CN106831602B - 一种银介导的4-取代-2-氨基-5-氟嘧啶类化合物的制备方法及应用 - Google Patents

一种银介导的4-取代-2-氨基-5-氟嘧啶类化合物的制备方法及应用 Download PDF

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CN106831602B
CN106831602B CN201611107951.4A CN201611107951A CN106831602B CN 106831602 B CN106831602 B CN 106831602B CN 201611107951 A CN201611107951 A CN 201611107951A CN 106831602 B CN106831602 B CN 106831602B
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赵晓明
赵明珠
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Abstract

本发明涉及一种4‑取代‑2‑氨基‑5‑氟嘧啶类化合物的制备方法及其应用，该化合物的结构式为：

Description

一种银介导的4-取代-2-氨基-5-氟嘧啶类化合物的制备方法 及应用
技术领域
本发明属于有机合成化学领域，涉及一种4-取代-2-氨基-5-氟嘧啶化合物制备方法及其应用。
背景技术
含2-氨基-5-氟嘧啶类化合物是重要的药物合成片段，具有较强的生物活性，它在药物研发中有着重要的应用。如礼来公司研发的Abemaciclib Mesylate作为一种潜在的治疗乳腺癌和非小细胞肺癌的周期性依赖性激酶(CDK4/6)抑制剂，目前处于临床三期阶段。Fostamatinib Disodium Hydrate是一种潜在的治疗特发性血小板减少性紫癜的脾酪氨酸激酶和Fms样酪氨酸激酶-3抑制剂，具有氟代氨基嘧啶的片段。另一例含此结构的是处于临床二期研发中的BTK激酶和JAK激酶抑制剂Spebrutinib，适用于治疗类风湿性关节炎、慢性淋巴细胞白血病和淋巴瘤。(a)Frederick,M.O.；Kjell,D.P.Tetrahedron Lett.2015,56,949-951.(b)Colonna,L.；Catalano,G.；Chew,C.；D'Agati,V.；Thomas,J.W.；Wong,F.S.；Schmitz,J.；Masuda,E.S.；Reizis,B.；Tarakhovsky,A.；Clynes,R.J.Immunol.2010,185,1532-1543.(c)Padilla,F.；Bhagirath,N.；Chen,S.；Chiao,E.；Goldstein,D.M.；Hermann,J.C.；Hsu,J.；Kennedy-Smith,J.J.；Kuglstatter,A.；Liao,C.；Liu,W.；Lowrie Jr.,L.E.；Luk,K.C.；Lynch,S.M.；Menke,J.；Niu,L.；Owens,T.D.；Yang,O.C.；Railkar,A.；Schoenfeld,R.C.；Slade,M.；Steiner,S.；Tan,Y.C.；Villasenor,A.G.；Wang,C.；Wanner,J.；Xie,W.；Xu,D.；Zhang,X.；Zhou,M.；Lucas,M.C.J.Med.Chem.2013,56,1677-1692.(d)Singh J.；Petter R.；Tester R.W.；Kluge,A.F.；Mazdiyasni,H.；Westlin III,W.F.；Niu,D.；Qiao,L.U.S.Patent 8,338,439.(2012).
目前，2-氨基-5-氟嘧啶类化合物主要有两类制备方法。其一，是通过含氟的片段与盐酸胍通过关环的方式；其二，是通过含氟底物的氨化策略。但是通过2-氨基嘧啶类底物直接氟化的方法未见文献报道。(a)Funabiki,K.；Ohtsuki,T.；Ishihara,T.；Yamanaka,H.Chem.Lett.1995,3,239-240.(b)Berger,J.；Flippin,L.A.；Greenhouse,R.；Jaime-Figueroa,S.；Liu,Y.；Miller,A.K.；Aubry,K.；Putman,D.G.；Weinhardt,K.K.；Zhao,S.H.U.S.Patent5,952,331.(1999).
