CN107759614B - 一类噁唑并吡啶季铵盐类化合物、其制备方法及用途 - Google Patents

一类噁唑并吡啶季铵盐类化合物、其制备方法及用途 Download PDF

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CN107759614B
CN107759614B CN201610674303.0A CN201610674303A CN107759614B CN 107759614 B CN107759614 B CN 107759614B CN 201610674303 A CN201610674303 A CN 201610674303A CN 107759614 B CN107759614 B CN 107759614B
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朱维良
李波
薛溯塑
李小龙
刘鹏
张勇
徐志建
蔡婷婷
陈凯先
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Shanghai Institute of Materia Medica of CAS
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Abstract

本发明涉及一种如式1所示的噁唑并吡啶季铵盐类化合物、制备方法及其作为合成中间体的转化应用。本发明提供的式1所示的噁唑并吡啶季铵盐类化合物的制备方法主要包括由2‑氧乙缩醛(或缩酮)基‑(取代)吡啶类化合物在酸的作用下发生分子内环化反应制得；本发明提供的式1所示的噁唑并吡啶季铵盐类化合物作为合成中间体的转化应用主要包括其与不同的亲核试剂反应获得N‑取代吡啶酮类化合物或者2‑取代吡啶类化合物。

Description

一类噁唑并吡啶季铵盐类化合物、其制备方法及用途
技术领域
本发明涉及有机化学及药物化学领域，具体涉及可作为有机合成中间体及治疗肿瘤或癌症、糖尿病、心血管病、中枢神经系统疾病、抗菌消炎等的噁唑并吡啶季铵盐类化合物、制备方法及其作为合成中间体的转化应用。
背景技术
季铵盐(四级铵盐)为铵离子中的四个氢原子都被烃基取代而生成的化合物。其中四个烃基可以相同，也可以不同；阴离子多是卤素负离子(F、Cl、Br、I)，也可是酸根(如HSO4 -、RCOO-等)。季铵盐类化合物在医药、化工等领域都有着极其广泛的应用，如用于杀菌剂、消毒剂、柔软抗静电剂、絮凝剂破乳剂、钻井液、VES压裂液、减阻剂、增稠剂、阴离子增效剂、相转移催化剂等。
其中，噁唑季铵盐是一种很重要的有机合成试剂，它可以发生1,3-偶极环加成反应(Albert Padwa,Edward M.Burgess,Henry L.Gingrich,David M.Roush.On theproblem of regioselectivity in the 1,3-dipolar cycloaddition reaction ofmunchnones and sydnones with acetylenic dipolarophiles.J.Org.Chem.1982,47)、可以用来制备氮杂卡宾化合物(Ung G,Mendoza-Espinosa D,Bertrand G.Ynamides:stableligand equivalents of unstable oxazol-4-ylidenes(novel mesoionic carbenes).Chem Commun(Camb).,2012,48,7088–7090)、(Zhang J,Fu J,Su X,Qin X,Zhao M,ShiM.Chem.Abnormal oxazol-4-ylidene and thiazol-4-ylidene rhodium complexes:synthesis,structure,and properties.Chem Commun(Camb).,2012,48,9625–9627)、可以用作制备药物活性分子中间体(Pandey PS,Srinivasa Rao T.An efficient synthesisof N-3,4-diphenyl-5-(4-fluorophenyl)-2-isopropyl-1H-3-pyrrolecarboxamide,akey intermediate for atorvastatin synthesis.Bioorg Med Chem Lett.2004Jan5；14(1):129-31)等。吡啶季铵盐除了本身是一种很重要的有机合成试剂，可以发生亲核加成、Michael加成、1,3-偶极加成、亲核取代和σ-迁移重排等反应(Osyanin VA,Osipov DV,Klimochkin YN.Reactions of o-quinone methides with pyridinium methylides:adiastereoselective synthesis of1,2-dihydronaphtho[2,1-b]furans and 2,3-dihydrobenzofurans.J Org Chem.2013Jun 7；78(11):5505-20)外，该类化合物还具有不同的生理活性，如甲基丙烯酰氧十二烷基溴吡啶(12-methacryloyloxydodecylpyridiniumbromide,MDPB)和氯化十六烷吡啶(Cetylpyridinium chloride,CPC)可以用于口腔消毒剂(Sreenivasan P1,Gaffar A.Antiplaque biocides and bacterial resistance:areview.J Clin Periodontol.2002Nov；29(11):965-74)；来自于海洋生物的3-烷基吡啶季铵盐多聚物具有抗肺癌活性(Zovko A1,Viktorsson K,Lewensohn R,
Figure BDA0001080447480000021
K,
Figure BDA0001080447480000022
M,Xing H,Kem WR,Paleari L,Turk T.APS8,a polymeric alkylpyridinium salt blocksα7nAChR and induces apoptosis in non-small cell lung carcinoma.MarDrugs.2013Jul 16；11(7):2574-94)；来源于传统中药活性成分的盐酸小檗碱，为异喹啉类生物碱，分子结构中具有吡啶季铵盐片段，临床广泛用于治疗肠炎菌痢等，现代研究表明，其还具有抗肿瘤、糖尿病、心血管病、中枢神经系统疾病等药理作用(Singh IP,MahajanS.Berberine and its derivatives:a patent review(2009-2012).Expert Opin TherPat.2013,23(2):215-231)。
噁唑并吡啶季铵盐类化合物鲜有文献报道，仅有的几篇文献以吡啶噁唑酮类化合物为主，该类化合物作为中间体可以发生1,3-偶极环加成反应用以制备杂环化合物(Kazhkenov ZG1,Bush AA,Babaev EV.Dakin-West trick in the design of novel 2-alkyl(aralkyl)derivatives of oxazolo[3,2-a]pyridines.Molecules.2005Sep 1；10(9):1109-18)。这些方法在制备吡啶并噁唑季铵盐类化合物时需要先制备氮取代吡啶酮类化合物，再经过分子内关环获得。其中前一步制备氮取代吡啶酮类原料化合物时需要用到卤代烷烃类化合物与吡啶酮类化合物反应，此种方法的缺点在于卤代烷烃类化合物与吡啶酮类化合物的反应存在反应位点的竞争性，既可生成氮取代吡啶酮类化合物产物，又可生成氧取代吡啶类化合物副产物，从而造成产率不高。本申请的方法则采取另外一种策略，即通过醇类化合物与2位卤代吡啶类化合物反应制备氧取代吡啶类化合物，以此为原料，再通过酸性条件下的分子内关环反应获得目标产物，反应选择性较高，副产物少，从而提高总收率。
发明内容
本发明的一个目的是提供一种式1所示噁唑并吡啶季铵盐类化合物；
本发明的另一个目的是提供式1所述噁唑并吡啶季铵盐类化合物的制备方法；
本发明的再一个目的是提供式1所述噁唑并吡啶季铵盐类化合物作为合成中间体的转化应用。
本发明所涉及的噁唑并吡啶季铵盐类化合物可以作为有机合成中间体及药物分子结构单元，具有潜在的开发应用价值。
一种如式1所示的噁唑并吡啶季铵盐类化合物：
Figure BDA0001080447480000031
其中，
Figure BDA0001080447480000032
代表双键或单键；
