CN115093369A - 一种3,4-二氢异喹啉-1-酮类化合物的合成方法 - Google Patents
一种3,4-二氢异喹啉-1-酮类化合物的合成方法 Download PDFInfo
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 8
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical group C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
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- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 1
- QKNDAUTYSODFJV-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;sodium Chemical compound [Na].C[Si](C)(C)N[Si](C)(C)C QKNDAUTYSODFJV-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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
Description
技术领域
本发明涉及有机合成领域,更确切地说,它涉及一种3,4-二氢异喹啉-1-酮类化合物的合成方法。
背景技术
3,4-二氢异喹啉-1-酮类化合物是广泛存在于天然生物碱和制药行业中的母核结构,含3,4-二氢异喹啉-1-酮母核的代表性生物碱有Corydaldine、Thalifoline、N-methylcoryaldine、Minalrestat、Narciclasine等。含有该类骨架的化合物具有广泛的抗人类免疫缺陷病毒、抗菌、抗抑郁、抗癌、抗氧化、抗血栓等多种生物活性。因此,这种重要内酰胺环核的有效合成方法的开发一直是药物化学和合成化学领域的研究热点。
早期,3,4-二氢异喹啉-1-酮类化合物的合成主要依赖于活性酰胺或酰胺前体—包括氨基甲酸酯、异氰酸酯、叠氮酰胺、和尿素的分子内环化。然而,这些方法的强酸性条件限制了底物范围。近几年,人们对这类化合物的制备进行了大量的研究,具有代表性的方法包括:(1)钯催化羰基插入法;(2)过渡金属催化的C-H键活化方法;(3)环己胺氧化法;(4)无金属参与的多米诺反应等。
以上研究为制备3,4-二氢异喹啉-1-酮提供了多条有效的合成方法,尽管取得了实质性的进展并在制药领域得到应用,这些方法依然存在一些不能忽视的缺点,包括过渡金属的使用、复杂底物的预先制备、反应条件苛刻以及后处理繁琐等问题。因此,寻找适用性更加广泛、更加经济、绿色、便利的合成方法,在本领域有着非常重要的理论价值和现实意义。
发明内容
本发明的目的是克服现有技术中的不足,提供了一种3,4-二氢异喹啉-1-酮类化合物的合成方法,包括:
S1、在惰性气体保护下,将式(Ⅰ)所示的化合物溶于非质子溶剂中,边搅拌边依次加入1~2mol/L的碱的四氢呋喃溶剂和式(Ⅱ)所示的的化合物;
S2、在加热条件下进行反应,然后从反应产物中收集式(Ⅲ)所示化合物
其中,式(Ⅰ)与式(Ⅱ)中的芳香基团选自苯基、取代苯基、萘基、吡啶、呋喃和噻吩中的任意一种。
作为优选,S2中,所述在加热条件下进行反应的温度为60–100℃,反应时间为12–16小时。
作为优选,S1中,所述碱选自六甲基二硅基氨基钠。
作为优选,式(Ⅰ)化合物、式(Ⅱ)化合物和碱的摩尔比为1:1~2:2~3。
作为优选,S1中,所述非质子溶剂选自1,4-二氧六环、环戊基甲醚、甲苯、四氢呋喃和乙二醇二甲醚中的任意一种。
本发明的有益效果是:本发明提供的3,4-二氢异喹啉-1-酮类化合物的合成方法绿色高效、操作简便,具有更加广泛的适用性,并且更加经济,在本领域有着非常重要的理论价值和现实意义。
附图说明
图1为本申请提供的一种3,4-二氢异喹啉-1-酮类化合物的合成方法的流程图。
具体实施方式
下面结合实施例对本发明做进一步描述。下述实施例的说明只是用于帮助理解本发明。应当指出,对于本技术领域的普通人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
本发明实施例提供的3,4-二氢异喹啉-1-酮类化合物的合成方法如下:
在惰性气体保护下,将式(Ⅰ)所示的化合物0.2mmol溶于2mL的1,4二氧六环或甲苯中,边搅拌边依次加入式(Ⅱ)所示的的化合物0.24mmol和0.6mmol六甲基二硅基胺基钠(也可以采用六甲基二硅基胺基锂来替代)的四氢呋喃溶剂0.3mL,在60–100℃下反应12–16h,然后加入3滴水淬灭,用少量硅胶粉和无水硫酸钠滤过,用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离(PE:EA=10:1~3:2)得到产物(Ⅲ)。
其中,式(Ⅰ)与式(Ⅱ)中的芳香基团选自苯基、取代苯基、萘基、吡啶、呋喃、噻吩中的任意一种。
本发明合成的一系列3,4-二氢异喹啉-1-酮衍生物的结构如下:
以下通过实例来进一步说明。
实施例1:
