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Methods for syntheses of N-methyl-DL-aspartic acid derivatives

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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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References

  • AF AbdelMagid KG Carson BD Harris CA Maryanoff RD Shah (1996) ArticleTitleReductive amination of aldehydes and ketones with sodium triacetoxyborohydride. Studies on direct and indirect reductive amination procedures J Org Chem 61 3849–3862 Occurrence Handle10.1021/jo960057x Occurrence Handle1:CAS:528:DyaK28XivFShu7o%3D

    Article  CAS  Google Scholar 

  • DW Aswad (1995) Deamidation and isoaspartate formation in peptides and proteins CRC Press Boca Raton

    Google Scholar 

  • L Aurelio RTC Brownlee AB Hughes BE Sleebs (2000) ArticleTitleThe facile production of N-methyl amino acids via oxazolidinones Aust J Chem 53 425–433 Occurrence Handle10.1071/CH99082 Occurrence Handle1:CAS:528:DC%2BD3cXlsl2mtLY%3D

    Article  CAS  Google Scholar 

  • L Aurelio RTC Brownlee AB Hughes (2002) ArticleTitleA novel synthesis of N-methyl asparagine, arginine, histidine, and tryptophan Org Lett 4 3767–3769 Occurrence Handle12375939 Occurrence Handle10.1021/ol026799w Occurrence Handle1:CAS:528:DC%2BD38XntFSit7Y%3D

    Article  PubMed  CAS  Google Scholar 

  • L Aurelio JS Box RTC Brownlee AB Hughes MM Sleebs (2003) ArticleTitleAn efficient synthesis of N-methyl amino acids by way of intermediate 5-oxazolidinones J Org Chem 68 2652–2667 Occurrence Handle12662035 Occurrence Handle10.1021/jo026722l Occurrence Handle1:CAS:528:DC%2BD3sXhvVygsLo%3D

    Article  PubMed  CAS  Google Scholar 

  • L Aurelio RTC Brownlee AB Hughes (2004) ArticleTitleSynthetic preparation of N-methyl-alpha-amino acids Chem Rev 104 5823–5846 Occurrence Handle15584690 Occurrence Handle10.1021/cr030024z Occurrence Handle1:CAS:528:DC%2BD2cXptlOis7o%3D

    Article  PubMed  CAS  Google Scholar 

  • JF Briere P Charpentier G Dupas G Queguiner J Bourguignon (1997) ArticleTitleRegioselective reductions of various 3-aminosuccinimides; Application to the synthesis of two heterocyclic systems Tetrahedron 53 2075–2086 Occurrence Handle10.1016/S0040-4020(96)01157-X Occurrence Handle1:CAS:528:DyaK2sXhtFWquro%3D

    Article  CAS  Google Scholar 

  • K Burger J Spengler (2000) ArticleTitleA new approach to N-methylaspartic, N-methylglutamic, and N-methyl-alpha aminoadipic acid derivatives Eur J Org Chem 2000 199–204 Occurrence Handle10.1002/(SICI)1099-0690(200001)2000:1<199::AID-EJOC199>3.0.CO;2-8

    Article  Google Scholar 

  • K Burger H Schedel J Spengler (1999) ArticleTitleA new protection activation strategy for the synthesis of naturally occurring and non-natural alpha-N-alkylamino acids Amino Acids 16 287–295 Occurrence Handle10399017 Occurrence Handle10.1007/BF01388173 Occurrence Handle1:CAS:528:DyaK1MXkt1aksb4%3D

    Article  PubMed  CAS  Google Scholar 

  • K Burger J Spengler L Hennig R Herzschuh SA Essawy (2000) ArticleTitleSynthesis of derivatives of omega-isocyanato-alpha-methylamino, omega-ureido-alpha-methylamino, and N-alpha-methyl-alpha, omega- diaminoacids Mh Chemie 131 463–473 Occurrence Handle1:CAS:528:DC%2BD3cXltVaqtbc%3D

    CAS  Google Scholar 

  • S Chamoin HJ Roth C Borek A Jary H Maillot (2003) ArticleTitleAutomated parallel synthesis of N-alkylated-alpha-amino methyl esters in gram quantities Chimia 57 241–247 Occurrence Handle10.2533/000942903777679370 Occurrence Handle1:CAS:528:DC%2BD3sXltFegsLw%3D

    Article  CAS  Google Scholar 

  • JJ Chruma D Sames R Polt (1997) ArticleTitleGeneral method for the synthesis of N-methyl amino acids and N-aikyl amino esters from O’Donnelrs Schiff bases Tetrahedron Lett 38 5085–5086 Occurrence Handle10.1016/S0040-4039(97)01132-5 Occurrence Handle1:CAS:528:DyaK2sXkvVCjt7c%3D

