Process for the production of haloalkyl-substituted pyridine compounds

Abstract

PROCESS FOR THE PREPARATION OF HALOALKYL-SUBSTITUTED PYRIDINE COMPOUNDS The present invention relates to a process for the synthesis of haloalkyl-substituted pyridine compounds, a process for the preparation of pharmaceutically or agriculturally active compounds, preferably herbicidal compounds, and haloalkyl-substituted pyridine compounds.

Description

[Technical Field]

[0001] This application claims priority to European Patent Application Publication No. 20154938.3, filed on 31 January 2020, and the entire contents of this application are incorporated herein by reference for any purpose.

[0002] The present invention relates to a process for synthesizing haloalkyl-substituted pyridine compounds, a process for producing pharmaceutically or agrochemically active compounds, preferably herbicidal compounds, and haloalkyl-substituted pyridine compounds.

[0003] Certain haloalkyl-substituted pyridine compounds are useful, for example, as intermediates for the preparation of various agrochemically active substances. Japanese Patent Publication No. 201725054 discloses, for example, the use of trifluoromethyl-substituted nicotinic acid derivatives for the synthesis of heterocyclic amide compounds. RWLang et al, Helv. Chim. Acta, Vol 71 (1988) pp. 596-601 disclose antihypertensive agents based on certain 6-(trifluoromethyl)-substituted 2(1H)-pyridinones. Japanese Patent Publication No. 2019182864 discloses a method for producing pyridine compounds that requires the use of various solvents and multiple extraction steps, resulting in large amounts of contaminated solvent waste and organically contaminated aqueous waste.

[0004] The object of the present invention is to provide an efficient process for producing specific haloalkyl-substituted pyridine compounds, which starts from readily available starting materials, avoids waste and multiple purification steps, and enables good yield and product purity.

[0005] The present invention therefore relates to a process for producing a compound of formula (IV), comprising step (a) reacting a compound of formula (I) with a compound of formula (II) to form an intermediate product (III). [ka] (In the formula, R1 is selected from the group of C1-C4 alkyl groups.) which comprises step (a) carried out in the presence of a base and in the absence of a solvent, step (b) in which the intermediate product (III) is cyclized to the compound of formula (IV) by addition of an acid

Chemical Formula

[0006] Another object of the present invention is a process for purifying a compound of formula (IV), wherein the compound of formula (IV) containing impurities is reacted with a basic metal salt to form a product of formula (V), step (c)

Chemical Formula

[0007] The present invention further relates to the compound of formula (V).

[0008] The residue R 1 to R 4 are defined below.

[0009] In the context of the present invention, the singular forms are also intended to include the plural. All aspects and embodiments of the present invention may be combined. In the context of the present invention, the term "comprising" is intended to include the meanings of "consisting of" and "consisting essentially of". The endpoints of ranges are also included in the present disclosure, for example, a temperature range of 20°C to 50°C includes the values 20°C and 50°C. When a double bond is specifically represented by E / Z geometry, this is also intended to mean other geometric forms and mixtures thereof. Compounds having one or more stereocenters are intended to include all mixtures of stereoisomers, including stereochemically pure isomers. It should be noted that the compound of formula (IV) can also be expressed in its enol form as shown below. When the keto form is expressed, this includes the enol form.

Chem.

[0010] The compound of formula (III) likewise includes the keto form when depicted in its enol form.

[0011] In a first aspect, the present invention relates to a process for the preparation of a compound of formula (IV), comprising step (a) of reacting a compound of formula (I) with a compound of formula (II) to form an intermediate product (III)

Chem.

Chem.

[0012] R 1 is selected from the group of C1-C4 alkyl groups, including all isomers of propyl and butyl. Preferably, R 1 is methyl or ethyl, most preferably R 1 is ethyl.

[0013] R 2 is -CN or -C(O)NH2, with -CN being preferred.

[0014] R 3 is selected from the group consisting of CFH2, CClF2, CF2H, CF3 and CCl2F. R 3 is preferably CF3.

[0015] R 4 is selected from the group of C1-C4 alkyl groups, including all isomers of propyl and butyl. Preferably, R 4is methyl, ethyl, or n-butyl, most preferably R 4 It is ethyl.

