CN105801578B - 一种半饱和吡嗪衍生物的合成方法及应用 - Google Patents
一种半饱和吡嗪衍生物的合成方法及应用 Download PDFInfo
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- CN105801578B CN105801578B CN201610281562.7A CN201610281562A CN105801578B CN 105801578 B CN105801578 B CN 105801578B CN 201610281562 A CN201610281562 A CN 201610281562A CN 105801578 B CN105801578 B CN 105801578B
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- 239000000758 substrate Substances 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 1
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- C07—ORGANIC CHEMISTRY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
本发明属于医药化工合成技术领域,公开了一种半饱和吡嗪衍生物的合成方法及应用。所述合成方法为:在反应器中,加入化合物1、醇、金属催化剂、配体和溶剂,再加入碱为促进剂,通入惰性气体,在40~150℃下搅拌反应1~48小时后经分离提纯得到;所述的化合物1是指具有式(1)结构的化合物或3,4‑二氨基吡啶;所述的醇是指具有式(2)结构的醇、环己二醇或丙三醇。本发明以醇为原料一步合成半饱和吡嗪类化合物,并进一步制备了生物药物活性成分如6‑(2,3‑二苯基‑7,8‑二氢吡啶[2,3‑b]吡嗪‑5(6H))己酸乙酯。
Description
技术领域
本发明属于医药化工合成技术领域,具体涉及一种半饱和吡嗪衍生物的合成方法及应用。
背景技术
吡嗪类化合物在生物医药和功能性材料方面有着广泛用途,是一类备受化学家们关注的含氮杂环化合物。半饱和吡嗪类化合物是此类化学品的类似物,从药物化学和结构化学来说,半饱和的吡嗪衍生物可能具有更好的生物活性。日本化学家Yoshiizumi发现以其为骨架的羟肟酸是肝素结合性表皮生长因子的脱落抑制剂。近年来,C.S.John等人陆续发现具有四氢吡啶并吡嗪骨架的脂肪酸衍生物能够用于IP接受体,血管扩张,抗细胞增生。由于该类化合物具有特殊的不饱和氮杂环结构,很容易进行多种衍生化,是重要的合成中间体,在有机合成和功能材料领域具有广泛的用途。
传统的半饱和吡嗪类化合物的合成方法分两步进行:首先,以2,3-二氨基吡啶、邻二羰基化合物为原料,在碱或者酸的催化作用下,通过分子间缩合构建吡啶并吡嗪类化合物。然后,在10个标准大气压的氢气氛围中,利用钯碳催化还原吡啶环得到目标产物。其中,还原过程长达60小时以上,期间需要多次补加钯碳。由此可见,传统方法比较繁琐,高压氢气是严重的安全隐患,,所以在工业应用中受到极大限制(C.S.John,L.Catherine,M.S.Carl,PCT Int.062028,2011;(b)L.Catherine,M.S.Carl,C.S.John,PCT Int.050277,2013)。
近些年,关于合成半饱和吡啶并吡嗪的方法很少见诸报道,都需要两步以上的反应来合成:(1)将路易斯酸(BiCl3,ZrCl4,SnCl2等)负载在硅胶上催化2,3-二氨基吡啶和邻二羰基化合物的缩合反应(A.Kioumars,M.Farshid,S.Atena,D.Hossein Reza,G.Mitra,N.Bernhard,Journal of Organometallic Chemistry.2013,743,170-178;A.Kioumars,D.Hossein Reza,D.Hesam,Transition Metal Chemistry,2010,35,49-53.);(2)以甲苯作为溶剂,利用Au负载在碳上与氢氧化钠共同催化2,3-二氨基吡啶和邻二醇反应,催化剂可进行再回收(S.Nimesh,G.Edmond,J.Dhanaji V.,D.Eric,N.Irishi N.N.,ChemCatChem,2015,7,57-61.)。以上方法完成吡啶并吡嗪的合成后,需要经过高压氢还原步骤来得到相应的半饱和吡啶并吡嗪化合物。同时,以上技术仍然存在收率低和底物受限的问题。
