Improved and Large-Scale Synthesis of N-methyl-D-aspartic Acid

Xi, Liang; Wu, Di; Zhu, Hai‐Liang; Zhang, Conghai; Jin, Yi; Lin, Johnny Shinn‐Nan

doi:10.2174/1570179411666141113215036

Cited by 5 publications

(3 citation statements)

References 17 publications

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“…Taken as a whole, the most outstanding property of the studied enzyme is the capability to conduct a one-step chiral resolution of N-methyl-d,l-Asp under mild reaction condition without racemization. Compared with regular chemical synthesizing methods (i.e., Eschweiler-Clark reaction, reduction-methylation and hexafluoroacetone protection) [5,6,12], this enzymatic catalyzing route also shows the advantages of a simple process, easily obtainable raw materials and no need of toxic reagents. In addition, with other enzymes for the synthesis of N-methyl-amino acids normally requiring NADPH as the coenzyme, such as transaminase [11] and imine reductase [44], ChlfSOX would serve as a more effective candidate since there is no need of coenzyme regeneration during the catalyzing process.…”

Section: The Application Of Chlfsox For Chiral Resolution Of N-methyl-dl-aspartic Acidmentioning

confidence: 99%

“…N-methyl-d-apartic acid (NMDA), which plays a major role in neuroexcitatory events as well as in modulating Ca 2+ homeostasis, is a potent agonist of a glutamate receptor subtype which could be used for the treatment of diabetes, Parkinson's and Alzhermer's syndrome [1][2][3][4]. To date, several chemical methods for synthesizing N-monomethyl amino acids have been reported, including reductive methylation [5], Eschweiler-Clarke reaction [6], mono-N-methylation of solid-supported amino acid [7], amination of alkenes [8] and heterocylization method [9,10]. However, the above methods normally include multiple steps, and the reactions might involve the usage of toxic reagents or solid phase materials under harsh conditions [6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…To date, several chemical methods for synthesizing N-monomethyl amino acids have been reported, including reductive methylation [5], Eschweiler-Clarke reaction [6], mono-N-methylation of solid-supported amino acid [7], amination of alkenes [8] and heterocylization method [9,10]. However, the above methods normally include multiple steps, and the reactions might involve the usage of toxic reagents or solid phase materials under harsh conditions [6][7][8][9][10]. Racemization is another issue accompanied by the above methods [5].…”

Section: Introductionmentioning

confidence: 99%

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Chiral resolution of N-methyl-d,l-aspartic acid using a predicted N-demethylase from Chloroflexi bacterium 54-19

Zhang

2022

Syst Microbiol and Biomanuf

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N-methyl-d-aspartic acid (NMDA), an amino acid existing in human and animal central nervous system, exerts agonist action on one of the glutamate receptor subtypes and is clinically used for treatment of diabetes, Parkinson's and Alzheimer's syndrome. In this study, an enzymatic protocol for the chiral resolution of N-methyl-d,l-aspartic acid was built with a predicted N-demethylase (GenBank ID: OJV90073.1) from the genome of Chloroflexi bacterium 54-19. Through sequence alignment, the enzyme shares an identity of 32.19% to 2UZZ (PDB ID) with a conserved catalytic center. Recombinantly expressed in Bacillus subtilis WB600, the N-demethylase was characterized with optimal temperature and pH at 55 ℃ and 7.5, and adaptive temperature and pH were 40-60 ℃ and 6-8. The effects of organic solvents and metal ions were investigated as well. Compared with other previously reported sarcosine oxidases, the enzyme showed a specific N-demethylation activity against N-methyl-l-aspartic acid according to the analysis by chiral liquid chromatography, LC-MS/MS and a detection by polarimeter. The results demonstrated 76% of 4.5 mM N-methyl-d,l-aspartic acid could be chirally separated by 7 mg•L −1 enzyme after reaction of 80 min. This work provided a foundation for mild synthesis of NMDA in industry.

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Section: The Application Of Chlfsox For Chiral Resolution Of N-methyl-dl-aspartic Acidmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Chiral resolution of N-methyl-d,l-aspartic acid using a predicted N-demethylase from Chloroflexi bacterium 54-19

Zhang

2022

Syst Microbiol and Biomanuf

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Palladium‐Catalyzed Methylation of Nitroarenes with Methanol

2019

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Ap rocedure for the synthesis of N-methyl-arylamines directly from nitroarenes using methanol as green methylating agent was developed. The key to success is the use of aspecific catalyst system consisting of palladium acetate and the ligand 1-[2,6-bis(isopropyl)phenyl]-2-[tert-butyl(2-pyridinyl)phosphino]-1H-Imidazole (L1). The generality of this protocol is demonstrated in the synthesis of more than 20 Nmethyl-arylamines under comparably mild conditions.C ombining this novel methodology with subsequent coupling processes using the same catalyst allows for efficient diversification of aromatic nitro compounds to ab road variety of amines including drug molecules. Scheme 1. Representative examples of drugs containing N-methylamines. Scheme 2. a) Ligand design for Pd-catalyzeds ynthesis of N-methylarylamines. b) Potential further functionalization.

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Palladium‐Catalyzed Methylation of Nitroarenes with Methanol

2019

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A procedure for the synthesis of N‐methyl‐arylamines directly from nitroarenes using methanol as green methylating agent was developed. The key to success is the use of a specific catalyst system consisting of palladium acetate and the ligand 1‐[2,6‐bis(isopropyl)phenyl]‐2‐[tert‐butyl(2‐pyridinyl)phosphino]‐1H‐Imidazole (L1). The generality of this protocol is demonstrated in the synthesis of more than 20 N‐methyl‐arylamines under comparably mild conditions. Combining this novel methodology with subsequent coupling processes using the same catalyst allows for efficient diversification of aromatic nitro compounds to a broad variety of amines including drug molecules.

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Improved and Large-Scale Synthesis of N-methyl-D-aspartic Acid

Cited by 5 publications

References 17 publications

Chiral resolution of N-methyl-d,l-aspartic acid using a predicted N-demethylase from Chloroflexi bacterium 54-19

Chiral resolution of N-methyl-d,l-aspartic acid using a predicted N-demethylase from Chloroflexi bacterium 54-19

Palladium‐Catalyzed Methylation of Nitroarenes with Methanol

Palladium‐Catalyzed Methylation of Nitroarenes with Methanol

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