CN111116416B - 一种β-氨基丙烯腈类化合物的制备方法 - Google Patents
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明公开了一种β‑氨基丙烯腈类化合物的制备方法。它包括如下步骤：在溶剂中，如式Ⅰ所示的β‑氨基氰基丙烯酸酯在催化剂作用下进行反应，即得到如式Ⅱ所示的β‑氨基丙烯腈类化合物；
其中，R1为C1‑C12烷基、卤代C1‑C12烷基、C3‑C12环烷基、C2‑C12烯基、C2‑C12炔基、芳基、取代芳基、苄基或取代苄基；R2为氢、卤素、羟基、氨基、氰基、硝基、C1‑C12烷基或卤代C1‑C12烷基。本发明具有立体选择性好、收率高、原料β‑氨基氰基丙烯酸酯制备简单等特点，具有极大的实用价值。
Description
技术领域
本发明涉及一种β-氨基丙烯腈类化合物的制备方法，属于农药及医药重要中间体制备领域。
背景技术
β-氨基丙烯腈类化合物作为极化乙烯的一种，是合成噻唑类、喹诺啉类、吲哚类以及阿扎杂环类的重要中间体。同时也可以通过不对称催化氢化合成手性β-氨基腈，用于模拟肽骨架结构的构建。多年来β-氨基丙烯腈类化合物由于其灵活的反应特点受到了广泛的关注，但是目前该类化合物的合成方法报道较少。而关于β-氨基丙烯腈类化合物立体选择性的控制及构型确证更是鲜有报道。
Scheme 1：β-氨基丙烯腈类化合物合成路线
β-氨基丙烯腈类化合物通常通过α-氰基酮(Scheme 1(a),Journal of MedicinalChemistry 62(2019)5276-5297.)，苯基丙烯腈(Scheme 1(b),ChemistrySelect 1(2016)119–121.)或3-氨基-3-苯基丙烯腈为原料合成(Scheme 1(c),European Journal ofOrganic Chemistry 24(2008)4139–4147.)。文献Organic letters 11(2019)2956报道了α-氰基酮与苯胺在醋酸催化下反应得到了E型和Z型β-氨基丙烯腈类化合物混合物(minor:major＝45:55)。文献Organic letters 18(2016)1422–1425报道了苯基丙烯腈和苯胺在Cu(CF3SO3)2催化下得到了混合的β-氨基丙烯腈类化合物(E:Z＝44:56)。但是目前所报道的这些方法都是得到的E/Z构型的混合物，不能够很好解决产物几何构型选择性问题。
发明内容
本发明的目的是提供一种β-氨基丙烯腈类化合物的制备方法，本发明具有立体选择性好、收率高、原料β-氨基氰基丙烯酸酯制备简单等特点，具有极大的实用价值。
本发明是以β-氨基氰基丙烯酸酯为基本原料，在碱性催化剂催化下合成β-氨基丙烯腈类化合物，创新性的选用了β-氨基氰基丙烯酸酯结构的底物参与反应，得到了以E式结构为主的β-氨基丙烯腈类化合物，本发明的制备方法具有方法简化流畅，反应无苛刻条件，三废易于处理，生产循环快等特点，适合应用于工业化生产。
本发明提供的一种β-氨基丙烯腈类化合物的制备方法，包括如下步骤：在溶剂中，如式Ⅰ所示的β-氨基氰基丙烯酸酯在催化剂作用下进行反应，即得到如式Ⅱ所示的β-氨基丙烯腈类化合物；
其中，R1为C1-C12烷基、卤代C1-C12烷基、C3-C12环烷基、C2-C12烯基、C2-C12炔基、芳基、取代芳基、苄基或取代苄基；
R2为氢、卤素、羟基、氨基、氰基、硝基、C1-C12烷基或卤代C1-C12烷基。
本发明中，所述卤代C1-C12烷基中卤素、所述卤素均为氟、氯、溴或碘元素。
上述的制备方法中，R1为C2-C8烷基、卤代C2-C8烷基、C3-C8环烷基、C2-C8烯基、C2-C8炔基、苯基、卤代苯基、甲基取代苯基、甲氧基取代苯基、苄基、卤代苄基或吡啶基取代亚甲基。
本发明中，所述取代苄基或所述卤代苄基中取代位置均为苄基的苯环上的取代。
上述的制备方法中，所述反应的温度可为20℃～160℃，时间可为6～24小时，具体可为12小时、16小时。
上述的制备方法中，所述反应的温度优选可为80℃～160℃。
上述的制备方法中，所述反应的温度更优选可为120～160℃，具体可为120℃、160℃。
上述的制备方法中，所述溶剂为有机溶剂与水的混合溶剂；
所述有机溶剂选自乙酸甲酯、N,N-二甲基甲酰胺、甲苯、二甲苯、四氢呋喃和二甲基亚砜中的至少一种，优选二甲基亚砜与水的混合溶剂。
