CN111777529A - 一种1,4/1,5-氨基醇化合物及其制备方法 - Google Patents
一种1,4/1,5-氨基醇化合物及其制备方法 Download PDFInfo
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Abstract
本发明属于化学合成领域,涉及一种1,4/1,5‑氨基醇新化合物及其制备方法。本发明合成的1,4/1,5‑氨基醇化合物具有下式的结构:本发明所述制备1,4/1,5‑氨基醇化合物的技术路线,反应条件简单,路线简洁,收率较高,所用的试剂均为常用试剂,该方法具有高效、低成本、可兼容多种官能团,且可放大制备等特点。
Description
技术领域
本发明属于化学合成技术领域,涉及一种1,4/1,5-氨基醇新化合物及其制备方法。
背景技术
1,4和1,5-氨基醇具有氨基和羟基关键性官能团,在生物体内可与生命相关的生物大分子之间相互作用,因而成为许多天然产物及药物分子的关键中间片段,近年来也被广泛用于有机合成中的合成砌块及有机催化领域的配体化合物。例如,1,4和1,5-氨基醇结构很容易通过氧化产转化为化学药物中多用途的吡咯酰胺和哌啶酰胺合成砌块和用途更加广泛的多官能团化的呋喃衍生物片段,同时也能作为配体催化有机锌与羰基的不对称加成反应。然而,1,4/1,5-氨基醇制备方法有限,近期报道的方法主要有:Kobayashi小组实现了基于环外N,O-缩醛与烯醇硅醚进行亲核加成反应构筑1,4/1,5-氨基醇的方法(Kobayashi S.et al.J.Am.Chem.Soc.,2001,123,12510-12517);Guarna小组基于三甲基铝催化下的内酯氨解反应制备1,4-氨基醇的方法(Chan P.W.H.et al.Org.Biomol.Chem.,2016,14,844-848.);Reissig小组建立了基于二碘化钐介导的恶嗪类化合物开环反应构筑1,4-氨基醇的方法(Reissig H.U.et al.Eur.J.Org.Chem.2013,605-610);Chan小组建立了呋喃和吡喃衍生物与格氏试剂加成构筑1,4/1,5-氨基醇的新方法(ChanP.W.H.Org.Biomol.Chem.,2016,14,844-848)等。这些已知的方法都具有试剂不稳定、难于放大、副反应多、试剂危险等不同程度的局限性。因此,发展新的合成方法来实现新颖1,4和1,5-氨基醇的合成,可为新药分子及新催化剂的研发提供物质基础。
基于现有技术的现状,本申请的发明人拟提供一种1,4/1,5-氨基醇新化合物及其制备方法。
发明内容
本发明的目的是提供一类1,4/1,5-氨基醇新化合物及其制备方法。该方法具有高效、低成本、可兼容多种官能团,且可放大制备等特点。
本发明合成的1,4/1,5-氨基醇化合物,其特征在于具有如下结构式:
其中R为苄基、邻甲基苄基、间甲基苄基、对甲基苄基、邻氟苄基、间氟苄基、对氟苄基、邻三氟甲基苄基、间三氟甲基苄基、对三氟甲基苄基、间氯苄基、对氰基苄基、对乙酰氧基苄基、α-萘基、正癸基、环己基。
本发明的优选化合物是具有下述结构化合物:
(1)1,4-氨基醇化合物4Aa~o.
(2)1,5-氨基醇化合物4Ba~o.
