Novel method for synthesizing 6-bromine-3,4-dihydro-1H-[1,8] naphthyridine-2-ketone

A new method, naphthyridine technology, applied in the field of chemical synthesis, can solve the problems of low yield of naphthyridine-2-one, expensive excipients, high synthesis cost, etc., and achieve the effect of short synthesis process, low raw material cost and convenient operation

Inactive Publication Date: 2018-08-24
ASTATECH CHENGDU BIOPHARM CORP
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Problems solved by technology

[0003] In 2003, Mark A. Seefeld et al. reported a 2-amino-3 -Hydroxymethylpyridine is used as a raw material, and the method for obtaining 6-bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one through four-step reaction is simple, but in the third step When forming a ring, due to the high activity of benzyl bromide, many by-products will be generated when closing the ring, and it is not easy to control, resulting in 6-bromo-3,4-dihydro-1H-[1,8]naphthyridine The yield of -2-ketone is low, and the amount of waste water produced is large
[0005] In 2013, Jun Zhou et al. reported in the document "Rhodium(III)-Catalyzed Oxidative Olefination of Pyridines an Quinolines: Multigram-Scale Synthesis of Naphthyridinones" Org. Lett., Vol.15, No.13, 2013" through four One-step reaction to prepare the method for 6-bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one, but the excipients used in this method are expensive, resulting in high synthesis cost

Method used

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  • Novel method for synthesizing 6-bromine-3,4-dihydro-1H-[1,8] naphthyridine-2-ketone

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Embodiment 1

[0029] A new method for synthesizing 6-bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one:

[0030] S1. At room temperature, add acetic acid (456g) into a 1L three-necked flask, add 2-amino-3-hydroxymethylpyridine (87g, 1.0eq), cool down to 5-10°C, add bromine (123g, 1.1eq), after the dropwise addition is completed, keep the temperature, and the system reacts for 1-2h. After the reaction, add aqueous sodium hydroxide solution to the reaction system, stir for several minutes, add sodium bisulfite, and filter with suction to obtain The filter cake was dispersed in water again, sodium hydroxide aqueous solution was added to pH = 8, and the system was suction filtered again to obtain 2-amino-3-hydroxymethyl-5-bromopyridine with a yield of 63%.

[0031] S2. At room temperature, dissolve 2-amino-3-hydroxymethyl-5-bromopyridine (50g, 1.0eq) in toluene (267 g), cool down to 5-10°C, and slowly add thionyl chloride ( 73g, 2.5eq) into the reaction system, the dropwise addition is completed, a...

Embodiment 2

[0035] A new method for synthesizing 6-bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one:

[0036] S1. At room temperature, add acetic acid (487.2g) into a 1L three-necked flask, add 2-amino-3-hydroxymethylpyridine (87g, 1.0eq), cool down to 5-10°C, add bromine (123g , 1.3eq), after the dropwise addition is completed, keep the temperature, and the system reacts for 1-2h. After the reaction, add the aqueous sodium hydroxide solution to the reaction system, stir for several minutes, add sodium bisulfite, filter with suction, and The obtained filter cake was dispersed in water again, and aqueous sodium hydroxide solution was added to pH = 8, and the system was suction filtered again to obtain 2-amino-3-hydroxymethyl-5-bromopyridine with a yield of 62%.

[0037]S2. At room temperature, dissolve 2-amino-3-hydroxymethyl-5-bromopyridine (50g, 1.0eq) in toluene (290 g), cool down to 5-10°C, and slowly add thionyl chloride ( 73g, 3.0eq) into the reaction system, the dropwise addition is co...

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Abstract

The invention discloses a novel method for synthesizing 6-bromine-3,4-dihydro-1H-[1,8] naphthyridine-2-ketone and relates to the field of chemical synthesis. The method comprises the following steps:by using a four-step synthesis method, performing hydrogen substitution on a benzene ring on 2-amino-3-hydroxymethylpyridine by using bromine so as to generate 2-amino-3-hydroxymethyl-5-bromopyridine;substituting hydroxyl in the 2-amino-3-hydroxymethyl-5-bromopyridine by using chlorine in thionyl chloride so as to generate 2-amino-3-methyl chloride-5-bromopyridine hydrochloride; carrying out an annulation reaction of the 2-amino-3-methyl chloride-5-bromopyridine hydrochloride by using diethyl malonate so as to generate 6-bromine-3-nonanoic acid-ethyl ester-1,2,3,5-tetrahydro-1,8-naphthyridine-2-ketone; finally, under an alkali condition, removing carboxylic acid carbethoxy from the 6-bromine-3-nonanoic acid-ethyl ester-1,2,3,5-tetrahydro-1,8-naphthyridine-2-ketone, thereby obtaining a final product, namely 6-bromine-3,4-dihydro-1H-[1,8] naphthyridine-2-ketone. The method is low in raw material cost, simple in synthesis process, not harsh in reaction condition, safe and convenient to operate, high in final product yield, and applicable to large-scale industrial production.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a new method for synthesizing 6-bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one. Background technique [0002] Antimicrobial resistance of pathogens is a major concern worldwide, especially as methicillin Staphylococcus aureus and vancomycin become less and less effective against pathogens, making the study of antibiotic resistance a strategic sexual matters. Studies have found that inhibiting the biosynthesis of fatty acids in pathogens can effectively inhibit the growth of pathogens. At present, naphthyridone derivatives are one of the most effective substances for inhibiting pathogenic fatty acid synthesis. 6-Bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one is the most important intermediate in the synthesis of naphthyridinone derivatives, and there are many methods for its synthesis. [0003] In 2003, Mark A. Seefeld et al. reported a 2-amino-3 -Hydroxymethylpyridine is used as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 罗建业郭小军郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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