发明内容
本发明的目的是为了合成一种4-取代-2-氨基-5-氟嘧啶类化合物并将其应用在药物中间体的合成。
本发明的4-取代-2-氨基-5-氟嘧啶类化合物结构式是：
其中R可以是芳基、苯乙烯基或苯氨基。
本发明的目的可以通过以下技术方案来实现：
以4-取代-2-氨基嘧啶类化合物为底物，Selectfluor为氟源，银盐为添加剂，筛选合适溶剂，控制反应温度，反应时间控制2小时，再经分离纯化后，制备4-取代-2-氨基-5-氟嘧啶类化合物。
反应式如下：
其中R可以是芳基、苯乙烯基或苯氨基，F source为氟源，Ag salt为银盐，Solvent为有机溶剂，T是反应温度。
本发明方法中所述的氟源选自AgF2、AgF、CuF2、NFSI、Selectfluor，优选Selectfluor。
所述的银盐选自碳酸银、磷酸银、氧化银、硝酸银、醋酸银、四氟硼酸银，优选碳酸银。
所述的有机溶剂选自乙腈、二氧六环、二甲基甲酰胺、甲醇，优选乙腈。
所述的反应温度选自20℃～80℃，优选70℃。
所述的反应时间选自2～4小时，优选2小时。
所述的4-取代-2-氨基嘧啶类底物、Selectfluor、碳酸银的推荐摩尔优选1:1.2:2。
所述的分离纯化的方法为重结晶、薄层层析、柱层析的一种。如用硅胶薄层层析、柱层析的方法，所用展开剂为非极性溶剂与极性溶剂的混合溶剂。推荐硅胶薄层层析展开剂为石油醚/乙酸乙酯＝5/1，硅胶柱层析展开剂为石油醚/乙酸乙酯＝2/1。
所述制备所得的4-取代-2-氨基-5-氟嘧啶类化合物可用作药物中间体。
与现有技术相比，本发明具有以下特点：
1)首次实现了4-取代-2-氨基嘧啶类化合物直接氟化，具有反应时间较短、条件温和、底物适用范围广的特点；
2)发明的4-取代-2-氨基嘧啶类化合物直接氟化方法，以高达99:1的区域选择性在4-取代-2-氨基嘧啶类化合物实现了氟化。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
实施例1～22
所述实施例1～22反应式如下：
以4-苯基-2-氨基嘧啶底物为实例，筛选合适的氟源、银盐、温度、溶剂。其中Fsource指氟源，Ag salt指银盐，Solvent指反应溶剂，T指反应温度。
所述实施例1～22具体制备方法如下：
将4-苯基-2-氨基嘧啶、氟源、银盐、反应溶剂加到反应管中，控制反应温度，反应2小时后冷却至室温，加入1.0当量的三氟甲苯为内标，通过核磁氟谱来考察收率。
所述实施例1～22如下表所示：
其中，NFSI为N-氟代双苯磺酰胺；
Selectfluor属产品名，为氟试剂，分子式C7H14B2ClF9N2，来源市售，生产商：上海阿拉丁生化科技股份有限公司，品牌是“阿拉丁”；
MeCN为乙腈、Dioxane为二氧六环、DMF为N,N-二甲基甲酰胺、MeOH为甲醇；complex指反应产物为复杂的混合物；N.R.指反应未能进行；trace指反应产物为痕量；a粗品的氟谱收率；b反应时间为4小时。所述实施例8的获得了72％的氟谱收率，该实施例的条件为优选：氟源为1.2当量的Selectfluor，银盐为2.0当量的碳酸银，反应溶剂为乙腈，反应温度为70℃，反应时间2小时。
实施例23～39
在所述实施例8优选条件下对氨基嘧啶底物进行了拓展，来进行实施例23～39的操作。
所述实施例23～39反应式如下：
其中R可以是芳基、苯乙烯基或苯氨基。
所述实施例23～39具体制备方法如下：
分别称量0.1毫摩尔的4-取代-2-氨基嘧啶底物和0.12毫摩尔的Selectfluor以及0.2毫摩尔的碳酸银，一锅法加入反应管内，往反应管中加入2毫升的分析纯乙腈，封闭反应管，置入70℃的油浴中反应2个小时左右。反应结束后，冷却至室温，减压蒸馏掉乙腈，残留物经硅胶薄层层析(石油醚/乙酸乙酯＝5/1，v/v)分离得到目标产物4-取代-2-氨基-5-氟嘧啶类化合物。
