核苷连萘二酰亚胺衍生物及其合成方法和用途转让专利
申请号 : CN201210279911.3
文献号 : CN102775457B
文献日 : 2015-02-04
发明人 : 李小六 , 张平竹 , 魏超 , 张晓媛 , 李帅 , 陈华 , 王克让 , 杨海龙 , 张金超
申请人 : 河北大学
摘要 :
本发明公开了一种核苷连萘二酰亚胺衍生物及其制备方法和其在制备抗肿瘤药物制剂中的应用。该衍生物的制备方法为：（A）制备2-溴-1,4,5,8-萘四甲酸二酰亚胺和2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺；（B）将2-溴-1,4,5,8-萘四甲酸二酰亚胺与氨基取代核苷化合物混合，溶解于三乙胺，在微波辐射下反应，反应液经柱层析分离，得化学通式如（I）；（C）将2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺与氨基取代核苷化合物混合，溶解于三乙胺，在微波辐射下反应，再加入脂肪胺、芳香胺或氨基取代核苷的一种，反应液经柱层析分离，得化学通式如（II）。
权利要求 :
1.一种核苷连萘二酰亚胺衍生物，其特征是，所述核苷连萘二酰亚胺衍生物的化学通式如I或II所示：其中所述R为N,N-二甲基氨基或吡咯烷-1-基中的任意一种；m为1～7；n为1～
3；所述R1为5-甲基尿苷-5’-基、5-氟-2’-脱氧尿苷-5’-基中的任意一种；所述R2为N,N-二甲基氨基、N,N-二乙基氨基、吡咯烷-1-基、哌啶-1-基、苯基氨基、5-甲基尿苷-5’-氨基中的任意一种。
2.根据权利要求1所述核苷连萘二酰亚胺衍生物，其特征是，所述R为N,N-二甲基氨基，m为1～7，R1为5-甲基尿苷-5’-基。
3.根据权利要求1所述核苷连萘二酰亚胺衍生物，其特征是，所述R为N,N-二甲基氨基，m为1～7，R1为5-氟-2’-脱氧尿苷-5’-基。
4.根据权利要求1所述核苷连萘二酰亚胺衍生物，其特征是，所述R为吡咯烷-1-基，m为1～3，R1为5-甲基尿苷-5’-基。
5.根据权利要求1所述核苷连萘二酰亚胺衍生物，其特征是，所述R为N,N-二甲基氨基，m为1～3，R1为5-甲基尿苷-5’-基，n为1～3，R2为N,N-二甲基氨基、N,N-二乙基氨基、哌啶-1-基、吡咯烷-1-基、苯基氨基或5-甲基尿苷-5’-氨基中的任意一种。
6.根据权利要求5所述核苷连萘二酰亚胺衍生物，其特征是，所述R为N,N-二甲基氨基，m为1～3，R1为5-甲基尿苷-5’-基，n为1，R2为N,N-二甲基氨基。
7.根据权利要求5所述核苷连萘二酰亚胺衍生物，其特征是，所述R为N,N-二甲基氨基，m为1或3，R1为5-甲基尿苷-5’-基，n为1，R2为N,N-二乙基氨基、吡咯烷-1-基、哌啶-1-基、苯基氨基中的任意一种。
8.根据权利要求5所述核苷连萘二酰亚胺衍生物，其特征是，所述R为N,N-二甲基氨基，m为1～3，R1为5-甲基尿苷-5’-基，n为1～3，R2为5-甲基尿苷-5’-氨基。
9.根据权利要求1所述核苷连萘二酰亚胺衍生物，其特征是，所述R为吡咯烷-1-基，m为1～3，R1为5-甲基尿苷-5’-基，n为1，R2为吡咯烷-1-基。
10.一种权利要求1所述核苷连萘二酰亚胺衍生物的合成制备方法，其特征是，它包括以下步骤：
(A)2-溴-1,4,5,8-萘四甲酸二酰亚胺与2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺的制备(a)制备2-溴-1,4,5,8-萘四甲酸二酰亚胺：将1,4,5,8-萘四甲酸酐溶于发烟硫酸中，室温搅拌3h，加入I2，搅拌1h，分三批加入NaBr，每批间隔2h，其中1,4,5,8-萘四甲酸酐、I2和NaBr的用量按摩尔比为1:0.04:1.2计，在80℃的条件下，反应36h，冷却至室温后，加水过滤，得滤饼，将滤饼水洗，甲醇洗，干燥，得2-溴-1,4,5,8-萘四甲酸二酐；
将2-溴-1,4,5,8-萘四甲酸二酐溶于冰醋酸中，在18～25℃下滴加N,N-二甲基乙二胺或1-(2-氨乙基)吡咯烷，其中2-溴-1,4,5,8-萘四甲酸二酐与N,N-二甲基乙二胺或
1-(2-氨乙基)吡咯烷的摩尔比为1:10；氮气保护下，120℃油浴回流20min，冷却至室温，中和至弱碱性，萃取，洗涤，干燥，浓缩，硅胶色谱分离纯化，得2-溴-1,4,5,8-萘四甲酸二酰亚胺；
(b)制备2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺：将1,4,5,8-萘四甲酸酐溶于发烟硫酸中，室温搅拌3h，加入I2，搅拌1h，分五批加入NaBr，每批间隔1h，其中1,4,5,8-萘四甲酸酐、I2和NaBr的添加量按摩尔比为1:0.04:3.0计，在80℃的条件下，反应24h，加热至回流继续反应24h，冷却至室温，加水过滤，得滤饼，将滤饼水洗，甲醇洗，干燥，得固体产物2,6-二溴-1,4,5,8-萘四甲酸二酐；将固体产物溶于冰醋酸中，在18～25℃下滴加N,N-二甲基乙二胺或1-(2-氨乙基)吡咯烷，其中2,6-二溴-1,4,5,8-萘四甲酸二酐与N,N-二甲基乙二胺或1-(2-氨乙基)吡咯烷的摩尔比为1:10；氮气保护下，120℃油浴回流20min，冷却至室温，中和至弱碱性，萃取，洗涤，干燥，浓缩后经硅胶色谱分离纯化，得
2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺；
(B)化学通式(I)所示的化合物的制备
将2-溴-1,4,5,8-萘四甲酸二酰亚胺与氨基取代核苷化合物按摩尔比为1:1.0～1.2混合，得混合液，其中氨基取代核苷化合物为 R1为5-甲基尿苷-5’-基、
5-氟-2’-脱氧尿苷-5’-基中的任意一种，m为1～7；再将混合液溶于三乙胺中，120℃微波辐射下反应5min，将反应液浓缩，柱层析分离，得到化学通式(I)所示的化合物；
(C)化学通式(II)所示的化合物的制备
将2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺与氨基取代核苷化合物按摩尔比为1:1.2混合，得混合液，其中氨基取代核苷的化学通式为 m为1～7，R1为5-甲基尿苷-5’-基、5-氟-2’-脱氧尿苷-5’-基中的任意一种，再将混合液溶于三乙胺中，在120～150℃微波辐射下反应5min；在反应液中加入脂肪胺、芳香胺或氨基取代核苷，其中2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺与脂肪胺、芳香胺或氨基取代核苷的摩尔比为1:3，其中脂肪胺、芳香胺或氨基取代核苷的化学式通式为 n为1～3，R2为N,N-二甲基氨基、N,N-二乙基氨基、吡咯烷-1-基、哌啶-1-基、苯基氨基、5-甲基尿苷-5’-氨基中的任意一种；120℃微波辐射下反应15min；将反应液浓缩，柱层析分离，得到化学通式(II)所示的化合物。
11.权利要求1所述的核苷连萘二酰亚胺衍生物在制备抗肿瘤药物制剂中的应用。
说明书 :
核苷连萘二酰亚胺衍生物及其合成方法和用途
技术领域
[0001] 本发明涉及一种化合物及其合成方法和用途，具体地说是一种核苷连萘二酰亚胺衍生物及其合成方法和用途。
背景技术
[0002] 癌症，即恶性肿瘤，由于其早期症状隐匿、晚期病情发展迅速、易复发转移，已成为当今世界上死亡率最高的常见多发病之一。近20年期间，恶性肿瘤在死因中的构成比自12.6%升至17.9%，对人民的健康和社会的发展已构成严重的危害。因此，抗肿瘤药物研究长期以来一直被人们密切关注。
[0003] 近些年，针对癌症发生、发展的不同病理过程，有多种抗肿瘤药物用于临床，包括靶向作用于DNA及其相关过程的烷化剂、嵌插剂、核苷类抗代谢药物，及其它新靶点作用药物，如新生血管增生抑制剂、蛋白激酶抑制剂等。其中，以DNA为靶点的抗肿瘤药物研究一直是人们关注的焦点，它们通过嵌入DNA链、与沟槽结合等作用方式与DNA作用，干扰其复制和转录，抑制癌细胞增殖，达到治疗的目的。但是，由于这类抗肿瘤药物在杀伤癌细胞的同时，也可以非选择性地与正常细胞的DNA作用，对正常细胞造成损害，使其毒副作用大，长期使用易产生抗药耐药性。因此，深入系统研究高效低毒新型抗肿瘤药物已成为非常重要且急迫的目标和任务。
[0004] 恶性肿瘤的发生是多因素相互作用的结果，不能归结于单一因素的变化。大多数单个的配体（药物）和靶标如蛋白、DNA等的亲和力太弱，致使作用效率降低。因此，非常有必要针对目前抗肿瘤药物的亲和力弱、活性差的问题，以肿瘤细胞DNA为靶点，以增加药物分子与肿瘤细胞端粒DNA G-四链体多位点、多种方式的协同作用，提高与靶标的特异性识别及结合力，进一步开发高活性的抗肿瘤药物。
发明内容
[0005] 本发明的目的就是提供一种新的抗肿瘤药物，即核苷连萘二酰亚胺衍生物，同时提供该类化合物的制备方法及其在抗肿瘤药物制剂中的应用。
[0006] 一种核苷连萘二酰亚胺衍生物，其衍生物的化学通式如I或II所示：
[0007]
[0008] 其中R为脂肪氨基或脂肪环氨基；m为1～7；n为1～3；R1为核苷基；R2为核苷氨基、脂肪氨基、脂肪环氨基、杂环氨基或芳香氨基中的任意一种。
[0009] 所述R为N,N-二甲基氨基或吡咯烷-1-基中的任意一种；m为1～7；n为1～3；所述R1为5-甲基尿苷-5’-基、5-氟-2’-脱氧尿苷-5’-基或叠氮胸苷-5’-基中的任意一种；所述R2为N,N-二甲基氨基、N,N-二乙基氨基、吡咯烷-1-基、哌啶-1-基、苯基氨基、5-甲基尿苷-5’-氨基、吗啉-4-基、哌嗪-1-基、N-甲基哌嗪-4-基、卤代苯基氨基、硝基苯基氨基或烷氧基苯基氨基中的任意一种。
[0010] 所述R为N,N-二甲基氨基或吡咯烷-1-基中的任意一种；m为1～7；n为1～3；所述R1为5-甲基尿苷-5’-基、5-氟-2’-脱氧尿苷-5’-基中的任意一种；所述R2为N,N-二甲基氨基、N,N-二乙基氨基、吡咯烷-1-基、哌啶-1-基、苯基氨基、5-甲基尿苷-5’-氨基中的任意一种。
[0011] 所述R为N,N-二甲基氨基，m为1～7，R1为5-甲基尿苷-5’-基。
[0012] 所述R为N,N-二甲基氨基，m为1～7，R1为5-氟-2’-脱氧尿苷-5’-基。
[0013] 所述 R为吡咯烷-1-基，m为1～3，R1为5-甲基尿苷-5’-基。
[0014] 所述R为N,N-二甲基氨基，m为1～3，R1为5-甲基尿苷-5’-基，n为1～3，R2为N,N-二甲基氨基、N,N-二乙基氨基、哌啶-1-基、吡咯烷-1-基、苯基氨基或5-甲基尿苷-5’-氨基中的任意一种。
[0015] 所述R为N,N-二甲基氨基，m为1～3，R1为5-甲基尿苷-5’-基，n为1，R2为N,N-二甲基氨基。
[0016] 所述R为N,N-二甲基氨基，m为1或3，R1为5-甲基尿苷-5’-基，n为1，R2为N,N-二乙基氨基、吡咯烷-1-基、哌啶-1-基、苯基氨基中的任意一种。
[0017] 所述R为N,N-二甲基氨基，m为1～3，R1为5-甲基尿苷-5’-基，n为1～3，R2为5-甲基尿苷-5’-氨基。
[0018] 所述R为吡咯烷-1-基，m为1～3，R1为5-甲基尿苷-5’-基，n为1，R2为吡咯烷-1-基。
[0019] 本发明中基团的定义为：
[0020]
[0021] 本发明提供的核苷连萘二酰亚胺衍生物抗肿瘤药理实验表明，能够对A549，K-562和MCF-7人的肿瘤细胞株的增殖具显著的抑制作用，与药理上允许使用的载体均匀混合，按照常规的制剂方法可以制备成各种剂型的抗肿瘤药剂。
[0022] 如以本发明制备的化合物为活性成分，与水、蔗糖、山梨醇糖、果糖等组分组合制备成口服液体制剂；与赋形剂（蔗糖、葡萄糖、甘露糖、乳糖）、崩解剂（淀粉）、润滑剂（硬脂酸、滑石粉）、粘合剂（明胶）等组分组合制备成片剂或胶囊制剂。
[0023] 本发明还可作为活性成分与生理盐水、葡糖糖溶液或盐水与葡糖糖组成的混合载体制备成注射液。
[0024] 本发明在用于临床时可参考的有效剂量是：口服，一天总量0.8～1.2 g，分3～4次。医师也可依据患者个体差异，拟定服用剂量。
[0025] 由此，本申请人完成了该化合物用于抗肿瘤制剂的用途发明。
[0026] 本发明提供的核苷连萘二酰亚胺衍生物的合成制备方法，它包括以下步骤：
[0027] A、2-溴-1,4,5,8-萘四甲酸二酰亚胺与2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺的制备
[0028] a、制备2-溴-1,4,5,8-萘四甲酸二酰亚胺：将1,4,5,8-萘四甲酸酐溶于发烟硫酸中，室温搅拌3 h，加入I2，搅拌1 h，分三批加入NaBr，每批间隔2 h，其中1,4,5,8-萘四甲酸酐、I2和NaBr的用量按摩尔比为1:0.04:1.2计，在80℃的条件下，反应36 h，冷却至室温后，加水过滤，得滤饼，将滤饼水洗，甲醇洗，干燥，得2-溴-1,4,5,8-萘四甲酸二酐；将2-溴-1,4,5,8-萘四甲酸二酐溶于冰醋酸中，在18～25℃下滴加N,N-二甲基乙二胺或1-(2-氨乙基)吡咯烷，其中2-溴-1,4,5,8-萘四甲酸二酐与N,N-二甲基乙二胺或1-(2-氨乙基)吡咯烷的摩尔比为1:10；氮气保护下，120℃油浴回流20 min，冷却至室温，中和至弱碱性，萃取，洗涤，干燥，浓缩，硅胶色谱分离纯化，得2-溴-1,4,5,8-萘四甲酸二酰亚胺；
[0029] b、制备2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺：将1,4,5,8-萘四甲酸酐溶于发烟硫酸中，室温搅拌3 h，加入I2，搅拌1 h，分五批加入NaBr，每批间隔1 h，其中1,4,5,8-萘四甲酸酐、I2和NaBr的添加量按摩尔比为1:0.04:3.0计，在80℃的条件下，反应24 h，加热至回流继续反应24 h，冷却至室温，加水过滤，得滤饼，将滤饼水洗，甲醇洗，干燥，得固体产物；将固体产物溶于冰醋酸中，在18～25℃下滴加N,N-二甲基乙二胺或1-(2-氨乙基)吡咯烷，其中2-溴-1,4,5,8-萘四甲酸二酐与N,N-二甲基乙二胺或
1-(2-氨乙基)吡咯烷的摩尔比为1:10；氮气保护下，120℃油浴回流20 min，冷却至室温，中和至弱碱性，萃取，洗涤，干燥，浓缩后经硅胶色谱分离纯化，得2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺；
1-(2-氨乙基)吡咯烷的摩尔比为1:10；氮气保护下，120℃油浴回流20 min，冷却至室温，中和至弱碱性，萃取，洗涤，干燥，浓缩后经硅胶色谱分离纯化，得2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺；
[0030] B、化学通式（I）所示的化合物的制备
[0031] 将2-溴-1,4,5,8-萘四甲酸二酰亚胺与氨基取代核苷化合物按摩尔比为1:1.0～1.2混合，得混合液，其中氨基取代核苷化合物为 ，R1为5-甲基尿
苷-5’-基、5-氟-2’-脱氧尿苷-5’-基或叠氮胸苷-5’-基中的任意一种，m为1～7；
再将混合液溶于三乙胺中，120℃微波辐射下反应5 min，将反应液浓缩，柱层析分离，得到化学通式（I）所示的化合物；
苷-5’-基、5-氟-2’-脱氧尿苷-5’-基或叠氮胸苷-5’-基中的任意一种，m为1～7；
再将混合液溶于三乙胺中，120℃微波辐射下反应5 min，将反应液浓缩，柱层析分离，得到化学通式（I）所示的化合物；
[0032] C、化学通式（II）所示的化合物的制备
[0033] 将2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺与氨基取代核苷化合物按摩尔比为1:1.2混合，得混合液，其中氨基取代核苷的化学通式为 ，R1为5-甲基尿
苷-5’-基、5-氟-2’-脱氧尿苷-5’-基或叠氮胸苷-5’-基中的任意一种，再将混合液溶于三乙胺中，在120～150℃微波辐射下反应5 min；在反应液中加入脂肪胺、芳香胺或氨基取代核苷，其中2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺与脂肪胺、芳香胺或氨基取代核苷的摩尔比为1:3，其中脂肪胺、芳香胺或氨基取代核苷的化学式通式为 ，R2
为N,N-二甲基氨基、N,N-二乙基氨基、吡咯烷-1-基、哌啶-1-基、吗啉-4-基、哌嗪-1-基、N-甲基哌嗪-4-基、苯基氨基、卤代苯基氨基、硝基苯基氨基或烷氧基苯基氨基中任意一种；120℃微波辐射下反应15 min；将反应液浓缩，柱层析分离，得到化学通式（II）所示的化合物。
苷-5’-基、5-氟-2’-脱氧尿苷-5’-基或叠氮胸苷-5’-基中的任意一种，再将混合液溶于三乙胺中，在120～150℃微波辐射下反应5 min；在反应液中加入脂肪胺、芳香胺或氨基取代核苷，其中2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺与脂肪胺、芳香胺或氨基取代核苷的摩尔比为1:3，其中脂肪胺、芳香胺或氨基取代核苷的化学式通式为 ，R2
为N,N-二甲基氨基、N,N-二乙基氨基、吡咯烷-1-基、哌啶-1-基、吗啉-4-基、哌嗪-1-基、N-甲基哌嗪-4-基、苯基氨基、卤代苯基氨基、硝基苯基氨基或烷氧基苯基氨基中任意一种；120℃微波辐射下反应15 min；将反应液浓缩，柱层析分离，得到化学通式（II）所示的化合物。
[0034] 其制备该类衍生物的化学合成反应通式如下：
[0035] 反应流程（A）
[0036]
[0037] 反应流程（B）
[0038]
[0039] 反应流程（C）
[0040]
[0041]
[0042] 上述化学反应通式中：R为N,N-二甲基氨基或吡咯烷-1-基中的任意一种；m为1～7；n为1～3；所述R1为5-甲基尿苷-5’-基、5-氟-2’-脱氧尿苷-5’-基或叠氮胸苷-5’-基中的任意一种；所述R2为N,N-二甲基氨基、N,N-二乙基氨基、吡咯烷-1-基、哌啶-1-基、苯基氨基、5-甲基尿苷-5’-氨基、吗啉-4-基、哌嗪-1-基、N-甲基哌嗪-4-基、卤代苯基氨基、硝基苯基氨基或烷氧基苯基氨基中的任意一种。
具体实施方式
[0043] 下面实施例用于进一步详细说明本发明，但不以任何形式限制本发明。
[0044] 实施例1：
[0045] 合成化合物7a～7g
[0046] 化合物7a的化学反应流程如下：
[0047]
[0048] 上述反应式中：5为2-溴-1,4,5,8-萘四甲酸二酰亚胺，4a为5-甲基-2’,3’-丙叉基-5’-乙二胺基尿苷。
[0049] 具体方法为：
[0050] 将122 mg（0.36mmol）化合物4a，150mg（0.31mmol）化合物5溶解于10 mL三乙胺中，在120℃微波辐射条件下促进反应5 min，TLC检测原料消失；湿法上样，柱层析（二氯甲烷:甲醇=10:1）分离，得80 mg化合物6a；将80 mg化合物6a溶解在5mL三氟醋酸中，室温搅拌5 min，TLC检测原料消失，旋转蒸发蒸干三氟醋酸，干法上样，柱层析（二氯甲烷:甲醇=1:1）分离，得160mg化合物7a。
[0051] 本实施例中起始原料化合物5（2-溴-1,4,5,8-萘四甲酸二酰亚胺）的合成方法如下：
[0052] 将5.0g（18.65 mmol）的1,4,5,8-萘四甲酸二酐溶于93 mL含40%游离三氧化硫的发烟硫酸中，室温搅拌3h，加入0.19g（0.74mmol）I2，继续搅拌1h，分三批加入2.28 g的NaBr，每隔2 h加入一批，每批加入NaBr的量为0.76g（7.46mmol），在80℃条件下，反应36 h，所得反应液冷却至室温，将反应液倾入1 L 的冰水中，过滤，得滤饼，滤饼经水洗，甲醇洗，真空干燥，得7.90g淡黄色固体产物。再将5.70 g淡黄色固体溶于114 mL冰醋酸中，在18～25℃下滴加10.0mL（111.9 mmol）N,N-二甲基乙二胺，氮气保护下，120℃油浴回流20 min，冷却至室温，用饱和NaHCO3水溶液中和至pH=7～8，氯仿萃取，用饱和食盐水洗涤，无水NaSO4干燥，浓缩后经硅胶色谱分离纯化[V(二氯甲烷):V(甲醇) = 99:1]，得3.90 g化合物5（2-溴-1,4,5,8-萘四甲酸二酰亚胺）。
[0053] 本实施例中起始原料化合物4a（5-甲基-2’,3’-丙叉基-5’-乙二胺基尿苷）按照以下方法合成，其化学反应流程如下：
[0054]
[0055] 具体方法为：
[0056] 在100 mL单口瓶中加入34 mL干燥丙酮，搅拌下加入0.7mL浓硫酸，氮气保护下室温搅拌15 min，然后加入2.0g ( 7.7 mmol ) 5-甲基尿苷（化合物1），氮气保护下室温搅拌反应约6 h，TLC检测原料消失，反应完全，用无水碳酸钠中和至pH至7，过滤，滤液旋蒸蒸除丙酮，得2.25g白色固体化合物2，收率96.6%；将2.25g化合物2溶于10mL干燥吡啶中，冰水浴中氮气保护下滴加10 mL含2.5 g氯化苄（TsCl）的二氯甲烷溶液，反应1 h；滴加甲醇猝灭反应，浓缩，硅胶柱分离，得2.97 g化合物3，收率86%。
[0057] 将2.0 g ( 4.4 mmol )化合物3，5.0 mL CH3CN和1.2 mL乙二胺加入100 ml茄形瓶，氮气保护，室温搅拌3 h，TLC检测原料消失，反应完全，减压蒸去乙腈和未反应的乙二胺，得粗品，柱层析分离得1.3 g化合物4a（5-甲基-2’,3’-丙叉基-5’-乙二胺基尿苷）。
[0058] 参照本实施例中所述化合物4a 的制备方法，分别以丙二胺、丁二胺、戊二胺、己二胺、庚二胺、辛二胺代替乙二胺进行反应，便可以得到化合物4b～4g；同时，以化合物5和化合物4b～4g为原料采用制备化合物7a的制备工艺，便可制备中间体化合物6b～6g及化合物7b～7g。
[0059] 化合物7b～7g的其化学反应合成通式如下：
[0060]
[0061] 上述反应式中的m分别为2～7。1
[0062] 化合物5：黄色固体; mp. 265-267℃; H NMR(CDCl3, 600 MHz) δ: 2.38 (s,12H), 2.74 (t, 4H, J = 6.6 Hz), 4.40 (t, 4H, J = 7.8 Hz), 8.79 (d, 1H, J = 7.8 + +
Hz), 8.83 (d, 1H, 7.2 Hz), 8.96 (s, 1H); HRMS (ESI): calcd C22H24BrN4O4 [M+H]
487.0987. Found 487.0977。
22
Hz), 8.83 (d, 1H, 7.2 Hz), 8.96 (s, 1H); HRMS (ESI): calcd C22H24BrN4O4 [M+H]
487.0987. Found 487.0977。
22
[0063] 化合物4a：收率80%；淡黄色固体， mp. 118-119℃; [α] D -44.608 (c 1.0,1
CH3OH) H NMR (600 MHz, CD3OD) δ: (ppm) 1.39 (s, 3H, CH3), 1.62 (s, 3H, CH3),
1.91 (s, 3H, CH3), 2.85 (t, J = 12.6 Hz, 2H, CH2), 3.45-3.53 (m, 2H, CH2), 3.85 (qd, J = 12.0, 2.4 Hz, 2H, CH2), 4.32 (q, J = 2.4 Hz, 1H, CH), 4.95 (q, J =3.0 Hz, 1H, CH), 5.01 (q, J = 4.2 Hz, 1H, CH), 5.57 (d, J = 4.8 Hz, 1H, CH), 7.52 +
(d, J = 1.2 Hz, 1H, CH); MS (ESI) m/z: 341.2 ([M+H])。
CH3OH) H NMR (600 MHz, CD3OD) δ: (ppm) 1.39 (s, 3H, CH3), 1.62 (s, 3H, CH3),
1.91 (s, 3H, CH3), 2.85 (t, J = 12.6 Hz, 2H, CH2), 3.45-3.53 (m, 2H, CH2), 3.85 (qd, J = 12.0, 2.4 Hz, 2H, CH2), 4.32 (q, J = 2.4 Hz, 1H, CH), 4.95 (q, J =3.0 Hz, 1H, CH), 5.01 (q, J = 4.2 Hz, 1H, CH), 5.57 (d, J = 4.8 Hz, 1H, CH), 7.52 +
(d, J = 1.2 Hz, 1H, CH); MS (ESI) m/z: 341.2 ([M+H])。
[0064] 化合物4b: 收率50%; 淡黄色固体，mp. 104-105℃; [α] 22D -71.639 (c 1.0,1
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.39 (s, 3H, CH3), 1.62 (s, 3H, CH3),
1.77 (m, 2H, CH2), 1.91 (s, 3H, CH3); 2.70 (t, J = 7.2 Hz, 2H, CH2), 3.49 (m,
2H, CH2) , 3.85 (qd, J = 12.0 Hz, 2.4Hz, 2H, CH2), 4.31 (q, J = 1.8 Hz, H, CH),
4.95 (m, 2H, CH2), 5.53 (d, J = 4.2Hz, H, CH), 7.49 (d, J = 1.2Hz, H, CH); MS +
(ESI) m/z: 355.2 ([M+H])。
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.39 (s, 3H, CH3), 1.62 (s, 3H, CH3),
