CN111560017B - 一种基于氮杂双环[x，y，0]烷酮骨架的二肽模拟物及其制备方法 - Google Patents
一种基于氮杂双环[x，y，0]烷酮骨架的二肽模拟物及其制备方法 Download PDFInfo
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- AKKOHZZYMFFGAB-CFVMTHIKSA-N methyl (3S,6R,8aS)-6-(2-methylphenyl)-5-oxo-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carboxylate Chemical compound COC(=O)[C@@H]1CC[C@@H]2CC[C@@H](C(N12)=O)C1=C(C=CC=C1)C AKKOHZZYMFFGAB-CFVMTHIKSA-N 0.000 description 1
- YVZZAWNQVUBPGU-WOPDTQHZSA-N methyl (3S,6R,8aS)-6-(2-methylpropyl)-5-oxo-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carboxylate Chemical compound COC(=O)[C@@H]1CC[C@@H]2CC[C@@H](C(N12)=O)CC(C)C YVZZAWNQVUBPGU-WOPDTQHZSA-N 0.000 description 1
- SKNGTGRJOJZFMM-ZNMIVQPWSA-N methyl (3S,6R,8aS)-6-(3-methylphenyl)-5-oxo-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carboxylate Chemical compound COC(=O)[C@@H]1CC[C@@H]2CC[C@@H](C(N12)=O)C=1C=C(C=CC1)C SKNGTGRJOJZFMM-ZNMIVQPWSA-N 0.000 description 1
- YBNFDHJGPPREKQ-ZNMIVQPWSA-N methyl (3S,6R,8aS)-6-(4-cyanophenyl)-5-oxo-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carboxylate Chemical compound COC(=O)[C@@H]1CC[C@@H]2CC[C@@H](C(N12)=O)C1=CC=C(C=C1)C#N YBNFDHJGPPREKQ-ZNMIVQPWSA-N 0.000 description 1
- QCFVWCAXHQPLAO-ZNMIVQPWSA-N methyl (3S,6R,8aS)-6-(4-methylphenyl)-5-oxo-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carboxylate Chemical compound COC(=O)[C@@H]1CC[C@@H]2CC[C@@H](C(N12)=O)C1=CC=C(C=C1)C QCFVWCAXHQPLAO-ZNMIVQPWSA-N 0.000 description 1
- QFBKLDXMDWUJIO-DCAQKATOSA-N methyl (3S,6S,8aS)-5-oxo-6-propyl-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carboxylate Chemical compound O=C1N2[C@@H](CC[C@@H]2CC[C@@H]1CCC)C(=O)OC QFBKLDXMDWUJIO-DCAQKATOSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
本发明公开了一种基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物及其制备方法，该二肽模拟物具有如下结构：
其中，n＝1‑4；R1为氨基、烷胺基、取代的烷胺基、氮原子取代或非取代的烷基酰胺基、氮原子取代或非取代的芳基酰胺基、氮原子取代或非取代的杂芳基酰胺基、氮原子取代或非取代的烷氧基酰胺基、羟基、取代的烷氧基、取代的烷基、取代的芳基或取代的杂环芳基；X为O或NR3；R2和R3为氢原子、取代或非取代的烷基、取代或非取代的环烷基、取代或非取代的芳基、取代或非取代的杂芳基；所述取代基均指烷基、环烷基、芳基或杂环芳基，并提供该二肽模拟物的制备方法，本发明的二肽模拟物代谢稳定性好、生物利用度高、透膜能力强，制备方法路线较短、效率较高且具有通用性。
Description
技术领域
本发明涉及一种二肽模拟物及其制备方法，尤其涉及一种基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物及其制备方法。
背景技术