发明内容
为了解决以上现有技术的缺点和不足之处,本发明的首要目的在于提供一种半饱和吡嗪衍生物的合成方法。
本发明的另一目的在于提供一种以上述方法得到的半饱和吡嗪衍生物为中间体在生物药物活性分子合成中的应用。
本发明目的通过以下技术方案实现:
一种半饱和吡嗪衍生物的合成方法,包括以下步骤:
在反应器中,加入化合物1、醇、金属催化剂、配体和溶剂,再加入碱为促进剂,通入惰性气体,在40~150℃下搅拌反应1~48小时,反应结束后冷却至室温,稀释反应液,过滤,减压蒸除溶剂得粗产物,经柱层析提纯得到半饱和吡嗪衍生物;
所述的化合物1是指具有式(1)结构的化合物或3,4-二氨基吡啶;所述的醇是指具有式(2)结构的醇、环己二醇或丙三醇;
其中,R1为甲基、咪唑取代基或氢;R2和R3为相同或者不相同的氢、甲基、乙基或苯基;X为碳原子或氮原子。
上述合成方法所涉及的部分反应方程式如下:
所述的反应器优选schlenk管(史兰克管);所述的惰性气体为氮气或氩气。
所述化合物1与醇的摩尔比为1:(1~20);优选1:1.5。
所述的金属催化剂为醋酸铜、硫酸铜、氯化铁、醋酸钯、双三苯基膦二氯化钯、环辛二烯氯化铱、三氯化铱、十二羰基三钌、二氯双(4-甲基异丙基苯基)钌和双三苯基膦-1H-茚氯化钌中的一种或两种以上的混合;所述的配体为三苯基膦、邻菲罗啉、2-双环己基膦-2',4',6'-三异丙基联苯、三环己基磷、1,4-双(二苯基膦)丁烷、2,2-联吡啶、2-苯基吡啶、1,1-双(二苯基膦)二茂铁和4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)中的一种或两种以上的混合。
所述的溶剂为乙腈、四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、甲苯、甲醇、叔戊醇和水中的一种或两种以上的混合。
所述碱为碳酸钠、碳酸钾、碳酸铯、甲醇钠、叔丁醇钾、叔丁醇钠、叔丁醇锂、四甲基乙二胺和三乙胺中的一种或两种以上的混合;碱的加入量与化合物1的摩尔比为(0.5~5):1;优选0.5:1。
所述的柱层析提纯所用的洗脱液为石油醚:乙酸乙酯的体积比为(0.5~50):1的混合溶剂。
一种以上述方法得到的半饱和吡嗪衍生物为中间体在生物药物活性分子合成中的应用,所述应用包括以下步骤:
(1)在反应器中加入所述半饱和吡嗪衍生物、醛基酸酯化合物、三乙酰氧基硼氢化钠,乙酸和溶剂,在室温下进行搅拌反应,得到烷基酸酯取代的半饱和吡嗪衍生物。
(2)将步骤(1)的产物加入到甲醇和水的混合溶液中,室温条件下加入过量的氢氧化锂水溶液,升温回流反应,得到得到烷基酸取代的半饱和吡嗪衍生物药物活性分子。
所述的生物药物活性分子是指6-(2,3-二苯基-7,8-二氢吡啶[2,3-b]吡嗪-5(6H))己酸,所述应用包括以下步骤:
(1)在反应器中加入2,3-二苯基-5,6,7,8-四氢吡啶并吡嗪、6-醛基己酸乙酯、三乙酰氧基硼氢化钠,乙酸和溶剂,在室温下搅拌反应8小时后,冲入水稀释,用乙酸乙酯萃取3次,有机相依次经洗涤、干燥、过滤和减压旋蒸去除溶剂,再通过柱层析分离纯化,得到粗产物;将粗产物投入乙醇中,降温到0℃,加入硼氢化钠,搅拌15分钟,然后用丙酮猝灭,减压旋蒸去除溶剂,冲入水稀释,用乙酸乙酯多次萃取,合并有机相,干燥,过滤,旋干得产物6-(2,3-二苯基-7,8-二氢吡啶[2,3-b]吡嗪-5(6H)-亚甲基)己酸乙酯;
(2)将步骤(1)的产物加入到甲醇和水的混合溶液中,室温条件下加入过量的氢氧化锂水溶液,升温回流反应4小时,冷却到室温,蒸除低沸点溶剂,补加水稀释,利用乙酸乙酯多次萃取,合并有机相,然后依次经过洗涤、干燥和真空旋蒸去除溶剂,得到6-(2,3-二苯基-7,8-二氢吡啶[2,3-b]吡嗪-5(6H))己酸。
本发明的制备方法及所得到的产物具有如下优点及有益效果:
本发明以醇为原料一步合成半饱和吡嗪类化合物,具有合成步骤简单、合成方法操作安全、原料无毒、价格低廉和对功能团适应性好的优点。
附图说明
图1和图2分别为实施例1所得产物的氢谱图和碳谱图;
图3和图4分别为实施例2所得产物的氢谱图和碳谱图;
图5和图6分别为实施例3所得产物的氢谱图和碳谱图;
图7和图8分别为实施例4所得产物的氢谱图和碳谱图;
图9和图10分别为实施例5所得产物的氢谱图和碳谱图;
图11和图12分别为实施例6所得产物的氢谱图和碳谱图;
