CN109678815B - N-苄基苯甲酰胺类衍生物及其制备方法与制药用途 - Google Patents

N-苄基苯甲酰胺类衍生物及其制备方法与制药用途 Download PDF

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CN109678815B
CN109678815B CN201910018450.6A CN201910018450A CN109678815B CN 109678815 B CN109678815 B CN 109678815B CN 201910018450 A CN201910018450 A CN 201910018450A CN 109678815 B CN109678815 B CN 109678815B
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徐进宜
李文龙
徐盛涛
帅雯
徐飞杰
孙翃昊
马聪
朱哲英
姚鸿
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China Pharmaceutical University
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Abstract

本发明涉及药物化学领域，公开了一类具有抗肿瘤活性的N‑苄基苯甲酰胺类衍生物及其制备方法，还公开了含有所述化合物的药用组合物，以及所述化合物或其药用盐或含有其的组合物在制备治疗肿瘤以及抑制微管蛋白活性相关疾病或病症的药物中的应用。

Description

N-苄基苯甲酰胺类衍生物及其制备方法与制药用途
技术领域
本发明涉及药物化学领域，具体涉及一类具有抗肿瘤活性、抑制微管蛋白活性的N-苄基苯甲酰胺类衍生物及其制备方法与制药应用。
背景技术
微管是细胞骨架的主要组成部分，在维持细胞形态、细胞分裂、信号转导等过程中起着重要作用，因此，微管蛋白是一个非常有前景的新型化疗药物的靶标。微管蛋白抑制剂能阻止肿瘤细胞的过度增殖，是一类重要的抗肿瘤治疗药物。目前，临床上应用的微管抑制剂主要有以紫杉醇为代表的抑制微管蛋白解聚药物及以长春碱类为代表的抑制微管蛋白聚集药物。
在已经发现的四个微管蛋白结合位点中，作用于紫杉醇、Laulimalide和长春碱结合位点的微管蛋白抑制剂化学结构复杂，成药性较差，毒副作用大，容易产生耐药，进一步临床开发受限。而秋水仙碱结合位点的结合口袋体积较小，更适合开展结构简单的小分子抑制剂的研究。经典的靶向微管蛋白的药物，包括长春碱、长春新碱等只有在高浓度(接近最大耐受剂量)时才能够破坏肿瘤脉管系统，而作用于秋水仙碱结合位点的新型小分子抑制剂在远低于其最大耐受剂量时即可破坏肿瘤微管骨架。此外，由于肿瘤转移与侵袭也依赖于血管供给营养，因此，该类型的小分子抑制剂还具有抗瘤谱广，抑制肿瘤扩散。此外，作用于秋水仙碱结合位点的抑制剂与作用于其它结合位点的抑制剂相比，不容易发生耐药。这些特性使得作用于秋水仙碱结合位点的抑制剂备受关注，开发作用于秋水仙碱结合位点的抑制剂是寻找高效、低毒的小分子微管蛋白药物的有效策略。
风车子抑素A4(CA-4)是从天然产物中发现的一个作用于秋水仙碱结合位点的微管蛋白抑制剂，其在体内及体外都显示了较好的抗肿瘤活性。然而，CA-4 的诸多缺点如水溶性差、稳定性差等缺点限制了其在临床上的应用。因此，开发具有新骨架的微管蛋白抑制剂以解决CA-4的缺陷是该领域的一个研究热点。本发明发现一种具有全新结构的N-苄基苯甲酰胺类衍生物，其有望解决这些缺陷。
发明内容
本发明的一个目的在于提供一种通式I所示的N-苄基苯甲酰胺类衍生物或其可药用的盐。
本发明的另一个目的在于提供一种通式I所示的N-苄基苯甲酰胺类衍生物的制备方法。
本发明的再一个目的在于提供一种药用组合物，其包含治疗有效量的选自通式I所示的N-苄基苯甲酰胺类衍生物、其可药用的盐。
本发明的再一个目的在于提供一种微管蛋白抑制剂，其包含选自通式I所示的N-苄基苯甲酰胺类衍生物、其可药用的盐。
本发明的再一个目的在于提供通式I所示的N-苄基苯甲酰胺类衍生物、其可药用的盐、含有其的药物组合物以及通过抑制微管蛋白活性来治疗其他疾病或病症的药物中的应用。其中，所述肿瘤包括但不限于结肠癌、白血病、肝癌、乳腺癌、胃癌、胰腺癌等。
技术方案：基于上述目的，本发明所述的一种通式I所示的N-苄基苯甲酰胺类衍生物或其可药用的盐：
Figure BDA0001939948110000021
其中：
R1，R2各自独立地选自氢、C1-C4的酰基、取代的苯环或芳香杂环的甲酰基、芳香环、C1-C4的烷基；或者R1,R2连在一起共同形成饱和或不饱和的三至七元环状烷基包括氮杂环丙烷、氮杂环丙烷、吡咯、四氢吡咯、哌啶、吗啉、硫代吗啉、1,1-二氧化硫代吗啉、哌嗪、环己亚胺；
R3，R4各自独立地选自氢、C1-C4的烷基、C1-C4的酰基、C1-C4的烷氧基、取代的苯环或芳香杂环的甲酰胺基、取代的苯环或芳香杂环的苄胺基、取代的苯环或芳香杂环、硝基、醛基、三氟甲基、三氟甲氧基、羟基、C1-C4取代或不取代的氨基、卤素；
X，Y，Z各自独立地选自碳原子、氮原子；
R5，R6各自独立地选自C1-C4的烷基；
R7，R8，R9各自独立地选自C1-C4的烷氧基、C1-C4的烷硫基、C1-C4取代或不取代的氨基、羟基、卤素、C1-C4的烷基、磷酸酯基。
在一个优选的实施方案中，如上述通式I所示的N-苄基苯甲酰胺类衍生物、其可药用的盐，其中：
R1，R2优选氢、C1-C4的酰基、取代的苯环或芳香杂环的甲酰基、芳香环、 C1-C4的烷基；或者R1,R2连在一起共同形成饱和或不饱和的五或六元环状烷基包括吡咯、四氢吡咯、哌啶、吗啉、硫代吗啉、1,1-二氧化硫代吗啉、哌嗪；
R3优选氢、硝基、甲氧基、卤素、三氟甲基、羟基、C1-C4取代或不取代的氨基、醛基；
R4优选氢、C1-C4的烷基、C1-C4的酰基、C1-C4的烷氧基、取代的苯环或芳香杂环的甲酰胺基、取代的苯环或芳香杂环的苄胺基、取代的苯环或芳香杂环、硝基、醛基、三氟甲基、三氟甲氧基、羟基、C1-C4取代或不取代的氨基、卤素；
X，Y，Z各自独立地选自碳原子、氮原子；
R5，R6各自独立地选自C1-C4的烷基；
R7优选C1-C4的烷氧基、C1-C4的烷硫基、取代或不取代的氨基；
R8，R9优选羟基、卤素、磷酸酯基。
作为更优选的实施方案，本发明的通式I的化合物优选为如下具体化合物：
Figure BDA0001939948110000022
Figure BDA0001939948110000031
Figure BDA0001939948110000041
本发明通式I所示的化合物可用下列方法制备得到：
Figure BDA0001939948110000042
包括以下步骤：
(1)以不同取代的邻氟苯甲酸为原料，与不同取代的胺在二氧六环中反应，得到不同取代的邻氨基苯甲酸中间体；
(2)步骤(1)所得不同取代的邻氨基苯甲酸中间体再与不同取代的苄胺发生缩合反应，得目标产物。
本申请公开的化合物或其可药用的盐在制备微管蛋白抑制剂药物中的应用也在本发明的保护范围内。
本申请公开的化合物或其可药用的盐在制备抗肿瘤药物中的应用也在本发明的保护范围内。所述肿瘤包括但不限于结肠癌、白血病、肝癌、乳腺癌、胃癌、胰腺癌等。
本发明还公开了一种药物组合物，其包含化合物I及药学上可接受的载体。
所述药物组合物在制备微管蛋白抑制剂药物中的应用，以及在制备抗肿瘤药物中的应用也在本发明的保护范围内。
有益效果：本申请所述的N-苄基苯甲酰胺类衍生物为一类全新结构的化合物，通过药理实验可见，所述N-苄基苯甲酰胺类衍生物具有显著抑制微管蛋白活性的作用，并且效果显著优于阳性药CA-4；其体内外抗肿瘤活性也显著优于阳性药CA-4 及顺铂；另外，本类化合物相比于CA-4，其水溶性大大提高，稳定性也优于CA-4，因此，具有潜在的成药性前景。
具体实施方式
以下通过实施例形式展示具体的实施方式，对本发明内容进行进一步的详细说明，但不应当将此理解为本发明上述主题的范围仅限于以下的实施例，凡是基于本发明上述内容在本领域内所能实现的技术均应属于本发明的内容。
HepG2,A431,HCT-8,MDA-MB-231,K562购自南京凯基生物科技发展有限公司；顺铂、CA-4购自南京凯基生物科技发展有限公司。
实施例1
Figure BDA0001939948110000043
N-(4-甲氧基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
2-氟苯甲酸(5g,35.7mmol)溶于11mL浓硫酸中，冰浴下缓慢滴入11mL 浓硝酸，逐渐升至室温反应2h，反应结束后将反应液缓慢滴入到冰水中，有大量白色固体析出，抽滤，干燥，得2-氟-5-硝基苯甲酸4.7g，产率71.2％；将2- 氟-5-硝基苯甲酸(500mg,2.7mmol)溶于15mL二氧六环中，加入吗啉(1.2mL, 13.5mmol)，室温反应2h，旋干溶剂及多余的吗啉，加水溶解，10％稀盐酸酸化，抽滤，得2-吗啉基-5-硝基苯甲酸黄色固体520mg，产率76.4％；2-吗啉基-5- 硝基苯甲酸(80mg,0.32mmol)溶于10mL DCM中，分别加入对甲氧基苄胺(48 mg,0.35mmol)，羟基苯并三氮唑(51mg,0.38mmol)，EDCI(122mg,0.64 mmol)，室温搅拌2h后加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体103mg，产率88.0％；1H NMR(300MHz,CDCl3)δ8.84(d,J＝2.7Hz,1H),8.50(s,1H), 8.24(dd,J＝9.0,2.7Hz,1H),7.31(d,J＝8.3Hz,2H),7.16(d,J＝8.9Hz,1H),6.90 (d,J＝8.2Hz,2H),4.58(d,J＝5.6Hz,2H),3.81(s,3H),3.55(t,J＝4.5Hz,4H),3.01(t,J＝4.5Hz,4H)；13C NMR(75MHz,CDCl3)δ164.82,159.45,155.50,143.32, 129.84,129.78,128.28,127.36,126.93,119.40,114.40,66.41,55.43,52.77,43.57； ESI-MS m/z:371.1calcd for C19H21N3O5[M+H]+372.1.