所述实施例23～39当R不同时，目标产物4-取代-2-氨基-5-氟嘧啶类化合物的结构及性质分别如下：
实施例23：目标产物为4-苯基-2-氨基-5-氟嘧啶
白色固体，收率：61％，熔点：165.4–166.9℃。
1H NMR(400MHz,CDCl3):δ8.23(d,JHF＝3.4Hz,1H),8.07–7.98(m,2H),7.52–7.46(m,3H),5.08(s,2H).13C NMR(101MHz,CDCl3):δ159.64(d,JCF＝3.1Hz),152.61(d,JCF＝9.6Hz),150.72(d,JCF＝251.8Hz),147.02(d,JCF＝26.2Hz),133.49(d,JCF＝5.2Hz),130.77,128.93(d,JCF＝6.2Hz),128.61.19F NMR(376MHz,CDCl3):δ-152.49(s,1F).IR(KBr):νmax(cm-1)＝3323,3175,1652,1558,1473,1355,1274,1200.HRMS(ESI-TOF)m/zcalcd.for C11H9FN3 +[M+H]+:190.0775；found:190.0743.
实施例24：目标产物为4-(3-氟苯基)-2-氨基-5-氟嘧啶
白色固体，收率：65％，熔点：163.2–164.9℃。
1H NMR(400MHz,CDCl3):δ8.25(d,JHF＝3.5Hz,1H),7.84(d,J＝7.8Hz,1H),7.78(d,J＝10.1Hz,1H),7.45(dd,J＝14.0,8.0Hz,1H),7.19(td,J＝8.3,2.1Hz,1H),5.10(s,2H).13C NMR(101MHz,CDCl3):δ162.83(d,JCF＝245.9Hz),159.58(d,JCF＝2.8Hz),150.94(dd,JCF＝9.2,2.7Hz),150.83(d,JCF＝253.72Hz),147.42(d,JCF＝26.3Hz),135.54(dd,JCF＝7.8,5.4Hz),130.13(d,JCF＝8.0Hz),124.69(dd,JCF＝7.5,3.0Hz),117.72(d,JCF＝21.2Hz),115.83(dd,JCF＝23.5,6.1Hz).19F NMR(376MHz,CDCl3):δ-112.30(s,1F),-151.95(s,1F).IR(KBr):νmax(cm-1)＝3332,3178,1650,1567,1478,1445,1354,1269,1200.HRMS(ESI-TOF)m/z calcd.for C10H8F2N3 +[M+H]+:208.0681；found:208.0672.
实施例25：目标产物为4-(4-氟苯基)-2-氨基-5-氟嘧啶
白色固体，收率：68％，熔点：154.1–155.8℃。
1H NMR(400MHz,CDCl3):δ8.22(d,JHF＝3.7Hz,1H),8.07(dd,J＝8.1,5.5Hz,2H),7.20–7.14(m,2H),5.04(s,2H).13C NMR(101MHz,CDCl3):δ164.33(d,JCF＝251.9Hz),159.55(d,JCF＝3.4Hz),151.33(d,JCF＝9.5Hz),150.55(d,JCF＝252.9Hz),147.13(d,JCF＝26.3Hz),131.16(dd,JCF＝8.7,6.9Hz),129.59(dd,JCF＝5.5,3.3Hz),115.72(d,JCF＝21.7Hz).19F NMR(376MHz,CDCl3):δ-109.05(s,1F),-152.45(s,1F).IR(KBr):νmax(cm-1)＝3338,3175,1646,1583,1508,1480,1427,1352,1274,1203.HRMS(ESI-TOF)m/z calcd.forC10H8F2N3 +[M+H]+:208.0681；found:208.0666.
