Methods for syntheses of N-methyl-DL-aspartic acid derivatives.
A novel practical method for the synthesis of N-methyl-DL-aspartic acid 1 (NMA) and new syntheses for N-methyl-aspartic acid derivatives are described. NMA 1, the natural amino acid was synthesized by Michael addition of methylamine to dimethyl fumarate 5. Fumaric or maleic acid mono-ester and -amide were regioselectively transformed into beta-substituted aspartic acid derivatives. In the cases of maleamic 11a or fumaramic esters 11b, the alpha-amide derivative 13 was formed, but hydrolysis of the product provided N-methyl-DL-asparagine 9 via base catalyzed ring closure to DL-alpha-methylamino-succinimide 4, followed by selective ring opening. Efficient methods were developed for the preparation of NMA-alpha-amide 13 from unprotected NMA via sulphinamide anhydride 15 and aspartic anhydride 3 intermediate products. NMA diamide 16 was prepared from NMA dimethyl ester 6 and methylamino-succinimide 4 by ammonolysis. Temperature-dependent side reactions of methylamino-succinimide 4 led to diazocinone 18, resulted from self-condensation of methylamino-succinimide via nucleophyl ring opening and the subsequent ring-transformation.
Boros
M
M
Department for Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary. bormik@hogyes.sote.hu
Kökösi
J
J
Vámos
J
J
Kövesdi
I
I
Noszál
B
B
D000596:Amino Acids / Q000737:chemistry; D001216:Asparagine / Q000737:chemistry; D004952:Esters / Q000737:chemistry; D013058:Mass Spectrometry; D016202:N-Methylaspartate / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D013388:Succinimides / Q000737:chemistry
D000596:Amino Acids; D004952:Esters; D013388:Succinimides; C032620:succinimide; D016202:N-Methylaspartate; D001216:Asparagine