KR100459938B1 - Fluorine-substituted heterocyclic compounds as intermediate for synthesis of agrochemical and medicinal antagonist and method for preparing thereof - Google Patents

Abstract

The present invention is a 5-fluoropyrazole derivative represented by Formula 1a or 1b and 4-fluoro-6-hydroxy pyrimidine represented by Formula 2 A method for preparing a compound of the present invention, comprising reacting a substituted hydrazine derivative and a substituted guanidine derivative with a one-pot process, respectively, using a methyl 2-fluoroalkyl 2-phenylacetate derivative as a starting material. According to the process of the invention, 5-fluoro-pyrazole derivatives and 4-fluoro-6-hydroxy pyrimidine derivatives can be prepared, respectively, in regio-selective and high yield:

Wherein X is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 arylalkyloxy; R _F is a fluorine or trifluoromethyl group; R ₁ , R ₂ and R ₃ are each independently hydrogen, C _1-4 alkyl, C _1-4 aryl or C _1-4 arylalkyl groups.

Description

FLUORINE-SUBSTITUTED HETEROCYCLIC COMPOUNDS AS INTERMEDIATE FOR SYNTHESIS OF AGROCHEMICAL AND MEDICINAL ANTAGONIST AND METHOD FOR PREPARING THEREOF}

The present invention relates to the preparation of heterocyclic compounds having fluorine substituents, and more particularly 5-fluor-pyrazole having a phenyl group substituted at the 3 or 4 position, which can be usefully used as a synthetic intermediate in the manufacture of medicinal and pesticide substances. A regio-selective preparation of derivatives and 4-fluoro-6-hydroxy pyrimidine derivatives.

A method for synthesizing a pyrazole substituted with a fluorine group, which is an agricultural and pharmaceutical substance, is a method for producing 4-fluoro pyrazole by a condensation reaction of 2,3-difluoro-2-acrylate and hydrazine [Tetrahedron. Lett. 41, 8545-8548 (2000)], a method for reacting 2-trifluoromethyl acrylate with hydrazine [Eur. J. Org. Chem., 823-828 (2000)], Process for the preparation of pyrazoles substituted with fluorine groups at positions 3 and 5 in 2,2-difluorovinyl ketone [J. Org. Chem. 61, 2763-2769 (1996), and the like.

In addition, methods for preparing 5-fluoropyrazole compounds having bactericidal activity are disclosed in German Patent Nos. 19840322 and 19629898 (1998), European Patents 776 889 (1997), Japanese Patent Publication No. 01029364 (1989) and the like. Is disclosed.

On the other hand, U.S. Patent Nos. 5,726,124, 5,849,758 and 5,300,477, and European Patents 579,424 disclose pyrimidine derivatives containing fluorine groups used as herbicidal active substances, and Japanese Patent Laid-Open Nos. 63-238068 and 63 -216877 discloses pyrimidine derivatives containing fluorine groups which are used as bactericidal actives.

In addition, as a method for producing a fluorine-containing pyridine, a method of reacting 2,3-difluoro acrylate with a guanidine derivative [Terrahedron. Lett. 41, 8545-8548 (2000)], all of which are prepared from propyl ethers substituted with fluorine groups [J. Fluorine Chem., 27, 231-6 (1985)], alpha-chloro alpha-trifluoro methyl ketone Methods of reacting with guanidine and the like are known. However, these prior arts make it difficult to prepare 5-fluoropyrazol-3-one derivatives and 4-fluoro-6-hydroxypyrimidine derivatives having site selectivity, and yields are also low.

Accordingly, the present inventors used the 2-trifluoromethyl-phenylacetate derivative represented by the following Chemical Formula 3 as a starting material to prepare a 5-fluoro-4-phenylpyrazole derivative and 4- by a one-pot process. Fluor-5-phenyl-6-hydroxypyrimidine derivatives have been prepared in a site-selective and high yield.

Accordingly, it is an object of the present invention to provide a 5-fluoro-4-phenylpyrazole derivative having a phenyl group substituted at the 3 or 4 position and a process for preparing the same.

Another object of the present invention is to provide a 4-fluoro-5-phenyl-6-hydroxypyrimidine derivative having a phenyl group substituted at the 3 or 4 position and a method for preparing the same.

In order to achieve the above object, the present invention provides a 5-fluor pyrazole derivative having a phenyl group substituted in the 3 or 4 position of the general formula (1a) or (1b).