    Article  CAS  Google Scholar 

  • S Clarke RC Stephenson JD Lowenson (1992) Lability of asparagine and aspartic acid residues in proteins and peptides: spontaneous deamidation and isomerization reactions TJ Ahern MC Manning (Eds) Stability of protein pharmaceuticals, part A: chemical and physical pathways of protein degradation Plenum Press New York 2–23

    Google Scholar 

  • A D’Aniello P Spinelli A De Simone S D’Aniello M Branno F Aniello GH Fisher MM Di Fiore RK Rastogi (2003) ArticleTitleOccurrence and neuroendocrine role of D-aspartic acid and N-methyl-D-aspartic acid in Ciona intestinalis FEBS Lett 552 193–198 Occurrence Handle14527686 Occurrence Handle10.1016/S0014-5793(03)00921-9 Occurrence Handle1:CAS:528:DC%2BD3sXns12lu7w%3D

    Article  PubMed  CAS  Google Scholar 

  • TJ Deming (1997) ArticleTitleFacile synthesis of block copolypeptides of defined architecture Nature 390 386–389 Occurrence Handle9389476 Occurrence Handle10.1038/37084 Occurrence Handle1:CAS:528:DyaK2sXns12lurs%3D

    Article  PubMed  CAS  Google Scholar 

  • M Ebata Y Takahashi H Otsaka (1966) ArticleTitleThe preparation and some properties of N-monoalkylated L-amino acids Bull Chem Soc Jpn 39 2535–2538 Occurrence Handle5978709 Occurrence Handle10.1246/bcsj.39.2535 Occurrence Handle1:CAS:528:DyaF2sXkt1aisLc%3D

    Article  PubMed  CAS  Google Scholar 

  • M Falorni G Giacomelli F Nieddu M Taddei (1997) ArticleTitleA new diketopiperazine tetra-carboxylic acid as template for the homogeneous phase synthesis of chemical libraries Tetrahedron Lett 38 4663–4666 Occurrence Handle10.1016/S0040-4039(97)00961-1 Occurrence Handle1:CAS:528:DyaK2sXktlejuro%3D

    Article  CAS  Google Scholar 

  • GP Gasic M Hollmann (1992) ArticleTitleMolecular neurobiology of glutamate receptors Annu Rev Physiol 54 507–536 Occurrence Handle1314044 Occurrence Handle10.1146/annurev.ph.54.030192.002451 Occurrence Handle1:CAS:528:DyaK38XktVSqtLY%3D

    Article  PubMed  CAS  Google Scholar 

  • VS Goodfellow MV Marathe KG Kuhlman TD Fitzpatrick D Cuadrado W Hanson JS Zuzack SE Ross M Wieczorek M Burkard ET Whalley (1996) ArticleTitleBradykinin receptor antagonists containing N-substituted amino acids: In vitro and in vivo B-2 and B-1 receptor antagonist activity J Med Chem 39 1472–1484 Occurrence Handle8691478 Occurrence Handle10.1021/jm950716i Occurrence Handle1:CAS:528:DyaK28XhsVyhu74%3D

    Article  PubMed  CAS  Google Scholar 

  • A Hashimoto T Oka (1997) ArticleTitleFree D-aspartate and D-serine in the mammalian brain and periphery Prog Neurobiol 52 325–353 Occurrence Handle9247969 Occurrence Handle10.1016/S0301-0082(97)00019-1 Occurrence Handle1:CAS:528:DyaK2sXlt1Ghs7w%3D

    Article  PubMed  CAS  Google Scholar 

  • C Howes NW Alcock BT Golding RW Mccabe (1983) ArticleTitleCyclo-(l-asparagyl-l-asparagyl) [3s,6s)-3,6-bis(carbamoylmethyl)-piperazine-2,5-dione] – preparation and crystal-structure J Chem Soc Perkin Trans 1 2287–2291 Occurrence Handle10.1039/p19830002287

    Article  Google Scholar 

  • AR Katritzky JC Yao M Qi YT Chou DJ Sikora S Davis (1998) ArticleTitleRing opening reactions of succinimides Heterocycles 48 2677–2691 Occurrence Handle1:CAS:528:DyaK1MXltVejtA%3D%3D

    CAS  Google Scholar 

  • WR Li MM Joullié (1992) The didemnins: biological properties, chemistry, and total synthesis A-U Rahman (Eds) Studies in natural products chemistry NumberInSeries10 Elsevier Amsterdam 241–302

