本发明属化合物合成，主要涉及多取代2-氨基-3-氰基吡咯类衍生物新的制备方法的开发。
背景技术：
多取代2-氨基-3-氰基吡咯类衍生物是一类较为常见的多功能结构单元，在很多的天然产物、功能性材料、合成的药物分子和生物活性化合物中都有出现。此外，2-氨基-3-氰基吡咯类衍生物也是嘌呤类衍生物如吡咯嘧啶、吡咯三嗪以及吡咯嘧啶的合成前体。
虽然，knorr反应、paal-knorr聚合和hantzsch反应等经典方法都可以用来合成吡咯化合物。但是，上述方法对于2-氨基吡咯化合物的合成适用性差。2-氨基吡咯化合物的合成最常用的方法是以α-氨基酮以及乙腈衍生物为原料在碱性、加热条件下反应得到。然而，α-氨基酮原料的底物类型稀少、合成来源不多，因此对于一些复杂结构及结构多样性的2-氨基吡咯化合物的合成，上述方法有着较大的局限性。
技术实现要素：
本发明的目的是提供一种多取代2-氨基-3-氰基吡咯类衍生物的制备方法，该类化合物以乙酰醛单水合衍生物、香豆素衍生物、伯胺衍生物以及丙二腈为原料，通过一锅法四组分的多米诺反应制得。结构通式如下：
本发明提供的一种多取代2-氨基-3-氰基吡咯类衍生物的制备方法，具体通过以下步骤实现：
将乙酰醛单水合衍生物、香豆素衍生物以及伯胺衍生物在相应的溶剂中于室温下(25℃)搅拌反应30min，随后将丙二腈以及相应的碱加入上述体系，继续反应8h后得到化合物i。反应所用的溶剂可选用醇类溶剂，芳香溶剂或其他偶极溶剂，通常是1，2-二氯乙烷，反应所需碱包括无机碱和有机碱，通常是三乙胺，所得目标产物2-氨基-3-氰基吡咯类衍生物通过硅胶色谱柱层析的方法纯化(二氯甲烷/甲醇为洗脱剂)，反应式为：
其中：
r1为苯环、单取代的苯环(取代基可为卤素、羧基、烷氧基、烷基)、c2-c5链烷烃、环己烷烃，环己基甲烷烃、苄烷烃、苯丙烷烃；
r2为苯环、单取代芳环(取代基可为卤素、三氟甲基基、烷氧基、烷基)、噻吩基；
r3为o、nh、phnh、bnnh。
本发明方法制备的化合物为如下任一化合物：
2-氨基-5-(4-羟基-2-氧代-2h-色烯-3-基)-1-正戊基-4-(对甲苯基)-1h-吡咯-3-甲腈(实施例1)
2-氨基-5-(4-羟基-2-氧代-2h-色烯-3-基)-1-异丁基-4-(对甲苯基)-1h-吡咯-3-甲腈(实施例2)
叔丁基(2-(2-氨基-3-氰基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-1-基)乙基)氨基甲酸酯(实施例3)
2-氨基-1-苄基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-3-甲腈(实施例4)
2-氨基-5-(4-羟基-2-氧代-2h-色烯-3-基)-1-(3-苯丙基)-4-(对甲苯基)-1h-吡咯-3-甲腈(实施例5)
2-氨基-1-(环己基甲基)-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-3-甲腈(实施例6)
2-氨基-1-环己基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-3-甲腈(实施例7)
2-氨基-5-(4-羟基-2-氧代-2h-色烯-3-yl)-1-苯基-4-(对甲苯基1h-吡咯-3-甲腈(实施例8)
2-氨基-5-(4-羟基-2-氧代-2h-色烯-3-基)-1,4-二-对甲苯基-1h-吡咯-3-甲腈(实施例9)
2-氨基-1-(4-氯苯基)-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-3-甲腈(实施例10)
4-(2-氨基-3-氰基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-1-基)苯甲酸(实施例11)
2-氨基-1-苄基-4-(4-氯苯基)-5-(4-羟基-2-氧代-2h-色烯-3-基)-1h-吡咯-3-甲腈(实施例12)
2-氨基-1-苄基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-苯基-1h-吡咯-3-甲腈(实施例13)
2-氨基-1-苄基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(3-甲氧苯基)-1h-吡咯-3-甲腈实(施例14)
2-氨基-1-苄基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(4-(三氟甲基)p苯基)-1h-吡咯-3-甲腈(实施例15)
