Patent GB-783292-A (GB)
Title: Substituted alanines
Inventor: BERGEL FRANZ
Filed: 1954-12-03
Abstract: The resolution of p-bis-(2-chloroethyl)-amino-DL-phenylalanine (claimed per se in the parent Specification) into its D- and L-forms is effected by the following two methods: (1) ethanolic solutions of N-acetyl-p-nitro-DL-phenylalanine and brucine are mixed, the brucine salt of the L-isomer is allowed to crystallize from the mixed solutions and is recrystallized from ethanol, N-acetyl - p - nitro - L - phenylalanine is liberated from this salt by basification of an aqueous solution thereof, removal of the brucine and subsequent acidification, this compound is hydrolysed to p - nitro - L - phenylalanine, the latter is esterified and the ester is reacted with phthalic anhydride to form the N-o1-carboxy benzoyl derivative, this is heated with ethanolic hydrogen chloride to produce the N-phthaloyl derivative, this is catalytically hydrogenated to reduce the nitro group to an amino group, the amino compound is hydroxyethylated by treatment with ethylene oxide and the product is chlorinated with POCl3 or SOCl2 and subsequently hydrolysed to produce p-bis-(2-chloroethyl)-amino-L-phenylalanine; the brucine salt of N-acetyl - p - nitro - D - phenylalanine is isolated from the mother liquor after crystallization and separation of the L-isomer as described above and is recrystallized from water, N-acetyl-p-nitro - D - phenylalanine is liberated therefrom by basifying a solution thereof, removing the brucine therefrom and acidifying, and is then treated as described above for the L-isomer to give finally p-bis-(2-chloroethyl)-amino-D-phenylalanine; (2) methanolic solutions of p-nitro - N - phthaloyl - DL - phenylalanine and cinchonidine are mixed, the cinchonidine salt of the D-isomer is allowed to crystallize and is separated from the mother liquor, the cinchonidine salt of the L-isomer is isolated from this liquor and is recrystallized from aqueous ethanol and p-nitro-N-phthaloyl-L-phenylalanine is liberated therefrom by basification of an ethanolic solution thereof, removal of the cinchonidine and acidification, this compound is esterified, preferably as an ethyl ester, the ester is catalytically hydrogenated and subsequently treated as in method (1) to yield p-bis-(2 - chloroethyl) - amino - L - phenylalanine; the cinchonidine salt of p-nitro-N-phthaloyl-D-phenylalanine separated as above is recrystallized from methanol, p-nitro-N-phthaloylD-phenylalanine is liberated therefrom by basifying an ethanolic solution thereof, removing the cinchonidine and acidifying, this compound is esterified, preferably to the ethyl ester, and this ester is catalytically hydrogenated and further treated as in method (1) to yield p-bis-(2-chloroethyl) - amino - D - phenylalanine.  Examples describing each of the above processes are furnished and the preparation of ethyl p-nitro - L - phenylalaninate hydrochloride from p - nitro - L - phenylalanine and ethanolic hydrogen chloride is also given.  The Provisional Specification is less specific concerning the solvents used in the above resolutions.  Starting materials. p-Nitro-N-phthaloyl-DL-phenylalanine is produced by condensing p-nitrobenzyl chloride and diethyl phthalimidomalonic ester in methyl-ethyl ketone in the presence of sodium iodide, hydrolysing the resulting diethyl p-nitrobenzyl phthalimidomalonate with aqueous sodium carbonate and then with hydrochloric acid to give N-(o1-carboxy-benzoyl)-p-nitro-DL-phenylalanine and refluxing this with acetic anhydride.  N-acetyl-p-nitro-DL-phenylalanine is prepared by hydrolysing diethyl a -acetamido-a -p-nitrobenzylmalonate with aqueous sodium carbonate and then hydrochloric acid.