CN107224436B - 一类孪药型HMG-CoA还原酶抑制剂及其合成方法 - Google Patents

一类孪药型HMG-CoA还原酶抑制剂及其合成方法 Download PDF

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CN107224436B
CN107224436B CN201710484023.8A CN201710484023A CN107224436B CN 107224436 B CN107224436 B CN 107224436B CN 201710484023 A CN201710484023 A CN 201710484023A CN 107224436 B CN107224436 B CN 107224436B
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吴范宏
黄金文
索奇
吴岳林
李媛媚
李丹丹
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Zhejiang Jia Tai Technology Co.,Ltd.
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Abstract

本发明属于药物化学技术领域，具体为一种孪药型HMG‑CoA还原酶抑制剂及其合成方法。该类新型的孪药HMG‑CoA酶抑制剂制备方法反应步骤简单、无污染、适于工业化规模应用；HMG‑CoA酶抑制剂活性显著优于阳性对照药。

Description

一类孪药型HMG-CoA还原酶抑制剂及其合成方法
技术领域
本发明属于药物化学及药物合成技术领域，具体涉及一类孪药型HMG-CoA还原酶抑制剂及其合成方法。
背景技术
血浆中总胆固醇、低密度脂蛋白、甘油三酯中其中一种或多种水平升高，即为高脂血症。血脂水平过高，可直接引起一些严重危害人体健康的疾病，如动脉粥样硬化、冠心病、胰腺炎等。临床上用于治疗高血脂症的药物主要分为两大类，以降低血清总胆固醇和LDL胆固醇为主的有他汀类和树脂类，以降低血清三酰甘油为主的药物有贝特类和烟酸类。
贝特类降脂药，又称苯氧芳酸类降脂药，可通过增强脂蛋白脂酶的活性加速脂蛋白的分解，同时也能减少肝脏中脂蛋白的合成，从而降低血脂。这类药物的突出作用是显著降低甘油三酯。烟酸类药物属B族维生素，当用量超过其作为维生素作用的剂量时，可有明显的降脂作用。
临床上使用最广泛的调脂药物是他汀类，它是HMG-CoA还原酶抑制剂，通过可逆性的竞争辅酶使HMG-CoA不能转化为甲羟戊酸，从而抑制内源性胆固醇合成、降低低密度脂蛋白、升高高密度脂蛋白。
氟伐他汀单独或联合治疗混合型高脂血症研究表明氟伐他汀与苯扎贝特合用有效降低LDL-C水平24％，降低TG水平38％，升高HDL-C水平22％，优于单药治疗时的降脂疗效。辛伐他汀联合非诺贝特治疗高脂血症研究(SAFARI研究)纳入618例致动脉粥样硬化血脂异常的患者,分别接受辛伐他汀联合非诺贝特和单用辛伐他汀治疗。结果显示两药联合治疗较单一治疗进一步显著降低TG 23％和LDL-C 54％,同时进一步显著升高 HDL-C水平89％。上述研究表明,他汀与贝特联合能达到协同的调脂作用。烟酸与降脂常用药他汀类联合在全面调脂、减少心血管剩留危险、药物经济学评价等方面也具有明显优势。
综所上述，贝特类、烟酸类化合物与他汀类化合物联用有利于更好的降低血脂，利用贝特类、烟酸类化合物与他汀类化合物拼接合成新的降血脂化合物也具有了令人期待的意义。
发明内容
本发明的目的是提供一类新型的孪药型HMG-CoA还原酶抑制剂及其合成方法。
本发明提供的一类孪药型HMG-CoA还原酶抑制剂，其是贝特类化合物或烟酸类化合物通过链接子和他汀类药物链状连接形成的孪药；其中：链接子为
Figure GDA0002212262510000021
Figure GDA0002212262510000022
n为1～30的整数；贝特类化合物选自吉非贝齐、氯贝酸、非诺贝特酸、苯扎贝特或环丙贝特中任意一种；烟酸类化合物为烟酸或者阿昔莫司。
本发明中，他汀类药物为美伐他汀、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、西立伐他汀、阿托伐他汀、罗苏伐他汀或者匹伐他汀。
本发明中，链接子中，n为1～8的整数。
本发明还提供一种上述的HMG-CoA还原酶抑制剂的合成方法，具体步骤如下：
(1)将贝特类化合物或烟酸类化合物，和链接子发生反应，得到中间体；
(2)将他汀类药物转化为相应盐类衍生物，让中间体和他汀类药物的盐类衍生物在催化剂作用下反应，得到HMG-CoA还原酶抑制。
其中：步骤(1)中，所述链接子为
Figure GDA0002212262510000023
n为1～30的整数；贝特类化合物选自吉非贝齐、氯贝酸、非诺贝特酸、苯扎贝特或环丙贝特中任意一种；所述烟酸类化合物为烟酸或者阿昔莫司；步骤(2)中，催化剂为四丁基碘化铵，四丁基溴化铵或四丁基氟化铵。
本发明中，步骤(1)中，链接子为时，采用缩合体系采用EDCI/DMAP、EDCI/DIEA、HATU/DIEA、或DCC/DMAP体系进行缩合反应得到酯或酰胺类中间体；贝特类化合物或烟酸类化合物和链接子的摩尔比为1：1:1.1-1:1.3。
本发明中，步骤(2)中，他汀类药物为美伐他汀、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、西立伐他汀、阿托伐他汀、罗苏伐他汀或者匹伐他汀。
本发明中，步骤(2)中，他汀类药物和中间体的摩尔比为1：1.1～1:1.3；反应温度为室温。步骤(2)中，催化剂用量是他汀类药物质量的3％～12％。
本发明的一类新型的HMG-CoA还原酶抑制剂较以往所制备HMG-CoA还原酶抑制剂另外一大优点，该类孪药在体内代谢后产生的两种药物可以产生协同增效作用，达到增强活性，两者互补，达到既可以降低胆固醇水平，也可以降低人体甘油三酯水平。
和现有技术相比，本发明的有益效果在于：本发明开创性的将他汀类药物与烟酸、贝特类化合物拼接在一起，制备工艺具有操作简单，重复性好，应用前景巨大，适用于工业化生产等优点。
具体实施方式
下列实例仅仅为了说明方案的实施过程，包括但不限于其中的条件。
本发明的化合物能根据以下所述的一般方案使用适当的物质作为原料来制备，并且通过后面的实施例来具体举例说明。当然，实施例中的举例化合物制备步骤的条件和方法的各种已知合理的变化也能用于制备这些化合物。所述的分析测试仪器和条件除非另有说明，否则：HRMS高分辨质谱为瑞士布鲁克公司solanX-70 FT-MS，H-NMR核磁氢谱volanceⅢ 500M或Agilent 400 NMR或Bruker AMX-400型核磁共振仪测定，测试溶剂为 CDCl3。
实施例1 2-bromoethyl 2-(4-chlorophenoxy)-2-methylpropanoate(1a)的合成
Figure GDA0002212262510000031
取50ml的长颈茄形反应瓶，加入合适的搅拌子，加入497mg的氯贝酸，20mg DMAP(4-二甲氨基吡啶)，887.7mg的EDCI(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐)，用氮气置换内部气体三次，最后保持在氮气的氛围中，放于低温槽内，缓慢注射二氯甲烷40ml， 10分钟后注入200微升的1溴乙醇与10ml二氯甲烷的混合液。反应6小时，后处理反应。将反应液用15ml水洗三次，15ml饱和氯化钠洗涤一次，有机相用硫酸钠干燥，拌样，低温旋蒸，柱层析(EA:PE＝1：4)，得到产物1a,560mg,无色油状产物。1H NMR(500 MHz,CDCl3)δ7.20(d,J＝8.8Hz,2H),6.81(d,J＝8.8Hz,2H),4.48(t,J＝6.0Hz,2H),3.50(t, J＝6.0Hz,2H),1.61(s,6H)；13C NMR(126MHz,CDCl3)δ173.56,153.89,129.20,129.20, 127.43,120.69,120.69,79.51,64.60,28.33,25.37,25.37；HRMS：m/z 322.98660 calcd.for(C12H15BrClO3 +)[M+H]+,found 322.98623。
实施例2 3-bromopropyl 2-(4-chlorophenoxy)-2-methylpropanoate(2a)的合成
Figure GDA0002212262510000032
实验操作同实施例1,由氯贝酸与溴丙醇反应制得.1H NMR(500MHz,CDCl3)δ7.16(d, J＝8.8Hz,2H),6.73(d,J＝8.8Hz,2H),4.25(t,J＝6.0Hz,2H),3.24(t,J＝6.4Hz，2H)，2.09(dd，J＝12.4,6.2Hz,2H),1.55(s,6H)；13C NMR(126MHz,CDCl3)δ173.75,154.03,129.23,129.23,127.10,120.06,120.06,79.36,63.05,31.27,29.17,25.32,25.32.ESI-MS: m/z 335.00(M+H)+。
实施例3 5-bromopentyl-2-(4-chlorophenoxy)-2-methylpropanoate(3a)的合成
Figure GDA0002212262510000041
