CN112608275A - 一种2,8-双(三氟甲基)-4-羟基喹啉衍生物在制备和防治农业病害中的用途 - Google Patents
一种2,8-双(三氟甲基)-4-羟基喹啉衍生物在制备和防治农业病害中的用途 Download PDFInfo
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Abstract
本发明公开了一种2,8‑双(三氟甲基)‑4‑羟基喹啉衍生物在制备和防治农业病害中的用途。活性测试结果表明,本发明所述化合物对油菜菌核病菌、番茄灰霉病菌、小麦赤霉病菌和立枯丝核病菌四种植物病源真菌表现出潜在的抑制活性,可作为杀菌剂来开发。
Description
技术领域
本发明属于天然药物化学领域,公开了一种2,8-双(三氟甲基)-4-羟基喹啉衍生物的新用途,具体涉及2,8-双(三氟甲基)-4-羟基喹啉衍生物在制备和防治油菜菌核病菌,番茄灰霉病菌,小麦赤霉病菌,立枯丝核病菌中的用途。
背景技术
真菌引起的病害对农作物的生产和粮食的安全造成严重的影响。科学研究发现,超过19,000种不同类型的真菌可以引起植物病害,真菌造成的农作物损失已成为一个不可忽视的严重问题。例如,稻瘟病菌会给全世界带来约10-35%的收成损失;灰霉病菌会严重破坏200多种农作物,包括不同的水果和蔬菜,造成果实腐烂;立枯丝核病菌是一种土传真菌,侵害性非常强,破坏性大,寄主范围广,已知有160多种植物可被侵染,由真菌引起的农作物损失对社会经济造成了严重的损失。目前,控制农作物真菌危害的最有效方法仍然是化学杀菌剂的普遍使用,然而使用化学杀菌剂引起的不利影响已经出现,例如果蔬农残,环境污染以及耐药性的产生,因此,寻找更为高效、低毒的杀菌剂成为当务之急。
天然生物碱是生物在进化过程中与多种靶标相互作用产生的代谢产物,资源丰富,易于降解,对环境和非靶标生物的影响较小。通过结构修饰和简化从天然产物中寻找先导化合物已证明了其巨大的潜力和成功。奎宁(Quinine),俗称金鸡纳霜,也称为金鸡纳碱,是从茜草科植物金鸡纳树(Cinchona ledgeriana(Howard)Moens ex Trim)及其同属植物的树皮中分离得到的主要生物碱。课题组在前期研究奎宁结构简化(J.Agric.FoodChem.2019,67,11340-11353)时,发现2,8-双(三氟甲基)-4-羟基喹啉在防治油菜菌核病菌、立枯丝核病菌和小麦赤霉病菌方面表现了良好的抑制活性,具有进一步进行结构修饰从而获得活性化合物的潜力。基于以上发现,本发明将进一步对2,8-双(三氟甲基)-4-羟基喹啉的4位羟基进行结构优化,引入苯基哌嗪、苯胺、苯肼、苯腙、杂原子二唑环、双酰肼、磺酰肼、肉桂酸和烷醇胺等结构,测定所合成的化合物对油菜菌核病菌、番茄灰霉病菌、小麦赤霉病菌、立枯丝核病的抗菌活性,以期发现活性优异的杀菌候选药物。
发明内容
本发明目的是针对现有技术存在的缺陷,为农业生产提供一种2,8-双(三氟甲基)-4-羟基喹啉衍生物的新用途,即2,8-双(三氟甲基)-4-羟基喹啉衍生物在制备和防治油菜菌核病菌、番茄灰霉病菌、小麦赤霉病菌和立枯丝核病中的用途。
为实现上述目的,本发明提供了如下技术方法:一种制备和防治油菜菌核病菌、立枯丝核病菌、番茄灰霉病菌和小麦赤霉病菌的药物,其中含有治疗有效量的2,8-双(三氟甲基)-4-羟基喹啉衍生物a1~j2具有的结构式如化学式I所示:
化学式I
进一步地,本发明所述的2,8-双(三氟甲基)-4-羟基喹啉衍生物是按照文献(1)J.Med.Chem.2016,59,2362-2380;(2)Eur.J.Med.Chem.2017,125,890-901;(3)Molecules.2017,22,64;(4)J.Med.Chem.2016,59,6709-6728报道的合成方法获得的化合物,经硅胶柱层析等常规方法分离获得纯品,经核磁共振波谱、质谱鉴定等技术,确定了权利要求所述的2,8-双(三氟甲基)-4-羟基喹啉衍生物。经活性筛选结果表明,本发明所述的2,8-双(三氟甲基)-4-羟基喹啉衍生物对油菜菌核病菌、番茄灰霉病菌、小麦赤霉菌和立枯丝核病菌表现出一定的抑制作用,其中部分化合物表现出优异的抑制作用,可用于制备杀菌剂。
为了更好地理解本发明,以下通过具体实施方式,对本发明的上述内容做进一步的详细说明。但不应将此理解为对本发明的限制。
具体实施方式
实施例1:a1的合成
其具体合成操作如下:将2,8-双(三氟甲基)-4-羟基喹啉(3mmol)溶于适量的DMF中,再加入碳酸钾(4.2mmol),在80摄氏度回流5h,TLC点板监测。反应结束后,将混合入加入到水中,并用乙酸乙酯进行萃取,用水洗涤有机相,有机相用无水硫酸钠干燥,旋干有机相,以石油醚/二乙为洗脱剂经柱层析纯化得到中间体1。将中间体1(2mmol)用少量THF溶解,再加入15mL的10%NaOH水溶液,在室温下搅拌反应4h,TLC点板监测。反应结束后,将混合物减压旋蒸除去THF,用稀盐酸调节pH至酸性,析出大量白色固体,抽滤得到固体并用水反复洗涤,干燥得到中间体2。将中间体2(0.85mmol)溶于15mL的二氯亚砜中,80摄氏度回流反应4h,反应结束后减压旋干得到白色中间体3。在冰浴条件下向二氯甲烷(30mL)溶液中加入苯基哌嗪(1.3mmol),加入三乙胺(1.9mmol),再缓慢滴加中间体3(0.85mmol)的二氯甲烷溶液,在冰浴条件下反应30min,然后室温继续反应3h,TLC点板监测。反应结束后,将混合入加入30mL水中,用二氯甲烷萃取,用水洗涤有机相,有机相用无水硫酸钠干燥,旋干有机相得到固体,以石油醚/二乙为洗脱剂经柱层析纯化得到白色固体a1。
产率:76%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.32(dd,J=8.1,1.2Hz,1H),8.11(d,J=6.8Hz,1H),7.21(t,J=6.2Hz,1H),7.05(s,1H),6.93(d,J=7.8Hz,2H),6.85-6.78(m,3H),5.02(s,2H),3.94-3.73(m,8H).m/z:C23H19F6N3O2:484.13[M+H]+。
实施例2:a2的合成
实验步骤与实施例1同,仅以1-(4-甲氧基苯基)哌嗪代替苯基哌嗪。
产率:65%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.51(dd,J=8.5,1.4Hz,1H),8.15(d,J=7.3Hz,1H),7.68(t,J=7.9Hz,1H),7.14(s,1H),6.92(d,J=8.4Hz,2H),6.88-6.80(m,2H),5.07(s,2H),3.91-3.71(m,8H),3.12(s,3H).m/z:C24H21F6N3O3:514.14[M+H]+。
实施例3:a3的合成
实验步骤与实施例1同,仅以1-(4-氟基苯基)哌嗪代替苯基哌嗪。
产率:69%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.50(d,J=8.4Hz,1H),8.15(d,J=7.3Hz,1H),7.68(t,J=7.9Hz,1H),7.25(d,J=5.3Hz,2H),7.13(s,1H),6.87-6.78(m,2H),5.07(s,2H),3.79(dt,J=41.1,5.1Hz,4H),3.12(dt,J=42.3,4.8Hz,4H).m/z:C23H18F7N3O2:502.13[M+H]+。
实施例4:a4的合成
实验步骤与实施例1同,仅以1-(4-三氟基苯基)哌嗪代替苯基哌嗪。
产率:58%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.50(dd,J=8.5,1.4Hz,1H),8.15(d,J=7.2Hz,1H),7.68(t,J=7.9Hz,1H),7.52(d,J=8.5Hz,2H),7.14(s,1H),6.95(d,J=8.5Hz,2H),5.08(s,2H),3.86(t,J=5.2Hz,2H),3.77(t,J=5.1Hz,2H),3.36-3.32(m,4H).m/z:C24H18F9N3O2:552.13[M+H]+。
实施例5:a5的合成
实验步骤与实施例1同,仅以1-(3,4-二氯苯基)哌嗪代替苯基哌嗪。
产率:61%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.50(dd,J=8.5,1.5Hz,1H),8.15(d,J=7.3Hz,1H),7.68(t,J=7.9Hz,1H),7.31(d,J=8.9Hz,1H),7.13(s,1H),6.98(d,J=2.9Hz,1H),6.76(dd,J=8.9,2.9Hz,1H),5.07(s,2H),3.84(t,J=5.2Hz,2H),3.75(d,J=5.3Hz,2H),3.35-3.34(m,4H).m/z:C23H17Cl2F6N3O2:552.06[M+H]+。
实施例6:a6的合成
实验步骤与实施例1同,仅以1-(2-甲氧基苯基)哌嗪代替苯基哌嗪。
产率:82%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.60(d,J=8.5Hz,1H),8.35(d,J=7.3Hz,1H),7.89(t,J=7.9Hz,1H),7.64(s,1H),6.99(m,2H),6.91(d,J=3.9Hz,2H),5.47(s,2H),3.81(s,3H),3.66(m,4H),3.06(t,J=4.9Hz,2H),2.97(t,J=5.1Hz,2H).m/z:C24H21F6N3O3:514.26[M+H]+.
实施例7:a7的合成
实验步骤与实施例1同,仅以1-(2-氟苯基)哌嗪代替苯基哌嗪。
产率:76%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.71–8.52(m,1H),8.42–8.24(m,1H),8.00–7.79(m,1H),7.76–7.57(m,1H),7.32–7.12(m,2H),7.11–6.92(m,2H),5.62–5.38(m,2H),3.71(m,4H),3.09(m,4H).m/z:C23H18F7N3O2:502.24[M+H]+.
实施例8:a8的合成
实验步骤与实施例1同,仅以1-(2,4-二氟苯基)哌嗪代替苯基哌嗪。
产率:81%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.60(d,J=8.5Hz,1H),8.35(d,J=7.3Hz,1H),7.90(t,J=7.9Hz,1H),7.65(s,1H),7.24(ddd,J=12.2,9.0,2.9Hz,1H),7.11(td,J=9.3,5.9Hz,1H),7.03(td,J=8.6,2.9Hz,1H),5.48(s,2H),3.67(dt,J=9.5,4.8Hz,4H),3.07(t,J=4.9Hz,2H),2.98(t,J=5.1Hz,2H).m/z:C23H17F8N3O2:520.18[M+H]+.
