CN103772375A - 一种合成2,5-二羰基哌嗪类化合物的方法 - Google Patents
一种合成2,5-二羰基哌嗪类化合物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 28
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- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- -1 heteroaromatic aldehyde Chemical class 0.000 claims abstract description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 3
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- 150000004885 piperazines Chemical class 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Chemical group 0.000 claims description 2
- 229910052760 oxygen Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 abstract description 34
- 238000006058 Ugi-reaction Methods 0.000 abstract description 8
- 125000005842 heteroatom Chemical group 0.000 abstract description 5
- 150000001408 amides Chemical class 0.000 abstract description 3
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- 230000035484 reaction time Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
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- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 11
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- 238000010189 synthetic method Methods 0.000 description 11
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- 150000001299 aldehydes Chemical class 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
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- ZGTFNNUASMWGTM-UHFFFAOYSA-N 1,3-thiazole-2-carbaldehyde Chemical compound O=CC1=NC=CS1 ZGTFNNUASMWGTM-UHFFFAOYSA-N 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 238000005457 optimization Methods 0.000 description 1
- WPYJKGWLDJECQD-UHFFFAOYSA-N quinoline-2-carbaldehyde Chemical compound C1=CC=CC2=NC(C=O)=CC=C21 WPYJKGWLDJECQD-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及一种合成2,5-二羰基哌嗪类化合物的方法，反应中所述溶剂为甲醇、反应温度为45℃、反应时长为10-20小时，所述的R1为对4-甲基苯基，正丙级或苄基，所述的R2为甲氧酰基或乙氧酰基，所述醛为α位为杂原子的芳杂环醛。本发明中涉及的Ugi反应所使用的醛为α位为杂原子的芳杂环醛，这类醛参与Ugi反应后，其芳环上的杂原子能与Ugi产物中的酰胺形成分子内氢键，从而促进Micheal反应的顺利进行，实现反应条件温和的目的，所有反应一次完成，方便快速。
