CN117567419A - 一种3-胺甲基色酮衍生物合成方法 - Google Patents

一种3-胺甲基色酮衍生物合成方法 Download PDF

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CN117567419A
CN117567419A CN202311513787.7A CN202311513787A CN117567419A CN 117567419 A CN117567419 A CN 117567419A CN 202311513787 A CN202311513787 A CN 202311513787A CN 117567419 A CN117567419 A CN 117567419A
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李嗣锋
韩思杨
程斌
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Shenzhen Vocational And Technical University
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    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract

本发明涉及化学合成领域，具体为一种3‑胺甲基色酮衍生物合成方法，及进一步发展一种多取代的嘧啶衍生物合成方法；本发明通过构建邻羟基芳基烯胺酮与1,3,5‑三嗪烷的路易斯酸反应体系，经过Michael加成、环化反应及氢转移一步合成3‑胺甲基色酮衍生物，再通过与胍或眯进一步成环、开环反应可获得含胺甲基及酚羟基的多取代嘧啶衍生物。反应操作简便安全，原料易得，方法简洁高效，反应条件温和，无副产物，化合物官能团容忍度高，且后处理方便，产率普遍较高，可避免使用较难衍生化的色酮底物，底物适用性广、操作简单、适合大量合成。

Description

一种3-胺甲基色酮衍生物合成方法
技术领域
本发明涉及化学合成领域，具体为一种3-胺甲基色酮衍生物合成方法。
背景技术
色酮也被称为苯并-γ-吡喃酮，是广泛存在于植物中的有色天然产物，在药物化学及材料科学具有广泛的应用，不断引起越来越多生物化学家和化学家的关注。迄今为止，科学家们已经成功开发出各种方法制备不同类型的色酮衍生物。其中，以邻羟苯基胺基烯酮为原料，通过与另一组分发生Michael加成再分子内环加成及C-N键断裂等一系列反应过程，是合成碳-3位官能团化色酮衍生物的有效策略，受到了有机合成化学家持续而广泛的关注。令人高兴的是，利用前述烯胺酮为色酮骨架的前体，炔基(Chem.Commun.2016,52,12306-12309；Adv.Synth.Catal.2022,364,4440-4446)、吲哚-3-甲基(J.Org.Chem.2022,87,9270-9281)、三氟甲基(Org.Chem.Front.2020,7,2770-2775)、氰基(J.Org.Chem.2023,88,4017-4023)、卤素(Org.Lett.2017,19,146-149；Chin.Chem.Lett.2018,29,963-966；New J.Chem.2020,44,8120-8124；Tetrahedron 2020,76,130833)、胺基(Org.Chem.Front.2020,7,1107-1112)、芳基(Chem.Eur.J.2019,25,6907-6910；Chem.Commun.2020,56,2606-2609；J.Org.Chem.2021,86,4896-4916；Adv.Synth.Catal.2022,364,3512-3521)、磺基(Beilstein J.Org.Chem.2017,13,2017-2022；Eur.J.Org.Chem.2017,2017,4401-4404)、硫/硒氰基(RSC Adv.2016,6,66320-66323；New J.Chem.2019,43,16441-16444；New J.Chem.2020,44,2222-2227)、硫基(ChemCatChem 2017,9,465-468；Tetrahedron 2022,124,133018)、硒基(Adv.Synth.Catal.2021,363,1656-1661)等官能团成功引入到色酮的3-位，并可进一步与胍或眯生成多取代嘧啶衍生物(Org.Chem.Front.2020,7,2770-2775)，而合成3-胺甲基化色酮衍生物近年来才有报道。
现有方法还包括通过构建没有光敏剂和添加剂的蓝光催化下体系，实现了N-芳基甘氨酸对邻羟苯基胺基烯酮的蓝光诱导的脱羧串联环化反应，获得了一系列3-位胺甲基化的色酮衍生物(Adv.Synth.Catal.2022,364,2169-2173；CN 113651788A)。同年，他们还利用南极脂肪酶B假丝酵母(CALB)使N-芳基甘氨酸酯原位生成相应的N-芳基甘氨酸，在通过亚甲基蓝为光敏剂的蓝光催化下进一步发生光氧化脱羧反应，再经过与邻羟苯基胺基烯酮发生串联环化反应进而得到3-取代的色酮化合物(J.Org.Chem.2022,87,14965-14969)。尽管前述两种方法都获得了3-胺甲基色酮衍生物，然而反应时间较长。此外，胺甲基的供体N-芳基甘氨酸、N-芳基甘氨酸酯需要进一步合成，反应体系可见光的使用导致实验操作较繁琐，限制了该类化合物的简单合成。因此，寻找合适的胺甲基供体并发展一种反应条件温和、简单、高效的合成路线实现胺甲基试剂对邻羟苯基胺基烯酮的串联环化反应，可为获得3-胺甲基色酮衍生物提供便利。