    Google Scholar 

  • Y Liwschitz A Zilkha (1954) ArticleTitleSyntheses of aspartyl amides and peptides through N-benzyl-dl-aspartic acid J Am Chem Soc 76 3698–3701 Occurrence Handle10.1021/ja01643a030 Occurrence Handle1:CAS:528:DyaG2MXltlersA%3D%3D

    Article  CAS  Google Scholar 

  • Y Liwschitz Y Edlitz-Pfeffermann Y Lapidoth (1956) ArticleTitleSyntheses of aspartic acid derivatives. II. N-Alkylated alpha- and beta-asparagines J Am Chem Soc 78 3069–3072 Occurrence Handle10.1021/ja01594a034 Occurrence Handle1:CAS:528:DyaG28XnslKrtg%3D%3D

    Article  CAS  Google Scholar 

  • O Lutz Br Jirgensons (1930) ArticleTitleÜber eine neue Methode der Zuteilung optisch-aktiver α-Aminosäuren zur Rechts- oder Linksreihe I Mitteil Chem Ber 63B 448–460 Occurrence Handle1:CAS:528:DyaA3cXjt1yhtA%3D%3D Occurrence Handle10.1002/cber.19300630232

    Article  CAS  Google Scholar 

  • J Maddaluno A Corruble V Leroux G Ple P Duhamel (1992) ArticleTitleHandy access to chiral n,n′-disubstituted 3-aminopyrrolidines Tetrahedron 3 1239–1242 Occurrence Handle10.1016/S0957-4166(00)82081-9 Occurrence Handle1:CAS:528:DyaK3sXjvFemuw%3D%3D

    Article  CAS  Google Scholar 

  • M Mergler F Dick B Sax P Weiler T Vorherr (2003) ArticleTitleThe aspartimide problem in Fmoc-based SPPS Part I J Pept Sci 9 36–46 Occurrence Handle12587881 Occurrence Handle10.1002/psc.430 Occurrence Handle1:CAS:528:DC%2BD3sXht12qtbo%3D

    Article  PubMed  CAS  Google Scholar 

  • H Mori M Mishina (1995) ArticleTitleStructure and function of the nmda receptor-channel Neuropharmacology 34 1219–1237 Occurrence Handle8570021 Occurrence Handle10.1016/0028-3908(95)00109-J Occurrence Handle1:CAS:528:DyaK2MXptVyntbg%3D

    Article  PubMed  CAS  Google Scholar 

  • Y Nabuchi E Fujiwara H Kuboniwa Y Asoh H Ushio (1997) ArticleTitleThe stability and degradation pathway of recombinant human parathyroid hormone: Deamidation of asparaginyl residue and peptide bond cleavage at aspartyl and asparaginyl residues Pharm Res 14 1685–1690 Occurrence Handle9453054 Occurrence Handle10.1023/A:1012115426306 Occurrence Handle1:CAS:528:DyaK1cXktFKjtA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • C Oliyai RT Borchardt (1994) ArticleTitleChemical pathways of peptide degradation 6. Effect of the primary sequence on the pathways of degradation of aspartyl residues in model hexapeptides Pharm Res 11 751–758 Occurrence Handle8058648 Occurrence Handle10.1023/A:1018944800691 Occurrence Handle1:CAS:528:DyaK2cXlt1yju7Y%3D

    Article  PubMed  CAS  Google Scholar 

  • W Oppolzer P Cintas-Moreno O Tamura F Cardinaux (1993) ArticleTitleEnantioselective synthesis of -N-alkylamino acids via sultam-directed enolate hydroxyamination Helv Chim Acta 76 187–196 Occurrence Handle10.1002/hlca.19930760113 Occurrence Handle1:CAS:528:DyaK3sXitFenur4%3D

    Article  CAS  Google Scholar 

  • Orphanides GG (1979) Preparation of maleimides and dimaleimides. U.S. Pat. 4,154,737 (to E. I. du Pont de Nemours Co. Inc.)