[0016] In the most preferred embodiment of the process including steps (a) and (b), R 1 and R 4 It is ethyl, and R 3 is CF3, and R 2 It is -CN.

[0017] Step (a) is carried out in the presence of a base. The type of base is not particularly limited and can be selected from the group consisting of, for example, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride, sodium bicarbonate, sodium carbonate, potassium carbonate, ammonia, triethylamine, diisopropylethylamine, pyridine, and 4-(dimethylamino)pyridine. More preferred bases are triethylamine and diisopropylethylamine. Diisopropylethylamine is more easily recycled. The amount of base in step (a) is generally 0.7 to 2 molar equivalents, preferably 0.9 to 1.2 molar equivalents, and most preferably 1 to 1.05 molar equivalents, relative to the compound of formula (II). The base is defined as not being a solvent in the sense of the present invention.

[0018] Step (a) is generally carried out at a temperature of 0°C to 90°C, more preferably 10°C to 80°C, and most preferably 20°C to 70°C.

[0019] The addition time in step (a), calculated from the start of the addition of the last starting material / reagent, is generally 5 minutes to 5 hours, more preferably 10 minutes to 2 hours, and more preferably 30 to 60 minutes. The reaction time in step (a), calculated from the end of the addition of the last starting material / reagent, is generally 5 minutes to 5 hours, more preferably 10 minutes to 2 hours, and more preferably 30 to 60 minutes.

[0020] The order in which the starting materials and reactants are added to step (a) is not particularly limited. However, it is preferable to mix the base with the compound of formula (I), and then add the compound of formula (II) to the mixture of the base and the compound of formula (II). This order of addition can have a favorable effect on the reaction yield and the intermediate product mixture, and therefore on the impurity profile of the final product.

[0021] Step (a) is carried out in the absence of a solvent. "Absence of solvent" is intended to mean that no solvent is added to step (a) at all, which eliminates the possibility of actively adding a solvent to step (a). The compounds of formulas (I) and (II), as well as the bases, do not constitute "solvents" in the sense of the present invention. In step (a), R 4 It is observed that OH is released. 4 The liberation of OH is not inconsistent with the term “absence of solvent.” The inventors note that the absence of solvent in step (a) generally improves the reaction in step (a) in the sense that the reaction proceeds with fewer by-products and a higher turnover of starting materials. Additional solvents in step (a), such as aromatic or aliphatic hydrocarbons, dimethylformamide, acetonitrile, etc., would also result in an unfavorable mixture of solvents in workup and waste treatment.

[0022] Step (a) is generally expressed by equation (III) [ka] This yields a compound that can also be represented in its keto form, as described above. [ka]

[0023] It should be noted that the compound of formula (III) can also be represented in its salt form (IIIa), which is formed when the compound of formula (I) is deprotonated and added to the double bond of (II), nominally forming (III) or (IIIa). [ka]

[0024] Formally, (IIIa) is Et3NH derived from the base used in step (a). + Cation B such as + This also includes. The above expressions of compounds of formula (III) are interchangeable and always encompass when one formula related to (III) is expressed.

[0025] The process for producing the compound of formula (IV), including step (a), further includes step (b), in which the intermediate product (III) is cyclized to the compound of formula (IV) by the addition of an acid. The type of acid is not particularly limited and can be selected from the group consisting of, for example, HCl, HBr, H2SO4, CF3COOH, CF3SO3H, and CH3COOH or any combination thereof. Each of the above can be used as an aqueous solution or neat, with aqueous solutions being preferred. HCl and CF3SO3H are preferred, with HCl being the most preferred. The direction of addition in step (b) is not particularly limited, but generally, it is preferred to add the acid to the mixture obtained in step (a). The amount of acid used in step (b) is generally 1 to 3 molar equivalents relative to the compound of formula (II). Preferably, the amount of acid used in step (b) is 1 to 2, more preferably 1.1 to 1.3 molar equivalents relative to the compound of formula (II).