1.77 (m, 2H, CH2), 1.91 (s, 3H, CH3); 2.70 (t, J = 7.2 Hz, 2H, CH2), 3.49 (m,
2H, CH2) , 3.85 (qd, J = 12.0 Hz, 2.4Hz, 2H, CH2), 4.31 (q, J = 1.8 Hz, H, CH),
4.95 (m, 2H, CH2), 5.53 (d, J = 4.2Hz, H, CH), 7.49 (d, J = 1.2Hz, H, CH); MS +
(ESI) m/z: 355.2 ([M+H])。
[0065] 化合物4c: 收率78%; 淡黄色固体，mp. 88-89℃; [α] 22D -74.210 (c 1.0,1
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.39 (s,3H, CH3), 1.54 (m, 2H, CH2),
1.62 (s, 3H, CH3), 1.65 (m, 2H, CH2), 1.91 (s, 3H, CH3), 2.70 (t, J = 7.2 Hz,
2H, CH2), 3.42 (t, J = 7.2 Hz, 2H, CH2), 3.85 (qd, J = 12.0 Hz, 2.4 Hz, 2H, CH2),
4.31 (q, J = 2.4 Hz, H, CH),4.96 (m, 2H, CH2), 5.53 (d, J = 3.6 Hz, H, CH), 7.49 +
(d, J = 1.2 Hz, H, CH); MS (ESI) m/z: 369.2 ([M+H])。
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.39 (s,3H, CH3), 1.54 (m, 2H, CH2),
1.62 (s, 3H, CH3), 1.65 (m, 2H, CH2), 1.91 (s, 3H, CH3), 2.70 (t, J = 7.2 Hz,
2H, CH2), 3.42 (t, J = 7.2 Hz, 2H, CH2), 3.85 (qd, J = 12.0 Hz, 2.4 Hz, 2H, CH2),
4.31 (q, J = 2.4 Hz, H, CH),4.96 (m, 2H, CH2), 5.53 (d, J = 3.6 Hz, H, CH), 7.49 +
(d, J = 1.2 Hz, H, CH); MS (ESI) m/z: 369.2 ([M+H])。
[0066] 化合物4d：收率34%; 淡黄色固体，mp. 80-82℃; [α] 22D -67.293 (c 1.0,1
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.39 (s, 3H, CH3), 1.41-1.44 (m, 2H, CH2), 1.62 (s, 3H, CH3), 1.64-1.69 (m, 4H, CH2), 1.90-1.91 (m, 5H, CH3, CH2),
2.83 (t, J = 7.8 Hz, 2H, CH2), 3.43 (t, J = 6.6 Hz, 2H, CH2), 3.85 (td, J = 10.2 Hz, 1.8 Hz, 2H, CH2), 4.32 (d, J = 1.8 Hz, H, CH), 4.94-4.97 (m, 2H, 2CH), 5.54 +
(d, J = 3.6Hz, H, CH), 7.51 (s, H, CH); MS (ESI) m/z: 383.2 ([M+H])。
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.39 (s, 3H, CH3), 1.41-1.44 (m, 2H, CH2), 1.62 (s, 3H, CH3), 1.64-1.69 (m, 4H, CH2), 1.90-1.91 (m, 5H, CH3, CH2),
2.83 (t, J = 7.8 Hz, 2H, CH2), 3.43 (t, J = 6.6 Hz, 2H, CH2), 3.85 (td, J = 10.2 Hz, 1.8 Hz, 2H, CH2), 4.32 (d, J = 1.8 Hz, H, CH), 4.94-4.97 (m, 2H, 2CH), 5.54 +
(d, J = 3.6Hz, H, CH), 7.51 (s, H, CH); MS (ESI) m/z: 383.2 ([M+H])。
[0067] 化合物4e: 收率54%; 淡黄色固体，mp. 99-101℃; [α] 22D -81.328 (c 1.0,1
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.36 (s, 3H, CH3), 1.39-1.48 (m, 4H,
2CH2), 1.60 (s, 3H, CH3), 1.61-1.71 (m, 4H, 2CH2), 1.89 (s, 3H, CH3), 2.93 (t, J = 7.2 Hz, 2H, CH2), 3.39 (t, J = 7.2 Hz, 2H, CH2), 3.81-3.85 (m, 2H, CH2), 4.30 (s, H, CH), 4.93 (m, 2H, 2CH), 5.50-5.52 (m, H, CH), 7.49 (s, H, CH); MS (ESI) +
m/z: 395.2 ([M+H])。
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.36 (s, 3H, CH3), 1.39-1.48 (m, 4H,
2CH2), 1.60 (s, 3H, CH3), 1.61-1.71 (m, 4H, 2CH2), 1.89 (s, 3H, CH3), 2.93 (t, J = 7.2 Hz, 2H, CH2), 3.39 (t, J = 7.2 Hz, 2H, CH2), 3.81-3.85 (m, 2H, CH2), 4.30 (s, H, CH), 4.93 (m, 2H, 2CH), 5.50-5.52 (m, H, CH), 7.49 (s, H, CH); MS (ESI) +
m/z: 395.2 ([M+H])。
[0068] 化合物4f：收率36%; 淡黄色固体，mp. 88-90℃; [α] 22D -57.307 (c 1.0,1
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.39 (m, 7H, CH3, 2CH2), 1.54-1.57 (m,
2H, CH2), 1.62-1.64 (m, 5H, CH3, CH2), 1.90-1.94 (m, 5H, CH3, CH2), 2.73 (t, J = 7.2 Hz, 2H, CH2), 3.38-3.44 (m, 2H, CH2), 3.84 (qd, J = 12.0 Hz, 2.4 Hz, 2H, CH2), 4.32-4.31 (m, 1H, CH), 4.93-4.96 (m, 2H, 2CH), 5.52-5.54 (m, 1H, CH), +
7.50 (s, 1H, CH); MS (ESI) m/z: 407.2 ([M+H])。
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.39 (m, 7H, CH3, 2CH2), 1.54-1.57 (m,
2H, CH2), 1.62-1.64 (m, 5H, CH3, CH2), 1.90-1.94 (m, 5H, CH3, CH2), 2.73 (t, J = 7.2 Hz, 2H, CH2), 3.38-3.44 (m, 2H, CH2), 3.84 (qd, J = 12.0 Hz, 2.4 Hz, 2H, CH2), 4.32-4.31 (m, 1H, CH), 4.93-4.96 (m, 2H, 2CH), 5.52-5.54 (m, 1H, CH), +
7.50 (s, 1H, CH); MS (ESI) m/z: 407.2 ([M+H])。
[0069] 化合物4g：收率44%; 淡黄色固体，mp. 79-80℃; [α] 22D -84.176 (c 1.0,1
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.38 (m, 9H, CH3, 3CH2), 1.63-1.66 (m,
7H, CH3, 2CH2), 1.91 (m, 5H, CH3, CH2), 2.88 (t, J = 7.2 Hz, 2H, CH2), 3.38-3.43 (m, 2H, CH2), 3.82-3.87 (m, 2H, CH3), 4.31-4.32 (m, H, CH), 5.52-5.54 (m, H, +
CH), 7.52 (d, J = 1.2 Hz, H, CH); MS (ESI) m/z: 419.2 ([M+H])。
CH3OH); H NMR (600 MHz, CD3OD) δ (ppm) 1.38 (m, 9H, CH3, 3CH2), 1.63-1.66 (m,
7H, CH3, 2CH2), 1.91 (m, 5H, CH3, CH2), 2.88 (t, J = 7.2 Hz, 2H, CH2), 3.38-3.43 (m, 2H, CH2), 3.82-3.87 (m, 2H, CH3), 4.31-4.32 (m, H, CH), 5.52-5.54 (m, H, +
CH), 7.52 (d, J = 1.2 Hz, H, CH); MS (ESI) m/z: 419.2 ([M+H])。
[0070] 化合物6a：收率36%；红色固体， mp. 175-178℃; 1H NMR (600 MHz, CDCl3) δ:1.03 (s, 3H, CH3), 1.16 (s, 3H, CH3), 1.40 (s, 3H, CH3-7’), 2.29 (s, 6H, CH3-7),
2.38 (s, 6H, CH3-7), 2.60 (s, 2H, CH2), 2.72(bs, 2H, CH2), 3.56-3.83 (m, 6H, CH2), 4.08-4.22 (m, 5H, CH2-5, H-4’), 4.44 (s, 1H, H-2’), 4.67 (s, 1H, H-3’),
4.98 (s, 1H, H-4’), 6.78 (s, 1H, H-6’), 7.87 (s, 1H, H-2), 8.05 (d, J = 7.8 +
Hz, 1H, H-4), 8.34 (d, J = 7.2 Hz, 1H, H-3), 9.96 (s, 1H, H-8’); HRMS (ESI)
+
calcd C37H47N8O9 [M+H] 747.3460. Found: 747.3458。
2.38 (s, 6H, CH3-7), 2.60 (s, 2H, CH2), 2.72(bs, 2H, CH2), 3.56-3.83 (m, 6H, CH2), 4.08-4.22 (m, 5H, CH2-5, H-4’), 4.44 (s, 1H, H-2’), 4.67 (s, 1H, H-3’),
4.98 (s, 1H, H-4’), 6.78 (s, 1H, H-6’), 7.87 (s, 1H, H-2), 8.05 (d, J = 7.8 +
Hz, 1H, H-4), 8.34 (d, J = 7.2 Hz, 1H, H-3), 9.96 (s, 1H, H-8’); HRMS (ESI)
+
calcd C37H47N8O9 [M+H] 747.3460. Found: 747.3458。
[0071] 化合物6b: 收率41%; 红色固体; mp. 153-156℃; 1H NMR (600 MHz, CDCl3) δ: 1.20 ( s, 3H, CH3), 1.47 (s, 3H, CH3), 1.82 (s, 3H, CH3), 2.08 (m, 2H, CH2),2.28 (d, J = 3.6Hz, 12H, CH3), 2.55 (m, 4H, CH2), 3.47 (dd, J = 6.6 Hz, 12.6 Hz,
2H, CH2), 3.54 (dd, J = 6 Hz, 12 Hz, 2H, CH2), 3.80 (m, 2H, CH2), 4.14 (m, 5H, CH2-5, H-4’), 4.83 (d, J = 2.4 Hz, 1H, H-3’), 4.86 (d, J = 4.8 Hz, 1H, H-2’),
5.09 (d, J = 4.8 Hz, 1H, H-1’), 6.86 (s, 1H, H-6’), 7.83 (s, 1H, H-2), 8.02 (d, J = 7.8 Hz, 1H, H-4), 8.29 (d, J = 7.8 Hz,1H, H-3), 9.85 (s, 1H, H-8’); HRMS + +
(ESI) calcd C38H48N8NaO9 [M+Na] 783.3436. Found: 783.3437。
2H, CH2), 3.54 (dd, J = 6 Hz, 12 Hz, 2H, CH2), 3.80 (m, 2H, CH2), 4.14 (m, 5H, CH2-5, H-4’), 4.83 (d, J = 2.4 Hz, 1H, H-3’), 4.86 (d, J = 4.8 Hz, 1H, H-2’),
5.09 (d, J = 4.8 Hz, 1H, H-1’), 6.86 (s, 1H, H-6’), 7.83 (s, 1H, H-2), 8.02 (d, J = 7.8 Hz, 1H, H-4), 8.29 (d, J = 7.8 Hz,1H, H-3), 9.85 (s, 1H, H-8’); HRMS + +
(ESI) calcd C38H48N8NaO9 [M+Na] 783.3436. Found: 783.3437。
[0072] 化合物6c: 收率43%; 红色固体; mp. 134-137℃; 1H NMR (600 MHz, CDCl3) δ: 1.12 (s, 3H, CH3), 1.26 (s, 3H, CH3), 1.48 (s, 3H, CH3), 1.88 (bs, 4H, CH2),2.38 (s, 6H, CH3-7), 2.47 (s, 6H, CH3-7), 2.69 (s, 2H, CH2), 2.80 (s, 2H, CH2),
3.80-3.93 (m, 6H, CH2), 4.17 (s, 1H, H-4’), 4.23-4.31 (m, 4H, CH2-5) , 4.53 (d, J =2.4 Hz, 1H, H-3’), 4.76 (s, 1H, H-2’), 5.07 (s, 1H, H-1’), 6.87 (s,
1H, H-6’), 7.96 (s, 1H, H-2), 8.13 (d, J = 7.2 Hz, 1H, H-4), 8.42 (d, J = 7.8 + +
Hz, 1H, H-3), 10.04 (s, 1H, H-8’); HRMS (ESI) calcd C39H51N8O9 [M+H] 775.3773. Found: 775.3776。
3.80-3.93 (m, 6H, CH2), 4.17 (s, 1H, H-4’), 4.23-4.31 (m, 4H, CH2-5) , 4.53 (d, J =2.4 Hz, 1H, H-3’), 4.76 (s, 1H, H-2’), 5.07 (s, 1H, H-1’), 6.87 (s,
1H, H-6’), 7.96 (s, 1H, H-2), 8.13 (d, J = 7.2 Hz, 1H, H-4), 8.42 (d, J = 7.8 + +
Hz, 1H, H-3), 10.04 (s, 1H, H-8’); HRMS (ESI) calcd C39H51N8O9 [M+H] 775.3773. Found: 775.3776。
[0073] 化合物6d: 收率36%; 红色固体，mp. 177-181℃; 1H NMR (600 MHz, CDCl3) δ: (ppm) 1.33 (s, 3H, CH3), 1.52-1.57 (m, 5H, CH3, CH2), 1.72-1.76 (m, 2H, CH2),1.81-1.86 (m, 5H, CH3-5’, CH2), 2.36 (s, 6H, 2CH3-N), 2.40 (s, 6H, 2CH3-N),
2.66-2.70 (m, 4H, 2CH2), 3.39-3.52 (m, 4H, CH2-5’, CH2), 3.86-3.92 (m, 2H, CH2),
4.25-4.30 (m, 5H, CH-4’, 2CH2), 4.89-4.91 (m, 1H, CH-3’), 4.95 (dd, J = 4,2 Hz, 1H, CH-2’), 5.15 (d, J = 4.8 Hz, 1H, CH-1’), 6.89 (s, 1H, NH), 6.96 (s,
1H, CH-6), 7.97 (s, 1H, Ar-H-2), 8.16 (d, J = 7.8 Hz, 1H, Ar-H-3), 8.45 (d, J = -
7.8 Hz, 1H, Ar-H-4), 9.92 (m, 1H, NH-3); HR-ESI-MS: calcd for C40H52N8O9 [M+H],
789.3936, found: 789.3918。
2.66-2.70 (m, 4H, 2CH2), 3.39-3.52 (m, 4H, CH2-5’, CH2), 3.86-3.92 (m, 2H, CH2),
4.25-4.30 (m, 5H, CH-4’, 2CH2), 4.89-4.91 (m, 1H, CH-3’), 4.95 (dd, J = 4,2 Hz, 1H, CH-2’), 5.15 (d, J = 4.8 Hz, 1H, CH-1’), 6.89 (s, 1H, NH), 6.96 (s,
1H, CH-6), 7.97 (s, 1H, Ar-H-2), 8.16 (d, J = 7.8 Hz, 1H, Ar-H-3), 8.45 (d, J = -
7.8 Hz, 1H, Ar-H-4), 9.92 (m, 1H, NH-3); HR-ESI-MS: calcd for C40H52N8O9 [M+H],
789.3936, found: 789.3918。
[0074] 化合物6e: 收率32%; 红色固体, mp. 149-151℃; 1H NMR (600 MHz, CDCl3) δ: (ppm) 1.30 (s, 3H, CH3), 1.38-1.43 (m, 2H, CH2), 1.48-1.52 (m, 5H, CH3, CH2), 1.60-1.66 (m, 2H, CH2), 1.76-1.79 (m, 5H, CH3-5, CH2), 2.34 (s, 6H,2CH3-N), 2.38 (s, 6H, 2CH3-N), 2.64-2.69 (m, 4H, 2CH2), 3.28-3.32 (m, 1H, CH-5’), 3.40-3.43 (m, 1H, CH-5’), 3.46 (d, J = 6.0 Hz, 2H, CH2), 3.83 (dd, J = 28.2 Hz, 10.2 Hz, 2H, CH2), 4.20 (s, 1H, CH-4’), 4.22-4.27 (m, 4H, 2CH2-N),
4.83-4.85 (m, 1H, CH-3’), 4.89 (dd, J = 4.2 Hz, 1.8 Hz, 1H, CH-2’), 5.11 (d, J = 4.2 Hz, 1H, CH-1’), 6.80 (s, 1H, NH), 6.94 (s, 1H, CH-6), 7.93 (s, 1H, Ar-H-2), 8.12 (d, J = 7.8 Hz, 1H, Ar-H-3), 8.41 (d, J = 7.8 Hz, 1H, Ar-H-4), -
9.89 (t, J = 4.8 Hz, 1H, NH-3); HR-ESI-MS: calcd for C41H54N8O9 [M+H], 803.4093, found: 803.4078。
4.83-4.85 (m, 1H, CH-3’), 4.89 (dd, J = 4.2 Hz, 1.8 Hz, 1H, CH-2’), 5.11 (d, J = 4.2 Hz, 1H, CH-1’), 6.80 (s, 1H, NH), 6.94 (s, 1H, CH-6), 7.93 (s, 1H, Ar-H-2), 8.12 (d, J = 7.8 Hz, 1H, Ar-H-3), 8.41 (d, J = 7.8 Hz, 1H, Ar-H-4), -
9.89 (t, J = 4.8 Hz, 1H, NH-3); HR-ESI-MS: calcd for C41H54N8O9 [M+H], 803.4093, found: 803.4078。
[0075] 化合物6f: 收率30%; 红色固体，mp. 137-141℃; 1H NMR (600 MHz, CDCl3) δ: (ppm) 1.35 (s, 3H, CH3), 1.38-1.47 (m, 2H, CH2), 1.49-1.54 (m, 2H, CH2),1.58 (s, 3H, CH3), 1.60-1.65 (m, 2H, CH2), 1.81-1.84 (m, 5H, CH3-5, CH2), 2.38 (s, 6H, 2CH3-N), 2.42 (s, 6H, 2CH3-N), 2.68-2.72 (m, 4H, 2CH2), 3.30-3.36 (m,
1H, CH-5’), 3.42-3.46 (m, 1H, CH-5’), 3.53 (dd, J = 6.6 Hz, 6.0 Hz, 2H, CH2), 3.86-3.95 (m, 2H, CH2), 4.26 (m, 1H, CH-4’), 4.29-4.34 (m, 4H, 2CH2-N),
4.88-4.90 (m, 1H, CH-3’), 4.95 (dd, J = 4.2 Hz, 2.4 Hz, 1H, CH-2’), 5.17 (d, J = 4.8 Hz, 1H, CH-1’), 6.65 (s, 1H, NH), 7.01 (s, 1H, CH-6), 8.06 (s, 1H, Ar-H-2), 8.23 (d, J = 7.8 Hz, 1H, Ar-H-3), 8.52 (d, J = 7.8 Hz, 1H, Ar-H-4), -
10.01 (t, J = 5,2 Hz, 1H, NH-3); HR-ESI-MS: calcd for C42H56N8O9 [M+H], 817.4249, found: 817.4232。
1H, CH-5’), 3.42-3.46 (m, 1H, CH-5’), 3.53 (dd, J = 6.6 Hz, 6.0 Hz, 2H, CH2), 3.86-3.95 (m, 2H, CH2), 4.26 (m, 1H, CH-4’), 4.29-4.34 (m, 4H, 2CH2-N),
4.88-4.90 (m, 1H, CH-3’), 4.95 (dd, J = 4.2 Hz, 2.4 Hz, 1H, CH-2’), 5.17 (d, J = 4.8 Hz, 1H, CH-1’), 6.65 (s, 1H, NH), 7.01 (s, 1H, CH-6), 8.06 (s, 1H, Ar-H-2), 8.23 (d, J = 7.8 Hz, 1H, Ar-H-3), 8.52 (d, J = 7.8 Hz, 1H, Ar-H-4), -
10.01 (t, J = 5,2 Hz, 1H, NH-3); HR-ESI-MS: calcd for C42H56N8O9 [M+H], 817.4249, found: 817.4232。
[0076] 化合物6g: 收率35%; 红色固体，mp. 149-152℃; 1H NMR (600 MHz, CDCl3) δ: (ppm) 1.36-1.43 (m, 9H, CH3, 3CH2), 1.49-1.59 (m, 7H, CH3, 2CH2), 1.80-1.85 (m, 2H, CH2), 1.87 (m, 3H, CH3-5), 2.37-2.40 (m, 12H, 4CH3-N), 2.69 (q, J = 6.6 Hz, 4H, 2CH2), 3.24-3.30 (m, 1H, CH-5’), 3.40-3.46 (m, 1H, CH-5’), 3.55 (dd, J = 6.6 Hz, 6.0 Hz, 2H, CH2), 3.87-3.98 (m, 2H, CH2), 4.27-4.35 (m, 5H, CH-4’,2CH2-N), 4.89-4.91 (m, 1H, CH-3’), 4.95 (dd, J = 4.2 Hz, 2.4 Hz, 1H, CH-2’),
5.18 (d, J = 4.2 Hz, 1H, CH-1’), 6.53 (s, 1H, NH), 7.02 (s, 1H, CH-6), 8.10 (s, 1H, Ar-H-2), 8.26 (d, J = 7.8 Hz, 1H, Ar-H-3), 8.55 (d, J = 7.8 Hz, 1H, -
Ar-H-4), 10.05 (t, J = 5,2 Hz, 1H, NH-3); HR-ESI-MS: calcd for C43H58N8O9 [M+H],
