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Preparation method of quinolone compounds and intermediates thereof

A compound, selected technology, applied in the direction of organic chemistry, etc., can solve problems such as complex operation

Pending Publication Date: 2022-07-05
CHONGQING UNIV OF ARTS & SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the raw material of o-fluorobenzoic acid is easy to get in the method (c), it needs 5 steps to obtain the quinolone drug prodrug, and the operation is complicated

Method used

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  • Preparation method of quinolone compounds and intermediates thereof
  • Preparation method of quinolone compounds and intermediates thereof
  • Preparation method of quinolone compounds and intermediates thereof

Examples

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preparation example Construction

[0051] In a first aspect, the application provides a method for preparing a compound of formula I, comprising the steps of:

[0052] Combining the compound of formula A with R 5 NH 2 and R 6 Cl reacts in the presence of a base to form a compound of formula I,

[0053]

[0054] in:

[0055] X is selected from CR 2 or N;

[0056] Z is selected from CR 4 or N;

[0057] R 1 independently selected from hydrogen, alkyl, alkoxy, halogen, NO 2 , CN, optionally substituted amino, haloalkyl, aryl and heteroaryl;

[0058] R 2 and R 3 each independently selected from hydrogen, alkyl, alkoxy, halogen, amino, NO 2 , CN, haloalkyl, aryl, and heteroaryl; or R 2 with R 3 connected together to form a ring;

[0059] R 4 independently selected from hydrogen, alkyl, alkoxy, halogen, amino, NO2 , CN, haloalkyl, aryl and heteroaryl;

[0060] R 5 independently selected from alkyl optionally substituted with OH or SH, cycloalkyl optionally substituted with halogen, aryl and hetero...

Embodiment 1

[0226] Synthesis of ciprofloxacin and grifloxacin analogs:

[0227]

[0228] The steps of concrete synthesis of ciprofloxacin are as follows:

[0229] In a 25mL round-bottomed flask, first place 6,7-difluoro-3-formylchromone (0.5mmol), cyclopropylamine (1.2mmol), p-toluenesulfonyl chloride (0.5mmol) in water (5.0mL) middle. After 5 hours at 100°C, the reaction was complete if no 6,7-difluoro-3-formylchromone and p-toluenesulfonyl chloride remained by thin layer chromatography. After the reaction solution was cooled to room temperature, ethyl acetate was added to the reaction solution, 15.0 mL each time, and extracted three times. The organic phase was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target compound 1 in a yield of 67%. 1 H NMR (400MHz, CDCl 3 )δ11.16–10.86(m,1H),9.05(d,J=1.5Hz,1H),8.07(s,1H),7.63(dt,J=8.4,1.7Hz,2H),7.23(ddd,J = 9.8, 8.4, 1.5Hz, 1H), 7.18–7.07 (m, 1H), 3.00 (ddq, J=32.7, 7.6, 3.7Hz, 1H), 2.46 (s, ...

Embodiment 2

[0234] Synthesis of Norfloxacin and Pefloxacin:

[0235]

[0236] The specific steps of synthesizing norfloxacin are as follows:

[0237] In a 25mL round-bottomed flask, first place 6,7-difluoro-3-formylchromone (0.5mmol), ethylamine (0.5mmol), p-toluenesulfonyl chloride (0.5mmol) in acetonitrile (5.0mL) Then, potassium carbonate (0.6 mmol) was weighed into the reaction system. After the addition was completed, the temperature of the reaction system was raised to 60°C, and after 5 hours, it was detected by thin layer chromatography. If no 6,7-difluoro-3-formylchromone remained, it indicated that the reaction was completed (in this step, the middle Body 6 does not need to be separated). Potassium carbonate (0.6 mmol) was added to the reaction system, and then the reaction system was heated to 120° C. and reacted for 8 hours. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was cooled to room temperature, ethy...

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Abstract

The invention relates to a preparation method of quinolone compounds and intermediates thereof, in particular to a preparation method of quinolone and quinolinone medical intermediates. Specifically, the invention provides a preparation method of a compound shown in a formula I and a method for synthesizing a quinolone compound by taking the compound shown in the formula I as an intermediate, and the preparation method of the compound shown in the formula I comprises the following steps: reacting a compound shown in a formula A with R5NH2 and R6Cl in the presence of alkali to generate the compound shown in the formula I,

Description

technical field [0001] This application relates to the field of medicinal chemistry. In particular, the present application relates to the preparation methods of quinolones and their intermediates (eg, quinolone compounds), especially the preparation methods of quinolones and quinolone pharmaceutical intermediates. Background technique [0002] Quinolones, as drug skeletons, are widely used in clinical antibacterial, anticancer and cystic fibrosis treatment, and have many advantages such as broad antibacterial spectrum, strong medicinal activity, low toxicity and high efficacy. [0003] At present, the synthesis of quinolones mainly includes the following three methods: [0004] (a) Condensation of aniline derivatives with diethyl ethoxymethylene malonate; under the condition of ethyl polyphosphate or polyphosphoric acid, the ortho-functionalization of the amine group occurs, and a cyclization reaction occurs to obtain the key intermediate ; Through alkylation reaction, th...

Claims

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Application Information

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IPC IPC(8): C07D215/233C07D215/26C07D215/48C07D215/38C07D471/04C07D491/056C07D215/56C07D519/00C07D401/04C07D498/04C07D471/06C07D498/06C07D513/06
CPCC07D215/233C07D215/26C07D215/48C07D215/38C07D471/04C07D491/056C07D215/56C07D519/00C07D401/04C07D498/04C07D471/06C07D498/06C07D513/06
Inventor 雷杰陈中祝徐志刚唐典勇徐迦渝周昊亿夏丹丹刘垚曹艺华罗洁
Owner CHONGQING UNIV OF ARTS & SCI
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