【作者】 陈辉；

【导师】 滕大为；

【作者基本信息】 青岛科技大学 ， 化学工程（专业学位）， 2013， 硕士

【摘要】 喹啉酮类是半萜类喹啉生物碱中的一种,是一类存在于生物(主要是植物)体内、对人和动物有强烈生理作用的含氮的碱性物质。手性喹啉酮螺环化合物作为其衍生物中的一类,其不仅具有明显的生理和生物活性,而且广泛存在于各种生物碱和具有不同药理作用的活性分子结构中；其环上引入不同取代基或侧链,可产生不同的药理活性。因此,寻求一种通用的合成手性喹啉酮螺环化合物的方法显得尤为重要同时具有很好的理论意义。本论文共分为两部分,第一部分以消旋的2-硝基苯丙氨酸甲酯为原料,经还原关环,N-烷基化,氨基和羟基的保护,羟基的溴代,碱作用下碳的烷基化等反应合成螺[吡咯烷-2,3-喹啉酮]。再以拆分得到的手性纯的S-2-硝基苯丙氨酸甲酯为原料,经还原关环,N-烷基化,氨基和羟基的保护,羟基的溴代,碱作用下碳的烷基化等反应合成S-螺[吡咯烷-2,3-喹啉酮]。第二部分以消旋的2-硝基苯丙氨酸甲酯为原料,经还原关环,N-烷基化,羟基的溴代,碱作用下碳的烷基化等反应合成螺[吡咯烷-2,3-喹啉酮]。再以拆分得到的手性纯的S-2-硝基苯丙氨酸甲酯为原料,经还原关环,N-烷基化,羟基的溴代,碱作用下碳的烷基化等反应合成S-螺[吡咯烷-2,3-喹啉酮]。本论文分别以消旋和手性纯的2-硝基苯丙氨酸甲酯为原料合成了消旋和手性的螺[吡咯烷-2,3-喹啉酮],对N-烷基化反应进行了研究,确定了较佳反应条件：选择N’N-二甲基甲酰胺为溶剂,碳酸钾为碱试剂,收率在85%以上；对分子内酰胺键的未保护对碳的烷基化的影响进行了研究,形成螺碳原子时完全消旋；对分子内酰胺键的保护对碳的烷基化的影响进行了研究,确定了较佳的反应条件：以1.0M NaH为碱,使用对甲氧基苄氯为胺基保护基,以四氢呋喃为溶剂,反应温度为60℃；同时采用手性记忆策略对碱作用下的碳烷基化反应进行了研究,确定了较佳条件：以KHMDS作碱,形成的螺碳原子部分消旋,产物的e.e.值32%,收率为80%。本文得到了一条通用的合成手性喹啉酮螺环化合物的方法,为更深入的研究该类化合物的活性具有重要意义。更多还原

【Abstract】 Quinolone is a kind of alkaline substance which belongs to sesquiterpenoids quinoline alkaloid, it existed in the biological (mainly plant) vivo and has a strong physiological effect in humans and animals. As a kind of quionlone derivatives, chiral quinolone spirocompound not only has obvious physiological and biological activity but also widely exists in various alkaloids and active molecular structure which having different pharmacological effects; the ring on the introduction of different substituent group or side chains can produce different pharmacological activity. Therefore, it is important to seek a general method for the synthesis of chiral quinolone spirocompounds and has great theoretical significance.This paper is divided into two parts:the first part, spiro [pyrrolidine-2,3-quinolinone] were synthesized from racemic2-nitrobenzene alanine methyl ester through nitro reduction and ring-closure, N-alkylation, protection of hydroxide and amine, bromination, carbon alkylation reaction on the action of alkali. And then synthesis of S-spiro[pyrrolidine-2,3-quinolinone] through the reaction of nitro reduction and ring-closure, N-alkylation, protection of hydroxide and amine, bromination, carbon alkylation reaction on the action of alkali from pure S-2-nitrobenzene alanine methyl ester, which was obtained by split.The second part, spiro[pyrrolidine-2,3-quinolinone] were synthesized from racemic2-nitrobenzene alanine methyl ester through nitro reduction and ring-closure, N-alkylation, bromination, carbon alkylation reaction on the action of alkali. And then synthesis of S-spiro[pyrrolidine-2,3-quinolinone] through the reaction of nitro reduction and ring-closure, N-alkylation, bromination, carbon alkylation reaction on the action of alkali from pure S-2-nitrobenzene alanine methyl ester, which was obtained by split.Racemic and chiral spiro[pyrrolidine-2,3-quinolinone] were synthesized from racemic and chiral2-nitrobenzene alanine methyl ester respectively. The N-alkylation reaction was studied and the optimum reaction were determined:select N,N-dimethyl formamide as a solvent, potassium carbonate as alkali, yield reached above85%; studied the influence of intramolecular amide bond unprotection on the carbon alkylated, complete racemization occurred when forming spiro carbon atom; studied the influence of intramolecular amide bond protection on the carbon alkylated to determine the optimum reaction conditions:taking1.0M NaH as base, using PMB as amino protecting group, using THF as solvent, the reaction temperature is60℃; the carbon alkylation reaction under the action of alkali were studied through the use of chiral memory strategy and determine the optimum conditions:using K.HMDS as the base, the formation of spiro carbon atom partial racemization, the value of e.e. is32%, the yield is80%.A general synthetic method of chiral quinolone spirocompound was obtained, which is significance for further studies of their activity.更多还原