CN116120204A - 一种合成n-no化合物的方法 - Google Patents

一种合成n-no化合物的方法 Download PDF

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CN116120204A
CN116120204A CN202310045514.8A CN202310045514A CN116120204A CN 116120204 A CN116120204 A CN 116120204A CN 202310045514 A CN202310045514 A CN 202310045514A CN 116120204 A CN116120204 A CN 116120204A
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周强辉
庄林
李小倩
杨涛
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Abstract

本发明公开了一种合成N‑NO化合物的方法。该方法以简单易得的有机胺为起始原料，在硝化试剂的作用下，在25‑100℃下于有机溶剂中搅拌反应，即可得到N‑NO化合物。该方法具有原料廉价易得，反应条件温和，制备过程简单，化学选择性好，底物适用范围广，易于放大等优点，具有较大的应用潜力，为工业化生产奠定了良好的基础。

Description

一种合成N-NO化合物的方法
技术领域
本发明属于有机合成领域，具体涉及一种合成N-NO化合物的方法。
背景技术
亚硝化反应(Nitrosation)是向有机化合物分子中引入亚硝基(－NO)的过程。N-NO化合物存在于各种食品、化妆品和天然产品中([1]N-Nitroso Compounds:Occurrenceand Biological Effects,IARC Scientific Publishers,Lyon,1982)。由于其独特的致癌和诱变特性，也越来越受到关注([2]Chem.Rev.,2002,102,1091-1134)。目前已有许多N-NO化合物用于各种治疗，包括癌症、心血管疾病、中枢神经***疾病以及与免疫和生理障碍相关的疾病。除了具有重要的生物学意义，N-NO化合物还是有机合成中有价值的中间体([3]Org.Prep.Proced.Int.,1987,19,85-159),例如制备α-二取代肼([4]J.Am.Chem.Soc.,1951,73,4996–4996；[5]J.Org.Chem,1958,23,529–531)和介离子-杂环化合物([6]Tetrahedron,2010,66,553–568；[7]Chem.Rev.,1964,64,129–147)。最近，报道了N-NO作为无痕导向基团与过渡金属结合来活化芳基环中惰性C-H键。([8]J.Am.Chem.Soc.,2013,135,468–473；[9]J.Am.Chem.Soc.,2013,135,16625–16631；[10]Org.Lett.,2013,15,5294–5297；[11]J.Org.Chem.,2015,80,12588–12593)。这些C-H活化反应为构建各种具有重要生物学意义的杂环化合物提供了卓有成效的方法。
合成这类化合物的传统方法主要是利用亚硝酸钠和浓无机酸(如HCl、H2SO4)原位生成的亚硝酸([12]Chem.Ber.,1964,97,2713–2714；[13]Synth.Commun.,2010,40,654–660)。目前，它也是实验室和工厂生产N-NO类化合物的常用方法。除了这种传统的试剂，亚硝酰氯([14]J.Chem.Res.,Synop.,2000,420–422)、亚硝基四氟硼酸盐([15]Chem.Ber.,1956,89,2374–2377)、亚硝基冠醚加合物([16]J.Org.Chem.,2001,66,3619–3620)、Fremy’s salt([17]J.Chem.Soc.,Chem.Commun.,1983,301–302)和氮氧化物([18]J.Am.Chem.Soc.,1955,77,6008–6010)(N2O3、N2O4等)也被用于从相应的仲胺合成各种N-NO化合物。在过去的十年中，使用亚硝酸钠与固体酸([19]Tetrahedron Lett.,2003,44,3345–3349；[20]Synlett,2002,1621–162418；[21]J.Appl.Polym.Sci.,2009,114,2134–2138)或氮氧化物与不同固体载体([22]Tetrahedron Lett.,2010,51,2277–2280；[23]Synth.Commun.,2005,35,1517–1526；[24]Synthesis,2003,1591–1597)的组合，开发了各种非均相体系。但是这些方法大多都使用了强酸性条件，限制了它们在复杂合成中的应用。最近，已报道有硝基甲烷(CH3NO2)在氧化条件下(例如IBX或KI/TBHP或[Cu]/O2)([25]Chem.Commun.,2015,51,11638–11641；[26]J.Org.Chem.,2013,78,11366–11372；[27]J.Org.Chem.,2012,77,626–631)可用作产生亚硝基(NO)的替代来源的例子。由于外源氧化剂和苛刻的反应条件，该策略存在一些先天性问题，例如较差的官能团耐受性和低收率。由于当前试剂的局限性，市售的亚硝酸叔丁酯(TBN)([28]Green Chem.,2016,18,2323–2330)作为硝酸化试剂引起了化学家的兴趣。与无机亚硝酸盐不同，TBN不需要强酸条件，反应条件相对简单，但TBN在室温下见光易分解和空气介导下氧化，需要在惰性气氛下低温储存。
尽管亚硝化策略已经取得了显著的发展，但在反应效率、底物普适性和产物多样性等方面仍有很大的改进空间。因此发展高效、简洁的合成新方法，利用简单易得的原料合成N-NO化合物仍然是亚硝化反应领域的热点和难点。
发明内容
为了解决现有技术中存在的不足，本发明提供一种合成N-NO化合物的方法。该方法所用的原料廉价易得，反应条件温和，制备过程简单，化学选择性好，底物适用范围广，可以规模放大。
本发明提供的技术方案具体如下：
一种合成N-NO化合物的方法，包括以下步骤：