发明内容
本发明的主要目的在于利用1,3,5-三嗪烷提供的胺甲基实现对邻羟苯基胺基烯酮串联环化反应以获得3-胺甲基色酮衍生物。
本发明的技术方案具体如下：
一种3-胺甲基色酮衍生物合成方法，3-胺甲基取代色酮类衍生物的结构式如Ⅰ所示，
其中：R为氢、卤素、C1-C6烷基、C1-C20全氟烷基、C1-C6烷氧基、C6-C12芳基、苄基、C2-C10杂环基中单取代或多取代的一种；
R’为C1-C20烷基、环丙基、C1-C20全氟烷基、C6-C12芳基、苄基、C2-C8含烯基取代基、C2-C8含炔基取代基或C2-C10杂环基中的任意一种；
合成方法如下式所示：
式中，化合物Ⅰ制备步骤为：
S1、将化合物Ⅱ、化合物Ⅲ和催化剂置于有机溶剂中搅拌反应；
S2、待化合物III完全消失后，将反应混合物减压条件下除去有机溶剂；
S3、使用硅胶柱层析洗脱得到化合物I。
进一步的，所述化合物Ⅱ和化合物Ⅲ的摩尔比为Ⅱ:Ⅲ＝1.0:0.4-2.0。
进一步的，所述催化剂包括碘化亚铜、溴化亚铜、溴化锌、氯化铁、三氯化铟、三氯化铋、氯化亚铜、三氟甲磺酸铜、三氟甲磺酸亚铜、三氟甲磺酸锌、三氟甲磺酸银、三氟甲磺酸铟、三氟甲磺酸铁、三氟甲磺酸钪、三氟甲磺酸钇、三氟甲磺酸铋或三氟甲磺酸钕其中的一种或多种。
进一步的，所述有机溶剂包括乙酸乙酯、乙腈、二氯甲烷、二氯乙烷、氯仿、四氢呋喃、四氢吡喃、甲苯、N,N-二甲基丙烯基脲、N-甲基吡咯烷酮、二甲基甲酰胺或二甲基乙酰胺中的任意一种或至少两种组合。
进一步的，所述柱层析使用的洗脱液为石油醚和乙酸乙酯的混合液，体积比为V石油醚:V乙酸乙酯＝10:1～2:1。
本发明的有益效果为：
(1)本发明提供了一种3-胺甲基色酮衍生物的合成方法。
(2)本发明的制备方法选用路易斯酸为催化剂，反应无惰性气体保护、操作简便安全、原料易得、反应步骤少、可避免使用惰性的色酮衍生物、反应条件温和、无副产物、底物拓展范围广、化合物官能团容忍度高，产物收率可以达到89％。
(3)本发明使用易制得的1,3,5-三嗪烷衍生物为胺甲基前体，以邻羟苯基胺基烯酮为色酮骨架前体，还可克级制备3-胺甲基色酮类衍生物，经与胍或眯反应可进一步获得多取代的嘧啶化合物。
附图说明
图1为本发明实施例所得到的产物Ⅰ-19的核磁谱图(氢谱)；
图2为本发明实施例所得到的产物Ⅰ-19的核磁谱图(碳谱)；
图3为本发明实施例所得到的产物IV-4的核磁谱图(氢谱)；
图4为本发明实施例所得到的产物IV-4的核磁谱图(碳谱)；
具体实施方式
下面结合附图并通过具体的实施例进一步的说明本发明的技术方案：
以下是本发明制备化合物的最佳实施例。在以下所有实施例中，核磁谱检测通过Bruker 400,JEOL 400仪器在CDCl3中获得。δ值为内标相对值(CHCl3定标δ7.261H NMR和77.1613C NMR；DMSO-d6定标δ2.501H NMR和69.5213C NMR)。高分辨质谱(HRMS)通过4Gquadrupole time-of-flight(QTof)质谱仪器得到。
实施例1
实施例1的反应式，具体使用的化合物II-1、III-1以及产物Ⅰ-1结构如下，实验表明本发明优选的路易斯酸是三氟甲磺酸钪，优选的的溶剂时二氯乙烷，其反应产物的最高收率为77％，最好的原料摩尔比为化合物II和化合物III的摩尔比为II：III＝1:1，其中化合物II应是当量值，溶液的最优浓度为0.1M。
具体实验步骤是：于10毫升的直型反应管中，将38.2mg(0.2mmol，1.0当量)化合物III-1、63.0mg(0.2mmol，1.0当量)化合物III-1及19.7mg三氟甲磺酸钪(0.04mmol，0.2当量)溶于2mL的二氯乙烷中，室温下搅拌反应4小时。反应结束后，将反应混合物在水泵减压下旋转蒸发除去溶剂。残留物以200-300目硅胶，洗脱液(体积比V石油醚:V乙酸乙酯＝10:1～5:1)柱层析得到Ⅰ-1所示化合物，其产物经过核磁(氢谱、碳谱)鉴定。
Yellow solid,40mg,Yield＝80％,Rf＝0.5(PE/EA＝5:1),mp 126–127℃.1H NMR(400MHz,CDCl3)δ8.24(dd,J＝8.0,1.7Hz,1H),7.92(s,1H),7.68–7.64(m,1H),7.47–7.37(m,2H),7.21–7.14(m,2H),6.75–6.69(m,1H),6.67–6.63(m,2H),4.28(s,2H)；13C NMR(100MHz,CDCl3)δ178.15,156.67,153.27,147.57,133.82,129.45,125.77,125.27,123.95,121.36,118.30,118.16,113.50,40.55.
