CN104710417B - 氮杂吲哚类衍生物及其合成方法 - Google Patents
氮杂吲哚类衍生物及其合成方法 Download PDFInfo
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Abstract
本发明涉及本发明涉及一种氮杂吲哚类衍生物及其合成方法,具体的说是由氮杂吲哚类化合物通过傅克烷基化反应与不同类型的苄基醇作用选择性合成C‑3位烷基化的氮杂吲哚类衍生物。此方法反应条件温和,反应活性高,生成的产物专一,产率高,后处理简便,精简了合成步骤,能通过一步反应得到氮杂吲哚类衍生物。其中7‑氮杂吲哚类衍生物有很好的生理活性。
Description
技术领域
本发明属于有机化学方法学领域,涉及一种新方法的发明,尤其是一种氮杂吲哚类衍生物及其合成方法。其中7-氮杂吲哚类衍生物有很好的抗癌活性。
背景技术
恶性肿瘤的治疗长期以来是一个世界性的难题。以往对肿瘤的治疗是通过发现肿瘤并破坏来实现,现在随着对细胞信号传导途径研究的不断深入,人们对肿瘤细胞内部的癌基因及抗癌基因的作用了解得越来越深入,使得针对肿瘤的特异性分子靶点设计新的抗肿瘤药物成为可能。
蛋白酪氨酸激酶(protein tyrosine kinase,PTK)信号通路与肿瘤细胞的增殖、分化、迁移和凋亡有关,干扰或阻断酪氨酸激酶通路可以用于治疗肿瘤,因此筛选PTK抑制剂成为开发抗肿瘤药物的新途径。
发明内容
本发明的目的在于提供一种氮杂吲哚类衍生物及其合成方法,本方法反应条件温和、反应活性高,本反应生成的产物专一、产率高、后处理简便、精简了合成步骤,能通过一步反应得到氮杂吲哚类衍生物。
本发明实现目的的技术方案是:
一种氮杂吲哚类衍生物的合成方法,反应条件如下:
以下式所示的氮杂吲哚类化合物A与苄基醇通过反应合成氮杂吲哚类衍生物C,反应式如下:
上述反应使用的催化剂选自三氟甲磺酸﹑三氟乙酸﹑三氟化硼乙醚或浓硫酸至少一种;催化剂当量为1-20eq;溶剂任意选自二氯甲烷﹑1,2-二氯乙烷﹑三氟乙酸﹑乙酸﹑氯仿﹑乙酸乙酯至少一种;苄基醇B当量为1-10eq;氮杂吲哚类化合物A的反应浓度0.01-10mol/L;反应温度任意选自-78℃-100℃;反应时间任意选自0.5h~24h,所述当量为该物质与氮杂吲哚类化合物A的摩尔比。
而且,所述条件中采用3.0eq的三氟甲磺酸作催化剂,以二氯甲烷作溶剂,反应浓度为0.1mol/L,在室温20℃条件下反应2h。
而且,所述苄基醇的当量为3.0eq。
而且,具体操作步骤如下:
称取氮杂吲哚类化合物A置于烘干冷却的50ml两口反应瓶当中,加入溶剂,搅拌并确保其完全溶解,用注射器加入催化剂,反应液搅拌2分钟后,用注射器逐滴加入B,反应液变色。反应在40℃~-78℃温度下搅拌0.5h~24h小时,TLC检测反应完全后,反应液用饱和碳酸氢钠中和,用二氯甲烷萃取,合并有机相,有机相用饱和氯化钠溶液进行洗涤,无水硫酸钠进行干燥,目标产物用300目的硅胶柱层析进行纯化,得到目标产物氮杂吲哚类衍生物C。
而且,所述N可以是以氮杂吲哚命名的4﹑5﹑6﹑7位的任意位置的一个N,亦或者是5﹑7位均为N。
A1选自C6-C12芳香基、五元至十二元杂环芳香基、C3-C12环烷基、三元至十二元杂环烷基,其中任意基团可各自独立地被一个或多个R14取代;
R5选自氢﹑卤素﹑C1-C10烷基﹑C1-C10烷氧基;
R6选自氢﹑C1-C10烷基﹑C1-C10烷氧基;
R1﹑R2﹑R3﹑R4各自独立的选自氢﹑卤素﹑选自C6-C12芳香基、五元至十二元杂环芳香基、C3-C12环烷基、三元至十二元饱和或不饱和杂环烷基﹑羧酸酯基,其中任意基团可各自独立地被一个或多个R7取代。
而且,所述R7各自独立地选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-S(O)mR8、-SO2NR8R9、-S(O)2OR8、-NO2、-NR8R9、-(CR10R11)nOR8、-CN、-C(O)R8、-OC(O)R8、-O(CR10R11)nR8、-NR8C(O)R9、-O(C6C7)nNR8R9、-O(C6C7)nOR8、-(CR10R11)nC(O)OR8、-(CR10R11)NC(O)NCR8R9、-(CR10R11)nNCR8R9、-C(=NR10)NR8R9、-NR8C(O)NR9R10、-NR8S(O)pR9、-C(O)NR8R9,其中任意氢均可各自独立地被一个或多个R12取代;此外,取代基R7可与邻近的原子形成C6-C12芳香基、五元至十二元的杂环芳香基、C3-C12环烷基、三元至十二元杂环烷基;
R8,R9,R10和R11各自独立地选自氢、卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、C3-C12杂环烷基、C5-C12杂环芳香基;或任意两个连在同一个氮原子上的R8,R9,R10,R11均可分别与它们所连接的氮原子一起形成饱和或不饱和杂环,此处所述的杂环可选择性地包含一个或多个选自O、N或S的杂原子;或任意两个连在同一个碳原子上的R8,R9,R10,R11均可分别与它们所连接的碳原子一起形成C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基,其中任意氢均可各自独立地被一个或多个R12取代;或R8,R9,R10,R11中任意碳原子上的两个氢原子被氧代;
以上所述R12各自独立地选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、氨基、氰基、羟基、-O(C1-C12烷基)、-O(CH2)n(C3-C12环烷基)、-O(CH2)n(C6-C12芳香基)、-O(CH2)n三元至十二元杂环烷基、-O(CH2)n五元至十二元杂环芳香基,其中任意氢均可各自独立地被R13取代;
R13选自卤素、C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-O(C1-C12烷基)、-O(CH2)n(C3-C12环烷基)、-O(CH2)n(C6-C12芳香基)、-O(CH2)n三元至十二元杂环烷基、-O(CH2)n五元至十二元杂环芳香基、氰基,其中任意氢均可各自独立地被卤素、羟基、氰基、部分或完全卤代的C1-C12烷基、部分或完全卤代的C1-C12烷氧基、-C(O)、-S(O)或-S(O)2取代;
R14选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-S(O)mR8、-SO2NR8R9、-S(O)2OR8、-NO2、-NR8R9、-(CR10R11)nOR8、-CN、-C(O)R8、-OC(O)R8、-O(CR9R10)nR8、-NR8C(O)R9、-(CR10R11)nC(O)OR8、-(CR8R9)nOR8、-(CR9R10)nC(O)NCR8R9、-(CR10R11)nNCR8R9、-C(=NR10)NR8R9、-NR8C(O)NR9R10、-NR8S(O)pR9、-C(O)NR8R9、-(CR10R11)n三元至十二元杂环烷基、-(CR10R11)n三元至十二元环烷基、-(CR10R11)n(C6-C12芳香基)、-(CR10R11)n五元至十二元杂环芳香基,其中任意氢均可各自独立地被R7取代;
m选自0、1或2;
n选自0、1、2、3或4;
p选自1或2;
所述烷基、烯基、炔基、环烷基部分均可各自独立地被一个或多个选自以下的基团任选取代:羟基、氧代、卤素、氰基、硝基、三氟甲基、叠氮基、氨基、羧基、巯基。
饱和或不饱和烃基,例如C1-C12烷基、烷二基或烯基,包括与杂原子的结合,例如烷氧基,均可以分别是直链或带有支链的。
而且,所述合成氮杂吲哚类衍生物的反应式和步骤如下:
N可以是以氮杂吲哚命名的4﹑5﹑6﹑7位的任意位置的一个N或者两个N。
A1选自C6-C12芳香基、C5-C12杂环芳香基、C3-C12环烷基、三元至十二元杂环烷基,其中任意基团可各自独立地被一个或多个R11取代;
R1选自氢﹑卤素﹑选自C6-C12芳香基、五元至十二元杂环芳香基、C3-C12环烷基、C3-C12饱和或不饱和杂环烷基﹑羧酸酯基,其中任意基团可各自独立地被一个或多个R4取代;
R2选自氢﹑卤素﹑C1-C10烷基﹑C1-C10烷氧基;