在保护气体氛围下，以有机胺A为起始原料，加入硝化试剂B，于有机溶剂C中搅拌反应至完全，反应结束后将反应物分离即可得到式I所示的N-NO类化合物；
反应方程式如下：
Figure BDA0004055234710000021
R1、R2为各自独立的基团或者两者形成环状基团；若R1、R2均为独立基团，则选自氢、烷基、取代烷基、环烷基、芳基及取代芳基；若R1、R2形成环状基团，则环状基团选自环烷基、取代环烷基、杂环烷基和取代杂环烷基；
R3为氢、烷基；
R4为烷基、羟基、巯基、硅基、氨基、氰基、硝基、卤素、-COR中的一种或几种；其中，R为烷基；
x表示R4的个数，0≤x≤3；当x≥2时，两个基团可以相同也可以不同。
进一步，R1、R2均为独立基团，烷基为C1-C4的烷基；取代烷基的取代基为
Figure BDA0004055234710000031
R5、R6独立地选自氢、C1-C4的烷基，R7选自氢、C1-C4的烷基、C1-C4的烷氧基、呋喃基、吡啶基、C1-C4的烯基、C1-C4的烷基胺、C6-C12的芳基、
Figure BDA0004055234710000032
Figure BDA0004055234710000033
-COOMe；环烷基为C6-C12的环烷基；芳基为C6-C12的芳基；取代芳基为-Ar-R8，R8选自卤素、氰基。
更进一步，R1、R2为C1-C4的烷基，具体为为甲基、乙基、异丙基或丁基。
进一步，R1、R2形成环状基团，环烷基为C6-C12的环烷基；取代环烷基为-C-R9(结构式)，其中环烷基为C5-C12的环烷基，R9为环己基、苯基、、
Figure BDA0004055234710000034
-COOMe、
Figure BDA0004055234710000035
杂环烷基为含有N、S或O的C5-C7的环烷基；取代杂环烷基为-N-R10(结构式)，其中，杂环烷基为C5-C7的环烷基，R10为甲磺酰基、苯甲酰基、苯基。
进一步，所述R3中，烷基为C1-C6的烷基。
进一步，所述R4中，烷基为C1-C6的烷基；-COR中，R为C1-C6的烷基。
更进一步，硝化试剂B为1,4-二硝基吡唑、N-硝基吡唑、5-甲基-1,3-二硝基吡唑、4-氰基-1-硝基吡唑、4-碘-1-硝基吡唑、4-甲酯-1-硝基吡唑、1,3-二硝基吡唑。
进一步，所述溶剂C为甲醇、乙醇、异丙醇、叔丁醇、六氟异丙醇、四氢呋喃、2-甲基四氢呋喃、***、二甲基乙二醚、甲基叔丁基醚、1,4-二氧六环、1,3-二氧六环、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈中的任意一种或几种。优选的，溶剂D为六氟异丙醇。
进一步，所述保护气体为氩气或氮气。
进一步，所述反应温度为25-100℃。优选反应温度为80℃。
进一步，所述反应时间为1-72h。优选反应时间为16h。
进一步，所述反应物分离的方法为将反应混合物浓缩和柱层析纯化。所述浓缩过程可采用减压蒸馏等方法，例如用旋转蒸发仪减压浓缩。所述纯化方法可采用柱层析分离纯化。
本发明的方法可以高效地制备N-NO化合物，和现有技术相比，本发明具有以下有益效果：
i)本发明所涉及的主要原料有机胺，溶剂都为商品化试剂、且价格低廉，种类繁多；硝化试剂制备简单，只需一步反应即可得到；
i i)本发明反应条件简单，不需要酸和额外的氧化剂；
iii)本发明方法具有很好的底物适用范围和官能团兼容性；
iv)本发明方法可以大量(克级)制备N-NO化合物，具有较大的应用潜力，为工业化生产奠定了良好的基础。
具体实施方式
下面通过实例对本发明给予进一步说明，值得注意的是，本发明不仅限于下述的实施例。
实施例1：化合物I-1的制备
Figure BDA0004055234710000041
在氩气氛围下，向干燥并装有磁力搅拌子的反应管中加入N-甲基-苯基乙胺(27.0mg，0.2mmol)、1,4-二硝基吡唑(31.6mg,0.2mmol)和六氟异丙醇(1.0mL)，所得混合物于80℃反应16小时。反应结束后冷却至室温，混合物减压蒸馏除去溶剂，柱层析分离纯化得化合物I-1(黄色油状液体，66％产率)。1H NMR(400MHz,CDCl3):δ7.35–7.28(m,2.67H),7.28–7.22(m,1.38H),7.23–7.14(m,2.7H),4.46–4.29(t,J＝7.4Hz,2H),3.83–3.77(t,J＝7.4Hz,0.64H),3.57(s,1H),3.06(t,J＝7.4Hz,2H),3.00(s,3H),2.81(t,J＝7.4Hz,0.65H)；13C NMR(100MHz,CDCl3):δ138.1,137.4,129.0,128.9,128.8,128.8,127.1,127.0,55.2,47.3,39.9,35.3,32.2,32.0；HRMS(ESI-TOF):calc’d for C9H12N2NaO+[M+Na+]187.0842,found 187.0847。
其它硝化试剂条件下化合物I-1的制备
在氩气氛围下，向干燥并装有磁力搅拌子的反应管中加入N-甲基-苯基乙胺(27.0mg，0.2mmol)、4-氰基1-硝基吡唑(27.6mg,0.2mmol)和六氟异丙醇(1.0mL)，所得混合物于80℃反应16小时。反应结束后冷却至室温，混合物减压蒸馏除去溶剂，柱层析分离纯化得化合物I-1(黄色油状液体，47％产率)。
在氩气氛围下，向干燥并装有磁力搅拌子的反应管中加入N-甲基-苯基乙胺(27.0mg，0.2mmol)、4-甲酯-1-硝基吡唑(34.2mg,0.2mmol)和六氟异丙醇(1.0mL)，所得混合物于80℃反应16小时。反应结束后冷却至室温，混合物减压蒸馏除去溶剂，柱层析分离纯化得化合物I-1(黄色油状液体，37％产率)。
在氩气氛围下，向干燥并装有磁力搅拌子的反应管中加入N-甲基-苯基乙胺(27.0mg，0.2mmol)、1,3-二硝基吡唑(31.6mg,0.2mmol)和六氟异丙醇(1.0mL)，所得混合物于80℃反应16小时。反应结束后冷却至室温，混合物减压蒸馏除去溶剂，柱层析分离纯化得化合物I-1(黄色油状液体，20％产率)。
在氩气氛围下，向干燥并装有磁力搅拌子的反应管中加入N-甲基-苯基乙胺(27.0mg，0.2mmol)、5-甲基-1,3-二硝基吡唑(34.4mg,0.2mmol)和六氟异丙醇(1.0mL)，所得混合物于80℃反应16小时。反应结束后冷却至室温，混合物减压蒸馏除去溶剂，柱层析分离纯化得化合物I-1(黄色油状液体，64％产率)。
