论文总字数：13091字

摘 要

本论文主要研究抗男性早泄药物盐酸达泊西汀的A晶型,这种新晶型具有纯度髙、稳定性好等特点。盐酸达泊西汀晶型A的制备方法，其特征在于将盐酸达泊西汀溶于亲水性有机溶剂中，然后与低沸点亲脂性有机溶剂混合，析晶。其中亲水性有机溶剂选自甲醇、乙醇、异丙醇、乙二醇、N，N-二甲基乙酰胺、丙酮、乙腈当中。低沸点亲脂性有机溶剂选自石油醚、正戊烷、正己 烷、环己烷、乙醚、异丙醚、甲基叔丁基醚、乙酸甲酯和乙酸乙酯中。析晶的终点温度控制在50°C以下。进行关键中间体酒石酸达泊西汀的合成工艺研究及优化^[1]。

本论文的主要工作如下：

1)用结晶法拆分外消旋达泊西汀，得到中间体酒石酸达泊西汀。经过实验条件优化，得到的最佳工艺条件是：D-酒石酸与达泊西汀的摩尔比为1.1:1，在40%乙醇水溶液中拆分。在此最佳工艺条件下拆分收率达到46.5%，e.e%为99.6%。

2）进行盐酸达泊西汀的合成工艺及优化。对酒石酸达泊西汀进行碱解离得到达泊西汀游离碱，游离碱与稀盐酸成盐得到S-盐酸达泊西汀。经过实验条件优化，得到的最佳工艺条件是：结晶溶剂为10%异丙醇的正己烷溶液。在最佳条件下的收率达到80.5%, e.e%为99.6%，纯度99.8%。

盐酸达泊西汀新晶型A在用于制造治疗男性早泄、射精延迟、性要求低下、性高潮受 压抑疾病药物中的应用^[2]。是一种药物组合物，包含盐酸达泊西汀新晶型A和药用辅料。

关键词： 盐酸达泊西汀 合成路线 结晶

ABSTRACT

This thesis mainly studies the crystalline form of dupoxetine hydrochloride, which is an anti-male premature ejaculation drug. This new crystalline form has the characteristics of high purity and good stability. A method for preparing Dapoxicillin hydrochloride Form A is characterized in that Dapoxetine hydrochloride is dissolved in a hydrophilic organic solvent and then mixed with a low-boiling lipophilic organic solvent to devitrify crystals. The hydrophilic organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, ethylene glycol, N,N-dimethylacetamide, acetone and acetonitrile. The low boiling lipophilic organic solvent is selected from the group consisting of petroleum ether, n-pentane, n-hexane, cyclohexane, diethyl ether, isopropyl ether, methyl tert-butyl ether, methyl acetate and ethyl acetate. The endpoint temperature of crystallization is controlled below 50°C. The key synthetic intermediate Dapoxetine tartrate synthesis process research and optimization.

The main work of this paper is as follows:

1. Racemic Dapoxetine is resolved by crystallization to give intermediate M-5 Dapoxetine tartrate. After optimization of the experimental conditions, the optimum technological conditions were obtained: the molar ratio of D-tartaric acid to was 1.1:1, which was resolved in a 40% aqueous ethanol solution. Under the optimum process conditions, the resolution yield reached 46.5% and the e.e% was 99.6%.
2. The synthesis process and optimization of dapoxetine hydrochloride were performed. Alkaline dissociation of dapoxetine tartrate resulted in the free base of dapoxetine, and the free base was made into salt with dilute hydrochloric acid to obtain S-dapsylate hydrochloride. After optimizing the experimental conditions, the best process conditions were obtained as follows: The crystallization solvent was a 10% isopropanol solution in n-hexane. The yield reached 80.5% under optimal conditions, the e.e% was 99.6%, and the purity was 99.8%.

Dapoxetine hydrochloride new crystalline form A is used in the manufacture of medicaments for the treatment of men with premature ejaculation, delayed ejaculation, low sexual requirements, or orgasm suppressed disease. Is a pharmaceutical composition comprising Dapoxetine hydrochloride Form A and a pharmaceutical excipient.

Key words: Dapoxetine hydrochloride； Synthetic route; Crystallization

目 录

摘 要 I

ABSTRACT II

第一章 文献综述 1

1.1 盐酸达泊西汀的用途及理化性质 1

1.1.1 盐酸达泊西汀的基本信息 1

1.1.2 盐酸达泊西汀的性质和用途 1

1.1.3 盐酸达泊西汀的市场前景 2

1.2 盐酸达泊西汀的合成、结晶工艺和纯度测定 3

1.2.1 推荐合成路线 3

1.2.2 盐酸达泊西汀的结晶工艺 3

1.2.2.1结晶溶剂对收率的影响 3

1.2.3 高效液相色谱测定体系中盐酸达泊西汀的化学纯度 4

1.3 本课题的目的和意义 4

第二章 材料和方法 6

2.1 实验仪器 6

2.2 实验试剂 6

2.3 盐酸达泊西汀的结晶工艺 6

2.3.1 溶剂的选择 6

2.3.2 实验仪器 7

2.3.3 盐酸达泊西汀结晶实验步骤 7

2.3.3.1 酒石酸达泊西汀的合成路线 7

2.3.3.2 酒石酸达泊西汀的合成实验方法 7

2.3.3.3 盐酸达泊西汀的合成路线 8

2.3.3.4 盐酸达泊西汀的合成实验方法 8

2.3.4 脱色 8

2.3.5 溶液的热过滤 8

2.3.6 冷却结晶 9

2.3.7 晶体的分离、干燥 9

第三章 结果与讨论 10

3.1 实验结果 10

3.1.1 盐酸达泊西汀样品液相色谱图 10

3.2 重结晶溶剂的选择 11

3.3 脱色剂的选择 12

3.4 冷却结晶过程条件的选择 12

第四章 结论与展望 14

4.1 结论 14

4.2 展望 14

参 考 文 献 15

致 谢 17

第一章 文献综述

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