Methods for syntheses of N-methyl-DL-aspartic acid derivatives |
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Authors: | M. Boros J. Kökösi J. Vámos I. Kövesdi B. Noszál |
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Affiliation: | (1) Department for Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary;(2) EGIS Pharmaceuticals PLC, Budapest, Hungary;(3) Research Group for Drugs of Abuse and Doping Agents, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary |
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Abstract: | Summary. 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 α-amide derivative 13 was formed, but hydrolysis of the product provided N-methyl-DL-asparagine 9 via base catalyzed ring closure to DL-α-methylamino-succinimide 4, followed by selective ring opening. Efficient methods were developed for the preparation of NMA-α-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. |
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Keywords: | : N-methyl-aspartic acid – Regioselective ester and amide formation – Ring transformations – Methylamino succinimide – Diazocinone |
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