Patent Description:
Arylvinylsulphones have various industrial uses. For example, <NUM>-(arylsulphonyl)propene nitriles can be used as biocides in industrial processes, as disclosed in <CIT> and <CIT>.

A number of methods exist for preparing arylvinylsulphones. However, many of these methods employ solvents that are environmentally harmful, volatile, flammable and/or scarcely available, such as acetonitrile or sulfolane. In <CIT>, a process for the preparation of a compound of general formula (I) is disclosed which comprises mixing a sulfonyl halide, acrylonitrile, and a catalyst in a solvent, and adding base to eliminate a halide to form the desired product. The catalyst may be prepared from Cul and triethylamine hydrochloride in an acetonitrile solvent. Furthermore, the existing processes comprise number of steps, which increases the complexity of the processes. Furthermore, there are only limited possibilities to recirculate any of the used chemicals within the process. Consequently, there is a need for new effective method for preparing arylvinylsulphones, especially arylsulphonylpropene nitriles.

An object of the present invention is to minimise or possibly even eliminate the disadvantages existing in the prior art.

A further object of the present invention is to provide an efficient and simple method for preparing arylvinylsulphones.

Another object of the present invention is to provide a method for preparing arylvinylsulphones, preferably arylsulphonylpropene nitriles, where at least some of the chemicals can be recirculated within the process.

A further object of the present invention is to provide a safe method for preparing arylvinylsulphones,.

These objects are attained with the invention having the characteristics presented below in the characterising parts of the independent claims.

Some preferred embodiments of the invention are presented in the dependent claims.

The embodiments mentioned in this text relate, where applicable, to all aspects of the invention, even if this is not always separately mentioned.

Accordingly, the present invention provides a method for preparing a compound of formula (I)
<CHM>
where.

In a further aspect, the present invention provides a method for preparing a compound of formula (I)
<CHM>
where.

Now it has been surprisingly found that by using the method of the present invention it is possible to prepare arylvinylsulphones of formula (I), especially arylsulphonylpropene nitriles, by using easily available, relatively inexpensive, and safe starting materials and reagents. Furthermore, the invention open possibilities for recirculating at least a part of the reagents within the process, and thus reduces the amount of chemical waste produced and improves the overall process economy.

It has been found that catalyst complexes which include as a counterion an organic sulphonate are superior to comparable catalyst complexes which have a halide counterion such as a chloride counterion. Without wishing to be bound by theory, it is thought that the presence of halide counterions can contribute to the formation of undesirable polynuclear catalyst complexes which may increase impurity production in the preparation of compounds according to formula (I).

In the present context the term "catalyst complex" is used to denote a combination of individual atoms, groups of atoms, or molecules that have in the presence of a counterion a total net charge of zero that is able to catalyze a chemical reaction. The catalyst complex itself comprises a Cu(I) as the central atom or molecule as well as a ligand. A non-limiting example of such a catalyst complex is the Cu(I) methylmorpholine - complex in the presence of methane sulphonate or toluene sulphonate.

The method according to the present invention is especially suitable for preparing compounds of formula (I)
<CHM>
where.

In one embodiment of the invention, R1 in formula (I) represents a hydrogen atom, an alkyl group comprising <NUM> to <NUM> carbon atoms or an alkoxy group having <NUM> to <NUM> carbon atoms. R1 can be, for example, a methyl group, an ethyl group, a propyl group; a butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, or a tertiary butoxy group. Preferably, R1 represents a methyl group in the <NUM>-position.

R2 and R3 in formula (I) represent independently from each other and independently from R1 a hydrogen atom, an alkyl group comprising <NUM> to <NUM> carbon atoms or an alkoxy group having <NUM> to <NUM> carbon atoms. R2 and/or R3 may be, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, or a tertiary butoxy group. Preferably, both R2 and R3 represent a hydrogen atom.