R3选自氢﹑C1-C10烷基﹑C1-C10烷氧基;
所述R4各自独立地选自氢、卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-S(O)mR5、-SO2NR5R6、-S(O)2OR5、-NO2、-NR5R6、-(CR7R8)nOR5、-CN、-C(O)R5、-OC(O)R5、-O(CR7R8)nR5、-NR5C(O)R6、-O(C6C7)nNR5R6、-O(C6C7)nOR5、-(CR7R8)nC(O)OR5、-(CR7R8)NC(O)NCR5R6、-(CR7R8)nNCR5R6、-C(=NR7)NR5R6、-NR5C(O)NR6R7、-NR5S(O)pR6、-C(O)NR5R6,其中任意氢均可各自独立地被一个或多个R9取代;此外,取代基R4可与邻近的原子形成C6-C12芳香基、五元至十二元的杂环芳香基、C3-C12环烷基、三元至十二元杂环烷基;
R5,R6,R7和R8各自独立地选自氢、卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基;或任意两个连在同一个氮原子上的R5,R6,R7,R8均可分别与它们所连接的氮原子一起形成饱和或不饱和杂环,此处所述的杂环可选择性地包含一个或多个选自O、N或S的杂原子;或任意两个连在同一个碳原子上的R5,R6,R7,R8均可分别与它们所连接的碳原子一起形成C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基,其中任意氢均可各自独立地被一个或多个R9取代;或R5,R6,R7,R8中任意碳原子上的两个氢原子被氧代;
以上所述R9各自独立地选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、氨基、氰基、羟基、-O(C1-C12烷基)、-O(CH2)n(C3-C12环烷基)、-O(CH2)n(C6-C12芳香基)、-O(CH2)n三元至十二元杂环烷基、-O(CH2)n五元至十二元杂环芳香基,其中任意氢均可各自独立地被R10取代;
R10选自卤素、C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-O(C1-C12烷基)、-O(CH2)n(C3-C12环烷基)、-O(CH2)n(C6-C12芳香基)、-O(CH2)n三元至十二元杂环烷基、-O(CH2)n五元至十二元杂环芳香基、氰基,其中任意氢均可各自独立地被卤素、羟基、氰基、部分或完全卤代的C1-C12烷基、部分或完全卤代的C1-C12烷氧基、-C(O)、-S(O)或-S(O)2取代;
R11选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-S(O)mR5、-SO2NR5R6、-S(O)2OR5、-NO2、-NR5R6、-(CR7R8)nOR5、-CN、-C(O)R5、-OC(O)R5、-O(CR7R8)nR5、-NR5C(O)R6、-(CR7R8)nC(O)OR5、-(CR7R8)nOR5、-(CR7R8)nC(O)NCR5R6、-(CR7R8)nNCR5R6、-C(=NR7)NR5R6、-NR5C(O)NR6R7、-NR5S(O)pR6、-C(O)NR5R6、-(CR7R8)n三元至十二元杂环烷基、-(CR7R8)n三元至十二元环烷基、-(CR7R8)n(C6-C12芳香基)、-(CR7R8)n五元至十二元杂环芳香基,其中任意氢均可各自独立地被R4取代;
m选自0、1或2;
n选自0、1、2、3或4;
p选自1或2;
所述烷基、烯基、炔基、环烷基部分均可各自独立地被一个或多个选自以下的基团任选取代:羟基、氧代、卤素、氰基、硝基、三氟甲基、叠氮基、氨基、羧基、巯基。
饱和或不饱和烃基,例如C1-C12烷基、烷二基或烯基,包括与杂原子的结合,例如烷氧基,均可以分别是直链或带有支链的。
一种氮杂吲哚类衍生物,所述结构式如下:
而且,所述结构式选自如下结构式之一:
本发明具有以下优点:
1、本发明提供的新方法具有反应活性高、产物专一、产率高、且具有绿色原子经济性、环境友好等特点。
2、本发明提供的新方法反应条件温和、反应较快、在室温下即能反应完全,催化剂用水即可洗掉,后处理简便。
3、本方法中选择性地将氮杂吲哚类化合物的C-3位烷基化,能一步反应得到氮杂吲哚类衍生物,精简了合成步骤,节省了成本,对大规模的生产有重要意义。
4、本方法合成的氮杂吲哚类衍生物的方法是首次公布的方法,本发明产生产物是一类未见报道的新化合物。
附图说明
图1为化合物1a的lH-NMR谱图;
图2为化合物1a的13C-NMR谱图;
图3为化合物1a的高分辨质谱(HRMS)谱图;
图4为化合物40a的lH-NMR谱图;
图5为化合物40a的13C-NMR谱图;
图6为化合物40a的高分辨质谱(HRMS)谱图;
图7为化合物40a的X-射线单晶衍射结构图。
具体实施案例
下面结合实施例,对本发明进一步说明,下述实施例是说明性的,不是限定性的,不能以下述实施例来限定本发明的保护范围。
实施例1:不同氮杂吲哚类化合物与1-苯基乙醇反应
称取氮杂吲哚类化合物1b-15b(0.50mmol)置于烘干冷却的50ml两口反应瓶当中,加入无水二氯甲烷(5ml),搅拌并确保其完全溶解,在室温条件下用注射器加入三氟甲磺酸(225.12mg,1.50mmol),反应液搅拌2分钟后,用注射器逐滴加入苄基醇1c(183.24mg,1.50mmol),反应液变色。反应在常温下搅拌2小时,TLC检测反应完全后,反应液用饱和碳酸氢钠中和,用二氯甲烷萃取(20ml×3),合并有机相,有机相用饱和氯化钠溶液进行洗涤,无水硫酸钠进行干燥。目标产物用300目的硅胶柱层析进行纯化,得到目标产物1a-15a。
反应式如式4所示:
N可以是以氮杂吲哚命名的4﹑5﹑6﹑7位的任意位置的一个N或者两个N。
R2选自氢﹑卤素﹑C1-C10烷基﹑C1-C10烷氧基;
R1各自独立的选自氢﹑卤素﹑选自C6-C12芳香基、五元至十二元杂环芳香基、C3-C12环烷基、三元至十二元饱和或不饱和杂环烷基﹑羧酸酯基,其中任意基团可各自独立地被一个或多个R7取代。
所述R7各自独立地选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-S(O)mR8、-SO2NR8R9、-S(O)2OR8、-NO2、-NR8R9、-(CR10R11)nOR8、-CN、-C(O)R8、-OC(O)R8、-O(CR10R11)nR8、-NR8C(O)R9、-O(C6C7)nNR8R9、-O(C6C7)nOR8、-(CR10R11)nC(O)OR8、-(CR10R11)NC(O)NCR8R9、-(CR10R11)nNCR8R9、-C(=NR10)NR8R9、-NR8C(O)NR9R10、-NR8S(O)pR9、-C(O)NR8R9,其中任意氢均可各自独立地被一个或多个R12取代;此外,取代基R7可与邻近的原子形成C6-C12芳香基、五元至十二元的杂环芳香基、C3-C12环烷基、三元至十二元杂环烷基;
R8,R9,R10和R11各自独立地选自氢、卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、C3-C12杂环烷基、C5-C12杂环芳香基;或任意两个连在同一个氮原子上的R8,R9,R10,R11均可分别与它们所连接的氮原子一起形成饱和或不饱和杂环,此处所述的杂环可选择性地包含一个或多个选自O、N或S的杂原子;或任意两个连在同一个碳原子上的R8,R9,R10,R11均可分别与它们所连接的碳原子一起形成C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基,其中任意氢均可各自独立地被一个或多个R12取代;或R8,R9,R10,R11中任意碳原子上的两个氢原子被氧代;
以上所述R12各自独立地选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、氨基、氰基、羟基、-O(C1-C12烷基)、-O(CH2)n(C3-C12环烷基)、-O(CH2)n(C6-C12芳香基)、-O(CH2)n三元至十二元杂环烷基、-O(CH2)n五元至十二元杂环芳香基,其中任意氢均可各自独立地被R13取代;