实施例26：目标产物为4-(3-氯苯基)-2-氨基-5-氟嘧啶
白色固体，收率：62％，熔点：145.7–147.3℃。
1H NMR(400MHz,CDCl3):δ8.25(d,JCF＝3.4Hz,1H),8.06(s,1H),7.93(d,J＝7.6Hz,1H),7.48–7.40(m,2H),5.06(s,2H).13C NMR(101MHz,CDCl3):δ159.56(d,JCF＝2.8Hz),150.86(d,JCF＝9.3Hz),150.61(d,JCF＝259.6),147.46(d,JCF＝26.1Hz),135.16(d,JCF＝5.4Hz),134.73,130.77,129.84,128.90(d,JCF＝6.1Hz),127.11(d,JCF＝7.6Hz).19F NMR(376MHz,CDCl3):δ-151.98(s,1F).IR(KBr):νmax(cm-1)＝3339,3183,1645,1568,1553,1477,1431,1351,1274,1200.HRMS(ESI-TOF)m/z calcd.for C10H8ClFN3 +[M+H]+:224.0385；found:224.0408.
实施例27：目标产物为4-(4-氯苯基)-2-氨基-5-氟嘧啶
白色固体，收率：62％，熔点：127.0–128.9℃。
1H NMR(400MHz,CDCl3):δ8.24(s,1H),8.01(d,J＝7.9Hz,2H),7.46(d,J＝7.3Hz,2H),5.07(s,2H).13C NMR(101MHz,CDCl3):δ159.60(d,JCF＝3.0Hz),151.17(d,JCF＝9.1Hz),151.16(d,JCF＝9.2),150.88(d,JCF＝253.2),147.28(d,JCF＝26.2Hz),137.04,131.89(d,JCF＝5.4Hz),130.29(d,JCF＝6.8Hz),128.88.19F NMR(376MHz,CDCl3):δ-152.03(s,1F).IR(KBr):νmax(cm-1)＝3331,3186,1647,1594,1574,1473,1422,1353,1281,1203.HRMS(ESI-TOF)m/z calcd.for C10H8ClFN3 +[M+H]+:224.0385；found:224.0361.
实施例28：目标产物为4-(3,4-二氟苯基)-2-氨基-5-氟嘧啶
白色固体，收率：66％，熔点：129.2–130.7℃。
1H NMR(400MHz,CDCl3):δ8.24(d,JHF＝3.6Hz,1H),7.96(ddd,J＝11.4,7.8,1.9Hz,1H),7.90–7.82(m,1H),7.26(dd,J＝18.0,8.8Hz,1H),5.10(s,2H).13C NMR(101MHz,CDCl3):δ159.53(d,JCF＝2.9Hz),151.91(ddd,JCF＝254.9Hz,12.8Hz,1.4Hz),150.51(d,JCF＝253.5Hz),150.43(dd,JCF＝249.3Hz,12.8Hz),150.11–149.68(m),147.52(d,JCF＝26.3Hz),130.49–130.33(m),125.92–125.36(m),118.18(dd,JCF＝19.2,6.6Hz),117.46(d,JCF＝17.6Hz).19F NMR(376MHz,CDCl3):δ-133.57(d,J＝21.5Hz,1F),-136.75(d,J＝21.5Hz,1F),-152.08(s,1F).IR(KBr):νmax(cm-1)＝3310,3176,1645,1582,1558,1508,1474,1419,1351,1284,1203.HRMS(ESI-TOF)m/z calcd.for C10H7F3N3 +[M+H]+:226.0587；found:226.0663.