[0026] Step (b) is generally carried out at a temperature of 0°C to 100°C, more preferably 10°C to 90°C, and most preferably 20°C to 80°C.

[0027] The addition time in step (b), calculated from the start of the addition of the last starting material / reagent, is generally 5 minutes to 5 hours, more preferably 10 minutes to 2 hours, and more preferably 30 to 60 minutes. The reaction time in step (b), calculated from the end of the addition of the last starting material / reagent, is generally 5 minutes to 5 hours, more preferably 10 minutes to 2 hours, and more preferably 30 to 60 minutes.

[0028] In one embodiment of the process for producing compound (IV), formula R 4 The OH solvent is added to the reaction mixture obtained in step (a) before the addition of the acid in step (b). The inventors have found that this addition generally improves the overall yield and purity of compound (IV) in the sense that the reaction proceeds with fewer by-products, particularly with less polymerization and higher intermediate turnover. Formula R 4 The solvent for OH is preferably R 4 However, R such that is present in the compound of formula (II) 4 Solvent R is selected to correspond to step (b). 4 The amount of OH can be selected from 0.5 to 10 volume equivalents relative to the volume of the reaction mixture obtained in step (a). Preferably, R 4 The amount of OH is 1 to 5 volume equivalents, more preferably 1 to 2 volume equivalents, relative to the volume of the reaction mixture obtained in step (a).

[0029] The product of this process, the compound of formula (IV), can be suitably recovered after step (b) by methods known to those skilled in the art, for example, by removal of volatile substances by distillation. Compound (IV) can also be isolated by pouring the reaction mixture obtained in step (b) into water at a temperature of 0°C to 30°C, preferably 0°C to 20°C, such as ice water. The compound of formula (IV) can then often be precipitated, filtered, washed and dried. In another embodiment, the compound of formula (IV) can also be isolated after step (b) by adding water at a temperature of 20°C to 30°C, preferably 25°C to 30°C, which often results in phase separation, with the lower phase containing the crude product. Such a crude product can be used directly for further downstream processes, such as a process including step (c), which is further described below. The compound of formula (IV) can also be subjected to repeated crystallization as needed. Any of the above recovery steps can be combined.

[0030] Another object of the present invention is a process for purifying a compound of formula (IV), comprising the step (c) in which the compound of formula (IV) containing impurities is reacted with a basic metal salt to form a product of formula (V). [ka] (d) a step in which the compound of formula (V) is isolated as a solid compound, and Step (e) in which the compound of formula (V) is contacted with a base to obtain the purified compound of formula (IV). This process includes [something].

[0031] In steps (c), (d), and (e), R 1 and R 3 This is defined in the general and preferred definitions of processes (a) and (b) as described above. Specifically, R 3 Preferably, R is CF3. 1 It is preferably methyl or ethyl. M is an alkali or alkaline earth metal cation, and alkali metals are preferred, Na + and K + This is the most preferable. Depending on the number of charges of M (1+ or 2+), there are nominally one or two anionic structures in equation (V) for each M.

[0032] The designations (c), (d), and (e) do not imply that steps (a) and (b) of the previously described process must be performed before steps (c) to (e); the process comprising steps (c) to (e) is an independent process. However, in one embodiment, a combination of steps (a) to (e) is described.

[0033] The basic metal salt to which the compound of formula (IV) containing impurities is reacted in step (c) to form the product of formula (V) is a basic alkali metal salt. "Basic" is intended to mean that when dissolved, the salt forms an aqueous solution with a basic pH. Suitable basic metal salts are not particularly limited. They can be selected from the group consisting of hydroxides, oxides, carbonates, bicarbonates, acetates, alcoholates, trifluoroacetates, hydrides and phosphates of alkali metals and alkaline earth metals, with alkali metals being preferred. NaOH, NaOMe, KOMe, NaOEt, KOEt, KOH, Na2CO3, NaHCO3, K2CO3 and KHCO3 are particularly preferred, with NaHCO3, NaOEt and Na2CO3 being most preferred.

[0034] The amount of basic metal salt used in step (c) is generally 1 to 3 molar equivalents relative to the compound of formula (IV). Preferably, the amount of acid used in step (c) is 1 to 2, more preferably 1.1 to 1.3 molar equivalents relative to the compound of formula (IV).

