Patent GB-805859-A (GB)
Title: Improvements in or relating to the production of tropine derivatives
Filed: 1956-03-02
Abstract: Tropine derivatives having the general formula: <FORM:0805859/IV (b)/1> in which R1 is H, OH or an O-alkyl radical containing 1 to 3 carbon atoms and R2 is H, a C1-C3 alkyl radical or an aryl radical are obtained by reducing with hydrogen a nortropinone derivative having the general formula: <FORM:0805859/IV (b)/2> in which R1 is as defined above in the presence of an aldehyde R2CHO in which R2 is as defined above.  The propine derivatives of formula (I) may also be obtained by reducing a nortropinone derivative of formula (II) with catalytically activated or nascent hydrogen and subjecting the resulting nortropine derivative to the action of hydrogen in the presence of an aldehyde R2CHO or by acting upon a nortropinone derivative of formula (II) with an aldehyde R2CHO and hydrogen, separating the resulting N-substituted nortropinone derivative and reducing it with hydrogen.  The reduction with hydrogen in each type of procedure may be effected at atmospheric or superatmospheric pressure and at room temperature or elevated temperature.  The reduction may be effected with catalyticallyactivated or nascent hydrogen. Depending on whether a nortroponone derivative of formula (II) is reduced with catalytically-activated or nascent hydrogen derivatives of the tropine series or pseudo-tropine series are formed.  In examples: (1) a solution of nortropinone (obtained by heating a methanolic solution of nortropinone carbamate) and n - butanol in absolute methanol is hydrogenated in the presence of Raney nickel in an autoclave at 45 DEG  C. and under an initial pressure of 60 atmospheres to form N-butyl nortropine which is recovered as its hydrochloride; (2) a solution of nortropinone and benzaldehyde in methanol is hydrogenated as in (1) to form N-benzyl nortropine; (3) a solution of nortropinone carbamate in absolute methanol is heated to 40 DEG  C. and hydrogenated in the presence of Raney nickel at 40-45 DEG  C. and at an initial pressure of 60 atmospheres, the solution is separated from the catalyst by filtration and heated to dryness in a vacuum, the residue is dissolved in methanol and treated with ether and a current of dry carbon dioxide passed through to precipitate nortropine carbamate which is then heated in methanol solution to form nortropine, a solution of nortropine in methanol is then treated with formaldehyde and hydrogen in the presence of Raney nickel to form tropine which is recovered in the form of its hydrochloride; (4) a solution of 6-methoxy-nortropinone in methanol is hydrogenated as in (3) to form 6-methoxynortropine which is converted to the carbamate by treating with dry carbon dioxide, the carbamate is heated in methanolic solution to form 6-methoxynortropine which is then converted to 6-methoxytropine by reacting with formaldehyde and hydrogen in the presence of Raney nickel at atmospheric pressure and room temperature, the 6-methoxytropine being recovered in the form of its hydrochloride; (5) a solution of 6-ethoxynortropinone in ethanol is hydrogenated in an autoclave in the presence of Raney nickel and the resulting 6-ethoxynortropine is then treated with formaldehyde and hydrogen in the presence of Raney nickel to form 6-ethoxytropine which is converted to 6-ethoxytropine bromomethylate by dissolving in ethanol and adding methyl bromide; (6) 6-methoxynortropine obtained as in (4) is treated with n-butanol and hydrogen in the presence of Raney nickel at room temperature and at atmospheric pressure to form N-butyl-6-methoxynortropine which is converted to its bromomethylate by treatment with methyl bromide; (7) a solution of 6-methoxynortropine and benzaldehyde in methanol is treated with hydrogen as in (6) to form N-benzyl-6-methoxynortropine; (8) sodium is added portionwise to a boiling solution of 6-methoxy-nortropinone in ethanol and the resulting 6-methoxy-pseudo-nortropine is recovered and treated with formaldehyde and hydrogen in methanol solution in the presence of Raney nickel to form 6 - methoxy - pseudo - tropine bromomethylate which is recovered as its bromomethylate by treating with methyl bromide; (9) formaldehyde is introduced into a solution of nortropinone in methanol and the mixture is then treated with hydrogen at room temperature and atmospheric pressure in the presence of Raney nickel to form tropinone which is converted to its hydrochloride and the latter is hydrogenated in methanol in the presence of Raney nickel catalyst at 45 DEG  C. and at an initial pressure of 60 atmospheres to yield tropine hydrochloride. Nortropinone is obtained by adding a solution of succinic dialdehyde in hydrochloric acid (obtained by heating 2,5-diethoxytetrahydrofurane with hydrochloric acid) to a solution of acetone dicarboxylic acid, ammonium chloride and sodium acetate in water, allowing the mixture to stand for 3 days at 20-25 DEG  C., then adding potassium carbonate to render the mixture alkaline to litmus, extracting with chloroform, concentrating and drying the extract, taking up in ether, drying the ether solution and then treating with a current of dry carbon dioxide to form the carbamate which is then heated in methanol solution to form nortropinone.  6 - Methoxynortropinone is obtained by treating a mixture of acetone dicarboxylic acid, ammonium chloride and sodium acetate in aqueous solution with an hydrochloric acid solution of O-methylmalic dialdehyde (prepared by heating 2,3,5-trimethoxytetrahydrofurane with aqueous hydrochloric acid).  6-Ethoxynortropinone is obtained by adding an hydrochloric acid solution of O-ethylmalic dialdehyde (obtained by heating 2,3,5-triethoxytetrahydrofurane with aqueous hydrochloric acid) to a solution of a acetonedicarboxylic acid, ammonium chloride and sodium acetate in water.  Specifications 737,419, 756,008 and 764,227 are referred to.