实施例9:a9的合成
实验步骤与实施例1同,仅以1-(3-甲基苯基)哌嗪代替苯基哌嗪。
产率:65%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.67–8.54(m,1H),8.34(d,J=7.3Hz,1H),7.89(t,J=7.9Hz,1H),7.65(s,1H),7.13(t,J=7.8Hz,1H),6.81(t,J=1.8Hz,1H),6.78(dd,J=8.2,2.5Hz,1H),6.65(d,J=7.4Hz,1H),5.48(s,2H),3.65(dt,J=10.1,5.0Hz,4H),3.25(t,J=5.1Hz,2H),3.15(t,J=5.3Hz,2H),2.27(s,3H).m/z:C24H21F6N3O2:498.17[M+H]+.
实施例10:a10的合成
实验步骤与实施例1同,仅以1-(3-甲氧基苯基)哌嗪代替苯基哌嗪。
产率:64%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.64–8.55(m,1H),8.35(d,J=7.3Hz,1H),7.89(t,J=7.9Hz,1H),7.65(s,1H),7.15(t,J=8.2Hz,1H),6.58(dd,J=8.2,2.3Hz,1H),6.51(t,J=2.4Hz,1H),6.42(dd,J=8.2,2.3Hz,1H),5.49(s,2H),3.74(s,3H),3.65(m,4H),3.27(t,J=5.1Hz,2H),3.17(t,J=5.3Hz,2H).m/z:C24H21F6N3O3:514.17[M+H]+.
实施例11:a11的合成
实验步骤与实施例1同,仅以1-(2-嘧啶基)哌嗪代替苯基哌嗪。
产率:57%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.60(d,J=8.5Hz,1H),8.42(d,J=4.8Hz,2H),8.34(d,J=7.3Hz,1H),7.89(t,J=7.9Hz,1H),7.67(s,1H),6.70(t,J=4.8Hz,1H),5.49(s,2H),3.89(t,J=6.5Hz,2H),3.80(t,J=5.3Hz,2H),3.62(m,4H).m/z:C21H17F6N5O2:486.16[M+H]+.
实施例12:a12的合成
实验步骤与实施例1同,仅以1-(4-吡啶基)哌嗪代替苯基哌嗪。
产率:66%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.56(d,J=8.5Hz,1H),8.32(d,J=7.4Hz,1H),8.23(d,J=6.3Hz,2H),7.87(t,J=8.1Hz,1H),7.65(s,1H),7.00(d,J=6.5Hz,2H),5.48(s,2H),3.75–3.58(m,4H),3.58–3.47(m,4H).m/z:C22H18F6N4O2:485.31[M+H]+.
实施例13:a13的合成
实验步骤与实施例1同,仅以1-(2-吡嗪基)哌嗪代替苯基哌嗪。
产率:76%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.60(d,J=8.5Hz,1H),8.40(s,1H),8.35(d,J=7.3Hz,1H),8.17–8.09(m,1H),7.90(t,J=4.8Hz,2H),7.67(s,1H),5.49(s,2H),3.76–3.71(m,2H),3.67(m,2H),3.64(s,4H).m/z:C21H17F6N5O2:486.19[M+H]+.
实施例14:a14的合成
实验步骤与实施例1同,仅以1-(4-氯苯基)哌嗪代替苯基哌嗪。
产率:82%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.57(d,J=8.4Hz,1H),8.39–8.22(m,1H),7.94–7.78(m,1H),7.65(d,J=6.9Hz,1H),7.26(d,J=8.4Hz,2H),6.99(d,J=8.5Hz,2H),5.57–5.38(m,2H),3.76–3.52(m,4H),3.27(s,2H),3.16(s,2H).m/z:C23H18ClF6N3O2:518.13[M+H]+.
实施例15:a15的合成
实验步骤与实施例1同,仅以1-(2-吡啶基)哌嗪代替苯基哌嗪。
产率:85%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.60(d,J=8.5Hz,1H),8.35(d,J=7.4Hz,1H),8.15(dd,J=5.0,1.9Hz,1H),7.89(t,J=7.9Hz,1H),7.66(s,1H),7.58(ddd,J=8.9,7.0,2.0Hz,1H),6.89(d,J=8.6Hz,1H),6.69(dd,J=7.1,4.9Hz,1H),5.49(s,2H),3.63(m,6H),3.58–3.50(m,2H).m/z:C22H18F6N4O2:485.27[M+H]+.
实施例16:a16的合成
实验步骤与实施例1同,仅以哌嗪代替苯基哌嗪。
产率:53%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.60(d,J=8.5Hz,1H),8.35(d,J=7.4Hz,1H),7.89(t,J=7.9Hz,1H),7.66(s,1H),5.49(s,2H),3.80–3.43(m,8H).m/z:C17H15F6N3O2:408.07[M+H]+.
实施例17:a17的合成
实验步骤与实施例1同,仅以1-甲基哌嗪代替苯基哌嗪。
产率:56%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.58(d,J=8.4Hz,1H),8.34(d,J=7.3Hz,1H),7.89(t,J=7.9Hz,1H),7.60(s,1H),5.42(s,2H),3.50(m,4H),2.40(t,J=5.0Hz,2H),2.30(t,J=5.1Hz,2H),2.22(s,3H).m/z:C18H17F6N3O2:422.26[M+H]+.
实施例18:a18的合成
实验步骤与实施例1同,仅以吗啉代替苯基哌嗪。
产率:78%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.61–8.55(m,1H),8.35(d,J=7.3Hz,1H),7.89(t,J=7.9Hz,1H),7.63(s,1H),5.43(s,2H),3.68(t,J=4.6Hz,2H),3.61(t,J=4.8Hz,2H),3.53(t,J=4.6Hz,2H),3.51–3.47(m,2H).m/z:C17H14F6N2O3:409.07[M+H]+.
实施例19:a19的合成
实验步骤与实施例1同,仅以1-(2-甲氧基乙基)哌嗪代替苯基哌嗪。
产率:65%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.61–8.54(m,1H),8.34(d,J=7.3Hz,1H),7.89(t,J=7.9Hz,1H),7.60(s,1H),5.42(s,2H),3.49(m,6H),3.25(s,3H),2.55(m,2H),2.51(m,3H),2.45(m,2H).m/z:C20H21F6N3O3:466.13[M+H]+.
实施例20:b1的合成
实验步骤与实施例1同,仅以苯胺代替苯基哌嗪。
产率:69%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.34(s,1H),8.68(d,J=8.5Hz,1H),8.37(d,J=7.4Hz,1H),7.91(t,J=7.9Hz,1H),7.62(d,J=8.5Hz,3H),7.35(t,J=7.7Hz,2H),7.11(t,J=7.4Hz,1H),5.30(s,2H).m/z:C19H12F6N2O2:415.09[M+H]+。
实施例21:b2的合成
实验步骤与实施例1同,仅2-氟苯胺代替苯基哌嗪。
产率:72%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.17(s,1H),8.85-8.51(m,1H),8.46-8.19(m,1H),7.86(d,J=32.7Hz,2H),7.61(s,1H),7.26(d,J=38.7Hz,3H),5.35(s,2H).m/z:C19H11F7N2O2:433.06[M+H]+。
实施例22:b3的合成
实验步骤与实施例1同,仅3-氟苯胺代替苯基哌嗪。
产率:57%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.48(s,1H),8.68(d,J=8.5Hz,1H),8.37(d,J=7.3Hz,1H),7.91(t,J=7.9Hz,1H),7.76-7.62(m,3H),7.41(d,J=8.5Hz,2H),5.30(s,2H).m/z:C19H11F7N2O2:433.15[M+H]+。
实施例23:b4的合成
实验步骤与实施例1同,仅4-氟苯胺代替苯基哌嗪。
产率:63%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.47(s,1H),8.65(d,J=8.3Hz,1H),8.42(d,J=7.4Hz,1H),7.95(t,J=8.2Hz,1H),7.76-7.64(m,3H),7.43(d,J=8.6Hz,2H),5.35(s,2H).m/z:C19H11F7N2O2:433.12[M+H]+。
实施例24:b5的合成
实验步骤与实施例1同,仅4-氯苯胺代替苯基哌嗪。
产率:77%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.23(s,1H),8.61(d,J=8.4Hz,1H),8.35(d,J=7.2Hz,1H),7.93(t,J=7.7Hz,1H),7.61(s,1H),7.47(s,1H),7.35(d,J=8.0Hz,1H),7.21(t,J=7.5Hz,1H),6.90(d,J=7.2Hz,1H),5.24(s,2H).m/z:C19H11ClF6N2O2:449.07[M+H]+。
实施例25:b6的合成
实验步骤与实施例1同,仅2-甲基苯胺代替苯基哌嗪。
产率:73%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.37(s,1H),8.89-8.55(m,1H),8.48-8.21(m,1H),7.88(d,J=32.5Hz,2H),7.66(s,1H),7.31(d,J=34.7Hz,3H),5.43(s,2H),2.25(s,3H).m/z:C20H14F6N2O2:429.05[M+H]+。
实施例26:b7的合成
实验步骤与实施例1同,仅3-甲基苯胺代替苯基哌嗪。
产率:52%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.27(s,1H),8.68(d,J=8.5Hz,1H),8.37(d,J=7.4Hz,1H),7.91(t,J=7.9Hz,1H),7.63(s,1H),7.47(s,1H),7.40(d,J=8.1Hz,1H),7.22(t,J=7.8Hz,1H),6.93(d,J=7.6Hz,1H),5.28(s,2H),2.29(s,3H).m/z:C20H14F6N2O2:429.15[M+H]+。
实施例27:b8的合成
实验步骤与实施例1同,仅4-甲基苯胺代替苯基哌嗪。
产率:71%;白色固体;产率:52%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.25(s,1H),8.65(d,J=8.3Hz,1H),8.33(d,J=7.2Hz,1H),7.93(t,J=7.6Hz,1H),7.64(s,1H),7.43(s,1H),7.38(d,J=8.2Hz,1H),7.23(t,J=7.5Hz,1H),6.94(d,J=7.3Hz,1H),5.21(s,2H),2.27(s,3H).m/z:C20H14F6N2O2:429.62[M+H]+。
实施例28:b9的合成
实验步骤与实施例1同,仅2,4-二甲基苯胺代替苯基哌嗪。
产率:51%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.24(s,1H),8.63(d,J=8.5Hz,1H),8.36(d,J=7.1Hz,1H),7.92(t,J=7.2Hz,1H),7.65(s,1H),7.45(s,1H),7.22(t,J=7.5Hz,1H),6.95(d,J=7.1Hz,1H),5.23(s,2H),2.27(s,3H),2.15(s,3H).m/z:C21H16F6N2O2:443.23[M+H]+。
实施例29:b10的合成
实验步骤与实施例1同,仅3,5-二甲基苯胺代替苯基哌嗪。
产率:48%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.25(s,1H),8.61(d,J=8.4Hz,1H),8.37(d,J=7.3Hz,1H),7.91(t,J=7.5Hz,1H),7.43(s,1H),7.438(s,1H),7.26(t,J=7.5Hz,1H),6.93(d,J=7.1Hz,1H),5.21(s,2H),2.22(s,3H),2.10(s,3H).m/z:C21H16F6N2O2:443.18[M+H]+。
实施例30:b11的合成
实验步骤与实施例1同,仅4-溴苯胺代替苯基哌嗪。
产率:79%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.47(s,1H),8.65(d,J=8.5Hz,1H),8.34(d,J=7.3Hz,1H),7.89(t,J=7.9Hz,1H),7.67-7.55(m,3H),7.52(d,J=8.8Hz,2H),5.29(s,2H).m/z:C19H11BrF6N2O2:492.65[M+H]+。
实施例31:b12的合成
实验步骤与实施例1同,仅2,4-二氟苯胺代替苯基哌嗪。
产率:68%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.56(s,1H),8.68(d,J=8.6Hz,1H),8.43(d,J=7.5Hz,1H),7.94(t,J=7.6Hz,1H),7.48(s,1H),7.45(s,1H),7.35(t,J=7.8Hz,1H),6.98(d,J=7.5Hz,1H),5.24(s,2H).m/z:C19H10F8N2O2:451.37[M+H]+。
实施例32:c1的合成
实验步骤与实施例1同,以苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:54%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.28(d,J=2.0Hz,1H),8.82-8.78(m,1H),8.30(t,J=7.1Hz,1H),7.85-7.80(m,2H),7.60(s,1H),7.30-6.64(m,5H),5.23(s,2H).m/z:C19H13F6N3O2:430.11[M+H]+。
