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Preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene

A technology of methyl benzyl and methyl phenyl, applied in the field of medicinal chemistry, can solve the problems of high cost, low yield and complex process of the preparation method, and achieve the effects of easy purification, environmental friendliness and simple operation

Inactive Publication Date: 2015-09-09
SHANGHAI INST OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] In view of the above-mentioned technical problems in the prior art, the invention provides a kind of preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, described this The preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene solves the technical problems of high cost, complicated process and low yield in the preparation method in the prior art

Method used

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  • Preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Example 1 Preparation of 2-(4-fluorophenyl)thiophene III:

[0040]

[0041] Grignard reagent preparation: N 2 Under protection, magnesium chips (11.7g, 480mmol), THF (15.0mL) were added to a 500mL three-necked flask equipped with a thermometer, a reflux condenser, and a constant pressure dropping funnel, 2 drops of p-fluorobromobenzene, and 2 capsules of After iodine is heated to initiate the reaction, dissolve p-fluorobromobenzene (70.0g, 400mmol) in THF (250mL), then add the THF solution of p-fluorobromobenzene dropwise under heating and reflux, keep warm and reflux for 2h after dropping, and detect the conversion of raw materials by GC completely.

[0042] Coupling reaction: N 2Under protection, 2-bromothiophene (52.2g, 320mmol) was added to a 1000mL three-necked flask equipped with a thermometer, a reflux condenser, and a constant pressure dropping funnel, and bis(acetylacetonate)palladium (23.4mg, 0.0320mmol) was added under stirring. , THF (200mL), heated to...

Embodiment 2

[0043] Example 2 Preparation of 2-(4-fluorophenyl)thiophene III:

[0044]

[0045] Grignard reagent preparation: N 2 Under protection, magnesium chips (11.7g, 480mmol), THF (15.0mL) were added to a 500mL three-neck flask equipped with a thermometer, a reflux condenser, and a constant pressure dropping funnel, 2 drops of p-fluorobromobenzene, and 2 capsules of After iodine is heated to initiate the reaction, dissolve p-fluorobromobenzene (70.0g, 400mmol) in THF (250mL), then add the THF solution of p-fluorobromobenzene dropwise under heating and reflux, keep warm and reflux for 2h after dropping, and detect the conversion of raw materials by GC completely.

[0046] Coupling reaction: N 2 Under protection, 2-bromothiophene (52.2g, 320mmol) was added to a 1000mL three-neck flask equipped with a thermometer, a reflux condenser, and a constant pressure dropping funnel, and PdCl was added under stirring. 2 (dppf) (23.4mg, 0.0320mmol), THF (200mL), heated up to 50°C, then added...

Embodiment 3

[0047] Example 3 Preparation of 2-(4-fluorophenyl)thiophene III:

[0048]

[0049] Grignard reagent preparation: N 2 Under protection, magnesium chips (11.7g, 480mmol), THF (15.0mL) were added to a 500mL three-neck flask equipped with a thermometer, a reflux condenser, and a constant pressure dropping funnel, 2 drops of p-fluorobromobenzene, and 2 capsules of After iodine is heated to initiate the reaction, dissolve p-fluorobromobenzene (70.0g, 400mmol) in THF (250mL), then add the THF solution of p-fluorobromobenzene dropwise under heating and reflux, keep warm and reflux for 2h after dropping, and detect the conversion of raw materials by GC completely.

[0050] Coupling reaction: N 2 Under protection, 2-bromothiophene (52.2g, 320mmol) was added to a 1000mL three-neck flask equipped with a thermometer, a reflux condenser, and a constant pressure dropping funnel, and PdCl was added under stirring. 2 (dppf) (23.4mg, 0.0320mmol), THF (200mL), heated up to 50°C, then added...

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Abstract

The invention relates to a preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, which comprises the following steps: carrying out coupling reaction on 2-bromothiophene and p-bromofluorobenzene to obtain 2-(4-fluorophenyl)thiophene; carrying out Friedel-Craft reaction on the 2-(4-fluorophenyl)thiophene and 2-methyl-5-bromobenzoic acid to obtain 5-bromo-2-methylphenyl-2-(4-fluorophenyl)thienyl ketone; and finally, carrying out reduction reaction on the 5-bromo-2-methylphenyl-2-(4-fluorophenyl)thienyl ketone to obtain the 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene. By using the cheap and accessible p-bromofluorobenzene and 2-methyl-5-bromobenzoic acid as the raw materials for synthesizing the canagliflozin intermediate, the product is easy for purification, and the method is simple to operate and has the advantages of low cost and environment friendliness.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a canagliflozin intermediate 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, specifically a 2- -(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene preparation method. Background technique [0002] Canagliflozin, also known as Canagliflozin, has a trade name of Invokana and a chemical name of (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl) Thiophen-2-yl)methyl)-4-methyl-phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, which can decompose glucose and pass through the kidney Excretion to lower blood sugar levels, clinical studies have shown that canagliflozin alone in the treatment of type II diabetes is safe to take, well tolerated, has obvious weight loss effect and good blood sugar control. [0003] 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, as an important intermediate in the synthesis of canagliflozin, can be directly used as a synthet...

Claims

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Application Information

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IPC IPC(8): C07D333/12
CPCC07D333/12
Inventor 刘烽潘仙华张鑫李晓军赵东贤
Owner SHANGHAI INST OF TECH
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