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Synthesis of N-methyl-D-aspartic acid

A technology of aspartic acid and methyl, which is applied in the field of biochemical synthesis, can solve the problems of difficult separation of isomers, easy racemization of ester hydrolysis, and high toxicity and pollution of methyl iodide, so as to shorten the reaction time and obtain raw materials easily , Operational safety effect

Inactive Publication Date: 2013-06-19
ZHANG JIA GANG VINSCE BIO PHARM
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AI Technical Summary

Problems solved by technology

[0004] Jiang Guangyu, He Haiming and others have reported (Fine and Specialty Chemicals, Phase I, 2011): Using D-aspartic acid as raw material, carboxyl esterification protection, iodomethane aminomethylation, and alkali hydrolysis to obtain NMDA , this method is easy to produce aminodimethylation impurities, which need to be separated by column, the yield is reduced and the ester hydrolysis is easy to racemize, the isomers are difficult to separate, which increases the cost, and the methyl iodide is highly toxic and polluted, which is not conducive to large-scale production
[0005] The Department of Chemistry, University of Ottawa, Canada published a document (CANADIAN JOURNAL OF CHEMISTRY.VOL.49, 1971) reporting that D-aspartic acid was first amino-protected, then methylated with methyl iodide, catalyzed by NaH, then deprotected, and alkali hydrolyzed to obtain NMDA, although this method uses amino protection to solve the problem of amino dimethylation, but the demand for methylation reagents is large and expensive, the reaction steps are long, and the yield is low. Among them, the catalyst NaH is dangerous and unfavorable for industrial production.
[0006] At present, the imine reduction method is only suitable for a few amino acids, and aspartic acid is an inert aminomethylated amino acid, which has certain limitations.

Method used

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  • Synthesis of N-methyl-D-aspartic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Synthesis of N-BOC-D-Aspartic Acid

[0019] Add 80ml of acetone aqueous solution (volume ratio 1:1) to a 250ml three-neck flask equipped with a thermometer, and slowly add 10ml of triethylamine (7.26g, 0.07mol) under ice bath temperature control, stir for 10min, then add D-day Aspartic acid 5.0g (0.04mol), stir until it is completely dissolved, add about 13.8ml (13.11g, 0.06mol) of di-tert-butyl dicarbonate dropwise, continue stirring for 30min, then raise the temperature to 35-40°C and continue the reaction for 6-7h . After the reaction was completed, the reaction liquid was extracted twice with 50 ml of ether, combined with the organic phases, washed with 50 ml of water, combined with the water phases, adjusted to pH 3-4 with 0.1 mol / L citric acid aqueous solution, extracted twice with 50 ml of ether, combined with the organic phases, Dry 20g of magnesium sulfate, then concentrate under reduced pressure under 50°C to obtain a transparent oil, add 25ml of petroleum et...

Embodiment example 2

[0021] Synthesis of N,N-Methyl-BOC-D-Aspartic Acid

[0022] Add 30-40ml (48.8g) of anhydrous formic acid to a 250ml three-neck flask equipped with a thermometer and a reflux device with a drying tube, and add 4.02g (0.017mol) of N-BOC-D-aspartic acid in batches under an ice bath , stir and dissolve completely, then raise the temperature to 55-60°C, continue the reaction for about 1 hour, then cool down to room temperature, add about 1.6g (0.018mol) of paraformaldehyde in batches, first stir and react at room temperature for 1.5 hours, then heat and reflux for 4- 5h, until the carbon dioxide gas is completely released, the reaction solution is transparent yellow, the reaction is over, the reaction solution is directly concentrated under reduced pressure to obtain a dark brown oil, lowered to room temperature, stirred in an ice bath, a little n-hexane is added in batches, a brown solid is precipitated, filtered , filtered the mother liquor and precipitated a small amount of soli...

Embodiment example 3

[0024] Synthesis of N-methyl-D-aspartic acid

[0025] Add about 22ml of 37% concentrated hydrochloric acid into a 50ml beaker, then add 3g (0.012mol) of N,N-methyl-BOC-D-aspartic acid at room temperature, raise the temperature to about 63°C and continue stirring for about 5h. After the reaction is finished, cool down to room temperature, pour the reaction solution into a 500ml beaker, slowly adjust the pH to 5-6 with 0.5mol / L NaOH solution, and precipitate the solid, then stir for 30 minutes, the solid precipitates completely, then filter, and rinse the filter cake with a little ice ether , dried to obtain N-methyl-D-aspartic acid 2.6g (0.018mol), weight yield 86.7%, mp 190°C, content 98.5% (HPLC).

[0026] The present invention has been verified through multiple experiments that the final molar yield is about 40% to 50%, and the content is greater than 98% (HPLC).

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Abstract

The invention relates to an N-methyl-D-aspartic acid preparation method. The N-methyl-D-aspartic acid preparation method comprises the following steps of: carrying out amino protection reaction by taking D-aspartic acid as a starting raw material to obtain amino protected D-aspartic acid, then carrying out Leuchart Wallanch reaction to obtain an N-methyl product, and then removing protecting groups with strong acid to obtain the N-methyl-D-aspartic acid in the end. The N-methyl-D-aspartic acid preparation method is mainly characterized in that the amino protection is carried out before amino methylation to solve the dimethylation problem, oxalaldehydic acid is used as a methylation reagent, the use of toxic and expensive reagents such as methyl iodide and dimethyl sulfate is avoided, and the high-purity product can be obtained without needing the complex purification process under the condition that the technology is safe, environment-friendly and inexpensive and has good yield.

Description

technical field [0001] The invention belongs to biochemical synthesis technology, relates to a synthesis method of N-methyl-D-aspartic acid, relates to a special synthesis route, and specifically relates to amino protection to solve the problem of amino dimethylation. The aminomethylation of the present invention adopts a cheap, safe and environment-friendly methylation reaction. Background technique [0002] N-methyl-D-aspartic acid (N-methyl-D-aspartic acid, NMDA), is an N-methylated natural amino acid derivative, generally only exists in animals, and its precursor aspartic acid Amino acid and glutamic acid are both inert N-methylated amino acids. NMDA can regulate the growth axis of hypothalamus-pituitary gland and the secretion of growth hormone, pituitary hormone, gonadotropin and prolactin in animal adenohypophysis, and in the research of biochemical peptides, NMDA stabilizes the conformation of the main chain of the peptide and helps to obtain endogenous The informa...

Claims

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Application Information

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IPC IPC(8): C07C229/24C07C227/20
CPCY02P20/55
Inventor 彭学东张梅赵金召王龙
Owner ZHANG JIA GANG VINSCE BIO PHARM
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