831.4405, found: 831.4387。
5.18 (d, J = 4.2 Hz, 1H, CH-1’), 6.53 (s, 1H, NH), 7.02 (s, 1H, CH-6), 8.10 (s, 1H, Ar-H-2), 8.26 (d, J = 7.8 Hz, 1H, Ar-H-3), 8.55 (d, J = 7.8 Hz, 1H, -
Ar-H-4), 10.05 (t, J = 5,2 Hz, 1H, NH-3); HR-ESI-MS: calcd for C43H58N8O9 [M+H],
831.4405, found: 831.4387。
[0077] 化合物7a：收率79%，红色固体，mp. 174-178℃; 1H NMR (600 MHz, D2O) δ:1.59 (s, 3H, CH3-7’), 2.47(s, 6H, CH3-7), 2.56 (s, 6H, CH3-7), 2.71 (s, 2H, CH2), 2.81 (s, 2H, CH2), 3.60-3.73 (m, 6H, CH2), 3.80(s, 1H, H-4’), 4.01 (s,
1H, H-3’), 4.07 (broad s, 5H, CH2-5, H-2’), 4.88 (s, 1H, H-1’), 7.14 (s, 1H, H-6’), 7.53 (s, 1H, H-2), 7.79 (d, J = 7.8 Hz, 1H, H-4), 8.01 (d, J = 7.8 Hz,
13
1H, H-3); C NMR (600 MHz, D2O) δ: 12.60, 36.80, 37.55, 40.99, 41.68, 43.91,
44.04, 55.08, 60.41, 69.59, 71.96, 85.68, 92.34, 98.36, 113.64, 117.80,
119.62, 121.46, 124.12, 125.92, 127.87, 130.75, 136.98, 152.31, 153.05, +
162.25, 162.82, 163.13, 164.50, 170.97, 173.24; HRMS (ESI) calcd C34H43N8O9
+
[M+H] 707.3147. Found: 707.3151。
1H, H-3’), 4.07 (broad s, 5H, CH2-5, H-2’), 4.88 (s, 1H, H-1’), 7.14 (s, 1H, H-6’), 7.53 (s, 1H, H-2), 7.79 (d, J = 7.8 Hz, 1H, H-4), 8.01 (d, J = 7.8 Hz,
13
1H, H-3); C NMR (600 MHz, D2O) δ: 12.60, 36.80, 37.55, 40.99, 41.68, 43.91,
44.04, 55.08, 60.41, 69.59, 71.96, 85.68, 92.34, 98.36, 113.64, 117.80,
119.62, 121.46, 124.12, 125.92, 127.87, 130.75, 136.98, 152.31, 153.05, +
162.25, 162.82, 163.13, 164.50, 170.97, 173.24; HRMS (ESI) calcd C34H43N8O9
+
[M+H] 707.3147. Found: 707.3151。
[0078] 化合物7b：收率36%; 红色固体; mp. 162-164℃; 1H NMR (600 MHz, DMSO-d6) δ: 1.62 (s, 3H, CH3-7’), 1.99 (s, 2H, CH2), 2.33 (s, 6H, CH3-7), 2.36 (s, 6H, CH3-7), 2.64 (broad s, 4H, CH2), 3.44 (s, 2H, CH2), 3.54 (broad s, 2H, CH2),3.63 (s, 2H, CH2), 3.92 (d, J = 2.4 Hz, 1H, H-4’), 4.02 (m, 1H, H-3’), 4.07 (broad s, 4H, CH2-5), 4.13 (t, J = 5.4 Hz, 1H, H-2’), 5.42 (d, J = 6 Hz, 1H, H-1’), 7.48 (s, 1H, H-6’), 7.71 (s, 1H, H-2), 7.94 (d, J = 7.2 Hz, 1H, H-4),
13
8.19 (d, J = 7.8 Hz, 1H, H-3), 9.73 (s, 1H, H-8’); C NMR (600 MHz, D2O) δ:
12.53, 27.92, 35.47, 35.99, 39.02, 41.06, 43.57, 46.86, 55.11, 55.38, 60.73,
69.97, 73.00, 86.04, 91.98, 98.50, 113.10, 118.40, 120.52, 122.10, 124.49,
125.11, 126.63, 128.66, 131.25, 136.54, 152.10, 153.20, 163.16, 163.62,
163.85, 165.24, 173.28; HRMS (ESI+) calcd C35H45N8O9 [M+H] + 721.3304. Found:
721.3306。
13
8.19 (d, J = 7.8 Hz, 1H, H-3), 9.73 (s, 1H, H-8’); C NMR (600 MHz, D2O) δ:
12.53, 27.92, 35.47, 35.99, 39.02, 41.06, 43.57, 46.86, 55.11, 55.38, 60.73,
69.97, 73.00, 86.04, 91.98, 98.50, 113.10, 118.40, 120.52, 122.10, 124.49,
125.11, 126.63, 128.66, 131.25, 136.54, 152.10, 153.20, 163.16, 163.62,
163.85, 165.24, 173.28; HRMS (ESI+) calcd C35H45N8O9 [M+H] + 721.3304. Found:
721.3306。
[0079] 化合物7c：收率39%; 红色固体; mp. 147-149℃; 1H NMR (600 MHz, DMSO) δ: 1.31 (s, 3H, CH3-7’), 1.80 (t, J = 6.6 Hz, 2H, CH2), 1.89 (m, 2H, CH2),3.06 (s, 6H, CH3-7), 3.09 (s, 6H, CH3-7), 3.24 (t, J = 6 Hz, 2H, CH2), 3.57 (t, J = 6 Hz, 4H, CH2), 3.64 (broad s, 2H, CH2), 3.69-3.72 (m, 2H, CH2), 3.99 (d, J = 2.4 Hz, 1H, H-4’), 4.09 (broad s, 2H, H-2’, H-3’), 4.48 (broad s, 2H, CH2-5), 4.54 (t, J = 5.4 Hz, 2H, CH2-5), 4.88 (d, J = 6 Hz, 1H, H-1’), 6.79 (s, 1H, H-6’), 7.90 (s, 1H, H-2), 8.08 (d, J = 7.8 Hz, 1H, H-4), 8.29 (d, J =
13
7.8Hz, 1H, H-3); C NMR (600 MHz, D2O) δ: 12.60, 25.02, 25.10, 35.93, 36.61,
40.99, 42.77, 43.66, 43.76, 46.86, 55.20, 55.40, 60.67, 70.03, 72.58, 86.27,
92.34, 98.38, 112.84, 118.10, 120.35, 121.88, 124.41, 125.14, 126.55, 128.40,
131.14, 136.52, 151.63, 152.88, 163.05, 163.35, 163.65, 165.09, 173.19; HRMS (ESI+) calcd C36H47N8O9 [M+H] + 735.3460. Found: 735.3461。
13
7.8Hz, 1H, H-3); C NMR (600 MHz, D2O) δ: 12.60, 25.02, 25.10, 35.93, 36.61,
40.99, 42.77, 43.66, 43.76, 46.86, 55.20, 55.40, 60.67, 70.03, 72.58, 86.27,
92.34, 98.38, 112.84, 118.10, 120.35, 121.88, 124.41, 125.14, 126.55, 128.40,
131.14, 136.52, 151.63, 152.88, 163.05, 163.35, 163.65, 165.09, 173.19; HRMS (ESI+) calcd C36H47N8O9 [M+H] + 735.3460. Found: 735.3461。
[0080] 化合物7d： 收率79%; 红色固体，mp. 156-158℃; 1H NMR (600 MHz, CD3OD) δ: (ppm) 1.57-1.64 (m, 5H, CH3-5, CH2), 1.74-1.77 (m, 2H, CH2), 1.86-1.88 (m,2H, CH2), 2.58 (s, 6H, 2CH3-N), 2.64 (s, 6H, 2CH3-N), 2.94-3.00 (m, 4H, 2CH2),
3.35-3.43 (m, 2H, CH2), 3.50 (m, 2H, CH2), 3.75-3.79 (m, 2H, CH2), 4.06 (s, 1H, CH-4’), 4.15 (d, J = 6.6 Hz, 1H, CH-3’), 4.24-4.26 (m, 5H, CH-2’, 2CH2-N),
5.20 (d, J = 6.6 Hz, 1H, CH-1’), 7.26 (s, 1H, CH-6), 7.68-7.70 (m, 1H, Ar-H-2),
13
7.86-7.89 (m, 1H, Ar-H-3), 8.11-8.14 (m, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 172.88, 165.26, 162.74, 162.40, 162.31, 153.15, 151.44, 137.28,
130.31, 128.38, 126.95, 125.32, 123.53, 122.24, 118.97, 118.23, 112.53,
98.31, 93.93, 87.05, 72.69, 70.53, 60.87, 55.97, 43.98, 43.80, 42.69, 40.98,
37.21, 36.48, 28.56, 28.25, 24.06, 12.08; C37H49N8O9 [M+H]-, 749.3623, found:
749.3611。
3.35-3.43 (m, 2H, CH2), 3.50 (m, 2H, CH2), 3.75-3.79 (m, 2H, CH2), 4.06 (s, 1H, CH-4’), 4.15 (d, J = 6.6 Hz, 1H, CH-3’), 4.24-4.26 (m, 5H, CH-2’, 2CH2-N),
5.20 (d, J = 6.6 Hz, 1H, CH-1’), 7.26 (s, 1H, CH-6), 7.68-7.70 (m, 1H, Ar-H-2),
13
7.86-7.89 (m, 1H, Ar-H-3), 8.11-8.14 (m, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 172.88, 165.26, 162.74, 162.40, 162.31, 153.15, 151.44, 137.28,
130.31, 128.38, 126.95, 125.32, 123.53, 122.24, 118.97, 118.23, 112.53,
98.31, 93.93, 87.05, 72.69, 70.53, 60.87, 55.97, 43.98, 43.80, 42.69, 40.98,
37.21, 36.48, 28.56, 28.25, 24.06, 12.08; C37H49N8O9 [M+H]-, 749.3623, found:
749.3611。
[0081] 化合物7e： 收率94%; 红色固体，mp. 108-112℃; 1H NMR (600 MHz, CD3OD) δ: (ppm) 1.53-1.56 (m, 2H, CH2), 1.61-1.66 (m, 2H, CH2), 1.70-1.74 (m, 5H, CH3-5, CH2), 1.84-1.90 (m, 2H, CH2), 2.45 (s, 6H, 2CH3-N), 2.51 (s, 6H, 2CH3-N),2.76-2.82 (m, 4H, 2CH2), 3.42 (t, J = 7.2 Hz, 2H, CH2), 3.47 (t, J = 7.2 Hz,
2H, CH2), 3.77-3.82 (m, 2H, CH2), 4.09 (d, J = 2.4Hz, 1H, CH-4’), 4.18-4.22 (m, 5H, CH-3’, 2CH2-N), 4.35 (t, J = 7.2 Hz, 1H, CH-2’), 5.31 (d, J = 7.2 Hz, 1H, CH-1’), 7.40 (s, 1H, CH-6), 7.69 (s, 1H, Ar-H-2), 7.86 (d, J = 7.2
13
Hz, 1H, Ar-H-3), 8.10 (d, J = 7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CDCl3) δ (ppm) 173.07, 165.25, 162.67, 162.31, 162.25, 153.34, 151.45, 137.58, 130.24,
128.37, 127.04, 125.37, 123.42, 122.25, 118.86, 118.28, 112.74, 94.22, 86.92,
72.41, 70.57, 62.21, 60.91, 56.12, 5.96, 44.32, 44.09, 42.41, 40.94, 37.63,
36.84, 28.57, 28.42, 26.22, 25.81, 13.31, 12.14; HR-ESI-MS: calcd for C38H50N8O9 [M+H]-, 763.3779, found: 763.3766。
2H, CH2), 3.77-3.82 (m, 2H, CH2), 4.09 (d, J = 2.4Hz, 1H, CH-4’), 4.18-4.22 (m, 5H, CH-3’, 2CH2-N), 4.35 (t, J = 7.2 Hz, 1H, CH-2’), 5.31 (d, J = 7.2 Hz, 1H, CH-1’), 7.40 (s, 1H, CH-6), 7.69 (s, 1H, Ar-H-2), 7.86 (d, J = 7.2
13
Hz, 1H, Ar-H-3), 8.10 (d, J = 7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CDCl3) δ (ppm) 173.07, 165.25, 162.67, 162.31, 162.25, 153.34, 151.45, 137.58, 130.24,
128.37, 127.04, 125.37, 123.42, 122.25, 118.86, 118.28, 112.74, 94.22, 86.92,
72.41, 70.57, 62.21, 60.91, 56.12, 5.96, 44.32, 44.09, 42.41, 40.94, 37.63,
36.84, 28.57, 28.42, 26.22, 25.81, 13.31, 12.14; HR-ESI-MS: calcd for C38H50N8O9 [M+H]-, 763.3779, found: 763.3766。
[0082] 化合物7f： 收率87%; 红色固体, mp. 159-164℃; 1H NMR (600 MHz, CD3OD) δ: (ppm) 1.48-1.69 (m, 6H, 3CH2), 1.67-1.72 (m, 2H, CH2), 1.79-1.84 (m, 2H, CH2), 1.87 (s, 3H, CH3-5), 2.39 (d, J = 4.8 Hz, 12H, 4CH3-N), 2.58-2.60 (m, 2H, CH2), 2.64-2.66 (m, 2H, CH2), 3.34-3.38 (m, 2H, CH2-5’), 3.44 (t, J = 6.6 Hz,2H, CH2), 3.81-3.86 (m, 2H, CH2), 4.02 (t, J = 6.6 Hz, 2H, CH2), 4.06-4.08 (m,
2H, CH2), 4.11 (d, J = 2.4 Hz, 1H, CH-4’), 4.22 (dd, J = 6.0 Hz, 2.4 Hz, 1H, CH-3’), 4.44 (t, J = 6.0 Hz, 1H, CH-2’), 5.41 (d, J = 7.2 Hz, 1H, CH-1’), 7.46 (s, 1H, CH-6), 7.51 (s, 1H, Ar-H-2), 7.64 (d, J = 7.2 Hz, 1H, Ar-H-3), 7.88
13
(d, J = 7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 173.14, 164.81,
162.18, 161.75, 161.70, 153.35, 138.00, 129.95, 127.85, 126.44, 124.80,
123.22, 121.75, 118.56, 117.71, 112.89, 97.84, 94.65, 86.78, 72.11, 70.54,
60.92, 56.06, 55.92, 44.49, 44.44, 42.71, 41.17, 37.78, 37.20, 28.86, 28.75,
26.82, 26.63, 12.27; HR-ESI-MS: calcd for C39H52N8O9 [M+H]-, 777.3936, found:
777.3923。
2H, CH2), 4.11 (d, J = 2.4 Hz, 1H, CH-4’), 4.22 (dd, J = 6.0 Hz, 2.4 Hz, 1H, CH-3’), 4.44 (t, J = 6.0 Hz, 1H, CH-2’), 5.41 (d, J = 7.2 Hz, 1H, CH-1’), 7.46 (s, 1H, CH-6), 7.51 (s, 1H, Ar-H-2), 7.64 (d, J = 7.2 Hz, 1H, Ar-H-3), 7.88
13
(d, J = 7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 173.14, 164.81,
162.18, 161.75, 161.70, 153.35, 138.00, 129.95, 127.85, 126.44, 124.80,
123.22, 121.75, 118.56, 117.71, 112.89, 97.84, 94.65, 86.78, 72.11, 70.54,
60.92, 56.06, 55.92, 44.49, 44.44, 42.71, 41.17, 37.78, 37.20, 28.86, 28.75,
26.82, 26.63, 12.27; HR-ESI-MS: calcd for C39H52N8O9 [M+H]-, 777.3936, found:
777.3923。
[0083] 化合物7g： 收率74%; 红色固体, mp. 118-120℃; 1H NMR (600 MHz, CD3OD)δ: (ppm) 1.44-1.52 (m, 6H, 3CH2), 1.58-1.69 (m, 4H, 2CH2), 1.75 (s, 3H, CH3-5), 1.84-1.89 (m, 2H, CH2), 2.46 (d, J = 13.8 Hz, 12H, 4CH3-N), 2.75-2.79 (m, 4H, 2CH2), 3.37-3.40 (m, 2H, CH2), 3.48 (t, J = 7.2 Hz, 2H, CH2), 3.77-3.82 (m, 2H, CH2-5’), 4.10 (d, J = 2.4 Hz, 1H, CH-4’), 4.18-4.23 (m, 5H, CH-3’,2CH2-N), 4.36 (t, J = 6.6 Hz, 1H, CH-2’), 5.31 (d, J = 7.2 Hz, 1H, CH-1’),
7.39 (s, 1H, CH-6), 7.74 (s, 1H, Ar-H-2), 7.88 (d, J = 7.8 Hz, 1H, Ar-H-3),
13
8.13 (d, J = 7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 172.86,
165.52, 163.06, 162.71, 153.04, 151.80, 136.72, 130.24, 128.62, 127.20,
125.44, 123.48, 122.28, 119.41, 118.43, 112.16, 98.59, 92.97, 87.15, 73.02,
70.50, 60.83, 56.94, 55.64, 43.23, 43.07, 42.67, 41.40, 38.11, 36.43, 35.70,
28.77, 28.48, 28.43, 28.05, 26.30, 26.25, 11.59; HR-ESI-MS: calcd for C40H54N8O9 [M+H]-, 791.4092, found: 791.4078。
7.39 (s, 1H, CH-6), 7.74 (s, 1H, Ar-H-2), 7.88 (d, J = 7.8 Hz, 1H, Ar-H-3),
13
8.13 (d, J = 7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 172.86,
165.52, 163.06, 162.71, 153.04, 151.80, 136.72, 130.24, 128.62, 127.20,
125.44, 123.48, 122.28, 119.41, 118.43, 112.16, 98.59, 92.97, 87.15, 73.02,
70.50, 60.83, 56.94, 55.64, 43.23, 43.07, 42.67, 41.40, 38.11, 36.43, 35.70,
28.77, 28.48, 28.43, 28.05, 26.30, 26.25, 11.59; HR-ESI-MS: calcd for C40H54N8O9 [M+H]-, 791.4092, found: 791.4078。
[0084] 实施例2
[0085] 合成化合物11a～11c
[0086] 化合物11a～11c的化学反应通式如下：
[0087]
[0088] 上述反应式中：8为2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺，n为1，m为1～3，R2为N,N-二甲基氨基。
[0089] 具体方法为：
[0090] 在30 mL微波管中加入616 mg（1 mmol）化合物8、409 mg（1.2mmol）化合物4a～4c中的任意一种、10 mL新蒸TEA（三乙胺），120℃微波辐射辅助下反应5 min，TLC监测原料反应完全；蒸干溶剂，加入329μL（3 mmol）N,N-二甲基乙二胺，150℃微波辐射辅助下反应15 min，TLC监测反应完全；将反应液浓缩后，柱层析分离（二氯甲烷:甲醇=1～
5:1），得化合物10a～10c；取0.11mmol化合物10a～10c中的一种，室温下加入90%三氟醋酸水溶液5mL，室温搅拌5min，TLC监测反应完全，减压蒸除溶剂，柱层析分离（二氯甲烷：
甲醇：氨水=100～150:10～75:0.1～2），得化合物11a～11c。其中，当m为1、2、3时，所对应化合物4a、4b、4c，以化合物4a、4b、4c 和化合物8为原料，n为1，R2为N,N-二甲基氨基时，分别得中间体化合物10a、10b、10c；以及分别得对应的化合物11a、11b、11c。
5:1），得化合物10a～10c；取0.11mmol化合物10a～10c中的一种，室温下加入90%三氟醋酸水溶液5mL，室温搅拌5min，TLC监测反应完全，减压蒸除溶剂，柱层析分离（二氯甲烷：
甲醇：氨水=100～150:10～75:0.1～2），得化合物11a～11c。其中，当m为1、2、3时，所对应化合物4a、4b、4c，以化合物4a、4b、4c 和化合物8为原料，n为1，R2为N,N-二甲基氨基时，分别得中间体化合物10a、10b、10c；以及分别得对应的化合物11a、11b、11c。
