Process for the preparation of aryl vinyl sulfones

Abstract

This invention relates to a method for preparing arylvinyl sulfones. The method includes forming a first reaction mixture comprising a catalyst complex containing a halogenated Cu(I) and a ligand selected from monodentate, bidentate, or polydentate amine ligands, and further comprising an organosulfonate anion; a reactive solvent selected from (meth)acrylonitrile or alkyl (meth)acrylates; and an arylsulfonyl halide reactant. The reaction is carried out at an elevated temperature in the first reaction mixture to obtain an intermediate product. Unreacted reactive solvent is separated from the first reaction mixture, and the intermediate product is dissolved in a low-polarity solvent to form a second reaction mixture. A base is added to the second reaction mixture, wherein the intermediate product undergoes base-catalyzed elimination of halogen atoms from the intermediate product to form a compound of formula (I), preferably carried out under cooling. Finally, the desired compound is separated from the second reaction mixture.

Description

[0001] This invention relates to a method for preparing compounds of formula (I). Background Technology

[0002] Arylvinyl sulfones have a variety of industrial applications. For example, 3-(arylsulfonyl)acrylonitrile can be used as a biocide in industrial processes, as disclosed in WO 2019 / 042984 and WO 2019 / 042985.

[0003] Numerous methods exist for the preparation of aryl vinyl sulfones. However, many of these methods use environmentally harmful, volatile, flammable, and / or difficult-to-obtain solvents, such as acetonitrile or sulfolane. Furthermore, existing methods involve numerous steps, increasing their complexity. Additionally, there is a limited possibility of recycling any chemicals used in these methods. Therefore, new and efficient methods for the preparation of aryl vinyl sulfones (especially arylsulfonyl acrylonitrile) are needed.

[0004] The purpose of this invention is to minimize or even eliminate the drawbacks of the prior art.

[0005] Another object of the present invention is to provide an efficient and simple method for preparing aryl vinyl sulfones.

[0006] Another object of the present invention is to provide a method for preparing aryl vinyl sulfone (preferably aryl sulfonyl acrylonitrile), wherein at least some chemicals can be recycled in the process.

[0007] Another object of the present invention is to provide a safe method for preparing aryl vinyl sulfones. Invention Summary

[0008] These objectives are achieved by means of the present invention, which has the features of the characterizing portion of the independent claims shown below.

[0009] Some preferred embodiments of the present invention are shown in the dependent claims.

[0010] The embodiments mentioned herein (where feasible) relate to all aspects of the invention, even when not always mentioned separately.

[0011] Accordingly, the present invention provides a method for preparing compounds of formula (I).

[0012]

[0013] R1, R2, and R3 independently represent hydrogen atoms; halogen atoms; hydroxyl groups; alkyl groups; hydroxyalkyl groups; haloalkyl groups; alkoxy groups having 1 to 4 carbon atoms; amino groups; amide groups or alkylamino groups having 1 to 10 carbon atoms;

[0014] A represents a hydrogen atom or a C1-C5 alkyl group;

[0015] B represents a nitrile group; a carboxylic acid group, a carboxylic ester group, or a carboxylic amide group.

[0016] The method includes the following steps:

[0017] (a) forming a first reaction mixture, the first reaction mixture comprising

[0018] - Catalyst complexes comprising Cu(I) and ligands, wherein the ligands are selected from monodentate, bidentate, or polydentate amine ligands;

[0019] - Organic sulfonate ions;

[0020] -A reactive solvent selected from (meth)acrylonitrile or (meth)acrylate alkyl esters; and

[0021] -Arylsulfonyl halide reactants;

[0022] (b) The reaction is carried out at an elevated temperature in the first reaction mixture to obtain an intermediate product;

[0023] (c) Separate the unreacted reactive solvent from the first reaction mixture and dissolve the intermediate product in a low-polarity solvent to form a second reaction mixture;

[0024] (d) Adding a base to a second reaction mixture, wherein the intermediate product undergoes base-catalyzed elimination of halogen atoms from the intermediate product to form a compound of formula (I), preferably carried out under cooling; and

[0025] (e) Separate compound (I) from the second reaction mixture.