Description
技术领域
本发明涉及有机合成领域，尤其是一种合成2,5-二羰基哌嗪类化合物的方法，涉及利用Ugi反应与Micheal反应联用合成2,5-二羰基哌嗪类化合物。
背景技术
2,5-二羰基哌嗪（2,5-DKPs）类化合物是一类重要的杂环化合物，广泛存在于天然产物和食品药品中，具有良好的生物活性和较高的药用价值，受到各国科学家的关注。早期报道了各种合成这类化合物的方法，比如缩肽合成法，Ugi合成法，分子内Wittig合成法等，逐渐发展出了一系列行之有效的合成2,5-二羰基哌嗪类化合物的方法。
近期Santra和Andreana两位科学家报道了用Ugi反应与Micheal反应联用的策略，快速高效合成出一系列2,5-二羰基哌嗪类化合物。但是该反应需要微波辅助加热且反应条件较为苛刻（300W,200°C,and18bar）；当大位阻取代基的异腈（如叔丁基异腈）作为反应物时，未能得到预期的产物。这就为后续反应条件的优化创新留下了巨大的空间。
发明内容
本发明的目的是提供一种合成2,5-二羰基哌嗪类化合物的方法，本方法在温和的条件下应用Ugi反应与Micheal反应联用一锅煮的策略合成2,5-二羰基哌嗪类化合物，使大位阻取代基异腈（如叔丁基异腈）具有良好的底物试用性。
本发明实现目的的技术方案如下：
一种合成2,5-二羰基哌嗪类化合物的方法，合成路线如下：
所述溶剂为甲醇、反应温度为45℃、反应时长为10-20小时，所述的R1为对4-甲基苯基，正丙级或苄基，所述的R2为甲氧酰基或乙氧酰基，所述醛为α位为杂原子的芳杂环醛。
而且，所述X为氮或氧。
而且，所述的R3为叔丁基，正丁基，环己基或苄基。
本发明的优点和积极效果如下：
1、本发明中涉及的Ugi反应所使用的醛为α位为杂原子的芳杂环醛，这类醛参与Ugi反应后，其芳环上的杂原子能与Ugi产物中的酰胺形成分子内氢键，从而促进Micheal反应的顺利进行，实现反应条件温和的目的，所有反应一次完成，方便快速。
2、本申请首次运用新方法合成出了一系列2,5-DKPs类化合物，在建立该类化合物库的合成应用方面具有广阔的前景，适用于大位阻取代基异腈（如叔丁基异腈）。
具体实施案例
下面结合实施例，对本发明进一步说明，下述实施例是说明性的，不是限定性的，不能以下述实施例来限定本发明的保护范围。
一种合成2,5-二羰基哌嗪类化合物的方法，反应机理如下式所示：
本发明Ugi反应所使用的醛为α位为杂原子的芳杂环醛。这类醛参与Ugi反应后，其芳环上的杂原子能与Ugi产物中的酰胺形成分子内氢键，从而促进Micheal反应的顺利进行，实现反应条件温和的目的。
通过以下合成路线，应用Ugi反应与Micheal反应的联用，一锅煮合成出一系列的2,5-二羰基哌嗪类化合物。已合成的2,5-二羰基哌嗪类化合物的命名与结构如下表所示：
表1
具体命名与结构如上表1所示。
以上2,5-二羰基哌嗪类化合物均是通过以下合成通法合成的：
在圆底烧瓶中加入2.0mL甲醇，依次加入Ugi反应的四个组分，醛（0.20mmol）、胺（0.20mmol）、酸（0.20mmol）和异腈（0.24mmol），然后加热至45℃反应，10-20h后点板检测反 应完全后，用乙酸乙酯：二氯甲烷：石油醚=1：1：10至1：1：5作为流动相，柱层析得到表1所示各化合物，收率：62-96%。
下面通过实施例具体说明。
实施例1
在圆底烧瓶中加入2.0mL甲醇，依次加入，噻唑-2-醛22.6mg（0.20mmol）、对甲苯胺21.4mg（0.20mmol）、马来酸单甲酯26.0mg（0.20mmol）和叔丁基异腈16.6mg（0.24mmol），然后加热至45℃反应，10-20h后点板检测反应完全后，用乙酸乙酯：二氯甲烷：石油醚=1：1：10至1：1：5作为流动相，柱层析得到化合物172.2mg，收率：87%。
化合物1（结构如下式所示）的合成。
实施例1的合成方法同上述合成通法。
白色固体；收率：87%。
1H NMR(400MHz,DMSO-d6):δ8.87(s,0.5H,Ha),8.59(s,0.5H,Ha),7.90(t,J=3.2Hz,1H,thiazole),7.83(t,J=3.6Hz,1H,thiazole),7.21～6.92(m,4H,aryl),4.12(dd,J=5.2,10.8Hz,0.5H,Hb),3.87(dd,J=6.8,8.8Hz,0.5H,Hb),3.60(s,1.5H,-OCH 3),3.51(s,1.5H,-OCH 3),2.89～2.86(m,1H,Hc),2.71(dd,J=5.2,17.6Hz,0.5H,Hc),2.22(s,3H,-CH 3),2.13(dd,J=10.8,17.6Hz,0.5H,Hc),1.36(s,4.5H,t-Bu),1.32(s,4.5H,t-Bu)。