R13选自卤素、C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-O(C1-C12烷基)、-O(CH2)n(C3-C12环烷基)、-O(CH2)n(C6-C12芳香基)、-O(CH2)n三元至十二元杂环烷基、-O(CH2)n五元至十二元杂环芳香基、氰基,其中任意氢均可各自独立地被卤素、羟基、氰基、部分或完全卤代的C1-C12烷基、部分或完全卤代的C1-C12烷氧基、-C(O)、-S(O)或-S(O)2取代;
所述烷基、烯基、炔基、环烷基部分均可各自独立地被一个或多个选自以下的基团任选取代:羟基、氧代、卤素、氰基、硝基、三氟甲基、叠氮基、氨基、羧基、巯基。
饱和或不饱和烃基,例如C1-C12烷基、烷二基或烯基,包括与杂原子的结合,例如烷氧基,均可以分别是直链或带有支链的。
部分产物核磁及质谱数据如下:
1a:1HNMR(400MHz,DMSO)δ(ppm):11.40(s,1H),8.13(d,J=4.4Hz,1H),7.61(d,J=7.6Hz,1H),7.35(d,J=1.6Hz,1H),7.32–7.22(m,4H),7.15(t,J=7.2Hz,1H),6.91(dd,J=8.0Hz,4.8Hz,1H),4.31(q,J=7.2Hz,1H),1.63(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):149.32,147.29,142.81,128.70,127.58,127.41,126.30,122.57,119.05,118.79,115.16,36.76,22.37;HRMS(ESI)Calcd forC15H15N2(MH+)223.1230,found223.1228.
2a:1HNMR(400MHz,DMSO)δ(ppm):11.41(s,1H),8.69(s,1H),7.95(d,J=5.2Hz,1H),7.51(s,1H),7.34–7.18(m,5H),7.15(t,J=6.8Hz,1H),4.33(q,J=7.2Hz,1H),1.64(d,J=7.2Hz,3H);13CNMR(101MHz,DMSO)δ(ppm):147.21,137.37,134.75,134.17,130.92,128.72,127.57,126.42,126.31,119.74,114.10,36.48,22.59,21.22;HRMS(ESI)Calcdfor C15H15N2(MH+)223.1230,found223.1222.
3a:1HNMR(400MHz,DMSO)δ(ppm):11.28(s,1H),8.50(s,1H),8.07(d,J=5.6Hz,1H),7.35–7.22(m,6H),7.16(t,J=7.2Hz,1H),4.39(q,J=7.2Hz,1H),1.65(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):147.35,142.45,140.30,128.74,127.60,126.36,123.81,123.24,120.18,107.22,36.58,22.62;HRMS(ESI)Calcd for C15H15N2(MH+)223.1230,found223.1233.
4a:1HNMR(400MHz,DMSO)δ(ppm):11.06(s,1H),8.26(dd,J=4.4Hz,0.8Hz,1H),7.69(d,J=7.2Hz,1H),7.41(d,J=2.8Hz,1H),7.37(d,J=7.2Hz,2H),7.24(t,J=7.6Hz,2H),7.12(t,J=7.2Hz,1H),7.05(dd,J=8.0Hz,4.4Hz,1H),4.49(q,J=7.6Hz,1H),1.69(d,J=7.2Hz,3H);13CNMR(101MHz,DMSO)δ(ppm):147.67,144.71,142.05,129.30,128.50,127.69,126.01,125.97,120.46,118.64,116.63,35.70,22.58;HRMS(ESI)Calcd for C15H15N2(MH+)223.1230,found223.1227.
5a:1HNMR(400MHz,DMSO)δ(ppm):11.23(s,1H),8.33(d,J=2.0Hz,1H),7.95(d,J=2.0Hz,1H),7.47(d,J=2.4Hz,1H),7.34(d,J=7.2Hz,2H),7.28–7.19(m,3H),7.17–7.10(m,2H),4.46(q,J=7.2Hz,1H),1.66(d,J=7.2Hz,3H).13CNMR(101MHz,DMSO)δ(ppm):147.29,143.35,142.40,130.05,128.56,127.63,127.46,126.12,120.98,120.66,112.41,35.58,22.46;HRMS(ESI)Calcd for C15H14BrN2(MH+)301.0335,found301.0323.
6a:1HNMR(400MHz,DMSO)δ(ppm):11.90(s,1H),8.71(s,1H),8.10(s,1H),7.67(d,J=2.4Hz,1H),7.29–7.18(m,4H),7.16–7.08(m,1H),4.92(q,J=7.2Hz,1H),1.63(d,J=7.2Hz,3H)13CNMR(100MHz,DMSO)δ(ppm):147.77,139.59,134.96,134.28,129.06,128.62,127.77,126.11,120.12,111.43,35.56,24.27.HRMS(ESI)Calcd for C15H14BrN2(MH+)301.0335,found301.0330.
7a:1HNMR(400MHz,DMSO)δ(ppm):11.90(s,1H),8.00(d,J=4.8Hz,1H),7.52(d,J=2.0Hz,1H),7.28–7.18(m,5H),7.17–7.09(m,,1H),4.85(q,J=7.2Hz,1H),1.62(d,J=7.2Hz,3H);13CNMR(101MHz,DMSO)δ(ppm):149.63,147.78,143.27,128.59,127.79,126.09,125.25,123.74,119.78,118.93,117.82,36.03,24.04.HRMS(ESI)Calcd for C15H14BrN2(MH+)301.0335,found301.0326.
8a:1HNMR(400MHz,DMSO)δ(ppm):11.69(s,1H),8.19(d,J=2.4Hz,1H),7.78(d,J=2.0Hz,1H),7.46(d,J=2.0Hz,1H),7.33–7.23(m,4H),7.21–7.13(m,1H),4.32(q,J=6.8Hz,1H),1.61(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):147.58,146.96,142.79,129.28,128.80,127.58,126.45,124.71,120.88,118.76,110.44,36.39,22.30;HRMS(ESI)Calcdfor C15H14BrN2(MH+)301.0335,found301.0345.
9a:1HNMR(400MHz,DMSO)δ(ppm):11.69(s,1H),7.55(d,J=8.0Hz,1H),7.39(d,J=1.6Hz,1H),7.30–7.22(m,4H),7.19–7.12(m,1H),7.09(d,J=8.4Hz,1H),4.31(q,J=7.2Hz,1H),1.62(d,J=7.2Hz,3H);13CNMR(101MHz,DMSO)δ(ppm):148.51,146.99,133.88,130.46,128.77,127.55,126.41,123.28,119.39,118.37,118.14,36.63,22.29;HRMS(ESI)Calcdfor C15H14BrN2(MH+)301.0335,found301.0326.