[0026] In one approach, step (a) includes:

[0027] (i) forming a pre-reaction mixture, the pre-reaction mixture comprising

[0028] Catalyst complexes of Cu(I) and ligands;

[0029] - Organic sulfonate ions;

[0030] -A reactive solvent selected from (meth)acrylonitrile or (meth)acrylate alkyl esters; and

[0031] (ii) A certain amount of arylsulfonyl halide is added to the pre-reaction mixture to form the first reaction mixture.

[0032] In another aspect, the present invention provides a method for preparing compounds of formula (I).

[0033]

[0034] in

[0035] R1, R2, and R3 independently represent hydrogen atoms; halogen atoms; hydroxyl groups; alkyl groups; hydroxyalkyl groups; haloalkyl groups; alkoxy groups having 1 to 4 carbon atoms; amino groups; amide groups or alkylamino groups having 1 to 10 carbon atoms;

[0036] A represents a hydrogen atom; a C1-C5 alkyl group; or an alkoxycarbonyl group;

[0037] B represents a nitrile group; a carboxylic acid group, a carboxylic ester group, or a carboxylic amide group;

[0038] The method includes the following steps:

[0039] (1) Forming a pre-reaction mixture, the pre-reaction mixture comprising

[0040] -A catalyst complex of Cu(I) halide and a ligand, wherein the ligand is selected from monodentate, bidentate, or polydentate amine ligands; aryl sulfonate ions; and alkyl sulfonate ions; and

[0041] -A reactive solvent selected from (meth)acrylonitrile or (meth)acrylate alkyl esters;

[0042] (2) A certain amount of arylsulfonyl halide is added to the pre-reaction mixture to form the first reaction mixture;

[0043] (3) The reaction proceeds at an elevated temperature in the first reaction mixture, thereby yielding the intermediate product.

[0044] (4) Separate the unreacted reactive solvent from the first reaction mixture and dissolve the intermediate product in a low-polarity solvent to form a second reaction mixture;

[0045] (5) Adding a base to the second reaction mixture, wherein the intermediate product undergoes base-catalyzed elimination of halogen atoms from the intermediate product to form a compound of formula (I), preferably carried out under cooling; and

[0046] (6) Separate compound (I) from the second reaction mixture.

[0047] It has now been surprisingly discovered that aryl vinyl sulfones, particularly aryl sulfonyl acrylonitriles of formula (I), can be prepared using the method of the present invention, which uses readily available, relatively inexpensive, and safe raw materials and reagents. Furthermore, the present invention provides the possibility of recycling at least a portion of the reagents during the process, thereby reducing the amount of chemical waste generated and improving the overall cost of the process.

[0048] Catalytic complexes containing organic sulfonate ions as balancing ions have been found to be superior to comparable catalyst complexes with halogen anion balancing ions, such as chloride anions. Without theoretical constraints, the presence of halogen anion balancing ions is thought to promote the formation of undesirable polynuclear catalyst complexes, which can increase impurity generation during the preparation of compounds of formula (I).

[0049] In this document, the term "catalyst complex" is used to refer to a single atom, group of atoms, or combination of molecules capable of catalyzing a chemical reaction, having a total net charge of zero in the presence of a counterion. A catalyst complex itself comprises Cu(I) as a central atom or molecule and ligands. A non-limiting example of the aforementioned catalyst complex is a Cu(I)methylmorpholine complex in the presence of methanesulfonate or toluenesulfonate ions.

[0050] The method according to the invention is particularly suitable for preparing compounds of formula (I).

[0051]

[0052] in

[0053] R1, R2, and R3 independently represent hydrogen atoms; halogen atoms; hydroxyl groups; alkyl groups; hydroxyalkyl groups; haloalkyl groups; alkoxy groups having 1 to 4 carbon atoms; amino groups; amide groups or alkylamino groups having 1 to 10 carbon atoms;

[0054] A represents a hydrogen atom or a C1-C5 alkyl group; and

[0055] B represents a nitrile group; a carboxylic acid group, a carboxylic ester group, or a carboxylic amide group.

[0056] In one embodiment of the invention, R1 in formula (I) represents a hydrogen atom, an alkyl group comprising 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. R1 can be, for example, methyl, ethyl, propyl; butyl, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, or tert-butoxy. Preferably, R1 represents a 4-methyl group.