[0091] 本实施例中起始原料化合物8（2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺）的合成如下：
[0092] 将5.0 g（18.65mmol）1,4,5,8-萘四甲酸二酐溶于93 mL含40%游离三氧化硫的发烟硫酸中，室温搅拌3 h，加入0.19 g（0.74 mmol）I2，继续搅拌1h，分五批加入5.7 g的NaBr，每批间隔1h，每批加入NaBr的量为1.14g（11.19mmol），在80℃下，反应24h，加热至回流继续反应24 h，冷却至室温，将反应液倾入1 L冰水中，过滤，滤饼经水洗，甲醇洗，真空干燥，得黄色固体2,6-溴-1,4,5,8-萘四甲酸二酐7.90 g；再将5.00 g（11.70 mmol）2,6-溴-1,4,5,8-萘四甲酸酐溶于100 mL冰醋酸中，在18～25℃下滴加111.90 mmol的N,N-二甲基乙二胺，氮气保护下，油浴120℃回流20 min，冷却至室温，用饱和NaHCO3水溶液中和至pH=7～8，氯仿萃取，用饱和食盐水洗涤，无水NaSO4干燥，浓缩后经硅胶色谱分离纯化[V(二氯甲烷):V(甲醇)=99:1]，得化合物8（2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺）。
[0093] 化合物4a～4c的合成制备方法参见本发明中实施例1所示。
[0094] 化合物8：黄色固体; mp. 246~248 oC; 1H NMR (CDCl3, 600 MHz) δ: 2.37 (s, +12H), 2.71 (s, 4H), 4.37 (t, 4H, J = 6.6 Hz), 9.01 (s, 2H); MS (ESI), m/z: +
567.1 [M+H]。
567.1 [M+H]。
[0095] 化合物10a: 收率 64%；兰色固体， mp. 150-154℃; 1H NMR (600 MHz, D2O) δ:0.93 (s, 3H, CH3), 1.32 (s, 3H, CH3), 1.93 (s, 3H, CH3-7’), 2.63 (s, 6H, CH3),
2.68 (s, 6H, CH3-7), 2.70 (s, 6H, CH3-7), 2.77 (s, 2H, CH2), 2.98 (s, 2H, CH2),
3.07 (s, 2H, CH2), 3.71-3.78 (m, 8H, CH2), 4.03 (m, 1H, H-4’), 4.18-4.27 (m,
5H, CH2-5, H-3’), 4.62 (s, 1H, H-2’), 5.26 (broad s, 1H, H-1’), 7.34 (s, 1H, + +
H-6’), 7.53 (s, 1H, H-2), 7.61 (s, 1H, H-4); HRMS (ESI) calcd C41H57N10O9 [M+H]
833.4304. Found: 833.4336。
2.68 (s, 6H, CH3-7), 2.70 (s, 6H, CH3-7), 2.77 (s, 2H, CH2), 2.98 (s, 2H, CH2),
3.07 (s, 2H, CH2), 3.71-3.78 (m, 8H, CH2), 4.03 (m, 1H, H-4’), 4.18-4.27 (m,
5H, CH2-5, H-3’), 4.62 (s, 1H, H-2’), 5.26 (broad s, 1H, H-1’), 7.34 (s, 1H, + +
H-6’), 7.53 (s, 1H, H-2), 7.61 (s, 1H, H-4); HRMS (ESI) calcd C41H57N10O9 [M+H]
833.4304. Found: 833.4336。
[0096] 化合物10b: 收率 62%; 蓝色固体; mp. 171-174℃; 1H NMR (600 MHz, D2O) δ: 1.25 (s, 3H, CH3), 1.53 (s, 3H, CH3), 1.56 (s, 3H, CH3-7’), 2.12 (m, 2H, CH2), 3.03 (s, 6H, CH3), 3.04 (s, 6H, CH3), 3.05 (s, 6H, CH3), 3.49 (m, 4H, CH2),3.55 (m, 4H, CH2), 3.61 (s, 2H, CH2), 3.82 (s, 2H, CH2), 3.90 (s, 2H, CH2), 4.02 (s, 2H, H-3’, H-4’), 4.34 (s, 1H, H-2’), 4.49 (m, 4H, CH2-5), 5.42 (s, 1H, +
H-1’), 7.26 (s, 1H, H-6’), 7.70 (s, 1H, H-2), 7.78 (s, 1H, H-4); HRMS (ESI) +
calcd C42H59N10O9 [M+H] 847.4461. Found: 847.4462。
H-1’), 7.26 (s, 1H, H-6’), 7.70 (s, 1H, H-2), 7.78 (s, 1H, H-4); HRMS (ESI) +
calcd C42H59N10O9 [M+H] 847.4461. Found: 847.4462。
[0097] 化合物10c: 收率 68%; 蓝色固体; mp. 166-169℃; 1H NMR (600 MHz, CD3OD) δ: 1.22 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.66 (s, 3H, CH3-7’), 1.78 (m, 4H, CH2), 2.86 (s, 6H, CH3), 2.89 (s, 6H, CH3), 2.90 (s, 6H, CH3), 3.34 (bs, 10H, CH2), 3.75 (s, 3H, CH2, H-4’), 3.85 (s, 2H, CH2), 4.19 (s, 1H, H-3’), 4.37 (m,4H, CH2), 5.31 (d, J = 4.8Hz, 1H, H-1’), 7.29 (s, 1H, H-6’), 7.51 (s, 1H, H-2), + +
7.58 (s, 1H, H-4); HRMS (ESI) calcd C43H61N10O9 [M+H] 861.4617. Found: 861.4644。
7.58 (s, 1H, H-4); HRMS (ESI) calcd C43H61N10O9 [M+H] 861.4617. Found: 861.4644。
[0098] 化合物11a：收率 82%; 兰色固体; mp. 170-172℃; 1H NMR (600 MHz, D2O) δ:1.66 (s, 3H, CH3-7’), 3.03 (s, 6H, CH3), 3.05 (s, 12H, CH3), 3.42 (t, J = 12Hz,
2H, CH2), 3.49 (t, J = 12Hz, 2H, CH2), 3.54 (t, J = 12Hz, 2H, CH2), 3.61-3.78 (m, 7H, CH2, H-4’), 3.95 (s, 2H, H-2’, H-3’), 4.00 (t, J = 12Hz, 2H, CH2), 4.46 (s, 4H, CH2-5), 4.93 (d, J = 4.8Hz, 1H, H-1’), 7.18 (s, 1H, H-6’), 7.66 (s, 1H,
13
H-2), 7.74 (s, 1H, H-4); C NMR (150 MHz, D2O) δ: 12.67, 35.42, 35.61, 37.75,
41.72, 43.48, 43.58, 55.28, 55.44, 55.91, 60.57, 69.62, 71.96, 85.80, 92.36,
100.61, 102.66, 113.62, 116.78, 118.67, 120.38, 120.60, 124.40, 124.48,
137.10, 147.98, 150.06, 153.52, 162.90, 163.44, 165.08, 165.54, 173.56; HRMS (ESI+) calcd C38H53N10O9 [M+H]+ 793.3991. Found: 793.3975。
2H, CH2), 3.49 (t, J = 12Hz, 2H, CH2), 3.54 (t, J = 12Hz, 2H, CH2), 3.61-3.78 (m, 7H, CH2, H-4’), 3.95 (s, 2H, H-2’, H-3’), 4.00 (t, J = 12Hz, 2H, CH2), 4.46 (s, 4H, CH2-5), 4.93 (d, J = 4.8Hz, 1H, H-1’), 7.18 (s, 1H, H-6’), 7.66 (s, 1H,
13
H-2), 7.74 (s, 1H, H-4); C NMR (150 MHz, D2O) δ: 12.67, 35.42, 35.61, 37.75,
41.72, 43.48, 43.58, 55.28, 55.44, 55.91, 60.57, 69.62, 71.96, 85.80, 92.36,
100.61, 102.66, 113.62, 116.78, 118.67, 120.38, 120.60, 124.40, 124.48,
137.10, 147.98, 150.06, 153.52, 162.90, 163.44, 165.08, 165.54, 173.56; HRMS (ESI+) calcd C38H53N10O9 [M+H]+ 793.3991. Found: 793.3975。
[0099] 化合物11b：收率 80%; 蓝色固体; mp. 155-159℃; 1H NMR (600 MHz, D2O) δ: 1.48 (s, 3H, CH3-7’), 2.23 (m, 2H, CH2), 3.15 (s, 6H, CH3), 3.17 (s, 12H, CH3), 3.62-3.66 (m, 8H, CH2), 3.76 (s, 2H, CH2), 3.86 (s, 2H, CH2), 4.04 (s, 1H, H-4’), 4.13-4.16 (m, 2H, CH2), 4.25 (s, 1H, H-3’), 4.31 (s, 1H, H-2’), 4.61 (bs, 4H, CH2-5), 5.28 (s, 1H, H-1’), 7.26 (s, 1H, H-6’), 7.84 (s, 1H, H-2),13
7.90 (s, 1H, H-4); C NMR (150 MHz, D2O) δ: 12.63, 28.25, 36.22, 36.96, 39.03,
39.78, 40.96, 43.67, 44.17, 44.40, 46.83, 52.40, 55.22, 56.65, 56.95, 60.75,
69.98, 72.64, 86.05, 92.60, 99.55, 100.17, 113.43, 116.63, 116.66, 117.23,
119.18, 119.24, 123.54, 123.60, 137.15, 147.62, 148.00, 153.30, 161.88, + +
161.98, 164.56, 173.48; HRMS (ESI) calcd C39H55N10O9 [M+H] 807.4148. Found:
807.4141。
7.90 (s, 1H, H-4); C NMR (150 MHz, D2O) δ: 12.63, 28.25, 36.22, 36.96, 39.03,
39.78, 40.96, 43.67, 44.17, 44.40, 46.83, 52.40, 55.22, 56.65, 56.95, 60.75,
69.98, 72.64, 86.05, 92.60, 99.55, 100.17, 113.43, 116.63, 116.66, 117.23,
119.18, 119.24, 123.54, 123.60, 137.15, 147.62, 148.00, 153.30, 161.88, + +
161.98, 164.56, 173.48; HRMS (ESI) calcd C39H55N10O9 [M+H] 807.4148. Found:
807.4141。
[0100] 化合物11c: 收率 85%; 蓝色固体; mp. 189-182℃; 1H NMR (600 MHz, D2O) δ: 1.38 (s, 3H, CH3-7’), 1.82-1.89 (m, 4H, CH2), 3.06 (s, 6H, CH3), 3.08 (s,6H, CH3), 3.10 (s, 6H, CH3), 3.27 (s, 2H, CH2), 3.54 (s, 2H, CH2), 3.59-3.60 (m,
6H, CH2), 3.71-3.73 (m, 2H, CH2), 3.99 (s, 1H, H-4’), 4.04 (t, J = 12Hz, 2H, CH2), 4.10 (s, 2H, H-3’, H-2’), 4.55 (s, 4H, CH2-5), 4.88 (s, 1H, H-1’), 6.87
13
(s, 1H, H-6’), 7.75 (s, 1H, H-2), 7.82 (s, 1H, H-3); C NMR (150 MHz, D2O) δ:
13.34, 24.93, 25.58, 36.25, 36.37, 38.47, 41.66, 43.11, 44.13, 44.21, 47.48,
55.98, 56.03, 56.66, 61.29, 70.60, 73.07, 86.93, 93.05, 101.12, 103.29,
113.16, 117.55, 119.68, 120.83, 121.30, 125.22, 137.26, 148.62, 149.40, +
153.52, 163.96, 164.14, 165.88, 166.24, 173.81; HRMS (ESI) calcd C40H57N10O9 +
[M+H] 821.4304. Found: 821.4283。
6H, CH2), 3.71-3.73 (m, 2H, CH2), 3.99 (s, 1H, H-4’), 4.04 (t, J = 12Hz, 2H, CH2), 4.10 (s, 2H, H-3’, H-2’), 4.55 (s, 4H, CH2-5), 4.88 (s, 1H, H-1’), 6.87
13
(s, 1H, H-6’), 7.75 (s, 1H, H-2), 7.82 (s, 1H, H-3); C NMR (150 MHz, D2O) δ:
13.34, 24.93, 25.58, 36.25, 36.37, 38.47, 41.66, 43.11, 44.13, 44.21, 47.48,
55.98, 56.03, 56.66, 61.29, 70.60, 73.07, 86.93, 93.05, 101.12, 103.29,
113.16, 117.55, 119.68, 120.83, 121.30, 125.22, 137.26, 148.62, 149.40, +
153.52, 163.96, 164.14, 165.88, 166.24, 173.81; HRMS (ESI) calcd C40H57N10O9 +
[M+H] 821.4304. Found: 821.4283。
[0101] 实施例3
[0102] 合成化合物13a、13c、15a、15c、17a、17c、19a、19c、21a～21c
[0103] 化合物13a、13c、15a、15c、17a、17c、19a、19c、21a～21c的化学合成反应通式如下：
[0104]
[0105] 上述反应式中：8为2,6-二溴-1,4,5,8-萘四甲酸二酰亚胺，n为1～3，m为1～3；R2为N,N-二乙基氨基、吡咯烷-1-基、哌啶-1-基、苯基氨基或5-甲基尿苷-5’-氨基中的任意一种。
[0106] 上述反应中原料化合物m为1、2、3时，所对应的化合物4a、4b、4c；其制备方法同实施例1所示，同时，以化合物4a、4b、4c和化合物8为原料，采用实施例2制备化合物11a～11c的制备工艺，制备得各中间体化合物和终产物。
[0107] 其中：
[0108] 当n为1，m为1， R2为N,N-二乙基氨基时；得中间体化合物12a，化合物13a；
[0109] 当n为1，m为3， R2为N,N-二乙基氨基时；得中间体化合物12c，化合物13c；
[0110] 当n为1，m为1，R2为吡咯烷-1-基时，得中间体化合物14a，化合物15a；
[0111] 当n为1，m为1，R2为吡咯烷-1-基时，得中间体化合物14c，化合物15c；
[0112] 当n为1，m为1，R2为哌啶-1-基时，得中间体化合物16a，化合物17a；
[0113] 当n为1，m为3，R2为哌啶-1-基时，得中间体化合物16c，化合物17c；
[0114] 当n为1，m为1，R2为苯基氨基时，得中间体化合物18a，化合物19a；
[0115] 当n为1，m为3，R2为苯基氨基时，得中间体化合物18c，化合物19c；
[0116] 当n为1，m为1，R2为5-甲基尿苷-5’-氨基时，得中间体化合物20a，化合物21a；
[0117] 当n为2，m为2，R2为5-甲基尿苷-5’-氨基时，得中间体化合物20b，化合物21b；
[0118] 当n为3，m为3，R2为5-甲基尿苷-5’-氨基时，得中间体化合物20 c，化合物21c。
[0119] 化合物12a: 收率 61%; 蓝色固体; mp. 145-147℃; 1H NMR (600 MHz, CD3OD) δ: 0.99 (s, 3H, CH3), 1.17 (t, 6H, J = 7.2 Hz, CH3), 1.33 (s, 3H, CH3), 1.90 (s, 3H, CH3-7’), 2.38 (s, 12H, CH3-7), 2.58-2.64 (m, 6H, CH2), 2.73 (m, 4H, CH2), 2.88 (m, 2H, CH2), 3.45 (bs, 2H, CH2), 3.70-3.79 (m, 6H, CH2), 4.13 (s,5H, CH2-5, H-4’), 4.61 (s, 1H, H-3’), 4.68 (m, 1H, H-2’), 5.39 (m, 1H, H-1’), +
7.42 (s, 1H, H-6’), 7.49 (s, 1H, H-4), 7.53 (s, 1H, H-2); HRMS (ESI) calcd +
C43H61N10O9 [M+H] 861.4622. Found: 861.4630。
7.42 (s, 1H, H-6’), 7.49 (s, 1H, H-4), 7.53 (s, 1H, H-2); HRMS (ESI) calcd +
C43H61N10O9 [M+H] 861.4622. Found: 861.4630。
[0120] 化合物12c: 收率 63%; 蓝色固体; mp. 167-169℃; 1H NMR (600 MHz, CD3OD) δ: 1.28 (s, 3H, CH3), 1.44 (t, 6H, J = 7.2 Hz, CH3), 1.57 (s, 3H, CH3), 1.64 (s, 3H, CH3-7’), 1.89 (m, 4H, CH2), 3.03 (s, 6H, CH3-7), 3.05 (s, 6H, CH3-7),3.39 (m, 6H, CH2), 3.53-3.55 (m, 8H, CH2), 3.77-3.84 (m, 2H, CH2), 4.04 (t, J = 6.6 Hz, 2H, CH2), 4.27 (s, 1H, H-4’), 4.52 (bs, 4H, CH2-5), 4.78-4.80(m, 2H, H-3’, H-2’), 5.34 (s, 1H, H-1’), 7.34 (s, 1H, H-6’), 7.75 (s, 1H, H-4), 7.80 + +
(s, 1H, H-2); HRMS (ESI) calcd C45H65N10O9 [M+H] 889.4935. Found: 889.4928。
(s, 1H, H-2); HRMS (ESI) calcd C45H65N10O9 [M+H] 889.4935. Found: 889.4928。
[0121] 化合物14a: 收率 59%; 蓝色固体; mp. 158-161℃; 1H NMR (600 MHz, CD3OD) δ: 1.01 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.94 (s, 7H, CH2, CH3-7’), 2.39 (s, 6H, CH3-7), 2.40 (s, 6H, CH3-7), 2.60 (m, 4H, CH2), 2.76 (bs, 4H, CH2), 2.92 (t, J = 6.6 Hz, 2H, CH2), 3.49 (m, 2H, CH2), 3.68-3.80 (m, 6H, CH2), 4.08 (t, J = 8.4 Hz, 4H, CH2-5), 4.13 (s, 1H, H-4’), 4.63 (s, 1H, H-3’), 4.70 (s, 1H, H-2’), +5.39 (s, 1H, H-1’), 7.43 (s, 2H, H-2, H-4), 7.46 (s, 1H, H-6’); HRMS (ESI)
+
calcd C43H59N10O9 [M+H] 859.4466. Found: 859.4472。
+
calcd C43H59N10O9 [M+H] 859.4466. Found: 859.4472。
[0122] 化合物14c: 收率 61%; 蓝色固体; mp. 163-165℃; 1H NMR (600 MHz, CD3OD) δ: 1.28 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.68 (s, 3H, CH3-7), 1.88 (m, 4H, CH2), 2.13 (s, 4H, CH2), 3.43-3.65 (m, 14H, CH2), 3.82 (q, J = 12 Hz, 2H, CH2),4.01 (t, J = 5.4 Hz, 2H,CH2), 4.27 (s, 1H, H-4’), 4.50 (m, 4H, CH2), 4.81 (s,
1H, H-2’), 5.37 (s, 1H, H-1’), 7.35 (s, 1H, H-6’), 7.70 (s, 1H, H-4), 7.76 (s, + +
1H, H-2); HRMS (ESI) calcd C45H63N10O9 [M+H] 887.4779. Found: 887.4769。
1H, H-2’), 5.37 (s, 1H, H-1’), 7.35 (s, 1H, H-6’), 7.70 (s, 1H, H-4), 7.76 (s, + +
1H, H-2); HRMS (ESI) calcd C45H63N10O9 [M+H] 887.4779. Found: 887.4769。
[0123] 化合物16a: 收率 64%; 蓝色固体; mp. 165-168℃; 1H NMR (600 MHz, CD3OD) δ: 0.99 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.64 (m, 2H, CH2), 1.84 (m, 4H, CH2),1.89 (s, 3H, CH3-7’), 2.38 (s, 12H, CH3-7), 2.97-3.03 (m, 8H, CH2), 3.11 (bs,
2H, CH2), 3.63-3.88 (m, 8H, CH2), 4.18 (s, 1H, H-4’), 4.26 (s, 4H, CH2-5), 4.67 (s, 1H, H-3’), 4.71 (s, 1H, H-2’), 5.39 (s, 1H, H-1’), 7.46 (s, 1H, H-4), 7.49 + +
(s, 1H, H-2), 7.55 (s, 1H, H-6’); HRMS (ESI) calcd C44H61N10O9 [M+H] 873.4623. Found: 873.4631。
2H, CH2), 3.63-3.88 (m, 8H, CH2), 4.18 (s, 1H, H-4’), 4.26 (s, 4H, CH2-5), 4.67 (s, 1H, H-3’), 4.71 (s, 1H, H-2’), 5.39 (s, 1H, H-1’), 7.46 (s, 1H, H-4), 7.49 + +
(s, 1H, H-2), 7.55 (s, 1H, H-6’); HRMS (ESI) calcd C44H61N10O9 [M+H] 873.4623. Found: 873.4631。
[0124] 化合物16c: 收率 65%; 蓝色固体; mp. 127-130℃; 1H NMR (600 MHz, CD3OD) δ: 1.31 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.61 (m, 2H, CH2), 1.69 (m, 4H, CH2),1.84 (m, 4H, CH2), 1.88 (s, 3H, CH3-7’), 2.36 (s, 6H, CH3-7), 2.37 (s, 6H, CH3-7), 2.55-2.61 (m, 8H, CH2), 2.72 (t, J = 6.0 Hz, 2H, CH2), 3.27 (s, 2H, CH2), 3.36 (s, 2H, CH2), 3.53 (m, 2H, CH2), 3.84-3.89 (m, 2H, CH2), 3.95 (s,