实施例33:c2的合成
实验步骤与实施例1同,以2-氟苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:57%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.30(d,J=2.1Hz,1H),8.86-8.71(m,1H),8.33(t,J=7.3Hz,1H),7.98-7.82(m,2H),7.63(s,1H),7.30-6.64(m,4H),5.29(s,2H).m/z:C19H12F7N3O2:448.27[M+H]+。
实施例34:c3的合成
实验步骤与实施例1同,以3-氟苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:51%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.42-10.03(m,1H),8.77(d,J=8.5Hz,1H),8.36(d,J=7.2Hz,1H),8.25-8.17(m,1H),7.90(t,J=8.0Hz,1H),7.61(s,1H),7.15(q,J=7.6Hz,1H),6.73-6.56(m,1H),6.56-6.40(m,2H),5.27(s,2H).m/z:C19H12F7N3O2:448.11[M+H]+。
实施例35:c4的合成
实验步骤与实施例1同,以4-氟苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:62%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.23(d,J=2.9Hz,1H),8.81-8.72(m,1H),8.35(d,J=7.2Hz,1H),7.96-7.81(m,2H),7.60(s,1H),6.99(t,J=8.9Hz,2H),6.85-6.65(m,2H),5.24(s,2H).m/z:C19H12F7N3O2:448.16[M+H]+。
实施例36:c5的合成
实验步骤与实施例1同,以2-甲基苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:52%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.21(d,J=2.6Hz,1H),8.78(dd,J=8.6,1.4Hz,1H),8.35(d,J=7.1Hz,1H),8.00-7.77(m,1H),7.63(s,1H),7.36-7.23(m,1H),7.01(dd,J=10.0,7.4Hz,2H),6.76-6.59(m,2H),5.26(s,2H),3.35(s,3H).m/z:C20H15F6N3O2:444.05[M+H]+。
实施例37:c6的合成
实验步骤与实施例1同,以3-甲基苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:47%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.22(d,J=2.7Hz,1H),8.74(dd,J=8.4,1.3Hz,1H),8.34(d,J=7.2Hz,1H),8.02-7.75(m,1H),7.64(s,1H),7.35-7.25(m,1H),7.03(dd,J=9.8,7.2Hz,2H),6.74-6.53(m,2H),5.28(s,2H),3.33(s,3H).m/z:C20H15F6N3O2:444.13[M+H]+。
实施例38:c7的合成
实验步骤与实施例1同,以4-甲基苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:55%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.17(d,J=3.0Hz,1H),8.76(dd,J=8.6,1.4Hz,1H),8.35(d,J=7.1Hz,1H),7.98-7.79(m,1H),7.73(d,J=2.9Hz,1H),7.59(s,1H),6.95(d,J=8.1Hz,2H),6.68(d,J=8.3Hz,2H),5.25(s,2H),3.36(s,3H).m/z:C20H15F6N3O2:444.19[M+H]+。
实施例39:c8的合成
实验步骤与实施例1同,以4-溴苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:68%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.43-10.21(m,1H),8.76(d,J=8.1Hz,1H),8.43(s,1H),8.11(d,J=7.6Hz,1H),7.93(t,J=7.2Hz,1H),7.54(s,1H),7.47(d,J=8.3Hz,2H),6.82(d,J=8.1Hz,2H),5.21(s,2H).m/z:C19H12BrF6N3O2:508.52[M+H]+。
实施例40:c9的合成
实验步骤与实施例1同,以4-氯苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:61%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.41-10.25(m,1H),9.21(s,1H),8.68(d,J=8.2Hz,1H),8.43(d,J=7.3Hz,1H),7.82(t,J=8.2Hz,1H),7.65(s,1H),6.92(d,J=7.9Hz,2H),6.62(d,J=8.3Hz,2H),5.25(s,2H).m/z:C19H12ClF6N3O2:464.52[M+H]+。
实施例41:c10的合成
实验步骤与实施例1同,以4-氰基苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:53%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.43-10.20(m,1H),9.24(s,1H),8.72(d,J=8.3Hz,1H),8.48(d,J=7.5Hz,1H),7.86(t,J=8.4Hz,1H),7.67(s,1H),6.96(d,J=7.5Hz,2H),6.65(d,J=8.1Hz,2H),5.27(s,2H).m/z:C20H12F6N4O2:455.17[M+H]+。
实施例42:c11的合成
实验步骤与实施例1同,以4-三氟甲基苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:61%;淡黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.48-10.20(m,1H),8.79(d,J=8.5Hz,1H),8.56(s,1H),8.36(d,J=7.4Hz,1H),7.90(t,J=7.9Hz,1H),7.63(s,1H),7.47(d,J=8.4Hz,2H),6.89(d,J=8.4Hz,2H),5.28(s,2H).m/z:C20H12F9N3O2:498.08[M+H]+。
实施例43:c12的合成
实验步骤与实施例1同,以2,4-二氟苯肼代替苯基哌嗪,以乙酸乙酯代替最后一步溶剂二氯甲烷。
产率:61%;淡黄色固体;1HNMR(400MHz,DMSO-d6)δ:10.27(s,1H),8.78(d,J=8.4Hz,1H),8.35(d,J=7.1Hz,1H),7.90(t,J=8.0Hz,1H),7.83(s,1H),7.61(s,1H),7.22-7.12(m,1H),6.89(dd,J=7.0,4.8Hz,2H),5.24(s,2H).
m/z:C19H11F8N3O2:466.31[M+H]+。
实施例44:d1的合成
其具体合成操作如下:将中间体1(3.3mmol)加入到甲醇溶液(50mL)中,室温下缓慢加入水合肼(10mmol),然后在40摄氏度反应,可以观察到大量白色固体析出。将固体抽滤并用水洗涤,干燥之后得到中间体4。将化合物4(1mmol)和苯甲醛(1.3mmol)溶于乙醇溶液中,再加入0.1mL的冰乙酸后在80摄氏度回流反应8h,冷却至室温后得到白色固体,抽滤并用乙醇洗涤得到目标化合物d1。
产率:72%;白色固体;1H NMR(400MHz,DMSO-d6)δ:11.81(s,1H),8.60(d,J=8.4Hz,1H),8.33(d,J=7.7Hz,1H),8.06(s,1H),7.87(t,J=8.2Hz,1H),7.79-7.69(m,2H),7.64(d,J=7.3Hz,1H),7.47(d,J=7.4Hz,1H),7.46-7.43(m,2H),5.75(s,2H).m/z:C20H13F6N3O2:442.12[M+H]+。
实施例45:d2的合成
实验步骤与实施例44同,以2-氟苯甲醛代替苯甲醛。
产率:67%;白色固体;1H NMR(400MHz,DMSO-d6)δ:11.83(s,1H),8.62(d,J=8.5Hz,1H),8.36(d,J=7.8Hz,1H),8.09(s,1H),7.79-7.69(m,2H),7.64(d,J=7.4Hz,1H),7.51(d,J=7.8Hz,1H),7.46-7.43(m,2H),5.75(s,2H).m/z:C20H12F7N3O2:460.27[M+H]+。
实施例46:d3的合成
实验步骤与实施例44同,以3-氟苯甲醛代替苯甲醛。
产率:61%;白色固体;1H NMR(400MHz,DMSO-d6)δ:11.78(s,1H),8.61(d,J=8.45Hz,1H),8.33(d,J=7.7Hz,1H),8.12(s,1H),7.88(t,J=8.3Hz,1H),7.79-7.69(m,2H),7.45(d,J=7.6Hz,1H),7.48-7.42(m,2H),5.73(s,2H).m/z:C20H12F7N3O2:460.18[M+H]+。
实施例47:d4的合成
实验步骤与实施例44同,以4-氟苯甲醛代替苯甲醛。
产率:64%;白色固体;1H NMR(400MHz,DMSO-d6)δ:11.78(s,1H),8.61(d,J=8.45Hz,1H),8.33(d,J=7.7Hz,1H),8.12(s,1H),7.88(t,J=8.3Hz,1H),7.79-7.69(m,2H),7.45(d,J=7.6Hz,1H),7.48-7.42(m,2H),5.73(s,2H).m/z:C20H12F7N3O2:460.31[M+H]+。
实施例48:d5的合成
实验步骤与实施例44同,以2-甲基苯甲醛代替苯甲醛。
产率:67%;白色固体;1H NMR(400MHz,DMSO-d6)δ:11.76(s,1H),8.60(d,J=8.4Hz,1H),8.35(d,J=7.7Hz,1H),8.05(s,1H),7.76-7.64(m,2H),7.60(d,J=7.1Hz,1H),7.48(d,J=7.6Hz,1H),7.45-7.40(m,2H),5.73(s,2H),3.34(s,3H).m/z:C21H15F6N3O2:456.12[M+H]+。
实施例49:d6的合成
实验步骤与实施例44同,以3-甲基苯甲醛代替苯甲醛。
产率:74%;白色固体;1H NMR(400MHz,DMSO-d6)δ:11.74(s,1H),8.58(d,J=8.42Hz,1H),8.31(d,J=7.4Hz,1H),8.10(s,1H),7.85(t,J=8.1Hz,1H),7.76-7.64(m,2H),7.42(d,J=7.3Hz,1H),7.45-7.40(m,2H),5.72(s,2H),3.31(s,3H).m/z:C21H15F6N3O2:456.04[M+H]+。
实施例50:d7的合成
实验步骤与实施例44同,以4-甲基苯甲醛代替苯甲醛。
产率:70%;白色固体;1H NMR(400MHz,DMSO-d6)δ:11.71(s,1H),8.60(d,J=8.41Hz,1H),8.32(d,J=7.3Hz,1H),8.10(s,1H),7.85(t,J=8.2Hz,1H),7.76-7.67(m,2H),7.42(d,J=7.4Hz,1H),7.45-7.40(m,2H),5.70(s,2H).3.32(s,3H).m/z:C21H15F6N3O2:456.16[M+H]+。
实施例51:d8的合成
实验步骤与实施例44同,以4-氰基苯甲醛代替苯甲醛。
产率:57%;白色固体;1H NMR(400MHz,DMSO-d6)δ:11.79(s,1H),8.64(d,J=8.47Hz,1H),8.34(d,J=7.9Hz,1H),8.15(s,1H),7.89(t,J=8.5Hz,1H),7.81-7.71(m,2H),7.47(d,J=7.8Hz,1H),7.51-7.45(m,2H),5.77(s,2H).m/z:C21H12F6N4O2:467.07[M+H]+。
实施例52:d9的合成
实验步骤与实施例44同,以水杨代替苯甲醛。
产率:57%;白色固体;1HNMR(400MHz,DMSO-d6)δ:12.32(s,1H),11.23(d,J=7.52Hz,1H),8.65(d,J=8.44Hz,1H),8.32(d,J=7.5Hz,1H),8.16(s,1H),7.86(t,J=8.2Hz,1H),7.83-7.73(m,2H),7.45(d,J=7.6Hz,1H),7.42-7.36(m,2H),5.62(s,2H).m/z:C20H13F6N3O3:458.08[M+H]+。
实施例53:e1-e4的合成
e1和e3的制备:将中间体4(2.83mmol)和氢氧化钾(3.4mmol)加入乙醇溶液中,搅拌至反应物溶解,再滴加二硫化碳(5.7mmol),室温反应12h。反应结束后抽滤得到固体放干,将固体加入少量浓硫酸中,冰浴搅拌4h后,缓慢倒入冰水混合物中,过滤得到产物,然后溶解在10%氢氧化钠的水溶液中。将不溶物过滤,滤液用HCl将溶液酸化,并过滤得到产物e1。将化合物e1(1.5mmol)加入到30mL的二氯甲烷溶液中,在冰浴条件下加入三乙胺(1.5mmol),再加入碘甲烷(3mmol),室温反应5h,TLC点板监测。反应结束后将混合物倒入水中并用二氯甲烷萃取,有机相用无水硫酸钠干燥,减压旋干有机相,以石油醚/乙酸乙酯进行硅胶柱层析纯化得到化合物e3。
e2和e4的制备:将中间体4(2.83mmol)和氢氧化钾(3.4mmol)加入乙醇溶液中,搅拌至反应物溶解,再滴加二硫化碳(5.7mmol),先室温搅拌2h然后80摄氏度回流,TLC点板监测,反应结束旋干溶剂,然后加入盐水,用稀盐酸调节pH=5-6时析出沉淀,过滤得到白色产物e2。将化合物e2(1.5mmol)加入到30mL的二氯甲烷溶液中,在冰浴条件下加入三乙胺(1.5mmol),再加入碘甲烷(3mmol),室温反应5h,TLC点板监测。反应结束后将混合物倒入水中并用二氯甲烷萃取,有机相用无水硫酸钠干燥,减压旋干有机相,以石油醚/乙酸乙酯进行硅胶柱层析纯化得到化合物e4。
产率:43%;白色固体;1H NMR(400MHz,DMSO-d6)δ:14.80(s,1H),8.60-8.46(m,1H),8.36(d,J=7.3Hz,1H),7.90(t,J=7.9Hz,1H),7.79(s,1H),5.80(s,2H).
