CN115611806A - A kind of preparation method of 4-trifluoromethyl-3-cyanopyridine - Google Patents

Abstract

The present invention relates to the field of organic synthesis, in particular to a preparation method of 4-trifluoromethyl-3-cyanopyridine, comprising the following steps: using 2,6-dichloro-3-cyano-4-(trifluoromethyl Base) pyridine as starting raw material, diisopropylethylamine as acid binding agent, under the effect of hydrogen and catalyst, dechlorination prepares 4-trifluoromethyl-3-cyanopyridine. The invention uses diisopropylethylamine as an acid-binding agent in the hydrodechlorination process, has high selectivity, no side reaction, short reaction time, high product yield and purity, simple post-treatment, and is suitable for industrial production.

Description

A kind of preparation method of 4-trifluoromethyl-3-cyanopyridine

technical field

The invention relates to the technical field of organic synthesis, in particular to a preparation method of 4-trifluoromethyl-3-cyanopyridine.

Background technique

4-trifluoromethyl-3-cyanopyridine is a useful synthetic intermediate, and 4-trifluoromethylnicotinic acid can be synthesized through one-step alkali hydrolysis. 4-Trifluoromethylnicotinic acid is an aromatic compound containing trifluoromethyl, which has unique biological activity. It can be used as a precursor for preparing other pesticides or medicines, and has important value.

At present, 3-cyano-4-trifluoromethylpyridine is synthesized from 2,6-dichloro-3-cyano-4-trifluoromethylpyridine through hydrogenation catalytic reaction.

Patents CN101851193A, CN107286086A, CN108191749A, and CN112110855A all use triethylamine as an acid-binding agent in the catalytic hydrogenation reaction, but it is found in actual research that 2,6-dichloro-3-cyano-4-trifluoromethyl Pyridine and triethylamine can react under normal temperature and pressure conditions, and the reaction formula is as follows:

Therefore, using triethylamine as an acid-binding agent has serious side reaction interference, poor selectivity, and low yield.

Patents CN108586328A and CN109232407A use inorganic alkali sodium carbonate as an acid-binding agent in the hydrogenation catalytic reaction, but sodium carbonate has poor solubility in non-polar solvents, and the effect is not obvious. It needs to be used with solvents such as methanol or ethanol, but it has been proved by experiments that Methanol or ethanol reacts with 2,6-dichloro-3-cyano-4-trifluoromethylpyridine as follows:

Therefore, sodium carbonate is an acid-binding agent, and methanol or ethanol is a solvent, and there are many problems for the synthesis of 3-cyano-4-trifluoromethylpyridine. Moreover, sodium carbonate is relatively alkaline, which easily causes the hydrolysis of 2,6-dichloro-3-cyano-4-trifluoromethylpyridine.

Contents of the invention

The object of the present invention is to provide a kind of preparation method of 4-trifluoromethyl-3-cyanopyridine with short reaction time, high product yield, high purity and simple aftertreatment in view of the problems existing in the prior art.

In order to achieve the above object, the technical scheme of the present invention is: a kind of preparation method of 4-trifluoromethyl-3-cyanopyridine, comprises the steps:

With 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine as starting material, diisopropylethylamine as acid-binding agent, toluene and water as mixed solvent, in catalyst and hydrogen Under the effect of reaction preparation 4-trifluoromethyl-3-cyanopyridine, concrete reaction formula is as follows:

Preferably, the preparation method comprises: in an autoclave, add 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine, diisopropylethylamine, toluene and water, palladium carbon Catalyst, nitrogen replacement, filled with hydrogen, temperature rise reaction, sampling analysis, after the reaction is qualified, add water, filter to remove the catalyst, layer the mother liquor, desolventize the oil layer, and distill under reduced pressure to obtain 4-trifluoromethyl-3-cyanopyridine.

Preferably, the molar ratio of 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine to diisopropylethylamine is 1:1-10. Preferably, the molar ratio of 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine to diisopropylethylamine is 1:1-5.

Preferably, the mass ratio of the mixed solvent toluene to water is 45:1-3, and the mass of the mixed solvent toluene and water is 1 of the mass of 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine -10 times. Preferably, the mass of the mixed solvent toluene and water is 1-5 times the mass of 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine.

Preferably, the content of the palladium carbon catalyst Pd is 0.5%-10%; the amount of Pd/C is 0.05%-10% of the mass of 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine .

Preferably, the palladium-carbon catalyst Pd content is 0.5%-10%; the amount of Pd/C is 0.05%-5% of the mass of 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine . Preferably, the amount of Pd/C used is 0.5%-5% of the mass of 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine.

Preferably, the pressure of hydrogen is 0.1Mpa-10Mpa.

Preferably, the pressure of hydrogen is 0.1Mpa-5Mpa. Preferably, the pressure of hydrogen is 0.1Mpa-3Mpa.

Preferably, the reaction temperature during hydrogenation is 20°C-120°C. Preferably, the reaction temperature during hydrogenation is 50°C-100°C.

Preferably, the hydrogenation reaction time is 1-10 h. Preferably, the hydrogenation reaction time is 1-5h.

