CN115403593B - 一种环加成合成手性嘌呤[3,2-c]并噁唑化合物的方法 - Google Patents
一种环加成合成手性嘌呤[3,2-c]并噁唑化合物的方法 Download PDFInfo
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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Abstract
本发明公开了一种环加成合成手性嘌呤[3,2‑c]并噁唑化合物的方法，属于医药中间体技术领域。以(E)‑2,6‑二取代‑9‑丙烯酸酯(1)和芳基环氧乙烷二羧酸二酯(2)为原料，在Ni(ClO4)2·6H2O和双齿噁唑啉配体存在下，有机溶剂中反应，得到手性嘌呤[3,2‑c]并噁唑化合物；当使用20％molNi(ClO4)2·6H2O和24％molL7作为催化剂时，能以94％收率和75％ee单一获得目标产物，并且通过结晶浓缩能以69％收率和95％ee得到目标产物，反应可克级规模进行。
Description
技术领域
本发明涉及一种通过[3+2]环加成合成手性嘌呤[3,2-c]并噁唑化合物的方法，属于医药中间体中的有机合成技术领域。
背景技术
三环嘌呤是一类重要的嘌呤衍生物，经常作为天然产物和药物分子的结构核心。因此，它们在药物发现中受到了极大的关注。有研究表明，一些三环嘌呤衍生物比其母体双环化合物具有更有效或更多样化的药理活性。例如，在茶碱上添加第三个环，从而形成三环茶碱衍生物II，将母体化合物的药理特征从兴奋剂转变为具有低温活性的镇静剂。此外，三环嘌呤核苷表现出更好的抗HIV活性高于其母体化合物3'-azido-3'-deoxy-guanosine(AZG)。
目前，手性嘌呤[3,2-c]并噁唑化合物的合成方法还没有报道，在路易斯酸的作用下，使用环氧乙烷与不饱和偶极子之间的[3+2]环加成反应是构建五元氧环的有效方法，在实验前期需要对手性配体，催化剂等进行大量的筛选。
因此，开发一种简单、高效的合成手性嘌呤[3,2-c]并噁唑化合物的方法是非常有必要的。
发明内容
为了解决上述技术问题，本发明公开了一种环加成合成手性嘌呤[3,2-c]并噁唑化合物的方法。以(E)-2,6-二取代-9-丙烯酸酯(1)和芳基环氧乙烷二羧酸二酯(2)为原料，在Ni(ClO4)2·6H2O和双齿噁唑啉配体存在下，有机溶剂中反应，得到手性嘌呤[3,2-c]并噁唑化合物。该方法为手性嘌呤[3,2-c]并噁唑化合物的合成提供了一种高效、便捷的途径。此外，将手性嘌呤[3,2-c]并噁唑化合物分别在NaBH4和NH3/C2H5OH存在下进一步反应，可还原酯基得到新手性嘌呤[3,2-c]并噁唑化合物。
本发明提供了嘌呤[3,2-c]并噁唑化合物，其特征在于：包括下述通式化合物中消旋体和对应的手性化合物。
其结构通式为其中，R1为C1-C4烷基；R2为氢、卤素、吡咯烷基；R3为氢、卤素、氨基；R4为羧酸甲酯、乙酰基、羧酸乙酯、羧酸叔丁酯、羧酸苄酯；Ar为苯基、取代苯基、萘基、呋喃基、噻吩基，取代苯基中取代基选自C1-C4烷基、卤素、C1-C4烷氧基、腈基、硝基中的一种或多种。
本发明还提供了上述嘌呤[3,2-c]并噁唑化合物在制备抑制HCT-116和SW480药物中的应用。
本发明所述环加成合成手性嘌呤[3,2-c]并噁唑化合物的方法，其反应方程式如下：
