JP2023512000A - Process for the production of haloalkyl-substituted pyridine compounds - Google Patents

Abstract

A process for the manufacture of haloalkyl-substituted pyridine compounds. The present invention relates to a process for synthesizing haloalkyl-substituted pyridine compounds, a process for producing pharmaceutically or agriculturally active compounds, preferably herbicidal compounds, and haloalkyl-substituted pyridine compounds. [Selection figure] None

Description

This application claims priority from European Patent Application Publication No. 20154938.3, filed January 31, 2020, the entire contents of which are incorporated herein by reference for all purposes. be done.

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

Certain Haloalkyl-Substituted Pyridine Compounds are useful, for example, as intermediates for the preparation of a variety of agriculturally active substances. JP 201725054 discloses, for example, the use of trifluoromethyl-substituted nicotinic acid derivatives for the synthesis of heterocyclic amide compounds. R. W. Lang et al, Helv. Chim. Acta, Vol 71 (1988) p. 596-601 disclose certain 6-(trifluoromethyl)-substituted 2(1H)-pyridinones-based antihypertensive agents. JP2019182864A discloses a process for the preparation of pyridine compounds that requires the use of various solvents and multiple extraction steps, resulting in large wastes of contaminated solvents and aqueous wastes contaminated with organic matter. ing.

An efficient process for producing certain haloalkyl-substituted pyridine compounds that starts from readily available starting materials, avoids waste and multiple steps for purification, and produces good yields and products It is an object of the present invention to provide a process that allows for purity.

（式中、Ｒ１は、Ｃ１～Ｃ４アルキル基の群から選択される）
であって、塩基の存在下及び溶媒の不在下で行われる工程（ａ）を含み、
中間生成物（ＩＩＩ）が酸の添加によって式（ＩＶ）の化合物に環化される工程（ｂ）

を更に含むプロセスに関する。 The present invention therefore provides a process for the preparation of a compound of formula (IV), comprising the step (a) of reacting a compound of formula (I) with a compound of formula (II) to form intermediate product (III) )

(wherein R1 is selected from the group of C1-C4 alkyl groups)
comprising step (a) carried out in the presence of a base and in the absence of a solvent;
Step (b) in which the intermediate (III) is cyclized to the compound of formula (IV) by addition of acid

relates to a process further comprising

式（Ｖ）の化合物が固体化合物として単離される工程（ｄ）、及び
式（Ｖ）の化合物が、式（ＩＶ）の精製化合物を得るために酸と接触される工程（ｅ）
を含むプロセスである。 Another object of the present invention is a process for the purification of the compound of formula (IV), wherein the compound of formula (IV) containing impurities is reacted with a basic metal salt to form the product of formula (V) step (c)

Step (d) 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 an acid to obtain the purified compound of formula (IV)
It is a process that includes

The invention further relates to compounds of formula (V).

Residues R ¹ -R ⁴ are defined below.

In the context of the present invention, singular forms are also intended to include plural forms. All aspects and embodiments of the invention are combinable. In the context of the present invention, the term "comprising" is intended to include the meanings of "consisting of" and "consisting essentially of". Range endpoints are also included in this disclosure, eg, a temperature range of 20°C to 50°C includes the values 20°C and 50°C. Where double bonds are specifically represented in E/Z geometry, this is intended to mean also other geometries and mixtures thereof. Compounds with one or more stereocenters are intended to include all mixtures of stereoisomers, including stereochemically pure isomers. Note that compounds of formula (IV) can also be represented in their enol form as shown below. Where the keto form is expressed this includes the enol form.

Compounds of formula (III) also include the keto form when drawn in its enol form.

（式中、Ｒ１は、Ｃ１～Ｃ４アルキル基の群から選択される）
であって、塩基の存在下及び溶媒の不在下で行われる工程（ａ）を含み、
中間生成物（ＩＩＩ）が酸の添加によって式（ＩＶ）の化合物に環化される工程（ｂ）

を更に含むプロセスに関する。 In a first aspect, the present invention is a process for the preparation of a compound of formula (IV) comprising reacting a compound of formula (I) with a compound of formula (II) to form intermediate product (III) step (a)

(wherein R1 is selected from the group of C1-C4 alkyl groups)
comprising step (a) carried out in the presence of a base and in the absence of a solvent;
Step (b) in which the intermediate (III) is cyclized to the compound of formula (IV) by addition of acid

relates to a process further comprising

R ¹ is selected from the group of C ₁ -C ₄ alkyl groups including all isomers of propyl and butyl. Preferably R ¹ is methyl or ethyl, most preferably R ¹ is ethyl.

