CN101190915A - 抗血栓的n-丁基-2,2-二甲基-4-氧代-四氢咪唑并吡啶并吲哚及其合成和应用 - Google Patents
抗血栓的n-丁基-2,2-二甲基-4-氧代-四氢咪唑并吡啶并吲哚及其合成和应用 Download PDFInfo
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- XKVHMRBXIJTLBM-JEDNCBNOSA-N methyl (2s)-2-amino-5-(diaminomethylideneamino)pentanoate;hydrochloride Chemical class Cl.COC(=O)[C@@H](N)CCCN=C(N)N XKVHMRBXIJTLBM-JEDNCBNOSA-N 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了通式I的化合物,其中,R为CH(CH3)CH2CH3、CH(CH3)2、CH2CH(CH3)2、CH3、H、CH2C6H5、CH2C6H4-OH-p、吲哚-5-基-CH2、咪唑-4-基-CH2-、CH2CH2SCH3、CH2COCH3、CH2CH2CO2CH3、CH2CH2CO2H、CH2OH、CH(OH)CH3、CH2CH2CH2NHC(NH)NH2、CH2CONH2、CH2CH2CONH2、CH2SH、CH2CH2CH2CH2NHCBz或CH2CH2CH2CH2NH2。该化合物具有良好的抗血栓活性。本发明还提供该化合物的制备方法。
Description
技术领域
本发明涉及具有抗血栓活性的N-(1’-取代羧乙-1’-基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚,及其合成和应用。
背景技术
血管栓塞性疾病对心脑血管疾病的高死亡率负最重要的责任。血栓形成是血管栓塞性疾病发病的最重要的病因。寻找抗血栓药物是新药研究的热点之一。
血栓形成通常有三种原因:其一,血管壁上的血脂块脱落而流入血液中;其二,血小板的聚集能力过强,血液中有血小板聚集成的小块;其三,血液对血小板的腺溶能力下降。其中,第二个原因是导致血栓形成的重要原因,因此寻求抗血小板聚集的药物非常重要。阿司匹林就是常见的抗血小板聚集的药物。
1,2,3,4-四氢-β-咔啉-3-S-羧酸是中药薤白中的一种成分,具有抗血小板聚集活性(姚新生等,中国药物化学杂志,1995,5,134)。
然而,1,2,3,4-四氢-β-咔啉-3-S-羧酸在极性溶剂和非极性溶剂中的溶解度都不是很到,导致其生物利用度低,进而影响治疗和使用效果。
为了改进1,2,3,4-四氢-β-咔啉-3-S-羧酸在极性溶剂和非极性溶剂中的低溶解度,本发明人在1,2,3,4-四氢-β-咔啉-3-S-羧酸中引入L-氨基酸,获得了一类咔啉羧酸衍生物抗血栓剂(参见,中国专利申请号:200410074204.6)。该发明的咔啉羧酸衍生物通过将氨基酸引入咔啉羧酸的侧链制备而成。试验证实,该咔啉羧酸衍生物溶解度高,具有很高的抗血栓活性及抗血小板聚集活性。
在1,2,3,4-四氢-β-咔啉-3-S-羧酸中引入L-氨基酸获得的抗血栓好处,也意味着防止引入的L-氨基酸在体内代谢对于保持获得的抗血栓好处具有重要性。掩蔽N-(1,2,3,4-四氢-β-咔啉-3-甲酰基)-氨基酸中的L-氨基酸的最直接的办法是使引入的L-氨基酸与1,2,3,4-四氢-β-咔啉环生成第四个环。
发明内容
本发明的目的在于提供以下通式I的化合物
(通式I)
其中,R为CH(CH3)CH2CH3、CH(CH3)2、CH2CH(CH3)2、CH3、H、CH2C6H5、CH2C6H4-OH-p、吲哚-5-基-CH2、咪唑-4-基-CH2-、CH2CH2SCH3、CH2COCH3、CH2CH2CO2CH3、CH2CH2CO2H、CH2OH、CH(OH)CH3、CH2CH2CH2NHC(NH)NH2、CH2CONH2、CH2CH2CONH2、CH2SH、CH2CH2CH2CH2NHCBz或CH2CH2CH2CH2NH2。
本发明的目的还在于提供上述通式I化合物的制备方法。
本发明的另一目的在于上述通式I化合物的用途。
以下对本发明进行详细说明。
本发明提供了以下通式I的N-(1’-取代羧乙-1’-基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚化合物
(通式I)
其中,R为CH(CH3)CH2CH3、CH(CH3)2、CH2CH(CH3)2、CH3、H、CH2C6H5、CH2C6H4-OH-p、吲哚-5-基-CH2、咪唑-4-基-CH2-、CH2CH2SCH3、CH2COCH3、CH2CH2CO2CH3、CH2CH2CO2H、CH2OH、CH(OH)CH3、CH2CH2CH2NHC(NH)NH2、CH2CONH2、CH2CH2CONH2、CH2SH、CH2CH2CH2CH2NHCBz或CH2CH2CH2CH2NH2。
本发明中,通过依据在1,2,3,4-四氢-β-咔啉-3-S-羧酸中引入L-氨基酸生成N-(1,2,3,4-四氢-β-咔啉-3-甲酰基)-氨基酸可获得抗血栓好处,并依据防止所引入的L-氨基酸在体内代谢而可以保持所获得的抗血栓好处,而使得所引入的L-氨基酸与1,2,3,4-四氢-β-咔啉环之间生成第四个环,得到本发明通式I的N-(1’-取代羧乙-1’-基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚化合物,从而防止N-(1,2,3,4-四氢-β-咔啉-3-甲酰基)-氨基酸中的L-氨基酸由于在体内代谢而对抗血栓活性的负面作用。
本发明通式I化合物的特别实例包括:
1-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
N-(1’-羧基-2’-甲基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-3’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基)甲基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-(4-羟基)苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-吲哚基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-咪唑基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-3’-甲硫基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-羧基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-3’-羧基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’羧基-2’-羟基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
141-(1’-羧基-2’-羟基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-4’-胍基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-甲酰胺基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-3’-甲酰胺基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-巯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;或
1-(1’-羧基-5’-氨基)戊基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚。
本发明提供了上述通式I化合物的制备方法,该方法包括:L-色氨酸在酸催化下与甲醛进行Pictet-Spengler缩合而得到咔啉羧酸,将该咔啉羧酸的仲胺基进行保护,将保护后的产物与L-氨基酸甲酯进行偶联得到通式II的化合物(其中,R的定义与通式I化合物中相同,其中R1是甲基),将通式II化合物进行脱保护,然后将脱保护后的产物与丙酮进行缩合反应,然后进行皂化即得通式I化合物。
在本发明制备通式I化合物的方法中,L-色氨酸在酸催化下与甲醛进行Pictet-Spengler缩合而得到咔啉羧酸,催化所用的酸可以是一般的无机酸,然而优选使用硫酸,因为硫酸催化一般不会引入新的杂质。
在本发明制备通式I化合物的方法中,对咔啉羧酸的仲胺基进行保护时,可以采用一般的可脱除的氨基保护基,例如Boc、甲氧基苄基(PMB)和苄氧羰基(cbz)等进行保护,然而优选使用Boc。当使用Boc进行保护时,脱保护可优选在约4N的氯化氢乙酸乙酯中进行。
在本发明制备通式I化合物的方法中,脱保护的产物与丙酮的缩合反应可以在三乙胺催化下在甲醇中进行,所用甲醇与丙酮的体积比优选约为3∶1,三乙胺的用量优选为使用其调节pH为9-9.5,缩合反应优选在23-25℃的温度下进行,缩合反应优选避光进行,反应时间优选7-10天。缩合后的产物可优选在约2N的NaOH溶液中进行皂化反应而生成通式I的化合物。
在本发明制备通式I化合物的方法中,一个优选的实施方案为:L-色氨酸在稀硫酸催化下与甲醛进行Pictet-Spengler缩合反应,缩合生成的咔啉羧酸的仲胺基用Boc进行保护,所得N-Boc-咔啉羧酸与L-氨基酸甲酯进行偶联生成通式II的化合物,通式II的化合物用约4N的氯化氢乙酸乙酯脱除Boc,脱Boc的产物在三乙胺催化下在甲醇中与丙酮进行缩合反应,缩合所得产物在约2N NaOH溶液中进行皂化反应生成通式I化合物。具体反应路线如下所示:
反应路线
其中,条件i是用稀硫酸进行催化与甲醛进行缩合反应;条件ii是指用Boc进行保护;条件iii是指与L-氨基酸甲酯进行偶联;条件iv是指脱除Boc保护;条件v是指在NaOH溶液中进行皂化。
本发明的通式I化合物N-(1’-取代羧乙-1’-基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚,通过所引入的L-氨基酸与1,2,3,4-四氢-β-咔啉环之间生成第四个环,从而防止N-(1,2,3,4-四氢-β-咔啉-3-甲酰基)-氨基酸中的L-氨基酸由于在体内代谢而对抗血栓活性的负面作用,因此通式I化合物具有良好的抗血小板聚集的作用,因而具有良好的抗血栓作用。其可以用于制备抗血栓药物,治疗由血栓导致的疾病,例如动脉粥样硬化、动脉血栓栓塞和静脉血栓栓塞等。
具体实施方式
以下结合具体实施例来进一步描述本发明。本发明的特点和优点将随着这些描述而变得更清楚。但这些实施例仅是示例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不违背本发明精神和范围内所作的修改和替换均落入本发明范围内。
实施例1 1-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2a)的制备
1)S-咔啉羧酸的制备
将400ml水置于500ml的圆底烧瓶中,缓慢加入0.2ml浓硫酸。往得到的稀硫酸水溶液中加入5.0g(24.5mmol)L-色氨酸并超声振荡至L-色氨酸完全溶解。往得到的溶液中加入10ml浓度为35%的甲醛溶液。反应混合物室温搅拌6小时,薄层层析监测到L-色氨酸消失,终止反应。往反应溶液中缓慢滴加浓氨水,调反应混合物至pH6,静置半小时。减压滤出的生成的沉淀用水洗,将滤出的无色固体平铺于培养皿,置于柜子中空气干燥后得S-咔啉羧酸,为无色固体5.05g(95.4%)。Mp 280-282℃;EI/MS:217[M+H]+;IR(KBr):3450,3200,3000,2950,2850,1700,1601,1452,1070,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.99(s,1H),9.89(s,1H),7.30(t,J=7.5Hz,1H),7.22(t,J=8.0Hz,1H),7.01(d,J=8.0Hz,1H),6.81(d,J=7.5Hz,1H),4.01(t,J=4.8Hz,1H),3.75(dd,J=10.5Hz,J=5.0Hz,1H),3.64(dd,J=10.5Hz,J=2.4Hz,1H),2.91(d,J=10.5Hz,2H),2.86(s,1H).元素分析C12H12N2O2理论值C 66.65,H,5.59,N 12.96.实测值C 66.45,H 5.72,N 12.79。
2)N-Boc-S-咔啉羧酸的制备
将4.0g(18.5mmol)S-咔啉羧酸悬浮于40ml DMF中。冰浴搅拌下往该悬浮液中加入5.2g(23.9mmol)Boc2O。加三乙胺将反应混合物的pH值调至10,反应混合物室温搅拌48小时,薄层层析监测至S-咔啉羧酸消失,终止反应。将反应液倒入表面皿,在风扇下吹约24小时至干。将吹干的油状物用200ml乙酸乙酯溶解,然后置于250ml分液漏斗中,用KHSO4(5%)水溶液洗涤(20ml×3)。分出合并的乙酸乙酯层,在250ml三角瓶中加入无水硫酸钠干燥0.5h,常压过滤。滤液减压浓缩至干,析出白色固体。得到的白色固体中加入氯仿,减压过滤,得到N-Boc-S-咔啉羧酸,为无色固体4.50g(76.9%)。Mp 165-170℃;TOF/MS:317[M+H]+339[M+Na]+,355[M+K];IR(KBr):3452,3205,3001,2952,2848,1705,1645,1600,1450,1072,901cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.873(s,1H),9.862(s,1H),7.325(t,J=7.6Hz,1H),7.214(t,J=7.9Hz,1H),7.006(d,J=7.9Hz,1H),6.844(t,J=7.6Hz,1H),4.841(t,J=5.0Hz,1H),4.202(dd,J=10.2Hz,J=4.8Hz,1H),3.980(dd,J=10.2Hz,J=3.2Hz,1H),2.933(d,J=10.2Hz,2H),1.462(s,9H).元素分析C17H20N2O4理论值C 64.54,H,6.37,N 8.86.实测值C 64.41,H 6.25,N8.74。
3)N-Boc-S-咔啉酰-L-异亮氨酸甲酯的制备
冰浴冷却下往置于150ml烧瓶中的由1.20g(6.61mmol)盐酸L-异亮氨酸甲酯、2.00g(6.33mmol)N-Boc-S-咔啉羧酸、0.90g(6.67mmol)N-羟基苯并三唑(HOBt)和1.20g(6.61mmol)HCl·Ile-OMe与70ml THF构成的溶液中滴入1.70g(8.33mmol)二环己基羰二亚胺(DCC)和5ml THF构成的溶液。往得到的溶液通过滴入N甲基吗啉(NMM)与THF的溶液调pH值到8。反应混合物0℃搅拌2小时后抽滤,滤液减压浓缩至干。得到的残余物用150ml乙酸乙酯溶解、置于250ml分液漏斗中、依次用饱和碳酸氢钠水溶液洗(30ml×3)、饱和氯化钠水溶液洗(30ml×3)、5%硫酸氢钾水溶液洗(30ml×3)、饱和氯化钠水溶液洗(30ml×3)、饱和碳酸氢钠水溶液洗(30ml×3)、饱和氯化钠水溶液洗(30ml×3)。合并的乙酸乙酯层用无水硫酸钠干燥、过滤、滤液减压浓缩至干,得到2.70g(99%)目标化合物,为无色固体。IR(KBr):3445,3203,3006,2953,2842,1727,1644,1607,1452,1394,1372,1062,900cm-1;ESI+-MS(m/e)444[M+H]+;1H NMR(BHSC-500,DMSO-d6):δ=10.045(s,1H),7.965(s,1H),7.293(t,J=7.4Hz,1H),7.214(t,J=7.4Hz,1H),7.007(d,J=7.4Hz,1H),6.895(d,J=7.4Hz,1H),4.842(t,J=5.4Hz,1H),4.425(d,J=5.4Hz,1H),4.226(dd,J=10.2Hz,J=4.5Hz,1H),4.039(dd,J=10.2Hz,J=3.7Hz,1H),3.622(s,3H),2.953(d,J=6.7Hz,2H),2.877(m,J=6.0Hz,1H),1.473(s,9H),1.350(m,J=5.4Hz,2H),1.053(d,J=5.4Hz,3H),1.001(t,J=5.4Hz,3H).元素分析C24H33N3O5理论值C 64.99,H 7.50,N 9.47.实测值C 65.13,H7.61,N 9.33。