The beneficial effect of the present invention is: a kind of preparation method of 4-trifluoromethyl-3-cyanopyridine provided by the present invention, using diisopropylethylamine as acid-binding agent, toluene and water as mixed solvent system. Due to its large steric hindrance, diisopropylethylamine will not react with 2,6-dichloro-3-cyano-4-trifluoromethylpyridine. Its basicity is moderate and its energy is good. and the resulting hydrogen chloride to form hydrochloride. The diisopropylethylamine improves the selectivity and the reaction speed of the reaction, increases the reaction yield, thereby reduces the production cost. After diisopropylethylamine forms hydrochloride, diisopropylethylamine can be regenerated by adding alkali to neutralize hydrochloric acid, which can be recycled and used mechanically. Diisopropylethylamine is almost insoluble in water, has better stability than triethylamine, and almost no loss in the recovery process, so it is suitable for industrial production. Using a mixed solvent system of toluene and water avoids side reactions between alcohols and 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine, simplifies the post-reaction treatment process, and optimizes the reaction operate. A small amount of water mixed in toluene can effectively dissolve the diisopropylethylamine hydrochloride produced in the reaction process, making it dispersed in the reaction system in liquid form, avoiding the diisopropylethylamine hydrochloride Precipitated in solid form. The precipitation of diisopropylethylamine hydrochloride will wrap the palladium carbon catalyst, leading to catalyst deactivation. Therefore, the mixed solvent system of toluene and water, compared with a single toluene or alcohol solvent, can effectively avoid the problem of palladium carbon catalyst deactivation, and there will be no side reactions similar to alcohol solvents. The method has easy-to-obtain raw materials, low cost, short steps, simplified technological process, high product content and high yield, can greatly reduce cost, increase output, and is suitable for industrialized production.

Description of drawings

Fig. 1 is the nuclear magnetic spectrum of 4-trifluoromethyl-3-cyanopyridine of embodiment 1;

Fig. 2 is the mass spectrum of 4-trifluoromethyl-3-cyanopyridine of embodiment 1.

detailed description

Example 1

Add 450g toluene, 1.47g 5% palladium carbon catalyst, 144.60g 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine, 155.08g diisopropylethylamine, 10.0g of water, replace the hydrogen three times, pressurize to 0.5MPa, and raise the temperature to 50-60°C to react. Sampling analysis (GC) after 2 hours of reaction, the raw material content is less than 0.3% as the reaction is qualified;

After the reaction was completed, add 300 g of ice water and stir for 10 min, cool to room temperature, and remove the palladium-carbon catalyst by filtration; the filtered mother liquor is separated, the upper layer is an oil phase, and the lower layer is an aqueous phase;

The oil phase was subjected to normal pressure distillation precipitation, and after most of the toluene solvent was removed, vacuum distillation was performed to distill 101.20 g of the product, with a yield of 98.0% and a content of 99%.

The nuclear magnetic data is ¹ HNMR (400MHz, CDCl ₃ ): 9.12 (s, 1H), 9.06 (d, J=5.12Hz, 1H), 7.79 (d, J=5.12Hz, 1H). The mass spectrogram shows that the retention time of the product is 6.044min, and the corresponding molecular weight is 172.1 (the actual molecular weight is 172.11), so it is determined that the product is 4-trifluoromethyl-3-cyanopyridine.

Example 2

Add 450g toluene, 1.00g 10% palladium carbon catalyst, 144.60g 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine, 155.08g diisopropylethylamine, 10.0g of water, replace the hydrogen three times, pressurize to 0.5MPa, and raise the temperature to 50-60°C to react. Sampling analysis (GC) after 2 hours of reaction, the raw material content is less than 0.3% as the reaction is qualified;

After the reaction was completed, add 300 g of ice water and stir for 10 min, cool to room temperature, and remove the palladium-carbon catalyst by filtration; the filtered mother liquor is separated, the upper layer is an oil phase, and the lower layer is an aqueous phase;

The oil phase was subjected to normal pressure distillation and precipitation, and after removing most of the toluene solvent, it was subjected to vacuum distillation, and 100.17 g of the product was distilled out, with a yield of 97.0% and a content of 99%.

Example 3

Add 450g toluene, 5.00g 1% palladium carbon catalyst, 144.60g 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine, 155.08g diisopropylethylamine, 10.0g water, replace hydrogen three times, pressurize to 0.8MPa, heat up to 60-70°C to react. Sampling analysis (GC) after reaction 4h, raw material content is less than 0.3% and is regarded as reaction qualified;

After the reaction was completed, add 300 g of ice water and stir for 10 min, cool to room temperature, and remove the palladium-carbon catalyst by filtration; the filtered mother liquor is separated, the upper layer is an oil phase, and the lower layer is an aqueous phase;

The oil phase was subjected to normal pressure distillation precipitation, and after most of the toluene solvent was removed, vacuum distillation was performed to distill 99.14 g of the product, with a yield of 96.0% and a content of 99%.

