Novel method for preparing 3-halomethyl-substituted 1-methyl-1h-pyrazole-4-carbonitriles and derivatives and intermediates of 3-halomethyl-substituted 1-methyl-1h-pyrazole-4-carbonitriles

Abstract

The present invention relates to a process for the preparation of 3-halomethyl substituted 1-methyl-1H-pyrazol-4-carbonitrile compounds, including 3-halomethyl substituted 5-hydroxy-1-methyl-1H-pyrazol-4-carbonitrile compounds and derivatives thereof, which may be isolated and / or purified or generated in situ. The present invention also relates to a process for the preparation of an intermediate for the preparation of a 3-halomethyl substituted 1-methyl-1H-pyrazol-4-carbonitrile compound, which intermediate comprises a 3-halomethyl substituted 5-hydroxy-1-methyl-1H-pyrazol-4-carbonitrile compound. The present invention also relates to a process for the preparation of an intermediate for the preparation of a 3-halomethyl substituted 1-methyl-1H-pyrazol-4-carbonitrile compound. In addition, the present invention also relates to some novel derivatives of the 3-halomethyl substituted 1-methyl-1H-pyrazol-4-carbonitrile compounds, including the 3-halomethyl substituted 5-hydroxy-1-methyl-1H-pyrazol-4-carbonitrile compounds. Furthermore, the present invention relates to some novel derivatives of 3-halomethyl substituted 1-methyl-1H-pyrazol-4-carbonitrile compounds, including 3-halomethyl substituted 5-hydroxy-1-methyl-1H-pyrazol-4-carbonitrile compounds, such as the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-carbonitrile (Cl-DFPACN), for example, the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-carbonitrile (Cl-DFPACN), for example, the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-carbonitrile (Cl-DFPACN). And a compound of 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile (F-DFPACN), and a method for preparing the same.

Description

[0001] The present invention relates to a method for preparing a 3-halomethyl-substituted 1-methyl-1H-pyrazole-4-carbonitrile compound and its derivatives. The present invention also relates to a method for preparing an intermediate for preparing a 3-halomethyl-substituted 1-methyl-1H-pyrazole-4-carbonitrile compound. In addition, the present invention also relates to certain novel derivatives of a 3-halomethyl-substituted 1-methyl-1H-pyrazole-4-carbonitrile compound. Background Art

[0002] 4-Carbon nitrile pyrazole compounds are known, but due to the lack of commercially available suitable starting materials and suitable routes that meet today's energy-saving and environmental protection requirements, they have not been used on a large-scale industrial scale as intermediates.

[0003] For example, the synthesis of the halogen-free compound 5-hydroxy-1,3-dimethyl-1H-pyrazole-4-carbonitrile (HyMCNP) by deprotection of 5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carboxaldehyde (HyMCNP), whose chemical formula is shown below, is described in only one scientific paper (i.e., Bulletin of the Korean Chemical Society 26 (2005) 668-670). The pyrazole portion is prepared from 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxaldehyde as a precursor by reacting commercially available 1,3-dimethyl-5-pyrazolone with DMF and phosgene, as disclosed by Sumitomo in JP05001038. All of these are likely too complex for industrial purposes because they have no commercial applications.

[0004] The synthesis of 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile (HyCNP) with the chemical formula shown below has also been described in only one scientific article (i.e. Becher et al., January; in Journal of Organic Chemistry (1992), 57(7), 2127-34), which also discloses a method for synthesizing it from the corresponding 5-chloro-1-methyl-1H-pyrazole-4-carboxaldehyde.

[0005]

[0006] 3-Halomethylpyrazoles play an increasingly important role in the growing number of fluorinated active ingredients in the pharmaceutical and agrochemical industries, inevitably increasing the demand for new fluorinated building blocks. Their availability is primarily limited by the availability of suitable chemical substances and fluorinated raw materials. Due to the high costs and often the waste disposal efforts required for less environmentally friendly processes (e.g., low carbon efficiency, high waste content, and high energy consumption), the choice of synthetic routes, particularly in the agrochemical industry, is largely driven by economic considerations; therefore, the environmental profile is often treated as a "secondary factor" or ultimately put aside. For example, DFMMP (ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate or ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid) is a key building block of a rapidly growing family of new fungicides, such as Syngenta's Sedaxane, BASF's Fluxapyroxad and Bayer's Bixafen, which are currently produced via less environmentally friendly routes.

[0007] Of commercial importance is a group of fungicides, known as SDH-fungicides, based on 3-halomethylpyrazole compounds as building blocks, in which the pyrazole moiety is substituted in position 4 by a carboxylic acid function (COOH or -C(=O)OH).

[0008] Scheme 1 below shows some examples of compounds of interest, for example, the compounds Flupyrad, Bixafen, Fluoxathiapyr, Fluindapyr, Pydiflumetofen and Isoprazam:

[0009] Option 1:

[0010]

[0011] Option 1 (continued)

[0012]

[0013] In addition, a recent overview of general scientific developments and improvements is given in the scientific literature, for example, in the journal Pest Management Science 76 (2020), pages 3340-3347 (DOI: https: / / doi.org / 10.1002 / ps.5951). In Chinese patent application CN102718712 (Shanghai Kangpeng Chemical Co., Ltd.), the synthesis of 4-cyano-3-halomethylpyrazoles is disclosed, for example, by converting the corresponding acid chloride with 3-(dimethylamino)acrylonitrile to 4-halomethyl-2-[(dimethylamino)methylene]-3-oxobutanenitrile, as given in Scheme A below.

[0014] Option A:

[0015]

[0016] For example, with regard to its industrial application, this route suffers from the formation of a significant proportion of regioisomers during the cyclization reaction with monomethylhydrazine (MMH), as well as the formation of a large quantity of the amine × HCl salt cargo (which is rarely recoverable) contaminated with toxic substances and amine-based waste. Furthermore, since the substituent R1 mentioned in the starting material contains only chlorine atoms, a complex fluorination step with low catalyst life and waste formation must be performed during the synthesis of the less stable pyrazole system before the final hydrolysis of the CN- group (which is very facile) to yield the desired carboxylic acid functional group (COOH or –C(=O)OH). Although the synthetic route appears promising based on laboratory experiments presented in Chinese patent application CN102718712, the proposed synthetic route is not suitable for large-scale syntheses, such as pilot and / or industrial scales, due to issues with catalyst life, waste formation, and incomplete fluorination. Furthermore, the partially fluorinated side compounds formed in the proposed synthesis are highly toxic and difficult to remove from the corresponding main product. EP2128139 discloses fluorinated pyrazole carbonitrile derivatives and methods for preparing the same, as well as fluorinated pyrazole carboxylic acid derivatives obtained using the fluorinated pyrazole carbonitrile derivatives and methods for preparing the same. A fluorinated acrylonitrile derivative prepared from a fluoroacyl derivative and an aminoacrylonitrile derivative reacts with a hydrazine derivative to produce a fluorinated pyrazole carbonitrile derivative. The fluorinated pyrazole carbonitrile derivative reacts with water to produce a fluorinated pyrazole carboxylic acid derivative.

[0017] Another group of pyrazole derivatives that are gaining increasing industrial attention are 5-fluoro substituted pyrazole compounds. For example, the synthesis principles of these 5-fluoro substituted pyrazole compounds are disclosed in International Patent Applications WO 03 / 000686 and WO2004014138 (for CF3 derivatives) and WO2011061205, as outlined in Scheme B below.

[0018] Option B:

[0019]

[0020] Although the use of dimethylformamide (DMF) as a solvent in the synthesis and as a building block for the formation of the aldehyde moiety in these synthetic routes is a comfortable and easy-to-implement way for the synthesis, a disadvantage of this route is the lack of large-scale (e.g. pilot or industrial scale) availability of EDFAA for a given prior art example of a 5-fluoro-substituted pyrazole compound, or generally the lack of availability of halogenated acetoacetates for all other prior art examples mentioned above. In addition to this, another disadvantage is that halogenated C F2H-acetoacetates (e.g. EDFAA in the given prior art examples in the synthesis of 5-fluoro-substituted pyrazole compounds) are not very stable, and therefore these raw materials (e.g. EDFAA) must be stored under cooling conditions (<0° C.) to avoid degradation, and therefore such raw materials (e.g. EDFAA) are difficult to obtain commercially.

