Synthesis method of ozenoxacin

A synthesis method and technology of condensate, which are applied in the production of bulk chemicals, organic chemistry, etc., to achieve mild reaction conditions, improve yield and product quality, and reduce monitoring costs.

Inactive Publication Date: 2020-09-18
ZHEJIANG UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although the disclosed preparation methods can synthesize Aozeroxacin, there are obvious limitations and shortcomings in such preparation methods, such as the condensation product needs to be heated for a long time under strong acid conditions to remove the protective group, and the long-time heating The hydrolysis conditions will be accompanied by the formation of genotoxic impurity (ethyl methanesulfonate)

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  • Synthesis method of ozenoxacin
  • Synthesis method of ozenoxacin
  • Synthesis method of ozenoxacin

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Experimental program
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Effect test

Embodiment 1

[0031] (1) Preparation of intermediate II, namely N-(5-bromo-3-methyl-2-pyridyl)-N-tert-butoxycarbonylmethylamine

[0032] In a dry 1 L four-necked flask, protected by argon, add 40.2 g (0.2 mol) N-(5-bromo-3-methyl-2-pyridyl)methanamine, 53.4 g (0.24 mol) Boc acid anhydride and 200 mL THF, cooled to -10°C, then added dropwise 250 mL NaHMDS (1 M in THF), after all the addition was completed, the reaction temperature was raised to room temperature, and stirred for 2 hours.

[0033] Under cooling in an ice-water bath, 250 mL of 20% ammonium chloride solution was added dropwise, and after the addition was complete, the temperature was raised to room temperature and stirring was continued for 10 minutes. Subsequently, 200 mL of ethyl acetate was added for extraction, and the layers were separated after standing. The aqueous layer was extracted with 150 mL of ethyl acetate, and the organic phases were combined. First wash with 200 mL of saturated sodium bicarbonate solution, then ...

Embodiment 2

[0043] (1) Preparation of intermediate II, namely N-(5-bromo-3-methyl-2-pyridyl)-N-tert-butoxycarbonylmethylamine

[0044] In a dry 1 L four-neck flask, pass through nitrogen protection, add 40.2g (0.2 mol) N-(5-bromo-3-methyl-2-pyridyl)methanamine, 106.8g (0.48 mol) Boc anhydride and 200 mL of dioxane, cooled to -20°C, and then added 56.0 g (0.5 mol) of potassium tert-butoxide in batches. After all the potassium tert-butoxide was added, the reaction temperature was raised to room temperature, and stirred for 10 hours.

[0045] Under cooling in an ice-water bath, 250 ml of 20% ammonium chloride solution was added dropwise, and after the addition was complete, the temperature was raised to room temperature and stirring was continued for 10 minutes. Subsequently, 200 mL of ethyl acetate was added for extraction, and the layers were separated after standing. The aqueous layer was extracted with 150 mL of ethyl acetate, and the organic phases were combined. First wash with 200 mL...

Embodiment 3

[0055] (1) Preparation of intermediate II, namely N-(5-bromo-3-methyl-2-pyridyl)-N-tert-butoxycarbonylmethylamine

[0056] In a dry 1 L four-neck flask, pass through nitrogen protection, add 40.2 g (0.2 mol) N-(5-bromo-3-methyl-2-pyridyl) methylamine, 80.1 g (0.36 mol) Boc anhydride and 200mL of acetonitrile, cooled to 0°C, and then added 27.2g (0.4mol) sodium ethoxide in batches, after all the sodium ethoxide was added, the reaction temperature was raised to room temperature, and stirred for 48 hours.

[0057] Under cooling in an ice-water bath, 250 ml of 20% ammonium chloride solution was added dropwise, and after the addition was complete, the temperature was raised to room temperature and stirring was continued for 10 minutes. Subsequently, 200 mL of ethyl acetate was added for extraction, and the layers were separated after standing. The aqueous layer was extracted with 150 mL of ethyl acetate, and the organic phases were combined. First wash with 200 mL saturated sodium...

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Abstract

A synthesis method of ozenoxacin belongs to the technical field of medicinal chemistry and synthetic chemistry. The method comprises the following steps: (1) taking N-(5-bromo-3-methyl-2-pyridyl) methylamine as a raw material, and carrying out amino protection reaction to obtain an intermediate II; (2) with the intermediate II as a raw material, carrying out a boronation reaction to obtain an intermediate III; (3) carrying out Suzuki coupling reaction on the intermediate III and 7-chloro-1-cyclopropyl-8-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester to obtain a condensation compound intermediate IV; and (4) removing a protecting group from the condensation compound intermediate IV under an acidic condition, and hydrolyzing the condensation compound intermediate IV under an alkaline condition to obtain ozenoxacin. The method has the advantages that the generation of genotoxic impurities is effectively avoided, the yield and quality of the final product are improved, the reaction conditions are milder, the monitoring cost of the production process is reduced, and the method has a good industrial prospect.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and synthetic chemistry, and specifically relates to a method for synthesizing aozefloxacin. Background technique [0002] In recent years, as people's demand for medical treatment continues to increase, many drugs have come out one after another, such as broad-spectrum antibiotics such as quinolones. At the same time, the drug resistance mechanism of bacteria is also constantly updated, and its resistance to fluoroquinolones is continuously enhanced, which increases the number of drug-resistant strains and limits the application of drugs to a certain extent. Fluorine-free quinolones, which have the advantages of broad antibacterial spectrum, good antibacterial activity, elimination of toxicity caused by fluorine atoms, and less adverse reactions, have emerged as the times require, such as aozeroxacin. [0003] Ozenoxacin Chinese chemical name 1-cyclopropyl-8-methyl-7-[5-methyl-6-(met...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04Y02P20/55
Inventor刘宣淦季晓娟王昊羽
OwnerZHEJIANG UNIVERSITY OF SCIENCE AND TECHNOLOGY