Patent GB-805883-A (GB)
Title: Tertiary alcohol derivatives of 8-alkylnortropanes and the acid and quaternary ammonium salts thereof
Filed: 1956-06-27
Abstract: The invention comprises tertiary alcohols of the tropane series, of the general formula <FORM:0805883/IV (b)/1> (wherein R represents a straight or branched chain alkyl radical of 1-4 carbon atoms, n is from 0 to 3, and R2 and R3 each represent alkyl of 1-6 carbon atoms, cycloalkyl of 5 or 6 carbon atoms, cycloalkyl-alkyl of 6-10 carbon atoms, 2-thienyl, 2-pyridyl, or phenyl which may be substituted by an alkyl or alkoxy group of 1-4 carbon atoms) and their acid addition and quaternary ammonium salts, and the preparation thereof from compounds of the general formula <FORM:0805883/IV (b)/2> (wherein R1 represents hydrogen or a straight or branched chain alkyl radical of 1-4 carbon atoms) by the following processes: (a) (when R2 and R3 are identical) reacting an ester of formula (II) with a lithium or magnesium derivative prepared from an R2-halide (the lithium compound being normally used except when R2 is cycloalkyl); (b) (when R2 and R2 are identical or different but not both 2-pyridyl) reacting an ester of formula (II) with a Grignard reagent prepared from an R2 halide (other than a 2-halopyridine), or reacting an acid of formula (II) or an acid addition salt thereof with a lithium derivative prepared from an R2-halide (other than a cycloalkyl halide or a 2-halopyridine) to form a ketone of the general formula <FORM:0805883/IV (b)/3> (wherein R4 has the same meanings as R2 excepting 2-pyridyl), and reacting this with a lithium or magnesium derivative prepared from an R3-halide.  (The term "halide" throughout includes chloride, bromide and iodide).  Either process may be followed by conversion of the product into an acid addition salt by reaction with the appropriate acid, or into a quaternary ammonium salt by reaction with excess of an organic ester of sulphuric, a hydrohalic or an aromatic sulphonic acid in an organic solvent. Examples describe the preparation by method (a) of: (1) di - (2 - thienyl) - 3 - tropanecarbinol from methyl 3-tropanecarboxylate and 2-thienyl magnesium bromide; (2) diphenyl 3-tropanecarbinol (and its citrate and methobromide) from methyl 3-tropanecarboxylate and phenyl lithium; (3) 1 : 1-di-(2-thienyl)-2-(3-tropane)-ethanol (and its acetate and methobromide) from ethyl 3-tropaneacetate and the reaction product of phenyl lithium with thiophene; (4) 1 : 1-diphenyl-2-(3-tropane)-ethanol (and its hydrochloride and methobromide) from ethyl 3-tropaneacetate and phenyl lithium; (12) 1 : 1-diphenyl-3-(3-tropane)-propanol (and its hydrochloride and methobromide) similarly from ethyl b -(3-tropane)-propionate; (15) dimethyl-3-tropanecarbinol from methyl 3-tropanecarboxylate and methyl lithium; (16) 1 : 1-di-n-hexyl-2-[3-(N-isopropylnortropane)]-ethanol from methyl 3-(N-isopropylnortropane)-acetate and n-hexyl lithium; and by method (b) of: (5) 1 : 1-diphenyl-2-(3-tropane)-ethanol (isolated as its hydrobromide) by reacting 3-tropaneacetic acid hydrochloride with phenyl lithium in two stages via phenyl 3-tropanemethyl ketone; (6) 1-phenyl-1-(2-thienyl)-2-(3-tropane)-ethanol (and its maleate and methobromide) by preparing phenyl 3-tropanemethyl ketone as in (5) and reacting it with the reaction product of phenyl lithium with thiophene; (7) 1-phenyl-1-(2-pyridyl)-2-(3-tropane)-ethanol (and its hydriodide and methobromide) similarly using the reaction product of n-butyl lithium and 2-bromopyridine; (8) 1 - ethyl - 1 - phenyl - 2 - (3 - tropane) - ethanol (and its hydrochloride) similarly, using ethyl magnesium bromide; (9) 1-cyclohexyl-1-phenyl - 2 - (3 - tropane) - ethanol (and its hydrochloride and