CN108997232A - 一种组蛋白去乙酰化酶抑制剂的合成方法 - Google Patents
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Abstract
本发明公开了一种组蛋白去乙酰化酶抑制剂的合成方法,该化合物的结构式为
Description
技术领域
本发明涉及一种组蛋白去乙酰化酶抑制剂NSC746457(histone deacetylases,HDACi)的合成方法。
背景技术
随着药物发现、细胞信号分子探针的发展,如何快速并高效地合成杂环化合物已经成为当前该领域中的热点问题。组蛋白去乙酰化酶(histone deacetylase)是一类蛋白酶,它对染色体的结构修饰和基因的相关表达发挥着重要的作用。当前在肿瘤学的相关研究已经表明,组蛋白的乙酰化修饰对肿瘤的发生发展起重要作用。正常细胞体若出现核内组蛋白乙酰化与去乙酰化失去失衡,即会导致正常的细胞周期与细胞代谢行为的改变进而诱发形成肿瘤。组蛋白去乙酰化酶抑制剂通过增加细胞内组蛋白的乙酰化程度,提高p21等基因的表达水平等途径,抑制肿瘤细胞的增殖,诱导细胞分化和(或)凋亡。组蛋白去乙酰化酶抑制剂是一种新型有效的抗肿瘤治疗药物,具有极大的临床及社会应用价值,已成为肿瘤靶向治疗的研究新热点,其对肿瘤细胞迁移、侵袭、转移的抑制作用和抗肿瘤血管生成作用也被证实。
组蛋白去乙酰化酶抑制剂NSC746457的结构式如下所示:
其合成方法的关键是对1,2,3-三氮唑的合成。在之前的相关报道中1,2,3-三氮唑的合成主要是通过1,3-偶极子叠氮-炔环加成反应(AAC),但反应前体的多步合成限制了它的进一步应用。对于该抑制剂,已报道的合成方法需要以丙炔酸作为原料,通过对其氢碘化构筑反式碘代双键;Sonogashira偶联构筑共轭的炔;click反应构筑三唑。显而易见,多步合成非常繁琐。没有以廉价易得的化合物为起始原料,通过简单并直接的办法去合成该抑制剂。
发明内容
本发明所要解决的技术问题在于克服现有合成组蛋白去乙酰化酶抑制剂NSC746457的起始原料复杂、合成路线长、反应产率低、反应条件苛刻等缺点,提供一种简单高效的合成组蛋白去乙酰化酶抑制剂NSC746457的方法。
解决上述技术问题所采用的技术方案由下述步骤组成:
1、合成(Z)-构型的烯酯三唑
以二氯甲烷为溶剂,将5-溴代-2-糠醇、肉桂基叠氮、甲醇在路易斯酸和叔胺的作用下,-20℃~室温反应,反应结束后经减压浓缩、分离纯化,得到式I所示的(Z)-构型的烯酯三唑化合物。
2、合成(E)-构型的烯酯三唑化合物
将式I所示的(Z)-构型的烯酯三唑化合物溶于氯仿,在紫外光照下使(Z)-构型的烯酯三唑化合物发生光异构化反应,得到式II所示的(E)-构型的烯酯三唑化合物。
3、将式II所示的(E)-构型的烯酯三唑化合物溶于甲醇与四氢呋喃体积比为1:1的混合溶剂中,加入盐酸羟胺和氢氧化钠水溶液,将反应物倒入冰水混合物中,再加入酸析出白色固体,过滤、洗涤,得到组蛋白去乙酰化酶抑制剂。
上述步骤1中,所述的路易斯酸为SnCl4,所述的叔胺为吡啶、三乙胺或N,N-二异丙基乙胺。
上述步骤1中,优选5-溴代-2-糠醇、肉桂基叠氮、甲醇的摩尔比为1:1.1~1.5:1.3~2.0,SnCl4的加入量为5-溴代-2-糠醇摩尔量的1~1.3倍,叔胺的加入量为5-溴代-2-糠醇摩尔量的1.3~2.0倍。
上述步骤2中,所述的紫外光照波段为385~395nm,光照时间为3~5h。
上述步骤3中,优选(E)-构型的烯酯三唑化合物与盐酸羟胺、氢氧化钠的摩尔比为1:7~10:5~7,所述酸为浓盐酸。
本发明的有益效果如下:
本发明以肉桂基叠氮、5-溴-2-糠醇和甲醇为反应原料,在路易斯酸的作用下,通过一锅三组分反应合成高度官能团化的(Z)-构型的烯酯三唑。在这个新骨架生成反应中,涉及到一个[3+2]环加成/呋喃开环/酯化串联反应。在紫外光照条件下(Z)-构型的烯酯三唑发生光反应异构化生成(E)-构型的烯酯三唑,接下来用盐酸羟胺对(E)-构型的烯酯三唑进行取代胺化,即可得到组蛋白去乙酰化酶抑制剂NSC746457。本发明方法具有合成路线短、原料易得、合成过程用时短、目标化合物产率高、成本低廉等优点。
具体实施方式
下面结合实施例对本发明进一步详细说明,但本发明的保护范围不仅限于这些实施例。
实施例1
1、合成(Z)-构型的烯酯三唑
向25mL的圆底烧瓶里加入176mg(1.0mmol)5-溴-2-呋喃甲醇、191mg(1.2mmol)肉桂基叠氮、48mg(1.5mmol)甲醇、152mg(1.5mmol)三乙胺、5mL干燥的二氯甲烷,搅拌1min使混合均匀,然后将反应液置于冰水浴中,加入1.1mL1mol/L SnCl4的二氯甲烷溶液,再将反应液转移至室温下反应,并用薄层色谱法进行监测。待反应完全后,将反应物用饱和碳酸氢钠水溶液淬灭,然后用20mL二氯甲烷稀释,分离出有机相,将水相转移到分液漏斗中用二氯甲烷萃取(10mL×2次),合并有机层。有机相用10mL饱和食盐水清洗两次,分离有机相,用无水硫酸钠干燥2h。过滤、浓缩后得到(Z)-构型的烯酯三唑化合物粗品,该粗品用硅胶柱色谱法纯化(石油醚:乙酸乙酯=10:1作为洗脱剂),得到式I所示的纯净的(Z)-构型的烯酯三唑化合物145mg,其收率为54%,结构表征数据为:1H NMR(600MHz,CDCl3)δ7.73(s,1H),7.66(d,J=16.0Hz,1H),7.39(d,J=7.2Hz,2H),7.35(t,J=7.4Hz,2H),7.31(d,J=7.1Hz,1H),6.68(t,J=15.6Hz,2H),6.37-6.30(m,1H),5.16(dd,J=6.7,1.1Hz,2H),3.79(s,3H);13CNMR(151MHz,CDCl3)δ167.12,143.78,135.95,135.25,132.56,128.79,128.73,126.74,122.95,121.27,119.62,52.47,51.77;HRMS(ESI)C15H15N3NaO2[M+Na]+:理论值292.1062,实测值292.1066。
2、合成(E)-构型的烯酯三唑化合物
将纯净的(Z)-构型的烯酯三唑化合物置于20mL反应管中,加入4mL氯仿作为反应溶剂,在50W紫色LED(λem=385~395nm)灯光下持续照射4h,并采用薄层色谱法进行监测,待反应完全后,用旋转蒸发仪蒸除溶剂氯仿,浓缩得到(E)-构型的烯酯三唑化合物粗品,该粗品用硅胶柱色谱法纯化(石油醚:乙酸乙酯=100:1作为洗脱剂),得到式II所示的纯净的(E)-构型的烯酯三唑化合物85.2mg,其产率为59%,结构表征数据为:1H NMR(600MHz,CDCl3)δ7.73(s,1H),7.66(d,J=16.0Hz,1H),7.39(d,J=7.2Hz,2H),7.35(t,J=7.4Hz,2H),7.31(d,J=7.1Hz,1H),6.68(t,J=15.6Hz,2H),6.37-6.30(m,1H),5.16(dd,J=6.7,1.1Hz,2H),3.79(s,3H);13C NMR(151MHz,CDCl3)δ167.12,143.78,135.95,135.25,132.56,128.79,128.73,126.74,122.95,121.27,119.62,52.47,51.77;HRMS(ESI)C15H15N3NaO2[M+Na]+:理论值292.1062,实测值292.1066。
3、合成组蛋白去乙酰化酶抑制剂