4)N-(1’-甲氧羰基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1a)的制备
将2.0g(4.51mmol)N-Boc-S-咔啉酰-L-异亮氨酸甲酯置于100ml茄形瓶中并用8ml乙酸乙酯溶解。冰浴下往得到的溶液中缓慢滴入16ml 4N HCl/EtOAc。反应混合物0℃搅拌1.5小时后减压浓缩至干。残留物溶于60ml甲醇和20ml丙酮的混合溶剂中、用三乙胺调整pH值到9、避光反应7-10天、薄层层析监测至N-Boc-S-咔啉酰-L-异亮氨酸甲酯消失,终止反应。反应混合物减压浓缩至干、残留物用200ml乙酸乙酯溶解、溶液置于250ml分液漏斗中并用30ml饱和氯化钠水溶液洗(30ml×8)。洗后的乙酸乙酯层用无水硫酸钠干燥、0.5h后过滤。滤液减压浓缩至干。残留物用5ml甲醇溶解、静置、滤出0.8g(46%)目标化合物,为淡黄色固体。ESI+-MS(m/e)384[M+H]+;1H-NMR(CDCl3,300MHz δ=8.100(s,1H),7.425(t,J=7.5Hz,1H),7.252(t,J=7.5Hz,1H),7.093(d,J=7.5Hz,1H),7.060(d,J=7.5Hz,1H),4.391(t,J=6.6Hz,1H),3.914(t,J=6.6Hz,1H),3.763(dd,J=10.5Hz,J=4.2Hz,2H),3.666(s,3H),2.931(m,J=6.2Hz,1H),2.725(d,J=6.6Hz,2H),1.489(m,J=6.0Hz,2H),1.440(s,3H),1.209(s,3H),0.922(d,J=6.6Hz,3H),0.853(t,J=6.6Hz,3H).13C-NMR(CDCl3,300MHz)δ=171.911,171.243,136.257,131.082,127.109,121.612,119.519,118.076,110.749,108.013,78.953,60.665,57.410,52.135,41.569,33.937,25.457,24.929,23.883,18.657,16.391,11.207。元素分析C22H29N3O3理论值C 68.90,H 7.62,N 10.96;实测值C 68.77,H 7.53,N 10.96。
5)N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2a)的制备
将1.0g(2.61mmol)N-(1’-甲氧羰基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚溶于10ml甲醇中,冰浴下缓慢加入2N NaOH溶液10ml。薄层层析监测至N-(1’-甲氧羰基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚消失,终止反应。反应混合物用1N HCl调节pH值到7,减压浓缩除去甲醇,再用1N HCl调节pH值到3,析出无色沉淀。过滤,用蒸馏水洗涤沉淀,干燥,得到0.85g(88%)目标化合物,为无色固体。ESI+-MS(m/e)370[M+H]+;1H-NMR(CDCl3,300MHz δ=10.95(s,1H),8.310(s,1H),7.429(t,J=7.6Hz,1H),7.256(t,J=7.6Hz,1H),7.098(d,J=7.6Hz,1H),7.064(d,J=7.6Hz,1H),4.395(t,J=6.5Hz,1H),3.910(t,J=6.4Hz,1H),3.760(dd,J=10.0Hz,J=4.3Hz,2H),2.933(m,J=6.0Hz,1H),2.722(d,J=6.4Hz,2H),1.485(m,J=6.1Hz,2H),1.442(s,3H),1.206(s,3H),0.920(d,J=6.4Hz,3H),0.851(t,J=6.4Hz,3H).13C-NMR(CDCl3,300MHz)δ=174.552,171.601,136.263,131.100,127.104,121.603,119.515,118.068,110.744,108.007,78.946,60.661,57.404,52.131,41.565,33.932,25.454,24.925,23.878,18.653,16.388,11.202。元素分析C21H27N3O3理论值C 68.27,H7.37,N 11.37;实测值C 68.16,H 7.28,N 11.26。
实施例2 N-(1’-羧基-2’-甲基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2b)的制备
1)N-Boc-S-咔啉酰-L-缬氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由2.00g(6.33mmol)盐酸L-缬氨酸甲酯制得2.65g(97.5%)目标化合物,为无色固体。Mp 138-140℃;ESI/MS 430[M+H]+.IR(KBr):3443,3202,3001,2951,2845,1729,1648,1602,1450,1392,1370,1067,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.043(s,1H),7.962(s,1H),7.295(t,J=7.4Hz,1H),7.211(t,J=7.7Hz,1H),7.004(d,J=7.7Hz,1H),6.892(d,J=7.4Hz,1H),4.840(t,J=5.4Hz,1H),4.423(d,J=5.4Hz,1H),4.225(dd,J=10.2Hz,J=4.5Hz,1H),4.037(dd,J=10.2Hz,J=3.7Hz,1H),3.626(s,3H),3.103(m,J=5.4Hz,1H),2.951(d,J=6.7Hz,2H),1.474(s,9H),1.053(d,J=5.4Hz,6H).元素分析C23H31N3O5理论值C 64.32,H 7.27,N 9.78.实测值C 64.43,H 7.09,N9.67。
2)N-(1’-甲氧羰基-2’-甲基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1b)的制备
按照实施例1 制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.66mmol)N-Boc-S-咔啉酰-L-缬氨酸甲酯制得0.96g(56%)目标化合物,为无色固体。ESI+-MS(m/e)370[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.251(s,1H),7.503(t,J=7.5Hz,1H),7.313(t,J=7.5Hz,1H),7.127(d,J=7.5Hz,1H),7.102(d,J=7.5Hz,1H),3.981(d,J=6.5Hz,1H),3.844(t,J=5.5Hz,1H),3.735(s,3H),3.477(dd,J=4.5Hz,J=10.8Hz,1H),3.194(dd,J=4.5Hz,J=10.8Hz,1H),2.951(m,J=5.5Hz,1H),2.726(d,J=5.5Hz,2H),1.505(s,3H),1.442(s,3H),1.206(m,J=6.6Hz,3H),0.999(m,J=6.6Hz,3H)。13C-NMR(CDCl3,300MHz):δ=172.637,170.185,136.249,130.974,127.175,121.736,119.650,118.183,110.700,108.326,78.846,61.728,57.393,52.193,41.652,33.937,27.773,23.899,20.504,19.828,18.814。[α]D、元素分析C21H27N3O3理论值C 68.27,H 7.37,N 11.37;实测值C 68.14,H 7.25,N 11.23。
3)1-(1’-羧基-2’-甲基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2b)的制备
按照实施例1 制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.36mmol)N-(1’-甲氧羰基-2’-甲基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚制得0.41g(85%(目标化合物,为无色固体。ESI+-MS(m/e)356[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.88(s,1H),8.243(s,1H),7.510(t,J=7.6Hz,1H),7.304(t,J=7.6Hz,1H),7.133(d,J=7.6Hz,1H),7.115(d,J=7.6Hz,1H),3.975(d,J=6.3Hz,1H),3.840(t,J=5.8Hz,1H),3.472(dd,J=4.6Hz,J=10.5Hz,1H),3.199(dd,J=4.6Hz,J=10.5Hz,1H),2.944(m,J=5.6Hz,1H),2.721(d,J=5.6Hz,2H),1.503(s,3H),1.440(s,3H),1.211(m,J=6.5Hz,3H),0.993(m,J=6.5Hz,3H)。13C-NMR(CDCl3,300MHz)δ=173.111,170.782,136.914,131.301,127.668,122.015,120.104,118.766,111.015,108.816,79.043,62.232,57.891,52.778,42.005,34.117,28.302,24.102,20.906,20.007.元素分析C20H25N3O3理论值C 67.58,H 7.09,N 11.82;实测值C67.73,H 7.15,N 11.69。
实施例3 1-(1’-羧基-3’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2c)的制备
1)N-Boc-S-咔啉酰-L-亮氨酸甲酯的制备
按照实施例1 制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.20g(6.61mmol)盐酸L-亮氨酸甲酯制得2.78g(99.2%)目标化合物,为无色固体。IR(KBr):3443,3205,3002,2954,2845,1724,1642,1605,1455,1392,1370,1065,903cm-1;ESI+-MS(m/e)444[M+H]+;1H NMR(BHSC-500,DMSO-d6):δ=10.043(s,1H),7.962(s,1H),7.291(t,J=7.4Hz,1H),7.212(t,J=7.4Hz,1H),7.004(d,J=7.4Hz,1H),6.891(d,J=7.4Hz,1H),4.840(t,J=5.4Hz,1H),4.422(d,J=5.4Hz,1H),4.224(dd,J=10.2Hz,J=4.5Hz,1H),4.036(dd,J=10.2Hz,J=3.7Hz,1H),3.625(s,3H),2.950(d,J=6.7Hz,2H),1.877(d,J=6.0Hz,2H),1.473(s,9H),1.852(m,J=5.4Hz,1H),1.055(d,J=5.4Hz,6H).元素分析C24H33N3O5理论值C 64.99,H 7.50,N 9.47.实测值C65.15,H 7.63,N 9.60。
2)1-(1’-甲氧羰基-3’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1c)的制备
按照实施例1 制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.51mmol)N-Boc-S-咔啉酰-L-亮氨酸甲酯制得1.14g(65%)目标化合物,为无色固体。Mp 204-206℃、ESI+-MS(m/e)384[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.503(s,1H),7.434(t,J=7.2Hz,1H),7.254(d,J=7.2Hz,1H),7.064(d,J=7.2Hz,1H),7.007(d,J=7.2Hz,1H),4.438(t,J=4.9Hz,1H),3.997(t,J=5.2Hz,1H),3.664(s,3H),3.430(dd,J=4.2Hz,J=10.5Hz,1H),3.089(dd,J=4.2Hz,J=10.5Hz,1H),2.734(d,J=5.2Hz,2H),2.189(m,J=4.9Hz,2H),1.888(m,J=4.9Hz,1H),1.432(s,3H),1.273(s,3H),0.921(d,J=4.9Hz,6H).13C-NMR(CDCl3,300MHz)δ=171.647,171.342,136.266,131.123,127.159,121.637,119.535,118.093,110.758,108.087,78.475,57.360,52.852,52.465,41.668,39.064,25.210,25.061,23.611,22.473,22.374,19.787.[α]D=、元素分析C22H29N3O3理论值C 68.90,H 7.62,N 10.96;实测值C 68.79,H 7.75,N11.17。
3)1-(1’-羧基-3’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2c)的制备
按照实施例1 制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.31mmol)1-(1’-甲氧羰基-3’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚制得0.40g(83%)目标化合物,为无色固体。ESI+-MS(m/e)370[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.51(s,1H),8.461(s,1H),7.430(t,J=7.3Hz,1H),7.251(d,J=7.3Hz,1H),7.057(d,J=7.3 Hz,1H),7.002(d,J=7.3Hz,1H),4.434(t,J=4.7Hz,1H),3.994(t,J=5.3Hz,1H),3.427(dd,J=4.0Hz,J=10.2Hz,1H),3.085(dd,J=4.0Hz,J=10.2Hz,1H),2.737(d,J=5.3Hz,2H),2.184(m,J=4.8Hz,2H),1.885(m,J=4.8Hz,1H),1.433(s,3H),1.271(s,3H),0.925(d,J=4.9Hz,6H).13C-NMR(CDCl3,300MHz)δ=174.102,171.341,137.235,131.915,128.114,122.776,120.842,119.342,111.700,109.120,79.887,62.904,58.009,42.800,34.935,29.111,24.893,21.341,20.814.元素分析C21H27N3O3理论值C 67.27,H 7.37,N 11.37;实测值C 67.41,H 7.29,N11.55。