According to one embodiment R1, R2 and/or R3 in formula (I) may represent independently from each other a halogen atom, such as chlorine, fluorine or bromine; a hydroxy group; a hydroxy alkyl group preferably comprising <NUM> - <NUM> carbon atoms; a haloalkyl group preferably comprising <NUM> - <NUM> carbon atoms and/or fluorosubstituents, such as trifluoromethyl; an amino group; an alkylamino group having <NUM> to <NUM> carbon atoms; or an acylamido group having <NUM> to <NUM> carbon atoms.

In a preferable embodiment R1 represents a methyl group in the <NUM>-position of the aryl, and R2 and R3 both represent hydrogen.

According to one embodiment, group A in formula (I) represents a C1-C5 alkyl group or a hydrogen atom. Group A may be, for example, a methyl group, an ethyl group, a propyl group; a butyl group, or a pentyl group. Preferably, the group A is a hydrogen atom.

According to one embodiment, group B in formula (I) represents a nitrile group; a C1-C5 carboxylic acid group, a C1-C5 carboxylic acid ester group or a C1-C5 carboxylic acid amide group.

According to one embodiment of the invention the compound of formula (I) may be an arylsulphonylpropene nitrile. The compound of formula (I) may be selected from a group consisting of the compound according to formula (I) is <NUM>-[(<NUM>-methylphenyl)sulphonyl]-<NUM>-propenenitrile, <NUM>-phenylsulphonyl-<NUM>-propenenitrile, <NUM>-[(<NUM>-fluorophenyl)sulphonyl]-<NUM>-propenenitrile, <NUM>-[(<NUM>,<NUM>-dimethylphenyl)sulphonyl]-<NUM>-propenenitrile, <NUM>-[(<NUM>-trifluormethylphenyl)-sulphonyl]-<NUM>-propenenitrile, <NUM>-[(<NUM>,<NUM>-dimethylphenyl)sulphonyl]-<NUM>-propenenitrile, <NUM>-(<NUM>,<NUM>-dimethylphenyl)sulphonyl-<NUM>-propenenitrile, <NUM>-[(<NUM>,<NUM>,<NUM>-trimethylphenyl)sulphonyl]-<NUM>-propenenitrile, <NUM>-(<NUM>-methoxyphenyl) sulphonyl-<NUM>-propenenitrile, methyl (<NUM>-[(<NUM>-methyl-phenyl)sulphonyl]prop-<NUM>-enate, <NUM>-(<NUM>-acetylphenyl)sulphonyl-<NUM>-propenenitrile, and any of their isomers. According to one preferable embodiment of the present invention the compound according to formula (I) is selected from a group consisting of <NUM>-[(<NUM>-methylphenyl)sulphonyl]-<NUM>-propenenitrile; <NUM>-phenylsulphonyl-<NUM>-propenenitrile; <NUM>-[(<NUM>-trifluormethylphenyl)-sulphonyl]-<NUM>-propenenitrile; <NUM>-[(<NUM>,<NUM>,<NUM>-trimethylphenyl)sulphonyl]-<NUM>-propenenitrile; <NUM>-(<NUM>-methoxyphenyl)sulphonyl-<NUM>-propenenitrile; <NUM>-[(<NUM>-methylphenyl)sulphonyl]prop-<NUM>-enate; and any of their isomers. Preferably the compound of formula (I) may be <NUM>-[(<NUM>-methylphenyl)sulphonyl]-<NUM>-propenenitrile.

In the method of the present invention a first reaction mixture is formed in solution form by mixing the components of the first reaction mixture with each other, preferably under an inert atmosphere, e.g. under a nitrogen atmosphere. According to one embodiment the first reaction mixture may be formed at a temperature of <NUM> - <NUM>, preferably <NUM> - <NUM>, more preferably <NUM> - <NUM>. It is advantageous that the first reaction mixture may be formed in room temperature and no extensive heating is necessary. It has been observed that the components of the catalyst complex, i.e. Cu(I) and the ligand, effectively dissolve into the reactive solvent at the used temperature, thus simplifying the method. The forming of first reaction mixture is preferably free of any heating.

