Patent GB-646033-A (GB)
Title: Improvements in or relating to the manufacture of derivatives of amino-carboxylic acids
IPC: C07D263/44
Filed: 1947-07-29
Abstract: Alpha-amino carboxylic acid derivatives are prepared by allowing phosgene to interact, in the absence of a nitrogenous base or salt thereof, with an amino acid having the general formula <FORM:0646033/IV (b)/1> wherein R, R1 and R11 stand for hydrogen or hydrocarbon radicals, substituted or not, the same or different, or wherein R and R1 or R1 and R11 may be joined to form a ring, or with a salt thereof, e.g. a hydrochloride or metal salt.  Conveniently, phosgene is passed into a solution or suspension of the amino acid in an inert organic liquid medium, preferably in the absence of water. One or more of the following compounds may be obtained <FORM:0646033/IV (b)/2> <FORM:0646033/IV (b)/3> and <FORM:0646033/IV (b)/4> Formation of (1) is favoured by reacting at below 50 DEG  C., and formation of the others by reacting at above 50 DEG  C. and, in the case of (3), using starting materials wherein R is hydrogen. Compound (1) is converted into compound (3) by treating with a chlorinating agent such as thionyl chloride while compounds (2) and (3), or mixtures thereof, may be converted into compound (1) by treating with water, preferably in stoichiometrical amounts in admixture with an organic liquid which does not dissolve compound (1).  According to examples, phosgene is passed through: (1) a mixture of glycine in dioxane at 70 DEG  C., yielding on distillation a mixture of carbimido acetyl chloride and N-chloroformylamino acetyl chloride; treatment of the mixture with an ethereal solution of aniline yields phenyl-ureidoacetanilide; (2) a mixture of glycine, its hydrochloride or copper salt in dioxane, firstly at about 20 DEG C. and finally at 48-50 DEG  C., yielding anhydro-N-carboxy glycine; the same product is obtained by treating glycine in ethyl acetate or tetrahydrofuran under similar conditions or by treating the product of (1) with the appropriate amount of water in ether; (3) a mixture of sodium salt of sarcosine and ethyl acetate at 20 DEG  C., yielding anhydro-N-carboxy sarcosine; (4) a mixture of the sodium and potassium salts of N-phenyl glycine and ethyl acetate at 35-40 DEG C., yielding anhydro-N-carboxy-N-phenyl glycine; (5) a mixture of glycine and dioxane at 48-50 DEG  C. and then thionyl chloride is added and the temperature further maintained at 48-50 DEG  C., yielding carbimido-acetyl chloride; (6) a mixture of dl-glycine and dioxane at 48-50 DEG  C. and the product reacted with thinoyl chloride at 50\sB2 DEG  C., yielding a -carbimido propionyl chloride which with excess aniline in benzene forms phenyl ureido propionanilide; (7) a mixture of valine and solvent as in (5), yielding anhydro-N-carboxy valine and carbimido-isovaleryl chloride, the latter giving phenylureido-isovaleranilide on treatment with excess aniline in benzene, and anhydro-carboxy valine on treatment with the appropriate amount of water in ether; (8) a mixture of b -phenyl-a -alanine and solvent as in (5), yielding anhydro-N-carboxy-b -phenyl-a -alanine and carbimido-b -phenyl propionyl chloride; (9) a mixture of a -amino isobutyric acid and dioxane at 40-50 DEG  C., yielding anhydrocarboxy-a -aminoisobutyric acid.  Other starting materials mentioned are pyrrole-a -carboxylic acid, proline and a -amino cyclohexane carboxylic acid and their hydrochlorides and metal salts, while chloroform and ether are further examples of suitable solvents for use in the reaction.