Example 4

Add 450g toluene, 1.47g 5% palladium carbon catalyst, 144.60g 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine, 155.08g diisopropylethylamine, 10.0g of water, replaced by hydrogen three times, pressurized to 2.0MPa, heated to 50°C for reaction. Sampling analysis (GC) after 2 hours of reaction, the raw material content is less than 0.3% as the reaction is qualified;

After the reaction was completed, add 300 g of ice water and stir for 10 min, cool to room temperature, and remove the palladium-carbon catalyst by filtration; the filtered mother liquor is separated, the upper layer is an oil phase, and the lower layer is an aqueous phase;

The oil phase was subjected to normal pressure distillation and precipitation, and after removing most of the toluene solvent, it was subjected to vacuum distillation, and 100.17 g of the product was distilled out, with a yield of 97.0% and a content of 99%.

Example 5

Add 450g toluene, 1.47g 5% palladium carbon catalyst, 144.60g 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine, 155.08g diisopropylethylamine, 10.0g of water, replaced by hydrogen three times, pressurized to 0.5MPa, heated to 100°C for reaction. Sampling analysis (GC) after 1.5h of reaction, the raw material content is less than 0.3% as the reaction is qualified;

After the reaction was completed, add 300 g of ice water and stir for 10 min, cool to room temperature, and remove the palladium-carbon catalyst by filtration; the filtered mother liquor is separated, the upper layer is an oil phase, and the lower layer is an aqueous phase;

The oil phase was subjected to normal pressure distillation and precipitation, and after removing most of the toluene solvent, it was subjected to vacuum distillation, and 95.00 g of the product was distilled out, with a yield of 92.0% and a content of 99%.

Example 6

Add 450g toluene, 1.47g 5% palladium carbon catalyst, 144.60g 2,6-dichloro-3-cyano-4-(trifluoromethyl)pyridine, 300.00g diisopropylethylamine, 30.0g water, replace hydrogen three times, pressurize to 0.5MPa, heat up to 50-60°C to react. Sampling analysis (GC) after 2.5 hours of reaction, the raw material content is less than 0.3% as the reaction is qualified;

After the reaction was completed, add 300 g of ice water and stir for 10 min, cool to room temperature, and remove the palladium-carbon catalyst by filtration; the filtered mother liquor is separated, the upper layer is an oil phase, and the lower layer is an aqueous phase;

The oil phase was subjected to normal pressure distillation and precipitation, and after removing most of the toluene solvent, it was subjected to vacuum distillation, and 100.17 g of the product was distilled out, with a yield of 97.0% and a content of 99%.

The above is only a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Anyone skilled in the art can easily think of changes or substitutions within the technical scope disclosed in the present invention. All should be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention should be determined by the protection scope of the claims.

Claims (10)

1. A preparation method of 4-trifluoromethyl-3-cyanopyridine is characterized by comprising the following steps:

the method comprises the following steps of taking 2, 6-dichloro-3-cyano-4- (trifluoromethyl) pyridine as a starting material, diisopropylethylamine as an acid binding agent, and toluene and water as a mixed solvent, and reacting under the action of a catalyst and hydrogen to prepare the 4-trifluoromethyl-3-cyanopyridine, wherein the specific reaction formula is as follows:

2. the method of claim 1, wherein the method of making comprises: adding 2, 6-dichloro-3-cyano-4- (trifluoromethyl) pyridine, diisopropylethylamine, toluene, water and a palladium carbon catalyst into a high-pressure reaction kettle, introducing hydrogen after nitrogen replacement, heating for reaction, sampling and analyzing, adding water after the reaction is qualified, filtering to remove the catalyst, layering mother liquor, desolventizing an oil layer, and carrying out reduced pressure distillation to obtain the 4-trifluoromethyl-3-cyanopyridine.

3. The process according to claim 1, wherein the molar ratio of 2, 6-dichloro-3-cyano-4- (trifluoromethyl) pyridine to diisopropylethylamine is 1 to 10.

4. The method according to claim 1, wherein the mass ratio of the mixed solvent toluene to water is 45:1 to 3, the mass of the mixed solvent toluene and water is 1 to 10 times of the mass of 2, 6-dichloro-3-cyano-4- (trifluoromethyl) pyridine.

5. The method of claim 2, wherein the palladium on carbon catalyst is 0.5% to 10% Pd; the dosage of Pd/C is 0.05-10% of the mass of 2, 6-dichloro-3-cyano-4- (trifluoromethyl) pyridine.

6. The method as claimed in claim 5, wherein the palladium on carbon catalyst Pd is present in an amount of 0.5% to 10%; the dosage of Pd/C is 0.05-5% of the mass of 2, 6-dichloro-3-cyano-4- (trifluoromethyl) pyridine.

7. The method of claim 2, wherein the pressure of the hydrogen gas is 0.1Mpa to 10Mpa.

8. The method of claim 7, wherein the pressure of the hydrogen gas is 0.1Mpa to 5Mpa.

9. The process of claim 2, wherein the reaction temperature during hydrogenation is in the range of 20 ℃ to 120 ℃.

10. The process of claim 2, wherein the hydrogenation reaction time is from 1 to 10 hours.

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