.27mmol)和70％的过氧化叔丁醇水溶液(1.75g，13.62mmol)，室温反应4h，反应结束，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物27，1.42g，收率71％。
1H NMR(400MHz,CDCl3)δ:7.68(d,J＝8.2Hz,2H),7.30(d,J＝8.2Hz,2H),6.65(t,J＝8.5Hz,1H),6.58(t,J＝7.5Hz,1H),4.17–4.08(m,1H),4.04(dd,J＝10.4,3.9Hz,1H),3.17–3.05(m,2H),2.42(s,3H),2.15(dd,J＝12.9,5.1Hz,1H),2.09–1.99(m,2H),1.95(s,3H),1.92–1.86(m,2H),1.58(dtd,J＝17.8,12.7,5.1Hz,2H),1.38–1.25(m,1H),1.23(s,1H),1.05(s,3H).13C NMR(101MHz,CDCl3)δ:221.23,153.50,145.16,140.36,136.09,132.46,129.96,127.90,121.51,120.63,114.26,67.86,50.66,50.51,50.12,48.47,48.02,44.20,36.80,25.83,22.57,21.67,19.79,11.90.
化合物28的合成：
将化合物27(1.42g，3.22mmol)和叠氮化钠(627.9mg，9.66mmol)溶于无水的N,N-二甲基甲酰胺(24mL)。在氮气保护下，80℃反应2.5h，反应结束后，加入30mL水，水相用乙酸乙酯(3×65mL)萃取，合并有机相，依次用水(3×15mL)、饱和食盐水(4×20mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物28，741.1mg。产率为74％。
1H NMR(400MHz,CDCl3)δ:6.72(d,J＝7.9Hz,1H),6.60(d,J＝7.9Hz,1H),6.05(s,1H),3.54–3.40(m,2H),3.19(dd,J＝12.4,5.2Hz,1H),3.03(t,J＝6.6Hz,1H),2.24-2.19(m,4H),2.12(dd,J＝6.6,2.6Hz,1H),2.09–2.05(m,1H),2.00(dd,J＝11.4,3.6Hz,1H),1.93(d,J＝18.8Hz,1H),1.73–1.58(m,2H),1.36(qd,J＝12.8,5.9Hz,1H),1.12(s,3H).13CNMR(100MHz,CDCl3)δ:221.48,153.40,153.37,142.60,136.17,136.13,121.29,121.27,120.66,114.11,50.89,50.83,50.48,50.39,48.75,48.13,44.42,37.01,22.70,19.93,12.19.
化合物C56的制备：
将化合物28(50mg，0.16mmol)、苯乙炔(32.6mg，0.32mmol)、醋酸铜(48.0mg，0.24mmol)、抗坏血酸钠(63.4mg，0.32mmol)、水(2mL)和四氢呋喃(8mL)混合，反应12h，反应结束，加入8mL水，用乙酸乙酯(3×24mL)萃取，合并有机相，依次用水(6mL)、饱和食盐水(2×10mL)洗，用无水硫酸钠干燥，减压蒸干，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C56，46.4mg，收率70％，熔点:151-154℃。
IRνmax(cm-1):3367,2925,2867,1736,1599,1458,1361,1265,1054,972,912,817,765,729,695.HRMS(ESI)m/z calculated for C26H28O2N3[M+H]+:414.2176,found:414.2177.1H NMR(400MHz,CDCl3)δ:7.73(dd,J＝7.1,1.7Hz,2H),7.43-7.35(m,3H),7.33-7.29(m,1H),7.23(s,1H),6.72(s,2H),4.70(dd,J＝14.0,6.9Hz,1H),4.45(dd,J＝14.0,6.3Hz,1H),3.52(t,J＝6.6Hz,1H),2.93(dd,J＝12.2,5.2Hz,1H),2.28-2.01(m,3H),1.95(s,1H),1.90(s,3H),1.75(d,J＝11.4Hz,1H),1.57(ddt,J＝25.5,12.8,6.3Hz,2H),1.32(qd,J＝16.0,14.4,4.1Hz,1H),1.02(s,3H).13C NMR(100MHz,CDCl3)δ:220.19,153.91,147.87,142.25,135.84,130.18,128.98,128.42,125.83,121.71,121.02,120.71,114.50,51.22,50.89,50.71,49.78,48.66,47.97,43.49,36.86,22.72,19.83,11.83.