向25mL的圆底烧瓶里加入80.7mg(0.3mmol)(E)-构型的烯酯三唑化合物、5mL甲醇与四氢呋喃体积比为1:1的混合液、0.3mL质量分数为50%的盐酸羟胺水溶液和0.3mL5mol/L氢氧化钠水溶液,在冰盐浴中反应2min后,将反应液倒入3mL冰水,再加入0.6mL浓盐酸,将会有白色固体析出,过滤出白色固体,并用甲醇进行洗涤,即得到式III所示的纯净的组蛋白去乙酰化酶抑制剂NSC74645768mg,其产率为84.4%,结构表征数据为:1H NMR(600MHz,DMSO)δ10.25(s,1H),8.59(s,1H),7.63(d,J=16.0Hz,1H),7.48(d,J=7.4Hz,2H),7.35(t,J=7.3Hz,2H),7.28(t,J=7.1Hz,1H),6.70(d,J=15.8Hz,1H),6.63(d,J=16.0Hz,1H),6.56-6.48(m,1H),5.22(d,J=6.3Hz,2H);13C NMR(151MHz,DMSO)δ166.44,142.65,135.73,134.15,133.50,128.73,128.25,126.67,125.55,123.25,118.15,51.59;HRMS(ESI)C14H14N4NaO2[M+Na]+:理论值293.1014,实测值293.1011。
Claims (9)
1.一种组蛋白去乙酰化酶抑制剂的合成方法,该化合物的结构式如下所示:
其特征在于:
(1)合成(Z)-构型的烯酯三唑
以二氯甲烷为溶剂,将5-溴代-2-糠醇、肉桂基叠氮、甲醇在路易斯酸和叔胺的作用下,-20℃~室温反应,反应结束后经减压浓缩、分离纯化,得到式I所示的(Z)-构型的烯酯三唑化合物;
(2)合成(E)-构型的烯酯三唑化合物
将式I所示的(Z)-构型的烯酯三唑化合物溶于氯仿,在紫外光照下使(Z)-构型的烯酯三唑化合物发生光异构化反应,得到式II所示的(E)-构型的烯酯三唑化合物;
(3)将式II所示的(E)-构型的烯酯三唑化合物溶于甲醇与四氢呋喃体积比为1:1的混合溶剂中,加入盐酸羟胺和氢氧化钠水溶液,将反应物倒入冰水混合物中,再加入酸析出白色固体,过滤、洗涤,得到组蛋白去乙酰化酶抑制剂。
2.根据权利要求1所述的组蛋白去乙酰化酶抑制剂的合成方法,其特征在于:步骤(1)中,所述的路易斯酸为SnCl4。
3.根据权利要求1所述的组蛋白去乙酰化酶抑制剂的合成方法,其特征在于:步骤(1)中,所述的叔胺为吡啶、三乙胺或N,N-二异丙基乙胺。
4.根据权利要求1~3任意一项所述的组蛋白去乙酰化酶抑制剂的合成方法,其特征在于:步骤(1)中,所述的5-溴代-2-糠醇、肉桂基叠氮、甲醇的摩尔比为1:1.1~1.5:1.3~2.0。
5.根据权利要求1~3任意一项所述的组蛋白去乙酰化酶抑制剂的合成方法,其特征在于:步骤(1)中,所述的SnCl4的加入量为5-溴代-2-糠醇摩尔量的1~1.3倍。
6.根据权利要求1~3任意一项所述的组蛋白去乙酰化酶抑制剂的合成方法,其特征在于:步骤(1)中,所述的叔胺的加入量为5-溴代-2-糠醇摩尔量的1.3~2.0倍。
7.根据权利要求1所述的组蛋白去乙酰化酶抑制剂的合成方法,其特征在于:步骤(2)中,所述的紫外光照波段为385~395nm,光照时间为3~5h。
8.根据权利要求1所述的组蛋白去乙酰化酶抑制剂的合成方法,其特征在于:步骤(3)中,所述(E)-构型的烯酯三唑化合物与盐酸羟胺、氢氧化钠的摩尔比为1:7~10:5~7。
9.根据权利要求1所述的组蛋白去乙酰化酶抑制剂的合成方法,其特征在于:步骤(3)中,所述酸为浓盐酸。
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HENGTUO YANG,等: "Bifunctional Furfuryl Cations Strategy: Three-Component Synthesis of Enamidyl Triazoles", 《CHEM. EUR. J.》 * |
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