Typically, the Cu(I) is provided as a Cu(I) halide and may be, for example, Cu(I)chloride or Cu(I)bromide, preferably Cu(I)chloride. However, it is important to minimize the amount of halide added to reaction mixure to avoid the formation of unwanted polynuclear catalyst complexes. Preferably, the molar amount of halide ions in the first reaction mixture is no more than the molar amount of Cu(I). It is therefore preferred that no other sources of free halide ions are introduced if at all possible.

It is preferred that the organic sulphonate is supplied as a salt, preferably an ammonium salt, such as an N-methylmorpholinium salt.

The first reaction mixture comprises the catalyst complex of a Cu(I) and the ligand, as well as the organic sulphonate counterion and the reactive solvent. The ligand influences the reducing power of Cu(I). The ligand may be selected from monodentate amine ligands, bidentate amine ligands, polydentate amine ligands, aryl sulphonates, and alkyl sulphonates. Suitable monodentate, bidentate or polydentate amine ligands may be selected, for example, triethylamine, N-methylmorpholine, N,N,N',N'-tetramethylethylenediamine and N,N,N',N", N"-pentamethyldiethylenetriamine. According to a preferable embodiment the ligand may be a bidentate amine ligand, for example morpholine or a substituted morpholine. The ligand may be an alkyl morpholine, such as N-methylmorpholine.

The counterion component comprises an organic sulphonate which may be an aryl sulphonate or an alkyl sulphonate selected from a group of methanesulphonate, ethanesulphonate, benzenesulphonate, <NUM>-toluenesulphonate, and xylenesulphonate. Preferably the counterion is methanesulphonate or paratoluene sulphonate. The counterion may be present as an outer component of the catalyst complex because it is negatively charged and able to associate with a positively charged inner component comprising Cu(I), the ligand and optionally reactive solvent molecules.

The reactive solvent for the first reaction mixture may be selected from (meth)acrylonitrile or alkyl (meth)acrylates, such as methyl acrylate or methyl methacrylate. Preferably the reactive solvent may be acrylonitrile. According to one preferable embodiment of the present invention the first reaction mixture is free of all other solvents that the reactive solvent. This means that no other solvents than the reactive solvent are added to the first reaction mixture.

The catalyst complex of Cu(I) and the ligand, as defined above, is dissolved in the reactive solvent, whereby the first reaction mixture in solution form is obtained. The reactive solvent functions as a reactant, solvent and a co-ligand in the method according to the invention. The use of the reactive solvent, as defined, further improves the reducing power of Cu(I), and thus improves the efficiency of the reaction between the catalyst complex and the aryl sulphonyl halide, possibly even the yield of the reaction. The reactive solvent is preferably added in excess, which ensures the dissolution of the other components of the first reaction mixture. It has been found that the reactive solvent is able to dissolve the Cu(I)halide as well as the ligand effectively, even at room temperature. As noted above, no heating for forming the first reaction mixture is thus required. Furthermore, the excess reactive solvent enables exclusion of other solvents in the following process step when the reaction mixture is formed, as well as the desired reaction for obtaining the intermediate product for compound of formula (I). This simplifies the process and improves the conversion and/or yield of the process. However, only a small excess of reactive solvent may be added or needed.

The first reaction mixture may comprise particular material: it is possible that the catalyst complex may comprise minor amounts of Cu(II), which is not dissolved into the reactive solvent but remains in particle form. The amount of Cu(II) may be <NUM> - <NUM> mol-%, calculated from the total molar amount of copper in the first reaction mixture. Cu(II) ions may inhibit the polymerization reaction of the reactive solvent, such as acrylonitrile, in the reaction mixture in the successive method steps. This may be considered advantageous, as it can reduce the amount of undesired side reactions and formation of other compounds than the desired compound according to formula (I). The presence of Cu(II) is not necessary.

