WO2021152055A1

WO2021152055A1 - Process for the manufacture of haloalkyl substituted pyridine compounds

Info

Publication number: WO2021152055A1
Application number: PCT/EP2021/052048
Authority: WO
Inventors: Janis Jaunzems; Stefanie NAUERT; Etienne SCHMITT; Alexander Schulz; Uta Claassen
Original assignee: Solvay Sa
Priority date: 2020-01-31
Filing date: 2021-01-29
Publication date: 2021-08-05
Also published as: CN115038690A; JP2023512000A

Abstract

Process for the manufacture of haloalkyl substituted pyridine compounds The present invention relates to a process for the synthesis of haloalkyl substituted pyridine compounds, a process for manufacturing a pharmaceutically or agriculturally active compound, preferably a herbicidal compound, and a haloalkyl substituted pyridine compound.

Description

Process for the manufacture of haloalkyl substituted pyridine compounds

This application claims priority filed on 31 January 2020 in EUROPE with Nr 20154938.3, the whole content of this application being incorporated herein by reference for all purposes.

The present invention relates to a process for the synthesis of haloalkyl substituted pyridine compounds, a process for manufacturing a pharmaceutically or agriculturally active compound, preferably a herbicidal compound, and a haloalkyl substituted pyridine compound.

Certain haloalkyl substituted pyridine compounds are useful for example as intermediates for the preparation of various agriculturally active substances. JP2017025054 discloses, for example, the use of trifluoromethyl substituted nicotinic acid derivatives for the synthesis of heterocycle amide compounds. R.W. Lang et al, Helv. Chim. Acta, Vol 71 (1988) p. 596-601 discloses antihypertensives based on certain 6-(trifluoromethyl)-substituted 2(17/)- pyridinones. JP2019182864 discloses a manufacturing method for pyridine compounds that necessitates the use of a variety of solvents and multiple extraction steps, leading to a high amount of waste of contaminated solvents and aqueous waste contaminated with organics.

It is an object of the present invention to provide an efficient process for manufacturing of certain haloalkyl substituted pyridine compounds which allows for good yields and product purities, starting from readily available starting materials, avoiding waste and multiple steps for purification.

The invention thus concerns a process for the manufacture of a compound of formula (IV), which comprises a step (a) of reacting a compound of formula (I) and a compound of formula (II) to form the intermediary product (III)

(I) (H) (III) wherein R1 is selected from the group of Cl - C4 alkyl groups wherein step (a) is performed in the presence of a base and in the absence of a solvent, which further comprises a step (b) wherein the intermediary product (III) is cyclized into the compound of formula (IV) by addition of an acid.

Another object of the present invention is a process for the purification of a compound of formula (IV), wherein the process comprises a step (c) wherein the compound of formula (IV) comprising impurities is reacted with a basic metal salt to form the product of formula (V)

a step (d) wherein the compound of formula (V) is isolated as a solid compound and a step (e) wherein the compound of formula (V) is contacted with an acid to obtain a purified compound of formula (IV).

The invention further concerns the compound of formula (V).

The residues R¹ to R⁴ will be defined below.

In the context of the present invention, the singular form is intended also to include the plural. All aspects and embodiments of the present invention are combinable. In the context of the present invention, the term “comprising” is intended to include the meaning of “consisting of’ and “consisting essentially of’. Endpoints of ranges are also included in the disclosure, e.g. a temperature range of 20°C to 50°C includes the values 20°C and 50°C. When a double bond is depicted in a particular E/Z geometry, this is intended to also denote the other geometric form as well as mixtures thereof. Compounds bearing one or more stereocenters are intended to include all mixtures of the stereoisomers, including stereochemically pure isomers. It should be noted that the compound of formula (IV) can also be depicted in its enol form as shown below. When the keto form is depicted, this includes the enol form.

(IV) keto (IV) enol The compound of formula (III) likewise, when drawn in its enol form, includes the keto form.