实施例2
制备本发明的其它化合物的实施例所用的方法与实施例1相同，反应条件如下：于10毫升的直型反应管中，将52.0mg(0.2mmol，1.0当量)化合物III-16、63.0mg(0.2mmol，1.0当量)化合物III-1及19.7mg三氟甲磺酸钪(0.04mmol，0.2当量)溶于2mL的二氯乙烷中，室温下搅拌反应4小时。反应结束后，将反应混合物在水泵减压下旋转蒸发除去溶剂。残留物以200-300目硅胶，洗脱液(体积比V石油醚:V乙酸乙酯＝10:1～5:1)柱层析得到Ⅰ-1所示化合物，其产物经过核磁(氢谱、碳谱)鉴定如下：
Yellow solid,37mg,Yield＝58％,Rf＝0.4(PE/EA＝5:1),mp 123–124℃.1H NMR(400MHz,CDCl3)δ8.10(d,J＝2.5Hz,1H),7.97(s,1H),7.70(d,J＝2.5Hz,1H),7.20–7.15(m,2H),6.74(tt,J＝7.3,1.1Hz,1H),6.64–6.60(m,2H),4.29(s,2H)；13C NMR(100MHz,CDCl3)δ176.33,153.34,151.02,147.15,133.97,130.95,129.54,125.59,124.57,123.91,121.90,118.43,113.40,40.25.
实施例3
实施例3的反应式，具体使用的化合物I-1、V-3以及产物ⅠV-3结构如下，实验表明本发明优选的无机碱是碳酸钾，优选的的溶剂时二甲亚砜，其反应产物的最高收率为80％，最好的原料摩尔比为化合物I-1和化合物V-3的摩尔比为I-1：V-3＝1:2，其中化合物I-1应是当量值，溶液的最优浓度为0.1M。
具体实验步骤是：于10毫升的直型反应管中，将38.2mg(0.2mmol，1.0当量)化合物III-1、63.0mg(0.2mmol，1.0当量)化合物III-1及19.7mg三氟甲磺酸钪(0.04mmol，0.2当量)溶于2mL的二氯乙烷中，室温下搅拌反应4小时。反应结束后，将反应混合物在水泵减压下旋转蒸发除去溶剂。残留物以200-300目硅胶，洗脱液(体积比V石油醚:V乙酸乙酯＝10:1～5:1)柱层析得到Ⅰ-1所示化合物，其产物经过核磁(氢谱、碳谱)、质谱鉴定。
Yellow solid,57mg,Yield＝80％,Rf＝0.5(PE/EA＝5:1),mp 168–169℃.1H NMR(400MHz,CDCl3)δ12.34(s,1H),9.00(s,1H),8.46–8.34(m,2H),7.73(dd,J＝8.0,1.7Hz,1H),7.58–7.49(m,3H),7.44–7.39(m,1H),7.25–7.18(m,2H),7.16–7.12(m,1H),6.97–6.92(m,1H),6.84–6.77(m,1H),6.67–6.61(m,2H),4.52(s,2H),4.12(s,1H)；13C NMR(100MHz,CDCl3)δ163.82,161.99,161.15,158.78,147.09,136.30,132.95,131.53,130.37,129.63,129.09,128.25,126.80,119.61,119.06,118.85,118.64,113.26,44.76；RMS(ESI)m/z:[M+H]+354.1601,found 354.1601Calcd for C23H19N3O.
化合物I-1
3-((Phenylamino)methyl)-4H-chromen-4-one(40mg,Yield＝80％,Rf＝0.5(PE/EA＝5:1))was isolated as a yellow solid；mp 126–127℃.1H NMR(400MHz,CDCl3)δ8.24(dd,J＝8.0,1.7Hz,1H),7.92(s,1H),7.68–7.64(m,1H),7.47–7.37(m,2H),7.21–7.14(m,2H),6.75–6.69(m,1H),6.67–6.63(m,2H),4.28(s,2H)；13C NMR(100MHz,CDCl3)δ178.15,156.67,153.27,147.57,133.82,129.45,125.77,125.27,123.95,121.36,118.30,118.16,113.50,40.55.
