【作者】 Morris F. Hiji；

【导师】 袁其朋； Zheng Guojun；

【作者基本信息】 北京化工大学 ， 制药工程， 2007， 硕士

【摘要】 阿立哌唑是一种新型高选择性非典型抗精神病药物，为突触后膜多巴胺受体拮抗剂和脑内DA能前膜自身受体激动剂。本论文以廉价的肉桂酸和2，3-二氯苯胺为原料对一种合成阿立哌唑的新方法进行了研究。论文重点研究了一种苯基哌嗪合成的新方法。2，3-二氯苯胺的硫酸盐与浓硫酸和NaNO₂反应生成芳基重氮盐，经碘化钾取代得芳基碘化物，收率81％；该化合物在CuI的催化，脯氨酸做配体，二甲基亚砜为溶剂，K₂CO₃为缚酸剂的条件下，与哌嗪反应生成2，3-二氯苯基哌嗪，收率20％。该方法简单，原料易得，条件温和，产物容易分离。肉桂酸首先转化成肉桂酰氯，经胺解，Friedel-Crafts环合及氢化得到中间体7-羟基-3，4-二氢-2-（1H）-喹诺酮，收率37.36％。7-羟基-3，4-二氢-2-（1H）-喹诺酮（喹啉酮化合物）转化成7-（4-氯丁氧基）-3，4-二氢-2-（1H）-喹诺酮，收率79％，然后再与苯基哌嗪化合物偶合生成最终产物，收率72.5％。本文经7步反应合成了阿立哌唑，以肉桂酸计总收率为21.40％，产物经¹HNMR确认。更多还原

【Abstract】 Aripiprazole is the latest atypical antipsychotic drug that possesses both,post-synaptic dopamine receptor antagonist and dopamine auto-receptoragonist. By having dual activity, it can treat schizophrenia with fewestside-effects.The new pathway for the synthesis of aripiprazole from cheap raw materials,cinnamic acid and 2,3-dichloroaniline is presented.Cinnamic acid was first converted to acid chloride, followed by aminolysis,Friedel-Crafts cyclization and hydrogenation to form the first key intermediate,carbostyril compound with overall yield of 37.36%.The hydrogen sulphate salt of 2,3-dichloroaniline was converted to thecorresponding Aryl Iodide in good yield of 81% by reacting with conc. H₂SO₄and NaNO₂ to form intermediate diazonium salt, which was further displacedby KI. 2,3-dichlorophenylpiperazine（phenylpiperazine compound）, the 2nd keyintermediate, was obtained by reacting Aryl Iodide and piperazine in thepresence of CuI as catalyst, proline as ligand, K₂CO₃ as base and dimethylsulfoxide as solvent with yield of 20%. The method is simple, utilizes cheapcatalyst and ligand, insensitive to moisture, and it is easy to separate theproduct. 7-hydroxy-3,4-dihydro-2-（1H）-quinolinone （carbostyril compound） wasconverted into 7-（4-chlorobutoxy）-3,4-dihydro-2-（1H）-quinolinone with theyield of 79% and then coupled with phenylpiperazine compound to form finalproduct with yield of 72.5%. The overall yield from cinnamic acid was21.40% and the analytical test and physical properties were correct. Most ofmaterial, reagents and condition applied are simple, easy and cheap; severalsteps can undergo large-scale production.更多还原