实施例2
Figure BDA0001939948110000051
N-(4-甲硫基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成对甲硫基苄胺，按照实施例1的操作，得产物78mg,产率63.5％；1H NMR(300MHz,CDCl3)δ8.78(dd,J＝2.9,1.0Hz,1H), 8.60(t,J＝5.7Hz,1H),8.22(dd,J＝8.9,2.0Hz,1H),7.31(d,J＝8.2Hz,2H),7.24 (d,J＝8.1Hz,2H),7.15(d,J＝8.9Hz,1H),4.60(d,J＝5.8Hz,2H),3.58(t,J＝4.6 Hz,4H),3.02(t,J＝4.6Hz,4H),2.48(s,3H)；13C NMR(75MHz,CDCl3)δ165.01, 155.49,143.31,138.60,134.53,128.93,128.18,127.35,127.02,127.00,119.43, 66.47,52.80,43.64,15.91；ESI-MS m/z:387.1calcd for C19H21N3O4S[M+H]+388.1.
实施例3
Figure BDA0001939948110000052
N-(3-氟-4-甲氧基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成3-氟-4-甲氧基苄胺，按照实施例1的操作，得产物52mg,产率42.0％；1H NMR(300MHz,CDCl3)δ8.82(s,1H),8.62(s,1H), 8.25(d,J＝8.9Hz,1H),7.46-7.03(m,3H),6.95(t,J＝8.4Hz,1H),4.57(d,J＝5.8 Hz,2H),3.90(s,3H),3.60(s,4H),3.03(s,4H)；13C NMR(75MHz,CDCl3)δ 165.01,161.69,160.45,155.53,154.18,149.95(d,J＝20.1Hz),143.57,130.81(d,J ＝7.1Hz),128.25,127.48,127.10,124.30(d,J＝3.4Hz),119.58,116.33,116.08, 113.76,66.56,56.47,52.93,43.28；ESI-MS m/z:389.1calcd for C19H20FN3O5 [M+H]+390.1.
实施例4
Figure BDA0001939948110000061
N-(4-二甲氨基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成对二甲氨基苄胺，按照实施例1的操作，得产物99mg,产率81.2％；1H NMR(300MHz,CDCl3)δ8.86(d,J＝2.8Hz,1H),8.37 (s,1H),8.25(dd,J＝8.9,2.9Hz,1H),7.24(d,J＝9.4Hz,2H),7.15(d,J＝8.9Hz, 1H),6.71(d,J＝8.5Hz,2H),4.55(d,J＝5.5Hz,2H),3.56(t,J＝4.6Hz,4H),3.08- 2.99(m,4H),2.95(s,6H)；13C NMR(75MHz,CDCl3)δ164.66,155.49,150.49, 143.37,129.53,128.57,127.42,126.83,125.20,119.26,112.85,66.44,52.80,43.76, 40.69；ESI-MS m/z:384.2calcd forC20H24N4O4[M+H]+385.2.
实施例5
Figure BDA0001939948110000062
N-(3,4,5-三甲氧基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成3,4,5-三甲氧基苄胺，按照实施例1的操作，产物63mg,产率46.1％；1H NMR(300MHz,CDCl3)δ8.85(d,J＝2.8Hz,1H), 8.55(s,1H),8.27(dd,J＝8.9,2.8Hz,1H),7.18(d,J＝8.9Hz,1H),6.61(s,2H), 4.58(d,J＝5.8Hz,2H),3.86(s,6H),3.84(s,3H),3.64–3.56(m,4H),3.08-2.98 (m,4H)；13C NMR(75MHz,CDCl3)δ164.94,155.47,153.74,143.37,137.94, 133.58,128.26,127.36,126.99,119.45,105.58,66.47,61.03,56.36,52.85,44.45； ESI-MS m/z:431.2calcd for C21H25N3O7[M+H]+432.2.
实施例6
Figure BDA0001939948110000063
N-(4-三氟甲氧基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成对三氟甲氧基苄胺，按照实施例1的操作，得产物79mg,产率58.6％；1H NMR(300MHz,CDCl3)δ8.86(d,J＝2.8Hz,1H), 8.67(s,1H),8.27(dd,J＝8.9,2.8Hz,1H),7.43(d,J＝8.6Hz,2H),7.23(d,J＝8.6 Hz,2H),7.20(d,J＝9.0Hz,1H),4.67(d,J＝5.9Hz,2H),3.62-3.54(m,4H),3.06- 2.98(m,4H)；13C NMR(75MHz,CDCl3)δ165.04,155.54,148.93,143.46,136.88, 129.84,128.17,127.44,127.10,121.60,120.51(q,J＝255.8Hz),119.59,66.51, 52.89,43.25；ESI-MS m/z:425.1calcd for C19H18F3N3O5[M+H]+426.1.
实施例7
Figure BDA0001939948110000071
N-((6-甲氧基吡啶-3-基)甲基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成吡啶苄胺，按照实施例1的操作，得产物 115mg,产率97％；1H NMR(300MHz,CDCl3)δ8.85(d,J＝2.8Hz,1H),8.58(s, 1H),8.27(dd,J＝8.9,2.8Hz,1H),8.17(d,J＝2.4Hz,1H),7.65(dd,J＝8.5,2.5Hz, 1H),7.19(d,J＝8.9Hz,1H),6.79-6.73(m,1H),4.59(d,J＝5.8Hz,2H),3.94(s, 3H),3.65-3.59(m,4H),3.07-3.01(m,4H)；13C NMR(75MHz,CDCl3)δ165.07, 164.04,155.46,146.55,143.29,139.12,128.09,127.35,127.03,126.35,119.44, 111.35,66.55,53.65,52.78,40.89；ESI-MS m/z:372.1calcd for C18H20N4O5[M+H]+ 373.1.
实施例8
Figure BDA0001939948110000072
N-(3,4-二甲氧基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成3,4-二甲氧基苄胺，按照实施例1的操作，得产物85mg,产率66.9％；1H NMR(300MHz,CDCl3)δ8.85(d,J＝2.8Hz,1H), 8.55(s,1H),8.26(dd,J＝8.9,2.8Hz,1H),7.17(d,J＝8.9Hz,1H),6.93(dt,J＝4.9, 2.0Hz,2H),6.86(d,J＝8.6Hz,1H),4.59(d,J＝5.7Hz,2H),3.89(s,3H),3.88(s, 3H),3.61–3.51(m,4H),3.07-2.97(m,4H)；13C NMR(75MHz,CDCl3)δ164.84, 155.49,149.44,148.94,143.39,130.35,128.27,127.40,126.97,120.78,119.43, 111.68,111.35,66.44,56.09,56.07,52.83,43.98；ESI-MS m/z:401.2calcd for C20H23N3O6[M+H]+402.2.
实施例9
Figure BDA0001939948110000073
N-(4-乙氧基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成对乙氧基苄胺，按照实施例1的操作，得产物80mg,产率77.9％；1H NMR(300MHz,CDCl3)δ8.85(d,J＝2.8Hz,1H),8.51 (s,1H),8.25(dd,J＝8.9,2.8Hz,1H),7.30(d,J＝8.6Hz,2H),7.16(d,J＝8.9Hz, 1H),6.89(d,J＝8.6Hz,2H),4.58(d,J＝5.6Hz,2H),4.03(q,J＝7.0Hz,2H),3.58 –3.48(m,4H),3.06–2.97(m,4H),1.42(t,J＝7.0Hz,3H)；13C NMR(75MHz, CDCl3)δ164.69,158.83,155.51,143.39,129.77,129.73,128.41,127.43,126.90, 119.40,114.96,66.42,63.61,52.81,43.59,14.89；ESI-MS m/z:385.2calcd for C20H23N3O5[M+H]+386.2.
实施例10
Figure BDA0001939948110000081
N-(吡啶-4-基甲基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成3吡啶-4-甲胺，按照实施例1的操作，得产物89mg,产率82.4％；1H NMR(300MHz,CDCl3)δ8.97-8.76(m,2H),8.60(d, J＝6.1Hz,2H),8.29(dd,J＝8.9,2.8Hz,1H),7.29(d,J＝6.1Hz,2H),7.23(d,J＝ 8.9Hz,1H),4.68(d,J＝6.0Hz,2H),3.76-3.63(m,4H),3.15-3.03(m,4H)；13C NMR(75MHz,CDCl3)δ165.45,155.56,150.36,146.94,143.43,127.88,127.45, 127.26,122.79,119.70,66.67,52.93,42.85；ESI-MS m/z:342.1calcd for C17H18N4O4[M+H]+343.2.
实施例11
Figure BDA0001939948110000082
N-(4-氯苄基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成对氯苄胺，按照实施例1的操作，得产物 91mg,产率82.4％；1H NMR(300MHz,CDCl3)δ8.85(d,J＝2.8Hz,1H),8.66(s, 1H),8.27(dd,J＝8.9,2.8Hz,1H),7.34(d,J＝1.8Hz,4H),7.19(d,J＝8.9Hz,1H), 4.63(d,J＝5.8Hz,2H),3.65–3.53(m,4H),3.09-2.98(m,4H)；13C NMR(75MHz, CDCl3)δ165.16,155.51,143.33,136.41,133.94,129.74,129.20,128.01,127.36, 127.10,119.53,66.52,52.83,43.38；ESI-MS m/z:375.1calcd for C18H18ClN3O4 [M+H]+376.1.
