甾体激素药物合成中酮羰基保护方法的比较与应用研究
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摘要
甾体激素是在研究哺乳动物内分泌系统时发现的内源性物质,具有极重要的医药价值,在维持生命、调节性功能、机体发育、免疫调节、皮肤疾病治疗及生育控制方面有明确的作用。由于医学上的重要应用,甾体类化合物得到广泛的开发。
在各类甾体药物合成过程中,有些产品需要对中间体的某一个或两个酮羰基进行保护,以完成预期反应。因此,寻找适合的保护及去保护方法,提高保护和去保护反应效率,是进行技术再创新的一个突破点。
本文综述了酮羰基保护方法的发展和应用,并根据甾体药物生产中存在的实际问题进行了酮羰基保护的应用研究。重点研究了A.不同非均相催化剂催化的抗炎激素药物醋酸泼尼松龙制备中的酮羰基保护;B.不同非均相催化剂催化的倍他米松中间体制备过程中的酮羰基保护,同时进行了不同底物的筛选;C.不同保护方法对不同的3,17-二酮雄甾烷类中间体的选择性保护效果。
A和B的研究目的是解决实际生产中保护方法效率低或去保护效率低的问题,以期提高收率,降低成本,取得一定的社会效益和经济效益。C的研究目的是在甾体激素新能源大量发展的条件下,为经生物法获得的3,17-二酮-雄甾烷类中间体的深加工提供更为有效的途径。
对于问题A,本文分别研究了在活性炭负载磷钨酸和硅胶固载硫酸氢钠两种催化剂存在下,使用乙二醇、乙硫醇或巯基乙醇对酮羰基进行保护、还原、脱保护。研究结果表明,对于醋酸泼尼松龙制备过程中的酮羰基保护,使用巯基乙醇+硅胶固载硫酸氢钠的方案比现有工艺有优势。
对于问题B,本文研究了倍他米松中间体制备过程中,分别使用活性炭负载磷钨酸和硅胶固载硫酸氢钠两种催化剂,采用乙二醇、乙硫醇或巯基乙醇保护酮羰基,对现有工艺进行改进。新的硅胶固载硫酸氢钠比起目前生产中使用的催化剂优势明显,能较大程度地提高酮基保护率。目前该工艺改进已经完成了小试研究,正在准备中试化阶段。
对于问题C,本文研究了在活性炭负载磷钨酸和硅胶固载硫酸氢钠两种催化剂存在下,使用乙硫醇或巯基乙醇对不同的3,17-二酮雄甾烷类中间体进行选择性保护,效果较好,特别是使用巯基乙醇+硅胶固载硫酸氢钠的方案,得到的缩酮经精制后,能够满足下一步反应的需求。目前该项目正在小试总结阶段。
Steroid was discovered in the investigation of endocrine in the mammal, which has very important value in the medication, such as: maintaining life, adjusting Sex Hormones, growth of human body, adjusting the immune system, treatment for skin diseases and contraception. Because of their import application in medication, many kinds of steroid compounds have been developed.
This paper summaries the progress in protecting groups for carbonyl groups, and their utilization. Problems on the protection of several industry steroids have been investigated. This diploma focuses on three areas: A. various heterogeneous catalysts were studied in protecting carbonyl groups in the preparation of prednisolone. B. various heterogeneous catalysts were studied in protecting carbonyl groups in the preparation of betamethasone. C. different heterogeneous catalysts were studied for the carbonyl group protecting selectivity in the preparation of 3,17-dione androgens.
The purpose of studies on problems A and B is to solve the low conversion ratio of protection reactions on several industry steroids. It was expected to increase the conversion ratio so as to reduce the cost. The target to dissolve problem C is helpful for further application of development of 3,17-dione androgens, which is get from Fermentation
About A, the investigation includes that, under the catalyzing of various heterogeneous catalysts, glycol, ethanethiol or thioglycol were used for the protection. The reduction and deprotection methodologies, as well as the conversion ratio have also been improved. The result shows that the best combination is thioglycol plus SiO_2(?)NaHSO_4. The optimized condition has been successful passed through the bench test.
About B, the experiment results show that, with different heterogeneous catalysts, and glycol, ethanethiol or thioglycol as protection group, the most superior catalyst is SiO_2(?)NaHSO_4, which increase the conversion ratio. This project has been completed on bench test scale, now it has been prepared for the scale up experiment.