4H, CH2-5), 4.27 (s, 1H, H-4’), 4.94 (s, 1H, H-3’), 4.97 (s, 1H, H-2’), 5.51 (s, 1H, H-1’), 7.20 (s, 1H, H-4), 7.25 (s, 1H, H-2), 7.46 (s, 1H, H-6’); HRMS + +
(ESI) calcd C46H65N10O9 [M+H] 901.4936. Found: 901.4941。
4H, CH2-5), 4.27 (s, 1H, H-4’), 4.94 (s, 1H, H-3’), 4.97 (s, 1H, H-2’), 5.51 (s, 1H, H-1’), 7.20 (s, 1H, H-4), 7.25 (s, 1H, H-2), 7.46 (s, 1H, H-6’); HRMS + +
(ESI) calcd C46H65N10O9 [M+H] 901.4936. Found: 901.4941。
[0125] 化合物18a: 收率 32%; 蓝色固体; mp. 164-166℃; 1H NMR (600 MHz, CD3OD) δ: 1.19 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.86 (s, 3H, CH3-7’), 2.30 (s, 6H, CH3-7), 2.33 (s, 6H, CH3-7), 2.55-2.57 (m, 2H, CH2), 2.59-2.61 (m, 2H, CH2),3.48 (m, 2H, CH2), 3.59-3.64 (m, 4H, CH2), 3.72 (m, 2H, CH2), 3.82-3.92 (m, 2H, CH2), 4.17-4.19 (m, 4H, CH2-5), 4.22 (d, J = 7.8 Hz, 1H, H-4’), 4.82 (d, J =
6.0 Hz, 1H, H-3’), 4.88 (d, J = 6.6 Hz, 1H, H-2’), 5.13 (d, J = 6.0 Hz, 1H, H-1’), 6.67 (t, J = 7.8 Hz, 2H, Ph), 6.91 (s, 1H, Ph), 7.13 (d, J = 7.8 Hz, +
2H, Ph), 7.26 (s, 1H, H-6’), 7.83 (s, 1H, H-4), 7.93 (s, 1H, H-2); HRMS (ESI) +
calcd C45H57N10O9 [M+H] 881.4309. Found: 881.4313。
6.0 Hz, 1H, H-3’), 4.88 (d, J = 6.6 Hz, 1H, H-2’), 5.13 (d, J = 6.0 Hz, 1H, H-1’), 6.67 (t, J = 7.8 Hz, 2H, Ph), 6.91 (s, 1H, Ph), 7.13 (d, J = 7.8 Hz, +
2H, Ph), 7.26 (s, 1H, H-6’), 7.83 (s, 1H, H-4), 7.93 (s, 1H, H-2); HRMS (ESI) +
calcd C45H57N10O9 [M+H] 881.4309. Found: 881.4313。
[0126] 化合物18c: 收率 34%; 蓝色固体; mp. 138-141℃; 1H NMR (600 MHz, CD3OD) δ: 1.27 (s, 3H, CH3), 1.56 (s, 3H, CH3), 1.84 (m, 4H, CH2), 1.94 (s, 3H, CH3-7’), 2.75 (s, 6H, CH3-7), 2.82 (s, 6H, CH3-7), 3.11 (t, J = 6.0 Hz, 2H, CH2), 3.27 (s, 2H, CH2), 3.40 (s, 2H, CH2), 3.46 (s, 2H, CH2), 3.50-3.52 (m,2H, CH2), 3.62 (m, 3H, CH2, H-4’), 3.77-3.82 (m, 2H, CH2), 4.28 (s, 1H, H-3’),
4.32-4.38 (m, 4H, CH2-5), 4.77 (t, J = 5.4 Hz, 1H, H-2’), 5.28 (s, 1H, H-1’),
6.69 (t, J = 7.2 Hz, 1H, Ph), 6.82 (d, J = 8.4 Hz, 2H, Ph), 7.19 (t, J = 7.8 Hz, 3H, Ph,), 7.26 (s, 1H, H-6’), 7.61 (s, 1H, H-4), 7.70 (s, 1H, H-2); HRMS + +
(ESI) calcd C44H57N10O9 [M+H] 869.4309. Found: 869.4310。
4.32-4.38 (m, 4H, CH2-5), 4.77 (t, J = 5.4 Hz, 1H, H-2’), 5.28 (s, 1H, H-1’),
6.69 (t, J = 7.2 Hz, 1H, Ph), 6.82 (d, J = 8.4 Hz, 2H, Ph), 7.19 (t, J = 7.8 Hz, 3H, Ph,), 7.26 (s, 1H, H-6’), 7.61 (s, 1H, H-4), 7.70 (s, 1H, H-2); HRMS + +
(ESI) calcd C44H57N10O9 [M+H] 869.4309. Found: 869.4310。
[0127] 化合物20a: 收率31%；蓝色固体； mp. 179-186℃；1H NMR (600 MHz, CDCl3) δ (ppm) 1.27 (s, 3H, CH3), 1.56 (s, 3H, CH3), 1.94 (s, 3H, CH3-5), 2.38 (s,6H, 2CH3-N), 2.57-2.62 (m, 2H, CH2), 3.65 (m, 2H, CH2), 3.72-3.85 (m, 2H, CH2),
3.93-4.01 (m, 2H, CH2), 4.08-4.14 (m, 2H, CH2), 4.30 (s, 1H, CH-1’), 4.75-4.95 (m, 2H, CH-3’, CH-2’), 5.16 (d, J = 2.4 Hz, 1H, CH-1’), 6.96 (s, 1H, CH-6), -
7.56 (s, 1H, NH), 9.14 (s, 1H, NH-3); HR-ESI-MS: calcd for C52H68N12O14 [M+H],
1085.5056, found: 1085.5056。
3.93-4.01 (m, 2H, CH2), 4.08-4.14 (m, 2H, CH2), 4.30 (s, 1H, CH-1’), 4.75-4.95 (m, 2H, CH-3’, CH-2’), 5.16 (d, J = 2.4 Hz, 1H, CH-1’), 6.96 (s, 1H, CH-6), -
7.56 (s, 1H, NH), 9.14 (s, 1H, NH-3); HR-ESI-MS: calcd for C52H68N12O14 [M+H],
1085.5056, found: 1085.5056。
[0128] 化合物20b: 收率20%；蓝色固体； mp. 176-178℃；1H NMR (600 MHz, CDCl3) δ (ppm) 1.32 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.90 (s, 3H, CH3-5), 2.13 (m, 2H, CH2), 2.49 (s, 6H, 2CH3-N), 2.72-2.76 (m, 2H, CH2), 3.35 (m, 2H, CH2), 3.61-3.66 (m, 2H, CH2), 3.93-3.96 (m, 2H, CH2), 4.11 (s, 2H, CH 2), 4.29 (s, 1H, CH-4’),5.06 (m, 2H, CH-3’, CH-2’), 5.24 (s, 1H, CH-1’), 7.06 (s, 1H, CH-6), 7.42 (s, -
1H, NH), 8.89 (s, 1H, NH-3);HR-ESI-MS: calcd for C54H72N12O14 [M+H], 1113.5369, found: 1113.5394。
1H, NH), 8.89 (s, 1H, NH-3);HR-ESI-MS: calcd for C54H72N12O14 [M+H], 1113.5369, found: 1113.5394。
[0129] 化合物20c: 收率30%；蓝色固体； mp. 174-178℃；1H NMR (600 MHz, CDCl3) δ (ppm)
[0130] 1.35 (s, 3H, CH3), 1.59 (s, 3H, CH3), 1.81-1.86 (m, 4H, 2CH2), 1.90 (s, 3H, CH3-5), 2.39 (s, 6H, 2CH3-N), 2.57-2.60 (m, 2H, CH2), 3.29-3.30 (m,2H, CH2), 3.49-3.51 (m, 1H, CH-5’), 3.60-3.63 (m, 1H, CH-5’), 3.98 (dd, J =
18.6 Hz, 10.8Hz, 2H, CH2-N), 4.10 (m, 2H, CH2), 4.32 (s, 1H, CH-4’), 5.03-5.04 (m, 1H, CH-3’), 5.07-5.09 (m, 1H, CH-2’), 5.20 (d, J = 1.4 Hz, 1H, CH-1’),
6.99 (s, 1H, CH-6), 7.19 (s, 1H, NH), 7.45 (s, 1H, CH-Ar), 8.93 (s, 1H, NH-3); -
HR-ESI-MS: calcd for C56H76N12O14 [M+H], 1141.5682, found: 1141.5677。
18.6 Hz, 10.8Hz, 2H, CH2-N), 4.10 (m, 2H, CH2), 4.32 (s, 1H, CH-4’), 5.03-5.04 (m, 1H, CH-3’), 5.07-5.09 (m, 1H, CH-2’), 5.20 (d, J = 1.4 Hz, 1H, CH-1’),
6.99 (s, 1H, CH-6), 7.19 (s, 1H, NH), 7.45 (s, 1H, CH-Ar), 8.93 (s, 1H, NH-3); -
HR-ESI-MS: calcd for C56H76N12O14 [M+H], 1141.5682, found: 1141.5677。
[0131] 化合物13a: 收率 85%; 蓝色固体; mp. 175-178℃; 1H NMR (600 MHz, CD3OD) δ: 1.31 (t, 6H, J = 7.2 Hz, CH3), 1.81 (s, 3H, CH3-7’), 2.69 (s, 12H, CH3-7),3.01-3.07 (m, 8H, CH2), 3.18 (bs, 2H, CH2), 3.70-3.74 (m, 8H, CH2), 3.93 (s,
1H, H-4’), 4.04 (s, 2H, H-3’, H-2’), 4.24(s, 4H, CH2-5), 5.28 (s, 1H, H-1’),
13
7.46 (s, 1H, H-6’), 7.51 (s, 2H, H-2, H-4); C NMR (150 MHz, CD3OD) δ:10.54,
13.82, 37.45, 37.50, 37.69, 40.20, 42.19, 42.73, 45.04, 45.11, 48.00, 48.38,
51.31, 51.98, 55.21, 56.82, 56.94, 61.84, 71.15, 73.98, 87.76, 94.89, 101.76,
102.58, 114.61, 117.79, 118.66, 118.69, 121.26, 121.33, 125.56, 138.83, +
149.07, 149.98, 154.63, 163.39, 163.66, 166.20, 166.37, 174.42; HRMS (ESI) +
calcd C40H57N10O9 [M+H] 821.4309. Found: 821.4295。
1H, H-4’), 4.04 (s, 2H, H-3’, H-2’), 4.24(s, 4H, CH2-5), 5.28 (s, 1H, H-1’),
13
7.46 (s, 1H, H-6’), 7.51 (s, 2H, H-2, H-4); C NMR (150 MHz, CD3OD) δ:10.54,
13.82, 37.45, 37.50, 37.69, 40.20, 42.19, 42.73, 45.04, 45.11, 48.00, 48.38,
51.31, 51.98, 55.21, 56.82, 56.94, 61.84, 71.15, 73.98, 87.76, 94.89, 101.76,
102.58, 114.61, 117.79, 118.66, 118.69, 121.26, 121.33, 125.56, 138.83, +
149.07, 149.98, 154.63, 163.39, 163.66, 166.20, 166.37, 174.42; HRMS (ESI) +
calcd C40H57N10O9 [M+H] 821.4309. Found: 821.4295。
[0132] 化合物13c: 收率 85%; 蓝色固体; mp. 169-172℃; 1H NMR (600 MHz, CD3OD) δ: 1.20 (t, 6H, J = 7.2Hz, CH3), 1.77 (s, 3H, CH3-7’), 1.82 (m, 4H, CH2), 2.44 (s, 6H, CH3-7), 2.48 (s, 6H, CH3-7), 2.68 (s, 2H, CH2), 2.73 (s, 2H, CH2), 2.80 (dd, J = 12 Hz, 6Hz, 4H, CH2), 2.91 (t, J = 6.6 Hz, 2H, CH2), 3.28 (bs, 2H, CH2), 3.40 (s, 2H, CH2), 3.49 (s, 2H, CH2), 3.77-3.82 (m, 2H, CH2), 4.04 (s,4H, CH2-5), 4.07 (s, 1H, H-4’), 4.18(d, J = 6 Hz, 1H, H-3’), 4.35 (d, J = 6 Hz, 1H, H-2’), 5.32 (d, J = 7.2 Hz, 1H, H-1’), 7.24 (s, 1H, H-6’), 7.32 (s,
13
1H, H-4), 7.43 (s, 1H, H-2); C NMR (150 MHz, CD3OD) δ: 10.24, 13.60, 27.23,
27.39, 37.37, 37.40, 40.00, 42.15, 43.70, 44.69, 44.78, 48.40, 51.93, 56.72,
56.96, 56.98, 62.12, 71.66, 74.43, 88.37, 94.97, 101.47, 102.82, 113.68,
117.86, 118.65, 121.25, 121.41, 125.69, 125.83, 138.77, 149.11, 149.48, +
154.35, 163.48, 163.58, 166.43, 166.52, 174.22; HRMS (ESI) calcd C42H61N10O9 +
[M+H] 849.4622. Found: 849.4598。
13
1H, H-4), 7.43 (s, 1H, H-2); C NMR (150 MHz, CD3OD) δ: 10.24, 13.60, 27.23,
27.39, 37.37, 37.40, 40.00, 42.15, 43.70, 44.69, 44.78, 48.40, 51.93, 56.72,
56.96, 56.98, 62.12, 71.66, 74.43, 88.37, 94.97, 101.47, 102.82, 113.68,
117.86, 118.65, 121.25, 121.41, 125.69, 125.83, 138.77, 149.11, 149.48, +
154.35, 163.48, 163.58, 166.43, 166.52, 174.22; HRMS (ESI) calcd C42H61N10O9 +
[M+H] 849.4622. Found: 849.4598。
[0133] 化合物15a: 收率 85%; 蓝色固体; mp. 173-175℃; 1H NMR (600 MHz, CD3OD) δ: 1.84 (s, 3H, CH3-7’), 1.99 (s, 4H, CH2), 2.51 (s, 6H, CH3-7), 2.53 (s, 6H, CH3-7), 2.78 (bs, 4H, CH2), 3.02 (bs, 4H, CH2), 3.13 (s, 2H, CH2), 3.66-3.74 (m, 8H, CH2), 3.95 (s, 1H, H-4’), 4.08 (s, 1H, H-3’), 4.16 (s, 5H, CH2-5,13
H-2’), 5.21 (s, 1H, H-1’), 7.49 (s, 1H, H-6’), 7.50 (s, 2H, H-2, H-4); C NMR (150 MHz, CD3OD) δ:13.85, 24.35, 37.35, 38.23, 41.81, 42.14, 42.69, 45.47,
55.27, 55.43, 57.05, 57.15, 57.20, 61.91, 71.29, 73.80, 87.79, 95.10, 101.71,
102.24, 114.76, 117.66, 118.47, 121.09, 125.39, 125.44, 138.95, 148.96, +
149.76, 154.68, 163.24, 163.43, 166.09, 166.29, 174.45; HRMS (ESI ) calcd +
C40H55N10O9 [M+H] 819.4153. Found: 819.4120。
H-2’), 5.21 (s, 1H, H-1’), 7.49 (s, 1H, H-6’), 7.50 (s, 2H, H-2, H-4); C NMR (150 MHz, CD3OD) δ:13.85, 24.35, 37.35, 38.23, 41.81, 42.14, 42.69, 45.47,
55.27, 55.43, 57.05, 57.15, 57.20, 61.91, 71.29, 73.80, 87.79, 95.10, 101.71,
102.24, 114.76, 117.66, 118.47, 121.09, 125.39, 125.44, 138.95, 148.96, +
149.76, 154.68, 163.24, 163.43, 166.09, 166.29, 174.45; HRMS (ESI ) calcd +
C40H55N10O9 [M+H] 819.4153. Found: 819.4120。
[0134] 化合物15c: 收率 80%; 蓝色固体; mp. 184-186℃; 1H NMR (600 MHz, CD3OD) δ: 1.83 (m, 4H, CH2), 1.86 (s, 3H, CH3-7), 1.89 (m, 4H, CH2), 2.36 (s, 6H, CH3-7), 2.38 (s, 6H, CH3-7), 2.57 (m, 4H, CH2), 2.74 (bs, 4H, CH2), 2.88 (t, 2H, J = 6.6 Hz, CH2), 3.26 (s, 2H, CH2), 3.38 (s, 2H, CH2), 3.54 (s, 2H, CH2), 3.84 (m, 2H, CH2), 3.97 (m, 4H, CH2-5), 4.09 (s, 1H, H-4’), 4.22 (m, 1H, H-3’), 4.43 (t, 1H, J = 6.6 Hz, H-2’), 5.41 (d, 1H, J = 7.2 Hz, H-1’), 7.21 (s, 1H, H-4),13
7.24 (s, 1H, H-2), 7.51 (s, 1H, H-6’); C NMR (150 MHz, CD3OD) δ:13.68, 24.32,
27.32, 27.54, 38.48, 42.15, 42.45, 43.66, 45.62, 55.26, 55.67, 56.88, 56.92,
62.05, 71.64, 73.66, 87.72, 94.93, 100.71, 101.17, 114.64, 117.47, 117.88,
120.28, 120.34, 120.36, 124.78, 124.80, 138.72, 148.58, 148.79, 154.59, + +
162.72, 165.68, 165.78, 174.44; HRMS (ESI) calcd C43H59N10O9 [M+H] 847.4466. Found: 847.4448。
7.24 (s, 1H, H-2), 7.51 (s, 1H, H-6’); C NMR (150 MHz, CD3OD) δ:13.68, 24.32,
27.32, 27.54, 38.48, 42.15, 42.45, 43.66, 45.62, 55.26, 55.67, 56.88, 56.92,
62.05, 71.64, 73.66, 87.72, 94.93, 100.71, 101.17, 114.64, 117.47, 117.88,
120.28, 120.34, 120.36, 124.78, 124.80, 138.72, 148.58, 148.79, 154.59, + +
162.72, 165.68, 165.78, 174.44; HRMS (ESI) calcd C43H59N10O9 [M+H] 847.4466. Found: 847.4448。
[0135] 化合物17a: 收率 81%; 蓝色固体; mp. 174-176℃; 1H NMR (600 MHz, CD3OD) δ: 1.62 (m, 2H, CH2), 1.70 (m, 4H, CH2), 1.87 (s, 3H, CH3-7’), 2.39 (s, 12H, CH3-7), 2.63 (bs, 8H, CH2), 2.76 (t, J = 6.6 Hz, 2H, CH2), 3.47 (t, J = 6.0 Hz,2H, CH2), 3.66 (s, 2H, CH2), 3.72-3.81 (m, 4H, CH2), 3.98 (s, 1H, H-4’), 4.11 (m, 4H, CH2-5), 4.14 (s, 1H, H-3’), 4.33 (s, 1H, H-2’), 5.35 (s, 1H, H-1’),
13
7.48 (s, 2H, H-4, H-2), 7.53 (s, 1H, H-6’), 9.14 (s, 1H, H-8’); C NMR (150 MHz, CD3OD) δ:13.86, 24.59, 25.02, 37.84, 38.54, 40.79, 41.90, 42.66, 45.68,
55.29, 55.64, 57.02, 57.09, 58.35, 59.02, 61.88, 71.30, 73.65, 87.63, 95.10,
101.54, 101.68, 114.90, 117.78, 117.82, 118.22, 118.26, 120.74, 120.87,
125.16, 138.85, 148.91, 149.44, 154.59, 163.09, 163.16, 165.93, 165.97, + +
174.34, ; HRMS (ESI) calcd C40H57N10O9 [M+H] 833.4309. Found: 833.4297。
13
7.48 (s, 2H, H-4, H-2), 7.53 (s, 1H, H-6’), 9.14 (s, 1H, H-8’); C NMR (150 MHz, CD3OD) δ:13.86, 24.59, 25.02, 37.84, 38.54, 40.79, 41.90, 42.66, 45.68,
55.29, 55.64, 57.02, 57.09, 58.35, 59.02, 61.88, 71.30, 73.65, 87.63, 95.10,
101.54, 101.68, 114.90, 117.78, 117.82, 118.22, 118.26, 120.74, 120.87,
125.16, 138.85, 148.91, 149.44, 154.59, 163.09, 163.16, 165.93, 165.97, + +
174.34, ; HRMS (ESI) calcd C40H57N10O9 [M+H] 833.4309. Found: 833.4297。