m/z:C14H7F6N3OS2:411.32[M+H]+。
实施例54:e2的合成
实验步骤如实施例53所示。
产率:63%;白色固体;1H NMR(400MHz,DMSO-d6)δ:14.72(s,1H),8.51(d,J=8.3Hz,1H),8.32(d,J=7.2Hz,1H),7.85(t,J=7.6Hz,1H),7.80(s,1H),5.75(s,2H).m/z:C14H7F6N3O2S:396.02[M+H]+
实施例55:e3的合成
实验步骤如实施例53所示。
产率:47%;白色固体;1H NMR(400MHz,DMSO-d6)δ:8.51(dd,J=8.6,1.4Hz,1H),8.36(d,J=7.3Hz,1H),7.96-7.82(m,2H),6.05(s,2H),2.81(s,3H).m/z:C15H9F6N3OS2:426.02[M+H]+
实施例56:e4的合成
实验步骤如实施例53所示。
产率:67%;白色固体;1H NMR(400MHz,DMSO-d6)δ:8.53(dd,J=8.4,1.2Hz,1H),8.32(d,J=7.2Hz,1H),7.92-7.78(m,2H),6.03(s,2H),2.82(s,3H).m/z:C15H9F6N3O2S:410.15[M+H]+
实施例57:f1的合成
将中间体4(1mmol)加入到30mL的二氯甲烷中,在冰浴条件下加入三乙胺(0.5mmol),再缓慢加入氯乙酰氯(1mmol),冰浴反应30min后在室温下反应24h。反应完成后用卤水洗涤,有机相用无水硫酸钠干燥。旋干有机相得固体,以石油醚/二乙为洗脱剂经柱层析纯化得白色固体产品3a。
产率:73%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.32(d,J=2.4Hz,1H),9.71(d,J=2.2Hz,1H)),8.52(dd,J=8.2,1.1Hz,1H),8.32(d,J=7.2Hz,1H),7.93-7.87(m,2H),6.04(s,2H),4.15(s,2H).m/z:C15H10ClF6N3O3:431.07[M+H]+
实施例58:f2的合成
实验步骤如实施例57所示,仅以氯丙酰氯代替氯乙酰氯。
产率:62%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.31(d,J=2.2Hz,1H),9.58(d,J=2.3Hz,1H),8.53(dd,J=8.5,1.7Hz,1H),8.36(d,J=7.4Hz,1H),7.91-7.81(m,2H),6.03(s,2H),4.15(s,2H),2.33(s,2H).m/z:C16H12ClF6N3O3:445.13[M+H]+
实施例59:f3的合成
实验步骤如实施例57所示,仅以叔丁酰氯代替氯乙酰氯。
产率:53%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.34(d,J=1.8Hz,1H),9.34(d,J=2.5Hz,1H)),8.58(dd,J=8.1,1.6Hz,1H),8.41(d,J=6.5Hz,1H),7.93-7.54(m,2H),6.05(s,2H),4.18(m,1H),1.26(s,6H).m/z:C17H15F6N3O3:424.10[M+H]+
实施例60:f4的合成
实验步骤如实施例57所示,仅以正丁酰氯代替氯乙酰氯。
产率:77%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.30(d,J=1.5Hz,1H),9.32(d,J=2.1Hz,1H)),8.48(dd,J=7.5,1.5Hz,1H),8.37(d,J=6.2Hz,1H),7.91-7.50(m,2H),6.05(s,2H),4.76(t,J=3.2Hz,2H),4.18(m,2H),1.26(t,J=2.5Hz,3H).m/z:C17H15F6N3O3:424.12[M+H]+
实施例61:g1的合成
将中间体4(1mmol)溶于3ml无水吡啶,加入乙基磺酰氯(1mmol),在室温下反应3h。反应完成后旋干溶剂,加入40ml二氯甲烷溶解,用水和卤水洗涤有机相,有机相用无水硫酸钠干燥。旋干有机相得固体,以二氯甲烷/丙酮为洗脱剂经柱层析纯化得到目标化合物g1。
产率:43%;白色固体;1H NMR(400MHz,DMSO-d6)δ:10.32(d,J=2.5Hz,1H),9.54(d,J=2.4Hz,1H),8.45(dd,J=7.2,1.4Hz,1H),8.38(d,J=6.4Hz,1H),7.93-7.52(m,2H),6.04(s,2H),3.45(m,2H),1.43(t,J=5.2Hz,3H).m/z:C15H13F6N3O4S:446.32[M+H]+
实施例62:g2的合成
实验步骤如实施例61所示,仅以邻氟苯磺酰氯代替乙基磺酰氯。
产率:54%;黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.35(d,J=2.4Hz,1H),9.55(d,J=2.4Hz,1H),9.54(d,J=2.4Hz,1H),8.35(d,J=7.3Hz,1H),7.89(t,J=7.8Hz,1H),7.78(d,J=8.0Hz,2H),7.71-7.60(m,1H),7.53-7.38(m,1H),7.26(d,J=7.9Hz,1H),5.08(s,2H).m/z:C19H12F7N3O4S:512.04[M+H]+
实施例63:g3的合成
实验步骤如实施例61所示,仅以间氟苯磺酰氯代替乙基磺酰氯。
产率:59%;黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.36(d,J=2.2Hz,1H),9.56(d,J=2.3Hz,1H),9.51(d,J=2.2Hz,1H),8.33(d,J=7.1Hz,1H),7.86(t,J=7.5Hz,1H),7.76(d,J=7.2Hz,2H),7.72-7.60(m,1H),7.54-7.35(m,1H),7.24(d,J=7.9Hz,1H),5.07(s,2H).m/z:C19H12F7N3O4S:512.12[M+H]+
实施例64:g4的合成
实验步骤如实施例61所示,仅以间氟苯磺酰氯代替乙基磺酰氯。
产率:54%;黄色固体;1H NMR(400MHz,DMSO-d6)δ:10.32(d,J=2.5Hz,1H),9.54(d,J=2.1Hz,1H),9.52(d,J=2.4Hz,1H),8.35(d,J=7.2Hz,1H),7.82(t,J=7.2Hz,1H),7.74(d,J=7.5Hz,2H),7.74-7.61(m,1H),7.55-7.34(m,1H),7.26(d,J=7.9Hz,1H),5.03(s,2H).m/z:C19H12F7N3O4S:512.06[M+H]+
实施例65:h1的合成
将肉桂酸(1mmol)溶解于适量的二氯亚砜之中,80摄氏度回流反应4h。反应结束后减压除去二氯亚砜,直接进行下一步反应无须纯化。在冰浴条件下向50mL的圆底烧瓶中加入2,8-双(三氟甲基)-4-羟基喹啉(1mmol),再加入三乙胺(0.5mmol),搅拌10min后缓慢滴加制备好的肉桂酸酰氯,在冰浴条件下反应30min,然后再室温下反应3h。反应结束后将混合物倒入水中并用二氯甲烷萃取,合并有机相用无水硫酸钠干燥,以石油醚/二乙为洗脱剂硅胶柱层析得到目标化合物h1。
产率:67%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.36-8.24(m,1H),8.19(d,J=7.2Hz,1H),8.04(d,J=15.9Hz,1H),7.87(s,1H),7.74(t,J=7.9Hz,1H),7.68-7.60(m,2H),7.51-7.48(m,2H),7.46(d,J=5.6Hz,1H),6.78(d,J=16.0Hz,1H).m/z:C20H11F6NO2:412.07[M+H]+
实施例66:h2的合成
实验步骤如实施例65所示,仅以邻氟肉桂酸代替肉桂酸。
产率:75%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.24(d,J=8.5Hz,1H),8.14(d,J=7.3Hz,1H),8.07(d,J=16.2Hz,1H),7.80(s,1H),7.68(t,J=7.9Hz,1H),7.63-7.52(m,1H),7.40(m,1H),7.24-7.15(m,1H),7.12(dd,J=10.8,8.3Hz,1H),6.82(d,J=16.1Hz,1H).m/z:C20H10F7NO2:430.06[M+H]+
实施例67:h3的合成
实验步骤如实施例65所示,仅以间氟肉桂酸代替肉桂酸。
产率:71%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.30(d,J=8.5Hz,1H),8.21(d,J=7.2Hz,1H),7.99(d,J=16.0Hz,1H),7.87(s,1H),7.75(t,J=7.9Hz,1H),7.50-7.40(m,2H),7.36(d,J=9.5Hz,1H),7.24-7.13(m,1H),6.77(d,J=15.9Hz,1H).m/z:C20H10F7NO2:430.14[M+H]+
实施例68:h4的合成
实验步骤如实施例65所示,仅以对氟肉桂酸代替肉桂酸。
产率:75%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.28(d,J=8.3Hz,1H),8.24(d,J=7.4Hz,1H),7.95(d,J=14.0Hz,1H),7.85(s,1H),7.76(t,J=7.8Hz,1H),7.52-7.44(m,2H),7.38(d,J=9.4Hz,1H),7.25-7.12(m,1H),6.78(d,J=15.8Hz,1H).m/z:C20H10F7NO2:430.04[M+H]+
实施例69:h5的合成
实验步骤如实施例65所示,仅以对乙基肉桂酸代替肉桂酸。
产率:58%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.20(d,J=8.1Hz,1H),8.21(d,J=7.2Hz,1H),7.92(d,J=13.5Hz,1H),7.82(s,1H),7.70(t,J=7.5Hz,1H),7.50-7.43(m,2H),7.36(d,J=9.2Hz,1H),7.23-7.13(m,1H),6.74(d,J=15.8Hz,1H),3.45(m,2H),1.43(t,J=5.2Hz,3H).m/z:C22H15F6NO2:440.10[M+H]+
实施例70:h6的合成
实验步骤如实施例65所示,仅以邻甲基肉桂酸代替肉桂酸。
产率:55%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.24(d,J=8.4Hz,1H),8.13(d,J=7.3Hz,1H),7.94(d,J=15.9Hz,1H),7.80(s,1H),7.67(t,J=7.9Hz,1H),7.40(s,2H),7.30(t,J=7.8Hz,1H),7.24(d,J=7.7Hz,1H),6.69(d,J=15.9Hz,1H),2.36(s,3H).m/z:C21H13F6NO2:426.08[M+H]+
实施例71:h7的合成
实验步骤如实施例65所示,仅以间甲基肉桂酸代替肉桂酸。