实验操作同实施例1,由氯贝酸与5-溴戊醇反应制得.1H NMR(500MHz,CDCl3)δ7.19 (d,J＝8.7Hz,1H),6.77(d,J＝8.7Hz,1H),4.15(t,J＝6.5Hz,1H),3.37(t,J＝6.7Hz,1H), 1.83–1.73(m,1H),1.59(s,3H),1.39(dt,J＝15.1,7.6Hz,1H),1.24(dt,J＝15.2,7.6Hz,1H)； 13C NMR(126MHz,CDCl3)δ174.03,154.14,129.12,129.12,126.99,120.10,120.10, 79.42,65.40,33.72,32.53,28.28,27.66,25.34,25.34,25.02；ESI-MS:m/z363.67(M+H)+。
实施例4 6-bromohexyl 2-(4-chlorophenoxy)-2-methylpropanoate(4a)的合
Figure GDA0002212262510000042
实验操作同实施例1,由氯贝酸与6-溴己醇反应制得。1H NMR(500MHz,CDCl3)δ7.19 (d,J＝8.9Hz,2H),6.77(d,J＝8.9Hz,2H),4.15(t,J＝6.5Hz,2H),3.37(t,J＝6.7Hz,2H), 1.86–1.71(m,2H),1.62(dd,J＝14.8,7.6Hz,2H),1.59(s,6H),1.44–1.32(m,2H),1.27– 1.19(m,2H)；13C NMR(126MHz,CDCl3)δ174.04,154.15,129.12,129.12,127.06,120.18,120.18,79.47,65.39,33.65,32.53,28.29,27.67,25.35,25.35,25.02.ESI-MS:m/z 377.05(M+H)+。
实施例5 2-(4-chlorophenoxy)-2-methylpropanoate(5a)的合成
Figure GDA0002212262510000043
实验操作同实施例1,由氯贝酸与9-溴壬醇反应制得，无色油状产物。1H NMR(500MHz, CDCl3)δ7.17(d,J＝8.9Hz,2H),6.76(d,J＝8.9Hz,2H),4.14(t,J＝6.6Hz,2H),3.39(t,J＝ 6.8Hz,2H),1.89–1.78(m,2H),1.57(s,8H),1.39(dd,J＝14.5,7.2Hz,2H),1.23(s,8H)；13C NMR(126MHz,CDCl3)δ174.07,154.13,129.11,129.11,127.04,120.21,120.21,79.46, 65.64,34.04,32.79,29.28,29.05,28.65,28.43,28.13,25.77,25.35,25.35.ESI-MS:m/z 419.09(M+H)+。
实施例6 2-bromoethyl nicotinate(6a)的合成
Figure GDA0002212262510000044
实验操作同实施例1,由烟酸与溴乙醇反应制得，无色油状产物。1H NMR(500MHz,CDCl3)δ9.26(s,1H),8.81(s,1H),8.34(s,1H),7.43(s,1H),4.68(s,2H),3.68(s,2H)；13CNMR(126MHz,CDCl3)δ164.71,153.71,150.97,137.17,125.50,123.38,64.51,28.61； ESI-MS:m/z 229.98(M+H)+。
实施例7 3-bromopropyl nicotinate(7a)的合成
Figure GDA0002212262510000051
实验操作同实施例1,由烟酸与溴丙醇反应制得，无色油状产物。1H NMR(500MHz,CDCl3)δδ9.22(s,1H),8.80(d,J＝4.2Hz,1H),8.31(d,J＝7.9Hz,1H),7.45(dd,J＝7.7,5.0Hz,1H),4.52(dd,J＝11.6,5.7Hz,2H),3.60(t,J＝6.5Hz,2H),2.49–2.30(m,2H)；13C NMR(126MHz,CDCl3)125.73,123.28,62.99,31.43,29.42；ESI-MS:m/z 244.00(M+H)+。
实施例8 5-bromopentyl nicotinate(8a)的合成
Figure GDA0002212262510000052
实验操作同实施例1,由烟酸与5-溴戊醇反应制得，无色油状产物。1H NMR(500MHz, CDCl3)δ9.14(s,1H),8.69(d,J＝3.4Hz,1H),8.22(d,J＝7.5Hz,1H),7.32(dd,J＝18.4,11.6 Hz,1H),4.29(t,J＝6.2Hz,2H),3.40–3.31(m,2H),1.92–1.82(m,2H),1.78–1.66(m,2H), 1.59–1.50(m,2H)；13C NMR(125MHz,CDCl3)δ165.15,153.32,150.75,137.03,126.12, 123.33,65.05,33.48,32.16,27.74,24.58；ESI-MS:m/z 272.03(M+H)+。
实施例9 6-bromohexyl nicotinate(9a)的合成
实验操作同实施例1,由烟酸与6-溴己醇反应制得，无色油状产物。1H NMR(500MHz, CDCl3)δ9.23(s,1H),8.79(s,1H),8.31(d,J＝6.6Hz,1H),7.41(s,1H),4.37(s,2H),3.38(d, J＝47.8Hz,2H),1.90(s,2H),1.81(s,2H),1.51(s,4H).13C NMR(126MHz,CDCl3)δ 165.27,153.37,150.85,137.04,126.21,123.32,65.29,33.75,32.55,28.47,27.78,25.22. ESI-MS:m/z 286.04(M+H)+。
实施例10 9-bromononyl nicotinate(10a)的合成
Figure GDA0002212262510000061
实验操作同实施例1,由烟酸与9-溴壬醇反应制得，无色油状产物。1H NMR(500MHz, CDCl3)δ9.11(s,1H),8.65(d,J＝4.1Hz,1H),8.19(d,J＝7.8Hz,1H),7.30(dd,J＝7.5,5.1 Hz,1H),4.24(t,J＝6.6Hz,2H),3.28(t,J＝6.7Hz,2H),1.73(dd,J＝14.1,7.0Hz,2H),1.66 (dd,J＝14.2,6.9Hz,2H),1.31(s,4H),1.25–1.18(m,6H)；13C NMR(125MHz,CDCl3)δ 165.11,153.17,150.70,136.97,126.24,123.26,65.44,33.93(d,J＝2.7Hz),33.93(d,J＝ 2.7Hz),32.68,29.22,29.05,28.55(d,J＝5.8Hz),28.02,25.86；ESI-MS:m/z 328.06(M+H)+。
实施例11 2-bromoethyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate(11a)的合成
Figure GDA0002212262510000062
实验操作同实施例1,由非诺贝酸与溴乙醇反应制得，无色油状产物。1H NMR(500MHz, CDCl3)δ7.72(d,J＝8.8Hz,2H),7.69(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),4.48(t,J＝ 5.9Hz,2H),3.48(t,J＝5.9Hz,2H),1.70(s,6H)；13C NMR(125MHz,CDCl3)δ194.12, 173.22,159.46,138.35,136.33,132.04,132.04,131.19,131.19,130.52,128.55, 128.55,117.43,117.43,79.35,64.74,28.34,25.48,25.48.ESI-MS:m/z 425.01(M+H)+。
实施例12 3-bromopropyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate(12a)的合成
Figure GDA0002212262510000063
实验操作同实施例1,由非诺贝酸与溴丙醇反应制得，无色油状产物。1H NMR(500MHz, CDCl3)δ7.71(d,J＝8.2Hz,2H),7.67(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,2H),6.82(d,J＝ 8.3Hz,2H),4.26(t,J＝5.4Hz,2H),3.19(t,J＝6.0Hz,2H),2.09(dd,J＝16.1,10.3Hz,2H), 1.65(s,6H)；13C NMR(126MHz,CDCl3)δ194.09,173.54,159.57,138.32,136.26,132.16, 132.16,131.21,131.21,130.29,128.53,128.53,116.88,116.88,79.31,63.24,31.19,29.14, 25.43,25.43；ESI-MS:m/z 439.03(M+H)+。
