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3-ethyl-4-fluorobenzonitrile preparation method

A technology of fluorobenzonitrile and ethyl, which is applied in the field of preparation of 3-ethyl-4-fluorobenzonitrile, can solve problems such as difficult industrial production, hazards to operators and the environment, and no description of the specific purity of the product.

Active Publication Date: 2018-10-09
TOPHARMAN SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses highly toxic tetraethyl tin, which brings great harm to operators and the environment, and is difficult to carry out industrial production
At the same time, the product 3-ethyl-4-fluorobenzonitrile obtained by this preparation method is an oil, which is purified by cumbersome column chromatography, which is not conducive to industrial production, and does not describe the specific purity of the product

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 3-bromo-4-fluorobenzonitrile

[0044]

[0045] Dissolve 3-bromo-4-fluorobenzaldehyde (250g, 1.23mol) in acetonitrile (1.5L), then add sulfamic acid (67g, 1.48mol), and reflux for 4h. TLC shows that the conversion of the raw material is complete, and the reaction solution is concentrated To a small volume, add water (2L) and stir for 30 minutes, cool to 5-10°C and continue stirring for 10 minutes, filter, dissolve the filter cake with methyl tert-butyl ether (1.2L), wash twice with 500ml water, and saturate with 200ml Wash once with sodium bicarbonate solution, dry over anhydrous sodium sulfate, filter, absorb the filtrate with activated carbon (10g), filter, concentrate under reduced pressure to remove the solvent, add n-heptane (250ml), cool and stir in an ice-salt bath for 1h, filter, reduce Drying under pressure gave 3-bromo-4-fluorobenzonitrile (217 g, yield 88%). 1 H NMR (CDCl 3 ,400MHz): δ7.91(m,1H),7.63(m,1H),7.24(m,1H).

Embodiment 2

[0046] Example 2 3-bromo-4-fluorobenzonitrile

[0047]

[0048] Add tetrahydrofuran (100ml) into a 250ml reaction flask, add 3-bromo-4-fluorobenzaldehyde (10g, 49.2mmol) and ammonia water (40ml) under stirring, add elemental iodine (25g, 98.5mmol) in batches under cooling to 5°C ), then rose to ambient temperature and reacted for 2 to 3 hours. After the reaction was completed, the reaction solution was poured into 10% aqueous solution of sodium sulfite (200g), extracted twice with methyl tert-butyl ether (100ml), and dried over anhydrous sodium sulfate. , concentrated under reduced pressure to remove the solvent, added n-heptane (20ml), cooled to 0-10°C and stirred for 1h, filtered, and dried under reduced pressure to give 3-bromo-4-fluorobenzonitrile (9.6g, yield: 97.5 %). The NMR spectrum of this compound was determined to be the same as the product of Example 1.

Embodiment 3

[0049] Example 3 3-Ethyl-4-fluorobenzonitrile

[0050]

[0051]3-Bromo-4-fluorobenzonitrile (200g, 1mol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (4.08g, 5mmol) was dissolved in THF (1.2L), and 1.0M / L diethylzinc-n-hexane solution (600mL, 0.6mol) was added at 40-50°C. After dripping, the temperature was raised to 50-60°C for 4-5h. The raw material reacted completely. After the reaction solution was cooled to room temperature, it was added to 5% dilute hydrochloric acid (1 L), and the layers were separated. The organic layer was washed twice with 500 ml of water, and then concentrated under reduced pressure to remove the solvent. Then add n-hexane (600mL) and activated carbon (20g), reflux for 0.5h, cool to room temperature, filter, then add activated carbon (10g) to the filtrate, reflux for 0.5h, cool to room temperature, filter, and cool to -50°C to -60°C and filtered, and the filter cake was dried under reduced pressure at ...

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Abstract

The invention relates to a 3-ethyl-4-fluorobenzonitrile preparation method, a compound (II) has a coupling reaction with an ethyl coupling reagent in a solvent under the existence of a catalyst to obtain a compound (I), wherein X is chlorine, bromine, iodine, trifluorosulfonate, and methanesulfonate. The preparation method has the advantages that the materials are easy to get, the operation is safe and simple, the product purity is high, and the cost is low.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of 3-ethyl-4-fluorobenzonitrile, which is an important intermediate for preparing various new drugs under research. Background technique [0002] 3-Ethyl-4-fluorobenzonitrile is an important intermediate for preparing a variety of new drugs under research, such as TAS-116, a drug for the treatment of gastrointestinal stromal tumors in Phase II of Taiho Pharmaceutical Company. [0003] [0004] Patent WO2005105760 discloses its preparation method. The method uses tetrakis (triphenylphosphine) palladium as a catalyst, reacts by heating in the solvent hexamethylphosphoramide for 15 hours, and carries out coupling reaction of 3-bromo-4-fluorobenzonitrile and tetraethyltin to obtain 3 -Ethyl-4-fluorobenzonitrile. This method uses highly toxic tetraethyl tin, which brings great harm to operators and the environment, and is difficult to carry out industrializ...

Claims

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Application Information

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IPC IPC(8): C07C253/30C07C255/50
CPCC07C253/00C07C253/30C07C255/50
Inventor 朱富强张健蒋德辉
Owner TOPHARMAN SHANGHAI
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