实施例2：化合物I-2的制备
Figure BDA0004055234710000051
操作步骤同实施例1，区别在于所使用的有机胺为N-甲基苄胺(24.2mg)，得化合物I-2(黄色油状液体，64％产率)。1H NMR(400MHz,CDCl3):δ7.57-7.04(m,5H),5.30(s,1.35H),4.80(s,0.37H),3.69(s,0.57H),2.94(s,2.58H)；13C NMR(100MHz,CDCl3):δ134.6,133.9,129.2,129.1,128.7,128.5,128.2,128.1,57.8,47.9,38.6,31.1；HRMS(ESI-TOF):calc’d for C8H10N2NaO+[M+Na+]173.0685,found 173.0690。
实施例3：化合物I-3的制备
Figure BDA0004055234710000061
操作步骤同实施例1，区别在于所使用的有机胺为N-苄基异丙胺(29.8mg),得化合物I-3(黄色油状液体，95％产率)。1H NMR(400MHz,CDCl3):δ7.34–7.22(m,3.88H),7.13–7.04(m,2.17H),5.25(s,0.33H),4.94(p,J＝6.8Hz,0.21H),4.77(s,2H),4.58(p,J＝6.8Hz,1H),1.42(d,J＝6.8Hz,6H),1.00(d,J＝6.7Hz,1.13H)；13C NMR(100MHz,CDCl3):δ136.7,135.2,128.9,128.8,128.3,128.0,127.8,127.7,55.1,53.0,45.7,45.5,21.9,19.3；HRMS(ESI-TOF):calc’d for C10H14N2NaO+[M+Na+]201.0998,found 201.0998。
实施例4：化合物I-4的制备
Figure BDA0004055234710000062
操作步骤同实施例1，区别在于所使用的有机胺为N-甲基-2-萘甲胺(34.2mg)，得化合物I-4(黄色油状液体，81％产率)。1H NMR(400MHz,CDCl3):8.13–8.08(m,0.96H),7.93–7.83(m,2.88H),7.70–7.64(m,0.44H),7.57–7.49(m,3H),7.49–7.46(m,0.92H),7.45–7.41(m,1.24H),7.35–7.29(m,0.43H),5.78(s,2H),5.25(s,0.88H),3.54(s,1.32H),2.93(s,3H)；13C NMR(100MHz,CDCl3):δ134.2,133.9,131.8,131.3,129.9,129.8,129.4,129.1,129.0,128.2,128.0,127.2,127.2,126.5,126.5,125.4,125.4,123.2,123.1,55.9,45.9,38.2,30.8；HRMS(ESI-TOF):calc’d for C12H12N2NaO+[M+Na+]223.0842,found 223.0842。
实施例5：化合物I-5的制备
Figure BDA0004055234710000063
操作步骤同实施例1，区别在于所使用的有机胺为1,2,3,4-四氢异喹啉(26.6mg)，得化合物I-5(黄色油状液体，66％产率)。1H NMR(400MHz,CDCl3):δ7.37–7.07(m,4H),5.40(s,0.55H),4.84(s,1.3H),4.55(t,J＝5.9Hz,1.3H),3.89(t,J＝6.5Hz,0.55H),3.11(t,J＝5.9Hz,1.3H),2.97(t,J＝6.5Hz,0.55H)；13C NMR(100MHz,CDCl3):δ135.1,134.0,132.5,130.1,128.8,128.2,128.1,127.4(d,J＝3.3Hz),127.3,126.3,51.4,47.9,44.6,40.9,29.9,27.5；HRMS(ESI-TOF):calc’d for C9H10N2NaO+[M+Na+]185.0685,found 185.0684。
实施例6：化合物I-6的制备
Figure BDA0004055234710000071
操作步骤同实施例1，区别在于所使用的有机胺为十氢喹啉(27.8mg)，得化合物I-6(黄色油状液体，91％产率)。1H NMR(400MHz,CDCl3):δ5.26(ddt,J＝13.4,4.2,2.0Hz,1H),3.33(td,J＝10.7,3.4Hz,1H),2.47(dd,J＝13.4,3.0Hz,1H),2.34(td,J＝13.0,3.4Hz,1H),2.05–1.84(m,2H),1.76(tdd,J＝11.2,5.4,2.7Hz,4H),1.46–1.25(m,5H),1.26–1.10(m,1H)；13C NMR(100MHz,CDCl3):δ67.3,44.0,40.8,32.7,32.1,29.0,25.6,25.5,25.0；HRMS(ESI-TOF):calc’d for C9H16N2NaO+[M+Na+]191.1155,found 191.1149。
实施例7：化合物I-7的制备
Figure BDA0004055234710000072
操作步骤同实施例1，区别在于所使用的有机胺为环己亚胺(19.8mg)，得化合物I-7(黄色油状液体，64％产率)。1H NMR(400MHz,CDCl3):δ4.34–4.28(m,2H),3.67–3.60(m,2H),1.90–1.84(m,2H),1.77(ddt,J＝10.9,7.8,4.4Hz,2H),1.59(td,J＝7.8,7.1,3.6Hz,4H)；13C NMR(100MHz,CDCl3):δ52.2,46.4,29.5,28.8,28.2,24.7；HRMS(ESI-TOF):calc’dfor C6H12N2NaO+[M+Na+]151.0842,found 151.0840。
实施例8：化合物I-8的制备
Figure BDA0004055234710000073