实施例12
Figure BDA0001939948110000083
N-(1-(4-甲氧基苯基)乙基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成4-甲氧基-2’-甲基苄胺，按照实施例1的操作，得产物99mg,产率81.1％；1H NMR(300MHz,CDCl3)δ8.82(d,J＝2.8Hz, 1H),8.43(d,J＝7.7Hz,1H),8.24(dd,J＝8.9,2.8Hz,1H),7.34(d,J＝8.7Hz,2H), 7.16(d,J＝8.9Hz,1H),6.92(d,J＝8.7Hz,2H),5.36–5.27(m,1H),3.82(s,3H), 3.64-3.43(m,4H),3.00(dd,J＝5.5,3.9Hz,4H),1.61(d,J＝6.9Hz,3H)；13C NMR (75MHz,CDCl3)δ164.15,159.34,155.47,143.29,134.58,128.46,127.84,127.35, 126.85,119.39,114.36,66.32,55.46,52.75,49.02,21.47；ESI-MS m/z:385.2calcd for C20H23N3O5[M+H]+386.2.
实施例13
Figure BDA0001939948110000091
N-(4-羟基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成对羟基苄胺，按照实施例1的操作，得产物 65mg,产率81.1％；1H NMR(300MHz,DMSO-d6)δ9.35(s,1H),9.01(t,J＝6.0 Hz,1H),8.17(dd,J＝9.0,2.9Hz,1H),8.12(d,J＝2.8Hz,1H),7.15(t,J＝8.1Hz, 3H),6.73(d,J＝8.4Hz,2H),4.32(d,J＝5.9Hz,2H),3.51(t,J＝4.5Hz,4H),3.09 (t,J＝4.6Hz,4H)；13C NMR(75MHz,DMSO-d6)δ166.37,156.47,154.38,139.00, 129.33,129.15,126.89,126.14,125.50,117.56,115.09,65.53,50.48,42.33；ESI-MS m/z:357.1calcd for C18H19N3O5[M+H]+358.1.
实施例14
Figure BDA0001939948110000092
N-(3-羟基-4-甲氧基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
2-吗啉基-5-硝基苯甲酸(80mg,0.32mmol)溶于10mL DCM中，分别加入 TBS保护的3-羟基-4-甲氧基苄胺(93mg,0.35mmol)，羟基苯并三氮唑(51mg, 0.38mmol)，EDCI(122mg,0.64mmol)，室温搅拌2h后加水稀释，乙酸乙酯 (25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体121mg；将以上产物(121mg,0.24mmol)溶于无水10mL THF 中,加入四丁基氟化铵(75mg,0.29mmol)，室温搅拌15min后，加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA4:1)得黄色固体75mg，两步产率61.5％；1H NMR(300MHz,CDCl3) δ8.85(d,J＝2.8Hz,1H),8.51(s,1H),8.25(dd,J＝8.9,2.9Hz,1H),7.17(d,J＝8.9 Hz,1H),6.94(d,J＝1.9Hz,1H),6.89-6.81(m,2H),4.55(d,J＝5.6Hz,2H),3.90 (s,3H),3.57(t,J＝4.7Hz,4H),3.07-3.00(m,4H)；13C NMR(75MHz,CDCl3)δ 166.46,154.37,146.80,146.44,138.95,131.56,126.81,126.17,125.53,118.70, 117.51,115.40,112.13,65.57,55.71,50.50,42.39；ESI-MS m/z:387.1calcd for C19H21N3O6[M+H]+388.1.
实施例15
Figure BDA0001939948110000093
N-(4-三氟甲基苄基)-2-吗啡啉基-5-硝基苯甲酰胺
本实施例将对甲氧基苄胺替换成对三氟甲基苄胺，按照实施例1的操作，得产物99mg,产率81.1％；1H NMR(300MHz,CDCl3)δ8.81(d,J＝2.8Hz,1H), 8.77(t,J＝6.5Hz,1H),8.25(dd,J＝8.9,2.8Hz,1H),7.63(d,J＝8.0Hz,2H),7.51 (d,J＝8.0Hz,2H),7.20(d,J＝8.9Hz,1H),4.72(d,J＝6.0Hz,2H),3.70-3.55(m, 4H),3.14-2.99(m,4H)；13C NMR(75MHz,CDCl3)δ165.19,155.56,143.50, 142.09,130.31(q,J＝32.6Hz),128.54,128.07,127.48,127.18,125.99(q,J＝3.8 Hz),124.05(q,J＝270.5Hz),119.66,66.58,52.92,43.51；ESI-MS m/z:409.1calcd for C19H18F3N3O4[M+H]+410.1.
实施例16
Figure BDA0001939948110000101
N-(3-羟基-4-甲氧基苄基)-2-哌啶基-5-硝基苯甲酰胺
2-哌啶基-5-硝基苯甲酸(80mg,0.32mmol)溶于10mL DCM中，分别加入 TBS保护的3-羟基-4-甲氧基苄胺(93mg,0.35mmol)，羟基苯并三氮唑(51mg, 0.38mmol)，EDCI(122mg,0.64mmol)，室温搅拌2h后加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析 (PE/EA 4:1)得黄色固体105mg；将以上产物(105mg,0.21mmol)溶于无水 10mL THF中,加入四丁基氟化铵(66mg,0.25mmol)，室温搅拌15min后，加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA4:1)得黄色固体55mg，两步产率44.4％；1H NMR(300 MHz,DMSO-d6)δ9.00(t,J＝6.0Hz,1H),8.95(s,1H),8.13(q,J＝3.3Hz,2H), 7.16–7.08(m,1H),6.87(d,J＝8.2Hz,1H),6.80(d,J＝2.1Hz,1H),6.73(dd,J＝ 8.2,2.1Hz,1H),4.31(d,J＝5.9Hz,2H),3.74(s,3H),3.13(s,4H),1.50(s,6H)；13C NMR(75MHz,DMSO-d6)δ166.56,155.06,146.74,146.45,138.05,131.68,126.24, 126.17,125.74,118.48,117.56,115.26,112.11,55.71,51.51,42.34,25.08,23.38； ESI-MS m/z:385.4calcd for C20H23N3O5[M+H]+386.4.
实施例17
Figure BDA0001939948110000102
N-(3-羟基-4-甲氧基苄基)-2-((2-甲氧基乙基)氨基)-5-硝基苯甲酰胺
2-((2-甲氧基乙基)氨基)-5-硝基苯甲酸(80mg,0.33mmol)溶于10mL DCM 中，分别加入TBS保护的3-羟基-4-甲氧基苄胺(107mg,0.39mmol)，羟基苯并三氮唑(54mg,0.39mmol)，EDCI(128mg,0.66mmol)，室温搅拌2h后加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA4:1)得黄色固体121mg；将以上产物(121mg,0.25mmol) 溶于无水10mL THF中,加入四丁基氟化铵(66mg,0.30mmol)，室温搅拌15min 后，加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA4:1)得黄色固体65mg，两步产率52.0％；1H NMR (300MHz,DMSO-d6)δ9.31(s,1H),9.16(s,1H),8.95(s,1H),8.62(s,1H),8.14(d, J＝9.3Hz,1H),6.77(dd,J＝32.8,16.3Hz,4H),4.32(s,2H),3.75(s,3H),3.56(s, 2H),3.45(s,2H),3.30(s,3H)；13CNMR(75MHz,DMSO-d6)δ167.30,154.08, 146.68,146.44,134.63,131.83,128.12,125.51,118.11,114.86,113.11,112.20, 111.07,70.00,58.13,55.71,54.93,42.05；ESI-MS m/z:375.4calcd for C18H21N3O6 [M+H]+376.4.
实施例18
Figure BDA0001939948110000111
N-(3-羟基-4-甲氧基苄基)-2-哌嗪基-5-硝基苯甲酰胺
2-(4-叔丁氧羰基哌嗪基)-5-硝基苯甲酸(75mg,0.21mmol)溶于10mL乙腈中，分别加入TBS保护的3-羟基-4-甲氧基苄胺(69mg,0.25mmol)，HATU (122mg,0.32mmol)，Et3N(44μL,0.66mmol)，室温搅拌2h后有固体析出，抽滤得黄色固体80mg；将以上产物(80mg,0.14mmol)溶于无水10mL THF 中,加入四丁基氟化铵(42mg,0.16mmol)，室温搅拌15min后，加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA4:1)得粗品后溶于5mL DCM中，加入1mL三氟乙酸，反应结束后旋干溶剂及剩余的三氟乙酸，饱和碳酸氢钠水溶液调至中性后，乙酸乙酯(25 mL×3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析 (DCM/CH3OH 40:1)得黄色固体44mg，总收率53.7％；1H NMR(300MHz, DMSO-d6)δ9.04(s,2H),8.15(s,2H),7.15(s,1H),6.82(d,J＝25.3Hz,2H),5.76(s, 1H),4.30(s,2H),4.10-3.56(m,3H),3.15(s,4H),2.80(s,4H)；13CNMR(75MHz, DMSO-d6)δ166.49,154.41,146.74,146.43,138.71,131.61,126.54,126.18,125.64, 118.48,117.70,115.21,112.12,55.69,50.13,44.20,42.36；ESI-MS m/z:386.2calcd for C19H22N4O5[M+H]+387.2.
实施例19
Figure BDA0001939948110000112
N-(3-羟基-4-甲氧基苄基)-2-硫代吗啉基-5-硝基苯甲酰胺
2-硫代吗啉基-5-硝基苯甲酸(80mg,0.30mmol)溶于10mL DCM中，分别加入TBS保护的3-羟基-4-甲氧基苄胺(96mg,0.36mmol)，羟基苯并三氮唑(48 mg,0.36mmol)，EDCI(114mg,0.60mmol)，室温搅拌2h后加水稀释，乙酸乙酯萃取(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体92mg；将以上产物(92mg,0.18mmol)溶于无水10mL THF中,加入四丁基氟化铵(56mg,0.21mmol)，室温搅拌15min 后，加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体63mg，两步产率52.5％；1H NMR (300MHz,DMSO-d6)δ9.02(t,J＝6.0Hz,1H),8.97(s,1H),8.15(d,J＝9.3Hz, 2H),7.17(d,J＝8.9Hz,1H),6.88(d,J＝8.1Hz,1H),6.80(s,1H),6.73(d,J＝8.1 Hz,1H),4.31(d,J＝6.0Hz,2H),3.74(s,3H),3.49-3.38(m,4H),2.60(d,J＝4.7 Hz,4H)；13C NMR(75MHz,DMSO-d6)δ166.42,155.04,146.76,146.45,138.94, 131.63,127.23,126.07,125.54,118.58,118.50,115.24,112.21,55.74,52.96,42.35, 26.22；ESI-MS m/z:403.4calcd for C19H21N3O5S[M+H]+404.4.