产率:51%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.22(d,J=8.2Hz,1H),8.12(d,J=7.4Hz,1H),7.92(d,J=15.6Hz,1H),7.82(s,1H),7.68(t,J=7.6Hz,1H),7.42(s,2H),7.28(t,J=7.6Hz,1H),7.22(d,J=7.6Hz,1H),6.65(d,J=15.6Hz,1H),2.35(s,3H).m/z:C21H13F6NO2:426.03[M+H]+
实施例72:h8的合成
实验步骤如实施例65所示,仅以对甲基肉桂酸代替肉桂酸。
产率:67%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.22(d,J=8.1Hz,1H),8.22(d,J=7.2Hz,1H),7.92(d,J=13.0Hz,1H),7.82(s,1H),7.74(t,J=7.5Hz,1H),7.50-7.43(m,2H),7.41(d,J=9.2Hz,1H),7.23-7.11(m,1H),6.71(d,J=15.6Hz,1H),2.32(s,3H).m/z:C21H13F6NO2:426.06[M+H]+
实施例73:h9的合成
实验步骤如实施例65所示,仅以邻氯肉桂酸代替肉桂酸。
产率:72%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.22(d,J=8.3Hz,1H),8.12(d,J=7.2Hz,1H),8.03(d,J=15.8Hz,1H),7.75(s,1H),7.64(t,J=7.6Hz,1H),7.62-7.50(m,1H),7.36(m,1H),7.25-7.14(m,1H),7.14(dd,J=10.8,8.3Hz,1H),6.84(d,J=16.1Hz,1H).m/z:C20H10ClF6NO2:446.01[M+H]+
实施例74:h10的合成
实验步骤如实施例65所示,仅以间氯肉桂酸代替肉桂酸。
产率:66%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.25(d,J=8.4Hz,1H),8.14(d,J=7.4Hz,1H),8.05(d,J=15.8Hz,1H),7.76(s,1H),7.65(t,J=7.8Hz,1H),7.64-7.52(m,1H),7.38(m,1H),7.26-7.16(m,1H),7.16(dd,J=10.5,8.5Hz,1H),6.85(d,J=16.1Hz,1H).m/z:C20H10ClF6NO2:446.06[M+H]+
实施例75:h11的合成
实验步骤如实施例65所示,仅以对氯肉桂酸代替肉桂酸。
产率:62%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.27(d,J=8.4Hz,1H),8.16(d,J=7.5Hz,1H),8.06(d,J=15.4Hz,1H),7.75(s,1H),7.62(t,J=7.6Hz,1H),7.65-7.50(m,1H),7.36(m,1H),7.24-7.17(m,1H),7.14(dd,J=9.8,8.2Hz,1H),6.82(d,J=15.8Hz,1H).m/z:C20H10ClF6NO2:446.10[M+H]+
实施例76:h12的合成
实验步骤如实施例65所示,仅以2-溴-4-氟肉桂酸代替肉桂酸。
产率:69%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.31(d,J=7.8Hz,1H),8.22(d,J=5.6Hz,1H),8.04(d,J=15.2Hz,1H),7.65(s,1H),7.66(t,J=7.6Hz,1H),7.64-7.50(m,1H),7.26-7.19(m,1H),7.14(dd,J=8.6,8.2Hz,1H),6.88(d,J=15.8Hz,1H).m/z:C20H9BrF7NO2:507.14[M+H]+
实施例77:h13的合成
实验步骤如实施例65所示,仅以2,6-二氟肉桂酸代替肉桂酸。
产率:62%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.30(d,J=7.6Hz,1H),8.21(d,J=7.2Hz,1H),8.01(d,J=13.8Hz,1H),7.82(s,1H),7.67(t,J=7.6Hz,1H),7.46(m,1H),7.22-7.15(m,1H),7.16(dd,J=8.3,7.5Hz,1H),6.85(d,J=15.4Hz,1H).m/z:C20H9F8NO2:448.05[M+H]+
实施例78:h14的合成
实验步骤如实施例65所示,仅以3,4-二氯肉桂酸代替肉桂酸。
产率:67%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.31(d,J=7.8Hz,1H),8.24(d,J=7.5Hz,1H),8.03(d,J=13.5Hz,1H),7.84(s,1H),7.62(t,J=7.1Hz,1H),7.46(m,1H),7.22-7.15(m,1H),7.16(dd,J=8.3,7.5Hz,1H),6.85(d,J=15.4Hz,1H).m/z:C20H9Cl2F6NO2:479.34[M+H]+
实施例79:h15的合成
实验步骤如实施例65所示,仅以2,6-二氯肉桂酸代替肉桂酸。
产率:74%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.33(d,J=7.6Hz,1H),8.22(d,J=7.6Hz,1H),8.02(d,J=13.2Hz,1H),7.85(s,1H),7.78(t,J=7.6Hz,1H),7.52(m,1H),7.23-7.16(m,1H),7.12(dd,J=6.3,5.7Hz,1H),6.82(d,J=12.7Hz,1H).m/z:C20H9Cl2F6NO2:479.18[M+H]+
实施例80:h16的合成
实验步骤如实施例65所示,仅以邻三氟甲基肉桂酸代替肉桂酸。
产率:71%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.21(d,J=8.4Hz,1H),8.12(d,J=7.4Hz,1H),8.04(d,J=15.6Hz,1H),7.72(s,1H),7.67(t,J=7.8Hz,1H),7.63-7.52(m,1H),7.38(m,1H),7.26-7.15(m,1H),7.10(dd,J=9.4,8.2Hz,1H),6.75(d,J=15.8Hz,1H).m/z:C21H10Cl2F9NO2:480.07[M+H]+
实施例81:h17的合成
实验步骤如实施例65所示,仅以间三氟甲基肉桂酸代替肉桂酸。
产率:65%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.32(d,J=8.4Hz,1H),8.22(d,J=7.5Hz,1H),7.94(d,J=15.5Hz,1H),7.82(s,1H),7.73(t,J=7.8Hz,1H),7.48-7.43(m,2H),7.34(d,J=9.2Hz,1H),7.21-7.12(m,1H),6.75(d,J=15.4Hz,1H).m/z:C21H10Cl2F9NO2:480.11[M+H]+
实施例82:h18的合成
实验步骤如实施例65所示,仅以对三氟甲基肉桂酸代替肉桂酸。
产率:73%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.31(dd,J=8.6,1.3Hz,1H),8.22(d,J=7.2Hz,1H),8.05(d,J=16.0Hz,1H),7.87(s,1H),7.77(d,J=7.9Hz,3H),7.74(d,J=8.4Hz,2H),6.86(d,J=16.0Hz,1H).m/z:C21H10Cl2F9NO2:480.03[M+H]+
实施例83:h19的合成
实验步骤如实施例65所示,仅以2,4-二甲基肉桂酸代替肉桂酸。
产率:62%;白色固体;1H NMR(400MHz,CDCl3-d6)δ:8.32(d,J=7.7Hz,1H),8.25(d,J=7.4Hz,1H),8.02(d,J=13.4Hz,1H),7.85(s,1H),7.64(t,J=7.4Hz,1H),7.45(m,1H),7.23-7.14(m,1H),7.18(dd,J=8.4,7.6Hz,1H),6.86(d,J=15.2Hz,1H),2.41(s,3H),2.30(s,3H).m/z:C22H15Cl2F6NO2:440.10[M+H]+
实施例84:h20的合成
实验步骤如实施例65所示,仅以3,5-二甲基肉桂酸代替肉桂酸。
产率:65%;白色固体1H NMR(400MHz,CDCl3-d6)δ:8.33(d,J=7.6Hz,1H),8.24(d,J=7.2Hz,1H),8.01(d,J=13.5Hz,1H),7.84(s,1H),7.66(t,J=7.5Hz,1H),7.46(m,1H),7.24-7.20(dd,J=8.2,7.6Hz,1H),7.16(m,1H),6.86(d,J=14.3Hz,1H),2.42(s,3H),2.32(s,3H).m/z:C22H15Cl2F6NO2:440.06[M+H]+
实施例85:h21的合成
实验步骤如实施例65所示,仅以丙烯酸代替肉桂酸。
产率:65%;白色固体1H NMR(400MHz,CDCl3-d6)δ:8.31-8.11(m,2H),7.87-7.64(m,2H),6.88-6.75(m,1H),6.49(dd,J=17.3,10.5Hz,1H),6.33-6.14(m,1H).m/z:C14H7Cl2F6NO2:336.06[M+H]+
实施例86:i1的合成
其具体合成操作如下:氩气保护搅拌回流下,将POBr3(113.81mmol)于75℃下热熔后,加入2,8-双(三氟甲基)-4-羟基喹啉(28.45mmol),然后升温至150摄氏度,回流反应6h后,剧烈搅拌下,逐滴加入冰水中,有大量白色固体析出,抽滤并水洗,自然晾干后得中间体1,无需进一步纯化,直接投下步反应。氩气保护室温搅拌下,将(±)环氧丙醇(20.927mmol)溶于THF中,然后将NaH(26.159mmol)分三次加入反应体系中,15~30min后,加入中间体1(17.439mmol)。TLC监测反应进程,6h后反应完毕。真空旋干溶剂后,以乙酸乙酯萃取,并用蒸馏水洗三次,有机相无水硫酸钠干燥后,以石油醚:乙酸乙酯(8:1~3:1)进行硅胶柱层析分离,得中间体2。加热回流搅拌下,以异丙醇(10mL)为溶剂,先后加入1-(2-氟苯基)哌嗪(0.712mmol)、中间体2(0.593mmol),TLC检测下,8h后反应完毕,无需后处理,旋干溶剂后,以二氯甲烷:甲醇(200:1~50:1)硅胶柱层析分离,得白色固体i1。
产率:69%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.66(d,J=8.4Hz,1H),8.33(d,J=7.3Hz,1H),7.88(t,J=7.9Hz,1H),7.61(s,1H),7.18–7.06(m,2H),7.04–6.89(m,2H),5.24(d,J=5.0Hz,1H),4.50(dd,J=10.4,3.3Hz,1H),4.39(dd,J=10.4,5.9Hz,1H),4.21(m,1H),3.00(t,J=4.9Hz,4H),2.75–2.52(m,6H).m/z:C24H22F7N3O2:518.13[M+H]+.