[0035] Step (c) is generally carried out at a temperature of -10°C to 80°C, more preferably 10°C to 70°C, and most preferably 20°C to 50°C.

[0036] The addition time in step (c), calculated from the start of the addition of the last starting material / reagent, is generally 5 minutes to 5 hours, more preferably 10 minutes to 2 hours, and more preferably 30 to 60 minutes. The reaction time in step (c), calculated from the end of the addition of the last starting material / reagent, is generally 5 minutes to 5 hours, more preferably 10 minutes to 2 hours, and more preferably 30 to 60 minutes.

[0037] Step (c) is often carried out in a solvent, and a protic solvent is preferred. The presence of a protic solvent is thought to facilitate the formation of the compound of formula (V). The protic solvent is not particularly limited, but can be selected from, for example, alcohols, dimethylformamide, and acetonitrile. Alcohol is the most preferred solvent. The protic solvent is often used not only to dissolve or suspend the compound of formula (IV) containing impurities, but also to facilitate the addition of a basic metal salt, which is applied as a solution in the protic solvent. In another preferred embodiment, when the basic metal salt is almost insoluble, for example Na2CO3, it may be preferable to apply the basic metal salt in step (c) as a solid. The basic metal salt can also be applied, for example, as a slurry in the protic solvent. When alcohol is used as the solvent in step (c), the alcohol is preferably of formula R 1 Corresponding to OH, here, R 1 R in equation (IV) 1 This corresponds to the following. In many cases, the presence of water in process (c) has been observed to be detrimental. Water is due to the potential solubility of the intermediate in water, R 1 This can result in hydrolysis of the group containing the water, which can lead to the formation of additional by-products and loss of yield. Therefore, in a preferred embodiment, the water content in the reaction mixture in step (c) is less than 10% by weight (with respect to the weight of the reaction mixture in step (c)), preferably less than 5% by weight, and more preferably less than 1% by weight. The water content is measured according to a preferred method known to those skilled in the art, for example, Karl Fischer titration. The term “less than” includes the lower limit of the detection limit of the selected method, in which case the water content is indicated by “0” (zero).

[0038] In one embodiment, the amount of solvent in step (c) is selected from 0.5 to 10 volume equivalents relative to the volume of the compound of formula (IV) containing impurities. Preferably, the amount of protic solvent used is 1 to 5 volume equivalents, more preferably 3 to 4 volume equivalents, relative to the volume of the compound of formula (IV) containing impurities. The selection of the amount of solvent in step (c) can facilitate step (d).

[0039] In step (d), the compound of formula (V) is isolated as a solid compound. Often, the compound of formula (V) has already precipitated completely or partially in step (c), depending on the temperature and any solvent present. In step (d), the reaction mixture obtained from step (c) is preferably heated to a temperature of -20°C to 30°C, preferably -15°C to 10°C. At such temperatures, the recovery of the compound of formula (V) as a solid compound is optimized while any impurities generally remain in the solution of the fluid present, e.g., the solvent used in step (c). The compound of formula (V) is then recovered as a solid, e.g., by filtration, decantation, or spinning. The recovered compound of formula (V) can be washed with, for example, aprotic or protic solvents, but often high purity of the compound of formula (V) can be achieved without further washing. The recovered compound of formula (V) can be dried or used without drying in step (e). When the compound of formula (V) is dried, methods available to those skilled in the art include drying by airflow, in a vacuum, by air suction, by heating, or by applying a fluid in which compound (V) does not dissolve but forms an azeotrope with water and is subsequently removed by distillation.

[0040] The process for purifying the compound of formula (IV) further comprises step (e), in which the compound of formula (V) is contacted with an acid to obtain the purified compound of formula (IV). The type of acid is not particularly limited and can be selected from the group consisting of, for example, HCl, HBr, H2SO4, CF3COOH, CF3SO3H, and CH3COOH or any combination thereof. Each of the above can be used as an aqueous solution or neat, with aqueous solutions being preferred. HCl and H2SO4 are preferred, with HCl being the most preferred. The amount of acid used in step (e) is generally selected so as to reach a pH of 1 to 5, preferably 1.5 to 2.