实施例20
Figure BDA0001939948110000121
N-(3-羟基-4-甲氧基苄基)-2-(1,1-二氧代硫代吗啉)-5-硝基苯甲酰胺
将实施例19中的中间体(53mg,0.10mmol)溶于10mL DCM中，加入85％含量的间氯过氧苯甲酸(62mg,0.30mmol)，室温反应2h后，乙酸乙酯萃取 (25mL×3)，合并有机相，饱和硫代硫酸钠溶液洗，饱和碳酸氢钠溶液洗，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体41mg；将以上产物(41mg,0.07mmol)溶于无水10mL THF中,加入四丁基氟化铵(23 mg,0.09mmol)，室温搅拌15min后，加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体23mg，两步产率52.3％；1H NMR(300MHz,DMSO-d6)δ9.09-9.00(m, 1H),8.97(s,1H),8.27-8.08(m,2H),7.28(d,J＝8.8Hz,1H),6.88(d,J＝8.2Hz, 1H),6.78(d,J＝2.1Hz,1H),6.73(dd,J＝8.1,2.1Hz,1H),4.32(d,J＝5.9Hz,2H), 3.74(s,3H),3.65-3.48(m,4H),3.11(t,J＝5.1Hz,4H)；13C NMR(75MHz, DMSO-d6)δ166.27,153.54,146.79,146.48,139.92,131.58,127.65,126.01,125.41, 119.67,118.39,115.10,112.28,55.70,50.61,49.39,42.39；ESI-MS m/z:435.4calcd for C19H21N3O7S[M+H]+436.4.
实施例21
Figure BDA0001939948110000122
N-(3-羟基-4-甲氧基苄基)-2-四氢吡咯基-5-硝基苯甲酰胺
2-四氢吡咯基-5-硝基苯甲酸(80mg,0.34mmol)溶于10mL DCM中，分别加入TBS保护的3-羟基-4-甲氧基苄胺(109mg,0.41mmol)，羟基苯并三氮唑 (55mg,0.41mmol)，EDCI(130mg,0.68mmol)，室温搅拌2h后加水稀释，乙酸乙酯萃取(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体105mg；将以上产物(105mg,0.22mmol) 溶于无水10mL THF中,加入四丁基氟化铵(68mg,0.26mmol)，室温搅拌15min 后，加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体53mg，两步产率42.1％；1H NMR (300MHz,DMSO-d6)δ8.98(s,2H),8.27-7.77(m,2H),7.17-6.56(m,4H),4.46- 4.19(m,2H),3.74(s,3H),3.30(s,4H),1.85(s,4H)；13C NMR(75MHz,DMSO-d6) δ167.85,149.75,146.75,146.43,138.62,134.36,131.62,125.84,121.48,118.45, 115.25,113.36,112.10,55.71,49.85,42.43,25.15；ESI-MS m/z:371.4calcd for C19H21N3O5[M+H]+372.4.
实施例22
Figure BDA0001939948110000131
N-(3-羟基-4-甲氧基苄基)-2-二乙胺基-5-硝基苯甲酰胺
2-二乙胺基-5-硝基苯甲酸(80mg,0.34mmol)溶于10mL DCM中，分别加入TBS保护的3-羟基-4-甲氧基苄胺(109mg,0.41mmol)，羟基苯并三氮唑(55 mg,0.41mmol)，EDCI(130mg,0.68mmol)，室温搅拌2h后加水稀释，乙酸乙酯萃取(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体115mg；将以上产物(115mg,0.24mmol) 溶于无水10mL THF中,加入四丁基氟化铵(74mg,0.28mmol)，室温搅拌15min 后，加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体63mg，两步产率50.0％；1H NMR (300MHz,CDCl3)δ9.09(t,J＝5.4Hz,1H),8.85(d,J＝2.9Hz,1H),8.19(dd,J＝ 8.9,2.9Hz,1H),7.16(d,J＝9.0Hz,1H),6.97-6.88(m,1H),6.83(d,J＝2.2Hz, 2H),5.86(s,1H),4.53(d,J＝5.4Hz,2H),3.88(s,3H),3.12(q,J＝7.1Hz,4H),0.98 (t,J＝7.1Hz,6H)；13C NMR(75MHz,CDCl3)δ165.07,154.85,146.25,145.99, 142.78,131.10,129.04,127.26,126.22,121.87,119.80,114.36,110.92,56.12,47.60, 43.77,11.85；ESI-MS m/z:371.4calcd forC19H21N3O5[M+H]+372.4.
实施例23
Figure BDA0001939948110000132
N-(3-羟基-4-甲氧基苄基)-2-二甲胺基-5-硝基苯甲酰胺
2-二甲胺基-5-硝基苯甲酸(80mg,0.38mmol)溶于10mL DCM中，分别加入TBS保护的3-羟基-4-甲氧基苄胺(122mg,0.46mmol)，羟基苯并三氮唑(62 mg,0.46mmol)，EDCI(146mg,0.76mmol)，室温搅拌2h后加水稀释，乙酸乙酯萃取(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体109mg；将以上产物(109mg,0.24mmol) 溶于无水10mL THF中,加入四丁基氟化铵(74mg,0.28mmol)，室温搅拌15min 后，加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体82mg，两步产率62.6％；1H NMR (300MHz,DMSO-d6)δ8.97(d,J＝7.4Hz,2H),8.31-7.68(m,2H),6.89(t,J＝ 11.3Hz,2H),6.85-6.45(m,2H),4.29(d,J＝5.7Hz,2H),3.74(s,3H),2.95(s,6H)；13C NMR(75MHz,DMSO-d6)δ167.61,153.46,146.70,146.41,135.46,131.66, 126.02,125.79,122.66,118.38,115.18,114.32,112.11,55.67,42.35,41.89；ESI-MS m/z:345.4calcd for C17H19N3O5[M+H]+346.4.
实施例24
Figure BDA0001939948110000141
N-(3-羟基-4-甲氧基苄基)-2-吗啉基苯甲酰胺
邻氟苯甲酸(5g,35.7mmol)溶于20mL乙醇中，滴入催化量的浓硫酸，回流搅拌过夜，反应结束后旋去乙醇，乙酸乙酯萃取(25mL×3)，合并有机相，饱和碳酸氢钠溶液洗，饱和食盐水洗，无水硫酸钠干燥，浓缩后得无色油状产物邻氟苯甲酸乙酯4.9g；将邻氟苯甲酸乙酯(4.9g,29.1mmol)溶于20mL DMSO 中，滴入吗啉(12.7mL,145.7mmol)，120度搅拌过夜，反应结束后乙酸乙酯萃取(25mL×3)，合并有机相，水洗(25mL×3)，饱和食盐水洗，无水硫酸钠干燥，浓缩后得油状产物4.5g；将以上产物(4.5g,19.1mmol)溶于10mL甲醇中，加入10mL的10％的NaOH水溶液，80度搅拌2h后旋去甲醇，10％的稀盐酸调pH至4，有固体析出，抽滤得2-吗啉基苯甲酸3.2g，三步产率43.2％；将邻氟苯甲酸(50mg,0.24mmol)按实施例1中的操作得产物45g,两步产率 54.9％；1H NMR(300MHz,CDCl3)δ10.04(s,1H),8.22(dd,J＝7.8,1.8Hz,1H), 7.44(td,J＝7.7,1.8Hz,1H),7.26(dd,J＝7.5,1.4Hz,1H),7.20(td,J＝8.0,1.2Hz, 1H),6.97(d,J＝2.0Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.82(d,J＝8.2Hz,1H), 6.02(s,1H),4.55(d,J＝5.3Hz,2H),3.88(s,3H),3.61–3.44(m,4H),2.98–2.85 (m,4H)；13C NMR(75MHz,CDCl3)δ165.99,150.82,146.35,146.13,132.22, 131.87,131.60,127.77,125.29,120.50,119.99,114.70,110.91,66.88,56.11,53.47, 43.57；ESI-MS m/z:342.4calcd for C19H22N2O4[M+H]+343.4.
实施例25
Figure BDA0001939948110000142
N-(3-羟基-4-甲氧基苄基)-2-哌啶基苯甲酰胺
本实施例将吗啉替换成哌啶，按照实施例24的操作，得产物32mg；1H NMR(300MHz,CDCl3)δ10.61(s,1H),8.24(dd,J＝8.1,1.8Hz,1H),7.40(td,J＝7.6, 1.9Hz,1H),7.20(t,J＝7.7Hz,2H),6.96(d,J＝2.1Hz,1H),6.86-6.78(m,2H), 5.99(s,1H),4.55(d,J＝5.4Hz,2H),3.86(s,3H),2.81(d,J＝5.0Hz,4H),1.44(s, 6H)；13C NMR(75MHz,CDCl3)δ166.26,152.69,146.15,146.00,133.43,131.98, 131.56,127.66,124.84,120.98,119.84,114.68,110.93,56.16,54.83,43.49,26.24, 23.72；ESI-MS m/z:340.2calcd for C20H24N2O3[M+H]+341.4.
实施例26
Figure BDA0001939948110000143
N-(3-羟基-4-甲氧基苄基)-4-吗啉基烟酰胺
将4-吗啉基-3-烟酸(50mg,0.24mmol)按照实施例1中的操作得白色固体 46mg，两步产率56.1％；1H NMR(300MHz,CDCl3)δ8.96(s,1H),8.52(d,J＝5.6 Hz,1H),7.99(s,1H),6.94(d,J＝1.9Hz,1H),6.88(d,J＝5.6Hz,1H),6.85(d,J＝ 1.8Hz,1H),6.82(d,J＝8.1Hz,1H),4.53(d,J＝5.7Hz,2H),3.90(s,3H),3.59- 3.47(m,4H),3.04-2.93(m,4H)；13C NMR(75MHz,CDCl3)δ165.69,156.51, 152.41,151.94,146.72,146.38,131.05,122.44,119.91,114.78,112.62,111.04, 66.36,56.11,51.69,43.52；ESI-MS m/z:343.2calcdfor C18H21N3O4[M+H]+344.4.
