CN109485647A - 一种抗焦虑药物帕戈隆或帕秦克隆的制备方法 - Google Patents
一种抗焦虑药物帕戈隆或帕秦克隆的制备方法 Download PDFInfo
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Abstract
本发明公开了一种利用Rh(III)催化合成抗焦虑药物帕戈隆或者帕秦克隆及其类似物的方法，包括如下步骤：在铑催化剂和醋酸盐存在的条件下，苯甲醛与2‑氨基吡啶类化合物类化合物在溶剂中发生反应，原位产生一个有效的导向基团。该导向基团再在铑催化下与取代烯烃反应，反应完成后，经过后处理得到所述的氮杂环骨架的化合物。该制备方法使用铑进行催化两个独立的反应(酰胺形成和碳氢活化)，成功实现了自组装高效导向基的合成策略。反应从更简单的原料出发，在简洁温和的催化体系中，利用“一锅法”合成了新型取代特征的异吲哚酮骨架，操作简便，反应条件温和，收率高，原子经济性高。
Description
技术领域
本发明属于药物合成领域，具体涉及一种抗焦虑药物帕戈隆或帕秦克隆的制备方法。
背景技术
异吲哚酮(γ-内酰胺)是一个较多见而又重要的母核，在很多具有生物活性的分子中都有所体现，如下图所示。
因α位是具有较强络合力的N原子，故利用苯甲酰胺中的氮原子作为导向原子，并且参与形成γ-内酰胺的研究已多有报道。李兴伟课题组最早在2010年尝试使用N-苯基取代的芳甲酰胺作为底物，与丙烯酸酯反应构建起异吲哚酮骨架(Org.Lett.,2010,12,5430)。反应中首先生成了Heck产品中间体，进而发生迈克尔加成而环化。但底物中芳环若是呋喃、吲哚等杂环时不利于形成异吲哚酮产品，多是停留在了氧化Heck反应产品上,且反应条件较为苛刻。反应式如下：
2014年，于金权课题组对以上反应进行了改良。他们使用了N-全氟取代苯基芳甲酰胺作为底物(Chem.Sci.,2015,6,1923)，实际上就是增大酰胺中氮原子上取代基的拉电子能力，减弱酰胺键的异构化而增加其亲核性。这一工作虽然扩宽了底物类别，对于杂环如噻吩、呋喃、吡啶都有很好的适用性，且反应条件变得较为温和，但其底物的普适性仍不够广泛，且原料较为复杂，制备过程不够简单。
发明内容
本发明提供了一种抗焦虑药物帕戈隆或帕秦克隆的制备方法，该制备方法通过该“一锅法”合成策略可以一步从苯甲醛作为原料制备药物帕戈隆和帕秦克隆。
一种抗焦虑药物帕戈隆或帕秦克隆的制备方法，包括如下步骤：
包括如下步骤：在铑催化剂和醋酸盐存在的条件下，苯甲醛与2-氨基吡啶类化合物在溶剂中发生反应，原位生成含导向基团的中间体；该中间体再在铑催化下与取代烯烃反应，反应完成后，经过后处理得到所述的抗焦虑药物，所述的抗焦虑药物为抗焦虑药物帕戈隆和帕秦克隆；
作为优选，所述的铑催化剂为[Cp*RhCl2]2(CAS：12354-85-7)，用量为2.5mol％，该种铑催化剂对本发明中的底物的催化效率高。
作为优选，所述的醋酸盐为醋酸铜，用量为2eq。该醋酸盐起到氧化剂的作用，有助于铑催化剂在反应中的催化。
作为优选，以摩尔量计，苯甲醛、2-氨基吡啶类化合物和取代烯烃用量比为1:1.2～2:1.2～2。
作为优选，所述的溶剂为乙腈、水、甲醇、乙醇、DMF、DMSO和THF中的至少一种，这些溶剂都为极性溶剂，有利于底物中C-H键的断裂，作为进一步的优选，所述的溶剂为乙腈。
作为优选，反应的温度为80～110℃，反应温度过高，会使得副反应增多，反应温度过低，会降低反应物的转化率，作为进一步的优选，反应的温度为80℃。
作为优选，反应的氛围为空气、氮气中的一种，在这些氛围中，均能使反应更好进行，具有较高产率，作为进一步的优选，反应的氛围为N2氛围。
本发明中，反应的时间可以通过TLC进行监测，在80℃下搅拌4～12小时反应能够发生完全。
为了提高反应的收率，可以先将苯甲醛类化合物、2-氨基吡啶类化合物、Cu(OAc)2和[Cp*RhCl2]2加入Schlenk瓶中，然后对其进行抽真空处理再通入氮气，操作三次后，再加入溶剂和取代烯烃。
同现有技术相比，本发明的有益效果体现在：该反应采用“一锅法”制备，操作简单。反应中可自生成高效导向基团。
所述的反应式如下：
推测该反应机理为：
首先，芳香醛与2-氨基吡啶发生缩合反应生成中间体A，在原位产生一个有效的新型导向基团。接着，自组装导向基与取代烯烃在金属铑(III)催化下发生C-H活化、烯烃***以及环内加成等反应，得到异吲哚酮衍生物。
附图说明
图1为实施例1制得的产物的1HNMR谱图；
图2为实施例1制得的产物的13CNMR谱图；
图3为实施例2制得的产物的1HNMR谱图；
图4为实施例2制得的产物的13CNMR谱图。
具体实施方式
实施例1
在25mL的Schlenk瓶中，称入22mg(0.2mmol)对甲基苯甲醛(1.0eq)，Cu(OAc)265mg(2.0eq)，2-氨基1,8-二氮杂萘54mg(1.5eq)，[Cp*RhCl2]2 6mg(5％)。然后对其进行抽真空处理再通入氮气，操作三次后，加入2mL乙腈和不饱和羰基化合物50mg(2.0eq)，在80℃下氮气氛围中恒温搅拌。约10h后TLC检测反应完毕，加入些许硅胶，蒸出溶剂，固化，固体上样，进行柱色谱分离。可以制备得到帕戈隆(cas：133737-32-3)总收率约15％。
