Process for preparing an anticholinergic

#The invention relates to a new process for preparing (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane-bromide.

#The compound (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane-bromide is known from European Patent Application EP 418 716 A1 and has the following chemical structure:

#The compound has valuable pharmacological properties and is known by the name tiotropium bromide (BA679). Tiotropium bromide is a highly effective anticholinergic and can therefore provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease).

#The Examples which follow serve to illustrate some methods of synthesis carried out by way of example in order to prepare tiotropium bromide. They are intended to be taken as possible methods provided by way of example, without limiting the invention to their content.

#Preparation of the Tropenol Ester (VII)

#Ammonia (1.8 kg) is added to 10.9 kg of tropenol hydrochloride in toluene (95 l) at 25° C. The suspension obtained is stirred at constant temperature for about 1 h. The ammonium hydrochloride formed is then filtered off and rinsed with toluene (26 l). At an external temperature of about 50° C. some of the toluene (about 60 l) is distilled off in vacuo. After cooling to about 25° C., 15.8 kg of methyl di-(2-thienyl)glycolate is added and the resulting mixture is heated to 50° C. to dissolve it. Toluene (40 l) is placed in another apparatus and sodium hydride (2.7 kg) is added thereto at about 25° C. The solution previously prepared from tropenol and methyl glycolate is added to this solution within 1 hour at 30° C. After it has all been added the mixture is heated to 75° C. at reduced pressure for about 7 hours with stirring. The methanol formed is distilled off. The mixture remaining is cooled and added to a mixture of water (958 l) and 36% hydrochloric acid (13.2 kg). The aqueous phase is then separated off and washed with methylene chloride (56 l). After the addition of some more methylene chloride (198 l) the mixture thus obtained is adjusted to pH=9 with prepared soda solution (9.6 kg of soda in 45 l of water). The methylene chloride phase is separated off and the aqueous phase is stirred with methylene chloride (262 L). The methylene chloride phase is evaporated down to the residue at 65° C. The residue is taken up in toluene (166 l) and heated to 95° C. The toluene solution is cooled to 0° C. The crystals obtained are separated off, washed with toluene (33 l) and dried at about 50° C. for a maximum of 24 hours in a nitrogen current. Yield: 18.6 kg (83%); melting point: about 160° C. (measured by DSC at a heating rate of 10 K/min);