在过去的几十年里，多肽因其广泛的药理活性在新药研发中受到越来越多的关注。多肽中很多是重要的信号分子，可以与细胞膜上及细胞内的多种受体结合，产生相应的生理功能，也有很多可以用于蛋白-蛋白相互作用的研究中，因此多肽可以作为很多新药研发中的先导化合物。多肽存在固有的内在缺陷，如代谢稳定性差、生物利用度低、透膜能力差等，而且很多多肽的溶解度不理想，因此采用不同的方法对多肽进行结构改造，克服上述缺陷是以多肽为先导的药物研发中的常用方法。在对多肽的优化与改造中，用构象限制的拟肽替换多肽中的部分片段是一种已被广泛证实的有效策略。氮杂双环 [X.Y.0]烷酮氨基酸衍生物是一类研究的比较深入模拟二肽的拟肽。这类化合物中含有一个刚性的双环结构，在双环的多个位置可以引入取代基，可以通过改变手性中心的构型模拟特定的多肽构象并控制取代基的取向。最初设计这类化合物是作为模拟β转角的拟肽，但随后的应用已不限于模拟β转角。通过改变环的大小和手性中心的构型，可以设计多种具有不同结构的衍生物。做为模拟二肽的拟肽，吲哚嗪-2-酮氨基酸和吡咯氮卓-2- 酮氨基酸衍生物已经在多个新药研发项目，如ACE和NEP抑制剂，凝血酶抑制剂，半胱天冬酶(caspases)抑制剂，法尼基转移酶抑制剂，Smac模拟物，前列腺素F2α变构调节剂，整合素受体配体，ORL1拮抗剂，丙型肝炎病毒抑制剂等的研发中得到了广泛的应用。因为这类拟肽在新药研发中的广泛用途，发展新的有效的合成方法在新药研发方面有重要意义。目前报道的氮杂双环[X.Y.0]烷酮氨基酸衍生物的合成方法存在路线较长，收率较低的缺点。
发明内容
发明目的：本发明的第一目的为提供一种代谢稳定性好、生物利用度高、透膜能力强的基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物，本发明的第二目的为提供路线较短、效率较高且具有通用性的基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法。
技术方案：本发明的基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物，具有如下结构：
其中，n＝1-4；R1为氨基、烷胺基、取代的烷胺基、氮原子取代或非取代的烷基酰胺基、氮原子取代或非取代的芳基酰胺基、氮原子取代或非取代的杂芳基酰胺基、氮原子取代或非取代的烷氧基酰胺基、羟基、取代的烷氧基、取代的烷基、取代的芳基或取代的杂环芳基；X为O或NR3；R2和R3为氢原子、取代或非取代的烷基、取代或非取代的环烷基、取代或非取代的芳基、取代或非取代的杂芳基；取代基均指烷基、环烷基、芳基或杂环芳基。
本发明的基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法，包括如下步骤：
化合物1通过RCM反应生成化合物2；
化合物2与卤素、拟卤素或卤素替代物的加成再消除生成化合物3；
化合物3通过过渡金属催化的偶联反应引入R1生成化合物4；
氢化还原化合物4中的双键得到全顺式异构体化合物5，化合物5为基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物；
其中，n＝1-4；R1为氨基、烷胺基、取代的烷胺基、氮原子取代或非取代的烷基酰胺基、氮原子取代或非取代的芳基酰胺基、氮原子取代或非取代的杂芳基酰胺基、氮原子取代或非取代的烷氧基酰胺基、羟基、取代的烷氧基、取代的烷基、取代的芳基或取代的杂环芳基；X为O或NR3；R2和R3为氢原子、取代或非取代的烷基、取代或非取代的环烷基、取代或非取代的芳基、取代或非取代的杂芳基；取代基均指烷基、环烷基、芳基或杂环芳基。
有益效果：与现有技术相比，本发明具有如下显著优点：二肽模拟物谢稳定性好、生物利用度高、透膜能力强且溶解度高；合成步骤较短，合成操作简便，可以很方便地通过偶联引入不同的取代基，易于进行底物拓展。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1
(3S，8aR)-5-氧-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(2S，5R)-1-丙烯酰基-5-烯丙基吡咯烷-2-羧酸甲酯(16.67g，74.66mmol,1.0eq)溶于无水甲苯中(400ml)，氮气保护,加入催化量的Grubbs二代催化剂，回流反应24h。TLC监测反应完全后，浓缩反应液，硅胶柱层析分离(PE:EA＝2:1)得无色油状物(12.40g，收率85.1％)。1H NMR(300MHz,CDCl3):δ6.13(m,1H),5.35(m,1H), 3.94(m,1H),3.42(m,1H),3.18(s,3H),2.07(m,1H),1.82-1.49(m,4H),1.26(m,1H)； ESI-MS m/z calc’d for C16H17NO3[M+Na]+294.1,found 294.3.
实施例2
(3S，8aR)-6-溴-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-5-氧-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(3.09g,15.83mmol,1.0 eq)溶于DCM中(100ml)，0℃下缓慢滴加液溴(3.04g,18.99mmol,1.2eq)的DCM 溶液(0.5M)，室温反应3h。TLC监测反应完全后，将反应液移至冰浴中，缓慢滴加 DIPEA(4.09g,31.66mmol，2.0eq)，室温反应过夜。TLC监测反应完全后，浓缩反应液，硅胶柱层析分离(PE:EA＝2:1)得白色固体(3.53g，收率81.3％)。1H NMR(300MHz, CDCl3):δ6.96(m,1H),4.56(m,1H),3.91(m,1H),3.73(s,3H),2.60-1.80(m,6H)；13C NMR(75MHz,CDCl3):δ171.8,158.2,140.5,118.5,57.9,56.9,52.2,32.1,31.3,28.5.
