摘 要

硫酸依替米星是我国自主研发拥有产权的氨基糖苷类抗生素，改造于庆大霉素C1a 组分，而且抗菌的作用效果与庆大霉素大于或相似庆大霉素，由动物的耳毒性研究最终结果表明 本药耳毒性小于庆大霉素、奈替米星和阿米卡星的肾毒性也低于或小于庆大霉素［1］。自从 1999 年上市以来已经在临床医疗中使用将近二十年左右。近些年来，细菌耐药跟着时代的发展业迅速发展，尤其是革兰氏阴性菌耐药的问题日益明显，硫酸依替米星是否仍保持着比较好的抗菌作用和是否还有哪些突破口或者药效和应用领域能否实现新的突破这也是我们值得去研究的一种目的。更不用说它所具备的特点，不良反应相对于其他相应的药少，安全性高，毒性较低，交叉内药性少，单一用药和联合用药均为较满意的临床疗效等特点。而且临床上也用于治疗多种病常用治疗的有敏感菌引起的呼吸道感染，如急性支气管炎、社区肺部感染及泌尿生殖系统感染、慢性支气管炎急性发作等。也可以用于急慢性蜂组织炎及创伤、术后感染的治疗与预防。主要作用细胞体内的核糖体，抑制细菌蛋白质合成。再者如今我们所到之处都滋生新的细菌，更是在大城市雾霾等环境污染所导各种病菌侵袭我们，而且容易感染，对此人们对安全可靠有效的抗菌药物的需求是日益提升，再者现如今我们用的大多数药是进口，因此价格也很贵给患者带来经济压力等一系列困难，。因此我们更加深入的研究像硫酸依替米星这样的我国自主拥有产权的药合成的技术工艺，进一步提高药物质量和开发新药满足社会和人民需求。设计的流程设计，不仅仅对我们个人还是整个人类都有积极的贡献。

此次设计主要参照了近五年的此类药物的各类研究报告，根据DMG1a为原料，中间通过取代反应、中间体3, 2’,6’ -三-N-乙酰基庆大霉素Cla（P1）乙醛乙硼的合成反应、水解反应、缩合反应，最终使用炭脱色处置得到纯度较高的硫酸依替米星。此流程物料使用率高，反应不剧烈，纯度要求达标，事宜大规模的工业生产。

确定了硫酸依替米星的相应合路径之后，计算出相应的实际的工业参数和流程，依据实际参数的结果来选择设备选型，符合GMP的各种规范和要求以及车间的分布，管线布置，制作相应车间布置图等。

关键词：硫酸依替米星、抗生素类药物、工业参数、车间布置

Abstract

Etimicin Etimicin sulfate is an aminoglycoside antibiotic with property rights developed independently in China, which is modified from gentamicin C1a component, and its antimicrobial effect is greater than or similar to gentamicin. The final results of animal ototoxicity studies showed that the ototoxicity of this drug was lower than gentamicin, the renal toxicity of netilmicin and amikacin, was also lower than or less than gentamicin [1]. It has been used in clinical medicine for nearly twenty years since it was listed in 1999. In recent years, bacterial resistance has developed rapidly with the development of the times, especially the problem of resistance of Gram-negative bacteria is becoming more and more obvious, and whether etimicin sulfate still maintains a good antimicrobial effect, whether there are any breakthroughs or whether new breakthroughs can be achieved in the field of efficacy and application are also a goal worth studying, let alone its characteristics, such as fewer adverse reactions compared with other corresponding drugs, high safety, low toxicity, less cross resistance, the satisfactory clinical efficacy both single drug use and combination drug use and so on. In addition, it is also used to treat many diseases, such as respiratory tract infections caused by sensitive bacteria, including acute bronchitis, community pulmonary infections, urinary and reproductive system infections, acute attack of chronic bronchitis, etc. It can also be used for the treatment and prevention of acute and chronic cellulitis, trauma and post-operative infection. It mainly acts on ribosomes in cells and inhibits bacterial protein synthesis. Moreover, everywhere we go now, new bacteria are born, and all kinds of bacteria caused by environmental pollution such as haze in big cities invade us and are easy to be infected.nowadays, so the demand for safe, reliable and effective antibiotics is increasing. Moreover, most of the drugs we use today are imported, so the price is very expensive, which brings a series of difficulties to patients, such as economic pressure. Therefore, we will further study the technology and process of drug synthesis, such as etimicin sulfate, which is owned by our country independently, so as to further improve the quality of drugs and develop new drugs to meet the needs of the society and the people. The designed process design has a positive contribution both for us personally and for the whole human race.

The design mainly refers to the research reports of this kind of drugs in the past five years. Taking DMG1a as raw material, through the substitution reaction, the synthetic reaction of 3, 2', 6'-tri-N-acetylgentamicin Cla (P1) acetaldehyde ethyl boron (intermediate), hydrolysis and condensation. Finally, etemicin sulfate with higher purity was obtained by carbon decolorization treatment. This process has the advantages with high material utilization rate, low reaction, high purity and large-scale industrial production.

After determining the corresponding synthesis path of etimicin sulfate, the corresponding actual industrial parameters and process are calculated. The equipment selection is based on the results of the actual parameters, which conforms to the various specifications and requirements of GMP as well as the distribution of workshop, pipeline layout, and making corresponding workshop layout, etc.

Key words：etimicin sulfate, antibacterials, industrial parameters, worksho

目 录

摘 要 I

Abstract II

第一章 绪论

1.1 硫酸依替米星简述

1.2 硫酸依替米星产业的发展现状

1.2.1 氨基糖苷类抗生素药物的发展现状

1.2.2 硫酸依替米星的化学结构及基本特性

1.3 硫酸依替米星的药理、毒理作用

1.4 硫酸依替米星的药动学特性

1.5 设计依据

1.5.1 设计任务依据

1.5.2 设计遵循的技术法规

1.5.3 设计指导思想

1.6 本设计的目的和意义

第二章 硫酸依替米星合成路线的选择 5

2.1N一烷基化反应

2.2 工艺流程框图

第三章 物料衡算

3.1 生产总则

3.2 物料衡算

3.2.1 物料衡算的目的和意义

3.2.2 物料衡算的依据

3.2.3 物料衡算的基本理论

3.2.4 （中间体P1）合成工段物料衡算

3.2.5 (中间体P2)合成工段物料衡算 9

3.2.6 制备硫酸盐的合成工段计算

第四章 能量衡算 11

4.1 能量衡算的目的 2

4.2 热量平常方程式 2

4.3 （中间体P1）合成工段的能量衡算

4.4 P2合成工段能量衡算

4.5 P2制备硫酸盐工段能量衡算

章 主要设备选型 16

5.1 设备选型目的 16

5.2 设备选型的原则 17

5.3 设备选型的依据 17

5.4 主要贮罐的选型 18

5.4.1 醋酸钴贮罐 18

5.4.2 DMSO贮罐 18

5.4.3 醋酐贮罐 18

5.4.4 乙醛贮罐 18

5.4.5 乙醇贮罐 18

5.4.6 甲醇贮罐 18

5.4.7庆大霉素C_1a贮罐 18

5.5 反应釜选型 19

5.5.1 （中间体P2）合成工段反应釜选型 19

5.5.2 P2合成工段反应釜选型 19

5.5.3 制备硫酸盐工段反应釜选型 19

5.7 泵的选型 20

第六章 车间布置设计与管道设计 20

6.1 车间布置设计 21

6.1.2 车间布置设计的依据 21