Patent GB-598911-A (GB)
Title: Improvements in or relating to the production of amidines
Filed: 1945-03-22
Abstract: Therapeutically useful diamidines, of the general formula Am-B-O(CH2)nO-B-Am, wherein B represents a benzene nucleus, Am represents the amidine group, and n is an integer from 1 to 8, and wherein either or both of the benzene nuclei is or are substituted by one or more halogen (i.e. chlorine, bromine or iodine) atoms, and salts thereof, are manufactured from the corresponding dicyano compounds by methods known for the conversion of dicyano compounds into diamidines and salts thereof, e.g. by treating the dicyano compound in solution or suspension in an anhydrous alcohol (with or without an inert diluent such as chloroform or benzene) with anhydrous hydrochloric or hydrobromic acid, and treating the resulting imino-ether hydrohalide with ammonia or the corresponding imino-ether base with an ammonium salt, or by treating the dicyano compound with an alkali metal amide and hydrolysing the resulting alkali metal compound, or by the processes of Specifications 573,266 and 575,145.  The diamidines are isolated in the form of free bases or salts, and are preferably employed in the latter form, e.g. as local chemotherapeutic agents.  In examples, solutions of the following compounds in ethyl alcohol and chloroform are saturated with dry hydrogen chloride, and the resulting imino-ether hydrochlorides isolated and treated with ammoniacal ethanol: (1) 2-iodo-4 : 41-dicyano-a  : g -diphenoxypropane; (2) 2-bromo-4 : 41-dicyano-a  : e -diphenoxypentane; (3)2 : 21-dibromo-4 : 41-dicyano-a  : g -diphenoxypropane. In further examples: (4) 2 : 21-dibromo-4 : 41-dicyano-a  : g -diphenoxypropane is heated with sodamide in toluene, and the product is treated with hot dilute hydrochloric acid to produce 2 : 21-dibromo-4 : 41-diamidino-a  : g -diphenoxypropane dihydrochloride; (5) 2 : 21-dichloro-4 : 41-dicyano-a  : #x-diphenoxyhexane is treated with dry hydrogen chloride in ethanol and chloroform, the di-imino-ether hydrochloride is isolated and treated with caustic soda solution to liberate the base, which is treated with ammonium chloride to yield 2 : 21-dichloro-4 : 41-diamidino-a  : #x-diphenoxyhexane dihydrochloride; (6) 2 : 21-dibromo-4 : 41di-(ethyliminoether)-a  : g -diphenoxypropane dihydrochloride, prepared as in (3), is treated with aqueous caustic soda, and the liberated base is treated with ammonium isethionate in aqueous ethanol to form 2 : 21-dibromo-4 : 41-diamidino-a  : g -diphenoxypropane di-isethionate.  Reference is also made to the preparation of 2-bromo-4 : 41-diamidino-a  : g -diphenoxypropane and 2 : 21-diiodo-4 : 41-diamidino-a  : #x-diphenoxyhexane.  2-Iodo-4 : 41-dicyano-a  : g -diphenoxypropane is obtainable by condensing 2-iodo-4-cyanophenol with g -(4-cyanophenoxy)-propyl bromide in the presence of aqueous alcoholic caustic soda.  2-Bromo-4 : 41-dicyano-a  : e -diphenoxypentane is obtainable similarly from 2-bromo-4-cyanophenol and e -(4-cyanophenoxy)-phentyl bromide.  2 : 21-Dibromo-4 : 41-dicyano-a : g -diphenoxypropane is obtained by similarly condensing two molecular proportions of 2-bromo-4-cyanophenol with one of a  : g -dibromopropane.  2 : 21-Dichloro-4 : 41-dicyano-a  : #x-diphenoxyhexane is obtainable similarly from 2-chloro-4-cyanophenol and a  : #x-dibromohexane.  Specification 507,565 also is referred to.