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A method for synthesizing 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid

A technology of methoxybenzeneboronic acid and methoxycumene, which is applied in the field of pharmaceutical intermediate synthesis, and can solve problems such as large-scale production of unfavorable products, long synthesis routes, and lack of a large number of suppliers.

Active Publication Date: 2017-05-31
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The above method has defects such as long synthetic route, lack of a large number of suppliers in the individual reagent market, or poor reaction selectivity, which is not conducive to the large-scale production of this product

Method used

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  • A method for synthesizing 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid
  • A method for synthesizing 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid
  • A method for synthesizing 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid:

[0026]

[0027] The first step: in the reaction flask, add m-fluoroanisole (12.6 grams, 0.1 moles), 30% hydrogen peroxide (6.2 grams, 0.055 moles) and 130 milliliters of ethanol, after stirring evenly, add iodine (13.2 grams , 0.052 moles), dropwise addition is completed, the reaction solution dissolves clear, and the insulation reaction is continued for 2 hours, the detection reaction is complete, and saturated NaHSO is added 3 The reaction was quenched, 80 milliliters of ethyl acetate was layered, the organic layer was washed with saturated sodium chloride, and distilled to dryness to obtain 22.9 grams of 2-fluoro-4-methoxyiodobenzene;

[0028] Step 2: Mix 2-fluoro-4-methoxyiodobenzene (2.9 g, 91 mmol), isopropylboronic acid (8.0 g, 91 mmol), 1M aqueous sodium carbonate (0.14 mol) and 210 mL of DME After adding the reaction flask, nitrogen was blown into the page to remove oxygen, and finally 1mol% t...

Embodiment 2

[0031] Synthesis of 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid:

[0032]

[0033] The first step: in the reaction flask, add m-fluoroanisole (12.6 grams, 0.1 moles), 30% hydrogen peroxide (6.2 grams, 0.055 moles) and 130 milliliters of ethanol, after stirring evenly, add iodine (13.2 grams , 0.052 moles), dropwise addition is completed, the reaction solution dissolves clear, and the insulation reaction is continued for 2 hours, the detection reaction is complete, and saturated NaHSO is added 3 The reaction was quenched, 80 milliliters of ethyl acetate was layered, the organic layer was washed with saturated sodium chloride, and distilled to dryness to obtain 22.9 grams of 2-fluoro-4-methoxyiodobenzene;

[0034] Step 2: Mix 2-fluoro-4-methoxyiodobenzene (2.9 g, 91 mmol), isopropylboronic acid (8.0 g, 91 mmol), 1M aqueous potassium carbonate (0.14 mol) and 210 mL of DME After adding the reaction flask, nitrogen gas was blown into the page to remove oxygen, and finally ...

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Abstract

The invention discloses a synthesis method of 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid. The method includes: starting from m-fluoroanisole, carrying out reaction with iodine to conduct iodination, then performing catalytic coupling with isopropylboronic acid, finally conducting selective deprotonation / boronation under a large steric hindrance alkali condition, and performing hydrolysis to obtain a product. The method has the advantages of reasonable route design, simple operation and high selectivity, and is suitable for industrial amplification.

Description

technical field [0001] The invention relates to a method for synthesizing 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid, which belongs to the field of synthesis of pharmaceutical intermediates. Background technique [0002] Arteriosclerosis is the main cause of many diseases and deaths, especially in developed countries. Increasing high-density lipoprotein can effectively reduce sudden cerebrovascular diseases. Currently, one of the most effective drugs is Anacetrapib, which is used clinically as a cholesteryl ester transfer protein (CETP) inhibitor. [0003] As an important structural unit of ansertrapib, there are three main synthesis methods of 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid: [0004] Method 1. Starting from 2,4-difluorobromobenzene, S N The Ar reaction selectively yields 2-methoxy-4-fluorobromobenzene (first step), followed by the Friedel-Crafts reaction with an acetyl group to 2-fluoro-4-methoxy-5-bromoacetophenone (second Two steps), followed by...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02
CPCC07F5/025
Inventor 冷延国田利国于伟东
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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