R ² is -CN or -C(O)NH ₂ , with -CN being preferred.

^R3 is selected from the group consisting of _CFH2 , _CClF2 , _CF2H , _CF3 and _CCl2F . ^R3 is preferably _CF3 .

R ⁴ is selected from the group of C ₁ -C ₄ alkyl groups including all isomers of propyl and butyl. Preferably R ⁴ is methyl, ethyl or n-butyl, most preferably R ⁴ is ethyl.

In the most preferred embodiment of the process comprising steps (a) and (b), R ¹ and R ⁴ are ethyl, R ³ is CF ₃ and R ² is -CN.

Step (a) is performed in the presence of a base. The type of base is not particularly limited, and examples include sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, ammonia, triethylamine, diisopropylethylamine, pyridine and 4-(dimethyl amino) 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, most preferably 1 to 1.05 molar relative to the compound of formula (II) Equivalent. A base is defined as not a solvent in the sense of the present invention.

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

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

The order in which the starting materials and reactants are added to step (a) is not particularly limited. However, it is preferred to combine the base with the compound of formula (I) and then add the compound of formula (II) to the mixture of base and compound of formula (II). This order of addition can also favorably affect the yield of the reaction and the intermediate product mixture and hence the impurity profile of the final product.

Step (a) is performed in the absence of solvent. "No solvent" is intended to mean that no solvent is added to step (a), which precludes active addition of 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 invention. In step (a) it is observed that R ⁴ OH is liberated. The liberation of R ⁴ OH is consistent with the term "absence of solvent". We note that the absence of solvent in step (a) generally improves the reaction of step (a) in the sense that the reaction proceeds with fewer by-products and higher turnover of starting materials. ing. Additional solvents in step (a), such as aromatic or aliphatic hydrocarbons, dimethylformamide, acetonitrile, etc., will also result in an unfavorable mixture of solvents in workup and waste disposal.

の化合物をもたらし、それは、上で記載されたように、そのケト形でも表すことができる。

Step (a) generally comprises formula (III)

which can also be represented in its keto form as described above.

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

Formally, (IIIa) also includes cations B ⁺ such as Et ₃ NH ⁺ derived from the base used in step (a). The above representations of compounds of formula (III) are interchangeable and encompassed whenever one formula relating to (III) is represented.

The process of making the compound of formula (IV) comprising step (a) further comprises step (b) in which the intermediate product (III) is cyclized to the compound of formula (IV) by addition of 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 foregoing can be used as an aqueous solution or neat, with aqueous solutions being preferred. HCl and CF ₃ SO ₃ H are preferred, with HCl being most preferred. The direction of addition for 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 1-3 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).

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

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

In one aspect of the process for the preparation of compound (IV), a solvent of formula R ⁴ OH is added to the reaction mixture obtained by step (a) prior to the addition of acid in step (b). We believe that this addition improves the overall yield and purity of compound (IV) in the sense that the reaction generally proceeds with fewer by-products, especially less polymerization and higher turnover of intermediates. I found out. Solvents of formula R ⁴ OH are preferably selected such that R ⁴ corresponds to R ⁴ as present in compounds of formula (II). The amount of solvent R ⁴ OH added in step (b) can be selected from 0.5 to 10 volume equivalents relative to the volume of the reaction mixture obtained by step (a). Preferably, the amount of R ⁴ OH is 1-5 volume equivalents, more preferably 1-2 volume equivalents relative to the volume of the reaction mixture obtained by step (a).

The product of the process, a compound of formula (IV), can be conveniently recovered after step (b) by methods known to those skilled in the art, for example by removal of volatiles by distillation. Compound (IV) can also be isolated by pouring the reaction mixture obtained by 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) is treated with water at a temperature of 20°C to 30°C, preferably 25°C to 30°C, often resulting in phase separation, the lower phase comprising the crude product. It can also be isolated after step (b) by Such crude products can be used directly for further downstream processes, for example those processes comprising step (c) further described below. Compounds of formula (IV) may optionally be subjected to repeated crystallizations. Any of the above recovery steps can be combined.

