摘 要

如今，高血压和糖尿病患者越来越多，而高血压和糖尿病可以导致肾性贫血，由此可见，肾性贫血的患者也可能会越来越多。可博美作为一种新药用于治疗肾性贫血，并且在多方面都优于目前用于治疗肾性贫血的红细胞生成刺激剂。可博美的市场前景是非常广阔的，具有很好的研究价值和经济价值。

论文以4-羟基-7-苯氧基异喹啉-3-甲酸甲酯（3a）为原料在乙酸溶剂中与四甲基甲烷二胺反应得1-(二甲胺基)甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(3b)， 3b与乙酸酐反应得1-(乙酰氧基)甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(3c)和1-(乙酰氧基)甲基-4-乙酰氧基-7-苯氧基异喹啉-3-甲酸甲酯(3d)的混合物，化合物3d在吗啉存在下转化为化合物3c，化合物3c经Pd／C催化氢化可以得到1-甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(3e)，化合物3e与甘氨酸钠反应得2-（4-羟基-1-甲基-7-苯氧基异喹啉-3-甲酰氨基）乙酸（3f）的钠盐，再用乙酸酸化即可得可博美。

论文研究了反应的工艺条件，经研究得出如下结论：

1、4-羟基-7-苯氧基异喹啉-3-甲酸甲酯（3a）在乙酸溶剂中与四甲基甲烷二胺反应的最佳工艺条件是4-羟基-7-苯氧基异喹啉-3-甲酸甲酯（3a）和四甲基甲二胺为反应物，醋酸为溶剂，三者最佳摩尔比为1：1.45：14.77，反应温度为50-60℃，反应时间为5小时以上；

2、1-(二甲胺基)甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(3b)乙酸酐反应制备1-(乙酰氧基)甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(3c)的最佳工艺条件是烷基化产物无需分离直接与醋酐反应且不需要再加入溶剂醋酸，反应物最佳摩尔比为化合物3b:醋酐=1:3.07 ；反应温度为105℃，反应时间为10小时以上；

3、1-(乙酰氧基)甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯氢化制备1-甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯的最佳工艺条件是高压釜内氢气压强为20公斤，1-(乙酰氧基)甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯（3c）为反应物，催化剂为10%的湿钯碳，溶剂为乙酸乙酯，弱碱为碳酸氢钠，四者最佳摩尔比为1: 3.58: 27.47: 1.62；反应温度为105℃，反应时间为2小时以上；

4、1-甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯与甘氨酸钠反应制备2-（4-羟基-1-甲基-7-苯氧基异喹啉-3-甲酰氨基）乙酸的最佳工艺条件是1-甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(3e)和甘氨酸钠为反应物，甲醇为溶剂三者最佳摩尔比为1：2.78：115.99；反应温度为105℃，反应时间为5小时以上。

经研究得到较为理想的工艺条件，为进一步研究奠定了基础。

关键词：可博美；肾性贫血；红细胞生成刺激剂；合成路线；工艺研究

Abstract

Today, there are more and more hypertensive and diabetic patients. hypertension and diabetes can lead to renal anemia, it can be seen, renal anemia patients may also be more and more. As a new drug for the treatment of renal anemia, roxadustat in many ways superior to the current treatment for renal anemia erythropoiesis stimulants. Market prospects of roxadustat are very broad, so roxadustat have good research value and economic value.

According to the literature,4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (3a) is regard as the raw material to synthesize the roxadustat . The compound 3a is reacted with bis-dimethylaminomethane in acetic acid to get 1-((dimethylamino)methyl)-7-phenoxyisoquinoline-3-carboxylate(3b) and then the compound 3b is reacted with acetic anhydride to get a mixture of 1-((acetyloxy)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate(3c)and1-(acetyloxy) methyl-4-acetoxy-7-phenoxyisoquinoline-3-carboxylate(3d) . The compound 3d can be converted into compound 3c under the action of morpholine . The compound 3c is deoxygenated by Pd/C to get 4-hydroxy-1-methyl-7-phenoxyisoquine-3-carboxy-

-late.The compound 3e is reacted with sodium glycinate to get the sodium salt of 2- (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3--carboxamido) acetic acid (3f) and then acidiied with acetic acid to get compound 3f.

The paper studies the technological conditions of the reaction, and draws the following conclusions：

The optimum conditions for the reaction of methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (3a) with tetramethylammine diamine in an acetic acid solvent are 4-hydroxy-7-phenoxy (3a) and tetramethylmethylenediamine as the reactants, acetic acid as the solvent, the best molar ratio of the three is 1: 1.45: 14.77, the reaction temperature is 50-60 DEG C, the reaction time is more than 5 hours;

Synthesis of 1- (acetyloxy) methyl-4- (2-methyl-4-oxo-3-phenoxyisoquinoline-3

-carboxylic acid methyl ester (3b) Hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (3c) The optimum conditions are that the alkylated product does not need to be separated directly with acetic anhydride and does not require the addition of solvent acetic acid, the optimum molar ratio of the reactants As the compound 3b: acetic anhydride = 1: 3.07; the reaction temperature is 105 ℃, the reaction time is 10 hours or more;

3-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester 3-methyl-4-hydroxy-7-phenoxyisoquinoline- The optimum conditions for methyl 3-formate were 30 kg of hydrogen in the autoclave and methyl ester of 1- (acetoxy) methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate ) As the reactant, the catalyst is 10% wet palladium carbon, the solvent is ethyl acetate, the weak base is sodium bicarbonate, the best molar ratio is 1: 3.58: 27.47: 1.62; the reaction temperature is 105 ℃, the reaction time is more than 2 hours;

4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester was reacted with sodium glycinate to prepare 2- (4-hydroxy-1-methyl-7-phenoxyisoquinoline (3e) and sodium glycinate as the reactants, and methanol as the solvent. The optimum conditions were as follows: 1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate The best molar ratio of the three is 1: 2.78: 115.99; the reaction temperature is 105 ℃, the reaction time is 5 hours or more.

The study of the ideal conditions for the further study laid the foundation for further study.

Key words： roxadustat；renal anemia; erythropoiesis stimulants; synthetic route；craft research

目 录

第一章 绪论 1

1.1 前言 1

1.2 可博美的合成路线研究进展 2

第2章 实验部分 4

2.1 实验原料 4

2.2 实验仪器 4

2.3 1-(二甲胺基)甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯（3b）的合成 5

2.4 1-(乙酰氧基)甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(3c)的合成 5

2.5 1-甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(3e)的合成 6

2.6 2-（4-羟基-1-甲基-7-苯氧基异喹啉-3-甲酰氨基）乙酸（3f）的合成 7

第3章 结果与讨论 9

3.1 1-(二甲胺基)甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯（3b）的合成条件研究 9

3.2 1-(乙酰氧基)甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(3c)的合成条件研究 12

3.3 1-甲基-4-羟基-7-苯氧基异喹啉-3-甲酸甲酯(3e)的合成条件研究 14

3.4 2-（4-羟基-1-甲基-7-苯氧基异喹啉-3-甲酰氨基）乙酸（3f）的合成条件研究 17

第4章 结论 21

参考文献 22

致谢 24