实施例2
在圆底烧瓶中加入2.0mL甲醇，依次加入，咪唑-2-甲醛19.2mg（0.20mmol）、对甲苯胺21.4mg（0.20mmol）、马来酸单甲酯26.0mg（0.20mmol）和叔丁基异腈16.6mg（0.24mmol），然后加热至45℃反应，10-20h后点板检测反应完全后，用乙酸乙酯：二氯甲烷：石油醚=1：1：10至1：1：5作为流动相，柱层析得到化合物253.4mg，收率：67%。
化合物2（结构如下式所示）的合成。
实施例2的合成方法同上述合成通法。
白色固体；收率：67%。
1H NMR(400MHz,DMSO-d6):δ12.64(s,0.3H,NH),12.51(s,0.7H,NH),10.50(s,0.3H,Ha),10.37(s,0.7H,Ha),7.21～6.92(m,6H,imidazol and aryl overlap),3.87～3.79(m,1H,Hb),3.55(s,1H,-OCH 3),3.47(s,2H,-OCH 3),2.87～2.69(m,1.3H,Hc),2.21(s,1H,-CH 3),2.20(s,2H,-CH 3),2.04(dd,J=11.2,17.2Hz,0.7H,Hc),1.36(s,6H,t-Bu),1.33(s,3H,t-Bu)。
实施例3
在圆底烧瓶中加入2.0mmL甲醇，依次加入，吡啶-2-甲醛21.4mg（0.20mmol）、对甲苯胺21.4mg（0.20mmol）、马来酸单甲酯26.0mg（0.20mmol）和叔丁基异腈16.6mg（0.24mmol），然后加热至45℃反应，10-20h后点板检测反应完全后，用乙酸乙酯：二氯甲烷：石油醚=1：1：10至1：1：5作为流动相，柱层析得到化合物350.7mg，收率：62%。
化合物3（结构如下式所示）的合成。
实施例3的合成方法同上述合成通法。
白色固体；收率：62%。
1H NMR(400MHz,DMSO-d6):δ9.33(s,0.2H,Ha),9.08(s,0.8H,Ha),8.47(t,J=4.4Hz,1H,Py),7.91～7.86(m,1H,Py),7.50～7.42(m,1H,Py),7.34(d,J=8.8Hz,0.8H,Py),7.13～7.05(m,4H,aryl),4.00(dd,J=5.2,10.8Hz,0.8H,Hb),3.89(t,J=7.6Hz,0.2H,Hb),3.61(s,0.6H,-OCH 3),3.49(s,2.4H,-OCH 3),2.81(t,0.4H,Hc),2.66(dd,J=4.8,17.2Hz,0.8H,Hc),2.51(s,2.4H,-CH 3),2.50(s,0.6H,-CH 3),2.04(dd,J=10.4,17.2Hz,0.8H,Hc),1.37(s,7.2H,t-Bu),1.34 (s,2.8H,t-Bu)。
实施例4
在圆底烧瓶中加入2.0mL甲醇，依次加入，喹啉-2-甲醛31.4mg（0.20mmol）、对甲苯胺21.4mg（0.20mmol）、马来酸单甲酯26.0mg（0.20mmol）和叔丁基异腈16.6mg（0.24mmol），然后加热至45℃反应，10-20h后点板检测反应完全后，用乙酸乙酯：二氯甲烷：石油醚=1：1：10至1：1：5作为流动相，柱层析得到化合物488.2mg，收率：96%。
化合物4（结构如下式所示）的合成。
实施例4的合成方法同上述合成通法。
白色固体；收率：96%。
1H NMR(400MHz,DMSO-d6):δ9.80(s,0.9H,Ha),8.47(d,J=8.8Hz,1H,Py),8.01(dd,J=8.4,17.2Hz,2H,aryl),7.89(t,J=7.2Hz,1H,aryl),7.72(t,J=7.2Hz,1H,aryl),7.61(d,J=8.8Hz,0.1H,Py),7.43(d,J=8.8Hz,0.9H,Py),7.16～7.06(m,4H,aryl),4.06(d,J=4.8Hz,0.9H,Hb),3.92(t,0.1H,Hb),3.59(s,0.3H,-OCH 3),3.37(s,2.7H,-OCH 3),2.86(t,0.2H,Hc),2.66(dd,J=4.8,17.2Hz,0.9H,Hc),2.24(s,2.7H,-CH 3),2.20(s,0.3H,-CH 3),1.91(dd,J=11.2,17.2Hz,0.9H,Hc),1.42(s,9H,t-Bu)。
实施例5