实施例4 1-(1’-羧基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2d)的制备
1)N-Boc-S-咔啉酰-L-丙氨酸甲酯的制备
按照实施例1 制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.20g(6.61mmol)盐酸L-亮氨酸甲酯制得2.43g(95.6%)目标化合物,为无色固体。Mp 144-146℃;ESI/MS 402[M+H]+;IR(KBr):3451,3011,2949,2847,1730,1604,1450,1392,1370,1066,897cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.891(s,1H),7.980(s,1H),7.323(t,J=7.5Hz,1H),7.235(t,J=7.8Hz,1H),6.972(d,J=7.8Hz,1H),6.813(d,J=7.5Hz,1H),4.884(d,J=5.2Hz,1H),4.591(m,J=5.5Hz,1H),4.255(dd,J=10.0Hz,J=4.7Hz,1H),4.172(dd,J=10.1Hz,J=3.5Hz,1H),3.644(s,3H),2.94(d,J=10.1Hz,2H),1.556(d,J=5.2Hz,3H),1.437(s,9H).元素分析C21H27N3O5理论值C 62.83,H,6.78,N 10.47.实测值C 62.92,H 6.74,N 10.30。
2)1-(1’-甲氧羰基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1d)的制备
按照实施例1 制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.99mmol)N-Boc-S-咔啉酰-L-丙氨酸甲酯制得0.69g(41%)目标化合物,为无色固体。ESI+-MS(m/e)342[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.328(s,1H),7.437(t,J=7.2Hz,1H),7.256(d,J=7.2Hz,1H),7.053(d,J=7.2Hz,1H),7.000(d,J=7.2Hz,1H),4.431(t,J=4.8Hz,1H),3.990(t,J=5.4Hz,1H),3.660(s,3H),3.423(dd,J=4.3Hz,J=10.0Hz,1H),3.088(dd,J=4.3Hz,J=10.0Hz,1H),2.741(d,J=5.4Hz,2H),1.490(d,J=4.8Hz,3H),1.433(s,3H),1.271(s,3H).13C-NMR(CDCl3,300MHz)δ=173.555,170.811,136.706,131.442,127.725,122.304,120.113,118.905,111.202,108.890,70.879,60.131,51.011,44.551,42.107,30.113,29.107,25.004,14.115.元素分析C19H23N3O3理论值C66.84,H 6.79,N 12.31;实测值C 66.73,H 6.67,N 12.48。
3)1-(1’-羧基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2d)的制备
按照实施例1 制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.47mmol)1-(1’-甲氧羰基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚制得0.39g(80.5%)目标化合物,为无色固体。ESI+-MS(m/e)328[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.62(s,1H),8.332(s,1H),7.441(t,J=7.3Hz,1H),7.259(d,J=7.3Hz,1H),7.058(d,J=7.3Hz,1H),7.003(d,J=7.3Hz,1H),4.428(t,J=4.7Hz,1H),3.993(t,J=5.5Hz,1H),3.421(dd,J=4.2Hz,J=10.1Hz,1H),3.085(dd,J=4.2Hz,J=10.1Hz,1H),2.744(d,J=5.5Hz,2H),1.493(d,J=4.7Hz,3H),1.430(s,3H),1.275(s,3H).13C-NMR(CDCl3,300MHz)δ=174.211,171.097,137.303,132.007,128.114,122.978,120.895,119.251,112.073,109.400,71.118,60.966,45.260,42.900,30.987,29.893,25.915,14.898.元素分析C18H21N3O3理论值C 66.04,H 6.47,N 12.84;实测值C 66.19,H 6.60,N 12.69。
实施例5 1-(1’-羧基)甲基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2e)的制备
1)N-Boc-S-咔啉酰-L-甘氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由2.00g(6.33mmol)盐酸L-甘氨酸甲酯制得2.39g(97.6%)目标化合物,为无色固体。Mp 133-135℃;ESI/MS 388[M+H]+.IR(KBr):3448,3010,2945,2843,1732,1600,1453,1390,1371,1062,899cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.934(s,1H),8.025(s,1H),7.302(t,J=7.5Hz,1H),7.201(t,J=7.6Hz,1H),6.955(d,J=7.6Hz,1H),6.836(d,J=7.6Hz,1H),4.891(d,J=5.4Hz,1H),4.223(dd,J=10.2Hz,J=4.5Hz,1H),4.182(s,2H),4.194(dd,J=10.2Hz,J=3.7Hz,1H),3.663(s,3H),2.95(d,J=10.1Hz,2H),1.455(s,9H).[α]D 20=-101°(c=0.36,CHCl3∶CH3OH,1∶1,v/v);元素分析C20H25N3O5理论值C 62.00,H,6.50,N 10.85.实测值C 62.15,H 6.68,N 10.68。
2)1-(1’-甲氧羰基)甲基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1e)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(5.17mmol)N-Boc-S-咔啉酰-L-甘氨酸甲酯制得0.76g(45%)目标化合物,为无色固体。ESI-MS(m/e)329[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.522(s,1H),7.439(t,J=7.4Hz,1H),7.260(d,J=7.4Hz,1H),7.058(d,J=7.4Hz,1H),7.007(d,J=7.4Hz,1H),4.335(s,2H),3.977(t,J=5.6Hz,1H),3.662(s,3H),3.431(dd,J=4.1Hz,J=10.2Hz,1H),3.092(dd,J=4.1Hz,J=10.2Hz,1H),2.744(d,J=5.6Hz,2H),1.430(s,3H),1.276(s,3H).13C-NMR(CDCl3,300MHz)δ=172.167,170.825,136.651,131.224,124.333,121.922,120.400,119.113,111.363,109.223,71.112,61.166,50.958,44.551,42.867,30.200,29.535,25.531.元素分析C18H21N3O3理论值C 66.04,H 6.47,N 12.84;实测值C 66.20,H 6.59,N12.33。
3)1-(1’-羧基)甲基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2e)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.53mmol)1-(1’-甲氧羰基)甲基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚制得0.38g(78%)目标化合物,为无色固体。ESI-MS(m/e)314[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.866(s,1H),8.526(s,1H),7.434(t,J=7.3Hz,1H),7.263(d,J=7.3Hz,1H),7.052(d,J=7.3Hz,1H),7.001(d,J=7.3Hz,1H),4.331(s,2H),3.973(t,J=5.3Hz,1H),3.434(dd,J=4.2Hz,J=10.0Hz,1H),3.090(dd,J=4.2Hz,J=10.0Hz,1H),2.746(d,J=5.3Hz,2H),1.422(s,3H),1.370(s,3H).13C-NMR(CDCl3,300MHz)δ=175.274,173.155,136.704,131.247,124.383,122.402,120.423,119.511,111.554,109.677,71.250,61.334,45.121,43.224,30.761,29.807,25.535.元素分析C17H19N3O3理论值C65.16,H 6.11,N 13.41;实测值C 65.27,H 6.28,N 13.53。
实施例6 1-(1’-羧基-2’-苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2f)的制备
1)N-Boc-S-咔啉酰-L-苯丙氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.42g(6.61mmol)盐酸L-苯丙氨酸甲酯制得2.99g(99.0%)目标化合物,为无色固体。Mp150-152℃;ESI/MS 478[M+H]+;IR(KBr):3446,3205,3006,2948,2847,1731,1645,1603,1451,1392,1370,1069,904cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.920(s,1H),7.971(s,1H),7.314(t,J=7.5Hz,1H),7.282(t,J=7.9Hz,2H),7.195(t,J=7.6Hz,1H),7.140(d,J=7.6Hz,2H),7.025(t,J=7.6Hz,1H),6.963(d,J=7.8Hz,1H),6.807(d,J=7.6Hz,1H),4.935(d,J=5.4Hz,1H),4.822(t,J=5.4Hz,1H),4.274(dd,J=10.2Hz,J=4.5Hz,1H),4.185(dd,J=10.2Hz,J=3.4Hz,1H),3.625(s,3H),3.17(d,J=5.4Hz,2H),2.930(d,J=10.2Hz,2H),1.483(s,9H).元素分析C27H31N3O5理论值C 67.91,H6.54,N 8.80.实测值C 67.72,H 6.62,N 8.67。
2)1-(1’-甲氧羰基-2’-苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1f)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.19mmol)N-Boc-S-咔啉酰-L-苯丙氨酸甲酯制得0.98g(56%)目标化合物,为无色固体。ESI-MS(m/e)418[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.807(s,1H),7.416(t,J=7.2Hz,1H),7.271(t,J=7.5Hz,2H),7.259(d,J=7.2Hz,1H),7.144(d,J=7.5Hz,2H),7.079(t,J=7.5Hz,1H),7.058(d,J=7.2Hz,1H),7.006(d,J=7.2Hz,1H),4.988(t,J=4.5Hz,1H),4.372(dd,J=4.5Hz,J=10.5Hz,1H,),3.689(s,3H),3.564(d,J=4.5Hz,2H),3.275(d,J=5.5Hz,2H),2.910(d,J=4.5Hz,2H),1.281(s,3H),1.344(s,3H)。13C-NMR(DMSO-d6,300MHz)δ=171.144,170.443,138.284,136.042,135.886,132.540,132.391,129.804,128.279,126.606,120.548,118.422,112.551,105.754,77.955,56.766,56.049,52.299,41.198,33.789,24.319,23.346,22.882.元素分析C25H27N3O3理论值C 71.92,H 6.52,N10.06;实测值C 71.79,H 6.44,N 10.20。
3)1-(1’-羧基-2’-苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2f)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.20mmol)1-(1’-甲氧羰基-2’-苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚制得0.41g(85%)目标化合物,为无色固体。ESI-MS(m/e)404[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.800(s,1H),8.811(s,1H),7.419(t,J=7.3Hz,1H),7.276(t,J=7.4Hz,2H),7.255(d,J=7.3Hz,1H),7.141(d,J=7.4Hz,2H),7.076(t,J=7.4Hz,1H),7.054(d,J=7.3Hz,1H),7.009(d,J=7.3Hz,1H),4.985(t,J=4.3Hz,1H),4.370(dd,J=4.4Hz,J=10.2Hz,1H,),3.562(d,J=4.3Hz,2H),3.270(d,J=5.4Hz,2H),2.914(d,J=4.3Hz,2H),1.384(s,3H),1.349(s,3H)。13C-NMR(DMSO-d6,300MHz)δ=176.580,173.322,139.115,136.202,135.891,132.560,132.403,129.856,l28.287,126.622,120.561,118.445,112.593,105.762,77.971,56.794,56.088,41.223,33.802,25.192,23.355,22.887.元素分析C24H25N3O3理论值C 71.44,H 6.25,N 10.41;实测值C 71.60,H 6.32,N 10.29。