本发明在下文的陈述中,中间体通式是根据结构式中的编号,用阿拉伯数字表示。P表示氮原子保护基,具体为-Fmoc、-Boc、-Cbz、-COOMe、-COOEt、-COPh、-COCH2CH2Ph,R表示不同芳基或烷基取代基。
具体的,本发明的制备1,4/1,5-氨基醇化合物的方法按下述技术路线和步骤:
Scheme 1
化合物3是根据文献方法制备(Kobayashi S.et al.J.Am.Chem.Soc.,2001,123,12510-12517)。
步骤1:化合物3溶于有机溶剂,在-78℃至25℃之间加入一种金属亲核试剂,搅拌5-10分钟后加入路易斯酸反应2-12h,后处理得化合物4。
本发明中,步骤1中所说的有机溶剂指四氢呋喃、乙腈、二氯乙烷、二氯甲烷、环己烷或正己烷,特别是四氢呋喃。所说的一种金属亲核试剂指芳基和烷基取代的格氏试剂、单烷基锌试剂,特别是单烷基锌试剂。所说的路易斯酸指三氟甲磺酸钪、三氟甲磺酸镍、三氟甲磺酸酮、三氟甲磺酸钐、三氟甲磺酸铟、氯化锌、四氯化钛、三氟甲磺酸三甲基硅酯、三氟化硼乙醚、三甲基氯硅烷,特别是三甲基氯硅烷。
本发明所述制备1,4/1,5-氨基醇化合物的制备技术路线,反应条件简单,路线简洁,收率较高,所用的试剂均为常用试剂,而且,可大量制备。
具体实施方式
实施例1
合成化合物4Aa
氩气保护下,化合物3A(100mg,0.53mmol)溶于干燥四氢呋喃(3mL),于-78℃下缓慢滴加新制备的邻甲基苄基溴化锌试剂(2.14mL,1M in THF,4eq.)和三甲基氯硅烷(0.14mL,2eq.),反应12小时后,向反应体系加入1N HCl(0.6mL),体系置于冰浴下搅拌15min,加水稀释,并升至室温,乙酸乙酯萃取(5mL×3),合并有机相,用饱和食盐水洗,无水硫酸镁干燥,过滤浓缩,残渣经硅胶柱层析(PE/EA=2∶1)得白色固体化合物4Aa(123mg,79%)。1H NMR(400MHz,CDCl3,rotamers)δ7.17-7.09(m,4H),4.55-4.34(m,1H),3.91-3.69(m,1H),3.66-3.59(m,2H),2.81-2.70(m,2H),2.34(s,3H),1.98(s,1H),1.69-1.54(m,3H),1.46-1.30(m,10H)ppm.
化合物4Ab~o,4Ba~o的制备方法同4Aa。
合成化合物4Ab
白色固体(112mg,72%)。1H NMR(400MHz,CDCl3,rotamers)δ7.22-7.14(m,1H),7.10-6.93(m,3H),4.49-4.19(m,1H),3.92-3.75(m,1H),3.68-3.60(m,2H),2.83-2.65(m,2H),2.33(s,3H),1.79(s,1H),1.67-1.55(m,3H),1.45-1.36(m,10H)ppm.
合成化合物4Ac
白色固体(140mg,90%)。1H NMR(400MHz,CDCl3,rotamers)δ7.12-7.04(m,4H),4.48-4.28(m,1H),3.89-3.75(m,1H),3.64-3.59(m,2H),2.79-2.66(m,2H),2.31(s,3H),1.98(s,1H),1.67-1.54(m,3H),1.45-1.36(m,10H)ppm.
合成化合物4Ad
白色固体(120mg,76%)。1H NMR(400MHz,CDCl3,rotamers)δ7.25-7.15(m,2H),7.12-6.98(m,2H),4.53-4.28(m,1H),3.95-3.72(m,1H),3.68-3.62(m,2H),2.88-2.67(m,2H),1.93(s,1H),1.70-1.57(m,3H),1.46-1.31(m,10H)ppm.
合成化合物4Ae
白色固体(144mg,91%)。1H NMR(400MHz,CDCl3)δ7.28-7.21(m,1H),6.99-6.86(m,3H),4.45(d,J=8.4Hz,1H),3.90-3.78(m,1H),3.66-3.61(m,2H),2.81-2.71(m,2H),1.98(s,1H),1.67-1.54(m,3H),1.43-1.37(m,10H)ppm.
合成化合物4Af
(140mg,89%)。1H NMR(400MHz,CDCl3,rotamers)δ7.18-7.10(m,2H),7.03-6.92(m,2H),4.46-4.26(m,1H),3.89-3.75(m,1H),3.66-3.60(m,2H),2.79-2.69(m,2H),1.90(s,1H),1.67-1.54(m,3H),1.43-1.37(m,10H)ppm.
合成化合物4Ag
白色固体(156mg,85%)。1H NMR(400MHz,CDCl3,rotamers)δ7.68-7.57(m,1H),7.50-7.27(m,3H),4.52-4.31(m,1H),4.03-3.90(m,0.8H),3.88-3.74(m,0.2H),3.71-3.62(m,2H),3.07-2.94(m,1H),2.89-2.80(m,0.8H),2.72-2.62(m,0.2H),1.90(s,1H),1.71-1.47(m,4H),1.37-1.29(m,7.2H)1.25-1.15(m,1.8H)ppm.
合成化合物4Ah
白色固体(148mg,80%)。1H NMR(400MHz,CDCl3,rotamers)δ7.52-7.35(m,4H),4.47-4.32(m,1H),3.95-3.79(m,1H),3.67-3.62(m,2H),2.91-2.75(m,2H),1.79(s,1H),1.70-1.57(m,3H),1.43-1.32(m,10H)ppm.