化合物I-2
3-((p-Tolylamino)methyl)-4H-chromen-4-one(38mg,Yield＝72％,Rf＝0.5(PE/EA＝5:1))was isolated as a yellow solid；mp 142–143℃.1H NMR(400MHz,CDCl3)δ8.23(dd,J＝8.0,1.7Hz,1H),7.91(t,J＝1.2Hz,1H),7.68–7.63(m,1H),7.44–7.37(m,2H),6.98(d,J＝8.5Hz,2H),6.60–6.56(m,2H),4.25(d,J＝0.8Hz,2H),2.22(s,3H)；13CNMR(100MHz,CDCl3)δ178.19,156.68,153.29,133.80,129.94,127.47,125.78,125.24,123.97,121.48,118.30,113.75,40.94,20.51,1C is merged with other peaks.
化合物I-3
3-((m-Tolylamino)methyl)-4H-chromen-4-one(35mg,Yield＝66％,Rf＝0.5(PE/EA＝5:1))was isolated as a yellow solid；mp 112–113℃.1H NMR(400MHz,CDCl3)δ8.24(dd,J＝7.9,1.7Hz,1H),7.91(t,J＝1.1Hz,1H),7.69–7.63(m,1H),7.45–7.38(m,2H),7.09–7.03(m,1H),6.55(d,J＝8.0Hz,1H),6.48–6.44(m,2H),4.27(d,J＝1.2Hz,2H),2.26(s,3H)；13C NMR(100MHz,CDCl3)δ178.18,156.68,153.25,147.61,139.29,133.81,129.31,125.77,125.26,123.96,121.46,119.12,118.31,114.33,110.55,40.57,21.74.
化合物I-4
3-((o-Tolylamino)methyl)-4H-chromen-4-one(37mg,Yield＝70％,Rf＝0.6(PE/EA＝5:1))was isolated as a yellow solid；mp 125–126℃.1H NMR(400MHz,CDCl3)δ8.22(dd,J＝7.9,1.7Hz,1H),7.89(s,1H),7.67–7.62(m,1H),7.47–7.35(m,2H),7.12–7.01(m,2H),6.69–6.57(m,2H),4.32(d,J＝1.1Hz,2H),2.17(s,3H)；13C NMR(100MHz,CDCl3)δ178.21,156.68,153.33,145.48,133.85,130.46,127.24,125.82,125.29,123.98,123.03,121.30,118.33,117.81,110.43,40.57,17.66.
化合物I-5
3-(((4-Bromophenyl)amino)methyl)-4H-chromen-4-one(58mg,Yield＝88％,Rf＝0.5(PE/EA＝5:1))was isolated as a yellow solid；mp 119–120℃.1H NMR(400MHz,CDCl3)δ8.23(dd,J＝8.0,1.7Hz,1H),7.89(s,1H),7.70–7.65(m,1H),7.47–7.38(m,2H),7.24(d,J＝8.8Hz,2H),6.53(d,J＝8.8Hz,2H),4.24(s,2H)；13C NMR(100MHz,CDCl3)δ178.12,156.68,153.25,146.57,133.99,132.18,125.79,125.41,123.93,120.94,118.36,115.18,109.90,40.70.
化合物I-6
3-(((4-Chlorophenyl)amino)methyl)-4H-chromen-4-one(41mg,Yield＝72％,Rf＝0.4(PE/EA＝5:1))was isolated as a yellow solid；mp 112–113℃.1H NMR(400MHz,CDCl3)δ8.23(dd,J＝8.0,1.4Hz,1H),7.90(s,1H),7.70–7.65(m,1H),7.46–7.39(m,2H),7.13–7.09(m,2H),6.59–6.55(m,2H),4.24(d,J＝1.1Hz,2H)；13C NMR(100MHz,CDCl3)δ178.12,156.68,153.26,146.12,133.97,129.30,125.79,125.40,123.93,122.88,120.98,118.36,114.72,40.83.
化合物I-7
3-(((4-Fluorophenyl)amino)methyl)-4H-chromen-4-one(48mg,Yield＝89％,Rf＝0.3(PE/EA＝5:1))was isolated as a yellow solid；mp 150–151℃.1H NMR(400MHz,CDCl3)δ8.23(dd,J＝8.1,1.9Hz,1H),7.90(s,1H),7.69–7.65(m,1H),7.43(dd,J＝14.2,6.5Hz,2H),6.88(t,J＝8.8Hz,2H),6.59(dd,J＝8.9,4.3Hz,2H),4.23(s,2H)；13CNMR(100MHz,CDCl3)δ178.15,156.30(d,J＝235Hz),156.66,153.28,143.89,133.91,125.78,125.35,123.93,121.20,118.34,115.89(d,J＝22Hz),114.58(d,J＝7Hz),41.41；19F NMR(376MHz,CDCl3)δ125.89–126.96(m,1F).
