屈螺酮合成与粗品纯化工艺研究
发布时间：2019-02-16 03:34
【摘要】：孕激素屈螺酮(Drospirenone,6β,7β:15β,16β-二亚甲基-3-氧代-17α-孕甾-4-烯-21,17-羧内酯)是一种高效、低毒、无副作用的新一代甾体类避孕药,是目前唯一一种与天然孕酮药理特性相近的孕激素,为甾体类17α-螺内酯的衍生物。本文针对屈螺酮的合成工艺路线,纯化过程,检测系统等方面进行了探究。首先在原有的工艺路线基础上设计出新的合成路线;然后进行屈螺酮的合成实验研究;最后设计简便的层析检测系统,对产品进行检测和表征。(1)工艺路线研究中,确定了铬酸酐氧化工艺路线的可行性。针对铬酸酐氧化工艺路线进行了优化,重新设计了屈螺酮的合成工艺路线,使得所设计的合成路线,安全、环保且经济性良好。(2)合成屈螺酮的研究实验,在环氧物的合成过程中,确定了反应时间为3h,新鲜的叔丁醇钾的反应效果最为优异。在酯化物的合成过程中,确定了反应温度设定在80℃,反应时间为5h后,乙醇钠的效果优于乙醇钾的效果。在消除物的合成过程中,确定了反应时间为24h的,温度为120℃时,最适宜的pH值范围8～8.5。在屈螺酮(粗品)的合成过程中,确定了第一步反应时间为6h;第二步反应时间为2h。(3)屈螺酮粗品纯化实验,设计层析在线监控一体机,可以快速简便地对层析纯化过程进行实时监控。选择硅胶作为本实验的吸附剂;确定了环己烷与EA的混合溶液作为洗脱剂,并确定环己烷与EA的比值为1时,分离效果最好。对屈螺酮粗品中含有的杂质进行了分析,确定了杂质的种类以及产生的原因。对得到的产品进行全分析,分析结果表明屈螺酮产品符合USP36质量要求标准。通过IR分析以及元素分析表明屈螺酮中各元素含量与理论值吻合,说明产品在层析过程中未发生变质。(4)纯化工艺比较,通过对比吡啶-盐酸成盐法纯化工艺、亚硫酸钠-水溶液还原法纯化工艺与研究的新工艺---硅胶层析纯化法工艺三种工艺所得产品的外观、收率以及总纯度、单杂等多方面进行比较,结果表明硅胶层析纯化法所得的产品外观最好、纯化收率达到90.76%及总纯度达到99.84%和最大单杂为0.08%,说明本文设计的纯化工艺与其它工艺相比具有极大的优势。对层析过程进行数学模拟,通过GR模型拟合层析结果,并分析各参数对层析结果的影响,可为工业放大提供依据。通过对屈螺酮合成工艺以及纯化工艺的研究,所得的结果为工业化生产提供数据与理论基础,且在本公司进行大批量投产使用,提高了企业的生产效率,降低了企业的生产成本。
[Abstract]:The progesterone (Drospirenone,6 尾, 7 尾: 15 尾, 16 尾 -dimethylene-3-oxo-17 伪 -pregna-4ene-21- 1-1-carboxylactone) is a new generation of steroid contraceptive with low toxicity and no side effects. Progesterone is the only progesterone similar to the pharmacological properties of natural progesterone and is a derivative of steroid 17 伪-spironolactone. In this paper, the synthesis process, purification process and detection system of draconone were studied. Firstly, a new synthetic route was designed based on the original technological route, and then the experimental study on the synthesis of dracurone was carried out. Finally, a simple chromatographic detection system was designed to detect and characterize the product. (1) the feasibility of chromic anhydride oxidation process was determined in the study of the process route. In this paper, the oxidation process of chromic anhydride is optimized, and the synthetic route of duspirone is redesigned to make the synthesized route safe, environmentally friendly and economical. (2) the experimental study on the synthesis of duspirone is carried out. In the process of synthesis of epoxide, the reaction time was determined to be 3 h, and the reaction effect of fresh potassium tert-butanol was the best. In the process of esterification, the effect of sodium alcohol was better than that of potassium alcohol when the reaction temperature was set at 80 鈩，
本文编号：2423999
[Abstract]:The progesterone (Drospirenone,6 尾, 7 尾: 15 尾, 16 尾 -dimethylene-3-oxo-17 伪 -pregna-4ene-21- 1-1-carboxylactone) is a new generation of steroid contraceptive with low toxicity and no side effects. Progesterone is the only progesterone similar to the pharmacological properties of natural progesterone and is a derivative of steroid 17 伪-spironolactone. In this paper, the synthesis process, purification process and detection system of draconone were studied. Firstly, a new synthetic route was designed based on the original technological route, and then the experimental study on the synthesis of dracurone was carried out. Finally, a simple chromatographic detection system was designed to detect and characterize the product. (1) the feasibility of chromic anhydride oxidation process was determined in the study of the process route. In this paper, the oxidation process of chromic anhydride is optimized, and the synthetic route of duspirone is redesigned to make the synthesized route safe, environmentally friendly and economical. (2) the experimental study on the synthesis of duspirone is carried out. In the process of synthesis of epoxide, the reaction time was determined to be 3 h, and the reaction effect of fresh potassium tert-butanol was the best. In the process of esterification, the effect of sodium alcohol was better than that of potassium alcohol when the reaction temperature was set at 80 鈩，
本文编号：2423999
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