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Separation and purification method of 2-(4-fluorophenyl)thiophene

A purification method, fluorophenyl technology, applied in the field of separation and purification of 2-thiophene, can solve the problems of long time consumption, low melting point, high energy consumption, etc.

Pending Publication Date: 2021-09-10
江苏法安德医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, it is difficult to separate and purify
The traditional column chromatography separation method is cumbersome to operate, takes a long time, and is not conducive to industrial production
At present, domestic and foreign literature on the synthesis of this compound only mentions the purification method of recrystallization and vacuum distillation. Because of its special physical properties (low melting point and high boiling point), the purification yield is low, the operation is complicated, and High energy consumption is not conducive to industrial scale-up production

Method used

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  • Separation and purification method of 2-(4-fluorophenyl)thiophene
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  • Separation and purification method of 2-(4-fluorophenyl)thiophene

Examples

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Effect test

Embodiment 1

[0023] (1) Synthesis of 2-(4-fluorophenyl)thiophene:

[0024] in N 2 Under protection, add 1.63g of 2-bromothiophene, 25.9mg of 1,2-bis(diphenylphosphine)ethane nickel chloride, and 2.1mL of anhydrous tetrahydrofuran into the round bottom flask, cool down to t=2°C, stir, Add 10mL of 1M / L 4-fluorophenylmagnesium bromide (THF solution) dropwise, and control the temperature T≤30°C; then stir at 22°C for 1.5h, and quench the reaction solution with dilute hydrochloric acid.

[0025] (2) Separation and purification of 2-(4-fluorophenyl)thiophene:

[0026] The mixture obtained in the above reaction was extracted with n-heptane to extract the organic phase, dried over anhydrous sodium sulfate, filtered with diatomaceous earth, and the filtrate was collected. The HPLC spectrum of the filtrate is as follows: figure 1 Shown; Add organic solvent acetonitrile, stir at room temperature for 4h, leave to stand for 2h and then separate layers, the upper layer is a n-heptane phase, and its HP...

Embodiment 2

[0028] (1) Synthesis of 2-(4-fluorophenyl)thiophene:

[0029] in N 2 Under protection, add 1.63g of 2-bromothiophene, 25.9mg of 1,2-bis(diphenylphosphine)ethane nickel chloride, and 2.1mL of anhydrous tetrahydrofuran into the round bottom flask, cool down to t=2°C, stir, Add 10mL of 1M / L 4-fluorophenylmagnesium bromide (THF solution) dropwise, and control the temperature T≤30°C; then stir at 22°C for 1.5h, and quench the reaction solution with dilute hydrochloric acid.

[0030] (2) Separation and purification of 2-(4-fluorophenyl)thiophene:

[0031] Extract the organic phase of the above reaction mixture with cyclohexane, dry over anhydrous sodium sulfate, filter with diatomaceous earth, collect the filtrate, add the organic solvent acetonitrile, stir at room temperature for 3 hours, and separate layers after standing for 4 hours. The upper layer is the n-heptane phase, and the lower layer It is the acetonitrile phase, and the upper layer is taken by liquid separation, and t...

Embodiment 3

[0033] (1) Synthesis of 2-(4-fluorophenyl)thiophene:

[0034] in N 2 Under protection, add 1.63g of 2-bromothiophene, 25.9mg of 1,2-bis(diphenylphosphine)ethane nickel chloride, and 2.1mL of anhydrous tetrahydrofuran into the round bottom flask, cool down to t=2°C, stir, Add 10mL of 1M / L 4-fluorophenylmagnesium bromide (THF solution) dropwise, and control the temperature T≤30°C; then stir at 22°C for 1.5h, and quench the reaction solution with dilute hydrochloric acid.

[0035] (2) Separation and purification of 2-(4-fluorophenyl)thiophene:

[0036] Extract the organic phase of the above reaction mixture with cyclopentane, dry over anhydrous sodium sulfate, filter with diatomaceous earth, collect the filtrate, add organic solvent acetonitrile, stir at room temperature for 5 hours, and separate layers after standing for 3 hours. The upper layer is the n-heptane phase, and the lower layer It is the acetonitrile phase, and the upper layer is taken by liquid separation, and the ...

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Abstract

The invention discloses a separation and purification method of 2-(4-fluorophenyl)thiophene, which comprises the following steps: reacting 2-bromothiophene with 4-fluorophenyl magnesium bromide, extracting an organic phase from the obtained mixture by using an alkane organic solvent, conducting drying, conducting filtering, collecting filtrate, separating the obtained filtrate by using acetonitrile, taking the separated liquid at the upper layer, and removing the organic solvent to obtain the 2-(4-fluorophenyl)thiophene. Compared with the prior art, the invention provides a method for purifying 2-(4-fluorophenyl)thiophene through an extraction mode, and the method is simple and convenient to operate, relatively high in yield and very suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of compound separation and purification, and in particular relates to a method for separation and purification of 2-(4-fluorophenyl)thiophene. Background technique [0002] 2-(4-fluorophenyl)thiophene is an important intermediate in the synthesis of antidiabetic drug Canagliflozin, so the crude product 2-(4-fluorophenyl)thiophene needs to be purified. At present, there are three industrial synthetic routes: [0003] [0004] Synthetic route two and synthetic route three have all adopted Suzuki coupling reaction, and this type of reaction must use the catalyst of boronic acid compound and metal palladium ligand, and raw material price is more expensive, and cost is too high, so industrialization route is preferably route one, synthesizes The raw materials of route 1 are cheap, but the impurities produced during the synthesis process of this route are difficult to separate and purify by conventional method...

Claims

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Application Information

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IPC IPC(8): C07D333/12
CPCC07D333/12
Inventor 陈光张子恒计雄荣
Owner 江苏法安德医药科技有限公司
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