实施例27
Figure BDA0001939948110000151
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-三氟甲基苯甲酰胺
将2-吗啉基-5-三氟甲基苯甲酸(75mg,0.27mmol)按照实施例1中的操作得白色固体55mg，两步产率46.6％；1H NMR(300MHz,CDCl3)δ9.39(s,1H), 8.43(d,J＝2.3Hz,1H),7.68(dd,J＝8.4,2.4Hz,1H),7.24(d,J＝8.4Hz,1H),6.95 (d,J＝1.9Hz,1H),6.93–6.85(m,1H),6.83(d,J＝8.2Hz,1H),5.83(s,1H),4.55 (d,J＝5.4Hz,2H),3.89(s,3H),3.68–3.36(m,4H),2.95(dd,J＝5.5,3.6Hz,4H)；13C NMR(75MHz,CDCl3)δ164.92,153.51,146.40,146.13,131.25,129.35(q,J＝ 3.7Hz),128.90(q,J＝3.6Hz),128.40,126.99(q,J＝33.2Hz),123.92(q,J＝270.5 Hz),120.31,120.11,114.61,110.92,66.69,56.15,53.29,43.70；ESI-MS m/z:410.1 calcd for C20H21F3N2O4[M+H]+411.1.
实施例28
Figure BDA0001939948110000152
N-(3-羟基-4-甲氧基苄基)-2-哌啶基-5-三氟甲基苯甲酰胺
将2-哌啶基-5-三氟甲基苯甲酸(100mg,0.37mmol)按照实施例1中的操作得白色固体86mg，两步产率57.7％；1H NMR(300MHz,CDCl3)δ9.86(d,J＝ 6.9Hz,1H),8.47(d,J＝2.4Hz,1H),7.63(dd,J＝8.5,2.4Hz,1H),7.23(s,1H), 6.94(d,J＝2.0Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.81(d,J＝8.2Hz,1H),5.60 (s,1H),4.56(d,J＝5.5Hz,2H),3.88(s,3H),2.88(t,J＝4.7Hz,4H),1.51(d,J＝ 12.4Hz,6H)；13C NMR(75MHz,CDCl3)δ165.12,155.37,146.21,146.00,131.56, 129.07(q,J＝3.9Hz),128.65(q,J＝3.8Hz),128.25,126.29,120.87,119.93,114.57, 110.91,56.17,54.73,43.61,26.09,23.60；ESI-MS m/z:408.1calcd for C20H23F3N2O3 [M+H]+409.1.
实施例29
Figure BDA0001939948110000153
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-4-硝基苯甲酰胺
将2-吗啉基-4-硝基苯甲酸(75mg,0.30mmol)按实施例1的操作得产物65 mg，产率56.5％；1H NMR(300MHz,CDCl3)δ9.34(s,1H),8.31(d,J＝8.6Hz,1H), 8.06(dd,J＝8.6,2.1Hz,1H),8.00(d,J＝2.2Hz,1H),6.96(d,J＝1.9Hz,1H),6.91 -6.80(m,2H),5.73(s,1H),4.56(d,J＝5.5Hz,2H),3.91(s,3H),3.54(t,J＝4.6Hz, 4H),3.02-2.91(m,4H)；13CNMR(75MHz,CDCl3)δ164.30,151.56,149.91, 146.49,146.18,133.50,133.14,130.92,120.13,119.43,115.21,114.62,110.93, 66.55,56.15,53.33,43.77；ESI-MS m/z:387.1calcd for C19H21N3O6[M+H]+388.1.
实施例30
Figure BDA0001939948110000161
N-(3-羟基-4-甲氧基苄基)-2-吗啉基异烟酰胺
将3-吗啉基-4-烟酸(75mg,0.36mmol)按照实施例1中的操作得白色固体 50mg，两步产率40.7％；1H NMR(300MHz,CDCl3)δ9.60(t,J＝5.5Hz,1H),8.53 (d,J＝4.3Hz,2H),7.98(d,J＝5.0Hz,1H),6.97(s,1H),6.85(s,2H),4.54(d,J＝ 5.5Hz,2H),3.88(s,3H),3.51(t,J＝4.4Hz,4H),2.99(t,J＝4.6Hz,4H)；13C NMR (75MHz,CDCl3)δ164.00,146.77,146.68,146.32,145.05,143.09,134.62,130.73, 124.40,119.92,114.83,111.04,66.62,56.07,53.12,43.65；ESI-MS m/z:343.2calcd for C18H21N3O4[M+H]+344.4.
实施例31
Figure BDA0001939948110000162
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-氟苯甲酰胺
将2,5-二氟苯甲酸按实施例24中的操作，得产物56mg，产率32.1％；1H NMR(300MHz,CDCl3)δ10.35(t,J＝5.4Hz,1H),7.96(dd,J＝9.7,3.0Hz,1H),7.16(m, 2H),6.95(s,1H),6.89–6.79(m,2H),5.96(s,1H),4.53(d,J＝5.2Hz,2H),3.89(s, 3H),3.50(t,J＝4.4Hz,4H),2.86(t,J＝4.5Hz,4H)；13C NMR(75MHz,CDCl3)δ 164.47,160.16(d,J＝243.8Hz),146.85(d,J＝3.0Hz),146.38,146.13,131.37, 130.09(d,J＝6.9Hz),122.93(d,J＝7.9Hz),120.06,118.83(d,J＝22.4Hz),118.37 (d,J＝24.0Hz),114.67,110.91,66.86,56.13,53.70,43.72；ESI-MS m/z:360.1calcd for C19H21FN2O4[M+H]+361.1.
实施例32
Figure BDA0001939948110000163
N-(3-羟基-4-甲氧基苄基)-2-哌啶基-5-氟苯甲酰胺
将2-哌啶基-5-氟苯甲酸(75mg,0.34mmol)按实施例24中的操作，得产物 68mg，两步产率55.7％；1H NMR(300MHz,CDCl3)δ10.79(s,1H),7.97(dd,J＝ 9.9,3.2Hz,1H),7.19(dd,J＝8.8,4.9Hz,1H),7.08(ddd,J＝8.8,7.2,3.2Hz,1H), 6.95(d,J＝2.0Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.81(d,J＝8.2Hz,1H),5.62 (s,1H),4.54(d,J＝5.3Hz,2H),3.88(s,3H),2.79(d,J＝5.1Hz,4H),1.51–1.42(m, 6H)；13C NMR(75MHz,CDCl3)δ169.92,159.94(d,J＝243.4Hz),148.69(d,J＝ 2.8Hz),146.15,145.98,139.31,131.78,123.20(d,J＝7.9Hz),119.94,118.57(d,J ＝22.1Hz),117.96(d,J＝24.0Hz),118.12,117.80,114.63,110.90,56.19,55.07, 43.61,26.24,23.62；ESI-MS m/z:358.2calcd for C20H23FN2O3[M+H]+359.2.
实施例33
Figure BDA0001939948110000171
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-氯苯甲酰胺
将2-吗啉基-5-氯苯甲酸(75mg,0.43mmol)按实施例1中的操作，得产物 68mg，两步产率41.9％；1H NMR(300MHz,CDCl3)δ9.93(d,J＝6.6Hz,1H),8.19 (d,J＝2.7Hz,1H),7.39(dd,J＝8.5,2.8Hz,1H),7.13(d,J＝8.6Hz,1H),6.95(d,J ＝2.0Hz,1H),6.90–6.80(m,2H),5.88(s,1H),4.53(d,J＝5.3Hz,2H),3.89(s,3H), 3.50(t,J＝4.5Hz,4H),2.87(t,J＝4.6Hz,4H)；13C NMR(75MHz,CDCl3)δ 164.62,149.28,146.40,146.15,131.99,131.78,131.37,131.15,129.48,122.17, 120.06,114.66,110.94,66.79,56.15,53.51,43.70；ESI-MS m/z:376.1calcd for C19H21ClN2O4[M+H]+377.1.
实施例34
Figure BDA0001939948110000172
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-溴苯甲酰胺
将2-吗啉基-5-溴苯甲酸(83mg,0.29mmol)按实施例1中的操作，得产物 72mg，两步产率59.0％；1H NMR(300MHz,CDCl3)δ9.86(s,1H),8.33(d,J＝2.5 Hz,1H),7.54(dd,J＝8.5,2.5Hz,1H),7.06(d,J＝8.6Hz,1H),6.94(s,1H),6.90- 6.79(m,2H),5.84(s,1H),4.53(d,J＝5.3Hz,2H),3.89(s,3H),3.50(t,J＝4.5Hz, 4H),2.87(t,J＝4.5Hz,4H)；13C NMR(75MHz,CDCl3)δ164.56,149.78,146.41, 146.15,134.96,134.70,131.35,129.68,122.40,120.04,118.78,114.66,110.94, 66.75,56.14,53.42,43.69；ESI-MS m/z:420.1calcd for C19H21BrN2O4[M+H]+ 421.1.
实施例35
Figure BDA0001939948110000181
N-(3-羟基-4-甲氧基苄基)-2-哌啶基-5-溴苯甲酰胺
将2-哌啶基-5-溴苯甲酸(100mg,0.34mmol)按实施例1中的操作，得产物68mg，两步产率46.3％；1H NMR(300MHz,CDCl3)δ10.34(s,1H),8.36(d,J ＝2.6Hz,1H),7.50(dd,J＝8.5,2.6Hz,1H),7.06(d,J＝8.5Hz,1H),6.94(d,J＝2.0 Hz,1H),6.86(dd,J＝8.2,2.0Hz,1H),6.81(d,J＝8.2Hz,1H),5.62(s,1H),4.54(d, J＝5.4Hz,2H),3.88(s,3H),2.80(d,J＝5.2Hz,4H),1.50–1.44(m,6H)；13C NMR (75MHz,CDCl3)δ164.82,151.61,146.16,145.97,134.75,134.40,131.70,129.58, 122.90,119.91,118.32,114.59,110.89,56.19,54.83,43.59,26.15,23.61；ESI-MS m/z:418.1calcd for C20H23BrN2O3[M+H]+419.1.