Q、U各自独立地代表氧、硫或氮；
R1为位于吡啶环上的1-4个相同或不同的取代基，各取代基独立地选自氢、羟基、氨基、巯基、取代或未取代的烷基、取代或未取代的芳基、C1-C6烷氧基、C1-C6烷氨基、C1-C6烷硫基、C6-C12芳醚基、C6-C12芳氨基、C6-C12芳硫基、硝基、酰胺基、苯并二噁茂基或卤素；或者当R1为吡啶环上的2个或2个以上取代基时，其中2个相邻的取代基可彼此连接并且与吡啶环上的碳原子共同形成取代或未取代的芳基或含有0-3个独立选自O、S或N原子的5-7元环烷基；
R2、R3各自独立地代表氢、羟基、氨基、巯基、取代或未取代的烷基、取代或未取代的芳基、C1-C6烷氧基、C1-C6烷氨基、C1-C6烷硫基、C6-C12芳醚基、C6-C12芳氨基、C6-C12芳硫基或卤素；且当
Figure BDA0001080447480000041
为双键时，R3不存在；
R4代表氢、取代或未取代的烷基或取代或未取代的芳基；
Y为酸根阴离子，选自无机酸根离子、有机酸根离子和卤素离子，包括但不限于硝酸根离子、硫酸根离子、磷酸根离子、甲磺酸根离子、苯磺酸根离子、醋酸根离子、酒石酸根离子、枸橼酸根离子、马来酸根离子、琥珀酸根离子、柠檬酸根离子、水杨酸根离子、甘油酸根离子、抗坏血酸根离子、氟离子、氯离子、溴离子或碘离子。
所述取代或未取代的烷基包括取代或未取代的饱和、不饱和、直链、支链的全碳C1-C6烷基或含氧、氮或硫等杂原子的C1-C6烷基；其中，“所述取代或未取代”中的“取代”是指被选自卤素、芳基、C1-C6烷基中的一种或多种取代基所取代。
所述取代或未取代的芳基包括取代或未取代的苯基或含氧、氮、硫等杂原子的芳基；其中，“所述取代或未取代”中的“取代”是指被选自C1-C6烷氧基、卤素取代的C1-C6烷氧基、苄基(BnO)、羟基、氰基、C1-C3烷氧基羰基中的一种或多种取代基所取代。
所述的卤素是指氟、氯、溴或碘。
优选的，
Figure BDA0001080447480000051
代表单键；
优选的，U和Q各自独立地代表氧或硫；
优选的，R4代表取代或未取代的烷基；
优选的，R2、R3各自独立地代表氢、取代或未取代的烷基或取代或未取代的芳基；
优选的，R1为位于吡啶环上的1-4个相同或不同的取代基，各取代基独立地选自氢、烷基、芳基、C1-C6烷氧基、硝基、酰胺基、苯并二噁茂基；或者当R1为吡啶环上的2个或2个以上取代基时，其中2个相邻的取代基并且与吡啶环上的碳原子共同形成芳基。
所述的噁唑并吡啶季铵盐类化合物优选为：
Figure BDA0001080447480000052
Figure BDA0001080447480000061
本发明还提供了所述的噁唑并吡啶季铵盐类化合物的制备方法：
Figure BDA0001080447480000062
化合物S溶于溶剂中，加入酸NY，在一定温度下反应一段时间，蒸除溶剂，既得化合物I；
其中，R1、R2、R3、R4、U、Q、Y的定义同前所述。
所述的溶剂包括但不限于甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、二甲苯、氯苯、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、水等一种或一种以上组合溶剂；所述的溶剂优选为甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、水等一种或一种以上的组合溶剂。
所述的酸NY选自无机酸、有机酸和氢卤酸。包括但不限于硝酸、硫酸、磷酸、甲磺酸、苯磺酸、醋酸、酒石酸、枸橼酸、马来酸、琥珀酸、柠檬酸、水杨酸、甘油酸、抗坏血酸、氢氟酸、盐酸、氢溴酸或氢碘酸等一种或一种以上组合酸；所述的酸NY优选为甲磺酸、对甲苯磺酸、三氟甲磺酸、乙酸、三氟乙酸、盐酸、磷酸等一种或一种以上组合酸。
所述的一定温度为从零下80摄氏度至200摄氏度的任何温度；优选为从0摄氏度到100摄氏度的任何温度。
本发明还提供了所述的噁唑并吡啶季铵盐类化合物作为合成中间体的转化应用：
Figure BDA0001080447480000071
其中，R1、R2、R3、R4、U、Q、Y的定义同前所述。
W、Z各自独立的为O，R7N或S等；A为氢或锂、钠、镁、铜、锡等金属原子；R5为氢、取代或未取代的芳基或C1-C6烷基，所述“取代或未取代的芳基”中的“取代”是指被C1-C3烷氧基、硝基或卤素所取代；R6为氢、被取代或未取代的芳基所取代的C1-C6烷基，所述“取代或未取代的芳基”中的“取代”是指被C1-C3烷氧基、三氟甲基或卤素所取代；R7为氢、取代或未取代的C1-C6烷基，所述“取代或未取代”是指被C1-C3烷基、C1-C3烷氧基、硝基、三氟甲基或卤素所取代。
所述化合物I(化合物I可以从化合物S制备得到，产物经纯化或未经纯化或不经分离)溶于溶剂中，加入亲核试剂，所述亲核试剂为R5-WA、R6-ZA或无机碱，在零下80摄氏度至200摄氏度的温度下反应，蒸除溶剂，常规分离纯化处理，即获得N取代吡啶酮类化合物P或者2-取代吡啶类化合物T，当亲核试剂为无机碱时，W为O，R5为氢。
所述无机碱选自碳酸氢钠、氢氧化钠等。
所述的溶剂包括但不限于甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、二甲苯、氯苯、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、水等一种或一种以上组合溶剂；
有益效果
根据本发明的噁唑并吡啶季铵盐类化合物的制备方法条件温和、试剂易得、产物收率高、后处理方便等，具有较好的推广应用价值；并且根据所述方法合成的噁唑并吡啶季铵盐类化合物具有潜在的有机合成和药物化学用途，该类化合物可以进一步很方便的与不同亲核试剂反应，从而转化为药物分子中常见的N取代吡啶酮类化合物及2-取代吡啶类化合物，具有潜在的作为有机合成中间体及药物分子结构单元的开发应用价值。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但不限制本发明。
制备实施实例
本发明式1所述化合物的合成：
原料S-1到S-20的制备由商业化的2-氯吡啶类化合物或2-羟基吡啶类化合物为原料，参考文献Tetrahedron,2004,60,6113的方法制得。所用试剂如无特殊说明，均购自国药集团。
实施例1化合物I-1的制备
Figure BDA0001080447480000081
将化合物S-1溶于干燥的甲苯中，向其中加入过量的三氟乙酸，加热至50℃，保持干燥，反应过夜，将过量的酸和溶剂旋干，乙醚洗得到纯净的化合物I-1，收率为86％.1HNMR(400MHz,氯仿-d)δ7.62(dd,J＝7.0,2.0Hz,1H),7.52(ddt,J＝8.7,6.6,2.7Hz,1H),6.75(d,J＝9.1Hz,1H),6.47(q,J＝7.1Hz,1H),6.08–5.97(m,1H),3.78(q,J＝11.5,9.8Hz,2H),3.37(s,3H).13C NMR(125MHz,CDCl3)δ159.91,149.11,137.12,119.27,110.64,93.01,75.74,58.15.MS(EI)：265.
实施例2化合物I-2的制备
Figure BDA0001080447480000091
将化合物S-2溶于干燥的无水乙醚中，向其中加入过量的浓盐酸，立即有大量的黄色固体析出，搅拌3h后，过滤，无水乙醚洗得到纯净的化合物I-2，收率为92％。1H NMR(400MHz,氯仿-d)δ7.66(d,J＝7.3Hz,1H),6.88(dd,J＝1.9,1.0Hz,1H),6.43(dd,J＝7.3,2.0Hz,1H),6.07(dd,J＝4.8,3.6Hz,1H),3.87–3.70(m,2H),3.45(s,3H).13C NMR(125MHz,CDCl3)δ160.93,141.24,140.97,133.41,122.63,120.45,117.99,100.85,84.91,57.37,43.98.MS(EI)255.
实施例3化合物I-3的制备
Figure BDA0001080447480000092
制备方法同实施例2，将化合物S-2替换为化合物S-3得化合物I-3，收率为99％。1HNMR(400MHz,氯仿-d)δ9.28(s,1H),8.60(dd,J＝7.2,2.2Hz,1H),7.77(dd,J＝6.8,1.9Hz,1H),6.56(t,J＝6.9Hz,1H),6.22–6.09(m,1H),5.97(s,1H),3.93–3.69(m,2H),3.46(s,3H).13C NMR(125MHz,CDCl3)δ164.76,161.45,144.37,135.61,120.97,106.16,85.37,57.49,44.09.MS(ESI)195.
