CN110229104A - 茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法 - Google Patents
茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法 Download PDFInfo
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- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种茂钛/布朗斯特酸催化芳胺与α‑酮酯合成四氢喹啉类化合物的方法，该方法是通过3,5,6‑三氯水杨酸或5‑硝基水杨酸协同二氯二茂钛，在低级脂肪醇(甲醇、乙醇等)与水的绿色体系中，催化芳胺与α‑酮酯合成四氢喹啉类化合物的方法。本发明所用二氯二茂钛廉价易得、对空气和水稳定，反应体系绿色环保，无需使用贵金属，避免了催化剂、底物的预合成，为四氢喹啉衍生物的合成建立了一种温和、绿色、易操作的合成方法，且反应条件温和、反应时间短、原子经济性高、目标产物产率高。
Description
技术领域
本发明属于四氢喹啉类化合物的合成技术领域，具体涉及一种茂钛/布朗斯特酸催化芳胺与α-酮酯反应合成四氢喹啉类化合物的方法。
背景技术
四氢喹啉作为喹啉家族的一个重要亚类，已发现于天然产物中，如马提尼酸，是一种强效缓激肽拮抗剂，其次，在药物化学方面也有出色效用，例如托彻普(CP-529,414,Pfizer)，是一种强效的第一胆固醇酯转移蛋白抑制剂，也是有效的非核苷、逆转录酶的变构抑制剂和抗HIV化合物，四氢喹啉类结构还可作为有机配体和染料加以利用。
合成四氢喹啉类化合物的方法有多种，特别是过渡金属催化的分子内烯丙基胺化法，手性磷酸催化的N-芳基亚胺与富电子烯以及醛、胺、炔分子间的Povarov反应等。总之，生物活性四氢喹啉衍生物的合成方法已有相当充分的发展，而手性酸配体催化成为核心策略，但总体来说，手性催化剂的制备、贵金属的使用，以及复杂底物的预合成限制了其普适化应用。总之，以上方法有各自的局限性(区域选择性差，起始材料不易获得，步骤多，耗时长，条件恶劣等)。因此，寻找一种温和、高效、易操作的合成方法十分必要。
发明内容
本发明所要解决的技术问题在于克服现有四氢喹啉类化合物合成方法存在的缺点，提供一种催化剂廉价易得无毒、反应条件温和、反应时间短、反应产物单一、安全高效、产率高的四氢喹啉类化合物的合成方法。
解决上述技术问题所采用的方案是：以二氯二茂钛和布朗斯特酸为催化剂，乙醇和水为溶剂，将式I所示芳胺与式II所示α-酮酯在30～50℃下反应，得到式III所示四氢喹啉类化合物，反应方程式如下：
式中R1、R2各自独立的代表H、C1～C6烷基、C1～C4烷氧基、卤素中的任意一种；R3代表C1～C4烷基。优选R1、R2各自独立的代表H、甲基、叔丁基、甲氧基、Cl中任意一种，R3代表甲基或乙基。
上述的布朗斯特酸为3,5,6-三氯水杨酸或5-硝基水杨酸，优选3,5,6-三氯水杨酸。
上述合成方法中，优选芳胺与α-酮酯的摩尔比为1:1.1～1.5。
上述合成方法中，优选二氯二茂钛和布朗斯特酸的加入量均为芳胺摩尔量的4％～7％。
上述的低级脂肪醇为甲醇或乙醇，优选乙醇；所述低级脂肪醇和水的体积比优选1:5～1:8。
上述合成方法中，优选将式I所示芳胺与式II所示α-酮酯在40～50℃下反应6～10小时。
本发明的有益效果如下：
本发明以廉价易得、对空气和水不敏感的二氯二茂钛为路易斯酸前体，以3,5,6-三氯水杨酸或5-硝基水杨酸为布朗斯特酸，使用醇与水的绿色复配均相体系，构筑双酸协同反应媒介，活化底物，用作芳胺与α-酮酯选择性向四氢喹啉类化合物转化。
本发明建立了一种温和、绿色、易操作的合成方法，有效避免传统方法中有毒试剂的使用以及常用催化剂手性磷酸的预合成，大大降低了工作复杂程度，且所用催化剂对空气和水稳定，反应条件温和、反应时间短、原子经济性高、目标产物产率高。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明所要保护的范围不仅限于这些实施例。
实施例1
合成结构式如下的2-甲基-4-(苯基氨基)-1,2,3,4-四氢喹啉二乙酯-2,4-二羧酸酯
向装有磁力搅拌子的25mL样品瓶中依次加入12.45mg(0.05mmol)二氯二茂钛和12.07mg(0.05mmol)3,5,6-三氯水杨酸、250μL无水乙醇、1750μL超纯水、132μL(1.2mmol)丙酮酸乙酯和91μL(1mmol)苯胺，混合均匀后在40℃下搅拌6小时。通过TLC检测反应完成，然后在反应混合物中加入5mL 0.5mol/L的碳酸氢钠水溶液，用二氯甲烷萃取有机相(3×15mL)，经无水硫酸钠干燥并真空减压浓缩，粗产物通过硅胶(石油醚/乙酸乙酯)柱层析纯化，得到2-甲基-4-(苯基氨基)-1,2,3,4-四氢喹啉二乙酯-2,4-二羧酸酯，其收率为93％，结构表征数据为：1H NMR(600MHz,CDCl3)δ7.33(d,J＝8.2Hz,1H),7.17-7.09(m,3H),6.72-6.66(m,3H),6.43(d,J＝8.6Hz,2H),4.49(s,1H),4.23(tdd,J＝10.8,7.1,3.6Hz,2H),3.94(d,J＝7.7Hz,1H),3.89(dq,J＝14.2,7.1Hz,1H),3.37-3.31(m,1H),2.70(d,J＝13.6Hz,1H),1.50(s,3H),1.18(t,J＝7.1Hz,3H),0.68(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ176.06,172.87,145.14,143.83,130.11,128.82,127.07,119.69,118.48,117.96,115.77,114.28,61.87,61.44,60.36,55.16,36.32,28.05,14.13,13.31.