式（Ｖ）の化合物が固体化合物として単離される工程（ｄ）、及び
式（Ｖ）の化合物が、式（ＩＶ）の精製化合物を得るために塩基と接触される工程（ｅ）
を含むプロセスである。 Another object of the present invention is a process for the purification of the compound of formula (IV), wherein the compound of formula (IV) containing impurities is reacted with a basic metal salt to form the product of formula (V) step (c)

Step (d) 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)
It is a process that includes

In steps (c), (d) and (e) R ¹ and R ³ are defined in their general and preferred definitions as described above for steps (a) and (b). Specifically, R ³ is preferably CF ₃ . R ¹ is also preferably methyl or ethyl. M is a cation from the group of alkali or alkaline earth metals, preferably alkali metals, most preferably Na ⁺ and K ⁺ . There are nominally one or two anionic structures of formula (V) per M, depending on the number of charges on M (1+ or 2+).

The designations (c), (d) and (e) imply that steps (a) and (b) of the previously described process must occur prior to steps (c)-(e). the process including steps (c)-(e) is an independent process. However, in one embodiment, a combination of steps (a)-(e) is described.

The basic metal salt with 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 the salt forms an aqueous solution of basic pH when dissolved. Suitable basic metal salts are not particularly limited. They are for example selected from the group consisting of hydroxides, oxides, carbonates, bicarbonates, acetates, alcoholates, trifluoroacetates, hydrides and phosphates of alkali metals and alkaline earth metals. Alkali metals are preferred. NaOH, NaOMe, _KOMe , NaOEt, KOEt, _KOH , _Na2CO3 , NaHCO3, _K2CO3 and _KHCO3 are particularly preferred, NaHCO3 _{, NaOEt} and _Na2CO3 being most _preferred .

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

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

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

Step (c) is often carried out in a solvent, with protic solvents being preferred. The presence of protic solvent is believed to facilitate the formation of compounds of formula (V). The protic solvent is not particularly limited and can be selected from, for example, alcohols, dimethylformamide and acetonitrile. Alcohol is the most preferred solvent. Protic solvents are often used not only to dissolve or suspend the compound of formula (IV) containing impurities, but also to facilitate the addition of the basic metal salt, which is , applied as a solution in a protic solvent. In another embodiment, which is preferred when the basic metal salt is sparingly soluble, eg Na ₂ CO ₃ , it may be preferred that the basic metal salt is applied in step (c) as a solid. Basic metal salts can also be applied, for example, as a slurry in a protic solvent. When an alcohol is used as solvent in step (c), the alcohol preferably corresponds to formula R ¹ OH, where R ¹ corresponds to R ¹ in formula (IV). In many cases the presence of water in step (c) has been observed to be detrimental. Water can lead to hydrolysis of groups containing R ¹ due to potential solubility of intermediates in water, leading to 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 lower than 10% by weight (relative to the weight of the reaction mixture in step (c)), preferably lower than 5% by weight, and more preferably lower than 1% by weight. The water content is measured according to suitable methods known to those skilled in the art, such as Karl Fischer titration. The term "lower than" includes the detection limit of the selected method as the lower limit, where water content is indicated by "0" (zero).

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

In step (d) the compound of formula (V) is isolated as a solid compound. In many cases, the compound of formula (V) will already precipitate completely or partially during step (c), depending on the temperature and any solvent present. In step (d) the reaction mixture obtained from step (c) is preferably brought 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 solution in the fluids present, such as the solvent used in step (c). The compound of formula (V) is then recovered as a solid, for example by filtration, decantation or spinning. The recovered compound of formula (V) can be washed with, for example, an aprotic or protic solvent, but in many cases high purity of the compound of formula (V) is achieved without further washing. be able to. The recovered compound of formula (V) can be dried or used without drying in step (e). When the compound of formula (V) is dried by air flow, in vacuum, by air suction, by heating or in which compound (V) does not dissolve, it forms an azeotrope with water and then Methods available to those skilled in the art, such as drying by applying a fluid that is removed by distillation.

The process of 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 foregoing can be used as an aqueous solution or neat, with aqueous solutions being preferred. HCl and _H2SO4 are preferred, with HCl _being most preferred. The amount of acid used in step (e) is generally chosen to reach a pH of 1-5, preferably 1.5-2.

