【作者】 高岩；

【导师】 陈立功；

【作者基本信息】 天津大学 ， 药物化学， 2007， 硕士

【摘要】 甾体化合物分子中11β-羟基的引入在甾体药物化学中占有极为重要的地位。在工业生产中普遍采用的化学合成方法是卤素消除法,但该方法仍然存在以下难以解决的问题:(1)反应收率较低,仍有提升的空间;(2)所得产物中副产物?9(11)的含量较高,现有的生产水平只能将该副产物的含量控制在4.0-5.0%,并难以从目的产物中分离。为此,本文以9α-溴-11β,17α-羟基-6α-甲基孕甾-4-烯-3,20-酮-21-醋酸酯为原料,从卤素消除反应的反应机理入手,对其合成工艺进行了研究:(1)通过向反应体系中加入锌,并用三价铬盐替代不稳定的二价铬盐,实现了二价铬离子的循环使用,降低反应液中二价铬离子的使用量;(2)通过改变反应物的加入顺序和加入方式,使反应向有利于生成目的产物的方向进行;(3)利用正交分析法确定了6个实验参试因子,并设计了18组实验方案和五组补充实验,对反应的工艺参数进行了优化;(4)通过正交实验,发现了针对各设计目标的主要影响因素;(5)在所建立的最佳工艺条件下,进行了稳定性实验。通过上述合成工艺的研究,本文建立了以9α-溴-11β,17α-羟基-6α-甲基孕甾-4-烯-3,20-酮-21-醋酸酯为原料的卤素消除反应的最佳合成工艺,其反应收率可达75.0%以上,目的产物11β,17α-羟基-6α-甲基孕甾-4-烯-3,20-酮-21-醋酸酯的HPLC分析可达95.0%以上,副产物17α-羟基-6α-甲基孕甾-4,9-二烯-3,20-酮-21-醋酸酯在产物中所占比例可控制在2.5%以下,基本实现了设计目标。更多还原

【Abstract】 The importing of 11β-hydroxy into steroid occupies the extremely important position in the chemistry of steroid pharmaceuticals. The process for dehalogenation of a 9α-halosteroids is a prevalent way of chemosynthesis in industrialized process, but some kittle questions still exist. The first one is that the yields are extremely low and there is a large elevated space. The second is that the ratio of the corresponding undesired ?9(11) steroid to the 11β-hydroxy steroid is high. The ratio of ?9(11) is general 4-5% in the existing produce level. And the ratio is very important due to the difficulty of removing the ?9(11) compound from the 11β-hydroxy product.Therefore, the synthetic process is studied in the thesis based on radical mechanisms of the process for dehalogenation of 9α-halosteroids and starting with 9α-bromo-11β,17α-dihydroxypregna-6α-methylpregna-4-ene-3,20-dione-21-acetate. (1) Adding zinc powder into the reactive system and replacing unstable chromium (+2) with chromium (+3) , to recycle chromium(+2) and reduce amounts of chromium(+2) in the reactive system; (2) Changing the order and manner of adding the reactants to obtain more desired product; (3) Ascertaining six experimental factors by orthogonal experimental analysis method and design of 18 experiments and 5 complementary experimental projects to optimize reactive parameters; (4) Discovering the main influencing factors to the experimental aims by the orthogonal experiments; (5) Putting up the stability experiments with the founded optimal reactive parameters.By the study of the synthetic process the optimal synthetic process of the dehalogenation reaction is founded starting with 9α-bromo-11β,17α-dihydroxypregna -6α-methylpregna-4-ene-3,20-dione-21-acetate. The yield is more than 75.0%. The purity of the desired product determined by HPLC is more than 95.0% and the radio of the undesired product (11β,17α-dihydroxypregna-6α-methylpregna-4,9-diene-3,20- dione-21-acetate) is less than 2.5%. Basically the prospective goal came true.更多还原