10a:1HNMR(400MHz,DMSO)δ(ppm):12.67(s,1H),7.66(s,1H),7.32-7.06(m,5H),4.59(q,J=7.2Hz,1H),1.60(d,J=7.2Hz,3H);13CNMR(101MHz,DMSO)δ153.82,151.20,150.47,146.80,129.89,128.76,127.65,126.73,126.41,119.47,114.04,99.84,36.30,23.56;HRMS(ESI)Calcd for C14H11Cl2N3(M+Na)+314.0222,found314.0223.
11a:1HNMR(400MHz,DMSO)δ(ppm):11.93(s,1H),8.74(d,J=1.6Hz,1H),8.15(d,J=1.6Hz,1H),7.53(s,1H),7.34–7.23(m,4H),7.21–7.13(m,1H),4.40(q,J=7.2Hz,1H),3.82(s,3H),1.63(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):166.78,151.09,146.97,144.44,129.00,128.84,127.54,126.49,124.84,120.27,118.44,117.28,52.34,36.45,22.56;HRMS(ESI)Calcd for C17H16N2O2(M+Na)+303.1104,found303.1095.
12a:1HNMR(400MHz,DMSO)δ(ppm):11.25(s,1H),7.90(d,J=2.4Hz,1H),7.37–7.22(m,5H),7.20–7.10(m,2H),4.29(q,J=7.2Hz,1H),3.70(s,3H),1.62(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):150.48,147.20,144.79,132.72,128.69,127.62,126.29,123.57,118.90,118.40,110.56,56.43,36.65,22.33;HRMS(ESI)Calcd for C16H17N2O(MH+)253.1335,found253.1344.
13a:1HNMR(400MHz,DMSO)δ(ppm):11.24(s,1H),7.98(d,J=1.6Hz,1H),7.43(s,1H),7.33–7.22(m,5H),7.18–7.11(m,1H),4.28(q,J=7.2Hz,1H),2.27(s,3H),1.60(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):147.99,147.34,143.63,128.69,127.55,127.15,126.26,123.45,122.77,118.87,118.09,36.72,22.48,18.58;HRMS(ESI)Calcd forC16H17N2(MH+)237.1386,found237.1386.
14a:1HNMR(400MHz,DMSO)δ11.69(s,1H),8.13(d,J=2.4Hz,1H),7.66(d,J=2.4Hz,1H),7.49(d,J=2.0Hz,1H),7.35–7.22(m,5H),7.19–7.13(m,1H),4.32(q,J=7.2Hz,1H),1.62(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):147.54,146.96,140.88,128.79,127.58,126.45,124.91,122.05,119.98,118.81,36.43,22.26;HRMS(ESI)Calcd forC15H14ClN2(MH+)257.0840,found257.0833.
15a:1HNMR(400MHz,DMSO)δ(ppm):11.27(s,1H),8.03(d,J=3.6Hz,1H),7.66(d,J=7.6Hz,1H),7.32(d,J=7.2Hz,2H),7.25(t,J=7.6Hz,2H),7.13(t,J=7.2Hz,1H),6.86(dd,J=7.6Hz,4.4Hz,,1H),4.37(q,J=7.2Hz,1H),2.38(s,3H),1.68(t,J=7.6Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):148.39,146.60,141.22,132.38,128.57,127.47,126.58,126.02,119.75,115.03,113.79,35.45,20.93,12.11;IR(KBr):υ(cm-1):3143,3091,3052,2965,2839,2761,1582,1549,1532,1494,1450.HRMS(ESI)Calcd for C16H17N2(MH+)237.1386,found237.1388.
部分产物的产率如式5:
实施例2:7-氮杂吲哚与不同的苄基醇反应
称取7-氮杂吲哚1b(59.07mg,0.50mmol)置于烘干冷却的50ml两口反应瓶当中,加入无水二氯甲烷(5ml),搅拌并确保其完全溶解,在室温条件下用注射器加入三氟甲磺酸(225.12mg,1.50mmol),反应液搅拌2分钟后,用注射器逐滴加入苄基醇1c-12c(1.50mmol),反应液变色。反应在常温下搅拌2小时,TLC检测反应完全后,反应液用饱和碳酸氢钠中和,用二氯甲烷萃取(20ml×3),合并有机相,有机相用饱和氯化钠溶液进行洗涤,无水硫酸钠进行干燥。目标产物用300目的硅胶柱层析进行纯化,得到目标产物16a-27a。
反应式如式6所示:
R2选自氢﹑C1-C10烷基﹑C1-C10烷氧基;
R1选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-S(O)mR8、-SO2NR8R9、-S(O)2OR8、-NO2、-NR8R9、-(CR10R11)nOR8、-CN、-C(O)R8、-OC(O)R8、-O(CR9R10)nR8、-NR8C(O)R9、-(CR10R11)nC(O)OR8、-(CR8R9)nOR8、-(CR9R10)nC(O)NCR8R9、-(CR10R11)nNCR8R9、-C(=NR10)NR8R9、-NR8C(O)NR9R10、-NR8S(O)pR9、-C(O)NR8R9、-(CR10R11)n三元至十二元杂环烷基、-(CR10R11)n三元至十二元环烷基、-(CR10R11)n(C6-C12芳香基)、-(CR10R11)n五元至十二元杂环芳香基,其中任意氢均可各自独立地被R7取代;
所述R7各自独立地选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-S(O)mR8、-SO2NR8R9、-S(O)2OR8、-NO2、-NR8R9、-(CR10R11)nOR8、-CN、-C(O)R8、-OC(O)R8、-O(CR10R11)nR8、-NR8C(O)R9、-O(C6C7)nNR8R9、-O(C6C7)nOR8、-(CR10R11)nC(O)OR8、-(CR10R11)NC(O)NCR8R9、-(CR10R11)nNCR8R9、-C(=NR10)NR8R9、-NR8C(O)NR9R10、-NR8S(O)pR9、-C(O)NR8R9,其中任意氢均可各自独立地被一个或多个R12取代;此外,取代基R7可与邻近的原子形成C6-C12芳香基、五元至十二元的杂环芳香基、C3-C12环烷基、三元至十二元杂环烷基;
R8,R9,R10和R11各自独立地选自氢、卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、C3-C12杂环烷基、C5-C12杂环芳香基;或任意两个连在同一个氮原子上的R8,R9,R10,R11均可分别与它们所连接的氮原子一起形成饱和或不饱和杂环,此处所述的杂环可选择性地包含一个或多个选自O、N或S的杂原子;或任意两个连在同一个碳原子上的R8,R9,R10,R11均可分别与它们所连接的碳原子一起形成C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基,其中任意氢均可各自独立地被一个或多个R12取代;或R8,R9,R10,R11中任意碳原子上的两个氢原子被氧代;
以上所述R12各自独立地选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、氨基、氰基、羟基、-O(C1-C12烷基)、-O(CH2)n(C3-C12环烷基)、-O(CH2)n(C6-C12芳香基)、-O(CH2)n三元至十二元杂环烷基、-O(CH2)n五元至十二元杂环芳香基,其中任意氢均可各自独立地被R13取代;
R13选自卤素、C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-O(C1-C12烷基)、-O(CH2)n(C3-C12环烷基)、-O(CH2)n(C6-C12芳香基)、-O(CH2)n三元至十二元杂环烷基、-O(CH2)n五元至十二元杂环芳香基、氰基,其中任意氢均可各自独立地被卤素、羟基、氰基、部分或完全卤代的C1-C12烷基、部分或完全卤代的C1-C12烷氧基、-C(O)、-S(O)或-S(O)2取代;
m选自0、1或2;
n选自0、1、2、3或4;
p选自1或2;
所述烷基、烯基、炔基、环烷基部分均可各自独立地被一个或多个选自以下的基团任选取代:羟基、氧代、卤素、氰基、硝基、三氟甲基、叠氮基、氨基、羧基、巯基。
饱和或不饱和烃基,例如C1-C12烷基、烷二基或烯基,包括与杂原子的结合,例如烷氧基,均可以分别是直链或带有支链的;
部分产物核磁及质谱数据如下:
16a:1HNMR(400MHz,DMSO)δ(ppm):11.37(s,1H),8.13(dd,J=4.8Hz,1.2Hz,1H),7.64–7.56(m,1H),7.31(d,J=1.6Hz,1H),7.19(d,J=8.4Hz,2H),6.91(dd,J=7.6Hz,4.4Hz,1H),6.81(d,J=8.4Hz,2H),4.26(q,J=6.8Hz,1H),3.69(s,3H),1.60(d,J=7.2Hz,3H);13CNMR(101MHz,DMSO)δ(ppm):157.84,149.36,142.76,139.24,128.48,127.47,122.41,119.18,119.05,115.12,114.07,55.40,35.92,22.54;HRMS(ESI)Calcd for C16H17N2O(MH+)253.1335,found253.1344.
