Patent GB-867572-A (GB)
Title: Hydroxyl-and mercapto-alkanoyl-amino-carboxylic acid amides and process for their manufacture
Filed: 1957-10-01
Abstract: Hydroxy- and mercapto-alkanoyl-aminocarboxylic acid amides of the formula:  <FORM:0867572/IV (b)/1> wherein X represents oxygen or sulphur, R the divalent radical of an a -amino-carboxylic acid after the deduction of the amino and carboxylic groups and R1 represents hydrogen or the radical of an amino acid or peptide, are produced by the action of a hydrocarbon compound of an alkali or alkaline earth metal or an amide or tertiary alcoholate of such a metal, on an ester of the formula:  <FORM:0867572/IV (b)/2> By esterification of the hydroxyl or mercapto group (see first formula) with an a -amino acid followed by repetition of the molecular rearrangement, the peptide can be lengthened by any number of the same or different amino acid radicals.  Sodamide, potassium tertiary butylate, sodium phenyl or lithium phenyl may be used to effect the molecular rearrangement. The metal amides are preferably used in the presence of liquid ammonia; while the metallic alcoholates are employed in the corresponding alcohol. In Example 1, carbobenzoxy glycine anhydride is reacted with b -hydroxy-b -methyl propionic acid amide to give o-(carbobenzoxy-glycyl)b -hydroxy-b -methyl-propionic acid amide, which is then treated with hydrogen in the presence of hydrochloric acid and palladium charcoal to obtain o-glycyl-b -hydroxy-b methyl propionic acid amide hydrochloride. Molecular rearrangement of the latter, by means of potassium tertiary butylate in tertiary butanol, yields b -hydroxy-b -methyl propionyl-glycinamide.  In Example 2, Nbenzoyl-serine is esterified with diazomethane and the ester is treated with a methanolic solution of ammonia to give N-benzoyl serinamide.  The latter is reacted with carbobenzoxy glycine anhydride and the product is reduced with hydrogen in the presence of hydrochloric acid and palladium-charcoal to give o-glycyl-N-benzoyl-serinamide hydrochloride.  Molecular rearrangement of the latter compound, by means of sodium dissolved in liquid ammonia, yields Nbenzoyl-seryl-glycinamide.  Example 3 describes the preparation of o-glycyl-N-(benzoyl-glycyl)DL-serinamide hydrochloride, and its conversion into N-(benzoyl-glycyl)-DL-serylglycinamide. Example 4 describes the preparation of o-glycyl-N-benzoyl-L-serinamide hydrochloride, and its conversion into Nbenzoyl-L-seryl-glycinamide.  Example 5 describes the preparation of o-glycyl-N-benzoyl-DL-threoninamide perchlorate, and its conversion into N-benzoyl-DL-threonylglycinamide. Example 6 indicates the preparation of o-(carboxy-L-phenylalanyl)-N-benzoylL-seryl-glycine amide and its conversion into N- benzoyl- L- seryl- L- phenylalanylglycineamide. In Example 7, N-benzoyl-L-serinamide is treated with thionyl chloride followed by sodium carbonate to yield 2-phenyl-4-carbamino-oxazoline. The oxazoline is reacted with N-carbobenzoxy thioglycine to give s-(carbobenzoxy glycyl-N-benzoyl-L-cysteinamide, which is then treated with phosphonium iodide in glacial acetic acid to obtain s-glycyl-N-benzoyl-L-cystein-amide, and this is then treated with potassium tertiary butylate followed by benzyl alcohol to yield S-benzylN-benzoyl-L-cysteinyl-glycine amide.  In Example 8, leucine isopropyl ester is agitated with potassium carbonate and potassium tertiary butylate in tertiary butanol.  Seryl-leucine amide is formed, but undergoes further esterification and rearrangement whereby a serylpolyleucine amide is produced. Specification 831,973 is referred to.