包括以下步骤：以(E)-2,6-二取代-9-丙烯酸酯(1)和芳基环氧乙烷二羧酸二酯(2)为原料，在路易斯酸催化剂和配体存在下，有机溶剂中反应，得到手性嘌呤[3,2-c]并噁唑化合物3；
其中，R1为C1-C4烷基；R2为氢、卤素、吡咯烷基；R3为氢、卤素、氨基；R4为羧酸甲酯、乙酰基、羧酸乙酯、羧酸叔丁酯、羧酸苄酯；Ar为苯基、取代苯基、萘基、呋喃基、噻吩基，取代苯基中取代基选自C1-C4烷基、卤素、C1-C4烷氧基、腈基、硝基中的一种或多种。
进一步地，在上述技术方案中，所述路易斯酸催化剂选自Sc(OTf)3、Yb(OTf)3、Fe(OTf)3、Ni(ClO4)2·6H2O等。在最优选条件下，最佳催化剂为Ni(ClO4)2·6H2O。
进一步地，在上述技术方案中，所述配体选自如下结构：
进一步地，在上述技术方案中，所述有机溶剂选自二氯甲烷、甲苯、氯苯、1,2-二氯乙烷中的一种，最佳溶剂为二氯甲烷。
进一步地，在上述技术方案中，所述(E)-2,6-二取代-9-丙烯酸酯(1)、芳基环氧乙烷二羧酸二酯(2)、路易斯酸催化剂与双齿噁唑啉配体摩尔比为1：2-3：0.01-0.02：0.012-0.024。
进一步地，在上述技术方案中，所述反应温度为-20℃至30℃，优选反应温度为0℃。
进一步地，在上述技术方案中，所述手性嘌呤[3,2-c]并噁唑化合物可进一步衍生，从而得到更多类型手性嘌呤[3,2-c]并噁唑化合物。例如在硼氢化钠作用下还原酯基，得到产物5和6，在NH3/C2H5OH作用下得到产物7，分别对应结构如下：
进一步地，在上述技术方案中，上述酯基还原反应在四氢呋喃和甲醇混合溶剂中进行，还原反应在氨乙醇中进行。
具体实施方式
实施例1:
a Unless otherwise noted,the reaction conditions were as follows:Ni(ClO4)2·6H2O(20 mol％),L(24 mol％),1a(0.1 mmol),2a(0.2 mmol),and in solvent(1mL)at room temperature under N2for 72 h.b Determinedby 1H NMR analysis withCH2Br2 as an internal standard.c Isolated yields.d Determined by chiral HPLCanalysis.e MS instead of/>MS.f/>MS instead of/>MS.g At 0℃for 72 h.h At-10℃for 72 h.i At-20℃for 72 h.j Ni(ClO4)2·6H2O(10 mol％)and L7(12mol％)wereused.k The data in parentheses refer to the results after enrichment viacrystallization.
aUnless otherwise noted,reaction conditions:Cat.(20mol％),L(24mmol％),1a(0.1mmol),2a(0.2mmol),andin solvent(1mL)atroomtemperatureunderN2for72 h.bDeterminedby 1H NMRanalysiswithCH2Br2as aninternal standard.cIsolatedyields.dDeterminedbychiralHPLC analysis.eAt0℃for72h.