17a:1HNMR(400MHz,DMSO)δ(ppm):11.53(s,1H),8.13(d,J=4.8Hz,1H),7.70–7.34(m,3H),7.18(d,J=8.0Hz,1H),6.88(dd,J=8.0Hz,4.8Hz,1H),5.13(q,J=7.2Hz,1H),1.80(d,J=6.8Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):158.44,155.99,149.10,142.76,141.97,129.95,126.23,124.21,118.91,116.38,116.15,115.42,114.32,34.23,16.40.HRMS(ESI)Calcd for C15H12Cl2FN2(MH+)309.0356,found309.0369.
18a:1HNMR(400MHz,DMSO)δ(ppm):11.39(s,1H),8.13(d,J=3.6Hz,1H),7.50(d,J=8.0Hz,1H),7.25(d,J=1.6Hz,1H),7.18–7.12(m,1H),7.12–7.02(m,3H),6.90(dd,J=8.0Hz,4.8Hz,1H),4.49(q,J=7.2Hz,1H),2.38(s,3H),1.58(d,J=7.2Hz,3H).13CNMR(100MHz,DMSO)δ(ppm):149.32,144.86,142.80,135.25,130.60,127.29,126.90,126.44,126.19,123.03,119.05,118.58,115.18,32.63,21.60,19.55;HRMS(ESI)Calcd for C16H17N2(MH+)237.1386,found237.1381.
19a:1HNMR(400MHz,DMSO)δ(ppm):11.38(s,1H),8.13(d,J=4.0Hz,1H),7.60(d,J=7.6Hz,1H),7.32(s,1H),7.16(d,J=8.0Hz,2H),7.05(d,J=7.6Hz,2H),6.90(dd,J=7.8Hz,4.7Hz,1H),4.26(q,J=7.2Hz,1H),2.25(s,3H),1.60(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ149.33,144.26,142.77,135.15,129.26,127.45,122.47,119.05,118.96,115.12,36.35,22.41,21.03.HRMS(ESI)Calcd for C16H17N2(MH+)237.1386,found237.1382
20a:1HNMR(400MHz,DMSO)δ(ppm):11.49(s,1H),8.15(dd,J=4.4Hz,1.2Hz,1H),7.68–7.59(m,3H),7.54–7.46(m,2H),7.44(d,J=2.0Hz,1H),6.93(dd,J=8.0Hz,4.8Hz,1H),4.47(q,J=7.2Hz,1H),1.66(d,J=7.2Hz,3H).13CNMR(100MHz,DMSO)δ149.29,148.80,143.00,131.79,129.79,129.33,127.25,126.13,124.02,123.18,122.95,118.84,117.94,115.33,36.41,22.12.HRMS(ESI)Calcd for C16H14F3N2(MH+)291.1104,found291.1098.
21a:1HNMR(400MHz,DMSO)δ(ppm):11.48(s,1H),8.19–8.11(m,1H),7.68–7.58(m,3H),7.52(d,J=8.0Hz,2H),7.43(d,J=2.0Hz,1H),6.93(dd,J=8.0Hz,4.8Hz,1H),4.45(q,J=7.2Hz,1H),1.66(d,J=7.2Hz,3H).13CNMR(101MHz,DMSO)δ152.17,149.31,142.98,128.41,127.27,126.94,126.21,125.66,125.62,123.51,122.93,118.86,117.82,115.34,36.54,22.00.HRMS(ESI)Calcd for C16H14F3N2(MH+)291.1104,found291.1097.
22a:1HNMR(400MHz,DMSO)δ(ppm):11.44(s,1H),8.14(d,J=4.8Hz,1H),7.61(d,J=8.0Hz,1H),7.44(d,J=8.0Hz,2H),7.37(d,J=2.0Hz,1H),7.25(d,J=8.0Hz,2H),6.92(dd,J=7.6Hz,4.4Hz,1H),4.32(q,J=6.8Hz,1H),1.61(d,J=6.8Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):149.32,146.77,142.92,131.56,129.90,127.35,122.75,119.24,118.89,118.19,115.27,36.15,22.14;HRMS(ESI)Calcd for C15H14BrN2(MH+)301.0351,found301.03349.
23a:1HNMR(400MHz,DMSO)δ(ppm):11.45(s,1H),8.15(dd,J=4.4Hz,1.2Hz,1H),7.61(d,J=7.6Hz,1H),7.37(d,J=1.6Hz,1H),7.30(s,4H),6.92(dd,J=8.0Hz,4.8Hz,1H),4.33(q,J=6.8Hz,1H),1.61(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):149.32,146.32,142.91,130.79,129.47,128.64,127.36,122.74,118.90,118.27,115.26,36.10,22.19;HRMS(ESI)Calcd for C15H14ClN2(MH+)257.0835,found257.0833.
24a:1HNMR(400MHz,DMSO)δ(ppm):11.47(s,1H),8.15(d,J=4.4Hz,1H),7.66(d,J=7.6Hz,1H),7.41(d,J=2.0Hz,1H),7.33(s,1H),7.30–7.25(m,2H),7.24–7.17(m,1H),6.93(dd,J=7.6Hz,4.8Hz,1H),4.36(q,J=6.8Hz,1H),1.63(d,J=7.2Hz,3H).13CNMR(100MHz,DMSO)δ(ppm):150.01,149.28,142.96,133.37,130.60,127.42,127.32,126.35,126.33,122.85,118.89,118.03,115.31,36.38,22.10;HRMS(ESI)Calcd for C15H14ClN2(MH+)257.0840found.257.0833.
25a:1HNMR(400MHz,DMSO)δ(ppm):11.49(s,1H),8.15(dd,J=4.8Hz,1.2Hz,1H),7.53(d,J=6.8Hz,1H),7.47–7.41(m,1H),7.39(d,J=2.0Hz,1H),7.20(d,J=2.8Hz,3H),6.93(dd,J=8.0Hz,4.8Hz,1H),4.74(q,J=7.2Hz,1H),1.62(d,J=6.8Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):149.30,143.97,142.99,132.57,129.70,129.21,128.19,127.87,126.99,123.37,118.89,117.39,115.39,33.15,21.04;HRMS(ESI)Calcd for C15H13ClN2(MH+)257.0840,found257.0836.
