Patent GB-903765-A (GB)
Title: Improvements in and relating to preparation of amino acids
IPC: C07C255/24
Filed: 1958-11-20
Abstract: The invention comprises (1) the following compounds:-5-cyano-2-oximinovaleric acid; 4-cyano-2-oximinobutyric acid; 5-cyano-4-methyl-2-oximinovaleric acid; isopropyl 5-cyano-2-oximinovalerate; benzyl 5-cyano-2-oximinovalerate; methyl 5-cyano-2-acetoximinovalerate and 5-cyano-2-oximinovaleramide;  and (2) the preparation of omega-cyano-alpha-substituted carboxylic acids, or carboxylic functional derivatives thereof, by treating an oximino cyclic ketone which has from 5 to 7 carbon atoms in the ring and which is substituted on at least one alpha-carbon atom by an oximino group and is otherwise substituted on the other alpha-carbon atom, with an acylating agent and a base to break the ring of the ketone between the carbonyl carbon atom and one of the oximino-substituted alpha-carbon atoms.  The other alpha-carbon substituent in the cyclic oximino-ketone is preferably an amino group, a substituent which under the conditions of any subsequent hydrolysis or reduction is converted to an amino group (e.g. an oximino, an amido or a nitro group), or a substituent which may be subsequently readily replaced by an amino group (e.g. a halogen atom).  Subsequent cleavage products are omega-cyano-acids or acid functional derivatives thereof having amino, oximino, amido, nitro and halogen substituents in the alpha-position respectively.  The remaining positions of the cyclic oximino ketone reactant may be substituted by halogen atoms, by alkyl, aryl, hydroxy, alkoxy, acyloxy, mercapto, dialkyl- or diarylamino, acylamino, carboxy, or carbalkoxy groups, or by any other group which will not take part in the cleavage reaction.  Acylating agents used for cleavage include aliphatic and aromatic acid chlorides, carboxylic acid anhydrides, aromatic and aliphatic sulphonyl chlorides, ketones, alkyl chloroformates, phosphorus oxychloride, phosgene, thionyl chloride and phosphorus pentachloride.  Specified bases used for p  cleavage include alkali metal or alkaline earth metal hydroxides, amides, alkoxides, carbonates, bicarbonates, phenoxides, acetate, benzylate, cyanides and enolates, and amines (e.g. pyridine or phenyltrimethylammonium hydroxide) or ammonia.  The nature of the cleavage product is usually dependent upon the solvent used or the base used for cleavage.  Thus, using a ,a 1-dioximinocyclic ketones as starting materials, aqueous solvents lead to omega-cyano-alpha-oximinocarboxylic acids, alcoholic solvents lead to omega-cyano alpha-oximino carboxylic acid esters, non-hydroxylic solvents lead to omega-cyano-alpha-acyloximino-carboxylic acids and alkali metal amide cleavage agents lead to omega-cyano alpha-oximino carboxylic acid amides.  The cleavage reaction is normally run by dissolving the cyclic oximino-ketone in a solution of a base and adding the acylating agent thereto.  Alternatively, the acylating agent may be added first, giving a cyclic acyloximino ketone, which on treatment with the base gives an omega-cyano-alpha-substituted carboxylic acid, e.g. an omega-cyano-alpha-acyloximino-carboxylic acid.  Oximino-substituted acids may be subsequently purified by forming metal complexes.  The omega-cyano-alpha-substituted carboxylic acids may be subsequently, reduced to the corresponding omega-cyano-alpha-substituted carboxylic acids.  Thus, reduction of an omega-cyano-alpha-oximino-carboxylic acid yields an alpha, omega-diamino-carboxylic acid, e.g. 4-cyano-2-oximinobutyric acid yields ornithine.  Similarly, functional derivatives may also be reduced.  Thus, reduction of ethyl 5-cyano-2-oximino-valerate yields lysine.  Alpha, omega-diamino-carboxylic acids so obtained may be further reacted with cyanamide to form an omega-guanidino-alpha-amino-carboxylic acid.  Thus treatment of 2,5-diamino-valeric acid with cyanamide yields argenine and treatment of lysine with cyanamide yields homoargenine.  Omega - cyano-alpha-oximino acids may be esterified (e.g. with a large excess of ethanol in presence of an acid chloride) prior to reduction.  The omega-cyano-alpha - oximino - carboxylic acids may also be subjected to partial reduction to form the corresponding omega-cyano-alpha-amino - carboxylic acids.  Thus, 4-cyano-2-aminobutyric acid is obtained by selective reduction of 4-cyano-2-oximinobutyric acid.  The reduction treatment of the omega-cyano-alpha-substituted carboxylic acids may be preceded by partial or complete hydrolysis treatments, yielding the correspondingt omega-carbamido-or omega-carboxyl-alpha-substituted carboxylic acids, which may then be reduced at a suitable alpha-substitutent.  Thus 4-cyano-2-oximino-butyric acid may be hydrolyzed to 4-carbamido-2-oximinobutyric acid or to 4-carboxy-2-oximinobutyric acid and the latter two compounds may then be reduced to glutamine and glutamic acid respectively. Homoglutamine and homoglutamic acid may be similarly prepared.  a -Oximino cyclic ketone starting materials are prepared by nitrosation of the corresponding cyclic ketones with, for example, a mixture of an alkyl nitrite and hydrogen chloride; nitrous fumes; nitrosyl chloride; a mixture of an inorganic nitrite and acid; or a mixture of an alkyl nitrite and an alkoxide.