In a first aspect, the invention concerns a process for the manufacture of a compound of formula (IV), which comprises a step (a) of reacting a compound of formula (I) and a compound of formula (II) to form the intermediary product (III)

(I) (II) (III) wherein R1 is selected from the group of Cl - C4 alkyl groups wherein step (a) is performed in the presence of a base and in the absence of a solvent, which further comprises a step (b) wherein the intermediary product (III) is cyclized into the compound of formula (IV) by addition of an acid.

R¹ is selected from the group of Ci - C4 alkyl groups, including all isomers of propyl and butyl. Preferably, R¹ is methyl or ethyl, and most preferably, R¹ is ethyl.

R² is -CN or -C(0)NH₂, wherein -CN is preferred.

R³ is selected from the group consisting of CFH₂, CC1F₂, CF₂H, CF₃ and CC1₂F. R³ preferably is CF_3. R⁴ is selected from the group of Ci - C4 alkyl groups, including all isomers of propyl and butyl. Preferably, R⁴ is methyl, ethyl or n-butyl, and most preferably, R⁴ is ethyl.

In a most preferred aspect of the process comprising step (a) and (b), R¹ and R⁴ are ethyl, R³ is CF₃ and R² is -CN. Step (a) is performed in the presence of a base. The nature of the base is not particularly limited and can be, for example, selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium hydride, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, ammonia, triethylamine, diisopropylethylamine, pyridine and 4- (dimethylamino)pyridine. The more preferred bases are triethylamine and diisopropylethylamine. Diisopropylethylamine is more easily recycled. The amount of base in step (a) generally is from 0.7 to 2 molar equivalents relative to the compound of formula (II), preferably from 0.9 to 1.2 molar equivalents, and most preferably from 1 to 1.05 molar equivalents. It is defined that the base is not a solvent in the sense of the present invention. Step (a) generally is performed at a temperature of from 0°C to 90°C, more preferably of from 10°C to 80°C and most preferably at a temperature of from 20°C to 70°C.

The addition time in step (a), calculated from the start of the addition of the last starting material/reagent, generally is from 5 minutes to 5 hours, more preferably from 10 minutes to 2 hours, and more preferably from 30 to 60 minutes. The reaction time in step (a), calculated from the end of the addition of the last starting material/reagent, generally is from 5 minutes to 5 hours, more preferably from 10 minutes to 2 hours, and more preferably from 30 to 60 minutes. The order in which the starting materials and reactants are added to step (a) is not particularly limited. It is, though, preferred to admix the base and the compound of formula (I), and then to add the compound of formula (II) to the mixture of base and compound of formula (I). This addition order can have an advantageous impact on the yield of the reaction and the impurity profile of the intermediate product mixture, and thus, also the end product.

Step (a) is performed in the absence of a solvent. “Absence of a solvent” is intended to denote that no solvent is added to step (a), this excludes the active addition of a solvent to step (a). The compounds of formula (I) and (II), as well as the base, do not constitute a “solvent” in the sense of the present invention. It is acknowledged that in step (a), R⁴OH is liberated. The liberation of R⁴OH does not contradict the term “absence of a solvent”. The inventors have noted that the absence of a solvent in step (a) generally improves the reaction of step (a) in the sense that the reaction runs with less side products and a higher turnover of starting materials. Additional solvents in step (a), such aromatic or aliphatic hydrocarbons, dimethylformamide, acetonitrile or others, would also lead to disadvantageous mixtures of solvents in workup and waste treatment. The step (a) generally yields a compound of formula (III)

which, as described above, can also be represented by its keto form:

(III) keto form

It should be noted that the compound of formula (III) may also be represented in its salt form (Ilia), which is formed when the compound of formula (I) is deprotonated, adds to the double bond of (II) and nominally forms (III) or (Ilia):

Formally, (Ilia) also comprises the cation B⁺, such as Et₃NH⁺, which stems from the base used in step (a). The above representations of the compound of formula (III) are interchangeable and are encompassed whenever one formula relating to (III) is depicted.