26a:1HNMR(400MHz,DMSO)δ(ppm):11.50(s,1H),8.12(dd,J=4.8,1.6Hz,1H),7.40(s,3H),7.27(t,J=8.0Hz,1H),7.16(dd,J=8.0Hz,1.2Hz,1H),6.85(dd,J=8.0,4.8Hz,1H),5.14(q,J=7.2Hz,1H),1.79(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):149.11,142.66,139.90,135.16,130.14,129.42,126.31,123.96,119.02,115.30,114.99,33.82,16.61;HRMS(ESI)Calcd for C15H13Cl2N2(MH+)291.045,found291.0446.
27a:1HNMR(400MHz,DMSO)δ(ppm):11.40(s,1H),8.13(dd,J=4.8Hz,1.6Hz,1H),7.74(dd,J=1.2Hzand7.6Hz,1H),7.38(d,J=2.4Hz,1H),7.32(d,J=7.2Hz,2H),7.25(t,J=7.6Hz,2H),7.13(t,J=7.2Hz,1H),6.92(dd,J=7.6Hz,4.4Hz1H),4.01(t,J=7.6Hz,1H),2.24–2.09(m,1H),2.08–1.91(m,1H),0.86(t,J=7.6Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):149.18,145.92,142.78,128.63,128.12,127.30,126.26,122.52,119.29,117.85,115.18,44.52,28.46,13.13;HRMS(ESI)Calcd for C16H17N2(MH+)237.1386,found237.1385.
部分产物的产率如式7:
实施例3:不同的氮杂吲哚类化合物与不同的苄基醇反应
称取氮杂吲哚类化合物1b-15b(0.50mmol)置于烘干冷却的50ml两口反应瓶当中,加入无水二氯甲烷(5ml),搅拌并确保其完全溶解,在室温条件下用注射器加入三氟甲磺酸(225.12mg,1.50mmol),反应液搅拌2分钟后,用注射器逐滴加入不同的苄基醇1c-12c(1.50mmol),反应液变色。反应在常温下搅拌2小时,TLC检测反应完全后,反应液用饱和碳酸氢钠中和,用二氯甲烷萃取(20ml×3),合并有机相,有机相用饱和氯化钠溶液进行洗涤,无水硫酸钠进行干燥。目标产物用300目的硅胶柱层析进行纯化,得到目标产物28a-47a。
反应式如式8所示:
N可以是以氮杂吲哚命名的4﹑5﹑6﹑7位的任意位置的一个N或者两个N。
R2选自氢﹑卤素﹑C1-C10烷基﹑C1-C10烷氧基;
R3选自氢﹑C1-C10烷基﹑C1-C10烷氧基;
R1各自独立的选自氢﹑卤素﹑选自C6-C12芳香基、五元至十二元杂环芳香基、C3-C12环烷基、三元至十二元饱和或不饱和杂环烷基﹑羧酸酯基,其中任意基团可各自独立地被一个或多个R7取代。
而且,所述R7各自独立地选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-S(O)mR8、-SO2NR8R9、-S(O)2OR8、-NO2、-NR8R9、-(CR10R11)nOR8、-CN、-C(O)R8、-OC(O)R8、-O(CR10R11)nR8、-NR8C(O)R9、-O(C6C7)nNR8R9、-O(C6C7)nOR8、-(CR10R11)nC(O)OR8、-(CR10R11)NC(O)NCR8R9、-(CR10R11)nNCR8R9、-C(=NR10)NR8R9、-NR8C(O)NR9R10、-NR8S(O)pR9、-C(O)NR8R9,其中任意氢均可各自独立地被一个或多个R12取代;此外,取代基R7可与邻近的原子形成C6-C12芳香基、五元至十二元的杂环芳香基、C3-C12环烷基、三元至十二元杂环烷基;
R8,R9,R10和R11各自独立地选自氢、卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、C3-C12杂环烷基、C5-C12杂环芳香基;或任意两个连在同一个氮原子上的R8,R9,R10,R11均可分别与它们所连接的氮原子一起形成饱和或不饱和杂环,此处所述的杂环可选择性地包含一个或多个选自O、N或S的杂原子;或任意两个连在同一个碳原子上的R8,R9,R10,R11均可分别与它们所连接的碳原子一起形成C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基,其中任意氢均可各自独立地被一个或多个R12取代;或R8,R9,R10,R11中任意碳原子上的两个氢原子被氧代;
以上所述R12各自独立地选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、氨基、氰基、羟基、-O(C1-C12烷基)、-O(CH2)n(C3-C12环烷基)、-O(CH2)n(C6-C12芳香基)、-O(CH2)n三元至十二元杂环烷基、-O(CH2)n五元至十二元杂环芳香基,其中任意氢均可各自独立地被R13取代;
R13选自卤素、C1-C12烷基、C1-C12烷氧基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-O(C1-C12烷基)、-O(CH2)n(C3-C12环烷基)、-O(CH2)n(C6-C12芳香基)、-O(CH2)n三元至十二元杂环烷基、-O(CH2)n五元至十二元杂环芳香基、氰基,其中任意氢均可各自独立地被卤素、羟基、氰基、部分或完全卤代的C1-C12烷基、部分或完全卤代的C1-C12烷氧基、-C(O)、-S(O)或-S(O)2取代;
R4选自卤素、C1-C12烷基、C2-C12烯基、C2-C12炔基、C3-C12环烷基、C6-C12芳香基、三元至十二元杂环烷基、五元至十二元杂环芳香基、-S(O)mR8、-SO2NR8R9、-S(O)2OR8、-NO2、-NR8R9、-(CR10R11)nOR8、-CN、-C(O)R8、-OC(O)R8、-O(CR9R10)nR8、-NR8C(O)R9、-(CR10R11)nC(O)OR8、-(CR8R9)nOR8、-(CR9R10)nC(O)NCR8R9、-(CR10R11)nNCR8R9、-C(=NR10)NR8R9、-NR8C(O)NR9R10、-NR8S(O)pR9、-C(O)NR8R9、-(CR10R11)n三元至十二元杂环烷基、-(CR10R11)n三元至十二元环烷基、-(CR10R11)n(C6-C12芳香基)、-(CR10R11)n五元至十二元杂环芳香基,其中任意氢均可各自独立地被R7取代;
m选自0、1或2;
n选自0、1、2、3或4;
p选自1或2;
所述烷基、烯基、炔基、环烷基部分均可各自独立地被一个或多个选自以下的基团任选取代:羟基、氧代、卤素、氰基、硝基、三氟甲基、叠氮基、氨基、羧基、巯基。
饱和或不饱和烃基,例如C1-C12烷基、烷二基或烯基,包括与杂原子的结合,例如烷氧基,均可以分别是直链或带有支链的。
部分产物核磁及质谱数据如下:
28a:1HNMR(400MHz,DMSO)δ(ppm):11.23(s,1H),7.98(d,J=1.6Hz,1H),7.56(s,1H),7.36–7.29(m,3H),7.29-7.22(m,2H),7.17–7.10(m,1H),3.98(t,J=7.6Hz,1H),2.29(s,3H),2.21–2.08(m,1H),2.06–1.91(m,1H),0.85(t,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):147.88,146.00,143.61,128.62,128.09,127.04,126.23,123.49,122.71,119.13,117.15,44.53,28.60,18.60,13.19;HRMS(ESI)Calcd for C17H19N2(MH+)251.1543,found251.1542.
