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A kind of preparation method of high-purity 2-(4-fluorophenyl)thiophene

A technology of fluorophenyl and fluorophenylmagnesium bromide, which is applied in the field of preparation of high-purity 2-thiophene, can solve the problems of increased dosage, darker product color, increased cost, etc., and achieves reduced usage and improved reaction efficiency , the effect of improving quality

Active Publication Date: 2020-11-17
宁波人健化学制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The nickel catalyst used in this process is relatively economical, but the increase in dosage will indirectly increase the cost, and the impurity 2,2'-dithiophene is easy to be produced during the synthesis process, which will cause the color of the product to become darker

Method used

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  • A kind of preparation method of high-purity 2-(4-fluorophenyl)thiophene
  • A kind of preparation method of high-purity 2-(4-fluorophenyl)thiophene
  • A kind of preparation method of high-purity 2-(4-fluorophenyl)thiophene

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Experimental program
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Effect test

Embodiment 1

[0028] Under nitrogen conditions, magnesium chips (11.1g, 0.457mol), solvent tetrahydrofuran (140ml), a small amount of p-fluorobromobenzene (10g, 0.057mol) were added to a 500ml reaction flask, and the initiator iodine (0.1g) was added, stirred until The color faded. When the trigger was confirmed, the temperature was controlled at 36-40°C, and p-bromofluorobenzene (69.9g, 0.4mol) was added dropwise within 4h, controlled by GC. After the reaction was complete, the temperature was kept at 40°C, and the stirring was stopped.

[0029] Take a 1000ml reaction bottle, add 2-bromothiophene (74.5g, 0.457mol) and solvent tetrahydrofuran (150ml) under the protection of nitrogen, replace with nitrogen three times, add catalyst DPPE.NICl2 (0.48g, 0.0009mol) (not sieved after grinding , particle size 0-250 μm), the temperature is controlled at 20-25 ° C, the Grignard reagent prepared above is added dropwise, and the drop is completed within 5 hours, controlled by GC. After the reaction wa...

Embodiment 2

[0031] Under nitrogen conditions, magnesium chips (11.1g, 0.457mol), solvent tetrahydrofuran (140ml), a small amount of p-fluorobromobenzene (10g, 0.057mol) were added to a 500ml reaction flask, and the initiator iodine (0.1g) was added, stirred until The color faded. When the trigger was confirmed, the temperature was controlled at 36-40°C, and p-bromofluorobenzene (69.9g, 0.4mol) was added dropwise within 4h, controlled by GC. After the reaction was complete, the temperature was kept at 40°C, and the stirring was stopped.

[0032] Take a 1000ml reaction bottle, add 2-bromothiophene (74.5g, 0.457mol) and solvent tetrahydrofuran (150ml) under the protection of nitrogen, replace nitrogen three times, add catalyst DPPE.NICl2 (0.48g, 0.0009mol) and 260-mesh sieve, particle size 57-125μm), temperature control 20-25°C, dropwise add the above-prepared Grignard reagent, 5h drop complete, GC central control. After the reaction was complete, it was quenched with 5% dilute hydrochloric ...

Embodiment 3

[0034] Under nitrogen conditions, magnesium chips (11.1g, 0.457mol), solvent tetrahydrofuran (140ml), a small amount of p-fluorobromobenzene (10g, 0.057mol) were added to a 500ml reaction flask, and the initiator iodine (0.1g) was added, stirred until The color faded. When the trigger was confirmed, the temperature was controlled at 36-40°C, and p-bromofluorobenzene (69.9g, 0.4mol) was added dropwise within 4h, controlled by GC. After the reaction was complete, the temperature was kept at 40°C, and the stirring was stopped.

[0035] Take a 1000ml reaction bottle, add 2-bromothiophene (74.5g, 0.457mol) and solvent tetrahydrofuran (150ml) under the protection of nitrogen, replace with nitrogen three times, add catalyst DPPE.NICl2 (0.48g, 0.0009mol) and 120-mesh sieve, particle size 125-250μm), temperature control 20-25°C, dropwise add the above-prepared Grignard reagent, 5h complete dropwise, GC central control. After the reaction was complete, it was quenched with 5% dilute hyd...

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Abstract

The invention relates to a preparation method of high-purity 2-(4-fluorophenyl)thiophene. The method comprises the following steps: performing a kumada coupling reaction between a Grignard reagent 4-fluorophenyl magnesium bromide and 2-bromo-thiophene under the action of a catalyst 1,2-bis(diphenylphosphine)ethane nickel chloride, to obtain high-purity 2-(4-fluorophenyl)thiophene. The preparationmethod provided by the invention has the following advantages: the particle size and appearance of the catalyst DPPE.NICl2 are adjusted, then the DPPE.NICl2 in a specific particle size range has a better catalysis effect, and the dosage of the catalyst is greatly reduced; moreover, the reaction efficiency is appropriately increased, and the nickel residue in the product is perfectly controlled; meanwhile, the impurity 2,2'-bithiophene in the system is inhibited quite well. The product quality is remarkably improved while the cost is lowered. The preparation method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and relates to a preparation method of high-purity 2-(4-fluorophenyl)thiophene. Background technique [0002] Canagliflozin is the first SGLT-2 inhibitory drug approved by the FDA. It can lower blood sugar by breaking down glucose and excreting it through the kidneys. It has broad prospects for the treatment of type 2 diabetes in adults. In addition to good blood sugar control, canagliflozin has a more significant weight loss effect, and compared with glimepiride, canagliflozin causes far fewer hypoglycemic events. [0003] 2-(4-fluorophenyl)thiophene is an important intermediate in canagliflozin, so it is of great significance to study its preparation method suitable for industrial production. [0004] The literature reports its synthetic route, mainly contains two kinds: [0005] (1) Suzuki coupling reaction: [0006] [0007] The main documents are: WO2012019496, Chemical Commun...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/12
CPCC07D333/12
Inventor 丁同健汪卫敏郑飞
Owner 宁波人健化学制药有限公司
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