2-氨基-1-苄基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(噻吩-2-基)-1h-吡咯-3-甲腈(实施例16)
2-氨基-4-(4-氯苯基)-5-(2,4-二羟基喹唑啉-3-基)-1-正戊基-1h-吡咯-3-甲腈(实施例17)
2-氨基-4-(4-氯苯基)-5-(4-羟基-6-甲基-2-氧代-1,2-二羟基吡啶-3-基)-1-正戊基-1h-吡咯-3-甲腈(实施例18)
2-氨基-5-(1-苄基-4-羟基-6-甲基-2-氧代-1,2-二羟基吡啶-3-基)-4-(4-氯苯基)-1-正戊基-1h-吡咯-3-甲腈(实施例19)
2-氨基-4-(4-氯苯基)-5-(4-羟基-6-甲基-2-氧代-1-苯基-1,2-二羟基吡啶-3-基)-1-正戊基-1h-吡咯-3-甲腈(实施例20)
2-氨基-4-(4-氯苯基)-5-(4-羟基-6-甲基-2-氧代-2h-吡喃-3-基)-1-正戊基-1h-吡咯-3-甲腈(实施例21)
2-氨基-5-(4-羟基-6-甲基-2-氧代-2h-吡喃-3-基)-1-异丁基-4-(对甲苯基)-1h-吡咯-3-甲腈(实施例22)
叔丁基(2-(2-氨基-4-(4-氯苯基)-3-氰基-5-(4-羟基-6-甲基-2-氧代-1,2-二羟基吡啶-3-基)-1h-吡咯-1-基)乙基)氨基甲酸酯(实施例23)
2-氨基-4-(4-氯苯基)-5-(4-羟基-2-氧代-2h-色烯-3-基)-1-正戊基-1h-吡咯-3-甲腈(实施例24)。
本发明以简单易得的起始原料乙酰醛单水合衍生物、香豆素衍生物、伯胺衍生物以及丙二腈，通过一锅法四组分的多米诺反应合成多取代2-氨基-3-氰基吡咯类衍生物。本发明提供的制备方法设计合理，避免了传统多步合成策略中中间体需要纯化分离的缺点，简化了合成操作，提高了合成效率，降低制备成本，同时为复杂结构的2-氨基吡咯类化合物的结构多样性合成提供了一条有效的策略。
具体实施方式
本发明结合实施例作进一步的说明。
实施例1：2-氨基-5-(4-羟基-2-氧代-2h-色烯-3-基)-1-正戊基-4-(对甲苯基)-1h-吡咯-3-甲腈
将4-甲基苯甲酰甲醛水合物(0.5mmol,1.0当量),4-羟基香豆素(0.5mmol,1.0当量)以及正戊胺(0.5mmol,1.0当量)溶于3ml1，2-二氯乙烷，室温反应15mins.随后将丙二腈(0.5mmol,1.0当量)以及et3n(0.5mmol,1.0当量)加入到上述反应体系,继续反应8小时,反应的整个过程在氮气保护下进行。反应结束后,反应体系先用10ml的二氯甲烷稀释，加入5ml水,萃取，分离有机相，并减压蒸干。粗产物用柱层析分离纯化(硅胶200-300目,甲醇:二氯甲烷＝1:30)得到目标化合物。黄色固体,收率81％。m.p.:143.7–145.5℃.1hnmr(500mhz,cdcl3)δ7.89(dd,j＝7.9,1.4hz,1h),7.64–7.54(m,1h),7.37–7.30(m,2h),7.24(d,j＝8.1hz,2h),7.05(d,j＝8.0hz,2h),3.76(s,2h),3.55(t,j＝7.7hz,2h),2.27(s,3h),1.559-1.51(m,2h),1.23–1.17(m,4h),0.80(t,j＝7.0hz,3h).13cnmr(125mhz,cdcl3)δ165.21,162.64,153.64,147.54,137.02,133.25,129.63,129.53,127.60,125.56,124.43,124.21,116.88,116.76,114.85,111.82,95.88,75.79,43.93,29.31,28.78,22.13,21.17,13.78.hrms(esi):m/zcalcdforc26h26n3o3[m+h]+:428.1969,found:428.1974。
