CN102503887B - 一种制备1-(n-取代氨基)异喹啉类化合物方法 - Google Patents

一种制备1-(n-取代氨基)异喹啉类化合物方法 Download PDF

Info

Publication number
CN102503887B
CN102503887B CN201110341011.2A CN201110341011A CN102503887B CN 102503887 B CN102503887 B CN 102503887B CN 201110341011 A CN201110341011 A CN 201110341011A CN 102503887 B CN102503887 B CN 102503887B
Authority
CN
China
Prior art keywords
substituted
amino
reaction
isoquinoline compound
agotf
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201110341011.2A
Other languages
English (en)
Other versions
CN102503887A (zh
Inventor
黎文海
王越
陆涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CN201110341011.2A priority Critical patent/CN102503887B/zh
Publication of CN102503887A publication Critical patent/CN102503887A/zh
Application granted granted Critical
Publication of CN102503887B publication Critical patent/CN102503887B/zh
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

本发明涉及有机化学领域,具体涉及一种制备1-(N-取代氨基)异喹啉类化合物的方法。

Description

一种制备1-(N-取代氨基)异喹啉类化合物方法
技术领域
本发明涉及有机化学技术领域,具体为一种制备1-(N-取代氨基)异喹啉类化合物方法。 
背景技术
1-(N-取代氨基)异喹啉类化合物具有多种药理活性,例如抗肿瘤活性(Smith,A.L.,F.F.De Morin,et al.J.Med.Chem.52(20):6189-6192)、抗癌活性(Pierre,F.,P.C.Chua,et al.J.Med.Chem.54(2):635-654)。因此,它的合成受到人们的广泛关注。当前,合成1-(N-取代氨基)异喹啉类化合物方法主要是通过相应卤代异喹啉类化合物胺化来实现,通常需要强碱、高温、或贵金属催化剂。而卤代异喹啉类化合物的合成需要多步反应才能完成而且使用腐蚀性极强的POCl3等试剂。因此,开发以简单结构起始反应物,一步合成高度取代的1-(N-取代氨基)异喹啉类化合物具有重要意义。本发明提供了一种简单、方便、高效的制备高度取代的1-(N-取代氨基)异喹啉类化合物的新技术。 
发明内容
本发明使用邻炔基苯甲醛肟在温和条件下与异氰酸酯反应,在路易斯酸催化下发生环合反应并发生分子内重排,制得1-(N-取代氨基)异喹啉类化合物,其反应式如下: 
Figure BSA00000603826000011
其中化合物1邻炔基苯甲肟的R1为H或CH3,OCH3等各种供电子基团或F,Cl,CF3等各种吸电子基团,R2为H,n-Bu,cyclopropyl,Ph或4-Me-C6H4,4-MeOC6H4等各种供电子基团的芳香取代基,或4-Cl-C6H4等含吸电子基团的芳香取代基,化合物2异氰酸酯的R3为CH2COO(CH2)mCH3,CH2COPh,Ph或4-Me-C6H4,4-MeOC6H4等各种供电子基团的芳香取代基,或4-Cl-3-CF3-C6H4等含吸电子基团的芳香取代基;m=1至5。 
具体操作步骤为: 
邻炔基苯甲醛肟,异氰酸酯溶于有机溶剂中,加入路易斯酸,于室温反应至反应完全,浓缩后用柱层析分离得到相应的1-(N-取代氨基)异喹啉类化合物。 
该反应收率高,反应在中性环境中进行,无需碱参与,条件温和,操作方便,底物的适用范围广, 成本较低,副反应少,产品纯度高,可适合较大规模的制备,而且此类化合物具有多种生物活性,在新药研发领域有较好的运用前景。 
本发明的较佳反应条件为: 
(1)路易斯酸为AgOTf 
(1)邻炔基苯甲醛肟、AgOTf与异氰酸酯的摩尔比例为1∶0.1∶1.1; 
(2)溶剂为二氯甲烷; 
(3)反应温度为室温。 
具体实施方式
下面的实施例是对本发明的进一步说明,而不是限制本发明的范围。 
实施例1 N-(2-甲氧基-2-氧代-乙基)-3-苯基-1-氨基异喹啉的合成 
2-(2-苯乙炔基)苯甲醛肟(0.30mmol),2-甲氧基-2-氧代乙基异氰酸(0.33mmol)溶于2mL二氯甲烷中,加入AgOTf(0.03mmol),于室温反应24小时,浓缩后用柱层析分离得到相应的1-(N-取代氨基)异喹啉类化合物3a,收率89%。1H NMR(500MHz,CDCl3)δ8.14(d,J=7.5Hz,2H),7.91(s,1H),7.77(d,J=8.1Hz,1H),7.62(t,J=7.4Hz,1H),7.46-7.51(m,4H),7.27(s,1H),5.86(s,1H),4.53(d,J=4.9Hz,2H),3.84(s,3H),1.54(s,6H);13C NMR(75MHz,CDCl3):δ172.18,153.75,137.91,129.99,128.44,128,19,127.54,126.53,125.92,121.71,117.41,107.73,52.16,43.88;HRMS(ESI)calcd for C18H17N2O2:293.1285(M+H+),found:293.1277 
实施例2 N-(2-甲氧基-2-氧代-乙基)-3-苯基-6-氟-1-氨基异喹啉的合成 
Figure BSA00000603826000022
