Halogen-substituted compound, preparation method therefor, and use thereof

Abstract

A preparation method for a halogen-substituted compound is provided, where a piperazine derivative shown in formula I reacts with a halogenated acetyl halide derivative shown in formula VI to generate a halogen-substituted compound shown in formula II. The present invention further relates to a preparation method for preparing a pyrazole derivative by using a halogen-substituted compound, where a halogen-substituted compound shown in formula II reacts with methylhydrazine to close a pyrazole ring, to generate a halogen-substituted alkyl-1-methylpyrazole derivative shown in formula IV, or reacts with methylhydrazine benzaldehyde hydrazone to generate a hydrazone compound shown in formula III, which closes, under the action of an acid, a pyrazole ring to generate a halogen-substituted alkyl-1-methylpyrazole derivative shown in formula IV. The present invention further relates to a structure of an intermediate compound. The preparation methods for a halogen-substituted compound and a pyrazole derivative are suitable for industrial production.

Claims

1. A halogen-substituted compound, having a structure shown in formula II: ##STR00010## wherein: R.sup.1 is OR.sup.A or R.sup.A, wherein R.sup.A is C1-C8 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 2-methylcyclopropyl, 1-methycyclopentyl, 4-methylcyclohexyl, 3-methylphenyl(m-tolyl), 2,4-di-tert-butylphenyl, or 4-chlorophenyl; R.sup.4 is hydrogen, chlorine, fluorine, or C1-C8 alkyl; and X.sup.1 and X.sup.2 are each independently chlorine or fluorine.

2. A preparation method for the halogen-substituted compound according to claim 1, wherein: a piperazine derivative shown in formula I reacts with a halogenated acetyl halide derivative shown in formula VI to generate the halogen-substituted compound shown in formula II, wherein a reaction equation is as follows: ##STR00011## wherein: R.sup.1 is OR.sup.A or R.sup.A, wherein R.sup.A is C1-C8 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 2-methylcyclopropyl, 1-methycyclopentyl, 4-methylcyclohexyl, 3-methylphenyl(m-tolyl), 2,4-di-tert-butylphenyl, or 4-chlorophenyl; R.sup.4 is hydrogen, chlorine, fluorine, or C1-C8 alkyl; and X.sup.1, X.sup.2, and X.sup.3 are each independently chlorine or fluorine.

3. A preparation method for preparing a halogen-substituted alkyl-1-methyl pyrazole of formula IV, wherein: the halogen-substituted compound shown in formula II reacts with methylhydrazine to close a pyrazole ring, to generate a halogen-substituted alkyl-1-methylpyrazole shown in formula IV, wherein a reaction equation is as follows: ##STR00012## wherein: R.sup.1 is OR.sup.A or R.sup.A, wherein R.sup.A is C1-C8 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 2-methylcyclopropyl, 1-methycyclopentyl, 4-methylcyclohexyl, 3-methylphenyl(m-tolyl), 2,4-di-tert-butylphenyl, or 4-chlorophenyl; R.sup.4 is hydrogen, chlorine, fluorine, or C1-C8 alkyl; and X.sup.1 and X.sup.2 are each independently chlorine or fluorine.

4. The preparation method according to claim 3, wherein when R.sup.1 is OR.sup.A, the halogen-substituted alkyl-1-methylpyrazole shown in formula IV undergoes a hydrolysis reaction to generate a halogen-substituted alkyl-1-methyl-1H-pyrazole-4-carboxylic acid shown in formula V, wherein a reaction equation of the hydrolysis reaction is as follows: ##STR00013##

5. The preparation method according to claim 3, wherein when R.sup.1 is R.sup.A, the halogen-substituted alkyl-1-methylpyrazole shown in formula IV undergoes an oxidation reaction to generate a halogen-substituted alkyl-1-methyl-1H-pyrazole-4-carboxylic acid shown in formula V, wherein a reaction equation of the oxidation reaction is as follows: ##STR00014##

6. A preparation method for preparing a halogen-substituted alkyl-1-methyl pyrazole of formula IV, wherein: the halogen-substituted compound shown in formula II reacts with methylhydrazine benzaldehyde hydrazone to generate a hydrazone compound shown in formula III, wherein a reaction equation is as follows: ##STR00015## wherein: R.sup.1 is OR.sup.A or R.sup.A, wherein R.sup.A is C1-C8 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, 2-methylcyclopropyl, 1-methycyclopentyl, 4-methylcyclohexyl, 3-methylphenyl(m-tolyl), 2,4-di-tert-butylphenyl, or 4-chlorophenyl; R.sup.4 is hydrogen, chlorine, fluorine, or C1-C8 alkyl; and X.sup.1 and X.sup.2 are each independently chlorine or fluorine; and the hydrazone compound shown in formula III closes, under the action of an acid, a pyrazole ring to generate a halogen-substituted alkyl-1-methylpyrazole shown in formula IV, wherein a reaction equation is as follows: ##STR00016##

