CN110540553B - 含磷的喹啉类化合物及其制备方法和应用 - Google Patents
含磷的喹啉类化合物及其制备方法和应用 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
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Abstract
本发明提供了含磷的喹啉类化合物及其制备方法和应用。通过喹啉类化合物与二苯基磷氧类化合物，在光催化作用下直接构筑C‑P键的方法，实现相应含磷的喹啉类化合物的合成。本发明的方法反应条件温和，无需光催化剂，操作简单，环保。
Description
技术领域
本发明涉及有机化学领域，具体涉及含磷的喹啉类化合物及其制备方法和应用。
背景技术
有机膦化合物在有机合成、材料化学、药物化学、配位化学等领域有着广泛的应用。其中，芳基膦酸酯、芳基膦烷、磷杂环戊二烯以及它们的衍生物均在高分子阻燃材料、功能材料、有机合成、药物和生物化学方面有着较为重要的应用价值。例如，性能优异的聚合物阻燃剂单体DOPO-衣康酸和DOPO-环氧树脂，它们皆是由9,10-二氢-9-氧杂-10-磷杂菲-10氧化物（DOPO）衍生所得（参见非专利文献1）；有机电致发光材料含有二噻吩并磷杂环戊二烯、磷杂环戊二烯、磷杂聚苯撑乙烯等结构（参见非专利文献2）；结核分枝杆菌谷氨酰氨合成酶抵制剂（MTB-GS inhibitor)（参见非专利文献3）；治疗糖尿病的药物果糖1,6-二磷酸酶抑制剂（FBPase inhibitors）、CS-917和MB05032（参见非专利文献4）；用于仿生态多肽合成的对位磷酰基取代的苯丙氨酸（4-phosphonophenylalanine)及其结构类似物（参见非专利文献5）。这些物质都具有较好的生物活性。
因此，机膦化合物的合成方法就显得尤为重要。目前有机膦化合物主要是通过磷酸酯或磷氧化物，与亲电试剂在过渡金属的催化作用下制备得到。然而这些方法要用到昂贵的金属或用到有毒过渡金属，或者用到一些敏感的配体，或者需要较高温度等一些较为苟刻的条件。
喹啉作为药物结构中一类重要的药效基团，具有抗疟、抗菌、抗结核、抗癌、抗炎、抗高血压、抗HIV等诸多生理活性，在药物开发领域极具价值。
现有技术文献：
非专利文献1：赵小平, 李绍文, 杨军,等. 阻燃抗氧剂9,10-二氢-9-氧杂-10-膦菲-10-氧的合成[J]. 化学研究与应用, 2000, 12(6):648-650.
非专利文献2：Matano Y , Imahori H . Design and synthesis of phosphole-based π systems for novel organic materials[J]. Organic & BiomolecularChemistry, 2009, 7(7):1258.
非专利文献3：Nordqvist A , Nilsson M T , Röttger S , et al. Evaluationof the amino acid binding site of Mycobacterium tuberculosis glutaminesynthetase for drug discovery[J]. Bioorganic & Medicinal Chemistry, 2008, 16(10):5501-5513.
非专利文献4：Tsukada T , Takahashi M , Takemoto T , et al. Synthesis,SAR, and X-ray structure of tricyclic compounds as potent FBPase inhibitors[J]. Bioorganic & medicinal chemistry letters, 2009, 19(20):5909-5912.
非专利文献5：Oishi S , Kang S U , Liu H , et al. Synthesis of α,α-disubstituted 4-phosphonophenylalanine analogues as conformationally-constrained phosphotyrosyl mimetics[J]. Tetrahedron, 2004, 60(13):2971-2977.