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

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

Step (e) is generally carried out in the presence of a solvent that can be selected from the group of protic and aprotic solvents, preferably the solvent is a protic solvent. Suitable protic solvents are the same as defined for step (c). Most preferably step (e) is carried out in the presence of water. Although aqueous acid is often used in step (e), an additional protic solvent, preferably water, is usually advantageous to suspend the compound of formula (V) prior to addition of the acid. A preferred aprotic solvent is toluene. According to one embodiment, the compound of formula (IV) is converted into a pharmaceutically or agriculturally active compound, preferably a herbicidal compound, without further isolation, in the solvent in which step (e) is carried out. It is used in the next step such as the manufacturing process. The compound of formula (IV) is therefore not isolated from the solvent before further processing. In a preferred aspect according to this embodiment, the solvent is toluene.

According to another embodiment, after completion of the conversion of the compound of formula (V) to (IV) in step (e), the compound of formula (IV) is recovered as a solid, for example by filtration, decantation or spinning. be done. The recovered compound of formula (IV) can be washed with, for example, an aprotic or protic solvent. Since salts from steps (c)-(e) may be present in the recovered product, it may be preferable to perform one or more washing steps after recovery of the compound of formula (V). Washing is preferably done with water. The end of washing can advantageously be monitored by measuring the alkali or alkaline earth metal, eg sodium, content in the product, eg by ion-pair chromatography. It may be preferred to reach a metal content of 500 ppm or less, more preferably 300 ppm or less, most preferably 100 ppm or less. The recovered compound of formula (IV) can be recovered by air flow, in vacuum, by air suction, by heating (preferably staying below the melting point) or in which compound (IV) is not soluble, but when it is combined with water. Drying can be by methods available to those skilled in the art, such as drying by forming an azeotrope and then applying a fluid that is removed by distillation. When step (e) is carried out in an aprotic solvent, preferably toluene, drying is carried out by distillation of all fractions of the solvent when the solvent forms an azeotrope with water, whereby the product is It can also be dried. In another embodiment, when 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. .

In the process of purifying the compound of formula (IV), the process comprising steps (c)-(e), it is generally not limited by the process resulting in the compound of formula (IV) containing impurities. Suitable processes are described, for example, in WO2010037688, US20170348313, US2006276655, US201725054, US201876298, EP526732 and EP 0522392, all of which are hereby incorporated by reference for all purposes.

In one embodiment of the invention, the process for the preparation of the compound of formula (IV) comprising steps (a) and (b) also comprises steps (c)-(e) according to the invention.

（式中、Ｒ^１、Ｒ^３及びＭは、工程（ａ）～（ｅ）のいずれかに関する上記のようなそれらの一般的且つ好ましい定義において定義されている）
の化合物にも関する。具体的には、Ｒ^３は、好ましくは、ＣＦ_３である。Ｒ^１は、好ましくは、メチル又はエチルであり、エチルが好ましい。Ｍは、好ましくは、Ｎａ^＋又はＫ^＋であり、Ｎａ^＋が好ましい。好ましい実施形態において、式（Ｖ）の化合物は、その単離された固体形態である。特に、その単離された、固体形態での式（Ｖ）の化合物は、式（ＩＶ）の化合物、特に式（ＩＶ）の精製化合物を得るためのプロセスにおける有用な中間体である。式（Ｖ）の化合物は、ピリジン環の２位での更なる下流反応、例えば直接式（Ｖ）の化合物からのエーテル、ハライド（クロリド若しくはブロミドなどの）又はエステル形成のために使用することもできる。 The present invention provides the formula (V)

(wherein R ¹ , R ³ and M are defined in their general and preferred definitions as above for any of steps (a)-(e))
It also relates to compounds of Specifically, R ³ is preferably CF ₃ . R ¹ is preferably methyl or ethyl, preferably ethyl. M is preferably Na ⁺ or K ⁺ , Na ⁺ being preferred. In preferred embodiments, the compound of formula (V) is in its isolated solid form. In particular, the compound of formula (V) in its isolated, solid form is a useful intermediate in the process for obtaining the compound of formula (IV), especially the purified compound of formula (IV). Compounds of formula (V) may also be used for further downstream reactions at the 2-position of the pyridine ring, such as ether, halide (such as chloride or bromide) or ester formation directly from compounds of formula (V). can.

