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A kind of preparation method of 2,3-difluoro-6-methoxybenzoic acid

A technology of methoxybenzoic acid and difluoroanisole, which is applied in the field of compound preparation, can solve the problems of high cost and impact on large-scale industrial production, and achieve the effects of simplifying the production process, reducing production costs and high yield

Active Publication Date: 2019-01-11
SHANGYU HUALUN CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The Chinese invention patent document with the patent number CN 105523921 A discloses a preparation method of 2,3-difluoro-6-methoxybenzoic acid, which uses 2,3-difluoro-6-methoxybenzaldehyde , potassium hydroxide, hydrogen peroxide and other raw materials synthesized compound 2,3-difluoro-6-methoxybenzoic acid with complex structure, the product yield is high, and the crystallization effect is good, the purity is high, but the raw material 2,3 -Difluoro-6-methoxybenzaldehyde itself is not suitable for synthesis, and the cost is relatively high, which affects its large-scale industrial production

Method used

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  • A kind of preparation method of 2,3-difluoro-6-methoxybenzoic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Add 4000mL tetrahydrofuran and 463g diisopropylamine to the reaction flask, cool the system to -20°C with liquid nitrogen, stir under nitrogen protection, add dropwise 1800mL n-butyllithium (concentration is 2.5mol / L, the same below ), the temperature is controlled not to exceed -10°C, and after the dropwise addition is completed, a tetrahydrofuran solution of lithium diisopropylamide is obtained.

[0032] (2) Add 600g of 3,4-difluoroanisole and 6000mL of tetrahydrofuran to prepare a tetrahydrofuran solution of 3,4-difluoroanisole, lower the temperature to -70°C, and add lithium diisopropylamide to the tetrahydrofuran solution The tetrahydrofuran solution of the prepared 3,4-difluoroanisole was added dropwise, the temperature was controlled not to exceed -70°C, and the reaction was kept for 60 minutes after the dropwise addition was completed.

[0033] (3) Feed CO into the reaction solution at 2.3L / min 2 Gas, keep the temperature at -75~-70℃, pass CO 2 After 1 h o...

Embodiment 2

[0037] (1) Add 4000mL tetrahydrofuran and 450g diisopropylamine into the reaction flask, cool the system to -25°C with liquid nitrogen, stir under nitrogen protection, add 1700mL n-butyllithium dropwise, control the temperature not to exceed -10°C, drop After the addition was complete, a solution of lithium diisopropylamide in tetrahydrofuran was obtained.

[0038] (2) Add 580g of 3,4-difluoroanisole and 6500mL of tetrahydrofuran to prepare a tetrahydrofuran solution of 3,4-difluoroanisole, lower the temperature to -70°C, and add lithium diisopropylamide to the tetrahydrofuran solution The tetrahydrofuran solution of 3,4-difluoroanisole prepared was added dropwise, the temperature was controlled not to exceed -70°C, and the reaction was kept for 50 minutes after the dropwise addition was completed.

[0039] (3) Feed CO into the reaction solution at 2.2L / min 2 Gas, keep the temperature at -75~-70℃, pass CO 2 After 1 h of gas, the reaction was stirred for 30 min.

[0040] (4)...

Embodiment 3

[0043] (1) Add 5000mL tetrahydrofuran and 500g diisopropylamine into the reaction flask, cool the system to -20°C with liquid nitrogen, stir under nitrogen protection, add 2000mL n-butyllithium dropwise, control the temperature not to exceed -10°C, drop After the addition was complete, a solution of lithium diisopropylamide in tetrahydrofuran was obtained.

[0044] (2) Add 650g of 3,4-difluoroanisole and 7000mL of tetrahydrofuran to prepare a tetrahydrofuran solution of 3,4-difluoroanisole, lower the temperature to -70°C, and add lithium diisopropylamide to the tetrahydrofuran solution The tetrahydrofuran solution of the prepared 3,4-difluoroanisole was added dropwise, the temperature was controlled not to exceed -70°C, and the reaction was kept for 70 minutes after the dropwise addition was completed.

[0045] (3) Feed CO into the reaction solution at 2.5L / min 2 Gas, keep the temperature at -75~-70℃, pass CO2 After 1 h of gas, the reaction was stirred for 30 min.

[0046] (...

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Abstract

The invention provides a preparation method for 2, 3-difluoro-6-methoxy benzoic acid. The preparation method includes the steps: (1) preparing tetrahydrofuran solution of lithium diisopropylamide; (2) reducing temperature to range from -75 DEG C to -65 DEG C, dropping tetrahydrofuran solution of 3, 4-difluoroanisole into the tetrahydrofuran solution of the lithium diisopropylamide, and performing thermal reaction for 50-70 minutes after being dropped; (3) leading CO2 into reaction solution, keeping the temperature to range from -75 DEG C to -70 DEG C, and performing stirred reaction for 20-40 minutes; (4) dropping diluted hydrochloric acid into the reaction solution, keeping the temperature to range from 0 DEG C to 10 DEG C, adjusting pH (potential of hydrogen) to 1-2, and performing stirred reaction for 20-40 minutes to obtain a crude product; (5) post-processing the crude product to obtain the 2, 3-difluoro-6-methoxy benzoic acid serving as a target product. According to the preparation method, the 3, 4-difluoroanisole serves as raw materials, the raw materials are simple and easily obtained, the 2, 3-difluoro-6-methoxy benzoic acid is prepared by the aid of the lithium diisopropylamide of non-nucleophilic organic alkali, production process is simplified, production cost is reduced, and the 2, 3-difluoro-6-methoxy benzoic acid is high in yield.

Description

technical field [0001] The invention belongs to the field of compound preparation, in particular to a preparation method of 2,3-difluoro-6-methoxybenzoic acid. Background technique [0002] Many drug molecules contain fluorine, which is of interest to drug designers because of its special properties. In addition to hydrogen, fluorine has the smallest covalent bond radius, which is similar to hydrogen. The C-H bond of organic compounds is changed to C-F bond, which will not affect the size of the molecule, which means that it will not interfere with the three-dimensional effect of the molecule in the enzyme reaction. However, the binding energy of the C-F bond is higher than that of the C-H bond, so the fluorine-containing drug has greater stability to oxidation. [0003] The hydrogen on the benzene ring may be oxidized to a hydroxyl group during metabolic transformation in the body, and further condensed with glucuronic acid, which is easily excreted from the body and reduc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C51/15C07C51/02C07C65/21C07F1/02
CPCC07C51/02C07C51/15C07F1/02C07C65/21
Inventor 李典正赵大文黄光亮
Owner SHANGYU HUALUN CHEM
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