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Method for preparing poly-substituted 1, 5-naphthyridine compound

A compound and multi-substitution technology, applied in organic chemistry and other fields, can solve problems such as lack of flexibility in substitution forms

Active Publication Date: 2009-10-14
合肥华纳生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the substrate form of this method is fixed, the synthesized products have limitations and the substitution form lacks flexibility; at the same time, this method is powerless for the synthesis of 1,5-naphthyridine compounds with substituents on both rings

Method used

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  • Method for preparing poly-substituted 1, 5-naphthyridine compound
  • Method for preparing poly-substituted 1, 5-naphthyridine compound
  • Method for preparing poly-substituted 1, 5-naphthyridine compound

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Experimental program
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Embodiment 1

[0023] The preparation of embodiment 1 2-methyl-1,5-naphthyridine (R 1 , R 2 , R 3 for hydrogen, R 4 for 6-methyl)

[0024] Add 0.129 mol of ferrous sulfate heptahydrate, 1.59 mol of 3-aminopyridine and 5.56 mol of 2-butenal to the reactor in sequence, slowly add 2.8 mol of concentrated sulfuric acid, and heat to reflux for 12 hours. Cool to room temperature, neutralize to neutral with sodium hydroxide solution, filter, wash the filter cake with 1L ethyl acetate, extract the filtrate three times, combine the ethyl acetate phases, and rotary evaporate to recover ethyl acetate to obtain a concentrate. The product was distilled under reduced pressure to obtain 112.5 g of 2-methyl-1,5-naphthyridine with a yield of 50%. Colorless crystals, melting point 64°C-65°C. H NMR spectrum ( 1 H NMR, 300MHz, CDCl 3 )δ8.90-8.89 (m, 1H), 8.31-8.25 (m, 2H), 7.60-7.49 (m, 2H), 2.76 (s, 3H).

Embodiment 2

[0025] Embodiment 2 2-1, the preparation of methyl 5-naphthyridine acetate (R 1 , R 2 , R 3 for hydrogen, R 4 6-methylenecarbonyloxymethyl)

[0026] Add 69mmol of 2-methyl 1,5-naphthyridine to the reaction kettle, add redistilled tetrahydrofuran under anhydrous and oxygen-free conditions, raise the temperature to 50°C, add 208mmol of lithium diisopropylamide dropwise, after the dropwise addition Stir at 50°C for 30min, continue to add 76mmol of dimethyl carbonate dropwise, after the dropwise addition, stir at 50°C for 2h, quench the reaction with 20ml of 30% saturated ammonium chloride solution, extract three times with 50ml of ethyl acetate, combine organic phase, concentrated, and distilled under reduced pressure to obtain 7.8 g of methyl 2-1,5-naphthyridine acetate, with a yield of 56%, as colorless crystals, with a melting point of 68°C-70°C. H NMR spectrum ( 1 H NMR, 300MHz, CDCl 3 )δ8.95-8.93 (m, 1H), 8.37-8.33 (m, 2H), 7.66-7.59 (m, 2H), 4.06 (s, 2H), 3.72 (s, 3H)...

Embodiment 3

[0027] Example 3 The preparation of 2-hydroxyl-6-methyl-1,5-naphthyridine (R 1 is methyl, R 2 , R 3 for hydrogen, R 4 for 6-hydroxyl)

[0028] Add 1.8mmol ferrous sulfate heptahydrate, 145mmol 2-hydroxyl-5-aminopyridine and 290mmol 2-butenal in sequence in the reaction kettle, slowly add 110mmol concentrated sulfuric acid, heat and reflux for 2 hours, then cool the reaction system to room temperature, Neutralize to neutral with 88ml of 10% sodium hydroxide solution, filter, wash the filter cake with 150ml of ethyl acetate, extract the filtrate three times, combine the ethyl acetate phases, and remove the ethyl acetate by rotary evaporation to obtain a concentrate. The product was subjected to silica gel column chromatography with ethyl acetate as the eluent to obtain 13.9 g of 2-hydroxy-6-methyl 1,5-naphthyridine, a colorless solid with a yield of 60%. H NMR spectrum ( 1 H NMR, 300MHz, CDCl 3)δ8.04-8.01 (dd, 1H), 7.67 (d, 1H), 7.36-7.26 (d, 1H), 6.92-6.89 (d, 1H), 2.67-2...

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Abstract

The invention relates to a method for preparing a poly-substituted 1, 5-naphthyridine compound. The method comprises the steps of: mixing 3-aminopyridines compound shown in constitutional formula (II), (III) or (IV) with 2-alkenyl aldehyde or 2-alkenyl ketone; adding green vitriol as a catalyst; carrying out heating reflux reaction in sulphuric acid for 2 to 20 hours; cooling a reaction system till the temperature of the reaction system reaches room temperature and then regulating pH value to be neutral; filtering the reactants and extracting, concentrating, separating and refining the filtrate to obtain the poly-substituted 1, 5-naphthyridine compound shown in constitutional formula (I). The method can be applied to various substrates and materials are highly available; poly-substituted 1, 5-naphthyridine compound banks with diverse structures can be synthesized by optimizing and regulating substrates involved in the reaction, and the compounds can be widely applied to the fields such as pharmacochemistry, biomedicine, materials science and the like.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of multi-substituted 1,5-naphthyridine compounds. Background technique [0002] 1,5-Naphthyridine compounds are important heterocyclic compounds, they are widely distributed in nature, and many natural products contain 1,5-Naphthyridine rings in their structures. 1,5-Naphthyridine compounds are also important intermediates of various synthetic drugs. It has been found that 1,5-naphthyridine compounds have biological activities such as anti-malarial, anti-inflammatory, bactericidal, anti-viral, anti-cancer, anti-filtering pathogens, anti-asthma and anti-emetic. Research by medicinal chemists on the use of 1,5-naphthyridine compounds as receptor inhibitors such as TGF receptor inhibitors has also been ongoing. Many new functional materials such as new dyes and new luminescent materials developed in recent years contain 1,5-naphthyridine rings in ...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 刘迎春许峰高源
Owner 合肥华纳生物医药科技有限公司
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