化合物I-8
3-(((4-(Trifluoromethyl)phenyl)amino)methyl)-4H-chromen-4-one(43mg,Yield＝67％,Rf＝0.4(PE/EA＝5:1))was isolated as a yellow solid；mp 146–147℃.1H NMR(400MHz,DMSO)δ8.31(s,1H),8.09(d,J＝9.5Hz,1H),7.83–7.77(m,1H),7.63(d,J＝8.4Hz,1H),7.50(t,J＝7.5Hz,1H),7.37(d,J＝8.5Hz,2H),6.74(d,J＝8.4Hz,2H),6.65(t,J＝5.9Hz,1H),4.14(d,J＝5.7Hz,2H)；13C NMR(100MHz,DMSO)δ176.37,155.95,154.44,151.23,134.20,126.20(d,J＝4Hz),125.46,125.30(q,J＝268Hz),124.93,123.21,120.54,118.43,115.64(q,J＝31Hz),111.65,37.88；19F NMR(376MHz,DMSO)δ58.63–59.35(m,3F).
化合物I-9
3-(((4-(Trifluoromethoxy)phenyl)amino)methyl)-4H-chromen-4-one(46mg,Yield＝69％,Rf＝0.4(PE/EA＝5:1))was isolated as a white solid；mp 137–138℃.1HNMR(400MHz,CDCl3)δ8.23(dd,J＝8.0,1.7Hz,1H),7.91(s,1H),7.70–7.65(m,1H),7.46–7.40(m,2H),7.02(d,J＝9.0Hz,2H),6.62–6.58(m,2H),4.48(s,1H),4.25(s,2H)；13C NMR(100MHz,CDCl3)δ178.13,156.68,153.26,146.37,141.01,133.99,125.61(d,J＝38Hz,2C),123.93,122.62,120.99,118.36,113.79,77.16,40.80；19F NMR(376MHz,CDCl3)δ58.32–58.36(m,3F).
化合物I-10
3-(((4-Methoxyphenyl)amino)methyl)-4H-chromen-4-one(39mg,Yield＝70％,Rf＝0.6(PE/EA＝5:1))was isolated as a yellow solid；mp 126–127℃.1H NMR(400MHz,CDCl3)δ8.23(dd,J＝8.0,1.7Hz,1H),7.90(s,1H),7.68–7.64(m,1H),7.45–7.38(m,2H),6.78–6.74(m,2H),6.65–6.60(m,2H),4.22(s,2H),3.73(s,3H)；13C NMR(100MHz,CDCl3)δ178.19,156.68,153.29,133.80,129.94,127.47,125.78,125.24,123.97,121.48,118.30,113.75,40.94,20.51.
化合物I-11
3-(((2-Methoxyphenyl)amino)methyl)-4H-chromen-4-one(48mg,Yield＝86％,Rf＝0.5(PE/EA＝5:1))was isolated as a yellow solid；mp 130–131℃.1H NMR(400MHz,CDCl3)δ8.25(dd,J＝8.0,2.3Hz,1H),7.89(t,J＝1.2Hz,1H),7.67–7.63(m,1H),7.44–7.38(m,2H),6.87–6.77(m,2H),6.72–6.67(m,1H),6.60(dd,J＝7.8,1.4Hz,1H),4.33(d,J＝1.4Hz,2H),3.86(s,3H)；13C NMR(100MHz,CDCl3)δ177.93,156.64,153.27,147.23,137.42,133.68,125.77,125.14,123.89,121.47,121.31,118.25,117.23,110.30,109.66,55.54,39.87.
化合物I-12
6-Nethyl-3-((phenylamino)methyl)-4H-chromen-4-one(33mg,Yield＝62％,Rf＝0.4(PE/EA＝5:1))was isolated as a yellow solid；mp 115–116℃.1H NMR(400MHz,CDCl3)1H NMR(400MHz,Chloroform-d)δ8.01(d,J＝2.2Hz,1H),7.89(s,1H),7.47(dd,J＝8.6,2.3Hz,1H),7.33(d,J＝8.6Hz,1H),7.20–7.14(m,2H),6.72(tt,J＝7.3,1.1Hz,1H),6.67–6.62(m,2H),4.38(s,1H),4.27(s,2H),2.46(s,3H)；13C NMR(100MHz,CDCl3)δ178.22,154.96,153.19,147.62,135.25,135.11,129.43,125.01,123.62,121.10,118.13,118.05,113.52,40.60,21.09.