The aryl sulphonyl halide may be benzene sulphonyl halide, alkyl substituted benzene sulphonyl halide or halo-substituted benzene sulphonyl halide, such as toluene sulphonyl halide, xylene sulphonyl halide, <NUM>-methoxybenzene sulphonyl halide or <NUM>-chlorobenzene sulphonyl halide, preferably toluene sulphonyl chloride or toluene sulphonyl bromide, more preferably toluene sulphonyl chloride. For example, the aryl sulphonyl halide may be <NUM>-toluene sulphonyl halide, preferably <NUM>-toluene sulphonyl chloride or <NUM>-toluene sulphonyl bromide, more preferably <NUM>-toluene sulphonyl chloride. Aryl sulphonyl halide may be added in amount (in mol) of <NUM> - <NUM> equivalents, preferably <NUM> - <NUM> equivalents, more preferably <NUM> - <NUM> equivalents, relative to the amount (in mol) of the reactive solvent in the first reaction mixture. Aryl sulphonyl halide is dissolved in the first reaction mixture, under an endothermic process.

Preferably, the first reaction mixture does not contain any other solvent than the reactive solvent, i.e. the first reaction mixture is free of other solvents than the reactive solvent. The first reaction mixture may comprise the reactive solvent in amount (in mol) of at least <NUM> times, preferably at least <NUM> times, more preferably at least <NUM> times, of the amount (in mol) of the aryl sulphonyl halide. The molar amount of reactive solvent may be up to <NUM> times of the molar amount of the aryl sulphonyl halide.

In one arrangement, a pre-reaction mixture comprising the catalyst complex of the Cu(I) and the ligand, the organic sulphonate counterion and the reactive solvent is formed, to which the aryl sulfonyl halide is added to form the first reaction mixture. In another arrangement, no pre-reaction mixture is formed.

The aryl sulphonyl halide may be added to the pre-reaction mixture or first reaction mixture as one single dose, or as a plurality of successive doses, such as two, three or more successive doses. A continuous addition may also be possible. Preferably aryl sulphonyl halide is added as one single dose.

The amount of Cu(I)halide, preferably Cu(I)chloride in the first reaction mixture may be <NUM> - <NUM> mol-%, preferably <NUM>-<NUM> mol-%, more preferably <NUM> - <NUM> mol-% or <NUM> - <NUM> weight-%, calculated from the amount of the aryl sulphonyl halide in the first reaction mixture. The amount of the ligand, preferably alkyl sulphonate or aryl sulphonate, such as methanesulphonate, in the first reaction mixture may be <NUM>-<NUM> mol-% preferably <NUM>- <NUM> mol-%, more preferably <NUM> - <NUM> mol-%, calculated from the amount of the aryl sulphonyl halide in the first reaction mixture.

After the addition of the aryl sulphonyl halide to the first reaction mixture, and its dissolution, the reaction is allowed to proceed, preferably under inert atmosphere, e.g. nitrogen, at an elevated temperature, whereby an intermediate product is obtained. The reaction is a radical addition reaction. The reaction is preferably allowed to proceed at the elevated temperature, which is higher than the boiling point of the reactive solvent but below the boiling point of the reaction mixture. The reaction in the first reaction mixture may be allowed to proceed at the elevated temperature of <NUM> - <NUM>, preferably <NUM> - <NUM>, more preferably <NUM> - <NUM>. The reaction is allowed to proceed until desired conversion of the intermediate product is obtained. The reaction time may be, for example <NUM> - <NUM> hours, preferably <NUM>-<NUM> hours or <NUM> - <NUM> hours.

After the reaction has proceeded to the desired conversion, the unreacted reactive solvent may be separated from the first reaction mixture. The reactive solvent may be separated by any suitable separation method, e.g. by distilling. According to one preferable embodiment, the reactive solvent may be separated from the first reaction mixture, optionally purified, and then recycled back in the process to the step (a). In this manner it is possible to reuse the unreacted reactive solvent for making of the first reaction mixture and effectively reduce the amount of chemical waste which is produced.