化合物C57的制备：
制备方法同化合物C56，将苯乙炔改成4-甲氧基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C57，56.1mg，收率79％。熔点:165-167℃。
IRνmax(cm-1):3383,2925,1738,1661,1617,1562,1500,1457,1362,1250,1175,1031,835,726,534.HRMS(ESI)m/z calculated for C27H30O3N3[M+H]+:444.2282,found:444.2281.1H NMR(400MHz,CDCl3)δ:7.65(d,J＝8.7Hz,2H),7.31(s,1H),7.15(s,1H),6.90(d,J＝8.8Hz,2H),6.72(s,2H),4.68(dd,J＝14.0,7.0Hz,1H),4.43(dd,J＝14.0,6.3Hz,1H),3.80(s,3H),3.51(t,J＝6.6Hz,1H),2.93(dd,J＝12.7,5.6Hz,1H),2.28-2.01(m,3H),1.92(d,J＝20.8Hz,4H),1.74(d,J＝11.3Hz,1H),1.66-1.50(m,2H),1.32(ddd,J＝25.6,12.8,5.6Hz,1H),1.02(s,3H).13C NMR(100MHz,CDCl3)δ:220.04,159.77,153.93,147.76,142.35,135.90,127.17,122.96,121.72,121.04,119.89,114.48,114.40,55.43,51.24,50.95,50.70,49.73,48.69,48.01,43.52,36.88,22.74,19.85,11.83.
化合物C58的制备：
制备方法同化合物C56，将苯乙炔改成2-乙炔基吡啶，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C58，40.5mg，收率61％。熔点:142-145℃。
IRνmax(cm-1):3377,2925,2867,1736,1600,1473,1422,1365,1266,1096,1052,911,785,731.HRMS(ESI)m/z calculated for C25H27O2N4[M+H]+:415.2129,found:415.2130.1H NMR(400MHz,CDCl3)δ:8.67–8.40(m,1H),8.33–8.11(m,1H),7.99(s,1H),7.87–7.69(m,2H),7.26–7.21(m,1H),6.71(d,J＝7.9Hz,1H),6.64(d,J＝7.9Hz,1H),4.74(dd,J＝14.1,7.6Hz,1H),4.49(dd,J＝14.1,5.3Hz,1H),3.54(dd,J＝7.6,5.4Hz,1H),3.02–2.91(m,1H),2.26–2.06(m,3H),1.99(s,3H),1.91(d,J＝18.8Hz,1H),1.70(d,J＝11.4Hz,1H),1.65–1.48(m,2H),1.34(qd,J＝12.7,5.9Hz,1H),1.00(s,3H).13C NMR(100MHz,CDCl3)δ:219.73,154.13,149.88,149.15,147.97,142.10,137.57,135.81,123.26,123.02,121.71,121.02,120.72,114.56,51.20,51.10,50.70,49.75,48.81,48.05,43.56,36.87,22.76,19.87,11.99。
化合物C59的制备：
制备方法同化合物C56，将苯乙炔改成4-三氟甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C59，60.2mg，收率78％。熔点:148-152℃。
IRνmax(cm-1):3412,2927,1736,1622,1458,1326,1166,1124,1064,849,728,598.HRMS(ESI)m/z calculated for C27H27O2N3F3[M+H]+:482.2050,found:482.2053.1HNMR(400MHz,CDCl3)δ:7.83(d,J＝8.1Hz,2H),7.62(d,J＝8.1Hz,2H),7.43(s,1H),6.82-6.62(m,3H),4.74(dd,J＝14.0,6.8Hz,1H),4.49(dd,J＝14.0,6.4Hz,1H),3.53(t,J＝6.6Hz,1H),2.92(dd,J＝12.2,5.2Hz,1H),2.30-2.03(m,3H),1.94(d,J＝19.6Hz,1H),1.87(s,3H),1.79(d,J＝10.9Hz,1H),1.59(ddt,J＝25.5,12.8,6.3Hz,2H),1.33(qd,J＝12.8,5.7Hz,1H),1.04(s,3H).13C NMR(100MHz,CDCl3)δ:220.07,153.79,146.56,142.23,136.05,133.70,130.68,130.36,130.04,129.71,126.00,125.97,125.92,125.46,122.76,121.67,121.44,121.15,114.53,51.30,50.92,50.78,49.93,48.68,48.05,43.56,36.88,22.73,19.83,11.80.