实施例29：目标产物为4-(3,5-二氟苯基)-2-氨基-5-氟嘧啶
白色固体，收率：60％，熔点：159.5–161.6℃。
1H NMR(400MHz,CDCl3):δ8.27(d,JHF＝3.5Hz,1H),7.63(d,J＝6.7Hz,2H),6.95(ddd,J＝8.6,5.4,2.2Hz,1H),5.13(s,2H).13C NMR(101MHz,CDCl3):δ163.00(dd,JCF＝248.4Hz,JCF＝12.5Hz),159.53(d,JCF＝2.9Hz),150.51(d,JCF＝254.5Hz),149.56–149.41(m),147.88(d,JCF＝26.2Hz),136.55–136.31(m),112.11–111.768(m),106.11(dd,JCF＝25.4Hz,JCF＝25.4Hz).19F NMR(376MHz,CDCl3):δ-108.90(s,2F),-152.53(s,1F).IR(KBr):νmax(cm-1)＝3345,3198,1647,1603,1572,1474,1440,1355,1312,1200.HRMS(ESI-TOF)m/zcalcd.for C10H8F2N3 +[M+H]+:226.0587；found:226.0600.
实施例30：目标产物为4-(3,4-二氯苯基)-2-氨基-5-氟嘧啶
白色固体，收率：61％，熔点：154.0–155.7℃。
1H NMR(400MHz,CDCl3):δ8.25(d,JCF＝2.9Hz,1H),8.20(d,J＝1.8Hz,1H),7.91(dd,J＝8.5,1.1Hz,1H),7.55(d,J＝8.5Hz,1H),5.09(s,2H).13C NMR(101MHz,CDCl3):δ159.57(d,JCF＝2.9Hz),150.13(d,JCF＝254.32Hz),149.68(d,JCF＝9.0Hz),147.62(d,JCF＝26.0Hz),135.14,133.31(d,JCF＝5.5Hz),133.07,130.73(d,JCF＝6.6Hz),130.58,128.10(d,JCF＝8.0Hz).19F NMR(376MHz,CDCl3):δ-151.59(s,1F).IR(KBr):νmax(cm-1)＝3336,3203,1642,1588,1462,1415,1345,1196.HRMS(ESI-TOF)m/z calcd.for C10H7Cl2FN3 +[M+H]+:257.9996；found:257.9991.
实施例31：目标产物为4-(4-氰基苯基)-2-氨基-5-氟嘧啶
白色固体，收率：52％，熔点：198.1–199.2℃。
1H NMR(400MHz,CDCl3):δ8.30(d,JCF＝3.3Hz,1H),8.16(d,J＝8.2Hz,2H),7.78(d,J＝8.4Hz,2H),5.15(s,2H).13C NMR(101MHz,CDCl3):δ159.68(d,JCF＝2.9Hz),150.71(d,JCF＝253.7Hz),150.01(d,JCF＝9.1Hz),147.94(d,JCF＝26.1Hz),137.66(d,JCF＝5.4Hz),132.28,129.49(d,JCF＝6.8Hz),118.37,114.16.19F NMR(376MHz,CDCl3):δ-151.66(s,1F).IR(KBr):νmax(cm-1)＝3292,3160,2223,1641,1569,1483,1354,1220,1202.HRMS(ESI-TOF)m/z calcd.for C11H8FN4 +[M+H]+:215.0728；found:215.0731.
实施例32：目标产物为4-(2-甲氧基苯基)-2-氨基-5-氟嘧啶
白色固体，收率：34％，熔点：132.1–133.9℃。
1H NMR(400MHz,CDCl3):δ8.17(s,1H),7.44(m,2H),7.08(t,J＝7.4Hz,1H),7.01(d,J＝8.3Hz,1H),5.11(s,2H),3.85(s,3H).13C NMR(101MHz,CDCl3):δ159.66,157.29,153.49(d,JCF＝15.5Hz),150.73(d,JCF＝250.5Hz),145.49(d,JCF＝25.1Hz,131.51,130.40,123.18,120.87,111.36,55.80.19F NMR(376MHz,CDCl3):δ-148.79(s,1F).IR(KBr):νmax(cm-1)＝3324,3196,1652,1635,1603,1558,1471,1457,1351,1269,1199.HRMS(ESI-TOF)m/z calcd.for C11H11FN3O+[M+H]+:220.0881；found:220.0878.
