CN108218918A - 芳基偕二磷酸衍生物制备方法和用途 - Google Patents
芳基偕二磷酸衍生物制备方法和用途 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及药物化学和药物治疗性领域,具体涉及可作为β-内酰胺酶抑制剂的芳基偕二磷酸衍生物及其药物组合物和医药用途。
背景技术
β-内酰胺类抗生素是目前临床上使用最广泛的抗生素(如头孢菌素类、碳青霉烯类等),具有临床疗效好、毒性低、适应症广(对革兰氏阳性菌和革兰氏阴性菌均有较好的抑菌效果)等优点。β-内酰胺类抗生素主要通过抑制细菌胞壁粘肽合成酶(即青霉素结合蛋白,简称PBP)的催化活性,从而阻止细胞壁粘肽合成,进而导致细菌胞壁缺损、菌体膨胀裂解而亡。然而,如今具有高效抗性的β-内酰胺抗生素耐药“超级”细菌不断出现且在全球范围内快速蔓延(我国“超级”细菌耐药形势也十分严峻),已成为当前难治性感染的严重问题,因而解决抗生素耐药问题刻不容缓。病原菌产生的β-内酰胺酶种类繁多,目前已发现和鉴别了超过1300种不同亚型的β-内酰胺酶:根据氨基酸序列同源性,这些β-内酰胺酶被分为A、B、C和D四类;从催化机制上,β-内酰胺酶被分为两大类:丝氨酸β-内酰胺酶(SBL)和金属β-内酰胺酶(MBL)。根据SBL水解β-内酰胺抗生素的化学机制,人们开发了大量SBL抑制剂,其中克拉维酸、舒巴坦、他唑巴坦和阿维巴坦已被批准上市。克拉维酸、舒巴坦和他唑巴坦都包含四元β-内酰胺环,作用机制十分相似,主要是通过与SBL丝氨酸形成稳定的酰化-SBL复合物,从而抑制SBL的催化活性;而阿维巴坦是五并六元环结构,其不仅能与SBL丝氨酸形成稳定的酰化-SBL复合物,而且能经环合形成内酰胺环,从而使SBL长期处于抑制状态。近些年,人们又发展了硼酸类SBL抑制剂,如Vaborbactam。Vaborbactam主要是通过其硼酸基团与SBL丝氨酸形成共价复合物,临床上SBL抑制剂与β-内酰胺抗生素的复方药,如克拉维酸-阿莫西林(奥格门汀)、阿维巴坦-头孢他啶(艾尔健)等,具有临床疗效好、对病原菌敏感性高及最小抑菌浓度低等优点,为临床上控制耐药菌感染提供了有力的武器。尽管目前也有多种MBL抑制剂报道,大多数MBL抑制剂是通过与MBL活性位点的Zn离子螯合而发挥抑制作用,例如Captopril(降血压老药,被发现是MBL抑制剂)的巯基能与多种MBL亚型活性位点Zn离子螯合,但至今尚无进入临床试验的MBL抑制剂。因此,目前亟待开发具有临床应用前景的MBL小分子抑制剂,为靶向MBL克服抗生素耐药的创新药物研究提供候选化合物。本发明提供了一些取代芳基偕二磷酸衍生物合成和制备方法,并发现这些新的芳基偕二磷酸衍生物为MBL和SBL抑制剂。
发明内容
为解决上述问题,提出本发明。
本发明的一个目的是提供如式(I)所示的芳基偕二磷酸衍生物或其生理上可接受的盐。
其中DG为五元、六元含氮芳杂环、酰胺、肟醚、偶氮等具有导向能力的基团;芳环为苯环、奈环等芳香环或者吲哚环、喹啉等芳香杂环,R1为氢、卤素、烷基、甲氧基、羰基、硝基、三氟甲基、苯基等。R2为氢、乙基、正丁基等烷基、苯基、苄基等芳香基。
其中所述的衍生物为:
进一步优选,所述的衍生物为:
本发明的目的是提供包括治疗有效剂量的权利要求1-6所述的芳基偕二磷酸衍生物或其生理上可接受的盐的药物组合。
本发明的另一目的是提供上述芳基偕二磷酸衍生物或其生理上可接受的盐在制备用于治疗由细菌感染引起诸多临床应用。
本发明还提供了一种合成所述的衍生物的方法,它包括如下工艺流程:
具体地,它包括如下步骤:
(1)芳基偕二磷酸酯的制备
向一个干燥的15 ml封管中加入二苯基吡啶衍生物(0.3 mmol),以及亚甲基二磷酸四乙酯(0.36 mmol),催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)(5%mol),硫酸银(10% mol)和溶剂DCE(3ml),80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到产品,收率93%。
(2)芳基偕二磷酸的制备
与25ml干燥的双颈瓶中,加入干燥的DCM溶解上述合成的芳基偕二磷酸酯,在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4 h,反应完毕,加入10 mlH2O搅拌10 min,水层浓缩干燥的黄色粉末,收率96%。
药效试验证明,本发明化合物对β-内酰胺酶抑制剂有较好的抑制活性,尤其是化合物46抑制活性最佳,显著优于目前报道的一些β-内酰胺酶抑制剂小分子抑制剂,如卡托普利,本发明取代芳基偕二磷酸衍生物药效明确,为临床提供了一种新的用药选择。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但不应将此理解为本发明上述主题的范围仅限于以下实例,凡从本发明扩展到任何在本说明书中披露的新特征或任何新的组合均属于本发明的范围。
制备实施例
实施例1
化合物1的合成
向一个干燥的15ml封管中加入2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5% mol,硫酸银10% mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品,收率93%。
1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.5 Hz, 1H), 8.03 (d, J = 7.5Hz, 1H), 7.77 (td, J = 7.7, 1.4 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.48 –7.34 (m, 3H), 7.32 – 7.20 (m, 1H), 5.09 (t, J = 25.7 Hz, 1H), 4.29 – 3.87 (m,8H), 1.21 (t, J = 7.0 Hz, 6H), 1.15 (t, J = 7.0 Hz, 6H). 13C NMR (150 MHz,CDCl3) δ 159.09, 149.10, 140.62, 136.57, 131.20, 130.36, 128.31, 128.07,127.66, 124.55, 121.94, 63.31, 63.26, 62.74, 62.69, 39.78 (t, J=130.65Hz),16.25, 16.21, 16.17, 16.13; 31P NMR (162 MHz, CDCl3) δ 19.45。
实施例2
化合物2的合成
向一个干燥的15ml封管中加入邻甲基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品98.4mg,收率72%, 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J =4.5 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.75 (dd, J = 10.8, 4.5 Hz, 1H), 7.39(d, J = 7.7 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.21 (d, J = 7.5 Hz, 1H), 4.04(ddt, J = 23.8, 16.1, 8.0 Hz, 8H), 3.72 (t, J = 25.4 Hz, 1H), 2.02 (s, 3H),1.24 (t, J = 5.8 Hz, 6H), 1.18 (t, J = 7.0 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ158.25, 149.60, 136.73, 136.12, 129.48, 127.83, 127.77, 127.74, 125.57,122.14, 112.47, 63.38, 63.30, 62.79, 62.74, 41.45 (t, J = 131.25 Hz), 20.77,16.30, 16.26, 16.24, 16.20; 31P NMR (162 MHz, CDCl3) δ 19.12, 18.79。
实施例3
化合物3的合成
向一个干燥的15ml封管中加入邻甲氧基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品96.2mg,收率68%,. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.65(d, J = 4.4 Hz, 1H), 7.85 (t, J = 7.4 Hz, 1H), 7.45 – 7.31 (m, 4H), 7.08 (d,J = 7.5 Hz, 1H), 3.85 (ddd, J = 24.3, 15.2, 7.5 Hz, 8H), 3.67 (s, 3H), 1.12(t, J = 7.0 Hz, 6H), 1.02 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCL3) δ157.40, 149.08, 136.03, 129.78, 129.70, 128.99, 126.72, 122.17, 119.23,110.29, 63.39, 62.78, 55.76, 40.89 (t, J = 136.80 Hz), 16.32; 31P NMR (162MHz, DMSO-d 6 ) δ 18.69。
实施例4
化合物4的合成
