Study On The Preparation Of Medoxyprogesterone Acetate

Medroxyprogesterone acetate 2 is mainly used for the treatment of irregular menstruation,threatened abortion,functional uterine bleeding and so on.Its market prospect is considerable,high yield,low cost,the development of an easy operation,environment-friendly synthetic route is extremely significant for the industrial production.This thesis consists of two chapters,as follows:The first chapter:it firstly introduces development history of steroidal drugs and classification of steroidal drugs.Secondly it introduces structure-activity relationship,pharmacological effects,market conditions of medroxyprogesterone acetate 2.Then the synthetic methods of 17a-hydroxy progesterone raw materials are reviewed and evaluated,as well as the four synthetic routes of medroxyprogesterone acetate 2 in detail.In the second chapter:three synthetic routes of medroxyprogesterone acetate 2 were designed,experimentally verified and optimized,and the better reaction conditions for each synthetic route were obtained.Route A:firstly 17a-hydroxy progesterone 4 was used as starting material,which was transformed to the intermediate 16 by enol etherification,Mannich reaction and Hofmann elimination;Secondly,the intermediate 7 was obtained by hydrogenation reaction and configuration inversion;Finally medroxyprogesterone acetate 2 was obtained by acetylation reaction;The total reaction time was 14.5 h,and the total yield reached 56.4%.Content of product 2:95.0%(HPLC).Route B:17?-hydroxy progesterone 4 was used as starting material,which was transformed to the intermediate 17 by acylation reaction,followed by Mannich and Hofmann elimination to obtain the intermediate 11.Finally medroxyprogesterone acetate 2 was obtained by hydrogenation reaction and configuration inversion;The total reaction time was 16.5 h,and the total yield reached 62.7%.Content of product 2:99.6%(HPLC).Route C:17a-hydroxy progesterone 4 was used as starting material,which was transformed to the intermediate 8 by 17a acetylation reaction,followed by Mannich and Hofmann elimination reaction to obtain the intermediate 11,Finally medroxyprogesterone acetate 2 was obtained by hydrogenation reaction and configuration inversion;The total reaction time was 17.5 h,and the total yield reached 73.6%.Content of product 2:99.8%(HPLC).In summary,Three routes have been the expected product.Through the experimental analysis and data comparison,Route C is a preferred route,which avoids the production of by-product 21 and 6? methyl by-product 24,as well as significantly reduces the content of 6? methyl by-product 25.Route C has the higher purity of the product,the higher total yield,easier operation,higher security,and more environmental friendly.