实施例2：2-氨基-5-(4-羟基-2-氧代-2h-色烯-3-基)-1-异丁基-4-(对甲苯基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率79％。浅黄色固体,m.p.:231.7–233.4℃.1hnmr(500mhz,meod)δ7.87(dd,j＝8.0,1.3hz,1h),7.68–7.60(m,1h),7.39–7.31(m,2h),7.21(d,j＝8.1hz,2h),7.03(d,j＝8.0hz,2h),3.45(qd,j＝14.8,7.6hz,2h),2.23(s,3h),1.91(dt,j＝13.7,7.0hz,1h),0.86(d,j＝6.7hz,3h),0.81(d,j＝6.7hz,3h).13cnmr(126mhz,meod)δ165.68,163.96,153.27,149.26,136.23,132.97,130.61,128.50,127.47,124.99,124.16,123.86,118.11,116.20,115.44,111.76,96.18,72.19,50.48,28.70,19.77,18.93,18.78.hrms(esi):m/zcalcdforc25h24n3o3[m+h]+:414.1812,found:414.1812。
实施例3：叔丁基(2-(2-氨基-3-氰基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-1-基)乙基)氨基甲酸酯
制备方法同实施例1，收率76％。白色固体,m.p.:＞280℃.1hnmr(500mhz,cdcl3)δ7.79(d,j＝7.9hz,1h),7.50(dd,j＝10.7,4.9hz,1h),7.25(d,j＝6.4hz,1h),7.21(dd,j＝9.9,5.3hz,1h),7.08(d,j＝7.8hz,2h),6.94(d,j＝7.8hz,2h),3.71–3.60(m,3h),3.56-3.53(m,1h),3.23–3.15(m,1h),2.89(d,j＝14.7hz,1h),2.15(s,3h),1.33(s,9h).13cnmr(125mhz,cdcl3)δ166.20,164.05,156.97,153.38,148.40,136.59,133.10,129.82,129.10,127.50,125.52,124.51,124.17,117.97,116.50,115.52,111.82,95.29,80.69,74.83,43.30,39.93,28.09,20.92.hrms(esi):m/zcalcdforc28h28n4o5[m+h]+:501.2132,found:501.2135。
实施例4：2-氨基-1-苄基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率84％。黄色固体,m.p.:252.8–253.7℃.1hnmr(500mhz,meod)δ7.75(d,j＝7.2hz,1h),7.57(d,j＝6.9hz,1h),7.26(dd,j＝16.4,7.7hz,4h),7.18–7.10(m,5h),7.02(d,j＝6.8hz,2h),4.95(d,j＝16.4hz,2h),2.23(s,3h).13cnmr(125mhz,meod)δ165.86,163.93,153.21,149.01,136.35,136.26,132.87,130.37,128.65,128.29,127.49,127.24,126.74,125.41,124.02,123.89,117.98,116.17,115.42,112.07,95.96,73.07,46.85,20.03.hrms(esi):m/zcalcdforc28h22n3o3[m+h]+:448.1656,found:448.1657。
实施例5：2-氨基-5-(4-羟基-2-氧代-2h-色烯-3-基)-1-(3-苯丙基)-4-(对甲苯基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率87％。黄色固体,m.p.:＞280℃.1hnmr(500mhz,meod)δ7.83(dd,j＝7.9,1.2hz,1h),7.64(t,j＝7.8hz,1h),7.34(dd,j＝8.3,2.5hz,2h),7.20(d,j＝8.1hz,2h),7.01(d,j＝8.1hz,1h),6.95(d,j＝7.3hz,2h),6.84(t,j＝7.5hz,2h),6.77(d,j＝7.3hz,1h),3.55–3.48(m,2h),2.56(td,j＝6.9,3.6hz,2h),2.22(s,3h),2.06–1.97(m,2h).13cnmr(125mhz,meod)δ164.69,163.47,153.47,148.46,135.92,132.47,130.87,129.49,128.40,127.99,127.70,127.65,127.36,125.30,124.06,123.75,118.34,116.71,116.18,112.58,94.88,71.99,41.99,32.02,30.18,19.72.hrms(esi):m/zcalcdforc30h26n3o3[m+h]+:476.1969,found:476.1972。