操作步骤同实施例1，区别在于所使用的有机胺为吗啉(17.4mg)，得化合物I-8(黄色油状液体，61％产率)。1H NMR(400MHz,CDCl3):δ4.29(t,J＝5.0Hz,2H),3.87(dt,J＝12.0,5.1Hz,4H),3.65(t,J＝5.2Hz,2H)；13C NMR(100MHz,CDCl3):δ67.4,66.0,50.1,40.5；HRMS(ESI-TOF):calc’d for C4H8N2NaO2 +[M+Na+]139.0478,found 139.0474。
实施例9：化合物I-9的制备
Figure BDA0004055234710000081
操作步骤同实施例1，区别在于所使用的有机物为硫代吗啉(20.6mg)，得化合物I-9(黄色油状液体，57％产率)。1H NMR(400MHz,CDCl3):δ4.50(t,J＝5.4Hz,2H),4.06(t,J＝5.4Hz,2H),2.85(t,J＝5.4Hz,2H),2.58(t,J＝5.4Hz,2H)；13C NMR(100MHz,CDCl3):δ52.6,41.4,29.1,27.4；HRMS(ESI-TOF):calc’d for C4H8N2SNaO+[M+Na+]291.0105,found291.0109。
实施例10：化合物I-10的制备
Figure BDA0004055234710000082
操作步骤同实施例1，区别在于所使用的有机胺为1-(甲磺酰基)哌嗪(32.8mg)，得化合物I-10(黄色固体，41％产率)。1H NMR(400MHz,CDCl3):δ4.45–4.34(m,2H),4.00–3.89(m,2H),3.56–3.42(m,2H),3.23(t,J＝5.4Hz,2H),2.83(s,3H)；13C NMR(100MHz,CDCl3):δ49.4,46.5,45.0,39.1,36.0；HRMS(ESI-TOF):calc’d for C5H11N2SNaO3 +[M+Na+]216.0413,found 216.0412。
实施例11：化合物I-11的制备
Figure BDA0004055234710000083
操作步骤同实施例1，区别在于所使用的有机胺为双(2-甲氧基乙基)胺(26.6mg)，得化合物I-11(黄色油状液体，87％产率)。1H NMR(400MHz,CDCl3):δ4.36(t,J＝5.3Hz,2H),3.85(t,J＝5.4Hz,2H),3.72(t,J＝5.3Hz,2H),3.45(t,J＝5.4Hz,2H),3.36(s,3H),3.29(s,3H)；
13C NMR(100MHz,CDCl3):δ71.0,69.0,59.0,58.9,53.1,44.8；HRMS(ESI-TOF):calc’d for C6H14N2NaO3 +[M+Na+]185.0897,found 185.0897。
实施例12：化合物I-12的制备
Figure BDA0004055234710000091
操作步骤同实施例1，区别在于所使用的有机胺为二丁胺(25.8mg)，得化合物I-12(黄色油状液体，90％产率)。1H NMR(400MHz,CDCl3):δ4.07(t,J＝7.3Hz,2H),3.58-3.45(m,2H),1.82-1.66(m,2H),1.46(tdd,J＝7.7,6.4,3.5Hz,1H),1.38(q,J＝7.5Hz,2H),1.30(dt,J＝15.0,7.5Hz,2H),0.97(t,J＝7.4Hz,3H),0.91(t,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3):δ52.2,43.6,30.5,28.3,20.6,19.9,13.8,13.8；HRMS(ESI-TOF):calc’d forC8H18N2HO+[M+H+]159.1492,found 159.1490。
实施例13：化合物I-13的制备
Figure BDA0004055234710000092
操作步骤同实施例1，区别在于所使用的有机胺为二卞胺(39.5mg)，得化合物I-13(黄色油状液体，79％产率)。1H NMR(400MHz,CDCl3):δ7.40–7.36(m,3H),7.32–7.28(m,3H),7.25(dt,J＝7.0,1.9Hz,2H),7.07–7.03(m,2H),5.21(s,2H),4.67(s,2H)；13C NMR(100MHz,CDCl3):δ134.6,134.0,129.2,129.0,128.7,128.6,128.5,128.0,55.1,45.0；HRMS(ESI-TOF):calc’d for C14H14N2NaO+[M+Na+]249.0988,found 249.1000。
实施例14：化合物I-14的制备
Figure BDA0004055234710000093
操作步骤同实施例1，区别在于所使用的有机胺为二环己基胺(36.3mg),得化合物I-14(黄色固体，83％产率)。1H NMR(400MHz,CDCl3):δ4.86(tt,J＝11.8,3.8Hz,1H),3.70(tt,J＝9.8,4.6Hz,1H),1.97–1.83(m,6H),1.78(dt,J＝13.1,3.1Hz,2H),1.69(td,J＝13.6,5.7Hz,2H),1.62–1.54(m,2H),1.49–1.29(m,6H),1.24(dt,J＝12.7,3.1Hz,1H),1.20–1.11(m,1H)；13C NMR(100MHz,CDCl3):δ58.7,52.4,34.5,29.5,26.2,25.6,25.5,25.4；HRMS(ESI-TOF):calc’d for C12H22N2NaO+[M+Na+]233.1624,found 233.1625。
实施例15：化合物I-15的制备
Figure BDA0004055234710000101
操作步骤同实施例1，区别在于所使用的有机胺为N-甲基-N-呋喃基胺(22.2mg)，得化合物I-15(黄色油状液体，53％产率)。1H NMR(400MHz,CDCl3):δ7.42(t,J＝1.4Hz,1H),7.35(dd,J＝1.9,0.9Hz,0.43H),6.38(d,J＝1.4Hz,2H),6.33(dd,J＝3.3,1.9Hz,0.43H),6.30–6.27(m,0.43H),5.30(s,2H),4.75(s,0.86H),3.73(s,1.3H),3.00(s,3H)；13C NMR(100MHz,CDCl3):δ148.2,147.3,143.6,142.9,110.9,110.8,110.1,109.9,50.4,40.8,38.6,31.0；HRMS(ESI-TOF):calc’d for C6H8N2SHO+[M+H+]157.0430,found 157.0426。
