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Synthetic method of 1-cyclopropyl-4-oxo-7-fluoro-8-methoxy-1,4-dihydroquinoline-3-carboxylic acid

A dihydroquinoline and cyclopropyl technology, which is applied in the field of synthesis of new quinolone drug intermediates, can solve the problems of small supply, stable supply of raw materials, unsatisfactory atom economy, etc.

Active Publication Date: 2016-04-13
ZHEJIANG ZHONGXIN FLUORIDE MATERIALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although the synthesis steps of this route are not long, the supply of the starting material 2,4-difluoroacetophenone used in the market is relatively small, and the stable supply of raw materials is greatly restricted. Group protection and deprotection, atom economy is not ideal

Method used

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  • Synthetic method of 1-cyclopropyl-4-oxo-7-fluoro-8-methoxy-1,4-dihydroquinoline-3-carboxylic acid
  • Synthetic method of 1-cyclopropyl-4-oxo-7-fluoro-8-methoxy-1,4-dihydroquinoline-3-carboxylic acid

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Experimental program
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Effect test

Embodiment 1

[0063] In a 500ml dry reaction flask, replace the gas with nitrogen, add 22.8g of compound (I) and 150ml of anhydrous ether, and stir and cool the system to -78°C under the protection of nitrogen. o C. Slowly add 187 ml of 1.6M n-butyllithium n-hexane solution dropwise. o C stirred the reaction for 2 hours. Cool the system back to -78 o C, add 60 grams of trimethyl borate dropwise, after the dropwise addition, control the temperature at -50~-60 o C stirred the reaction for 2 hours. Return the reaction system to room temperature, add 200 ml of water to quench the reaction, and adjust it to acidity with 36% hydrochloric acid. After heating up and distilling to recover the organic solvent, control the temperature at 70-80 o C stirred the reaction for 6 hours. The system was cooled and crystallized, filtered and washed with water to obtain 27.0 g of compound (II).

Embodiment 2

[0065] Add 31.6 grams of compound (II), 150 milliliters of ethanol, 100 milliliters of water, and 30 milliliters of acetic acid into a 500 milliliter reaction bottle, stir at room temperature, add 34 grams of 30% hydrogen peroxide dropwise, after the addition is complete, control the temperature for 20 o C stirred and reacted for 30 hours, the system was lowered to room temperature, 200 ml of 10% sodium bisulfite solution was added dropwise, stirred for 1 hour after the dropwise addition, ethanol was recovered by distillation under reduced pressure, and the residue was extracted 3 times with ethyl acetate, each dosage 100 ml, the organic phases were combined, dried and concentrated to obtain 23.9 g of compound (III).

Embodiment 3

[0067] Add 26.2 grams of compound (III), 200 milliliters of tetrahydrofuran, and 83 grams of potassium carbonate to a 500 milliliter reaction bottle, stir at room temperature, add 38 grams of dimethyl sulfate dropwise, after the addition is complete, continue to stir for 10 hours, filter, and depressurize the filtrate Concentrate, recover the solvent, and distill the residue to obtain 26.8 g of compound (IV).

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Abstract

The invention discloses a synthesis method of 1-cyclopropyl-4-oxo-7-fluoro-8-methoxy-1,4-dihydroquinolyl-3-carboxylic acid. The synthesis method comprises the following reaction steps: reacting m-difluorophenyl with an organolithium reagent, reacting an obtained aryllithium intermediate with borate, quenching to obtain 2,6-difluorophenylboronic acid and 2,6-difluorophenylborate, reacting 2,6-difluorophenol obtained through oxidation with a methylating reagent, reacting the obtained 2,6-difluorophenylmethyl ether with the organolithium reagent, reacting the obtained corresponding aryllithium intermediate with carbon dioxide, reacting the obtained product with an acylchlorinating reagent to obtain 2,4-difluoro-3-methoxy benzoyl chloride, and performing cyclization, hydrolysis and the like to obtain the 1-cyclopropyl-4-oxo-7-fluoro-8-methoxy-1,4-dihydroquinolyl-3-carboxylic acid. The synthesis method has the advantages as follows: raw materials are easy to obtain; the yield in each step is high; the atom economy is high; the synthesis method is suitable for industrial application.

Description

Technical field: [0001] The present invention relates to a synthetic method of a novel quinolone pharmaceutical intermediate, in particular to a 1-cyclopropyl-4-oxo-7-fluoro-8-methoxy-1,4-dihydroquinoline - Synthetic method of 3-carboxylic acid. Background technique: [0002] Quinolones are a new type of synthetic high-efficiency broad-spectrum antibacterial drugs, which mainly act on Gram-negative bacteria, have weak effects on Gram-positive bacteria, and have good antibacterial effects on other antibiotic-resistant bacteria. [0003] Although quinolones have been widely used in the treatment of a variety of bacterial infections, the bacterial resistance caused by their irrational use has become a serious problem. Studies have shown that most methicillin-resistant Staphylococcus aureus (MRSA) There is resistance to existing quinolones, so the research on new powerful quinolones has never stopped. [0004] With the deepening of research, new quinolone antibacterial drugs a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/56
CPCC07D215/56
Inventor 袁其亮张佳炳徐鹏飞蒋贤波陈寅镐王超
Owner ZHEJIANG ZHONGXIN FLUORIDE MATERIALS CO LTD
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