发明内容
本发明的目的在于提供含磷的喹啉类化合物及其制备方法和应用。
本发明提供的含磷的喹啉类化合物，具有式（I）所示结构：
式中，R1、R2、R3独立地选自氢、C1~C8的烷基、C1~C8的烷氧基、卤素、硝基。
在一些优选的实施例中，R1、R2、R3独立地选自氢、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、氟、氯、溴、碘、硝基。
在一些优选的实施例中，R1的取代位置为喹啉中6、7或8号位，R2的取代位置为苯环中2、3或4号位，R3的取代位置为苯环中2、3或4号位。
在一些优选的实施例中，含磷的喹啉类化合物具有下列式中任一所示的结构：
上述的含磷的喹啉类化合物的制备方法，包括以下步骤：
在溶剂中，并在氧化剂参与的条件下，式（Ⅱ）喹啉类化合物和式（Ⅲ）所示的二苯基磷氧类化合物在光照条件下反应，得到所述的含磷的喹啉类化合物；
式中，R1独立地选自氢、C1~C8的烷基、C1~C8的烷氧基、卤素、硝基。
在一些优选的实施例中，R1独立地选自氢、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、氟、氯、溴、碘、硝基。
在一些优选的实施例中，R1的取代位置为喹啉中6、7或8号位，R2的取代位置为苯环中2、3或4号位，R3的取代位置为苯环中2、3或4号位。
在一些优选的实施例中，所述的喹啉类化合物具有下列式中任一所示的结构：
所述的二苯基磷氧类化合物具有下列式中任一所示的结构：
在一些优选的实施例中，所述的溶剂为乙腈、水或乙腈与水的混合溶剂；所述的氧化剂为过硫酸盐，例如过硫酸钾（K2S2O8）或过硫酸钠（Na2S2O8）。
在一些优选的实施例中，所述的反应还在三氟乙酸的参与下进行。
在一些优选的实施例中，所述的喹啉类化合物与二苯基磷氧类化合物的摩尔量之比为1:1~1:4，最佳比例为1:3.5。
在一些优选的实施例中，所述的光照条件为蓝光或日光灯发出的光，功率为24 w~40 w。
上述的含磷的喹啉类化合物可以应用于制备药物或作为磷配体。
本发明的有益效果如下：本发明利用光照这种较为友好的方式，直接在喹啉类化合物中成功构建了“双C-P键”，得到含“双C-P键”的化合物；本发明的方法反应条件温和，无需光催化剂，底物无需预活化，操作简单，步骤少，符合绿色发展的理念。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细说明。
图1所示为本发明实施例1中产物2,4-双二苯基磷氧基喹啉的氢谱图。
图2所示为本发明实施例1中产物2,4-双二苯基磷氧基喹啉的碳谱图。
图3所示为本发明实施例1中产物2,4-双二苯基磷氧基喹啉的磷谱图。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例和附图对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1：2,4-双二苯基磷氧基喹啉的合成
把二苯基磷氧 (141.60 mg, 0.7 mmol)和过硫酸钾 (189.23 mg, 0.7 mmol)放入光反应容器中，用橡皮塞把反应容器的管口塞住，然后抽真空、充N2气，如此置换反应容器中气体三次后，依次加入喹啉(23.6 ul, 0.2 mmol)、三氟乙酸 (20 ul)、乙腈4 ml；再次密封，在室温条件下，置于光反应容器中用蓝光照射、搅拌24 h后，取出，用乙酸乙酯萃取三次，取有机层，减压蒸馏，柱层析，最后得到目标产物2,4-双二苯基磷氧基喹啉（32.83 mg，产率为31%）。
核磁的氢谱、碳谱、磷谱鉴定产物为2，4-双二苯基磷氧基喹啉。氢谱图见图1，碳谱图见图2，磷谱图见图3，结构表征数据如下：
1H NMR (400 MHz, CDCl3)δ9.54(s,1H) ,8.045-8.02(m,2H) ,7.91–7.82(m,4H),7.75–
7.65(m,2H) ,7.46–7.40(m,2H) ,7.39-7.34(m,4H).
13C NMR(100 MHz,CDCl3)δ152.81 ,151 .58,146.38(d, J＝22.0Hz) ,142.64(d,J＝
2.1Hz) ,142.18(d, J＝17.1 Hz) ,132.33(d, J＝3.0 Hz) ,132.11(d, J＝9.0Hz) ,131.96(d, J＝
7.0 Hz) ,130.83(d, J＝11.0 Hz) ,130.17, 129.61(d, J＝1.4 Hz) ,128.56(d, J＝12.5 Hz) .
31P NMR (162MHz, CDCl3) δ20.47. HRMS(ESI-TOF) calculated for C20H16N2OP[M+H]+331.1000, found 331.0995.