上述的制备方法中，所述有机溶剂与所述水的体积比可为1～100:1，优选可为3:1、4:1、10:1、3～10:1、3～30:1、3～50:1或3～75:1。
上述的制备方法中，所述催化剂选自氢氧化钠、氢氧化钾、碳酸钠、碳酸铯、碳酸钾、氯化锂、溴化锂和氟化锂中的至少一种。
上述的制备方法中，所述催化剂与所述式Ⅰ所示的β-氨基氰基丙烯酸酯的摩尔比可为0.5～10:1，优选2:1、2～10:1、0.5～2:1、1～5:1或1.5～7.5:1。
上述的制备方法中，所述反应的后处理过程为将反应体系进行萃取，收集有机相减压蒸馏即得如式Ⅱ所示的β-氨基丙烯腈类化合物。
本发明中，采用本领域常规的试剂进行所述萃取，所述萃取具体采用乙酸乙酯和水进行，所述萃取后还包括对所述有机相进行水洗、饱和食盐水溶液洗涤；
所述有机相减压蒸馏所得的如式Ⅱ所示的β-氨基丙烯腈类化合物经重结晶提纯。
本发明上述方法制备得到的如式Ⅱ所示的β-氨基丙烯腈类化合物以E式构型为主，E/Z比可为3～99:1；当式Ⅱ所示的β-氨基丙烯腈类化合物为固体时，能通过重结晶得到E式构型产物；当式Ⅱ所示的β-氨基丙烯腈类化合物为液体时，能通过液相色谱或本领域其他常规方法进行分离。
本发明中，如式Ⅱ所示的β-氨基丙烯腈类化合物具体可为如式a、b、c、……、z所示的化合物以及式aa、ab、ac所示的化合物：
本发明具有以下优点：
创新性地引入β-氨基氰基丙烯酸酯作为反应底物，使用简单催化剂进行催化，使得反应立体选择性高，得到E式构型为主的产物；收率良好，操作简单，反应无苛刻条件，三废易于处理，生产循环快等特点，适合应用于工业化生产。
附图说明
图1为本发明实施例1中(E)3–苯基-3-(苯氨基)-丙烯腈(l)的单晶结构。
图2为本发明实施例3中(E)3-(叔丁氨基)-3-苯基丙烯腈(j)的单晶结构。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1：(E)3–苯基-3-(苯氨基)-丙烯腈(l)的制备
于100mL三口瓶中依次加入如式l-1所示的β-氨基氰基丙烯酸酯(8mmol,1eq)、氯化锂(16mmol,2eq)、二甲基亚砜(40mL)、水(10mL)，搅拌溶解，加热至160℃反应12小时，至原料反应完全。冷却至室温(25℃)后，加入100mL乙酸乙酯，有机相分别用(2×50mL)水和50mL饱和食盐水溶液洗涤，减压脱溶后，粗品用石油醚：乙酸乙酯＝4:1重结晶，得1.23克白色固体(E)3–苯基-3-(苯氨基)-丙烯腈(表1中l，式l)，收率70.0％。
产品经过单晶结构、1H NMR、13C NMR及MS确认：
其单晶结构如图1所示。1H NMR(300MHz,DMSO-d6)δ9.02(s,1H),7.72-7.04(m,10H),4.74(s,1H)；13C NMR(75MHz,DMSO-d6)δ160.4,140.1,135.4,130.5,129.4,128.7,128.6,124.3,122.6,121.3,65.1.HRMS(ESI-TOF)m/z:[M+H]+calcd for C15H12N2,221.1073；found,221.1068.
实施例2、(E)3-((4-甲氧苯基)氨基)-3-肉桂腈(n)的制备
于100mL三口瓶中依次加入如式n-1所示的β-氨基氰基丙烯酸酯(8mmol,1eq)、氯化锂(16mmol,2eq)、二甲基亚砜(40mL)、水(10mL)，搅拌溶解，加热至160℃反应12小时，至原料反应完全。冷却至室温后，加入100mL乙酸乙酯，有机相分别用(2×50mL)水和50mL饱和食盐水溶液洗涤，减压脱溶后，粗品用石油醚：乙酸乙酯＝4:1重结晶，得1.52克灰色固体(E)3-((4-甲氧苯基)氨基)-3-肉桂腈(表1中n,式n)，收率76.0％。
产品经过1H NMR、13C NMR及MS确认：
1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),7.63(m,2H),7.58–7.49(m,3H),7.24–7.13(m,2H),7.00–6.91(m,2H),4.42(s,1H),3.75(s,3H)；13C NMR(75MHz,DMSO-d6)δ161.5,156.6,135.5,132.6,130.4,128.6,128.6,125.2,121.6,114.7,62.8,55.4.HRMS(ESI-TOF)m/z:[M+H]+calcd for C16H14N2O,251.1179；found,251.1174.