7. The preparation method according to claim 6, wherein when R.sup.1 is OR.sup.A, the halogen-substituted alkyl-1-methylpyrazole shown in formula IV undergoes a hydrolysis reaction to generate a halogen-substituted alkyl-1-methyl-1H-pyrazole-4-carboxylic acid shown in formula V, wherein a reaction equation of the hydrolysis reaction is as follows: ##STR00017##

8. The preparation method according to claim 6, wherein when R.sup.1 is R.sup.A, the halogen-substituted alkyl-1-methylpyrazole shown in formula IV undergoes an oxidation reaction to generate a halogen-substituted alkyl-1-methyl-1H-pyrazole-4-carboxylic acid shown in formula V, wherein a reaction equation of the oxidation reaction is as follows: ##STR00018##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a high performance liquid chromatogram of N,N′-ethyl diacrylate piperazine in Example 1;

(2) FIG. 2 is a high performance liquid chromatogram of a halogen-substituted compound in Example 1;

(3) FIG. 3 is a gas chromatogram of 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid ethyl ester in Example 1; and

(4) FIG. 4 is a high performance liquid chromatogram of 3-fluoroalkyl-1-methyl-1H-pyrazole-4-carboxylic acid in Example 1.

DETAILED DESCRIPTION OF THE EMBODIMENTS

(5) The present invention is specifically described below by using examples. It should be noted that the following examples are merely used to further illustrate the present invention, and should not be understood as limitations on the scope of protection of the present invention. A person skilled in the art can make some non-essential improvements and adjustments to the present invention based on the foregoing content of the present invention.

(6) Unless otherwise defined, all professional and scientific terms used in this application have the same meaning as those familiar to a person skilled in the art. For example, C1-C8 alkyl refers to alkyl having a carbon chain length of 1-8, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, hexyl, heptyl, or octyl. C3-C8 cycloalkyl refers to cycloalkyl having a carbon chain length of 3-8, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclooctyl. C3-C8 cycloalkyl with a substituent is, for example, 2-methylcyclopropyl, 1-methylcyclopentyl, or 4-methylcyclohexyl. Aryl refers to a monovalent aromatic hydrocarbon group having a carbon chain length of 6-18, for example, phenyl, naphthyl, or anthracenyl. Aryl with a substituent is, for example, 3-methylphenyl(m-tolyl), 2,4-di-tert-butylphenyl, or 4-chlorine phenyl. Heteroaryl is, for example, furyl, pyrrolyl, indolyl, carbazolyl, or imidazolyl. Heteroaryl with a substituent refers to a group formed by substituting one or more hydrogen atoms of a heteroaryl group with a substituent.

(7) In the examples of the present invention, the halogenated acetyl halide derivative shown in formula VI being difluorine acetyl fluorine is used as an example:

(8) ##STR00009##

(9) When X.sup.1, X.sup.2, and X.sup.3 are fluorine, and R.sup.4 is hydrogen, the halogenated acetyl halide derivative shown in formula VI is difluorine acetyl fluorine.

(10) The difluorine acetyl fluorine gas can be formed through pyrolysis of tetrafluorine ether. The temperature of the pyrolysis reaction is 200° C. to 400° C., and the catalyst is aluminum oxide.

Example 1

(11) A preparation method for a pyrazole derivative of this embodiment included the following steps:

(12) 28.2 g (0.1 mol) of N,N′-ethyl diacrylate piperazine (shown in formula I, where R.sup.1 was OC.sub.2H.sub.5, and a high performance liquid chromatogram was shown in FIG. 1), 200 g of chloroform, and 22.2 g (0.22 mol) of triethylamine were added into a reaction flask, the temperature was controlled within 10° C. to 30° C., 21.5 g (0.22 mol) of difluorine acetyl fluorine (DFAF) was introduced, after the introduction of the gas was finished, the temperature was kept for reacting for 5 hours, a solvent was concentrated at a reduced pressure, 100 g of water was added into the residue, and the mixture was stirred for 30 minutes, and was filtered and dried to obtain 42.9 g of a corresponding halogen-substituted compound (shown in formula II, where a high performance liquid chromatogram was shown in FIG. 2), where the yield was 98%. 39 g (0.0889 mol) of the halogen-substituted compound product was suspended in 200 g of chloroform, the mixture was stirred and cooled to −25° C., 20.5 g (0.178 mol) of methylhydrazine (MMH) of which a concentration was 40% was added dropwise, after the addition was finished, the temperature was kept for reacting for 30 minutes and then, was raised to room temperature, a water layer was separated and removed, an organic layer was concentrated to dryness, and the residue was recrystallized by adding petroleum ether, to obtain 30.8 g of 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid ethyl ester (EDFMPA) (shown in formula IV), where the yield was 85%, and a gas chromatogram was shown in FIG. 3.