[0041] Step (e) is generally carried out at a temperature of 0°C to 50°C, more preferably 0°C to 40°C, and most preferably 5°C to 20°C. Temperatures such as those disclosed support the effective isolation of the product.

[0042] The addition time in step (e), calculated from the start of the addition of the last starting material / reagent, is generally 5 minutes to 5 hours, more preferably 10 minutes to 2 hours, and more preferably 30 to 60 minutes. The reaction time in step (a), calculated from the end of the addition of the last starting material / reagent, is generally 5 minutes to 5 hours, more preferably 10 minutes to 2 hours, and more preferably 30 to 60 minutes.

[0043] Step (e) is generally carried out in the presence of a solvent which can be selected from the group of protic and aprotic solvents, preferably a protic solvent. Preferred protic solvents are the same as those defined with respect to step (c). Most preferably, step (e) is carried out in the presence of water. Although aqueous acids are often used in step (e), an additional protic solvent, preferably water, is usually advantageous to suspend the compound of formula (V) before the addition of the acid. A preferred aprotic solvent is toluene. According to one embodiment, the compound of formula (IV) is used in a subsequent step, such as a process for producing a pharmaceutically or agrochemically active compound, preferably a herbicide, without further isolation in the solvent in which step (e) was carried out. The compound of formula (IV) is therefore not isolated from the solvent before further treatment. In a preferred embodiment according to this embodiment, the solvent is toluene.

[0044] According to another embodiment, after the conversion of the compound of formula (V) to (IV) in step (e) is completed, the compound of formula (IV) is recovered as a solid by, for example, filtration, decantation, or spinning. The recovered compound of formula (IV) can be washed with, for example, an aprotic or protic solvent. Since salts from steps (c) to (e) may be present in the recovered product, it may be preferable to perform one or more washing steps after the recovery of the compound of formula (V). Washing is preferably performed with water. The end of washing can be advantageously monitored, for example, by measuring the alkali or alkaline earth metal content, for example sodium, in the product by ion-pair chromatography. It may be preferable to reach a metal content of 500 ppm or less, more preferably 300 ppm or less, and most preferably 100 ppm or less. The recovered compound of formula (IV) can be dried by methods available to those skilled in the art, such as by airflow, in a vacuum, by air suction, by heating (preferably remaining below the melting point), or by applying a fluid in which compound (IV) does not dissolve but which forms an azeotrope with water and is subsequently removed by distillation. If step (e) is carried out in an aprotic solvent, preferably toluene, drying can also be carried out by distillation of all fractions of the solvent, where the solvent forms an azeotrope with water, thereby drying the product. In another embodiment, if step (e) is carried out in a solvent, preferably an aprotic solvent such as toluene, drying can also be carried out by adding a drying agent known to those skilled in the art, such as sodium sulfate.

[0045] In a process for purifying a compound of formula (IV), the process includes steps (c) to (e), and is not limited to the process by which a compound of formula (IV) containing impurities is obtained. Preferred processes are described, for example, in International Publication No. 2010037688, U.S. Patent Application Publication No. 20170348313, U.S. Patent Application Publication No. 2006276655, Japanese Patent Publication No. 201725054, Japanese Patent Publication No. 201876298, European Patent No. 526732 and European Patent No. 0522392, all of which are incorporated herein by reference for all purposes.

[0046] In one embodiment of the present invention, a process for producing a compound of formula (IV), comprising steps (a) and (b), also comprises steps (c) to (e) according to the present invention.

[0047] The present invention relates to formula (V) [ka] (In the formula, R 1 , R 3 (and M is defined in the general and preferred definitions of any of the above processes (a) to (e)) It also relates to the compounds of R. 3 Preferably, it is CF3. 1 is preferably methyl or ethyl, with ethyl being preferred. M is preferably Na + or K + And Na + This is preferred. In preferred embodiments, the compound of formula (V) is its isolated solid form. In particular, the isolated, solid form of the compound of formula (V) is a useful intermediate in the process of obtaining the compound of formula (IV), especially the purified compound of formula (IV). The compound of formula (V) can also be used for further downstream reactions at the 2-position of the pyridine ring, for example, for ether, halide (such as chloride or bromide) or ester formation from the compound of formula (V) directly.