[0021] One object of the present invention is therefore to overcome the disadvantages of the prior art processes for preparing 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compounds and their derivatives, which are useful 3-halomethylpyrazole compounds for the increasing number of fluorinated active ingredients in the pharmaceutical and agrochemical industries, and to overcome the limitations of the prior art processes. In this context, the present invention also aims to provide a cost-competitive green route that exhibits a significantly lower environmental impact than the processes known in the prior art.

[0022] Therefore, an object of the present invention is to provide a method for preparing 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compounds and derivatives thereof, which method is industrially feasible, for example, easily amplified to large scale, for example, to provide pilot scale and / or industrial scale yields of the pyrazoles and derivatives thereof. Another object of the present invention is that the method particularly shows improved (e.g., good) selectivity and low energy consumption for the target product. In particular, another object of the present invention is to provide such improved and / or optimized methods for preparing the pyrazoles and derivatives thereof, wherein the product can be easily purified and / or separated, for example, by only low energy consumption methods, and wherein preferably the method for purification and / or separation does not require distillation.

[0023] The objects of the present invention are solved as defined in the claims and / or embodiments and are described in detail below. Summary of the Invention

[0024] The objects of the invention are solved as defined in the claims and are described in detail hereinafter.

[0025] The present invention relates to a process for preparing 3-halomethyl-substituted 1-methyl-1H-pyrazole-4-carbonitrile compounds, including 3-halomethyl-substituted 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile compounds and derivatives thereof, as defined in each claim and further described herein. The present invention also relates to a process for preparing intermediates for preparing 3-halomethyl-substituted 1-methyl-1H-pyrazole-4-carbonitrile compounds, as defined in each claim and further described herein, including 3-halomethyl-substituted 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile compounds, as defined in each claim and further described herein. In addition, the present invention relates to certain novel derivatives of 3-halomethyl-substituted 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile compounds, as defined in each claim and further described herein.

[0026] For example, the present invention relates to a process for preparing 3-halomethyl substituted 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile compounds of formula (I) and derivatives thereof, as defined in each claim and hereinafter.

[0027] The first aspect of the present invention relates to a method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound having formula (I),

[0028] wherein Me represents a methyl group, R3 represents hydrogen or a hydroxyl group, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen,

[0029] It is characterized in that the carbonitrile compound of formula (II) reacts with monomethylhydrazine of formula (III) to obtain a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound having formula (I),

[0030] wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is oxo (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine,

[0031] Me-NH-NH2(III), (MMH), wherein Me represents a methyl group.

[0032] The term C1 to C4 alkyl refers to a straight or branched chain alkyl group selected from methyl, ethyl, propyl (including straight chain propyl, i.e., n-propyl; and branched chain propyl, i.e., isopropyl) and butyl (including straight chain butyl, i.e., n-butyl; and branched chain butyl, i.e., isobutyl and tert-butyl). Preferably, C1 to C2 alkyl, i.e., methyl and ethyl, more preferably methyl.

[0033] For example, the derivatives of the compound of formula (I) are: the corresponding carboxylic acid derivatives of the compound of formula (I), i.e., wherein the carbonitrile group is converted into a carboxylic acid group; the 3-halomethyl-substituted 1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I), wherein the 5-hydroxyl group is reduced to hydrogen; the corresponding carboxylic acid derivatives of the compound of formula (I), wherein the 5-hydroxyl group is also reduced to hydrogen; the 5-halogenated derivatives of the compound of formula (I) and / or the corresponding carboxylic acid derivatives of the above-mentioned compound of formula (I), wherein halo refers to halogen, preferably chlorine or fluorine, more preferably fluorine.

[0034] The present invention also relates to a process for preparing an intermediate for preparing a 3-halomethyl-substituted 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile compound, as described in each claim and herein. Furthermore, the present invention relates to certain novel derivatives of a 3-halomethyl-substituted 5-hydroxy-1H-pyrazole-4-carbonitrile compound, as described in the claims and herein below.

[0035] Examples of derivatives of 3-halomethyl-substituted 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile compounds are 3-halomethyl-substituted 1-methyl-1H-pyrazole-4-carbonitrile compounds, 3-halomethyl-substituted 5-halo-1-methyl-1H-pyrazole-4-carbonitrile compounds, 3-halomethyl-substituted 1-methyl-1H-pyrazole-4-carbonate compounds, and 3-halomethyl-substituted 5-halo-1-methyl-1H-pyrazole-4-carbonate compounds. A novel derivative according to the present invention is the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (X), as further shown below, Cl-DFPACN. Another novel derivative according to the present invention is the compound 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile (XI), also as further shown below, F-DFPACN.

[0036] In the case of 3-halomethyl substituted 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile compounds, these compounds can exist in equilibrium with two tautomeric forms (keto-enol-tautomerism), the 5-hydroxy form (enol-form) and the 5-oxo form (keto-form).

[0037] For example, in the 3-halomethyl-substituted 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I),

[0038] R3 is a hydroxyl group (-OH), then optionally, wherein the hydroxyl group (-OH) undergoes keto-enol tautomerism, and the hydroxyl group (-OH) together with the carbon atom to which it is bound and the adjacent carbon atom constitutes an enol form (C=CH-OH), which is in equilibrium with the keto form (CH-C=O) or is partially or completely converted from the enol form (C=CH-OH) to the keto form (CH-C=O). Such keto-enol tautomerism is generally known to those skilled in the art and is exemplified in the context of the present invention as follows:

[0039]

[0040] In general terms, the present invention relates to a process for preparing 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compounds of formula (I), such as 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compounds as defined in the claims and below, such as 3-halomethyl-substituted 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile compounds and 3-halomethyl-substituted 1-methyl-1H-pyrazole-4-carbonitrile compounds. In this process, the carbonitrile compounds of formula (II) as defined in the claims and below and their preparation starting from haloacetic acid halide compounds of formula (IV) are key aspects of the process of the invention.

[0041] wherein X represents fluorine or chlorine, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen. A specific example of the haloacetic acid halide compound of formula (IV) is difluoroacetyl fluoride (DFAF); i.e., a haloacetic acid halide compound of formula (IV) wherein X is fluorine and Y is hydrogen. Another specific example of the haloacetic acid halide compound of formula (IV) is difluoroacetyl chloride (DFAC); i.e., a haloacetic acid halide compound of formula (IV) wherein X is chlorine and Y is hydrogen.

[0042] A haloacetic acid halide compound of formula (IV) reacts with a nitrile compound of formula (V) in the presence of a base to obtain a carbonitrile compound of formula (II), which is used as an intermediate compound or starting compound for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I).

[0043] wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached. According to the present invention, a specific example of a nitrile compound of formula (V) is the compound ethyl cyanoacetate (ECA) (e.g., a nitrile compound of formula (V) wherein R is ethyl, R1 is an oxo group (=O), and R2 is hydrogen), which is added to, for example, the compound difluoroacetyl fluoride (DFAF) or the compound difluoroacetyl chloride (DFAC) to obtain the compound ethyl 2-cyano-4,4-difluoro-3-oxobutanoate (ECNDFA).

[0044] The above reaction is carried out in the presence of a base, which means that the reaction is carried out under basic (alkaline) conditions. Basic (alkaline) conditions can range from basic (alkaline) conditions to more strongly basic (alkaline) conditions. The term "base" (basic compound) is generally understood to be a compound that can accept hydrogen cations (H + ) substances, also known as protons; and bases can be inorganic bases or organic bases. Bases can be divided into weak (mild) bases to strong bases.

[0045] According to the present invention, another specific example of the nitrile compound of formula (V) is the compound 2-(ethoxymethylene)-3-oxo-4,4-difluoro-butanecarbonitrile (EPN) (for example as a Z-isomer, an E-isomer or a Z / E-mixture), that is, the nitrile compound of formula (V) (for example as a Z-isomer, an E-isomer or a Z / E-mixture), wherein R is an ethyl group, R1 and R2 together are the bond between the C atoms to which they are attached, which is added to, for example, the compound difluoroacetyl fluoride (DFAF) or the compound difluoroacetyl chloride (DFAC) to obtain the compound 2-cyano-4,4-difluoro-3-oxobutanoic acid ethyl ester (ECNDFA).

