摘 要

近些年来，由于科技水平的进步，现代社会生活水平不断提高，人类开始把抗癌进程放入视野，研究各类抗癌药物慢慢成为了现代药学研究的重中之重，来那度胺正是现在最畅销的抗癌药物之一。

然而由于各类生产技术的不成熟，使得来那度胺的现今大多数合成工艺不仅过程繁琐，造价昂贵，而且还容易产生有毒性的副产物。并且在早些年，来那度胺的合成工艺集中在国外，我们故采取了新的合成以及精制工艺，来有效的降低来那度胺的生产成本和生产过程的毒性，在过程中始终使用液相色谱进行监测纯度。

在本文研究中，我们拟以3-硝基邻苯二甲酰亚胺为原料合成3-羟基-4-硝基异吲哚啉-1-酮，再选择合适的还原剂对羰基进行选择性还原，从而成功的避免了紫外灯的运用，避免了有毒性的重要一步。在此基础上通控制变量得到最佳投料比和最佳精制方案，并且减少了反应步骤，仅用七步就可完成来那度胺制备，精制过程也用三步即可。

精制过程中间体3使用了调pH重结晶法，先将中间体3溶解，将溶液调节为酸性再调节为碱性精制。中间体4使用了精馏精制法，收集100℃到110℃之间的馏分，最终生成产物来那度胺使用了重结晶精制法，采用体积比20：1的异丙醇和二氯甲烷混合液重结晶。几乎每一步的纯度都达到98%以上，在精制之后基本可以在99.75%以上，完全达到了制药的标准，之后便可扩大生产，在大工厂中批量生产。

这是在前人的实验方案之下我们实验室对于来那度胺的工艺的新探索，也必将成为来那度胺的研究之路上一个重要节点。

关键词： 3-硝基邻苯二甲酰亚胺 精制提纯 液相色谱

Abstract

In recent years, due to the progress of science and technology, the living standard of modern society has been improved constantly. Human beings have begun to put the anticancer process into the field of vision, and the study of various kinds of anticancer drugs has gradually become the top priority of modern pharmaceutical research. Linadomide is one of the best-selling anti-cancer drugs.

However, due to the immaturity of various production technologies, most of the current synthesis processes of renalamine are not only cumbersome, expensive, but also easy to produce toxic by-products. And in earlier years, the synthetic process of Lenadamide was concentrated abroad, so we adopted a new synthesis and refining process to effectively reduce the production cost and the toxicity of the production process. Liquid chromatography is always used to monitor purity during the process.

In our experiment, we used 3-nitro-phthalimide as raw material to synthesize 3-hydroxy-4-nitroisoindolin-1-one, and then selected suitable reductant for selective reduction of carbonyl group. Thus successfully avoid the use of ultraviolet lamp, avoid an important step of toxicity. Then the best feed ratio and the best refining scheme are obtained by variable control, and the reaction steps are reduced, the reaction is completed in only seven steps, and the refining process also takes three steps. The purity of almost every step can reach more than 99%. After refining, it can be basically more than 99.75%, which is completely up to the standard of pharmacy. Then the production can be expanded to big production in large factories.

In the refining process, the intermediate 3 was dissolved by adjusting pH recrystallization method, and the solution was adjusted to acid and then adjusted to alkaline refining. Intermediate 4 was purified by distillation, and distillate was collected from 100 ℃ to 110 ℃. The final product was recrystallized and recrystallized with isopropanol and dichloromethane mixed with 20:1 volume ratio of isopropanol and dichloromethane. The purity of almost every step is over 98%. After refining, the purity can be above 99.75%, which completely meets the standard of pharmacy, and then it can be expanded to mass production in large factories.

This is a new exploration of the process of linalamine in our laboratory under the previous experimental plan, and it will certainly become an important part in the research of it.

Key words：detection for purification of 3-nitrophthalimide Liquid Chromatography

目录

Abstract 4

第一章 绪论 6

1.1实验目的意义 6

1.2抗癌药物来那度胺 7

1.2.1简介 7

1.2.2作用机理 7

1.2.3 作用优势 8

1.3前人的研究 8

1.4精制工艺 9

1.4.1 精制定义 9

1.4.2 精制的重要性 9

1.4.3 研究来那度胺精制工艺的意义 10

1.5 研究目标 11

第二章 实验部分 11

2.1实验所用的主要仪器 11

2.2实验主要试剂 12

2.3实验过程 13

2.3.1实验总步骤（实验工艺总路线） 13

2.4精制除杂 17

2.4.1第三步反应精制 17

2.4.2第四步精制 19

2.4.3 第七步精制 24

2.5最终讨论 28

第三章 结果和讨论 28

第四章 总结和展望 31

4.1总结 31

4.2展望 31

参考文献 32

致谢 34

第一章 绪论

随着科技的进步和社会的发展，现代社会人类生活水平不断提高，人们对于健康的要求越来越高，抗癌逐步进入人们的视线之中，研究各种各样的抗癌药物，慢慢成为了现代医学研究的重点方面。近二十年来，抗癌药物来那度胺的研究不断的更新着抗癌的最新进程，全球各个主要国家都在快速的推进着来那度胺的研究。目前，都已经有了很大的进展，并且在实验室中已经相当成熟，开始进入了大工厂的阶段，并且不断地改进着在实验室中和在大工厂中的工艺。近些年来，医学技术不断得到发展，越来越多的疾病在得到救治。但是在恶性肿瘤方面，仍旧是人类的大敌，强烈地威胁着人类的健康^[13]。大量的癌症病例告诉我们，我们都处于各种致癌威胁之中，化学物质烷化剂，电离辐射，环境污染、自由基毒素、微生物(细菌、真菌、病毒等)及其代谢毒素、遗传特性、内分泌失衡、免疫功能紊乱等等各种致癌物质、致癌因素的作用下导致身体正常细胞发生癌变，使得我们受到各种各样的癌症威胁^[12]。

在此背景下，抗癌药物来那度胺越来越成为了广大科学家研究领域的集合点，成为了药学研究的接近中心的位置，因此，我课题组对于抗癌药物来那度胺的研究，也就显得尤为重要，对于来那度胺的合成过程中的除杂精制，也是很重要的一环。