Patent GB-575677-A (GB)
Title: Improvements in the production of 2-amino hexane and therapeutic compositions derived therefrom
Inventor: SHONLE HORACE ABBOTT
Filed: 1943-03-23
Abstract: 2-Amino hexane, which may be used as such or in the form of an acid addition salt for the treatment of nasal congestion (see Group VI), may be prepared by reacting hexanone-2 with hydroxylamine and reducing the resulting hexanone-2-oxime with hydrogen by means of a hydrogenation catalyst such as Raney nickel; desirably the hydroxylamine is prepared in the presence of the hexanone-2 by reacting hydroxylamine sulphate, hydrochloride or other salt with a base such as sodium hydroxide or carbonate; a slight excess of hydroxylamine is used and the hexanone-2-oxime obtained is dried, for example, with a dehydrating agent such as sodium or magnesium sulphate, before the reduction step. According to a further method, hexanone-2 is heated with ammonia and hydrogen in the presence of a hydrogenation catalyst such as Raney nickel; desirably an excess of ammonia and hydrogen is used, the reaction being carried out conveniently in a bomb, the ammonia being dissolved in ethanol or other solvent.  Acid addition salts of 2-amino hexane are prepared by reacting the amine with an equivalent of the desired acid, suitably in a solvent such as ethyl ether, ethanol or water.  Racemic mixtures of the d-and l-forms of the amine and its salts are obtained by these processes and may be resolved by any of the well-known methods. Examples 1 and 2 describe the preparation of 2-amino hexane according to both of the above-described methods.  In example (3), 2-amino hexane sulphate is prepared by evaporating a mixture of 2-amino hexane, absolute alcohol and aqueous sulphuric acid to dryness and washing the white solid residue with ethyl ether-ethanol mixture and finally with dry ethyl ether.  Example (4) describes the preparation of the amine hydrochloride which comprises passing hydrochloric acid gas into an ethyl ether solution of the amine, filtering off the precipitated amine hydrochloride and recrystallising from ethanol-ethyl ether.  Example (5) describes the reaction of 2-amino hexane with an alcoholic solution of d-camphoric acid to give the amine d-camphorate.  Other acid salts may be prepared similarly from malic acid, benzoic acid, glycollic acid, nicotinic acid, maleic acid, gluconic acid, succinic acid, acetic acid, propionic acid, malonic acid, hydrobromic acid and phosphoric acid.  The Specification as open to inspection under Sect. 91 describes further methods for the preparation of 2 - amino hexane; thus hexanone-2 may be heated with four molar equivalents of formamide or ammonium formate, so yielding the formyl derivative of 2-amino hexane which is freed of water-soluble compounds by water washing and refluxed with concentrated hydrochloric acid; the resulting amine hydrochloride is treated with sodium hydroxide to liberate the amine base. Alternatively, hexanone-2 may be reacted with hydroxylamine as above, and the hexanone-2 oxime reduced by means of sodium and a primary alcohol such as ethanol.  Examples of these methods are given.  This subject-matter does not appear in the Specification as accepted.ALSO:2-amino hexane and its acid addition salts (see Group IV) may be employed as vasconstrictors.  2-amino hexane may be administered topically as a solution in a suitable solvent, such as cottonseed oil, or liquid petrolatum, or in a jelly or ointment, or may utilized directly by inhalation.  The acid addition salts may be administered in a water solution such as an isotonic water solution, a sugar solution, such as glucose, a physiological saline solution or isotonic water solution; they may be used topically in a jelly prepared by incorporating the acid addition salt in water, glycerine, and some thickening agent such as gum tragacanth, sodium alginate or methyl cellulose.  In addition, the 2-amino hexane or an acid addition salt may be combined with local anaesthetic bases or their acid addition salts; preferably the acid addition salts of both are employed and such combinations may be used in aqueous solutions, jellies and ointments.  Specified anaesthetic bases are cocaine, procaine, D -(2-methyl-piperidino)-propyl benzoate, p-amino-benzoyl-dimethylamino-methyl butanol, p-amino benzoyl D -di-p-butlylamino propanol, p-amino-benzoyl-n-2-2-dimethyl-3-diethylaminopropanol, monoisobutylaminoethyl-p-aminobenzoate, piperidinopropanediol-di-phenylurethane, 2-butyl oxyquinolinecarboxylic acid-4-diethyl-ethylenediamine and D -diethylamino propylcinnamate.  The acid addition salts of 2-amino hexane referred to are those derived from acetic, propionic, glycollic, malic, maleic, malonic, gluconic, succinic, benzoic, camphoric, nicotinic, hydrobromic, hydrochloric, sulphuric and phosphoric acids.  According to Examples (6) an inhalant comprises 2-amino hexane, menthol, camphor, oil of thyme and liquid petrolatum (7) a jelly comprises 2-amino hexane sulphate, glycerine, tragacanth, methyl salicylate, sodium phosphate and water to make (8) an an ointment comprises 2-amino hexane, menthol, camphor, oil of wintergreen, anhydrous wool fat, liquid petrolatum, and white petrolatum to make (9) a nasal spray comprises 2-amino hexane sulphate, chlorbutanol and physiological saline.  In Example (8) the amine may be replaced by the above mentioned acid salts, while in Example (6) oil soluble acid addition salts such as 2-amino hexane oleate may replace the amine.  The d- and 1- forms of the amine and its acid addition salts of racernic mixtures may be used above.