After the separation of the unreacted reactive solvent the obtained intermediate product is dissolved to a low polarity solvent to form a second reaction mixture. The intermediate product may be dissolved into a low polarity solvent, which has a relative polarity of <<NUM>, preferably <<NUM>, or even <<NUM>, to form the second reaction mixture. For purposes of the present context, the relative polarity values given, for example, in <NPL>, or in other similar handbooks, can be used. The low polarity of the low polarity solvent reduces its ability to mix with water, which simplifies the separation of the intermediate product from the aqueous phase. The low polarity solvent may be considered hydrophobic. The low polarity solvent may be free of carboxyl or hydroxyl groups. Low polarity solvents suitable for use in the present invention may be selected, for example, from a group consisting of ethyl acetate, butyl acetate, tetrahydrofuran, dioxane and toluene. According to one preferable embodiment the low polarity solvent is ethyl acetate.

Cu(I) typically precipitates from the liquid phase of the second reaction mixture after the addition of the low polarity solvent. The Cu(I) precipitate may be easily separated from the liquid phase of the second reaction mixture that comprises the low polarity solvent and the intermediate product, e.g. by filtration.

After dissolving the intermediate product to the low polarity solvent for forming the second reaction mixture, and optional separation of Cu(I) precipitate, a base may be added to the second reaction mixture for elimination of the halogen atom from the intermediate product to form the compound according to formula (I). The intermediate product undergoes an elimination reaction in the presence of the base, where the halogen atom is removed from the intermediate product, i.e. a base-catalyzed elimination of the halogen atom, and the compound according to formula (I) is obtained. The base used may be an inorganic base, an organic base or a combination of an inorganic and organic base, preferably a combination of inorganic and organic base. The elimination reaction is exothermic, and therefore the base is preferably added, and the elimination reaction is allowed to proceed under cooling. According to one preferable embodiment the second reaction mixture is maintained in a temperature of <NUM> - <NUM>, preferably <NUM> - <NUM>, more preferably <NUM> - <NUM>, during the elimination of halogen atom from the intermediate product.

The base may be added to the second reaction mixture relative to the amount of the dissolved intermediate in the second reaction mixture in an amount (in mol) of at least <NUM> equivalents, such as in the range <NUM> to <NUM>, preferably <NUM> to <NUM> equivalents, most preferably around <NUM> equivalent; or at least <NUM> equivalent, or even at least <NUM> equivalents, although high amounts are less preferred.

According to one embodiment of the invention the base added to the second reaction mixture may be or comprise an inorganic base, preferably selected from a group comprising bicarbonates and carbonates of alkali metals and carbonates of alkaline earth metals or any mixtures thereof. For example, the inorganic base may be selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium bicarbonate, lithium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate or any mixture thereof. According to one preferable embodiment sodium bicarbonate or sodium carbonate is used as inorganic base.

According to one embodiment of the invention the base added to the second reaction mixture may be or comprise an organic base, preferably selected from trialkylamines, such as triethylamine, trimethylamine; N-methylmorpholine; N-methylpyrrolidine; N,N-diisopropylethylamine (Hünig's base); <NUM>,<NUM>-diazabicyclo-[<NUM>. <NUM>]octane (DABCO); <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (DBU); or <NUM>,<NUM>-diaza-bicyclo[<NUM>. <NUM>]non-<NUM>-ene (DBN), or any mixtures thereof.

According to one preferable embodiment of the present invention the base may be a combination of an inorganic base and an organic base, as defined above. The base may comprise <NUM> - <NUM> equivalent, preferably <NUM> - <NUM> equivalent, of an inorganic base and <NUM> - <NUM> equivalent, preferably <NUM> - <NUM> equivalent, of an organic base, given as molar equivalents. The inorganic and organic base may be added to the second reaction mixture, or separately but simultaneously, or separately and successively. Preferably the inorganic base is added first, followed by addition of organic base.