29a:1HNMR(400MHz,DMSO)δ(ppm):11.24(s,1H),7.90(d,J=2.8Hz,1H),7.38–7.30(m,3H),7.30–7.21(m,3H),7.14(t,J=7.2Hz,1H),3.99(t,J=7.6Hz,1H),3.73(s,3H),2.22–2.07(m,1H),2.06–1.93(m,1H),0.85(t,J=7.2Hz3H);13CNMR(100MHz,DMSO)δ(ppm):150.55,145.89,144.66,132.74,128.62,128.15,126.24,123.49,119.17,117.46,110.40,56.46,44.39,28.49,13.16;HRMS(ESI)Calcd for C17H19N2O(MH+)267.1492,found267.1482.
30a:1HNMR(400MHz,DMSO)δ(ppm):11.69(s,1H),8.19(d,J=2.4Hz,1H),7.92(d,J=2.4Hz,1H),7.49(d,J=2.4Hz,1H),7.36–7.30(m,2H),7.27(t,J=7.6Hz,2H),7.18–7.12(m,1H),4.03(t,J=7.6Hz,1H),2.21–2.08(m,1H),2.04–1.92(m,1H),0.85(t,J=7.6Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):147.43,145.60,142.75,129.16,128.72,128.12,126.40,124.63,121.18,117.85,110.51,44.04,28.46,13.06;HRMS(ESI)Calcd for C16H16BrN2(MH+)315.0491,found315.0486.
31a:1HNMR(400MHz,DMSO)δ(ppm):11.69(s,1H),8.13(d,J=2.4Hz,1H),7.80(d,J=2.4Hz,1H),7.51(d,J=2.0Hz,1H),7.33(d,J=7.2Hz,2H),7.26(t,J=7.6Hz,2H),7.15(t,J=7.2Hz,1H),4.02(t,J=7.6Hz,1H),2.20–2.08(m,1H),2.05–1.92(m,1H),0.85(t,J=7.6Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):147.40,145.59,140.85,128.71,128.12,126.39,126.36,124.84,122.13,120.27,117.90,44.11,28.41,13.05;HRMS(ESI)Calcd forC16H16ClN2(MH+)271.0997,found271.1001.
32a:1HNMR(400MHz,DMSO)δ(ppm):11.90(s,1H),7.98(d,J=2.8Hz,1H),7.54(s,1H),7.39–7.01(m,6H),4.61(s,1H),2.21–2.03(m,,H),2.03–1.87(m,1H),0.88(s,3H);13CNMR(100MHz,DMSO)δ(ppm):149.44,145.95,143.14,128.54,128.50,126.19,125.09,123.63,119.87,118.21,117.99,43.52,30.48,13.39;HRMS(ESI)Calcd for C16H16BrN2(MH+)315.0491,found315.0504.
33a:1HNMR(400MHz,DMSO)δ(ppm):11.69(s,1H),7.68(d,J=8.4Hz,1H),7.43(d,J=2.4Hz,1H),7.35–7.21(m,4H),7.17–7.07(m,2H),4.02(t,J=7.6Hz,1H),2.20–2.08(m,1H),2.05–1.92(m,1H),0.85(t,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):148.36,145.60,133.84,130.36,128.69,128.09,126.38,123.22,118.48,118.38,44.34,28.39,13.04;HRMS(ESI)Calcd for C16H16BrN2(MH+)315.0491,found315.0493.
34a:1HNMR(400MHz,DMSO)δ(ppm):11.39(s,1H),7.98(s,1H),7.69–7.28(m,3H),7.00(s,1H),5.10(q,J=7.2Hz,1H),2.21(s,3H),1.78(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):147.78,143.60,142.00,129.93,126.08,124.43,123.64,118.79,116.33,116.10,113.62,34.21,18.67,16.52;HRMS(ESI)Calcd for C16H14Cl2FN2(MH+)323.0513,found323.0518.
35a:1HNMR(400MHz,DMSO)δ(ppm):11.40(s,1H),7.92(d,J=2.8Hz,1H),7.65–7.31(m,3H),6.71(d,J=2.4Hz,1H),5.10(q,J=7.2Hz,1H),3.63(s,3H),1.80(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):158.47,150.46,144.62,141.86,132.33,129.98,125.33,122.22,118.77,116.37,116.14,113.64,109.50,56.13,34.23,16.38;HRMS(ESI)Calcdfor C16H14Cl2FN2O(MH+)339.0462,found339.0450.
36a:1HNMR(400MHz,DMSO)δ(ppm):11.99(s,1H),7.98(d,J=4.8Hz,1H),7.54(s,1H),7.49–7.36(m,1H),7.32(t,J=8.8Hz,1H),7.18(d,J=5.2Hz,1H),5.25(q,J=7.2Hz,1H),1.74(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):158.35,155.91,149.63,143.14,130.64,130.14,127.42,122.92,119.78,118.32,115.89,115.66,114.78,34.61,18.44;HRMS(ESI)Calcd for C15H11BrCl2FN2(MH+)386.9461,found386.9462.
37a:1HNMR(400MHz,DMSO)δ(ppm):11.82(s,1H),7.62–7.43(m,2H),7.39(t,J=8.4Hz,1H),7.13–7.03(m,2H),5.11(q,J=6.8Hz,1H),1.79(d,J=6.8Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):148.33,141.65,133.79,129.91,129.22,124.87,122.29,122.11,118.69,117.96,116.56,116.33,115.03,34.13,16.39;HRMS(ESI)Calcd for C15H11BrCl2FN2(MH+)386.9461,found386.9447.
38a:1HNMR(400MHz,DMSO)δ(ppm):11.31(s,1H),8.19(d,J=2.0Hz,1H),7.93(d,J=2.0Hz,1H),7.55(d,J=1.2Hz,1H),7.42(s,1H),7.31(t,J=8.8Hz,1H),5.21(q,J=7.2Hz,1H),1.80(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):158.25,155.81,143.41,142.50,142.41,,129.91,128.71,122.30,120.95,116.34,115.79,115.56,112.38,33.25,16.86;HRMS(ESI)Calcd for C15H11BrCl2FN2(MH+)386.9461,found386.9464.
39a:1HNMR(400MHz,DMSO)δ(ppm):11.23(s,1H),8.34(d,J=2.0Hz,1H),7.93(d,J=2.0Hz,1H),7.52(d,J=2.4Hz,1H),7.38(d,J=7.2Hz,2H),7.24(t,J=7.6Hz,2H),7.12(t,J=7.6Hz,1H),4.15(t,J=7.6Hz,1H),2.33–2.18(m,1H),2.10–1.94(m,1H),0.83(t,J=7.6Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):146.11,143.60,142.41,129.95,128.54,128.18,127.57,126.12,120.96,119.54,112.35,43.66,28.90,13.34;HRMS(ESI)Calcd forC16H16BrN2(MH+)315.0491,found315.0496.
40a:1HNMR(400MHz,DMSO)δ(ppm):11.26(s,1H),8.03(dd,J=4.8Hz,1.6Hz1H),7.81(d,J=7.6Hz,1H),7.34(d,J=7.2Hz,2H),7.24(t,J=7.6Hz,2H),7.12(t,J=7.2Hz,1H),6.89(dd,J=8.0Hz,4.8Hz,1H),4.04(dd,J=7.2and8.8,Hz,1H),2.39(s,3H),2.26–2.08(m,2H),0.84(t,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):148.41,146.04,141.21,133.17,128.59,127.86,126.66,126.01,119.75,115.11,112.13,43.80,27.17,13.35,12.19;HRMS(ESI)Calcd for C17H19N2(MH+)251.1543,found251.1538.
41a:1HNMR(400MHz,DMSO)δ(ppm):11.34(s,1H),8.04(dd,J=4.8Hz,1.6Hz,1H),7.69(d,J=7.2Hz,1H),7.49(dd,J=8.8Hz,5.2Hz,1H),7.34(t,J=8.8Hz,1H),6.93(dd,J=7.6Hz,4.8Hz,1H),5.18(q,J=7.2Hz,1H),2.21(s,3H),1.85(d,J=7.6Hz,3H).13CNMR(100MHz,DMSO)δ(ppm):158.43,155.98,147.79,143.07,141.16,134.11,130.52,129.55,126.56,121.37,116.01,115.42,108.80,35.41,17.36,12.96;HRMS(ESI)Calcd forC16H14Cl2FN2(MH+)323.0513,found323.0515.