图13和图14分别为实施例7所得产物的氢谱图和碳谱图;
图15和图16分别为实施例8所得中间产物的氢谱图和碳谱图;
图17和图18分别为实施例9所得目的产物的氢谱图和碳谱图;
图19和图20分别为实施例9所得目的产物的氢谱图和碳谱图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1
在schlenk管中加入0.5毫摩尔2,3-二氨基吡啶、0.75毫摩尔2,3-丁二醇、0.25毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130℃搅拌反应5小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为3:1的石油醚:乙酸乙酯混合溶剂,产率83%。
所得产物的氢谱图及碳谱图分别如图1和图2所示,结构表征数据如下:
1H NMR(400MHz,CDCl3):δ4.87(brs,1H),3.39(t,J=5.6Hz,2H),2.87(t,J=5.6Hz,2H),2.35(s,3H),2.30(s,3H),1.97-2.04(m,2H)。
13C NMR(100MHz,CDCl3):δ150.14,146.54,138.34,135.04,41.31,29.70,21.54,21.19,20.48。
IR(KBr):3260,2950,2851,1575,1510,1447,1419,1345,1214,1167,864,795,766cm-1。
MS(EI,m/z):163[M]+。
HRMS(ESI):Calcd.for C19H13N3[M+H]+:164.1182;found:164.1183。
根据以上数据推断所得产物的结构如下式所示:
实施例2
在schlenk管中加入0.5毫摩尔2,3-二氨基吡啶、0.75毫摩尔环己二醇、0.25毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130℃搅拌反应5小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为5:1的石油醚:乙酸乙酯混合溶剂,产率86%。
所得产物的氢谱图及碳谱图分别如图3和图4所示,结构表征数据如下:
1H NMR(400MHz,CDCl3):δ4.88(brs,1H),3.40(s,2H),2.88(s,2H),2.75(s,2H),2.68(s,2H),2.02(s,2H),1.83(s,4H)。
13C NMR(101MHz,CDCl3):δ150.11,147.11,139.24,136.15,41.34,31.38,30.72,29.98,23.21,22.90,21.53。
IR(KBr):3248,2940,2859,1580,1505,1440,1345,1165,1065,1069,760,668cm-1。
MS(EI,m/z):189[M]+。
HRMS(ESI):Calcd.for C11H15N3[M+H]+:190.1339;found:190.1339。
根据以上数据推断所得产物得结构如下式所示:
实施例3
在schlenk管中加入0.5毫摩尔2,3-氨基吡啶、0.75毫摩尔1,2-二苯基乙二醇、0.25毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在140℃搅拌反应15小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率71%。
所得产物的氢谱图及碳谱图分别如图5和图6所示,结构表征数据如下:
1H NMR(400MHz,CDCl3):δ7.10-7.29(m,10H),5.42(brs,1H),3.26(t,J=5.2Hz,2H),2.94(t,J=6.4Hz,2H),1.96-2.00(m,2H)。
13C NMR(101MHz,CDCl3):δ150.48,148.01,140.37,139.57,139.46,137.31,129.60,129.52,128.06,127.99,127.86,126.95,41.25,30.14,21.36。
IR(KBr):3240,3057,2950,2856,1580,1498,1448,1418,1346,1236,1171,1068,1007,771,735,698cm-1。
MS(EI,m/z):287[M]+。