实施例4化合物I-4的制备
Figure BDA0001080447480000101
制备方法同实施例2，将化合物S-2替换为化合物S-4得化合物I-4，收率为82％。1HNMR(400MHz,氯仿-d)δ8.83–8.72(m,1H),8.17(ddd,J＝10.1,3.2,1.2Hz,1H),6.61(d,J＝10.1Hz,1H),6.11–5.98(m,1H),3.83(qdd,J＝12.1,4.0,1.1Hz,2H),3.51(d,J＝1.2Hz,3H).13C NMR(125MHz,CDCl3)δ161.38,134.60,133.67,131.41,119.88,86.11,58.29,44.34.MS(ESI)197.
实施例5化合物I-5的制备
Figure BDA0001080447480000102
制备方法同实施例2，将化合物S-2替换为化合物S-5得化合物I-5，收率为80％。1HNMR(400MHz,氯仿-d)δ7.12(dd,J＝7.2,1.7Hz,1H),6.66(dd,J＝7.4,1.6Hz,1H),6.28–6.14(m,2H),3.86(s,3H),3.78–3.70(m,2H),3.41(s,3H).13C NMR(125MHz,CDCl3)δ158.08,149.87,122.41,112.25,105.13,85.08,57.53,55.90,44.60.MS(ESI)182.
实施例6化合物I-6的制备
Figure BDA0001080447480000103
制备方法同实施例2，将化合物S-2替换为化合物S-6得化合物I-6，收率为77％。1HNMR(400MHz,氯仿-d)δ7.36(d,J＝7.1Hz,1H),6.38(s,1H),6.13(d,J＝8.2Hz,1H),6.08(d,J＝5.1Hz,1H),3.83–3.65(m,2H),3.40(s,3H),2.21(s,3H).13C NMR(125MHz,CDCl3)δ162.61,151.76,130.80,119.14,108.97,84.66,57.49,44.85,21.35.HRMS(ESI)计算值(计算值)C9H12O2NCl202.0629[M+H]+,实测值(found)202.0635.
实施例7化合物I-7的制备
Figure BDA0001080447480000111
制备方法同实施例2，将化合物S-2替换为化合物S-7得化合物I-7，收率为86％。1HNMR(400MHz,氯仿-d)δ8.48–8.41(m,1H),7.70(ddd,J＝8.3,7.0,1.3Hz,1H),7.60–7.49(m,2H),7.28(d,J＝7.6Hz,1H),6.62(d,J＝7.6Hz,1H),6.26(t,J＝5.2Hz,1H),3.78(d,J＝5.2Hz,2H),3.43(s,3H).13CNMR(125MHz,CDCl3)δ161.99,136.33,132.38,127.52,126.69,125.63,125.41,124.76,106.37,84.25,56.88,44.19.HRMS(ESI)m/z:计算值C12H12O2N+202.0863,实测值202.0868.
实施例8化合物I-8的制备
Figure BDA0001080447480000112
制备方法同实施例2，将化合物S-2替换为化合物S-8得化合物I-8，收率为98％。1HNMR(400MHz,甲醇-d4)δ9.10(d,J＝9.3Hz,1H),8.33(d,J＝8.1Hz,1H),8.26–8.16(m,2H),7.91(ddd,J＝8.2,5.4,2.6Hz,1H),7.69(d,J＝9.2Hz,1H),7.16(dd,J＝6.6,2.5Hz,1H),5.43(dd,J＝11.5,2.5Hz,1H),5.29(dd,J＝11.5,6.6Hz,1H),3.52(d,J＝1.0Hz,3H).13CNMR(125MHz,MeOD4)δ162.43,151.61,135.22,133.58,130.40,128.10,125.05,116.94,108.39,89.66,75.23,53.39.LRMS(ESI):202.
实施例9化合物I-9的制备
Figure BDA0001080447480000121
制备方法同实施例2，将化合物S-2替换为化合物S-9得化合物I-9，收率为96％。1HNMR(400MHz,丙酮-d6)δ8.17(s,1H),8.04(s,1H),7.82(s,1H),7.34(s,2H),7.14(s,1H),6.94(s,1H),6.19(s,2H),5.52(s,1H),5.43(s,1H),4.12(d,J＝19.5Hz,6H),3.17(s,3H).13C NMR(125MHz,丙酮)δ161.60,153.19,149.69,148.48,146.87,136.49,134.49,129.66,125.51,124.32,123.91,119.06,110.75,109.36,108.83,102.23,91.20,61.47,56.51,55.76.HRMS(ESI)计算值C21H20O6N 382.1291[M+H]+,实测值382.1286.
实施例10化合物I-10的制备
Figure BDA0001080447480000131
制备方法同实施例2，将化合物S-2替换为化合物S-10得化合物I-10，收率为88％。1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝9.0Hz,1H),8.03(d,J＝8.9Hz,1H),7.92(s,1H),7.52–7.32(m,7H),7.29(s,2H),6.78(s,1H),5.34(s,2H),5.22(s,2H),4.05(s,3H),3.98(s,3H),3.88(s,3H),2.93(s,3H).13C NMR(125MHz,DMSO)δ161.07,152.95,149.70,146.15,137.12,136.55,134.49,128.93,128.46,128.36,126.11,124.97,124.76,122.35,119.07,114.07,113.14,110.53,91.16,76.57,70.40,62.28,57.43,56.48,55.86.ESI-LR:474.
实施例11化合物I-11的制备
Figure BDA0001080447480000132
制备方法同实施例2，将化合物S-2替换为化合物S-11得化合物I-11，收率为92％。1H NMR(400MHz,氯仿-d)δ7.80(d,J＝8.9Hz,1H),7.74(d,J＝9.0Hz,1H),7.54(s,1H),7.19(s,2H),7.12(s,1H),6.12(s,1H),4.96(d,J＝7.7Hz,1H),4.09–3.87(m,15H),2.97(s,3H).
实施例12化合物I-12的制备
Figure BDA0001080447480000141
制备方法同实施例2，将化合物S-2替换为化合物S-12得化合物I-12，收率为99％。1H NMR(DMSO-d6,400MHz)δ8.54(1H,d,J＝7.7Hz),8.32(2H,d,J＝3.6Hz),8.24(2H,d,J＝8.5Hz),8.16(1H,s),7.96(2H,d,J＝7.7Hz),6.81(1H,d,J＝6.4Hz),5.45(1H,dd,J＝11.1,2.1Hz),5.30(1H,dd,11.1,6.4Hz),3.94(3H,s),3.88-3.91(1H,m),2.94(3H,s).HRMS(ESI):计算值C20H18O4N+336.1230,实测值336.1239.
实施例13化合物I-13的制备
Figure BDA0001080447480000142
制备方法同实施例2，将化合物S-2替换为化合物S-13得化合物I-13，收率为94％。1H NMR(DMSO-d6,400MHz)δ8.50(d,J＝8.0Hz，1H),8.29(d,J＝3.9Hz，2H),8.04(s，1H),7.41(d,J＝2.0Hz，1H),7.37–7.33(m，1H),7.24(d,J＝8.3Hz，1H),6.88(d,J＝5.9Hz，1H),5.41(d,J＝11.1Hz，1H),5.31(dd,J＝11.1,6.1Hz，1H),3.88(d,J＝1.3Hz，6H),3.80-3.84(m，1H),2.97(d,J＝1.1Hz，3H).HRMS(ESI)m/z:计算值C20H20O4N+338.1387,实测值338.1391.
实施例14化合物I-14的制备
Figure BDA0001080447480000151
制备方法同实施例2，将化合物S-2替换为化合物S-14得化合物I-14，收率为99％。1H NMR(DMSO-d6,500MHz)δ8.43(d,J＝8.9Hz，1H),8.23(d,J＝4.9Hz，2H),8.10(d,J＝8.2Hz，1H),7.94(s，1H),7.88(d,J＝8.2Hz，1H),7.83(s，1H),7.70(d,J＝7.0Hz，1H),7.55(s，1H),6.77(dd,J＝6.0,1.8Hz，1H),5.36(dd,J＝11.0,1.8Hz，1H),5.26(dd,11.0,6.0Hz，1H),3.09-3.12(m，1H),2.94(s，3H).HRMS(ESI)m/z:计算值C18H16O3N+294.1125,实测值294.1122.