实施例13 5-bromopentyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate(13a)的合成
Figure GDA0002212262510000071
实验操作同实施例1,由非诺贝酸与5-溴戊醇反应制得，无色油状产物。1H NMR(500 MHz,CDCl3)δ7.72(d,J＝8.7Hz,2H),7.68(d,J＝8.3Hz,2H),7.42(d,J＝8.4Hz,2H),6.85 (d,J＝8.7Hz,2H),4.15(t,J＝6.4Hz,2H),3.28(t,J＝6.6Hz,2H),1.76(dt,J＝14.0,6.9Hz, 2H),1.66(s,6H),1.62–1.54(m,2H),1.39–1.29(m,2H)；13C NMR(126MHz,CDCl3)δ194.02,173.63,159.68,138.30,136.35,132.03,132.03,131.16,131.16,130.29,128.53,128.53,117.13,117.13,79.39,65.33,33.37,32.06,27.56,25.45,25.45,24.42.ESI-MS:m/z 467.06(M+H)+。
实施例14 6-bromohexyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate(14a)的合成
Figure GDA0002212262510000072
实验操作同实施例1,由非诺贝酸与6-溴己醇反应制得，无色油状产物。1H NMR(500 MHz,CDCl3)δ7.71(d,J＝8.8Hz,2H),7.66(d,JJ＝8.4Hz,2H),6.83(d,J＝8.7Hz,2H),4.13(t,J＝6.4Hz,2H),3.29(t,J＝6.7Hz,2H),1.75–1.67(m,2H),1.65(s,6H),1.60–1.52(m,2H),1.34(dt,J＝15.0,7.6Hz,2H),1.19(dt,J＝15.1,7.7Hz,2H).13C NMR(126MHz,CDCl3)δ193.94,173.61,159.69,138.27,136.35,131.99,131.99,131.14,131.14,130.24,128.52,128.52,117.12,117.12,79.38,65.51,33.61,32.47,28.21,27.59,25.43,25.43,24.95.ESI-MS:m/z 481.08(M+H)+。
实施例15 9-bromononyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate(15a)的合成
Figure GDA0002212262510000073
实验操作同实施例1,由非诺贝酸与9-溴壬醇反应制得，无色油状产物。1H NMR(500 MHz,CDCl3)δ7.70(d,J＝8.3Hz,2H),7.66(dd,J＝8.3,1.4Hz,2H),7.42–7.36(m,2H),6.83(d,J＝7.7Hz,2H),4.12(t,J＝5.9Hz,2H),3.33(td,J＝6.7,2.1Hz,2H),1.80–1.73(m,2H),1.64(d,J＝1.0Hz,6H),1.55(s,2H),1.33(s,2H),1.18(s,8H)；13C NMR(126MHz,CDCl3)δ193.86,173.60,159.70,138.25,136.36,131.97,131.97,131.13,131.13,130.20,128.50,128.50,117.16,117.16,79.39,65.73,33.91,32.73,29.22,28.97,28.59,28.36,28.05,25.70,25.43,25.43.ESI-MS:m/z C26H32BrClO4,523.13(M+H)+。
实施例16 2-bromoethyl 2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropanoate( 16a)的合成
Figure GDA0002212262510000081
实验操作同实施例1,由苯扎贝特酸与溴乙醇反应制得，无色油状产物。1H NMR(500 MHz,CDCl3)δ7.63(d,J＝7.3Hz,2H),7.35(d,J＝7.3Hz,2H),7.07(d, J＝7.1Hz,2H),6.81(d,J＝7.1Hz,2H),6.47(s,1H),4.47(s,2H),3.61(d,J＝5.2Hz,2H), 3.50(s,2H),2.84(s,2H),1.62(s,6H).13C NMR(126MHz,CDCl3)δ173.89,166.50,153.92, 137.58,132.97,132.63,129.55,129.55,128.78,128.78,128.36,128.36,119.53,119.53, 79.14,64.52,41.33,34.73,28.46,25.44,25.44.ESI-MS:m/z 468.06(M+H)+.
实施例17 3-bromopropyl 2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropanoate (编号17a)的合成
Figure GDA0002212262510000082
实验操作同实施例1,由苯扎贝特酸与溴丙醇反应制得，无色油状产物。HRMS:m/z482.07283 calcd.for(C22H26BrClNO4 +)[M+H]+,found 482.07310.1H NMR(500MHz,CDCl3) δ7.63(d,J＝8.2Hz,2H),7.36(d,J＝8.2Hz,2H),7.08(d,J＝8.1Hz,2H),6.77(d,J＝8.1Hz,2H),6.44(s,1H),4.29(t,J＝8.5Hz,2H),3.77-3.63(m,2H),3.36-3.21(m,2H),2.84(t,J＝6.8 Hz,2H),2.25-2.05(m,2H),1.60(s,6H).13C NMR(125MHz,CDCl3)δ174.24,166.59,15415, 137.65,133.02,132.42,129.66,129.66,128.83,128.83,128.38,128.38,118.90,118.90, 79.08,63.04,41.38,34.74,31.39,29.29,25.47,25.47.
实施例18 5-bromopentyl 2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropanoate (编号18a)的合成
Figure GDA0002212262510000091
实验操作同实施例1,由苯扎贝特酸与5-溴戊醇反应制得，无色油状产物。 High-resolution EI-MS:m/z 510.10413 calcd.for(C24H30BrClNO4 +)[M+H]+,found510.10232.1H NMR(500MHz,CDCl3)δ7.63(d,J＝8.2Hz,2H),7.36(s,2H),7.08(d,J＝7.5Hz,2H),6.79(s,2H),6.42-6.34(m,,1H),4.17(s,2H),3.63(s,2H),3.34(s,2H),2.85(s,2H), 1.88-1.81(m,,1H),1.60(s,6H),1.42-1.33(m,2H).13C NMR(125MHz,CDCl3)δ174.25,166.78,154.04,137.60,133.54,132.28,129.51,129.51,128.54,128.54,127.96,127.96,119.27,119.27,78.85,64.91,41.33,34.80,33.42,31.97,27.63,.25.44,25.44,24.49.
实施例19 6-bromohexyl 2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropanoate(编号19a)的合成
Figure GDA0002212262510000092
实验操作同实施例1,由苯扎贝特酸与6-溴己醇反应制得，无色油状产物。 High-resolution EI-MS:m/z 524.11978 calcd.for(C25H32BrClNO4 +)[M+H]+,found 524.11810.1H NMR(500MHz,CDCl3)δ7.64(d,J＝7.7Hz,2H),7.34(d,J＝7.7Hz,2H),7.06(d,J＝7.6 Hz,2H),6.78-6.74(m,3H),4.22-4.07(m,2H),3.67-3.51(m,2H),3.40-3.26(m,2H),2.90-2.76(m,2H),1.84-1.63(m,4H),1.58(s,6H),1.42-1.28(m,4H).13C NMR(125MHz,CDCl3)δ174.25,166.69,153.65,137.18,132.78,132.19,129.39,129.39,128.64,128.64,128.36,128.36,119.16,119.16,79.11,65.31,41.34,34.64,33.71,32.47,28.19,.27.59,25.33,25.33,24.94.