实施例6：2-氨基-1-(环己基甲基)-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率72％。棕色固体,m.p.:153.5–154.9℃.1hnmr(500mhz,meod)δ7.89(d,j＝7.9hz,1h),7.65(dd,j＝11.4,4.3hz,1h),7.381-7.339(m,2h),7.21(d,j＝8.0hz,2h),7.03(d,j＝7.9hz,2h),3.51-3.45(m,2h),2.25(s,3h),1.67–1.59(m,6h),1.15-1.08(m,2h),0.90–0.81(m,3h).13cnmr(125mhz,meod)δ165.26,163.25,152.49,148.33,135.35,132.07,129.88,127.64,126.65,124.02,123.30,123.06,117.33,115.37,114.89,111.33,95.27,71.41,48.56,37.17,29.48,29.30,25.09,24.69,24.68,18.93.hrms(esi):m/zcalcdforc28h28n3o3[m+h]+:454.2125,found:454.2124。
实施例7：2-氨基-1-环己基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率58％。棕色固体,m.p.:165.3–167.0℃.1hnmr(500mhz,meod)δ7.88(dd,j＝7.9,1.4hz,1h),7.65–7.58(m,1h),7.36–7.31(m,2h),7.19(d,j＝8.1hz,2h),7.00(d,j＝8.0hz,2h),3.82–3.67(m,1h),2.23(s,3h),1.97–1.76(m,6h),1.67–1.54(m,2h),1.386-1.355(m,1h),1.279-1.214(m,2h).13cnmr(125mhz,meod)δ165.13,163.24,152.06,147.91,136.04,132.66,130.75,128.52,127.59,124.54,124.20,123.94,117.41,116.26,115.63,111.98,94.46,72.24,46.61,32.54,26.04,24.86,20.00.hrms(esi):m/zcalcdforc27h25n3o3[m+h]+:439.1890,found:439.1892。
实施例8：2-氨基-5-(4-羟基-2-氧代-2h-色烯-3-yl)-1-苯基-4-(对甲苯基1h-吡咯-3-甲腈
制备方法同实施例1，收率47％。棕色固体,m.p.:252.3–251.4℃.1hnmr(500mhz,cdcl3)δ7.68(dd,j＝10.7,4.9hz,1h),7.41(dt,j＝9.9,5.3hz,1h),7.36–7.20(m,7h),7.11(d,j＝7.9hz,2h),6.99(d,j＝7.9hz,2h),3.65(s,2h),2.16(s,3h).13cnmr(125mhz,cdcl3)δ165.51,163.45,153.28,148.08,136.77,134.56,132.75,129.63,129.36,129.22,129.19,127.57,127.54,125.56,124.11,123.84,117.79,116.43,115.01,112.61,95.81,73.08,20.96.hrms(esi):m/zcalcdforc27h20n3o3[m+h]+:434.1499,found:434.1499。
实施例9：2-氨基-5-(4-羟基-2-氧代-2h-色烯-3-基)-1,4-二-对甲苯基-1h-吡咯-3-甲腈
制备方法同实施例1，收率52％。棕色固体,m.p.:238.2–239.4℃.1hnmr(500mhz,meod)δ7.78(dd,j＝7.9,1.3hz,1h),7.53–7.48(m,1h),7.36–7.29(m,4h),7.23(d,j＝7.9hz,2h),7.18(d,j＝7.9hz,2h),7.05(d,j＝7.9hz,2h),2.27(s,3h),2.25(s,3h).13cnmr(126mhz,meod)δ164.67,162.42,153.23,148.98,139.02,136.19,132.36,130.68,129.57,128.49,128.42,128.33,127.93,127.73,127.46,124.51,123.91,123.67,118.06,116.63,115.95,113.00,95.33,71.57,19.76.hrms(esi):m/zcalcdforc28h22n3o3[m+h]+:448.1656,found:448.1655。