The process to manufacture the compound of formula (IV) which comprises the step (a) further comprises a step (b) wherein the intermediary product (III) is cyclized into the compound of formula (IV) by addition of an acid. The nature of the acid is not particularly limited and can be, for example, selected from the group consisting of HC1, HBr, H₂SO₄, CF₃COOH, CF₃SO₃H and CH₃COOH or any combination thereof. Each of the foregoing can be used as aqueous solution or neat, wherein an aqueous solution is preferred. Preferred are HC1 and CF SO₃H, wherein HC1 is most preferred. The addition direction 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 to be used in step (b) generally is from 1 to 3 molar equivalents relative to the compound of formula (II). Preferably, the amount of acid to be used in step (b) is from 1 to 2, and more preferably from 1.1 to 1.3 molar equivalents relative to the compound of formula (II). Step (b) generally is performed at a temperature of from 0°C to 100°C, more preferably of from 10°C to 90°C and most preferably at a temperature of from 20°C to 80°C.

The addition time in step (b), calculated from the start of the addition of the last starting material/reagent, generally is from 5 minutes to 5 hours, more preferably from 10 minutes to 2 hours, and more preferably from 30 to 60 minutes. The reaction time in step (b), calculated from the end of the addition of the last starting material/reagent, generally is from 5 minutes to 5 hours, more preferably from 10 minutes to 2 hours, and more preferably from 30 to 60 minutes. In one aspect of the process for the manufacture of compound (IV), a solvent of formula R⁴OH is added to the reaction mixture obtained by step (a) before addition of the acid in step (b). The inventors have found that by this addition, the overall yield and purity of compound (IV) generally is improved in the sense that the reaction runs with less side products, in particular with less polymerisations, and a higher turnover of the intermediates. The solvent of formula R⁴OH preferably is selected such that R⁴ corresponds to R⁴ as present in the compound of formula (II). The amount of solvent R⁴OH to be added to 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 R⁴OH is 1 to 5 volume equivalents, and more preferably 1 to 2 volume equivalents relative to the volume of the reaction mixture obtained by step (a).

The product of the process, the compound of formula (IV), can be suitably recovered after step (b) by methods known to the skilled person, for example by removal of the volatiles by distillation. Compound (IV) can also be isolated by pouring the reaction mixture obtained by step (b) into water at a temperature of from 0°C to 30°C, preferably from 0°C to 20°C, for example ice water. The compound of formula (IV) then often precipitates and can be filtered, washed and dried. In another aspect, the compound of formula (IV) can also be isolated after step (b) by adding water at a temperature of from 20°C to 30°C, preferably from 25°C to 30°C, which leads often to a phase separation, in which the lower phase comprises the crude product. Such crude product can be used directly, for example, for further downstream processes such as the process comprising the step (c) which will be explained further below. The compound of formula (IV) can also be submitted to, if need be repeated, crystallization. Any of the above recovery steps can be combined.

a step (d) wherein the compound of formula (V) is isolated as a solid compound and a step (e) wherein the compound of formula (V) is contacted with a base to obtain a purified compound of formula (IV).

In steps (c), (d) and (e), R¹ and R³ are defined, in their general and preferred definitions, as described above for steps (a) and (b). Specifically, R³ preferably is CF_3. Also, R¹ preferably is methyl or ethyl. M is a cation of the alkali or earth alkali metal group, wherein alkali metals are preferred, and Na⁺ and K⁺ are most preferred. Depending on the charge number of M (1+ or 2+), nominally one or two anion structures of formula (V) are present per M.

The denomination (c), (d) and (e) do not denote that steps (a) and (b) of the previously described process must have been performed before steps (c)-(e); the process comprising steps (c)-(e) is an independent process. In one embodiment, though, a combination of steps (a)-(e) will be described.

