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Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene

A methylphenyl and fluorophenyl technology is applied in the field of preparation of 2--5-[methyl]thiophene, can solve the problems of difficult storage, easy oxidation yield and the like, and achieves low production cost and high reaction yield. The effect of high rate and less waste

Inactive Publication Date: 2016-04-20
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The α, β unsaturated aldehydes used in this reaction have the problems of not being easy to store (easy to oxidize in air) and low yield

Method used

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  • Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene
  • Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene
  • Preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene

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Experimental program
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Effect test

Embodiment 1

[0031] A preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene, comprising the following steps:

[0032] Step 1: Preparation of (5-nitro-2-methylphenyl)(5-bromo-2-thiophene)methanone (IV)

[0033]Dissolve 5-nitro-2-methyl-benzoyl chloride (VI) (47mmol) in a mixed solvent of ethanol (45ml) and water (10ml), and add tris(dibenzylideneacetone)dipalladium (0.58 g mmol), tricyclohexylphosphine (2.35mmol), potassium carbonate (47mmol) and 5-bromothiophene-2-boronic acid (VII) (23.5mmol), the reaction was stirred at 60°C for 20h, cooled to room temperature, and washed with excess anhydrous The water in the system was removed with magnesium sulfate, ethyl acetate (20ml×3) was added to dissolve, the magnesium sulfate was removed by filtration, the filtrate was collected and concentrated to obtain the crude product, ethanol (5ml) was added, and recrystallized to obtain (5-nitro-2- Methylphenyl)(5-bromo-2-thiophene)methanone (IV) (90% yield).

[0034] 1 ...

Embodiment 2

[0045] Step 1: Preparation of (5-nitro-2-methylphenyl)(5-bromo-2-thiophene)methanone (IV)

[0046] Dissolve 5-nitro-2-methyl-benzoyl chloride (VI) (47mmol) in a mixed solvent of ethanol (45ml) and water (10ml), and add tris(dibenzylideneacetone)dipalladium (0.50 mmol), tricyclohexylphosphine (2.35 mmol), potassium carbonate (47 mmol) and 5-bromothiophene-2-boronic acid (VII) (16 mmol), the reaction was stirred at 90 ° C for 24 h, cooled to room temperature, and excess anhydrous sulfuric acid was used for the reaction. The water in the system was removed with magnesium, ethyl acetate (20ml×3) was added to dissolve, the magnesium sulfate was removed by filtration, the filtrate was collected and concentrated to obtain the crude product, ethanol (5ml) was added, and recrystallized to obtain (5-nitro-2-methyl) phenyl)(5-bromo-2-thiophene)methanone (IV) (93% yield). The data of hydrogen spectrum and mass spectrum are the same as those of Example 1, the same below.

[0047] Step 2:...

Embodiment 3

[0054] Step 1: Preparation of (5-nitro-2-methylphenyl)(5-bromo-2-thiophene)methanone (IV)

[0055] Dissolve 5-nitro-2-methyl-benzoyl chloride (VI) (47mmol) in a mixed solvent of ethanol (45ml) and water (10ml), and add tris(dibenzylideneacetone)dipalladium (0.65 mmol), tricyclohexylphosphine (2.0 mmol), potassium carbonate (42 mmol) and 5-bromothiophene-2-boronic acid (VII) (40 mmol), the reaction was stirred at 60 ° C for 24 h, cooled to room temperature, and an excess of anhydrous sulfuric acid was used for the reaction. The water in the system was removed with magnesium, ethyl acetate (20ml×3) was added to dissolve, the magnesium sulfate was removed by filtration, the filtrate was collected and concentrated to obtain the crude product, ethanol (5ml) was added, and recrystallized to obtain (5-nitro-2-methyl) phenyl)(5-bromo-2-thiophene)methanone (IV) (79% yield).

[0056] Step 2: Preparation of (5-nitro-2-methylphenyl)(5-(4-fluorophenyl)-2-thiophene)methanone (III)

[0057...

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Abstract

The invention discloses a preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl) methyl] thiophene. The 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl) methyl] thiophene is prepared by performing twice Suzuki cross-coupling reactions between 5-nitro-2-methyl-benzoyl chloride and 5-bromothiophene-2-boronic acid first and then between a reaction product and 4-fluorophenylboronic acid, a reducing reaction and a Sandmeyer reaction. The preparation method belongs to the field of preparation of medicine intermediates. The preparation method can be used for preparing a medicine Invokana for treating type-II diabetes. The preparation method has the characteristics of simple operation, good process stability, high yield, few solid, liquid and gas wastes, low production cost and good product quality.

Description

technical field [0001] The invention relates to a preparation method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene, and belongs to the field of preparation of pharmaceutical intermediates. Background technique [0002] 2-(4-Fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene is a pharmaceutical intermediate for the synthesis of Canagliflozin. Tanabe Mitsubishi Pharmaceutical Co., Ltd. disclosed the method of synthesizing canagliflozin as an intermediate in several patents such as CN200480022007.8, CN200980151648.6, CN201310090402.0, CN201310358939.0. [0003] The synthetic method of 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene currently has the following several approaches: [0004] (1) Friedel-Crafts reaction. The typical method of this reaction is the condensation reaction of 2-substituted thiophene and acid halide or acid anhydride under the catalysis of anhydrous AlCl3 to generate a thiophene containing a substituent at the 2...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/12C07D409/10
CPCC07D333/12C07D333/20C07D333/28C07D409/10
Inventor 翟光喜汪洋
Owner SHANDONG UNIV