实施例15化合物I-15的制备
Figure BDA0001080447480000152
制备方法同实施例2，将化合物S-2替换为化合物S-15得化合物I-15，收率为91％。1H NMR(DMSO-d6,400MHz)δ8.54(d,J＝8.2Hz，1H),8.32-8.33(m，2H),8.16(s，1H),7.82-7.89(m，2H),7.69-7.77(m，1H),7.58-7.62(m，1H),6.79(dd,J＝6.3,2.2Hz，1H),5.44(dd,J＝11.1,2.2Hz，1H),5.33(dd,J＝11.1,6.3Hz，1H),4.21–3.94(m，1H),2.96(s，3H).HRMS(ESI)m/z:计算值C19H15O3F3N+362.0999,实测值362.1008.
实施例16化合物I-16的制备
Figure BDA0001080447480000161
制备方法同实施例2，将化合物S-2替换为化合物S-16得化合物I-16，收率为96％。1H NMR(DMSO-d6,400MHz)δ8.55(d,J＝8.1Hz，1H),8.33(d,J＝5.3Hz，2H),8.20(d,J＝8.3Hz，2H),8.16(s，1H),8.01(d,J＝8.2Hz，2H),6.80(dd,J＝6.3,2.2Hz，1H),5.48(dd,J＝11.1,2.2Hz，1H),5.30(dd,J＝11.1,6.5Hz，1H),3.44–3.35(m，1H),2.96(s，3H).HRMS(ESI)m/z:计算值C19H15O2N2 +303.1128,实测值303.1126.
实施例17化合物I-17的制备
Figure BDA0001080447480000162
制备方法同实施例2，将化合物S-2替换为化合物S-17得化合物I-17，收率为92％。1H NMR(DMSO-d6,400MHz)δ8.49(d,J＝8.3Hz，1H),8.28(d,J＝3.8Hz，2H),8.01(s，1H),7.73(d,J＝8.1Hz，2H),7.21(d,J＝8.7Hz，2H),6.80(dd,J＝5.5,1.8Hz，1H),5.41(dd,J＝10.4,1.8Hz，1H),5.31(dd,10.4,5.5Hz，1H),4.16(q,J＝6.8Hz，2H),4.09-4.12(m，1H),2.96(s，3H),1.39(t,J＝7.1Hz，3H).HRMS(ESI)m/z:计算值C20H20O3N[M]+322.1438,实测值322.1440.
实施例18化合物I-18的制备
Figure BDA0001080447480000171
制备方法同实施例2，将化合物S-2替换为化合物S-18得化合物I-18，收率为99％。1H NMR(DMSO-d6,400MHz)δ8.50(d,J＝8.1Hz，1H),8.29(dd,J＝4.0,1.3Hz，2H),8.09–8.08(m，1H),7.15(d,J＝2.0Hz，2H),6.95(dd,J＝6.0,2.1Hz，1H),5.41(dd,J＝11.0,2.0Hz，1H),5.36(dd,J＝11.0,6.1Hz，1H),3.89(s，6H),3.77(s，3H),3.70-3.73(m，1H),3.00(s，3H).HRMS(ESI)m/z:计算值C21H22O5N+368.1492,实测值368.1487.
实施例19化合物I-19的制备
Figure BDA0001080447480000172
制备方法同实施例2，将化合物S-2替换为化合物S-19得化合物I-19，收率为97％。1H NMR(DMSO-d6,400MHz)δ8.50(d,J＝8.2Hz，1H),8.30(d,J＝3.7Hz，2H),8.05(s，1H),7.75(d,J＝8.1Hz，2H),7.61(d,J＝8.2Hz，2H),6.82(dd,J＝6.1,1.8Hz，1H),5.42(dd,J＝11.1,1.8Hz，1H),5.30(dd,J＝11.1,6.2Hz，1H),4.64(s，2H),4.20(s，1H),3.10-3.13(m，1H),2.93(s，3H).HRMS(ESI)m/z:计算值C19H18O3N+308.1281,实测值308.1280.
实施例20化合物I-20的制备
Figure BDA0001080447480000181
制备方法同实施例2，将化合物S-2替换为化合物S-20得化合物I-20，收率为85％。1H NMR(DMSO-d6,400MHz)δ8.51(d,J＝8.2Hz，1H),8.30(d,J＝4.3Hz，2H),8.09(s，1H),7.64–7.58(m，1H),7.40–7.34(m，2H),7.24(s，1H),6.85(dd,J＝6.2,2.1Hz，1H),5.42(dd,J＝11.1,2.1Hz，1H),5.31(dd,11.1,6.2Hz，1H),3.88(s，3H),3.80-3.82(m，1H),2.95(s，3H).HRMS(ESI)m/z:计算值C19H18O3N+308.1281,实测值308.1290.
本发明式1所述噁唑并吡啶季铵盐类化合物作为合成中间体转化为N取代吡啶酮类化合物和2-取代吡啶类化合物的应用实施例：
实施例21化合物P-1的制备
Figure BDA0001080447480000182
以化合物S-1为原料，将化合物S-1(1mmol)溶于甲苯(5ml)，加入三氟乙酸(3mmol)搅拌，升温至50℃反应。反应完毕后，反应液用冰水降温，加入饱和碳酸氢钠溶液搅拌。减压蒸干溶剂，残余物通过硅胶柱分离纯化得到产物，得到油状产物P-1(84％收率)。
1H NMR(400MHz,氯仿-d)δ7.50(dd,J＝7.0,2.1Hz,1H),7.37(ddd,J＝8.9,6.5,2.0Hz,1H),6.57(ddd,J＝9.2,1.4,0.7Hz,1H),6.33–6.26(m,1H),6.02(dd,J＝5.5,4.4Hz,1H),3.77(p,J＝11.7,10.9Hz,2H),3.37(d,J＝0.6Hz,4H).13C NMR(125MHz,氯仿-d)δ162.71,139.34,131.71,120.23,106.04,85.76,63.59,56.75.HRMS(EI)计算值C8H11NO3[M]+:169.0739,实测值:169.0743.
实施例22化合物P-2的制备
Figure BDA0001080447480000191
2-(2,2-二甲氧基乙氧基)-3-甲基吡啶(以购买的2-氯-3-甲基吡啶和羟基乙醛缩二甲醇为原料，按照Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-3-甲基吡啶，得到油状产物P-2(55％收率)。
1H NMR(400MHz,氯仿-d)δ7.37(dt,J＝7.2,1.3Hz,1H),7.26(ddd,J＝6.7,2.1,1.1Hz,1H),6.23(t,J＝6.8Hz,1H),6.08(dd,J＝5.6,4.4Hz,1H),3.79(qd,J＝11.7,5.0Hz,2H),3.39(s,3H),2.18(t,J＝0.9Hz,3H).13C NMR(125MHz,氯仿-d)δ163.00,136.66,129.17,128.87,105.84,86.07,63.78,56.75,16.57.HRMS(ESI)计算值C9H13NO3[M+Na]+:206.0793,实测值206.0791.
实施例23化合物P-3的制备
Figure BDA0001080447480000192
以化合物S-5为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-5，得到油状产物P-3(76％收率)。
1H NMR(400MHz,氯仿-d)δ7.10(dd,J＝7.1,1.6Hz,1H),6.63(dd,J＝7.4,1.6Hz,1H),6.21(t,J＝7.2Hz,1H),6.07(t,J＝5.1Hz,1H),3.81(s,3H),3.78–3.70(m,2H),3.33(s,3H).13C NMR(125MHz,氯仿-d)δ157.99,149.17,122.35,111.97,104.97,86.06,63.33,56.67,55.40.HRMS(EI)计算值C9H13NO4[M]+:199.0845,实测值199.0848.
实施例24化合物P-4的制备
Figure BDA0001080447480000201
2-(2,2-二甲氧基乙氧基)-3-硝基吡啶(以购买的2-氯-3-硝基吡啶和羟基乙醛缩二甲醇为原料，按照Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-3-硝基吡啶，得到油状产物P-4(26％收率)。
1H NMR(400MHz,氯仿-d)δ8.40(dd,J＝7.6,2.1Hz,1H),7.92(dd,J＝6.8,2.1Hz,1H),6.45(t,J＝7.2Hz,1H),6.11(t,J＝3.9Hz,1H),3.95(dd,J＝12.2,3.5Hz,1H),3.81(dd,J＝12.2,4.2Hz,1H),3.45(s,3H).13C NMR(125MHz,Acetone)δ153.88,139.82,137.59,102.57,87.06,61.93,56.22.HRMS(EI)计算值C8H10N2O5[M]+:214.0590,实测值214.0595.