向一个干燥的15ml封管中加入间甲基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品131.2mg,收率96%, 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J= 4.3 Hz, 1H), 7.82 (s, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.53 (d, J = 7.8 Hz,1H), 7.33 (d, J = 7.8 Hz, 1H), 7.24 (dd, J = 6.8, 5.5 Hz, 1H), 7.19 (d, J =7.7 Hz, 1H), 5.14 (t, J = 25.8 Hz, 1H), 4.15 – 3.97 (m, 8H), 2.42 (s, 3H),1.21 (t, J = 7.0 Hz, 6H), 1.15 (t, J = 7.0 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ159.16, 148.92, 138.07, 137.66, 136.56, 131.83, 130.24, 128.49, 127.79,124.58, 121.70, 63.21, 63.17, 62.67, 62.63, 39.57 (t, J = 130.65 Hz), 21.36,16.27, 16.23, 16.15, 16.11; 31P NMR (162 MHz, CDCl3) δ 19.58。
实施例5
化合物5的合成
向一个干燥的15ml封管中加入间甲氧基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品117.4mg,收率83%, 1H NMR (400 MHz, CDCl3) δ 8.68(d, J = 4.4 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.77 (td, J = 7.7, 1.3 Hz,1H), 7.56 (d, J = 7.8 Hz, 1H), 7.267 (d, J = 8.0 Hz, 1H), 7.00 – 6.95 (m,2H), 4.89 (t, J = 25.8 Hz, 1H), 4.16 – 3.93 (m, 8H), 3.84 (s, 3H), 1.22 (t, J= 7.1 Hz, 6H), 1.17 (t, J = 7.1 Hz, 6H); 13C NMR (150 MHz, CDCL3) δ 158.90,158.74, 149.12, 141.88, 136.58, 132.38, 124.47, 122.05, 119.82, 115.73,113.99, 63.19, 62.62 , 55.29, 39.06 (t, J = 130.50 Hz), 16.24; 31P NMR (162MHz, CDCl3) δ 19.73。
实施例6
化合物6的合成
向一个干燥的15ml封管中加入间氯2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品111.3mg,收率78%, 1H NMR (600 MHz, DMSO-d 6 ) δ 8.69 (d,J = 4.4 Hz, 1H), 7.97 (t, J = 7.7 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.64 (d,J = 7.8 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.54 (s, 1H), 7.48 – 7.42 (m, 1H),5.21 (t, J = 25.3 Hz, 1H),. 3.90 (tdt, J = 26.4, 15.6, 7.6 Hz, 8H), 1.11 (t,J = 7.0 Hz, 6H), 1.01 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 157.72,149.18, 142.03, 136.71, 133.49, 132.52, 130.16, 128.24, 126.96, 124.39,122.34, 63.21, 62.71, 39.35 (t, J = 130.0 Hz), 16.14; 31P NMR (162 MHz, DMSO-d 6 ) δ 18.75。
实施例7
化合物7的合成
向一个干燥的15ml封管中加入间硝基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(60:1)得到黄色油状物产品113.8mg,收率78%,1H NMR (600 MHz, DMSO-d 6 ) δ 8.74 (d, J= 4.3 Hz, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.27 (s, 1H), 8.10 (d, J = 8.6 Hz,1H), 8.04 (t, J = 7.7 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.55 – 7.48 (m, 1H),5.40 (t, J = 25.0 Hz, 1H), 4.14 – 3.70 (m, 8H), 1.12 (t, J = 7.0 Hz, 6H),1.02 (t, J = 7.0 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 157.01, 149.39, 147.00,141.68, 137.22, 136.47, 132.50, 125.14, 124.61, 122.95, 122.73, 63.45, 63.41,63.16, 63.12, 40.29 (t, J = 130.5 Hz), 16.27, 16.23, 16.22, 16.18; 31P NMR(162 MHz, DMSO-d 6 ) δ 17.85。
实施例8
化合物8的合成
向一个干燥的15ml封管中加入间三氟甲基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(70:1)得到黄色油状物产品85.6mg,收率56%, 1H NMR (600 MHz, DMSO-d 6 ) δ8.72 (d, J = 4.5 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 8.00 (t, J = 7.7 Hz, 1H),7.87 (d, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51 – 7.45(m, 1H), 5.30 (t, J = 25.1 Hz, 1H), 4.02 – 3.83 (m, 8H), 1.12 (t, J = 7.0 Hz,6H), 1.00 (t, J = 7.0 Hz, 6H). 13C NMR (150 MHz, CDCL3) δ 157.78, 149.28,141.14, 136.86, 132.73, 131.74, 129.74 (q, J = 32.4 Hz), 128.76(s), 127.08(s), 124.78 (s), 124.57 (s), 122.51 (s), 63.32, 63.27, 62.93, 62.89, 40.02(t, J = 130.50 Hz), 16.23, 16.18, 16.15, 16.11; 31P NMR (162 MHz, DMSO-d 6 ) δ18.36, 18.35。
实施例9
化合物9的合成
向一个干燥的15ml封管中加入间羧酸甲酯2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(60:1)得到黄色油状物产品94.4mg,收率63%, 1H NMR (600 MHz, DMSO-d 6 ) δ8.71 (d, J = 4.3 Hz, 1H), 8.10 – 7.94 (m, 4H), 7.64 (d, J = 7.7 Hz, 1H), 7.50– 7.44 (m, 1H), 5.29 (t, J = 24.8 Hz, 1H), 4.10 – 3.66 (m, 11H), 1.11 (t, J =6.9 Hz, 6H), 0.99 (dd, J = 8.6, 4.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ158.16, 149.02, 140.55, 136.81, 133.68, 131.37, 130.73 129.22, 128.97,128.68, 124.57, 122.29, 63.27, 62.79, 40.04 (t, J = 130.20 Hz), 16.13; 31P NMR(162 MHz, DMSO-d 6 ) δ 18.34。
实施例10
化合物10的合成
向一个干燥的15ml封管中加入对甲基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品131.2mg,收率96%, 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J= 4.4 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.1 Hz, 1H), 7.57 (d, J= 7.8 Hz, 1H), 7.25 (s, 2H), 7.23 (s, 1H), 4.91 (t, J = 25.7 Hz, 1H), 4.11 –3.96 (m, 8H), 2.38 (s, 3H), 1.21 (t, J = 7.1 Hz, 6H), 1.16 (t, J = 7.1 Hz,6H). 13C NMR (150 MHz, CDCl3) δ 159.12, 149.07, 137.37, 136.55, 131.06,130.99, 129.15, 124.80, 124.53, 121.88, 63.24, 62.63, 39.56 (t, J = 130.00Hz), 21.06, 16.18; 31P NMR (162 MHz, CDCl3) δ 19.59。
实施例11
化合物11的合成