实施例20 9-bromononyl 2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropanoate(编号20a)的合成
Figure GDA0002212262510000093
实验操作同实施例1,由苯扎贝特酸与9-溴壬醇反应制得，无色油状产物。 High-resolution EI-MS:m/z 566.16673calcd.for[M+H]+(C28H38BrClNO4 +),found 566.16535.1H NMR(500MHz,CDCl3)δ7.62(d,J＝8.2Hz,2H),7.33-7.28(m,2H),7.04(d,J＝8.1Hz, 2H),6.76(d,J＝8.1Hz,2H),6.61(s,1H),4.13(t,J＝6.5Hz,2H),3.69-3.51(m,2H), 3.39-3.31(m,2H),2.90-2.71(m,2H),1.84-1.52(m,10H),1.39-1.24(m,10H).13C NMR(125 MHz,CDCl3)δ174.35,166.49,154.08,137.43,132.93,132.37,129.42,129.42,128.62,128.62,128.37,128.37,119.32,119.32,79.05,65.52,41.43,34.69,34.10,32.73,29.23,29.00,.28.61,28.38,28.07,25.71,25.28,25.28.
实施例21 (3R,5S,E)-2-((2-(4-chlorophenoxy)-2-methylpropanoyl)oxy)ethyl7-(3-(4-fluorophen -yl)-1-isopropyl-1H-indol-2-yl)-3，5-dihydroxyhept-6-enoate(1b)的合成
取50ml的长颈茄形反应瓶，加入氟伐他汀钠(300mg，0.692mmoL)，化合物1a(267mg，0.830mmoL)，四丁基碘化铵10-30mg，而后加入DMF 20ml，用氮气置换内部气体三次，最后保持在氮气的氛围中，室温放置。反应10小时，后处理反应。向反应液中加入10ml纯净水，放于125ml的分液漏斗中，用EA:PE＝1：1的溶液萃取，每次倒入30ml 混合溶剂，连续萃取3次，集中有机相，用清水15ml洗涤三次，15ml饱和氯化钠洗涤一次，有机相用硫酸钠干燥，爬制备板(EA:PE＝1：1)，即可分离出产物淡黄色油状产物1b (91mg，20.3％)。1H NMR(500MHz,CDCl3)δ7.58–7.47(m,2H),7.41(dd,J＝7.9,5.9Hz, 2H),7.23–7.13(m,3H),7.08(dt,J＝17.9,7.6Hz,3H),6.78(d,J＝8.7Hz,2H),6.74–6.67 (m,1H),5.71(dd,J＝16.0,5.4Hz,1H),4.84(qd,J＝13.6,6.8Hz,1H),4.46(t,J＝11.2Hz, 1H),4.42–4.36(m,2H),4.36–4.26(m,2H),4.17(dd,J＝15.1,5.5Hz,1H),3.72(d,J＝11.2 Hz,2H),2.36(ddd,J＝19.6,16.6,6.0Hz,2H),1.67(d,J＝6.8Hz,6H),1.59(d,J＝9.9Hz,6H), 1.55(d,J＝4.5Hz,1H),1.49(d,J＝14.3Hz,1H)；19F NMR(375MHz,CDCl3)δ-116.85(s)；13C NMR(125MHz,CDCl3)δ174.02(s),172.05(s),161.39(d,J＝244.5Hz),153.94(s), 138.68(s),135.01(s),133.68(s),132.04(s),131.98(s),131.74(d,J＝3.0Hz),129.20(s), 129.20(s),128.38(s),127.25(s),121.74(s),120.41(s),120.41(s),119.63(s),119.41(s), 118.42(s),115.33(s),115.16(s),114.53(s),111.70(s),79.41(s),72.21(s),68.28(s),62.98(s),62.23(s),47.75(s),42.14(s),41.39(s),25.28(s),25.28(s),21.77(s),21.77(s)；HR-MS:m/z 652.24718 calcd.for(C36H40ClFNO7 +)[M+H]+,found 652.30199；
实施例22
(3R,5S,E)-3-((2-(4-chlorophenoxy)-2-methylpropanoyl)oxy)propyl7-(3-(4-fluorophenyl) -1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate(化合物2b)的合成
Figure GDA0002212262510000111
实验操作同实施例21，由氟伐他汀钠与化合物2a反应制得，淡黄色油状产物。 HR-ESI-MS:m/z 666.26283 calcd.for[M+H]+(C37H42ClFNO7 +),found 666.26038；19F NMR(375MHz,CDCl3)δ-116.87(s)；1H NMR(500MHz,CDCl3)δ7.56(d,J＝8.3Hz,2H),7.42 (dd,J＝8.2,5.7Hz,2H),7.21(d,J＝8.8Hz,3H),7.16–7.07(m,3H),6.79(d,J＝8.8Hz,2H), 6.72(d,J＝16.0Hz,1H),5.74(dd,J＝16.0,5.5Hz,1H),4.88(dt,J＝14.0,6.9Hz,1H),4.50(d,J＝4.4Hz,1H),4.26(t,J＝6.2Hz,2H),4.23(s,1H),4.09(t,J＝6.1Hz,2H),3.89(d,J＝49.6 Hz,2H),2.52–2.39(m,2H),1.97(p,J＝6.0Hz,2H),1.67(d,J＝6.9Hz,6H),1.64(s,1H), 1.61(s,6H),1.53(d,J＝14.4Hz,1H)；13C NMR(126MHz,CDCl3)δ174.02,172.26,161.38 (d,J＝244.6Hz),154.05,138.86,135.04,133.73,132.06,132.00,131.77(d,J＝3.1Hz), 129.24,129.24,128.38,127.26,121.77,120.39,120.39,119.66,119.41,118.43,115.34, 115.17,114.51,111.73,79.53,72.17,68.28,61.89,61.03,47.77,42.27,41.59,27.79, 25.34,25.34,21.76,21.76.