[0136] 化合物17c: 收率 87%; 蓝色固体; mp. 166-169℃; 1H NMR (600 MHz, CD3OD) δ: 1.64 (m, 2H, CH2), 1.73 (m, 4H, CH2), 1.86 (s, 7H, CH2, CH3-7’), 2.41 (s,6H, CH3-7), 2.43 (s, 6H, CH3-7), 2.50 (s, 2H, CH2), 2.65 (m, 8H, CH2), 2.78 (t, J = 6.6 Hz, 2H, CH2), 3.46 (s, 2H, CH2), 3.55 (s, 2H, CH2), 3.80-3.87 (m, 2H, CH2), 4.08 (s, 4H, CH2-5), 4.10 (s, 1H, H-4’), 4.21 (d, J = 6.0 Hz, 1H, H-3’),
4.43 (t, J = 6.6 Hz, 1H, H-2’), 5.39 (d, J = 6.6 Hz, 1H, H-1’), 7.36 (s, 1H,
13
H-4), 7.42 (s, 1H, H-2), 7.50 (s, 1H, H-6’); C NMR (125 MHz, CD3OD) δ: 13.73,
25.41, 27.10, 27.81, 28.02, 38.67, 40.96, 42.30, 43.90, 45.90, 55.85, 57.43,
57.50, 58.51, 62.39, 71.97, 73.76, 88.36, 95.99, 101.05, 101.31, 114.42,
117.75, 117.78, 120.60, 120.64, 125.12, 139.35, 148.74, 149.01, 154.77, + +
162.78, 162.92, 165.80, 166.12, 174.50; HRMS (ESI) calcd C43H61N10O9 [M+H]
861.4623. Found: 861.4602。
4.43 (t, J = 6.6 Hz, 1H, H-2’), 5.39 (d, J = 6.6 Hz, 1H, H-1’), 7.36 (s, 1H,
13
H-4), 7.42 (s, 1H, H-2), 7.50 (s, 1H, H-6’); C NMR (125 MHz, CD3OD) δ: 13.73,
25.41, 27.10, 27.81, 28.02, 38.67, 40.96, 42.30, 43.90, 45.90, 55.85, 57.43,
57.50, 58.51, 62.39, 71.97, 73.76, 88.36, 95.99, 101.05, 101.31, 114.42,
117.75, 117.78, 120.60, 120.64, 125.12, 139.35, 148.74, 149.01, 154.77, + +
162.78, 162.92, 165.80, 166.12, 174.50; HRMS (ESI) calcd C43H61N10O9 [M+H]
861.4623. Found: 861.4602。
[0137] 化合物19a: 收率 85%; 蓝色固体; mp. 161-164℃; 1H NMR (600 MHz, CD3OD) δ: 1.85 (s, 3H, CH3-7’), 2.48 (s, 6H, CH3-7), 2.54 (s, 6H, CH3-7), 2.73 (s, 2H, CH2), 2.84 (s, 2H, CH2), 3.41-3.46 (m, 4H, CH2), 3.55 (s, 2H, CH2), 3.72-3.82 (m, 2H, CH2), 3.99 (s, 1H, H-4’), 4.08-4.16 (m, 5H, CH2-5, H-3’), 4.28 (s,1H, H-2’), 5.40 (s, 1H, H-1’), 6.70 (t, J = 7.8 Hz, 1H, Ph), 6.80 (d, J = 7.8 Hz, 2H, Ph), 7.19 (t, J = 7.8 Hz, 2H, Ph), 7.37 (s, 1H, H-6’), 7.41 (s, 1H,
13
H-4), 7.53 (s, 1H, H-2), 9.02 (s, 1H, H-8’); C NMR (150 MHz, CD3OD) δ: 13.81,
37.14, 37.94, 38.04, 41.90, 43.04, 43.36, 43.46, 44.16, 45.19, 45.24, 57.01,
62.06, 71.45, 74.05, 88.04, 95.32, 101.56, 101.80, 114.31, 114.75, 118.10,
118.29, 118.33, 118.65, 120.93, 121.07, 125.32, 125.40, 130.47, 139.12,
149.33, 149.58, 150.07, 154.86, 163.24, 163.43, 166.10, 166.17, 174.52; HRMS + +
(ESI) calcd C42H53N10O9 [M+H] 841.3996. Found: 841.3989。
13
H-4), 7.53 (s, 1H, H-2), 9.02 (s, 1H, H-8’); C NMR (150 MHz, CD3OD) δ: 13.81,
37.14, 37.94, 38.04, 41.90, 43.04, 43.36, 43.46, 44.16, 45.19, 45.24, 57.01,
62.06, 71.45, 74.05, 88.04, 95.32, 101.56, 101.80, 114.31, 114.75, 118.10,
118.29, 118.33, 118.65, 120.93, 121.07, 125.32, 125.40, 130.47, 139.12,
149.33, 149.58, 150.07, 154.86, 163.24, 163.43, 166.10, 166.17, 174.52; HRMS + +
(ESI) calcd C42H53N10O9 [M+H] 841.3996. Found: 841.3989。
[0138] 化合物19c: 收率 82%; 蓝色固体; mp. 169-172℃; 1H NMR (600 MHz, CD3OD) δ: 1.76 (bs, 4H, CH2), 1.88 (s, 3H, CH3-7’), 2.29 (s, 6H, CH3-7), 2.34 (s, 6H, CH3-7), 2.50 (s, 2H, CH2), 2.58 (s, 2H, CH2), 3.19 (s, 2H, CH2), 3.38 (s, 4H, CH2), 3.50 (s, 2H, CH2), 3.81-3.88 (m, 4H, CH2-5), 3.97 (s, 2H, CH2), 4.13 (s,1H, H-4’), 4.24 (d, J = 5.4 Hz, 1H, H-3’), 4.46 (t, J = 5.4 Hz, 1H, H-2’),
5.42 (d, J = 7.2 Hz, 1H, H-1’), 6.70 (t, J = 7.8 Hz, 1H, Ph), 6.78 (d, J =
7.8 Hz, 2H, Ph), 7.19 (t, J = 7.8 Hz, 3H, Ph, H-4), 7.25 (s, 1H, H-2), 7.52
13
(s, 1H, H-6’); C NMR (150 MHz, CD3OD) δ:13.75, 27.60, 27.78, 38.55, 38.62,
42.11, 43.22, 43.32, 43.66, 43.79, 43.98, 45.86, 57.27, 62.22, 71.75, 73.61,
88.09, 95.84, 101.07, 101.28, 114.06, 114.37, 117.75, 117.89, 117.93, 118.49,
120.57, 125.03, 125.07, 130.29, 139.00, 148.88, 148.94, 149.73, 154.56, + +
162.84, 162.93, 165.78, 166.03, 174.36; HRMS (ESI) calcd C44H57N10O9 [M+H]
869.4309. Found: 869.4310。
5.42 (d, J = 7.2 Hz, 1H, H-1’), 6.70 (t, J = 7.8 Hz, 1H, Ph), 6.78 (d, J =
7.8 Hz, 2H, Ph), 7.19 (t, J = 7.8 Hz, 3H, Ph, H-4), 7.25 (s, 1H, H-2), 7.52
13
(s, 1H, H-6’); C NMR (150 MHz, CD3OD) δ:13.75, 27.60, 27.78, 38.55, 38.62,
42.11, 43.22, 43.32, 43.66, 43.79, 43.98, 45.86, 57.27, 62.22, 71.75, 73.61,
88.09, 95.84, 101.07, 101.28, 114.06, 114.37, 117.75, 117.89, 117.93, 118.49,
120.57, 125.03, 125.07, 130.29, 139.00, 148.88, 148.94, 149.73, 154.56, + +
162.84, 162.93, 165.78, 166.03, 174.36; HRMS (ESI) calcd C44H57N10O9 [M+H]
869.4309. Found: 869.4310。
[0139] 化合物21a: 收率88%； 蓝色固体； mp. 178-185℃； 1H NMR (600 MHz, d6-DMSO) δ (ppm) 1.77 (s, 3H, CH3-5), 2.23 (s, 6H, 2CH3-N), 2.47 (m, 2H, CH2), 3.62-3.64 (m, 6H, 3CH 2), 3.87 (s, 1H, CH-4’), 3.99 (m, 3H, CH-3’, CH2-N), 4,14 (s,1H, CH-2’), 5.21-5.45 (m, 4H, CH-1’, 2OH, NH), 7.49-7.58 (m, 3H, CH-6, CH-Ar, NH),13
9.15 (s, H, NH-3); C NMR (150 MHz, d6-DMSO) δ (ppm) 172.42, 165.23, 162.07,
153.58, 148.45, 136.40, 129.54, 128.75, 124.75, 120.22, 117.49, 113.68,
100.97, 92.11, 86.44, 73.26, 70.21, 61.17, 56.00, 49.07, 44.63, 21.51,13.82; -
HR-ESI-MS: calcd for C46H60N12O14 [M+H], 1005.4430, found: 1005.4451。
9.15 (s, H, NH-3); C NMR (150 MHz, d6-DMSO) δ (ppm) 172.42, 165.23, 162.07,
153.58, 148.45, 136.40, 129.54, 128.75, 124.75, 120.22, 117.49, 113.68,
100.97, 92.11, 86.44, 73.26, 70.21, 61.17, 56.00, 49.07, 44.63, 21.51,13.82; -
HR-ESI-MS: calcd for C46H60N12O14 [M+H], 1005.4430, found: 1005.4451。
[0140] 化合物21b: 收率80%；蓝色固体； mp. 175-180℃；1H NMR (600 MHz, d6-DMSO) δ (ppm) 1.67 (s, 3H, CH3-5), 2.01 (s, 2H, CH2), 2.57 (s, 6H, 2CH3-N), 2.95, (s,2H, CH2), 3.46 (m, 4H, 2CH2), 3.64 (m, 2H, CH2), 3.95 (s,1H, CH-4’), 4.03 (s,
1H, CH-3’), 4.15-4.20 (m, 3H, CH-2’, CH2-N), 5.49 (m, 1H, CH-1’), 7.28 (s,
13
1H, CH-6), 7.54 (s, 1H, CH-Ar), 7.66 (s,1H, NH), 9.06 (s, 1H, NH-3); C NMR (150 MHz, d6-DMSO) δ (ppm) 171.99, 164.95, 161.84, 153.17, 147.91, 136.84,
124.21, 119.65, 117.07, 113.29, 100.31, 92.58, 86.45, 72.91, 70.13, 60.94,
56.05, 44.93, 40.50, 37.04, 28.51, 26.76, 24.66, 13.53; HR-ESI-MS: calcd for -
C48H64N12O14 [M+H], 1033.4743, found: 1033.4696。
1H, CH-3’), 4.15-4.20 (m, 3H, CH-2’, CH2-N), 5.49 (m, 1H, CH-1’), 7.28 (s,
13
1H, CH-6), 7.54 (s, 1H, CH-Ar), 7.66 (s,1H, NH), 9.06 (s, 1H, NH-3); C NMR (150 MHz, d6-DMSO) δ (ppm) 171.99, 164.95, 161.84, 153.17, 147.91, 136.84,
124.21, 119.65, 117.07, 113.29, 100.31, 92.58, 86.45, 72.91, 70.13, 60.94,
56.05, 44.93, 40.50, 37.04, 28.51, 26.76, 24.66, 13.53; HR-ESI-MS: calcd for -
C48H64N12O14 [M+H], 1033.4743, found: 1033.4696。
[0141] 化合物21c: 收率85%；蓝色固体； mp. 173-180℃；1H NMR (600 MHz, CD3OD) δ (ppm) 1.62 (s, 3H, CH3-5), 1.89 (m, 4H, 2CH2), 3.00 (s, 6H, 2CH3-N), 3.41-3.52 ’ ’(m, 6H, 3CH2), 3.76 (s, 2H, CH2), 4.06 (m, 1H, CH-4), 4.13-4.14 (m, 1H, CH-3), ’
4.24 (t, J = 6.0 Hz, H, CH-2 ), 4.49-4.53 (m, 2H, CH2), 5.16 (d, J = 6.6 Hz, ’ 13
1H, CH-1), 7.26 (s, 1H, CH-6), 7.72 (s, 1H, CH-Ar); C NMR (150 MHz, CD3OD) δ (ppm) 172.92, 165.57, 162.76, 153.10, 148.34, 137.35, 124.73, 120.14, 117.78,
117.45, 115.83, 112.44, 100.88, 93.82, 87.15, 72.63, 70.56, 60.85, 55.54,
42.88, 42.39, 40.82, 35.44, 25.98, 12.15; HR-ESI-MS: calcd for C50H68N12O14 -
[M+H], 1061.5056, found: 1061.5051。
4.24 (t, J = 6.0 Hz, H, CH-2 ), 4.49-4.53 (m, 2H, CH2), 5.16 (d, J = 6.6 Hz, ’ 13
1H, CH-1), 7.26 (s, 1H, CH-6), 7.72 (s, 1H, CH-Ar); C NMR (150 MHz, CD3OD) δ (ppm) 172.92, 165.57, 162.76, 153.10, 148.34, 137.35, 124.73, 120.14, 117.78,
117.45, 115.83, 112.44, 100.88, 93.82, 87.15, 72.63, 70.56, 60.85, 55.54,
42.88, 42.39, 40.82, 35.44, 25.98, 12.15; HR-ESI-MS: calcd for C50H68N12O14 -
[M+H], 1061.5056, found: 1061.5051。
[0142] 实施例4
[0143] 合成化合物24a～24c
[0144]
[0145] 上述反应方程式中：当m为1、2、3时，所对应的化合物4a、4b、4c，以化合物4a、4b、4c和化合物22为原料，采用实施例1中制备7a～7c的方法及工艺参数，分别制得中间体化合物23a、23b、23c以及化合物24a、24b、24c。
[0146] 本实施例中其原料化合物22的化学反应式：
[0147]
[0148] 化合物22的具体合成方法同实施例1中制备化合物5，且仅用1-(2-氨乙基)吡咯烷替代化合物N,N-二甲基乙二胺后进行反应，即可得化合物22，两步总产率35%。
[0149] 化合物22：黄色固体; mp. 245-248℃; 1H NMR(CDCl3, 600 MHz) δ: 1.78 (m,8H), 2.65 (s, 8H), 2.82 (m, 4H), 4.38 (m, 4H,), 8.81 (d, 1H, J = 7.8 Hz), 8.76 + +
(d, 1H, J = 7.2 Hz), 8.93 (s, 1H); HRMS (ESI): calcd C26H29BrN4O4 [M+H] 539.1294. Found 593.1288。
(d, 1H, J = 7.2 Hz), 8.93 (s, 1H); HRMS (ESI): calcd C26H29BrN4O4 [M+H] 539.1294. Found 593.1288。
[0150] 化合物23a: 收率 41%; 红色固体; mp. 168-171℃; 1H NMR (600 MHz, CD3OD) δ: 1.28 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.63 (s, 3H, CH3-7’), 2.12 (bs, 8H, CH2-8), 3.54-3.63 (m, 12H, CH2), 3.77-3.80 (m, 6H, CH2), 4.16(s, 1H, H-4’),4.46-4.49 (m, 4H, CH2-5), 4.60 (s, 1H, H-3’), 4.78 (s, 1H, H-2’), 5.32 (s, 1H, H-1’), 7.30 (s, 1H, H-6’), 7.90 (s, 1H, H-2), 8.05 (d, J = 7.8 Hz, 1H, H-4), +
8.34 (d, J = 7.8 Hz, 1H, H-3), 9.99 (s, 1H, H-8’); HRMS (ESI) calcd C37H47N8O9 +
[M+H] 747.3460. Found: 747.3458。
8.34 (d, J = 7.8 Hz, 1H, H-3), 9.99 (s, 1H, H-8’); HRMS (ESI) calcd C37H47N8O9 +
[M+H] 747.3460. Found: 747.3458。
[0151] 化合物23b: 收率 38%; 红色固体; mp. 171-175℃; 1H NMR (600 MHz, CDCl3) δ: 1.25 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.58 (s, 3H, CH3-7’), 1.90-1.94(m, 2H, CH2), 2.13 (bs, 8H, CH2-8), 3.37-3.67 (m, 16H, CH2), 3.86 (s, 2H, CH2), 4.27(s,1H, H-4’), 4.55 (s, 4H, CH2-5), 4.76 (s, 1H, H-3’), 4.97 (s, 1H, H-2’), 5.17 (s, 1H, H-1’), 7.00 (s, 1H, H-6’), 7.95 (s, 1H, H-2), 8.12 (d, J = 7.8 Hz, +
1H, H-4), 8.40 (d, J = 7.8 Hz, 1H, H-3), 9.88 (s, 1H, H-8’); HRMS (ESI) calcd +
C37H47N8O9 [M+H] 747.3460. Found: 747.3458。
1H, H-4), 8.40 (d, J = 7.8 Hz, 1H, H-3), 9.88 (s, 1H, H-8’); HRMS (ESI) calcd +
C37H47N8O9 [M+H] 747.3460. Found: 747.3458。
[0152] 化合物23c: 收率 42%; 红色固体; mp. 166-170℃; 1H NMR (600 MHz, CDCl3) δ: 1.26 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.59 (s, 3H, CH3-7’), 1.95 (m, 4H, CH2), 2.14 (s, 8H, CH2-8), 3.38-3.68 (m, 14H, CH2), 3.86 (s, 4H, CH2), 4.28(s,1H, H-4’), 4.55 (s, 4H, CH2-5), 4.76 (s, 1H, H-3’), 4.98 (s, 1H, H-2’), 5.17 (s, 1H, H-1’), 7.01 (s, 1H, H-6’), 7.95 (s, 1H, H-2), 8.13 (d, J = 7.8Hz, +
1H, H-4), 8.40 (d, J = 7.8Hz, 1H, H-3), 9.89 (s, 1H, H-8’); HRMS (ESI) calcd +
C37H47N8O9 [M+H] 747.3460. Found: 747.3458。
1H, H-4), 8.40 (d, J = 7.8Hz, 1H, H-3), 9.89 (s, 1H, H-8’); HRMS (ESI) calcd +
C37H47N8O9 [M+H] 747.3460. Found: 747.3458。
[0153] 化合物24a：收率 80%; 红色固体; mp. 167-169℃; 1H NMR (600 MHz, CD3OD) δ: 1.68 (s, 3H, CH3-7’), 1.93 (s, 4H, CH2-8), 1.99 (s, 4H, CH2-8), 2.92 (s, 4H, CH2), 2.99 (s, 2H, CH2), 3.12 (s, 4H, CH2), 3.17 (s, 2H, CH2), 3.71-3.86 (m, 6H, CH2), 3.94 (s, 1H, H-4’), 4.07 (s, 1H, H-3’), 4.19 (s, 1H, H-2’), 4.26-4.35 (m,4H, CH2-5), 5.20 (s, 1H, H-1’), 7.33 (s, 1H, H-6’), 7.80 (s, 1H, H-2), 7.94 (d,
13
J = 7.8 Hz, 1H, H-4), 8.20 (d, J = 7.2 Hz, 1H, H-3); C NMR (150 MHz, CD3OD) δ:
13.59, 24.38, 38.93, 39.77, 42.27, 43.08, 54.40, 55.42, 55.53, 71.55, 73.76,
88.19, 95.60, 114.70, 119.98, 120.68, 123.77, 125.05, 126.96, 128.43, 129.93,
131.69, 139.07, 153.66, 154.70, 163.65, 163.96, 164.21, 166.70, 174.25; HRMS + +
(ESI) calcd C38H47N8O9 [M+H] 759.3466. Found: 759.3448。
13
J = 7.8 Hz, 1H, H-4), 8.20 (d, J = 7.2 Hz, 1H, H-3); C NMR (150 MHz, CD3OD) δ:
13.59, 24.38, 38.93, 39.77, 42.27, 43.08, 54.40, 55.42, 55.53, 71.55, 73.76,
88.19, 95.60, 114.70, 119.98, 120.68, 123.77, 125.05, 126.96, 128.43, 129.93,
131.69, 139.07, 153.66, 154.70, 163.65, 163.96, 164.21, 166.70, 174.25; HRMS + +
(ESI) calcd C38H47N8O9 [M+H] 759.3466. Found: 759.3448。