向一个干燥的15ml封管中加入对叔丁基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品143.3mg,收率96%, 1H NMR (600 MHz, DMSO-d 6 ) δ 8.66(d, J = 4.4 Hz, 1H), 7.98 – 7.89 (m, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.42 (d,J = 10.1 Hz, 2H), 7.40 – 7.36 (m, 1H), 5.40 (t, J = 25.5 Hz, 1H), 4.01 – 3.74(m, 8H), 1.32 (s, 9H), 1.08 (t, J = 7.0 Hz, 6H), 0.98 (t, J = 7.0 Hz, 6H). 13CNMR (150 MHz, CDCl3) δ 158.68, 151.23, 148.57, 137.05, 130.08, 128.80,127.52, 124.67, 124.44, 121.85, 63.24, 63.20, 62.60, 62.55, 39.95(t, J =131.4 Hz), 34.69 (s), 31.09 (s), 16.27, 16.23, 16.18, 16.14; 31P NMR (162 MHz,DMSO-d 6 ) δ 19.46。
实施例12
化合物12的合成
向一个干燥的15ml封管中加入对氟2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品99.2mg,收率72%, 1H NMR (600 MHz, DMSO-d 6 ) δ 8.66 (d, J= 4.3 Hz, 1H), 7.94 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 10.6 Hz, 1H), 7.56 (d,J = 7.9 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.43 – 7.39 (m, 1H), 7.28 (t, J =7.9 Hz, 1H), 5.31 (t, J = 25.1 Hz, 1H), 3.98 – 3.80 (m, 8H), 1.10 (t, J = 7.0Hz, 6H), 0.99 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 162.06 (d, J =246.0 Hz), 158.17, 149.04, 136.74, 131.88 (d, J = 8.4 Hz), 130.74 (s), 124.53(s), 122.02 (s), 118.21 (s), 117.98 (s), 114.71(d, J = 21.1 Hz), 63.24,63.92, 39.93 (t, J = 130.9 Hz), 16.01; 31P NMR (162 MHz, DMSO) δ 18.58, 18.57。
实施例13
化合物13的合成
向一个干燥的15ml封管中加入对氯基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品124.2mg,87%, 1H NMR (600 MHz, DMSO-d) δ 8.67 (d, J =4.6 Hz, 1H), 7.95 (t, J = 7.7 Hz, 1H), 7.85 (s, 1H), 7.58 (d, J = 7.9 Hz,1H), 7.51 (q, J = 8.5 Hz, 2H), 7.42 (dd, J = 7.3, 5.0 Hz, 1H), 5.32 (t, J =25.1 Hz, 1H), 4.00 – 3.81 (m, 8H), 1.11 (t, J = 7.0 Hz, 6H), 0.99 (t, J = 7.0Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 158.08, 149.14, 138.95, 136.74, 134.16,131.46 , 131.12, 130.42, 127.77, 124.51, 122.17, 63.33, 63.28, 62.85,62.81,39.79 (t, J = 132.0 Hz), 16.23, 16.19, 16.15, 16.11; 31P NMR (162 MHz, DMSO-d)δ 18.55。
实施例14
化合物14的合成
向一个干燥的15ml封管中加入对乙酰基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品124.2mg,收率84%, 1H NMR (600 MHz, DMSO-d 6 ) δ 8.70(d, J = 4.7 Hz, 1H), 8.44 (d, J = 1.5 Hz, 1H), 7.98 (t, J = 8.1 Hz, 2H), 7.63(d, J = 7.9 Hz, 2H), 7.45 (dd, J = 7.5, 4.9 Hz, 1H), 5.33 (t, J = 25.4 Hz,1H), 3.97 – 3.83 (m, 8H), 2.60 (s, 3H), 1.09 (t, J = 7.0 Hz, 6H), 1.00 (t, J= 7.0 Hz, 6H), 13C NMR (100 MHz, CDCl3) δ 197.56, 158.02, 149.16, 144.61,136.79, 136.40, 131.91, 130.66, 129.05, 126.85, 124.55, 122.50, 63.21, 62.83,39.55 (t, J = 131.0 Hz), 26.66, 16.17; 31P NMR (162 MHz, DMSO-d 6 ) δ 18.80。
实施例15
化合物15的合成
向一个干燥的15ml封管中加入对苯基2-苯基吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品149.0mg,收率96%, 1H NMR (600 MHz, DMSO-d 6 ) δ 8.69 (d,J = 4.2 Hz, 1H), 8.19 (s, 1H), 7.96 (t, J = 7.7 Hz, 1H), 7.73 (d, J = 8.0 Hz,1H), 7.68 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.0 Hz,1H), 7.52 (t, J = 7.5 Hz, 2H), 7.41 (dd, J = 9.5, 5.2 Hz, 2H), 5.43 (t, J =25.2 Hz, 1H), 3.99 – 3.81 (m, 8H), 1.11 (t, J = 7.0 Hz, 6H), 0.96 (t, J = 7.0Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 158.8, 149.07, 140.49, 139.93, 139.35,136.52, 130.73, 129.88, 128.72, 127.49), 126.91, 125.93, 124.41, 121.85,63.19, 62.64, 39.78 (t, J = 133.0 Hz), 16.14; 31P NMR (162 MHz, DMSO-d 6 ) δ19.27。
实施例16
化合物16的合成
向一个干燥的15ml封管中加入2-(1-奈)吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品132.7mg,收率90%,1H NMR (600 MHz, DMSO-d 6 ) δ 8.70(d, J = 4.3 Hz, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.98 (dd, J = 7.4, 5.9 Hz,2H), 7.91 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.59 – 7.54 (m, 2H),7.46 – 7.42 (m, 1H), 5.44 (t, J = 25.6 Hz, 1H), 4.00 – 3.90 (m, 4H), 3.84(ddd, J = 25.5, 12.6, 7.7 Hz, 4H), 1.11 (t, J = 7.0 Hz, 6H), 0.94 (t, J = 7.0Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 157.27, 149.72, 138.52, 136.10, 132.67,132.50, 128.10, 127.84, 127.27, 126.60, 126.29, 126.13, 125.87, 122.47,63.15, 62.73, 42.04 (t, J = 132.0 Hz), 16.15; 31P NMR (162 MHz, DMSO-d 6 ) δ18.71, 18.15。
实施例17
化合物17的合成
向一个干燥的15ml封管中加入2-(2-奈)吡啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/ MeOH(80:1)得到黄色油状物产品134.2mg,收率91%, 1H NMR (600 MHz, DMSO-d 6 ) δ 8.70 (d,J = 4.3 Hz, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.98 (dd, J = 7.4, 5.9 Hz, 2H),7.91 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.59 – 7.54 (m, 2H), 7.46– 7.42 (m, 1H), 5.44 (t, J = 25.6 Hz, 1H), 4.00 – 3.90 (m, 4H), 3.84 (ddd, J= 25.5, 12.6, 7.7 Hz, 4H), 1.11 (t, J = 7.0 Hz, 6H), 0.94 (t, J = 7.0 Hz,6H); 13C NMR (100 MHz, CDCl3) δ 159.04, 148.81, 136.91, 132.76, 132.26,130.92, 129.97, 128.06, 127.75, 126.71, 126.60, 125.66, 124.99, 122.03,119.24, 63.31, 62.74, 39.53 (t, J = 129.1 Hz), 16.21; 31P NMR (162 MHz, DMSO-d 6 ) δ 19.24。