[0046] Thus, in this aspect of the invention, an example intermediate in the process for preparing 1,3-dimethyl-1H-pyrazole-4-carbonitrile compounds and derivatives thereof is represented by a carbonitrile compound of formula (II), which is prepared starting from a haloacetic acid halide compound of formula (IV),

[0047] wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the carbon atoms to which they are attached, and Y represents hydrogen, fluorine, or chlorine. A specific example of a carbonitrile compound of formula (II) is the compound ethyl 2-cyano-4,4-difluoro-3-oxobutanoate (ECNDFA); i.e., a compound of formula (II) wherein R is ethyl, R1 is an oxo group (=O), R2 is hydrogen, and Y represents hydrogen. Another specific example of a carbonitrile compound of formula (II) is the compound 2-(ethoxymethylene)-3-oxo-4,4-difluorobutyronitrile (EMOCN) (e.g. as a Z-isomer, an E-isomer or a Z / E-mixture), i.e. a compound of formula (II) (e.g. as a Z-isomer, an E-isomer or a Z / E-mixture), wherein R is ethyl, R1 and R2 together are a bond between the C atoms to which they are attached, and Y represents hydrogen. DETAILED DESCRIPTION

[0048] As briefly described in the Summary of the Invention, defined in the Claims, and further detailed in the following description and Examples herein, the present invention relates, for example, to a process for preparing 3-halomethyl-substituted 5-hydroxy-1-methyl-1H-pyrazole-4-carbonitrile compounds of formula (I) and derivatives thereof, as defined in each of the Claims and hereinafter.

[0049] A first aspect of the present invention relates to a method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound having formula (I), characterized in that a carbonitrile compound of formula (II) is reacted with monomethylhydrazine of formula (III) to obtain a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound having formula (I),

[0050] wherein Me represents a methyl group, R3 represents hydrogen or a hydroxyl group, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen,

[0051] wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine,

[0052] Me-NH-NH2(III), (MMH), wherein Me represents a methyl group.

[0053] According to the method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) of the present invention, one aspect is characterized in that the carbonitrile compound of formula (II) as defined above, wherein R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, is prepared by the following process:

[0054] The haloacetic acid halide compound of formula (IV)

[0055] wherein X represents fluorine or chlorine, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen,

[0056] and a nitrile compound of formula (V)

[0057] wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached,

[0058] reacting to obtain a carbonitrile compound of formula (II) as defined herein, wherein the reaction is carried out in the presence of a base.

[0059] Likewise, the above reaction is carried out in the presence of a base, which means that the reaction is carried out under alkaline (basic) conditions. The alkaline (basic) conditions can range from alkaline (basic) conditions to more alkaline (basic) conditions. The term "base" (basic compound) is generally understood to be a compound that can accept hydrogen cations (H + ) substances, also known as protons; and bases can be inorganic bases or organic bases. Bases can be classified as weak (mild) bases to strong bases.

[0060] In this document, the terms "alkaline" and "basic" are used synonymously to define the pH conditions in the reaction according to the present invention, taking into account the selection of a base to be added to the reaction that will provide a pH range above pH = 7 under aqueous conditions (e.g., in water); for example, a pH range of about pH>7 to about pH = 12.

[0061] As used herein, the terms "mildly alkaline" and "mildly alkaline" are used as synonyms to define mild pH conditions in reactions according to the present invention, taking into account the selection of a base to be added to the reaction that will provide a pH range of pH=7 or higher but below pH=10 under aqueous conditions (e.g., in water); for example, a pH range of about pH>7 to about pH=10. As used herein, the terms "strongly alkaline" and "strongly alkaline" pH conditions are used as synonyms to define strong pH conditions in reactions according to the present invention, taking into account the selection of a base to be added to the reaction that will provide a pH range of pH=10 or higher under aqueous conditions (e.g., in water); for example, a pH range of about pH>10 to about pH=12. As used herein, the terms "mild" and "weak" are used synonymously.

[0062] To avoid any misunderstanding, it is emphasized that the aforementioned pH values or pH ranges are merely used to select a suitable base to be added to the reaction. This does not mean that these pH values or pH ranges are actually measurable in the reaction according to the present invention, since the reaction according to the present invention is preferably not carried out under aqueous conditions, but rather under anhydrous or moisture-free conditions. This is because the reaction according to the present invention is preferably not carried out under aqueous conditions, but rather under anhydrous or moisture-free conditions, since, for example, the acyl halide compound may react unintentionally or undesirably with the base added in the process according to the present invention.

[0063] Therefore, the terms "under alkaline conditions", "under alkaline conditions", "under mild alkaline conditions", "in the presence of a strong base" are synonymous with the reaction according to the invention being carried out "in the presence of a base", for example, "in the presence of a mild base" or "in the presence of a strong base". As mentioned above, the person skilled in the art selects the base to be added to the reaction according to the invention with reference to the pH value or pH range provided by the base under aqueous conditions (e.g., in water).

[0064] In the reaction according to the present invention, the desired "alkaline" or "alkaline" pH conditions, such as "mildly alkaline" or "mildly alkaline" pH conditions or "strongly alkaline" or "strongly alkaline" pH conditions, can be achieved in any manner known to those skilled in the art. In this document, any "alkaline compound" or "alkaline compound" generally known to those skilled in the art, i.e., any so-called "base", can be used to achieve the desired pH or desired pH range in the reaction according to the present invention. The base can be any inorganic base or organic base, as well as any combination thereof. For example, so-called strong bases, such as those generally known to those skilled in the art, can be used to achieve a pH range above pH=10; for example, a pH range of about pH>10 to about pH=12. So-called weak ("mild") bases, such as those generally known to those skilled in the art, can be used in the reaction according to the present invention to achieve a pH range of above pH=7 but below about pH=10, for example, a pH range of about pH>7 to about pH=10.

[0065] Examples of weak ("mild") bases are generally organic amines, which can be aliphatic amines, including alicyclic amines (e.g., piperidine, piperazine, pyrrolidine), aliphatic diamines (e.g., ethylenediamine, 1,2-diaminopropylene, 1,3-diaminopropylene), and / or aromatic amines (e.g., pyridine). These amine bases are preferably anhydrous ("water-free"). Such amines (preferably "anhydrous" or "water-free") are well known to those skilled in the art and include, for example, similar amines selected from aliphatic amines such as triethylamine, tributylamine, triethanolamine, N,N-diisopropylamine (Hünig's base), and aromatic amines such as pyridine, picoline (including all isomers thereof), N,N-dimethylaminopyridine, and generally all substituted or unsubstituted anilines; see also https: / / www.sciencedirect.com / topics / chemistry / basicity for more suitable examples. Linear or cyclic aliphatic diamines, such as ethylenediamine and piperazine, are also suitable. If desired, linear or cyclic aliphatic triamines may also be used.

[0066] In the context of the present invention, the terms "anhydrous" or "water-free" are synonymous meanings that, in the case of compounds or reactants, they are used in essentially anhydrous form (e.g., particularly in the case of essentially no free water), and in the case of reactions or processes, they are carried out under essentially anhydrous conditions (e.g., particularly in the case of essentially no free water). Thus, it is carried out under essentially anhydrous conditions. Therefore, in the context of the present invention, the synonymous terms "essentially anhydrous" or "water-free" mean that preferably any water still present is only a trace amount of water, preferably any water still present is less than 100 ppm (<100 ppm). Of course, it is also possible to use moist amines (up to 10% water), but depending on the water content, before the cyclization begins (i.e., when "anhydrous" or "water-free" conditions are preferably achieved), the starting material (acid halide) is first consumed by hydrolysis (due to the water content present). However, although theoretically possible, the presence of water makes this method less efficient and is therefore only used in practice as an exception, as acid halides (e.g., acid chlorides) are expensive.