实施例7 1-(1’-羧基-2’-(4-羟基)苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2g)的制备
1)N-Boc-S-咔啉酰-L-酪氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.53g(6.61mmol)盐酸L-酪氨酸甲酯制得2.87g(92%)目标化合物,为无色固体。Mp 143-145℃;ESI-MS 494[M+H]+;IR(KBr):3439,3203,3001,2955,2847,1732,1644,1601,1453,1391,1372,1062,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.990(s,1H),8.024(s,1H),7.371(t,J=7.6Hz,1H),7.223(t,J=7.7Hz,1H),7.152(d,J=7.5Hz,2H),7.024(d,J=7.5Hz,1H),6.961(d,J=7.7Hz,1H),6.915(d,J=7.5Hz,2H),4.980(s,1H),4.935(d,J=5.4Hz,1H),4.806(t,J=5.6Hz,1H),4.292(m,J=5.2Hz,2H),3.643(s,3H),3.157(d,J=5.2Hz,2H),2.975(d,J=5.0Hz,2H),1.493(s,9H).元素分析C27H31N3O6理论值C 65.71,H 6.33,N 8.51.实测值C 65.67,H 6.50,N 8.67。
2)1-(1’-甲氧羰基-2’-(4-羟基)苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1g)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.06mmol)N-Boc-S-咔啉酰-L-酪氨酸甲酯制得0.76g(43%)目标化合物,为无色固体。Mp 212-214℃、ESI-MS(m/e)434[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.792(s,1H),7.405(t,J=7.2Hz,1H),7.272(t,J=7.2Hz,1H),7.257(t,J=7.5Hz,2H),7.149(d,J=7.5Hz,2H),7.056(d,J=7.2Hz,1H),7.017(d,J=7.2Hz,1H),5.638(s,1H),4.800(dd,J=4.8Hz,J=10.8Hz,1H),3.823(t,J=5.8Hz,1H),3.664(s,3H),3.661(d,J=5.8Hz,2H),3.237(d,J=4.8Hz,2H),2.890(d,J=5.8Hz,2H),1.433(t,3H),1.268(s,3H).13C-NMR(DMSO-d6,300MHz)δ=171.003,170.534,155.987,136.034,132.573,130.710,128.271,126.688,120.540,118.414,117.466,115.035,110.897,105.804,78.021,56.807,56.321,52.217,41.255,30.681,24.841,23.355,17.989。元素分析C25H27N3O4理论值C 69.27,H 6.28,N9.69;实测值C 69.41,H 6.39,N 9.55。
3)1-(1’-羧基-2’-(4-羟基)苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2g)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.15mmol)1-(1’-甲氧羰基-2’-(4-羟基)苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.38g(79%)目标化合物,为无色固体.ESI-MS(m/e)420[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.699(s,1H),8.783(s,1H),7.400(t,J=7.3Hz,1H),7.267(t,J=7.3Hz,1H),7.254(t,J=7.4Hz,2H),7.146(d,J=7.4Hz,2H),7.053(d,J=7.3Hz,1H),7.014(d,J=7.3Hz,1H),5.635(s,1H),4.796(dd,J=4.5Hz,J=10.2Hz,1H),3.820(t,J=5.6Hz,1H),3.658(d,J=5.6Hz,2H),3.233(d,J=4.7Hz,2H),2.887(d,J=5.6Hz,2H),1.430(t,3H),1.267(s,3H).13C-NMR(DMSO-d6,300MHz)δ=176.817,173.903,156.112,136.150,132.968,131.022,128.764,121.645,120.582,118.766,117.973,115.122,111.120,106.223,78.516,56.853,56.377,52.726,41.284,30.705,24.849,23.368。元素分析C24H25N3O4理论值C 68.72,H 6.01,N 10.02;实测值C 68.87,H 6.11,N 9.86。
实施例8 1-(1’-羧基-2’-吲哚基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2h)的制备
1)N-Boc-S-咔啉酰-L-色氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由2.00g(6.33
mmol)盐酸L-色氨酸甲酯制得2.78g(85%)目标化合物,为无色固体。Mp 161-163℃;ESI-MS 517[M+H]+;IR(KBr):3442,3204,3000,2948,2839,1729,1642,1604,1448,1391,1372,1062,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.872(s,1H),9.863(s,1H),8.095(s,1H),7.324(t,J=7.5Hz,1H),7.307(t,J=7.4Hz,1H),7.126(d,J=7.8Hz,1H),7.114(t,J=7.8Hz,1H),7.103(d,J=7.6Hz,1H),7.095(t,J=7.8Hz,1H),7.046(d,J=7.6Hz,1H),6.981(d,J=7.5Hz,1H),6.835(s,1H),4.94(d,J=5.4Hz,1H),4.762(t,J=5.3Hz,1H),4.291(d,J=5.2Hz,2H),3.644(s,3H),3.192(d,J=5.4Hz,2H),2.955(d,J=6.4Hz,2H),1.496(s,9H).元素分析C29H32N4O5理论值C 67.43,H6.24,N 10.85实测值C 67.55,H 6.34,N 10.72。
2)1-(1’-甲氧羰基-2’-吲哚基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1h)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(3.88mmol)N-Boc-S-咔啉酰-L-色氨酸甲酯制得0.80g(45%)目标化合物,为无色固体。Mp 204-206℃、ESI-MS(m/e)457[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.862(s,1H),8.775(s,1H),7.567(t,J=7.8Hz,1H),7.415(t,J=7.8Hz,1H),7.325(t,J=7.8Hz,1H),7.268(t,J=7.8Hz,1H),7.262(d,J=7.8Hz,1H),7.247(t,J=7.8Hz,1H),7.022(d,J=7.8Hz,1H),7.010(d,J=7.8Hz,1H),6.779(s,1H),4.691(dd,J=4.5Hz,J=9.9Hz,1H),3.781(t,J=4.7Hz,1H),3.694(s,3H),3.480(m,J=4.0Hz,2H),3.199(d,J=4.5Hz,2H),2.911(d,J=4.7Hz,2H),1.500(s,3H),1.232(s,3H).13C-NMR(DMSO-d6,300MHz)δ=170.855,170.641,136.034,135.985,132.532,132.383,127.595,126.663,124.389,120.894,120.556,118.447,118.002,117.482,111.400,110.864,110.551,105.787,77.972,56.882,56.654,52.217,41.223,27.690,24.434,23.750,23.363.元素分析C27H28N4O3理论值C 71.03,H 6.18,N 12.27;实测值C 71.15,H 6.10,N 12.11。
3)1-(1’-羧基-2’-吲哚基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2h)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.10mmol)1-(1’-甲氧羰基-2’-吲哚基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.44g(90%)目标化合物,为无色固体。ESI-MS(m/e)443[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.761(s,1H),8.853(s,1H),8.742(s,1H),7.560(t,J=7.6Hz,1H),7.411(t,J=7.6Hz,1H),7.318(t,J=7.6Hz,1H),7.263(t,J=7.6Hz,1H),7.217(d,J=7.6Hz,1H),7.243(t,J=7.6Hz,1H),7.015(d,J=7.6Hz,1H),7.002(d,J=7.6Hz,1H),6.773(s,1H),4.685(dd,J=4.4Hz,J=9.7Hz,1H),3.776(t,J=4.6Hz,1H),3.475(m,J=4.2Hz,2H),3.190(d,J=4.6Hz,2H),2.903(d,J=4.6Hz,2H),1.446(s,3H),1.332(s,3H).13C-NMR(DMSO-d6,300MHz)δ=176.033,173.400,136.225,136.030,133.363,132.577,128.114,127.252,124.987,121.453,121.102,119.222,118.673,118.006,111.965,111.334,111.008,106.264,78.301,57.340,57.111,41.737,27.690,24.906,23.759,23.368.元素分析C26H26N4O3理论值C 70.57,H 5.92,N 12.66;实测值C 70.45,H 6.07,N 12.54。
实施例9 1-(1’-羧基-2’-咪唑基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2i)的制备
1)N-Boc-S-咔啉酰-L-组氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.36g(6.61mmol)盐酸L-组氨酸甲酯制得2.36g(80%)目标化合物,为无色固体。Mp 162-164℃;ESI-MS 454[M+H]+;IR(KBr):3442,3206,3004,2949,2839,1730,1643,1601,1454,1391,1368,1062,902cm-1;1H NMR(BHSC-500,DMSO-d6):δ=12.980(s,1H),9.962(s,1H),8.053(s,1H),7.475(s,1H),6.85(s,1H),7.362(t,J=7.4Hz,1H),7.206(t,J=7.7Hz,1H),7.164(d,J=7.7Hz,1H),6.985(t,J=7.4Hz,1H),4.937(t,J=5.3Hz,1H),4.835(t,J=5.4Hz,1H),4.266(d,J=5.2Hz,2H),3.645(s,3H),3.194(d,J=5.4Hz,2H),2.925(d,J=5.2Hz,2H),1.493(s,9H).元素分析C24H29N5O5理论值C 61.66,H6.25,N 14.98.实测值C 61.52,H 6.38,N 14.77。
2)1-(1’-甲氧羰基-2’-咪唑基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1i)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.28mmol)N-Boc-S-咔啉酰-L-组氨酸甲酯制得0.61g(35%)目标化合物,为无色固体。Mp 204-206℃、ESI-MS(m/e)408[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.072(s,1H),8.885(s,1H),7.411(s,1H),7.265(t,J=7.3Hz,1H),7.184(d,J=7.3Hz,1H),7.025(d,J=7.3Hz,1H),7.009(d,J=7.3Hz,1H),6.820(s,1H),4.700(dd,J=4.3Hz,J=9.5Hz,1H),3.823(t,J=4.8Hz,1H),3.690(s,3H),3.482(m,J=4.3Hz,2H),3.193(d,J=4.3Hz,2H),2.905(d,J=4.8Hz,2H),1.442(s,3H),1.400(s,3H)13C-NMR(DMSO-d6,300MHz)δ=171.119,170.992,136.440,136.228,135.175,134.864,132.007,123.393,121.800,120.759,120.204,112.920,111.432,70.978,59.889,51.648,50.971,45.202,27.698,29.430,23.758,23.665.元素分析C22H25N5O3理论值C 64.85,H 6.18,N 17.19;实测值C 64.73,H 6.10,N 17.32。
3)1-(1’-羧基-2’-咪唑基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2i)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.23mmol)1-(1’-甲氧羰基-2’-咪唑基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.41g(85%)目标化合物,为无色固体。ESI-MS(m/e)394[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.889(s,1H),10.621(s,1H),8.662(s,1H),7.436(s,1H),7.268(t,J=7.2Hz,1H),7.187(d,J=7.2Hz,1H),7.029(d,J=7.2Hz,1H),7.013(d,J=7.2Hz,1H),6.835(s,1H),4.802(dd,J=4.5Hz,J=9.2Hz,1H),3.855(t,J=4.9Hz,1H),3.488(m,J=4.5Hz,2H),3.196(d,J=4.5Hz,2H),2.912(d,J=4.5Hz,2H),1.433(s,3H),1.412(s,3H).13C-NMR(DMSO-d6,300MHz)δ=176.808,173.220,136.437,135.894,135.247,134.872,132.014,123.397,121.826,120.766,120.213,112.927,111.435,70.980,59.895,51.666,45.211,27.721,29.435,23.761,23.669.元素分析C21H23N5O3理论值C 64.11,H 5.89,N 17.80;实测值C 64.24,H 6.01,N 17.69。