实施例2：2,4-双二苯基磷氧基喹啉的合成
把二苯基磷氧 (141.60 mg, 0.7 mmol)和过硫酸钾 (189.23 mg, 0.7 mmol)放入光反应容器中，用橡皮塞把反应容器的管口塞住，然后抽真空、充N2气，如此置换反应容器中气体三次后，依次加入喹啉(23.6 ul, 0.2 mmol)、三氟乙酸 (20 ul)、乙腈4 ml；再次密封，在室温条件下，置于光反应容器中用普通日光灯（24 w）照射、搅拌24 h后，取出，用乙酸乙酯萃取三次，取有机层，减压蒸馏，过柱，最后得到目标产物（44.48 mg，产率为42%）。
表1 反应在蓝光和日光灯照射条件下效果对比
实验表明，该反应在蓝光和日光灯的条件下都能进行反应，但在日光灯照射条件下，产率更高。考虑到反应的效率，该反应优选在普通日光灯照射条件下进行。
实施例3：2,4-双二苯基磷氧基喹啉的合成
把二苯基磷氧 (141.60 mg, 0.7 mmol)和过硫酸钠 (166.66 mg, 0.7 mmol)放入光反应容器中，用橡皮塞把反应容器的管口塞住，然后抽真空、充N2气，如此置换反应容器中气体三次后，依次加入喹啉(23.6 ul, 0.2 mmol)、三氟乙酸 (20 ul)、乙腈4 ml；再次密封，在室温条件下，置于光反应容器中用普通日光灯（24 w）照射、搅拌24 h后，取出，用乙酸乙酯萃取三次，取有机层，减压蒸馏，过柱，最后得到目标产物（37.07mg，产率为35 %）。
表2 氧化剂分别为过硫酸钾和过硫酸钠的效果对比
实验表明，该反应使用过硫酸钾或过硫酸钠作氧化剂都能进行，但使用过硫酸钾产率更高。考虑到反应的效率，优选过硫酸钾作为氧化剂。
实施例4：2,4-双二苯基磷氧基喹啉的合成
把二苯基磷氧 (141.60 mg, 0.7 mmol)和过硫酸钾 (189.23 mg, 0.7 mmol)放入光反应容器中，用橡皮塞把反应容器的管口塞住，然后抽真空、充N2气，如此置换反应容器中气体三次后，依次加入喹啉 (23.6 ul, 0.2 mmol)、三氟乙酸 (20 ul)、水4 ml；再次密封，在室温条件下，置于光反应容器中用普通日光灯（24 w）照射、搅拌24 h后，取出，用乙酸乙酯萃取三次，取有机层，减压蒸馏，过柱，最后得到目标产物（33.89 mg，产率为32 %）。
实施例5：2,4-双二苯基磷氧基喹啉的合成
把二苯基磷氧 (141.60 mg, 0.7 mmol)和过硫酸钾 (189.23 mg, 0.7 mmol)放入光反应容器中，用橡皮塞把反应容器的管口塞住，然后抽真空、充N2气，如此置换反应容器中气体三次后，依次加入喹啉 (23.6 ul, 0.2 mmol)、三氟乙酸 (20 ul)、乙腈和水各2ml；再次密封，在室温条件下，置于光反应容器中用普通日光灯（24 w）照射、搅拌24 h后，取出，用乙酸乙酯萃取三次，取有机层，减压蒸馏，过柱，最后得到目标产物（68.80 mg，产率为65 %）。
表3 反应溶剂效果对比
实验表明，该反应使用乙腈与水的混合溶剂作为反应溶剂比使用单一的乙腈或水作为混合溶剂效果更高好。考虑到反应的效率，优选乙腈和水混合溶剂为反应溶剂，且两者的体积比为1:1。
实施例6：2,4-双二苯基磷氧基喹啉的合成
把二苯基磷氧 (141.60 mg, 0.7 mmol)和过硫酸钾 (189.23 mg, 0.7 mmol)放入光反应容器中，用橡皮塞把反应容器的管口塞住，然后抽真空、充N2气，如此置换反应容器中气体三次后，依次加入喹啉 (23.6 ul, 0.2 mmol)、乙腈和水各2 ml （不加三氟乙酸）；再次密封，在室温条件下，置于光反应容器中用普通日光灯（24 w）照射、搅拌24 h后，取出、用乙酸乙酯萃取三次，取有机层，减压蒸馏，过柱，最后得到目标产物（33.89 mg，产率为32 %）。