[0067] The process for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) according to the present invention is characterized in that, on the other hand, a carbonitrile compound of formula (II) as defined above, wherein R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, is reacted with monomethylhydrazine (MMH) of formula (III) to obtain a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) as defined above, wherein Me represents a methyl group, R3 represents a hydroxyl group, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

[0068] For example, the method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) according to another aspect of the present invention is characterized in that, in one aspect, the carbonitrile compound of formula (II) as defined above—R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen—is prepared by the following process:

[0069] The haloacetic acid halide compound of formula (IV)

[0070] wherein X represents fluorine or chlorine, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen,

[0071] and a nitrile compound of formula (V)

[0072] wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen,

[0073] Reaction to obtain a carbonitrile compound of formula (II) as defined in claim 3, wherein the reaction is carried out in the presence of a base (for example, under alkaline (basic) conditions), wherein R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

[0074] According to the method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) according to the present invention, in another aspect, it is characterized in that a carbonitrile compound of formula (II) as defined above - wherein R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, methyl or ethyl), R1 and R2 together represent a bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen - is reacted with monomethylhydrazine (MMH) of formula (III) to obtain a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I), wherein Me represents a methyl group, R3 represents a hydroxyl group, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

[0075] For example, according to another aspect of the present invention, the method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound having formula (I) is characterized in that, in one aspect, the carbonitrile compound of formula (II) as defined above, wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 and R2 together represent the bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, is prepared by the following process:

[0076] The haloacetic acid halide compound of formula (IV)

[0077] wherein X represents fluorine or chlorine, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen,

[0078] and a nitrile compound of formula (V)

[0079] wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 and R2 together represent the bond between the C atoms to which they are attached,

[0080] Reaction to obtain a carbonitrile compound of formula (II) as defined above, wherein the reaction is carried out in the presence of a base (e.g., under alkaline (basic) conditions), wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 and R2 together represent the bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

[0081] In yet another aspect, the present invention relates to a process for preparing a carbonitrile compound of formula (II),

[0082] wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen,

[0083] And the method is characterized in that the haloacetic acid halide compound of formula (IV)

[0084] wherein X represents fluorine or chlorine, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen,

[0085] and a nitrile compound of formula (V)

[0086] wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached,

[0087] reacting to obtain a carbonitrile compound of formula (II), wherein the reaction is carried out in the presence of a base (eg, under basic conditions).

[0088] For example, in one option of the method according to another aspect of the present invention, a method for preparing a carbonitrile compound of formula (II) as defined above, in one aspect, is characterized in that a haloacetic acid halide compound of formula (IV) as defined above is reacted with a nitrile compound of formula (V) as defined above, wherein the reaction is carried out in the presence of a base (e.g., under alkaline conditions) to obtain a carbonitrile compound of formula (II), wherein in the carbonitrile compound of formula (II), R represents a C1 to C4 alkyl group (straight or branched) , preferably C1 to C2 alkyl (for example, methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, wherein in the nitrile compound of formula (V), R represents a C1 to C4 alkyl (straight chain or branched), preferably a C1 to C2 alkyl (for example, methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, wherein in the obtained carbonitrile compound of formula (II), R represents a C1 to C4 alkyl (straight chain or branched), preferably a C1 to C2 alkyl (for example, methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen.

[0089] For example, in one option of the method according to said further aspect of the present invention, a method for preparing a carbonitrile compound of formula (II) as defined above, in one aspect, is characterized in that a haloacetic acid halide compound of formula (IV) as defined above is reacted with a nitrile compound of formula (V) as defined above, wherein the reaction is carried out in the presence of a base (e.g., under alkaline conditions) to obtain a carbonitrile compound of formula (II), wherein in the carbonitrile compound of formula (II), R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group ( For example, methyl or ethyl), R1 and R2 together represent the bond between the C atoms to which they are connected, wherein in the nitrile compound of formula (V), R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, methyl or ethyl), R1 and R2 together represent the bond between the C atoms to which they are connected, wherein in the obtained carbonitrile compound of formula (II), R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, methyl or ethyl), R1 and R2 together represent the bond between the C atoms to which they are connected.

[0090] The present invention also relates to a useful new compound, methyl 2-cyano-4,4-difluoro-3-oxobutanoate. In addition to this compound (corresponding to the carbonitrile compound of formula (II), wherein R is methyl), in the context of the present invention, the following 2-cyano-4,4-difluoro-3-oxobutanoic acid C1 to C4 alkyl (straight or branched) ester compounds corresponding to the carbonitrile compound of formula (II) can also be used,

[0091] wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (eg, methyl or ethyl), more preferably, R1 is an oxo group (=O), R2 is hydrogen, and Y represents hydrogen.

[0092] Furthermore, the present invention relates to a method for preparing a carboxylic acid derivative of a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I),

[0093] wherein Me represents a methyl group, R3 represents hydrogen or a hydroxyl group, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen,

[0094] And the method is characterized in that the carbonitrile group of the compound of formula (I) is hydrolyzed (for example, with HCl / H2O hydrolysis, or any hydrolysis method described herein and known to those skilled in the art)

[0095] Thus, a 3-halomethyl-1-methyl-1H-pyrazole-4-carboxylic acid compound having the formula (VI) is obtained,

[0096] wherein Me represents methyl, R3 represents hydrogen or hydroxy, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

[0097] Hydrolysis refers to treatment under acidic aqueous conditions, for example, treatment with an acid solution in water (H2O) in an amount such that the pH is less than pH = 7. The actual pH less than pH = 7 is not important, it is sufficient that the hydrolysis is acidic, and thus, a convenient bulk acid can be used in commercially available form or in a diluted concentration adjusted as needed.

[0098] The hydrolysis in the method according to the present invention can be carried out in a manner known to those skilled in the art, using aqueous mineral and / or organic acids, preferably dilute aqueous mineral and / or organic acids. Dilute hydrochloric acid (HCl) is most suitable and sufficient for the hydrolysis used in accordance with the present invention because it is an inexpensive, bulk product. Hydrochloric acid is produced in solutions of up to 38% HCl (concentrated grade). Chemically, higher concentrations of slightly over 40% can be achieved, but the evaporation rate is so high that storage and handling require additional precautions, such as pressurization and cooling. Therefore, bulk technical grades are 30% to 35%, optimized to balance transportation efficiency and product losses through evaporation. Aqueous HCl solutions are typically sold at concentrations of 20% to 32%. Aqueous HCl solutions with dilute concentrations of typically 10% to 12% can be used for the hydrolysis used in accordance with the present invention. Organic acids such as trifluoroacetic acid and trifluoromethanesulfonic acid are also suitable, typically at dilute concentrations of 10% to 12%.

[0099] Furthermore, the present invention relates to a method for preparing a carboxylic acid derivative of a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I),

[0100] wherein Me represents a methyl group, R3 represents hydrogen or a hydroxyl group, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen,

[0101] And the method is characterized in that,

[0102] (ii) reducing the hydroxyl group (R3) of the compound of formula (I) (e.g., in a manner known to those skilled in the art, for example, with hydrogen in the presence or absence of a hydrogenation catalyst, with hydrogen (H2) over a noble metal catalyst (e.g., on Pt, Pd), or with hydrogen (H2) over a Raney nickel catalyst; sodium amalgam [Na(Hg)], sodium lead alloy [Na+Pb]; or an inorganic reducing agent, such as NaBH4 [sodium borohydride], LiAlH4 [lithium aluminum hydride, a very strong reducing agent], Red-Al [NaAlH 2( OCH2CH2OCH3)2, a safer and more stable alternative to lithium aluminum hydride])

[0103] and

[0104] (ii) hydrolyzing the carbonitrile group of the compound of formula (I) (e.g., hydrolysis with HCl / H2O, or any hydrolysis method described above and known to those skilled in the art),

[0105] Thus, a 3-halomethyl-1-methyl-1H-pyrazole-4-carboxylic acid compound having the formula (VI) is obtained,

[0106] wherein Me represents methyl, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

[0107] Regarding the above reduction, it is worth mentioning that, in the case of a pyrazole compound having a CF2Cl group, the use of hydrogen (H2) as a reducing agent (using conventional catalysts such as Pd, Pt, etc.) or the use of Raney nickel as a catalyst has the advantage that the CF2Cl group is then also reduced to produce a pyrazole compound having a CF2H group. Both methods (using conventional catalysts / H2 or using Raney nickel, which can be used in the absence of H2) have the following advantages: if CF2Hal is used as a starting material instead of CF2H, then CF2Hal will be reduced to pyrazole and then to CF2H together with the pyrazole-OH in a single step, i.e., the two reactions occur simultaneously.