[0154] 化合物24b: 收率 85%; 红色固体; mp. 168-171℃; 1H NMR (600 MHz, CD3OD) δ: 1.77 (s, 3H, CH3-7’), 1.87 (bs, 8H, CH2-8), 2.10-2.14 (m, 2H, CH2), 2.76 (s, 4H, CH2), 2.81-2.84 (m, 8H, CH2), 3.53 (t, J = 6.6Hz, 2H, CH2), 3.64 (t, J = 7.2Hz, 2H, CH2), 3.82-3.89 (q, J = 9.6Hz, 2H, CH2), 4.11-4.16 (m, 5H, CH2-5, H-4’), 4.24 (m, 1H, H-3’), 4.45 (s, 1H, H-2’), 5.44 (d, J = 6.6Hz, 1H, H-1’),7.53 (s, 1H, H-6’), 7.58 (s, 1H, H-2), 7.78 (d, J = 7.8Hz, 1H, H-4), 8.02 (d,
13
J = 7.8Hz, 1H, H-3); C NMR (150 MHz, CD3OD) δ: 13.75, 24.39, 29.89, 39.41,
40.17, 42.08, 54.24, 54.32, 55.32, 62.30, 71.85, 74.18, 88.26, 95.57, 114.39,
119.32, 120.09, 123.35, 124.90, 126.38, 128.03, 129.37, 131.62, 138.98, +
152.61, 154.70, 163.24, 163.29, 163.72, 163.30, 174.37; HRMS (ESI) calcd +
C39H49N8O9 [M+H] 773.3622. Found: 773.3602。
13
J = 7.8Hz, 1H, H-3); C NMR (150 MHz, CD3OD) δ: 13.75, 24.39, 29.89, 39.41,
40.17, 42.08, 54.24, 54.32, 55.32, 62.30, 71.85, 74.18, 88.26, 95.57, 114.39,
119.32, 120.09, 123.35, 124.90, 126.38, 128.03, 129.37, 131.62, 138.98, +
152.61, 154.70, 163.24, 163.29, 163.72, 163.30, 174.37; HRMS (ESI) calcd +
C39H49N8O9 [M+H] 773.3622. Found: 773.3602。
[0155] 化合物24c: 收率 83%; 红色固体; mp. 137-141℃; 1H NMR (600 MHz, CD3OD) δ: 1.43 (s, 3H, CH3-7’), 1.91 (s, 4H, CH2), 2.11 (bs, 8H, CH2-8), 3.34-3.42 (m,4H, CH2), 3.64-3.67 (m, 6H, CH2), 3.70-3.73 (m, 6H, CH2), 4.03 (s, 1H, H-4’),
4.08 (d, J = 7.2Hz, 1H, H-3’,), 4.13 (m, 1H, H-2’), 4.55 (s, 4H, CH2-5), 5.07 (d, J = 7.6Hz, 1H, H-1’), 7.06 (s, 1H, H-6’), 8.03 (s, 1H, H-2), 8.14 (d, J
13
= 7.8Hz, 1H, H-4), 8.40 (d, J = 7.8Hz, 1H, H-3); C NMR (150 MHz, CD3OD) δ:
13.34, 24.20, 26.82, 27.05, 37.67, 38.05, 42.15, 43.95, 54.00, 54.03, 55.64,
55.69, 62.29, 71.98, 74.44, 88.70, 94.97, 113.88, 117.21, 119.15, 120.27,
124.25, 125.30, 127.18, 128.76, 130.42, 132.05, 138.14, 153.27, 154.44, + +
164.35, 164.50, 164.73, 167.16, 174.07; HRMS (ESI) calcd C40H51N8O9 [M+H]
787.3779. Found: 787.3755。
4.08 (d, J = 7.2Hz, 1H, H-3’,), 4.13 (m, 1H, H-2’), 4.55 (s, 4H, CH2-5), 5.07 (d, J = 7.6Hz, 1H, H-1’), 7.06 (s, 1H, H-6’), 8.03 (s, 1H, H-2), 8.14 (d, J
13
= 7.8Hz, 1H, H-4), 8.40 (d, J = 7.8Hz, 1H, H-3); C NMR (150 MHz, CD3OD) δ:
13.34, 24.20, 26.82, 27.05, 37.67, 38.05, 42.15, 43.95, 54.00, 54.03, 55.64,
55.69, 62.29, 71.98, 74.44, 88.70, 94.97, 113.88, 117.21, 119.15, 120.27,
124.25, 125.30, 127.18, 128.76, 130.42, 132.05, 138.14, 153.27, 154.44, + +
164.35, 164.50, 164.73, 167.16, 174.07; HRMS (ESI) calcd C40H51N8O9 [M+H]
787.3779. Found: 787.3755。
[0156] 实施例5
[0157] 合成化合物28a～28c
[0158] 化合物28a～28c的化学反应通式如下：
[0159]
[0160]
[0161] 上述反应中：当m为1、2、3时，分别对应化合物4a、4b、4c，其制备方法同实施例1所示。以化合物4a、4b、4c和化合物25为原料，采用实施例2制备化合物11a～11c的制备工艺，且用1-(2-氨乙基)吡咯烷代替制备化合物11a～11c中的N,N-二甲基乙二胺为原料，分别合成的化合物中间体化合物27a、27b、27c，最终化合物28a、28b、28c。
[0162] 本实施例中其原料化合物25的制备化学反应方程式：
[0163]
[0164] 化合物25的合成同实施例2中化合物8的合成方法，且将化合物8的合成方法中的N,N-二甲基乙二胺改用1-(2-氨乙基)吡咯烷即可制得化合物25，两步总产率31%。
[0165] 化合物25：黄色固体; mp. 235-238℃; 1H NMR (CDCl3, 600 MHz) δ: 1.78 (m,8H), 2.66 (s, 8H), 2.84 (m, 4H), 4.38 (t, 4H, J = 7.2 Hz), 8.75 (s, 2H); HRMS + +
(ESI): calcd C26H27Br2N4O4 [M+H] 617.0399. Found 617.0394。
(ESI): calcd C26H27Br2N4O4 [M+H] 617.0399. Found 617.0394。
[0166] 化合物27a: 收率 60%; 蓝色固体; mp. 178-190℃; 1H NMR (600 MHz, CD3OD) δ: 1.12 (s, 3H, CH3), 1.50 (s, 3H, CH3), 1.81 (s, 3H, CH3-7’), 2.16 (s, 12H, CH2), 3.52-3.64 (m, 18H, CH2), 3.85-3.92 (m, 6H, CH2), 3.99 (d, J = 7.2Hz, 2H, CH2), 4.25 (s, 1H, H-4’), 4.49 (m, 4H, CH2-5), 4.71 (s, 2H, H-3’, H-2’), 5.44 (s, 1H, H-1’), 7.50 (s, 1H, H-6’), 7.65 (s, 2H, H-2, H-4); HRMS (ESI+) calcd C47H63N10O9 [M+H]+ 911.4779. Found: 911.4775。
[0167] 化合物27b: 收率 62%; 蓝色固体; mp. 169-172℃; 1H NMR (600 MHz, CD3OD) δ: 1.23 (s, 3H, CH3), 1.54 (s, 3H, CH3), 1.85-1.89 (m, 15H, CH3-7’, CH2), 2.11 (m, 2H, CH2), 2.74 (bs, 16H, CH2), 2.91 (m, 2H, CH2), 3.42-3.47 (m, 4H, CH2),3.62-3.64 (m, 2H, CH2), 3.81-3.88 (q, 2H, CH2), 4.08 (s, 4H, CH2-5), 4.28 (s,
1H, H-4’), 4.97 (s, 1H, H-2’), 5.54 (s, 1H, H-1’), 7.40 (s, 2H, H-2, H-4), 7.49 (s, 1H, H-6’); HRMS (ESI+) calcd C48H65N10O9 [M+H]+ 925.4936. Found: 871.4470。
1H, H-4’), 4.97 (s, 1H, H-2’), 5.54 (s, 1H, H-1’), 7.40 (s, 2H, H-2, H-4), 7.49 (s, 1H, H-6’); HRMS (ESI+) calcd C48H65N10O9 [M+H]+ 925.4936. Found: 871.4470。
[0168] 化合物27c: 收率 53%; 蓝色固体; mp. 159-162℃; 1H NMR (600 MHz, CD3OD) δ: 1.31 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.85-1.89 (m, 20H, CH3-7’, CH2), 2.72 (m, 17H, CH2), 2.87-2.89 (s, 2H, CH2), 3.37-3.42 (m, 2H, CH2), 3.52 (s, 2H, CH2), 3.83-3.89 (m, 2H, CH2), 3.98-4.04 (m, 4H, CH2-5), 4.27 (s, 1H, H-4’), 4.97 (s, 1H, H-2’), 5.50 (s, 1H, H-1’), 7.24 (s, 2H, H-2, H-4), 7.45 (s, 1H, H-6’);13
C NMR (150 MHz, CD3OD) HRMS (ESI+) calcd C48H65N10O9 [M+H]+ 925.4936. Found:
871.4470。
C NMR (150 MHz, CD3OD) HRMS (ESI+) calcd C48H65N10O9 [M+H]+ 925.4936. Found:
871.4470。
[0169] 化合物28a: 收率 58%; 蓝色固体; mp. 186-188℃; 1H NMR (600 MHz, CD3OD) δ: 1.86 (s, 3H, CH3-7’), 1.94 (bs, 12H, CH2), 2.81 (s, 4H, CH2), 2.95 (bs,14H, CH2), 3.46 (s, 2H, CH2), 3.58 (s, 2H, CH2), 3.77-3.82 (m, 4H, CH2), 4.02 (s, 1H, H-4’), 4.14 (s, 5H, CH2-5, H-2’), 4.31 (s, 1H, H-2’), 5.40 (s, 1H,
13
H-1’), 7.34 (s, 2H, H-2, H-4), 7.58 (s, 1H, H-6’); C NMR (150 MHz, CD3OD) δ:13.79, 24.44, 24.65, 39.44, 39.53, 42.04, 42.67, 42.75, 43.01, 43.08,
54.39, 55.42, 55.89, 55.83, 62.15, 71.54, 73.94, 74.00, 88.16, 95.84, 101.92,
101.95, 114.78, 114.87, 117.88, 118.33, 121.01, 121.11, 125,53, 125.64,
139.19, 149.17, 149.70, 154.95, 163.21, 163.29, 166.18, 166.27, 174.53; HRMS + +
(ESI) calcd C44H59N10O9 [M+H] 871.4466. Found: 871.4470。
13
H-1’), 7.34 (s, 2H, H-2, H-4), 7.58 (s, 1H, H-6’); C NMR (150 MHz, CD3OD) δ:13.79, 24.44, 24.65, 39.44, 39.53, 42.04, 42.67, 42.75, 43.01, 43.08,
54.39, 55.42, 55.89, 55.83, 62.15, 71.54, 73.94, 74.00, 88.16, 95.84, 101.92,
101.95, 114.78, 114.87, 117.88, 118.33, 121.01, 121.11, 125,53, 125.64,
139.19, 149.17, 149.70, 154.95, 163.21, 163.29, 166.18, 166.27, 174.53; HRMS + +
(ESI) calcd C44H59N10O9 [M+H] 871.4466. Found: 871.4470。
[0170] 化合物28b: 收率 65%; 蓝色固体; mp.178-181℃; 1H NMR (600 MHz, CD3OD) δ: 1.64 (s, 3H, CH3-7’), 1.75-1.79 (bs, 12H, CH2), 1.99 (m, 2H, CH2), 2.88 (bs,18H, CH2), 3.53 (m, 4H, CH2), 3.64 (s, 2H, CH2), 3.84-3.86 (m, 2H, CH2), 4.12 (m, 5H, CH2-5, H-4’), 4.24 (s, 1H, H-3’), 4.43 (s, 1H, H-2’), 5.48 (s, 1H,
13
H-1’), 7.33 (s, 1H, H-4), 7.34 (s, 1H, H-2), 7.57 (s, 1H, H-6’); C NMR (150 MHz, CD3OD) δ: 13.24, 22.98, 23.03, 23.15, 28.03, 28.88, 29.91, 38.66, 40.92,
48.50, 52.29, 52.41, 53.53, 53.97, 60.56, 69.68, 72.86, 85.86, 91.40, 99.90,
112.57, 116.41, 116.60, 119.23, 123.81, 123.95, 135.61, 147.35, 147.56, + +
152.62, 161.24, 164.32, 164.55, 170.66; HRMS (ESI) calcd C45H61N10O9 [M+H]
885.4622. Found: 885.4587。
13
H-1’), 7.33 (s, 1H, H-4), 7.34 (s, 1H, H-2), 7.57 (s, 1H, H-6’); C NMR (150 MHz, CD3OD) δ: 13.24, 22.98, 23.03, 23.15, 28.03, 28.88, 29.91, 38.66, 40.92,
48.50, 52.29, 52.41, 53.53, 53.97, 60.56, 69.68, 72.86, 85.86, 91.40, 99.90,
112.57, 116.41, 116.60, 119.23, 123.81, 123.95, 135.61, 147.35, 147.56, + +
152.62, 161.24, 164.32, 164.55, 170.66; HRMS (ESI) calcd C45H61N10O9 [M+H]
885.4622. Found: 885.4587。
[0171] 化合物28c: 收率 63%; 蓝色固体; mp. 163-166℃; 1H NMR (600 MHz, CD3OD) δ: 1.75-1.90 (m, 19H, CH3-7’, CH2), 2.78-2.90 (m, 18H, CH2), 3.43-3.49 (m, 4H, CH2), 3.80 (m, 2H, CH2), 4.08 (s, 5H, CH2-5, H-4’), 4.18 (s, 1H, H-3’), 4.35 (s, 1H, H-2’), 5.32 (s, 1H, H-1’), 7.27 (s, 2H, H-2, H-4), 7.42 (s, 1H, H-6’);13
C NMR (150 MHz, CD3OD) δ: 13.73, 24.07, 24.32, 24.45, 27.52, 27.65, 39.60,
40.20, 42.25, 42.67, 43.73, 54.03, 54.94, 55.20, 55.32, 55.82, 58.22, 62.16,
71.67, 73.70, 87.91, 95.27, 100.70, 101.01, 114.69, 117.46, 117.73, 120.25,
124.75, 138.87, 148.57, 148.76, 154.67, 162.58, 165.60, 165.69, 174.45; HRMS + +
(ESI) calcd C46H63N10O9 [M+H] 899.4779. Found: 899.4747。
C NMR (150 MHz, CD3OD) δ: 13.73, 24.07, 24.32, 24.45, 27.52, 27.65, 39.60,
40.20, 42.25, 42.67, 43.73, 54.03, 54.94, 55.20, 55.32, 55.82, 58.22, 62.16,
71.67, 73.70, 87.91, 95.27, 100.70, 101.01, 114.69, 117.46, 117.73, 120.25,
124.75, 138.87, 148.57, 148.76, 154.67, 162.58, 165.60, 165.69, 174.45; HRMS + +
(ESI) calcd C46H63N10O9 [M+H] 899.4779. Found: 899.4747。
[0172] 实施例6
[0173] 合成化合物36a～36g
[0174] 化合物36a～36g的化学反应通式如下：
[0175]
[0176] 上述反应式中：m为1～6时，分别对应化合物35a～35g，以化合物5和化合物35a～35g为原料，制备的化合物36a～36g。
[0177] 其具体合成方法为：
[0178] 将100 mg 化合物35a～35g中的一种、150 mg化合物 5 溶解在10 mLN,N-二甲基甲酰胺中，加入1 mL 三乙胺，120℃下微波辐射促进反应5 min，TLC检测原料消失；旋蒸蒸除DMF，柱层析（二氯甲烷:甲醇=10:1），得80 mg化合物36a～36g。
[0179] 本实施例中原料化合物35a～35g的制备反应通式如下：
[0180]
[0181] 上述反应式中m为1～7。
[0182] 具体制备方法：
[0183] 将10 g (40.7mmol)化合物29 放入250 mL的烧瓶中，加入100 mL新蒸吡啶溶解，冰浴冷却下，氮气保护，分三批共加入9 g (61.0 mmol, 1.5eq) 叔丁基二甲基氯硅烷(TBDMSCl)，冰浴反应4 h后，TLC检测原料消失，反应结束，滴加甲醇分解未反应的TBDMSCl，蒸除溶剂，得粗品化合物30。
[0184] 在化合物30反应液中加入30 mL吡啶，将烧瓶放入冰浴中，氮气保护，滴加6.5 mL (61.0 mmol, 1.5eq)醋酸酐，反应10 h，TLC检测原料消失，反应结束，然后加5 mL蒸馏水分解未反应完的醋酸酐；旋蒸出大量溶剂后，在反应液中加约800 mL乙酸乙酯，用1 mol/L 的稀盐酸洗去吡啶至中性，饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，得白色固体化合物31。
[0185] 将化合物31溶于100 mL甲醇中，加入7 g (61.0 mmol, 1.5 eq) 对甲苯磺酸，室温搅拌2 h，TLC监测原料消失，反应结束后，将碳酸氢钠中和至pH为7，柱层析分离（乙酸乙酯：石油醚=2：1），得6.8 g化合物32，总收率为58%。
[0186] 将6.8 g (23.6 mmol)化合物 32 溶于100 mL吡啶中，氮气保护，冰浴冷却，滴加3.5 mL (47.2 mmol, 2 eq)甲基磺酰氯，反应3 h。TCL检测原料消失，反应结束。加5 mL甲醇分解未反应的甲基磺酰氯，乙酸乙酯萃取，用1 M 的稀盐酸洗至中性，饱和食盐水洗，无水硫酸钠干燥，抽滤，浓缩有机相，真空干燥，得粗品化合物33。
[0187] 将粗品化合物33溶解在100 mL 无水甲醇中，加入4 g (71.0 mmol, 3 eq) 甲醇钠，氮气保护，室温搅拌，TLC检测原料消失，稀盐酸中和至 pH为7，浓缩，硅胶柱层析（乙酸乙酯:石油醚 = 2:1），得346 g化合物 34，两步总收率76%。
[0188] 将1.0 g 化合物 34 溶解在5 mL乙腈中，加入5 mL 乙二胺，油浴50℃，反应1 h，将乙腈蒸出，用乙酸乙酯洗反应液，反应液变粘稠，柱层析（甲醇），得284 mg 化合物35a，收率32%。
[0189] 同理用丙二胺、丁二胺、戊二胺、己二胺、庚二胺、辛二胺代替上述制备化合物35a中所用的乙二胺，即可制备其化合物35b～35g。
[0190] 化合物35a: 收率32%; 粘稠液体；1H NMR (600 MHz, CD3OD) δ (ppm)2.22-2.30 (m, 1H, CH2-2’), 2.86-2.95 (m, 4H, 2CH2-N), 2.99-3.02 (m, 2H, CH2-5’), 3.92-3.94 (m, 1H, CH-1’), 4.25-4.28 (m, 1H, CH-3’), 6.24 (td, J = 6.6 Hz, 1.8 Hz, 1H, CH-4’), 7.77 (dd, J = 6.0 Hz, 1.2 Hz, 1H, CH-6); MS (ESI) m/z: +
289.3 ([M+H])。
289.3 ([M+H])。
[0191] 化合物35b: 收率19%; 淡黄色固体，mp. 101-102℃; 1H NMR (600 MHz, CD3OD) δ (ppm): 1.80-1.85 (m, 2H, CH2), 2.23-2.30 (m, 1H, CH2-2’), 2.80-2.82 (m, 2H, CH2-N), 2.83-2.88 (m, 1H, CH-5’), 2.91-2.94 (m, 1H, CH-5’), 2.96-2.98 (m, 2H, CH2-N), 3.92-3.95 (m, 1H, CH-1’), 4.23-4.25 (m, 1H, CH-3’), 6.23 (t, J = 6.6 +Hz, 1H, CH-4’), 7.72 (d, J = 6.0 Hz, 1H, CH-6); MS (ESI) m/z: 303.3 ([M+H])。
[0192] 化合物35c: 收率39%; 淡黄色固体，mp. 91-93℃; 1H NMR (600 MHz, CD3OD) δ (ppm): 1.64-1.70 (m, 4H, 2CH2), 2.25-2.27 (m, 2H, CH2-N), 2.70-2.74 (m, 2H, CH2-2’), 2.85-2.96 (m, 3H, CH2-N, CH-5’), 2.95 (dd, J = 8.4 Hz, 4.2 Hz, 1H, CH-5’), 3.92-3.95 (m, 1H, CH-4’), 4.22 (dd, J = 6.0 Hz, 4.8 Hz, 1H, CH-3’),6.25 (t, J = 7.2 Hz, 1H, CH-1’), 7.68 (d, J = 6.0 Hz, 1H, CH-6); MS (ESI) m/z: +
317.3 ([M+H])。
317.3 ([M+H])。
[0193] 化合物35d: 收率5%; 淡黄色固体，mp. 156-158℃; 11H NMR (600 MHz, CD3OD) δ (ppm): 1.40-1.47 (m, 2H, CH2), 1.55-1.67 (m, 2H, CH2), 2.27-2.32 (m, 2H, CH2-2’), 2.72 (t, J = 7.2 Hz, 2H, CH2), 2.83-2.95 (m, 4H, 2CH2), 3.94-3.97 (m,1H, CH-4’), 4.25-4.28 (m, 1H, CH-3’), 6.21 (t, J = 6.6 Hz, 1H, CH-1’), 7.75 +
(d, J = 6.6 Hz, 1H, CH-6). MS (ESI) m/z: 330.3 ([M+H])。
(d, J = 6.6 Hz, 1H, CH-6). MS (ESI) m/z: 330.3 ([M+H])。
[0194] 化合物35e: 收率52%; 淡黄色固体，mp. 64-66℃; 1H NMR (600 MHz, CD3OD) δ (ppm): 1.40-1.41 (m, 4H, 2CH2), 1.56-1.65 (m, 4H, 2CH2), 2.28 (t, J = 5.4 Hz,2H, CH2-2’), 2.71 (t, J = 7.2 Hz, 2H, CH2-N), 2.85-2.95 (m, 4H, CH2-5’, CH2-N),