The second reaction mixture may preferably comprise water. Water may be introduced to the second reaction mixture together or after addition of base, preferably for example after addition of the inorganic and/or organic base. The water amount in the second reaction mixture may be <NUM> - <NUM> weight-%, preferably <NUM> - <NUM> weight-%, more preferably <NUM> - <NUM> weight-%, calculated from the amount of the inorganic base in the second reaction mixture. Efficient stirring of the second reaction mixture during the elimination reaction prevents the phase separation between the water and the low polarity solvent. The water content of the second reaction mixture enables a phase transfer process involving the organic base and inorganic base, if both present, that improves the efficiency of the base-catalyzed elimination reaction.

After the elimination reaction is complete, the compound according to Formula (I) is separated from the second reaction mixture. Usually a precipitate comprising organic and inorganic salts, such as copper salts, and the like. The precipitate may be easily separated from the organic solvent phase, e.g. by filration. The compound according to Formula (I) remains in the organic solution phase of the second reaction mixture, formed by the low polarity solvent. The organic phase may be washed by using a mixture of sodium chloride and an organic acid, such as acetic acid or citric acid. A relatively pure compound according to Formula (I) may be obtained by removing the organic phase, e.g. by evaporation, whereby the compound according to Formula (I) is crystallized, and a solid or semi-solid product is obtained.

The term "comprises" as used throughout the description and claims herein means "includes or consists of". The term denotes the inclusion of at least the features following the term and does not exclude the inclusion of other features which have not been explicitly mentioned. The term may also denote an entity which consists only of the features following the term.

Embodiments of the invention are described more closely in the following non-limiting examples.

The following chemicals and reagents were used in the Example: <NUM>-methylmorpholine, Sigma-Aldrich, purum ><NUM>%.

The used chemicals and solvents methanol (MeOH), toluene, ethyl acetate (EtOAc), sodium carbonate, acetic acid, sodium chloride were reagent grade purity and obtained from commercial sources.

<NUM> mol methanesulfonic acid, MsOH (<NUM>% solution in methanol) was added slowly to a stirred <NUM> mol solution of <NUM>-methylmorpholine, NMM (<NUM>% solution in methanol) under cooling with cold water/ice. Temperature during the addition was kept under <NUM>. After the addition of MsOH was completed, methanol was removed under reduced pressure on rotary evaporator and a yellowish oily residue was obtained. <NUM> of toluene was added to the residue and evaporated on rotary evaporator. Azeotropic drying was repeated with same amount of toluene. Evaporation was continued until the salt crystallizes. <NUM>-methylmorpholinium hydromethanesulfonate, NMM*MsOH, was formed in quantitative yield.

<NUM> CuCl (<NUM> mol), <NUM> NMM*MsOH (<NUM> mol) prepared in Step I and <NUM> acrylonitrile (<NUM> mol) was charged in a <NUM> <NUM>-neck round-bottom flask under nitrogen atmosphere. The pre-reaction mixture was stirred <NUM> at room temperature under nitrogen atmosphere. Almost clear yellow-greenish solution of Cu(I)-complex with NMM and acrylonitrile was formed in <NUM> -<NUM> minutes.

<NUM> toluenesulfonyl chloride (<NUM> mol) was added in one portion to the pre-reaction mixture prepared in Step II. The obtained first reaction mixture was stirred about <NUM> under nitrogen atmosphere. Temperature was raised to <NUM> during <NUM>. Stirring and heating at <NUM> was continued overnight. The reaction flask was cooled to room temperature and the obtained intermediate product was analysed by thin layer chromatography, TLC (ethyl acetate:hexane <NUM>:<NUM>).

Acrylonitrile was removed from the first reaction mixture obtained in Step III under reduced pressure and <NUM> ethyl acetate was added in two portion and evaporated. This removed possible traces of acrylonitrile.

