Synthesis Research For Iloperidone, Metixene Hydrochloride And Brinzolamide

Studies on the asymmetric catalytic synthesis and organic processes of Orlistat,Atorvastatin,Brinzolamide,Metixene Hydrochloride,Iloperidone,Agomelatine and Chinomethionate were described in this thesis that consists of six items listed below.Chapter 1:We examined the effects of various achiral additives on(S)-BINOL/Ti(IV)catalyzed Mukaiyama-aldol reaction of aldehydes with Chan's diene to uncover that under LiCl mediated condition the reaction could be performed at room temperature with high enantioselectivities of up to 99%ee to afford optically active ?-hydroxy-?-ketoesters which are also essential intermediates of drugs used in treatment of hyperlipidemia and arteriosclerosis.The asymmetric total synthesis of diet drug Orlistat was presented.The key step Mukaiyama-aldol reaction followed by Noyori reduction and Frater-Seebach alkylation was employed to construct three key chiral centers of the Orlistat side chain.A new practical synthetic method of the key chiral intermediate towards Lipitor(Atorvastatin Calcium)was developed.The synthesis of the key intermediate commenced with asymmetric Mukaiyama-aldol reaction of 1,3-Bis(timethylsiloxy)-1-tert-butoxybuta-1,3-diene to genarate the desired ester in high yield with good enantioselectivity.Asymmetric Methoxydiethylborane reduction followed by subsequent protection with 2,2-dimethoxypropane,and deprotection of Phth afforded the key chiral intermediate successfully in a 4-steps sequence that was considered to be much shorter and more efficient.Chapter 2:The scalable asymmetric synthesis of Brinzolamide was achiev ed via a practical 4-steps reaction sequence in high yields with good enantiosel ectivities.Reduction of 3-Acetyl-5-chloro-2-thiophenesulfonamide with(+)-B-chl orodiisopinocampheylborane and subsequent cyclization of the resulting alcohol under basic condition produced(S)-3,4-Dihydro-6-chloro-4-hydroxy-4H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide,which was alkylated with 3-bromopropyl methyl,tre ated with BuLi followed by SO2 and hydroxylamine to afford the sulfonamide.Successive secondary hydroxyl tosylation and amination gave desired Brinzola mide.Chapter 3:An efficient and cost-effective way to synthesize metixene hydrochloride was reported.We started the approach with Ullmann coupling of 2-mercaptobenzoic and iodobenzene to provide 2-(phenylthio)benzoic acid.After polyphosphoric acid catalyzed Friedel-Crafts cyclization,subsequent NaBH4-AlCl3 reductive removal of carbonyl and N-alkylation with N-methyl-3-chloromethylpiperidine,the desired Metixene hydrochloride was successfully obtained in high yield.This improved scalable process was carried out under mild condition without any hazardous reagents.Chapter 4:A novel synthetic route and optimized process of Iloperidone,an antipsychotic drug was described.The target molecule was synthesized via oximination of(2,4-difluorophenyl)-piperidin-4-ylmethanone hydrochloride to give(2,4-difluorophenyl)-piperidin-4-ylmethanone oxime hydrochloride,followed by N-alkylation with 4-(3-chloropropoxy)-3-methoxy-phenylethanone,and final cyclization in the presence of potassium hydroxide.Chapter 5:The new synthetic method and improved scalable process of Agomelatine were reported.The synthesis of Agomelatine commenced with 7-methoxytetralone and acetonitrile via condensation and dehydrogenated under DDQ-AcOH condition to provide the corresponding cyanide intermediate which was then reduced and acetylated.Chapter 6:The optimized synthesis of Chinomethionate from benzene-1,2-diamine in 4 steps was reported herein.Most of the intermediates were highly crystallizable.Commercially available 4-methylbenzene-1,2-diamine was condensed with oxalic acid in aqueous hydrochloric acid to afford 6-methylquinoxaline-2,3(1H,4H)-dione,which underwent chlorination,thiolation and carbonation to provide the desired Chinomethionate in high overall yield.The advantages of this method include good yields,short reaction times,and simple procedures and,in most cases,the product is precipitated from the reaction media.