实施例10：2-氨基-1-(4-氯苯基)-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率42％。棕色固体,m.p.:＞280℃.1hnmr(500mhz,meod)δ7.79(dd,j＝7.9,1.4hz,1h),7.57–7.52(m,1h),7.39(d,j＝8.6hz,2h),7.34(d,j＝8.1hz,2h),7.31(d,j＝8.1hz,2h),7.25(t,j＝7.5hz,1h),7.21(d,j＝8.2hz,1h),7.07(d,j＝8.0hz,2h),2.26(s,3h).13cnmr(125mhz,meod)δ166.79,164.45,153.27,149.02,136.41,134.54,134.12,132.55,130.43,129.24,129.14,128.52,127.47,125.00,123.97,123.77,117.70,116.41,115.95,113.54,95.18,72.09,19.74.hrms(esi):m/zcalcdforc27h19cln3o3[m+h]+:468.1109,found:468.1111。
实施例11：4-(2-氨基-3-氰基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(对甲苯基)-1h-吡咯-1-基)苯甲酸
制备方法同实施例1，收率40％。棕色固体,m.p.:＞280℃.1hnmr(500mhz,meod)δ7.89-7.81(m,1h),7.64–7.59(m,1h),7.44-7.42(m,4h),7.32(t,j＝7.5hz,1h),7.16-6.97(m,5h),2.02(s,3h).13cnmr(125mhz,meod)δ167.97,166.42,163.88,153.66,149.63,135.37,134.26,134.02,131.97,130.83,129.16,128.46,127.57,127.50,124.7,122.30,121.51,119.08,117.37,115.85,113.33,95.44,71.62,20.35.hrms(esi):m/zcalcdforc28h20n3o5[m+h]+:478.1397,found:478.1403。
实施例12：2-氨基-1-苄基-4-(4-氯苯基)-5-(4-羟基-2-氧代-2h-色烯-3-基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率91％。灰白色固体,m.p.:257.4–258.7℃.1hnmr(500mhz,meod)δ7.77(dd,j＝7.9,1.1hz,1h),7.60–7.53(m,1h),7.31(d,j＝8.5hz,2h),7.27(d,j＝8.3hz,2h),7.20-7.17(m,4h),7.16–7.08(m,3h),4.93(d,j＝16.4hz,1h),4.80(d,j＝16.4hz,1h).13cnmr(125mhz,meod)δ166.22,163.87,153.29,148.92,135.87,133.08,132.52,131.90,129.04,128.52,128.32,127.53,126.80,124.15,124.12,124.09,117.73,116.38,115.42,112.99,95.44,73.27,47.10.hrms(esi):m/zcalcdforc27h19cln3o5[m+h]+:468.1109,found:468.1108。
实施例13：2-氨基-1-苄基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-苯基-1h-吡咯-3-甲腈