3.94-3.97 (m, 1H, CH-4’), 4.25 (q, J = 4.8 Hz, 1H, CH-3’), 6.24 (t, J = 6.6 +
Hz, 1H, CH-1’), 7.72 (d, J = 6.6 Hz, 1H, CH-6); MS (ESI) m/z: 345.5 ([M+H])。
3.94-3.97 (m, 1H, CH-4’), 4.25 (q, J = 4.8 Hz, 1H, CH-3’), 6.24 (t, J = 6.6 +
Hz, 1H, CH-1’), 7.72 (d, J = 6.6 Hz, 1H, CH-6); MS (ESI) m/z: 345.5 ([M+H])。
[0195] 化合物35f: 收率35%; 淡黄色固体，mp. 58-59℃; 1H NMR (600 MHz, CD3OD) δ (ppm): 1.34 (brs, 6H, 3CH2), 1.57-1.60 (m, 4H, 2CH2), 2.28-2.27 (m, H, CH2-2’),2.69 (t, J = 7.2 Hz, 2H, CH2), 2.82-2.84 (m, 2H, CH2), 2.86-2.94 (m, 2H, CH2-5’), 3.94-3.96 (m, 1H, CH-4’), 4.24-4.26 (m, 1H, CH-3’), 6.26 (t, J = 6.6 +
Hz, 1H, CH-1’), 7.69 (d, J = 6.0 Hz, 1H, CH-6); MS (ESI) m/z: 359.3 ([M+H])。
Hz, 1H, CH-1’), 7.69 (d, J = 6.0 Hz, 1H, CH-6); MS (ESI) m/z: 359.3 ([M+H])。
[0196] 化合物35g: 收率35%; 淡黄色固体; mp. 62-63℃; 1H NMR (600 MHz, CD3OD) δ (ppm): 1.36 (brs, 8H, 4CH2), 1.56-1.59 (m, 4H, 2CH2), 2.27-2.31 (m, H, CH2-2’), 2.67-2.71 (m, 2H, CH2), 2.82-2.93 (m, 4H, CH2-5’, CH2), 3.93-3.96 (m,1H, CH-4’), 4.5 (dd, J = 6.6 Hz, 4.2 Hz, 1H, CH-3’), 6.26 (t, J = 6.6 Hz, 1H, +
CH-1’), 7.74 (d, J = 6.6 Hz, 1H, CH-6); MS (ESI) m/z: 374.6 ([M+H])。
CH-1’), 7.74 (d, J = 6.6 Hz, 1H, CH-6); MS (ESI) m/z: 374.6 ([M+H])。
[0197] 化合物36a：收率35%; 红色固体；mp. 163-167℃；1H NMR (600 MHz, CD3OD) δ (ppm) 2.18-2.18 (m, 2H, CH2-2’), 2.39 (d, J = 4.8 Hz, 12H, 4CH3-N), 2.63 (t, J = 7.2 Hz, 2H, CH2), 2.69 (t, J = 6.6 Hz, 2H, CH2), 2.95 (dd, J = 6.6 Hz, 6.0 Hz,1H, CH-5’), 3.03-3.14 (m, 3H, CH-5’, CH2), 3.58 (m, 2H, CH2), 3.97 (dd, J = 6.0 Hz, 4.2 Hz, 1H, CH-4’), 4.08-4.16 (m, 4H, 2CH2), 4.39-4.42 (m, 1H, CH-3’), 6.06 (t, J = 6.6 Hz, 1H, CH-1’), 7.67 (s, 1H, CH-6), 7.77-7.82 (m, 2H, 2Ar-H), 8.01 + +
(d, J = 7.8 Hz, 1H, Ar-H-4); HRMS (ESI) calcd C33H39FN8O8 [M] 694.2875. Found:
694.2871。
(d, J = 7.8 Hz, 1H, Ar-H-4); HRMS (ESI) calcd C33H39FN8O8 [M] 694.2875. Found:
694.2871。
[0198] 化合物36b：收率 20%; 红色固体; mp. 128-131℃；1H NMR (600 MHz, CD3OD) δ (ppm) 2.09-2.11 (m, 2H, CH2), 2.24-2.27 (m, 2H, CH2-2’), 2.48 (d, J = 4.2 Hz, 12H, 4CH3-N), 2.75-2.81 (m, 4H, 2CH2), 3.01-3.11 (m, 4H, 2CH2), 3.58-3.60 (m, H, CH2), 4.02-4.05 (m, 1H, CH-4’), 4.16-4.21 (m, 4H, 2CH3-N,), 4.29-4.32 (m, 1H, CH-3’), 6.05 (t, J = 6.6 Hz, 1H, CH-1’), 7.70 (s, 1H, CH-6), 7.84 (d, J = 7.2 Hz, 1H, Ar-H-2), 7.87 (d, J = 6.6 Hz, 1H, Ar-H-3), 8.07-8.08 (m,13
1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.35, 162.83, 162.40, 151.71,
149.85, 141.32, 139.76, 130.44, 128.63, 127.24, 125.55, 124.88, 124.65,
123.71, 122.56, 119.13, 118.59, 98.88, 85.83, 85.26, 71.63, 56.16, 56.07, +
50.76, 46.76, 44.44, 44.40, 40.81, 39.28, 37.46, 37.04, 28.65; HRMS (ESI) +
calcd C34H41FN8O8 [M] 708.3031. Found: 708.3027。
1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.35, 162.83, 162.40, 151.71,
149.85, 141.32, 139.76, 130.44, 128.63, 127.24, 125.55, 124.88, 124.65,
123.71, 122.56, 119.13, 118.59, 98.88, 85.83, 85.26, 71.63, 56.16, 56.07, +
50.76, 46.76, 44.44, 44.40, 40.81, 39.28, 37.46, 37.04, 28.65; HRMS (ESI) +
calcd C34H41FN8O8 [M] 708.3031. Found: 708.3027。
[0199] 化合物36c：收率 39%; 红色固体; mp. 152-157℃；1H NMR (600 MHz, CD3OD) δ (ppm) 1.82-1.86 (m, 2H, CH2), 1.89-1.92 (m, 2H, CH2), 2.22-2.24 (m, 2H, CH2-2’), 2.42 (d, J = 2.4 Hz, 12H, 4CH3-N), 2.65-2.68 (m, 2H, CH2), 2.72-2.74 (m, 2H, CH2), 2.89-2.91 (m, 2H, CH2), 2.94-3.02 (m, 2H, CH2-5’), 3.49-3.50 (m,2H, CH2), 3.97-3.99 (m, H, CH-4’), 4.13-4.18 (m, 4H, 2CH3-N), 4.25 (dd, J = 5.2 Hz, 4.8 Hz, 1H, CH-3’), 6.05-6.07 (m, 1H, CH-1’), 7.66-7.68 (m, 1H, CH-6),
13
7.85-7.87 (m, 2H, 2Ar-H), 8.09-8.12 (m, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.48, 163.01, 162.69, 162.64, 151.79, 149.80, 130.60, 128.86, 127.40,
125.74, 124.82, 124.59, 123.79, 122.75, 119.24, 98.98, 85.54, 85.12, 71.59,
56.29, 56.17, 50.87, 48.94, 44.73, 44.68, 42.64, 39.35, 37.80, 37.21, 26.84, + +
26.52; HRMS (ESI) calcd C35H43FN8O8 [M] 722.3138. Found: 722.3131。
13
7.85-7.87 (m, 2H, 2Ar-H), 8.09-8.12 (m, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.48, 163.01, 162.69, 162.64, 151.79, 149.80, 130.60, 128.86, 127.40,
125.74, 124.82, 124.59, 123.79, 122.75, 119.24, 98.98, 85.54, 85.12, 71.59,
56.29, 56.17, 50.87, 48.94, 44.73, 44.68, 42.64, 39.35, 37.80, 37.21, 26.84, + +
26.52; HRMS (ESI) calcd C35H43FN8O8 [M] 722.3138. Found: 722.3131。
[0200] 化合物36d：收率 23%; 红色固体; mp.155-160℃；1H NMR (600 MHz, CD3OD) δ (ppm) 1.63-1.68 (m, 2H, CH2), 1.73-1.77 (m, 2H, CH2), 1.89-1.92 (m, 2H, CH2), 2.18-2.28 (m, 2H, CH2-2’), 2.42 (d, J = 2.4 Hz, 12H, 4CH3-N), 2.69 (t, J = 7.2 Hz, 2H, CH2), 2.74 (t, J = 7.2 Hz, 2H, CH2), 2.82 (t, J = 7.2 Hz, 2H, CH2), 2.91-3.00 (m, 2H, CH2-5’), 3.55 (t, J = 7.2 Hz, 2H, CH2), 3.96-3.98 (m, H, CH-4’), 4.22-4.6 (m, 5H, 2CH3-N, CH-3’), 6.10 (t, J = 6.6 Hz 1H, CH-1’),7.82 (d, J = 7.8 Hz, 1H, CH-6), 7.85 (s, 1H, Ar-H-2), 8.00 (d, J = 7.8 Hz,
13
1H, Ar-H-4), 8.26 (d, J = 7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.42, 162.92, 162.57, 162.50, 151.74, 141.54, 139.98, 130.43, 128.76,
127.32, 125.63, 124.63, 124.40, 123.63, 122.60, 119.12, 118.67, 98.76, 85.67,
84.96, 71.74, 56.26, 56.15, 50.96, 49.17, 44.62, 44.57, 42.66, 38.22, 37.77, + +
37.19, 28.83, 28.56, 24.41; HRMS (ESI) calcd C36H45FN8O8 [M] 736.3344. Found:
736.3349。
13
1H, Ar-H-4), 8.26 (d, J = 7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.42, 162.92, 162.57, 162.50, 151.74, 141.54, 139.98, 130.43, 128.76,
127.32, 125.63, 124.63, 124.40, 123.63, 122.60, 119.12, 118.67, 98.76, 85.67,
84.96, 71.74, 56.26, 56.15, 50.96, 49.17, 44.62, 44.57, 42.66, 38.22, 37.77, + +
37.19, 28.83, 28.56, 24.41; HRMS (ESI) calcd C36H45FN8O8 [M] 736.3344. Found:
736.3349。
[0201] 化合物36e：收率 20%; 红色固体; mp.127-130℃；1H NMR (600 MHz, CD3OD) δ (ppm) 1.61-1.68 (m, 4H, 2CH2), 1.81-1.88 (m, 4H, 2CH2), 2.20-2.24 (m, 1H, CH2-2’), 2.34-2.39 (m, 1H, CH2-2’), 2.52 (d, J = 6.0 Hz, 12H, 4CH3-N), 2.79-2.85 (m, 4H, 2CH2), 3.08 (t, J = 7.2 Hz, 2H, CH2), 3.23-3.31 (m, 2H, CH2-5’), 3.46 (bs, 2H, CH2), 4.06-4.09 (m, H, CH-4’), 4.16-4.20 (m, 4H, 2CH3-N,), 4.30-4.33 (m, 1H, CH-3’), 6.03 (t, J = 6.6 Hz 1H, CH-1’), 7.62-7.63 (m, 1H, CH-6),13
7.78-7.81 (m, 2H, 2Ar-H), 8.04-8.05 (m, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.14, 162.62, 162.25, 162.17, 161.74, 161.51, 151.40, 150.39, 141.30,
139.75, 130.23, 128.33, 126.89, 125.63, 125.41, 125.24, 123.43, 122.14,
118.89, 118.20, 117.80, 115.86, 98.24, 87.04, 82.71, 71.73, 55.96, 55.89.
49.59, 44.09, 44.00, 38.14, 37.40, 36.75, 28.54, 26.50, 26.21, 25.98; HRMS + +
(ESI) calcd C37H47FN8O8 [M] 750.3541. Found: 750.3547。
7.78-7.81 (m, 2H, 2Ar-H), 8.04-8.05 (m, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.14, 162.62, 162.25, 162.17, 161.74, 161.51, 151.40, 150.39, 141.30,
139.75, 130.23, 128.33, 126.89, 125.63, 125.41, 125.24, 123.43, 122.14,
118.89, 118.20, 117.80, 115.86, 98.24, 87.04, 82.71, 71.73, 55.96, 55.89.
49.59, 44.09, 44.00, 38.14, 37.40, 36.75, 28.54, 26.50, 26.21, 25.98; HRMS + +
(ESI) calcd C37H47FN8O8 [M] 750.3541. Found: 750.3547。
[0202] 化合物36f：收率 38%; 红色固体; mp.176-179℃；1H NMR (600 MHz, CD3OD) δ (ppm) 1.53-1.62 (m, 8H, 4CH2), 1.79-1.89 (m, 4H, 2CH2), 2.25-2.29 (m, 1H, CH2-2’), 2.36-2.42 (m, 1H, CH2-2’), 2.53 (s, 6H, 2CH3-N), 2.58 (s, 6H, 2CH3-N),2.88-2.91 (m, 4H, 2CH2), 3.05-3.08 (m, 2H, CH2-5’), 3.52 (t, J = 7.2 Hz, 2H, CH2), 4.09-4.12 (m, 1H, CH-4’), 4.27-4.29 (m, 4H, 2CH2-N(CH3)), 4.33-4.36 (m,
1H, CH-3’), 6.15 (t, J = 6.6 Hz, 1H, CH-1’), 7.80-7.81 (m, 2H, CH-6, Ar-H),
13
7.98 (d, J = 7.8 Hz, 1H, Ar-H-4), 8.24 (d, J = 7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.35, 162.90, 162.60, 162.47, 151.68, 141.82, 140.25,
130.43, 128.71, 127.21, 125.54, 125.39, 125.16, 123.61, 122.46, 119.17,
118.57, 98.57, 86.84, 82.15, 71.76, 56.08, 56.03, 49.53, 44.33, 44.21, 42.79, +
38.37, 37.40, 36.70, 28.89, 28.58, 26.56, 26.34; HRMS (ESI) calcd C38H49FN8O8 +
[M] 764.3657. Found: 764.3652。
1H, CH-3’), 6.15 (t, J = 6.6 Hz, 1H, CH-1’), 7.80-7.81 (m, 2H, CH-6, Ar-H),
13
7.98 (d, J = 7.8 Hz, 1H, Ar-H-4), 8.24 (d, J = 7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.35, 162.90, 162.60, 162.47, 151.68, 141.82, 140.25,
130.43, 128.71, 127.21, 125.54, 125.39, 125.16, 123.61, 122.46, 119.17,
118.57, 98.57, 86.84, 82.15, 71.76, 56.08, 56.03, 49.53, 44.33, 44.21, 42.79, +
38.37, 37.40, 36.70, 28.89, 28.58, 26.56, 26.34; HRMS (ESI) calcd C38H49FN8O8 +
[M] 764.3657. Found: 764.3652。
[0203] 化合物36g：收率 24%; 红色固体; mp.122-125℃；1H NMR (600 MHz, CD3OD) δ (ppm) 1.48-1.52 (m, 6H, 3CH2), 1.59-1.60 (m, 2H, CH2), 1.67-1.68 (m, 2H, CH2),1.83-1.87 (m, 2H, CH2), 2.23-2.26 (m, 2H, CH2-2’), 2.44 (d, J = 2.4 Hz, 12H,
4CH3-N), 2.70-2.77 (m, 4H, 2CH2), 2.85 (t, J = 7.2 Hz, 2H, CH2), 3.00-3.08 (m,
2H, CH2-5’), 3.47 (t, J = 6.6 Hz, 2H, CH2), 3.97-3.98 (m, 1H, CH-4’), 4.19-4.25 (m, 5H, CH-3’, 2CH2-N(CH3)), 6.01 (t, J = 6.6 Hz, 1H, CH-1’), 7.73 (s, 1H, CH-6), 7.81 (s, 1H, Ar-H-2), 7.92 (d, J = 7.8 Hz, 1H, Ar-H-4), 8.18 (d, J =
13
7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.25, 162.71, 162.35,
162.28, 151.49, 150.64, 141.45, 139.89, 130.28, 128.49, 127.03, 125.38,
125.04, 124.81, 123.48, 122.37, 118.94, 118.35, 98.42, 86.23, 83.91, 71.67,
56.15, 50.25, 48.96, 44.47, 44.44, 42.75, 39.38, 38.76, 37.66, 37.09, 28.94, +
28.86, 28.78, 27.83, 27.32, 26.63, 25.84, 22.79; HRMS (ESI) calcd C39H51FN8O8 +
[M] 778.3814. Found: 778.3808。
4CH3-N), 2.70-2.77 (m, 4H, 2CH2), 2.85 (t, J = 7.2 Hz, 2H, CH2), 3.00-3.08 (m,
2H, CH2-5’), 3.47 (t, J = 6.6 Hz, 2H, CH2), 3.97-3.98 (m, 1H, CH-4’), 4.19-4.25 (m, 5H, CH-3’, 2CH2-N(CH3)), 6.01 (t, J = 6.6 Hz, 1H, CH-1’), 7.73 (s, 1H, CH-6), 7.81 (s, 1H, Ar-H-2), 7.92 (d, J = 7.8 Hz, 1H, Ar-H-4), 8.18 (d, J =
13
7.8 Hz, 1H, Ar-H-4); C NMR (150 MHz, CD3OD) δ (ppm) 165.25, 162.71, 162.35,
162.28, 151.49, 150.64, 141.45, 139.89, 130.28, 128.49, 127.03, 125.38,
125.04, 124.81, 123.48, 122.37, 118.94, 118.35, 98.42, 86.23, 83.91, 71.67,
56.15, 50.25, 48.96, 44.47, 44.44, 42.75, 39.38, 38.76, 37.66, 37.09, 28.94, +
28.86, 28.78, 27.83, 27.32, 26.63, 25.84, 22.79; HRMS (ESI) calcd C39H51FN8O8 +
[M] 778.3814. Found: 778.3808。
[0204] 实施例1～6合成的化合物结构及化合物中的基团如表1所示。
[0205] 表1 化合物结构
[0206]
[0207] 实施例7
[0208] 化合物对A549，MCF-7和K562人的肿瘤细胞株的增殖抑制作用测试方法[0209] 采用改进的Mosmann’s MTT染色法测定。4
[0210] 具体操作如下：在96孔板接种细胞悬液，90 μL/孔，细胞密度2×10 个/mL，在37℃下，二氧化碳浓度为5%的培养箱中培养24 h，孔中加10 μL相应浓度药物（100 μmol/L），继续培养44 h，加MTT 10 μL/孔培养4 h，从培养箱中取出，倒板，加100 μL/孔的DMSO溶解MTT，测量570 nm波长下肿瘤细胞的OD值（OD为被检测物吸收掉的光密度），计算肿瘤细胞的抑制率。本发明中所有试验均至少重复3次。
[0211] 其计算公式如下：抑制率（%）= (OD对照组-OD给药组)/ OD对照组×100% ，其中对照组为试验中不给药组，再以抑制率、浓度梯度、剂量值等参数采用Excell软件计算得到其化合物对应的IC50。其中IC50计算公式为：LOG IC50=LOG(Cm)-LOG(B)×(A-0.5))。
[0212] 式中：Cm：药物最大浓度；B：浓度梯度(最大浓度/相临浓度) ；A：抑制率之和(小数)。
[0213] 本发明实施例1～6所公开的化合物及相同条件下顺铂、氟脲苷药物的体外抗肿瘤活性测试结果如表2所示。
[0214] 表2 药物体外抗肿瘤活性的IC50 值
[0215]
[0216] IC50值为药物诱导肿瘤细胞凋亡50%时药物的浓度，其IC50值越小，其抑制肿瘤的作用越大。从表2的数据可以看出，本发明化学通式（I）或（II）所示34个化合物对A549，K-562和MCF-7人的肿瘤细胞株所得的IC50值明显小于顺铂和氟脲苷的IC50值或与之相当，可见，本发明提供的化合物对A549，K-562和MCF-7人的肿瘤细胞具有显著的抑制作用，绝大部分化合物在抑制肿瘤明显好于顺铂和氟脲苷或与顺铂和氟脲苷相当。
[0217] 实施例8
[0218] 取实施例1制备的15 g化合物7a，乳糖30 g，硬脂酸镁1.5 mg，聚乙烯醇 3 mg，玉米淀粉25 g，制备成口服片剂300片，每片含50 mg化合物7a。
[0219] 本发明实施例中制备的化合物的检测仪器分别为：
[0220] 化合物熔点由SGW X-4显微熔点仪测定；核磁共振谱(1H NMR,13C NMR)由FT-NMR