化合物I-13
6,7-Dimethyl-3-((phenylamino)methyl)-4H-chromen-4-one(43mg,Yield＝77％,Rf＝0.4(PE/EA＝5:1))was isolated as a yellow solid；mp109–110℃.1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.86(s,1H),7.21–7.14(m,3H),6.72(tt,J＝7.3,1.1Hz,1H),6.67–6.63(m,2H),4.39(s,1H),4.25(s,2H),2.37(s,1H),2.35(s,1H)；13C NMR(100MHz,CDCl3)δ178.11,155.28,152.92,147.70,144.36,134.61,129.42,125.27,121.85,120.99,118.34,118.09,113.56,40.67,20.57,19.49.
化合物I-14
6-Bromo-3-((phenylamino)methyl)-4H-chromen-4-one(45mg,Yield＝68％,Rf＝0.4(PE/EA＝5:1))was isolated as a yellow solid；mp 92–93℃.1H NMR(400MHz,CDCl3)δ8.35(d,J＝2.5Hz,1H),7.90(s,1H),7.73(dd,J＝8.9,2.5Hz,1H),7.33(d,J＝8.9Hz,1H),7.20–7.14(m,2H),6.73(tt,J＝7.3,1.1Hz,1H),6.65–6.61(m,2H),4.33(s,1H),4.27(s,2H)；13C NMR(100MHz,CDCl3)δ176.80,155.41,153.41,147.38,136.80,129.49,128.39,125.19,121.63,120.29,118.69,118.29,113.45,40.43.
化合物I-15
6-Chloro-3-((phenylamino)methyl)-4H-chromen-4-one(38mg,Yield＝67％,Rf＝0.5(PE/EA＝5:1))was isolated as a yellow solid；mp 102–103℃.1H NMR(400MHz,CDCl3)δ8.17(d,J＝2.6Hz,1H),7.88(s,1H),7.58(dd,J＝9.0,2.6Hz,1H),7.37(d,J＝9.0Hz,1H),7.18–7.13(m,2H),6.71(tt,J＝7.3,1.1Hz,1H),6.63–6.59(m,2H),4.25(s,2H)；13C NMR(100MHz,CDCl3)δ176.97,155.00,153.43,147.40,134.08,131.25,129.50,125.17,124.82,121.53,120.07,118.30,113.46,40.43.
化合物I-16
6,8-Dichloro-3-((phenylamino)methyl)-4H-chromen-4-one(37mg,Yield＝58％,Rf＝0.4(PE/EA＝5:1))was isolated as a yellow solid；mp 123–124℃.1H NMR(400MHz,CDCl3)δ8.10(d,J＝2.5Hz,1H),7.97(s,1H),7.70(d,J＝2.5Hz,1H),7.20–7.15(m,2H),6.74(tt,J＝7.3,1.1Hz,1H),6.64–6.60(m,2H),4.29(s,2H)；13C NMR(100MHz,CDCl3)δ176.33,153.34,151.02,147.15,133.97,130.95,129.54,125.59,124.57,123.91,121.90,118.43,113.40,40.25.
化合物I-17
6-Fluoro-3-((phenylamino)methyl)-4H-chromen-4-one(40mg,Yield＝74％,Rf＝0.5(PE/EA＝5:1))was isolated as a yellow solid；mp 118–119℃.1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.86(dd,J＝8.2,3.0Hz,1H),7.46–7.42(m,1H),7.41–7.35(m,1H),7.20–7.14(m,2H),6.72(tt,J＝7.3,1.1Hz,1H),6.66–6.62(m,2H),4.28(s,2H)；13C NMR(100MHz,CDCl3)δ177.39(d,J＝2Hz),159.60(d,J＝245.7Hz),153.49,152.90,147.44,129.47,125.01(d,J＝7.1Hz),122.15(d,J＝25.5Hz),120.79,120.45(d,J＝8.1Hz),118.25,113.45,110.51(d,J＝23.4Hz),40.41；19F NMR(376MHz,CDCl3)δ114.87–114.92(m,1F).
化合物I-18
6-Methoxy-3-((phenylamino)methyl)-4H-chromen-4-one(42mg,Yield＝75％,Rf＝0.4(PE/EA＝5:1))was isolated as a yellow solid；mp 117–118℃.1H NMR(400MHz,CDCl3)δ7.91(t,J＝1.1Hz,1H),7.58(d,J＝3.1Hz,1H),7.37(d,J＝9.1Hz,1H),7.27–7.24(m,1H),7.20–7.15(m,2H),6.72(tt,J＝7.3,1.1Hz,1H),6.67–6.63(m,2H),4.28(d,J＝1.1Hz,2H),3.90(s,3H)；13C NMR(100MHz,CDCl3)δ177.98,157.04,153.12,151.59,147.62,129.45,124.52,124.08,120.53,119.74,118.17,113.53,104.62,56.06,40.64.