HRMS(ESI):Calcd.for C19H17N3[M+H]+:288.1495;found:288.1499。
根据以上数据推断所得产物得结构如下式所示:
实施例4
在schlenk管中加入0.5毫摩尔6-甲基-2,3-二氨基吡啶、0.75毫摩尔2,3-丁二醇、0.25毫摩尔叔丁醇钾、0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇、充入N2保护,在130℃搅拌反应15小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为3:1的石油醚:乙酸乙酯混合溶剂,产率65%。
所得产物的氢谱图及碳谱图分别如图7和图8所示,结构表征数据如下:
1H NMR(400MHz,CDCl3):δ4.56(brs,1H),3.55(s,1H),2.87(t,J=6.4Hz,2H),2.35(s,3H),2.30(s,3H),1.90-2.15(m,1H),1.60-1.74(m,1H),1.25(d,J=6.4Hz,3H)。
13C NMR(101MHz,CDCl3):δ149.83,146.57,138.42,134.82,47.00,29.36,28.67,22.16,21.20,20.47。
IR(KBr):3259,2933,2859,1564,1431,1338,1178,980,765cm-1。
MS(EI,m/z):177[M]+。
HRMS(ESI):Calcd.for C10H15N3[M+H]+:178.1339;found:178.1339。
根据以上数据推断所得产物得结构如下式所示:
实施例5
在schlenk管中加入0.5毫摩尔4-甲基-2,3-二氨基吡啶、0.75毫摩尔环己二醇、0.5毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130℃搅拌反应10小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为5:1的石油醚:乙酸乙酯混合溶剂,产率62%。
所得产物的氢谱图及碳谱图分别如图9和图10所示,结构表征数据如下:
1H NMR(400MHz,CDCl3):δ5.13(brs,1H),3.31(s,2H),3.38-3.50(m,2H),2.97-3.13(m,1H),2.77(s,3H),2.69(s,3H),2.00-2.11(m,1H),1.66-1.95(m,5H),1.32(d,J=6.8Hz,3H)。
13C NMR(101MHz,CDCl3):δ149.53,146.91,140.11,139.16,38.22,33.36,31.38,30.75,28.87,23.24,22.90,20.05。
IR(KBr):3243,2926,2859,1581,1508,1436,1344,1183,672cm-1。
MS(EI,m/z):203[M]+。
HRMS(ESI):Calcd.for C12H17N3[M+H]+:204.1495;found:204.1498。
根据以上数据推断所得产物得结构如下式所示:
实施例6
在schlenk管中加入0.5毫摩尔4-甲基-2,3-二氨基吡啶、0.75毫摩尔乙二醇、0.25毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130℃搅拌反应12小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为12:1的石油醚:乙酸乙酯混合溶剂,产率70%。
所得产物的氢谱图及碳谱图分别如图11和图12所示,结构表征数据如下:
1H NMR(400MHz,CDCl3):δ7.30(s,1H),6.28(s,1H),4.96(brs,1H),3.53(brs,1H),3.40(s,2H),3.33(s,2H),1.95(s,3H)。
13C NMR(101MHz,CDCl3):δ146.67,136.27,127.69,126.93,116.14,40.70,16.06。
IR(KBr):3228,2923,2854,1605,1575,1488,1352,1232,1135,1065,845,793cm-1。
MS(EI,m/z):149[M]+。
HRMS(ESI):Calcd.for C8H11N3[M+H]+:105.1026;found:105.1025。