化合物Ⅲ-1的制备与表征:
取10mL反应管,加入搅拌子,在氮气保护下加入式(Ⅰ-1)所示的化合物(48.2mg,0.2mmol),加入1,4二氧六环(2.0mL),搅拌溶解,依次加入式(Ⅱ-1)所示的的化合物0.24mmol,六甲基二硅基胺基钠(2.0mol/L,0.3mL,0.6mmol),在100℃下反应12h后加入3滴水淬灭,用少量硅胶粉和无水硫酸钠滤过,用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离(PE:EA=10:1)洗脱得到化合物III-1,白色固体,产率为88%;1H NMR(500MHz,CDCl3):δ7.41–7.35(m,4H),7.34–7.31(m,1H),6.96(s,1H),6.82(s,1H),6.55(s,1H),4.72(dd,J=11.2,4.0Hz,1H),3.13(dd,J=15.3,11.2Hz,1H),3.00(dd,J=15.3,4.2Hz,1H),2.68(s,3H),2.31(s,3H)。
实施例2
化合物III-2的制备与表征:
制备条件同实施例1,白色固体,产率为86%;1H NMR(500MHz,CDCl3):δ7.43–7.40(m,2H),7.35–7.32(m,2H),6.97(s,1H),6.84(s,1H),6.10(s,1H),4.71(dd,J=11.8,4.0Hz,1H),3.16(dd,J=15.3,11.8Hz,1H),2.97(dd,J=15.3,3.8Hz,1H),2.69(s,3H),2.32(s,3H),1.33(s,9H)。
实施例3
化合物III-3的制备与表征:
制备条件同实施例1,白色固体,产率为91%;1H NMR(500MHz,CDCl3):δ7.62–7.58(m,4H),7.48–7.44(m,4H),7.39–7.35(m,1H),6.98(s,1H),6.85(s,1H),6.24(s,1H),4.78(dd,J=11.4,4.1Hz,1H),3.19(dd,J=15.3,11.3Hz,1H),3.05(dd,J=15.3,4.1Hz,1H),2.71(s,3H),2.33(s,3H)。
实施例4
化合物III-4的制备与表征:
制备条件同实施例1,白色固体,产率为81%;1H NMR(500MHz,CDCl3):δ7.62(d,J=8.0Hz,2H),7.51(d,J=8.0Hz,2H),6.96(s,1H),6.81(s,1H),6.76(s,1H),4.82(t,J=7.5Hz,1H),3.13–3.09(m,2H),2.64(s,3H),2.30(s,3H)。
实施例5
化合物III-5的制备与表征:
制备条件同实施例1,淡黄色固体,产率为75%;1H NMR(500MHz,CDCl3):δ7.39–7.34(m,2H),7.08–7.03(m,2H),6.96(s,1H),6.82(s,1H),6.24(s,1H),4.72(dd,J=11.2,4.2Hz,1H),3.11(dd,J=15.3,11.1Hz,1H),3.00(dd,J=15.3,4.2Hz,1H),2.67(s,3H),2.31(s,3H)。
实施例6
化合物III-6的制备与表征:
制备条件同实施例1,白色固体,产率为84%;1H NMR(500MHz,CDCl3):δ7.46(dd,J=7.3,2.1Hz,1H),7.38(dd,J=7.5,1.7Hz,1H),7.28–7.22(m,2H),6.96(s,1H),6.82(s,1H),6.12(s,1H),5.25–5.22(m,1H),3.23(dd,J=15.4,4.8Hz,1H),3.06(dd,J=15.4,9.2Hz,1H),2.70(s,3H),2.30(s,3H)。
实施例7
化合物III-7的制备与表征:
制备条件同实施例1,白色固体,产率为70%;1H NMR(500MHz,CDCl3):δ8.60(d,J=2.2Hz,1H),8.55(dd,J=4.8,1.6Hz,1H),7.74–7.72(m,1H),7.31–7.28(m,1H),6.95(s,1H),6.80(s,1H),6.58(s,1H),4.80–4.77(m,1H),3.15–3.08(m,2H),2.64(s,3H),2.29(s,3H)。
实施例8
化合物III-8的制备与表征:
制备条件同实施例1,白色固体,产率为86%;1H NMR(500MHz,CDCl3):δ7.23(dd,J=5.1,1.2Hz,1H),7.04–7.03(m,1H),6.98–6.95(m,2H),6.85(s,1H),6.31(s,1H),5.01–4.98(m,1H),3.21(dd,J=15.3,9.7Hz,1H),3.16(dd,J=15.3,4.7Hz,1H),2.67(s,3H),2.31(s,3H)。
实施例9
化合物III-9的制备与表征:
制备条件同实施例1,白色固体,产率为87%;1H NMR(500MHz,CDCl3):δ7.42–7.37(m,4H),7.35–7.32(m,1H),7.29(t,J=7.5Hz,1H),7.15(d,J=7.6Hz,1H),7.02(d,J=7.4Hz,1H),6.38(s,1H),4.75(dd,J=11.5,4.1Hz,1H),3.19(dd,J=15.3,11.4Hz,1H),3.05(dd,J=15.4,4.1Hz,1H),2.72(s,3H)。