Formula 1a

Formula 1b

Wherein X is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 arylalkyloxy; R _F is a fluorine or trifluoromethyl group; R ₁ and R ₂ are each independently hydrogen, C _1-4 alkyl, C _1-4 aryl or C _1-4 arylalkyl group.

In Formula 1a or 1b, preferably R ₁ is hydrogen, methyl, phenyl, substituted phenyl, benzyl or substituted benzyl.

The compound of Formula 1a or 1b may be prepared by Scheme 1 below using, for example, 2-trifluoromethyl-phenylacetate derivative represented by the following Formula 3 as a starting material.

Wherein X, R _F and R ₁ are as defined above and R ₂ ′ is a C _1-4 alkyl, C _1-4 aryl or C _1-4 arylalkyl group.

As shown in Scheme 1, the 2-trifluoromethyl-phenylacetate derivative (3) and the excess substituted hydrazine derivative (4) were subjected to the present invention by defluorination reaction, addition-removal reaction and condensation reaction in the presence of a solvent. The compound (1a or 1b) of can be synthesized. At this time, β, β-difluoroacrylate (5), which is a synthetic intermediate produced by the reaction with 2-trifluoromethyl-phenyl acetate derivative (3) and hydrazine derivative (4), was subjected to a one-pot process. This compound (1a or 1b) can be obtained.

The pyrazol-3-one derivative (1a ') prepared by the reaction of the starting material 2-trifluoromethyl-phenyl acetate derivative (3) with hydrazine derivative (4) is a 3-hydroxy pyrazole derivative (1b'). ) And tautomer. 5-Fluoro-pyra, respectively, by reacting them with a suitable compound represented by R ₂ 'Y in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride or potassium hydride, for example an alkyl group, an aryl group or an arylalkyl group containing compound. A pyrazole (1b '') is obtained in which the sol-on derivative (1a '') and 5-fluoro-3-alkylether are substituted.

In this reaction, the hydrazine derivative (4) can be used in 2 to 5 equivalents, preferably 3 to 4 equivalents based on the weight of methyl 2-trifluoromethylphenylacetate (3). In addition, the hydrazine derivative (4) may be used for reaction after anionization using a base such as sodium hydride or butyllithium.

Solvents that may be used in the reaction include tetrahydrofuran, methanol, ethanol, isopropanol, dimethyl sulfoxide (DMSO), acetonitrile or 1,4-dioxane, among which acetonitrile or 1,4-dioxane desirable. The reaction temperature may vary depending on the solvent and reactants used, the range of 20 to 150 ℃ is good, 60 to 120 ℃ is preferred.

The present invention also provides a 4-fluoro-6-hydroxypyrimidine derivative having a phenyl group substituted at the 3 or 4 position represented by the following general formula (2).

Formula 2

Wherein X is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 arylalkyloxy; R _F is a fluorine or trifluoromethyl group; R ₃ is hydrogen, C _1-4 alkyl, C _1-4 aryl or C _1-4 arylalkyl group.

The compound of Formula 2 may be prepared by the following Scheme 2:

Wherein X, R _F and R ₃ are as defined above.

As shown in Scheme 2, the starting material 2-trifluoromethyl-phenyl acetate derivative (3) and the excess substituted guanidine derivative (6) in the presence of a solvent for defluorination reaction, addition-removal reaction and condensation reaction The compound (2) can be synthesized by this.

At this time, β, β-difluoroacrylate (5), which is a synthetic intermediate produced by the reaction with 2-trifluoromethyl-phenyl acetate derivative (3) and guanidine derivative (6), was purified in a one-pot process. This yields compound (2).

In this reaction, the guanidine derivative (6) may be used in 2 to 5 equivalents, preferably 3 to 4 equivalents based on the weight of methyl 2-trifluoromethylphenylacetate (3). In addition, the guanidine derivative 6 may be used for the reaction in the form of a guanidine salt using a base such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate.

Solvents that can be used in the reaction include acetonitrile, 1,4-dioxane, 5-30% 1,4-dioxane aqueous solution, of which 5-10% 1,4-dioxane aqueous solution is preferred. The reaction temperature may vary depending on the solvent and the reactants used, the range of 60 to 120 ℃ is good, 60 to 120 ℃ is preferred. The reaction time may vary depending on the solvent, but may be 4 to 48 hours, preferably heated to reflux for 16 to 24 hours.

2-trifluoromethyl-phenylacetate derivative (3) used as starting materials in Scheme 1 and Scheme 2 is a known method [Synth. Commun, 28, 1981-1987 (1998) and J. Fluorine Chem., 76, 91-93 (1996).