实施例25化合物P-5的制备
Figure BDA0001080447480000211
2-(2,2-二甲氧基乙氧基)-3-(三氟甲基)吡啶(以购买的2-氯-3-三氟甲基吡啶和羟基乙醛缩二甲醇为原料，按照Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-3-(三氟甲基)吡啶，得到油状产物P-5(61％收率)。
1H NMR(400MHz,氯仿-d)δ7.85–7.77(m,1H),7.74(dd,J＝7.0,2.0Hz,1H),6.38(t,J＝7.0Hz,1H),6.03(dd,J＝5.0,4.0Hz,1H),3.87–3.80(m,1H),3.75(dd,J＝12.1,4.9Hz,1H),3.39(s,3H),3.28–3.17(m,1H).13C NMR(125MHz,氯仿-d)δ158.47,138.79,138.75,136.37,123.21,121.06,119.93,119.68,104.15,86.37,86.28,62.89,57.06,56.98.HRMS(ESI)计算值C9H10NO3F3[M+Na]+:260.0510,实测值260.0509.
实施例26化合物P-6的制备
Figure BDA0001080447480000212
以化合物S-3为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-3，得到油状产物P-6(59％收率)。
1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝4.2Hz,1H),8.36(dd,J＝7.2,2.2Hz,1H),7.88(dd,J＝6.7,2.2Hz,1H),7.65(d,J＝4.2Hz,1H),6.58(t,J＝6.9Hz,1H),5.94(t,J＝4.6Hz,1H),5.21(t,J＝6.1Hz,1H),3.60(ddd,J＝6.7,4.7,2.3Hz,2H),3.25(s,3H).13C NMR(125MHz,DMSO-d6)δ164.56,161.69,143.78,138.11,106.30,86.67,61.60,56.60,38.81,38.60.HRMS(EI)计算值C9H12N2O4[M]+:212.0797,实测值212.0799.
实施例27化合物P-7的制备
Figure BDA0001080447480000221
以化合物S-6为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-6，得到油状产物P-7(19％收率)。
1H NMR(400MHz,氯仿-d)δ7.38(d,J＝7.1Hz,1H),6.44–6.37(m,1H),6.16(dd,J＝7.2,1.8Hz,1H),6.01(t,J＝5.0Hz,1H),3.83–3.66(m,2H),3.37(s,3H),2.28–2.17(m,3H).13C NMR(125MHz,氯仿-d)δ162.76,151.26,130.63,118.55,108.85,85.54,63.71,56.68,20.82.HRMS(ESI)计算值C9H13NO3[M+Na]+:206.0793,实测值206.0799.
实施例28化合物P-8的制备
Figure BDA0001080447480000222
以化合物S-2为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-2，得到油状产物P-8(51％收率)。
1H NMR(400MHz,氯仿-d)δ7.71–7.63(m,1H),6.85(dd,J＝1.9,1.0Hz,1H),6.43(dd,J＝7.3,2.0Hz,1H),5.98(t,J＝4.4Hz,1H),3.88–3.73(m,2H),3.41(s,3H),2.97–2.89(m,1H).13C NMR(125MHz,氯仿-d)δ161.56,141.17,140.90,133.83,124.84,122.66,120.48,117.73,117.70,117.66,101.18,101.16,86.29,63.01,57.02,HRMS(ESI)计算值C9H10NO3F3[M+Na]+:260.0510,实测值260.0508.
实施例29化合物P-9的制备
Figure BDA0001080447480000231
2-(2,2-二甲氧基乙氧基)-5-甲基吡啶(以购买的2-氯-5-甲基吡啶和羟基乙醛缩二甲醇为原料，按照Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-5-甲基吡啶，得到油状产物P-9(26％收率)。
1H NMR(400MHz,氯仿-d)δ7.27–7.20(m,2H),6.57–6.51(m,1H),6.03(t,J＝5.1Hz,1H),3.77(dd,J＝5.0,1.3Hz,2H),3.37(s,3H),2.12(d,J＝1.0Hz,3H).13C NMR(125MHz,氯仿-d)δ162.07,142.15,128.91,119.78,115.33,85.73,63.57,56.76.HRMS(EI)计算值C9H13NO3[M]+:183.0895,实测值183.0892.
实施例30化合物P-10的制备
Figure BDA0001080447480000232
以化合物S-4为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-4，得到油状产物P-10(22％收率)。
1H NMR(400MHz,氯仿-d)δ8.78(d,J＝3.1Hz,1H),8.16(dd,J＝10.0,3.1Hz,1H),6.60(d,J＝10.0Hz,1H),5.96(t,J＝3.7Hz,1H),3.96(dd,J＝12.2,3.4Hz,1H),3.78(dd,J＝12.2,4.1Hz,1H),3.48(s,4H).13C NMR(125MHz,氯仿-d)δ161.35,134.63,133.02,130.92,129.42,129.25,119.21,86.77,62.95,57.49.HRMS(ESI)计算值C9H10N2O5[M+Na]+:237.0487,实测值237.0485.
实施例31化合物P-11的制备
Figure BDA0001080447480000241
2-(2,2-二甲氧基乙氧基)-5-(三氟甲基)吡啶(以购买的2-氯-5-三氟甲基吡啶和羟基乙醛缩二甲醇为原料，同Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-5-(三氟甲基)吡啶，得到油状产物P-11(78％收率)。
1H NMR(400MHz,氯仿-d)δ7.92–7.88(m,1H),7.50(dd,J＝9.6,2.7Hz,1H),6.67–6.60(m,1H),5.97(t,J＝4.3Hz,1H),3.85(dd,J＝12.1,3.9Hz,1H),3.76(dd,J＝12.0,4.8Hz,1H),3.42(s,3H),2.93(s,1H).13C NMR(125MHz,氯仿-d)δ161.98,135.01,134.99,132.02,131.97,131.93,131.89,126.05,123.90,121.76,120.74,110.28,110.00,109.72,109.45,86.36,63.02,62.90,57.13.HRMS(ESI)计算值C9H10NO3F3[M+Na]+:260.0510,实测值260.0513.
实施例32化合物P-12的制备
Figure BDA0001080447480000251
以化合物S-8为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-8，得到固体产物P-12(89％收率)。
1H NMR(400MHz,氯仿-d)δ8.12(d,J＝8.7Hz,1H),7.69(d,J＝9.4Hz,1H),7.55(dd,J＝7.8,1.7Hz,1H),7.51–7.46(m,1H),7.26–7.22(m,1H),6.76–6.71(m,1H),6.68(d,J＝9.4Hz,1H),4.27(dd,J＝11.8,7.2Hz,1H),4.00(dd,J＝11.8,6.0Hz,1H),3.39(s,3H).13C NMR(125MHz,氯仿-d)δ163.35,139.89,137.26,129.68,128.55,122.22,120.89,120.76,116.21,86.77,61.65,56.41.HRMS(EI)计算值C12H13NO3[M]+:219.0895,实测值219.0898.
实施例33化合物P-13的制备
Figure BDA0001080447480000252
2-(2,2-二甲氧基乙氧基)-4-甲基喹啉酮(以购买的2-氯-4-甲基喹啉和羟基乙醛缩二甲醇为原料，同Tetrahedron,2004,60,6113中的制备方法制得)为原料，按实施例21的制备方法，将化合物S-1替换为2-(2,2-二甲氧基乙氧基)-4-甲基喹啉酮，得到固体产物P-13(84％收率)。
1H NMR(400MHz,氯仿-d)δ8.14(dd,J＝8.7,1.0Hz,1H),7.70(dd,J＝8.0,1.6Hz,1H),7.49(ddd,J＝8.7,7.1,1.6Hz,1H),7.28–7.23(m,1H),6.79–6.70(m,1H),6.56(d,J＝1.4Hz,1H),4.27(dd,J＝11.7,7.2Hz,1H),3.99(dd,J＝11.8,6.0Hz,1H),3.39(s,3H),2.47(d,J＝1.1Hz,3H).13C NMR(125MHz,氯仿-d)δ163.17,147.44,137.06,129.49,124.81,122.09,121.65,120.14,116.51,115.97,86.66,61.71,56.33,18.69.HRMS(EI)计算值C13H15NO3[M]+:233.1052,实测值233.1056.