化合物I-19
6,7-Dimethoxy-3-((phenylamino)methyl)-4H-chromen-4-one(42mg,Yield＝68％,Rf＝0.4(PE/EA＝5:1))was isolated as a yellow solid；mp 138–139℃.1H NMR(400MHz,CDCl3)δ7.95(dd,J＝9.0,1.0Hz,1H),7.91(d,J＝1.0Hz,1H),7.19–7.15(m,2H),7.04(dd,J＝9.0,0.7Hz,1H),6.72(td,J＝7.4,1.0Hz,1H),6.66–6.63(m,2H),4.37(s,1H),4.25(s,2H),3.99(d,J＝0.8Hz,3H),3.94(d,J＝1.1Hz,3H)；13C NMR(100MHz,CDCl3)δ177.70,156.61,152.97,151.08,147.57,136.74,129.45,121.20,120.73,118.78,118.14,113.53,110.18,61.72,56.58,40.44.
化合物I-20
6-Nitro-3-((phenylamino)methyl)-4H-chromen-4-one(36mg,Yield＝61％,Rf＝0.4(PE/EA＝5:1))was isolated as a yellow solid；mp 115–116℃.1H NMR(400MHz,CDCl3)δ9.10(dd,J＝2.9,1.2Hz,1H),8.49(dd,J＝9.2,2.7Hz,1H),7.96(s,1H),7.59(dd,J＝9.2,1.1Hz,1H),7.18(t,J＝7.4Hz,2H),6.78–6.72(m,1H),6.66–6.61(m,2H),4.32(s,2H)；13C NMR(100MHz,CDCl3)δ176.69,159.43,153.58,147.14,144.86,129.57,128.12,123.87,122.66,122.42,120.15,118.51,113.40,40.24；RMS(ESI)m/z:[M+H]+297.0870,found 297.0870Calcd for C16H12N2O4.
化合物IV-1
2-(2-Amino-5-((phenylamino)methyl)pyrimidin-4-yl)phenol,48mg,Yield＝83％,Rf＝0.2(PE/EA＝5:1)was isolated as a yellow solid；mp 170–171℃.1H NMR(400MHz,DMSO)δ10.40(s,1H),8.18(s,1H),7.29(dd,J＝7.6,1.7Hz,1H),7.257.2–0(m,1H),7.00–6.93(m,2H),6.90(dd,J＝8.2,1.1Hz,1H),6.83(td,J＝7.5,1.1Hz,1H),6.58(s,2H),6.47(tt,J＝7.3,1.1Hz,1H),6.43–6.38(m,2H),5.90(t,J＝5.7Hz,1H),3.92(d,J＝5.7Hz,2H)；13C NMR(100MHz,DMSO)δ158.53,130.36,129.95,128.85,118.85,116.06,115.98,112.21,41.73；RMS(ESI)m/z:[M+H]+293.1396,found 293.1397Calcd forC17H16N4O.
化合物IV-2
2-(2-Methyl-5-((phenylamino)methyl)pyrimidin-4-yl)phenol,39mg,Yield＝67％,Rf＝0.2(PE/EA＝5:1)was isolated as a yellow solid；mp 181–182℃.1H NMR(400MHz,CDCl3)δ8.81(s,1H),7.69(dd,J＝8.0,1.5Hz,1H),7.4–7.34(m,1H),7.24–7.16(m,2H),7.08(dd,J＝8.3,1.3Hz,1H),6.93–6.87(m,1H),6.82–6.76(m,1H),6.63–6.58(m,2H),4.45(s,2H),2.77(s,3H)；13C NMR(100MHz,CDCl3)δ165.08,163.64,160.64,158.97,147.07,132.86,130.33,129.56,125.83,119.51,118.79,118.65,113.22,44.65,25.53；RMS(ESI)m/z:[M+H]+292.1444,found 292.1444Calcd for C18H17N3O.
化合物IV-3
2-(2-Phenyl-5-((phenylamino)methyl)pyrimidin-4-yl)phenol,57mg,Yield＝80％,Rf＝0.5(PE/EA＝5:1)was isolated as a yellow solid；mp 168–169℃.1H NMR(400MHz,CDCl3)δ12.34(s,1H),9.00(s,1H),8.46–8.34(m,2H),7.73(dd,J＝8.0,1.7Hz,1H),7.58–7.49(m,3H),7.44–7.39(m,1H),7.25–7.18(m,2H),7.16–7.12(m,1H),6.97–6.92(m,1H),6.84–6.77(m,1H),6.67–6.61(m,2H),4.52(s,2H),4.12(s,1H)；13C NMR(100MHz,CDCl3)δ163.82,161.99,161.15,158.78,147.09,136.30,132.95,131.53,130.37,129.63,129.09,128.25,126.80,119.61,119.06,118.85,118.64,113.26,44.76；RMS(ESI)m/z:[M+H]+354.1601,found 354.1601Calcd for C23H19N3O.
