达格列净5-溴-2-氯-4’-乙氧基二苯甲烷的合成

摘要：达格列净用于2型糖尿病的治疗，是一种钠-葡萄糖协同转运蛋白2抑制剂，它是由关键中间体5-溴-2-氯-4'-乙氧基二苯甲烷为原料来合成的，因此对合成5-溴-2-氯-4'-乙氧基二苯甲烷的研究非常重要。本次论文将通过两种合成路线，来对达格列净的重要中间体5-溴-2-氯-4'-乙氧基二苯甲烷的合成进行研究，路线一以2-氯-5-溴苯甲酸为原料，经草酰氯处理生成酰氯化合物，然后与苯乙醚在三氯化铝催化下发生F-C酰基化反应生成中间体对位酮和异构体邻位酮，经结晶得到对位酮5-溴-2-氯-4'-乙氧基二苯甲酮，然后经三乙基硅烷在三氟化硼乙醚作用下还原成目标化合物。路线二以5-溴-2-羟基苯甲酸为起始原料，与羰基二咪唑生成活性中间体，然后与甲氧基甲基胺盐酸盐反应生成Weinreb酰胺，再与制备的格氏试剂反应，生成5-溴-2-氯-4'-乙氧基二苯甲酮，再经还原可以得到目标产物。并对其合成条件进行优化，其较优F-C酰基化合成条件为:草酰氯用量为原料的1.05当量，三氯化铝的较佳用量为原料1的1.1当量，苯乙醚用量为原料1.1倍当量，最佳温度控制在0- 5度。57641

关键词：5-溴-2-氯-4'-乙氧基二苯甲烷, 达格列净，F-C酰基化，Weinreb酰胺

Synthesis of 5-bromo-2-chloro-4'-ethoxy diphenyl methan

Abstract: The Dapagliflozin for the treatment of type 2 diabetes is a sodium-glucose cotransporter 2 inhibitors, and is synthesized using the key intermediate 5-bromo-2-chloro-4'-ethoxy diphenyl methane as raw material. The synthesis of 5-bromo-2-chloro-4'-ethoxy diphenyl methane is an important study for the synthesis of Dapagliflozin. In this paper, the key intermediate was synthesized by two routes. Route 1: 2-chloro-5-bromo-benzoic acid was used as raw materials, and oxalyl chloride was used as chlorination reagent，then Friedel-Crafts acetylation of anisole to get 2-chloro-5-bromo-4'-benzophenone, and tehn was reducted by triethylsilane boron and trifluoride diethyl etherate to get the target compound. Route 2: 5-bromo-2-hydroxybenzoic acid was used as raw material , reacted with carbonyl imidazole to generate reactive intermediates, and then reacted with methoxy methyl amine hydrochloride generated Weinreb amide，and reacted with Grignard reagent to get 2-chloro-5-bromo-4'-benzophenone , then was reducted to obtain the key intermediate. The optimal conditions for Friedel-Crafts acetylation were determined: oxalyl chloride in an amount of 1.05 equivalents of starting material 5-bromo-2-hydroxybenzoic acid, aluminum trichloride is used in an amount 1.1 times equivalent the amount of anisole equivalent to 1.1 times the raw material, the temperature controlled at 0-5 degrees.

Keywords：5-bromo-2-chloro-4'-ethoxy diphenyl methane ； Dapagliflozin； F-C acylation, Weinreb amide

1 前言 1

1.1 达格列净研究背景 1

1.1.1研究达格列净的意义 1

1.2 达格列净及其中间体的简介 2

1.3 发展趋势 3

2 实验方案和实验路线 6

2.1 实验方案的确定 6

2.2 合成路线的确定 7

2.3薄层层析（TLC）方法 8

3 实验部分 10

3.1 仪器及试剂 10

3.1.1 实验仪器 10

3.1.2 实验试剂 10

3.2 实验方法达格列净5-溴-2-氯-4’-乙氧基二苯甲烷的合成:http://www.751com.cn/yixue/lunwen_62436.html