42a:1HNMR(400MHz,DMSO)δ(ppm):11.37(s,1H),8.66(s,1H),7.96(d,J=5.6Hz,1H),7.52(d,J=2.0Hz,1H),7.36–7.29(m,3H),7.28–7.21(m,2H),7.17–7.10(m,1H),4.03(t,J=7.6Hz,1H),2.23–2.10(m,1H),2.09–1.95(m,1H),0.86(t,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):145.86,137.30,134.66,134.00,131.25,128.66,128.11,126.47,126.28,118.81,114.03,44.23,28.74,13.13;HRMS(ESI)Calcd for C16H17N2(MH+)237.1386,found237.1383.
43a:1HNMR(400MHz,DMSO)δ(ppm):11.51(s,1H),8.69(s,1H),7.91(d,J=5.6Hz,1H),7.65-7.43(m,2H),7.39(t,J=8.8Hz,1H),6.78(d,J=5.6Hz,1H),5.14(q,J=7.2Hz,1H),1.82(d,J=7.2Hz,3H).13CNMR(101MHz,DMSO)δ(ppm):141.90,137.76,134.98,133.95,130.67,129.92,127.96,116.41,116.18,115.28,112.97,33.97,16.68;HRMS(ESI)Calcdfor C15H12Cl2FN2(MH+)309.0356,found309.0349.
44a:1HNMR(400MHz,DMSO)δ(ppm):11.31(s,1H),8.63(s,1H),8.08(d,J=5.6Hz,1H),7.39–7.31(m,3H),7.31–7.23(m,3H),7.15(t,J=7.2Hz,1H),4.10(t,J=7.6Hz,1H),2.26–2.11(m,1H),2.10–1.93(m,1H),0.87(t,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):145.94,142.35,140.26,140.14,128.67,128.15,126.32,124.06,123.13,119.22,107.19,44.27,28.70,13.13;HRMS(ESI)Calcd for C16H17N2(MH+)237.1386,found237.1385.
45a:1HNMR(400MHz,DMSO)δ(ppm):11.45(s,1H),8.08(d,J=5.6Hz,2H),7.65–7.36(m,3H),7.34(d,J=5.6Hz,1H),5.19(q,J=7.2Hz,1H),1.82(d,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):142.10,141.05,140.28,140.12,129.96,125.05,123.83,116.50,116.27,115.76,107.46,34.10,16.67;HRMS(ESI)Calcd for C15H12Cl2FN2(MH+)309.0356,found309.0356.
46a:1HNMR(400MHz,DMSO)δ(ppm):11.05(s,1H),8.28(dd,J=4.8Hz,1.6Hz,1H),7.68(dd,J=8.0Hz,1.6Hz,1H),7.46(d,J=2.8Hz,1H),7.44–7.39(m,2H),7.27-7.21(m,2H),7.11(t,J=7.2Hz,1H),7.05(dd,J=8.4Hz,4.8Hz,1H),4.19(t,J=8.0Hz,1H),2.35–2.23(m,1H),2.11-1.96(m,1H),0.84(t,J=7.2Hz,3H);13CNMR(100MHz,DMSO)δ(ppm):146.51,144.96,142.05,129.22,128.48,128.25,126.08,126.00,119.32,118.61,116.58,43.84,29.00,13.43;HRMS(ESI)Calcd for C16H17N2(MH+)237.1386,found237.1384.
47a:1HNMR(400MHz,DMSO)δ(ppm):11.12(s,1H),8.13(dd,J=4.8Hz,1.6Hz,1H),7.68(dd,J=8.4Hz,1.6Hz,1H),7.53–7.34(m,2H),7.30(t,J=8.8Hz,1H),7.00(dd,J=8.0Hz4.4Hz,1H),5.25(q,J=7.2Hz,1H),1.82(d,J=7.2Hz,3H);13CNMR(101MHz,DMSO)δ(ppm):158.25,155.82,144.83,142.77,142.16,129.15,127.27,122.37,122.19,116.51,115.99,115.65,115.42,33.38,16.95;HRMS(ESI)Calcd for C15H11Cl2FN2(MH+)309.0356,found309.0354.
部分产物的产率如式9:
本发明应用傅克烷基化反应在氮杂吲哚类化合物的3位直接引入苯基取代物最后获得了成功,并且发现此方法具有很强的适用性以及广泛性,一步反应就可以完成,精简了合成步骤,节省了成本,对大规模的合成有重要意义,后处理也快捷方便,能够获得较高产率的化合物,是一种全新的方法。
合成的氮杂吲哚类衍生物是一类未见报道的新化合物,均为全新的结构,对构建具有药理活性的抗癌小分子化合物有着非同寻常的意义。
生物实验部分
7-氮杂吲哚类衍生物具有各种良好的生物活性,如具有抗肿瘤作用,抗炎症作用,例如下面的结构表现了很好的生理活性:
Claims (5)
1.一种氮杂吲哚类衍生物的合成方法,其特征在于:反应条件如下:
以下式所示的氮杂吲哚类化合物A与苄基醇B通过反应合成氮杂吲哚类衍生物C,反应式如下:
上述反应使用的催化剂为三氟甲磺酸;催化剂当量为2-4eq;以二氯甲烷、氯仿、1,2-二氯乙烷、三氟乙酸、乙酸乙酯作溶剂;苄基醇B当量为2-4eq;氮杂吲哚类化合物A的反应浓度0.05-1mol/L;在20℃~25℃条件下反应1~8h,所述当量为该物质与氮杂吲哚类化合物A的摩尔比;
A1为苯基,所述A1中的任意基团各自独立地被一个或多个R14取代;R14选自:氢、卤素、C1-C12烷基;
R5选自:氢、卤素、C1-C10烷基;
R6选自:C1-C10烷基、C1-C10烷氧基;
R1和R3为氢;
R2选自:氢、卤素、三元至十二元饱和或不饱和杂环烷基;
所述R2可被一个或多个R7取代;
所述R7选自:卤素、C1-C12烷基、三元至十二元杂环烷基。
2.根据权利要求1所述的氮杂吲哚类衍生物的合成方法,其特征在于:所述条件中采用2eq、3eq、4eq的三氟甲磺酸作催化剂,以二氯甲烷、氯仿、二氯乙烷作溶剂,反应浓度为0.05mol/L、0.1mol/L、0.2mol/L、0.3mol/L、0.4mol/L、0.5mol/L或1mol/L,在20℃~25℃条件下反应1~8h。
3.根据权利要求1或2所述的氮杂吲哚类衍生物的合成方法,其特征在于:所述苄基醇的当量为2eq、3eq或4eq。
4.根据权利要求1或2所述的氮杂吲哚类衍生物的合成方法,其特征在于:具体操作步骤如下:
称取氮杂吲哚类化合物A置于烘干冷却的50ml两口反应瓶当中,加入溶剂,搅拌并确保其完全溶解,用注射器加入催化剂,反应液搅拌后,用注射器逐滴加入B,反应液变色;在20℃~25℃条件下反应1~8h,TLC检测反应完全后,反应液用饱和碳酸氢钠中和,用二氯甲烷萃取,合并有机相,有机相用饱和氯化钠溶液进行洗涤,无水硫酸钠进行干燥,目标产物用300目的硅胶柱层析进行纯化,得到目标产物氮杂吲哚类衍生物C。
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