表4 反应中加三氟乙酸与不加三氟乙酸效果对比
实验表明，反应体系中加入三氟乙酸比不加三氟乙酸的效果明显要好，优选反应体系中加入三氟乙酸。
实施例7：2,4-双二苯基磷氧基喹啉的合成
把二苯基磷氧 (141.60 mg, 0.7 mmol)和过硫酸钾 (189.23 mg, 0.7 mmol)放入光反应容器中，用橡皮塞把反应容器的管口塞住，然后抽真空、充N2气，如此置换反应容器中气体三次后，依次加入喹啉 (23.6 ul, 0.2 mmol)、乙腈和水各2 ml （不加三氟乙酸）；再次密封，在室温条件下，置于暗箱中搅拌24 h后，取出、用乙酸乙酯萃取三次，取有机层，减压蒸馏，过柱，最后只得到产率为8%的目标化合物。此实验表明光照对反应起关键作用。
实施例8：2, 4― 二[双（对甲基苯基）磷氧基]喹啉的合成
把双(对甲基苯基)氧化膦(161.17 mg, 0.7 mmol, CAS: 2409-61-3, 厂家：安耐吉化学)和过硫酸钾 (189.23 mg, 0.7 mmol)放入光反应容器中，用橡皮塞把反应容器的管口塞住，然后抽真空、充N2气，如此置换反应容器中气体三次后，依次加入喹啉 (23.6ul, 0.2 mmol)、三氟乙酸 (20 ul)、乙腈和水各2 ml；再次密封，在室温条件下，置于光反应容器中用普通日光灯（24 w）照射、搅拌24 h后，取出，用乙酸乙酯萃取三次，取有机层，减压蒸馏，过柱，最后得到目标产物（71.44 mg，产率为61 %）。
实施例9：2, 4― 二[双（对氯苯基）磷氧基]喹啉的合成
把双(对氯苯基)氧化膦（189.75 mg, 0.7 mmol, CAS: 15948-60-4)和过硫酸钾(189.23 mg, 0.7 mmol)放入光反应容器中，用橡皮塞把反应容器的管口塞住，然后抽真空、充N2气，如此置换反应容器中气体三次后，依次加入喹啉 (23.6 ul, 0.2 mmol)、三氟乙酸 (20 ul)、乙腈和水各2 ml；再次密封，在室温条件下，置于光反应容器中用普通日光灯（24 w）照射、搅拌24 h后，取出，用乙酸乙酯萃取三次，取有机层，减压蒸馏，过柱，最后得到目标产物（77.41 mg，产率为58 %）。
显然，本发明的上述实施例仅仅是为清楚也说明本发明所作的举例，而并非是对本发明的实施方式的限定，对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无法对所有的实施方式予以穷举，凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。
Claims (4)
1.含磷的喹啉类化合物的制备方法，其中所述含磷的喹啉类化合物具有式（I）所示结构：
式中，R1、R2、R3独立地选自氢、C1~C8的烷基、C1~C8的烷氧基、卤素、硝基，R1的取代位置为喹啉中6、7或8号位；
其特征在于，所述的含磷的喹啉类化合物的制备方法包括以下步骤：
在溶剂中，并在氧化剂参与的条件下，式（Ⅱ）所示的喹啉类化合物和二苯基磷氧类化合物在光照条件下反应，得到所述的含磷的喹啉类化合物；
式中，R1独立地选自氢、C1~C8的烷基、C1~C8的烷氧基、卤素、硝基；
其中，所述的氧化剂为过硫酸钾或过硫酸钠；
所述的二苯基磷氧类化合物具有下列式中任一所示的结构：
2.根据权利要求1所述的方法，其特征在于：所述的喹啉类化合物具有下列式中任一所示的结构：
3.根据权利要求1所述的方法，其特征在于：所述的溶剂为乙腈、水或乙腈与水的混合溶剂。
4.根据权利要求1所述的方法，其特征在于：所述的反应还在三氟乙酸的参与下进行。
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