化合物C60的制备：
制备方法同化合物C56，将苯乙炔改成4-甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C60，52.0mg，收率76％。熔点:156-158℃。
IRνmax(cm-1):3374,2925,2867,1736,1599,1499,1456,1361,1266,1223,1054,910,818,727,518.HRMS(ESI)m/z calculated for C27H30O2N3[M+H]+:428.2333,found:428.2333.1H NMR(400MHz,CDCl3)δ:7.63(d,J＝7.9Hz,2H),7.37(s,1H),7.19(d,J＝7.9Hz,2H),6.72(s,2H),4.69(dd,J＝14.0,7.0Hz,1H),4.44(dd,J＝14.0,6.3Hz,1H),3.52(t,J＝6.6Hz,1H),2.93(dd,J＝12.2,5.2Hz,1H),2.35(s,3H),2.25–1.98(m,4H),1.96(d,J＝10.1Hz,1H),1.90(s,3H),1.74(d,J＝11.3Hz,1H),1.58(dtd,J＝17.8,12.8,5.1Hz,2H),1.43–1.24(m,1H),1.02(s,3H).13C NMR(100MHz,CDCl3)δ:220.14,153.91,147.95,142.29,138.31,135.86,129.65,127.37,125.75,121.70,121.01,120.35,114.49,51.23,50.92,50.70,49.75,48.68,47.98,43.50,36.87,22.73,21.36,19.84,11.82.
化合物C61的制备：
制备方法同化合物C56，将苯乙炔改成4-氯苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C61，53.8mg，收率75％。熔点:153-156℃。IRνmax(cm-1):3397,2925,2868,1735,1600,1484,1456,1361,1266,1093,1054,973,835,730,517.HRMS(ESI)m/z calculated for C26H27O2N3Cl[M+H]+:448.1786,found:448.1788.1H NMR(400MHz,CDCl3)δ:7.78-7.56(m,2H),7.38-7.31(m,3H),6.86(s,1H),6.79-6.60(m,2H),4.71(dd,J＝14.0,6.8Hz,1H),4.45(dd,J＝14.0,6.4Hz,1H),3.51(t,J＝6.6Hz,1H),2.93(dt,J＝12.2,6.2Hz,1H),2.19-2.05(m,3H),1.93(d,J＝18.9Hz,1H),1.86(s,3H),1.77(d,J＝11.3Hz,1H),1.58(ddt,J＝25.5,12.8,6.4Hz,2H),1.43-1.25(m,1H),1.03(s,3H).13C NMR(100MHz,CDCl3)δ:220.04,153.79,146.87,142.26,135.99,134.15,129.18,128.75,127.08,121.67,121.10,120.74,114.50,51.27,50.92,50.74,49.85,48.67,48.03,43.54,36.88,22.73,19.85,11.80.