产物核磁共振数据：1H NMR(CDCl3,600MHz),δ:8.98(d,J＝9.0Hz,1H),8.23(d,J＝8.4Hz,1H),8.11(d,J＝8.4Hz,1H),7.95(d,J＝7.2Hz,1H),7.67–7.60(m,2H),7.55–7.50(m,1H),7.43(d,J＝8.4Hz,1H),6.18(dd,J1＝7.8Hz,J2＝3.0Hz,1H),3.64(dd,J1＝16.8Hz,J2＝3.6Hz,1H),3.09(dd,J1＝17.2Hz,J2＝7.8Hz,1H),2.40–2.31(m,2H),1.46–1.37(m,3H),0.80(d,J＝6.0Hz,6H).
13C NMR(CDCl3,150MHz),δ:208.4,168.6,154.5,154.2,154.0,146.0,139.1,138.7,133.8,131.4,128.8,124.7,123.5,122.3,119.1,116.5,57.0,45.4,41.9,32.4,27.7,22.4。
实施例2
依据实施例1一样的步骤，更换为如下反应物，可以制备得到帕秦克隆，收率为20％。而如果首先制备反应中生成的中间体下酰胺(通过酰氯和胺缩合)，既是通过如下第二个反应式可以以更高的效率得到帕秦克隆，产率可以达到68％。具体来讲，在25mL的Schlenk瓶中，称入56.6mg(0.2mmol)酰胺(1.0eq)，Cu(OAc)2 65mg(2.0eq)，[Cp*RhCl2]26mg(5％)。然后对其进行抽真空处理再通入氮气，操作三次后，加入2mL乙腈和不饱和酰胺化合物78mg(2.0eq)，在80℃下氮气氛围中恒温搅拌。约10h后TLC检测反应完毕，加入些许硅胶，蒸出溶剂，固化，固体上样，进行柱色谱分离(乙酸乙酯与石油醚体积比例为1:1，TLC检测发现产品极性比不饱和酰胺稍微大一些)。
产物核磁共振数据：1H NMR(CDCl3,600MHz),δ:8.94(d,J＝9.0Hz,1H),8.20(d,J＝9.0Hz,1H),8.08(d,J＝8.4Hz,1H),7.91(d,J＝7.8Hz,1H),7.67(d,J＝7.8Hz,1H),7.62(t,J＝7.2Hz,1H),7.50(t,J＝7.2Hz,1H),7.38(d,J＝7.8Hz,1H),6.09(dd,J1＝9.0Hz,J2＝3.0Hz,1H),3.97–3.92(m,4H),3.85–3.77(m,2H),3.70(dd,J1＝15.0Hz,J2＝3.0Hz,1H),3.65–3.56(m,2H),2.74(dd,J1＝14.4Hz,J2＝9.0Hz,1H),1.71–1.52(m,4H).
13C NMR(CDCl3,150MHz),δ:168.6,167.8,154.3,154.1,153.9,145.7,139.0,138.7,133.6,131.1,128.8,124.5,123.9,122.1,119.0,116.3,106.9,64.5,57.8,44.0,40.0,36.9,35.6,34.9。
Claims (6)
1.一种抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，包括如下步骤：在铑催化剂和醋酸盐存在的条件下，苯甲醛与2-氨基吡啶类化合物在溶剂中发生反应，原位生成含导向基团的中间体；该中间体再在铑催化下与取代烯烃反应，反应完成后，经过后处理得到所述的抗焦虑药物，所述的抗焦虑药物为帕戈隆或帕秦克隆；
所述的2-氨基吡啶类化合物的结构如式(I)或(II)所示：
所述的取代烯烃的结构如式(II)或(III)所示：
2.根据权利要求1所述的抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，所述的铑催化剂为[Cp*RhCl2]2，用量为苯甲醛的2-6mol％。
3.根据权利要求1和2所述的抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，所述的醋酸盐为醋酸铜，用量为苯甲醛摩尔量的1.2～2.0倍。
4.根据权利要求1所述的抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，所述的溶剂为乙腈、水、甲醇、乙醇、DMF、DMSO和THF中的至少一种。
5.根据权利要求1所述的抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，反应的温度为60～110℃。
6.根据权利要求1所述的抗焦虑药物帕戈隆或帕秦克隆的制备方法，其特征在于，反应的氛围为空气、氮气中的一种。
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