The basic metal salt with which compound of formula (IV) comprising impurities is reacted in step (c) to form the product of formula (V) is a basic alkali metal salt. “Basic” intends to denote that the salt forms an aqueous solution with a basic pH when dissolved. Suitable basic metal salts are not particularly limited. They can, for example, be selected from the group consisting of hydroxides, oxides, carbonates, bicarbonates, acetates, alcoholates, trifluoroacetates, hydrides and phosphates of alkali metals and earth alkali metals, wherein alkali metals are preferred. Particularly preferred are NaOH, NaOMe, KOMe, NaOEt, KOEt, KOH, Na₂C0₃, NaHC0₃, K₂C0₃ and KHC0₃, wherein NaHC0₃, NaOEt and Na₂C0₃ are most preferred.

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

Step (c) generally is performed at a temperature of from -10°C to 80°C, more preferably of from 10°C to 70°C and most preferably at a temperature of from 20°C to 50°C. The addition time in step (c), calculated from the start of the addition of the last starting material/reagent, generally is from 5 minutes to 5 hours, more preferably from 10 minutes to 2 hours, and more preferably from 30 to 60 minutes. The reaction time in step (c), calculated from the end of the addition of the last starting material/reagent, generally is from 5 minutes to 5 hours, more preferably from 10 minutes to 2 hours, and more preferably from 30 to 60 minutes.

Step (c) often is carried out in a solvent, wherein a protic solvent is preferred. It is believed that the presence of a protic solvent facilitates the formation of the compound of formula (V). Protic solvents are not particularly limited, but can be, for example, selected from alcohols, dimethylformamide and acetonitrile. Alcohols are the most preferred solvents. The protic solvent is often used not only to dissolve or suspend the compound of formula (IV) comprising impurities, but also to facilitate the addition of the basic metal salt wherein the basic metal salt is applied as solution in the protic solvent. In another aspect, which is preferred when the basic metal salt is scarcely soluble, for example Na₂C0₃, it can be preferred that the basic metal salt is applied to step (c) as a solid. The basic metal salt can also be applied as a slurry, for example in the protic solvent. When an alcohol is used as solvent in step (c), the alcohol preferably corresponds to formula R'OH, wherein R¹ corresponds to R¹ in formula (IV). Often, the presence of water in step (c) has been observed to be detrimental. Water can lead to hydrolysis of the group comprising R¹, may lead to formation of additional side products and loss of yield because of potential solubility of the intermediate in water. Thus, in a preferred aspect, the content of water in the reaction mixture in step (c) is lower than 10 wt% (relating to the weight of the reaction mixture in step (c)), preferably lower than 5 wt% and more preferably lower than 1 wt%. The water content is measured according to suitable methods known to the skilled person, for example Karl-Fischer- Titration. The term “lower than” includes as lower limit the detection limit of the chosen method, in which case the water content is denoted as “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 the compound of formula (IV) comprising impurities. Preferably, the amount of, preferably protic, solvent is used in an amount of 1 to 5 volume equivalents, and more preferably 3 to 4 volume equivalents relative to the volume of relative to the volume of the compound of formula (IV) comprising impurities. The 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. Often, the compound of formula (V) already precipitates fully or partially during step (c), depending on temperature and any solvents present. In step (d), the reaction mixture obtained from step (c) preferably is brought to a temperature of from -20°C to 30°C, preferably of from -15°C to 10°C. At such a temperature, the recovery of the compound of formula (V) as a solid compound is optimized while any impurities generally stay in solution of the fluids present, for example the solvent used in step (c). The compound of formula (V) then is recovered as a solid, for example by filtration, decantation or spinning. The recovered compound of formula (V) can be washed, for example with aprotic or protic solvents, but often, a 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). If the compound of formula (V) is dried, methods available to the skilled person, such as drying by air stream, in vacuum, by air suction, by applying heat, or by applying a fluid in which the compound (V) is not soluble but which forms an azeotrope with water, which is then removed by distillation.