The intermediate product was dissolved in <NUM> of ethyl acetate for forming a second reaction mixture. At this stage Cu(I) containing precipitate formed and was separated from the liquid phase by filtering. The liquid phase, i.e. the second reaction mixture was placed in <NUM> round-bottom flask. <NUM> Na<NUM>CO<NUM> was added under stirring, temperature <NUM>. After addition of <NUM> of deionized water a slow gas evaluation started, temperature of the mixture was <NUM>. <NUM> NMM (<NUM> mol-% of toluenesulfonyl chloride amount) was added in one portion. Temperature of the reaction mixture was <NUM>. Samples for analysis with ultra performance liquid chromatography, UPLC were taken at time <NUM>; <NUM> <NUM>; <NUM> <NUM>; <NUM> <NUM>; <NUM> <NUM>; <NUM> <NUM>. In the last sample , the content of E-<NUM>-[(<NUM>-methylphenyl)sulfonyl]-<NUM>-propenenitrile was <NUM> weight-% (<NUM> % yield from theoretical), no intermediate product was found.

A yellow organic liquid phase was separated from semi-solid precipitate formed during elimination reaction by decanting. The precipitate was washed twice with <NUM> ethyl acetate. The ethyl acetate solutions were combined with the organic liquid phase. The combined organic phase was washed with three times with <NUM> (per time) washing solution comprising <NUM> NaCl, <NUM> acetic acid and <NUM> deionized water and once with <NUM> DI-water. The washing was conducted by stirring on magnetic stirrer (<NUM> rpm, <NUM>).

After washing, the organic liquid phase was placed in a rotary evaporator and ethyl acetate was evaporated to dry. A reaction product crystallized during evaporation. <NUM> methanol was added to the crystallized reaction product and refluxed <NUM> on water bath, cooled slowly to room temperature, and placed into fridge overnight (<NUM>).

The product was filtered, washed with <NUM> of cold methanol and dried under reduced pressure on water bath (<NUM> - <NUM>).

<NUM>,<NUM> of toluenesulphonic acid, TosOH*H<NUM>O, (about <NUM>. 028mol) was dissolved in <NUM> of MeOH. <NUM>,<NUM> of N-methylmorpholine was added and resulted solution was evaporated to dry in a rotary evaporator with a water bath temperature of <NUM>-<NUM>. A colourless crystalline salt was obtained at quantitative yield.

In a <NUM> round bottom reaction flask was charged <NUM>,<NUM> CuCl (about <NUM>,6mmol), <NUM>,<NUM> NMM*TosOH (about 4mmol), <NUM>,<NUM> toluene sulphonyl chloride, TosCl, (about <NUM>,05mol) and <NUM>,<NUM> acrylonitrile (about <NUM>,1715mol).

The resulted clear yellowish-green reaction mixture was refluxed (Tset= <NUM>) and magnetically stirred under N<NUM> for <NUM>.

A conversion of TosCl of about <NUM>% was achieved as measured by H<NUM> NMR, CDCl<NUM>.

Unreacted acrylonitrile was evaporated using a rotary evaporator with a water bath at a temperature of <NUM>-<NUM>. An oily product was formed. Ethyl acetate, EtOAc, (<NUM>) was added and evaporation was repeated to remove residual acetonitrile.

The oily reaction product was dissolved in <NUM> EtOAc and transferred into a <NUM> round bottom reaction flask. <NUM>,<NUM> of Na<NUM>CO<NUM> (about 23mmol), <NUM> of water and <NUM>,<NUM> of N-methylmorpholine (about 5mmol) were added.

A yellowish reaction mixture was obtained. No crystalline product was observed in organic solution. The reaction mixture was stirred overnight at room temperature.

Next morning the organic phase was separated in a separation funnel. The water layer was washed twice with <NUM> of EtOAc. Combined organic phases were washed twice with <NUM> 1wt% citric acid/10wt% NaCl.