实施例16：化合物I-16的制备
Figure BDA0004055234710000102
操作步骤同实施例1，区别在于所使用的有机胺为N-甲基-N-(3-甲基吡啶)胺(24.3mg)，得化合物I-16(黄色油状液体，43％产率)。1H NMR(400MHz,CDCl3):δ8.63(d,J＝4.9Hz,1H),8.59(d,J＝2.2Hz,1H),8.55(d,J＝4.9Hz,0.45H),8.46(s,0.45H),7.60(dd,J＝7.6,2.1Hz,1H),7.46(dd,J＝7.7,2.0Hz,0.45H),7.34(dd,J＝7.9,4.8Hz,1H),7.26(q,J＝5.1Hz,0.45H),5.34(s,2H),4.80(s,0.9H),3.75(s,1.35H),2.95(s,3H)；13C NMR(100MHz,CDCl3):δ150.4,149.7,149.6,149.6,136.3,135.9,130.4,124.2,124.0,55.1,45.6,38.7,31.1；HRMS(ESI-TOF):calc’d for C7H9N3NaO+[M+Na+]174.0638,found174.0639。
实施例17：化合物I-17的制备
Figure BDA0004055234710000103
操作步骤同实施例1，区别在于所使用的有机胺为N-烯丙基苄胺(29.4mg)，得化合物I-17(黄色油状液体，66％产率)。1H NMR(400MHz,CDCl3):δ7.36–7.32(m,2H),7.29–7.23(m,2H),7.09–7.06(m,1H),5.86(ddt,J＝16.6,10.2,6.3Hz,0.51H),5.52(ddt,J＝16.5,10.2,6.1Hz,0.61H),5.33–5.27(m,0.81H),5.24(s,1.51H),5.13(dd,J＝10.3,1.3Hz,0.63H),5.00(dd,J＝17.1,1.4Hz,0.61H),4.75(s,1.03H),4.63(dt,J＝6.2,1.4Hz,1.07H),4.04(dt,J＝6.1,1.5Hz,1.22H)；13C NMR(100MHz,CDCl3):δ134.8,134.2,131.9,129.3,129.2,129.0,128.7,128.5(d,J＝7.0Hz),128.0,120.6,119.5,55.4,54.1,45.4,45.0；HRMS(ESI-TOF):calc’d for C10H12N2NaO+[M+Na+]199.0842,found 199.0839。
实施例18：化合物I-18的制备
Figure BDA0004055234710000111
操作步骤同实施例1，区别在于1H NMR(400MHz,CDCl3):δ7.58–7.52(m,2H),7.48(dd,J＝8.9,7.0Hz,2H),7.40–7.31(m,2H),3.46(s,3H)；13C NMR(100MHz,CDCl3):δ142.5,129.6,127.5,119.4,31.7；HRMS(ESI-TOF):calc’d for C7H8N2HO+[M+H+]137.0709,found137.0708。
实施例19：化合物I-19的制备
Figure BDA0004055234710000112
操作步骤同实施例1，区别在于所使用的有机胺为4-溴-N,N-二甲基苯胺(40.0mg)，得化合物I-19(黄色固体，80％产率)。1H NMR(400MHz,CDCl3):δ7.59(d,J＝8.8Hz,2H),7.43(d,J＝8.9Hz,2H),3.42(s,3H)；13C NMR(100MHz,CDCl3):δ141.5,132.7,120.8,120.5,31.3；HRMS(ESI-TOF):calc’d for C7H7N2BrHO+[M+H+]214.9815,found214.9814。
实施例20：化合物I-20的制备
Figure BDA0004055234710000113
操作步骤同实施例1，区别在于所使用的有机胺为4-二甲氨基苯甲腈(29.2mg)，得化合物I-20(黄色油状液体，75％产率)。1H NMR(400MHz,CDCl3):δ7.78(d,J＝8.9Hz,2H),7.71(d,J＝8.9Hz,2H),3.44(s,3H)；13C NMR(100MHz,CDCl3):δ145.7,133.8,118.4(d,J＝5.1Hz),110.5,30.3；HRMS(ESI-TOF):calc’d for C8H7N3HO+[M+H+]162.0662,found162.0659。
实施例21：化合物I-21的制备
Figure BDA0004055234710000121
操作步骤同实施例1，区别在于所使用的有机胺为4-溴-N-乙基-N-甲基苯胺(42.8mg)，得化合物I-21(黄色油状液体，63％产率)。1H NMR(400MHz,CDCl3):δ7.60(d,J＝8.9Hz,1H),7.43(d,J＝8.9Hz,1H),4.05(q,J＝7.1Hz,2H),1.16(t,J＝7.2Hz,2H)；13C NMR(100MHz,CDCl3):δ140.6,132.8,127.7,120.9,39.1,11.9。
实施例22：化合物I-22的制备
Figure BDA0004055234710000122
操作步骤同实施例1，区别在于所使用的有机胺为吲哚啉(23.8mg)，得化合物I-22(黄色油状液体，59％产率)。1H NMR(400MHz,CDCl3):δ7.90–7.80(m,1H),7.36–7.31(m,2H),7.25–7.21(m,1H),4.19–4.12(m,2H),3.25–3.18(m,2H)；13C NMR(100MHz,CDCl3):δ141.0,132.2,128.5,127.2,126.3,112.3,46.3,26.2；HRMS(ESI-TOF):calc’d for C8H8N2HO+[M+H+]149.0704,found 149.0704。