实施例2
合成结构式如下的2,7-二甲基-4-(对甲苯基氨基)-1,2,3,4-四氢喹啉-2,4-二甲酸二乙酯
本实施例中，用等摩尔4-甲基苯胺替换实施例1中的苯胺，其他步骤与实施例1相同，得到固体2,7-二甲基-4-(对甲苯基氨基)-1,2,3,4-四氢喹啉-2,4-二甲酸二乙酯，其收率为90％，结构表征数据为：1H NMR(600MHz,CDCl3)δ7.04(s,1H),6.89-6.79(m,3H),6.52(d,J＝7.3Hz,1H),6.25(d,J＝7.0Hz,2H),4.34(s,1H),4.20(s,1H),4.08(s,1H),3.78(s,2H),3.31(s,1H),3.17(s,1H),2.59(d,J＝13.5Hz,1H),2.11(d,J＝17.5Hz,6H),1.38(s,3H),1.12(d,J＝5.3Hz,3H),0.60(s,3H)；13C NMR(151MHz,CDCl3)δ176.12,173.02,142.71,141.51,130.73,129.62,129.20,127.54,127.19,126.82,119.70,115.76,115.22,114.36,61.68,61.28,60.35,55.17,36.42,27.97,20.59,20.41,14.11,13.26.
实施例3
合成结构式如下的6-(叔丁基)-4-((4-(叔丁基)苯基)氨基)-2-甲基-二乙基-1,2,3,4-四氢喹啉-2,4-二羧酸酯
本实施例中，用等摩尔对叔丁基苯胺替换实施例1中的苯胺，其他步骤与实施例1相同，得到固体6-(叔丁基)-4-((4-(叔丁基)苯基)氨基)-2-甲基-二乙基-1,2,3,4-四氢喹啉-2,4-二羧酸酯，其收率为85％，结构表征数据为：1H NMR(600MHz,CDCl3)δ7.17-7.15(m,1H),7.09(dd,J＝8.5,2.3Hz,1H),7.04(d,J＝8.6Hz,2H),6.56(d,J＝8.5Hz,1H),6.30(d,J＝8.6Hz,2H),4.21-4.10(m,2H),3.87-3.74(m,2H),3.34-3.26(m,1H),3.19(d,J＝14.0Hz,1H),2.57(d,J＝14.0Hz,1H),1.39(s,3H),1.19(s,3H),1.17(s,9H),1.12(s,9H),0.55(t,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ176.30,173.28,142.43,141.20,141.02,140.69,127.12,126.03,125.41,123.69,118.90,115.30,114.95,114.59,61.61,61.35,60.68,55.11,36.54,34.06,33.85,31.58,31.55,31.50,29.72,28.15,14.20,13.14.
实施例4
合成结构式如下的6-氯-4-((4-氯苯基)氨基)-2-甲基-1,2,3,4-四氢喹啉-2,4-二羧酸酯
本实施例中，用等摩尔4-氯苯胺替换实施例1中的苯胺，其他步骤与实施例1相同，得到固体6-氯-4-((4-氯苯基)氨基)-2-甲基-1,2,3,4-四氢喹啉-2,4-二羧酸酯，其收率为72％，结构表征数据为：1H NMR(600MHz,CDCl3)δ7.04(s,1H),6.89-6.79(m,3H),6.52(d,J＝7.3Hz,1H),6.27(dd,J＝18.0,7.4Hz,2H),4.34(s,1H),4.19(dd,J＝19.4,12.9Hz,1H),4.11-4.04(m,1H),3.85-3.74(m,2H),3.33-3.28(m,1H),3.18(d,J＝13.8Hz,1H),2.58(t,J＝13.9Hz,1H),2.11(d,J＝17.5Hz,6H),1.38(s,3H),1.11(t,J＝12.0Hz,3H),0.60(s,3H)；13C NMR(151MHz,CDCl3)δ170.09,166.22,138.43,133.36,132.36,131.59,128.39,128.33,125.71,125.58,117.14,107.04,67.77,61.39,52.41,49.83,28.68,20.19,13.02,0.00.