在圆底烧瓶中加入2.0mL甲醇，依次加入，3-苯基异恶唑-5-甲醛34.6mg（0.20mmol）、对甲苯胺21.4mg（0.20mmol）、马来酸单甲酯26.0mg（0.20mmol）和叔丁基异腈16.6mg（0.24mmol），然后加热至45℃反应，10-20h后点板检测反应完全后，用乙酸乙酯：二氯甲烷：石油醚=1：1：10至1：1：5作为流动相，柱层析得到化合物588.2mg，收率：96%。
化合物5（结构如下式所示）的合成。
实施例5的合成方法同上述合成通法。
白色固体；收率：83%。
1H NMR(400MHz,DMSO-d6):δ7.92(d,2H,aryl),7.67(s,1H,Ha),7.52(t,3H,aryl),7.47(s,1H,isoxazole),7.24(d,2H,J=8.0Hz,aryl),7.20(d,2H,J=8.0Hz,aryl),4.33(t,J=7.6Hz,1H,Hb),3.66(s,3H,-OCH 3),2.98～2.79(m,2H,Hc),2.22(s,1H,-CH 3),1.35(s,9H,t-Bu)。
实施例6
化合物6（结构如下式所示）的合成。
实施例6的合成方法同上述合成通法。
白色固体；收率：83%。
1H NMR(400MHz,DMSO-d6):δ7.96～7.93(m,2H,aryl),7.77(m,0.2H,Ha),7.51(t,3H,aryl),7.40(s,0.8H,Ha),7.33(s,0.8H,Ha),7.33(s,0.8H,isoxazole),7.14(s,0.2H,isoxazole),4.23～4.14(m,1H,Hb),3.63(s,2.4H,-OCH 3),3.53(s,0.6H,-OCH 3),3.41～3.00(m,2H,NCH 2CH2CH3),2.85～2.40(m1H,Hc),1.61(dd,J=7.2,14.8Hz,0.4H,NCH2CH 2CH3),1.40～1.32(m,10.6H,t-Bu and NCH2CH 2CH3overlap),0.84(t,J=7.2,14.8Hz,0.6H,NCH2CH2CH 3),0.69(t,J=7.2,14.8Hz,2.4H,NCH2CH2CH 3)。
实施例7
化合物7（结构如下式所示）的合成。
实施例7的合成方法同上述合成通法。
白色固体；收率：87%。
1H NMR(400MHz,DMSO-d6):δ7.89(t,2H,aryl),7.51(t,3H,aryl),7.30～6.98(m,7H,aryl, isoxazole and Ha overlap),4.50(d,J=15.6Hz,1H,Hb),4.34～4.25(m,2H,benzyl),3.63(s,2.8H,-OCH 3),3.52(s,0.2H,-OCH 3),3.17(d,J=5.2Hz,0.1H,Hc),2.86～2.67(m,1.9H,Hc),1.27(s,0.7H,t-Bu),1.24(s,8.3H,t-Bu)。
实施例1
化合物8（结构如下式所示）的合成。
实施例8的合成方法同上述合成通法。
白色固体；收率：90%。
1H NMR(400MHz,DMSO-d6):δ7.90(s,2.4H,aryl and Ha overlap),7.66(s,0.6H,Ha),7.52(s,3H,aryl),7.45(s,0.6H,isoxazole),7.23(t,2.4H isoxazole and aryl overlap),7.11(d,2H,J=8.0Hz,aryl),7.20(d,2H,J=8.0Hz,aryl),4.34～4.26(m,1H,Hb),4.14～3.93(m,2H,-OCH 2CH3),2.95～2.76(M,1.5H,Hc),2.50～2.39(m,0.5H,Hc),2.23(s,1.2H,-CH 3),2.21(s,1.8H,-CH 3),1.37(s,3.6H,t-Bu),1.34(s,3.6H,t-Bu),1.20(t,1.8H,J=7.2Hz,-OCH2CH 3),1.04(t,1.2H,J=6.8Hz,-OCH2CH 3)。
实施例9
化合物9（结构如下式所示）的合成。
实施例9的合成方法同上述合成通法。
白色固体；收率：78%。
1H NMR(400MHz,DMSO-d6):δ8.59～8.39(m,1H,Ha),7.89(d,2H,aryl),7.52(s,3.5H, aryl and isoxazole overlap),7.31(s,0.5H,isoxazole),7.24～7.13(m,4H,aryl),4.40～4.05(m,1H,Hb),4.01～3.96(m,2H,-OCH 2CH3),3.20(s,2H,NCH 2CH2CH2CH3),2.88～2.77(m,1.5H,Hb),2.32～2.23(m,3.5H,Hband-CH3overlap),1.49～0.82(m,10H,-OCH2CH2and n-Bu overlap)。