Another object according to the invention is a process for producing a pharmaceutically or agriculturally active compound, preferably a herbicidal compound, comprising steps (a) and (b) or steps (c) to (e), Or a process comprising a process comprising steps (a)-(e). Exemplary processes for the preparation of pharmaceutically or agriculturally active compounds from compounds of formula (IV) are described, for example, in U.S. Patent Application Publication Nos. 20170348313, 201725054 and 201876298. disclosed.

The process according to the invention starts from readily available raw materials, avoids waste and multiple steps for purification, and allows good yields and product purities. For example, isolation of compound (V) avoids waste and multiple steps associated with purification in the process of manufacturing compound of formula (IV) or purification of compound of formula (IV). The compound of formula (V), when subjected to an extractive step for purification in the presence of water, results in yield loss, higher waste and acid as an impurity that can be difficult to separate, formula (IV ) tends to decompose to the free acid of the compound. Performing extraction at low temperatures can help control such degradation, but performing extraction at low temperatures on an industrial scale is even more disadvantageous than extraction at room temperature. Cold 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 solid products according to the invention is easier to handle than subjecting the compound of formula (V) to an extractive step in purification. Column chromatography reported in JP201725054A for the purification of compounds of formula (IV) is generally disadvantageous on an industrial scale due to solvent consumption, contaminated column material and overall handling. . Crystallization and vacuum distillation for product purification have also been tested by the applicant, but in some cases various impurities were found not to be efficiently removed by such techniques. The process according to the invention comprising steps (a) and (b), steps (c) to (e) or steps (a) to (e) is therefore particularly advantageous on an industrial scale.

If the disclosure of any patent, patent application and publication incorporated herein by reference contradicts the description in this application to the extent that it may obscure terminology, this description shall control. .

The following examples are intended to further illustrate the invention without intending to limit its scope.

Starting materials are commercially available or can be prepared according to processes disclosed in the prior art.

シアノ酢酸エチル（６７．３ｇ、０．５９ｍｏｌ、１ｅｑ）を６３．２ｇ（１．０５ｅｑ、０．６３ｍｏｌ）のトリエチルアミンと室温で混合した。ＥＴＦＢＯ（１００ｇ、０．５９ｍｏｌ、１ｅｑ）を撹拌下で添加した。発熱反応が観察され、その間に温度が４０℃の温度に達した。添加後、反応温度を５０℃に１時間維持した。粗混合物の^１Ｈ－ＮＭＲ及びＧＣは、ＥＴＦＢＯの完全転化を示した。 Example 1: Step (a) using ethyl 2-cyanoacetate and 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (ETFBO) in the presence of triethylamine

Ethyl cyanoacetate (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 a temperature of 40°C. After the addition, the reaction temperature was maintained at 50° C. for 1 hour. ¹ H-NMR and GC of the crude mixture showed complete conversion of ETFBO.

実施例１の反応生成物を２００ｇのＥｔＯＨで希釈した。混合物を７４℃に加熱した。８１．３ｇの３２％ＨＣｌ（１．２ｅｑ、７０．１ｍＬ）を徐々に添加した。反応温度を添加中に７４℃～８５℃に維持した。添加の完了後、反応混合物を７８～８０℃で９０分間撹拌した。粗混合物の分析（^１Ｈ－ＮＭＲ）は、出発原料の完全転化を示した。 Example 2: Cyclization of the product of Example 1 by addition of step (b) acid

The reaction product of 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 slowly added. The reaction temperature was maintained between 74°C and 85°C during the addition. After the addition was complete, the reaction mixture was stirred at 78-80°C for 90 minutes. Analysis ( ¹ H-NMR) of the crude mixture showed complete conversion of the starting material.

実施例２において得られた混合物を室温まで冷却させ、次いで氷水（８００ｍｌ）に注ぎ込んだ。有機相は、固化し、濾別した。フィルターケーキを冷水で２回洗浄した。フィルターケーキを４００ｍＬのエタノールに懸濁させた。撹拌下で３７．５２ｇのＮａ_２ＣＯ_３（０．６ｅｑ）を添加した。微細な懸濁液を３０分間５５℃に加熱した。この時間中にＣＯ_２発生が観察された。混合物を－１０℃に冷却した。懸濁液を濾過し、フィルターケーキを無色になるまで小部分の冷ＥｔＯＨで洗浄した。フィルターケーキを部分乾燥させた。 Example 3: Conversion of the product of Example 2 to compounds of general formula (V)

The mixture obtained in Example 2 was allowed to cool 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 Na ₂ CO ₃ (0.6 eq) were 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 small portions of cold EtOH until it was colorless. The filter cake was partially dried.