5-Fluoro-pyrazolone derivatives having a substituted phenyl group and 4-fluoro-6-hydroxypyrimidine derivatives having a substituted phenyl group according to the present invention are useful as raw materials for herbicides or agricultural fungicides, and also rheumatoid or It can be usefully used as a synthetic intermediate of anti-inflammatory agents.

The invention can be better understood by the following examples, which are intended for the purpose of illustration of the invention and are not intended to limit the scope of protection defined by the appended claims.

Example

Preparation 1: Methyl 2-trifluoromethyl-phenylacetate

Synth. Methyl 2-trifluoromethyl-phenylacetate was prepared using the method known in Commun, 28, 1981-1987 (1998) and J. Fluorine Chem., 76, 91-93 (1996) as follows.

Sodium hydride (12.8 g, 0.32 mol) was suspended in 200 ml of dried ether while passing nitrogen through a 500 ml three-necked flask, and methanol (12 ml, 0.3 mol) was slowly added at room temperature. The reaction solution was stirred at room temperature for 30 minutes, cooled to -78 ° C, stirred for 30 minutes while slowly adding 2,2-difluoro-1-trifluoromethylstyrene (20.8g, 0.1mol) and warmed slowly to 5 ° C. I was. The reaction solution was added to water, and the organic layer was extracted and dried over anhydrous magnesium sulfate. The organic layer was concentrated and vacuum distilled to give the title compound (14.6 g) (yield 67%).

b.p .: 111-120 ° C. (10 mmHg).

¹ H NMR (CDCl ₃ ): δ 7.45-7.24 (m, 5H), 4.32 (q, 1H), 3.75 (s, 3H). GC-MS (m / z): 218 (M ⁺ , 20), 159 (23), 140 (23), 109 (100), 105 (55), 89 (29), 63 (34), 59 (30 )

Example 1 Synthesis of 5-Fluoro-4-phenyl-1-methylpyrazol-3-one (Compound 2)

Methyl 2-trifluoromethyl-phenylacetate (0.218 g, 1 mmol) synthesized in Preparation 1 was dissolved in 1,4-dioxane (10 ml), and then methylhydrazine (0.138 g, 3 mmol) was added thereto. The resulting solution was heated to reflux for 24 hours, then cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, and then the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by evaporation under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 1: 1) to give the title compound (0.161 g) (yield: 84%).

b.p .: 182-183 ℃

¹ H NMR (CDCl ₃ / DMSO-d ₆ ): δ 7.63-7.22 (m, 6H). ¹⁹ F NMR (CDCl ₃ / CFCl ₃ ) -129.86 (1F, s) ppm. GC-MS (m / z): 192 (M ⁺ , 100), 134 (27), 99 (67), 63 (23), 47 (26)

Example 2: Synthesis of 1,4-diphenyl-5-fluoro-pyrazol-3-one (Compound 3)

Phenylhydrazine (0.32 g, 3 mmol) was dissolved in 10 ml of tetrahydrofuran (THF), cooled to −78 ° C., and n-butyllithium (1.2 ml, 3 mmol) was added for 30 minutes, followed by synthesis in Preparation 1 above. THF (3 ml) in which methyl 2-trifluoromethyl-2-phenylacetate (0.218 g, 1 mmol) was dissolved was added. After stirring for 1 hour while maintaining the temperature, the mixture was warmed to room temperature, neutralized with 2% aqueous hydrogen chloride solution, the organic layer was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 4: 1) to obtain the title compound as a white solid (yield: 72%).

¹ H NMR (CDCl ₃ ): δ 7.78-7.22 (m, 11 H). ¹⁹ F NMR (CDCl ₃ / CFCl ₃ ) -125.918 (1F, s) ppm. GC-MS (m / z): 254 (28, M ⁺ +1), 225 (13), 150 (14), 134 (18), 77 (100), 50 (47)

Example 3: of 3-ethoxy-5-fluoro-1-methyl-4-phenylpyrazole (Compound 24) and 2-ethyl-5-fluoro-4-phenyl-pyrazol-3-one (compound 22) synthesis

5-Fluoro-4-phenyl-1-methylpyrazol-3-one (0.192 g, 1 mmol) and potassium carbonate (0.138 g, 1 mmol) prepared in Example 1 were dissolved in acetone (10 ml) and kept at room temperature for 10 minutes. After stirring, ethane iodide (0.08 ml. 1 mmol) was added. The reaction product was heated to reflux for 8 hours, the solvent was removed by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) to 3-ethoxy-5-fluoro-1-methyl-4-phenylpyrazole and its residue. A tautomer, 2-ethyl-5-fluoro-4-phenyl-pyrazol-3-one, was obtained.