实施例23(3R,5S,E)-5-((2-(4-chlorophenoxy)-2-methylpropanoyl)oxy)pentyl7-(3-(4-fluoro phenyl)-1-isopropyl-1H-indol-2-yl)-3，5-dihydroxyhept-6-enoate(化合物3b)的合成
Figure GDA0002212262510000121
实验操作同实施例21，由氟伐他汀钠与化合物3a反应制得，淡黄色油状产物。 HR-ESI-MS:m/z 694.29414 calcd.for(C39H46ClFNO7 +)[M+H]+,found 694.30123；19F NMR(375MHz,CDCl3)δ-116.89(s)；1H NMR(500MHz,CDCl3)δ7.57(dd,J＝7.8,3.4Hz,2H), 7.43(dd,J＝7.8,5.9Hz,2H),7.22(d,J＝8.7Hz,3H),7.16–7.06(m,3H),6.80(d,J＝8.7Hz,2H),6.73(d,J＝15.9Hz,1H),5.75(d,J＝5.4Hz,1H),4.88(dq,J＝13.7,6.9Hz,1H),4.52(d, J＝4.4Hz,1H),4.24(d,J＝2.0Hz,1H),4.18(t,J＝6.4Hz,2H),4.11(t,J＝6.6Hz,2H),3.87 (d,J＝51.3Hz,2H),2.55–2.44(m,2H),1.68(d,J＝6.9Hz,6H),1.64(d,J＝8.1Hz,2H),1.62 (s,6H),1.59(d,J＝7.6Hz,1H),1.53(d,J＝14.2Hz,1H),1.34(t,J＝11.2Hz,2H),1.30–1.26 (m,2H)；13C NMR(125MHz,CDCl3)δ174.13,172.66,161.37(d,J＝244.6Hz),154.15, 138.85,135.00,133.74,132.04,131.98,131.75(d,J＝3.2Hz),129.15,129.15,128.36, 127.06,121.73,120.21,120.21,119.63,119.39,118.34,115.31,115.14,114.46,111.71, 79.49,72.20,68.39,65.44,64.82,47.75,42.22,41.48,28.39,28.33,25.47,25.47,25.35, 21.76,21.76。
实施例24(3R,5S,E)-6-((2-(4-chlorophenoxy)-2-methylpropanoyl)oxy)hexyl7-(3-(4-fluoro phenyl)-1-isopropyl-1H-indol-2-yl)-3，5-dihydroxyhept-6-enoate(化合物4b)的合成
Figure GDA0002212262510000122
实验操作同实施例21，由氟伐他汀钠与化合物4a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.87(s)；1H NMR(500MHz,CDCl3)δ7.58–7.48(m,2H), 7.41(dd,J＝7.8,5.9Hz,2H),7.19(d,J＝8.6Hz,3H),7.09(dd,J＝13.4,7.4Hz,3H),6.78(d,J ＝8.7Hz,2H),6.70(d,J＝15.9Hz,1H),5.71(dd,J＝15.9,5.3Hz,1H),4.86(dt,J＝13.8,6.9 Hz,1H),4.49(s,1H),4.22(s,1H),4.15(dd,J＝12.8,6.4Hz,2H),4.09(dd,J＝13.1,6.6Hz,2H),3.82(d,J＝59.1Hz,2H),2.59–2.40(m,2H),2.05(s,1H),1.66(d,J＝6.7Hz,6H),1.62(d,J＝7.9Hz,2H),1.59(s,6H),1.55(d,J＝6.2Hz,1H),1.48(dd,J＝26.3,10.9Hz,2H),1.42 –1.36(m,1H),1.35–1.29(m,2H),1.25(d,J＝6.9Hz,2H).13C NMR(125MHz,CDCl3)δ174.12,172.68,161.37(d,J＝244.6Hz),154.15,138.82,135.00,133.73,132.04,131.97,131.75(d,J＝3.1Hz),129.14,129.14,128.36,127.07,121.72,120.22,120.22,119.62,119.38,118.35,115.30,115.13,114.48,111.69,79.50,72.20,68.39,65.43,64.82,47.74, 42.23,41.45,28.39,28.32,25.46,25.46,25.35,25.35,21.76,21.76；HR-ESI-MS:m/z 708.30978 calcd for(C40H48ClFNO7 +)[M+H]+,found 708.30690。
实施例25(3R,5S,E)-9-((2-(4-chlorophenoxy)-2-methylpropanoyl)oxy)nonyl7-(3-(4-fluoro phenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate(化合物5b)的合成
Figure GDA0002212262510000131
实验操作同实施例21，由氟伐他汀钠与化合物5a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.87(s)；1H NMR(500MHz,CDCl3)δ7.59–7.52(m,2H),7.49 –7.34(m,2H),7.21(d,J＝8.2Hz,3H),7.12(t,J＝7.0Hz,3H),6.80(d,J＝8.5Hz,2H),6.73 (d,J＝15.9Hz,1H),5.73(dd,J＝15.9,5.1Hz,1H),4.88(dt,J＝13.6,6.8Hz,1H),4.52(s,1H),4.25(s,1H),4.20–4.10(m,4H),3.86(t,J＝46.5Hz,2H),2.55–2.44(m,2H),1.68(d,J＝6.7Hz,6H),1.67–1.62(m,4H),1.62(s,6H),1.60–1.56(m,1H),1.53(d,J＝14.2Hz,1H),1.39–1.33(m,2H),1.29(s,2H),1.26(s,6H).13C NMR(125MHz,CDCl3)δ174.14,172.75,161.38(d,J＝244.7Hz),154.15,138.81,134.99,133.74,132.04,131.97,131.75(d,J＝3.3Hz),129.12,129.12,128.37,127.07,121.71,120.27,120.27,119.61,119.39,118.33,115.30,115.13,114.48,111.69,79.50,72.22,68.44,65.66,65.12,47.74,42.22,41.42,29.35,29.13,29.07,28.52,28.43,25.86,25.77,25.35,25.35,21.76,21.76；HR-ESI-MS:m/z750.35673 calcd for(C43H54ClFNO7 +)[M+H]+,found 750.35412。
实施例26 2-(((3R,5S,E)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6 -enoyl)oxy)ethyl nicotinate(化合物6b)的合成
Figure GDA0002212262510000141
实验操作同实施例21，由氟伐他汀钠与化合物6a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.90(s)1H NMR(500MHz,CDCl3)δ9.22(d,J＝0.7Hz,1H), 8.75(d,J＝4.7Hz,1H),8.31(d,J＝7.9Hz,1H),7.53(t,J＝8.7Hz,2H),7.39(dd,J＝13.7,5.9 Hz,3H),7.18(t,J＝7.5Hz,1H),7.08(dd,J＝12.1,5.0Hz,3H),6.69(d,J＝15.9Hz,1H),5.70(dd,J＝16.0,5.4Hz,1H),4.84(dt,J＝14.0,7.0Hz,1H),4.58(d,J＝3.7Hz,2H),4.49(dd,J＝ 8.3,4.1Hz,3H),4.25(d,J＝3.8Hz,1H),3.88(s,2H),2.52(dd,J＝5.7,4.0Hz,2H),1.65(d,J ＝6.9Hz,6H),1.60(dd,J＝15.8,5.8Hz,1H),1.52(d,J＝14.3Hz,1H).13C NMR(101MHz, CDCl3)δ172.06,164.98,161.36(d,J＝244.5Hz),153.39,150.73,138.81,137.47,135.02, 133.65,132.02,131.94,131.71(d,J＝3.2Hz),128.36,125.82,123.55,121.73,119.62, 119.38,118.44,115.30,115.09,114.53,111.66,72.11,68.21,63.01,62.34,47.73,42.30, 41.70,21.73,21.73.HR-ESI-MS:m/z 561.23954 calcd.for(C32H34FN2O6 +)[M+H]+,found 561.23795。
实施例27 3-(((3R,5S,E)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoyl)oxy)propyl nicotinate(化合物7b)的合成
Figure GDA0002212262510000142