实施例3
(3S，8aR)-6-(((叔丁氧羰基)氨基)-5-甲基-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-溴-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(0.10g，0.36 mmol，1.0eq)置于封管中，再加入氨基甲酸叔丁酯(127mg,1.08mmol,3eq),三(二亚苄基丙酮)二钯(17mg,5％eq.)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(21mg,10％eq.)，碳酸铯(0.18g,0.56mmol,1.5eq)，溶于甲苯(4mL)中，氮气保护条件下，110℃反应24h。 TLC监测反应完全后冷却至室温，反应液用水稀释，EA萃取三次。合并有机相，有机相用饱和NaCl水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(PE:EA＝2:1) 得白色固体(88mg，收率77.7％)。1H NMR(300MHz,CDCl3):δ7.21(s,1H),6.82(m, 1H),4.56(m,1H),3.82(m,1H),3.75(s,3H),2.61-2.11(m,5H),1.80(m,1H),1.46(s,9H)；13C NMR(75MHz,CDCl3):δ172.1,160.5,153.0,128.5,113.8,80.3,57.6,57.1,52.5,31.6, 29.0,28.6,28.3.
实施例4
(3S，6S，8aS)-6-(((叔丁氧羰基)氨基)甲基-5-氧代八氢吲哚-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-(((叔丁氧羰基)氨基)-5-甲基-1,2,3,5,8,8a-六氢吲哚嗪-3- 羧酸甲酯(88mg)溶于甲醇中，加入5％钯碳(8.8mg)，通入氢气室温反应2h。TLC 监测反应完全后，硅藻土过滤，滤液浓缩得白色固体(79mg，收率90.0％)。1H NMR(300 MHz,CDCl3):δ5.59(s,1H),4.57(m,1H),4.24(m,1H),3.79-3.72(m,4H),2.48(m,1H), 2.31-2.10(m,4H),1.83-1.69(m,3H),1.49(s,9H)；13C NMR(75MHz,CDCl3):δ172.1, 169.7,155.9,79.9,58.3,56.8,52.5,49.9,32.1,29.1,28.3,27.1,26.8；ESI-MS m/z calc’d for C15H24N2O5[M+H]+313.18,found 313.25.
实施例5
(3S，8aR)-5-氧代-6-苯基-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-溴-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(0.10g，0.36mmol，1.0eq)置于封管中，再加入四(三苯基膦)钯(21mg,0.018mmol,5％eq)，苯硼酸(38mg，0.36mmol，1.0eq)，碳酸铯(0.24g,0.73mmol，2.0eq)，溶于二氧六环(4mL)和水(1mL)的混合溶液中，氮气保护条件下，100℃反应12h。TLC监测反应完全后冷却至室温，反应液用水稀释，EA萃取三次。合并有机相，有机相用饱和NaCl 水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(PE:EA＝2:1)得白色固体(85mg，收率85.9％)。1H NMR(300MHz,CDCl3):δ7.48-7.44(m,2H),7.34-7.23(m,3H),6.71(m, 1H),4.59(m,1H),3.90(m,1H),3.73(s,3H),2.68-2.45(m,2H),2.25-2.06(m,3H),1.90(m, 1H)；13C NMR(75MHz,CDCl3):δ172.8,163.2,136.5,136.1,135.8,128.5,127.9,127.7, 57.8,56.8,52.4,32.0,30.8,28.6.
实施例6
(3S，6R，8aS)-5-氧代-6-苯基八氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-5-氧代-6-苯基-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(85mg)溶于甲醇中，加入5％钯碳(8.5mg)，通入氢气室温反应1h。TLC监测反应完全后，硅藻土过滤，滤液浓缩得白色固体(77mg，收率90.0％)。1H NMR(300MHz,CDCl3):δ 7.32-7.19(m,5H),4.52(m,1H),3.86(m,1H),3.76(s,3H),3.63(m,1H),2.22-1.76(m,8H)；13C NMR(75MHz,CDCl3):δ172.3,171.5,142.6,128.6,128.4,126.7,61.0,58.4,52.4,45.8, 31.6,30.7,28.2,24.3；ESI-MS m/z calc’d for C16H19NO3[M+H]+274.14,found 274.25.
实施例7
(3S，8aR)-5-氧代-6-(邻甲苯基)-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-溴-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(0.10g，0.36 mmol，1.0eq)置于封管中，再加入四(三苯基膦)钯(21mg,0.018mmol,5％eq)，邻甲基苯硼酸(49mg，0.36mmol，1.0eq)，碳酸铯(0.24g,0.73mmol，2.0eq)，溶于二氧六环(4mL)和水(1mL)的混合溶液中，氮气保护条件下，100℃反应12h。TLC监测反应完全后冷却至室温，反应液用水稀释，EA萃取三次。合并有机相，有机相用饱和NaCl水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(PE:EA＝2:1)得白色固体(55mg，收率52.9％)。1H NMR(300MHz,CDCl3):δ7.22-7.12(m,4H),6.52(m,1H), 4.59(m,1H),3.98(m,1H),3.72(s,3H),2.68-2.48(m,2H),2.27(m,1H),2.21(s,3H),2.13 (m,1H),2.00-1.71(m,2H).