About C, the study in this thesis shows that, with different heterogeneous catalysts, and ethanethiol or thioglycol as protection groups, the results are encouraging. The most excellent catalyst which has higher selectivity for this method is thioglycol plus SiO_2(?)NaHSO_4, and the refined product could be used to the next process directly. This study has successfully passed the bench test.
在各类甾体药物合成过程中,有些产品需要对中间体的某一个或两个酮羰基进行保护,以完成预期反应。因此,寻找适合的保护及去保护方法,提高保护和去保护反应效率,是进行技术再创新的一个突破点。
本文综述了酮羰基保护方法的发展和应用,并根据甾体药物生产中存在的实际问题进行了酮羰基保护的应用研究。重点研究了A.不同非均相催化剂催化的抗炎激素药物醋酸泼尼松龙制备中的酮羰基保护;B.不同非均相催化剂催化的倍他米松中间体制备过程中的酮羰基保护,同时进行了不同底物的筛选;C.不同保护方法对不同的3,17-二酮雄甾烷类中间体的选择性保护效果。
A和B的研究目的是解决实际生产中保护方法效率低或去保护效率低的问题,以期提高收率,降低成本,取得一定的社会效益和经济效益。C的研究目的是在甾体激素新能源大量发展的条件下,为经生物法获得的3,17-二酮-雄甾烷类中间体的深加工提供更为有效的途径。
对于问题A,本文分别研究了在活性炭负载磷钨酸和硅胶固载硫酸氢钠两种催化剂存在下,使用乙二醇、乙硫醇或巯基乙醇对酮羰基进行保护、还原、脱保护。研究结果表明,对于醋酸泼尼松龙制备过程中的酮羰基保护,使用巯基乙醇+硅胶固载硫酸氢钠的方案比现有工艺有优势。
对于问题B,本文研究了倍他米松中间体制备过程中,分别使用活性炭负载磷钨酸和硅胶固载硫酸氢钠两种催化剂,采用乙二醇、乙硫醇或巯基乙醇保护酮羰基,对现有工艺进行改进。新的硅胶固载硫酸氢钠比起目前生产中使用的催化剂优势明显,能较大程度地提高酮基保护率。目前该工艺改进已经完成了小试研究,正在准备中试化阶段。
对于问题C,本文研究了在活性炭负载磷钨酸和硅胶固载硫酸氢钠两种催化剂存在下,使用乙硫醇或巯基乙醇对不同的3,17-二酮雄甾烷类中间体进行选择性保护,效果较好,特别是使用巯基乙醇+硅胶固载硫酸氢钠的方案,得到的缩酮经精制后,能够满足下一步反应的需求。目前该项目正在小试总结阶段。
Steroid was discovered in the investigation of endocrine in the mammal, which has very important value in the medication, such as: maintaining life, adjusting Sex Hormones, growth of human body, adjusting the immune system, treatment for skin diseases and contraception. Because of their import application in medication, many kinds of steroid compounds have been developed.
This paper summaries the progress in protecting groups for carbonyl groups, and their utilization. Problems on the protection of several industry steroids have been investigated. This diploma focuses on three areas: A. various heterogeneous catalysts were studied in protecting carbonyl groups in the preparation of prednisolone. B. various heterogeneous catalysts were studied in protecting carbonyl groups in the preparation of betamethasone. C. different heterogeneous catalysts were studied for the carbonyl group protecting selectivity in the preparation of 3,17-dione androgens.
The purpose of studies on problems A and B is to solve the low conversion ratio of protection reactions on several industry steroids. It was expected to increase the conversion ratio so as to reduce the cost. The target to dissolve problem C is helpful for further application of development of 3,17-dione androgens, which is get from Fermentation
About A, the investigation includes that, under the catalyzing of various heterogeneous catalysts, glycol, ethanethiol or thioglycol were used for the protection. The reduction and deprotection methodologies, as well as the conversion ratio have also been improved. The result shows that the best combination is thioglycol plus SiO_2(?)NaHSO_4. The optimized condition has been successful passed through the bench test.
About B, the experiment results show that, with different heterogeneous catalysts, and glycol, ethanethiol or thioglycol as protection group, the most superior catalyst is SiO_2(?)NaHSO_4, which increase the conversion ratio. This project has been completed on bench test scale, now it has been prepared for the scale up experiment.
About C, the study in this thesis shows that, with different heterogeneous catalysts, and ethanethiol or thioglycol as protection groups, the results are encouraging. The most excellent catalyst which has higher selectivity for this method is thioglycol plus SiO_2(?)NaHSO_4, and the refined product could be used to the next process directly. This study has successfully passed the bench test.
引文
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