实施例87:i2的合成
实验步骤与实施例86同,仅以1-(4-吡啶基)哌嗪代替1-(2-氟苯基)哌嗪。
产率:64%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.68(d,J=8.4Hz,1H),8.33(d,J=7.1Hz,1H),8.25(d,J=6.9Hz,2H),7.88(t,J=8.0Hz,1H),7.61(s,1H),7.19(d,J=7.1Hz,2H),5.56–5.37(m,1H),4.50(dd,J=10.3,3.6Hz,1H),4.40(dd,J=10.3,5.8Hz,1H),4.28(m,1H),3.71(t,J=5.2Hz,4H),2.83–2.64(m,6H).m/z:C23H22F6N4O2:501.13[M+H]+.
实施例88:i3的合成
实验步骤与实施例86同,仅以吗啉代替1-(2-氟苯基)哌嗪。
产率:55%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.63(d,J=8.4Hz,1H),8.30(d,J=7.2Hz,1H),7.85(t,J=8.0Hz,1H),7.58(s,1H),5.12(m,J=5.2Hz,1H),4.47(dd,J=10.3,3.4Hz,1H),4.36(dd,J=10.4,5.9Hz,1H),4.19(m,J=9.5,5.8Hz,1H),3.58(t,J=4.6Hz,4H),2.66–2.52(m,8H).m/z:C18H18F6N2O3:425.10[M+H]+.
实施例89:i4的合成
实验步骤与实施例86同,仅以1-乙基哌嗪代替1-(2-氟苯基)哌嗪。
产率:58%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.64(d,J=8.4Hz,1H),8.32(d,J=7.1Hz,1H),7.87(t,J=8.0Hz,1H),7.58(s,1H),5.28(s,1H),4.46(dd,J=10.3,3.4Hz,1H),4.35(dd,J=10.3,5.9Hz,1H),4.16(m,J=8.3,6.6Hz,1H),3.82–3.44(m,4H),2.83–2.53(m,8H),1.06(t,J=7.2Hz,3H).m/z:C20H23F6N3O2:452.13[M+H]+.
实施例90:i5的合成
实验步骤与实施例86同,仅以1-甲基哌嗪代替1-(2-氟苯基)哌嗪。
产率:76%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.64(d,J=8.4Hz,1H),8.32(d,J=7.3Hz,1H),7.87(t,J=7.9Hz,1H),7.58(s,1H),5.25(s,1H),4.46(dd,J=10.4,3.4Hz,1H),4.35(dd,J=10.3,5.9Hz,1H),4.21–4.11(m,1H),2.73–2.52(m,10H),2.30(s,3H).m/z:C19H21F6N3O2:438.13[M+H]+.
实施例91:i6的合成
实验步骤与实施例86同,仅以1-异丙基哌嗪代替1-(2-氟苯基)哌嗪。
产率:55%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.64(d,J=8.4Hz,1H),8.32(d,J=7.3Hz,1H),7.87(t,J=7.9Hz,1H),7.58(s,1H),5.23(s,1H),4.47(dd,J=10.4,3.3Hz,1H),4.36(dd,J=10.4,5.9Hz,1H),4.15(m,J=5.5,5.0Hz,1H),3.67–3.41(m,2H),2.81–2.53(m,9H),1.00(d,J=6.5Hz,6H).m/z:C21H25F6N3O2:466.16[M+H]+.
实施例92:i7的合成
实验步骤与实施例86同,仅以1-新丁基哌嗪代替1-(2-氟苯基)哌嗪。
产率:52%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.65(d,J=8.4Hz,1H),8.33(d,J=7.2Hz,1H),7.88(t,J=8.0Hz,1H),7.59(s,1H),5.21(s,1H),4.47(dd,J=10.4,3.3Hz,1H),4.37(dd,J=10.4,5.9Hz,1H),4.15(m,1H),3.00(m,J=16.5Hz,1H),2.77–2.25(m,9H),1.10–0.80(m,9H).m/z:C22H27F6N3O2:480.18[M+H]+.
实施例93:i8的合成
实验步骤与实施例86同,仅以1-乙酰基哌嗪代替1-(2-氟苯基)哌嗪。
产率:54%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.65(d,J=8.4Hz,1H),8.33(d,J=7.2Hz,1H),7.88(t,J=7.9Hz,1H),7.60(s,1H),5.26(d,J=5.1Hz,1H),4.48(dd,J=10.3,3.4Hz,1H),4.37(dd,J=10.3,6.0Hz,1H),4.19(m,1H),3.48–3.39(m,10H),2.60(dd,J=12.8,6.3Hz,1H),2.52(m,1H),1.98(s,3H).m/z:C20H21F6N3O3:466.10[M+H]+.
实施例94:i9的合成
实验步骤与实施例86同,仅以1-(4-氟苯基)哌嗪代替1-(2-氟苯基)哌嗪。
产率:62%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.65(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.59(s,1H),7.14–7.05(m,2H),7.03–6.90(m,2H),5.22(d,J=5.0Hz,1H),4.48(dd,J=10.4,3.3Hz,1H),4.37(dd,J=10.4,5.9Hz,1H),4.20(m,J=8.5Hz,1H),2.99(t,J=4.9Hz,4H),2.72–2.51(m,6H).m/z:C24H22F7N3O2:518.15[M+H]+.
实施例95:i10的合成
实验步骤与实施例86同,仅以1-(4-氯苯基)哌嗪代替1-(2-氟苯基)哌嗪。
产率:64%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.64(d,J=8.4Hz,1H),8.30(d,J=7.2Hz,1H),7.85(t,J=8.9Hz,1H),7.58(s,1H),7.19(d,J=8.9Hz,2H),6.90(d,J=8.9Hz,2H),5.23(d,J=5.1Hz,1H),4.48(dd,J=10.4,3.3Hz,1H),4.37(dd,J=10.3,6.0Hz,1H),4.19(m,J=6.1Hz,1H),3.10(t,J=5.0Hz,4H),2.60(m,6H).m/z:C24H22ClF6N3O2:534.12[M+H]+.
实施例96:i11的合成
实验步骤与实施例86同,仅以苄胺代替1-(2-氟苯基)哌嗪。
产率:51%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.56(d,J=8.4Hz,1H),8.32(d,J=7.5Hz,1H),7.85(t,J=8.0Hz,1H),7.58(s,1H),7.36(d,J=7.0Hz,2H),7.28(t,J=7.3Hz,2H),7.22(m,J=7.1,5.0Hz,1H),5.34(s,1H),4.48(dd,J=10.2,3.9Hz,1H),4.36(dd,J=10.2,6.0Hz,1H),4.14(m,J=5.7Hz,1H),3.83(s,2H),2.83(dd,J=12.0,5.5Hz,1H),2.76(dd,J=12.0,6.7Hz,1H).m/z:C21H18F6N2O2:445.08[M+H]+.
实施例97:i12的合成
实验步骤与实施例86同,仅以4-氟苄胺代替1-(2-氟苯基)哌嗪。
产率:52%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.55(d,J=8.5Hz,1H),8.32(d,J=7.3Hz,1H),7.84(t,J=7.9Hz,1H),7.58(s,1H),7.36(dd,J=8.4,5.6Hz,2H),7.05(t,J=8.7Hz,2H),5.31(s,J=11.5Hz,1H),4.47(dd,J=10.2,3.8Hz,1H),4.36(dd,J=10.2,6.0Hz,1H),4.10(m,J=5.4Hz,1H),3.75(s,2H),2.75(dd,J=12.1,5.9Hz,1H),2.69(dd,J=12.0,6.5Hz,1H).m/z:C21H17F7N2O2:463.07[M+H]+.
实施例98:i13的合成
实验步骤与实施例86同,仅以4-氯苄胺代替1-(2-氟苯基)哌嗪。
产率:60%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.54(d,J=8.5Hz,1H),8.32(d,J=7.3Hz,1H),7.84(t,J=7.9Hz,1H),7.58(s,1H),7.36(d,J=8.2Hz,2H),7.29(d,J=8.3Hz,2H),5.32(s,1H),4.47(dd,J=10.2,3.8Hz,1H),4.36(dd,J=10.2,6.0Hz,1H),4.18–4.04(m,1H),3.77(s,2H),2.75(dd,J=12.0,5.7Hz,1H),2.70(dd,J=12.0,6.4Hz,1H).m/z:C21H17ClF6N2O2:479.07[M+H]+.
实施例99:i14的合成
实验步骤与实施例86同,仅以4-甲氧基苄胺代替1-(2-氟苯基)哌嗪。
产率:55%;白色固体;1HNMR(400MHz,DMSO-d6)δ8.57(dd,J=8.5,1.4Hz,1H),8.34(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.58(s,1H),7.38–7.30(m,2H),6.94–6.85(m,2H),5.32(s,1H),4.46(dd,J=10.4,4.1Hz,1H),4.37(dd,J=10.3,5.8Hz,1H),4.25(m,1H),3.94(s,2H),3.73(s,3H),2.96(dd,J=12.2,4.4Hz,1H),2.86(dd,J=12.3,7.7Hz,1H).m/z:C22H20F6N2O3:475.10[M+H]+.
实施例100:i15的合成
实验步骤与实施例86同,仅以4-三氟甲基苄胺代替1-(2-氟苯基)哌嗪。
产率:49%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.61(d,J=8.4Hz,1H),8.34(d,J=7.3Hz,1H),7.87(t,J=7.9Hz,1H),7.79(m,4H),7.59(s,1H),5.33(s,1H),4.49(m,2H),4.27(s,2H),4.15(m,1H),3.40(m,2H).m/z:C22H17F9N2O2:513.09[M+H]+.