实施例18
化合物18的合成
向一个干燥的15ml封管中加入3-苯基异喹啉0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/ MeOH(70:1)得到黄色油状物产品118.0mg,收率80%, 1H NMR (400 MHz, DMSO-d 6 ) δ 9.44 (s,1H), 8.20 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.91 – 7.86 (m, 1H),7.83 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 5.7 Hz, 1H),7.47 (dd, J = 9.2, 5.5 Hz, 2H), 5.30 (t, J = 25.4 Hz, 1H), 3.98 – 3.78 (m,8H), 1.08 (t, J = 7.0 Hz, 6H), 0.98 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz,CDCl3) δ 152.51, 151.85, 140.94, 136.21, 131.12, 130.77, 130.59, 128.18,128.05, 127.64, 127.43, 127.37,127.19, 126.68, 120.84, 63.21, 62.62, 40.03(t, J = 133.2 Hz), 16.20; 31P NMR (162 MHz, DMSO-d 6 ) δ 19.33。
实施例19
化合物19的合成
向一个干燥的15ml封管中加入苯并喹啉0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/ MeOH(70:1)得到黄色油状物产品72.6mg,收率52%, 1H NMR (400 MHz, DMSO-d 6 ) δ 9.35 (t, J =26.6 Hz, 1H), 9.01 (d, J = 3.3 Hz, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.19 (d, J= 7.1 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.89 (d, J= 8.7 Hz, 1H), 7.78 – 7.69 (m, 2H), 4.10 – 3.96 (m, 4H), 3.75 (qd, J = 17.1,9.6 Hz, 4H), 1.12 (t, J = 7.0 Hz, 6H), 0.78 (t, J = 7.0 Hz, 6H). 13C NMR (100MHz, CDCl3) δ 146.28, 136.27, 135.40, 132.74, 129.29, 128.73, 127.67, 127.26,125.39, 121.19, 62.67, 62.51, 39.50 (t, J = 129.2Hz), 16.19, 16.00; 31P NMR(162 MHz, DMSO-d 6 ) δ 20.59。
实施例20
化合物20的合成
向一个干燥的15ml封管中加入邻甲基2-苯基嘧啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml,80℃下搅拌12小时。反应完成后,减压浓缩,柱层析,DCM/ MeOH(60:1)得到黄色油状物产品89.0mg,收率65%, 1H NMR (600 MHz, DMSO-d 6 ) δ 8.97 (d, J= 4.9 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 4.9 Hz, 1H), 7.34 (t, J= 7.7 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 4.06 (t, J = 25.2 Hz, 1H), 3.95 –3.73 (m, 8H), 2.05 (s, 3H), 1.10 (t, J = 7.0 Hz, 6H), 1.00 (t, J = 7.0 Hz,6H); 13C NMR (150 MHz, CDCl3) δ 166.96, 156.93, 139.26, 136.75, 129.75,128.38, 128.27, 128.11, 118.97, 63.41, 63.37, 62.75, 62.70, 41.02 (t, J =130.5 Hz), 20.81, 16.24; 31P NMR (162 MHz, DMSO-d 6 ) δ 18.78。
实施例21
化合物21的合成
向一个干燥的15ml封管中加入间羧酸甲酯2-苯基嘧啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/ MeOH(60:1)得到黄色油状物产品136.6mg,收率91%, 1H NMR (600 MHz, DMSO-d 6 ) δ9.03 (d, J = 4.5 Hz, 2H), 8.65 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.03 (d, J= 8.1 Hz, 1H), 7.57 (t, J = 4.7 Hz, 1H), 6.48 (t, J = 25.6 Hz, 1H), 4.03 –3.93 (m, 4H), 3.92 – 3.82 (m, 7H), 1.10 (t, J = 7.0 Hz, 6H), 0.97 (t, J = 6.9Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 166.46, 165.76, 157.04, 137.53, 134.96,132.76, 132.02, 130.19, 129.41, 119.05, 63.28, 63.24, 62.76, 62.72, 52.17,39.65 (t, J = 130.5 Hz), 16.15; 31P NMR (162 MHz, DMSO-d 6 ) δ 18.58.
实施例22
化合物22的合成
向一个干燥的15ml封管中加入间甲基2-苯基嘧啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(60:1)得到黄色油状物产品130.4mg,收率93%, 1H NMR (600 MHz, DMSO-d 6 ) δ 8.94(d, J = 4.8 Hz, 2H), 7.81 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 4.8Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 6.23 (t, J = 26.0 Hz, 1H), 3.88 (dddd, J =29.3, 19.5, 11.2, 7.3 Hz, 8H), 2.36 (s, 3H), 1.08 (t, J = 7.0 Hz, 6H), 0.95(t, J = 7.0 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 166.73, 156.90, 137.36,137.12, 132.01, 131.71, 130.55, 126.43, 118.62, 63.09, 62.52, 38.86 (t, J =130.5 Hz), 21.07, 16.17; 31P NMR (162 MHz, DMSO-d 6 ) δ 19.63。
实施例23
化合物23的合成
向一个干燥的15ml封管中加入间甲氧基2-苯基嘧啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(70:1)得到黄色油状物产品116.2mg,收率82%, 1H NMR (400 MHz, DMSO-d 6 ) δ 8.97(d, J = 4.8 Hz, 2H), 7.79 (d, J = 8.7 Hz, 1H), 7.54 (s, 1H), 7.50 (t, J = 4.8Hz, 1H), 7.11 (dd, J = 8.7, 2.4 Hz, 1H), 6.20 (t, J = 26.1 Hz, 1H), 3.93 (dd,J = 16.7, 8.0 Hz, 4H), 3.88 – 3.76 (m, 8H), 1.10 (t, J = 7.0 Hz, 6H), 0.96(t, J = 7.0 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 166.32, 158.76, 156.87,138.38, 133.01, 121.35, 118.77, 116.32, 115.85, 63.05, 62.46, 55.28, 38.40(t, J = 130.5 Hz), 16.13; 31P NMR (162 MHz, DMSO-d 6 ) δ 19.76。
实施例24
化合物24的合成