在反应条件的筛选过程中，考察了配体、温度和溶剂对反应的影响，最终确定了Ni(ClO4)2·6H2O为最佳催化剂，L7为最佳配体，0℃为最佳反应温度，选定二氯甲烷为最佳溶剂。
反应条件的考察：
在氮气气氛下，向Schlenk管中加入Ni(ClO4)2.6H2O(20mol％)、L7(22mol％)和活化MS(60mg)。抽真空并用氮气回填3次。然后使用注射器将DCM(0.5mL)装入管中并在室温下搅拌直至形成蓝色复合物(约1小时)。在0℃下，向该混合物中加入嘌呤化合物1a(0.1mmol)和3-苯基环氧乙烷-2,2-二羧酸二乙酯2a(0.2mmol,2.0eq)/DCM(0.5mL)溶液。TLC监测反应完成，将混合物通过短硅胶垫，使用DCM作为流动相，真空浓缩得到粗产物，然后通过硅胶柱色谱(PE/EA＝5/1-3/1)纯化，得到51.7mg白色固体3a，94％yield,75％ee.通过方法A进一步结晶后浓缩得到产物37.9mg油状3a，69％yield,95％ee.[α]D 24＝65.7(c＝0.28,CH2Cl2).HPLC CHIRALCEL ID-H,n-hexane/2-propanol＝80/20,flow rate＝0.8mL/min,254nm,18.090min(minor),20.098min(major).TLC:Rf＝0.30(PE/EA＝4:1)[UV].1HNMR(600MHz,CDCl3)δ8.02(d,J＝14.4Hz,1H),7.57-7.52(m,2H),7.46-7.34(m,3H),7.03(s,1H),6.44(s,1H),5.94(d,J＝14.4Hz,1H),4.27-4.16(m,3H),4.13(dq,J＝10.8,7.2Hz,1H),4.06(dq,J＝10.8,7.2Hz,1H),3.97(dq,J＝10.8,7.2Hz,1H),1.28(t,J＝7.2Hz,3H),1.20(t,J＝7.2Hz,3H),1.14(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ166.7,166.4,165.1,157.5,152.9,139.6,135.7,134.9,129.9,128.7,126.8,127.8,103.5,95.3,86.4,84.3,63.5,63.1,60.6,14.5,13.85,13.81.HRMS(ESI):calcd for C24H25Cl2N4O7 +[M+H]+requires m/z551.1095,found m/z 551.1022.
化合物晶体富集方法A：将分离纯化的化合物缓慢滴加甲醇使化合物刚好溶解，再缓慢加入3-5倍体积的正己烷溶液，室温静置析出固体，收集并浓缩上清液。化合物结晶富集方法B：在分离纯化的化合物中缓慢滴加甲醇，使化合物刚好溶解，再缓慢加入3-5倍体积的正己烷溶液，-5℃静置析出固体，收集并浓缩上清液。
实施例2:
根据实施例1中最佳反应条件，仅仅将反应底物进行改变，反应结果如下：[b]代表通过方法A或B进一步结晶浓缩得到结果。
典型化合物表征数据如下：
3b,White solid,m.p.＝135.7-137.4℃.51％yield,98％ee(crystallizationby methodA).HPLC CHIRALCEL ID-H,n-hexane/2-propanol＝80/20,flow rate＝0.8mL/min,254nm,14.142min(minor),17.133min(major).[α]D 24＝87.3(c＝0.55,CH2Cl2).TLC:Rf＝0.35(PE/EA＝5:1).1H NMR(400MHz,CDCl3)δ8.03(d,J＝14.4Hz,1H),7.57-7.51(m,2H),7.42-7.36(m,3H),7.02(s,1H),6.43(s,1H),5.96(d,J＝14.2Hz,1H),4.24-4.09(m,2H),4.09-3.92(m,2H),3.74(s,3H),1.20(t,J＝7.2Hz,3H),1.13(t,J＝7.2Hz,3H).13CNMR(150MHz,CDCl3)δ166.8,166.7,165.1,157.5,152.9,139.6,135.7,135.0,129.8,128.7,126.7,103.0,95.3,86.4,84.3,63.5,63.1,51.7,13.8.HRMS(ESI):calcd forC23H22Cl2N4O7Na+[M+Na]+requires m/z 559.07 58,found m/z559.0762.