根据以上数据推断所得产物得结构如下式所示:
实施例7
在schlenk管中加入0.5毫摩尔6-(1H-咪唑基)-2,3-二氨基吡啶、0.75毫摩尔乙二醇、0.25毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130℃搅拌反应12小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为1:1的石油醚:乙酸乙酯混合溶剂,产率41%。
所得产物的氢谱图及碳谱图分别如图13和图14所示,结构表征数据如下:
1H NMR(400MHz,CDCl3):δ8.12(s,1H),7.43(s,1H),7.12(s,1H),6.70(d,J=7.2Hz,1H),6.47(d,J=7.2Hz,1H),5.06(brs,1H),3.53(t,J=4.4Hz,2H),3.47(brs,1H),3.39(t,J=4.4Hz,2H)。
13C NMR(101MHz,CDCl3):δ146.16,139.01,134.66,129.23,127.67,120.23,116.53,101.71,40.69,40.10。
IR(KBr):3251,2922,2853,1611,1484,1352,1311,1274,1227,1122,1058,1000,801,753,656cm-1。
MS(EI,m/z):201[M]+。
HRMS(ESI):Calcd.for C10H11N5[M+H]+:202.1087;found:202.1090。
根据以上数据推断所得产物得结构如下式所示:
实施例8
在schlenk管中加入0.5毫摩尔2,3-二氨基吡嗪,0.75毫摩尔乙二醇、0.25毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130℃搅拌反应12小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为1:3的石油醚:乙酸乙酯混合溶剂,产率41%。
所得中间产物的氢谱图及碳谱图分别如图15和图16所示,结构表征数据如下:
1H NMR(400MHz,CDCl3):δ7.09(s,2H),6.66(s,2H),3.30(s,4H)。
13C NMR(101MHz,CDCl3):δ145.17,129.79,40.55。
IR(KBr):3212,2927,2868,1598,1544,1445,1363,1308,1230,1181,965,808,744cm-1。
MS(EI,m/z):136[M]+。
HRMS(ESI):Calcd.for C6H8N4[M+H]+:137.0821;found:137.0822。
根据以上数据推断所得中间产物的结构如下式所示:
实施例9
在schlenk管中加入0.5毫摩尔3,4-二氨基吡啶,0.75毫摩尔2,3-丁二醇、0.25毫摩尔叔丁醇钾,0.005毫摩尔十二羰基三钌、0.015毫摩尔4,5-双二苯基膦-9,9-二甲基氧杂蒽、1.2毫升叔戊醇,充入N2保护,在130℃搅拌反应12小时后,停止加热及搅拌,冷却至室温,稀释反应液,过滤,减压旋蒸去除溶剂,再通过柱层析分离纯化,得到目标产物,所用的柱层析洗脱液为体积比为1:2的石油醚:乙酸乙酯混合溶剂,产率39%。
所得中间产物的氢谱图及碳谱图分别如图17和图18所示,结构表征数据如下:
1H NMR(400MHz,CDCl3):δ4.06(s,2H),8.02(s,1H),3.22(t,J=6.0Hz,2H),2.93(t,J=6.0Hz,2H),2.50(s,3H),2.49(s,3H)。
13C NMR(101MHz,CDCl3):δ149.68,149.13,147.54,146.97,49.80,43.60,31.70,21.69,21.57。
IR(KBr):3294,2927,2855,1673,1560,1447,1406,1226,1166,1013,822,749cm-1。
MS(EI,m/z):163[M]+。
HRMS(ESI):Calcd.for C9H13N3[M+H]+:164.1182;found:164.1183。
根据以上数据推断所得中间产物的结构如下式所示:
实施例10
