Patent GB-791761-A (GB)
Title: Amino-propyl substituted caffeine derivatives and process for their manufacture
Filed: 1954-08-17
Abstract: The invention comprises substituted caffeines of the general formula: <FORM:0791761/IV (b)/1> wherein R1 represents hydrogen or a halogen atom, or an alkoxy group containing up to 3 carbon atoms, R2 and R3 represent hydrogen or a methyl or ethyl group, and R4 and R5 represent methyl or ethyl groups or together with the nitrogen atom the radical of a saturated heterocyclic system, and acid addition salts thereof, and the preparation thereof by reacting an 8-halogeno caffeine with a butyric acid nitrile of the general formula: <FORM:0791761/IV (b)/2> wherein R1, R2, R3, R4 and R5 have the above significance, in the presence of an acid binding agent, and the cyano substituted compound thus obtained is treated with a strong inorganic acid.  A suitable 8-halogeno-caffeine for use in the above process is 8-chloro-caffeine.  Suitable butyric acid nitrile reactants are alpha-phenyl-gamma - diethylamino (and diethylamino, piperidino, pyrrolidino and morpholino)-butyric acid nitrile, alpha - phenyl (and alpha - m-methoxyphenyl) - beta - methyl - gamma - dimethylamino - butyric acid nitrile, alphameta - methoxy (and chloro) - phenyl - gammadimethylamino - butyric acid nitrile, and alpha - phenyl (and m - methoxyphenyl)-gamma-dimethylamino-valeric acid nitrile.  The acid binding agent may be an alkali, an alkali metal amide such as sodamide or an alkali metal alcoholate.  Acids from which the acid addition salts may be derived are inorganic acids, e.g. the hydroholic acids such as hydrochloric, hydrobromic and hydroidic acids, sulphuric acid and phosphoric acid, and organic acids, e.g. aceturic, acetic, lactic, oxalic, succinic, maleic, tartaric malic and p-amino-salicylic acid, an amino-sulphonic acid, a phenol-sulphonic acid, and a hydroxyethanesulphonic acid.  In the examples the following compounds are prepared: 1 - phenyl - 1 - caffeyl - (81) - 3-dimethylaminopropane and the hydrochloride thereof (the intermediate compound is alpha-phenyl - alpha - caffeyl - (8) - gamma - dimethylamino butyric acid nitrile); 1-phenyl-1-caffeyl-(81) - 3 - piperidinopropane and the hydrochloride thereof (the intermediate compound is alpha - phenyl - alpha - caffeyl - (8) - gamma-piperidinobutyric acid nitrile); a mixture of 1 - phenyl - 1 - caffeyl - (81) - 2 - methyl - 3 - dimethylaminopropane and 1 - phenyl - 1-caffeyl - (81) - 3 - dimethylaminobutane and the hydrochlorides thereof (the intermediate compounds are a mixture of alpha - phenyl-alpha - caffeyl - (8) - beta - methyl - gamma - dimethylaminobutyric acid nitrile and alphaphenyl - alpha - caffeyl - (8) - gamma - dimethylaminovaleric acid nitrile); 1-m-methoxyphenyl-1 - caffeyl - (81) - 3 - dimethylaminopropane and the hydrochloride thereof (the intermediate compound is alpha - m - methoxy - phenylalpha - caffeyl - (8) - gamma - dimethylamino-butyric acid nitrile); 1 - phenyl - 1 - caffeyl-(81) - 3 - diethylaminopropane (the intermediate compound is alpha - phenyl - alpha-caffeyl - (8) - gamma - diethylaminobutyric acid nitrile); 1 - p - chlorophenyl - 1 - caffeyl-(81) - 3 - dimethylaminopropane and the hydrochloride thereof (the intermediate compound is alpha - p - chlorophenyl - alpha - caffeyl - (8)-gamma - dimethylaminobutyric acid nitrile; and 1 - phenyl - 1 - caffeyl - (81) - 3 - morpholinopropane (the intermediate compound is alpha - phenyl - alpha - caffeyl - (8) - gammamorpholinobutyric acid nitrile).  Starting compounds.  A mixture of alphaphenyl - beta - methyl - gamma - dimethylaminobutyric acid nitrile and alpha-phenyl-gamma-dimethylaminovaleric acid nitrile is obtained by reacting phenylacetonitrile and 1-dimethylamino-2-chlororopane in the presence of sodamide, and alpha - (m - methoxyphenyl) - gamma-dimethylamino-butyric acid nitrile is obtained by reacting m-methoxyphenylacetonitrile and dimethylaminoethyl chloride.