实验操作同实施例21，由氟伐他汀钠与化合物7a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.91(s)1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.69(d,J＝ 4.0Hz,1H),8.27(d,J＝7.9Hz,1H),7.52(d,J＝8.3Hz,2H),7.38(dd,J＝8.1,5.8Hz,2H), 7.33(dd,J＝7.7,5.0Hz,1H),7.16(t,J＝7.7Hz,1H),7.06(t,J＝8.1Hz,3H),6.70(d,J＝15.9Hz,1H),5.74(dd,J＝16.0,5.4Hz,1H),4.84(dt,J＝13.9,6.9Hz,1H),4.48(d,J＝3.9Hz,1H), 4.42(t,J＝6.1Hz,2H),4.28(s,2H),4.26(t,J＝6.0Hz,3H),2.56–2.41(m,2H),2.17–2.06 (m,2H),1.66(d,J＝13.7Hz,1H),1.62(d,J＝6.8Hz,6H),1.57–1.50(m,1H)；13C NMR(100 MHz,CDCl3)δ172.16,165.05,161.35(d,J＝244.6Hz),153.21,150.57,139.13,137.40, 135.06,133.74,132.03,131.96,131.76(d,J＝3.3Hz),128.36,126.16,123.60,121.76, 119.66,119.39,118.38,115.33,115.12,114.49,111.71,71.98,68.10,62.11,61.32,47.74, 42.45,41.92,27.98,21.73,21.73；HR-ESI-MS:m/z 575.25519 calcd.for[M+H]+ (C33H36FN2O6 +),found 575.25358。
实施例28 5-(((3R,5S,E)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoyl)oxy)pentyl nicotinate(化合物8b)的合成
Figure GDA0002212262510000151
实验操作同实施例21，由氟伐他汀钠与化合物8a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.90(s)1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.66(s,1H), 8.27(d,J＝6.3Hz,1H),7.51(d,J＝5.4Hz,2H),7.35(d,J＝23.2Hz,3H),7.15(s,1H),7.05(s,3H),6.70(d,J＝15.7Hz,1H),5.75(d,J＝12.4Hz,1H),4.83(s,1H),4.49(s,3H),4.32(s,2H), 4.24(s,1H),4.11(s,2H),2.48(s,2H),1.71(d,J＝37.9Hz,4H),1.61(d,J＝4.1Hz,6H),1.56– 1.28(m,4H).13C NMR(101MHz,CDCl3)δ172.27,165.07,161.33(d,J＝244.5Hz),152.97, 150.44,139.34,137.46,135.08,133.79,132.01,131.94,131.76(d,J＝3.2Hz),128.35, 126.48,123.62,121.75,119.66,119.37,118.30,115.32,115.11,114.44,111.71,71.88, 68.08,65.29,64.44,47.72,42.53,42.05,28.21,28.21,22.52,21.72,21.72；HR-ESI-MS: m/z 603.28649 calcd.for[M+H]+(C35H40FN2O6 +),found 603.28730。
实施例29 6-(((3R,5S,E)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoyl)oxy)hexyl nicotinate(化合物9b)的合成
Figure GDA0002212262510000152
实验操作同实施例21，由氟伐他汀钠与化合物9a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.86(s)；1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.71(d,J＝ 3.7Hz,1H),8.29(d,J＝7.8Hz,1H),7.52(d,J＝8.2Hz,2H),7.43–7.31(m,3H),7.17(t,J＝ 7.6Hz,1H),7.07(dd,J＝11.8,5.1Hz,3H),6.70(d,J＝15.9Hz,1H),5.74(dd,J＝15.9,5.3Hz,1H),4.84(dt,J＝13.8,6.8Hz,1H),4.50(s,3H),4.33(t,J＝6.4Hz,2H),4.24(s,1H),4.11(t,J ＝6.4Hz,2H),2.48(dd,J＝14.4,10.2Hz,2H),1.87–1.66(m,4H),1.63(d,J＝6.6Hz,6H), 1.55(d,J＝14.0Hz,2H),1.40(d,J＝37.6Hz,4H)；13C NMR(101MHz,CDCl3)δ172.39,165.17,162.55,153.06,150.55,139.19,137.34,135.04,133.77,132.01,131.93,131.75(d, J＝3.2Hz),128.36,126.45,123.52,121.72,119.62,119.36,118.29,115.30,115.09,114.44,111.68,72.01,68.18,65.44,64.70,47.71,42.44,41.88,28.46(d,J＝4.6Hz),28.46(d,J＝4.6Hz),25.64(d,J＝7.4Hz),25.64(d,J＝7.4Hz),21.72,21.72；HR-ESI-MS:m/z 617.30214 calcd.for(C36H42FN2O6 +)[M+H]+,found 617.30315。
实施例30 9-(((3R,5S,E)-7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6- enoyl)oxy)nonyl nicotinate(化合物10b)
Figure GDA0002212262510000161
实验操作同实施例21，由氟伐他汀钠与化合物10a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.91(s)；1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.69(d,J＝ 3.2Hz,1H),8.28(d,J＝7.5Hz,1H),7.51(d,J＝7.9Hz,2H),7.35(dd,J＝16.8,6.5Hz,3H), 7.20–7.12(m,1H),7.04(d,J＝8.0Hz,3H),6.69(d,J＝15.9Hz,1H),5.73(dd,J＝15.9,5.1 Hz,1H),4.88–4.78(m,1H),4.42(d,J＝49.0Hz,3H),4.31(t,J＝6.1Hz,2H),4.22(s,1H), 4.08(s,2H),2.54–2.41(m,2H),1.73(d,J＝6.5Hz,2H),1.61(d,J＝6.0Hz,8H),1.56–1.46 (m,2H),1.40(s,2H),1.30(s,8H)；13C NMR(101MHz,CDCl3)δ172.41,165.17,161.34(d,J ＝244.7Hz),152.95,150.50,139.19,137.39,135.07,133.77,132.01,131.94,131.75(d,J＝3.3Hz),128.37,126.56,123.54,121.73,119.63,119.37,118.33,115.31,115.10,114.46,111.68,71.98,68.15,65.66,64.94,47.71,42.46,41.92,29.34,29.11,29.11,28.60,28.53, 25.93,25.85,21.72,21.72；HR-ESI-MS:m/z 659.34909 calcd.for(C39H48FN2O6 +)[M+H]+, found 659.34590。
实施例31(3R,5S,E)-2-((2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoyl)oxy)ethyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoat(化合物11b)的合成
Figure GDA0002212262510000171
实验操作同实施例21，由氟伐他汀钠与化合物11a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.90(s)；1H NMR(500MHz,CDCl3)δ7.58(d,J＝8.3Hz,2H), 7.45(dd,J＝8.2,5.7Hz,2H),7.26–7.18(m,3H),7.17–7.08(m,3H),6.81(d,J＝8.8Hz,2H),6.74(d,J＝16.0Hz,1H),5.76(dd,J＝16.0,5.5Hz,1H),4.89(dq,J＝13.9,6.9Hz,1H),4.52(d, J＝4.4Hz,1H),4.27(dd,J＝13.9,7.7Hz,3H),4.11(t,J＝6.1Hz,2H),3.92(d,J＝49.6Hz, 2H),2.54–2.42(m,2H),1.99(dd,J＝12.3,6.1Hz,2H),1.69(d,J＝6.9Hz,6H),1.67–1.63 (m,2H),1.63(s,6H),1.60–1.49(m,2H)；HR-ESI-MS:m/z 778.25589 calcd.for[M+Na]+ (C43H43ClFNNaO8 +),found 778.25113。
实施例32(3R,5S,E)-3-((2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoyl)oxy)propyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate(化合物12b)的合成
Figure GDA0002212262510000172