实施例34化合物P-14的制备
Figure BDA0001080447480000261
以化合物S-7为原料，按实施例21的制备方法，将化合物S-1替换为化合物S-7，得到固体产物P-14(63％收率)。
1H NMR(400MHz,DMSO-d6)δ8.28–8.21(m,1H),7.73(ddd,J＝8.2,7.0,1.3Hz,1H),7.70–7.64(m,1H),7.53(ddd,J＝8.1,7.0,1.4Hz,1H),7.35(d,J＝7.6Hz,1H),6.69(d,J＝7.6Hz,1H),5.97(t,J＝5.4Hz,1H),5.19(s,1H),4.14(s,1H),3.66(dd,J＝11.7,5.6Hz,1H),3.58(dd,J＝11.7,5.3Hz,1H),3.22(s,3H),3.17(s,3H).13C NMR(125MHz,DMSO-d6)δ161.53,136.62,132.61,127.21,126.69,126.12,125.22,105.45,85.32,85.32,61.86,55.94.HRMS(EI)计算值C12H13NO3[M]+:219.0895,实测值219.0894.
化合物P-15至P-29的制备方法：
实施例35化合物P-15的制备
Figure BDA0001080447480000262
以化合物S-1为原料，将化合物S-1(1mmol)溶于甲苯(5ml)，加入三氟醋酸(3mmol)搅拌反应。升温至50℃反应。反应完毕，反应液减压蒸干溶剂得到残余物。残余物再用甲苯溶解或分散，加入亲核试剂反应，搅拌过夜。反应完毕，减压蒸干溶剂得到残余物，残余物通过硅胶柱分离得到产物。亲核试剂为苯胺，得到油状产物P-15(27％收率)。
1H NMR(400MHz,氯仿-d)δ7.50(dd,J＝7.0,2.0Hz,1H),7.36(ddd,J＝8.9,6.4,2.0Hz,1H),7.19(t,J＝7.7Hz,2H),6.73(dd,J＝11.2,7.7Hz,3H),6.60(d,J＝9.2Hz,1H),6.26(t,J＝6.8Hz,1H),6.12(dd,J＝6.7,4.0Hz,1H),3.55(dd,J＝13.7,3.9Hz,1H),3.36(s,3H),3.35–3.29(m,1H).13C NMR(125MHz,氯仿-d)δ162.99,147.34,139.68,131.66,129.30,120.82,117.97,113.08,106.44,85.36,57.30,47.95.HRMS(EI)计算值C14H16N2O2[M]+:244.1212,实测值244.1218.
实施例36化合物P-16的制备
Figure BDA0001080447480000271
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间甲氧基苯胺，得到油状产物P-16(32％收率)。
1H NMR(400MHz,氯仿-d)δ7.49(dd,J＝7.0,2.0Hz,1H),7.37(ddd,J＝8.9,6.5,2.0Hz,1H),7.08(t,J＝8.3Hz,1H),6.60(d,J＝9.1Hz,1H),6.35–6.23(m,4H),6.12(dd,J＝6.7,4.0Hz,1H),4.21(s,1H),3.79(s,3H),3.54(dd,J＝13.5,4.0Hz,1H),3.39–3.26(m,4H).13C NMR(125MHz,氯仿-d)δ162.54,160.37,148.29,139.23,131.16,129.57,120.34,106.01,105.54,103.12,98.33,84.86,56.85,54.67,47.51.HRMS(EI)计算值C15H18N2O3[M]+:274.1317,实测值274.1329.
实施例37化合物P-17的制备
Figure BDA0001080447480000281
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为对甲氧基苯胺，得到油状产物P-17(53％收率)。
1H NMR(400MHz,氯仿-d)δ7.53–7.44(m,1H),7.36(ddd,J＝8.7,6.6,2.1Hz,1H),6.78(d,J＝8.5Hz,2H),6.69(d,J＝8.7Hz,2H),6.59(d,J＝9.2Hz,1H),6.26(t,J＝6.8Hz,1H),6.09(dd,J＝6.9,3.8Hz,1H),4.12(s,1H),3.74(s,3H),3.49(dd,J＝13.5,3.7Hz,1H),3.34(s,3H),3.26(dd,J＝13.5,6.8Hz,1H).13C NMR(125MHz,氯仿-d)δ162.48,152.13,140.70,139.32,131.28,120.24,114.21,106.12,84.88,56.79,55.26,48.51.HRMS(EI)计算值C15H18N2O3[M]+:274.1317,实测值274.1326.
实施例38化合物P-18的制备
Figure BDA0001080447480000282
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间硝基苯胺，得到油状产物P-18(11％收率)。
1H NMR(400MHz,氯仿-d)δ7.56–7.46(m,3H),7.42–7.34(m,1H),7.28(d,J＝16.2Hz,1H),7.04–6.97(m,1H),6.61(d,J＝9.1Hz,1H),6.29(t,J＝6.8Hz,1H),6.13–6.06(m,1H),4.74–4.53(m,1H),3.63–3.53(m,1H),3.42(dd,J＝13.5,6.3Hz,1H),3.38(d,J＝1.1Hz,3H).13C NMR(125MHz,氯仿-d)δ162.59,148.80,147.76,139.39,130.80,129.36,120.42,118.17,111.94,106.49,106.27,84.90,56.96,47.24.HRMS(EI)计算值C14H15N3O4[M]+:289.1063,实测值289.1058.
实施例39化合物P-19的制备
Figure BDA0001080447480000291
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间氯苯胺，得到油状产物P-19(36％收率)。
1H NMR(400MHz,氯仿-d)δ7.51–7.45(m,1H),7.38(ddd,J＝8.9,6.5,2.0Hz,1H),7.08(t,J＝8.2Hz,1H),6.69(dd,J＝5.1,2.6Hz,2H),6.60(t,J＝9.2Hz,2H),6.28(t,J＝6.8Hz,1H),6.09(dd,J＝6.5,4.2Hz,1H),4.26(s,1H),3.57–3.45(m,1H),3.37(s,4H).13CNMR(125MHz,氯仿-d)δ163.01,148.51,139.73,135.00,131.45,130.26,120.89,117.81,112.88,111.19,106.54,85.31,57.37,47.76.
实施例40化合物P-20的制备
Figure BDA0001080447480000301
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为对溴苯胺，得到油状产物P-20(65％收率)。
1H NMR(400MHz,氯仿-d)δ7.47(dd,J＝6.8,1.9Hz,1H),7.42–7.33(m,1H),7.25(dd,J＝7.8,2.3Hz,2H),6.59(dd,J＝8.7,1.4Hz,3H),6.27(t,J＝6.7Hz,1H),6.07(dd,J＝6.7,4.0Hz,1H),4.20(s,1H),3.58–3.44(m,1H),3.41–3.20(m,4H).13C NMR(125MHz,氯仿-d)δ162.96,146.34,139.75,131.97,131.46,120.86,114.64,109.59,106.53,85.30,57.38,47.90.
实施例41化合物P-21的制备
Figure BDA0001080447480000302
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为苯酚钠，得到油状产物P-21(14％收率)。
1H NMR(400MHz,氯仿-d)δ7.61(dd,J＝7.0,2.1Hz,1H),7.39(ddd,J＝8.9,6.5,2.1Hz,1H),7.32–7.24(m,4H),7.02–6.91(m,3H),6.64–6.57(m,1H),6.29(dt,J＝5.8,2.6Hz,2H),4.26(dd,J＝10.6,3.1Hz,1H),4.16(dd,J＝10.6,5.4Hz,1H),3.44(d,J＝0.6Hz,3H).13C NMR(125MHz,氯仿-d)δ162.77,158.14,139.80,132.49,129.47,121.41,120.80,114.70,106.23,84.34,68.33,57.41.