实施例23：化合物I-23的制备
Figure BDA0004055234710000123
操作步骤同实施例1，区别在于所使用的有机胺为1,2,3,4-四氢喹啉(26.6mg),得化合物I-23(黄色固体，40％产率)。1H NMR(400MHz,CDCl3):δ8.07(d,J＝8.1Hz,1H),7.33–7.26(m,2H),7.22(d,J＝4.1Hz,1H),3.90(t,J＝6.4Hz,2H),2.88–2.73(m,2H),2.01(p,J＝6.3Hz,2H)；13C NMR(100MHz,CDCl3):δ137.7,129.3,127.8,127.0,126.4,116.5,42.6,27.3,21.0；HRMS(ESI-TOF):calc’d for C9H0N2HO+[M+H+]163.0866,found 163.0866。
实施例24：化合物I-24的制备
Figure BDA0004055234710000124
操作步骤同实施例1，区别在于所使用的有机胺为N,N-二甲基乙二胺(17.6mg)，硝化试剂B增加到2.0当量，于25℃反应16h，得化合物I-24(黄色油状液体，62％产率)。1H NMR(400MHz,CDCl3):δ4.54(s,6H),4.28(t,J＝6.2Hz,2.4H),3.96(t,J＝6.2Hz,2.4H),3.79(s,3H),3.75(s,1.3H),3.70(s,1H),3.07(s,6H),3.04(s,3H)；13C NMR(100MHz,CDCl3):δ51.3,49.4,42.9,41.5,40.1,39.6,32.4,31.9；HRMS(ESI-TOF):calc’d for C4H10N4NaO2 +[M+Na+]169.0696,found 169.0693。
实施例25：化合物I-25的制备
Figure BDA0004055234710000131
操作步骤同实施例1，区别在于所使用的有机胺为卡维地洛(81.3mg)，得化合物I-25(黄色油状液体，65％产率)。1H NMR(400MHz,CDCl3):δ8.33(d,J＝7.8Hz,0.7H),8.29(d,J＝7.8Hz,1H),8.15(d,J＝6.0Hz,1.4H),7.37(ddd,J＝8.3,3.9,1.5Hz,3H),7.34–7.29(m,2H),7.17(dddd,J＝9.0,8.0,6.5,1.6Hz,2H),7.06(dd,J＝8.1,5.4Hz,2H),6.99–6.91(m,2H),6.89(dd,J＝4.7,2.7Hz,2H),6.83(dt,J＝7.8,2.1Hz,2H),6.69(d,J＝8.0Hz,1H),6.64(d,J＝8.0Hz,0.7H),4.77(ddd,J＝14.8,10.7,4.4Hz,3H),4.67(ddd,J＝14.6,6.3,3.7Hz,1H),4.55(dd,J＝14.6,9.0Hz,1H),4.50–4.38(m,4H),4.37–4.30(m,2H),4.28–4.17(m,5H),4.11(ddd,J＝12.7,5.9,2.9Hz,1H),4.00(dd,J＝13.7,7.8Hz,0.7H),3.77(s,3H),3.72(s,2H)；13C NMR(100MHz,CDCl3):δ155.0,155.0,149.6,148.9,147.5,147.4,141.1,138.9(d,J＝2.8Hz),126.8,125.3,125.3,123.2,123.1,122.6,122.4,122.1,121.2,121.1,112.0,114.0,113.1,112.9,112.8,111.9,111.6,110.2,110.2,104.3,104.3,101.4,70.3,70.1,69.1,68.8,68.4,65.4,58.3,55.8,55.7,53.5,49.7,46.6；
HRMS(ESI-TOF):calc’d for C24H25N3HO5 +[M+H+]436.1867,found 436.1865。
实施例26：化合物I-26的制备
Figure BDA0004055234710000132
操作步骤同实施例1，区别在于所使用的有机胺为曲昔匹特(58.9mg)，得化合物I-26(白色固体，54％产率)。1H NMR(400MHz,CDCl3):δ6.96(s,1H),6.92(s,1H),6.47(d,J＝7.5Hz,0.5H),6.34(d,J＝7.2Hz,0.5H),4.55(dd,J＝13.1,4.0Hz,0.5H),4.44–4.23(m,1H),4.13(ddd,J＝20.7,13.0,5.3Hz,2H),3.85(d,J＝3.9Hz,9H),3.76–3.61(m,1H),2.15–2.02(m,1H),2.00–1.90(m,0.5H),1.89–1.67(m,1.5H),1.58(ddd,J＝9.8,7.0,3.8Hz,0.5H)；13C NMR(100MHz,CDCl3):δ167.2,167.0,153.3(d,J＝2.1Hz),141.2(d,J＝9.2Hz),129.6,129.5,104.7,104.6,61.0,56.5(d,J＝3.6Hz),54.3,50.3,46.7,46.4,43.8,39.4,29.7,29.6,23.4,21.6；HRMS(ESI-TOF):calc’d for C15H21N3HO5 +[M+H+]324.1554,found324.1559。
实施例27：化合物I-27的制备
Figure BDA0004055234710000141
操作步骤同实施例1，区别在于所使用的有机胺为沃替西汀(59.7mg)，得化合物I-27(白色固体，57％产率)。1H NMR(400MHz,CDCl3):δ7.37(d,J＝7.8Hz,1H),7.17(d,J＝2.0Hz,1H),7.12–7.02(m,2H),7.00(dd,J＝7.9,1.5Hz,1H),6.92(td,J＝7.6,1.4Hz,1H),6.56(dd,J＝7.9,1.5Hz,1H),4.58–4.35(m,2H),4.15–3.90(m,2H),3.28(t,J＝5.1Hz,2H),3.04(t,J＝5.3Hz,2H),2.37(s,3H),2.33(s,3H)；13C NMR(100MHz,CDCl3):δ148.0,142.4139.7,136.2,134.9,132.0,128.1,127.5,126.7,125.9,125.5,120.3,52.3,50.8,50.5,40.3,21.4,20.8；HRMS(ESI-TOF):calc’d for C18H21N3SHO+[M+H+]328.1478,found328.1478。