实验操作同实施例21，由氟伐他汀钠与化合物12a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.89(s)；1H NMR(500MHz,CDCl3)δ7.75(d,J＝8.5Hz,2H), 7.69(d,J＝8.2Hz,2H),7.54(d,J＝8.1Hz,2H),7.41(d,J＝8.0Hz,4H),7.18(t,J＝7.6Hz, 1H),7.08(t,J＝8.6Hz,3H),6.87(d,J＝8.5Hz,2H),6.72(d,J＝15.9Hz,1H),5.74(dd,J＝16.0,5.4Hz,1H),4.87(dt,J＝13.7,6.8Hz,1H),4.49(s,1H),4.24(dd,J＝18.3,12.5Hz,3H), 4.02(dd,J＝20.0,14.1Hz,4H),2.57–2.34(m,2H),1.98–1.89(m,2H),1.78–1.50(m,14H)； HR-ESI-MS:m/z 770.28905 calcd.for(C44H46ClFNO8 +)[M+H]+,found 770.28487。
实施例33(3R,5S,E)-5-((2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoyl)oxy)pentyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate(化合物13b)的合成
Figure GDA0002212262510000181
实验操作同实施例21，由氟伐他汀钠与化合物13a反应制得，淡黄色油状产物。19FNMR(376MHz,CDCl3)δ-116.90(s)；1H NMR(500MHz,CDCl3)δ7.75(d,J＝8.6Hz,2H), 7.69(d,J＝8.2Hz,2H),7.54(d,J＝8.2Hz,2H),7.41(t,J＝7.1Hz,4H),7.17(t,J＝7.7Hz, 1H),7.07(dd,J＝15.0,7.6Hz,3H),6.88(d,J＝8.6Hz,2H),6.72(d,J＝15.9Hz,1H),5.74(dd, J＝16.0,5.4Hz,1H),4.87(dt,J＝13.9,6.9Hz,1H),4.50(d,J＝4.1Hz,1H),4.21(d,J＝10.2Hz,1H),4.17(t,J＝6.3Hz,2H),4.12–4.07(m,2H),4.01(t,J＝6.5Hz,2H),2.52–2.36(m,2H),1.81–1.45(m,19H)；HR-ESI-MS:m/z 798.32035 calcd.for(C46H50ClFNO8 +)[M+H]+,found 798.32310。
实施例34(3R,5S,E)-6-((2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoyl)oxy)hexyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate(化合物14b)的合成
实验操作同实施例21，由氟伐他汀钠与化合物14a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.87(s)；1H NMR(500MHz,CDCl3)δ7.76(d,J＝8.5Hz,2H), 7.71(d,J＝8.2Hz,2H),7.56(d,J＝7.6Hz,2H),7.43(dd,J＝15.1,7.9Hz,4H),7.20(t,J＝7.6 Hz,1H),7.10(t,J＝7.0Hz,3H),6.89(d,J＝8.5Hz,2H),6.73(d,J＝15.9Hz,1H),5.74(dd,J ＝15.9,5.4Hz,1H),4.88(dt,J＝13.8,6.8Hz,1H),4.51(s,1H),4.24(s,1H),4.17(dd,J＝14.8, 8.5Hz,2H),4.02(dt,J＝46.6,12.7Hz,4H),2.55–2.37(m,2H),1.71(s,6H),1.67(d,J＝6.9 Hz,6H),1.58(ddd,J＝28.3,17.0,10.3Hz,6H),1.32–1.22(m,4H)；HR-ESI-MS:m/z834.31794 calcd.for(C47H51ClFNNaO8 +)[M+Na]+,found834.32638。
实施例35(3R,5S,E)-9-((2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoyl)oxy)nonyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate(化合物15b)的合成
Figure GDA0002212262510000191
实验操作同实施例21，由氟伐他汀钠与化合物15a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.86(s)；1H NMR(500MHz,CDCl3)δ7.75(d,J＝8.6Hz,2H), 7.69(d,J＝8.3Hz,2H),7.54(d,J＝8.1Hz,2H),7.42(dd,J＝12.6,7.9Hz,4H),7.18(t,J＝7.6 Hz,1H),7.08(dd,J＝16.0,8.0Hz,3H),6.88(d,J＝8.6Hz,2H),6.71(d,J＝15.9Hz,1H),5.74(dd,J＝15.9,5.4Hz,1H),4.87(dt,J＝13.8,6.9Hz,1H),4.50(s,1H),4.23(s,1H),4.14–4.07 (m,4H),4.05(d,J＝12.5Hz,2H),2.57–2.41(m,2H),1.71–1.58(m,18H),1.25(dd,J＝15.4, 8.2Hz,10H)；HR-ESI-MS:m/z 876.36489 calcd.for(C50H57ClFNNaO8 +)[M+Na]+,found 876.35871。
实施例36(3R,5S,E)-2-((2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropanoyl)oxy) ethyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3，5-dihydroxyhept-6-enoate(化合物 16b)的合成
Figure GDA0002212262510000192
实验操作同实施例21，由氟伐他汀钠与化合物16a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.85(s)；1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.4Hz,2H), 7.51(d,J＝8.3Hz,2H),7.37(dd,J＝8.2,5.7Hz,2H),7.28(d,J＝8.4Hz,2H),7.16(t,J＝7.7 Hz,1H),6.77(d,J＝8.2Hz,3H),6.66(d,J＝16.0Hz,1H),5.70(dd,J＝16.0,5.5Hz,1H),4.80(dt,J＝13.9,6.9Hz,1H),4.47–4.39(m,1H),4.39–4.32(m,2H),4.31–4.22(m,2H),4.16(dd,J＝9.7,6.6Hz,1H),4.00(dd,J＝40.8,34.2Hz,2H),3.55(q,J＝13.8Hz,2H),2.78(t,J＝ 7.1Hz,2H),2.46–2.34(m,2H),1.77–1.46(m,14H)；HR-ESI-MS:m/z 821.29754calcd.for [M+Na]+(C45H48ClFN2NaO8 +),found 821.29483。
实施例37(3R,5S,E)-3-((2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropanoyl)oxy) propyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3，5-dihydroxyhept-6-enoate(化合物 17b)的合成
Figure GDA0002212262510000201
实验操作同实施例21，由氟伐他汀钠与化合物17a反应制得，淡黄色油状产物。19FNMR(376MHz,CDCl3)δ-116.88(s)；1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.4Hz,2H), 7.54–7.46(m,2H),7.37(dd,J＝8.3,5.7Hz,2H),7.31(d,J＝8.4Hz,2H),7.16(t,J＝7.5Hz, 1H),7.06(t,J＝7.4Hz,5H),6.74(d,J＝8.4Hz,2H),6.65(s,1H),6.54(t,J＝5.3Hz,1H),5.69(dd,J＝16.0,5.5Hz,1H),4.82(dt,J＝13.9,7.0Hz,1H),4.47–4.41(m,1H),4.22(t,J＝6.0Hz,2H),4.17(d,J＝6.8Hz,1H),3.97(t,J＝6.1Hz,4H),3.58(dd,J＝12.9,6.6Hz,2H),2.81(t,J＝6.9Hz,2H),2.50–2.36(m,2H),1.94(dt,J＝11.7,5.8Hz,2H),1.62(d,J＝7.0Hz,6H), 1.58(s,6H),1.55–1.45(m,2H)；HR-ESI-MS:m/z 835.31319 calcd.for(C46H50ClFN2NaO8 +)[M+Na]+,found 835.31244。
实施例38(3R,5S,E)-5-((2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropanoyl)oxy) pentyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3，5-dihydroxyhept-6-enoate(化合物 18b)的合成