向一个干燥的15ml封管中加入2-苯基嘧啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(50:1)得到黄色油状物产品196.7mg,收率90%, 1H NMR (400 MHz, DMSO-d 6 ) δ 9.04(d, J = 4.9 Hz, 2H), 7.83 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 4.8 Hz, 1H), 7.50(t, J = 7.9 Hz, 1H), 4.41 (t, J = 25.5 Hz, 2H), 3.86 (ddd, J = 23.2, 15.2,7.4 Hz, 16H), 1.11 (t, J = 7.0 Hz, 12H), 1.01 (t, J = 7.0 Hz, 12H); 13C NMR(150 MHz, CDCl3) δ 165.75, 156.93, 130.56, 129.43, 128.24, 119.18, 63.26,62.68, 41.16 (t, J = 130.5 Hz), 16.21; 31P NMR (162 MHz, DMSO-d 6 ) δ 18.70。
实施例25
化合物25的合成
向一个干燥的15ml封管中加入对甲基2-苯基嘧啶0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(50:1)得到黄色油状物产品164.9mg,收率74%, 1H NMR (400 MHz, DMSO-d 6 ) δ 9.02(d, J = 4.9 Hz, 2H), 7.65 (s, 2H), 7.54 (t, J = 4.9 Hz, 1H), 4.48 (t, J =25.6 Hz, 2H), 3.94 – 3.77 (m, 16H), 2.36 (s, 3H), 1.11 (t, J = 7.0 Hz, 12H),1.01 (t, J = 7.0 Hz, 12H); 13C NMR (150 MHz, CDCl3) δ 165.89, 156.84, 137.98,136.46, 131.23, 129.14, 118.96, 63.19, 62.62, 40.91 (t, J = 130.5 Hz), 21.55,16.21; 31P NMR (162 MHz, DMSO-d 6 ) δ 18.79。
实施例26
化合物26的合成
向一个干燥的15ml封管中加入N-(2-嘧啶)吲哚0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品96.8mg,收率67%, 1H NMR (400 MHz, DMSO-d 6 ) δ 8.99(d, J = 4.8 Hz, 2H), 8.18 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.49(t, J = 4.8 Hz, 1H), 7.22 (dt, J = 20.5, 7.2 Hz, 2H), 7.06 (s, 1H), 6.13 (t,J = 25.9 Hz, 1H), 4.02 – 3.85 (m, 8H), 1.13 (t, J = 7.0 Hz, 6H), 1.02 (t, J =7.0 Hz, 6H); 13C NMR (101 MHz, CDCL3) δ 158.07, 136.79, 128.60, 128.05,123.43, 122.06, 120.61, 117.14, 114.40, 110.87, 63.53, 62.84, 37.27 (t, J =130.5 Hz), 16.23; 31P NMR (162 MHz, DMSO-d 6 ) δ 17.28。
实施例27
化合物27的合成
向一个干燥的15ml封管中加入1-苯基吡唑0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品105.9mg,收率82%. 1H NMR (600 MHz, DMSO-d 6 ) δ 8.02(s, 1H), 7.89 (d, J = 7.1 Hz, 1H), 7.82 (s, 1H), 7.52 – 7.45 (m, 2H), 7.41(d, J = 7.3 Hz, 1H), 6.55 (d, J = 1.3 Hz, 1H), 4.69 (t, J = 25.1 Hz, 1H),4.00 – 3.91 (m, 4H), 3.90 – 3.80 (m, 4H), 1.15 (t, J = 7.0 Hz, 6H), 1.01 (t,J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 140.91, 139.95, 131.51, 131.49,128.32, 128.25, 126.61 126.25, 106.64, 63.33, 62.86, 38.30 (t, J = 126.0Hz),16.23, 16.16, 16.13, 16.01; 31P NMR (162 MHz, DMSO-d 6 ) δ 18.33。
实施例28
化合物28的合成
向一个干燥的15ml封管中加入3-甲基苯基甲氧基肟谜0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/ MeOH(80:1)得到黄色油状物产品67.9mg,收率52%, 1H NMR (400 MHz, DMSO-d 6 ) δ8.46 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J = 7.9 Hz,1H), 5.13 (t, J = 25.8 Hz, 1H), 4.07 – 4.00 (m, 4H), 3.90 – 3.80 (m, 7H),2.30 (s, 3H), 1.20 (t, J = 7.0 Hz, 6H), 1.02 (t, J = 7.0 Hz, 6H); 13C NMR (150MHz, CDCll3) δ 148.59, 137.86, 131.24, 130.53, 130.36, 63.70, 63.23, 62.09,39.46 (t, J = 132.0Hz), 20.92, 16.23, 16.19, 16.11, 16.07; 31P NMR (162 MHz,DMSO-d 6 ) δ 18.82。
实施例29
化合物29的合成
向一个干燥的15ml封管中加入邻甲基偶氮苯0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品134.1mg,收率90%, 1H NMR (600 MHz, CDCl3) δ 7.93(d, J = 7.2 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.44 – 7.38 (m, 2H), 7.32 (q,J = 7.1 Hz, 2H), 7.26 (d, J = 7.9 Hz, 1H), 5.27 (t, J = 25.5 Hz, 1H), 4.14 –3.99 (m, 8H), 2.71 (s, 3H), 2.43 (s, 3H), 1.23 (t, J = 7.1 Hz, 6H), 1.15 (t,J = 7.1 Hz, 6H); 13C NMR (150 MHz, DMSO-d 6 ) δ 151.08, 149.49, 138.31, 132.26,132.12, 132.07, 129.49, 129.25, 127.79, 127.33, 114.70, 63.04, 63.00, 62.78,62.76, 20.81, 17.85, 16.54, 16.50, 16.32, 16.30; 31P NMR (162 MHz, DMSO-d 6 ) δ18.68。
实施例30
化合物30的合成
向一个干燥的15ml封管中加入小檗碱前体0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(60:1)得到黄色油状物产品67.89mg,收率38%, 1H NMR (400 MHz, DMSO-d 6 ) δ 9.39(s, 1H), 7.87 (s, 1H), 7.79 (s, 2H), 7.00 (dd, J = 17.3, 8.1 Hz, 2H), 6.08(s, 2H), 5.47 (t, J = 27.4 Hz, 1H), 4.01 – 3.80 (m, 14H), 1.08 (t, J = 7.0Hz, 6H), 1.02 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 146.35, 132.27,124.43, 122.65, 122.55, 120.33, 120.19, 107.56, 101.17, 62.99, 62.44, 61.62,57.01,56.96, 38.28 (t, J = 132.0 Hz), 16.21; 31P NMR (162 MHz, DMSO-d 6 ) δ18.87。
实施例31
化合物31的合成
向一个干燥的15ml封管中加入小檗碱前体0.3mmol,以及亚甲基二磷酸四乙酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(60:1)得到黄色油状物产品71.46mg,收率40%, 1H NMR (400 MHz, DMSO-d 6 ) δ 9.44(s, 1H), 7.91 (s, 1H), 7.78 (q, J = 9.0 Hz, 2H), 7.35 (s, 1H), 7.12 (s, 1H),6.13 (s, 2H), 5.17 (t, J = 25.4 Hz, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.89(ddd, J = 20.9, 12.4, 7.3 Hz, 8H), 1.10 (t, J = 7.0 Hz, 6H), 1.02 (t, J = 7.0Hz, 6H); δ13C NMR (100MHz, CDCl3) δ 150.40, 148.87, 147.22, 147.12, 146.78,143.79, 132.02, 122.76, 122.60, 121.60, 120.37, 120.15, 110.89, 110.59,101.34, 63.13, 62.67, 61.60, 56.99,56.95, 39.95 (t, J = 133.0 Hz), 16.18; 31PNMR (162 MHz, DMSO-d 6 ) δ 19.39。