实施例42化合物P-22的制备
Figure BDA0001080447480000311
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为苯硫酚钠，得到油状产物P-22(98％收率)。
1H NMR(400MHz,氯仿-d)δ7.49(dd,J＝7.0,2.0Hz,1H),7.43(dd,J＝8.0,1.4Hz,2H),7.33(td,J＝6.6,3.2Hz,1H),7.31–7.24(m,2H),7.22–7.14(m,1H),6.57–6.51(m,1H),6.26–6.20(m,1H),6.08(dd,J＝7.1,3.9Hz,1H),3.38–3.32(m,4H),3.21(dd,J＝14.2,7.1Hz,1H).13C NMR(125MHz,氯仿-d)δ162.67,139.61,135.36,131.52,129.47,128.95,126.40,120.81,106.31,85.59,57.39,38.53.HRMS(EI)计算值C14H15NSO2[M]+:261.0823,实测值261.0828.
实施例43化合物P-23的制备
Figure BDA0001080447480000312
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为甲胺，得到油状产物P-23(73％收率)。
1H NMR(400MHz,氯仿-d)δ9.57(s,1H),7.99–7.91(m,1H),7.87(ddd,J＝8.8,6.9,1.6Hz,1H),6.98–6.85(m,2H),6.15(dd,J＝7.0,4.9Hz,1H),4.04(dd,J＝12.5,4.8Hz,1H),3.60(dd,J＝12.5,6.9Hz,1H),3.34(s,3H),3.06(d,J＝4.2Hz,3H).
实施例44化合物P-24的制备
Figure BDA0001080447480000321
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为丙胺，得到油状产物P-24(75％收率)。
1H NMR(400MHz,氯仿-d)δ9.75(s,1H),7.95(d,J＝6.8Hz,1H),7.86–7.76(m,1H),6.94(d,J＝9.2Hz,1H),6.87(t,J＝6.9Hz,1H),6.30(dd,J＝8.3,4.5Hz,1H),4.20(dd,J＝12.5,4.4Hz,1H),3.58(dd,J＝12.5,8.1Hz,1H),3.46–3.32(m,5H),1.76(p,J＝7.4Hz,2H),1.04–0.96(m,3H).13C NMR(125MHz,氯仿-d)δ153.86,142.17,133.71,112.16,111.33,92.15,63.78,58.00,45.50,21.29,11.22.HRMS(EI)计算值C11H18N2O2[M]+:210.1368,实测值210.1374.
实施例45化合物P-25的制备
Figure BDA0001080447480000322
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为异丙胺，得到油状产物P-25(95％收率)。
1H NMR(400MHz,氯仿-d)δ9.16(s,1H),8.02–7.92(m,1H),7.81(t,J＝8.0Hz,1H),6.97(d,J＝9.3Hz,1H),6.87(t,J＝6.9Hz,1H),6.47(dd,J＝8.6,4.4Hz,1H),4.21(dd,J＝12.5,4.4Hz,1H),3.88(h,J＝6.6Hz,1H),3.58–3.50(m,1H),3.41(s,3H),1.48–1.33(m,6H).13C NMR(125MHz,氯仿-d)δ153.08,142.74,134.33,112.57,111.67,92.31,63.47,57.93,46.97,21.81,21.30.HRMS(EI)计算值C11H18N2O2[M]+:210.1368,实测值210.1372.
实施例46化合物P-26的制备
Figure BDA0001080447480000331
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为二丙胺，得到油状产物P-26(33％收率)。
1H NMR(400MHz,氯仿-d)δ7.46(dd,J＝7.0,2.1Hz,1H),7.37–7.31(m,1H),6.55(ddt,J＝9.2,1.3,0.7Hz,1H),6.25(td,J＝6.6,6.0,1.3Hz,1H),6.06(dd,J＝6.8,3.8Hz,1H),3.32(d,J＝0.7Hz,3H),2.76–2.56(m,6H),1.01(td,J＝7.1,0.8Hz,6H).13C NMR(125MHz,氯仿-d)δ162.76,139.32,132.32,120.62,105.90,85.32,56.87,56.53,47.96,11.74.
实施例47化合物P-27的制备
Figure BDA0001080447480000332
以化合物S-8为原料，按照实施例35的制备方法，将化合物S-1替换为化合物S-8，亲核试剂为苯硫酚钠，得到油状产物P-27(43％收率)。
1H NMR(400MHz,氯仿-d)δ8.09(d,J＝8.6Hz,1H),7.64–7.57(m,1H),7.53–7.43(m,2H),7.42–7.34(m,2H),7.26–7.13(m,4H),6.80(t,J＝6.9Hz,1H),6.63(d,J＝9.4Hz,1H),3.73–3.53(m,2H),3.37(s,3H).13C NMR(125MHz,氯仿-d)δ163.40,140.08,137.46,134.92,130.15,130.05,129.09,128.88,126.61,122.56,121.41,121.35,116.56,85.95,77.34,77.09,76.83,56.76,36.47.
实施例48化合物P-28的制备
Figure BDA0001080447480000341
以化合物S-7为原料，按照实施例35的制备方法，将化合物S-1替换为化合物S-7，亲核试剂为苯硫酚钠，得到油状产物P-28(39％收率)。
1H NMR(400MHz,氯仿-d)δ8.49–8.41(m,1H),7.72–7.64(m,1H),7.56–7.49(m,2H),7.47–7.41(m,2H),7.31–7.21(m,3H),7.20–7.13(m,1H),6.56(d,J＝7.6Hz,1H),6.25(dd,J＝6.8,5.1Hz,1H),3.41–3.26(m,5H).13C NMR(125MHz,氯仿-d)δ162.41,136.76,135.32,132.60,129.90,128.94,127.97,126.98,126.52,125.97,125.95,125.13,106.81,85.08,77.29,77.24,77.03,76.78,57.07,38.69.
实施例49化合物P-29的制备
Figure BDA0001080447480000342
以化合物S-7为原料，按照实施例35的制备方法，将化合物S-1替换为化合物S-7，亲核试剂为异丙胺，得到油状产物P-29(45％收率)。
1H NMR(400MHz,氯仿-d)δ8.43(d,J＝8.0Hz,1H),7.72–7.61(m,1H),7.58–7.47(m,2H),7.27(d,J＝7.6Hz,1H),6.58(d,J＝7.6Hz,1H),6.20(dd,J＝6.6,5.3Hz,1H),3.34(s,3H),3.04–2.81(m,3H),2.09(s,1H),1.08(dd,J＝6.1,1.6Hz,6H).
化合物T-1至T-8的制备方法：
制备方法同P-15的制备。
实施例50化合物T-1的制备
Figure BDA0001080447480000351
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为苄胺，得到油状产物T-1(75％收率)。
1H NMR(400MHz,氯仿-d)δ8.17–8.08(m,1H),7.47–7.29(m,6H),6.66–6.56(m,1H),6.40(d,J＝8.4Hz,1H),4.88(s,1H),4.53(d,J＝5.8Hz,2H).13C NMR(125MHz,氯仿-d)δ158.64,148.22,139.18,137.49,128.64,127.41,127.25,113.17,106.80,46.33.HRMS(EI)计算值C12H12N2[M]+:184.1000,实测值184.0995.
实施例51化合物T-2的制备
Figure BDA0001080447480000352
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间甲氧基苄胺，得到油状产物T-2(68％收率)。
1H NMR(400MHz,氯仿-d)δ8.12(s,1H),7.41(s,1H),7.27(s,1H),6.98(s,2H),6.82(s,1H),6.60(s,1H),6.40(s,1H),5.08(s,1H),4.51(s,2H),3.80(s,3H).HRMS(EI)计算值C13H14N2O[M]+:214.1106,实测值214.1105.
实施例52化合物T-3的制备
Figure BDA0001080447480000361
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为对甲氧基苄胺，得到油状产物T-3(54％收率)。
1H NMR(400MHz,氯仿-d)δ8.13(s,1H),7.42(s,1H),7.30(s,3H),6.91(s,2H),6.59(s,1H),6.40(s,1H),4.83(s,1H),4.44(s,2H),3.82(s,3H).HRMS(EI)计算值C13H14N2O[M]+:214.1106,实测值214.1107.