3e,White solid,m.p.118.2-120.8℃.32.1 mg,56％yield,95％ee(crystallization by methodA).HPLC CHIRALCEL ID-H,n-hexane/2-propanol＝80/20,flowrate＝0.8 mL/min,254 nm,10.230 min(minor),13.907 min(major).[α]D 24＝9.3(c＝0.22,CH2Cl2).TLC:Rf＝0.35(PE/EA＝5:1).1H NMR(600 MHz,CDCl3)δ8.01(d,J＝14.4 Hz,1H),7.35-7.29(m,2H),7.26(t,J＝7.8 Hz,1H),7.19(d,J＝7.2 Hz,1H),6.99(s,1H),6.44(s,1H),5.94(d,J＝14.4 Hz,1H),4.26-4.10(m,4H),4.05(dq,J＝10.8,7.2 Hz,1H),3.98(dq,J＝10.8,7.2 Hz,1H),2.37(s,3H),1.28(t,J＝7.2Hz,3H),1.20(t,J＝7.2 Hz,3H),1.14(t,J＝7.2 Hz,3H).13C NMR(150MHz,CDCl3)δ166.7,166.4,165.1,157.5,152.8,139.5,138.5,135.7,134.9,130.5,128.6,127.8,127.3,123.8,103.5,95.3,86.4,84.3,63.5,63.0,60.5,21.5,14.4,13.8.HRMS(ESI):calcd for C25H27Cl2N4O7 +[M+Na]+requiresm/z 587.1071,found m/z 587.1079.
3f,White solid,m.p.＝92.7-99.4℃.29％yield,99％ee(crystallization bymethod B).HPLC CHIRALCEL IE-H,n-hexane/2-propanol＝85/15,flow rate＝0.5mL/min,250 nm,13.163 min(minor),14.582 min(major).[α]D 24＝46.3(c＝0.24,CH2Cl2).TLC:Rf＝0.40(PE/EA＝5:1).1H NMR(400 MHz,CDCl3)δ8.02(d,J＝14.4 Hz,1H),7.50-7.36(m,2H),7.22-7.06(m,2H),6.94(s,1H),6.51(s,1H),6.12(d,J＝14.4Hz,1H),4.27-4.13(m,4H),4.13-3.99(m,2H),1.30(t,J＝7.2Hz,3H),1.18(t,J＝7.2Hz,3H),1.13(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ166.5,166.1,165.3,161.9,160.3,157.5,152.9,139.2,134.9,132.1(d,JC-F＝9.0Hz),128.9(d,JC-F＝3.0Hz),128.0,124.2(d,JC-F＝3.0Hz),123.8(d,JC-F＝12.0Hz),116.3(d,JC-F＝19.5Hz),103.8,93.7,86.5,84.6(d,JC-F＝3.0Hz),63.5,63.3,60.5,14.4,13.8,13.7.19F NMR(565MHz,CDCl3)δ-115.06.HRMS(ESI):calcd for C24H24Cl2FN4O7 +[M+H]+requires m/z 569.1001,found m/z 569.1008.
实施例3:
根据实施例1中最佳反应条件，仅仅将反应底物进行改变，反应结果如下：[b]代表通过方法A或B进一步结晶浓缩得到结果。[c]代表在室温条件下反应72小时。
典型化合物表征数据如下：
3ba,White solid,m.p.＝134.2-136.8℃.62％yield,98％ee(crystalliza tionby method A).HPLC CHIRALCEL OD-H,n-hexane/2-propanol＝80/20,flow rate＝0.6mL/min,250 nm,14.982 min(major),23.130 min(minor).[α]D 24＝66.7(c＝0.19,CH2Cl2).TLC:Rf＝0.35(PE/EA＝5:1).1H NMR(400 MHz,CDCl3)δ7.98(d,J＝14.4 Hz,1H),7.60-7.50(m,2H),7.44-7.33(m,3H),7.01(s,1H),6.47(s,1H),5.95(d,J＝14.4 Hz,1H),4.26-4.16(m,3H),4.16-4.03(m,2H),4.02-3.90(m,1H),1.28(t,J＝7.2 Hz,4H),1.20(t,J＝7.2Hz,3H),1.14(t,J＝7.2 Hz,3H).13C NMR(150 MHz,CDCl3)δ166.7,166.4,165.1,159.06(d,JC-F＝18.0Hz),157.4(d,JC-F＝219.0 Hz),139.93(d,JC-F＝16.5 Hz),135.8,134.7,129.8,128.7,126.8,103.7,95.6,86.4,85.0,63.5,63.1,60.6,14.4,13.8.19F NMR(565 MHz,CDCl3)δ-49.96.HRMS(ESI):calcd for C24H24Cl FN4O7Na+[M+Na]+requires m/z 557.1210,found m/z 557.1217.