实施例28：化合物I-28的制备
Figure BDA0004055234710000142
操作步骤同实施例1，区别在于所使用的有机胺为氟西汀(61.9mg)，得化合物I-28(无色油状液体，57％产率)。1H NMR(400MHz,CDCl3):δ7.44(dd,J＝9.0,3.0Hz,2.66H),7.39–7.27(m,4.06H),6.88(dd,J＝9.1,2.9Hz,2.94H),5.22(dd,J＝8.4,4.2Hz,2.56H),5.12(dd,J＝8.5,4.4Hz,1H),4.41(dt,J＝14.3,7.3Hz,0.33H),4.30(ddd,J＝13.8,7.7,5.8Hz,1H),3.84–3.76(m,0.66H),3.75(s,1H),3.07(s,3H),2.45(dtd,J＝14.0,8.0,5.8Hz,1H),2.30(dtd,J＝14.5,7.4,4.2Hz,1H),2.19–2.04(m,0.66H)；13C NMR(150MHz,CDCl3):δ160.2,160.1,140.0,139.0,129.2,129.1,128.5,128.4,127.02(q,J＝3.7Hz),125.9,125.9,124.4(d,J＝269.7Hz),123.4(q,J＝32.7Hz),78.1,77.6,50.6,42.6,39.7,37.2,34.7,32.0；19F NMR(376MHz,CDCl3):δ-61.64(d,J＝5.7Hz)；HRMS(ESI-TOF):calc’dfor C17H17N2F3HO2 +[M+H+]339.1315,found339.1314。
实施例29：化合物I-29的制备
Figure BDA0004055234710000151
操作步骤同实施例1，区别在于所使用的有机胺为L-脯氨酸甲酯(25.8mg)，得化合物I-29(黄色油状液体，75％产率)。1H NMR(400MHz,CDCl3):δ5.28(dd,J＝8.2,3.4Hz,0.55H),4.56-4.48(m,1H),4.45(q,J＝6.3,5.8Hz,1H),4.42-4.32(m,1H),3.79(s,1.76H),3.71(s,3H),3.69-3.58(m,1H),2.33(tdd,J＝13.1,7.3,3.6Hz,2H),2.21(t,J＝6.3Hz,1H),2.14 -1.99(m,3H)；
13C NMR(100MHz,CDCl3):δ171.1,169.3,62.1,58.1,53.1,52.7,50.1,45.8,29.1,28.0,23.4,21.3；HRMS(ESI-TOF):calc’d for C6H10N2HO3 +[M+H+]181.0584,found181.0580。
实施例30：化合物I-30的制备
Figure BDA0004055234710000152
操作步骤同实施例1，区别在于所使用的有机胺为N-甲基丙氨酸甲酯盐酸盐(38.1mg)，溴化物为2-溴-3-甲基-N-(2-叔丁基-4-苯基苯基)苯甲酰胺(30.7mg)，得化合物I-30(黄色油状液体，59％产率)。1H NMR(400MHz,CDCl3):5.50(q,J＝7.4Hz,1H),5.22(q,J＝7.4Hz,0.33H),3.80(s,1H),3.78(s,3H),3.70(s,1H),3.02(s,3H),1.68(d,J＝7.4Hz,3H),1.43(d,J＝7.4Hz,1H)；13C NMR(150MHz,CDCl3):δ169.9,168.6,59.7,52.0,51.8,49.9,35.3,28.6,14.8,12.3；HRMS(ESI-TOF):calc’d for C5H10N2HO3 +[M+H+]147.0764,found 147.0760。
实施例31：化合物I-31的制备
Figure BDA0004055234710000153
操作步骤同实施例1，区别在于所使用的碘化物为L-脯氨酰-L-苯丙酰-L-戊酸甲酯(71.5mg)，得化合物I-31(黄色油状液体，40％产率)。1H NMR(400MHz,CDCl3):δ7.32–7.20(m,3H),7.22–7.12(m,2H),6.63(dd,J＝16.0,7.8Hz,1H),6.34(t,J＝9.3Hz,1H),5.14(dd,J＝8.3,2.8Hz,0.36H),4.77–4.63(m,1H),4.60(q,J＝7.4Hz,0.72H),4.44(ddd,J＝8.2,5.0,2.5Hz,1H),4.39(td,J＝6.6,6.0,2.0Hz,0.38H),4.20–4.08(m,0.75H),3.71(d,J＝2.8Hz,3H),3.57(dt,J＝14.3,8.5Hz,0.46H),3.45(ddd,J＝14.1,7.1,2.8Hz,0.42H),3.19–3.07(m,1H),3.09–2.95(m,1H),2.35(dd,J＝6.7,3.2Hz,0.4H),2.26(dt,J＝9.6,4.9Hz,0.73H),2.19–1.93(m,4H),1.93–1.84(m,1H),1.82–1.53(m,2H),0.88(dd,J＝6.9,2.5Hz,3.52H),0.84(dd,J＝6.9,3.7Hz,4H)；13C NMR(100MHz,CDCl3):δ170.9,169.4(d,J＝4.8Hz),168.6,166.9,135.5,135.3,128.5,128.5,127.9,127.8,126.3,126.2,62.4,58.7,56.6,53.9(d,J＝2.2Hz),51.3(d,J＝5.0Hz),49.6,45.3,45.0,36.9(d,J＝6.0Hz),30.3(d,J＝4.9Hz),27.5,26.0,22.2,18.0,16.9(d,J＝5.0Hz)；HRMS(ESI-TOF):calc’d forC20H28N4HO5 +[M+H+]405.2132,found 405.2128。