The process for the purification of a compound of formula (IV) further comprises a step (e) wherein the compound of formula (V) is contacted with an acid to obtain a purified compound of formula (IV). The nature of the acid is not particularly limited and can be, for example, selected from the group consisting of HC1, HBr, H₂S0₄, CF₃COOH, CF₃SO₃H and CH₃COOH or any combination thereof. Each of the foregoing can be used as aqueous solution or neat, wherein an aqueous solution is preferred. Preferred are HC1 and H₂SO₄, wherein HC1 is most preferred. The amount of acid to be used in step (e) generally is selected such that a pH of from 1 to 5, preferably of from 1.5 to 2 is reached. Step (e) generally is performed at a temperature of from 0°C to 50°C, more preferably of from 0°C to 40°C and most preferably at a temperature of from 5°C to 20°C. The temperatures as disclosed support effective isolation of the product.

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

Step (e) generally is performed in the presence of a solvent, which can be selected from the groups of protic and aprotic solvent, wherein preferably the solvent is a protic solvent. Suitable protic solvents are the same as defined for step (c). Most preferably, step (e) is performed in the presence of water. While aqueous acids are often used in step (e), additional protic solvent, preferably water, to suspend the compound of formula (V) before addition of the acid usually is advantageous. A preferred aprotic solvent is toluene. According to one embodiment, the compound of formula (IV) is used in a next step, such as a process for manufacturing a pharmaceutically or agriculturally active compound, preferably a herbicidal compound, without further isolation, in the solvent in which step (e) was performed. The compound of formula (IV) is thus 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. The recovered compound of formula (IV) can be washed, for example with aprotic or protic solvents. As salts from steps (c) - (e) maybe present in the recovered product, it can be preferred to perform one or more washing steps after recovery of the compound of formula (V). The washing is preferably performed with water. Conclusion of washing can be advantageously monitored by measurement of the alkali or earth alkali metal, e.g. sodium, content in the product, for example with ion-pair chromatography. It can be preferred to reach metal contents of equal to or lower than 500 ppm, more preferably equal to than 300 ppm, and most preferably of equal to or lower than 100 ppm. The recovered compound of formula (IV) can be dried by methods available to the skilled person, such as drying by air stream, in vacuum, by air suction, by applying heat (it is preferred to stay below the melting point), or by applying a fluid in which the compound (IV) is not soluble but which forms an azeotrope with water, which is then removed by distillation. If step (e) is performed in an aprotic solvent, preferably toluene, drying can also be performed by distillation of a fraction of all of the solvent if it forms an azeotrope with water, thereby dying the product. In another aspect, if step (e) is performed in a solvent, preferably an aprotic solvent such as toluene, drying can also be performed by adding drying agents known to the skilled person, such as sodium sulphate. In the process for the purification of a compound of formula (IV), wherein the process comprises steps (c) - (e), it is generally not restricted by which process the compound of formula (IV) comprising impurities is obtained. Suitable processes are described, for example, in W02010037688, US20170348313, US2006276655, JP2017025054, JP2018076298, EP526732 and EP0522392, all of which are hereby included by reference for all purposes.

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

The invention also concerns a compound of formula (V)

wherein R¹, R³ and M are defined in their general and preferred definitions as above for any of steps (a) to (e). Specifically, R³ preferably is CF_3. R¹ preferably is methyl or ethyl, wherein ethyl is preferred. M preferably is Na⁺ or K⁺, wherein Na⁺ is preferred. In a preferred embodiment, the compound of formula (V) is in its isolated solid form.. The compound of formula (V), specifically in its isolated, solid form, is a useful intermediate in the process to obtain a compound of formula (IV), specifically a purified compound of formula (IV). The compound of formula (V) can also be used for further downstream reactions on the position 2 in the pyridine ring, for example ether, halides (such as chloride or bromide) or ester formation directly out of the compound of formula (V). Another object according to the present invention is a process for manufacturing a pharmaceutically or agriculturally active compound, preferably a herbicidal compound, which comprises the processes comprising steps (a) and (b), or steps (c) to (e), or steps (a)-(e). Exemplary processes for the manufacturing of pharmaceutically or agriculturally active compounds from compounds of formula (IV) are disclosed, for example, in US20170348313, JP2017025054 and JP2018076298.