实施例10 1-(1’-羧基-3’-甲硫基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2j)的制备
1)N-Boc-S-咔啉酰-L-蛋氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.32g(6.61mmol)盐酸L-蛋氨酸甲酯制得2.80g(96%)目标化合物,为无色固体。Mp 159-161℃;ESI/MS 462[M+H]+;IR(KBr):3441,3203,3004,2953,2847,1732,1641,1603,1454,1390,1372,1061,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.041(s,1H),7.974(s,1H),7.322(t,J=7.5Hz,1H),7.223(t,J=7.8Hz,1H),6.990(d,J=7.8Hz,1H),6.814(d,J=7.5Hz,1H),4.865(t,J=5.3Hz,1H),4.453(t,J=5.5Hz,1H),4.286(d,J=5.1Hz,2H),3.685(s,3H),2.937(d,J=5.3Hz,2H),2.424(t,J=5.4Hz,2H),2.282(d,J=5.6Hz,2H),2.107(s,3H),1.445(s,9H).元素分析C23H31N3O5S理论值C 59.85,H6.77,N 9.10.实测值C 59.67,H 6.59,N 9.04。
2)1-(1’-甲氧羰基-3’-甲硫基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1j)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.34mmol)N-Boc-S-咔啉酰-L-蛋氨酸甲酯制得1.11g(64%)目标化合物,为无色固体。Mp 190-191℃、ESI-MS(m/e)402[M+H]+;1H-NMR(CDCl3,300MHz)δ=7.997(s,1H),7.473(t,J=7.2Hz,1H),7.292(t,J=7.2Hz,1H),7.088(d,J=7.2Hz,1H),7.023(d,J=7.2Hz,1H),4.137(t,J=4.2Hz,1H),3.928(t,J=5.2Hz,1H),3.721(s,3H),3.480(dd,J=4.5Hz,J=10.8Hz,1H),3.139(dd,J=4.5Hz,,J=10.8Hz,1H),2.809(d,J=5.2Hz,2H),2.577(m,J=4.2Hz,2H),2.415(m,J=4.2Hz,2H),2.151(s,3H),1.479(s,3H),1.363(s,3H)。13C-NMR(DMSO-d6,300MHz)δ=171.804,170.913,136.249,131.148,127.134,121.637,119.535,118.085,110.766,108.005,78.442,57.294,52.629,52.514,41.726,31.481,28.663,24.806,23.528,22.951,15.097。元素分析C21H27N3O3S理论值C62.82,H 6.78,N 10.47;实测值C 62.95,H 6.90,N 10.63。
3)1-(1’-羧基-3’-甲硫基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2j)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.25mmol)1-(1’-甲氧羰基-3’-甲硫基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.45g(92%)目标化合物,为无色固体。ESI-MS(m/e)388[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.762(s,1H),8.695(s,1H),7.475(t,J=7.4Hz,1H),7.296(t,J=7.4Hz,1H),7.091(d,J=7.4Hz,1H),7.027(d,J=7.4Hz,1H),4.141(t,J=4.4Hz,1H),3.932(t,J=5.3Hz,1H),3.483(dd,J=4.6Hz,J=10.5Hz,1H),3.143(dd,J=4.6Hz,,J=10.5Hz,1H),2.812(d,J=5.3Hz,2H),2.581(m,J=4.4Hz,2H),2.420(m,J=4.4Hz,2H),2.155(s,3H),1.464(s,3H),1.350(s,3H)。13C-NMR(DMSO-d6,300MHz)δ=177.165,173.536,136.245,131.150,127.686,122.009,120.367,118.558,111.204,108.738,78.900,57.773,53.227,42.036,31.638,29.232,25.117,24.303,23.155,15.112。元素分析C20H25N3O3S理论值C 61.99,H 6.50,N 10.84;实测值C 62.12,H 6.62,N10.69。
实施例11 1-(1’-羧基-2’-羧基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2k)的制备
1)N-Boc-S-咔啉酰-L-天冬氨酸二甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.31g(6.61mmol)盐酸L-天冬氨酸二甲酯制得2.79g(96%)目标化合物,为无色固体。Mp158-160℃;ESI-MS 460[M+H]+;IR(KBr):3441,3210,3004,2955,2841,1732,1643,1604,1453,1390,1371,1061,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.050(s,1H),8.051(s,1H),7.373(t,J=7.4Hz,1H),7.252(t,J=7.4Hz,1H),7.006(d,J=7.6Hz,1H),6.954(d,J=7.4Hz,1H),4.926(d,J=5.5Hz,1H),4.773(t,J=5.5Hz,1H),4.242(d,J=5.6Hz,2H),3.625(s,3H),3.581(s,3H),2.917(d,J=5.2Hz,2H),2.855(d,J=5.4Hz,2H),1.494(s,9H).元素分析C23H29N3O7理论值C 60.12,H 6.36,N 9.14.实测值C 60.03,H 6.49,N 8.99。
2)1-(1’-甲氧羰基-2’-甲氧羰基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1k)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.36mmol)N-Boc-S-咔啉酰-L-天冬氨酸二甲酯制得0.97g(56%)目标化合物,为无色固体。Mp 234-236℃、ESI-MS(m/e)400[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.782(s,1H),7.411(t,J=7.5Hz,1H),7.301(t,J=7.5Hz,1H),7.007(d,J=7.5Hz,1H),6.995(d,J=7.5Hz,1H),4.439(t,J=4.5Hz,1H),3.971(t,J=5.4Hz,1H),3.648(s,3H),3.639(s,3H),3.443(dd,J=4.2Hz,J=10.8Hz,1H),3.274(dd,J=4.2Hz,J=10.8Hz,1H),2.886(d,J=4.5Hz,2H),2.796(d,J=4.2Hz,2H),1.465(s,3H),1.377(s,3H).13C-NMR(DMSO-d6,300MHz)δ=171.020,170.979,169.866,135.911,134.762,132.424,121.631,120.606,118.463,113.515,110.914,71.054,56.511,52.637,51.747,50.074,41.223,34.407,24.583,23.501,23.280。元素分析C21H25N3O5理论值C 63.14,H 6.31,N 10.52;实测值C 63.30,H 6.45,N 10.37。
3)1-(1’-羧基-2’-羧基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2k)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.25mmol)1-(1’-甲氧羰基-2’-甲氧羰基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.42g(90%)目标化合物,为无色固体。ESI-MS(m/e)372[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.708(s,1H),10.692(s,1H),8.786(s,1H),7.423(t,J=7.3Hz,1H),7.315(t,J=7.3Hz,1H),7.011(d,J=7.3Hz,1H),7.004(d,J=7.3Hz,1H),4.462(t,J=4.7Hz,1H),3.977(t,J=5.6Hz,1H),3.450(dd,J=4.5Hz,J=10.2Hz,1H),3.327(dd,J=4.5Hz,J=10.2Hz,1H),2.887(d,J=4.7Hz,2H),2.799(d,J=4.5Hz,2H),1.460(s,3H),1.382(s,3H).13C-NMR(DMSO-d6,300MHz)δ=176.853,175.904,172.217,136.134,134.777,132.428,122.313,120.992,119.400,113.805,111.030,71.111,57.000,47.745,41.568,34.901,25.136,23.521,23.342。元素分析C19H21N3O5理论值C61.45,H 5.70,N 11.31;实测值C 61.33,H 5.58,N 11.47。
实施例12 1-(1’-羧基-3’-羧基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2l)的制备
1)N-Boc-S-咔啉酰-L-谷氨酸二甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.40g(6.61mmol)盐酸L-谷氨酸二甲酯制得2.93g(98%)目标化合物,为无色固体。Mp 154-156℃;ESI-MS 474[M+H]+;IR(KBr):3441,3203,3000,2944,2831,1731,1645,1604,1455,1390,1372,1067,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.890(s,1H),8.044(s,1H),7.393(t,J=7.6Hz,1H),7.282(t,J=7.6Hz,1H),7.015(d,J=7.7Hz,1H),6.844(d,J=7.6Hz,1H),4.906(d,J=5.4Hz,1H),4.437(t,J=5.6Hz,1H),4.225(d,J=5.5Hz,2H),3.663(s,3H),3.647(s,3H),2.968(d,J=5.4Hz,2H),2.281(t,J=5.6Hz,2H),2.245(t,J=5.7Hz,2H),1.434(s,9H).元素分析C24H31N3O7理论值C 60.88,H6.60,N 8.87.实测值C 60.73,H 6.49,N 8.69。
2)1-(1’-甲氧羰基-3’-甲氧羰基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1l)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.23mmol)N-Boc-S-咔啉酰-L-谷氨酸二甲酯制得0.84g(48%)目标化合物,为无色固体。Mp 234-236℃、ESI-MS(m/e)414[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.775(s,1H),7.472(t,J=7.5Hz,1H),7.293(t,J=7.5Hz,1H),7.078(d,J=7.5Hz,1H),7.046(d,J=7.5Hz,1H),4.134(t,J=4.7Hz,1H),3.904(t,J=5.6Hz,1H),3.716(s,3H),3.677(s,3H),3.486(dd,J=4.2Hz,J=10.3Hz,1H),3.116(dd,J=4.2Hz,J=10.3Hz,1H),2.749(d,J=5.6Hz,2H),2.681(d,J=4.7Hz,2H),2.496(d,J=4.7Hz,2H),1.473(s,3H),1.367(s,3H).13C-NMR(DMSO-d6,300MHz)δ=171.026,170.983,169.870,135.915,134.770,132.430,121.637,120.612,118.469,113.521,110.922,71.062,56.517,52.643,51.751,50.080,41.231,34.415,26.887,24.599,23.507,23.288。元素分析C22H27N3O5理论值C 63.91,H 6.58,N 10.16;实测值C 64.06,H 6.72,N 10.00。
3)1-(1’-羧基-3’-羧基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2l)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.21mmol)1-(1’-甲氧羰基-3’-甲氧羰基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.43g(92%)目标化合物,为无色固体。ESI-MS(m/e)386[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.755(s,1H),10.746(s,1H),8.781(s,1H),7.478(t,J=7.4Hz,1H),7.311(t,J=7.4Hz,1H),7.082(d,J=7.4Hz,1H),7.050(d,J=7.4Hz,1H),4.138(t,J=4.8Hz,1H),3.910(t,J=5.5Hz,1H),3.492(dd,J=4.4Hz,J=10.2Hz,1H),3.117(dd,J=4.4Hz,J=10.2Hz,1H),2.753(d,J=5.5Hz,2H),2.685(d,J=4.8Hz,2H),2.502(d,J=4.8Hz,2H),1.470(s,3H),1.365(s,3H).13C-NMR(DMSO-d6,300MHz)δ=177.022,176.971,170.455,136.144,135.587,132.436,121.642,120.621,118.476,113.527,110.928,71.070,56.525,52.647,41.242,34.410,26.893,24.605,23.511,23.294。[α]D、元素分析C20H23N3O5理论值C 62.33,H 6.01,N 10.90;实测值C 62.15,H 6.11,N 10.75。