实施例5
合成结构式如下的7-甲氧基-4-((3-甲氧基苯基)氨基)-2-甲基-1,2,3,4-四氢喹啉-2,4-二羧酸酯
本实施例中，用等摩尔3-甲氧基苯胺替换实施例1中的苯胺，其他步骤与实施例1相同，得到固体7-甲氧基-4-((3-甲氧基苯基)氨基)-2-甲基-1,2,3,4-四氢喹啉-2,4-二羧酸酯，其收率为83％，结构表征数据为：1H NMR(600MHz,CDCl3)δ7.65(d,J＝8.7Hz,1H),6.97(t,J＝8.0Hz,1H),6.45(s,1H),6.24(dd,J＝8.2,1.9Hz,1H),6.22-6.19(m,2H),6.16(t,J＝2.2Hz,1H),6.10(d,J＝2.5Hz,1H),5.21(s,1H),4.47(s,1H),4.23(pt,J＝10.0,5.0Hz,2H),4.17-4.05(m,2H),3.67(s,6H),3.38(s,1H),1.45(s,3H),1.29(t,J＝7.1Hz,3H),1.18(d,J＝7.1Hz,3H)；13C NMR(151MHz,CDCl3)δ174.05,166.04,160.87,160.78,147.85,144.22,130.10,129.82,128.17,127.85,110.14,107.93,104.45,103.95,101.09,99.43,61.79,60.94,58.61,55.12,55.08,53.46,27.41,14.25,14.13.
实施例6
合成结构式如下的2-甲基-4-(苯基氨基)-1,2,3,4-四氢喹啉二甲基-2,4-二羧酸酯
本实施例中，用等摩尔丙酮酸甲酯替换实施例1中的丙酮酸乙酯，其他步骤与实施例1相同，得到固体2-甲基-4-(苯基氨基)-1,2,3,4-四氢喹啉二甲基-2,4-二羧酸酯，其收率为92％，结构表征数据为：1H NMR(600MHz,CDCl3)δ7.18(d,J＝6.3Hz,1H),7.06(dt,J＝14.6,7.3Hz,3H),6.66-6.58(m,3H),6.33(d,J＝7.6Hz,2H),4.44(s,1H),3.88(s,1H),3.67(s,3H),3.23(d,J＝14.0Hz,1H),3.06(s,3H),2.60(d,J＝14.0Hz,1H),1.41(s,3H)；13C NMR(151MHz,CDCl3)δ175.13,172.42,143.78,142.53,129.05,128.46,127.75,125.96,118.46,117.34,117.00,116.08,114.62,113.26,111.67,111.38,59.37,54.10,51.65,50.67,35.26,26.93.
实施例7
本实施例中，用等摩尔的5-硝基水杨酸替换实施例1中的3,5,6-三氯水杨酸，反应时间延长至10小时，其他步骤与实施例1相同，得到固体2-甲基-4-(苯基氨基)-1,2,3,4-四氢喹啉二乙酯-2,4-二羧酸酯，产率为84％。
实施例8
本实施例中，用等体积甲醇替换实施例1中的乙醇，其他步骤与实施例1相同，得到固体2-甲基-4-(苯基氨基)-1,2,3,4-四氢喹啉二乙酯-2,4-二羧酸酯，其收率为88％。
Claims (10)
1.一种茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法，其特征在于：以二氯二茂钛和布朗斯特酸为催化剂，低级脂肪醇和水为溶剂，将式I所示芳胺与式II所示α-酮酯在30～50℃下反应，得到式III所示四氢喹啉类化合物；
式中R1、R2各自独立的代表H、C1～C6烷基、C1～C4烷氧基、卤素中的任意一种；R3代表C1～C4烷基；
上述的布朗斯特酸为3,5,6-三氯水杨酸或5-硝基水杨酸。
2.根据权利要求1所述的茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法，其特征在于：所述的R1、R2各自独立的代表H、甲基、叔丁基、甲氧基、Cl中任意一种。
3.根据权利要求1所述的茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法，其特征在于：所述的R3代表甲基或乙基。
4.根据权利要求1所述的茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法，其特征在于：所述芳胺与α-酮酯的摩尔比为1:1.1～1.5。
5.根据权利要求1所述的茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法，其特征在于：所述二氯二茂钛和布朗斯特酸的加入量均为芳胺摩尔量的4％～7％。
6.根据权利要求5所述的茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法，其特征在于：所述的布朗斯特酸为3,5,6-三氯水杨酸。
7.根据权利要求1所述的茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法，其特征在于：所述的低级脂肪醇为乙醇或甲醇。
8.根据权利要求7所述的茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法，其特征在于：所述的低级脂肪醇为乙醇。
9.根据权利要求1或7或8所述的茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法，其特征在于：所述低级脂肪醇和水的体积比为1:5～1:8。
10.根据权利要求1所述的茂钛/布朗斯特酸催化芳胺与α-酮酯合成四氢喹啉类化合物的方法，其特征在于：将式I所示芳胺与式II所示α-酮酯在40～50℃下反应6～10小时。
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