The processes according to the present invention allow for good yields and product purities, starting from readily available starting materials, avoiding waste and multiple steps for purification. For example, isolation of compound (V) avoids waste and multiple steps for purification in processes for the manufacture of a compound of formula (IV) or purification of a compound of formula (IV). It has been observed that the compound of formula (V), when submitted to extraction steps for purification in the presence of water, tends to decompose into the free acid of the compound of formula (IV), which leads to yield loss, higher waste and the acid as impurity which may be difficult to separate. Performing the extraction at low temperatures can help controlling such decomposition, but it is even more disadvantageous to perform extraction at low temperatures on an industrial scale than extractions at room temperature. Low temperature extraction may also lead to larger volumes of solvents, such as water, in order to optimize the purity of the intended product. Overall, the relatively simple recovery of solid product according to the present invention is easier to handle than submitting the compound of formula (V) to extraction steps in purification. Column chromatography, which has been reported in JP2017025054 for purification of a compound of formula (IV), generally is disadvantageous on industrial scale due to solvent consumption, contaminated column material and overall handling. Crystallization and vacuum distillation for purification of the product was also tested by the applicant, but it was found that in some cases, a variety of impurities could not efficiently be removed by such techniques. Thus, the processes according to the present invention, comprising steps (a) and (b), steps (c) to (e) or steps (a) to (e), are particularly advantageous on an industrial scale.

Should the disclosure of any patents, patent applications, and publications which are incorporated herein by reference conflict with the description of the present application to the extent that it may render a term unclear, the present description shall take precedence. The following examples are intended to further explain the invention without intending to limit the scope. The starting materials can be obtained commercially or manufactured according to processes disclosed in the prior art.

Example 1: Step (a) with ethyl 2-cyanoacetate and 4-ethoxy- 1, 1,1 -trifluorobut-3- en-2-one (ETFBO) in the presence of triethylamine

Ethylcyanoacetate (67.3 g, 0.59 mol, 1 eq) were mixed with 63.2 g (1.05 eq, 0.63 mol) triethylamine at room temperature. ETFBO (100 g, 0.59 mol, 1 eq) was added under stirring. An exotherm reaction was observed, during which the temperature reached a temperature of 40°C. After addition, the reaction temperature was maintained for 1 hour at 50°C. 'H-NMR and GC of the crude mixture showed full conversion of ETFBO.

Example 2: Step (b) cyclization of the product of example 1 by addition of an acid

The reaction product of example 1 was diluted with 200 g EtOH. The mixture was heated to 74°C. 81.3g of 32% HC1 (1.2eq, 70.1 mL) were added progressively. The reaction temperature was maintained between 74°C and 85°C during addition. After completed addition, the reaction mixture was stirred at 78-80°C for 90 minutes. Analytics ('H-NMR) of the crude mixture showed full conversion of the starting material.

Example 3 : Conversion of the product of example 2 into a compound 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 ethanol. Under stirring, 37.52 g NaiCC^ (0.6 eq) was added. The fine suspension was heated to 55°C for 30 minutes. During this time, CO2 evolution was observed. The mixture was cooled to -10°C. The suspension was filtered , the filter cake was washed with small portions of cold EtOH until colourless. The filter cake was partially dried. Example 4: conversion of the product of example 3 into ETFPMOC

The material obtained in example 3 was mixed with 800 mL ice water. 81.3 g 32% HC1 (1.2 eq) were added; the reached a pH of 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 x 50 mL). The resulting solid was dried overnight in an air stream. The product had a purity of 99%and was recovered in 61% yield (84.7 g), calculated from example 1. Example 5: Step (a) with ethyl 2-cyanoacetate and 4-ethoxy-l,l,l-trifluorobut-3- en-2-one (ETFBO) in the presence of diisopropylethylamine, followed by step b) Ethylcyanoacetate (18.82 g, 148.7 mmol, 1 eq) were mixed with 20.2 g (1.05 eq, 156.1 mmol) diisopropylethylamine at room temperature. ETFBO (25 g,