实施例36
Figure BDA0001939948110000182
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-羟基苯甲酰胺
(A)将2-吗啉基-5-溴苯甲酸乙酯(500mg,1.59mmol)溶于20mL二氧六环中，分别加入二(三苯基磷)二氯化钯(110mg,0.16mmol)，联硼酸吡那醇酯(613 mg,2.39mmol)，醋酸钾(470mg,4.77mmol)，氮气保护，80度条件反应3h，反应结束后抽滤，滤液浓缩后柱层析(PE/EA 20:1)得495mg产物，产率86.1％；将以上产物(320mg,0.89mmol)溶于20mL甲醇中，滴入2mL 30％的双氧水，室温搅拌30min，反应结束后旋去甲醇，乙酸乙酯萃取(25mL×3)，合并有机相，饱和碳酸氢钠溶液洗，饱和食盐水洗，无水硫酸钠干燥，浓缩后得2-吗啉-5- 羟基苯甲酸乙酯208mg，产率93.4％；将2-吗啉-5-羟基苯甲酸乙酯(200mg,0.80 mmol)溶于20mL乙腈中，分别加入溴苄(0.11mL,0.96mmol)，碳酸钾(170 mg,1.2mmol)，80度搅拌2h，反应结束后乙酸乙酯萃取(25mL×3)，合并有机相，水洗(25mL×3)，饱和食盐水洗，无水硫酸钠干燥，浓缩后得油状产物 255mg，将该产物溶于10mL甲醇中，加入10mL的10％的NaOH水溶液，80 度搅拌2h后旋去甲醇，10％的稀盐酸调pH至4，有固体析出，抽滤得2-吗啉基-5-苄氧基苯甲酸156mg，两步产率62.7％.
(B)将2-吗啉基-5-苄氧基苯甲酸(90mg,0.29mmol)溶于10mL DCM中，分别加入TBS保护的3-羟基-4-甲氧基苄胺(92mg,0.34mmol)，羟基苯并三氮唑 (47mg,0.35mmol)，EDCI(120mg,0.58mmol)，室温搅拌2h后加水稀释，乙酸乙酯萃取(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体105mg；将该产物(105mg,0.19mmol) 溶于无水10mL THF中,加入四丁基氟化铵(74mg,0.28mmol)，室温搅拌15min后，加水稀释，乙酸乙酯(25mL×3)，合并有机相，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(PE/EA 4:1)得黄色固体56mg；将该产物溶于10mL 无水甲醇中，加入5mg钯碳，氢气条件下反应2h，抽滤，滤液浓缩后柱层析 (PE/EA 4:1)得黄色固体20mg产物，三步产率16.8％；1H NMR(300MHz, DMSO-d6)δ10.32(s,1H),9.50(s,1H),8.96(s,1H),7.37(s,1H),7.20(s,1H),6.88- 6.74(m,4H),4.35(s,2H),3.74(s,3H),3.43(s,4H),2.75(s,4H)；13CNMR(75MHz, DMSO-d6)δ164.98,154.38,146.86,146.61,142.56,131.62,129.42,122.92,118.65, 118.36,116.46,115.28,112.25,66.18,55.73,53.26,42.38；ESI-MS m/z:358.2calcd for C19H22N2O5[M+H]+359.2.
实施例37
Figure BDA0001939948110000191
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-甲氧基苯甲酰胺
(A)将2-吗啉-5-羟基苯甲酸乙酯(120mg,0.48mmol)溶于10mL无水THF 中，氮气保护，冰浴下加入60％的钠氢(29mg,0.72mmol)，搅拌15min后加入硫酸二甲酯(0.45mL,0.53mmol)，室温搅拌30min，反应结束后乙酸乙酯萃取(25mL×3)，合并有机相，水洗(25mL×3)，饱和食盐水洗，无水硫酸钠干燥，浓缩后得油状产物95mg，将该产物溶于10mL甲醇中，加入10mL 的10％的NaOH水溶液，80度搅拌2h后旋去甲醇，10％的稀盐酸调pH至4，有固体析出，抽滤得2-吗啉基-5-甲氧基苯甲酸65mg，两步产率57.5％.
(B)将2-吗啉基-5-甲氧基苯甲酸(65mg,0.27mmol)按照实施例1中的操作得产物55mg，产率54.9％；1H NMR(300MHz,CDCl3)δ10.67(s,1H),7.84(d,J＝ 3.2Hz,1H),7.17(d,J＝8.8Hz,1H),7.03–6.94(m,2H),6.87(dd,J＝8.3,2.0Hz, 1H),6.82(d,J＝8.2Hz,1H),5.87(s,1H),4.54(d,J＝5.2Hz,2H),3.89(s,3H),3.84 (s,3H),3.49(t,J＝4.5Hz,4H),2.85(t,J＝4.6Hz,4H)；13C NMR(75MHz,CDCl3) δ165.47,157.18,146.29,146.10,143.97,131.68,128.93,122.72,120.02,118.88, 115.11,114.68,110.88,67.01,56.14,55.74,53.72,43.69；ESI-MS m/z:372.2calcd for C20H24N2O5[M+H]+373.2.
实施例38
Figure BDA0001939948110000192
N-(3-羟基-4-甲氧基苄基)-2-哌啶基-5-甲氧基苯甲酰胺
将2-哌啶-5-甲氧基苯甲酸(100mg,0.43mmol)按实施例37的操作得产物 62mg，产率39.5％；1H NMR(300MHz,CDCl3)δ11.08(s,1H),7.85(d,J＝3.2Hz, 1H),7.16(d,J＝8.8Hz,1H),6.98-6.92(m,2H),6.87(dd,J＝8.2,2.1Hz,1H),6.81 (d,J＝8.2Hz,1H),5.61(s,1H),4.55(d,J＝5.3Hz,2H),3.88(s,3H),3.83(s,3H), 2.78(d,J＝5.2Hz,4H),1.44(s,6H)；13C NMR(75MHz,CDCl3)δ165.82,156.82, 146.08,145.95,145.86,132.07,128.72,122.95,119.88,118.78,116.32,114.78, 114.64,110.88,56.19,55.70,55.02,43.55,26.35,23.70；ESI-MS m/z:370.2calcd for C21H26N2O4[M+H]+371.2.
实施例39
Figure BDA0001939948110000201
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-二甲胺基苯甲酰胺
将2-吗啉基-5-硝基苯甲酸乙酯(5g,17.9mmol)溶于40mL醋酸与乙醇(1： 1)的混合溶剂中，加入还原型铁粉(6g,107.2mmol)，回流搅拌2h后，旋去溶剂，加入饱和碳酸氢钠水溶液调至中性，抽滤，滤液乙酸乙酯萃取(50mL×3)，合并有机相，水洗(25mL×3)，饱和食盐水洗，无水硫酸钠干燥，浓缩后柱层析(4：1)得黄色固体3.5g，产率76.1％；2-吗啉基-5-氨基苯甲酸乙酯(200mg, 0.8mmol)溶于5mL醋酸中，滴入甲醛水溶液5mL后，加入氰基硼氢化钠(200 mg,3.2mmol)，室温搅拌30min后，旋去醋酸，加入饱和碳酸氢钠水溶液调至中性，抽滤，滤液乙酸乙酯萃取(25mL×3)，合并有机相，水洗(25mL×3)，饱和食盐水洗，无水硫酸钠干燥，浓缩后的产物溶于10mL甲醇中，加入10mL 的10％的NaOH水溶液，80度搅拌2h后旋去甲醇，10％的稀盐酸调pH至4，有固体析出，抽滤得2-吗啉基-5-二甲氨基苯甲酸154mg，三步产率61.6％；将 2-吗啉基-5-二甲氨基苯甲酸(75mg,0.3mmol)按实施例18的操作得产物52mg, 产率45.2％；1H NMR(300MHz,CDCl3)δ10.84(s,1H),7.70(d,J＝3.2Hz,1H), 7.13(d,J＝8.8Hz,1H),6.96(d,J＝2.0Hz,1H),6.89–6.76(m,3H),5.91(s,1H), 4.54(d,J＝5.2Hz,2H),3.88(s,3H),3.47(d,J＝5.1Hz,4H),2.97(s,6H),2.82(t,J ＝4.6Hz,4H)；13C NMR(75MHz,CDCl3)δ166.21,148.43,146.23,146.06,140.19, 131.90,128.07,122.42,119.99,115.70,115.08,114.69,110.86,67.13,56.14,53.73, 43.65,40.81；ESI-MS m/z:385.2calcd for C21H26N2O4[M+H]+386.2.
实施例40
Figure BDA0001939948110000202
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-乙酰胺基苯甲酰胺
2-吗啉基-5-氨基苯甲酸乙酯(200mg,0.8mmol)溶于10mL DCM中，分别加入醋酐(96μL,0.96mmol)与三乙胺(133μL,0.96mmol)，室温搅拌2h后，乙酸乙酯萃取(25mL×3)，合并有机相，水洗(25mL×3)，饱和食盐水洗，无水硫酸钠干燥，浓缩后的产物溶于10mL甲醇中，加入10mL的10％的NaOH 水溶液，80度搅拌2h后旋去甲醇，10％的稀盐酸调pH至4，有固体析出，抽滤得2-吗啉基-5-乙酰氨基苯甲酸132mg，三步产率62.6％；将2-吗啉基-5-乙酰氨基苯甲酸(75mg,0.28mmol)按实施例18的操作得产物49mg，产率43.4％；1H NMR(300MHz,DMSO-d6)δ10.02(s,1H),9.89(d,J＝5.9Hz,1H),8.96(s,1H), 7.98(s,1H),7.77(d,J＝8.6Hz,1H),7.22(d,J＝8.7Hz,1H),6.87(d,J＝8.2Hz, 1H),6.82(s,1H),6.76(d,J＝8.1Hz,1H),4.36(s,2H),3.74(s,3H),3.45(t,J＝4.2 Hz,4H),2.96-2.67(m,4H),2.03(s,3H)；13C NMR(75MHz,DMSO-d6)δ168.22, 165.34,146.79,146.57,145.74,135.73,131.66,128.82,121.99,121.18,120.76, 118.68,115.33,112.22,66.04,55.73,52.92,42.38,23.91；ESI-MS m/z:399.2calcd for C21H25N3O5[M+H]+400.2.
实施例41
Figure BDA0001939948110000211
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-(对甲氧基苯甲酰胺基)苯甲酰胺
2-吗啉基-5-氨基苯甲酸乙酯(200mg,0.8mmol)溶于无水10mL THF中，分别滴入对甲氧基苯甲酰氯(164mg,0.96mmol)与三乙胺(222μL,1.2mmol)，室温搅拌2h后，乙酸乙酯萃取(25mL×3)，合并有机相，水洗(25mL×3)，饱和食盐水洗，无水硫酸钠干燥，浓缩后的产物溶于10mL甲醇中，加入10mL 的10％的NaOH水溶液，80度搅拌2h后旋去甲醇，10％的稀盐酸调pH至4，有固体析出，抽滤得2-吗啉基-5-(对甲氧基苯甲酰基)苯甲酸105mg，两步产率40.4％；将2-吗啉基-5-(对甲氧基苯甲酰基)苯甲酸(75mg,0.23mmol)按实施例18的操作得产物45mg，产率40.2％；1H NMR(300MHz,CDCl3)δ10.49 (s,1H),8.48(s,1H),8.41-8.34(m,1H),8.09(s,1H),7.89(d,J＝8.5Hz,2H),7.23 (s,1H),6.96(s,1H),6.93(s,2H),6.81(d,J＝1.2Hz,2H),5.94(s,1H),4.46(d,J＝ 5.2Hz,2H),3.89(s,3H),3.85(s,3H),3.49(s,4H),2.88(s,4H)；13C NMR(75MHz, DMSO-d6)δ165.48,164.71,161.93,146.84,146.58,146.08,135.66,131.70,129.61, 128.76,126.70,123.24,122.24,120.86,118.65,115.35,113.60,112.22,66.04,55.72, 55.44,52.91,42.38；ESI-MS m/z:491.2calcd forC27H29N3O6[M+H]+492.2.
