利用微流光反应器高效制备去氢孕酮药物的研究

Dydrogesterone is a synthetic progestogen with potent efficacy but low side effects. The preparation of 9β-H,10α-CH3-pregna-4,6-diene-3,20-dione ethylene ketal (abbreviated as 9β-H,10α-CH3-ketal), the key intermediate for the synthesis of dydrogesterone, relies on a UV light triggered photoreaction. However, low mass transfer and heat transfer efficiencies occurred in this photoreaction limits the collection yield of 9β-H,10α-CH3-ketal. Microflow photoreactors are particularly unique with respect to conventional batch reactors in that considerably high efficiency in both mass and heat transfer can be achieved, which encourages us to explore the photochemical synthesis of 9β-H,10α-CH3-ketal using such kind of photoreactor. It is expected that the collection yield of 9β-H,10α-CH3-ketal may be improved greatly by combing the features of microflow photoreactor and the proper irradiation conditions optimized by us. The research may reduce the cost of dydrogesterone and pave the way for scaling up. Also, the study may open a new avenue for efficient synthesis of 9β-H,10α-CH3-steroid compounds, which show promising application in the development of novel anti-inflammatory, anti-allergic and endocrine drugs.

去氢孕酮是一种人工合成的高效低毒孕酮药物，合成其所需9β-H,10α-CH3-去氢黄体酮缩酮中间体依赖于光化学反应，但低的传热传质效率限制其光反应收率的提高。本项目拟利用微流光反应器开展9β-H,10α-CH3-去氢黄体酮缩酮的光化学合成，设计研制新型微流光反应器，借助微流光反应器传热传质效率高的特点来解决该光反应所面临的问题，结合我们对该光反应光照波长优化的已有基础，进一步大幅度提高9β-H,10α-CH3-去氢黄体酮缩酮光反应收率，降低其制备成本，为去氢孕酮的放量制备奠定基础。本项目的顺利实施还将为9β-H,10α-CH3甾族化合物的合成提供新方法，该类化合物在新型高效低毒消炎、抗过敏、调控内分泌等类药物研发中应用前景广阔

去氢孕酮是一种人工合成的高效低毒孕酮药物，合成其所需9β-H,10α-CH3-去氢黄体酮缩酮中间体依赖于光化学反应。但在传统光化学反应中所使用的光反应器（Batch光反应器），因其传热传质效率低，严重制约了9β-H,10α-CH3-去氢黄体酮缩酮中间体的收率。针对这一问题，我们基于微流反应器传质传热效率高的特点，利用新型微流光反应器开展9β-H,10α-CH3-去氢黄体酮缩酮光化学合成的研究，希望大幅度提高目标产物9β,10α-去氢黄体酮缩酮的收率，降低其制备成本。本项目的深入研究为9β-H,10α-CH3甾族化合物的合成提供新方法，进而推动了基于9β-H,10α-CH3甾族化合物的新型高效低毒消炎、抗过敏、调控内分泌等类药物的研发。.基于上述研究计划，我们设计并构建了新型双波长微流光反应器。双波长微流光反应器由光系统I和光系统II构成，原料9α-H,10β-CH3-去氢黄体酮缩酮的光反应液流经两个光系统，接受不同能量的光照，先后发生开环和翻转关环两步光化学异构化反应转化成目标产物9β-H,10α-CH3-去氢黄体酮缩酮。新型双波长微流光反应器大幅度提高了原料9α-H,10β-CH3-去氢黄体酮缩酮的转化率和目标产物9β-H,10α-CH3-去氢黄体酮缩酮的收率。.上述工作充分显示利用双波长微流光反应器制备9β-H,10α-CH3-去氢黄体酮缩酮能够克服传统光反应器中传质传热效率低的缺陷，能够解决去氢孕酮药物合成效率低的问题。双波长微流光反应器的研发为开发新型高效低毒消炎、抗过敏、调控内分泌、抑制衰老和避孕等的9β-H,10α-CH3甾族类药物提供的广阔的应用前景。