Patent GB-694067-A (GB)
Title: Basic bicyclic alcohols and process for the manufacture thereof
Filed: 1951-04-06
Abstract: The invention comprises the following compounds: 1 - azabicyclo - (2 : 2 : 2) - 3 - octanol (hydroxyquinuclidine), 1-azabicyclo-(3 : 2 : 1)-6-octanol (hydroxy - isotropane), 1 - azabicyclo - (3 : 3 : 1) - 4 - nonanol (hydroxy - isogranatanine) and 1-azabicyclo - (3 : 3 : 1) - 2 - methyl - 4 - nonanol; salts of the above; esters of the above with certain araliphatic carboxylic acids (see below); salts of the esters. These are prepared as follows: (1) a 3- or 4-carbalkoxy-pyridine is treated with the appropriate alkyl halo-alkanoate and the resulting N-carbalkoxyalkyl-C-carbalkoxy-pyridinium halide hydrogenated to the piperidine; or a 3- or 4-carbalkoxypiperidine is reacted with an alkyl alkenoate; the esterifying groups have 1-7 carbon atoms; (2) the resulting N-carboxyalkyl-C-carbalkoxypiperidine is ring-closed by the Dieckmann method (heating with alkali-metal, e.g. potassium, in toluene or other inert solvent); (3) the product is hydrolysed and decarboxylated to the 1-azabicyclo-alkanone, e.g. by heating with hydrochloric acid; (4) reduction to the 1-azabicyclo-alkanol is effected by catalytic hydrogenation (platinum or Raney nickel), by lithium aluminium hydride or by an alkali metal (e.g. sodium) and alcohol; (5) esterification is achieved with a reactive derivative (e.g. halide) of the desired acid, preferably using the alkali metal derivative of the azabicycloalkanol; (6) the alcohols and esters form salts by treatment with inorganic acids, organic acids, e.g. hydrochloric, hydrobromic, sulphuric, phosphoric, tartaric, picric, and with quaternizing agents, e.g. methyl and ethyl bromides, methyl sulphate, benzyl chloride and bromide, methyl toluene-p-sulphonate. In the examples the following compounds are made: (1) 1-carbethoxymethyl - 4 - carbomethoxy - pyridinium bromide (from methyl isonicotinate, ethyl bromacetate and ethanol), 1-carbethoxymethyl-4-carbomethoxypiperidine (containing some 4-carbethoxy derivative due to ester interchange with the ethanol solvent), 1-azabicyclo-(2 : 2 : 2)-3-octanone (via hydrochloride) and picrate, 1 - azabicyclo - (2 : 2 : 2) - 3 - octanol (via hydrochloride) and picrate; (2) diphenylacetic ester of 1 - azabicyclo - (2 : 2 : 2) - 3 - octanol, and sulphate, methobromide and ethobromide; (3) fluorene - 9 - carboxylic ester of 1 - azabicyclo - (2 : 2 : 2)-3-octanol, and hydrochloride and sulphate; (4) diphenylchloracetic ester of 1-azabicyclo - (2 : 2 : 2) - 3 - octanol, hydrolysed to the benzilic ester; also hydrochloride and methobromide of the latter; (5) acetyltropic ester of 1 - azabicyclo - (2 : 2 : 2) - 3 - octanol, hydrolysed to a mixture of the tropic and atropic esters; (6) acetylmandelic ester of 1 - azabicyclo - (2 : 2 : 2) - 3 - octanol, isolated as hydrochloride; (7) 1-carbethoxymethyl-3-carbethoxypyridinium p  bromide (from ethyl nicotinate, ethyl bromacetate and ethanol), 1-carbethoxymethyl - 3 - carbethoxypiperidine, 1 - azabicyclo - (3 : 2 : 1) - 6 - octanone (via hydrochloride) and picrate, 1-azabicyclo-(3 : 2 : 1)-6-octanol (via hydrochloride) and picrate; (8) diphenylacetic ester of 1-azabicyclo-(3 : 2 : 1)-6-octanol, as hydrochloride; (9) fluorene-9-carboxylic ester of 1-azabicyclo-(3 : 2 : 1) - 6 - octanol, as hydrochloride; (10) 1-carbethoxyethyl-3-carbethoxypiperidine (from ethyl nipecotinate and ethyl acrylate), 1-azabicyclo-(3 : 3 : 1)-4-nonanone (via hydrochloride) and picrate, 1-azabicyclo - (3 : 3 : 1) - 4 - nonanol (via hydrochloride); (110 diphenylacetic ester of 1-azabicyclo - (3 : 3 : 1) - 4 - nonanol, as hydrochloride; (12) 1-(b -carbethoxyisopropyl)-3-carbethoxypiperidine (from ethyl nipecotinate and ethyl crotonate), 1 - azabicyclo - (3 : 3 : 1) - 2 - methyl - 4 - nonanone (as hydrochloride), 1 - azabicyclo - (3 : 3 : 1) - 2 - methyl - 4 - nonanol (via hydrochloride) and picrate; (13) diphenylacetic ester of 1-azabicyclo-(3 : 3 : 1)-2-methyl-4-nonanol, as hydrochloride.  The araliphatic acids from which esters may be derived are phenylacetic, fluorene-9-carboxylic, xanthene-9-carboxylic and acids derived from these by substituting hydroxyl, acetoxyl or hydroxymethyl on the a -carbon atom, e.g. mandelic, tropic and benzilic acids; also atropic acid.