论文总字数：17772字

摘 要

恶性肿瘤是一种严重威胁生命健康安全的常见疾病，目前国内对于恶性肿瘤的临床治疗存在早期确诊率低，后期治疗不规范等不足。并且对于癌细胞已转移的晚期恶性肿瘤患者，局部手术治疗效果较差，全身化疗不良反应较为严重，此时分子靶向药物对于全身治疗有较大优势。

新开发的分子靶向广谱抗癌药物卡博替尼（Cabozantinib,CBTN），是一种多靶点抑制剂，药理作用为针对VEGF受体、MET、AXL和其他受体酪氨酸激酶，通过血管生成、抗凋亡、侵袭性、转移和耐药性参与肿瘤的发展和进展,从而达到抑制肿瘤细胞生长的作用。自上市以来，CBTN在欧美等国家已被广泛应用于多种晚期癌症的并取得了显著效果。

目前CBTN在国内还没有上市，国内针对此药物合成的研究较少，同时市场价格较为昂贵，其原研公司对化合物的专利期即将到期，鉴于国内庞大的医药市场，CBTN在中国仿制药市场有很大的预期价值。本课题研究CBTN一种关键中间体的合成，通过实验最终确认了一条合成路线。选择以丙二酸二乙酯为原料与1，2-二溴乙烷在苄基三乙基氯化铵等溶液条件下合成1,1-环丙基二羧酸，一定条件提纯后加入二氯亚砜在无水四氢呋喃等条件下生成酰氯，随后酰氯与4-氟苯胺在一定条件下生成所需关键中间体1-[(4- 氟苯基 ) 氨基甲酰基 ] 环丙烷羧酸。与之前的合成路线相比，起始原料成本更加低廉，卤化反应速度加快，极大减少了合成时间，为CBTN的工业合成提供了一条可行路线。

关键词：癌症 CBTN TKI 医药中间体

Synthesis of key intermediates for CBTN

Abstract

Malignant tumors are a common disease that seriously threatens life, health and safety. At present, the clinical treatment of malignant tumors in China has low early diagnosis rates and late treatment irregularities. Moreover, for patients with advanced malignant tumors whose cancer cells have metastasized, local surgical treatment is less effective and systemic chemotherapy adverse reactions are more serious. At this time, molecular targeted drugs have a greater advantage for systemic treatment.

The newly developed molecular targeting broad-spectrum anti-cancer drug, cabozantinib, is a multi-targeted inhibitor. Apoptosis, invasiveness, metastasis and drug resistance are involved in the development and progression of tumors, thereby achieving the effect of inhibiting the growth of tumor cells. Since its launch, cabozantinib has been widely used in a variety of advanced cancers in Europe and the United States and has achieved significant results.

At present,cabozantinib is not yet listed in the country, there are few domestic researches on this drug synthesis, and the market price is relatively expensive. The patent period of its original research company's compound is about to expire. There is great expected value in China's generic drug market. This subject studies the synthesis of a key intermediate of cabozantinib, and finally confirmed a synthetic route through experiments. Select diethyl malonate as raw material and 1,2-dibromoethane under the conditions of benzyltriethylammonium chloride to synthesize 1,1-cyclopropyldicarboxylic acid. After purification under certain conditions, add two Chlorosulfoxide generates acid chloride under conditions such as anhydrous tetrahydrofuran, and then the acid chloride and 4-fluoroaniline under certain conditions form the desired key intermediate 1-[(4-fluorophenyl) carbamoyl] cyclopropanecarboxylic acid. Compared with the previous synthetic route, the starting material cost is lower, the halogenation reaction speed is accelerated, the synthesis time is greatly reduced, and a feasible route is provided for the industrial synthesis of cabozantinib.

Key Words: Cancer; Cabozantinib; TKI; Pharmaceutical Intermediate

目 录

摘 要 Ⅰ

Abstract Ⅱ

第一章 文献综述 1

1.1前言 1

1.2药物中间体简介 1

1.3癌症及与卡博替尼相关的癌症的介绍 2

1.3.1 癌症 2

1.3.2 晚期肾细胞癌 3

1.3.3 肝细胞癌 4

1.3.4 非小细胞肺癌 4

1.3.5 甲状腺髓样细胞癌 5

1.4卡博替尼简介 5

1.4.1 卡博替尼的发展史 5

1.4.2 卡博替尼的一般化学结构 5

1.4.3卡博替尼的作用机制 6

1.4.4 卡博替尼的药动学（Pharmacokinetics，PK） 6

1.4.5 卡博替尼的临床研究 7

1.5卡博替尼的市场展望 7

1.6 研究背景 8

1.7 研究的目的和意义 8

第二章 CBTN关键中间体的合成 9

2.1合成工艺路线的选择 9

2.2实验仪器及药品 10

2.3 卡博替尼关键中间体的合成 11

2.3.1 1,1-环丙基二羧酸的制备 11

2.3.2 酰氯的制备 12

2.3.3化合物1-(4-氟苯基氨基甲酰基)环丙烷羧酸的制备 12

2.4讨论 13

2.4.1制备酰氯的卤化剂选择 13

2.4.2 制备酰氯时反应温度选择 13

2.4.3 原料4-氟苯胺投料量的选择 13

2.5 反应进度监测及产物确定 14

2.6 三废处理方案 15

结 论 16

参考文献 17

致谢 19

请支付后下载全文，论文总字数：17772字