[0108] According to the aforementioned method for preparing a carboxylic acid derivative of a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound having formula (I) as defined above, wherein in the compound of formula (I), Me represents a methyl group, R3 represents a hydroxyl group, and Y represents hydrogen, it is further characterized in that

[0109] (i) reducing the hydroxyl group (R3) of the compound of formula (I) (e.g. in a manner known to those skilled in the art, for example with hydrogen (H2) over a noble metal catalyst (e.g. Pt, Pd) or over a Raney nickel catalyst, or an inorganic reducing agent such as NaBH4, LiAlH4),

[0110] and

[0111] (ii) hydrolyzing the carbonitrile group of the compound of formula (I) (e.g., hydrolysis with HCl / H2O, or any hydrolysis method described above and known to those skilled in the art)

[0112] Thus, a 3-halomethyl-1-methyl-1H-pyrazole-4-carboxylic acid compound having the formula (VIII) is obtained,

[0113]

[0114] The present invention also relates to novel compounds of formula (X): 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile,

[0115]

[0116] The present invention also relates to a process for preparing the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (X), characterized in that the compound 5-hydroxy-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (IX) is reacted with a chlorinating agent (for example, PCl3, POCl3, PCl5 or SOCl2) to replace the 5-hydroxy group in the compound of formula (VI) with chlorine, thereby obtaining the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (X):

[0117]

[0118] In addition to the above-mentioned chlorinating agents (such as PCl3, POCl3, PCl5 or SOCl2), those skilled in the art can select other chlorinating agents as needed, such as tetraethylammonium chloride, although it is not feasible from an economic point of view (see, for example https: / / onlinelibrary.wiley.com / doi / 10.1002 / anie.199723421 ); or AlCl3 (aluminum trichloride), but both are economically unfeasible and there may be a risk that the halomethyl groups in the carbonitrile compound will also be attacked.

[0119] In addition, the present invention also relates to a method for preparing the compound of formula (VIII) 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid,

[0120]

[0121] The method is characterized by

[0122] (i) reducing the chloro substituent of the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (IX) (e.g., in a manner known to those skilled in the art, such as with hydrogen (H2) over a noble metal catalyst (e.g., Pt, Pd) or over a Raney nickel catalyst, or an inorganic reducing agent such as NaBH4, LiAlH4), and

[0123] (ii) hydrolyzing the carbonitrile group of the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (IX) (e.g., hydrolysis with HCl / H2O, or any hydrolysis method described above and known to those skilled in the art)

[0124] Thus, a 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid compound having the formula (VIII) is obtained,

[0125]

[0126] The present invention also relates to novel compounds of formula (XI): 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile,

[0127]

[0128] The present invention also relates to a method for preparing a compound of formula (XI) 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile, characterized in that a 5-hydroxy-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (IX) is reacted with a fluorinating agent (for example, with SF4, or with other fluorinating agents such as X-tal Fluor-M) to replace the 5-hydroxy group in the compound of formula (IX) with fluorine, thereby obtaining a compound of formula (XI) 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile:

[0129]

[0130] In addition to the fluorinating agent SF4 or the previously mentioned fluorinating agents such as X-tal Fluor-M, other fluorinating agents can also be used: fluorescent bodies, or the OH group is first converted into a leaving group (for example, converted into a cheap tosylate, an expensive triflate), and then a cheap fluorinating agent such as KF also works (used under Halex conditions). Fluorinating agents are generally known to those skilled in the art and are used under generally known conditions. Halex conditions are also known to those skilled in the art. In addition to the aforementioned fluorinating agents, other fluorinating agents can also be used, such as 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (Selectfluor), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor), amine x nHF (for example, triethylamine x 3HF), Ohlah reagent and / or trifluoroethylamine x 3HF.

[0131] Furthermore, the present invention relates to a process for preparing the compound 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid of formula (XII),

[0132]

[0133] It is characterized in that the carbonitrile group of the compound 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (XII) is hydrolyzed (for example, by hydrolysis with HCl / H2O, or any hydrolysis method described above and known to those skilled in the art),

[0134] Thus, a 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid compound having the formula (XII) is obtained:

[0135]

[0136] In the following, the advantages of the new inventive production route of 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compounds of formula (I) are provided,

[0137] wherein Me is methyl, R3 and Y each have the meaning as defined above, and the relevant starting materials and / or intermediates used therefrom according to the present invention will be further exemplified.

[0138] For example, according to the present invention, it has now surprisingly been found that, in order to overcome all of these mentioned disadvantages, haloacetyl chlorides and haloacetyl fluorides can be readily reacted with cyanoacetic acid esters, wherein the reaction is carried out in the presence of a base (e.g. under alkaline conditions) to form ethyl 2-cyano-4-halomethyl-3-oxobutanoate (or methyl ester). In order to avoid the necessity of a subsequent fluorination step, which has all the disadvantages of the above-mentioned prior art, it is very preferred that all the required F atoms (fluorine atoms) in the 3-methyl group of the pyrazole are already present before the cyclization reaction with monomethylhydrazine (MMH).

[0139] On the one hand, when using aqueous methylhydrazine (for example, 40% MMH aqueous solution), two phases are formed (for example, referring to embodiment 5 of this paper), therefore it is suggested to stir the reaction mixture vigorously.On the other hand, preferably, in order to realize suitable industrial suitable reaction rate, instead of stirring vigorously, there are two kinds of alternatives for the reaction with methylhydrazine.In the first alternative, cosolvent (for example acetonitrile) is added in the reaction with methylhydrazine, to enhance stirring effect and two-phase mixing, or cosolvent (for example acetonitrile) is added in the reaction with methylhydrazine, its amount makes two-phase conversion, at least major part is converted into single phase.In the second alternative, simply use more concentrated aqueous methylhydrazine (>40% MMH aqueous solution) or even almost 100% methylhydrazine (usually 98% MMH) in the reaction.The preparation of more concentrated methylhydrazine (>40%MMH) is known in the art, for example, described in US3219550 (FMC).

[0140] After the cyclization reaction with MMH, followed by acid-induced hydrolysis (here using the halomethyl group = CF2H as an example), the corresponding difluoromethylpyrazole carboxylic acid (DFMPA) is obtained. An inventive example of one aspect of the present invention and the general method of the present invention as described above and defined in the claims is given in Scheme C below, where difluoroacetyl fluoride (DFAF) and difluoroacetyl chloride (DFAC) give 3-difluoromethyl-4-carboxylic acid (DFPA), but trifluoroacetyl fluoride (TFAF) and / or trifluoroacetyl chloride (TFAC) are also represented. For example, chlorodifluoroacetyl fluoride (CDFAF) and / or chlorodifluoroacetyl chloride (CDFAC) are also very convenient as fluorination starting materials, especially because the CClF2- group is very stable and can be converted into the desired CF2H- group at a later stage of the present invention.

[0141] The novel process routes of the present invention utilize readily available raw materials, for example, fluorination in a stable precursor compound, followed by prior art downstream steps. For example, in one aspect, the method of the present invention is illustrated by a reaction sequence using the compound ECNDFA (ethyl 2-cyano-4,4-difluoro-3-oxobutanoate) as an intermediate, as shown in Scheme C below. For example, in another alternative aspect, the method of the present invention is illustrated by a reaction sequence using the compound EMOCN (2-(ethoxymethylene)-3-oxo-4,4-difluoro-butyronitrile) as an intermediate, as shown in Scheme F below.

[0142] For halomethyl = CF2H (i.e., Y in the compound of formula (I) is hydrogen), an example method of the present invention is given in the equation of Scheme C below, illustrating the reaction sequence with the compound ECNDFA (ethyl 2-cyano-4,4-difluoro-3-oxobutanoate) as an intermediate.