[0048] Another object of the present invention is a process for producing a pharmaceutically or agrochemically active compound, preferably a herbicidal compound, comprising steps (a) and (b), or steps (c) to (e), or a process comprising steps (a) to (e). Exemplary processes for producing a pharmaceutically or agrochemically active compound from a compound of formula (IV) are disclosed, for example, in U.S. Patent Application Publication No. 20170348313, Japanese Patent Publication No. 201725054, and Japanese Patent Publication No. 201876298.

[0049] The process according to the present invention starts from readily available raw materials, avoids waste and multiple steps for purification, and enables good yield and product purity. For example, the isolation of compound (V) avoids waste and multiple steps in the process of producing compound (IV) or the purification of compound (IV). When compound (V) is subjected to an extraction step for purification in the presence of water, it tends to decompose into the free acid of compound (IV), resulting in yield loss, higher waste, and acid as an impurity that can be difficult to separate. Performing extraction at low temperatures can help control such decomposition, but performing extraction at low temperatures on an industrial scale is even more disadvantageous than extraction at room temperature. Low-temperature extraction can also lead to larger amounts of solvent, such as water, to optimize the purity of the intended product. In general, the relatively simple recovery of the solid product according to the present invention is easier to handle than subjecting compound (V) to an extraction step in purification. For the purification of the compound of formula (IV), column chromatography, as reported in Japanese Patent Publication No. 201725054, is generally disadvantageous on an industrial scale due to solvent consumption, contaminated column material, and overall handling. Crystallization and vacuum distillation for product purification were also tested by the applicant, but in some cases it was found that various impurities could not be efficiently removed by such techniques. Therefore, the process according to the present invention, comprising steps (a) and (b), steps (c) to (e), or steps (a) to (e), is particularly advantageous on an industrial scale.

[0050] If any disclosure of a patent, patent application, or publication incorporated herein by reference conflicts with the description of this application to such an extent that it could obscure the terminology, the description herein shall prevail.

[0051] The following embodiments are intended to further illustrate the present invention without the intention of limiting its scope.

[0052] The starting materials are either commercially available or can be manufactured according to processes disclosed in the prior art.

[0053] Example 1: Step (a) using 2-ethyl cyanoethyl and 4-ethoxy-1,1,1-trifluorobuta-3-en-2-one (ETFBO) in the presence of triethylamine. [ka] Ethyl cyanoethyl acetate (67.3 g, 0.59 mol, 1 eq) was mixed with 63.2 g (1.05 eq, 0.63 mol) of triethylamine at room temperature. ETFBO (100 g, 0.59 mol, 1 eq) was added under stirring. An exothermic reaction was observed, during which the temperature reached 40°C. After the addition, the reaction temperature was maintained at 50°C for 1 hour. The crude mixture was then... 1 1H-NMR and GC demonstrated complete conversion of ETFBO.

[0054] Example 2: Step (b) Cyclization of the product from Example 1 by adding acid [ka] The reaction product from Example 1 was diluted with 200 g of EtOH. The mixture was heated to 74°C. 81.3 g of 32% HCl (1.2 eq, 70.1 mL) was gradually added. The reaction temperature was maintained at 74°C to 85°C during the addition. After the addition was complete, the reaction mixture was stirred at 78-80°C for 90 minutes. Analysis of the crude mixture ( 1 ¹H-NMR showed complete conversion of the starting material.

[0055] Example 3: Conversion of the product of Example 2 to a compound of general formula (V) [ka] The mixture obtained in Example 2 was cooled to room temperature and then poured into ice water (800 ml). The organic phase solidified and was filtered off. The filter cake was washed twice with cold water. The filter cake was suspended in 400 ml of ethanol. 37.52 g of Na2CO3 (0.6 eq) was added under stirring. The fine suspension was heated to 55°C for 30 minutes. CO2 evolution was observed during this time. The mixture was cooled to -10°C. The suspension was filtered and the filter cake was washed with a small amount of cold ethanol until it became colorless. The filter cake was partially dried.

