RU2642924C1 - Method of producing 5-phenyl-3- (trifluoromethyl) -1n-pyrazole-4-amine - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method of producing 5-phenyl-3-(trifluoromethyl)-1N-pyrazole-4-amine, which has the formula

given below. This compound is the key in the synthesis of hybrid molecules that have different types of biological activity. The essence of the method is that 4,4,4-trifluoro-1-fenilbutadionate of lithium is treated with sodium nitrite in glacial acetic acid under cooling, and then with the excess of hydrazine hydrate. In this case, acetic acid is used as the organic solvent.

EFFECT: method allows to process in a single reactor, without isolation of intermediates, without the use of high or low pressure, at a temperature of 10 to 20 degrees, which leads to increase of the selectivity of the process, reduction of the number of operations when selecting the target compounds and provides the target compound with a yield of 93%.

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Description

1. The technical field to which the invention relates.

The invention relates to the field of organic chemistry, namely to an improved method for producing 5-phenyl-3- (trifluoromethyl) -1H-pyrazol-4 amine (1)

(hereinafter - aminopyrazole 1) - a key compound in the synthesis of hybrid molecules with various types of biological activity (Emmadi, NR, Bingi, C., Kotapalli, SS, Ummanni, R., Nanubolu, JB, Atmakur, K., Synthesis and evaluation of novel fluorinated pyrazolo-1,2,3-triazole hybrids as antimycobacterial agents, Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.Org/10.1016/j.bmcl.2015.05.0544).

The invention can be used in research institutes to create new drugs and in the pharmaceutical industry.

2. The level of technology

One of the areas of modern medical chemistry is the creation of "multifunctional drugs" by combining various pharmacophores in one base, which have the ability to interact with several "targets". Such drugs have a more predictable pharmacokinetic profile, they significantly reduced the risk of incompatibility with other drugs by reducing the number of different drugs prescribed to the patient.

Hybrid compounds have already been obtained, including fragments of 3-trifluoromethylpyrazole and 1,2,3-triazole, which showed antimycobacterial activity against M. smegmatis, activity against lung cancer cells. In addition, these structures can be considered as potential anti-tuberculosis agents with low cytotoxicity (Emmadi, NR, Bingi, C., Kotapalli, SS, Ummanni, R., Nanubolu, J. B., Atmakur, K., Synthesis and evaluation of novel fluorinated pyrazolo-1,2,3-triazole hybrids as antimycobacterial agents, Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl. 2015.05.044).

From literary sources it is known that aminopyrazole 1 is obtained in three stages with the isolation and purification of intermediate products at each stage.

In the first step, the reaction of 4,4,4-trifluoro-1-phenylbutanedione (diketone 2) with a nitrosating agent, for example sodium nitrite, in an organic solvent, for example in acetic acid, gives 4,4,4-trifluoro-1-phenyl-1 2,3-butanetrione-2-oxime (oxime 3).

In the second step, oxime 3 is treated with hydrazine or hydrazine hydrate to give 4-nitroso-5-phenyl-3-trifluoromethyl-1H-pyrazole (nitrosopyrazole 4).

In a third step, nitrosopyrazole 4 is reduced to aminopyrazole 1 by various methods, for example, hydrogen using a palladium catalyst.

In the patent (Patent; Aventis Pharmaceuticals Inc .; US 2005/9859; (2005); (A1) English), aminopyrazole 1 is prepared in three stages. At the first stage, according to the method described in the article (Saloutin VI, Burgart YV, Skryabina ZE, Kuzueva OG, J. Fluor. Chem., 1997, 84, p 107), the interaction of diketone 2 with sodium nitrite in acetic acid gives oxime 3. At the end of the reaction, oxime 3 is extracted from the reaction mass with diethyl ether (3 times 50 ml). The extract was washed with saturated sodium hydrogen carbonate solution to pH 7, then washed with water and dried under reduced pressure for 2 hours.