实施例32
化合物32的合成
向一个干燥的15ml封管中加入2-苯基吡啶0.3mmol,以及亚甲基二磷酸四丁酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品83.04mg,收率50%, 1H NMR (600 MHz, CDCl3) δ 8.69(d, J = 4.8 Hz, 1H), 8.02 (d, J = 6.6 Hz, 1H), 7.78 (t, J = 6.8 Hz, 1H), 7.55(d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.39(s, 1H), 5.12 (t, J = 25.8 Hz, 1H), 3.99 (ddt, J = 25.0, 16.9, 6.8 Hz, 8H),1.57 – 1.53 (m, 4H), 1.52 – 1.47 (m, 4H), 1.30 – 1.25 (m, 8H), 0.86 (dt, J =14.7, 7.4 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ 159.09, 148.97, 140.43, 136.48,131.28, 130.27, 128.30, 128.17, 127.49, 124.44, 121.83, 66.70, 66.31, 39.64(t, J = 132.0 Hz), 32.33, 18.50, 13.51; 31P NMR (162 MHz, DMSO-d 6 ) δ 19.31。
实施例33
化合物33的合成
向一个干燥的15ml封管中加入2-苯基吡啶0.3mmol,以及亚甲基二磷酸四苄酯0.36mmol,催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(CAS号12354-85-7)5%mol,硫酸银10%mol和溶剂DCE 3ml. 80℃下搅拌24小时。反应完成后,减压浓缩,柱层析,DCM/MeOH(80:1)得到黄色油状物产品172.21mg,收率82%, 1H NMR (600 MHz, DMSO-d 6 ) δ 8.64(d, J = 4.3 Hz, 1H), 7.97 (d, J = 6.7 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.45(dt, J = 11.5, 6.6 Hz, 3H), 7.37 – 7.34 (m, 1H), 7.34 – 7.21 (m, 13H), 7.18(d, J = 4.6 Hz, 4H), 7.06 (d, J = 6.7 Hz, 4H), 5.74 (dd, J = 26.9, 24.3 Hz,1H), 4.98 – 4.80 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 158.96, 148.78, 140.56,136.72, 136.25, 131.60, 130.51, 128.55, 128.34, 128.30, 128.12, 128.03,127.99, 127.85, 127.77, 124.54, 121.92, 68.39, 68.17, 40.10(t, J = 131.0 Hz);31P NMR (162 MHz, DMSO-d 6 ) δ 20.04。
实施例34
化合物34的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物1(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率96%。1H NMR (400 MHz, D2O) δ 8.65 (d, J = 5.0 Hz,1H), 8.51 (td, J = 8.0, 1.5 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.90 (t, J =7.4 Hz, 2H), 7.57 – 7.48 (m, 1H), 7.44 – 7.38 (m, 2H), 3.41 (t, J = 23.6 Hz,1H); 13C NMR (150 MHz, D2O) δ 152.15, 146.90, 141.03, 132.14, 131.41, 131.25,130.60, 128.71, 127.77, 125.77, 112.52, 32.00 (t, J = 115.5 Hz); 31P NMR (162MHz, D2O) δ 16.69。
实施例35
化合物35的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物2(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10ml H2O搅拌10min,水层浓缩干燥的黄色粉末,收率97%, 1H NMR (400 MHz, D2O) δ 8.81 (s, 1H),8.64 (s, 1H), 8.04 (d, J = 6.6 Hz, 2H), 7.75 (s, 1H), 7.47 (d, J = 5.3 Hz,1H), 7.32 (d, J = 7.2 Hz, 1H), 1.99 (s, 3H); 13C NMR (150 MHz, D2O) δ 158.25,149.60, 136.73, 136.12, 129.48, 127.77,127.74, 125.57, 122.14, 112.51, 41.45(t, J = 130.5 Hz), 20.77; 31P NMR (162 MHz, D2O) δ 14.87。
实施例36
化合物36的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物4(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率95%, 1H NMR (400 MHz, D2O) δ 8.63 (s, 1H), 8.49 (s,1H), 8.02 (s, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.23(d, J = 6.9 Hz, 1H), 3.85 (t, J = 23.1 Hz, 1H), 2.30 (s, 3H); 13C NMR (100MHz,D2O) δ 152.26, 146.94,146.89, 142.50, 141.08, 131.48, 131.21, 129.06 (s),128.70, 128.65, 125.62, 20.67; 31P NMR (162 MHz, D2O) δ 17.32。
实施例37
化合物37的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物5(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率92%, 1H NMR (400 MHz, D2O) δ 8.66 (s, 1H), 8.52 (t,J = 7.6 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.93 (s, 1H), 7.79 (d, J = 8.6 Hz,1H), 7.21 – 7.06 (m, 1H), 6.99 (d, J = 2.4 Hz, 1H), 3.73 (s, 3H), 3.37 (t, J= 23.7 Hz, 1H); 13C NMR (100 MHz, D2O) δ 158.19, 151.65, 147.05, 141.28,133.06, 132.01, 128.73, 126.10, 123.83, 117.35, 116.41, 55.67;. 31P NMR (162MHz, D2O) δ 16.11。
实施例38
化合物38的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物7(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率91%, 1H NMR (400 MHz, D2O) δ 8.83 (d, J = 4.8 Hz,1H), 8.68 (t, J = 7.4 Hz, 1H), 8.42 (s, 2H), 8.22 (d, J = 7.6 Hz, 2H), 8.10(d, J = 5.9 Hz, 1H), 3.64( t, J = 23.4 Hz, 1H); 13C NMR (100 MHz, D2O) δ149.84, 147.39, 146.44, 141.84, 140.84, 133.12, 132.07, 129.06, 126.83,126.33, 125.77; 31P NMR (162 MHz, D2O) δ 16.07。
实施例39
化合物39的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物8(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率95%, 1H NMR (400 MHz, D2O) δ 8.80 (d, J = 4.7 Hz,1H), 8.65 (td, J = 8.0, 1.5 Hz, 1H), 8.24 – 8.12 (m, 2H), 8.10 – 8.02 (m,1H), 7.92 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 3.58 (t, J = 23.7 Hz, 1H); 13CNMR (100MHz, D2O) δ 150.73, 147.17, 141.49, 133.02, 131.48, 128.86, 128.26,128.01, 126.48, 124.94; 31P NMR (162 MHz, D2O) δ 14.88。