实施例33：目标产物为4-(3-甲氧基苯基)-2-氨基-5-氟嘧啶
白色固体，收率：32％，熔点：133.2–135.6℃。
1H NMR(400MHz,CDCl3):δ8.25(s,1H),7.65–7.53(m,2H),7.40(t,J＝8.0Hz,1H),7.04(d,J＝8.2Hz,1H),5.07(s,1H),3.88(s,2H).13C NMR(101MHz,CDCl3):δ159.75,159.56(d,JCF＝2.9Hz),152.34(d,JCF＝9.3Hz),150.69(d,JCF＝250.9Hz),147.11(d,JCF＝26.4Hz),134.73(d,JCF＝5.2Hz),129.63,121.51(d,JCF＝7.4Hz),116.90,113.85(d,JCF＝5.5Hz),55.43.19F NMR(376MHz,CDCl3):δ-151.90(s,1F).IR(KBr):νmax(cm-1)＝3342,3171,1654,1560,1475,1417,1354,1277,1260,1202.HRMS(ESI-TOF)m/z calcd.for C11H11FN3O+[M+H]+:220.0881；found:220.0867.
实施例34：目标产物为4-(4-甲氧基苯基)-2-氨基-5-氟嘧啶
白色固体，收率：30％，熔点：148.8–150.9℃。
1H NMR(400MHz,CDCl3):δ8.17(d,JHF＝3.9Hz,1H),8.05(d,J＝8.9Hz,2H),6.99(d,J＝9.0Hz,2H),5.02(s,2H),3.87(s,3H).13C NMR(101MHz,CDCl3):δ161.71,159.50(d,JCF＝2.9Hz),152.08(d,JCF＝9.3Hz),150.57(d,JCF＝251.0Hz),146.58(d,JCF＝26.4Hz),130.64(d,JCF＝7.0Hz),125.93(d,JCF＝5.5Hz),114.00,55.41.19F NMR(376MHz,CDCl3):δ-152.45(s,1F).IR(KBr):νmax(cm-1)＝3323,3196,1652,1576,1558,1507,1472,1457,1257,1203.HRMS(ESI-TOF)m/z calcd.for C11H11FN3O+[M+H]+:220.0881；found:220.0893.
实施例35：目标产物为4-(4-甲基苯基)-2-氨基-5-氟嘧啶
白色固体，收率：30％，熔点：142.6–143.7℃.
1H NMR(400MHz,CDCl3):δ8.20(d,JHF＝2.7Hz,1H),7.93(d,J＝8.0Hz,2H),7.29(d,J＝7.8Hz,2H),5.07(s,2H),2.42(s,3H).13C NMR(101MHz,CDCl3):δ159.58(d,JCF＝3.0Hz),152.60(d,JCF＝9.4Hz),150.69(d,JCF＝251.6Hz),146.79(d,JCF＝26.3Hz),141.19,130.68(d,JCF＝5.3Hz),129.35,128.87(d,JCF＝6.5Hz),21.53.19F NMR(376MHz,CDCl3):δ-152.38(s,1F).IR(KBr):νmax(cm-1)＝3326,3182,1648,1573,1473,1421,1351,1200.HRMS(ESI-TOF)m/z calcd.for C11H11FN3 +[M+H]+:204.0932；found:204.0944.