Example 4: Conversion of the product of Example 3 to ETFPMOC The material obtained in Example 3 was mixed with 800 mL of ice water. 81.3 g of 32% HCl (1.2 eq) was added; a pH of 1-2 was reached. 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 x 50 mL). The resulting solid was dried overnight in a stream of air. The product was recovered in 61% yield (84.7 g), calculated from Example 1, with a purity of 99%.

Example 5: Step (a) using ethyl 2-cyanoacetate and 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (ETFBO) in the presence of diisopropylethylamine followed by step b)
Ethyl cyanoacetate (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 under stirring in 15 minutes. An exothermic reaction was observed during which the temperature reached a temperature of 50°C and was maintained between 40-50°C by adjusting the addition rate. After the addition, the reaction temperature was maintained at 50° C. for 1.5 hours. ¹ H-NMR and GC of the crude mixture 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 formed. The solid was checked by ¹ H-NMR. The crude product contained approximately 80% by weight product. The filtrate was treated with 2M aqueous NaOH until the two phases separated. Approximately 70% of diisopropylethylamine could be recovered after phase separation.

Example 6: Examples 1 and 2 are repeated replacing ethyl cyanoacetate with methylmalonamide.

Example 7: Starting with the material obtained from Example 6, Examples 3 and 4 are repeated.

Claims (15)

A process for the preparation of a compound of formula (IV) in step (a) of reacting a compound of formula (I) with a compound of formula (II) to form intermediate product (III)

(wherein R ¹ is selected from the group of C ₁ -C ₄ alkyl groups,
R ² is —CN or —C(O)NH ₂ ,
^R3 is selected from the group consisting of _CFH2 , _CClF2 , _CF2H , _CF3 and _CCl2F ;
R ⁴ is selected from the group of C ₁ -C ₄ alkyl groups)
comprising step (a) carried out in the presence of a base and in the absence of a solvent;
step (b) wherein said intermediate (III) is cyclized to said compound of formula (IV) by addition of acid

a process further comprising 2. The process of claim 1, wherein said reaction mixture obtained by step (a) is added with a solvent of formula ^R4OH prior to the addition of said acid in step (b). 3. A process according to claim 1 or 2, wherein ^R1 is methyl or ethyl, preferably ethyl. The process of any one of claims 1-3, wherein R ² is -CN. The process of any one of claims 1-4, wherein R ³ is CF ₃ . A process according to any one of claims 1 to 5, wherein R ⁴ is methyl, ethyl or n-butyl, with ethyl being preferred. A process for the purification of a compound of formula (IV), wherein said compound of formula (IV) containing impurities is reacted with a basic metal salt to form the product of formula (V) in step (c).

(wherein R ¹ is selected from the group of C ₁ -C ₄ alkyl groups,
^R3 is selected from the group consisting of _CFH2 , _CClF2 , _CF2H , _CF3 and _CCl2F ;
M is a cation of the alkali or alkaline earth group);
Step (d) wherein said compound of formula (V) is isolated as a solid compound and step (e) wherein said compound of formula (V) is contacted with an acid to obtain the purified compound of formula (IV)
process including. 8. The process of claim 7, wherein ^R3 is _CF3 . 9. Process according to claim 7 or 8, wherein ^R1 is methyl or ethyl, preferably ethyl. A process according to any one of claims 7 to 9, wherein M is Na ⁺ or K ⁺ . A process according to any one of claims 7 to 10, wherein step (c) is carried out at a temperature between -10°C and 80°C, preferably between 20°C and 50°C. The process of any one of claims 1-6, further comprising the process of any one of claims 7-11. Formula (V)

(wherein R ¹ , R ³ and M are defined as in any one of claims 7-10)
compound. 12. The compound of claim 11, isolated as a solid. Process for producing a pharmaceutically or agriculturally active compound, preferably a herbicidal compound, comprising a process according to any one of claims 1-12.