实施例8
(3S，6R，8aS)-5-氧代-6-(邻甲苯基)八氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-5-氧代-6-(邻甲苯基)-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(55 mg)溶于甲醇中，加入5％钯碳(5.5mg)，通入氢气室温反应1h。TLC监测反应完全后，硅藻土过滤，滤液浓缩得白色固体(49mg，收率90.0％)。1H NMR(300MHz,CDCl3): δ7.34(m,1H),7.21-7.13(m,3H),4.55(m,1H),4.07(m,1H),3.78(s,3H),3.65(m,1H), 2.31(s,3H),2.25-2.06(m,4H),2.01-1.71(m,4H)；13C NMR(75MHz,CDCl3):δ 172.6, 172.1,140.7,135.5,130.5,128.0,126.9,126.2,61.2,58.6,52.5,41.9,31.6,28.8,28.2,24.2, 19.4；ESI-MS m/z calc’d for C17H21NO3[M+H]+288.16,found 288.25.
实施例9
(3S，8aR)-5-氧代-6-(间甲苯基)-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-溴-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(0.10g，0.36 mmol，1.0eq)置于封管中，再加入四(三苯基膦)钯(21mg,0.018mmol,5％eq)，间甲基苯硼酸(49mg，0.36mmol，1.0eq)，碳酸铯(0.24g,0.73mmol，2.0eq)，溶于二氧六环(4mL)和水(1mL)的混合溶液中，氮气保护条件下，100℃反应12h。TLC监测反应完全后冷却至室温，反应液用水稀释，EA萃取三次。合并有机相，有机相用饱和NaCl水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(PE:EA＝2:1)得白色固体(80mg，收率76.9％)。1H NMR(300MHz,CDCl3):δ 7.30(m,1H),7.24-7.08(m,3H), 6.71(m,1H),4.60(m,1H),3.93(m,1H),3.73(s,3H),2.65-2.42(m,2H),2.34(s,3H), 2.26-2.09(m,3H),1.94(m,1H).
实施例10
(3S，6R，8aS)-5-氧代-6-(间甲苯基)八氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-5-氧代-6-(间甲苯基)-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(80 mg)溶于甲醇中，加入5％钯碳(8.0mg)，通入氢气室温反应1h。TLC监测反应完全后，硅藻土过滤，滤液浓缩得白色固体(72mg，收率90.0％)。1H NMR(300MHz,CDCl3): δ 7.23-6.99(m,4H),4.53(m,1H),3.84(m,1H),3.76(s,3H),3.63(m,1H),2.33(s,3H), 2.21-1.75(m,8H)；13C NMR(75MHz,CDCl3):δ172.2,171.8,142.4,138.1,129.2,128.4, 127.4,125.3,61.0,58.4,52.4,45.7,31.6,30.6,28.2,24.4,21.4；ESI-MS m/z calc’d for C17H21NO3[M+H]+288.16,found 288.25.
实施例11
(3S，8aR)-5-氧代-6-(对甲苯基)-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-溴-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(0.10g，0.36 mmol，1.0eq)置于封管中，再加入四(三苯基膦)钯(21mg,0.018mmol,5％eq)，对甲基苯硼酸(49mg，0.36mmol，1.0eq)，碳酸铯(0.24g,0.73mmol，2.0eq)，溶于二氧六环(4mL)和水(1mL)的混合溶液中，氮气保护条件下，100℃反应12h。TLC监测反应完全后冷却至室温，反应液用水稀释，EA萃取三次。合并有机相，有机相用饱和NaCl水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(PE:EA＝2:1)得白色固体(100mg，收率96.1％)。1H NMR(300MHz,CDCl3):δ7.38-7.34(m,2H),7.14-7.11(m, 2H),6.68(m,1H),4.60(m,1H),3.91(m,1H),3.73(s,3H),2.67-2.45(m,2H),2.33(s,3H), 2.26-2.10(m,3H),1.92(m,1H).