实验操作同实施例21，由氟伐他汀钠与化合物18a反应制得，淡黄色油状产物。19FNMR(376MHz,CDCl3)δ-116.86(s)；1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.5Hz,2H), 7.52(d,J＝8.5Hz,2H),7.38(dd,J＝8.5,5.6Hz,2H),7.30(d,J＝8.5Hz,2H),7.16(t,J＝7.9 Hz,1H),7.11–6.99(m,5H),6.76(d,J＝8.5Hz,2H),6.69(dd,J＝14.9,10.7Hz,2H),5.71(dd, J＝16.0,5.5Hz,1H),4.82(td,J＝13.9,6.9Hz,1H),4.49–4.41(m,1H),4.23–4.18(m,1H),4.14(t,J＝6.4Hz,2H),4.00(t,J＝6.6Hz,2H),3.56(dd,J＝13.1,6.8Hz,2H),2.80(t,J＝7.1 Hz,2H),2.49–2.37(m,2H),1.82–1.37(m,18H),1.29(dd,J＝15.9,8.9Hz,2H)；HR-ESI-MS: m/z 863.34449 calcd.for(C48H54ClFN2NaO8 +)[M+Na]+,found 863.33518。
实施例39(3R,5S,E)-6-((2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropanoyl) oxy)hexyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate(化合物19b)的合成
实验操作同实施例21，由氟伐他汀钠与化合物19a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.91(s)；1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.2Hz,2H), 7.51(d,J＝8.1Hz,2H),7.38(dd,J＝7.4,6.0Hz,2H),7.29(d,J＝8.1Hz,2H),7.15(t,J＝7.5 Hz,1H),7.05(dd,J＝13.1,8.5Hz,5H),6.76(d,J＝8.1Hz,2H),6.67(d,J＝16.0Hz,1H),5.70(dd,J＝16.0,5.3Hz,1H),4.82(dt,J＝13.7,6.8Hz,1H),4.81–4.39(m,3H),4.45(s,1H),4.19 (s,1H),4.13(t,J＝6.2Hz,2H),4.03(t,J＝6.5Hz,2H),3.60–3.47(m,2H),2.78(t,J＝6.8Hz, 2H),2.46(dt,J＝24.1,12.1Hz,2H),1.82–1.34(m,18H),1.25(d,J＝6.1Hz,4H)；HR-ESI-MS:m/z 877.36014 calcd.for(C49H56ClFN2NaO8 +)[M+Na]+,found 877.35494。
实施例40(3R,5S,E)-9-((2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropanoyl)oxy) nonyl 7-(3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl)-3,5-dihydroxyhept-6-enoate(化合物20b) 的合成
Figure GDA0002212262510000221
实验操作同实施例21，由氟伐他汀钠与化合物20a反应制得，淡黄色油状产物。19FNMR(375MHz,CDCl3)δ-116.91(s)；1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.5Hz,2H), 7.52(d,J＝8.4Hz,2H),7.43–7.35(m,2H),7.31(d,J＝8.4Hz,2H),7.16(t,J＝7.7Hz,1H), 7.06(dd,J＝14.1,8.6Hz,5H),6.77(d,J＝8.4Hz,2H),6.68(d,J＝15.9Hz,1H),6.62(t,J＝5.5Hz,1H),5.71(dd,J＝16.0,5.5Hz,1H),4.83(dt,J＝13.9,6.9Hz,1H),4.50–4.41(m,1H), 4.20(s,1H),4.14(t,J＝6.6Hz,2H),4.08(t,J＝6.6Hz,2H),3.57(dd,J＝12.9,6.7Hz,2H), 2.80(t,J＝6.9Hz,2H),2.51–2.39(m,2H),1.83–1.45(m,18H),1.24(s,10H)；HR-ESI-MS calcd.:m/z 919.40709 for(C52H62ClFN2NaO8 +)[M+Na]+,found919.39901。
实施例41化合物活性测
材料和仪器。HMG-CoA Reductase Assay Kit(美国Sigma Aldrich公司此试剂盒中包括:HMGR，HMG-CoA，NADP-H，缓冲液，阳性对照溶液)，辅助材料为96孔板、超纯水、精密移液器(1-100μl，10-1000μl，2-20μl和0.5-2μl各一把)及其配套一次性枪头，酶标仪(配计算机系统)
药剂配制和准备。将10mL的5倍浓度缓冲液稀释成1倍缓冲液(即10mL的5倍液加40mL的超纯水)，在用96孔板的情况下，1mL的1倍液可进行5个样的测试，保存于冰中待用，剩余的5倍缓冲液于-20℃保存。25mg的NADPH需要补充1.5mL的1倍缓冲液，混合均匀-20℃保存。
测试样品准备。按要求称取大约1-5mg的样品，移液枪精确加入计算量的0.1％的NaOH溶解到蒸馏水/四氢呋喃混合溶剂(体积比1:1)所得溶液，低温超声约5mins后溶解完全，所得溶液即为0.01mol/L的测试样品原始溶液。
依次稀释得到10-4，10-5，10-6，10-7，10-8，10-9六个浓度冷藏备用。
方法和流程
解冻：解冻酶需要在冰上随周围环境冷却，尽量不要将酶放在冰上超过60min，因为放置时间过长会导致酶的活性降低。其他解冻可在室温下进行，一旦解冻应保存在冰上。
仪器调校:实验开始前将温度调至37℃，吸收波长为340nm，准备好动态程序。96孔板样品每20秒读一次数，总计10-20min。
根据以下kit提供的表格及流程加入合适体积的反应液
Figure GDA0002212262510000231
测试步骤:
a.在每个孔内加入定量的1倍缓冲液；
b.加待测样品的于除空白和阳性对照以外的孔内
c.加补充过缓冲液的NADPH于每个孔内
d.加底物HMG-CoA于每个孔内
e.加酶HMGR于除空白以外的孔内
f.将反应液混合均匀，尤其用96孔板测样时至少要在测第一次吸光地之前强力搅拌 10秒
g.开启动态程序，观察吸光度的变化
从计算机程序中点选有信息的数据点，所得数据即为测试原始数据。
数据处理原理。
根据kit介绍的方法进行活性测试，得到吸光度下降曲线，下降的斜率表明了不同样品对HMGR酶的抑制效果，对所得的斜率曲线进行数学处理和拟合，根据kit的技术支持，由以下公式计算活性数据：
其中:参数12.44表示12.44mM/cm，由于NADPH在340nm下的减弱系数为 6.22mM/cm，在反应机理中未两倍的NADPH，故为12.44
TV为反应液的总体积，96孔板为0.2mL
V表示还原酶的体积，即在每次测试中所用的酶的体积
0.6表示使用mg-Protein单位(mgP)/mL下的浓度，一般为0.50-0.70，这里试剂盒提供的浓度为0.6
LP表示光路宽度，96孔板为0.55cm
Unit定义为在37℃下每min1μmol的NADPH转化为NADP+，具体单位为μmol/min/mg蛋白质
表示340nm处紫外吸光度随时间的变化率。这段时间就是上面强调的匀速反应阶段这段时间，因此在实际选取数据点(吸光度，时间)时，要通过做曲线图的方法来找出这段时间。
定义抑制率为
Figure GDA0002212262510000241
其中[活性数据Activity]表示依据公式对应测试计算出的Activity活性数值，[活性数据Sample] 表示加入抑制剂样品后的活性数值。附表后的他汀对照为同一批测试值，作为测试的阳性对照。
部分所合成化合物对HMG-CoA还原酶(HMGR)的酶活性的抑制作用，实验结果如下表1所示。
表1他汀衍生物HMGR酶抑制活性数据(IC50，nM)
Figure GDA0002212262510000242
注11*为对照品氟伐他汀钠
从对HMG-CoA还原酶的半抑制浓度(IC50)比较，化合物2b，3b，6b，9b，12b， 13b，14b，15b，16b，17b的活性显著优于阳性对照药氟伐他汀钠，而通过2b-17b的活性，可以发现烟酸类药物、贝特类药物与氟化他汀拼接的产物相对于氟伐他汀钠的 HMG-CoA的抑制活性有部分的增强，可见在人体能接受的情况下，2b、3b、6b、9b、 12b、13b、14b、15b、16b、17b可以作为潜在的药物，用于治疗高胆固醇并伴有高甘油三酯疾病。

Claims (6)

1.一种孪药型HMG-CoA还原酶抑制剂，其特征在于，其是烟酸类化合
物通过链接子和他汀类药物链状连接形成的孪药；其中：链接子为
Figure FDA0002212262500000011
Figure FDA0002212262500000012
n为1～8的整数；烟酸类化合物为烟酸；他汀类药物为氟伐他汀。
2.一种根据权利要求1所述的孪药型HMG-CoA还原酶抑制剂的合成方法，其特征在于，具体步骤如下：
(1)将烟酸类化合物和链接子反应得到中间体；
(2)将他汀类药物转化为相应盐类衍生物，让中间体和他汀类药物的盐类衍生物在催化剂作用下反应，得到孪药型HMG-CoA还原酶抑制；
其中：步骤(1)中，所述链接子为
Figure FDA0002212262500000013
n为1～8的整数；所述烟酸类化合物为烟酸；步骤(2)中，催化剂为四丁基碘化铵，四丁基溴化铵或四丁基氟化铵；他汀类药物为氟伐他汀，其呈钠盐或钙盐。
3.根据权利要求2的合成方法，其特征在于，步骤(1)中，链接子为
Figure FDA0002212262500000014
时，采用缩合体系进行缩合反应得到酰胺或酯的中间体；烟酸类化合物和链接子的摩尔比为1：1:1.1-1:1.3。
4.根据权利要求2所述的合成方法，其特征在于，步骤(1)中，链接子为
Figure FDA0002212262500000015
时，采用单边烷基化反应制备中间体。
5.根据权利要求2所述的合成方法，其特征在于，步骤(2)中，他汀类药物和中间体的摩尔比为1：1.1～1:1.3；反应温度为室温。
6.根据权利要求2所述的合成方法，其特征在于，步骤(2)中，催化剂用量是他汀类药物质量的3％～12％。
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