3ca，Colorless oil.29％yield,31％ee.HPLC CHIRALCEL IG,n-hexane/2-propanol＝80/20,flow rate＝0.6 mL/min,250 nm,46.639 min(major),53.495 min(minor).[α]D 25＝-9.3(c＝0.12,CH2Cl2).TLC:Rf＝0.35(PE/EA＝2:1).1H NMR(600 MHz,CDCl3)δ8.50(s,1H),8.13(d,J＝14.4 Hz,1H),7.97(s,1H),7.54-7.50(m,2H),7.42-7.39(m,3H),6.58(s,1H),6.38(s,1H),5.96(d,J＝14.4 Hz,1H),4.25-4.15(m,3H),4.12(m,1H),4.04(m,2H),1.29(t,J＝7.2 Hz,3H),1.21(t,J＝7.2 Hz,3H),1.08(t,J＝7.2 Hz,3H).13C NMR(150 MHz,CDCl3)δ167.1,166.6,165.4,155.3,152.8,136.4,135.8,135.1,129.9,128.8,126.6,101.5,97.6,85.8,83.6,63.2,63.0,60.3,14.5,13.84,13.81.HRMS(ESI):calcd for C24H24ClFN4O7Na+[M+Na]+requires m/z 505.1694,found m/z 505.1699.
3ja,Colorless oil.69％yield,34％ee.HPLC CHIRALCEL AD-H,n-hexane/2-propanol＝80/20,flow rate＝0.8mL/min,250nm,10.316min(minor),13.562min(major).[α]D 25＝11.5(c＝0.15,CH2Cl2).TLC:Rf＝0.40(PE/EA＝4:1).1H NMR(600MHz,CDCl3)δ7.94(d,J＝14.4Hz,1H),7.57-7.51(m,2H),7.40-7.39(m,3H),7.04(s,1H),6.46(s,1H),6.30(d,J＝14.4Hz,1H),4.19(dq,J＝10.8,7.2Hz,1H),4.13(dq,J＝10.8,7.2Hz,1H),4.04(dq,J＝10.8,7.2Hz,1H),3.97(dq,J＝10.8,7.2Hz,2H),2.27(s,3H),1.21(t,J＝7.2Hz,3H),1.13(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ196.2,166.8,165.1,157.6,152.9,139.8,135.7,134.0,129.9,128.7,127.9,126.8,112.0,95.3,86.4,84.3,63.5,63.1,28.7,13.9,13.8.HRMS(ESI):calcd for C23H22Cl2N4O6Na+[M+Na]+requires m/z 543.0809,found m/z543.0814.
