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Preparation method for fluoroquinolones intermediate 2,4-dichloro-5-fluorobenzoyl chloride

A technology of fluorobenzoyl chloride and fluoroquinolones, applied in the field of drug synthesis, can solve the problems of unfavorable industrialized production, hidden safety hazards and high cost, and achieve the effects of reducing production risks, reducing pollution and reducing production costs

Active Publication Date: 2019-05-10
HEADING NANJING PHARMTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The main purpose of the present invention is to solve the problems of potential safety hazards, high cost and unfavorable industrial production in the preparation of compound 2,4-dichloro-5-fluorobenzoyl chloride in the prior art, and to provide a fluoroquinolone intermediate The preparation method of 2,4-dichloro-5-fluorobenzoyl chloride

Method used

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  • Preparation method for fluoroquinolones intermediate 2,4-dichloro-5-fluorobenzoyl chloride
  • Preparation method for fluoroquinolones intermediate 2,4-dichloro-5-fluorobenzoyl chloride
  • Preparation method for fluoroquinolones intermediate 2,4-dichloro-5-fluorobenzoyl chloride

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preparation example Construction

[0043] The preparation method of this fluoroquinolone intermediate 2,4-dichloro-5-fluorobenzoyl chloride comprises the steps:

[0044] Step 1: Alkaline hydrolysis reaction

[0045] Heating the prepared compound (IV) into a molten state, adding an alkaline reagent, maintaining the molten state, stirring for reaction, adding a solvent, refluxing, and fully reacting to obtain compound V* and 2,4-dichlorofluorobenzene;

[0046] Step 2: Acylation reaction

[0047] Control the temperature at 49-51°C, slowly add sulfone dichloride dropwise to compound V*, raise the temperature to 69-71°C, stir and react to obtain compound 2,4-dichloro-5-fluorobenzoyl chloride.

[0048] In this example, this example provides a method for converting compound 2,4-dichlorofluorobenzene into compound II, comprising the following steps:

[0049] Step 1: Add raw material 2,4-dichlorofluorobenzene (100g, 0.606mol) into carbon tetrachloride (107.4g, 0.667mol), stir and dissolve, then add ferric chloride (1....

Embodiment 1

[0055] Add compound IV (100g) to the reaction flask, keep the temperature at 90-100°C, compound IV is in molten state, add sodium hydroxide (1.5eq, 16g), keep the temperature at 90-100°C, stir for 1 hour , Let the sodium hydroxide fully disperse, slowly raise the temperature to about 110°C, the system will react and release heat by itself, and the temperature will rise to 140-150°C, the temperature of the water bath is controlled at 120-130°C, at this time, HPLC detects that the remaining raw materials are 10-30% , lower the temperature to about 110°C, add 1,4-dioxane (100ml) at one time, reflux for about 3 hours, HPLC detects that the remaining raw materials are less than 1%, distill at atmospheric pressure, remove dioxane and water, and obtain a mixture compound V* and 2,4-dichlorofluorobenzene;

[0056] In the above mixture (compound V* and 2,4-dichlorofluorobenzene), keep the temperature at about 50°C, slowly add thionyl chloride (1.3eq, 42g) dropwise, raise the temperatur...

Embodiment 2

[0058] Add compound IV (500g) to the reaction flask, keep the temperature at 90-100°C, compound IV is in molten state, add sodium hydroxide (1.5eq, 80.4g), keep the temperature at 90-100°C, stir for 1 hour , Let the sodium hydroxide fully disperse, slowly raise the temperature to about 110°C, the system will react and release heat by itself, and the temperature will rise to 140-150°C, the temperature of the water bath is controlled at 120-130°C, at this time, HPLC detects that the remaining raw materials are 10-30% , lower the temperature to about 110°C, add 1,4-dioxane (500ml) at one time, reflux for about 3 hours, HPLC detects that the remaining raw materials are less than 1%, distill at atmospheric pressure, remove dioxane and water, and obtain a mixture compound V* and 2,4-dichlorofluorobenzene;

[0059] In the above mixture (compound V* and 2,4-dichlorofluorobenzene), keep the temperature at about 50°C, slowly add thionyl chloride (1.3eq, 207g) dropwise, raise the tempera...

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Abstract

The invention discloses a preparation method for fluoroquinolones intermediate 2,4-dichloro-5-fluorobenzoyl chloride, and belongs to the technical field of the pharmaceutical synthesis. Through changing a compound IV into a compound V* and raw material 2,4-dichlor fluorbenzene, easy explosive materials of hydrogen peroxide and the like are avoided from being used. The compound V*, through a one-step reaction, is changed into the compound 2,4-dichloro-5-fluorobenzoyl chloride. A synthesized product is higher in purity, a total yield of a two-step reaction is higher, the generated starting raw material 2,4-dichlor fluorbenzene can be recycled, and carboxylate (V*) is changed into acyl chloride (II), and hydrochloric acid is not generated, pollution can be reduced. The method is more superiorto an existing technology, capable of increasing a resource utilization rate, reducing a production risk, reducing production cost, and more suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a fluoroquinolone intermediate, in particular to a preparation method of a fluoroquinolone intermediate 2,4-dichloro-5-fluorobenzoyl chloride, and belongs to the technical field of pharmaceutical synthesis. Background technique [0002] Quinolones are artificially synthesized antibacterial drugs containing 4-quinolone core as the basic structure. Since the advent of norfloxacin in the late 1970s, the research and development of the third generation of quinolones-fluoroquinolones has led to the development of antibacterial drugs. Many new drugs with clinical value emerged, such as ofloxacin, ciprofloxacin, romefloxacin, and fleroxacin, which became one of the main clinical anti-infective drugs, second only to cephalosporins and penicillins drug. The structural characteristics of fluoroquinolones are that there is a fluorine atom at the 6-position and a substituted amino group at the 7-position. There are...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/60C07C63/70
Inventor 李文森张文琦
Owner HEADING NANJING PHARMTECH CO LTD
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