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Intermediate of delafloxacin and preparation method thereof

The technology of a general formula compound and an alkyl group, which is applied to an intermediate of delafloxacin and its preparation field, can solve the problems of increasing hydroxyl protection steps, reducing yield and purity, and achieving comprehensive comparison of purity and yield, and reaction operation Simple, high-yield effect

Active Publication Date: 2014-07-23
SHANGHAI INST OF PHARMA IND +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This route uses compound 9 as a raw material, so that one step of chlorination needs to be introduced in the reaction route, and the protection step of hydroxyl group is added. NCS chlorination in the route may cause chlorination at multiple sites, thereby introducing impurities, reducing yield and purity

Method used

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  • Intermediate of delafloxacin and preparation method thereof
  • Intermediate of delafloxacin and preparation method thereof
  • Intermediate of delafloxacin and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of the compound represented by formula 5 where R is ethyl:

[0039]

[0040] Add compound 3 (20g, 0.071mol), triethyl orthoformate (18.97mL, 0.11mol) and acetic anhydride (20.21mL, 0.21mol) into a three-necked flask, stir and heat to reflux for reaction (~139℃) for 3h, and reduce to At room temperature, the reaction solution was diluted with NMP-acetonitrile (50mL-50mL), and 1mL distilled water was added to prepare compound 4 directly into the next reaction without separation.

[0041] Add 2,6-diamino-3,5-difluoropyridine (11.38g, 0.078mol), NMP-acetonitrile (50mL-50mL) into a three-necked flask, stir to dissolve, add dropwise the previous reaction solution at room temperature, dropwise The reaction was stirred at room temperature for 1h. The reaction solution was added dropwise to 160 mL of distilled water to precipitate a bright yellow solid, filtered, and washed with acetonitrile-water (48 mL-24 mL) and water (50 mL) successively, and dried under vacuum at 60...

Embodiment 2

[0043] Preparation of the compound represented by formula 5 where R is ethyl:

[0044]

[0045] Add compound 3 (20g, 0.071mol), triethyl orthoformate (18.97mL, 0.11mol) and acetic anhydride (20.21mL, 0.21mol) into a three-necked flask, stir and heat to 100℃, reflux and react for 10h, then cool to room temperature. The solution was diluted with NMP (100 mL), and 1 mL of distilled water was added to prepare compound 4 directly into the next reaction without separation.

[0046] Add 2,6-diamino-3,5-difluoropyridine (11.38g, 0.078mol), acetonitrile (100mL) to a three-necked flask, stir to dissolve, at room temperature, add dropwise the reaction solution from the previous step, and stir the reaction at room temperature. 1h. The reaction liquid was added dropwise to 160 mL of distilled water to precipitate a bright yellow solid, which was filtered and dried to obtain 28.1 g of yellow powder with 98.1% HPLC. Melting point: 148-150℃1HNMR (400MHz, CDCl3) δ 1.13 (t, 3H), 4.25 (q, 2H), 4.66...

Embodiment 3

[0048] Preparation of the compound represented by formula 5 where R is ethyl:

[0049]

[0050] Add compound 3 (20g, 0.071mol), triethyl orthoformate (18.97mL, 0.11mol) and acetic anhydride (20.21mL, 0.21mol) into a three-necked flask, stir and heat to reflux for reaction (~139℃) for 3h, and reduce to At room temperature, the reaction solution was diluted with NMP (100 mL), and 1 mL of distilled water was added to prepare compound 4 directly into the next reaction without separation.

[0051] Add 2,6-diamino-3,5-difluoropyridine (11.38g, 0.078mol), NMP (100mL) to a three-necked flask, stir to dissolve, add dropwise the reaction solution from the previous step at room temperature, and stir the reaction at room temperature. 1.5h. The reaction liquid was added dropwise to 160 mL of distilled water, and a bright yellow solid was precipitated, which was dried to obtain 25.2 g of yellow powder with 98.0% HPLC. Melting point: 148-150℃1HNMR (400MHz, CDCl3) δ 1.13 (t, 3H), 4.25 (q, 2H), 4...

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PUM

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Abstract

The present invention relates to a new intermediate of delafloxacin and a preparation method thereof. The new compound with a fluoroquinolone mother nucleus structure is shown as follows. The new compound can be prepared from raw materials in the prior art by a one step reaction, the reaction operation is simple, and the yield is high. The purity and comprehensive yield are greatly improved compared with that of the prior art when the compound is used in synthesis of new fluoroquinolone antibacterial agent delafloxacin and its salts.

Description

Technical field [0001] The invention relates to the technical field of preparation methods of delafloxacin, in particular to an intermediate of delafloxacin and a preparation method thereof. Background technique [0002] Since the discovery of norfloxacin in the late 1970s, fluoroquinolone drugs have developed rapidly, and a large number of products have been marketed. Because it has a fluorine atom at the 6 position of the quinolone ring in the mother nucleus, it is called a fluoroquinolone. Delafloxacin (the structural formula is shown in the following formula) is a fluoroquinolone compound with a new structure developed by Yunaga Pharmaceutical Co., Ltd. (No.: WQ-3034), the chemical name is 1-(6-amino-3,5-di Fluoro-2-pyridyl)-8-chloro-6-fluoro-7-(3-hydroxy-1-aza-1-cyclobutanyl)-4-oxo-1,4-dihydro-3- Quinoline carboxylic acid, then the American Abbott Company obtained its development license (No.: ABT-492), and Rib-X Company is now conducting Phase III clinical trials. [0003]...

Claims

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Application Information

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IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 孔锐袁哲东刘相奎陈姗
Owner SHANGHAI INST OF PHARMA IND
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