实施例40
化合物40的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物10(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率94%, 1H NMR (400 MHz, D2O) δ 8.64 (s, 1H),8.50 (t, J = 7.6 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J= 7.8 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.24 (s, 1H), 3.42 (t, J = 24.0 Hz,1H), 2.25 (s, 3H); 13C NMR (100 MHz, D2O) δ 152.19, 146.96, 141.16, 138.51,132.24, 131.88, 131.62, 130.46, 128.66, 128.39, 125.83, 42.85 (t, J=123.0Hz),19.97; 31P NMR (162 MHz, D2O) δ 15.93。
实施例41
化合物41的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物12(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率93%, 1H NMR (400 MHz, D2O) δ 8.83 (d, J = 5.3Hz, 1H), 8.69 (t, J = 8.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.15 – 8.04 (m,1H), 7.83 (d, J = 10.0 Hz, 1H), 7.63 (dd, J = 8.6, 5.9 Hz, 1H), 7.33 (t, J =8.2 Hz, 1H), 3.59 (t, J = 22.1 Hz, 1H).; 13C NMR (100MHz, D2O) δ 149.04,136.74, 131.92, 131.83, 130.84 (dd, J = 16.0, 7.7 Hz), 124.53, 122.02,118.21, 117.98, 114.81, 114.60, 39.94(t, J=130.0Hz); 31P NMR (162 MHz, D2O) δ15.66。
实施例42
化合物42的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物14(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率98%, pale yellow powder, 1H NMR (400 MHz,D2O) δ 8.77 (s, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 8.15 (d, J = 7.3 Hz, 1H),8.07 – 7.94 (m, 2H), 7.61 (d, J = 7.8 Hz, 1H), 3.56 (t, J = 23.5 Hz, 1H),2.65 (s, 3H); 13C NMR (100 MHz, D2O) δ 202.70, 150.88, 147.17, 141.60, 138.40,136.37, 133.14, 131.78, 130.78, 128.79, 127.19, 126.50, 43.42 (t, J=123.4Hz),26.55; 31P NMR (162 MHz, D2O) δ 14.99。
实施例43
化合物43的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物11(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率98%, 1H NMR (600 MHz, D2O) δ 8.67 (s, 1H),8.52 (s, 1H), 8.14 – 7.97 (m, 2H), 7.92 (s, 1H), 7.51 (s, 1H), 7.40 (s, 1H),3.52 (t, J = 21.9 Hz, 1H), 1.25 (s, 9H); 13C NMR (100MHz, D2O) δ 157.72,154.64, 154.59. 149.36, 143.56, 133.48, 131.14, 130.97, 128.12, 127.65,36.95, 32.71; 31P NMR (162 MHz, D2O) δ 18.48。
实施例44
化合物44的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物15(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率94%, 1H NMR (600 MHz, D2O) δ 8.70 (d, J = 4.6Hz, 1H), 8.55 (t, J = 7.2 Hz, 1H), 8.20 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H),7.95 (s, 1H), 7.70 (d, J = 7.2 Hz, 3H), 7.52 (d, J = 7.9 Hz, 1H), 7.45 (t, J= 7.3 Hz, 2H), 7.41 – 7.34 (m, 1H), 3.58 (t, J = 23.9 Hz, 1H); 13C NMR (100MHz, D2O) δ 158.81, 149.07, 140.49, 139.93, 139.35, 136.52, 130.73, 129.88,128.72, 127.49, 126.91, 125.93, 124.41, 121.85, 39.79 (t, J=130.0Hz); 31P NMR(162 MHz, D2O) δ 15.78。
实施例45
化合物45的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物16(100 mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率96%, 1H NMR (400 MHz, D2O) δ 8.81 (s, 1H),8.63 (t, J = 7.2 Hz, 1H), 8.05 (t, J = 8.2 Hz, 3H), 8.01 – 7.89 (m, 2H), 7.48(t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 3.26(t, J = 25.0 Hz, 1H); 13C NMR (100 MHz, D2O) δ 150.36, 147.36, 142.31, 131.96,131.62, 131.34, 130.58, 128.44, 127.98, 126..86, 126.69, 124.22, 123.31; 31PNMR (162 MHz, D2O) δ 15.33。
实施例46
化合物46的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物17(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率97%, 1H NMR (600 MHz, D2O) δ 8.70 (d, J = 4.6Hz, 1H), 8.55 (t, J = 7.2 Hz, 1H), 8.20 (s, 1H), 8.11 (d, J = 7.7 Hz, 1H),7.95 (s, 1H), 7.70 (d, J = 7.2 Hz, 3H), 7.52 (d, J = 7.9 Hz, 1H), 7.45 (t, J= 7.3 Hz, 2H), 7.41 – 7.34 (m, 1H), 3.58 (t, J = 23.9 Hz, 1H). 13C NMR (100MHz, D2O) δ 159.00, 148.83, 136.91, 132.78, 132.24, 130.97, 129.99, 128.06,127.75, 126.71, 126.55, 125.66, 124.95, 122.03, 39.56 (t, J=131.3Hz); 31P NMR(162 MHz, D2O) δ 16.35。
实施例47
化合物47的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物18(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率92%, 1H NMR (600 MHz, D2O) δ 9.54 (d, J = 6.8Hz, 1H), 8.42 (d, J = 11.2 Hz, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.18 (d, J =8.2 Hz, 1H), 8.11 (t, J = 7.2 Hz, 1H), 7.92 (d, J = 5.6 Hz, 1H), 7.55 (t, J =7.2 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 3.53 (t, J =23.4 Hz, 1H). 13C NMR (100 MHz, D2O) δ 152.51, 151.87, 140.97, 136.18, 131.12,130.77, 130.64, 128.04, 127.66, 127.43, 127.37, 127.16, 126.65, 120.86, 40.08(t, J=131.0Hz); 31P NMR (162 MHz, D2O) δ 16.16。
