Patent GB-618591-A (GB)
Title: Improvements in or relating to the preparation of amino acids and intermediates therefor
IPC: C07C233/45
Filed: 1945-10-30
Abstract: An a -substituted acetamido malonic ester is prepared by condensing an acetamidomalonic di-ester with a compound of the formula RCH2X, wherein X is halogen and R is hydrogen or a monovalent organic radical, in the presence of sodium alcoholate and recovering the corresponding a -(RCH2-) substituted acetamidomalonic ester.  The latter may be de-esterified by hydrolysis in dilute alkali to form a -(RCH2-) substituted acetamidomalonic acid and the product then decarboxylated by refluxing it with dilute mineral acid to yield an acid of the formula RCH2.CH(NHCOCH3)COOH which on further hydrolysis with concentrated mineral acid yields an amino acid having the formula RCH2.CH(NH2)COOH.  The latter may also be obtained by heating the a -(RCH2-) substituted acetamido malonic acid to reflux in concentrated mineral acid for two to six hours whereby both decarboxylation and deacetylation are effected.  The group R may be alkyl, e.g. ethyl, propyl and isopropyl, a substituted alkyl group such as an alkyl-thioalkyl group of the formula -CH2SCH3, an aryl group, e.g. phenyl or a heterocyclic group such as b -indolyl.  The compound RCH2X also includes a compound having the formula X-CH2.CH2.SCH2CH2SCH2CH2X from which a bis-amino acid may be obtained.  In examples: (1) acetamido malonic ester and benzyl chloride are added to a solution of sodium in absolute ethanol and the mixture refluxed and then filtered.  The filtrate is evaporated under reduced pressure and the residue cooled and washed on to a filter yielding diethyl benzylacetamidomalonate which is then refluxed with aqueous sodium hydroxide solution, the solution cooled, acidified with hydrochloric acid and then heated under reflux.  The solution is filtered hot and dl-N-acetylphenyl alanine is obtained which may be converted to dl-phenyl-alanine by hydrolysis, e.g. by heating with concentrated mineral acid; (2) isobutyl bromide is reacted with diethylacetamidomalonate in the presence of sodium alcoholate as in (1), the crude diethyl isobutylacetamidomalonate obtained is refluxed with aqueous sodium hydroxide solution, acidified with concentrated hydrochloric acid and then refluxed to obtain dl-N-acetylleucine which may be hydrolysed to dl-leucine, e.g. by heating with concentrated mineral acid; (3) n-propyl bromide and diethyl acetamidomalonate are reacted as in (1), the respective products being diethyl n-propyl acetamidomalonate, dl-N-acetylnorvaline and dl-norvaline; (4) n-butyl bromide, diethyl acetamido malonate and a small amount of potassium iodide are added to a solution of sodium in absolute ethanol, nitrogen being passed through the apparatus, the mixture is heated under reflux, filtered hot and the filtrate evaporated under reduced pressure, the residue is taken up in water containing a little sodium bisulphite, then saturated with salt and extracted with ether to yield diethyl-n-butyl acetamido malonate which is then treated as in (1) to obtain dl-N-acetylnorleucine and dl-norleucine respectively; (5) ethylene-bis-(betachlorethyl sulphide) is reacted with ethyl acetamido malonate as in (1) to yield ethylene-bis-(gamma, gamma-dicarboxy-gamma-acetamido propyl sulphide) which is refluxed with an aqueous alcoholic solution of sodium hydroxide and then with concentrated hydrochloric acid, concentrated to dryness, the residue extracted with boiling ethanol and excess pyridine added, on standing o ,o 1-bimethionine separates out.  Specification 599,481 is referred to.  The Specification as open to inspection under Sect. 91 also states that the group R may be a beta-iminazolyl group.  This subject-matter does not appear in the Specification as accepted.