制备方法同实施例1，收率87％。白色固体,m.p.:219.3–220.8℃.1hnmr(500mhz,meod)δ7.77(d,j＝8.3hz,1h),7.65–7.58(m,1h),7.41–7.35(m,2h),7.30(dd,j＝11.6,4.4hz,2h),7.24(dd,j＝10.4,4.7hz,2h),7.21–7.12(m,6h),4.99(d,j＝16.5hz,1h).13cnmr(125mhz,meod)δ166.31,163.95,153.24,149.21,136.44,133.52,132.79,128.17,127.85,127.59,127.09,126.70,126.45,125.21,123.93,123.79,117.86,116.07,115.68,112.61,95.76,72.61,40.67.hrms(esi):m/zcalcdforc27h20n3o5[m+h]+:434.1499,found:434.1451。
实施例14：2-氨基-1-苄基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(3-甲氧苯基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率79％。黄色固体,m.p.:＞280℃.1hnmr(500mhz,meod)δ7.78(d,j＝8.0hz,1h),7.65–7.54(m,1h),7.35–7.14(m,2h),7.23–7.05(m,6h),6.98(d,j＝7.0hz,1h),6.89(m,6h),3.64(s,3h).13cnmr(125mhz,meod)δ164.38,159.39,153.35,148.80,136.20,134.81,132.71,128.95,128.39,127.32,126.84,124.69,124.08,123.92,120.07,118.09,116.34,116.22,113.66,112.71,112.63,95.29,73.00,54.36,46.99.hrms(esi):m/zcalcdforc28h22n3o4[m+h]+:464.1605,found:464.1610。
实施例15：2-氨基-1-苄基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(4-(三氟甲基)苯基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率80％。浅黄色固体,m.p.:＞280℃.1hnmr(500mhz,meod)δ7.94(d,j＝7.7hz,1h),7.65(d,j＝8.1hz,2h),7.48(dd,j＝12.7,7.8hz,3h),7.36–7.05(m,7h),4.91(s,2h).13cnmr(125mhz,meod)δ175.77,166.55,153.85,148.51,139.13,136.86,131.36,128.14,127.76,126.88,126.85,125.81(c-f,j＝33hz),124.56,124.40(c-f,j＝274hz),124.35,124.32,124.1(c-f,j＝4hz),2122.91,121.03,120.50,120.22,115.89,91.65,71.27,46.52.hrms(esi):m/zcalcdforc28h19f3n3o3[m+h]+:502.1373,found:502.1377。
实施例16：2-氨基-1-苄基-5-(4-羟基-2-氧代-2h-色烯-3-基)-4-(噻吩-2-基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率64％。棕色固体,m.p.:＞280℃.1hnmr(500mhz,dmso-d6)δ7.80(d,j＝7.5hz,1h),7.41-7.37(m,1h),7.35–7.32(m,2h),7.21–7.16(m,5h),7.11–7.09(m,2h),7.34(dd,j＝7.8,3.9hz,1h),5.57(s,2h),4.79(q,j＝16.4hz,1h).13cnmr(125mhz,dmso-d6)δ167.10,164.23,154.59,148.13,139.95,138.11,130.82,129.37,128.66,128.39,127.88,127.47,127.12,126.40,125.42,123.22,122.23,121.29,119.88,116.09,113.34,69.07,46.04.hrms(esi):m/zcalcdforc25h18n3o3s[m+h]+:440.1063,found:440.1066.
