CN111217754B - 一种5-氨基-4-氰基吡唑的制备方法 - Google Patents

一种5-氨基-4-氰基吡唑的制备方法 Download PDF

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CN111217754B
CN111217754B CN201811423383.8A CN201811423383A CN111217754B CN 111217754 B CN111217754 B CN 111217754B CN 201811423383 A CN201811423383 A CN 201811423383A CN 111217754 B CN111217754 B CN 111217754B
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唐萌
张倩
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Lanzhou University
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Abstract

本发明属于有机化学领域，涉及一种5‑氨基‑4‑氰基吡唑的制备方法。本发明公开一种5‑氨基‑4‑氰基吡唑的制备方法。以苯磺酰腙和丙二腈为原料制备了一系列的5‑氨基‑4‑氰基吡唑，该反应通过苯磺酰腙N‑官能团化丰富了5‑氨基‑4‑氰基吡唑1‑位取代基的多样性，1‑位取代基为氢原子、甲基、乙基、苯基、烯丙基、炔丙基、氰甲基、苄基、乙酰乙酯基。

Description

一种5-氨基-4-氰基吡唑的制备方法
技术领域
本发明属于有机化学领域，涉及一种5-氨基-4-氰基吡唑的制备方法。
背景技术
近年来，大量研究和实践表明吡唑类化合物具有广泛的生物活性，无论在医药领域还是在农药领域吡唑类化合物都得到了广泛的应用，而且吡唑环上取代位点和取代基的多样性变化使市场化的吡唑类化合物日益丰富。如式一所示，5-氨基-4-氰基吡唑常通过单取代肼和丙二腈衍生物的环化反应制备，该反应被文献多次报道(Org.Lett.,2016,18,4206-4209；Org.Prep.Proced.Int.,1981,13,379-382)。受制于单取代肼的种类，反应中R2取代基多样性受到很大限制，目前R2多局限于烷基。5-氨基-4-氰基吡唑是一类重要的有机合成中间体。如式一所示，5-氨基-4-氰基吡唑和甲酰胺通过简单的缩合环化反应可制备吡唑并[3,4-d]嘧啶衍生物。吡唑并[3,4-d]嘧啶类化合物作为高选择性c-Src激酶抑制剂(ACS Chem.Biol.,2012,7,1393-1398)、磷脂酶D强效抑制剂(Chem.Biol.Drug Des.,2014,84,270-281)和钙依赖性蛋白激酶1抑制剂用于预防弓形虫感染(J.Med.Chem.,2013,56,3068-3077)，在医药领域有广泛的应用。
Figure BDA0001878346170000011
本发明在三氯化铝的条件下，以苯磺酰腙和丙二腈为原料制备了一系列的5-氨基-4-氰基吡唑，该反应通过苯磺酰腙N-官能团化丰富了R2取代基的多样性，R2为氢原子、甲基、乙基、苯基、烯丙基、炔丙基、氰甲基、苄基、乙酰乙酯基。
发明内容
本发明的目的是公开一种5-氨基-4-氰基吡唑的制备方法，其反应通式如式二所示。
Figure BDA0001878346170000012
其中R1为：烷基、苯基、取代苯基、呋喃基、噻吩基；R2为：氢原子、甲基、乙基、苯基、烯丙基、炔丙基、氰甲基、苄基、乙酰乙酯基；
反应所用三氯化铝为市售分析纯三氯化铝；所用溶剂为：1,2-二氯乙烷、二氯甲烷、氯仿、四氯化碳；所用温度为加热回流；反应中苯磺酰腙:丙二腈:三氯化铝的摩尔比为1:2.5:2.5。
具体实施方式
以下为本发明的实施例，但本发明的内容并不局限于此。
实施例：5-氨基-4-氰基吡唑化合物的制备：
氩气保护下，将苯磺酰腙(0.2mmol)溶于1,2-二氯乙烷(2mL)中，加丙二腈(0.6mmol)，AlCl3(0.5mmol)，加热回流反应至苯磺酰腙完全消失，产物乙酸乙酯(200mL)萃取，有机相用饱和Na2CO3溶液洗，食盐水洗，无水MgSO4干燥，减压蒸除溶剂，柱层析分离得5-氨基-4-氰基吡唑。
谱图数据如下：
Figure BDA0001878346170000021
1H NMR(300MHz,CDCl3)δ＝3.63(s,3H),4.61(brs,2H),7.35-7.46(m,3H),7.85-7.88(m,2H)；13C NMR(75MHz,CDCl3)δ＝34.7,73.3,115.6,126.1,128.7,129.0,131.1,150.3,151.5ppm；
Figure BDA0001878346170000022