EtOAc was then evaporated using a rotary evaporator, <NUM> MeOH added and evaporation repeated. <NUM> MeOH was added, the mixture was refluxed without mixing and cooled slowly to room temperature. The product was filtered, washed with <NUM> of cold MeOH and dried at <NUM>-<NUM> under reduced pressure (<NUM>-40mbar). Colorless crystals were obtained.

Upon redissolution it was found that the product was <NUM>% pure, with approximately <NUM>% insolubles and <NUM>% other impurities.

The above pure product was analysed by GC-MS. The purity of the sample was about <NUM>,<NUM>% using this analytical method.

In a <NUM> round bottom reaction flask was charged <NUM>,<NUM> CuCl (about 1mmol), <NUM>,<NUM> triethylamine chloride, Et<NUM>N*HCl, (about <NUM>,55mmol), <NUM>,<NUM> toluene sulphonyl chloride, TosCl, (about <NUM>,1mol) and <NUM>,<NUM> acrylonitrile (about <NUM>,2mol).

The resulting clear yellowish reaction mixture was refluxed (Tset= <NUM>) and magneticallly stirred under N<NUM> for <NUM>.

The reaction product was dissolved in <NUM> EtOAc and transferred into <NUM> round bottom reaction flask. <NUM>,<NUM> of Na<NUM>CO<NUM> (about 45mmol), <NUM> of water and <NUM> of N-methylmorpholine (about 10mmol) were added. A small amount of crystalline product was observed in organic solution. The solution was almost colorless. The reaction mixture was stirred overnight at room temperature.

Next morning the organic phase was separated in the separation funnel. The water layer was washed twice with <NUM> of EtOAc. Combined organic phases were washed twice with <NUM> 1wt% citric acid/10wt% NaCl. EtOAc was evaporated, <NUM> MeOH added and evaporation repeated. <NUM> MeOH was added, the mixture was refluxed without mixing and cooled slowly to room temperature.

The product was filtered, washed with <NUM> of cold MeOH and dried at <NUM>-<NUM> under reduced pressure (<NUM>-40mbar). Colorless crystals were obtained.

Comparative Example <NUM> was based on a catalyst complex containing relatively high amounts of chloride as a counterion with no organic sulphonate present. The addition reaction resulted in an intermediate product in which the organic phase contained some crystalline precipitate not observed in the corresponding Example <NUM> according to the invention. The elimination product of Comparative Example <NUM> was found to contain significantly more solids and other impurities after washing and recrystallisation.

Claim 1:
Method for preparing a compound of formula (I)
<CHM>
where
R1, R2, and R3 independently represent a hydrogen atom; a halogen atom; a hydroxy group, an alkyl group; a hydroxy alkyl group; a haloalkyl group; an alkoxy group having <NUM> to <NUM> carbon atoms; an amino group; an alkylamino group or an acylamido group having <NUM> to <NUM> carbon atoms;
A represents a hydrogen atom; a C1-C5 alkyl group; or an alkoxycarbonyl group;
B represents a nitrile group;a carboxylic acid group, a carboxylic acid ester group or a carboxylic acid amide group;
the method comprising steps of-
(a) forming a first reaction mixture comprising
- a catalyst complex comprising Cu(I) and a ligand, wherein the ligand is selected from mono-, bi- or polydentate amine ligands;
- an organic sulphonate counterion;
- a reactive solvent selected from (meth)acrylonitrile or alkyl (meth)acrylate; and
- an aryl sulfonyl halide reactant;
(b) allowing a reaction to proceed in the first reaction mixture at an elevated temperature, whereby an intermediate product is obtained;
(c) separating the unreacted reactive solvent from the first reaction mixture, and dissolving the intermediate product to a low polarity solvent to form a second reaction mixture;
(d) adding a base to the second reaction mixture, wherein the intermediate product undergoes a base-catalyzed elimination of the halogen atom from the intermediate product to form the compound according to Formula (I), preferably under cooling; and
(e) separating the compound according to Formula (I) from the second reaction mixture.