In the second stage, oxime 3 is dissolved in ethanol and treated with hydrazine. After removal of ethanol, reprecipitation of the solid residue from diethyl ether with hexane and subsequent recrystallization from chloroform, nitrosopyrazole 4 is obtained.

In the third stage, nitrosopyrazole 4 is reduced to aminopyrazole 1. For this, a catalytic hydrogenation reaction that requires increased pressure is used. As a catalyst, expensive metal palladium deposited on a carbon substrate (Pd / C) is used.

A solution of nitrosopyrazole 4 in ethanol is treated with a 10% Pd / C catalyst and hydrogenated at 50 psi (3.5 bar) for 7.5 hours. At the end of the reaction, the reaction mixture was filtered through celite and washed with ethanol. The filtrate was concentrated to give aminopyrazole 1 as a yellow powder.

The main disadvantages of obtaining aminopyrazole 1 in this way:

1. The inability to carry out the process in one reactor. The process is carried out in three stages, each of which requires its own equipment, reagents and solvents.

2. As the starting compound, diketone 2 is used, which is commercially available but very expensive, and its synthesis and purification are very laborious.

4. The recovery process of nitrosopyrazole 4 is carried out under pressure, which requires special equipment.

5. In the process of reduction of nitrosopyrazole 4, expensive metal palladium supported on a carbon substrate (Pd / C) is used as a catalyst.

3. The process of isolation of reaction products at each stage involves many operations, requires significant reagents, solvents, labor and time.

Stage 1. The selection of oxime 3 from the reaction mass involves the following operations:

1 Extraction of crude oxime 3 with diethyl ether.

2. Washing the ether extract with saturated NaHCO ₃ solution to pH 7.

3. Washing the ether extract with water, separating the ether layer.

4. Drying the ether extract under reduced pressure for 2 hours.

Stage 2. The selection of nitrosopyrazole 4 from the reaction mass involves the following operations:

1. Ethanol Removal

2. Reprecipitation of nitrosopyrazole 4 from diethyl ether with hexane.

3. Filtering

4. Recrystallization of nitrosopyrazole 4 from chloroform.

Stage 3. The selection of aminopyrazole 1 from the reaction mass involves the following operations:

1. Filtration of aminopyrazole 1 through celite from the catalyst.

2. Rinsing of celite with ethanol to extract aminopyrazole 1.

3. Removal of ethanol.

Thus, only the process of separation of aminopyrazole 1 and intermediates of its synthesis (oxime 3 and nitrosopyrazole 4) from the reaction mass requires 11 labor-intensive operations.

In this patent, the authors do not give the yield of aminopyrazole 1, since it is not their target product (it is used as a key compound to obtain more complex structures).

A known method for producing aminopyrazole 1 (Emmadi, NR, Bingi, C., Kotapalli, SS, Ummanni, R., Nanubolu, JB, Atmakur, K., Synthesis and evaluation of novel fluorinated pyrazolo-1,2,3-triazole hybrids as antimycobacterial agents, Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.05.05.044) from diketone 2 - prototype.

In this paper, a simpler method for the preparation of aminopyrazole 1 was proposed. The authors eliminated the hydrogenation step (abandoned the Pd / C catalyst) using the same hydrazine hydrate (10-fold excess) as the reducing agent used to produce nitrosopyrazole 4. However, despite to the changes introduced, the process of obtaining aminopyrazole 1 includes two stages with the isolation and purification of intermediate oxime 3, which requires a series of operations.

In the first stage, the interaction of diketone 2 with sodium nitrite in glacial acetic acid after distilling off the acetic acid under reduced pressure, treating the residue with an aqueous solution of NaHCO ₃ , extracting the crude product with ethyl acetate, drying the resulting solution over anhydrous Na ₂ SO ₄ , filtering from Na ₂ SO ₄ and distillation of ethyl acetate under reduced pressure gives oxime 3 (Oxime 3 yield not shown).