实施例42
Figure BDA0001939948110000212
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-糠酰胺基苯甲酰胺
本实施例将对甲氧基苯甲酸替换成2-呋喃甲酸，按照实施例41的操作，得产物34mg,产率39.2％；1H NMR(300MHz,CDCl3)δ10.35(t,J＝5.4Hz,1H), 8.32(m,2H),8.02(d,J＝2.8Hz,1H),7.53(s,1H),7.24(d,J＝4.4Hz,1H),6.97(s, 1H),6.83(t,J＝6.1Hz,2H),6.56(s,1H),5.89(s,1H),4.55(d,J＝5.2Hz,2H),3.89 (s,3H),3.55–3.44(m,4H),2.89(t,J＝4.5Hz,4H)；13C NMR(75MHz,CDCl3)δ 165.20,156.35,147.70,147.04,146.43,146.19,144.60,135.07,131.47,128.33, 123.87,122.73,122.19,120.02,115.56,114.75,112.71,110.96,66.91,56.16,53.62, 43.72；ESI-MS m/z:451.2calcd for C24H25N3O6[M+H]+452.2.
实施例43
Figure BDA0001939948110000221
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-(吡啶-4-甲酰胺基)苯甲酰胺
本实施例将对甲氧基苯甲酸替换成4-吡啶甲酸，按照实施例41的操作，得产物43mg,产率42.2％；1H NMR(300MHz,DMSO-d6)δ10.57(s,1H),9.77(t,J＝5.8Hz,1H),8.94(s,1H),8.83-8.70(m,2H),8.19(d,J＝2.6Hz,1H),7.95(dd,J＝ 8.7,2.7Hz,1H),7.92-7.79(m,2H),7.29(d,J＝8.8Hz,1H),6.88(d,J＝8.2Hz, 1H),6.83(d,J＝2.0Hz,1H),6.77(dd,J＝8.2,2.0Hz,1H),4.38(d,J＝5.7Hz,2H), 3.74(s,3H),3.48(t,J＝4.2Hz,4H),2.83(t,J＝4.5Hz,4H)；13C NMR(75MHz, DMSO-d6)δ165.42,163.74,150.30,146.84,146.72,146.56,141.65,134.74,131.67, 128.91,123.34,122.41,121.57,120.88,118.67,115.35,112.20,66.00,55.72,52.82, 42.38；ESI-MS m/z:462.2calcd for C25H26N4O5[M+H]+463.2.
实施例44
Figure BDA0001939948110000222
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-(对甲氧基苄基)苯甲酰胺
2-吗啉基-5-氨基苯甲酸乙酯(200mg,0.8mmol)溶于无水10mL甲醇中，加入对甲氧基苯甲醛(116μL,0.96mmol)，室温搅拌2h后加入硼氢化钠(46mg, 1.2mmol)，室温搅拌15min后，加入饱和氯化铵溶液淬灭，乙酸乙酯萃取(25 mL×3)，合并有机相，水洗(25mL×3)，饱和食盐水洗，无水硫酸钠干燥，浓缩后的产物溶于10mL甲醇中，加入10mL的10％的NaOH水溶液，80度搅拌2h后旋去甲醇，10％的稀盐酸调pH至4，有固体析出，抽滤得2-吗啉基-5- (对甲氧基苯甲胺基)苯甲酸190mg，两步产率66.9％；将2-吗啉基-5-(对甲氧基苯甲胺基)苯甲酸(75mg,0.22mmol)按实施例18的操作得产物68mg，产率65.4％；1H NMR(300MHz,CDCl3)δ10.84(d,J＝5.4Hz,1H),7.62(d,J＝3.0 Hz,1H),7.32-7.25(m,2H),7.05(d,J＝8.6Hz,1H),6.96(d,J＝1.9Hz,1H),6.92- 6.74(m,4H),6.65(dd,J＝8.5,3.0Hz,1H),5.95(s,1H),4.52(d,J＝5.1Hz,2H), 4.27(s,2H),3.87(s,3H),3.79(s,3H),3.46(s,4H),2.79(d,J＝4.7Hz,4H)；13C NMR(75MHz,CDCl3)δ165.92,158.94,146.27,146.08,146.00,140.98,131.80, 131.19,128.88,128.44,122.73,119.99,115.62,115.55,114.72,114.13,110.86, 67.08,56.12,55.39,53.75,47.87,43.64；ESI-MS m/z:477.2calcd for C27H31N3O5 [M+H]+478.2.
实施例45
Figure BDA0001939948110000223
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-(呋喃-2-甲胺基)苯甲酰胺
本实施例将对甲氧基苯甲醛替换成2-呋喃甲醛，按照实施例44的操作，得产物55mg,产率54.2％；1H NMR(300MHz,CDCl3)δ10.84(t,J＝5.3Hz,1H), 7.63(d,J＝3.0Hz,1H),7.35(d,J＝1.8Hz,1H),7.08(d,J＝8.6Hz,1H),6.95(d,J ＝1.9Hz,1H),6.88-6.80(m,2H),6.73(dd,J＝8.6,3.0Hz,1H),6.31(dd,J＝3.2, 1.8Hz,1H),6.25(d,J＝3.2Hz,1H),6.01(s,1H),4.52(d,J＝5.2Hz,2H),4.33(s, 2H),4.23(s,1H),3.88(s,3H),3.45(d,J＝4.8Hz,4H),2.80(t,J＝4.6Hz,4H)；13C NMR(75MHz,CDCl3)δ165.84,152.46,146.28,146.07,145.41,142.04,141.45, 131.70,128.38,122.70,119.94,116.10,115.65,114.66,110.88,110.43,107.26, 67.02,56.11,53.70,43.59,41.45；ESI-MS m/z:437.2calcd for C24H27N3O5[M+H]+ 438.2.
实施例46
Figure BDA0001939948110000231
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-(吡啶-4-甲胺基)苯甲酰胺
本实施例将对甲氧基苯甲醛替换成4-吡啶甲醛，其他操作均同实施例44，得产物52mg,产率50.2％；1H NMR(300MHz,DMSO-d6)δ10.45(d,J＝6.3Hz, 1H),8.95(d,J＝3.0Hz,1H),8.56-8.42(m,2H),7.38-7.29(m,2H),7.24(d,J＝ 2.9Hz,1H),7.10(d,J＝8.6Hz,1H),6.86(d,J＝8.2Hz,1H),6.79(s,1H),6.74(dd, J＝8.1,2.1Hz,1H),6.62(dd,J＝8.7,3.0Hz,1H),6.53(d,J＝6.9Hz,1H),4.39- 4.26(m,4H),3.73(s,3H),3.40(dd,J＝5.9,3.2Hz,4H),2.70(t,J＝4.6Hz,4H)；13C NMR(75MHz,DMSO-d6)δ165.23,149.56,146.83,146.59,146.45,140.22,131.66, 128.78,122.71,122.18,118.62,115.27,115.17,114.83,113.92,112.23,66.22,55.71, 53.28,45.47,42.37；ESI-MS m/z:448.2calcd forC25H28N4O4[M+H]+449.2.
实施例47
Figure BDA0001939948110000232
N-(3-羟基-4-甲氧基苄基)-4'-甲氧基-4-吗啉基-[1,1'-联苯]-3-甲酰胺
将3-乙氧羰基-4-吗啉基苯硼酸吡那醇酯(200mg,0.55mmol)溶于20mL DMF中，加入4-溴苯甲醚(123mg,0.66mmol)，四(三苯基磷)钯(60mg,0.06 mmol)，碳酸钾(152mg,1.1mmol)，90度条件反应2h后，反应结束后乙酸乙酯萃取(25mL×3)，合并有机相，水洗(25mL×3)，饱和食盐水洗，无水硫酸钠干燥，浓缩后得油状产物柱层析(PE/EA 5:1)得157mg产物，将该产物溶于10mL甲醇中，加入10mL的10％的NaOH水溶液，80度搅拌2h后旋去甲醇，10％的稀盐酸调pH至4，有固体析出，抽滤得4'-甲氧基-4-吗啉基-[1,1'-联苯]-3-甲酸82mg，两步产率47.4％；将4'-甲氧基-4-吗啉基-[1,1'-联苯]-3-甲酸(75 mg,0.24mmol)按实施例18的操作得产物62mg，两步产率57.9％；1H NMR(300 MHz,CDCl3)δ10.06(d,J＝4.8Hz,1H),8.44(d,J＝2.4Hz,1H),7.62(dd,J＝8.3, 2.5Hz,1H),7.60–7.51(m,2H),7.22(d,J＝8.3Hz,1H),7.05-6.90(m,3H),6.88 (dd,J＝8.2,2.0Hz,1H),6.83(d,J＝8.2Hz,1H),5.88(s,1H),4.57(d,J＝5.3Hz, 2H),3.88(s,3H),3.85(s,3H),3.52(t,J＝4.4Hz,4H),2.92(t,J＝4.6Hz,4H)；13C NMR(75MHz,CDCl3)δ166.00,159.37,149.36,146.31,146.10,137.67,132.33, 131.68,129.95,129.89,128.09,127.98,121.00,120.04,114.68,114.35,110.90, 66.94,56.14,55.46,53.54,43.64；ESI-MS m/z:448.2calcd forC26H28N2O5[M+H]+ 449.2.
