Patent GB-587244-A (GB)
Title: Improvements relating to the synthesis of amino acid derivatives and salts thereof
IPC: C07D317/58
Filed: 1944-07-21
Abstract: Phenalkyl compounds of general formula <FORM:0587244/IV/1> wherein R1 represents H or alkyl (1 to 2 carbon atoms), R2 represents alkyl (1 to 5 carbon atoms), R3 represents alkoxy or hydroxyalkylamino (1 to 5 carbon atoms), R4 and R5 each represent H, alkyl (1 to 2 carbon atoms) or alkoxy (1 to 5 carbon atoms), or R4 and R5 together are methylenedioxy, R6 represents H or halogen, n is either zero or 1 and X represents alkylene (2 to 5 carbon atoms of which at least 2 are in the direct chain connecting the nitrogen atom with the COR3 group), and salts thereof, are obtained by treating a secondary phenalkyl amino alcohol having at least 2 carbon atoms in the chain between the phenyl group and the nitrogen atom and with the OH- group attached to the carbon atom in said chain next the ring, with an aliphatic acid ester (3 to 6 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 the desired amino-ester salt is isolated by adding an alkyl alcohol (1 to 5 carbon atoms) and a strong acid to the mixture after refluxing.  Conversion of the foregoing esters to the corresponding amides is effected by customary methods, e.g. by treatment with an alkylolamine; advantageously, b -alanine derivatives are amidated by the Stoll method, viz., converting the ester to the corresponding azide, prior to treating with an alkylolamine.  Specified compounds obtained according to the invention are: N - methyl - N - (b  - hydroxy - b  - phenyl) isopropyl b -alanine methyl ester hydrochloride, l - N - methyl - N - (b  - hydroxy - b  - phenyl) isopropyl b -alanine ethyl ester hydrochloride, N - methyl - N - (b  - hydroxy - b  - 2 : 5 - dimethoxyphenyl) ethyl b -alanine methyl ester hydrochloride, N - methyl - N - (b  - hydroxy - b  - 2 : 5 - dimethoxyphenyl) ethyl-b -alanine n-amyl ester hydrochloride, N - methyl - N - (g -carbomethoxypropyl - b  - hydroxy - b  - 2 : 5 - dimethoxyphenyl) ethylamine hydrochloride, N - methyl - N - (b  - hydroxy - b  - 2 : 5 - dimethoxyphenyl) ethyl - b  - alanine hydroxy ethyl amide acid oxalate, N - methyl - N - (b  - hydroxy - b  - 3 : 4 - dimethoxyphenyl) ethyl-b -alanine methyl ester hydrochloride, N - methyl - N - (g  - carbethoxypropyl - b  - hydroxy - b  - 3 : 4 - methylenedioxy - 6 - bromo - phenyl) isopropylamine hydrochloride, N - ethyl - N - (b  - hydroxy - a  - ethyl - b  - p - tolyl) ethyl b -alanine-methyl ester hydroiodide, N-methyl-N-(b -hydroxy-b -2-methoxy-5-methyl phenyl) ethyl b -alanine hydrochloride, N-n-amyl-N-(g -hydroxy - g  - 3 : 4 - diethoxyphenyl) propyl b -alanine methyl ester phosphate, N-ethyl-N-(e -carbethoxy - n - amyl - b  - hydroxy - 4 - methoxy - phenyl) ethyl amine sulphate, N-methyl-N-(g -hydroxy-g -3-amyloxyphenyl) propyl b -alanine methyl ester malate.  Many examples are given of the process.  The Provisional Specification describes also compounds of general formula <FORM:0587244/IV/2> wherein A represents an anion corresponding to an acid, X represents alkylene (2 to 6 carbon atoms) of which at least 2 are in the direct chain connecting N and -CO-, n is an integer (1 to 5), R1 represents hydroxy or methoxy and alkyl (1 to 5 carbon atoms), R3 represents alkyl (1 to 5 carbon atoms), R4 represents H or alkyl (1 to 5 carbon atoms), R5 represents alkoxy (1 to 5 carbon atoms), R6 represents H or -OH, or alkoxy or alkyl (1 to 5 carbon atoms), R6 represents H, -OH, halogen or alkoxy or alkyl (1 to 5 carbon atoms) or R6 and R7 together represent methylenedioxy, and R8 represents H, halogen or alkyl (1 to 5 carbon atoms). Quaternary salts are obtained by treating the corresponding tertiary bases with alkyl halides or sulphates.  