In the second stage, a solution of oxime 3 in ethanol is treated with hydrazine hydrate. The reaction mass is heated with stirring for 16 hours. At the end of the reaction (TLC control), ethanol was concentrated, the residue was dissolved in ethyl acetate and washed with a 3N hydrochloric acid solution. The organic layer was separated, the aqueous fraction was neutralized with a 10 N NaOH solution and extracted with ethyl acetate. The organic extract was dried over Na ₂ SO ₄ , filtered from Na ₂ SO ₄ and concentrated. A pale yellow aminopyrazole 1 precipitate is obtained. Yield 75%. Mp 123-125 ° C.

Synthesis Procedure (Emmadi, NR, Bingi, C., Kotapalli, SS, Ummanni, R., Nanubolu, JB, Atmakur, K., Synthesis and evaluation of novel fluorinated pyrazolo-1,2,3-triazole hybrids as antimycobacterial agents, Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/i.bmcl. 2015.05.044) - prototype:

Stage 1. To a solution of 5 g (23.1 mmol) of 4,4,4-trifluoro-1-phenylbutadione in 8 ml. glacial acetic acid at 0 ° C add 1.91 g (27.7 mmol) of sodium nitrite in 8 ml. water. The reaction mass is stirred at 0 ° C for 1 hour. At the end of the reaction (TLC control), acetic acid is distilled off under reduced pressure. The crude product is shaken with an aqueous solution of NaHCO ₃ , (5 ml), extracted with ethyl acetate and incubated over anhydrous Na ₂ SO ₄ and the solution is filtered. After distilling off ethyl acetate under reduced pressure, 4,4,4-trifluoro-1-phenyl-1,2,3-butanetrione-2-oxime (oxime 3) is obtained.

Step 2. To a solution of 4,4,4-trifluoro-1-phenyl-1,2,3-butanetrion-2-oxime in 50 ml of ethanol was added dropwise 11.7 g (230.00 mmol) of hydrazine hydrate, heated with stirring for 16 hours . At the end of the reaction (TLC control), the reaction mass is concentrated, dissolved in ethyl acetate and washed with a 3N hydrochloric acid solution. The organic layer was separated, the aqueous fraction was neutralized with a 10N NaOH solution and then extracted with ethyl acetate. The organic extract was dried over Na ₂ SO ₄ and concentrated. 4 g (75%) of 5-phenyl-3- (trifluoromethyl) -1H-pyrazole-4 amine (aminopyrazole 1) are obtained in the form of a light yellow precipitate. Mp 123-125 ° C.

The main disadvantages of obtaining aminopyrazole 1 in this way:

1. The inability to carry out the process in one reactor. The process is carried out in two stages, each of which requires its own equipment, reagents and solvents.

2. As the starting compound, diketone 2 is used, which is commercially available but very expensive, and its synthesis and purification are very laborious.

3. The process of isolation of reaction products at each stage involves many operations, requires significant reagents, solvents, labor and time.

Stage 1. The selection of oxime 3 from the reaction mass involves the following operations:

1. Distillation of acetic acid under reduced pressure.

2. Treatment of crude oxime 3 with an aqueous solution of NaHCO ₃ .

3. Extraction of crude oxime 3 with ethyl acetate.

4. Drying the resulting solution over anhydrous Na ₂ SO ₄ .

5. Filtration from Na ₂ SO ₄ .

6. Distillation of ethyl acetate under reduced pressure.

Stage 2. The selection of aminopyrazole 1 from the reaction mass involves the following operations:

1. Rinsing a solution of aminopyrazole 1 in ethyl acetate with 3N hydrochloric acid solution.

2. Separation of the organic layer.

3. The neutralization of the aqueous fraction 10 with a solution of NaOH.

4. Extraction of aminopyrazole 1 from the aqueous fraction with ethyl acetate.

5. Aging to dry the organic extract over Na ₂ SO ₄ .

6. Filtration from Na ₂ SO ₄ .

7. Removal of solvent (ethyl acetate).

Thus, the process of isolating aminopyrazole 1 and the intermediate of its synthesis (oxime 3) from the reaction mass requires 13 labor-intensive operations. The yield of the desired aminopyrazole 1 is 75%.