实施例3、(E)3-(叔丁氨基)-3-苯基丙烯腈(j)的制备
于100mL三口瓶中依次加入如式j-1所示的β-氨基氰基丙烯酸酯(8mmol,1eq)、氯化锂(16mmol,2eq)、二甲基亚砜(40mL)、水(10mL)，搅拌溶解，加热至160℃反应12小时，至原料反应完全。冷却至室温后，加入100mL乙酸乙酯，有机相分别用(2×50mL)水和50mL饱和食盐水溶液洗涤，减压脱溶后，粗品用石油醚：乙酸乙酯＝4:1重结晶，得1.3克黄色固体(E)3-(叔丁氨基)-3-苯基丙烯腈(表1中j，式j)，收率81.0％。
产品经过单晶、1H NMR、13C NMR及MS确认：
其单晶结构如图1所示。1H NMR(300MHz,DMSO-d6)δ7.53–7.39(m,5H),6.44(s,1H),4.28(s,1H),1.36(s,9H)；13C NMR(75MHz,DMSO-d6)δ161.0,137.5,129.6,128.6,128.2,122.2,61.4,51.8,28.3.HRMS(ESI-TOF)m/z:[M+H]+calcd for C13H16N2,201.1386；found,201.1387.
实施例4、3-(正己胺基)-3-肉桂腈(f)的制备
于100mL三口瓶中依次加入如式f-1所示的β-氨基氰基丙烯酸酯(8mmol,1eq)、碳酸铯(16mmol,2eq)、二甲基亚砜(30mL)、水(10mL)，搅拌溶解，加热至120℃反应16小时，至原料反应完全。冷却至室温后，加入100mL乙酸乙酯，有机相分别用(2×50mL)水和50mL饱和食盐水溶液洗涤，减压脱溶后，得1.64克油状液体3-(正己胺基)-3-肉桂腈(表1中f，即式f)，E:Z＝90:10，收率90.0％。
产品经过1H NMR、13C NMR及MS确认：
1H NMR(300MHz,DMSO-d6)δ7.52–7.43(m,5H),7.07-7.04(t,J＝4.8Hz,1H),4.07(s,0.9H),3.94(s,0.1H),3.53-3.47(m,0.2H),3.06-2.99(m,1.8H),1.61-1.54(m,2H),1.38-1.31(m,6H),0.92-0.88(t,J＝6.7Hz,3H)；13C NMR(75MHz,DMSO-d6)δ162.7,136.1,129.9,128.4,128.3,122.4,58.3,43.5,31.1,27.4,26.4,22.2,14.0.HRMS(ESI-TOF)m/z:[M+H]+calcd for C15H20N2,229.1699；found,229.1699.
通过上述实施例1方法制备得到的其他β-氨基丙烯腈类化合物，其有关理化数据及NMR数据分别如表1、2所示。
表1部分化合物理化数据
注释：1表示原位反应立体选择性，HPLC检测反应原液；2表示反应总收率，以E型结构为主，含微量Z型化合物，能通过液相色谱进行分离；3表示E型结构总收率。
表2部分化合物核磁氢谱数据
Claims (10)
1.一种β-氨基丙烯腈类化合物的制备方法，包括如下步骤：在溶剂中，如式Ⅰ所示的β-氨基氰基丙烯酸酯在催化剂作用下进行反应，即得到如式Ⅱ所示的β-氨基丙烯腈类化合物；
其中，R1为C1-C12烷基、卤代C1-C12烷基、C3-C12环烷基、C2-C12烯基、C2-C12炔基、芳基、取代芳基、苄基、吡啶基取代亚甲基或取代苄基；
R2为氢、卤素、羟基、氨基、氰基、硝基、C1-C12烷基或卤代C1-C12烷基。
2.根据权利要求1所述的制备方法，其特征在于：R1为C2-C8烷基、卤代C2-C8烷基、C3-C8环烷基、C2-C8烯基、C2-C8炔基、苯基、卤代苯基、甲基取代苯基、甲氧基取代苯基、苄基或卤代苄基。
3.根据权利要求1或2所述的制备方法，其特征在于：所述反应的温度为20℃～160℃，时间为6～24小时。
4.根据权利要求3所述的制备方法，其特征在于：所述反应的温度为80℃～160℃。
5.根据权利要求4所述的制备方法，其特征在于：所述反应的温度为120～160℃。
6.根据权利要求5所述的制备方法，其特征在于：所述溶剂为有机溶剂与水的混合溶剂；
所述有机溶剂选自乙酸甲酯、N,N-二甲基甲酰胺、甲苯、二甲苯、四氢呋喃和二甲基亚砜中的至少一种。
7.根据权利要求6所述的制备方法，其特征在于：所述有机溶剂与所述水的体积比为1～100:1。
8.根据权利要求1或2所述的制备方法，其特征在于：所述催化剂选自氢氧化钠、氢氧化钾、碳酸钠、碳酸铯、碳酸钾、氯化锂、溴化锂和氟化锂中的至少一种。
9.根据权利要求1或2所述的制备方法，其特征在于：所述催化剂与所述式Ⅰ所示的β-氨基氰基丙烯酸酯的摩尔比为0.5～10:1。
10.根据权利要求1或2所述的制备方法，其特征在于：所述反应的后处理过程为将反应体系进行萃取，收集有机相减压蒸馏即得如式Ⅱ所示的β-氨基丙烯腈类化合物。
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