实施例13 1-(1’-羧基-2’-羟基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2m)的制备
1)N-Boc-S-咔啉酰-L-丝氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.03g(6.61mmol)盐酸L-丝氨酸甲酯制得2.43g(92%)目标化合物,为无色固体。Mp 139-141℃;ESI-MS 418[M+H]+.IR(KBr):3442,3200,3001,2952,2845,1730,1644,1606,1455,1392,1370,1067,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.950(s,1H),7.972(s,1H),7.291(t,J=7.6Hz,1H),7.224(t,J=7.9Hz,1H),6.995(d,J=7.9Hz,1H),6.830(t,J=7.6Hz,1H),4.872(d,J=5.4Hz,1H),4.526(t,J=5.6Hz,1H),4.197(d,J=5.2Hz,2H),4.133(d,J=5.6Hz,2H),3.634(s,3H),2.95(d,J=5.6Hz,1H),2.925(d,J=5.6Hz,1H),2.288(s,1H),1.454(s,9H).元素分析C21H27N3O6理论值C 60.42,H 6.52,N10.07.实测值C 60.31,H 6.36,N 10.24。
2)1-(1’-甲氧羰基-2’-羟基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1m)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.80mmol)N-Boc-S-咔啉酰-L-丝氨酸甲酯制得0.89g(52%)目标化合物,为无色固体。Mp 196-197℃、ESI-MS(m/e)358[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.857(s,1H),7.409(t,J=7.4Hz,1H),7.293(t,J=7.4Hz,1H),7.014(d,J=7.4Hz,1H),6.971(d,J=7.4Hz,1H),5.012(t,J=5.4Hz,1H),4.176(t,J=5.4Hz,2H),4.094(t,J=4.4Hz,1H),3.814(dd,J=4.2Hz,J=10.2Hz,1H),3.623(s,3H),3.440(dd,J=4.2Hz,J=10.2Hz,1H),2.879(d,J=4.4Hz,2H),2.453(s,1H),1.375(s,3H),1.307(s,3H)。13C-NMR(CDCl3,300MHz)δ=170.987,169.446,135.911,132.556,126.663,120.573,118.438,117.499,110.897,105.886,78.137,58.390,56.816,56.511,52.044,41.445,24.492,23.338,19.275。元素分析C19H23N3O4理论值C 63.85,H 6.49,N 11.76;实测值C 62.95,H 6.60,N 11.59。
3)1-(1’-羧基-2’-羟基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2m)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.40mmol)1-(1’-甲氧羰基-2’-羟基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.44g(91%)目标化合物,为无色固体。ESI-MS(m/e)344[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.772(s,1H),8.863(s,1H),7.411(t,J=7.3Hz,1H),7.297(t,J=7.3Hz,1H),7.018(d,J=7.3Hz,1H),6.985(d,J=7.3Hz,1H),5.007(t,J=5.6Hz,1H),4.182(t,J=5.3Hz,2H),4.113(t,J=4.7Hz,1H),3.820(dd,J=4.4Hz,J=10.0Hz,1H),3.444(dd,J=4.4Hz,J=10.2Hz,1H),2.883(d,J=4.7Hz,2H),2.450(s,1H),1.378(s,3H),1.312(s,3H)。13C-NMR(CDCl3,300MHz)δ=175.100,170.623,136.107,132.599,126.687,121.034,118.496,117.808,111.019,106.251,78.604,58.398,58.022,57.144,41.486,24.513,23.344,19.296。元素分析C18H21N3O4理论值C 62.96,H 6.16,N 12.24;实测值C 63.11,H6.27,N 12.41。
实施例14 1-(1’-羧基-2’-羟基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2n)的制备
1)N-Boc-S-咔啉酰-L-苏氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.12g(6.61mmol)盐酸L-苏氨酸甲酯制得2.37g(87%)目标化合物,为无色固体。Mp 140-142℃;ESI-MS 432[M+H]+;IR(KBr):3437,3200,3002,2951,2844,1735,1649,1600,1450,1392,1370,1065,901cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.981(s,1H),7.870(s,1H),7.343(t,J=7.4Hz,1H),7.254(t,J=7.6Hz,1H),6.952(d,J=7.6Hz,1H),6.724(d,J=7.4Hz,1H),4.870(t,J=5.4Hz,1H),4.673(m,J=5.6Hz,1H),4.485(t,J=5.6Hz,1H),3.991(m,J=5.2Hz,2H),3.653(s,3H),2.974(d,J=5.7Hz,2H),2.195(d,J=3.7Hz,1H),1.474(s,9H),1.19(d,J=5.6Hz,3H).元素分析C22H29N3O6理论值C61.24,H 6.77,N 9.74.实测值C 61.40,H 6.91,N 9.55。
2)1-(1’-甲氧羰基-2’-羟基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1n)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.64mmol)N-Boc-S-咔啉酰-L-苏氨酸甲酯制得0.72g(42%)目标化合物,为无色固体。Mp 196-197℃、ESI-MS(m/e)372[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.669(s,1H),7.403(t,J=7.5Hz,1H),7.290(t,J=7.5Hz,1H),7.010(d,J=7.5Hz,1H),6.975(d,J=7.5Hz,1H),5.010(t,J=5.5Hz,1H),4.173(m,J=5.6Hz,1H),4.097(d,J=4.6Hz,1H),3.811(dd,1H,J=4.3Hz,J=10.1Hz,1H),3.620(s,3H),3.435(dd,1H,J=4.3Hz,J=10.1Hz,1H),2.879(d,1H,J=5.5Hz,2H),2.453(s,1H),1.375(s,3H),1.307(s,3H),1.286(d,J=4.6Hz,3H)。13C-NMR(CDCl3,300MHz)δ=171.544,170.135,136.037,132.598,126.685,120.623,118.608,117.637,111.229,106.104,78.715,65.466,58.412,57.159,56.573,52.119,41.607,24.513,23.357,19.286。元素分析C20H25N3O4理论值C 64.67,H 6.78,N11.31;实测值C 64.84,H 6.90,N 11.20。
3)1-(1’-羧基-2’-羟基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2n)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.35mmol)1-(1’-甲氧羰基-2’-羟基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.43g(89%)目标化合物,为无色固体。ESI-MS(m/e)358[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.637(s,1H),8.662(s,1H),7.411(t,J=7.4Hz,1H),7.287(t,J=7.4Hz,1H),7.012(d,J=7.4Hz,1H),6.978(d,J=7.4Hz,1H),5.006(t,J=5.6Hz,1H),4.170(m,J=5.8Hz,1H),4.093(d,J=4.7Hz,1H),3.816(dd,1H,J=4.2Hz,J=10.2Hz,1H),3.433(dd,1H,J=4.2Hz,J=10.2Hz,1H),2.879(d,J=4.7Hz,2H),2.450(s,1H),1.372(s,3H),1.309(s,3H),1.286(d,J=4.7Hz,3H)。13C-NMR(CDCl3,300MHz)δ=176.903,173.256,136.055,132.628,126.693,120.634,118.625,117.643,111.240,106.181,78.724,65.453,58.430,57.175,56.582,41.614,24.527,23.362,19.289。元素分析C19H23N3O4理论值C 63.85,H 6.49,N 11.76;实测值C 64.01,H 6.57,N 11.56。
实施例15 1-(1’-羧基-4’-胍基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2o)的制备
1)N-Boc-S-咔啉酰-L-精氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.48g(6.61mmol)盐酸L-精氨酸甲酯制得2.43g(79%)目标化合物,为无色固体。Mp 168-170℃;ESI-MS 487[M+H]+;IR(KBr):3443,3207,3001,2948,2842,1731,1645,1602,1453,1390,1372,1061,904cm-1;1H NMR(BHSC-500,DMSO-d6):δ=10.221(s,1H),8.452(s,2H),8.270(s,1H),8.224(s,1H),8.017(s,1H),7.293(t,J=7.6Hz,1H),7.185(t,J=7.7Hz,1H),7.044(d,J=7.7Hz,1H),6.961(d,J=7.6Hz,1H),4.905(d,J=5.3Hz,1H),4.426(t,J=4.2Hz,1H),4.251(d,J=5.0Hz,2H),3.655(s,3H),2.947(d,J=4.1Hz,2H),2.680(t,J=5.4Hz,2H),1.925(m,J=5.5Hz,2H),1.583(m,J=5.5Hz,2H),1.576(s,9H).元素分析C24H34N6O5理论值C 59.24,H 7.04,N 17.27.实测值C 59.38,H 7.19,N 17.31。
2)1-(1’-甲氧羰基-4’-胍基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1o)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.12mmol)N-Boc-S-咔啉酰-L-精氨酸甲酯制得0.79g(45%)目标化合物,为无色固体。Mp 196-197℃、ESI-MS(m/e)427[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.787(s,2H),8.722(s,1H),8.224(s,1H),7.360(t,J=7.5Hz,1H),7.279(t,J=7.5Hz,1H),7.003(d,J=7.5Hz,1H),6.957(d,J=7.5Hz,1H),6.504(s,1H),4.661(t,J=5.6Hz,1H),4.018(t,J=4.8Hz,1H),3.815(dd,J=4.2Hz,J=10.3Hz,1H),3.628(s,3H),3.439(dd,J=4.2Hz,J=10.3Hz,1H),2.863(d,J=4.8Hz,2H),2.589(t,J=4.6Hz,2H),1.900(m,J=4.6Hz,2H),1.574(m,J=4.6Hz,2H),1.376(s,3H),1.313(s,3H)。13C-NMR(CDCl3,300MHz)δ=173.402,173.337,172.194,135.748,135.100,132.499,122.600,120.679,119.643,113.555,111.717,71.333,60.706,51.903,50.417,47.007,40.665,27.334,27.008,25.884,24.510,23.362。元素分析C22H30N6O3理论值C 61.95,H 7.09,N 19.70;实测值C 62.10,H 6.98,N 19.56。
3)1-(1’-羧基-4’-胍基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2o)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.17mmol)1-(1’-甲氧羰基-4’-胍基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.33g(69%)目标化合物,为无色固体。ESI-MS(m/e)413[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.781(s,1H),8.793(s,2H),8.732(s,1H),8.231(s,1H),7.363(t,J=7.4Hz,1H),7.282(t,J=7.4Hz,1H),7.011(d,J=7.4Hz,1H),6.963(d,J=7.4Hz,1H),6.522(s,1H),4.663(t,J=5.5Hz,1H),4.022(t,J=4.7Hz,1H),3.821(dd,J=4.3Hz,J=10.2Hz,1H),3.443(dd,J=4.3Hz,J=10.2Hz,1H),2.860(d,J=4.7Hz,2H),2.594(t,J=4.5Hz,2H),1.903(m,J=4.5Hz,2H),1.579(m,J=4.5Hz,2H),1.373(s,3H),1.316(s,3H)。13C-NMR(CDCl3,300MHz)δ=176.904,173.708,172.033,135.757,135.130,132.509,122.644,121.132,120.300,113.561,111.753,71.390,60.722,51.963,47.132,41.554,27.631,27.458,26.000,24.537,23.370。元素分析C21H28N6O3理论值C 61.15,H 6.84,N 20.37;实测值C 61.28,H 6.92,N 20.22。