实施例32：化合物I-32的制备
Figure BDA0004055234710000161
操作步骤同实施例1，区别在于所使用的有机胺为L-脯氨酰-L-苯丙氨酰甘氨酸甲酯(38.1mg)，溴化物为2-溴-3-甲基-N-(2-叔丁基-4-苯乙烯基苯基)苯甲酰胺(66.7mg)，得化合物I-32(黄色油状液体，37％产率)。1H NMR(400MHz,CDCl3):δ7.35–7.21(m,3.6H),7.20–7.09(m,2H),6.70(dd,J＝43.8,8.0Hz,1H),6.51(dt,J＝35.1,5.4Hz,1H),5.14(dd,J＝8.3,2.8Hz,0.35H),4.76(td,J＝8.2,6.5Hz,0.35H),4.65(ddd,J＝8.0,5.1,2.9Hz,1H),4.46–4.30(m,0.67H),4.20–4.08(m,0.67H),4.07–3.98(m,1H),3.98–3.89(m,1H),3.73(s,3H),3.55(dt,J＝10.3,7.0Hz,0.34H),3.42(ddd,J＝14.4,8.6,3.4Hz,0.34H),3.18(ddd,J＝14.1,6.5,2.8Hz,1H),3.09(q,J＝7.3Hz,0.64H),3.00(ddd,J＝14.0,8.0,3.4Hz,1H),2.33(ddd,J＝13.1,6.7,3.3Hz,0.41H),2.26–2.09(m,1H),2.10–1.93(m,2H),1.87(ddq,J＝13.1,7.4,3.6Hz,0.42H),1.64(dddd,J＝15.1,8.9,7.5,4.4Hz,0.34H)；13C NMR(100MHz,CDCl3):δ170.8(d,J＝5.0Hz),170.1(d,J＝4.3Hz),169.7,168.0,136.6,136.5,129.5,129.3,128.9,128.8,127.3,127.2,63.6,59.8,54.7(d,J＝2.8Hz),52.6(d,J＝4.1Hz),50.6,46.3,46.0,41.4,37.9,37.8,28.4,27.0,23.1,21.2；HRMS(ESI-TOF):calc’d forC17H22N4HO5 +[M+H+]363.1663,found 363.1656。
实施例33：化合物I-28的克级制备
Figure BDA0004055234710000171
在氩气氛围下，向干燥并装有磁力搅拌子的50mL反应管中加入卡维地洛(2.03g，5.0mmol)、1,4-二硝基吡唑(790.0mg,5mmol)和六氟异丙醇(10.0mL)，所得混合物于80℃反应16小时。反应结束后冷却至室温，混合物减压蒸馏除去溶剂，柱层析分离纯化得化合物I-1(黄色油状液体，1.48g，68％产率)。
以上所述，仅为本发明较佳的具体实施方式，但本发明保护的范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内所做的任何修改，等同替换和改进等，均应包含在发明的保护范围之内。

Claims (10)

1.一种合成N-NO化合物的方法，其特征在于，包括以下步骤：
在保护气体氛围下，以有机胺A为起始原料，加入硝化试剂B，于有机溶剂C中搅拌反应至完全，反应结束后将反应物分离即可得到式I所示的N-NO类化合物；
反应方程式如下：
Figure FDA0004055234700000011
R1、R2为各自独立的基团或者两者形成环状基团；若R1、R2均为独立基团，则选自氢、烷基、取代烷基、环烷基、芳基及取代芳基；若R1、R2形成环状基团，则环状基团选自环烷基、取代环烷基、杂环烷基和取代杂环烷基；
R3为氢、烷基；
R4为烷基、羟基、巯基、硅基、氨基、氰基、硝基、-COR中的一种或几种；其中，R为烷基；
x表示R4的个数，0≤x≤3；当x≥2时，两个基团可以相同也可以不同。
2.根据权利要求1所述的方法，其特征在于：R1、R2均为独立基团，烷基为C1-C4的烷基；取代烷基为
Figure FDA0004055234700000012
R5、R6独立地选自氢、C1-C4的烷基，R7选自氢、C1-C4的烷基、C1-C4的烷氧基、呋喃基、吡啶基、C1-C4的烯基、C1-C4的烷基胺、C6-C12的芳基、
Figure FDA0004055234700000013
-COOMe；环烷基为C6-C12的环烷基；芳基为C6-C12的芳基；取代芳基为-Ar-R8，R8选自卤素、氰基。
3.根据权利要求1所述的方法，其特征在于：R1、R2形成环状基团，环烷基为C6-C12的环烷基；取代环烷基结构式为-C-R9，其中环烷基为C5-C12的环烷基，R9为环己基、苯基、
Figure FDA0004055234700000014
-COOMe、
Figure FDA0004055234700000015
杂环烷基为含有N、S或O的C5-C7的环烷基；取代杂环烷基结构式为-N-R10，其中，杂环烷基为C5-C7的环烷基，R10为甲磺酰基、苯甲酰基、苯基。
4.根据权利要求1所述的方法，其特征在于：所述R3中，烷基为C1-C6的烷基。
5.根据权利要求1所述的方法，其特征在于：所述R4中，烷基为C1-C6的烷基；-COR中，R为C1-C6的烷基。
6.根据权利要求1所述的方法，其特征在于：所述溶剂C为甲醇、乙醇、异丙醇、叔丁醇、六氟异丙醇、四氢呋喃、2-甲基四氢呋喃、***、二甲基乙二醚、甲基叔丁基醚、1,4-二氧六环、1,3-二氧六环、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、C4-12的饱和烷烃、C3-12的氟代或者氯代烷烃、苯、甲苯、二甲苯、三甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、N-甲基吡咯烷酮、乙腈、C3-12的饱和烷基腈中的任意一种或几种。
7.根据权利要求1所述的方法，其特征在于：所述保护气体为氩气或氮气。
8.根据权利要求1所述的方法，其特征在于：所述反应温度为25-100℃。
9.根据权利要求1所述的方法，其特征在于：所述反应时间为1-72h。
10.根据权利要求1所述的方法，其特征在于：所述反应物分离的方法为将反应混合物浓缩和柱层析纯化。
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