Condensation of methyl 2-(chlorosulfonyl)benzoate (I) with 2-(trifluoromethyl)aniline (II) in the presence of DMAP and pyridine yielded sulfonamide (III), which was then cyclized in refluxing xylene to provide the saccharin derivative (IV). Further condensation with tert-butyl acetate (V) using potassium bis(trimethylsilyl)amide as the base afforded ketoester (VI). Then, bromination with NBS in CCl4 gave (VII), which was cyclized to the benzothiazine (VIII) with K2CO3 in DMF. Treatment with trifluoromethanesulfonic anhydride and pyridine in CH2Cl2 furnished the vinyl triflate (IX), and this was then coupled with boronic acid (X) in the presence of Pd(PPh3)4 and K2CO3 to produce (XI). Finally, the tert-butyl ester was cleaved with trifluoroacetic acid in CH2Cl2.
A new, more efficient synthesis has been reported for the intermediate (XVIII). The saccharin derivative (IV) was prepared by two alternative routes. Thus, 2-sulfobenzoic acid cyclic anhydride (XII) was treated with two equivalents of 2-(trifluoromethyl)aniline (II) to give the anilinium salt (XIII), which was cyclized with POCl3 to produce (IV). Also, starting from benzenesulfonyl chloride (XIV), the corresponding sulfonamide (II) was obtained by reaction with aniline (II). Ortho lithiation with n-butyllithium at low temperature, followed by CO2 quenching, afforded carboxylic acid (XVI), which upon treatment with Ac2O and methanesulfonic acid cyclized to the saccharin (IV). Then, the saccharin ring was opened by treatment with NaOMe, and subsequent treatment with methyl bromoacetate furnished diester (XVII). Finally, Claisen cyclization promoted by TiCl4 formed the key intermediate (XVIII).