Studies On The Synthesis Of Ripasudil Hydrochloride

Glaucoma is a heterogeneous ocular disease characterized by painless neuro-degeneration of retinal ganglion cells(RGCs)death,resulting in irreversible vision loss and optic nerve injury and eventually leading to blindness.It is the second leading cause of blindness that severely affecting more than 60 million patients worldwide.The pathogenesis of glaucoma is complicated and some of the risk factors contributing to glaucoma have been identified,but the elevated intraocular pressure(IOP)is believed to be the major factor for the glaucoma.Thus,IOP-lowering medications become the primary treatment strategy.Despite the availability of multiple medicines and surgical treatments,because of the inadequate intraocular pressure lowering,many patients still progress to become visually handicapped from glaucoma due to therapeutic failure.Therefore seeking for new novel drugs and treatments has evoked more and more attention.Rho/ROCK signal pathway,which has an effective modulation to IOP,has already become the focus in the treatment of glaucoma.Rho/ROCKs inhibitors are novel potential class of glaucoma therapeutics that can increase the facility of fluid outflow from the eye to lower the intraocular pressure and have mild side effect and better tolerance.UP to now,there are a series of novel ROCK inhibitors have been under investigation for the treatment of glaucoma,and four ROCK inhibitors are in different stages of clinical trials.Ripasudil is a selective ROCK inhibitor,developed by Kowa Company,Ltd,was approved in Japan in September 2014 for the treatment of glaucoma and ocular hypertension.Several synthetic methods for Ripasudil have been reported,but there are shortcomings including complicated operations,the use of dangerous reagents,environmental pollution,low yield and difficult in industrial production.In this study,we prepared Ripasudil hydrochloride according to the reported methods and made some optimizations in some synthetic steps.Under the alkaline conditions,the amino group of(S)-2-aminopropan-l-ol was reacted with 2-nitrobenzenesulfonyl chloride to give the sulfonamide 1,followed by the mesylation of its primary hydroxyl group in the presence of NMM.The reaction of the methanesulfonate 2 with 3-aminopropan-l-ol afforded the N-alkylated diamino alcohol 3,which underwent the intramolecular Mitsunobu N-alkyl cyclization with Ph3P and DIAD to give 1,4-diazepane 4 smoothly.After the protection of amino group in 4 with Boc,the 2-nitrobenzenesulfonyl group was removed by the reaction with benzenethiol to give the Boc-protected secondary amine 6,which was reacted with 4-fluoroisoquinoline-5-sulfonyl chloride hydrochloride to give the sulfonamide 7.The Boc protective group was finally removed with hydrochloric acid in ethanol to give the Ripasudil hydrochloride.In the process of preparing intermediate 7,the crystallization conditions,including the solvent ratio,crystallization temperature and time were optimized.In the process of removing the Boc protective group,the reaction and workup conditions were also investigated.Through this study the synthetic process for Ripasudil hydrochloride was finally established.In addition,the main related impurities in the synthesis of Ripasudil hydrochloride were also prepared and characterized.