methobromide) by reacting ethyl 3-tropaneacetate with cyclohexyl magnesium bromide and the resulting cyclohexyl 3-tropanemethyl ketone with phenyl lithium; (10) 1 - (2 - cyclohexylethyl) - 1 - phenyl - 2 - (3 - tropane) - ethanol (and its hydrochloride, citrate and methobromide) similarly via 2-cyclohexylethyl 3-tropanemethyl ketone, using 2-cyclohexylethyl magnesium bromide in the first stage; (11) 1-(p-anisyl)-1-phenyl-2-[3-(N - isopropylnortropane)] - ethanol by reacting methyl 3 - (N - isopropylnortropane) - acetate with p-anisyl magnesium bromide and the resulting p-anisyl 3-(N-isopropylnortropane)-methyl ketone with phenyl lithium; (13) 1 - ethyl - 1 - (2 - pyridyl) - 3 - (3 - tropane) - propanol by reacting ethyl b -(3-tropane)-propionate with ethyl magnesium bromide and the resulting ethyl b -(3-tropane)-ethyl ketone with the reaction product of n-butyl lithium with 2-bromopyridine; (14) 1-(2-pyridyl)-1-p-tolyl-4-(3-tropane)-butanol by reacting ethyl g -(3-tropane)-butyrate with p-tolyl magnesium bromide and the resulting p-tolyl g -(3-tropane)-propyl ketone with the reaction product of n-butyl lithium with 2-bromopyridine; (17) 1-cyclopentyl - 1 - phenyl - 4 - (3 - tropane) - butanol by reacting ethyl g -(3-tropane)-butyrate with cyclopentyl magnesium bromide and the resulting cyclopentyl 3 - (3 - tropane) - propyl ketone with phenyl lithium.  Further examples (18-23) describe the quaternation of diphenyl 3-tropanecarbinol with diethyl sulphate, of 1 : 1 - diphenyl - 2 - (3 - tropane) - ethanol with methyl p-toluenesulphonate, diethyl sulphate, butyl bromide and butyl iodide, and of 1-cyclohexyl - 1 - phenyl - 2 - (3 - tropane) - ethanol with butyl bromide.  Other saltforming and quaternating agents specified are: tartaric, camphorsulphonic, propionic, butyric, succinic, glutaric, adipic, ascorbic, lactic, levulinic, malic, mandelic, cinnamic, gluconic, methanesulphonic, benzenesulphonic, fumaric, citraconic, itaconic, lauric, stearic, myristic, palmitic, linoleic, aspartic, sulphoacetic, sulphuric, sulphamic, phosphoric and nitric acids; methyl, ethyl, butyl, isobutyl, benzyl and naphthylmethyl chlorides, methyl iodide, propyl, allyl, methallyl, crotyl, benzyl and phenethyl bromides, ethylene bromhydrin and chlorhydrin, dimethyl sulphate, methyl benzenesulphonate and ethyl toluenesulphonate.  The products are useful as therapeutic agents acting on the parasympathetic and central nervous systems or as intermediates for such agents. Carboxylic acids and esters of the tropane series of the general formula (II) above are prepared as follows: (a) compounds in which n=0 by acylating a 3-hydroxytropane-3-carboxylic acid ester (e.g. methyl a -ecgonine) by means of a fatty acid anhydride having 4-8 carbon atoms in the molecule (preferably acetic anhydride), pyrolysing the product by passage through a packed column at about 350-500 DEG  C. to form an unsaturated ester, and subjecting this to catalytic hydrogenation of the double bond followed, if desired, by refluxing with excess of hydrochloric acid to form the hydrochloride of the free acid, from which other esters may be prepared; (b) compounds in which n=1, 2 or 3 by carrying out the requisite number of times one of the following reaction sequences: <FORM:0805883/IV (b)/4> and, if desired, esterification, or alcoholysis <FORM:0805883/IV (b)/5> (the starting material and the acid chloride being in the form of hydrochloride salts, and the final product being the free acid if an aqueous medium is used, otherwise an ester); (c) compounds in which n=1 by subjecting an N-alkyl-nor-tropinone to the following reaction sequence: <FORM:0805883/IV (b)/6> The preparation of the starting materials for the examples i described in detail.