实施例36：目标产物为4-(2-噻吩基苯基)-2-氨基-5-氟嘧啶
白色固体，收率：32％，熔点：134.5–135.2℃。
1H NMR(400MHz,CDCl3):δ8.19(d,JHF＝3.3Hz,1H),7.93–7.88(m,1H),7.56(d,J＝5.0Hz,1H),7.18(t,J＝4.4Hz,1H),4.98(s,2H).13C NMR(101MHz,CDCl3):δ159.32(d,JCF＝2.6Hz),148.80(d,JCF＝253.7),147.43(d,JCF＝10.8Hz),146.33(d,JCF＝24.6Hz),137.83(d,JCF＝7.2Hz),131.23(d,JCF＝12.1Hz),130.38(d,JCF＝3.2Hz),128.65(d,JCF＝1.8Hz).19F NMR(376MHz,CDCl3):δ-150.82(s,1F).IR(KBr):νmax(cm-1)＝3447,3381,1647,1606,1472,1400,1202.HRMS(ESI-TOF)m/z calcd.for C8H7FN3S+[M+H]+:196.0339；found:196.0354.
实施例37：目标产物为4-(3-吡啶基苯基)-2-氨基-5-氟嘧啶
白色固体，收率：42％，熔点：160.2–162.0℃。
1H NMR(400MHz,CDCl3):δ9.27(s,1H),8.72(d,J＝3.7Hz,1H),8.34(d,J＝8.0Hz,1H),8.28(d,J＝3.3Hz,1H),7.43(dd,J＝7.8,4.8Hz,1H),5.14(s,2H).13C NMR(101MHz,CDCl3):δ159.72(d,JCF＝2.8Hz),151.37,150.70(d,JCF＝253.7),150.03(d,JCF＝8.4Hz),149.88(d,JCF＝10.3Hz),147.46(d,JCF＝25.6),136.14(d,JCF＝6.1Hz),129.49(d,JCF＝5.8Hz),123.42.19F NMR(376MHz,CDCl3):δ-152.16(s,1F).IR(KBr):νmax(cm-1)＝3321,3175,1642,1588,1468,1350,1270,1203.HRMS(ESI-TOF)m/z calcd.for C9H8FN4 +[M+H]+:191.0728；found:191.0708.
实施例38：目标产物为4-(3-硝基苯胺基)-2-氨基-5-氟嘧啶
白色固体，收率：42％，熔点：229.5–231.3℃。
1H NMR(400MHz,DMSO):δ9.60(s,1H),8.65(t,J＝1.9Hz,1H),8.45(d,J＝8.1Hz,1H),7.97(d,J＝3.7Hz,1H),7.84(dd,J＝8.1,1.3Hz,1H),7.57(t,J＝8.2Hz,1H),6.35(s,2H).13C NMR(101MHz,DMSO):δ159.73(d,JCF＝3.3Hz),149.71(d,JCF＝10.4Hz),148.41,142.20(d,JCF＝19.2Hz),141.34,140.21(d,JCF＝244.1Hz),130.24,126.56,117.01,114.80.19F NMR(376MHz,DMSO):δ-167.74(s,1F).IR(KBr):νmax(cm-1)＝3482,3370,3309,3170,1634,1616,1580,1533,1458,1354,1336,1244,1230.HRMS(ESI-TOF)m/z calcd.forC10H8FN5NaO2 +[M+Na]+:272.0554；found:272.0533.
实施例39：目标产物为4-苯乙烯基-2-氨基-5-氟嘧啶
白色固体，收率：45％，熔点：143.6–145.7℃。
1H NMR(400MHz,CDCl3):δ8.15(s,1H),7.90(d,J＝16.0Hz,1H),7.61(d,J＝7.0Hz,2H),7.42–7.34(m,3H),7.19(d,J＝16.0Hz,1H),4.96(s,1H).13C NMR(101MHz,CDCl3):δ159.38(d,JCF＝2.8Hz),150.78(d,JCF＝11.1Hz),150.24(d,JCF＝252.8),145.98(d,JCF＝23.9Hz),138.11(d,JCF＝4.0Hz),135.77,129.57,128.89,127.86,118.21.19F NMR(376MHz,CDCl3):δ-155.75(s,1F).IR(KBr):νmax(cm-1)＝3333,3200,1648,1578,1469,1422,1352,1255,1214,1192,983.HRMS(ESI-TOF)m/z calcd.for C12H11FN3 +[M+H]+:216.0932；found:216.0901.
