论文总字数：18404字

摘 要

盐酸法舒地尔是一种可用于治疗心脑血管疾病的药，其分子构造是5-异喹啉磺酰胺衍生物，是一种RHO激酶抑制物，其通过增强肌球蛋白轻链磷酸酶的活性扩张血管，削弱内皮细胞的张力，改善脑组织微循环，不发生也不加重脑的盗血，同时可拮抗炎性因子，保护神经抗凋亡，促进神经再生^[1]。它抑制了RHO激酶参与的细胞黏附、细胞迁移、平滑肌细胞收缩、胞质分裂的调节，从而抑制了动脉粥样硬化的发生与发展^[2]。心脑血管疾病作为一种发病率和致死率都很高的疾病，其治疗药物必须从治疗效果和经济性上同时考虑,法舒地尔作为一种新型高效的心脑血管保护药物，对其合成工艺进行研究，建立利于生产的工艺路线具有重要意义。因此，本文探讨了盐酸法舒地尔这种比较热门的仿制药品种的原料药合成及相应的质量研究。

本文优选了一条利于生产的合成路线—以5—异喹啉磺酸为起始原料，经过酰化、游离、缩合、分离、成盐的工艺路线，最终得到盐酸法舒地尔精制品^[3]。在质量研究方面，选择采用高效液相色谱法进行含量以及有关物质的测定;盐酸法舒地尔潜在的有机杂质包括起始原料、中间体、工艺副产物和降解产物等，本文将初步介绍其杂质谱情况，之后通过生产过程中关键步骤的控制，使得盐酸法舒地尔及其制剂的有机杂质得到有效的控制^[4]。

关键词：高效液相色谱法；有关物质；含量测定；盐酸法舒地尔；合成

Synthesis and Quality Study of Fasudil Hydrochloride API

Abstract

Fasudil hydrochloride is a novel drug with a wide range of pharmacological effects. Its molecular structure is a 5-isoquinoline sulfonamide derivative, which is a RHO kinase inhibitor and expands blood vessels by increasing the activity of myosin light chain phosphatase. Reduce the tension of endothelial cells, improve brain microcirculation, does not produce or aggravate brain stealing, and can antagonize inflammatory factors, protect the nerve against apoptosis, and promote nerve regeneration . It inhibits the involvement of RHO kinases in cell adhesion, cell migration, smooth muscle cell contraction, and regulation of cytokinesis, thereby inhibiting the occurrence and development of atherosclerosis.As a disease with high morbidity and mortality, cardiovascular and cerebrovascular diseases must be considered simultaneously in terms of therapeutic effect and economy. Therefore, this article describes the synthesis of raw material drugs and corresponding quality studies of this popular generic version of Fasudil hydrochloride.

Based on the process route of the literature, the process route of acylation, free, condensation, separation, and salt formation was selected based on 5-isomeric wolinene sulfonic acid, and Fasudil hydrochloride was finally obtained. Fine products. In this paper, the quality control methods of fasudil hydrochloride drug substance were studied. HPLC method was used to determine the content and related substances, and the possible impurities and their control methods were briefly analyzed.

The potential organic impurities of fasudil hydrochloride include starting materials, intermediates, process by-products and degradation products. Through the literature query and characteristic analysis, this article will initially introduce its impurity spectrum and then control the key steps in the production process. As well as comprehensive product quality standards, the organic impurities of Fasudil hydrochloride and its formulations are effectively extracted.

Keywords:HPLC；Synthesis；Relevant substances；Content measurement；Fasudil hydrochloride

目录

摘 要 II

Abstract III

第一章 绪论 1

1.1 心脑血管疾病概述 1

1.2 盐酸法舒地尔理化特性 1

第二章 盐酸法舒地尔的合成工艺研究 2

2.1合成路线分析 2

2.2 生产工艺研究 4

2.2.1酰化工序 （5-异喹啉磺酰氯盐酸盐的制备） 4

2.2.2 游离、缩合、成盐工序 5

2.2.3 精制工序 6

2.3盐酸法舒地尔的结构表征 6

2.3.1核磁共振氢谱 6

2.3.2质谱 6

2.3.3元素分析 6

第三章 盐酸法舒地尔的质量研究 7

3.1盐酸法舒地尔的含量测定 7

3.1.1测定条件 7

3.1.2含量测定方法 7

3.1.3空白溶剂干扰试验 7

3.1.4线性和范围 7

3.1.5准确度实验 7

3.1.6精密度实验 8

3.1.7系统适用性 9

3.1.8样品测定 9

3.2有关物质的测定 10

3.2.1测定方法 10

3.2.2专属性试验 10

3.2.3检测限 12

3.2.4 系统适用性 13

3.2.5 溶液稳定性 13

3.2.6样品测定 14

3.3有机杂质的分析和控制 15

3.3.1 盐酸法舒地尔的杂质谱 15

3.3.2有机杂质分析 16

3.3.3基因毒性杂质分析 19

3.3.4 关键步骤控制 21

第四章 结语 22

致 谢 23

参考文献(References) 24

附录 25

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