[0057] In formula (I), R2 and R3 represent hydrogen atoms independently of each other and independently of R1, and are alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms. R2 and / or R3 can be, for example, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, or tert-butoxy. Preferably, both R2 and R3 represent hydrogen atoms.

[0058] According to one embodiment, R1, R2 and / or R3 in formula (I) may independently represent halogen atoms such as chlorine, fluorine or bromine; hydroxyl group; preferably a hydroxyalkyl group containing 1-4 carbon atoms; preferably a haloalkyl group containing 1-4 carbon atoms and / or a fluorine-substituent such as trifluoromethyl; amino group; alkylamino group having 1 to 10 carbon atoms; or amide group having 1 to 10 carbon atoms.

[0059] In a preferred embodiment, R1 represents a methyl group at the 4-position of an aryl group, and both R2 and R3 represent hydrogen.

[0060] According to one embodiment, group A in formula (I) represents a C1-C5 alkyl group or a hydrogen atom. Group A can be, for example, methyl, ethyl, propyl; butyl, or pentyl. Preferably, group A is a hydrogen atom.

[0061] 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.

[0062] According to one embodiment of the present invention, the compound of formula (I) can be an arylsulfonyl acrylonitrile. The compound of formula (I) can be selected from compounds of formula (I), which are 3-[(4-methylphenyl)sulfonyl]-2-acrylonitrile, 3-phenylsulfonyl-2-acrylonitrile, 3-[(4-fluorophenyl)sulfonyl]-2-acrylonitrile, 3-[(2,4-dimethylphenyl)sulfonyl]-2-acrylonitrile, 3-[(4-trifluoromethylphenyl)sulfonyl]-2-acrylonitrile, 3-[(3,4-dimethylphenyl)sulfonyl]-2-acrylonitrile, 3-(2,5-dimethylphenyl)sulfonyl-2-acrylonitrile, 3-[(2,4,6-trimethylphenyl)sulfonyl]-2-acrylonitrile, 3-(4-methoxyphenyl)sulfonyl-2-acrylonitrile, (3-[(4-methylphenyl)sulfonyl]-2-acrylonitrile ... 2-Acrylonitrile, 3-(4-acetylphenyl)sulfonyl-2-acrylonitrile, and any of their isomers. According to a preferred embodiment of the invention, the compound of formula (I) is selected from 3-[(4-methylphenyl)sulfonyl]-2-acrylonitrile; 3-phenylsulfonyl-2-acrylonitrile; 3-[(4-trifluoromethylphenyl)sulfonyl]-2-acrylonitrile; 3-[(2,4,6-trimethylphenyl)sulfonyl]-2-acrylonitrile; 3-(4-methoxyphenyl)sulfonyl-2-acrylonitrile; 3-[(4-methylphenyl)sulfonyl]prop-2-acrylonitrile; and any of their isomers. Preferably, the compound of formula (I) can be 3-[(4-methylphenyl)sulfonyl]-2-acrylonitrile.

[0063] In the method of the present invention, the components of the first reaction mixture are mixed together in solution form, preferably under an inert atmosphere, such as a nitrogen atmosphere. According to one embodiment, the first reaction mixture can be formed at a temperature of 15-40°C, preferably 20-30°C, more preferably 25-30°C. Advantageously, the first reaction mixture can be formed at room temperature and does not require extensive heating. It has been observed that the components of the catalyst complex, namely Cu(I) and the ligands, are effectively soluble in the reactive solvent at the temperature used, thereby simplifying the method. The formation of the first reaction mixture preferably does not involve any heating.

[0064] Generally, 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 the reaction mixture to avoid the formation of undesirable polynuclear catalyst complexes. Preferably, the molar amount of halide anion in the first reaction mixture does not exceed the molar amount of Cu(I). Therefore, it is preferable not to introduce other sources of free halide anions if possible.

[0065] Preferably, the organic sulfonate is supplied as a salt, preferably an ammonium salt such as N-methylmorpholineonium salt.