合成化合物4Ai
白色固体(141mg,77%)。1H NMR(400MHz,CDCl3,rotamers)δ7.58-7.51(m,2H),7.33-7.28(m,2H),4.47-4.32(m,1H),3.96-3.80(m,1H),3.67-3.62(m,2H),2.89-2.77(m,2H),1.82(s,1H),1.69-1.56(m,3H),1.43-1.33(m,10H)ppm.
合成化合物4Aj
白色固体(145mg,87%)。1H NMR(400MHz,CDCl3,rotamers)δ7.26-7.15(m,3H),7.13-7.01(m,1H),4.48-4.31(m,1H),3.90-3.77(m,1H),3.67-3.61(m,2H),2.80-2.69(m,2H),1.88(s,1H),1.69-1.55(m,3H),1.45-1.36(m,10H)ppm.
合成化合物4Ak
白色固体(132mg,83%)。1H NMR(400MHz,CDCl3,rotamers)δ7.62-7.55(m,2H),7.33-7.28(m,2H),4.45-4.27(m,1H),3.96-3.79(m,1H),3.67-3.62(m,2H),2.88-2.77(m,2H),1.67-1.54(m,4H),1.40-1.34(m,10H)ppm.
合成化合物4Al
白色固体(175mg,95%)。1H NMR(400MHz,CDCl3)δ8.01-7.93(m,2H),7.28-7.23(m,2H),4.48(d,J=8.4Hz,1H),3.39-3.33(q,2H),3.94-3.80(m,1H),3.66-3.59(m,2H),2.88-2.77(m,2H),1.96(s,1H),1.69-1.55(m,3H),1.43-1.36(m,13H)ppm.
合成化合物4Am
白色固体(60mg,34%)。1H NMR(400MHz,CDCl3,rotamers)δ8.22-8.05(m,1H),7.89-7.69(m,2H),7.57-7.45(m,2H),7.41-7.25(m,2H),4.60(d,J=7.9Hz,1H),4.07-3.88(m,1H),3.59-3.49(m,2H),3.42-3.29(m,0.8H),3.17-3.03(m,1.2H),2.01(s,1H),1.75-1.44(m,4H),1.43-1.35(m,7.2H),1.22-1.10(m,1.8H)ppm.
合成化合物4An
淡黄色油(33mg,19%)。1H NMR(400MHz,CDCl3,rotamers)δ5.58-5.48(m,0.3H),5.18-5.08(m,0.3H),4.46-4.24(m,1H),3.97-3.75(m,1H),3.69-3.63(m,2H),3.62-3.39(m,1H),2.22-2.11(m,0.7H),1.97-1.89(m,0.7H),1.64-1.54(m,3H),1.46-1.43(m,10H),1.32-1.23(m,16H),0.94-0.83(m,3H)ppm.
合成化合物4Ao
淡黄色油(35mg,24%)。1H NMR(400MHz,CDCl3,rotamers)δ5.56-5.34(m,1H),5.07(d,J=9.1Hz,1H),4.04-3.93(m,1H),3.72-3.64(m,2H),1.96-1.86(m,2H),1.78-1.67(m,5H),1.61-1.51(m,2H),1.50-1.44(m,9H),1.36-1.23(m,6H)ppm.
合成化合物4Ba
白色固体(126mg,86%)。1H NMR(400MHz,CDCl3)δ7.31-7.16(m,5H),4.35(d,J=8.4Hz,1H),1H),3.89-3.77(m,1H),3.64-3.57(m,2H),2.83-2.70(m,2H),1.59-1.44(m,5H),1.43-1.33(m,11H)ppm.
合成化合物4Bb
白色固体(130mg,84%)。1H NMR(400MHz,CDCl3,rotamers)δ7.16-7.08(m,4H),4.44-4.16(m,1H),3.88-3.67(m,1H),3.63-3.57(m,2H),2.81-2.69(m,2H),2.34(s,3H),1.67(s,1H),1.59-1.47(m,4H),1.42-1.31(m,11H)ppm.
合成化合物4Bc
白色固体(86mg,55%)。1H NMR(400MHz,CDCl3,rotamers)δ7.22-7.14(m,1H),7.07-6.93(m,3H),4.42-4.14(m,1H),3.89-3.75(m,1H),3.64-3.57(m,2H),2.80-2.64(m,2H),2.35-2.29(m,3H),1.71(s,1H),1.60-1.46(m,4H),1.44-1.32(m,11H)ppm.