Specified phenalkyl ammonium compounds are: N - methyl - N - phenethyl - b  - alaninium ethyl ester bromide, N-methyl-N-(b -hydroxy-b -phenylisopropyl)-b -alaninium ethyl- and the corresponding methyl-ester chlorides, N-ethyl-N-(b -2 : 5-dimethylphenylisopropyl)-b -alaninium methyl ester chloride, methyl n-butyl-b  - (2 - methyl - 5 - isopropylphenyl) - isopropyl-g -carbomethoxypropyl ammonium iodide, N-ethyl - N - benzyl - N - (b  - 3 : 4 - dimethoxyphenylpropyl) - b  - alaninium methyl ester chloride, N - methyl - N - (3 : 4 - dimethoxyphenethyl) - b  - alaninium ethyl ester chloride, N-methyl-N-(2 : 5 - dimethoxyphenethyl) - b  - alaninium ethyl ester chloride, N - methyl - N - homopiperonyl - b  - alaninium ethyl ester acid oxalate, methyl-2 : 5-dimethoxyphenethyl - g  - carbomethoxypropyl ammonium chloride, l-N-methyl-N-(b -hydroxy-b  - 3 : 4 - dimethoxyphenyl) - ethyl - b  - alaninium methyl ester chloride, d - N - methyl - N - (b - hydroxy-b -3 : 4-dimethoxyphenyl) isopropyl-b -alaninium methyl ester bromide, N-ethyl-N-methyl-N-(b -hydroxy-b -3 : 4-dimethoxyphenyl) isopropyl b -alaninium ethyl ester iodide, N,N-dimethyl-N-(b -hydroxy-b -3 : 4-dimethoxy-6-chlorophenylisopropyl) - b  - alaninium methyl ester chloride, dimethyl-g -carbethoxypropyl-b -hydroxy-b -(3 : 4-methylenedioxy-6-bromophenyl) isopropyl ammonium iodide, N,N-diethyl-N-p-chlorophenethyl - b  - alaninium ethyl ester chloride, N-methyl-N-n-propyl-N-(g -hydroxy-g  - p - bromophenyl - n - propyl) - b  - alaninium methyl ester chloride, N-n-amyl-N-(#s-hydroxy-#s - p - tolylbutyl) - b  - alaninium methyl ester malate, l-N-methyl-N-(b -2-hydroxy-5-bromophenylheptyl) - b  - alaninium ethyl ester d-tartrate, N-methyl-N-(a -3 : 4-dihydroxybenzyl-n-hexyl)-b -alaninium methyl ester sulphate, methyl - a  - (3 - methoxy - 4 - hydroxy - 5 - bromobenzyl) - n - propyl, e - carbethoxy amyl ammonium acid phosphate, N-methyl-N-(3 : 4-dimethoxyphenethyl)-b -alaninium n-amyl ester acid oxalate, N - methyl - N - (4 - methoxy - 3 - chlorophenethyl) - b  - alaninium - n - butyl ester chloride, methyl-2 : 3-dimethoxyphenethyl-a -methyl - b - carboisobutoxyethyl ammonium bromide, N - methyl - N - (b  - 3 : 4 - dimethoxyphenylisopropyl) - b  - alaninium, ethanolamide acid oxalate, N : N - dimethyl - N - (b  - hydroxy - b  - 3 : 4 - dimethoxyphenylethyl) - b  - alaninium b -hydroxyisopropylamide chloride, N-n-butyl-N - (4 - methoxy - 3 - bromophenylisopropyl) - b - alaninium ethanolamide bromide, N-n-propyl-N - (b  - methoxy - b  - 4 - n - butylphenylethyl) - b  - alaninium ethyl ester chloride, N-methyl-N-(#z - hydroxy - #z - 3 : 4 - diethoxyphenylhexyl)-b -alaninium methyl ester bromide, methyl-g -hydroxy - g  - mesityl - n - propyl - b  - methyl - b -carbomethoxy ethyl ammonium chloride, methyl-2 : 5-dimethylphenethyl-a -n-butyl-b -carbethoxy ethyl ammonium bromide, N - methyl-N-(b -methoxy-b -4-n-propoxyphenylethyl) - b  - alaninium methyl ester bromide, methyl - 3 : 4 - dimethoxyphenethyl - #z - carbo - methoxy hexyl ammonium bromide, N-methyl-N-(2-methoxy-5-n-amylphenethyl)-b -aluminium methyl ester nitrate, g  - (ethyl - 3 : 4 - dimethoxyphenethylamino) - butyric acid ethanolamide ethochloride, N-methyl-N-(b -4-hydroxy - 3 : 5 - diiodophenylisopropyl) - b  - alaninium ethyl ester chloride, dimethyl-3-hydroxy-4-methoxy-6-iodophenethyl-g -carbomethoxy - n - propyl ammonium bromide, N - methyl - N - (p-hydroxyphenethyl) - b  - alaninium ethyl ester chloride, N : N - dimethyl - N - (p - hydroxyphenethyl) - b  - alaninium ethyl ester chloride.  Many examples of the process are also included.