[0066] The first reaction mixture comprises a catalyst complex of Cu(I) and a ligand, as well as an organic sulfonate balance ion and a reactive solvent. The ligand affects the reducing power of Cu(I). The ligand can be selected from monodentate amine ligands, bidentate amine ligands, polydentate amine ligands, aryl sulfonates, and alkyl sulfonates. Suitable monodentate, bidentate, or polydentate amine ligands can be selected from, for example, triethylamine, N-methylmorpholine, N,N,N',N'-tetramethylethylenediamine, and N,N,N',N'”,N”-pentamethyldiethylenetriamine. According to a preferred embodiment, the ligand can be a bidentate amine ligand, such as morpholine or a substituted morpholine. The ligand can be an alkylmorpholine, such as N-methylmorpholine.

[0067] The balancing ion component comprises an organic sulfonate, which may be an aryl sulfonate or an alkyl sulfonate, selected from methanesulfonate, ethanesulfonate, benzenesulfonate, 4-toluenesulfonate, and xylenesulfonate. Preferably, the balancing ion is a methanesulfonate or p-toluenesulfonate. The balancing ion can exist as an external component of the catalyst complex because it is negatively charged and can bind to a positively charged internal component, which comprises Cu(I), a ligand, and optionally a reactive solvent molecule.

[0068] The reactive solvent used in the first reaction mixture can be selected from (meth)acrylonitrile or alkyl (meth)acrylates, such as methyl acrylate or methyl methacrylate. Preferably, the reactive solvent can be acrylonitrile. According to a preferred embodiment of the invention, the first reaction mixture does not contain any solvents other than the reactive solvent. This means that no solvents other than the reactive solvent are added to the first reaction mixture.

[0069] As defined above, the catalyst complex of Cu(I) and the ligand is dissolved in a reactive solvent to obtain a first reaction mixture in solution form. In the method according to the invention, the reactive solvent acts as a reactant, solvent, and co-ligand. The use of the reactive solvent, as defined, further improves the reducing power of Cu(I), thereby improving the reaction efficiency between the catalyst complex and the arylsulfonyl halide, and possibly even improving the reaction yield. 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 can effectively dissolve the halogenated Cu(I) and the ligand even at room temperature. As mentioned above, the formation of the first reaction mixture does not require heating. In addition, the excess reactive solvent allows for the exclusion of other solvents in subsequent process steps for forming the reaction mixture and in the desired reaction for obtaining the intermediate product of formula (I). This simplifies the method and improves the conversion and / or yield. However, only a small excess of reactive solvent may be added or required.

[0070] The first reaction mixture may contain a particular substance: the catalyst complex may contain a minor amount of Cu(II), which is insoluble in the reactive solvent and remains in particulate form. The amount of Cu(II) may be 0.5-5 mol-%, calculated based on the total molar amount of copper in the first reaction mixture. Cu(II) ions can inhibit the polymerization of reactive solvents such as acrylonitrile in the reaction mixture during successive process steps. This can be considered advantageous because it reduces the amount of undesirable side reactions and the formation of compounds other than the desired compound of formula (I). The presence of Cu(II) is not essential.

[0071] The aryl sulfonyl halide can be a benzenesulfonyl halide, an alkyl-substituted benzenesulfonyl halide, or a halogen-substituted benzenesulfonyl halide, such as a toluenesulfonyl halide, a xylenesulfonyl halide, a 4-methoxybenzenesulfonyl halide, or a 4-chlorobenzenesulfonyl halide, preferably a toluenesulfonyl chloride or a toluenesulfonyl bromide, more preferably a toluenesulfonyl chloride. For example, the aryl sulfonyl halide can be a 4-toluenesulfonyl halide, preferably a 4-toluenesulfonyl chloride or a 4-toluenesulfonyl bromide, more preferably a 4-toluenesulfonyl chloride. The aryl sulfonyl halide can be added in an amount (in moles) of 0.2-0.5 equivalents, preferably 0.3-0.5 equivalents, more preferably 0.35-0.4 equivalents, relative to the amount of reactive solvent in the first reaction mixture. The aryl sulfonyl halide dissolves in the first reaction mixture under endothermic conditions.