  • J Orpiszewski N Schormann B Kluve-Beckerman JJ Liepnieks Benson (2000) ArticleTitleMD Protein aging hypothesis of Alzheimer disease FASEB J 14 1255–1263 Occurrence Handle10834947 Occurrence Handle1:CAS:528:DC%2BD3cXjvFyjtL8%3D

    PubMed  CAS  Google Scholar 

  • D Papaioannou C Athanassopoulos V Magafa N Karamanos G Stavropoulos A Napoli G Sindona DW Aksnes GW Francis (1994) ArticleTitleRedox N-alkylation of tosyl protected amino-acid and peptide esters Acta Chem Scand 48 324–333 Occurrence Handle1:CAS:528:DyaK2cXmtVGqurs%3D Occurrence Handle10.3891/acta.chem.scand.48-0324

    Article  CAS  Google Scholar 

  • GR Pettit Y Kamano CL Herald Y Fujii H Kizu MR Boyd FE Boettner DL Doubek JM Schmidt JC Chapuis C Michel (1993) ArticleTitleIsolation of dolastatins 10–15 from the marine mollusk dolabella-auricularia Tetrahedron 49 9151–9170 Occurrence Handle10.1016/0040-4020(93)80003-C Occurrence Handle1:CAS:528:DyaK2cXltFSg

    Article  CAS  Google Scholar 

  • PS Piispanen PM Pihko (2005) ArticleTitleDirect synthesis of N-substituted, functionalized aspartic acids using alkali maleates and amines Tetrahedron Lett 46 2751–2755 Occurrence Handle10.1016/j.tetlet.2005.02.159 Occurrence Handle1:CAS:528:DC%2BD2MXis1eltLw%3D

    Article  CAS  Google Scholar 

  • M Prashad D Har B Hu HY Kim O Repic TJ Blacklock (2003) ArticleTitleAn efficient and practical N-methylation of amino acid derivatives Org Lett 5 125–128 Occurrence Handle12529121 Occurrence Handle10.1021/ol0268440 Occurrence Handle1:CAS:528:DC%2BD38Xps1GgsL8%3D

    Article  PubMed  CAS  Google Scholar 

  • GV Reddy DS Iyengar (1999) ArticleTitleA simple and rapid protocol for N-methyl-alpha-amino acids Chem Lett 28 299–300 Occurrence Handle10.1246/cl.1999.299

    Article  Google Scholar 

  • Reppe W, Ufer H (1937) N-substituted aspartic acids and their functional derivatives and process of producing them. 1246815; Patent; I.G.Farbenind. U.S. Patent 2,200,220

  • AE Roher JD Lowenson S Clarke C Wolkow R Wang RJ Cotter IM Reardon HA Zurcherneely RL Heinrikson MJ Ball BD Greenberg (1993) ArticleTitleStructural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimers-disease J Biol Chem 268 3072–3083 Occurrence Handle8428986 Occurrence Handle1:CAS:528:DyaK3sXhsVGjsb0%3D

    PubMed  CAS  Google Scholar 

  • M Sato F Inoue N Kanno Y Sato (1987) ArticleTitleThe occurrence of N-methyl-D-aspartic acid in muscle extracts of the blood shell, Scapharca broughtonii Biochem J 241 309–311 Occurrence Handle3551926 Occurrence Handle1:CAS:528:DyaL2sXjtVamtQ%3D%3D

    PubMed  CAS  Google Scholar 

  • H Schedel K Burger (2000) ArticleTitleSynthesis of alpha-N-ethylamino acids and their derivatives Mh Chemie 131 1011–1018 Occurrence Handle1:CAS:528:DC%2BD3cXnsFOntLc%3D

    CAS  Google Scholar 

  • S Sciuto M Piattelli R Chillemi (1979) ArticleTitleN-methyl-l-aspartic acid from the red alga halopytis-incurvus Phytochemistry 18 1058–1058 Occurrence Handle10.1016/S0031-9422(00)91478-X Occurrence Handle1:CAS:528:DyaE1MXmtVOgtbs%3D

    Article  CAS  Google Scholar 

  • A Seleni S D’Aniello AF Perna D Ingrosso (2000) ArticleTitleOccurrence of D-aspartic acid and N-methyl-D-aspartic acid in rat neuroendocrine tissues and their role in the modulation of luteinizing hormone and growth hormone release FASEB J 14 699–714 Occurrence Handle10744627

    PubMed  Google Scholar 

  • PA Stadler A Hofmann (1962) ArticleTitleChemische Bestimmung der absoluten Konfiguration der Lysergsäure 54. Mitteilung über Mutterkornalkaloide Helv Chim Acta 45 2005–2011 Occurrence Handle10.1002/hlca.19620450636 Occurrence Handle1:CAS:528:DyaF3sXislCktw%3D%3D

    Article  CAS  Google Scholar 

  • JP Tam MW Riemen RB Merrifield (1988) ArticleTitleMechanism of aspartimide formation: the effects of protecting groups, acid, base temperature and time Pept Res 1 6–18 Occurrence Handle2980781 Occurrence Handle1:CAS:528:DyaK3cXmtlWqurs%3D

    PubMed  CAS  Google Scholar 

  • B Thern J Rudolph G Jung (2002) ArticleTitleTriphosgene as highly efficient reagent for the solid-phase coupling of N-alkylated amino acids – total synthesis of cyclosporin O Tetrahedron Lett 43 5013–5016 Occurrence Handle10.1016/S0040-4039(02)00657-3 Occurrence Handle1:CAS:528:DC%2BD38XkvVensLg%3D

    Article  CAS  Google Scholar 

  • Thomas PD (1976) Organic acid derivatives. U.S. Pat. 3,953,616 (to Pfizer Inc.)

