Patent GB-576943-A (GB)
Title: Improvements in the production of 2-amino-4-methyl hexane and therapeutic compositions derived therefrom
Inventor: SHONLE HORACE ABBOTT
Filed: 1943-03-17
Abstract: 2-Amino-4-methylhexane is prepared according to the following methods: (1) 4-methylhexanone-2- is reacted with hydroxylamine to produce the corresponding oxime which is reduced by treatment with hydrogen; (2) 4-methylhexanone-2 is reacted with formamide or ammonium formate and the reaction product hydrolysed with a mineral acid to give the acid addition salt of 2-amino-4-methylhexane from which the free amine may be liberated by treatment with a base; (3) 4-methylhexanone-2 is reacted with ammonia and hydrogen in the presence of a hydrogenation catalyst. Acid addition salts of the amine are prepared by reaction with an equivalent of the desired acid; this may be carried out in a suitable solvent such as water, ethanol or ethyl ether.  Racemic mixtures of the amine and its acid addition salts are obtained which may be resolved by well-known methods.  The amine and its salts may be used as vasoconstrictors in reducing congestion of the nasal passage (see Group VI).  In examples: (1) an aqueous solution of 4-methyl-hexanone-2 and hydroxylamine hydrochloride is stirred and aqueous sodium carbonate added with cooling; the water immiscible layer of 4-methyl hexanone-2 oxime is removed, dried with sodium or magnesium sulphate and reduced by reaction with sodium in absolute alcohol; (2) a solution of 4-methyl-hexanone-2 in absolute ethanol which has been saturated with anhydrous ammonia is reacted with hydrogen in the presence of Raney nickel, the reaction product being filtered and the resulting amine recovered by fractional distillation; (3) ammonium formate (4 mols.) and 4-methylhexanone-2 (1 mol.) are heated at 150 DEG  to 185 DEG  C. for 8-10 hours and the product washed with water giving a water-insoluble material comprising the formyl derivative of 2-amino-4-methylhexane; this is refluxed with concentrated hydrochloric acid to form the acid addition salt of the amine which is treated with aqueous caustic soda to liberate the free base; (4) 4-methylhexanone-2-oxime dissolved in ethanol is reduced by means of hydrogen in the presence of Raney nickel and the resulting amine recovered as in (2) above; (5) a mixture of 2-amino-4-methylhexane in absolute alcohol and the requisite amount of aqueous sulphonic acid is evaporated to dryness yielding the amine sulphate as a white solid; similarly, salts may be prepared from hydrochloric, hydrobromic, phosphoric, malic, maleic, malonic, acetic, propionic, succinic, glycollic, benzoic and nicotinic acids and n-hexyl sulphonic acid.ALSO:2-Amino-4-methylhexane and its acid addition salts (see Group IV) may be employed as vasoconstrictors for the treatment of congestion of the nasal passage.  The amine itself may be utilised directly by inhalation or may be administered in solvents such as cottonseed oil or liquid petrolatum, or in jellies and ointments. The amine salts may be used in isotonic water solution, in a sugar solution such as glucose, or in physiological saline, or in jellies prepared by incorporating the salt in water, glycerine and a viscous medium or thickening agent such as gum tragacanth, sodium alginate or methyl cellulose.  In addition, the amine or preferably an acid addition salt thereof may be combined with a local anaesthetic base or its salt; suitable bases are cocaine, procaine, D -(2-methyl-piperidine)-propyl benzoate, p-aminobenzoyl-dimethylamino-methylbutanol, p-aminobenzoyl-D -di-butylamino propanal, p-aminobenzoyl-2:2-dimethyl-3-diethyl-aminopropanol, monoisobutylaminoethyl-p-aminobenzoate, piperidinopropanediol-diphenylurethane, 2- butyloxyquinoline carboxylic acid-4-diethyl-ethylene diamine, and D -diethylaminopropyl cinnamate. Such combinations may be used in solutions, jellies or ointments. Raceinic mixtures of the d- and l-forms of the amine or acid salt, or the resolved d- or l-forms may be used as vasoconstrictors.  Acid addition salts of 2 amino-4-methyl hexane which are described include those derived from sulphuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, n-hexyl sulphonic acid, malic acid, maleic acid, malonic acid, acetic acid, propionic acid, succinic acid, p glycollic acid, gluconic benzoic acid and nicotinic acid. According to Examples (6) An inhalant comprises 2-amino-4-methyl hexane, menthol camphor, oil of thyme and liquid petrolatum.  (7) A jelly comprises 2-amino-4-methylhexane, glycerine tragacanth, methyl salicylate, sodium phosphate and water.  (8) an ointment comprises 2-amino-4-methylhexane, menthol, camphor, oil of wintergreen, anhydrous wool fat, liquid petrolatum and white petrolatum.  (9) A nasal spray comprises 2-amino-4-methylhexane, chlorbutanol and physiological saline.  In Example 8 the amine may be replaced by its acid addition salts and in Example 6 oil soluble acid addition salts of the amine such as 2-amino-4-methyl-hexane oleate may be used in place of the amine.