化合物C62的制备：
制备方法同化合物C56，将苯乙炔改成4-氟苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C62，47.7mg，收率69％。熔点:146-147℃。
IRνmax(cm-1):3393,2926,2868,1736,1599,1561,1498,1458,1362,1266,1224,1157,1097,1054,841,815,728,526.HRMS(ESI)m/z calculated for C26H27O2N3F[M+H]+:432.2082,found:432.2084.1H NMR(400MHz,CDCl3)δ:7.78-7.55(m,2H),7.33(s,1H),7.06(t,J＝8.6Hz,2H),6.85(s,1H),6.79-6.61(m,2H),4.72(dd,J＝14.0,6.9Hz,1H),4.46(dd,J＝14.0,6.4Hz,1H),3.52(t,J＝6.6Hz,1H),2.99-2.90(m,1H),2.29-2.01(m,3H),1.94(d,J＝19.0Hz,1H),1.88(s,3H),1.77(d,J＝11.3Hz,1H),1.59(ddt,J＝25.4,12.8,6.3Hz,2H),1.41-1.22(m,1H),1.03(s,3H).13C NMR(101MHz,CDCl3)δ:220.01,164.02,161.56,153.81,147.08,142.31,136.01,127.65,127.57,126.51,126.48,121.67,121.10,120.42,116.09,115.87,114.49,51.28,50.95,50.75,49.82,48.69,48.05,43.56,36.89,22.75,19.86,11.81.
效果实施例
本发明的活性测试采用了MTS的检测方法，MTS为MTT类似物，全称为3-(4，5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium。此方法通过活细胞线粒体中琥珀酸脱氢酶能够代谢还原MTS，生成可溶性的甲臜(Formazan)化合物，该化合物的光密度OD(490nM)值与活细胞数目成正比，通过光密度OD的测定值来衡量化合物的抗肿瘤活性。本发明挑选五种肿瘤细胞：HL-60,A549,SMMC-7721,MCF-7和SW480进行实验，检测以顺铂和紫杉醇作为阳性对照。化合物的IC50值通过浓度效应生长曲线计算确定。
MTS具体的检测方法参照：
[1]D.K.Kim,D.H.Ryu,J.Y.Lee,N.Lee,Y.W.Kim,J.S.Kim,K.Chang,G.J.Im,T.K.Kim and W.S.Choi,Journal of medicinal chemistry,2001,44,1594-1602；
[2]R.Cao,Q.Chen,X.Hou,H.Chen,H.Guan,Y.Ma,W.Peng and A.Xu,Bioorganic&medicinal chemistry,2004,12,4613-4623。
部分化合物按照MTT方法进行了白血病、肝癌、肺癌、乳腺癌和结肠癌5种细胞株的抗肿瘤细胞毒活性筛选，其半数抑制剂量(IC50值，μM)测定结果与已商品化的抗癌药物——顺铂(DDP)和紫杉醇相比较于下表1和表2中。
表1化合物C1-C32,C36,B1,B2的细胞毒活性数据
Figure BDA0001613015610000621
Figure BDA0001613015610000631
表2化合物C33-C62,B3的细胞毒活性数据
Figure BDA0001613015610000632
Figure BDA0001613015610000641
以上活性数据显示化合物C21，C28，C30，C31具有一般的体外细胞毒活性。化合物C33，C34，C35，C37，C38，C39对乳腺癌细胞(MCF-7)具有显著的体外细胞毒活性。化合物C40，C41，C42，C43，C44，C45，C46，C47对结肠癌细胞(SW480)具有显著的体外细胞毒活性。化合物C45，C46，C47具有广谱的体外抗癌细胞毒活性。
化合物B1、B2和B3的结构如下所示：
Figure BDA0001613015610000642
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (13)

1.一种如下所示的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐：
Figure FDA0003909083930000011
其特征在于，R1为H或卤素；
R2为OH；
X为C；
R为H、卤素、C1-C6的烷基、卤素取代的C1-C6的烷基，或C1-C6的烷氧基。
2.一种如下所示的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐：
Figure FDA0003909083930000012
其特征在于，R1为H或卤素；
R2为H、OH或OTs；
X选自C或N；
R为H、卤素、C1-C6的烷基、卤素取代的C1-C6的烷基，或C1-C6的烷氧基。
3.如权利要求1或2所述的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐，其特征在于，
所述卤素为氟、氯、溴或碘；
和/或，所述C1-C6的烷基为C1-C4的烷基；
和/或，所述卤素取代的C1-C6的烷基中的卤素取代基的个数为一个或多个；
和/或，所述C1-C6的烷氧基为C1-C4的烷氧基。