实施例48
化合物48的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物19(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率92% , 1H NMR (400 MHz, D2O) δ 8.87 (d, J =3.8 Hz, 2H), 7.78 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 7.0 Hz, 1H), 7.44 (s,1H), 7.32 – 7.00 (m, 2H); 13C NMR (100 MHz, D2O) δ 159.33, 136.36, 126.64,123.43, 122.21, 120.58, 119.17, 112.53; 31P NMR (162 MHz, D2O) δ 15.60。
实施例49
化合物49的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物31(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率88% ,1H NMR (600 MHz, D2O) δ 9.54 (d, J = 7.1Hz, 1H), 8.22 (d, J = 14.8 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.91 (d, J =8.7 Hz, 1H), 7.36 (s, 1H), 6.87 (s, 1H), 5.95 (s, 2H), 3.99 (s, 6H), 3.41 (t,J = 23.4 Hz, 1H).. 13C NMR (100 MHz, D2O) δ 150.40, 148.87, 147.26, 147.10,146.78, 143.75, 131.96, 122.76, 122.60, 121.60, 120.34, 120.14, 110.92,110.59, 101.34, 61.60, 56.99, 56.95, 39.90(t, J=134.0Hz); 31P NMR (162 MHz,D2O) δ 16.16。
实施例50
化合物50的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物26(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率95% , 1H NMR (600 MHz, D2O) δ 8.82 (d, J =4.7 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.3 Hz, 1H), 7.39 (d, J =4.5 Hz, 1H), 7.25 – 7.11 (m, 2H), 7.00 (s, 1H), 5.02 (t, J = 25.2 Hz, 1H); 13CNMR (150 MHz, D2O) δ 159.27, 155.74, 136.38, 129.84, 128.16, 123.49, 122.21,120.56, 119.13, 112.51, 38.15 (t, J=121.5Hz); 31P NMR (162 MHz, D2O) δ 18.20。
实施例51
化合物51的合成
与25ml干燥的双颈瓶中,加入干燥的DCM溶解化合物27(100mg),在氩气保护下加入溴代三甲基硅烷(TMS-Br)6.0当量。氩气保护下室温搅拌4h,反应完毕,加入10mlH2O搅拌10min,水层浓缩干燥的黄色粉末,收率92% ,1H NMR (400 MHz, D2O) δ 7.99 (s, 1H),7.91 (dd, J = 20.3, 7.4 Hz, 2H), 7.52 (d, J = 7.1 Hz, 1H), 7.43 (t, J = 7.4Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 6.65 (s, 1H), 3.76 (t, J = 23.2 Hz, 1H);13C NMR (100 MHz, D2O) δ 139.36, 137.37, 134.17, 133.01, 130.64, 130.24,128.54, 127.44; 31P NMR (162 MHz, D2O) δ 15.91。
以下通过具体活性试验证明本发明的有益效果。
本发明还提供了上述芳基偕二磷酸衍生物、它的盐或水合物作为NDM-1 MBL,VIM-2 MBL,TEM-1 SBL, and KPC-2 SBL蛋白的抑制剂。具体的本发明化合物对体外NDM-1 MBL,VIM-2 MBL, TEM-1 SBL, and KPC-2 SBL蛋白的抑制活性的测试方法如下:
实验方法
蛋白的制备:利用PCR仪扩增VIM-2基因(aa: 27-266),并克隆到N端带有His标签和TEV蛋白酶切位点的PET28载体当中。将VIM-2蛋白在大肠杆菌(DE3)中表达,37℃培养2-4小时,直至OD600达到0.6~0.8,加入终浓度为0.3mM异丙基β-D-1-硫代吡喃半乳糖苷(IPTG)诱导VIM-2蛋白表达,20℃摇菌过夜。4000r/min离心15min收集菌体,并重悬于裂解缓冲液(20mMTris-HCl,250mM NaCl,pH8.0),使用高压破菌仪破碎细胞,15,000r/min离心30min除去细胞碎片,收集上清并加入Ni-NTA柱(Roche)中,用含5mM咪唑的Wash buffer(20mM Tris-HClpH 8.0, 250mM NaCl, 5mM 咪唑)大量冲洗,以除去非特异性结合的蛋白。最后用含250mM咪唑的洗脱buffer(20mM Tris-HCl pH 8.0, 250mM NaCl,250mM咪唑)洗脱目的蛋白。收集并浓缩目的蛋白,使用脱盐柱将VIM-2蛋白脱盐到20mM Tris-HCl pH7.5,200mM NaCl的缓冲液中。收集VIM-2蛋白并浓缩至15mg/ml,并加入1mM三(2-羧乙基)膦(TCEP)储存于-80℃。通过SDS-PAGE监测纯化过程,蛋白浓度由Nanno Drop 2000光谱光度计(ThermoScientific)测定。其余三种蛋白皆用类似的方法制得。
活性测试步骤:将所有受试化合物溶解于100%的DMSO溶剂中配成100mM的母液,再用VIM-2等缓冲溶液分别将其稀释成3.6 mM、1.2 mM、400μM等三倍稀释的化合物工作液。每个测试孔中加入10μL化合物工作液,30μL VIM-2缓冲溶液,10μL VIM-2蛋白(200pM),于25℃下反应10分钟,再每个测试孔加入10μL VIM-2底物后,立即使用Thermo VARIOSKAN LUX酶标仪在激发光波长为380nM和发射光波长为460nM测试以上反应液的动力学反应过程的荧光强度。化合物浓度从600μM至0.03μM 3倍稀释测定IC50,每个浓度设置3个平行组。抑制率使用以下公式计算:抑制率(%)= ,其中ΔFa为相同时间不含测受试化合物的荧光强度的变化值,ΔFc为相同时间含受试化合物的荧光强度的变化值。使用Graphpad Prism软件(La Jolla,CA)获得IC50 / pIC50 / s.e.pIC50值3)。
实验结果:
通过以上实验方法,测试了本发明中化合物针对NDM-1 MBL,VIM-2 MBL, TEM-1 SBL,and KPC-2 SBL蛋白的半数有效抑制浓度(IC50),具体见表1和表2。
表 1 芳基偕二磷酸酯衍生物对临床β内酰胺酶NDM-1、VIM-2、TEM-1和KPC-2 的抑制活性
表 2. 芳基偕二磷酸衍生物对临床β内酰胺酶NDM-1, VIM-2, TEM-1 and KPC-2 的抑制活性
实验结论
由表1,2可见本发明中化合物对NDM-1,VIM-2,TEM-1有较好的抑制活性,对KPC-2有一定抑制活性。其中化合物28,30,34,35,36,39,40,41,42,43,44,45,46,47,49,50抑制活性最佳,显著优于目前报道的一些MBL小分子抑制剂,如EDTA、卡托普利。另外化合44,45, 46,47, 49对TEM-1 SBL表现出微摩尔及的抑制活性。因此本发明中的化合物有望发展成为MBL/SBL的双重抑制剂。
Claims (8)
1.结构如下通式(I)所示的芳基偕二磷酸衍生物或其生理上可接受的盐及其作为β-内酰胺酶抑制剂的药物组合物和医药用途,
,
其中R1、R2 各自独立为H或者各种取代基。
2.根据权利要求1所述的一种通式(I)的芳基偕二磷酸衍生物或其生理上可接受的盐,其特征在于:所述R2为氢,或者链长为1~10的饱和直链烷烃,或者主链长为1~10的饱和支链烷烃,或者芳基、取代芳基,苄基。
3.根据权利要求1所述的一种通式(I)的芳基偕二磷酸衍生物或其生理上可接受的盐,其特征在于:所述R1为氢,C1~4烃基、C1~4烷氧基、C1~4烷酰基、C1~4烷酰氧基、C1~4烷磺酰基、C1~4酰胺、C1~4磺酰胺、卤素、三氟甲基、硝基、氰基、烷氨基、氨基、羟基、羧基中的1个或者多个。
4.根据权利要求1所述的一种通式(I)的芳基偕二磷酸衍生物或其生理上可接受的盐,其特征在于:所述芳环为苯环,萘环;芳杂环为五元、六元含氮,含氧,含硫芳杂环或者苯并五元、六元含氮,含氧,含硫芳杂环。
5.根据权利要求1所述的一种通式(I)的芳基偕二磷酸衍生物或其生理上可接受的盐,其特征在于:所述的DG(导向基团)为:五元、六元含氮芳杂环,酰胺,肟醚,偶氮。
6.根据权利要求3所述的一种通式(I)的芳基偕二磷酸衍生物或其生理上可接受的盐,其特征在于:所述的芳环取代基为1-3个。
7.根据权利要求1-6所述的一种通式(I)的芳基偕二磷酸衍生物或其生理上可接受的盐的医药用途,其特征在于:可作为β-内酰胺酶抑制剂及其药物组合物和医药用途。
8.根据权利要求1-6所述的一种通式(I)的芳基偕二磷酸衍生物或其生理上可接受的盐的合成方法和工艺流程。
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