[0056] Example 4: Conversion of the product from Example 3 to ETFPMOC The raw materials obtained in Example 3 were mixed with 800 mL of ice water. 81.3 g of 32% HCl (1.2 eq) was added; the pH was reached to 1-2. Some foaming was observed. The mixture was stirred for 20 minutes under ice cooling. The resulting suspension was filtered, and the granular solid product was washed with cold water (100 mL + 4 × 50 mL). The obtained solid was dried overnight in an airflow. The product had a purity of 99% and was recovered in a 61% yield (84.7 g), calculated from Example 1.

[0057] Example 5: Step (a) and subsequent step (b) using 2-ethyl cyanoethyl and 4-ethoxy-1,1,1-trifluorobuta-3-en-2-one (ETFBO) in the presence of diisopropylethylamine Ethyl cyanoethyl acetate (18.82 g, 148.7 mmol, 1 eq) was mixed with 20.2 g (1.05 eq, 156.1 mmol) of diisopropylethylamine at room temperature. ETFBO (25 g, 148.7 mmol, 1 eq) was added over 15 minutes with stirring. An exothermic reaction was observed, during which the temperature reached 50°C, which was maintained at 40-50°C by adjusting the addition rate. After addition, the reaction temperature was maintained at 50°C for 1.5 hours. Crude mixture 11H-NMR and GC showed complete conversion of ETFBO. 108.44 g of HCl (32%) was added at 50°C, and the resulting mixture was stirred at 50°C for 1.5 hours. The reaction mixture was then cooled with ice, and a solid was formed. 1 The reaction was checked by 1H-NMR. The crude product contained approximately 80% by weight of the product. The filtrate was treated with 2M aqueous NaOH until the two phases separated. Approximately 70% of the diisopropylethylamine could be recovered after phase separation.

[0058] Example 6: Repeat Examples 1 and 2 by replacing ethyl cyanoethyl with methylmalonamide.

[0059] Example 7: Starting with the raw materials obtained from Example 6, the steps in Examples 3 and 4 were repeated.

Claims

1. A method for producing a compound of formula (IV), Step (a) of reacting the compound of formula (I) with the compound of formula (II) to form an intermediate product (III). 【Chemistry 1】 (In the formula, R １ C １ ~C ４ Selected from the group of alkyl groups, R ２ is -CN or -C(O)NH ２ And, R ３ is CFH ２ , CClF ２ , CF ２ H, CF ３ and CCl ２ F, selected from the group consisting of R ４ C １ ~C ４ (Selected from the group of alkyl groups) (a) a step carried out in the presence of a base and in the absence of a solvent; (b) The intermediate product (III) is cyclized to the compound of formula (IV) by the addition of an acid; 【Chemistry 2】 (c) A compound of formula (IV) containing impurities is reacted with a basic metal salt to form a product of formula (V). 【Transformation 3】 (In the formula, R １ C １ ~C ４ Selected from the group of alkyl groups, R ３ CFH ２ , CClF ２ CF ２ H, CF ３ and CCl ２ Selected from the group consisting of F, M is an alkaline or alkaline earth group cation); (d) a step in which the compound of formula (V) is isolated as a solid compound; and (e) A step in which the compound of formula (V) is contacted with an acid to obtain a purified compound of formula (IV). Includes, In step (b), before adding the acid, formula R ４ A method in which the OH solvent is added to the reaction mixture obtained by step (a).

2. R １ The method according to claim 1, wherein is methyl or ethyl.

3. R ２ The method according to claim 1 or 2, wherein is -CN.

4. R ３ CF ３ The method according to any one of claims 1 to 3.

5. R ４ The method according to any one of claims 1 to 4, wherein is methyl, ethyl, or n-butyl.

6. M is Na ＋ or K ＋ The method according to any one of claims 1 to 5.

7. The method according to any one of claims 1 to 6, wherein step (c) is carried out at a temperature of -10°C to 80°C.

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