化合物IV-4
2-(2-(4-Methoxyphenyl)-5-
((phenylamino)methyl)pyrimidin-4-yl)phenol,68mg,Yield＝88％,Rf＝0.4(PE/EA＝5:1)was isolated as a yellow solid；mp 183–184℃.1H NMR(400MHz,CDCl3)δ12.49(s,1H),8.89(s,1H),8.32(d,J＝8.6Hz,2H),7.72(d,J＝9.6Hz,1H),7.39(t,J＝3.2Hz,1H),7.22(t,J＝7.8Hz,2H),7.12(d,J＝8.2Hz,1H),7.01(d,J＝8.5Hz,2H),6.91(t,J＝3.6Hz,H),6.80(t,J＝3.2Hz,2H),6.63(d,J＝7.9Hz,2H),4.45(s,2H),4.11(s,1H),3.88(s,3H)；13C NMR(100MHz,CDCl3)δ163.68,162.49,161.73,161.15,158.82,147.17,132.82,130.34,129.95,129.61,128.86,125.80,119.54,119.10,118.76,118.56,114.40,113.25,55.57,44.74；RMS(ESI)m/z:[M+H]+384.1707,found384.1707Calcd forC24H21N3O2.
化合物IV-5
2-(2-(4-Chlorophenyl)-5-
((phenylamino)methyl)pyrimidin-4-yl)phenol,60mg,Yield＝78％,Rf＝0.3(PE/EA＝5:1)was isolated as a yellow solid；mp 176–177℃.1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.33(d,J＝8.7Hz,2H),7.71(d,J＝7.8Hz,1H),7.49(d,J＝8.7Hz,2H),7.42(t,J＝8.4Hz,1H),7.21(t,J＝7.4Hz,2H),7.14(d,J＝8.2Hz,1H),6.95(d,J＝3.6Hz,1H),6.80(td,J＝7.4,1.1Hz,1H),6.64–6.60(m,2H),4.53(s,2H)；13C NMR(100MHz,CDCl3)δ163.86,161.07,158.51,147.03,137.82,134.80,133.02,130.37,129.64,129.54,129.31,127.15,119.72,119.05,118.90,118.61,113.25,44.69(1C is merged with otherpeaks)；RMS(ESI)m/z:[M+H]+388.1211,found 388.1211Calcd for C23H18ClN3O.
对于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。

Claims (5)

1.一种3-胺甲基色酮衍生物合成方法，3-胺甲基取代色酮类衍生物的结构式如Ⅰ所示，
其中：R为氢、卤素、C1-C6烷基、C1-C20全氟烷基、C1-C6烷氧基、C6-C12芳基、苄基、C2-C10杂环基中单取代或多取代的一种；
R’为C1-C20烷基、环丙基、C1-C20全氟烷基、C6-C12芳基、苄基、C2-C8含烯基取代基、C2-C8含炔基取代基或C2-C10杂环基中的任意一种；
其特征在于，合成方法如下式所示：
式中，化合物Ⅰ制备步骤为：
S1、将化合物Ⅱ、化合物Ⅲ和催化剂置于有机溶剂中搅拌反应；
S2、待化合物III完全消失后，将反应混合物减压条件下除去有机溶剂；
S3、使用硅胶柱层析洗脱得到化合物I。
2.根据权利要求1所述的一种3-胺甲基色酮衍生物的合成方法，其特征在于：所述化合物Ⅱ和化合物Ⅲ的摩尔比为Ⅱ:Ⅲ＝1.0:0.4-2.0。
3.根据权利要求1所述一种3-胺甲基色酮衍生物合成方法，其特征在于：催化剂包括碘化亚铜、溴化亚铜、溴化锌、氯化铁、三氯化铟、三氯化铋、氯化亚铜、三氟甲磺酸铜、三氟甲磺酸亚铜、三氟甲磺酸锌、三氟甲磺酸银、三氟甲磺酸铟、三氟甲磺酸铁、三氟甲磺酸钪、三氟甲磺酸钇、三氟甲磺酸铋或三氟甲磺酸钕其中的一种或多种。
4.根据权利要求1所述的一种3-胺甲基色酮衍生物的合成方法，其特征在于：所述有机溶剂包括乙酸乙酯、乙腈、二氯甲烷、二氯乙烷、氯仿、四氢呋喃、四氢吡喃、甲苯、N,N-二甲基丙烯基脲、N-甲基吡咯烷酮、二甲基甲酰胺或二甲基乙酰胺中的任意一种或至少两种组合。
5.根据权利要求1所述的一种3-胺甲基色酮衍生物的合成方法，其特征在于：所述柱层析使用的洗脱液为石油醚和乙酸乙酯的混合液，体积比为V石油醚:V乙酸乙酯＝10:1～2:1。
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