实施例12
(3S，6R，8aS)-5-氧代-6-(对甲苯基)八氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-5-氧代-6-(对甲苯基)-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(100 mg)溶于甲醇中，加入5％钯碳(10.0mg)，通入氢气室温反应1h。TLC监测反应完全后，硅藻土过滤，滤液浓缩得白色固体(90mg，收率90.0％)。1H NMR(300MHz,CDCl3): δ7.20-7.09(m,4H),4.54(m,1H),3.87(m,1H),3.76(s,3H),3.64(m,1H),2.31(s,3H), 2.23-2.04(m,4H),2.00-1.74(m,4H)；13C NMR(75MHz,CDCl3):δ172.4,172.1,139.3, 136.4,129.3,128.2,61.2,58.5,52.5,45.2,31.6,30.6,28.2,24.2,21.0；ESI-MS m/z calc’d forC17H21NO3[M+H]+288.16,found 288.25.
实施例13
(3S，8aR)-6-(4-氰基苯基)-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-溴-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(0.10g，0.36 mmol，1.0eq)置于封管中，再加入四(三苯基膦)钯(21mg,0.018mmol,5％eq)，对氰基苯硼酸(64mg，0.43mmol，1.2eq)，碳酸铯(0.24g,0.73mmol，2.0eq)，溶于二氧六环(4mL)和水(1mL)的混合溶液中，氮气保护条件下，100℃反应12h。TLC监测反应完全后冷却至室温，反应液用水稀释，EA萃取三次。合并有机相，有机相用饱和NaCl水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(PE:EA＝2:1)得白色固体(98mg，收率90.7％)。1H NMR(300MHz,CDCl3):δ7.63-7.53(m,4H),6.86(m,1H), 4.65(m,1H),3.96(m,1H),3.74(s,3H),2.74(m,1H),2.57(m,1H),2.31-2.17(m,3H),1.92 (m,1H).
实施例14
(3S，6R，8aS)-6-(4-氰基苯基)-5-氧代八氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-(4-氰基苯基)-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯 (98mg)溶于甲醇中，加入5％钯碳(9.8mg)，通入氢气室温反应2h。TLC监测反应完全后，硅藻土过滤，滤液浓缩得白色固体(88mg，收率90.0％)。1H NMR(300MHz, CDCl3):δ7.63(d,J＝9.00Hz,2H),7.47(d,J＝9.00Hz,2H),4.56(m,1H),3.97(m,1H), 3.77(s,3H),3.67(m,1H),2.29-1.88(m,7H),1.66(m,1H)；13C NMR(75MHz,CDCl3):δ 172.1,170.6,147.8,132.4,129.3,118.8,110.7,61.1,58.5,52.6,45.7,31.4,30.3,28.1,24.2； ESI-MS m/z calc’dfor C17H18N2O3[M+H]+299.14,found 299.20.
实施例15
(3S，8aR)-6-(2-甲基丙-1-烯-1-基)-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-溴-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(0.10g，0.36 mmol，1.0eq)置于封管中，再加入四(三苯基膦)钯(21mg,0.018mmol,5％eq)，2，2- 二甲基乙烯基硼酸(36mg，0.36mmol，1.0eq)，碳酸铯(0.24g,0.73mmol，2.0eq)，溶于二氧六环(4mL)和水(1mL)的混合溶液中，氮气保护条件下，100℃反应12h。 TLC监测反应完全后冷却至室温，反应液用水稀释，EA萃取三次。合并有机相，有机相用饱和NaCl水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(PE:EA＝2:1)得白色固体(71mg，收率78.1％)。1H NMR(300MHz,CDCl3):δ6.36(m,1H),6.07(m,1H), 4.56(m,1H),3.83(m,1H),3.75(s,3H),2.63-2.45(m,2H),2.22-2.10(m,3H),1.92(m,1H), 1.85(s,3H),1.78(s,3H),；13C NMR(75MHz,CDCl3):δ172.8,164.0,137.2,134.9,133.0, 119.2,57.5,56.7,52.3,31.9,30.8,28.5,26.8,19.8.
实施例16
(3S，6R，8aS)-6-异丁基-5-氧代八氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-(2-甲基丙-1-烯-1-基)-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(71mg)溶于甲醇中，加入5％钯碳(7.1mg)，通入氢气室温反应2h。TLC监测反应完全后，硅藻土过滤，滤液浓缩得白色固体(64mg，收率90.0％)。1H NMR(300 MHz,CDCl3):δ4.43(m,1H),3.72(s,3H),3.54(m,1H),2.35(m,1H),2.09-1.63(m,11H), 0.93(d,J＝6Hz,3H),0.89(d,J＝6Hz,3H)；13C NMR(75MHz,CDCl3):δ173.4,172.7, 59.4,58.0,52.2,40.6,37.6,31.8,28.2,25.5,25.4,23.4,21.5；ESI-MS m/z calc’d for C14H23NO3[M+H]+254.18,found 254.25.
