【作者】 郑志刚；

【导师】 李艳妮； 黄汉忠；

【作者基本信息】 天津大学 ， 制药工程， 2009， 硕士

【摘要】 厄洛替尼(Erlotinib)是由OSI、Genetech和Roche共同开发的一种表皮生长因子受体抑制剂(Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor,EGFR-TKI)。现在临床上主要用于非小细胞肺癌(Non-small Cell Lung Cancer,NSCLC)和胰腺癌的治疗。本文根据文献资料确定了6步反应合成厄洛替尼的方法:由3,4-二羟基苯甲酸乙酯和2-氯乙基甲基醚烷基化得到3,4-二-(2-甲氧乙氧)苯甲酸乙酯(1);经过硝化、铁粉还原并成盐制得2-氨基-4,5-二-(2-甲氧乙氧)-苯甲酸乙酯盐酸盐(3);(3)与甲酰胺环合得到6,7-二-(2-甲氧乙氧)-4(3H)-喹唑啉酮(4);以POCl3为氯化剂,N,N-二甲基苯胺为催化剂进行氯代反应得到4-氯-6,7-二-(2-甲氧乙氧)-喹唑啉(5);最后,化合物(5)与3-乙炔苯胺在N2保护下反应得到厄洛替尼的盐酸盐。在合成厄洛替尼的同时,还参照文献及相关专利,以间硝基苯甲醛和丙二酸为起始原料,通过Knoevenagel缩合反应、溴加成、除溴-脱羧、消除、还原等一系列步骤得到了中间体3-乙炔苯胺。在合成方法上主要作了如下改进:采用较为廉价的2-氯乙基甲基醚,通过加强缚酸剂的碱性、提高反应温度合成(1),缩短了反应时间,减少了卤代烃的用量;硝化时适当提高反应温度,提高转化率;在(3)的合成中,采用95%乙醇-冰乙酸的反应体系,克服了铁泥过滤难的问题,不仅收率高,而且后处理容易;确定了合成(5)的卤代剂、最佳反应时间和后处理方法,使反应更加完全,后处理操作简便。通过本文方法合成的厄洛替尼(以3,4-二羟基苯甲酸乙酯为基准物料)的总收率为44.8%,并用IR,1HNMR、MS确证了其结构。结果证明此方法操作简便,条件温和,适合较大规模生产。更多还原

【Abstract】 Erlotinib is an epidermal growth factor receptor inhibitor (EGFR-TKI) which was developed by OSI,Genetech and Roche. It is used for the treatment of Non-Small Cell Lung Cancer (NSCLC) and Pancreatic Cancer in clinic.The thesis determined a six-step route to synthesize Erlotinib by the methods of literature. O-alkylation between ethyl 3,4-dihydroxybenzoate and 1-Chloro-2- methoxy-ethane gaved Ethyl 3 , 4-bis(2-methoxyethoxy)benzoate(1). Ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate hydrochloride(3) was obtained from (1) via nitration,reduction and salt formation. Cyclization between (3) and formamide gaved 6,7-Bis-(2-methoxyethoxy)-quinazolin-4(3H)-one(4). (4) is chloro-substituted by POCl3 and N,N-dimethylaniline as the catalyzer. At last,the hydrochloride salt of Erlotninb can be obtained from (5) and 3-ethynylphenylamine via N-alkylation. By the way,3-ethynylphenylamine was synthesized via Knoevenagel condensation,bromine addition,debromination-decarboxylation,elimination and reduction from m-nitrobenzaldehyde and malonate.The main improvements of the method are:reaction time is shortened and feed capacity of halohydrocarbon is reduced because of the reinforce of alkalinity of acid-binding and increase the temperature;the conversion rate of (2) is increased by the higher reaction temperature;raising the yield and reducing the cost of the synthesis of compound(3) due to changing the reaction system;Determine the best reaction time and the way of purification during the synthesis of compound (5).The overall yield of Erlotinib synthesized by the method is 44.8% on the basis of ethyl 3,4-dihydroxybenzoate. The structure of Erlotinib was confirmed by IR,1HNMR,MS. The result indicates that the method is simple,convenient.更多还原