GB517830A - Method of preparing quinuclidine and derivatives thereof - Google Patents

Abstract

517,830. Quinuclidine.KASTEL TVORNICA KEMIJSKOFARMACEUTSKIH PROIZVODA D. D., and PRELOG, V. Aug. 8, 1938, No. 23336. Convention date, Aug. 6, 1937. [Classes 2 (ii) and 2 (iii)] Quinuclidine and its derivatives of the general formula are prepared by reacting ammonia with trihalogen derivatives of the general formula where R1 R2 R3R4 each represent hydrogen or an alkyl acyl or carboxyl group and X, Y, Z represent halogen atoms. The action of ammonia takes place at a raised temperature preferably above 100‹C.and in some cases at an elevated pressure. In examples (1) 3-(2- bromo - ethyl) - 1:5 - dibromppentane is heated to 130‹-140‹C. for three hours in an autoclave with a 20 per cent. solution of ammonia in methyl alcohol. The reaction product is distilled, shaken with benzene-sulpho-chloride and caustic soda to remove ammonia and primary and secondary bases, and extracted with ether to give quinuclidine.Similarly 2-ethyl-quinuclidine may be obtained from 3-(2-bromobutyl) 1:5-dibromo pentane; (2) the ester of 1:5-dibromo-pentane-K-bromopropionic acid -3 is heated for six hours to 130‹-140‹C.with a 20 per cent. solution of ammonia in methyl alcohol and the product worked up as in example .(1) to give quinuclidine carboxylic acid -(2). The parent trihalogen compounds may be prepared by the action of hydrohalic acids on compounds of the general formula where U is a group which can easily be replaced by halogen such as hydroxyl, alkoxy or phenoxy, and V is a group which facilitates the introduction of halogen into the molecule in the alpha-position in respect to it such as a carbonyl or a carboxyl group. In example (1) above the parent 3-(2-bromo-ethyl)-1:5-dibromopentane is prepared from 4 - # - hydroxyethyltetrahydropyran by the action of hydrobromic acid for six hours at 100‹-110‹C.In example (2) above the parent material is prepared from tetrahydropyranyl-4-acetic acid. This is converted into its acid chloride with thionyl chloride, then treated with zinc ethyl iodide to give 1-(tetrahydropyranyl-4)-butanone-2 which is reduced by sodium in damp ether to 4-#-hydroxybutyltetrahydropyran. This is then halogenated with hydrobromic acid as above to give 1:5- dibromo-pentane-propionic acid -3 which is brominated with bromine in the presence of red phosphorus to the ester of 1:5-dibromopentonealpha-bromopropionic acid -3.