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NMDA receptor antagonist intermediate, its synthesis and use

A technology of receptor antagonists and synthetic methods, applied in the field of intermediates of receptor antagonists, to achieve the effect of short synthetic route and simple method

Inactive Publication Date: 2008-01-02
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently, Yves P. Auberson developed a new compound called NVP-AAM077, which is considered to be an NR2A subtype-specific antagonist. At present, some laboratories have used this compound to study the relationship between NMDA receptor subtype function and synaptic plasticity. Research, the results obtained about NR2A subtype mediating LTP induction and NR2B subtype mediating LTD induction have attracted great attention from the academic community, but there is little relevant research on the total synthesis and pharmacodynamic function of NVP-AAM077 to report

Method used

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  • NMDA receptor antagonist intermediate, its synthesis and use
  • NMDA receptor antagonist intermediate, its synthesis and use
  • NMDA receptor antagonist intermediate, its synthesis and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]

[0033]Compound 1 (8g, 67mmol) and oxalic acid (10g, 68mmol) were dissolved in hydrochloric acid solution (4N, 450ml), and then heated to reflux for 6 hours. After the reaction, cool naturally, adjust the PH value to be neutral, then filter, dissolve the brown solid with ether, wash with water, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate to obtain a brown solid, and dry the solid Weighed 11.6 g, 99% yield.

[0034] 1 HNMR (300MHz, CDCl 3 ): δ11.90 (1H, s), 11.21 (1H, S), 6.98-6.94 (3H, m), 2.33 (3H, s) ppm.

Embodiment 2

[0036]

[0037] Compound 2 (11.6g, 65.9mmol) was dissolved in freshly distilled thionyl chloride (250ml), N,N-dimethylformamide (DMF, 0.5ml) was added, and then heated to reflux for 3 hours. After the reaction was completed, it was allowed to cool naturally, and then the reactant was poured into ice water (1000ml), stirred continuously, then filtered, and dried to obtain a brownish-yellow solid. Under nitrogen protection, freshly distilled tetrahydrofuran (THF, 100ml) and sodium methoxide / methanol solution (25%, 30ml) were successively added to the brownish-yellow solid, and stirred at room temperature for 1 hour. Finish the reaction, add ethyl acetate (300ml) to the reactant, wash with water (200ml) three times, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, column chromatography, use n-hexane as eluent, obtain Product 14.2 g, yield 98%.

[0038] 1 H NMR (300MHz, CDCl 3 ): δ7.58(1H, dd, J=2.1Hz, J=7.8Hz), 7.37-7.31(2H, m), 4.13(3H, s)...

Embodiment 3

[0040]

[0041] To the mixture of compound 3 (9g, 4.4mmol) and bromobutyrolactam (NBS, 7.83g, 4.4mmol), α, α-isobutylonitrile (a, a-azoisobutyronitrile, 715mg, 0.44mmol) Add 1,2-dichloroethane (200ml) to the mixture, and heat to reflux for 40 minutes under the irradiation of a 500-watt sun lamp. Cool naturally to room temperature, add silica gel (18 g, 60-230 μ), remove the solvent under reduced pressure, put the solid mixture on a silica gel column, rinse with n-hexane: ethyl acetate = 70: 1, and obtain 8.38 g of the product. The rate is 91%.

[0042] 1 HNMR (300MHz, CDCl 3 ): δ7.66(1Hmdd, J=1.5Hz, J=8.4Hz), 7.50(1H,dd, J=1.2Hz, J=6.9Hz), 7.39-7.34(1H, m), 4.96(2H, s), 4.12 (3H, s), 4.07 (3H, s) ppm.

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Abstract

A NMDA acceptor antagonist intermediate, its synthesis and use are disclosed. In structural formula, R1=NO2 halogen, alkyl of C1~C4, alkoxy of C1~C4, halogenated alkyl or alkyl amido. The procedure is carried out by synthesizing acceptor antagonist intermediate from (s)-1-(4-R substituted-phenyl)ethamine, reacting with chlorhydric acid to obtain final product or synthesizing (s)-1-(4-R substituted-phenyl)ethamine from 3-diamino phenylmethane by four-step reacting and reacting with chlorhydric acid to obtain final product.

Description

technical field [0001] This patent relates to an intermediate, synthesis method and application of a receptor antagonist, specifically a kind of NMDA receptor antagonist (1-(R substituted phenyl)-ethylamino)-(2,3-dicarbonyl -1,2,3,4-tetrahydroquinoxaline-5-)-methyl)-phosphoric acid intermediate synthesis method. Background technique [0002] NMDA receptor is a voltage-dependent ligand-gated ion channel. The opening of the channel requires the combination of glutamate and glycine, and is regulated by polyamines, Mg2+, H, Zn, etc. Molecular cloning studies have found that NMDA receptors contain three gene families: NR1, NR2 and NR3. Recombinant receptor experiments confirmed that NMDA receptors are composed of different subunits, NR1 subunit is an essential component, and different NR2 subunits are assembled with it to form NMDA receptor subtypes with different channel characteristics. The NR2B subunit is expressed early in development and is responsible for the establishmen...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
Inventor 姚祝军李纲琴陈磊
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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