实施例10
化合物III-10的制备与表征:
选用的非质子溶剂和反应温度以外的制备条件同实施例1,以DME为溶剂,在80℃下反应,白色固体,产率为87%;1H NMR(500MHz,CDCl3):δ7.41–7.30(m,7H),7.09(d,J=7.4Hz,1H),6.31(s,1H),4.78–4.74(m,1H),3.21(dd,J=15.4,11.1Hz,1H),3.09(dd,J=15.4,4.0Hz,1H)。
实施例11
化合物III-11的制备与表征:
反应温度以外的制备条件同实施例1,在60℃下反应,白色固体,产率为83%;1HNMR(500MHz,CDCl3):δ7.62(d,J=7.9Hz,1H),7.42–7.33(m,5H),7.22(t,J=7.7Hz,1H),7.15(d,J=7.4Hz,1H),6.21(s,1H),4.78–4.74(m,1H),3.24(dd,J=15.4,11.3Hz,1H),3.09(dd,J=15.3,3.8Hz,1H)。
实施例12
化合物III-12的制备与表征:
制备条件同实施例1,白色固体,产率为89%;1H NMR(500MHz,CDCl3):δ7.40–7.35(m,5H),7.34–7.31(m,1H),6.91(d,J=8.4Hz,1H),6.76(d,J=7.4Hz,1H),6.01(s,1H),4.74–4.71(m,1H),3.94(s,3H),3.17(dd,J=15.3,11.2Hz,1H),3.04(dd,J=15.3,3.8Hz,1H)。
实施例13
化合物III-13的制备与表征:
制备条件同实施例1,白色固体,产率为98%;1H NMR(500MHz,CDCl3):δ7.46–7.41(m,5H),7.40–7.33(m,6H),7.24(d,J=7.5Hz,1H),7.20(d,J=7.4Hz,1H),6.06(s,1H),4.90–4.87(m,1H),3.28(dd,J=15.5,10.8Hz,1H),3.18(dd,J=15.6,4.1Hz,1H)。
实施例14
化合物III-14的制备与表征:
制备条件同实施例1,白色固体,产率为60%;1H NMR(500MHz,CDCl3):δ7.44–7.34(m,8H),7.19(d,J=7.3Hz,1H),7.08–7.05(m,2H),6.11(s,1H),4.87–4.84(m,1H),3.26(dd,J=15.6,10.8Hz,1H),3.16(dd,J=15.6,4.2Hz,1H).。
实施例15
化合物III-15的制备与表征:
制备条件同实施例1,白色固体,产率为92%;1H NMR(500MHz,CDCl3):δ8.57–8.56(m,2H),7.46(t,J=7.6Hz,1H),7.42–7.33(m,5H),7.26–7.24(m,3H),7.14(d,J=7.5Hz,1H),6.16(s,1H),4.88–4.85(m,1H),3.27(dd,J=15.7,10.7Hz,1H),3.18(dd,J=15.6,4.4Hz,1H)。
实施例16
化合物III-16的制备与表征:
制备条件同实施例1,白色固体,产率为85%;1H NMR(500MHz,CDCl3):δ8.55–8.53(m,2H),7.68–7.66(m,1H),7.47(t,J=7.6Hz,1H),7.42–7.33(m,5H),7.28(dd,J=7.8,4.9Hz,1H),7.25(d,J=7.9Hz,1H),7.19(d,J=7.6Hz,1H),6.20(s,1H),4.88–4.85(m,1H),3.27(dd,J=15.6,10.7Hz,1H),3.19(dd,J=15.6,4.3Hz,1H)。
Claims (7)
2.根据权利要求1所述的3,4-二氢异喹啉-1-酮类化合物的合成方法,其特征在于,S2中,所述在加热条件下进行反应的温度为60–100℃,反应时间为12–16小时。
3.根据权利要求2所述的3,4-二氢异喹啉-1-酮类化合物的合成方法,其特征在于,S1中,所述碱选自六甲基二硅基氨基钠。
4.根据权利要求3所述的3,4-二氢异喹啉-1-酮类化合物的合成方法,其特征在于,S1中,式(Ⅰ)化合物、式(Ⅱ)化合物和碱的摩尔比为1:1~2:2~3。
5.根据权利要求4所述的3,4-二氢异喹啉-1-酮类化合物的合成方法,其特征在于,S1中,所述非质子溶剂选自1,4-二氧六环、环戊基甲醚、甲苯、四氢呋喃和乙二醇二甲醚中的任意一种。
6.根据权利要求5所述的3,4-二氢异喹啉-1-酮类化合物的合成方法,其特征在于,S1中,所述惰性气体为氮气。
7.根据权利要求6所述的3,4-二氢异喹啉-1-酮类化合物的合成方法,其特征在于,S2包括:
S201、在加热条件下进行反应;
S202、加入水淬灭;
S203、用硅胶粉和无水硫酸钠滤过;
S204、用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离,其中PE:EA=10:1~3:2,获得式(Ⅲ)所示化合物。
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