1H NMR(400MHz,DMSO)δ＝2.46(s,1H),4.19(brs,2H),7.45-7.50(m,3H),7.93-7.97(m,2H)；13C NMR(100MHz,DMSO)δ＝17.6,117.7,126.6,129.6,130.8,155.6ppm；HRMS(ESI):Calcd for C10H8N4[M+H]+:185.0822,found:185.0823.
Figure BDA0001878346170000023
1H NMR(300MHz,CDCl3)δ＝1.42(t,J＝7.2Hz,3H),3.97(q,J＝7.2Hz,2H),4.51(brs,2H),7.35-7.46(m,3H),7.88-7.91(m,2H)；13C NMR(75MHz,CDCl3)δ＝14.1,42.9,73.7,115.6,126.2,128.7,129.0,131.2,150.3,150.7ppm；HRMS(ESI):Calcd for C12H12N4[M+H]+:213.1135,found:213.1139.
Figure BDA0001878346170000024
1H NMR(300MHz,CDCl3)δ＝4.23(brs,2H),5.24(s,2H),7.22-7.26(m,2H),7.34-7.47(m,6H),7.93-7.96(m,2H)；13C NMR(75MHz,CDCl3)δ＝52.5,74.5,115.2,126.3,126.9,128.5,128.7,129.1,129.3,131.1,134.3,150.4,151.3ppm；
Figure BDA0001878346170000025
1H NMR(300MHz,CDCl3)δ＝4.53(brs,2H),4.63-4.65(m,2H),5.21(d,J＝17.4Hz,1H),5.33(d,J＝10.5Hz,1H),5.89-6.02(m,1H),7.35-7.45(m,3H),7.88-7.91(m,2H)；13CNMR(75MHz,CDCl3)δ＝51.1,73.9,115.4,118.7,126.2,128.7,129.0,130.1,131.1,150.4,151.6ppm；HRMS(ESI):Calcd for C13H12N4[M+Na]+:247.0954,found:247.0947.
Figure BDA0001878346170000031
1H NMR(300MHz,CDCl3)δ＝2.56(t,J＝2.4Hz,1H),4.75(brs,2H),4.84(d,J＝2.4Hz,2H),7.39-7.47(m,3H),7.88-7.91(m,2H)；13C NMR(75MHz,CDCl3)δ＝38.6,74.5,75.1,75.7,115.0,126.3,128.7,129.2,130.8,150.7,151.7ppm；HRMS(ESI):Calcd forC13H10N4[M+Na]+:245.0798,found:245.0794.
Figure BDA0001878346170000032
1H NMR(300MHz,DMSO)δ＝5.29(s,2H),7.18(s,2H),7.39-7.50(m,3H),7.75-7.80(m,2H)；13C NMR(75MHz,DMSO)δ＝36.7,71.1,110.0,116.0,126.6,129.5,130.0,131.5,151.3,154.6ppm；HRMS(ESI):Calcd for C12H9N5[M+H]+:224.0931,found:224.0929.
Figure BDA0001878346170000033
1H NMR(300MHz,DMSO)δ＝1.22(t,J＝7.2Hz,3H),4.17(q,J＝7.2Hz,2H),4.90(s,2H),6.86(brs,2H),7.38-7.46(m,3H),7.77-7.80(m,2H)；13C NMR(75MHz,DMSO)δ＝14.2,49.0,61.3,70.0,116.0,125.8,128.9,129.0,131.5,149.5,154.4,167.5ppm；HRMS(ESI):Calcd for C14H14N4O2[M+H]+:271.1190,found:271.1194.
Figure BDA0001878346170000034
1H NMR(300MHz,CDCl3)δ＝3.65(s,3H),4.62(brs,2H),7.27-7.38(m,2H),7.44-7.49(m,2H)；13C NMR(75MHz,CDCl3)δ＝34.8,114.7,126.8,130.0,130.2,130.4,131.3,133.0,149.5,150.7ppm；HRMS(ESI):Calcd for C11H9ClN4[M+H]+:233.0589,found:233.0594.