(13) 30.8 g (0.151 mol) of 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid ethyl ester (EDFMPA) was added into the reaction flask, 100 g of water and 6.7 g of hydrogen sodium oxide were added, the mixture was stirred for reacting for 2 hours at 70° C., after the reaction was finished, hydrochloric acid was added dropwise to neutralize the product to a pH value of 2, the product was cooled to 10° C., filtered, washed with a small amount of cold water, and dried, to obtain 25.2 g of 3-fluoroalkyl-1-methyl-1H-pyrazole-4-carboxylic acid (DFMPA) (shown in formula V), where the yield was 95%, the purity detected through high performance liquid chromatography was 99%, and a high performance liquid chromatogram was shown in FIG. 4.

Example 2

(14) A preparation method for a pyrazole derivative of this embodiment included the following steps:

(15) 28.2 g (0.1 mol) of N,N′-ethyl diacrylate piperazine (shown in formula I, where R.sup.1 was OC.sub.2H.sub.5), 200 g of chloroform, and 22.2 g (0.22 mol) of triethylamine were added into a reaction flask, the temperature was controlled within 10° C. to 30° C., 21.5 g (0.22 mol) of difluorine acetyl fluorine (DFAF) was introduced, after the introduction of the gas was finished, the temperature was kept for reacting for 5 hours, after the reaction was finished, 26.8 g (0.2 mol) of methylhydrazine benzaldehyde hydrazone (BzH) was added dropwise, the temperature was raised to 50° C. and was kept for reacting for 3 hours, a solvent was evaporated at a reduced pressure, 200 g of chloroform and 5 g of sulfuric acid were further added to the residue for reacting at room temperature for 8 hours, 50 g of water was added, an organic layer was separated and heated to 60° C., and 90 g of a sodium hydroxide solution of which a concentration was 10% was added dropwise. After the addition was finished, the reaction continued for 3 hours, after the reaction was finished, a water layer was separated, hydrochloric acid was added dropwise to neutralize the product to a pH value of 2, and the product was cooled to 10° C., filtered, washed with water, and dried, to obtain 26 g of 3-fluoroalkyl-1-methyl-1H-pyrazole-4-carboxylic acid (DFMPA) (shown in formula V), where the total yield was 73.8%, and the purity detected through high performance liquid chromatography was 99%.

Example 3

(16) A preparation method for a pyrazole derivative of this embodiment included the following steps:

(17) 22.2 g (0.1 mol) of N,N′-divinylmethylketopiperazine (shown in formula I, where R.sup.1 was CH.sub.3), 200 g of chloroform, and 22.2 g (0.22 mol) of triethylamine were added into a reaction flask, the temperature was controlled within 10° C. to 30° C., 21.5 g (0.22 mol) of difluorine acetyl fluorine (DFAF) was introduced, after the introduction of the gas was finished, the temperature was kept for reacting for 5 hours, 26.8 g (0.2 mol) of methylhydrazine benzaldehyde hydrazone (BzH) was added dropwise, the temperature was raised to 50° C. and was kept for reacting for 3 hours, a solvent was evaporated at a reduced pressure, 200 g of chloroform and 5 g of sulfuric acid were further added to the residue for reacting at room temperature for 8 hours, 50 g of water was added, an organic layer was separated and concentrated to dryness, was recrystallized by adding petroleum ether, and was filtered and dried to obtain 27.2 g of a 3-trifluoromethyl-1-methyl-4-acetylpyrazole derivative (shown in formula IV), where the yield was 78%.

(18) 25 g (0.14 mol) of the 3-trifluoromethyl-1-methyl-4-acetylpyrazole derivative, 80 g of acetic acid, 1 g of manganese nitrate, and 1 g of ferric nitrate were added into the reaction flask, the temperature was raised to 80° C., oxygen was introduced for reacting for 20 hours, the acetic acid was evaporated at a reduced pressure, 80 g of water was added to the residue, the mixture was stirred, heated to 80° C., cooled to 10° C., filtered, and dried to obtain 24 g of 3-fluoroalkyl-1-methyl-1H-pyrazole-4-carboxylic acid (DFMPA) (as shown in formula V), where the yield was 95%, and the purity detected through high performance liquid chromatography was 99%.

(19) Obviously, the foregoing examples are merely examples provided for clearly illustrating the present invention, and are not intended to limit the implementations of the present invention. A person of ordinary skill in the art may alternatively make other changes or modifications in different forms based on the foregoing description. It is unnecessary and impossible to exhaustively list all the implementations in this application. Moreover, the obvious changes or modifications derived from the spirit of the present invention still fall within the scope of protection of the present invention.