合成化合物4Bd
白色固体(142mg,91%)。1H NMR(400MHz,CDCl3)δ7.13-7.03(m,4H),4.34(d,J=8.1Hz,1H),3.86-3.73(m,1H),3.63-3.57(m,2H),2.78-2.64(m,2H),2.32(s,3H),1.63-1.45(m,5H),1.44-1.33(m,11H)ppm.
合成化合物4Be
白色固体(117mg,75%)。1H NMR(400MHz,CDCl3,rotamers)δ7.25-7.12(m,2H),7.11-6.95(m,2H),4.45-4.15(m,1H),3.88-3.69(m,1H),3.64-3.58(m,2H),2.86-2.60(m,2H),1.71(s,1H),1.62-1.47(m,4H),1.42-1.31(m,11H)ppm.
合成化合物4Bf
白色固体(147mg,93%)。1H NMR(400MHz,CDCl3)δ7.27-7.21(m,1H),7.00-6.86(m,3H),4.35(d,J=8.1Hz,1H),3.88-3.74(m,1H),3.65-3.60(m,2H),2.80-2.71(m,2H),1.63-1.46(m,5H),1.44-1.35(m,11H)ppm.
合成化合物4Bg
白色固体(140mg,90%)。1H NMR(400MHz,CDCl3,rotamers)δ7.17-7.10(m,2H),7.02-6.93(m,2H),4.39-4.16(m,1H),3.85-3.72(m,1H),3.64-3.59(m,2H),2.77-2.68(m,2H),1.70(s,1H),1.58-1.45(m,4H),1.44-1.35(m,11H)ppm.
合成化合物4Bh
白色固体(93mg,51%)。1H NMR(400MHz,CDCl3,rotamers)δ7.68-7.57(m,1H),7.49-7.28(m,3H),4.47-4.31(m,0.8H),4.29-4.16(m,0.2H),4.00-3.86(m,0.8H),3.85-3.73(m,0.2H),3.67-3.59(m,2H),3.06-2.94(m,1H),2.88-2.79(m,0.8H),2.69-2.58(m,0.2H),1.70-1.41(m,7H),1.37-1.29(m,7.2H)1.24-1.17(m,1.8H)ppm.
合成化合物4Bi
白色固体(174mg,96%)。1H NMR(400MHz,CDCl3,rotamers)δ7.52-7.35(m,4H),4.41-4.21(m,1H),3.90-3.76(m,1H),3.65-3.59(m,2H),2.88-2.75(m,2H),1.68(s,1H),1.61-1.47(m,4H),1.43-1.32(m,11H)ppm.
合成化合物4Bj
白色固体(184mg,99%)。1H NMR(400MHz,CDCl3,rotamers)δ7.58-7.51(m,2H),7.33-7.27(m,2H),4.41-4.17(m,1H),3.91-3.78(m,1H),3.66-3.60(m,2H),2.86-2.77(m,2H),1.62-1.47(m,5H),1.42-1.33(m,11H)ppm.
合成化合物4Bk
白色固体(151mg,92%)。1H NMR(400MHz,CDCl3,rotamers)δ7.26-7.15(m,3H),7.10-7.02(m,1H),4.41-4.15(m,1H),3.87-3.72(m,1H),3.66-3.60(m,2H),2.78-2.68(m,2H),1.64-1.46(m,5H),1.45-1.35(m,11H)ppm.
合成化合物4Bl
白色固体(150mg,94%)。1H NMR(400MHz,CDCl3,rotamers)δ7.62-7.55(m,2H),7.33-7.28(m,2H),4.41-4.22(m,1H),3.91-3.74(m,1H),3.65-3.60(m,2H),2.86-2.77(m,2H),1.66(s,1H),1.59-1.47(m,4H),1.40-1.34(m,11H)ppm.
合成化合物4Bm
白色固体(191mg,96%)。1H NMR(400MHz,CDCl3)δ8.01-7.93(m,2H),7.28-7.23(m,2H),4.45-4.31(m,3H),3.91-3.78(m,1H),3.63-3.58(m,2H),2.88-2.76(m,2H),1.72(s,1H),1.60-1.46(m,4H),1.44-1.34(m,14H)ppm.
合成化合物4Bn
浅黄色油状(14mg,8%)。1H NMR(400MHz,CDCl3)δ4.35-4.21(m,1H),3.67-3.62(m,2H),3.59-3.50(m,1H),1.79(s,1H),1.65-1.52(m,3H),1.48-1.41(m,14H),1.30-1.24(m,16H),0.90-0.85(m,3H)ppm.