  • N Todoroki K Shibata T Yamada Y Kera R Yamada (1999) ArticleTitleDetermination of N-methyl-D-aspartate in tissues of bivalves by high-performance liquid chromatography J Chromatogr 728B 41–47

    Google Scholar 

  • SH van Leeuwen PJLM Quaedflieg QB Broxtermanc RMJ Liskampa (2002) ArticleTitleSynthesis of amides from unprotected amino acids by asimultaneous protection-activation strategy using dichlorodialkyl silanes Tetrahedron Lett 43 9203–9207 Occurrence Handle10.1016/S0040-4039(02)02275-X Occurrence Handle1:CAS:528:DC%2BD38Xos1ant7k%3D

    Article  CAS  Google Scholar 

  • G Verardo P Geatti E Pol AG Giumanini (2002) ArticleTitleSodium borohydride: a versatile reagent in the reductive N monoalkylation of -amino acids and -amino methyl esters Can J Chem 80 779–788 Occurrence Handle10.1139/v02-083 Occurrence Handle1:CAS:528:DC%2BD38XlvFektLk%3D

    Article  CAS  Google Scholar 

  • B Vitoux A Aubry MT Cung M Marraud (1986) ArticleTitleN-methyl peptides. 7. Conformational perturbations induced by n-methylation of model dipeptides Int J Pept Protein Res 27 617–632 Occurrence Handle1:CAS:528:DyaL2sXktVOmtbs%3D Occurrence Handle10.1111/j.1399-3011.1986.tb01058.x

    Article  CAS  Google Scholar 

  • T Watanabe K Shibata Y Kera R Amada (1998) ArticleTitleOccurrence of free D-aspartate and aspartate racemase in the blood shell Scapharca broughtonii Amino Acids 14 353–360 Occurrence Handle9871479 Occurrence Handle10.1007/BF01318854 Occurrence Handle1:CAS:528:DyaK1cXltVGgt7g%3D

    Article  PubMed  CAS  Google Scholar 

  • JC Watkins (1962) ArticleTitleThe synthesis of some acidic amino acids possessing neuropharmacological activity J Med Pharm Chem 5 1187–1199 Occurrence Handle10.1021/jm01241a010 Occurrence Handle1:CAS:528:DyaF3sXktVersrY%3D

    Article  CAS  Google Scholar 

  • JC Watkins RH Evans (1981) ArticleTitleExcitatory amino-acid transmitters Annu Rev Pharmacol Toxicol 21 165–204 Occurrence Handle6112965 Occurrence Handle10.1146/annurev.pa.21.040181.001121 Occurrence Handle1:CAS:528:DyaL3MXitVarsbo%3D

    Article  PubMed  CAS  Google Scholar 

  • K Wisniewski AM Kotodziejczyk (1997) ArticleTitlePmc-protected amino acid esters as substrates in N-alkylamino acid synthesis Tetrahedron Lett 38 483–486 Occurrence Handle10.1016/S0040-4039(96)02350-7 Occurrence Handle1:CAS:528:DyaK2sXotFektg%3D%3D

    Article  CAS  Google Scholar 

  • A Zilkha MD Bachi (1959) ArticleTitleSyntheses of N-Alkyl-aspartic acids and N2-Alkyl-alpha-asparagines J Org Chem 24 1096–109 Occurrence Handle10.1021/jo01090a015 Occurrence Handle1:CAS:528:DyaF3cXivVentg%3D%3D

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department for Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary

    M. Boros, J. Kökösi, J. Vámos & B. Noszál

  2. EGIS Pharmaceuticals PLC, Budapest, Hungary

    I. Kövesdi

  3. Research Group for Drugs of Abuse and Doping Agents, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary

    B. Noszál

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  1. M. Boros
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  2. J. Kökösi
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  3. J. Vámos
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  4. I. Kövesdi
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Boros, M., Kökösi, J., Vámos, J. et al. Methods for syntheses of N-methyl-DL-aspartic acid derivatives. Amino Acids 33, 709–717 (2007). https://doi.org/10.1007/s00726-006-0453-4

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