实施例101:i16的合成
实验步骤与实施例86同,仅以4-甲基苄胺代替1-(2-氟苯基)哌嗪。
产率:52%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.54(d,J=8.4Hz,1H),8.32(d,J=7.3Hz,1H),7.84(t,J=7.9Hz,1H),7.58(s,1H),7.18(d,J=7.7Hz,2H),7.02(d,J=7.7Hz,2H),5.26(d,J=5.0Hz,1H),4.46(dd,J=10.2,3.8Hz,1H),4.35(dd,J=10.2,6.0Hz,1H),4.08(m,J=5.1Hz,1H),3.70(s,2H),2.72(dd,J=6.1Hz,1H),2.68(dd,J=12.4,6.7Hz,1H),2.22(s,3H).m/z:C22H20F6N2O2:459.09[M+H]+.
实施例102:i17的合成
实验步骤与实施例86同,仅以糠胺代替1-(2-氟苯基)哌嗪。
产率:56%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.61(d,J=8.5Hz,1H),8.33(d,J=7.0Hz,1H),7.87(t,J=7.9Hz,1H),7.59(s,1H),7.56(d,J=1.9Hz,1H),6.37(m,1H),6.27(d,J=3.2Hz,1H),5.36(s,1H),4.46(dd,J=10.3,3.7Hz,1H),4.33(dd,J=10.2,6.2Hz,1H),4.13–4.07(m,1H),3.77(s,2H),2.94(m,1H),2.76(dd,J=11.3,6.1Hz,1H).m/z:C19H16F6N2O3:435.03[M+H]+.
实施例103:i18的合成
实验步骤与实施例86同,仅以2-氨甲基噻吩代替1-(2-氟苯基)哌嗪。
产率:59%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.65–8.53(d,1H),8.32(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.58(s,1H),7.34(dd,J=5.0,1.3Hz,1H),6.98(d,J=3.4Hz,1H),6.93(dd,J=5.1,3.4Hz,1H),5.42–5.25(s,1H),4.47(dd,J=10.2,3.8Hz,1H),4.35(dd,J=10.2,6.1Hz,1H),4.21–4.07(m,1H),3.97(s,2H),2.82(dd,J=12.0,5.7Hz,1H),2.75(dd,J=12.1,6.5Hz,1H).m/z:C19H16F6N2O2S:451.13[M+H]+.
实施例104:i19的合成
实验步骤与实施例86同,仅以2-氟苄胺代替1-(2-氟苯基)哌嗪。
产率:64%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.58(d,J=8.5Hz,1H),8.32(d,J=7.4Hz,1H),7.85(t,J=7.9Hz,1H),7.58(s,1H),7.46(t,J=7.7Hz,1H),7.25(m,J=7.1Hz,1H),7.11(m,J=8.0,6.4Hz,2H),5.32(s,J=6.6Hz,1H),4.47(dd,J=10.2,3.8Hz,1H),4.36(dd,J=10.2,6.1Hz,1H),4.11(m,1H),3.81(s,2H),2.76(m,J=10.2Hz,2H).m/z:C21H17F7N2O2:463.07[M+H]+.
实施例105:i20的合成
实验步骤与实施例86同,仅以3-氟苄胺代替1-(2-氟苯基)哌嗪。
产率:56%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.56(d,J=8.4Hz,1H),8.33(d,J=7.2Hz,1H),7.84(t,J=7.9Hz,1H),7.59(s,1H),7.29(d,J=8.5Hz,1H),7.20–7.13(m,2H),6.98(td,J=8.5,2.7Hz,1H),5.25(d,J=5.5Hz,1H),4.47(dd,J=10.2,3.8Hz,1H),4.36(dd,J=10.2,6.0Hz,1H),4.11(m,1H),3.79(s,2H),2.75(dd,J=12.0,5.9Hz,1H),2.69(dd,J=11.9,6.3Hz,1H).m/z:C21H17F7N2O2:462.13[M+H]+.
实施例106:i21的合成
实验步骤与实施例86同,仅以N-甲基-4-氟苄胺代替1-(2-氟苯基)哌嗪。
产率:75%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.42(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.80(t,J=7.9Hz,1H),7.53(s,1H),7.26(dd,J=8.3,5.6Hz,2H),6.88(t,J=8.7Hz,2H),5.17(d,J=5.3Hz,1H),4.41(dd,J=10.2,3.4Hz,1H),4.33(dd,J=10.2,5.0Hz,1H),4.12(m,J=7.9Hz,1H),3.56(d,J=13.1Hz,1H),3.43(d,J=13.2Hz,1H),2.67(dd,J=12.6,7.5Hz,1H),2.43(dd,J=12.6,5.6Hz,1H),2.26(s,3H).m/z:C22H19F7N2O2:477.09[M+H]+.
实施例107:i22的合成
实验步骤与实施例86同,仅以2-氯苄胺代替1-(2-氟苯基)哌嗪。
产率:66%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.58(d,J=8.5Hz,1H),8.32(d,J=7.3Hz,1H),7.85(t,J=7.9Hz,1H),7.58(s,1H),7.52(dd,J=6.8,2.7Hz,1H),7.37(dd,J=6.8,2.5Hz,1H),7.22(m,J=7.9,7.0,3.8Hz,2H),5.25(m,1H),4.48(dd,J=10.2,3.8Hz,1H),4.37(dd,J=10.2,5.9Hz,1H),4.12(s,1H),3.85(s,2H),2.80(dd,J=12.0,5.7Hz,1H),2.74(dd,J=12.0,6.4Hz,1H).m/z:C21H17ClF6N2O2:479.04[M+H]+.
实施例108:i23的合成
实验步骤与实施例86同,仅以N-甲基-4-氯苄胺代替1-(2-氟苯基)哌嗪。
产率:66%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.40(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.80(t,J=7.9Hz,1H),7.54(s,1H),7.26(d,J=8.1Hz,2H),7.11(d,J=8.2Hz,2H),5.18(d,J=5.3Hz,1H),4.41(dd,J=10.2,3.3Hz,1H),4.34(dd,J=10.1,4.8Hz,1H),4.19–4.06(m,1H),3.58(d,J=13.4Hz,1H),3.44(d,J=13.4Hz,1H),2.68(dd,J=12.6,7.5Hz,1H),2.43(dd,J=12.6,5.5Hz,1H),2.27(s,3H).m/z:C22H19ClF6N2O2:493.06[M+H]+.
实施例109:i24的合成
实验步骤与实施例86同,仅以N-甲基-3-氯苄胺代替1-(2-氟苯基)哌嗪。
产率:65%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.42(d,J=8.5Hz,1H),8.31(d,J=7.4Hz,1H),7.80(t,J=7.9Hz,1H),7.54(s,1H),7.29(s,1H),7.20(d,J=7.6Hz,1H),7.13(t,J=7.7Hz,1H),7.04(d,J=7.9Hz,1H),5.22(d,J=5.1Hz,1H),4.42(dd,J=10.2,3.4Hz,1H),4.34(dd,J=10.2,4.9Hz,1H),4.15(m,1H),3.60(d,J=13.5Hz,1H),3.48(d,J=13.4Hz,1H),2.70(dd,J=12.6,7.3Hz,1H),2.43(m,1H),2.28(s,3H).m/z:C22H19ClF6N2O2:493.07[M+H]+.
实施例110:i25的合成
实验步骤与实施例86同,仅以4-溴苄胺代替1-(2-氟苯基)哌嗪。
产率:55%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.54(d,J=8.5Hz,1H),8.33(d,J=7.4Hz,1H),7.84(t,J=7.9Hz,1H),7.58(s,1H),7.41(d,J=8.0Hz,2H),7.28(d,J=8.0Hz,2H),5.28(s,1H),4.46(dd,J=10.1,3.8Hz,1H),4.35(dd,J=10.2,6.0Hz,1H),4.08(m,J=5.5Hz,1H),3.73(s,2H),2.76(m,1H),2.67(dd,J=12.2,6.4Hz,1H).m/z:C21H17BrF6N2O2:524.98[M+H]+.
实施例111:i26的合成
实验步骤与实施例86同,仅以N-甲基苄胺代替1-(2-氟苯基)哌嗪。
产率:68%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.45(d,J=8.4Hz,1H),8.30(d,J=7.3Hz,1H),7.81(t,J=7.9Hz,1H),7.53(s,1H),7.24(d,J=8.1Hz,2H),7.12(t,J=7.4Hz,2H),7.05(t,J=7.3Hz,1H),5.18(d,J=5.2Hz,1H),4.43(dd,J=10.2,3.2Hz,1H),4.32(dd,J=10.2,5.2Hz,1H),4.13(m,J=8.5Hz,1H),3.59(d,J=13.2Hz,1H),3.45(d,J=13.1Hz,1H),2.68(dd,J=12.6,7.4Hz,1H),2.45(dd,J=12.7,5.7Hz,1H),2.26(s,3H).m/z:C22H20F6N2O2:459.10[M+H]+.
实施例112:i27的合成
实验步骤与实施例86同,仅以2,4-二氟苄胺代替1-(2-氟苯基)哌嗪。
产率:44%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.59(d,J=8.4Hz,1H),8.33(d,J=7.3Hz,1H),7.86(t,J=7.9Hz,1H),7.57(m,2H),7.19(td,J=10.0,2.7Hz,1H),7.04(td,J=8.5,2.6Hz,1H),5.58(s,1H),4.47(dd,J=10.3,3.9Hz,1H),4.37(dd,J=10.3,5.8Hz,1H),4.23–4.15(m,1H),3.93(s,2H),2.92(dd,J=12.2,4.9Hz,1H),2.84(dd,J=12.2,7.2Hz,1H).m/z:C21H16F8N2O2:481.06[M+H]+.
实施例113:i28的合成
实验步骤与实施例86同,仅以3,5-二氟苄胺代替1-(2-氟苯基)哌嗪。
产率:61%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.54(d,J=8.4Hz,1H),8.31(d,J=7.3Hz,1H),7.83(t,J=7.9Hz,1H),7.57(s,1H),7.05(dd,J=2.4Hz,1H),7.03(dd,J=2.3Hz,1H),6.95(tt,J=9.4,2.5Hz,1H),5.31(s,1H),4.47(dd,J=10.1,3.9Hz,1H),4.37(dd,J=10.2,5.8Hz,1H),4.09(m,J=5.6Hz,1H),3.79(s,2H),2.75(dd,J=12.1,5.9Hz,1H),2.69(dd,J=12.0,6.3Hz,1H).m/z:C21H16F8N2O2:481.08[M+H]+.
实施例114:i29的合成
实验步骤与实施例86同,仅以六氢吡啶代替1-(2-氟苯基)哌嗪。
产率:57%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.64(d,J=8.4Hz,1H),8.32(d,J=7.3Hz,1H),7.87(t,J=7.8Hz,1H),7.59(s,1H),5.07(s,J=5.3Hz,1H),4.47(dd,J=10.4,3.4Hz,1H),4.36(dd,J=10.4,5.9Hz,1H),4.19(m,1H),2.66–2.55(m,6H),1.52(m,4H),1.40(m,2H).m/z:C19H20F6N2O2:423.10[M+H]+.
