【作者】 贺琼；

【导师】 陆明； 方永勤；

【作者基本信息】 南京理工大学 ， 应用化学， 2010， 硕士

【摘要】 2-氨基-6-溴吡啶是一种重要的医药合成中间体,用于合成新型治疗炎症、糖尿病、高血压、神经性损伤、HIV病毒感染和增生类疾病的药物。2-氨基-6-溴吡啶的合成方法一般有环化法、氨化法和水解法。环化法是以环氧氯丙烷为原料,经与KCN作用开环、再在HBr中环化制得,该方法收率高,污染严重；氨化法是以2,6-二溴-3-二甲氨基吡啶为原料,在液氨中与氨基钾反应制得,该方法副反应多、收率很低；水解法是以2-甲基吡啶N-氧化物为起始原料,经硝化、氧化、Curtius重排、水解、碱化后制得,该方法流程多,收率低。在分析了2-氨基-6-甲基吡啶合成方法的基础上,本人设计了新的合成制备途径。以2-氨基-6-甲基吡啶为原料,经溴代、KMnO4氧化、酰化、霍夫曼水解后制得目标产物2-氨基-6-溴吡啶,用红外光谱法和核磁共振谱对中间体和产物进行了结构表征。实验得到了中间体和目标产物的较佳合成工艺条件：2-溴-6-甲基吡啶在n(Br2):n(2-氨基-6-甲基吡啶)=3：1,-15～-10℃条件下,收率为87.1%；2-羧基-6-溴吡啶在n(KMnO4):n(2-溴-6-甲基吡啶)=3：1,水为溶剂,80℃条件下,收率为44.1%；6-溴-2-吡啶甲酰氯在n(2-羧基-6-溴吡啶)：n(SOCl2)=1:5, DMF为催化剂,回流条件下,收率为92.4%；6-溴吡啶-2-甲酰胺在n(6-溴吡啶-2-甲酰氯)：n(氨水)=1：6；将6-溴吡啶-2-甲酰氯加入氨水中,-10℃条件下,收率为83.6%；2-氨基-6-溴吡啶在n(6-溴吡啶-2-甲酰胺)：n(Br2)=1:1.2, NaOH溶液浓度10%,70℃条件下,收率为81.0%；目标产物2-氨基-6-溴吡啶的总收率为24.0%。实验结果表明,此合成路线方法可行,操作简单,三废排放少,为放大试验和工业化生产提供了依据。更多还原

【Abstract】 2-amino-6-bromopyridine is a kind of important pharmaceutical intermediates which can be used to synthesize medicines against inflammation, diabetes, high blood pressure, nerve injury, HIV infection and proliferative.2-amino-6-bromopyridine was prepared by cyclization, amination and hydrolysis protocol in common. Cyclization method was started with epichlorohydrin as raw material, ring was opened with potassium cyanide, and then it was cyclized in the hydrobromic acid again. The yield was high with more pollution waste. In amination method, 2,6-dibromo-3-dimethylaminopyridine was selected as raw material, reaction was proceeded with amino-potassium in liquid ammonia with low-yield and much side effect. In hydrolysis method,2-amino-6-bromopyridine was synthesized from 2-methyl-pyridine N-oxide by nitration, oxidation, Curtius rearrangement, hydrolysis, alkalization, and the yield was low with complex process.On the basis that synthetic methods of 2-amino-6-bromopyridine were analyzed, a new synthetic method was designed.In the paper,2-amino-6-bromopyridine was synthesized from 2-amino-6-methylpyridine through brominating, oxidating, acylating, Hoffman hydrolysis reaction. Structures of the intermediates and target product were characterized by IR and 1H NMR.Optimum conditions of intermediates and target product were obtained as follows:with n (liquid bromine):n(2-amino-6-methylpyridine)=3:1 under-15～-10℃, the yield of 2-bromo-6-methylpyridine was 87.1%. With n(potassium permanganate): n(2-bromo-6-methylpyridine)=3:1 in water,6-bromopicolinic acid was prepared in 44.4% yield under 80℃. While DMF as the catalyst, n(6-bromopicolinic acid):n(thionyl chloride)=1:5,6-bromopyridine-2-carboxylicacid chloride came to the yield of 92.4%. When n(6-bromopyridine-2-carboxylicacid chloride):n(ammonia):=1:6 under-10℃, 6-bromopyridine-2-carboxylicacid chloride was mixed in ammonia, the yield of 6-bromopyridine-2-carboxamide was 83.6%. At 70℃n(6-bromopyridine-2-carboxamide):n(liquid bromine)=1:1.2, the yield of 2-amino-6-bromopyridine was 81.0% with w(NaOH)=10% sodium hydroxide solution. The overall yield of target product 2-amino-6-bromopyridine was 24.0%.The experimental result showed that our synthetic route was feasible with easy-operation and less pollution waste which could provide with basis for amplification and industrization.更多还原