实施例17：2-氨基-4-(4-氯苯基)-5-(2,4-二羟基喹唑啉-3-基)-1-正戊基-1h-吡咯-3-甲腈
制备方法同实施例1，收率73％。白色固体,m.p.:＞280℃.1hnmr(500mhz,dmso-d6)δ11.45(s,1h),10.50(s,1h),7.80(d,j＝7.7hz,1h),7.51(t,j＝7.2hz,1h),7.36–7.19(m,5h),7.13(t,j＝7.2hz,1h),6.02(s,2h),3.69–3.42(m,2h),1.52–1.32(m,2h),1.17–0.99(m,4h),0.67(t,j＝6.2hz,3h).13cnmr(125mhz,dmso-d6)δ163.69,162.46,149.11,139.28,133.83,131.77,130.98,129.42,128.58,123.94,121.72,121.27,119.02,115.54,115.02,114.76,102.25,71.02,43.10,28.85,28.39,21.96,14.01.hrms(esi):m/zcalcdforc25h24cln4o2[m+h]+:447.1582,found:447.1586。
实施例18：2-氨基-4-(4-氯苯基)-5-(4-羟基-6-甲基-2-氧代-1,2-二羟基吡啶-3-基)-1-正戊基-1h-吡咯-3-甲腈
制备方法同实施例1，收率87％。白色固体,m.p.:＞280℃.1hnmr(500mhz,meod)δ7.29(d,j＝8.5hz,2h),7.18(d,j＝8.5hz,2h),3.55(dddd,j＝22.8,13.8,8.4,5.5hz,2h),2.23(s,3h),1.55(ddt,j＝22.6,13.6,11.1hz,2h),1.33–1.11(m,4h),0.82(t,j＝6.8hz,3h).13cnmr(126mhz,meod)δ168.58,165.65,148.14,146.94,133.13,131.52,128.90,127.77,121.44,118.48,114.94,99.93,99.52,71.74,43.09,28.74,28.40,21.84,17.86,12.99.hrms(esi):m/zcalcdforc22h24cln4o2[m+h]+:411.1582,found:411.1582。
实施例19：2-氨基-5-(1-苄基-4-羟基-6-甲基-2-氧代-1,2-二羟基吡啶-3-基)-4-(4-氯苯基)-1-正戊基-1h-吡咯-3-甲腈
制备方法同实施例1，收率89％。白色固体,m.p.:218.2–220.2℃.1hnmr(500mhz,dmso-d6)δ10.53(s,1h),7.37–7.29(m,4h),7.26(t,j＝7.5hz,3h),7.03(d,j＝7.4hz,2h),5.89(s,2h),5.34–5.13(m,2h),3.47(dd,j＝15.8,9.3hz,2h),2.19(s,3h),1.55–1.29(m,2h),1.17–0.98(m,4h),0.79(t,j＝5.8hz,3h).13cnmr(125mhz,dmso-d6)δ166.10,164.33,148.49,148.46,138.07,134.34,130.68,129.29,128.97,128.44,127.46,126.36,119.61,119.03,116.98,100.19,99.69,70.41,46.28,43.00,28.96,28.55,22.08,20.54,14.18.hrms(esi):m/zcalcdforc29h30cln4o2[m+h]+:501.2052,found:501.2056。
实施例20：2-氨基-4-(4-氯苯基)-5-(4-羟基-6-甲基-2-氧代-1-苯基-1,2-二羟基吡啶-3-基)-1-正戊基-1h-吡咯-3-甲腈
制备方法同实施例1，收率94％。白色固体,m.p.:261.8–263.3℃.1hnmr(500mhz,dmso-d6)δ10.56(s,1h),7.51(t,j＝7.2hz,2h),7.48–7.40(m,1h),7.35(d,j＝8.1hz,2h),7.30(d,j＝7.9hz,2h),7.21(d,j＝7.0hz,1h),7.13(d,j＝7.2hz,1h),5.96(s,1h),5.87(s,2h),3.48(d,j＝6.5hz,2h),1.87(s,3h),1.47(d,j＝24.4hz,2h),1.17–0.99(m,4h),0.81(t,j＝6.0hz,3h).13cnmr(125mhz,dmso-d6)δ166.42,164.51,148.51,147.71,139.22,134.31,130.66,129.88,129.78,129.27,129.10,128.75,128.53,119.65,119.06,116.57,99.95,70.39,42.90,28.82,28.46,22.01,21.67,14.16.hrms(esi):m/zcalcdforc28h28cln4o2[m+h]+:487.1895,found:487.1894。