148.7 mmol, 1 eq) was added under stirring in 15 minutes. An exotherm reaction was observed, during which the temperature reached a temperature of 50°C and was maintained at between 40 and 50°C by adjusting addition speed. After addition, the reaction temperature was maintained for 1.5 hours at 50°C.

'H-NMR and GC of the crude mixture showed full conversion of ETFBO.

108.44 g HC1 (32%) was added at 50°C and the resulting mixture was stirred for 1.5 hours at 50°C. The reaction mixture was then cooled in ice; a solid formed.

The solid was checked with 'H-NMR The crude product contained appr. 80 wt% of product.

The filtrate was treated with 2M aq. NaOH until two phases separated. Approximately 70% of the diisopropylethylamine could be recovered after phase separation. Example 6: Examples 1 and 2 are repeated, exchanging ethylcyanoacetate for methylmalonamide.

Example 7: Example 3 and 4 are repeated, starting with the material obtained from example 6

Claims

1. Process for the manufacture of a compound of formula (IV), which comprises a step (a) of reacting a compound of formula (I) and a compound of formula (II) to form the intermediary product (III)

wherein R¹ is selected from the group of Ci - C4 alkyl groups

R² is -CN or -C(0)NH₂

R³ is selected from the group consisting of CFH₂, CC1F₂, CF₂H, CF₃ and CC1₂F

R⁴ is selected from the group of Ci - C4 alkyl groups wherein step (a) is performed in the presence of a base and in the absence of a solvent, which further comprises a step (b) wherein the intermediary product (III) is cyclized into the compound of formula (IV) by addition of an acid.

2. The process according to claim 1 wherein to the reaction mixture obtained by step (a) is added a solvent of formula R⁴OH before addition of the acid in step (b).

3. The process according to claim 1 or 2, wherein R¹ is methyl or ethyl, preferably ethyl.

4. The process according to anyone of claims 1 to 3, wherein R² is -CN.

5. The process according to anyone of claims 1 to 4, wherein R³ is CF₃.

6. The process according to anyone of claims 1 to 5, wherein R⁴ is methyl, ethyl or n-butyl, wherein ethyl is preferred.

7. A process for the purification of a compound of formula (IV), wherein the process comprises a step (c) wherein the compound of formula (IV) comprising impurities is reacted with a basic metal salt to form the product of formula (V)

wherein R¹ is selected from the group of Ci - C₄ alkyl groups

R³ is selected from the group consisting of CFH₂, CC1F₂, CF₂H, CF₃ and CC1₂F M is a cation of the alkali or earth alkali group; a step (d) wherein the compound of formula (V) is isolated as a solid compound and a step (e) wherein the compound of formula (V) is contacted with an acid to obtain a purified compound of formula (IV).

8. The process according to claim 7, wherein R³ is CF₃.

9. The process according to claim 7 or 8, wherein R¹ is methyl or ethyl, preferably ethyl.

10. The process according to anyone of claims 7 to 9, wherein M is Na⁺or

K⁺.

11. The process according to anyone of claims 7 to 10, wherein step (c) is performed at a temperature of from -10°C to 80°C, preferably at a temperature of from 20°C to 50°C.

12. The process according to anyone of claims 1 to 6 which further comprises the process according to anyone of claims 7 to 11.

13. A compound of formula (V)

wherein R¹, R³ and M are defined as in anyone of claims 7 to 10.

14. A compound according to claim 11, isolated as a solid.

15. A process for manufacturing a pharmaceutically or agriculturally active compound, preferably a herbicidal compound, which comprises the processes according to anyone of claim 1 to 12.