实施例16 1-(1’-羧基-2’-甲酰胺基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2p)的制备
1)N-Boc-S-咔啉酰-L-天冬酰胺甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.21g(6.61mmol)盐酸L-天冬酰胺甲酯制得2.13g(76%)目标化合物,为无色固体。Mp 127-129℃;ESI-MS:444[M+H]+.IR(KBr):3440,3203,3005,2942,2833,1735,1642,1604,1453,1394,1372,1067,903cm-1;1H NMR(BHSC-500,DMSO-d6):δ=8.871(s,1H),8.012(s,1H),7.296(t,J=7.4Hz,1H),7.217(t,J=7.4Hz,1H),7.008(d,J=7.4Hz,1H),6.827(d,J=7.4Hz,1H),6.053(s,2H),4.927(d,J=5.5Hz,1H),4.422(t,J=5.5Hz,1H),4.246(d,J=5.6Hz,2H),3.674(s,3H),2.942(d,J=5.4Hz,2H),2.688(t,J=5.5Hz,2H),1.466(s,9H).[α]D 20=-51°(c=0.38,CHCl3∶CH3OH,1∶1,v/v);元素分析C22H28N4O6理论值C 59.45,H 6.35,N 12.60.实测值C 59.61,H 6.50,N 12.47。
2)1-(1’-甲氧羰基-2’-甲酰胺基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1p)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.50mmol)N-Boc-S-咔啉酰-L-天冬酰胺甲酯制得0.69g(40%)目标化合物,为无色固体。Mp 196-197℃、ESI-MS(m/e)385[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.770(s,1H),7.413(t,J=7.4Hz,1H),7.322(t,J=7.4Hz,1H),7.012(d,J=7.4Hz,1H),6.998(d,J=7.4Hz,1H),6.217(s,2H),4.559(t,J=4.7Hz,1H),3.956(t,J=5.6Hz,1H),3.667(s,3H),3.450(dd,J=4.0Hz,J=10.1Hz,1H),3.277(dd,J=4.0Hz,J=10.1Hz,1H),2.883(d,J=5.6Hz,2H),2.790(d,J=4.7Hz,2H),1.460(s,3H),1.375(s,3H).13C-NMR(DMSO-d6,300MHz)δ=177.111,172.968,171.875,135.937,134.776,132.431,121.650,120.614,118.469,113.522,111.033,71.107,56.583,51.145,46.220,45.588,34.996,24.617,23.511,23.289。元素分析C20H24N4O4理论值C 62.49,H 6.29,N 14.57;实测值C 62.63,H 6.41,N 14.40。
3)1-(1’-羧基-2’-甲酰胺基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2p)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.30mmol)1-(1’-甲氧羰基-2’-甲酰胺基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.31g(65%)目标化合物,为无色固体。ESI-MS(m/e)371[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.724(s,1H),8.780(s,1H),7.425(t,J=7.4Hz,1H),7.319(t,J=7.4Hz,1H),7.014(d,J=7.4Hz,1H),7.009(d,J=7.4Hz,1H),6.223(s,2H),4.468(t,J=4.6Hz,1H),3.975(t,J=5.5Hz,1H),3.454(dd,J=4.3Hz,J=10.0Hz,1H),3.331(dd,J=4.3Hz,J=10.0Hz,1H),2.883(d,J=4.6Hz,2H),2.791(d,J=4.6Hz,2H),1.463(s,3H),1.385(s,3H).13C-NMR(DMSO-d6,300MHz)δ=176.859,175.926,172.255,136.206,135.304,132.469,122.357,121.947,119.436,113.822,111.035,71.119,57.008,47.753,41.574,34.923,25.138,23.525,23.346。元素分析C19H22N4O4理论值C 61.61,H5.99,N 15.13;实测值C 61.74,H 5.85,N 15.27。
实施例17 1-(1’-羧基-3’-甲酰胺基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2q)的制备
1)N-Boc-S-咔啉酰-L-谷氨酰胺甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.30g(6.61mmol)盐酸L-谷氨酰胺甲酯制得2.38g(82%)目标化合物,为无色固体。Mp 122-124℃;ESI-MS(m/e)459[M+H]+.IR(KBr):3445,3200,3001,2940,2835,1733,1640,1602,1452,1391,1370,1065,900cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.916(s,1H),8.007(s,1H),7.292(t,J=7.4Hz,1H),7.203(t,J=7.4Hz,1H),7.005(d,J=7.4Hz,1H),6.806(d,J=7.4Hz,1H),6.054(s,2H),4.925(d,J=5.5Hz,1H),4.413(t,J=5.5Hz,1H),4.245(d,J=5.6Hz,2H),3.677(s,3H),2.945(d,J=5.4Hz,2H),2.186(t,J=5.5Hz,2H),2.140(t,J=5.5Hz,2H),1.464(s,9H).[α]D 20=-56°(c=0.38,CHCl3∶CH3OH,1∶1,v/v);元素分析C23H30N4O6理论值C 60.25,H 6.59,N 12.22.实测值C 60.73,H6.49,N 8.69。
2)1-(1’-甲氧羰基-3’-甲酰胺基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1q)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.37mmol)N-Boc-S-咔啉酰-L-谷氨酰胺甲酯制得0.78g(45%)目标化合物,为无色固体。Mp 234-236℃、ESI-MS(m/e)399[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.771(s,1H),7.468(t,J=7.5Hz,1H),7.290(t,J=7.5Hz,1H),7.072(d,J=7.5Hz,1H),7.041(d,J=7.5Hz,1H),6.231(s,2H),4.132(t,J=4.8Hz,1H),3.913(t,J=5.5Hz,1H),3.681(s,3H),3.482(dd,J=4.4Hz,J=10.1Hz,1H),3.120(dd,J=4.4Hz,J=10.1Hz,1H),2.745(d,J=5.5Hz,2H),2.683(m,J=4.8Hz,2H),2.492(t,J=4.8Hz,2H),1.475(s,3H),1.363(s,3H).13C-NMR(DMSO-d6,300MHz)δ=176.021,172.987,170.872,135.933,134.776,132.438,121.641,120.636,118.503,113.765,111.205,71.154,56.549,52.687,50.682,44.898,31.433,25.881,24.908,23.514,23.296。元素分析C21H26N4O4理论值C 63.30,H 6.58,N 14.06;实测值C 63.45,H 6.70,N 14.22。
3)1-(1’-羧基-3’-甲酰胺基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2q)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.26mmol)1-(1’-甲氧羰基-3’-甲酰胺基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.34g(70%)目标化合物,为无色固体。ESI-MS(m/e)386[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.750(s,1H),8.764(s,1H),7.472(t,J=7.5Hz,1H),7.300(t,J=7.5Hz,1H),7.074(d,J=7.5Hz,1H),7.037(d,J=7.5Hz,1H),6.237(s,2H),4.136(t,J=4.7Hz,1H),3.908(t,J=5.6Hz,1H),3.488(dd,J=4.2Hz,J=10.0Hz,1H),3.113(dd,J=4.2Hz,J=10.0Hz,1H),2.750(d,J=5.6Hz,2H),2.681(t,J=4.7Hz,2H),2.507(m,J=4.7Hz,2H),1.467(s,3H),1.369(s,3H).13C-NMR(DMSO-d6,300MHz)δ=177.026,176.969,171.534,136.140,135.583,132.432,121.636,120.614,118.471,113.523,110.922,71.068,56.521,52.641,44.966,31.418,25.899,24.807,23.520,23.290。元素分析C20H24N4O4理论值C 62.49,H 6.29,N 14.57;实测值C 62.63,H 6.40,N 14.45。
实施例18 1-(1’-羧基-2’-巯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2r)的制备
1)N-Boc-S-咔啉酰-L-半胱氨酸甲酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由1.13g(6.61mmol)盐酸L-半胱氨酸甲酯制得2.33g(85%)目标化合物,为无色固体。Mp 151-153℃;ESI-MS(m/e)420[M+H]+;IR(KBr):3445,3203,3000,2944,2840,1731,1643,1601,1453,1390,1372,1061,898cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.933(s,1H),7.974(s,1H),7.321(t,J=7.5Hz,1H),7.225(t,J=7.8Hz,1H),7.007(d,J=7.8Hz,1H),6.886(d,J=7.5Hz,1H),4.932(t,J=5.3Hz,1H),4.725(t,J=5.5Hz,1H),4.217(d,J=5.3Hz,2H),3.684(s,3H),3.162(d,J=5.5Hz,2H),2.906(d,J=5.6Hz,2H),1.622(s,1H),1.453(s,9H).元素分析C21H27N3O5S理论值C 58.18,H 6.28,N 9.69.实测值C58.27,H 6.33,N 9.57。
2)1-(1’-甲氧羰基-2’-巯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1r)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(4.62mmol)N-Boc-S-咔啉酰-L-半胱氨酸甲酯制得0.65g(38%)目标化合物,为无色固体。Mp 234-236℃、ESI-MS(m/e)374[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.654(s,1H),7.324(t,J=7.5Hz,1H),7.286(t,J=7.5Hz,1H),7.010(d,J=7.5Hz,1H),6.968(d,J=7.5Hz,1H),4.899(t,J=5.6Hz,1H),4.082(t,J=4.6Hz,1H),3.810(dd,1H,J=4.3Hz,J=10.1Hz,1H),3.654(s,3H),3.437(dd,1H,J=4.3Hz,J=10.1Hz,1H),3.170(t,J=5.6Hz,2H),2.873(d,1H,J=4.6Hz,2H),1.670(s,1H),1.371(s,3H),1.303(s,3H)。13C-NMR(CDCl3,300MHz)δ=172.989,172.161,135.934,132.567,126.669,120.580,118.442,117.503,111.218,106.425,78.226,58.409,56.148,51.602,45.847,25.960,24.993,23.335,19.272。元素分析C19H23N3O3S理论值C 61.10,H 6.21,N 11.25;实测值C 61.25,H 6.10,N 11.41。
3)1-(1’-羧基-2’-巯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2r)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由0.50g(1.34mmol)1-(1’-甲氧羰基-2’-巯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚得0.39g(82%)目标化合物,为无色固体。ESI-MS(m/e)358[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.780(s,1H),8.859(s,1H),7.417(t,J=7.4Hz,1H),7.301(t,J=7.4Hz,1H),7.024(d,J=7.4Hz,1H),6.991(d,J=7.4Hz,1H),4.920(t,J=5.7Hz,1H),4.186(t,J=4.7Hz,1H),3.454(dd,J=4.3Hz,J=10.1Hz,1H),3.220(dd,J=4.3Hz,J=10.1Hz,1H),3.177(t,J=5.7Hz,2H),2.881(d,J=4.7Hz,2H),1.755(s,1H),1.376(s,3H),1.311(s,3H)。13C-NMR(CDCl3,300MHz)δ=175.121,171.625,136.113,132.582,126.683,121.024,118.492,117.776,111.227,106.500,78.336,58.429,56.262,46.316,25.228,24.977,23.591,23.403。元素分析C18H21N3O3S理论值C 60.15,H 5.89,N 11.69;实测值C 60.27,H 6.03,N 11.54。