合成化合物4Bo
浅黄色油状(15mg,14%)。1H NMR(400MHz,CDCl3,rotamers)δ5.47-5.31(m,1H),5.10-4.88(m,1H),4.04-3.90(m,1H),3.71-3.61(m,2H),1.97-1.86(m,2H),1.75-1.66(m,3H),1.63-1.52(m,4H),1.50-1.42(m,11H),1.40-1.18(m,6H)ppm.
实施例2
合成化合物4Aa
氩气保护下,化合物3A(100mg,0.53mmol)溶于干燥四氢呋喃(3mL),于-78℃下缓慢滴加新制备的苄基溴化锌试剂(2.14mL,1M in THF,4eq.)和三氟甲磺酸三甲基硅酯(0.19mL,2eq.),反应12小时后,向反应体系加入1N HCl(0.6mL),体系置于冰浴下搅拌15min,加水稀释,并升至室温,乙酸乙酯萃取(5mL×3),合并有机相,用饱和食盐水洗,无水硫酸镁干燥,过滤浓缩,残渣经硅胶柱层析(PE/EA=2∶1)得白色固体化合物4Aa(123mg,79%)。
实施例3
合成化合物4Aa
氩气保护下,化合物3A(100mg,0.53mmol)溶于干燥四氢呋喃(3mL),于-78℃下缓慢滴加新制备的苄基溴化锌试剂(2.14mL,1M in THF,4eq.)和三氟化硼乙醚(0.14mL,2eq.),反应12小时后,向反应体系加入1N HCl(0.6mL),体系置于冰浴下搅拌15min,加水稀释,并升至室温,乙酸乙酯萃取(5mL×3),合并有机相,用饱和食盐水洗,无水硫酸镁干燥,过滤浓缩,残渣经硅胶柱层析(PE/EA=2∶1)得白色固体化合物4Aa(123mg,79%)。
实施例4
合成化合物4Aa
氩气保护下,化合物3A(100mg,0.53mmol)溶于干燥四氢呋喃(3mL),于-78℃下缓慢滴加新制备的苄基溴化锌试剂(2.14mL,1M in THF,4eq.)和四氯化钛(0.12mL,2eq.),反应12小时后,向反应体系加入1N HCl(0.6mL),体系置于冰浴下搅拌15min,加水稀释,并升至室温,乙酸乙酯萃取(5mL×3),合并有机相,用饱和食盐水洗,无水硫酸镁干燥,过滤浓缩,残渣经硅胶柱层析(PE/EA=2∶1)得白色固体化合物4Aa(123mg,79%)。
实施例5
合成化合物4Aa
氩气保护下,化合物3A(100mg,0.53mmol)溶于干燥四氢呋喃(3mL),于-78℃下缓慢滴加新制备的苄基溴化锌试剂(2.14mL,1M in THF,4eq.)和三氟甲磺酸钪(521mg,2eq.),反应12小时后,向反应体系加入1N HCl(0.6mL),体系置于冰浴下搅拌15min,加水稀释,并升至室温,乙酸乙酯萃取(5mL×3),合并有机相,用饱和食盐水洗,无水硫酸镁干燥,过滤浓缩,残渣经硅胶柱层析(PE/EA=2∶1)得白色固体化合物4Aa(123mg,79%)。
Claims (9)
4.按权利要求3所述的方法,其特征在于,步骤1所述的有机溶剂指四氢呋喃、乙腈、二氯乙烷、二氯甲烷、环己烷或正己烷。
5.按权利要求3或4所述的方法,其特征在于,步骤1所述的有机溶剂是四氢呋喃。
6.按权利要求3所述的方法,其特征在于,步骤1所述的一种金属亲核试剂指芳基和烷基取代的格氏试剂、单烷基锌试剂。
7.按权利要求3或6所述的方法,其特征在于,步骤1所述的一种金属亲核试剂是单烷基锌试剂。
8.按权利要求3所述的方法,其特征在于,步骤1所述的路易斯酸指三氟甲磺酸钪、三氟甲磺酸镍、三氟甲磺酸酮、三氟甲磺酸钐、三氟甲磺酸铟、氯化锌、四氯化钛、三氟甲磺酸三甲基硅酯、三氟化硼乙醚、三甲基氯硅烷。
9.按权利要求3或8所述的方法,其特征在于,步骤1所述的路易斯酸是三甲基氯硅烷。
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