实施例115:i30的合成
实验步骤与实施例86同,仅以二乙胺代替1-(2-氟苯基)哌嗪。
产率:70%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.64(d,J=8.4Hz,1H),8.32(d,J=7.3Hz,1H),7.87(t,J=7.9Hz,1H),7.59(s,2H),5.18(s,1H),4.47(dd,J=10.4,3.1Hz,1H),4.38(dd,J=10.3,5.6Hz,1H),4.07(m,2H),2.76–2.53(m,4H),0.96(t,J=7.1Hz,6H).m/z:C18H20F6N2O2:411.10[M+H]+.
实施例116:i31的合成
实验步骤与实施例86同,仅以四氢吡咯代替1-(2-氟苯基)哌嗪。
产率:65%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.67(d,J=8.4Hz,1H),8.33(d,J=7.3Hz,1H),7.88(t,J=7.9Hz,1H),7.61(s,1H),5.53(s,1H),4.48(dd,J=10.3,3.6Hz,1H),4.38(dd,J=10.4,5.8Hz,1H),4.22(m,1H),2.96(dd,J=12.6,5.8Hz,1H),2.78(m,5H),1.93–1.70(m,4H).m/z:C18H18F6N2O2:409.08[M+H]+.
实施例117:i32的合成
实验步骤与实施例86同,仅以二甲胺代替1-(2-氟苯基)哌嗪。
产率:57%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.65(d,J=8.4Hz,1H),8.33(d,J=7.2Hz,1H),7.88(t,J=7.9Hz,1H),7.60(s,1H),5.30(s,1H),4.47(dd,J=10.3,3.2Hz,1H),4.34(dd,J=10.3,6.0Hz,1H),4.21–4.06(m,1H),2.61(dd,J=12.5,6.5Hz,1H),2.51–2.44(m,1H),2.29(s,6H).m/z:C16H16F6N2O2:383.08[M+H]+.
实施例118:i33的合成
实验步骤与实施例86同,仅以3-甲基哌啶代替1-(2-氟苯基)哌嗪。
产率:61%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.71(d,J=8.5Hz,1H),8.39(d,J=7.3Hz,1H),7.94(t,J=7.9Hz,1H),7.65(d,J=2.0Hz,1H),5.31(s,2H),4.54(dd,J=10.6,3.2Hz,1H),4.43(dd,J=10.5,5.9Hz,1H),4.26(s,1H),3.06–2.82(m,2H),2.81–2.62(m,3H),2.17–2.00(m,1H),1.76–1.53(m,5H),0.87(d,J=6.8Hz,3H).m/z:C20H22F6N2O2:437.12[M+H]+.
实施例119:i34的合成
实验步骤与实施例86同,仅以4-甲基哌啶代替1-(2-氟苯基)哌嗪。
产率:63%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.63(d,J=8.4Hz,1H),8.31(d,J=7.1Hz,1H),7.86(t,J=9.4Hz,1H),7.57(s,1H),5.18(s,1H),4.46(dd,J=10.4,3.3Hz,1H),4.35(dd,J=10.4,6.0Hz,1H),4.14(m,1H),3.01–2.54(m,6H),2.12–1.89(m,3H),1.53(m,2H),0.85(d,J=6.4Hz,3H).m/z:C20H22F6N2O2:437.13[M+H]+.
实施例120:i35的合成
实验步骤与实施例86同,仅以苯胺代替1-(2-氟苯基)哌嗪。
产率:44%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.67(d,J=8.4Hz,1H),8.34(d,J=7.3Hz,1H),7.88(t,J=7.9Hz,1H),7.58(d,J=2.1Hz,2H),7.06(t,J=7.7Hz,1H),6.64(d,J=8.0Hz,2H),6.53(t,J=7.2Hz,1H),5.50(m,1H),4.52(dd,J=10.4,3.6Hz,1H),4.41(dd,J=10.5,5.7Hz,1H),4.19(m,1H),3.74(dd,J=15.1,5.6Hz,1H),3.65(dd,J=15.1,6.7Hz,1H).m/z:C20H16F6N2O2:431.12[M+H]+.
实施例121:i36的合成
实验步骤与实施例86同,仅以4-甲氧基苯胺代替1-(2-氟苯基)哌嗪。
产率:55%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.66(d,J=8.4Hz,1H),8.34(d,J=7.4Hz,1H),7.88(t,J=7.9Hz,1H),7.58(s,1H),6.75–6.67(m,2H),6.63–6.58(m,2H),5.24(m,1H),4.51(dd,J=10.4,3.5Hz,1H),4.40(dd,J=10.3,6.0Hz,1H),4.18(m,J=6.0,5.4Hz,1H),3.62(s,3H),3.29(m,1H),3.21–3.14(m,1H).m/z:C21H18F6N2O3:461.05[M+H]+.
实施例122:j1的合成
其具体合成操作如下:氩气保护搅拌回流下,将POBr3(113.81mmol)于75℃下热熔后,加入2,8-双(三氟甲基)-4-羟基喹啉(28.45mmol),然后升温至150℃,回流反应6h后,剧烈搅拌下,逐滴加入冰水中,有大量白色固体析出,抽滤并水洗,自然晾干后得中间体1,无需进一步纯化,直接投下步反应。氩气保护下,将中间体1(1.453mmol)溶于甲苯(10mL),室温搅拌下,依次加入Pd2(dba)3(0.00727mmol)、P(t-Bu)3(0.01743mmol)、三丁基乙烯基锡(1.599mmol),TLC检测下4h后反应完毕。然后加入氟化钾(2mL,1M in H2O)和乙酸乙酯(5mL),继续搅拌30min后,将反应混合物用硅藻土过滤,并以适量乙酸乙酯洗涤,真空浓缩后,以石油醚:乙酸乙酯(8:1~3:1)进行硅胶柱分离,得中间体2。将中间体2(1.168mmol)溶解于二氯甲烷(10mL)中,加入m-CPBA(2.919mmol)和碳酸钾(1.401mmol),搅拌回流反应过夜,TLC检测反应完毕后,将反应混合物用硅藻土过滤,并以二氯甲烷:甲醇(4:1)洗涤,然后真空浓缩,以石油醚:乙酸乙酯(8:1~3:1)进行硅胶柱层析分离,得中间体3。加热回流搅拌下,以异丙醇(10mL)为溶剂,先后加入1-(4-氟苯基)哌嗪(0.712mmol)、中间体3(0.593mmol),TLC检测下,10h后反应完毕,无需后处理,旋干溶剂后,以二氯甲烷:甲醇(200:1~50:1)硅胶柱层析分离,得白色固体j1。
产率:33%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.57(d,J=8.6Hz,1H),8.34(d,J=7.3Hz,1H),8.12(s,1H),7.88(t,J=8.0Hz,1H),7.29–7.20(m,2H),7.08–6.99(m,2H),6.02(d,J=4.4Hz,1H),5.61(dt,J=7.7,4.0Hz,1H),3.71(s,2H),2.87(dd,J=12.5,4.3Hz,1H),2.77(dd,J=12.5,6.8Hz,1H).m/z:C20H15F7N2O:433.14[M+H]+.
实施例123:j2的合成
实验步骤与实施例122同,仅以4-氯苄胺代替4-氟苄胺。
产率:36%;白色固体;1H NMR(400MHz,DMSO-d6)δ8.57(d,J=8.6Hz,1H),8.34(d,J=7.3Hz,1H),8.12(s,1H),7.88(t,J=7.9Hz,1H),7.29–7.25(m,2H),7.22(d,J=8.5Hz,2H),6.02(d,J=4.3Hz,1H),5.61(dt,J=7.8,3.9Hz,1H),3.72(s,2H),2.87(dd,J=12.6,4.3Hz,1H),2.77(dd,J=12.5,6.8Hz,1H).m/z:C20H15ClF6N2O:448.99[M+H]+.
实施例124:化合物a1-j2的抗植物病原菌活性的试验方法及结果
本发明的抗菌活性测定采用马铃薯葡萄糖琼脂培养基(PDA培养基)进行。其制备方法如下:先将马铃薯洗净去皮,称取200g切成小块,加水煮烂(煮沸20-30分钟,马铃薯块能被玻璃棒戳破即可),用八层纱布过滤,加热,再加15g琼脂,继续加热搅拌混匀,待琼脂溶解完后,加入葡萄糖20g,搅拌均匀,稍冷却后再补足水分至1000毫升,分装锥形瓶,加塞、包扎,115摄氏度灭菌2h,备用。将化合物a1-j2分别用DMSO溶解,以商业化杀菌剂嘧菌酯作为对照药物,加入培养基中,混合均匀,使培养基中的化合物浓度分别为50μg/mL。倒平板,冷却后分别接菌,置于23摄氏度培养箱中培养,以空白对照菌丝长满培养皿为限,测定各化合物的抑菌率。所有试验设三个平行组或重复三次。抑菌率的计算按下述计算公式进行:
对农业病害真菌的活性数据如下表1:
注:实验中每个设置进行三次重复,表中数据为三次重复的平均值
由表1可知,2,8-双(三氟甲基)-4-羟基喹啉衍生物对油菜菌核病菌、番茄灰霉病菌、小麦赤霉病菌和立枯丝核病菌表现出不同程度的抑制活性,其中部分化合物在50ppm对农业病害真菌表现出优异的活性,抑制率达到了90%以上。因此本发明所述的化合物具可望开发成为新型抗菌药物。
Claims (6)
1.本发明涉及一种2,8-双(三氟甲基)-4-羟基喹啉衍生物在制备和防治农业病害中的应用,是2,8-双(三氟甲基)-4-羟基喹啉衍生物的新用途。
3.根据权利要求2所述的一种2,8-双(三氟甲基)-4-羟基喹啉衍生物中任一化合物在制备和防治油菜菌核病菌引起的病害的药物中的用途。
4.根据权利要求2所述的一种2,8-双(三氟甲基)-4-羟基喹啉衍生物中任一化合物在制备和防治番茄灰霉病菌引起的病害的药物中的用途。
5.根据权利要求2所述的一种2,8-双(三氟甲基)-4-羟基喹啉衍生物中任一化合物在制备和防治小麦赤霉病菌引起的病害的药物中的用途。
6.根据权利要求2所述的一种2,8-双(三氟甲基)-4-羟基喹啉衍生物中任一化合物在制备和防治立枯丝核病菌引起的病害的药物中的用途。
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WO1996032015A1 (de) * | 1995-04-08 | 1996-10-17 | Basf Aktiengesellschaft | Synergistische fungizide zusammensetzungen aus chinolinderivaten und cytochrom b/c-inhibitors |
CN108477170A (zh) * | 2018-03-30 | 2018-09-04 | 兰州大学 | 一种喹啉类化合物及其制备方法和在防治植物病害中的用途 |
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CN108477170A (zh) * | 2018-03-30 | 2018-09-04 | 兰州大学 | 一种喹啉类化合物及其制备方法和在防治植物病害中的用途 |
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