实施例17
(3S，8aR)-5-氧代-6-丙基-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-6-溴-5-氧代-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(0.10g，0.36 mmol，1.0eq)置于封管中，再加入四(三苯基膦)钯(21mg,0.018mmol,5％eq)，丙基硼酸(38mg，0.43mmol，1.2eq)，碳酸铯(0.24g,0.73mmol，2.0eq)，溶于二氧六环 (4mL)和水(1mL)的混合溶液中，氮气保护条件下，100℃反应12h。TLC监测反应完全后冷却至室温，反应液用水稀释，EA萃取三次。合并有机相，有机相用饱和NaCl 水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(PE:EA＝2:1)得白色固体(62mg，收率71.6％)。1H NMR(300MHz,CDCl3):δ6.25(m,1H),4.55(m,1H),3.75-3.72(m,4H), 2.41-2.33(m,3H),2.18-2.07(m,4H),1.82(m,1H),1.49-1.40(m,2H),0.93-0.88(m,3H).
实施例18
(3S，6S，8aS)-5-氧代-6-丙基八氢吲哚嗪-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，8aR)-5-氧代-6-丙基-1,2,3,5,8,8a-六氢吲哚嗪-3-羧酸甲酯(62mg)溶于甲醇中，加入5％钯碳(6.2mg)，通入氢气室温反应2h。TLC监测反应完全后，硅藻土过滤，滤液浓缩得白色固体(56mg，收率90.0％)。1H NMR(400MHz,CDCl3):δ 4.46(m, 1H),3.72(s,3H),3.55(m,1H),2.36(m,1H),2.14-1.95(m,4H),1.89-1.70(m,4H), 1.63-1.34(m,4H),0.92(t,J＝8.00Hz,3H)；13C NMR(100MHz,CDCl3):δ173.7,172.4, 59.8,58.2,52.2,39.2,34.2,31.7,28.2,26.1,25.2,20.6,14.0；ESI-MS m/z calc’d for C13H21NO3[M+H]+240.16,found 240.20.
实施例19
(3S，9aS)-5-氧代-2,3,5,8,9,9a-六氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯的结构及制备方法如下：
将原料(2S，5S)-1-丙烯酰基-5-(3-丁烯基-1)吡咯烷-2-羧酸甲酯(10.07g,42.44mmol, 1.0eq)溶于无水甲苯(300ml)中，加入Grubbs二代催化剂(0.30g,0.03eq)，氮气保护，回流24h。TLC监测反应完全后，旋除溶剂，硅胶柱层析分离(PE:EA＝2:1)得黄色固体(5g，收率56.3％)。1H NMR(300MHz,CDCl3):δ6.29(m,1H),5.91(m,1H),4.59(m, 1H),3.94-3.66(m,4H),2.47-1.83(m,8H)；13C NMR(75MHz,CDCl3):δ172.7,165.6, 140.9,125.4,60.5,58.3,52.0,32.9,32.3,29.7,27.7.
实施例20
(3S)-6-溴-5-氧代-2,3,5,8,9,9a-六氢-1H-吡咯并[1,2-a]氮杂-3-羧酸酯的结构及制备方法如下：
将原料(3S，9aS)-5-氧代-2,3,5,8,9,9a-六氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯(5g, 23.90mmol,1.0eq)溶于DCM(100mL)中，0℃下缓慢滴加液溴(4.58g,28.67mmol,1.2eq)的DCM溶液(0.5M)，室温反应3h。TLC监测反应完全后，将反应液降至0℃，缓慢滴加DIPEA(6.18g,47.79mmol,2.0eq)室温反应过夜。TLC监测反应完全后，旋除溶剂，硅胶柱层析分离(PE:EA＝2:1)得黄色固体(5.46g，收率79.3％)。1H NMR(300MHz, CDCl3):δ6.91(m,1H),4.59(m,1H),3.89(m,1H),3.75(s,3H),2.58(m,1H),2.37-2.16(m, 3H),2.11-2.01(m,3H),1.88(m,1H)；13C NMR(75MHz,CDCl3):δ172.4,162.9,140.3, 118.5,60.7,58.0,52.4,35.2,31.0,28.1,27.5.
实施例21
(3S，9aS)-5-氧代-6-苯基-2,3,5,8,9,9a-六氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯的结构及制备方法如下：
将原料(3S)-6-溴-5-氧代-2,3,5,8,9,9a-六氢-1H-吡咯并[1,2-a]氮杂-3-羧酸酯(0.10g， 0.34mmol，1.0eq)置于封管中，再加入四(三苯基膦)钯(20mg,0.017mmol,5％eq)，苯硼酸(42mg，0.34mmol，1.0eq)，碳酸铯(0.22g,0.69mmol，2.0eq)，溶于二氧六环(4mL)和水(1mL)的混合溶液中，氮气保护条件下，100℃反应12h。TLC监测反应完全后冷却至室温，反应液用水稀释，EA萃取三次。合并有机相，有机相用饱和 NaCl水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(PE:EA＝2:1)得白色固体 (80mg，收率81.0％)。1H NMR(300MHz,CDCl3):δ7.54-7.51(m,2H),7.37-7.29(m,3H), 6.67(m,1H),4.60(m,1H),4.04(m,1H),3.81(s,3H),2.81(m,1H),2.45-2.31(m,2H), 2.23-2.04(m,4H),1.92(m,1H)；13CNMR(75MHz,CDCl3):δ173.0,168.1,139.4,137.3, 133.6,128.2,127.6,127.3,59.6,57.4,52.3,36.5,30.5,28.4,24.4.