The objective of the invention is to develop a simple and convenient method for producing aminopyrazole 1, which would increase the yield of the final product, reduce the number of operations and carry out the process in one reactor.

The problem is solved by the proposed method for producing aminopyrazole 1 by the interaction of lithium 4,4,4-trifluoro-1-phenylbutadionate (hereinafter referred to as diketonate 5) instead of the corresponding diketon 2 with sodium nitrite in glacial acetic acid and subsequent processing of the reaction mixture (without isolation of oxime 3) a multiple excess of hydrazine hydrate.

3. The invention

The essence of the invention lies in the fact that in the proposed method for the production of aminopyrazole 1 instead of diketone 2, the more available lithium 4,4,4-trifluoro-1-phenylbutadionate diketonate 5 is used, and acetic acid is used as a solvent, which allows the process to be carried out in a single reactor, without isolation of the intermediate oxime 3.

In the first stage, after treating diketonate 5 with sodium nitrite without precipitating oxime 3, an 8-fold excess of hydrazine hydrate is added to the reaction mass and kept at room temperature until the nitroso derivative 4 is completely reduced to aminopyrazole 1 (control of the composition of the reaction mass by TLC and GC-MS )

The use of acetic acid as an organic solvent allows the process to be carried out in a single reactor, without isolation of intermediate oxime 3, without the use of high or low pressure, at a temperature of 10 to 20 ° C, which leads to an increase in the selectivity of the process (according to GC-MS, by-products practically absent) and provides the desired aminopyrazole 1 with a yield of 93%. The process of isolating the target product is extremely simple: at the end of the reaction, a precipitate precipitates, which is filtered off, washed on the filter with water and dried in air. This allows you to reduce almost all the operations that are used in the prototype method.

The method is as follows. Lithium 4,4,4-trifluoro-1-phenylbutadionate, glacial acetic acid are placed in a flat-bottomed flask equipped with a stirrer, an ice bath, a reflux condenser and a dropping funnel, and cooled to 10-16 ° C with stirring. An aqueous solution of sodium nitrite is added dropwise to the resulting solution with vigorous stirring. The reaction mass is stirred for 1 hour, cooled in an ice bath to 10-16 ° C, after which, with vigorous stirring, an 8-fold excess of hydrazine hydrate is added dropwise, stirred for 2-3 hours. Next, the reaction mass is maintained at room temperature for 20 hours. The precipitate formed is filtered off, washed on the filter with water and dried in air.

The composition and structure of the obtained product are established using data of chromatography-mass spectrometry (GC-MS), elemental analysis, IR and NMR ( ¹ H, ¹⁹ F) spectroscopy.

4. Information confirming the invention

4.1. Synthesis of 5-phenyl-3- (trifluoromethyl) -1H-pyrazol-4 amine 1.

The production method includes one chemical step: the reaction of lithium 4,4,4-trifluoro-1-phenylbutadionate with sodium nitrite in glacial acetic acid in a molar ratio of 1: 1.15, followed by treatment of the reaction mass with an 8-fold excess of hydrazine hydrate without the release of oxime 3.

An analytical sample of aminopyrazole 1 is obtained by recrystallization from chloroform. Aminopyrazole 1 has the following physicochemical characteristics: white matter, mp = 123-125 ° C, soluble in ethanol, acetone, chloroform, diethyl ether, ethyl acetate; not soluble in water. According to GC / MS data, the substance does not contain impurities: the chromatogram contains one peak with τ _beats = 19.78.