2-(2-苯乙炔基)-4-氟苯甲醛肟(0.30mmol),2-甲氧基-2-氧代乙基异氰酸(0.33mmol)溶于2mL二氯甲烷中,加入AgOTf(0.03mmol),于室温反应24小时,浓缩后用柱层析分离得到相应的1-(N-取代氨基)异喹啉类化合物3b,收率87%。1H NMR(300MHz,CDCl3)δ8.10(d,J=8.4Hz,2H),7.85-7.82(m,1H),7.44-7.50(m,2H),7.32-7.41(m,2H),7.26-7.39(m,1H),7.09-7.15(m,1H),6.02(s,1H),4.48(d,J=5.1Hz,2H),3.83(s,3H); 13C NMR(75MHz,CDCl3):δ172.21,163.35(d,1JCF=248.6Hz),153.69,139.83(d,3JCF=10.1Hz),129.92,128.51,127.67,126.63,124.72,115.47(d,2JCF=24.6Hz),114.34(d,2JCF=20.5Hz),107.34(d,2JCF=3.5Hz),52.25,43.86;HRMS(ESI)calcd for C18H16FN2O2:311.1190(M+H+),found:311.1181 
实施例3 N-(2-乙氧基-2-氧代-乙基)-3-丁基-1-氨基异喹啉的合成 
Figure BSA00000603826000031
2-(2-丁基乙炔基)苯甲醛肟(0.30mmol),2-乙氧基-2-氧代乙基异氰酸(0.33mmol)溶于2mL二氯甲烷中,加入AgOTf(0.03mmol),于室温反应24小时,浓缩后用柱层析分离得到相应的1-(N-取代氨基)异喹啉类化合物3c,收率82%。1H NMR(300MHz,CDCl3):δ7.79(d,J=8.4Hz,1H),7.59(d,J=7.8Hz,1H),7.46-7.54(m,1H),7.34-7.39(m,1H),6.79(s,1H),5.77(s,1H),4.37(d,J=5.1Hz,2H),4.22-4.29(m,2H),2.70(t,J=7.5Hz,2H),1.69-1.80(m,2H),1.37-1.44(m,2H),1.28-1.34(m,3H),0.96-0.98(m,3H);13C NMR(75MHz,CDCl3):δ171.77,153.65,137.81,129.51,126.57,124.91,121.49,108.96,61.06,43.86,37.64,31.34,22.42,14.17;HRMS(ESI)calcd for C17H23N2O2:287.1754(M+H+),found:287.1743 
实施例4 N-苄基-3-苯基-6-氟-1-氨基异喹啉的合成 
Figure BSA00000603826000032
2-(2-苯乙炔基)-4-氟苯甲醛肟(0.30mmol),2-苯基甲基异氰酸(0.33mmol)溶于2mL二氯甲烷中,加入AgOTf(0.03mmol),于室温反应24小时,浓缩后用柱层析分离得到相应的1-(N-取代氨基)异喹啉类化合物3d,收率82%。1H NMR(300MHz,CDCl3):δ8.09-8.13(m,2H),7.67-7.72(m,1H),7.41-7.50(m,4H),7.23-7.38(m,6H),7.08-7.26(m,1H),5.44(s,1H),4.94(d,J=5.1Hz,2H);13C NMR(75MHz,CDCl3):δ163.21(d,1JCF=248.4Hz),154.24,150.25,139.99(d,3JCF=10.1Hz),139.79,139.72,128.66,128.41,128.11,127.32,127.08,126.76,124.17(d,3JCF=9.0Hz),115.08(d,2JCF=24.8Hz),114.20,111.13(d,2JCF=20.3Hz),106.66(d,4JCF=4.2Hz),45.95;HRMS(ESI)calcd for C22H18FN2:329.1449(M+H+),found:329.1440 
实施例5 N-(4-氯-3-三氟甲基苯基)-3-苯基-6,7-二甲氧基-1-氨基异喹啉的合成 
Figure BSA00000603826000041
2-(2-苯乙炔基)-4,5-二甲氧基苯甲醛肟(0.30mmol),4-氯-3-三氟甲基苯基异氰酸(0.33mmol)溶于2mL二氯甲烷中,加入AgOTf(0.03mmol),于室温反应24小时,浓缩后用柱层析分离得到相应的1-(N-取代氨基)异喹啉类化合物3e,收率95%。1H NMR(300MHz,CDCl3):δ8.36(d,J=2.4Hz,2H),8.04-8.07(m,2H),7.72(dd,J1=8.7Hz,J2=2.4Hz,2H),7.55(s,1H),7.34-7.49(m,4H),7.05(s,1H),6.98(s,1H),6.93(s,1H),4.01(s,1H),3.99(s,3H);13C NMR(75MHz,CDCl3):δ152.61,149.75,149.36,147.26,139.67,139.24,134.84,128.60,128.42,126.26(q,1JCF=256.2Hz),126.25,122.97,118.49,118.42,118.34,118.27,112.49,109.69,106.51,100.35,56.09,55.93;HRMS(ESI)calcd for C24H19ClF3N2O2:459.1087(M+H+),found:459.1093 
实施例6 N-苯基-3-环丙基-6-氟-1-氨基异喹啉的合成 
Figure BSA00000603826000042
2-(2-环丙乙炔基)苯甲醛肟(0.30mmol),苯基异氰酸(0.33mmol)溶于2mL二氯甲烷中,加入AgOTf(0.03mmol),于室温反应24小时,浓缩后用柱层析分离得到相应的1-(N-取代氨基)异喹啉类化合物3f,收率84%。 1H NMR(300MHz,CDCl3):δ7.79-7.84(m,1H),δ7.63-7.66(m,1H),7.31-7.37(m,2H),7.21-7.24(m,2H),7.09-7.16(m,1H),7.02-7.07(m,2H),6.96(s,1H),1.98-2.07(m,1H),1.10-1.25(m,2H),0.93-0.97(m,2H);13CNMR(75MHz,CDCl3):δ163.32(d,1JCF=229.2Hz),155.27,151.75,140.46,140.16(d,3JCF=10.2Hz),128.82,124.54(d,3JCF=9.6Hz),122.54,119.90,114.74(d,2JCF=24.9Hz),113.96,110.09(d,2JCF=20.4Hz),109.18(d, 4JCF=4.2Hz),16.93,8.88;HRMS(ESI)calcd for C18H16FN2:279.1298(M+H+),found:279.1302 。