2-氨基-5-氟嘧啶类化合物是重要的药物片段，具有较强的生物活性，它在药物研发中有着重要的应用。所述实施例23～39制备的4-取代-2-氨基-5-氟嘧啶类化合物可进一步应用于药物中间体的合成。下面结合具体实施例对其应用进一步进行详细说明。
实施例40：
本实施例选自实施例37所述的4-(3-吡啶基苯基)-2-氨基-5-氟嘧啶，将其应用于伊马替尼氟化中间体的制备，反应式如下：
所述实施例40具体制备方法如下：
在10毫升反应管中依次加入4-(3-吡啶基)-2-氨基-5-氟嘧啶(38毫克，0.2毫摩尔)，CuI(9.5毫克，0.05毫摩尔)，无水K2CO3(55毫克，0.4毫摩尔)。氩气置换三次后，再依次加入2mL二氧六环，2-溴-4-硝基甲苯(43毫克，0.2毫摩尔)，DMEDA(4.4毫克，0.05毫摩尔)，100℃反应30小时。停止反应并冷却至室温，用乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩后残留物经硅胶薄层层析(石油醚/乙酸乙酯＝5/1，v/v)，制得目标产物45.3毫克。
所述实施例40目标产物为4-(3-吡啶基)-2-(2-甲基-5-硝基苯基)氨基-5-氟嘧啶
黄色粉末，收率：45％，熔点：208.2–209.5℃。
1H NMR(400MHz,CDCl3):δ9.38(d,J＝1.9Hz,2H),8.77(s,1H),8.56(d,J＝8.0Hz,1H),8.48(d,J＝3.1Hz,1H),7.87(dd,J＝8.3,2.1Hz,1H),7.53(dd,J＝7.8,4.9Hz,1H),7.36(d,J＝8.3Hz,1H),7.17(s,1H),2.47(s,3H).13C NMR(101MHz,CDCl3):δ155.92(d,JCF＝2.7Hz),151.86,151.25(d,JCF＝257.2Hz),150.17(d,JCF＝10.7Hz),149.70(d,JCF＝10.0Hz),147.87(d,JCF＝26.2Hz),147.08,138.4,136.25(d,JCF＝5.2Hz),133.53,130.83,129.92(d,JCF＝3.4Hz),123.85,117.38,114.19,18.29.19F NMR(376MHz,CDCl3):δ-147.25(s,1F).IR(KBr):νmax(cm-1)＝3422,1548,1525,1444,1416,1397,1343,1299,1264.HRMS(ESI-TOF)m/z calcd.for C16H13FN5O2 +[M+H]+:326.1048；found:326.1052.
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和应用本发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于这里的实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。

Claims (2)

1.一种4-取代-2-氨基-5-氟嘧啶类化合物的制备方法，其特征在于，其包括如下步骤：
其中，R选自取代苯基、吡啶基、噻吩基、苯乙烯基或苯氨基；
以4-取代-2-氨基嘧啶类化合物为底物，Selectfluor为氟源，银盐为添加剂，筛选合适溶剂，控制反应温度，反应时间控制2小时，再经分离纯化后，生成4-取代-2-氨基-5-氟嘧啶类化合物；
所述4-取代-2-氨基嘧啶类化合物、Selectfluor、银盐的摩尔比为1:1.2:2；
所述银盐选自碳酸银、磷酸银、氧化银、硝酸银、醋酸银或四氟硼酸银；
所述溶剂选自乙腈、二氧六环、二甲基甲酰胺或甲醇；
所述反应温度为25～80℃。
2.根据权利要求1所述的一种4-取代-2-氨基-5-氟嘧啶类化合物的制备方法，其特征在于，合成得到的产品经过薄层层析或柱层析分离纯化制备。
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