<3-ethoxy-5-fluoro-1-methyl-4-phenylpyrazole>

Melting point: 57-58 ℃

¹ H NMR (CDCl ₃ ): δ 7.69-7.13 (m, 5H), 4.30 (q, 2H), 3.62 (s, 3H), 1.43 (t, 3H). GC-MS (m / z): 220 (100), 192 (67), 135 (10), 120 (14), 104 (28), 43 (18)

<2-Ethyl-5-fluoro-4-phenyl-pyrazol-3-one>

¹ H NMR (CDCl ₃ ): δ 7.77-7.11 (m, 5H), 3.51 (q, 2H), 2.91 (s, 3H), 1.18 (t, 3H). GC-MS (m / z): 220 (100), 192 (48), 135 (42), 104 (31)

Example 4: Synthesis of 4-Fluoro-5-phenyl-6-hydroxypyrimidine (Compound 26)

Methyl 2-trifluoromethyl-2-phenylacetate (0.218 g, 1 mmol) and formamidine hydrochloride (0.242 g, 3 mmol) synthesized in Preparation 1 were dissolved in an aqueous 75% 1,4-dioxane solution and carbonated therein. Potassium (0.207 g, 1.5 mmol) was added and heated to reflux for 24 hours. The solvent was distilled off under reduced pressure, the organic layer was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 1: 4) to give the title compound as a white solid (yield: 74%).

Melting Point: 183-184 ℃

¹ H NMR (CDCl ₃ / Aceton-d ₆ ): δ 12.78 (bs, 1H), 8.01 (s, 1H), 7.57-7.40 (m, 5H). GC-MS (m / z): 190 (100, M ⁺ +1), 162 (11), 135 (7)

Similar to Examples 1-4, various compounds of Formula 1a or 1b, and Formula 2 according to the present invention were obtained, and the compounds obtained in the above Examples are shown in Tables 1 and 2 below.

According to the present invention, a 5-fluoro-pyrazol-3-one derivative prepared by reacting the starting material methyl 2-fluoroalkyl 2-phenylacetate derivative with a substituted hydrazine derivative or a substituted guanidine derivative in a one-pot process or 4-Fluoro-6-hydroxy pyrimidine derivatives can be usefully used as synthetic intermediates of pharmaceuticals and pesticides, and the method of the present invention is site selective and high in yield.

Simple modifications and variations of the present invention can be readily made by those skilled in the art, and all such modifications or changes can be seen to be included in the scope of the present invention.

Claims (12)

5-Fluoro-3 substituted of Formula 1a or 1b comprising reacting a methyl 2-fluoroalkyl 2-phenylacetate derivative of Formula 3 with a substituted hydrazine derivative (R ₁ -NHNH ₂ ) in the presence of a solvent Process for preparing pyrazole derivatives: Formula 3 Formula 1a Formula 1b Where X is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 arylalkyloxy; R _F is a fluorine or trifluoromethyl group; R ₁ and R ₂ are each independently hydrogen, C _1-4 alkyl, C _1-4 aryl or C _1-4 arylalkyl groups. The method of claim 1, Wherein the solvent is selected from the group consisting of tetrahydrofuran, methanol, ethanol, isopropanol, dimethylsulfoxide (DMSO), acetonitrile and 1,4-dioxane. The method of claim 1, The process is characterized in that the reaction is carried out in the temperature range of 20 to 150 ℃. The method of claim 1, Wherein the hydrazine derivative is used in 2 to 5 equivalents based on the weight of methyl 2-trifluoromethylphenylacetate. The method of claim 1, Wherein the hydrazine derivative is used for reaction after anionization with sodium hydride or butyllithium. 5-Fluoro-3 substituted pyrazole derivatives having a substituted phenyl group at the 3 or 4 position of Formula 1a or 1b, prepared by the method of any one of claims 1 to 5: Formula 1a Formula 1b Where X is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 arylalkyloxy; R _F is a fluorine or trifluoromethyl group; R ₁ and R ₂ are each independently hydrogen, C _1-4 alkyl, C _1-4 aryl or C _1-4 arylalkyl groups. delete delete delete delete delete delete