[0143] Option C:

[0144]

[0145] Haloacetyl halide raw materials are commercially available or can be produced in situ.For example, difluoroacetyl fluoride (DFAF) can be prepared by the pyrolysis of CF2=CF-OEt or corresponding-OMe derivatives (CF2=CF-OMe).CF2=CF-OEt or corresponding-OMe derivatives (CF2=CF-OMe) can be commercially available on a very large industrial scale because they are made of tetrafluoroethylene (see, for example, JP2011073984, EP694523).For example, as described in patent application EP0691322, IN2008DE01665 and CN103524325, trifluoroacetyl fluoride (TFAF) is made of trichloroacetyl chloride (TCAC).As described in patent documentation US3883407 and EP659729, haloacetyl chloride is prepared on an industrial scale.Some 2-cyano-4-halomethyl-3-oxobutanoic acid ethyl esters (or methyl esters), especially halomethyl=CF3, are known. In patent application WO2021123798, a CF3 derivative (ethyl 2-cyano-4,4,4-trifluoro-3-oxo-butyrate) is provided and is prepared from trifluoroacetic anhydride (TFAH) and ethyl cyanoacetate in CH2Cl2 with NEt3 as a base. TFAH is a good raw material in chemistry, but does not meet the required economic benefits (for example, only half of the starting molecules remain in the desired product). In European patent application EP1067121, the raw materials are ethyl trifluoroacetate and metallic sodium as a base, which is also difficult to handle on an industrial scale. The corresponding CF2H-derivative (ethyl 2-cyano-4,4-difluoro-3-oxobutyrate) is mentioned in patent application WO2008004698 and is prepared from difluoroacetic acid using NaOEt (sodium acetate) base and PCl3 in a complex three-step reaction. In addition to the challenging effort required, it also results in low yields and is not feasible on an industrial scale. In patent application WO2018203298, ethyl 2-cyano-4,4-difluoro-3-oxobutanoate is described and prepared from ethyl difluoroacetate (DFAEt) in ethanol / Na, which is also very challenging on an industrial scale due to the handling of Na-metal (sodium metal) and the use of DFAEt, which is already a downstream product of difluoroacetic acid (DFA) and is industrially prepared by hydrolysis outside of DFAF. In addition to the handling of DFA and the difficulty in purification, this is not economical at all.

[0146] Methyl 2-cyano-4,4-difluoro-3-oxobutanoate is a novel compound and is therefore included as part of the present invention.

[0147] Methyl 2-cyano-4,4,4-trifluoro-3-oxobutanoate is already mentioned in patent applications WO2021108404, JP2008285482, WO2007046548, and WO2008004698, and is described therein as being prepared by methods that are also unsuitable for large-scale industrial production. However, the process of the present invention provides a convenient route to methyl 2-cyano-4,4,4-trifluoro-3-oxobutanoate.

[0148] If desired (e.g., for strategic reasons and possibly taking into account the prior art), instead of a direct single-step reduction, for example, the reduction of DFPACN to DFPA as shown in Scheme D below (this option also applies to the pyrazole analog compounds defined herein), first the hydroxyl group (at the 5-position) of DFPACN (or the pyrazole analog compound defined herein) can be converted (e.g., by chlorination with PCl 3 ) to the corresponding chlorinated pyrazole derivative compound at the 5-position, or the hydroxyl group (at the 5-position) can be converted to the corresponding fluorinated pyrazole compound at the 5-position (e.g., by fluorination with SF 4 or other fluorinating agents such as X-tal Fluor-M). These two compounds, 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile (Cl-DFPACN) of formula (X) and 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile (XI) (F-DFPACN), were hitherto unknown and are therefore included in the novel compounds of the present invention.

[0149] Plan D:

[0150]

[0151] Reduction and hydrolysis of the compound Cl-DFPACN produces DFPA (3-difluoromethyl-1-methyl-pyrazole-4-carboxylic acid), while reduction and hydrolysis of the compound F-DFPACN produces a 5-fluoro-derivative (3-difluoromethyl-1-methyl-5-fluoro-pyrazole-4-carboxylic acid; F-DFPA). Since the F atom at the 5-position of pyrazole is generally stable, especially under the reduction conditions used in the method of the present invention, the resulting pyrazole product is always DFPA substituted by fluorine (F) at the 5-position (F-DFPA), as shown in Scheme E below.

[0152] Plan E:

[0153]

[0154] The corresponding 5-chlorinated 3-trifluoromethyl-substituted CN-pyrazole derivatives are known and described in Nature Communications (2014), 5, 4123 and Green Chemistry (2018), 20(1), 266-273. However, compared with the method of the present invention, the 5-chlorinated 3-trifluoromethyl-substituted CN-pyrazole derivatives are prepared in different ways in the prior art. For example, according to the prior art, they are prepared from 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-methanol or 5-chloro-1-methyl-3-(trifluoromethyl)pyrazole-4-carboxaldehyde.

[0155] An alternative aspect of the present method for obtaining 4-cyano-3-halomethylpyrazoles is the synthesis and use of 2-(ethoxymethylene)-3-oxo-4-halobutyronitrile (e.g., as a Z / E mixture). The reaction sequence is outlined below for compounds in which the halomethyl group is CF2H, but the reaction is also valid for compounds in which the halomethyl group is CF3 or CF2Cl; and the reaction sequence outlined below is equally applicable to using an acid chloride (e.g., DFAC) or an acid fluoride (e.g., DFAF) as a starting material. For example, in this alternative aspect, the present method is illustrated by the reaction sequence using the compound EMOCN (2-(ethoxymethylene)-3-oxo-4,4-difluoro-butyronitrile) as an intermediate, as shown in Scheme F below.

[0156] Plan F

[0157]

[0158] Plan F (continued)

[0159]

[0160] Also in this alternative process aspect of the present invention, for example, the hydrolysis of the 4-cyano derivative DFPACN will ultimately produce DFPA. The compound required for this alternative reaction sequence, 2-(ethoxymethylene)-3-oxo-4,4-difluorobutyronitrile (EPN) (and similar other 2-(ethoxymethylene)-3-oxo-4-halobutyronitrile compounds) is commercially available, and its synthesis is described, for example, in Chinese patent application CN109912454 using ethyl formate from acetonitrile; or alternatively, for example, the reaction of acrylonitrile with ethanol on the corresponding 3,3-diethoxypropionitrile compound, as disclosed in patent applications JP06087781, CN102633680 and CN109369423.

[0161] Example

[0162] The following examples are intended to further illustrate the present invention but are not intended to limit its scope.

[0163] Example 1:

[0164] Difluoroacetyl fluoride (DFAF) is added to ethyl cyanoacetate (ECA) to form ethyl 2-cyano-4,4-difluoro-3-oxobutanoate (ECNDFA); see Scheme G.

[0165]

[0166]

[0167] In a typical three-necked glass flask equipped with a magnetic stirrer, dropping funnel, and reflux condenser, 100 g (0.88 mol) of ethyl cyanoacetate was added to a solution of 101.0 g (0.9 mol) of KO-tBu (potassium tert-butoxide) in CHCN (acetonitrile) at room temperature (rt). 88.2 g (0.9 mol) of DFAF was bubbled into the solution through a deep tube from a stainless steel cylinder (mounted on a balance with flexible tubing). After the DFAF addition was complete and stirred for 1 hour, the solution was poured into ice water, and the organic phase was dried over NaSO and filtered. The filtrate was concentrated in vacuo at 0.01 mbar and distilled on a 20 cm Weiss column to obtain ethyl 2-cyano-4,4-difluoro-3-oxobutanoate (ECNDFA) in 91% yield at a transition temperature of 83.2°C. 1 H(CDCl3):d=5.9(t),3.8(q),4.6(s),1.3(t).

[0168] Instead of KO-tBu (potassium tert-butoxide), other bases can also be used, for example 1.5 equivalents of NBu3 (tributylamine) can be used instead of KO-tBu.

[0169] The reaction according to Example 1 can also be carried out using difluoroacetyl chloride (DFAC) instead of difluoroacetyl fluoride (DFAF) and / or using methyl cyanoacetate (MCA) instead of ethyl cyanoacetate (ECA). If methyl cyanoacetate (MCA) is used, the reaction produces methyl 2-cyano-4,4-difluoro-3-oxobutanoate (MCNDFA).