Figure BDA0001878346170000041
1H NMR(300MHz,DMSO)δ＝3.60(s,3H),6.80(brs,2H),7.43-7.51(m,2H),7.73-7.77(m,2H)；13C NMR(75MHz,CDCl3)δ＝34.9,70.0,115.8,124.1,125.1,128.5,130.8,133.5,133.6,147.0,153.4ppm；HRMS(ESI):Calcd for C11H9ClN4[M+H]+:233.0589,found:233.0596.
Figure BDA0001878346170000042
1H NMR(300MHz,CDCl3)δ＝3.71(d,J＝1.8Hz,3H),4.44(brs,2H),7.26-7.44(m,3H),7.67(d,J＝7.8Hz,1H)；13C NMR(75MHz,CDCl3)δ＝34.8,104.6,114.4,127.4,127.8,130.6,131.0,131.5,132.3,133.3,150.3ppm；
Figure BDA0001878346170000043
1H NMR(300MHz,CDCl3)δ＝3.69(d,J＝3Hz,3H),4.49(brs,2H),7.40(dd,J＝8.4,3.0Hz,2H),7.83(dd,J＝8.4,2.7Hz,2H)；13C NMR(75MHz,CDCl3)δ＝34.8,115.2,127.3,128.9,129.6,134.9,149.1,151.3ppm；
Figure BDA0001878346170000044
1H NMR(300MHz,DMSO)δ＝2.30(s,3H),3.57(s,3H),6.62(brs,2H),7.23(d,J＝7.8Hz,2H),7.65-7.68(m,2H)；13C NMR(75MHz,DMSO)δ＝21.5,35.4,70.4,116.8,126.2,129.6,130.0,138.8,149.3,153.8ppm；
Figure BDA0001878346170000045
1H NMR(300MHz,CDCl3)δ＝2.42(s,3H),3.61(s,3H),4.55(brs,2H),7.21-7.33(m,3H),7.39(d,J＝7.2Hz,1H)；13C NMR(75MHz,CDCl3)δ＝20.2,34.6,76.0,115.1,125.7,128.9,129.6,130.5,130.7,136.7,150.6,151.9ppm；
Figure BDA0001878346170000051
1H NMR(300MHz,DMSO)δ＝3.56(s,3H),3.77(s,3H),6.60(brs,2H),6.70-7.00(m,2H),6.68-7.72(m,2H)；13C NMR(75MHz,DMSO)δ＝35.0,55.5,69.9,110.0,114.5,124.6,127.3,148.9,153.4,159.9ppm；
Figure BDA0001878346170000052
1H NMR(400MHz,CDCl3)δ＝3.62(s,3H),4.38(brs,2H),6.43(t,J＝1.6Hz,1H),6.85(d,J＝3.2Hz,1H),7.42(s,1H)；13C NMR(100MHz,DMSO)δ＝34.8,73.0,108.9,111.4,114.4,142.8,145.8,150.6ppm；HRMS(ESI):Calcd for C9H8N4O[M+H]+:189.0771,found:189.0772.
Figure BDA0001878346170000053
1H NMR(400MHz,DMSO)δ＝3.52(s,3H),6.70(brs,2H),7.09(dd,J＝5.2,4.0Hz,1H),7.46-7.47(m,1H),7.51(dd,J＝5.2,0.8Hz,1H)；13C NMR(100MHz,DMSO)δ＝35.2,69.9,116.1,125.1,126.8,128.3,134.7,144.8,153.4ppm；HRMS(ESI):Calcd for C9H8N4S[M+H]+:205.0542,found:205.0544.
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (1)

1.一种5-氨基-4-氰基吡唑的制备方法，其反应通式如式一所示：
Figure FDA0004053950880000011
其中R1为：苯基、呋喃基、噻吩基；R2为：氢、甲基、乙基、炔丙基、氰甲基、苄基；
反应所用铝盐为：三氯化铝、三溴化铝；所用溶剂为：1,2-二氯乙烷、二氯甲烷、氯仿、四氯化碳；所用温度为加热回流。
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