Claims (1)

1.一种1-(N-取代氨基)异喹啉类化合物的制备方法,其特征在于在邻位具有炔基取代的苯甲醛肟在温和条件下与异氰酸酯反应,在AgOTf催化下发生环合反应并发生分子内重排,制得1-(N-取代氨基)异喹啉类化合物,其反应式如下:
Figure FSB0000114281250000011
具体操作步骤为:
将邻炔基苯甲醛肟,异氰酸酯溶于二氯甲烷中,加入AgOTf,邻炔基苯甲醛肟、异氰酸酯和AgOTf的摩尔比例为1∶1.1∶0.1,于室温反应至反应完全,浓缩后用柱层析分离得到相应的1-(N-取代氨基)异喹啉类化合物;
R1为H,CH3,OCH3,F,Cl;
R2为n-Bu,环丙烷基,Ph;
R3为CH2COO(CH2)mCH3,Ph,4-Me-C6H4,4-Cl-3-CF3-C6H4;m=1至5。
CN201110341011.2A 2011-11-02 2011-11-02 一种制备1-(n-取代氨基)异喹啉类化合物方法 Expired - Fee Related CN102503887B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201110341011.2A CN102503887B (zh) 2011-11-02 2011-11-02 一种制备1-(n-取代氨基)异喹啉类化合物方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201110341011.2A CN102503887B (zh) 2011-11-02 2011-11-02 一种制备1-(n-取代氨基)异喹啉类化合物方法