(1)在反应器中加入2.0毫摩尔实施例3所得2,3-二苯基-5,6,7,8-四氢吡啶并吡嗪、3.0毫摩尔6-醛基己酸乙酯、3.0毫摩尔三乙酰氧基硼氢化钠,2.0毫摩尔乙酸和10毫升二氯甲烷,在室温下搅拌反应8小时后,冲入少量水稀释,用乙酸乙酯萃取3次,有机依次经洗涤、干燥、过滤和减压旋蒸去除溶剂,再通过柱层析分离纯化,得到粗产物;将粗产物投入乙醇中,降温到0℃,加入硼氢化钠,搅拌15分钟,低温下用少量丙酮猝灭,减压旋蒸去低溶剂,冲入水稀释,用乙酸乙酯多次萃取,合并有机相,干燥,过滤,旋干得目标产物6-(2,3-二苯基-7,8-二氢吡啶[2,3-b]吡嗪-5(6H))己酸乙酯,收率68%。
(2)将步骤(1)的1.3毫摩尔产物加入到30毫升四氢呋喃、10毫升甲醇和10毫升水的混合溶液中,室温条件下加入10毫升的7.8毫摩尔氢氧化锂水溶液,升温回流反应4小时,冷却到室温,旋掉低沸点溶剂,补加少量水稀释,利用乙酸乙酯多次萃取,合并有机相,然后依次经过洗涤、干燥和真空旋蒸去除溶剂,得到6-(2,3-二苯基-7,8-二氢吡啶[2,3-b]吡嗪-5(6H))己酸,收率95%。
所得目标产物的氢谱图及碳谱图分别如图19和图20所示,结构表征数据如下:
1H NMR(400MHz,CDCl3):δ7.35-7.45(m,2H),7.28-7.34(m,2H),7.16-7.24(m,6H),3.66(t,J=7.2Hz,2H),3.44(d,J=5.6Hz,2H),3.01(t,J=6.4Hz,2H),2.32(t,J=7.2Hz,2H),2.04-2.12(m,2H),1.65-1.73(m,4H),1.36-1.45(m,2H)。
13C NMR(101MHz,CDCl3):δ179.36,150.22,147.45,139.80,139.76,138.12,137.42,129.84,129.59,128.00,127.79,127.69,126.84,47.76,34.00,30.51,26.67,26.44,24.52,21.18。
IR(KBr):3056,2934,2859,1709,1558,1496,1448,1368,1346,1232,1177,1071,1018,800,770,700cm-1。
MS(EI,m/z):401[M]+。
HRMS(ESI):Calcd.for C25H27N3O2[M+H]+:402.2176;found:402.2180。
根据以上数据推断所得目标产物得结构如下式所示:
本实施例所涉及的反应方程式如下:
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其它的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (7)
1.一种半饱和吡嗪衍生物的合成方法,其特征在于包括以下步骤:
在反应器中,加入化合物1、醇、金属催化剂、配体和溶剂,再加入碱为促进剂,通入惰性气体,在40~150℃下搅拌反应1~48小时,反应结束后冷却至室温,稀释反应液,过滤,减压蒸除溶剂得粗产物,经柱层析提纯得到半饱和吡嗪衍生物;
所述的化合物1是指具有式(1)结构的化合物;所述的醇是指具有式(2)结构的醇;
上述合成方法的反应方程式如下:
其中,R1为甲基、咪唑取代基或氢;R2和R3为相同或者不相同的氢、甲基、乙基或苯基;X为碳原子或氮原子;
所述的金属催化剂为十二羰基三钌;所述的配体为4,5-双二苯基膦-9,9-二甲基氧杂蒽。
2.根据权利要求1所述的一种半饱和吡嗪衍生物的合成方法,其特征在于:所述的反应器是指schlenk管;所述的惰性气体为氮气或氩气。
3.根据权利要求1所述的一种半饱和吡嗪衍生物的合成方法,其特征在于:所述化合物1与醇的摩尔比为1:(1~20)。
4.根据权利要求3所述的一种半饱和吡嗪衍生物的合成方法,其特征在于:所述化合物1与醇的摩尔比为1:1.5。
5.根据权利要求1所述的一种半饱和吡嗪衍生物的合成方法,其特征在于:所述的溶剂为乙腈、四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、甲苯、甲醇、叔戊醇和水中的一种或两种以上的混合。
6.根据权利要求1所述的一种半饱和吡嗪衍生物的合成方法,其特征在于:所述碱为碳酸钠、碳酸钾、碳酸铯、甲醇钠、叔丁醇钾、叔丁醇钠、叔丁醇锂、四甲基乙二胺和三乙胺中的一种或两种以上的混合;碱的加入量与化合物1的摩尔比为(0.5~5):1。
7.根据权利要求6所述的一种半饱和吡嗪衍生物的合成方法,其特征在于:所述碱的加入量与化合物1的摩尔比为0.5:1。
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