One-pot method for preparing 2, 4, 5-trifluoro-3-methoxybenzoic acid

A technology of methoxybenzoic acid and trifluorophthalic acid salt, applied in the field of pharmaceutical synthesis, can solve the problems of high price of tetrafluorophthalic acid, difficulty in purifying the target product, long process route, etc., and achieves easy industrialization. Short production and process routes, and the effect of improving the reaction yield

Pending Publication Date: 2020-09-15
ZHEJIANG HUAJI BIOTECH
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0008] The disadvantage of existing 2,4,5-trifluoro-3-methoxybenzoic acid synthetic method is: in route one, N-methyltetrafluorophthalimide is carried out in alkaline aqueous solution Relief of fluorine, but after hydrolytic defluorination, 2,4,5-trifluoro-3-hydroxybenzoic acid needs to be separated first, and then the subsequent reaction can not be carried out continuously in the same reaction vessel, resulting in a longer process route; although route 2 It is a "one-pot method" for synthesizing 2,4,5-trifluoro-3-methoxybenzoic acid, but the price of tetrafluorophthalic acid is relatively high, and existing routes including route 1 and route 2 In the synthetic route, a large amount of sodium hydroxide needs to be used, resulting in more side reactions, making it difficult to refine the target product

Method used

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  • One-pot method for preparing 2, 4, 5-trifluoro-3-methoxybenzoic acid
  • One-pot method for preparing 2, 4, 5-trifluoro-3-methoxybenzoic acid
  • One-pot method for preparing 2, 4, 5-trifluoro-3-methoxybenzoic acid

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Experimental program
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Embodiment 1

[0057] The present embodiment prepares the technique of 2,4,5-trifluoro-3-methoxybenzoic acid in one pot (processing route is as follows figure 1 shown), including the following steps:

[0058] (1) Using zinc chloride as a catalyst, place N-methyltetrafluorophthalimide in an alkaline environment, and undergo hydrolysis defluorination and hydroxylation to obtain 4-hydroxyl salt-3,5,6 - Trifluorophthalate;

[0059] Specifically, add water 3000kg, N-methyltetrafluorophthalimide 1000kg, 30% liquid caustic soda 2000kg and zinc chloride 50kg (N-methyltetrafluorophthalimide The molar ratio of sodium hydroxide to sodium hydroxide is 1:3.1, and the molar ratio of N-methyltetrafluorophthalimide to zinc chloride is 100:8.5), heat up to 100°C for 8 hours, and cool down after the reaction to below 35°C;

[0060] The reaction formula is shown in formula (I):

[0061]

[0062] (2) Add acid to the reaction system, and obtain 2,4,5-trifluoro-3-hydroxybenzoic acid through decarboxylation...

Embodiment 2

[0073] In this embodiment, a one-pot method for preparing 2,4,5-trifluoro-3-methoxybenzoic acid comprises the following steps:

[0074] (1) Using zinc chloride as a catalyst, place N-methyltetrafluorophthalimide in an alkaline environment, and undergo hydrolysis defluorination and hydroxylation to obtain 4-hydroxyl salt-3,5,6 - Trifluorophthalate;

[0075] Specifically, add 3000kg of water and 1000kg of N-methyltetrafluorophthalimide into the reactor, and then add 30% liquid caustic soda and zinc chloride, wherein, N-methyltetrafluorophthalimide The mol ratio of imine and sodium hydroxide is 1:2, and the mol ratio of N-methyltetrafluorophthalimide and zinc chloride is 100:10; the temperature is raised to 100° C. for 8 hours, and the reaction ends ( The liquid phase detects that the content of N-methyltetrafluorophthalimide in the reaction system is less than 1%) and then cools down to below 35°C;

[0076] (2) Add acid to the reaction system, and obtain 2,4,5-trifluoro-3-hydr...

Embodiment 3

[0081] In this embodiment, a one-pot method for preparing 2,4,5-trifluoro-3-methoxybenzoic acid comprises the following steps:

[0082] (1) Using zinc chloride as a catalyst, place N-methyltetrafluorophthalimide in an alkaline environment, and undergo hydrolysis defluorination and hydroxylation to obtain 4-hydroxyl salt-3,5,6 - Trifluorophthalate;

[0083] Specifically, add 3000kg of water and 1000kg of N-methyltetrafluorophthalimide into the reactor, and then add 30% liquid caustic soda and zinc chloride, wherein, N-methyltetrafluorophthalimide The molar ratio of imine to sodium hydroxide is 1:3.5, and the molar ratio of N-methyltetrafluorophthalimide to zinc chloride is 100:7; the temperature is raised to 100° C. for 9 hours, and the reaction ends ( The liquid phase detects that the content of N-methyltetrafluorophthalimide in the reaction system is less than 1%) and then cools down to below 35°C;

[0084] (2) Add acid to the reaction system, and obtain 2,4,5-trifluoro-3-h...

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Abstract

The invention discloses a one-pot method for preparing 2, 3, 4, 5-trifluoro-3-methoxybenzoic acid. The method comprises the step of obtaining 4-hydroxysalt-3, 5, 6-trifluorophthalate, and the step comprises: by taking a metal halide as a catalyst, putting N-methyl tetrafluorophthalimide into an alkaline environment, and carrying out hydrolysis defluorination and hydroxylation reaction to obtain the 4-hydroxy-3, 5, 6-trifluorophthalate. The raw material cost is low, the process route is short, and only about 8-10 hours are consumed for synthesizing the 4-hydroxy-3, 5, 6-trifluorophthalate; andthe method has the advantages of reduction of the alkali use amount by 50% or above, few side reactions or no side reactions, realization of the total molar yield of the reaction reaching 85%, and realization of the product purity reaching 99.8% or above.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular to a process for preparing 2,4,5-trifluoro-3-methoxybenzoic acid in one pot. Background technique [0002] 2,4,5-Trifluoro-3-methoxybenzoic acid (2,4,5-Trifluoro-3-Methoxy Benzoic Acid) is a synthetic compound of gatifloxacin, balofloxacin, moxifloxacin (moxifioxacin) and other key intermediates of new fluoroquinolone antibacterial drugs, due to its irreplaceability, the synthesis process of 2,4,5-trifluoro-3-methoxybenzoic acid has been carried out in the past ten years Improvement, the synthetic routes suitable for industrialized production mainly include: [0003] Route 1, using N-methyltetrafluorophthalimide as a raw material (referring to the U.S. invention patent whose publication number is US05380926), includes step (1) and step (2): [0004] (1) [0005] (2) [0006] Route 2, using tetrafluorophthalic acid as raw material (see literature: Tian Zhiming, Liu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/00C07C51/41C07C51/02C07C51/38C07C65/03C07C51/367C07C65/21B01J27/138
CPCC07C51/00C07C51/41C07C51/412C07C51/02C07C51/38C07C51/367B01J27/138C07C65/03C07C65/21
Inventor 温兴锋温超群李瑞军孙建仁
Owner ZHEJIANG HUAJI BIOTECH
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