实施例10
化合物10（结构如下式所示）的合成。
实施例10的合成方法同上述合成通法。
白色固体；收率：87%。
1H NMR(400MHz,DMSO-d6):δ8.35(d,J=8.0Hz,0.1H,Ha),8.21(d,J=8.0Hz,0.9H,Ha),7.89(t,2H,aryl),7.52～7.49(m,4H,aryl and isoxazole overlap),7.26～7.10(m,4H,aryl),4.36(t,J=7.6Hz,0.9H,Hb),4.30～4.25(m,0.1H,Hb),3.74(d,J=7.6Hz,1H,Hd),3.63(s,2.7H,-OCH 3),3.53(s,0.3H,-OCH 3),2.85(d,J=7.2Hz,3H,Hc),2.21(s,3H,-CH 3),1.87～1.05(m,10H,cyclohexyl)。
实施例11
化合物11（结构如下式所示）的合成。
实施例11的合成方法同上述合成通法。
白色固体；收率：76%。
1H NMR(400MHz,CDCl3):δ7.71(d,0.3H,Ha),7.89～(m,2H,aryl),7.51(t,3H,aryl),7.48～6.24(m,10H,aryl),7.06(t,3H,aryl),6.96(s,0.7H,isoxazole),6.80(t,J=5.6Hz,Ha),6.71 (s,0.3H,isoxazole),4.67～4.43(m,2H,benzyl),4.25～4.16(m,1H,Hb),3.62(s,2.1H,-OCH 3),3.60(s,0.9H,-OCH 3),2.86～2.61(m,1.9H,Hc),2.28(s,1H,-CH 3)。
Claims (3)
1.一种合成2,5-二羰基哌嗪类化合物的方法，其特征在于：合成路线如下：
所述溶剂为甲醇、反应温度为45℃、反应时长为10-20小时，所述的R1为对4-甲基苯基，正丙级或苄基，所述的R2为甲氧酰基或乙氧酰基，所述醛为α位为杂原子的芳杂环醛。
2.根据权利要求1所述的合成2,5-二羰基哌嗪类化合物的方法，其特征在于：所述X为氮或氧。
3.根据权利要求1所述的合成2,5-二羰基哌嗪类化合物的方法，其特征在于：所述的R3为叔丁基，正丁基，环己基或苄基。
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Non-Patent Citations (6)
| Title |
|---|
| ANDREAS HARTUNG，等: "One-Pot Ugi/Aza-Michael Synthesis of Highly Substituted 2,5-Diketopiperazines with Anti-Proliferative Properties", 《MOLECULES》 * |
| CHRISTOPHER HULME，等: "Novel applications of ethyl glyoxalate with the Ugi MCR", 《TETRAHEDRON LETTERS》 * |
| SOUMAVA SANTRA，等: "A One-Pot, Microwave-Influenced Synthesis of Diverse Small Molecules by Multicomponent Reaction Cascades", 《ORGANIC LETTERS》 * |
| SOUMAVA SANTRA，等: "A Rapid, One-Pot, Microwave-Influenced Synthesis of Spiro-2,5-diketopiperazines via a Cascade Ugi/6- Exo-Trig Aza-Michael Reaction", 《THE JOUR NAL OF ORGANIC CHEMISTR Y》 * |
| STEFANO MARCACCINI，等: "A facile synthesis of 2,5-diketopiperazines based on isocyanide chemistry", 《TETRAHEDRON LETTERS》 * |
| 苏毅，等: "哌嗪合成工艺最新进展", 《精细与专用化学品》 * |
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