Patent GB-586645-A (GB)
Title: Improvements relating to the synthesis of amino acid derivatives and salts thereof
Filed: 1944-07-19
Abstract: Compounds of general formula <FORM:0586645/IV/1> wherein both R1 and R2 represent H, or one represents H and the other alkyl (1 to 2 carbon atoms), R3 represents H or alkyl (1 to 5 carbon atoms), R4 represents alkoxy or hydroxy alkylamino (1 to 5 carbon atoms), R5 represents alkoxy (1 to 5 carbon atoms), R6 represents H, halogen or alkyl (1 to 2 carbon atoms) or alkoxy (1 to 5 carbon atoms), R5 and R6 together represent methylenedioxy, R7 represents H or halogen, n is either zero or 1, and X represents an alkylene radical containing from 2 to 6 carbon atoms, of which at least 2 are in the direct chain connecting the nitrogen atom with the-COR4 group, and salts thereof, are obtained (when R4 represents alkoxy), by treating a secondary phenalkylamine substituted in the ring at least once with alkoxy (1 to 5 carbon atoms) and having at least 2 carbon atoms in a hydrocarbon chain between the phenyl group and the nitrogen atom with an aliphatic acid ester (3 to 7 carbon atoms), which acid is either substituted by halogen on a carbon atom at least once removed from the carboxy group, or which is an a b -unsaturated acid.  Preferably, the reactants are dissolved in a mutual solvent, being refluxed after standing for at least 2 hours and conveniently the product is acidified, extracted with a solvent, treated with an alkali and re-acidified to isolate the requisite acid salt.  The foregoing esters are converted to amides, e.g. by treatment with an alkylolamine.  Where, in the phenalkylamine reactant, R3 represents benzyl, or other aralkyl radical, it may be eliminated from the ester obtained, by catalytic hydrogenation.  The products are stabilized as salts, e.g. hydrochlorides, sulphates, phosphates, tartrates, malates, succinates or hydrobromides.  The Specification contains a list of phenalkyl compounds which may be prepared in accordance with the process of the invention.  Numerous examples of the process of the invention are given.  d -(3 : 4-Dimithoxyphenyl)-n-hexylmethylamine is obtained by effecting a Friedel-Crafts reaction of veratrole with the linear anhydride of pimelic acid, catalytically hydrogenating the resulting e -veratroyl caproic acid to d -veratryl heptanoic acid, converting this product, through its ethyl ester, to the corresponding hydrazide, which is converted to d -veratryl n-hexylamine, and to the final product by the Decker method.  3-Methoxy-4-n-propoxyphenethylamine is obtained by propylating vanillin to 3-methoxy-4-n-propoxybenzaldehyde and proceeding as in the synthesis of homoveratrylamine.  b -(2-Methoxy-5-methyl)-phenylethylamine is obtained by treating 2 - methoxy - 5 - methyl phenylaldehyde with malonic acid and piperidine in pyridine, the product being reduced by sodium amalgam to 2-methoxy-5-methyl hydrocinnamic acid, treated with ammonia at 220 DEG  C. to obtain the corresponding amide, followed by treatment with sodium hypochlorite and sodium hydroxide to obtain the desired product.  The Provisional Specification discloses many additional products which may also be obtained in accordance with the process of the invention.