实施例48
Figure BDA0001939948110000241
N-(3-羟基-4-甲氧基苄基)-4'-甲氧基-4-哌啶基-[1,1'-联苯]-3-甲酰胺
本实施例将吗啉替换成哌啶，按照实施例47的操作，得产物52mg，产率 48.9％；1HNMR(300MHz,CDCl3)δ10.52(t,J＝4.9Hz,1H),8.47(d,J＝2.4Hz, 1H),7.62-7.53(m,3H),7.23(d,J＝8.4Hz,1H),7.00-6.93(m,3H),6.89(dd,J＝ 8.2,2.1Hz,1H),6.81(d,J＝8.2Hz,1H),5.61(s,1H),4.58(d,J＝5.4Hz,2H),3.88 (s,3H),3.84(s,3H),2.87(t,J＝4.6Hz,4H),1.48(s,6H)；13C NMR(75MHz, CDCl3)δ166.26,159.23,151.25,146.10,145.96,137.15,132.61,132.03,129.75, 129.59,128.06,127.84,121.42,119.87,114.64,114.28,110.90,56.17,55.44,54.88, 43.53,26.29,23.74；ESI-MS m/z:446.2calcd forC27H30N2O4[M+H]+447.2.
实施例49
Figure BDA0001939948110000242
5-(呋喃-2-基)-N-(3-羟基-4-甲氧基苄基)-2-吗啉苯甲酰胺
本实施例将对甲氧基溴苯替换成2-溴呋喃，按照实施例47的操作，得产物 62mg，产率56.9％；1H NMR(300MHz,CDCl3)δ9.94(s,1H),8.49(d,J＝2.3Hz, 1H),7.75(dd,J＝8.4,2.4Hz,1H),7.47(d,J＝1.8Hz,1H),7.20(d,J＝8.4Hz,1H), 6.97(d,J＝2.1Hz,1H),6.94-6.78(m,2H),6.71(d,J＝3.4Hz,1H),6.48(dd,J＝ 3.5,1.8Hz,1H),5.74(s,1H),4.57(d,J＝5.4Hz,2H),3.90(s,3H),3.66–3.39(m, 4H),2.92(t,J＝4.6Hz,4H)；13C NMR(75MHz,CDCl3)δ165.75,153.01,149.58, 146.33,146.12,142.31,131.56,128.03,128.01,127.34,127.03,120.84,120.02, 114.69,111.89,110.92,105.59,66.86,56.12,53.44,43.64；ESI-MS m/z:408.2calcd for C23H24N2O5[M+H]+409.2.
实施例50
Figure BDA0001939948110000251
N-(3-羟基-4-甲氧基苄基)-2-吗啉基-5-(吡啶-4-基)苯甲酰胺
本实施例将对甲氧基溴苯替换成4-溴吡啶，其他操作均同实施例47，得产物54mg，产率53.9％；1H NMR(300MHz,CDCl3)δ9.74(t,J＝5.4Hz,1H),8.66(d, J＝5.1Hz,2H),8.51(d,J＝2.3Hz,1H),7.73(dd,J＝8.4,2.3Hz,1H),7.55(d,J＝ 5.1Hz,2H),7.30(s,1H),6.98(s,1H),6.86(q,J＝8.3Hz,2H),6.15(s,1H),4.58(d, J＝5.3Hz,2H),3.90(s,3H),3.55(t,J＝4.4Hz,4H),2.96(t,J＝4.5Hz,4H)；13C NMR(75MHz,CDCl3)δ165.61,151.52,150.24,147.11,146.52,146.28,134.44, 131.44,130.54,130.32,128.47,121.46,121.01,119.98,114.75,110.99,66.81,56.14, 53.44,43.68；ESI-MS m/z:419.2calcd forC24H25N3O4[M+H]+420.2.
实施例51
Figure BDA0001939948110000252
5-((5-氟-2-吗啉基苯甲酰胺基)甲基)-2-甲氧基苯基磷酸二钠盐
实施例31(500mg,1.39mmol)溶于二氯甲烷中，分别滴入三氯氧磷(697 μL,7.5mmol)及吡啶(605μL,7.5mmol)，室温搅拌15h后，加入饱和碳酸钠水溶液继续搅拌2h，反应液浓缩，C18柱层析过得产物208mg，产率30.9％。1H NMR(300MHz,DMSO-d6)1H NMR(300MHz,CDCl3)δ8.77(t,J＝6.1Hz, 1H),7.82(dd,J＝8.0,2.7Hz,1H),7.13(td,J＝8.2,2.7Hz,1H),7.01-6.88(m,4H), 4.49(dt,J＝6.2,0.9Hz,2H),3.84(s,2H),3.77(ddd,J＝6.7,5.5,1.4Hz,4H),3.20 (qdd,J＝12.8,6.5,5.5Hz,4H)；13C NMR(75MHz,DMSO-d6)δ167.96,167.94, 159.76,157.74,150.72,150.68,147.55,147.49,143.99,143.96,133.85,133.83, 125.35,125.28,122.75,120.72,120.66,120.60,120.56,118.15,118.11,116.12, 115.96,112.94,112.92,66.88,56.02,50.13,45.76.ESI-MS m/z:484.1calcd for C19H20FN2O7PNa2[M-Na]-461.1.
实施例52
片剂
Figure BDA0001939948110000253
取上述配方，用常规方法制备成片剂。
下面是本发明部分化合物的药理实验结果：
抗增殖实验
1.实验方法
2.细胞消化、计数、制成浓度为5×104个/mL的细胞悬液，96孔板中每孔加入100μl细胞悬液(每孔5×103个细胞)；
3.96孔板置于37℃，5％CO2培养箱中培养24小时；
4.用完全培养基稀释药物至所需浓度，每孔加入100μL相应的含药培养基；
5.96孔板置于37℃，5％CO2培养箱中培养72小时；
6.MTT法：
1)将96孔板进行MTT染色，λ＝490nm，测定OD值。
2)每孔加入20μL MTT(5mg/mL)，在培养箱继续培养4小时；
3)弃去培养基，每孔加入150μL DMSO溶解，摇床10分钟轻轻混匀；λ＝ 490nm，酶标仪读出每孔的OD值。
6.计算抑制率。
Figure BDA0001939948110000261
2.实验结果
表1本发明化合物对5种人类癌细胞株抗增殖活性的IC50值(μM)
Figure BDA0001939948110000262
Figure BDA0001939948110000271
下面是部分化合物的体外抗微管蛋白聚集的实验
1.实验方法
化合物按照相应要求配置成母液，按照倍数稀释成终浓度后用于后续试验。浓度设置为5个，每个浓度生物学重复3次。将2mg/mL微管蛋白(细胞骨架) 的量重新悬浮于PEM缓冲液[80mM PIPES(pH6.9)，0.5mM EGTA，2mM MgCl2和15％甘油]中，然后在冰上与化合物或溶剂DMSO预孵育5分钟。在检测微管蛋白聚合反应之前，加入含有GTP的PEG至终浓度为3mg/mL。通过Berthold LB941微孔板式多功能酶标仪，30分钟后在340nm检测吸光度。通过设置空白对照组，Graphpad计算得出不同化合物的IC50，结果以μM为单位。
2.实验结果
表2本发明部分化合物的体外微管蛋白聚集的药理实验结果：
实施例 抑制微管蛋白聚集IC<sub>50</sub>(μM)
16 1.89
19 1.93
25 2.03
27 2.22
31 1.88
32 2.02
33 2.45
37 2.34
38 2.08
CA-4 2.54
下面是部分化合物的水溶性实验
1.实验方法
1.1实验仪器与条件
HPLC型号：Agilent 1100；色谱柱：Lichrospher C18(5um,4.6×250mm)；柱温：37℃；流速：1.0ml/min；进样量：10μL；检测波长：210nm
2.2实验步骤
准确称定各样品，用甲醇配制成浓度为0.01,0.05,0.1,0.2,0.4,1mg/mL 标准液，HPLC进样得到主峰峰面积，并计算标准曲线。然后取适当过量的待测化合物(>10mg)，分别溶解在PBS中，37℃下恒温摇床孵育24小时。离心取10μL上清液进注HPLC测定各化合物的主峰面积，再通过标准曲线计算出相应的溶解度。
2.实验结果
表3本发明部分化合物的水溶性结果：
Figure BDA0001939948110000281
Figure BDA0001939948110000291
下面是部分化合物的体内抗肿瘤实验
1、实验方法
由上海斯莱克实验动物有限责任公司提供，周龄为3周，体重12-16g的雌性Balb/c裸鼠70只。收集培养的肝癌H22细胞，计数、调整使细胞悬液浓度为 1.5×107个/ml，于裸小鼠右侧腋窝皮下每只接种0.1ml。用游标卡尺测量裸鼠移植瘤的直径，接种肿瘤细胞7天后，肿瘤长至50-75mm3时，每组10只将裸鼠随机分为6组。衍生物溶于DMSO，再滴入poloxamer母液，最后加生理盐水至所需剂量。DMSO终浓度为1％，poloxamer终浓度为2％。各组裸鼠给药，模型组腹腔注射等量溶媒，每天注射1次，持续21天；阳性对照组尾静脉注射20 mg/kg顺铂，每天注射1次，持续21天；实验组静脉注射20mg/kg实施例10,17, 20,24。每天注射1次，持续21天；给药21天结束后处死裸鼠，通过手术剥取瘤块，称重。计算肿瘤生长抑制率(％)，用SPSS17.0对结果进行分析，组间用 t检验进行统计学分析处理，其计算公式如下：
Figure BDA0001939948110000292
2、实验结果
表4 部分实施例的体内抗肿瘤活性
Figure BDA0001939948110000293

Claims (7)

1.一种N-苄基苯甲酰胺类衍生物或其可药用的盐，其特征在于，选自化合物1-51或其可药用的盐：
Figure FDA0003858471170000011
Figure FDA0003858471170000021
2.权利要求1所述N-苄基苯甲酰胺类衍生物或其可药用的盐在制备微管蛋白抑制剂药物中的应用。
3.权利要求1所述N-苄基苯甲酰胺类衍生物或其可药用的盐在制备抗肿瘤药物中的应用。
4.根据权利要求3所述的应用，其特征在于，所述肿瘤为结肠癌、白血病、肝癌、乳腺癌、胃癌或胰腺癌。
5.一种药物组合物，其特征在于，包含权利要求1所述N-苄基苯甲酰胺类衍生物或其可药用的盐。
6.权利要求5所述药物组合物在制备微管蛋白抑制剂药物中的应用。
7.权利要求5所述药物组合物在制备抗肿瘤药物中的应用。
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