Preparation of thiazolo(3,4,5-de)(4,1)benzothiazepine-6,6-dioxide derivative, useful for treating or preventing convulsions and glutaminergic disorders, requires few stages and chromatographic purifications

摘要

Method for preparing 2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine-6,6-dioxide methanesulfonate (10). Method for preparing 2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine-6,6-dioxide methanesulfonate of formula (10) comprises: (a) protecting 4-trifluoromethylaniline by refluxing with di-tert-butyl-carbonate in monochlorobenzene; (b) converting the product to 2-hydroxymethyl-4-trifluoromethyl phenylcarbamate (12) without isolation of the intermediate 2-formyl compound; (c) reacting (12) with thioglycolic acid in presence of p-toluenesulfonic acid to form 7-trifluoromethyl-1,5-dihydro-3H-[4,1]benzothiazepin-2-one (6); (d) reducing (6) to 7-trifluoromethyl-1,2,3,5-tetrahydro[4,1]benzothiazepine (7); (e) reacting (7) with bromine and potassium thiocyanate in acetic acid to form 2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine hydrobromide (8); and (f) oxidizing (8) to the free base form of (10) then treatment with methanesulfonic acid to give (10). [Image] Independent claims are also included for the following: (1) preparation of (6) by step (c); (2) preparation of the (S)-6-oxide of 2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine; (3) preparation of (8) by steps (a)-(e); and (4) tert-butyl 2-hydroxymethyl-4-trifluoromethylphenyl carbamate (8); and 2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepin-6-oxide trifluoroacetate as new intermediates. ACTIVITY : Anticonvulsant; Vasotropic; Neuroprotective; Nootropic; Antiparkinsonian; Tranquilizer; Antidepressant; Neuroleptic; Analgesic; Antiinflammatory; Anorectic; Antimigraine; Antiemetic. No details of tests for these activities are given. MECHANISM OF ACTION : None given.