实施例4:克级规模验证
实施例5:
在反应管中，将化合物3a(0.1mmol,95％ee)溶解在THF/CH3OH(v/v＝1:1,1.0mL)中。然后分批添加NaBH4(6.0eq)。将反应混合物在室温下搅拌直至原料3a转化完毕。加入饱和NH4Cl水溶液(0.5mL)。水相EA(3×5mL)萃取，合并有机相浓缩，通过硅胶快速色谱法(PE/EA＝3/1)纯化残余物，得到23.7mg无色油状5，收率51％，98％ee和19.1mg白色固体6，收率44％，99％ee。化合物5：HPLC CHIRAL CEL ID-H,n-hexane/2-propanol＝80/20,flow rate＝0.8mL/min,254nm,9.460min(minor),11.780min(major).[α]D 25＝17.7(c＝0.15,CH2Cl2).TLC:Rf＝0.25(PE/EA＝3:1).1H NMR(400MHz,CDCl3)δ8.15(d,J＝14.4Hz,1H),7.60-7.52(m,2H),7.48-7.38(m,3H),6.51(s,1H),5.90(s,1H),5.74(d,J＝14.4Hz,1H),4.27-4.14(m,2H),3.77-3.55(m,4H),2.16(s,1H),2.00(s,1H),1.30(t,J＝7.2Hz,3H).13CNMR(150MHz,CDCl3)δ166.9,158.4,151.9,139.1,138.2,135.9,129.5,128.9,126.5,101.0,94.3,86.7,82.3,63.3,62.6,60.7,14.5.HRMS(ESI):calcd for C20H20Cl2N4O5Na+[M+Na]+requires m/z 489.0703,found m/z 489.0707；化合物6，熔点114.1-116.7℃。HPLCCHIRALCEL ID-H,n-hexane/2-propanol＝80/20,flow rate＝0.8mL/min,254nm,15.185min(major),21.582min(minor).[α]D 25＝7.8(c＝0.25,CH2Cl2).TLC:Rf＝0.30(PE/EA＝3:1).1H NMR(600MHz,CDCl3)δ8.14(d,J＝14.4Hz,1H),7.61-7.58(m,2H),7.45-7.41(m,3H),6.25(s,1H),5.77-5.70(m,2H),4.27-4.18(m,3H),3.78-3.63(m,2H),1.95(s,1H),1.30(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ166.6,157.7,153.1,140.1,138.6,134.9,129.6,129.1,128.9,126.6,101.4,95.7,82.4,81.2,61.8,60.7,14.5.HRMS(ESI):calcdfor C19H18Cl2N4O4Na+[M+Na]+requires m/z 459.0597,found m/z 459.0599.
实施例6:
在耐压反应管中，将化合物3a(0.1mmol)溶解在NH3/C2H5OH(2.0mL)中，反应混合物在90℃油浴中搅拌过夜。反应完成，将残余物通过硅胶快速色谱法(PE/EA＝3/1)纯化，得到32.9mg白色固体产物7，收率62％，97％ee。m.p.154.1-157.7℃.HPLC CHIRALCEL IA,n-hexane/2-propanol＝90/10,flow rate＝0.8mL/min,254nm,14.526min(major),16.443min(minor).[α]D 25＝67.9(c＝0.22,CH2Cl2).TLC:Rf＝0.30(PE/EA＝3:1).1H NMR(600MHz,CDCl3)δ8.01(d,J＝14.4Hz,1H),7.63-7.54(m,2H),7.46-7.33(m,3H),6.90(s,1H),6.34(s,1H),5.78(d,J＝14.4Hz,1H),5.08(s,2H),4.18(m,3H),4.14-3.87(m,3H),1.27(t,J＝7.2Hz,3H),1.21-1.11(m,6H).13C NMR(150MHz,CDCl3)δ167.2,165.3,159.1,157.4,151.3,141.1,136.5,136.0,129.5,129.0,128.5,127.6,127.0,120.0,101.0,96.4,86.6,84.2,63.2,62.8,60.3,14.5,13.8.HRMS(ESI):calcd for C19H19Cl2N4O4 +[M+H]+requires m/z 532.1594,found m/z 532.1520.
