【作者】 康松；

【导师】 高瑞昶； 周子清；

【作者基本信息】 天津大学 ， 制药工程， 2007， 硕士

【摘要】 诺孕酯做为新一代孕激素,研究已表明,在药理、药效、毒性、临床等方面,其安全性、稳定性均优于第二代孕激素左炔诺孕酮和第三代孕激素去氧孕烯和孕二烯酮,已广泛用作口服避孕药、痤疮治疗药和妇女激素替代疗法治疗更年期综合症。目前,我国每年都需要从国外大量进口。本文采用左炔诺孕酮双酯化以及双酯酸水解工艺,最终成功合成了诺孕酯,突破了国外对该产品产业化的技术壁垒。与文献报道的合成方法相比,该方法不仅具有反应条件温和、易于控制、选择性高、无二次污染等优点,同时提高了诺孕酯产品收率。首先,本文系统研究了微生物发酵、环合氢化、锂氨、沃氏氧化、炔化水解、双酯化、酸水解及肟化反应在多种因素作用和影响下反应的最佳条件。解决了有立体障碍的17位羟基酰化的关键技术问题,产物的质量和收率均有较大幅度的提高。在此基础上确定了诺孕酯最有效的合成方法。合成产物左炔诺孕酮、重要的中间体及终产物诺孕酯,经高压液相色谱确认纯度后,与Ortho公司诺孕酯样品进行紫外光谱、红外光谱、质子核磁共振、碳核磁共振、质谱等波谱分析,确证化学结构无误,质量与国外样品基本一致。在诺孕酯合成的基础上,本文对诺孕酯的生物医学特性进行了初步的研究。本文研究结果对工业化设计具有重要的理论和实际意义。更多还原

【Abstract】 As a new generation progesterone product, norgestimate is superior to the second-generation progesterone product levonorgestrel and the third-generation progesterone products-desogestrel and gestodene in terms of pharmacological, pharmacodynamic, toxicological and clinical aspects, as well as its safety and stability profiles. It is widely used as an oral contraceptive, acne therapy, and hormone replacement therapy for menopausal symptoms in women. At present, a significant amount of the products needs to be imported from foreign countries every year. In this paper, a process of di-esterification of levonorgesterol and hydrolysis of di-ester acids is adopted, and finally norgestimate is successfully synthesized, thus making a breakthrough on the foreign technical barrier in product commercialization. As compared with the synthetic methods reported in literature, the method not only has such advantages as reaction conditions mild, control easy, selectivity high and no secondary contamination, but also improves the recovery rate of norgestimate product at the same time.First, this paper investigates the optimal conditions for the reactions under actions and effects of multiple factors in microbial fermentation, cyclization and hydrogenation, lithium ammonium, wolf oxidation, alkyne hydrolysis, di-esterization, acid hydrolysis and oximization reactions; and solved the key technical issues in 17-hydroxy-acylation with stereoscopic barriers. The quality and recovery rate of the product are both greatly improved. On this basis is established the most effective synthetic method for norgestimate.The substances prepared in this paper such as Levonorgestrel, key intermediates and final product, after purity qualification with HPLC, was subjected to analyze by UV,IR,HNMR,CNMR and Mass. When analyzing concurrently with Ortho’s Norgestimate specimen, the data obtained from analytical sample is identical to authentic, so thus the chemical structure and the quality of tittle compound are proved concretly.On the basis of norgestimate synthesis, the bio-medical characteristics of norgestimate are preliminarily studied in this paper. The findings in the paper have important theoretical and practical significance for the industrialization designs.更多还原