实施例22
(3S，6R，9aS)-5-氧代-6-苯基八氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，9aS)-5-氧代-6-苯基-2,3,5,8,9,9a-六氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯(80mg)溶于甲醇中，加入5％钯碳(8.0mg)，通入氢气室温反应1h。TLC监测反应完全后，硅藻土过滤，滤液浓缩得白色固体(72mg，收率90.0％)。1H NMR(300MHz, CDCl3):δ7.39-7.32(m,2H),7.27(m,1H),7.16-7.12(m,2H),4.83(m,1H),4.28(m,1H), 3.78(s,3H),3.53(m,1H),2.46(m,1H),2.12-2.01(m,4H),1.79-1.68(m,5H)；13C NMR(75 MHz,CDCl3):δ175.9,172.4,136.2,129.0,126.7,126.6,61.5,58.7,52.5,51.1,34.1,32.9, 27.5,26.4,22.4；ESI-MS m/z calc’d for C17H21NO3[M+H]+288.16,found 288.25.
实施例23
(3S，9aS)-6-(2-甲基丙-1-烯-1-基)-5-氧代-2,3,5,8,9,9a-六氢-1H-吡咯并[1,2-a] 氮杂-3-羧酸甲酯的结构及制备方法如下：
将原料(3S)-6-溴-5-氧代-2,3,5,8,9,9a-六氢-1H-吡咯并[1,2-a]氮杂-3-羧酸酯(0.10g， 0.34mmol，1.0eq)置于封管中，再加入四(三苯基膦)钯(20mg,0.017mmol,5％eq)，2， 2-二甲基乙烯基硼酸(34mg，0.34mmol，1.0eq)，碳酸铯(0.22g,0.69mmol，2.0eq)，溶于二氧六环(4mL)和水(1mL)的混合溶液中，氮气保护条件下，100℃反应12h。 TLC监测反应完全后冷却至室温，反应液用水稀释，EA萃取三次。合并有机相，有机相用饱和NaCl水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离(PE:EA＝2:1)得白色固体(68mg，收率74.6％)。1H NMR(300MHz,CDCl3):δ6.18(m,1H),5.94(m,1H), 4.54(t,J＝7.5Hz,,1H),3.95(m,1H),3.79(s,3H),2.67(m,1H),2.32-1.98(m,7H),1.83(s, 3H),1.76(s,3H)；13C NMR(75MHz,CDCl3):δ173.0,168.6,136.6,136.0,134.3,121.9, 59.6,57.3,52.3,36.4,30.6,28.3,26.5,24.5,19.8.
实施例24
(3S，6R，9aS)-6-异丁基-5-氧代八氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯的结构及制备方法如下：
将原料(3S，9aS)-6-(2-甲基丙-1-烯-1-基)-5-氧代-2,3,5,8,9,9a-六氢-1H-吡咯并[1,2-a] 氮杂-3-羧酸甲酯(68mg)溶于甲醇中，加入5％钯碳(6.8mg)，通入氢气室温反应2h。 TLC监测反应完全后，硅藻土过滤，滤液浓缩得白色固体(61mg，收率90.0％)。1H NMR(300MHz,CDCl3):δ4.57(m,1H),3.91(m,1H),3.73(s,3H),2.38(m,1H),2.23(m,1H), 2.09-1.96(m,3H),1.86-1.73(m,4H),1.70-1.59(m,3H),1.44(m,1H),1.11(m,1H), 0.89-0.86(m,6H)；13C NMR(75MHz,CDCl3):δ175.5,173.3,60.2,58.7,52.1,42.6,41.2, 34.7,33.2,30.0,29.6,27.7,25.5,22.8,22.7；ESI-MS m/z calc’d for C15H25NO3[M+H]+ 268.19,found 268.25。
Claims (9)
1.一种基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法，所述二肽模拟物具有如下结构：
其中，n＝1-4；R1为氨基、烷胺基、取代的烷胺基、氮原子取代或非取代的烷基酰胺基、氮原子取代或非取代的芳基酰胺基、氮原子取代或非取代的杂芳基酰胺基、氮原子取代或非取代的烷氧基酰胺基、羟基、取代的烷氧基、取代的烷基、取代的芳基或取代的杂环芳基；X为O或NR3；R2和R3为氢原子、取代或非取代的烷基、取代或非取代的环烷基、取代或非取代的芳基、取代或非取代的杂芳基；所述取代基均指烷基、环烷基、芳基或杂环芳基；
其特征在于，所述制备方法包括如下步骤：
(1)化合物1通过RCM反应生成化合物2；
(2)化合物2与卤素、拟卤素或卤素替代物的加成再消除生成化合物3；
(3)化合物3通过过渡金属催化的偶联反应引入R1生成化合物4；