4.如权利要求1或2所述的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐，其特征在于，
所述C1-C6的烷基为甲基，乙基，丙基，异丙基或正丁基；
和/或，所述卤素取代的C1-C6的烷基中的卤素取代基的个数为一个或多个；所述卤素为氟；
和/或，所述C1-C6的烷氧基为甲氧基，乙氧基或丙氧基。
5.如权利要求1所述的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐，其特征在于，
当所述R1为卤素时，所述R为卤素，或者卤素取代的C1-C6的烷基；
当所述R1为H时，所述R为卤素取代的C1-C6的烷基。
6.如权利要求2所述的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐，其特征在于，所述R2为OH或OTs。
7.如权利要求1或2所述的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐，所述类赤霉素化合物选自下列任一化合物：
Figure FDA0003909083930000021
Figure FDA0003909083930000031
8.一种如权利要求1所述的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐的制备方法，其包括以下步骤：在铜的催化作用下，将式VI所示的化合物式VII所示的化合物进行环加成反应，得到如权利要求1所述的化合物；其中，R3为CH3，
Figure FDA0003909083930000032
代表单键，R6为H，R8为OH，R7为CH2，R1，R2和R定义如权利要求1所述；
Figure FDA0003909083930000033
9.一种如权利要求2所述的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐的制备方法，其包括以下步骤：或在铜的催化作用下，将式VI所示的化合物式VII所示的化合物进行环加成反应，得到如权利要求2所述的化合物；其中，R3为CH3，
Figure FDA0003909083930000034
代表双键，R6为O，R8为OH，R7为CH2，R1，R2和R定义如权利要求2所述；
Figure FDA0003909083930000035
10.一种药物组合物，其特征在于，包括治疗有效量的如权利要求1-7任一项所述的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐，和一种或多种药学上可接受的载体或赋形剂。
11.如权利要求1-7任一项所述的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐在制备治疗和/或预防抗肿瘤药物中的应用。
12.如权利要求11所述的应用中，所述抗肿瘤药物为抗乳腺癌药物和/或抗肠癌药物。
13.一种如权利要求1-7任一项所述的类赤霉素化合物、其互变异构体、光学异构体或药学上可接受的盐的中间体如下所示：
Figure FDA0003909083930000041
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1560044A (zh) * 2004-02-27 2005-01-05 云南大学 3,15-二羰基赤霉酸类化合物及其酯和盐
WO2010062372A2 (en) * 2008-11-03 2010-06-03 President And Fellows Of Harvard College Methods for modulating nf-kb using gibberellins

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AR051597A1 (es) * 2004-11-01 2007-01-24 Merck & Co Inc Moduladores de los receptores de estrogeno
CN102108075A (zh) * 2009-12-28 2011-06-29 中国药科大学 由赤霉素ga3合成新颖衍生物的合成方法及其应用
WO2013142873A2 (en) * 2012-03-23 2013-09-26 The Board Of Trustees Of The University Of Illinois Complex and structurally diverse compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1560044A (zh) * 2004-02-27 2005-01-05 云南大学 3,15-二羰基赤霉酸类化合物及其酯和盐
WO2010062372A2 (en) * 2008-11-03 2010-06-03 President And Fellows Of Harvard College Methods for modulating nf-kb using gibberellins

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
<SOLID STATE PHOTOAROMATIZATIOIV OF 3-KEY!O-GIBBERELLIB A3>;G. Adam and B. Voigt;<Tetrahedron Letters>;19711027(第48期);全文 *

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