Found,%: C 52.89; H 3.63; N, 18.36; F 24.82. Gross formula: C ₁₀ H ₈ F ₃ N ₃ . Calculated,%: 52.87; H 3.55; N, 18.49; F 25.09. IR spectrum (dra), v / cm ^-1 : 3378 sr, 3236 s, 3158 s, 3059 s, (NH _shaft ); 1608 words, 1591 cf. (C = N, N-H _def. ); 1313 s, 1163 s, 1141 s, 1105 s. (CF). ¹ H NMR spectrum (500 MHz, DMSO d ₆ ), δ (ppm): 4.25 s (2H, NH ₂ ), [7.31-7.38 m (1H), 7.45-7.52 m (2H), 7.64-7.69 m (2H) Ph], 13.34 br. from. (1H, NH). ¹⁹ F NMR spectrum (470.5 MHz, DMSO d ₆ ), δ (ppm): 103.08 s (CF ₃ ).

Mass spectrum, m / z (I ^Rel ,%): 227 (58) [M] ⁺ ; 208 (9) [M-F] ^+; 178 (9), 132 (10) [M-CF ₃ CN] ⁺ ; 104 (100) [Ph-C = NH] ⁺ ; 103 (9) [Ph-CN] ⁺ ; 77 (50) [Ph] ⁺ ; 69 (6%) [CF ₃ ] ⁺ ; 51 (19); 28 (13).

The method for producing aminopyrazole 1 is illustrated by the following example.

Example 1. Obtaining 5-phenyl-3- (trifluoromethyl) -1H-pyrazol-4 amine 1.

To a solution of 1 g (4.5 mmol) of lithium 4,4,4-trifluoro-1-phenylbutadionate in 3 ml of glacial acetic acid, 0.36 g (5.2 mmol) of sodium nitrite in 3 ml of water is added with stirring. The reaction mass is stirred for 1 hour, after which 1.8 g (36.0 mmol) of hydrazine hydrate are added and stirred for 3 hours. Next, the reaction mass is maintained at room temperature for 20 hours. The precipitate formed is filtered, washed with water on a filter, and dried in air. 0.95 g of 5-phenyl-3- (trifluoromethyl) -1H-pyrazol-4 amine 1 is obtained in the form of a yellow powder. Yield 93%. T. pl. = 123-125 ° C.

This technical solution allows to obtain aminopyrazole 1 in one reactor (one-pot), increase the yield of the target product from 75 to 93% and significantly reduce the number of operations during the isolation of the target product (from 13 in the prototype method to 3).

It should be noted that the technical sample of aminopyrazole 1 obtained by the proposed method, according to GC-MS, contains 96% of the basic substance (τ _beats = 19.80) and can be used in further syntheses without further purification.

Due to the simplicity of the hardware design, this technical solution can be scaled to obtain larger batches of aminopyrazole 1 (up to industrial ones).

The starting compound, diketonate 5, is more accessible than the corresponding diketon 2, since it is an intermediate in the synthesis of the latter. Diketonate 5 is obtained from available reagents: by condensation of ethyl trifluoroacetic acid ethyl acetate with acetophenone under the action of lithium hydride and is used without purification as a technical product. In addition, diketonate 5 is more stable during storage and more convenient for use in chemical processes than the corresponding diketon 2. The characteristics of diketonate 5 are given in the work (N.S.Boltacheva, V.I. Filyakova, E.F. Khmara, O.V. Koryakova , V.N. Charushin, “Synthesis and Structure of Fluoroalkyl-Containing Lithium 1,3-Diketonates,” Russian Chemical Chemistry (J. Ros. Chemical Chemical Society named after DI Mendeleev), 2009, vol. LIII, No. 1, p. 54-63).

Claims (3)

The method of obtaining 5-phenyl-3- (trifluoromethyl) -1H-pyrazole-4 amine of the formula 1

the interaction of the 1,3-dicarbonyl compound with sodium nitrite in glacial acetic acid under cooling, followed by treatment with an excess of hydrazine hydrate in an organic solvent, characterized in that lithium 4,4,4-trifluoro-1-phenylbutadionate is used as the dicarbonyl compound, which treated with sodium nitrite, then with excess hydrazine hydrate, and acetic acid is used as an organic solvent.