实施例7:
本发明采用上述方法合成了系列消旋化合物，并用MTT法测试了上述化合物对肿瘤细胞细胞活性。使用3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide(MTT)测定评估合成化合物细胞活性，将每孔5×103个细胞密度将细胞接种到96孔板中，将细胞培养在37℃/5％CO2培养箱中24h。然后用各种梯度稀释浓度化合物，对照药物5-FU或者稀释剂(DMSO)处理48h。将含化合物、5-FU或稀释剂(DMSO)培养基更换成180μL新鲜培养基以及20μL MTT溶液(5mg/mLPBS溶液)，放置于37℃，5％CO2培养箱中孵育4h，然后将含有MTT培养基更换成DMSO(150μL)，用酶标仪(Multiskan FC/Thermo)在570nm波长处测定每个空吸光度，每个浓度测试三次。数据通过GraphPad Pism 6软件进行分析。代表性化合物的抗肿瘤活性结果如下：
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (6)
1.嘌呤[3,2-c]并噁唑化合物，其特征在于：包括下述通式化合物中消旋体和对应的手性化合物，其结构通式为其中：R1为C1-C4烷基；R2为氢、卤素、吡咯烷基；R3为氢、卤素、氨基；R4为羧酸甲酯、乙酰基、羧酸乙酯、羧酸叔丁酯、羧酸苄酯；Ar为苯基、取代苯基、萘基、呋喃基、噻吩基，取代苯基中取代基选自C1-C4烷基、卤素、C1-C4烷氧基、腈基、硝基中的一种或多种。
2.如权利要求1所述嘌呤[3,2-c]并噁唑化合物在制备抑制HCT-116和SW480药物中的应用。
3.一种环加成合成手性嘌呤[3,2-c]并噁唑化合物的方法，其特征在于，包括如下步骤：以(E)-2,6-二取代-9-丙烯酸酯(1)和芳基环氧乙烷二羧酸二酯(2)为原料，在路易斯酸催化剂和配体存在下，有机溶剂中反应，得到手性嘌呤[3,2-c]并噁唑化合物3；其反应方程式如下：
其中，R1为C1-C4烷基；R2为氢、卤素、吡咯烷基；R3为氢、卤素、氨基；R4为羧酸甲酯、乙酰基、羧酸乙酯、羧酸叔丁酯、羧酸苄酯；Ar为苯基、取代苯基、萘基、呋喃基、噻吩基，取代苯基中取代基选自C1-C4烷基、卤素、C1-C4烷氧基、腈基、硝基中的一种或多种；所述路易斯酸催化剂选自Ni(ClO4)2·6H2O；所述配体选自
4.根据权利要求3所述环加成合成手性嘌呤[3,2-c]并噁唑化合物的方法，其特征在于：(E)-2,6-二取代-9-丙烯酸酯(1)、芳基环氧乙烷二羧酸二酯(2)、路易斯酸催化剂与双齿噁唑啉配体摩尔比为1：2-3：0.01-0.02：0.012-0.024。
5.根据权利要求3所述环加成合成手性嘌呤[3,2-c]并噁唑化合物的方法，其特征在于：有机溶剂选自二氯甲烷、甲苯、氯苯或1,2-二氯乙烷；反应温度为-20℃至30℃。
6.一种合成手性嘌呤[3,2-c]并噁唑化合物的方法，其特征在于，包括如下步骤：采用权利要求3-5中任意一项得到手性嘌呤[3,2-c]并噁唑化合物3，然后手性嘌呤[3,2-c]并噁唑化合物3在硼氢化钠作用下还原得到产物5和6；或在NH3/C2H5OH作用下得到产物7，分别对应结构如下：
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| CN108864115A (zh) * | 2018-08-08 | 2018-11-23 | 河南师范大学 | [3+2]环加成不对称脱芳构化合成手性非芳香嘌呤核苷的方法 |
| CN109485661A (zh) * | 2018-11-23 | 2019-03-19 | 河南师范大学 | [3+2]环加成合成苯并唑并噁唑类化合物的方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2004303445A1 (en) * | 2003-12-24 | 2005-07-07 | Biota Scientific Management Pty Ltd | Polycyclic agents for the treatment of respiratory syncytial virus infections |
| CN108864115A (zh) * | 2018-08-08 | 2018-11-23 | 河南师范大学 | [3+2]环加成不对称脱芳构化合成手性非芳香嘌呤核苷的方法 |
| CN109485661A (zh) * | 2018-11-23 | 2019-03-19 | 河南师范大学 | [3+2]环加成合成苯并唑并噁唑类化合物的方法 |
Non-Patent Citations (1)
| Title |
|---|
| Meng-Cheng Zhang,et al..Highly Chemoselective Synthesis of Purino[3,2‑c]oxazoles via the Asymmetric Dearomative [3+2] Cycloaddition of Purines with Donor−Acceptor Oxiranes.《Org. Lett.》.2022,第24卷7527-7532. * |
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