Studies On The Synthetic Process Of Olmesartan Medoxomil

Olmesartan medoxomil,one of the sartans,is an angiotensin ? receptor antagonist developed by Sankyo company.Olmesartan medoxomil is a prodrug that is rapidly converted into olmesartan by ester hydrolysis in vivo.Much attention was paid due to its high bioavailability,long elimination half-life,low side effect,and then the market of olmesartan medoxomil would have broad prospect and high economic benefit which could be obtained by the production of olmesartan medoxomil.Developing a simple,economical,green synthetic process of olmesartan medoxomil was focused in this paper.A comprehensive survey of olmesartan medoxomil's synthetic routes was reviewed.The advantages and disadvantages of each synthetic route were evaluated,and the third synthetic route was chose as the suitable synthetic route for industrial-scale production.The advantages of the third synthetic route involved mild reaction conditions,short synthetic steps,commercial starting materials and easy operation.Lots of advantages were found in the third synthetic route,but it still has much room for improvement.The main improvements were provided by our lab and listed as followed:1)the first stepThe operation of the solvent DMF's recovery was simplified;K2CO3 was chosen as the acid binding agent instead of t-BuOK,and the reaction conditions became milder than before.Water removing by MgSO4 was replaced by the azeotropic water removing.Recrystallization was chosen as the purification method instead of column chromatography.2)the second stepThe hydrolysis and esterification solvent were unified into one solvent DMF instead of the hydrolysis solvent dioxone and the esterification solvent DMAc,and the separation of the intermediate was removed.LiOH was replaced by cheaper KOH.3)the third stepTernary solvent(acetic acid,ethyl acetate and water)was replaced by binary solvent(acetone and water)as the reaction solvent and acetone could be easily recycled because of simple separation of acetone and water.The efficient elimination of trityl alcohol was achieved.The combination of deprotection and purification by recrystallization in one step was achieved.In conclusion,an efficient process of olmesartan medoxomil was developed with an overall yield of 74%,and the HPLC purity of the product can be more than 99.0%.The costs of raw materials could be as low as ? 866 Yuan/kg,so the process was suitable for industrial production.