实施例19 1-(1’-羧基-5’-氨基)戊基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2s)的制备
1)N-Boc-S-咔啉酰-L-ε-苄氧羰基-赖氨酸苄酯的制备
按照实施例1制备N-Boc-S-咔啉酰-L-异亮氨酸甲酯的操作,由3.76g(6.61mmol)对甲苯磺酸L-ε-苄氧羰基-赖氨酸苄酯制得3.87g(94%)目标化合物,为无色固体。Mp 134-136℃;ESI-MS(m/e)593[M+H]+.IR(KBr):3442,3007,2940,2848,1730,1605,1455,1391,1370,1066,897cm-1;1H NMR(BHSC-500,DMSO-d6):δ=9.952(s,1H),8.035(s,1H),7.962(s,1H),7.285(t,J=7.6Hz,1H),7.227(t,J=7.2Hz,1H),7.193(t,J=7.6Hz,1H),7.174(d,J=7.2Hz,2H),7.155(t,J=7.2Hz,2H),6.968(d,J=7.6Hz,1H),6.851(d,J=7.6Hz,1H),5.366(s,2H),4.905(d,J=5.5Hz,1H),4.414(t,J=4.4Hz,1H),4.205(dd,J=10.0Hz,J=4.5Hz,1H),4.186(dd,J=10.0Hz,J=3.7Hz,1H),3.647(s,3H),2.984(t,J=4.4Hz,2H),2.933(d,J=10.0Hz,2H),1.915(m,J=4.4Hz,2H),1.550(m,J=4.4Hz,2H),1.463(s,9H),1.292(m,J=4.4Hz,2H).[α]D 20=-22°(c=0.39,CHCl3∶CH3OH,1∶1,v/v);元素分析C32H40N4O7理论值C 64.85,H,6.80,N9.45.实测值C 64.98,H 6.69,N 9.62。
2)1-(1’-苄氧羰基-5’-苄氧羰氨基)戊基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(1s)的制备
按照实施例1制备N-(1’-羧基-2’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的操作,由2.00g(3.07mmo1)N-Boc-S-咔啉酰-L-ε-苄氧羰基赖氨酸苄酯制得1.00g(55%)目标化合物,为无色固体。Mp 234-236℃、ESI-MS(m/e)609[M+H]+;1H-NMR(CDCl3,300MHz)δ=8.863(s,1H),8.017(s,1H),7.320(t,J=7.5Hz,1H),7.297(t,J=7.5Hz,1H),7.292(t,J=7.5Hz,1H),7.282(t,J=7.5Hz,1H),7.280(d,J=7.3Hz,2H),7.277(d,J=7.3Hz,2H),7.274(t,J=7.3Hz,2H),7.271(t,J=7.3Hz,2H),7.007(d,J=7.5Hz,1H),6.966(d,J=7.5Hz,1H),5.395(s,2H),5.363(s,2H),4.561(t,J=5.6Hz,1H),4.055(t,J=4.6Hz,1H),3.757(dd,J=4.2Hz,J=10.2Hz,1H),3.490(dd,1H,J=4.2Hz,J=10.2Hz,1H),2.977(d,J=5.6Hz,2H),2.870(d,J=4.6Hz,2H),1.879(m,J=5.6Hz,2H),1.568(m,J=5.6Hz,2H),1.370(s,3H),1.312(s,3H),1.336(m,J=5.6Hz,2H),。13C-NMR(CDCl3,300MHz)δ=173.221,172.138,160.806,141.101,140.897,135.930,135.601,132.571,128.881,128.704,128.651,128.516,126.484,126.300,121.583,120.733,117.528,111.237,106.436,78.222,72.606,69.804,58.420,52.495,45.924,45.080,32.552,29.954,24.990,23.764,23.337,22.276。元素分析C36H40N4O5理论值C 71.03,H 6.62,N 9.20;实测值C 71.19,H 6.74,N 9.37。
3)1-(1’-羧基-5’-氨基)戊基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚(2s)的制备
将500mg(0.87mmol)1-(1’-苄氧羰基-5’-苄氧羰氨基)戊基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚溶于20ml无水乙醇中,加入50mg Pd/C(5%),通氢气6小时,薄层层析监测原料消失,终止反应。反应液过滤,滤液减压浓缩,得到252mg(80%)目标物,为无色固体。Mp 234-236℃、ESI-MS(m/e)385[M+H]+;1H-NMR(CDCl3,300MHz)δ=10.743(s,1H),8.868(s,1H),7.322(t,J=7.4Hz,1H),7.293(t,J=7.4Hz,1H),7.013(d,J=7.4Hz,1H),6.978(d,J=7.4Hz,1H),6.800(s,2H),4.565(t,J=5.7Hz,1H),4.059(t,J=4.8Hz,1H),3.763(dd,J=4.3Hz,J=10.1Hz,1H),3.492(dd,J=4.3Hz,J=10.1Hz,1H),2.973(d,J=4.8Hz,2H),2.872(t,J=5.6Hz,2H),1.877(m,J=5.6Hz,2H),1.564(m,J=5.6Hz,2H),1.373(s,3H),1.315(s,3H),1.332(m,J=5.6Hz,2H)。13C-NMR(CDCl3,300MHz)δ=176.894,172.985,135.934,135.612,132.577,121.587,120.739,117.532,111.241,106.440,71.220,58.426,52.499,45.928,45.086,32.560,29.959,24.997,23.762,23.335,22.273。元素分析C21H28N4O3理论值C 65.60,H 7.34,N 14.57;实测值C 65.76,H7.45,N 14.41。
试验例实施例1-19的化合物2a-s的抗血栓活性评价
1)实验动物
SD雄性大鼠,体重200-260g(购自北京医科大学实验动物部,许可证号为医动字第01-3056)
2)实验材料
聚乙烯管(外径1.6mm及1.3mm两种)、肝素(50IU/ml)、戊巴比妥钠(5%)。
3)测定方法与结果
雄性SD大鼠(体重200g至260g)腹腔注射戊巴比妥钠溶液进行麻醉,分离出右颈总动脉和左颈外静脉,在聚乙烯管的中段放入事先称重的6cm长的丝线,以肝素生理盐水(50IU/kg)充满聚乙烯管,将一端插入左颈外静脉,用注射器将生理盐水(3ml/kg)、阿司匹林(30mg/kg)的生理盐水溶液、化合物2a-s(剂量为2.01mg/kg)的生理盐水溶液从另一端缓慢注入聚乙烯管中,此时管中原有的肝素已被推入左颈外静脉中,管内大部分为被测化合物溶液,然后将注射药物端插入右颈总动脉。血液从右颈总动脉经聚乙烯管流向左颈外静脉,15min后中断血流,取出丝线称重,总重量减去丝线重量即为血栓湿重。统计各组的血栓湿重的均值和标准差(X±S),并作t检验,结果列入下表1中。
表1化合物2a-s在大鼠模型上的抗血栓活性
化合物 | 血栓湿重(X±SDmg) |
NS | 20.97±3.18 |
Asprine | 13.22±1.67b |
2a | 10.20±3.01c |
2b | 16.03±5.52b |
2c | 10.48±2.19c |
2d | 14.80±3.93b |
2e | 17.49±4.83a |
2f | 8.50±4.02c |
2g | 13.51±5.97b |
2h | 9.54±5.09d |
2i | 14.07±3.52b |
2j | 9.56±3.18c |
2k | 11.77±5.45b |
2l | 14.97±4.72b |
2m | 13.20±7.25b |
2n | 16.40±4.81b |
2o | 10.81±3.73b |
2p | 10.67±3.57d |
2q | 13.06±3.68b |
2r | 8.23±3.21c |
2s | 15.71±6.93b |
n=11;NS=生理盐水;a)与生理盐水相比,P<0.05;b)与生理盐水相比,P<0.01;c)与Aspirin相比,P<0.01;d)与Aspirin相比,P<0.05。
从表中的数据可以看到,在2.01mg/kg剂量下,化合物2a-s都具有可以与30mg/kg剂量阿司匹林相比的抗血栓活性。其中2.01mg/kg剂量下的2a、2c、2f、2h、2j、2p和2r的抗血栓活性则比30mg/kg剂量下的阿司匹林明显增强。2a-s的抗血栓活性明显增强显然来自新的N-(1’-取代羧乙-1’-基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚的结构本身。
Claims (10)
2.根据权利要求1的通式I的化合物,该化合物是:
1-(1’-羧基-2’-基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
N-(1’-羧基-2’-甲基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-3’-甲基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基)甲基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-(4-羟基)苯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-吲哚基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-咪唑基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-3’-甲硫基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-羧基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-3’-羧基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-羟基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
14 1-(1’-羧基-2’-羟基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-4’-胍基)丁基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-甲酰胺基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-3’-甲酰胺基)丙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;
1-(1’-羧基-2’-巯基)乙基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚;或
1-(1’-羧基-5’-氨基)戊基-2,2-二甲基-4-氧代-四氢咪唑并[1’,2’:1,5]吡啶并[3,4-b]吲哚。
4.根据权利要求3所述的方法,其特征在于:所述催化L-色氨酸与甲醛进行Pictet-Spengler缩合的酸为硫酸。
5.根据权利要求3所述的方法,其特征在于:对咔啉羧酸的仲胺基进行保护时,所用的保护基为可脱除的氨基保护基,例如Boc、甲氧基苄基(PMB)或苄氧羰基(CBz)。
6.根据权利要求5所述的方法,其特征在于:所述保护基为Boc。
7.根据权利要求3所述的方法,其特征在于:脱保护的产物与丙酮的缩合反应在三乙胺催化下在甲醇中进行。
8.根据权利要求7所述的方法,其特征在于:所用甲醇与丙酮的体积比约为3∶1;或者,三乙胺的用量为使用其调节pH为9-9.5;或者,缩合反应在23-25℃的温度下进行;或者,缩合反应避光进行;或者,缩合反应时间为7-10天。
9.根据权利要求3所述的方法,其特征在于,该方法包括:L-色氨酸在稀硫酸催化下与甲醛进行Pictet-Spengler缩合反应,缩合生成的咔啉羧酸的仲胺基用Boc进行保护,所得N-Boc-咔啉羧酸与L-氨基酸甲酯进行偶联生成通式II的化合物,通式II的化合物用约4N的氯化氢乙酸乙酯脱除Boc,脱Boc的产物在三乙胺催化下在甲醇中与丙酮进行缩合反应,缩合所得产物在约2N NaOH溶液中进行皂化反应生成通式I化合物。
10.权利要求1所述的通式I化合物在制备抗血栓药物中的应用。
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CN102827245A (zh) * | 2011-06-13 | 2012-12-19 | 首都医科大学 | N-[2-(3-乙酰基-2-氧代-2h-吡啶-1-基)-乙酰]-l-氨基酸,其合成方法及应用 |
CN106349340A (zh) * | 2015-07-13 | 2017-01-25 | 首都医科大学 | 吡啶并吲哚并咪唑酮丁酰-Asp-氨基葡萄糖,其制备,活性和应用 |
WO2021103683A1 (zh) * | 2019-11-25 | 2021-06-03 | 长沙理工大学 | 一种基于甲醛媒介作用选择性检测l-酪氨酸的方法 |
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CN102250203A (zh) * | 2010-05-19 | 2011-11-23 | 首都医科大学 | β-咔啉类氨基酸苄酯及其制备和应用 |
CN102250203B (zh) * | 2010-05-19 | 2014-01-15 | 首都医科大学 | β-咔啉类氨基酸苄酯及其制备和应用 |
CN102827245A (zh) * | 2011-06-13 | 2012-12-19 | 首都医科大学 | N-[2-(3-乙酰基-2-氧代-2h-吡啶-1-基)-乙酰]-l-氨基酸,其合成方法及应用 |
CN106349340A (zh) * | 2015-07-13 | 2017-01-25 | 首都医科大学 | 吡啶并吲哚并咪唑酮丁酰-Asp-氨基葡萄糖,其制备,活性和应用 |
WO2021103683A1 (zh) * | 2019-11-25 | 2021-06-03 | 长沙理工大学 | 一种基于甲醛媒介作用选择性检测l-酪氨酸的方法 |
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