Studies On The Oxidative Elimination Of 1,2-2H Sterides And The Synthesis Of Vardenafil

Finasteride is a specific inhibitor for type-Ⅱ 5α-reductase during the metabolic process of testosterone,which can effectively reduce the concentration of dihydrotestosterone in blood and prostate.Thus,Finasteride is used in the treatment of benign prostatic hyperplasia.In addition,finasteride has a very good development potential in male hair loss and female hirsutism and other diseases.Dihydrofinasteride is an important intermediate for the preparation of finasteride,which can be converted to finasteride by dehydrogenation.A large number of dehydrogenation methods of dihydrofinasteride to finasteride have been reported,but some shortcomings still exist,such as harsh reaction conditions,poor selectivity,complex byproducts and poor yields.Therefore,it is of great theoretical and practical significance to develop an efficient and gentle method to prepare finasteride.In the second chapter of this paper,the dihydrocafenamine intermediate was successfully prepared by multi-step reaction with progesterone as the starting material,and 2-iodohydrofenadine was prepared via iodination of dihydrocafenamine.The effects of different recrystallization solvents on the recrystallization yield and purity of 2-iododipentanol were investigated,and 2-iodohydrofenadine was obtained in high purity.high purity of 2-iodohydrofenadine was synthesized by using dihydrocanthamine as the starting material.Then,the effects of different alkalis,oxidizing agents,solvents,reaction time and the ratio of substrates to the reaction were investigated,and the optimum reaction conditions were obtained as follows:the best oxidant was potassium peroxydisulfate,the best solvent is THF,the optimum reaction temperature is room temperature,and the best ratio of the substrates is n2-iodohydrofenadine/npotassium persulfate = 2.0.The oxidative eliminations of 2-iodohydrofenadine,2-iodo-3-oxo-4-aza-5α-androst-17β-formic acid and 2-iodo-3-oxo-4-aza-5α-androst-17β-methyl formate were investigated under the optimized conditions,anf the corresponding products were obtained in high yield with purity of 99.8%.This method has the advantages of stable materials,mild reaction conditions,friendly environment,high yield and high purity.This method provides an efficient method for the preparation of finasteride and its analogues.Vardenafil is one of the PDE V inhibitors,marketed for the treatment of male erectile dysfunction(MED),pulmonary arterial hypertension(PAH)and other diseases.Comparing to PDE V inhibitors,vardenafil has some advantages such as less dosage and fast onset of action.The synthesis process of vardenafil is so complicated that its price is very high.There for,it is worth modifying the synthesis process of vardenafil.After evaluation of raw materials and reaction yield,2-butyl amino propionic acid and n-butyl chloride were used as raw materials.The desired vardenafil was obtained through six steps,such as substitution reaction,condensation reaction and sulfonation reaction.In this paper,the condensation reaction was modified,and the key mediate compound 4 was obtained via a "one-pot" reaction in good yield,which simplified the experimental operation and made it more suitable for industrial production.The preparation of vardenafil monohydrochloride has rarely reported at present.Solvents,amount of hydrochloric acid and temperature were studied to optimize the reaction.The optimal condition for the muriatic reaction was finally identified as followings:VDCM/Vether=2.0,1.0 mol/L hydrochloric acid ether solution,0 0C.The vardenafil monohydrochloride was obtained in the yield of 96%,when the reaction was performed at the optimal condition.