摘要：糖尿病是如今高发的主要慢性病之一，预防和治疗糖尿病就成为了备受关注的话题。SGTL-2抑制剂能够有效治疗Ⅱ型糖尿病，目前已知的有达格列净及其类似物比如伊格列净、卡格列净等药物都己上市并已得到广泛应用。但传统的SGTL-2抑制剂合成路线对于温度条件要求苛刻，需极低温，这给抑制剂的实际工业化生产造成很大阻碍。本论文创新设计出一种新型SGTL-2抑制剂螺环16化合物的合成路线，具有较好实际操作性。80909

本课题主要针对新型SGTL-2抑制剂螺环16的关键中间体10——(3-溴-2-甲氧基-6-甲基苯基)（4-乙基苯基）甲烷，进行了创新合成并且还优化了反应条件。将原料E-丁烯醛与乙酰乙酸甲酯，以乙醇为条件缩合关环得6-甲基-2-氧代环己基-3-烯甲酸甲酯。其后在乙酸条件下进行溴的取代反应和加成反应制备出3-溴-6-甲基水杨酸甲酯。再将产物溶解在丙酮中，加碘甲烷和碳酸钾，发生甲基化反应，碱解生成羧酸化合物2-甲氧基-3-溴-6-甲基苯甲酸。又经傅克酰基化反应得到(3-溴-2-甲氧基-6-甲基苯基)（4-乙基苯基）甲酮，最后在乙腈中，加三乙基硅烷，三氟化硼乙醚，经过还原羰基成亚甲基反应得到目标产物(3-溴-2-甲氧基-6-甲基苯基)（4-乙基苯基）甲烷，并通过核磁确认其结构。该关键中间体的合成创新，作为制备新型抑制剂螺环16化合物的基础，为优化达格列净类似物的生产工艺提供了极大的便利，在生产合成中具有重要意义。

毕业论文关键词：达格列净；抑制剂；中间体; 合成路线

Synthesis of Key Intermediate (3-Bromo-2-methoxy-6-methylphenyl) (4-ethylphenyl)  methane of Dapagliflozin derivatives

Abstract：As one of the major chronic diseases of human health killers in the 21st century, prevention and treatment of diabetes is a topic of concern。SGTL-2 inhibitors are effective in the treatment of type Ⅱ diabetes, such as Ipragliflpzin, Dapagliflozin , Canagliflozin and other drugs have been listed and widely used。 However, the conventional SGTL-2 inhibitor synthesis route is very demanding for temperature conditions ,they need very low temperatures, which is a significant obstacle to the actual industrial production of the inhibitor。 In this paper, we designed a new synthetic line of SGTL-2 inhibitor Compounds 16, which has good practicality。

In this paper, the novel intermediate 18 - (3-bromo-2-methoxy-6-methylphenyl) (4-ethylphenyl) methane of the novel SGTL-2 inhibitor compound 16 was synthesized。 The reaction conditions were optimized。 The raw materials E-butenal and methyl acetoacetate were condensed to give 6-methyl-2-oxocyclohexyl-3-enecarboxylate under ethanol。 Followed by substitution reaction and addition reaction of bromine under acetic acid to prepare methyl 3-bromo-6-methylsalicylate。 And then the product dissolved in acetone, iodized methane and potassium carbonate, methylation reaction, alkaline hydrolysis of carboxylic compounds 2-methoxy-3-bromo-6-methylbenzoic acid。 (3-bromo-2-methoxy-6-methylphenyl) (4-ethylphenyl) methanone, and finally in acetonitrile, triethylsilane, oron trifluoride ether (3-bromo-2-methoxy-6-methylphenyl) (4-ethylphenyl) methane can be obtained by reducing the carbonyl to methylene to give the desired product。The synthesis of the key intermediates as a basis for the preparation of novel inhibitors of Spiro 16 is a great convenience for optimizing the production process of Dapagliflozin net analogs and is of great importance in production synthesis。

Keywords: Dapagliflozin;inhibitor; intermediate; synthesis route;

目录

1 绪论 2

1。1糖尿病概述 2

1。1。1 糖尿病的定义及诊断 2