(4)氢化还原化合物4中的双键得到全顺式异构体化合物5，所述化合物5即为基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物。
2.根据权利要求1所述基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法，其特征在于，所述二肽模拟物为如下结构之一：
5a:(3S，6S，8aS)-6-(((叔丁氧羰基)氨基)甲基-5-氧代八氢吲哚-3-羧酸甲酯；
5b:(3S，6R，8aS)-5-氧代-6-苯基八氢吲哚嗪-3-羧酸甲酯；
5c:(3S，6R，8aS)-5-氧代-6-(邻甲苯基)八氢吲哚嗪-3-羧酸甲酯；
5d:(3S，6R，8aS)-5-氧代-6-(间甲苯基)八氢吲哚嗪-3-羧酸甲酯；
5e:(3S，6R，8aS)-5-氧代-6-(对甲苯基)八氢吲哚嗪-3-羧酸甲酯；
5f:(3S，6R，8aS)-5-氧代-6-(4-氰基苯基)八氢吲哚嗪-3-羧酸甲酯；
5g:(3S，6R，8aS)-5-氧代-6-异丁基八氢吲哚嗪-3-羧酸甲酯；
5h:(3S，6R，8aS)-5-氧代-6-丙基八氢吲哚嗪-3-羧酸甲酯；
5i:(3S，6R，8aS)-5-氧代-6-环丁基八氢吲哚嗪-3-羧酸甲酯；
5j:(3S，6R，8aS)-5-氧代-6-环戊基八氢吲哚嗪-3-羧酸甲酯；
5k:(3S，6R，8aS)-5-氧代-6-环己基八氢吲哚嗪-3-羧酸甲酯；
5l:(3S，6S，9aS)-6-氨基-5-氧代八氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯；
5m:(3S，6S，9aS)-6-((二叔丁氧羰基)氨基)-5-氧代八氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯；
5n:(3S，6S，9aS)-6-((叔丁氧羰基)氨基)-5-氧代八氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯；
5o:(3S，6R，9aS)-5-氧代-6-苯基八氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯；
5p:(3S，6R，9aS)-5-氧代-6-异丁基八氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯；
5q:(3S，6R，9aS)-5-氧代-6-环丁基八氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯；
5r:(3S，6R，9aS)-5-氧代-6-环戊基八氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯；
5s:(3S，6R，9aS)-5-氧代-6-环己基八氢-1H-吡咯并[1,2-a]氮杂-3-羧酸甲酯。
3.根据权利要求1所述基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法，其特征在于，步骤(1)的制备过程如下：将化合物1溶于溶剂中，在氮气保护下，加入催化剂，回流至反应完全后，浓缩、纯化。
4.根据权利要求3所述基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法，其特征在于：所述溶剂为无水甲苯，所述催化剂为Grubbs催化剂。
5.根据权利要求1所述基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法，其特征在于，步骤(2)的制备过程如下：将化合物2溶于溶剂中，-20℃-0℃下滴加卤素、拟卤素或卤素替代物溶液中的一种，反应完全后，将反应液移至冰浴中，滴加有机碱，反应完全后，浓缩、纯化。
6.根据权利要求5所述基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法，其特征在于：所述溶剂为DCM。
7.根据权利要求1所述基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法，其特征在于，步骤(3)的制备过程如下：在化合物3中加入用于偶联的试剂、催化剂、配体和碱，用氮气交换后加入溶剂，反应在氮气保护条件下进行，反应完全后将反应液稀释，萃取、干燥、浓缩及纯化。
8.根据权利要求7所述基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法，其特征在于：所述溶剂为DMF、DMSO、DME、DMA、1,4-二氧六环、乙腈、乙酸乙酯、1,2-二氯乙烷、氯仿、四氯化碳、甲苯、二甲苯、吡啶、四氢呋喃、正己烷、正庚烷、水、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇中的一种。
9.根据权利要求1所述基于氮杂双环[X，Y，0]烷酮骨架的二肽模拟物的制备方法，其特征在于，步骤(4)的制备过程如下：将化合物4溶于溶剂中，加入催化剂，通入氢气反应完全，滤除催化剂后滤液浓缩、纯化。
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