[0170] Example 2:

[0171] In a simplified workup, difluoroacetyl fluoride (DFAF) was added to ethyl cyanoacetate (ECA) to form ethyl 2-cyano-4,4-difluoro-3-oxobutanoate (ECNDFA).

[0172] Example 1 was repeated, but the workup was performed by filtering the organic phase instead of concentrating over SiO2 (silica gel). The isolated yield of ethyl 2-cyano-4,4-difluoro-3-oxobutanoate (ECNDFA) after vacuum distillation on a 20 cm Viggen column was 96%.

[0173] Similarly, the reaction according to Example 2 can also be carried out using difluoroacetyl chloride (DFAC) instead of difluoroacetyl fluoride (DFAF), and / or using methyl cyanoacetate (MCA) instead of ethyl cyanoacetate (ECA). If methyl cyanoacetate (MCA) is used, the reaction produces methyl 2-cyano-4,4-difluoro-3-oxobutanoate (MCNDFA).

[0174] Example 3:

[0175] An alternative one-pot method for preparing DFPA from 2-(ethoxymethylene)-3-oxo-4,4-difluorobutyronitrile is described: the addition of difluoroacetyl fluoride to 3-ethoxy-2-propenenitrile is initiated by palladium acetate, using NEt3 (triethylamine) as a base, followed by regioselective MMH addition.

[0176] In the 50ml 3-neck glass flask in the oil bath of magnetic stirring apparatus, deep tube and reflux condenser are housed, 0.556g (2.5mmol) palladium acetate II is joined in toluene (75mL) degassed solution of 3-ethoxypropene cyanide (10.3mL, 100mmol) and triethylamine (14mL, 100mmol).Under room temperature (RT), 0.98g (0.01mol) DFAF is bubbled into solution by deep tube from stainless steel cylinder (being placed on the balance with flexible tube).Reaction mixture was stirred 1 day in 100 ℃ oil bath, was then cooled to room temperature.Slowly add 0.51g (110mmol) MMH (using as 40% solution) and stir for 12 hours. The solution was then acidified with 38% HCl (HCl in a cylinder can also be used to reduce wastewater formation) and then filtered through a pad of diatomaceous earth (diatomaceous earth, sometimes referred to by trade names such as Celite), rinsing the filter cake with some toluene. Concentration in vacuum-induced crystallization, completed by storage at 4°C overnight, yielded 92% regioisomerically pure DFPA crystals after drying. The MPa (melting point) was measured at 201°C.

[0177] Similarly, the reaction according to Example 3 can also be carried out using 3-methoxy-2-propenenitrile to prepare DFPA through a one-pot process of 2-(methoxymethylene)-3-oxo-4,4-difluorobutyronitrile.

[0178] Example 4

[0179] An alternative one-pot preparation of DFPA from 2-(ethoxymethylene)-3-oxo-4,4-difluorobutyronitrile (EPN). Difluoroacetyl fluoride (DFAF) is added to 3-ethoxy-2-propenenitrile (EPN) using n-BuLi (n-butyllithium), followed by regioselective MMH addition; see Scheme H below.

[0180] Plan H:

[0181]

[0182] A solution of 3-ethoxyacrylonitrile (2.0 g, 2.1 mL, 21 mmol) in anhydrous THF (100 mL) was treated with a hexane solution of n-butyllithium (1.6 M, 14.4 mL, 23 mmol) at -78°C and stirred for 20 minutes. 2.25 g (0.023 mol) of DFAF was then added to the solution from a stainless steel cylinder (mounted on a balance with flexible tubing) over 30 minutes. The reaction was stirred at -78°C for 3 hours and allowed to warm to 0°C. 1.06 g (23 mmol) of MMH (used as a 40% aqueous solution) was slowly added to the resulting solution using a syringe and stirred for 5 hours. The solution was then acidified with 38% HCl (HCl in a cylinder can also be used to reduce the formation of wastewater) and concentrated in vacuo until crystallization began. After drying, storage at 4°C overnight produced 96% regioisomerically pure DFPA crystals. The Mp (melting point) was measured at 201.5°C.

[0183] Example 5:

[0184] DFPA was synthesized by cyclization of ethyl 2-cyano-4,4-difluoro-3-oxobutanoate with monomethylhydrazine (MMH); see Scheme J below.

[0185] Plan J:

[0186]

[0187] A solution of 10 g (0.052 mol) of ethyl 2-cyano-4,4-difluoro-3-oxobutanoate (prepared in Example 1) in 10 mL of toluene and 2.4 g (0.053 mol) of MMH (40% aqueous solution) were added, and the two-phase system was stirred vigorously at room temperature for 3 hours. The organic phase was separated and dried over NaSO. The filtrate was homogeneously hydrogenated in 10 mL of ethanol using 5% Pd / C (a freshly prepared catalyst according to Org. Synth. 1946, 26, 77) in a stainless steel autoclave (5 hours, 10 bar H). The mixture was then treated in 38% HCl / water (pH = 1), resulting in the formation of DFPA as white crystals in a 96% yield after concentration of the mixture.

[0188] Example 6:

[0189] Synthesis of DFPA using Raney nickel (without hydrolysis)

[0190] Example 5 was repeated, but instead of hydrogenating over Pd / C, Raney nickel (Fluka, Cat. No. 83440) was used. The solution was stirred vigorously at room temperature for 6 hours, then filtered (5 cm silica gel column) and concentrated in vacuo until the first crystals were observed on the flask wall. Final crystallization was completed at 4°C. DFPA was isolated in 98% yield, containing only trace amounts of DFPACN.

[0191] Example 7:

[0192] Synthesis of DFPA using Raney nickel and hydrolysis

[0193] Example 6 was repeated, and after filtration, 38% HCl / water was added. The isolated DFPA yield was 96% and the purity was 99.9% (no DFPACN was detected).

[0194] Example 8:

[0195] DFPA was synthesized in one pot using CDFPACN starting from chlorodifluoroacetyl chloride (CDFAC) and Raney nickel for reduction; see Scheme K below.

[0196] Plan K:

[0197]

[0198] Plan K (continued):

[0199]

[0200] In a typical three-necked glass flask equipped with a magnetic stirrer, dropping funnel, and reflux condenser, 100 g (0.88 mol) of ethyl cyanoacetate was added to a CHCN solution of 101.0 g (0.9 mol) of KO-tBu. At room temperature (RT), 134 g (0.9 mol) of CDFAC was added dropwise from the dropping funnel through a deep tube. After the CDFAC addition was complete and stirring continued for an additional hour, 41.5 g (0.9 mol) of MMH (used as a 40% aqueous solution) was added, the solution was placed in ice water, and filtered through a short silica gel column. Raney nickel (Fluka, cat. no. 83440) was added to the filtrate, and the suspension was stirred vigorously at room temperature for 6 hours. It was then filtered again (5 cm silica gel column) and concentrated in vacuo until the first crystals were observed on the flask wall. Crystallization was completed overnight at 4°C, and DFPA was isolated in an 89% yield.

[0201] Example 9:

[0202] Synthesis of 5-fluoro-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid (F-DFPA); see Scheme L below

[0203] Plan L:

[0204]

[0205] Plan L (continued):

[0206]

[0207] In a 250 mL glass flask with a stirrer and a cooler, 50 g (0.262 mol) of ECNDFA prepared in Example 1 and 12.4 g (0.270 mol) of anhydrous MMH were added at room temperature and stirred for 1 hour. S After drying with O₄ (filtering into a stainless steel cylinder with a deep tube made of 1.4571), 29.2 g (0.270 mol) of SF₄ were added from another stainless steel cylinder containing SF₄ (dosed from the cylinder on a balance connected to flexible tubing) and shaken for a further hour. 50 mL of ice water (acidified to pH = 1) was slowly added to the deep tube. Extraction with CH₂Cl₂, concentration, and recrystallization from isopropanol / water gave 38.8 g (76% yield) of F-DFPA as white crystals.

