摘要：度他雄胺，化学名称为(5α,17β)-N-[2,5-双(三氟甲基)苯基]-3-氧代-4-氮杂雄甾-1-烯-17-甲酰胺，是一种新型的5α还原酶抑制剂，主要用于预防与治疗良性前列腺增生症（BPH），市场前景非常广阔，但是目前国内还不能大规模生产。本课题的研究目的是摸索出一条今后能用于工业化大生产的合成路线，要求原料来源充足，反应条件温和，合成步骤少，成本低，环境污染少等。本课题是以M4酸（雄甾-3-酮-1-烯-4-氮杂-5α-17β-羧酸）为起始原料，经卤置换和N-酰化反应得到产物度他雄胺。通过工艺条件对照实验，本文优化了这几步反应的实验过程，增强了各步反应的稳定性和重复性，提高了产物收率和纯度，降低了实验成本，为今后工业化生产摸索出了一条相对可行的工艺路线。34313
毕业论文关键词：度他雄胺；(5α,17β)-N-[2,5-双(三氟甲基)苯基]-3-氧代-4-氮杂雄甾-1-烯-17-甲酰胺；5α还原酶抑制剂；雄甾-3-酮-1-烯-4-氮杂-5α-17β-羧酸；合成
The Research on Synthesis of Dutasteride
Abstract: Dutasteride, chemical name (5α,17β)-N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-
azaandrost-l-ene-17-carboxamide, is a new kind of 5α reductase inhibitor which is used for anti-benign prostatic hyperplasia, and has very broad market prospects. At present, it can’t be produced on a large scale in our country. The topic is aimed at finding a synthetic process which can be applied for major industrial production in the future, with abundant raw materials, mild reaction condition, few synthetic steps, low cost and less environmental pollution. Dutasteride is synthesized by halogen substitution reaction and N-acylation reaction steps based on 4-aza-5α-androstan-1-ene-3-one-17β-carboxylic acid as the starting material. Through the contrast experiment, we optimize experiment condition, enhance stability and reproducibility of each reaction, improve the productivity and purity of product, reduce production cost and determine a relatively feasible process which can be applied for major industrial production in the future.
Key Words: Dutasteride; (5α,17β)-N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-l-
ene-17-carboxamide; 5α Reductase inhibitor; 4-Aza-5α-androstan-1-ene-3-one-17β-carboxylic acid; Synthesis
目 录
1 前言 1
1.1 度他雄胺的简介 1
1.2 度他雄胺的药理学研究 1
1.3 度他雄胺的药代动力学及不良反应 2
1.4 临床应用 2
1.4.1 度他雄胺治疗前列腺增生症 2
1.4.2 度他雄胺治疗前列腺癌 3
1.5 度他雄胺的市场情况 4
2 文献综述与方案论证 6
2.1 文献综述 6
2.1.1 以M4酸为原料制备度他雄胺 6
2.1.2 以雄烯二酮为原料制备度他雄胺 7
2.1.3 以孕烯酮酸为原料制备度他雄胺 7
2.2方案论证 8
2.3 确定实验路线 8
3 实验部分 10
3.1 试剂及仪器 10
3.1.1 试剂 10
3.1.2 仪器 10
3.2 实验方法 11
3.2.1度他雄胺的合成 11
3.2.2 度他雄胺的精制 14
4 实验讨论 16
4.1 度他雄胺的合成过程 16
4.1.1 M4酸/氯化亚砜的摩尔比对收率的影响 16
4.1.2 吡啶用量对收率的影响 16
4.1.3 溶剂体系对收率的影响 17
4.1.4 反应温度对收率的影响 17 M4酸为原料度他雄胺的合成研究:http://www.youerw.com/yixue/lunwen_31782.html