实施例53化合物T-4的制备
Figure BDA0001080447480000362
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间三氟甲基苄胺，得到油状产物T-4(39％收率)。
1H NMR(400MHz,氯仿-d)δ8.16–8.10(m,1H),7.64(s,1H),7.56(dd,J＝11.8,7.8Hz,2H),7.50–7.40(m,2H),6.68–6.60(m,1H),6.40(d,J＝8.4Hz,1H),5.01(d,J＝8.1Hz,1H),4.62(d,J＝5.7Hz,2H).13C NMR(125MHz,氯仿-d)δ158.23,148.13,140.45,137.63,130.62,129.06,124.04,113.57,107.09,45.73.HRMS(ESI)计算值C13H12N2F3[M+H]+:253.0947,实测值253.0941.
实施例54化合物T-5的制备
Figure BDA0001080447480000371
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为对氯苄胺，得到油状产物T-5(40％收率)。
1H NMR(400MHz,氯仿-d)δ8.12(ddd,J＝5.1,1.9,0.9Hz,1H),7.43(ddd,J＝8.4,7.2,1.9Hz,1H),7.32(s,4H),6.63(ddd,J＝7.2,5.1,1.0Hz,1H),6.37(dt,J＝8.3,0.9Hz,1H),4.92(s,1H),4.51(d,J＝5.9Hz,2H).13C NMR(125MHz,氯仿-d)δ158.37,148.19,137.55,132.90,128.74,113.40,106.92,45.56.HRMS(ESI)计算值C12H12N2Cl[M+H]+:219.0684,实测值219.0682.
实施例55化合物T-6的制备
Figure BDA0001080447480000372
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为间溴苄胺，得到油状产物T-6(85％收率)。
1H NMR(400MHz,氯仿-d)δ8.15–8.09(m,1H),7.53(s,1H),7.46–7.39(m,2H),7.31(d,J＝7.8Hz,1H),7.22(t,J＝7.8Hz,1H),6.66–6.60(m,1H),6.38(d,J＝8.4Hz,1H),4.96(s,1H),4.53(d,J＝5.8Hz,2H).13C NMR(125MHz,氯仿-d)δ158.26,148.14,141.78,137.60,130.30,125.86,122.74,113.47,107.01,45.59.HRMS(ESI)计算值C12H12N2Br[M+H]+:263.0178,实测值263.0184.
实施例56化合物T-7的制备
Figure BDA0001080447480000381
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为苯乙胺，得到油状产物T-7(67％收率)。
1H NMR(400MHz,氯仿-d)δ8.10(s,1H),7.44(s,1H),7.34(s,2H),7.27(s,3H),6.59(s,1H),6.38(s,1H),4.58(s,1H),3.57(s,2H),2.95(s,2H).13CNMR(125MHz,氯仿-d)δ158.53,148.08,139.18,137.44,128.79,128.58,126.40,112.86,106.80,43.30,35.64.HRMS(EI)计算值C13H14N2[M]+:198.1157,实测值198.1158.
实施例57化合物T-8的制备
Figure BDA0001080447480000382
以化合物S-1为原料，按照实施例35的制备方法，亲核试剂为苯丙胺，得到油状产物T-8(77％收率)。
1H NMR(400MHz,氯仿-d)δ8.13–8.06(m,1H),7.43(ddd,J＝8.8,7.2,1.9Hz,1H),7.34–7.29(m,2H),7.26–7.18(m,3H),6.62–6.54(m,1H),6.36(d,J＝8.4Hz,1H),4.57(s,1H),3.37–3.26(m,2H),2.76(t,J＝7.7Hz,2H),2.03–1.93(m,2H).
综上，本发明申请保护的噁唑并吡啶季铵盐类化合物能够很方便的转化为N取代吡啶酮类化合物和2-取代吡啶类化合物，具有在药化领域应用的潜在价值，如化合物P-1到P-29可以进一步合成阿扎胞苷(胞嘧啶核苷类药物)类似物；化合物T-1到T-8可以作为中间体进一步合成吡苄明(抗组胺药)及其类似物，用于创新药物的发现与合成研究。
Figure BDA0001080447480000391

Claims (6)

1.一种噁唑并吡啶季铵盐类化合物作为合成中间体的转化应用：
Figure FDF0000020317030000011
其中，Q、U为氧；
R1为位于吡啶环上的1-4个相同或不同的取代基，各取代基独立地选自氢、羟基、巯基、取代或未取代的烷基、取代或未取代的芳基、C1-C6烷氧基、C1-C6烷硫基、C6-C12芳醚基、C6-C12芳硫基、硝基、酰胺基、苯并二噁茂基或卤素；或者当R1为吡啶环上的2个或2个以上取代基时，其中2个相邻的取代基可彼此连接并且与吡啶环上的碳原子共同形成取代或未取代的芳基或含有0-3个独立选自O、S或N原子的5-7元环烷基；
R2、R3各自独立地代表氢；
R4代表氢、取代或未取代的烷基；
Y包括硝酸根离子、硫酸根离子、磷酸根离子、甲磺酸根离子、苯磺酸根离子、醋酸根离子、酒石酸根离子、枸橼酸根离子、马来酸根离子、琥珀酸根离子、柠檬酸根离子、水杨酸根离子、甘油酸根离子、抗坏血酸根离子、三氟乙酸根离子、氟离子、氯离子、溴离子或碘离子；
所述取代或未取代的烷基包括取代或未取代的饱和、不饱和、直链、支链的全碳C1-C6烷基；其中，“所述取代或未取代”中的“取代”是指被选自卤素、芳基中的一种或多种取代基所取代；
所述取代或未取代的芳基包括取代或未取代的苯基；其中，“所述取代或未取代”中的“取代”是指被选自C1-C6烷氧基、卤素取代的C1-C6烷氧基、苄基、羟基、氰基、C1-C3烷氧基羰基中的一种或多种取代基所取代；
所述的卤素是指氟、氯、溴或碘；
Z为R7N；
A为氢；
R6为氢、被取代或未取代的芳基所取代的C1-C6烷基，所述“取代或未取代的芳基”中的“取代”是指被C1-C3烷氧基、三氟甲基或卤素所取代；
R7为氢；
所述化合物I溶于溶剂中，加入亲核试剂，所述亲核试剂为R6-ZA，在零下80摄氏度至200摄氏度的温度下反应，蒸除溶剂，分离纯化，即获得2-取代吡啶类化合物T，
Figure FDF0000020317030000021
代表单键。
2.根据权利要求1所述的转化应用：其中，R1为位于吡啶环上的1-4个相同或不同的取代基，各取代基独立地选自氢、取代或未取代的烷基、取代或未取代的芳基、C1-C6烷氧基、硝基、酰胺基、苯并二噁茂基；或者当R1为吡啶环上的2个或2个以上取代基时，其中2个相邻的取代基并且与吡啶环上的碳原子共同形成芳基。
3.根据权利要求1所述的转化应用，所述的噁唑并吡啶季铵盐类化合物选自：
Figure FDF0000020317030000022
Figure FDF0000020317030000031
4.根据权利要求1-3任一项所述的转化应用，其中，所述噁唑并吡啶季铵盐类化合物通过以下方法制备：
Figure FDF0000020317030000032
化合物S溶于溶剂中，加入酸，在一定温度下反应一段时间，蒸除溶剂，得化合物I；其中，R1、R2、R3、R4、U、Q、Y的定义同相对应的权利要求；
在化合物S制备化合物I过程中所述的溶剂包括甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、二甲苯、氯苯、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、水中的一种或一种以上组合溶剂；
所述的一定温度包括从零下80摄氏度至200摄氏度的任何温度，
所述酸选自硝酸、硫酸、磷酸、甲磺酸、苯磺酸、醋酸、酒石酸、枸橼酸、马来酸、琥珀酸、柠檬酸、水杨酸、甘油酸、抗坏血酸、氢氟酸、盐酸、氢溴酸、氢碘酸、对甲苯磺酸、三氟甲磺酸、乙酸、以及三氟乙酸中的一种或一种以上组合酸。
5.根据权利要求4所述的转化应用，其中，
所述的溶剂为甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、水一种或一种以上的组合溶剂；所述的一定温度为从0摄氏度到100摄氏度的任何温度。
6.根据权利要求1所述的转化应用，在化合物I制备化合物T过程中所述的溶剂包括甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、二甲苯、氯苯、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、水中的一种或一种以上组合溶剂。
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