Synthesis method of 2, 4, 5-trifluoro-3-methoxybenzoyl chloride

A technology of methoxybenzoyl chloride and methoxybenzoic acid, which is applied in the field of drug synthesis, can solve the problems of high price of tetrafluorophthalic acid, difficulty in refining the target product, long process route, etc., and achieve short time consumption, The effect of reducing the usage amount and speeding up the reaction process

Active Publication Date: 2020-09-08
ZHEJIANG HUAJI BIOTECH
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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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  • Synthesis method of 2, 4, 5-trifluoro-3-methoxybenzoyl chloride
  • Synthesis method of 2, 4, 5-trifluoro-3-methoxybenzoyl chloride
  • Synthesis method of 2, 4, 5-trifluoro-3-methoxybenzoyl chloride

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Embodiment 1

[0054] A kind of synthetic method of present embodiment 2,4,5-trifluoro-3-methoxybenzoyl chloride (process route such as figure 1 shown), including the following steps:

[0055] (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;

[0056] Specifically, add water 3000kg, N-methyltetrafluorophthalimide 1000kg, 30% liquid caustic soda 2000kg and zinc chloride 50kg (N-methyltetrafluorophthalimide The molar ratio to sodium hydroxide is 1:3.1, and the molar ratio of N-methyltetrafluorophthalimide to zinc chloride is 100:8.5), and the temperature is raised to 100°C for 8 hours, and the reaction ends (liquid The content of N-methyltetrafluorophthalimide in the phase detection reaction system is less than 1%) and then cooled to below 35°C;

[0057] The reaction formula is shown in formula (I):

[0058]

[0059] (2) Add ...

Embodiment 2

[0074] A kind of synthetic method of 2,4,5-trifluoro-3-methoxybenzoyl chloride of the present embodiment comprises the following steps successively:

[0075] (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;

[0076] 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;

[0077] (2) Add acid to the reaction system, and obtain ...

Embodiment 3

[0084] A kind of synthetic method of 2,4,5-trifluoro-3-methoxybenzoyl chloride of the present embodiment comprises the following steps successively:

[0085] (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;

[0086] 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;

[0087] (2) Add acid to the reaction system, and obta...

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Abstract

The invention discloses a synthesis method of 2, 4, 5-trifluoro-3-methoxybenzoyl chloride. The method comprises the following steps of: (1) using a metal halide as a catalyst, putting N-methyltetrafluorophthalimide in an alkaline environment, and carrying out hydroxylation reaction to obtain a sodium salt of 4-hydroxy-3, 5, 6-trifluorophthalic acid; (2) adding acid into the reaction system, and carrying out decarboxylation reaction to obtain 2, 4, 5-trifluoro-3-hydroxybenzoic acid; (3) sequentially adding a methylation reagent and acid into the reaction system under an alkaline condition, andcarrying out methylation reaction and acidification reaction to obtain 2, 4, 5-trifluoro-3-methoxybenzoic acid; and (4) mixing the 2, 4, 5-trifluoro-3-methoxybenzoic acid with thionyl chloride, and carrying out acylation reaction so as to obtain the 2, 4, 5-trifluoro-3-methoxybenzoyl chloride. The synthesis method disclosed by the invention is short in route, small in alkali dosage and few in sidereaction, the total molar yield of the reaction reaches 82.5%, and the purity of the product reaches 99.6% or above.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular to a synthesis method of 2,4,5-trifluoro-3-methoxybenzoyl chloride. Background technique [0002] 2,4,5-Trifluoro-3-methoxybenzoyl chloride is a key intermediate in the synthesis of gatifloxacin, balofloxacin, moxifioxacin and other new fluoroquinolone antibacterial drugs , and 2,4,5-trifluoro-3-methoxybenzoyl chloride must be made from 2,4,5-trifluoro-3-methoxybenzoic acid (2,4,5-Trifluoro-3- Methoxy Benzoic Acid) on the carboxylic acyl chloride from. [0003] The carboxyl chloride of 2,4,5-trifluoro-3-methoxybenzoic acid is a relatively routine operation, so if the synthesis process of 2,4,5-trifluoro-3-methoxybenzoyl chloride is required The improvement is mainly to improve the synthesis process of 2,4,5-trifluoro-3-methoxybenzoic acid. Currently, the synthetic routes of 2,4,5-trifluoro-3-methoxybenzoic acid suitable for industrial production mainly include: [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/60C07C65/21C07C51/64
CPCC07C51/00C07C51/60C07C51/02C07C51/367C07C51/64C07C65/21C07C65/03Y02P20/55Y02P20/584
Inventor 温超群温兴锋李瑞军孙建仁
Owner ZHEJIANG HUAJI BIOTECH
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