Patent EP-2036898-A2 (EP)
Title: Method for manufacturing 1.3 dioxolane 2ones and carboxylic acid esters by transacylation under alkaline  reaction conditions
IPC: C07D409/14
Filed: 2007-09-13
Abstract: Preparation of 1,3-dioxolan-2-one compound of formula (I) comprises reacting 2-hydroxycarboxylic acid ester compound (II) with a carbonyl group containing compound (III) in a suitable solvent under the addition of a suitable base catalyst and in the presence of zeolite. Preparation of 1,3-dioxolan-2-one compound of formula (I) comprises reacting 2-hydroxycarboxylic acid ester compound of formula (R 3-O-C(=O)-C(R 1)(R 2)(OH)) (II) with a carbonyl group containing compound of formula (C(=O)(R 4)(R 5)) (III) in a suitable solvent under the addition of a suitable base catalyst and in the presence of zeolite. R 1, R 2(hetero)aryl (optionally substituted by one or more substituents) or H; R 3CH 3, C 2H 5, propyl, isopropyl, isopropenyl, butyl, N-succinimide, N-phthalimide, phenyl, nitrophenyl, fluorophenyl, pentafluorophenyl, vinyl or 2-allyl; and either R 4, R 5H, (1-6C)-alkyl; or R 4R 5optionally substituted and optionally saturated carbocyclic or heterocyclic ring containing one or more heteroatoms, which are S, N or O. Where: R 4and R 5cannot be simultaneously H. Independent claims are included for: (1) the preparations of hydroxy group substituted carbonyl compound of formula (R 6-O-C(=O)-C(R 1)(R 2)(OH)) (V) comprising either reacting (II) with (III) in a suitable solvent under the addition of a suitable base catalyst and in the presence of zeolite to obtain (I) and reacting (I) with an alcoholic compound of formula (R 6-O-H) (VII) in a suitable solvent under the addition of a suitable base catalyst and in the presence of zeolite, or reacting (II), (III) and (VII) in a suitable solvent under the addition of a suitable base catalyst and in the presence of zeolite; (2) a process for the preparation of tiotropium salt of formula (Xa) comprising reacting (II) with (1S,2R,7S)-7-hydroxy-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.0,2,4]nonane hexafluorophosphate and (III), preferably acetone, under the addition of a base catalyst in form of a tert.alcoholate, and the presence of zeolite to obtain (1S,2R,7S)-7-hydroxy-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.0,2,4]nonane hexafluorophosphate, and reacting the obtained (1S,2R,7S)-7-hydroxy-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.0,2,4]nonane hexafluorophosphate with a salt of formula (cation +>X ->) without isolating; (3) 1,3-dioxolan-2-one compound (I), preferably 2,2-dimethyl-5,5-di-thiophen-2-yl-[1,3]dioxolan-4-one (Ia) and 8,8-dimethyl-3-oxo-2,2-di-thiophen-2-yl-1,4-dioxa-8-azonia-spiro[4.5]decane (Ib); and (4) a salt of 8,8-dimethyl-3-oxo-2,2-di-thiophen-2-yl-1,4-dioxa-8-azonia-spiro[4.5]decane of formula (Id), where the substituent at the nitrogen is substituted by alkyl, preferably methyl, ethyl, n-propyl, isopropyl and the thienyl residue is optionally substituted by one or more substituents of fluoro, chloro, bromo, iodo, CN, 1-4C-alkyl, 1-4C-alkoxy, hydroxyor trifluoromethane. R 6an organic residue; X ->a negatively charged anion, preferably Cl, Br, I, sulfate, phosphate, methane sulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluene sulfonate or trifluoromethane sulfonate; cation +>Li +>, Na +>, K +>, Mg 2+>, Ca 2+>or organic cation with a quaternary N (preferably N,N-dialkylimidazolium or tetraalkylammonium), and X 1 ->Cl, Br, I, sulfate, phosphate, methane sulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluene sulfonate. [Image] [Image] [Image] ACTIVITY : Respiratory-Gen.; Antiasthmatic. MECHANISM OF ACTION : Muscarinic receptor inhibitor.