Method for manufacturing scopinium salts

摘要

Preparing N-methylscopinium salts (I) comprises: converting ester compounds (2a) or their solvates or hydrates in the presence of a solvent and base to hydroxy compounds (3a); and reacting (3a) without isolation with a cationic salt to give (I). Preparing N-methylscopinium salts of formula (I) comprises: converting ester compounds of formula (2a) or their solvates or hydrates in the presence of a solvent and base to hydroxy compounds of formula (3a); and reacting (3a) without isolating with a cationic salt of formula (Kat+>Y1->) to give (I). Y1->single negatively charged lipophilic anion comprising hexafluorophosphate, tetrafluoroborate, tetraphenylborate or saccharinate, preferably hexafluorophosphate or tetraphenylborate; X->single negatively charged anion comprising Cl, Br, I, methanesulfonate, p-toluenesulfonate, nitrate or trifluoromethanesulfonate, preferably Br; R : 1-4C alkyl, 2-6C alkenyl or 1-4C alkylene-phenyl (all optionally substituted by OH, hydroxymethyl or 1-4C alkoxy), preferably CH3, -CH2-CH3, -CH2-CH2-OH, -CH(OH)-CH3, -CH2-phenyl, -CH(OH)-phenyl or -CH(CH2OH)-phenyl (preferred); and Kat+>cation comprising Li+>, Na+>, K+>, Mg2+> or Ca2+>. An independent claim is included for a preparation of tiotropium salts of formula (4a) comprising preparation (I); reaction of (I) with dithienylglycolic acid compounds of formula (5a) in the presence of solvent to give tiotropium salts of formula (6a); and reaction of (6a) without isolation with a cationic salt of formula (Kat+>X1a->) (b) to give (4a). X1a->single negatively charged anion comprising Cl, Br, I, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate or trifluoromethanesulfonate; and R1>OCH3, OC2H5, propoxy, isopropoxy, isopropenyloxy, butoxy, O-N-succinimide, O-N-pthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy or 2-allyloxy, -S-methyl, -S-ethyl or -S-phenyl. In formula (b), Kat+>cation comprising Li+>, Na+>, K+>, Mg2+>, Ca2+> or organic cation having quaternary N. [Image] [Image].