Publications (2)

Publication Number Publication Date
CN102503887A CN102503887A (zh) 2012-06-20
CN102503887B true CN102503887B (zh) 2014-04-23

Family

ID=46216037

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201110341011.2A Expired - Fee Related CN102503887B (zh) 2011-11-02 2011-11-02 一种制备1-(n-取代氨基)异喹啉类化合物方法

Country Status (1)

Country Link
CN (1) CN102503887B (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103319405A (zh) * 2013-06-15 2013-09-25 复旦大学 一种多取代的异喹啉氮氧偶极子化合物的制备方法
CN103965165B (zh) * 2014-05-15 2017-01-04 复旦大学 一种抑制凋亡抑制蛋白的异喹啉化合物及其制备方法与应用

Also Published As

Publication number Publication date
CN102503887A (zh) 2012-06-20

Similar Documents

Publication Publication Date Title
Qin et al. Rh (III)-catalyzed oxime ether-directed heteroarylation of arene through oxidative C–H/C–H cross-coupling
CN105294536B (zh) 一种制备3-亚氨基异吲哚啉酮类化合物的方法
CN105001028A (zh) 一种不对称共轭二炔烃类化合物的合成方法
Demir et al. Gold (I)/Zn (II) catalyzed tandem hydroamination/annulation reaction of 4-yne-nitriles
CN103224436A (zh) 一种邻氨基二芳基甲酮化合物的制备方法
Lu et al. Palladium-catalyzed allylation of tautomerizable heterocycles with alkynes
Wang et al. Palladium-catalyzed one pot 2-arylquinazoline formation via hydrogen-transfer strategy
CN102503887B (zh) 一种制备1-(n-取代氨基)异喹啉类化合物方法
Shen et al. One-pot synthesis of 4 (3H)-quinazolinones from azides, alkynes, anilines, and carbon monoxide
CN105013535B (zh) 一种制备不对称共轭二炔烃类化合物的催化剂及其合成方法
CN112480015B (zh) 一种多组分一锅法合成2-三氟甲基取代的喹唑啉酮的方法
CN102399164B (zh) 一种由硝基甲烷合成氯霉素的方法
CN113651813A (zh) 一种2,3-二氢喹啉-4-酮生物活性骨架及其合成方法和应用
Xu et al. Synthesis of 5-alkyl-5-aryl-γ-lactams from 1-aryl-substituted nitroalkanes and methyl acrylate via Michael addition and reductive lactamization
CN101786983A (zh) 2-氨基-1,2-二氢异喹啉化合物的制备方法
JP6119022B2 (ja) 軸不斉を有するピリジン誘導体又はその塩、及びその製造方法並びにそれからなる不斉触媒
CN105001029A (zh) 一种光催化二芳基醚衍生物的合成方法
CN102399163B (zh) 一种由4-氯苯甲醛制备氯霉素的方法
Jiang et al. Reactions of methylenecyclopropanes and vinylidenecyclopropanes with N-fluorodibenzenesulfonimide
WO2015115519A1 (ja) ビピリジル化合物
CN101812022B (zh) 芳基嘧啶的邻位单乙酰氧基取代化合物及其方法
CN102633802A (zh) 一种合成2-氯-7H-吡咯并[2,3-d]嘧啶的中间体及其制法
CN104327025B (zh) 一种4-芳基萘内酯类衍生物的制备方法
CN103848830A (zh) 合成咪唑并[1,2-a]吡啶衍生物的一种简易方法
CN103214394B (zh) 一种炔基亚胺衍生物

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20140423

Termination date: 20141102

EXPY Termination of patent right or utility model