[0208] Note: 1.4571 / AISI 316Ti is an austenitic chromium-nickel stainless steel stabilized with titanium. Special properties: Good corrosion resistance to low levels of hydrochloric acid and organic acids. See for example, https: / / www.materialgrades.com / 1- 4571-stainless-steel-titanium-austenite-material-2241.html .

Claims

1. A method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound having formula (I), wherein Me represents a methyl group, R3 represents hydrogen or a hydroxyl group, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, It is characterized in that The carbonitrile compound of formula (II) reacts with monomethylhydrazine (MMH) of formula (III) to obtain the 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I), wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine, Me-NH-NH2(III), wherein Me represents a methyl group.

2. The method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) according to claim 1, wherein The carbonitrile compound of formula (II) as defined in claim 1, wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, is prepared by the following process: The haloacetic acid halide compound of formula (IV) wherein X represents fluorine or chlorine, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, and a nitrile compound of formula (V) wherein R represents a C1 to C4 alkyl group (straight or branched), Preferably C1 to C2 alkyl (e.g., methyl or ethyl), R1 is oxo (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached, The reaction is carried out in the presence of a base to obtain the carbonitrile compound of formula (II) as defined in claim 1.

3. The method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) according to claim 1, wherein A carbonitrile compound of formula (II) as defined in claim 1, wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (for example, a methyl or ethyl group), R1 is an oxo group (=O), R2 is hydrogen, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, is reacted with monomethylhydrazine (MMH) of formula (III) to obtain a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) as defined in claim 1, wherein Me represents a methyl group, R3 represents a hydroxyl group, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

4. The method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) according to claim 3, wherein: The carbonitrile compound of formula (II) as defined in claim 1, wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, is prepared by the following process: The haloacetic acid halide compound of formula (IV) wherein X represents fluorine or chlorine, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, and a nitrile compound of formula (V) wherein R represents a C1 to C4 alkyl group (straight or branched), Preferably C1 to C2 alkyl (eg, methyl or ethyl), R1 is oxo (=O), R2 is hydrogen, reacting in the presence of a base to obtain a carbonitrile compound of formula (II) as defined in claim 3, wherein R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

5. The method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) according to claim 1, wherein: A carbonitrile compound of formula (II) as defined in claim 1, wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 and R2 together represent a bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, is reacted with a monomethylhydrazine (MMH) of formula (III) to obtain a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I), wherein Me represents a methyl group, R3 represents a hydroxyl group, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

6. The method for preparing a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) according to claim 5, characterized in that: The carbonitrile compound of formula (II) as defined in claim 1, wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 and R2 together represent the bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, is prepared by the following process: The haloacetic acid halide compound of formula (IV) wherein X represents fluorine or chlorine, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, and a nitrile compound of formula (V) wherein R represents a C1 to C4 alkyl group (straight or branched), Preferably C1 to C2 alkyl (e.g., methyl or ethyl), R1 and R2 together represent the bond between the C atoms to which they are attached, reacting in the presence of a base to obtain a carbonitrile compound of formula (II) as defined in claim 5, wherein R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, methyl or ethyl), R1 and R2 together represent the bond between the C atoms to which they are attached, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

7. A method for preparing a carbonitrile compound of formula (II) wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, It is characterized in that The haloacetic acid halide compound of formula (IV) reacts with the nitrile compound of formula (V) in the presence of a base to obtain the carbonitrile compound of formula (II), wherein X represents fluorine or chlorine, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, wherein R represents a C1 to C4 alkyl group (straight or branched), preferably a C1 to C2 alkyl group (e.g., methyl or ethyl), R1 is an oxo group (=O), R2 is hydrogen, or R1 and R2 together represent a bond between the C atoms to which they are attached.

8. The method for preparing a carbonitrile compound of formula (II) as defined in claim 7 according to claim 7, characterized in that A haloacetic acid halide compound of formula (IV) as defined in claim 7 is reacted with a nitrile compound of formula (V) as defined in claim 7 in the presence of a base to obtain the carbonitrile compound of formula (II), wherein in the carbonitrile compound of formula (II) as defined in claim 7, R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, methyl or ethyl), R1 is an oxo group (=O), and R2 is hydrogen, wherein in the nitrile compound of formula (V) as defined in claim 7, R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, methyl or ethyl), R1 is an oxo group (=O), and R2 is hydrogen, wherein in the obtained carbonitrile compound of formula (II), R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, methyl or ethyl), R1 is an oxo group (=O), and R2 is hydrogen.

9. The method for preparing a carbonitrile compound of formula (II) as defined in claim 7 according to claim 7, characterized in that A haloacetic acid halide compound of formula (IV) as defined in claim 7 is reacted with a nitrile compound of formula (V) as defined in claim 7 in the presence of a base to obtain the carbonitrile compound of formula (II), wherein in the carbonitrile compound of formula (II) as defined in claim 7, R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, a methyl or ethyl group), and R1 and R2 together represent the bond between the C atoms to which they are connected, wherein in the nitrile compound of formula (V) as defined in claim 7, R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, a methyl or ethyl group), and R1 and R2 together represent the bond between the C atoms to which they are connected, wherein in the obtained carbonitrile compound of formula (II), R represents a C1 to C4 alkyl group (straight chain or branched), preferably a C1 to C2 alkyl group (for example, a methyl or ethyl group), and R1 and R2 together represent the bond between the C atoms to which they are connected.

10. The compound methyl 2-cyano-4,4-difluoro-3-oxobutanoate.

11. A method for preparing a carboxylic acid derivative of a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I), wherein Me represents a methyl group, R3 represents hydrogen or a hydroxyl group, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, It is characterized in that In the first step, the 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) is prepared by the process defined in any one of claims 1 to 9, In the second step, the carbonitrile group of the compound of formula (I) is hydrolyzed. Thus, a 3-halomethyl-1-methyl-1H-pyrazole-4-carboxylic acid compound having the formula (VI) is obtained, wherein Me represents methyl, R3 represents hydrogen or hydroxy, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

12. A method for preparing a carboxylic acid derivative of a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I), wherein Me represents a methyl group, R3 represents hydrogen or a hydroxyl group, and Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen, It is characterized in that (i) reducing the hydroxyl group (R3) of the compound of formula (I), and (ii) hydrolyzing the carbonitrile group of the compound of formula (I), Thus, a 3-halomethyl-1-methyl-1H-pyrazole-4-carboxylic acid compound having the formula (VI) is obtained, wherein Me represents methyl, Y represents hydrogen, fluorine or chlorine, preferably Y represents hydrogen.

13. A process for preparing a carboxylic acid derivative of a 3-halomethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (I) as defined in claim 11 according to claim 12, wherein in the compound of formula (I), Me represents a methyl group, R3 represents a hydroxyl group, and Y represents hydrogen, It is characterized in that (i) reducing the hydroxyl group (R3) of the compound of formula (I), and (ii) hydrolyzing the carbonitrile group of the compound of formula (I), Thus, a 3-halomethyl-1-methyl-1H-pyrazole-4-carboxylic acid compound having the formula (VIII) is obtained, 14. The compound of formula (X): 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile, 15. A method for preparing the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (X), characterized in that: The compound 5-hydroxy-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (IX) is reacted with a chlorinating agent (e.g., PCl 3 ) to replace the 5-hydroxy group in the compound of formula (VI) with chlorine to obtain the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (X):

16. A method for preparing the compound 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid of formula (VIII), It is characterized by (i) reducing the chloro substituent of the compound of formula (IX) 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile, and (ii) hydrolyzing the carbonitrile group of the compound 5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (IX), Thus, a 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid compound having the formula (VIII) is obtained, 17. The compound of formula (XI): 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile, 18. A method for preparing the compound 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (XI), characterized in that: The 5-hydroxy-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile compound of formula (IX) is reacted with a fluorinating agent (e.g., with SF4, or with other fluorinating agents such as X-tal Fluor-M) to replace the 5-hydroxy group in the compound of formula (IX) with fluorine to obtain the compound of formula (XI) 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile:

19. A method for preparing the compound 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid of formula (XII), It is characterized in that The carbonitrile group in the compound 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonitrile of formula (XII) is hydrolyzed (for example, using HCl / H2O) to obtain a 5-fluoro-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid compound having formula (XII):

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