实施例21：2-氨基-4-(4-氯苯基)-5-(4-羟基-6-甲基-2-氧代-2h-吡喃-3-基)-1-正戊基-1h-吡咯-3-甲腈
制备方法同实施例1，收率82％。黄色固体,m.p.:143.7–245.6℃.1hnmr(500mhz,dmso-d6)δ11.72(s,1h),7.35(d,j＝8.5hz,2h),7.22(d,j＝8.2hz,2h),6.05(s,1h),5.97(s,2h),3.55–3.37(m,2h),2.21(s,3h),1.44(dd,j＝13.9,6.9hz,2h),1.16(dd,j＝9.2,5.3hz,4h),0.79(t,j＝6.8hz,3h).13cnmr(125mhz,dmso-d6)δ170.44,164.36,163.96,148.71,133.80,131.08,129.27,128.69,120.76,118.65,114.24,100.22,92.87,70.68,42.93,28.89,28.36,22.05,19.96,14.12.hrms(esi):m/zcalcdforc22h23cln3o3[m+h]+:412.1422,found:412.1422。
实施例22：2-氨基-5-(4-羟基-6-甲基-2-氧代-2h-吡喃-3-基)-1-异丁基-4-(对甲苯基)-1h-吡咯-3-甲腈
制备方法同实施例1，收率80％。黄色固体,m.p.:188.3–190.1℃.1hnmr(500mhz,meod)δ7.19(d,j＝7.9hz,2h),7.05(d,j＝7.8hz,2h),5.99(s,1h),3.41(d,j＝18.9hz,1h),2.28(s,3h),2.23(s,3h),1.93-1.89(m,1h),0.85(d,j＝6.6hz,3h),0.82(d,j＝6.6hz,3h).13cnmr(125mhz,meod)δ171.09,166.25,163.76,148.57,135.75,131.25,128.34,127.46,123.55,118.34,113.03,100.43,93.88,71.73,50.27,28.51,19.79,18.88,18.79,18.45.hrms(esi):m/zcalcdforc22h24n3o3[m+h]+:378.1812,found:378.1815。
实施例23：叔丁基(2-(2-氨基-4-(4-氯苯基)-3-氰基-5-(4-羟基-6-甲基-2-氧代-1,2-二羟基吡啶-3-基)-1h-吡咯-1-基)乙基)氨基甲酸酯
制备方法同实施例1，收率84％。白色固体,m.p.:＞280℃.1hnmr(500mhz,meod)δ7.22(d,j＝8.4hz,2h),7.18(d,j＝8.5hz,2h),5.81(s,1h),3.66–3.63(m,2h),3.25–3.12(m,1h),2.98(d,j＝14.1hz,1h),2.19(s,3h),1.39(s,9h).13cnmr(126mhz,meod)δ168.48,165.59,157.06,148.56,146.96,132.30,132.13,128.91,128.26,122.48,118.25,114.29,100.34,99.41,79.98,73.23,43.01,39.83,28.02,18.59.hrms(esi):m/zcalcdforc24h27cln5o4[m+h]+:484.1746,found:484.1747。
实施例24：2-氨基-4-(4-氯苯基)-5-(4-羟基-2-氧代-2h-色烯-3-基)-1-正戊基-1h-吡咯-3-甲腈
制备方法同实施例1，收率88％。白色固体,m.p.:＞280℃.1hnmr(500mhz,meod)δ7.89(dd,j＝8.0,1.3hz,1h),7.65–7.59(m,1h),7.37–7.30(m,2h),7.27(d,j＝8.5,2h),7.19(d,j＝8.5,2h),3.63–3.51(m,2h),1.59(dddd,j＝20.1,15.9,11.4,7.7hz,2h),1.30–1.17(m,4h),0.76(t,j＝7.1hz,3h).13cnmr(125mhz,meod)δ166.45,164.19,153.39,148.51,133.14,132.37,132.08,128.99,128.28,124.25,124.20,123.68,118.00,116.47,115.58,112.37,95.33,72.81,43.43,28.89,28.48,21.90,13.15.hrms(esi):m/zcalcdforc25h23cln3o3[m+h]+:448.1422,found:4481426。