[0072] Preferably, the first reaction mixture does not contain any solvent other than the reactive solvent, that is, the first reaction mixture does not contain any solvent other than the reactive solvent. The first reaction mixture may contain the reactive solvent in an amount (in moles) at least 1.5 times, preferably at least 2 times, and more preferably at least 3 times (in moles) relative to the amount of the arylsulfonyl halide. The molar amount of the reactive solvent may be up to 5 times the molar amount of the arylsulfonyl halide.

[0073] In one embodiment, a pre-reaction mixture comprising a catalyst complex containing Cu(I) and a ligand, an organic sulfonate ion, and a reactive solvent is formed, and an arylsulfonyl halide is added to it to form a first reaction mixture. In another embodiment, no pre-reaction mixture is formed.

[0074] The arylsulfonyl halide can be added as a single dose or as multiple consecutive doses, such as 2, 3 or more successive doses, to the pre-reaction mixture or the first reaction mixture. It is also possible to add it continuously. Preferably, the arylsulfonyl halide is added as a single dose.

[0075] The amount of Cu(I) halide, preferably Cu(I) chloride, in the first reaction mixture can be 2.5-30 mol%, preferably 5-20 mol%, more preferably 7.5-15 mol% or 7.5-12.5 mol%, calculated based on the amount of arylsulfonyl halide in the first reaction mixture. The amount of ligand, preferably alkylsulfonate or arylsulfonate such as methanesulfonate, in the first reaction mixture can be 7-45 mol%, preferably 10-30 mol%, more preferably 12.5-22.5 mol%, calculated based on the amount of arylsulfonyl halide in the first reaction mixture.

[0076] After the arylsulfonyl halide is added to and dissolved in the first reaction mixture, the reaction is carried out, preferably under an inert atmosphere such as nitrogen, at an elevated temperature, thereby obtaining the intermediate product. The reaction is a free radical addition reaction. Preferably, the reaction is carried out at an elevated temperature above the boiling point of the reactive solvent but below the boiling point of the reaction mixture. The reaction in the first reaction mixture can be carried out at an elevated temperature of 80-95°C, preferably 85-92°C, more preferably 88-90°C. The reaction is carried out until the desired conversion of the intermediate product is obtained. The reaction time can be, for example, 5-30 hours, preferably 10-24 hours or 18-24 hours.

[0077] After the reaction has proceeded to the desired conversion, the unreacted reactive solvent can be separated from the first reaction mixture. The reactive solvent can be separated by any suitable separation method, such as distillation. According to a preferred embodiment, the reactive solvent can be separated from the first reaction mixture, optionally purified, and then recycled back to step (a) in the method. In this way, the unreacted reactive solvent can be reused to prepare the first reaction mixture and the amount of chemical waste generated can be effectively reduced.

[0078] After separating the unreacted reactive solvent, the obtained intermediate product is dissolved in a low-polarity solvent to form a second reaction mixture. The intermediate product can be dissolved in a low-polarity solvent having a relative polarity of <0.4, preferably <0.3, or even <0.25, thereby forming the second reaction mixture. For the purposes of this document, relative polarity values ​​provided, for example, in Reichardt, C. (ed.) and Welton, T. (ed.), "Solvents and Solvent Effects in Organic Chemistry", 4th Ed., 2011, Wiley-VCH Verlag GmbH & Co., Weinheim, Appendix A, or other similar manuals can be used. The low polarity of the low-polarity solvent reduces its miscibility with water, which simplifies the separation of the intermediate product from the aqueous phase. The low-polarity solvent can be considered hydrophobic. The low-polarity solvent may be free of carboxyl or hydroxyl groups. The low-polarity solvent suitable for use in this invention can be selected, for example, ethyl acetate, butyl acetate, tetrahydrofuran, dioxane, and toluene. According to a preferred embodiment, the low-polarity solvent is ethyl acetate.

[0079] After the addition of a low-polarity solvent, Cu(I) generally precipitates from the liquid phase of the second reaction mixture. The Cu(I) precipitate can be readily separated from the liquid phase of the second reaction mixture, which contains the low-polarity solvent and the intermediate product, for example, by filtration.

[0080] After dissolving the intermediate product in a low-polarity solvent to form a second reaction mixture and optionally separating it with a Cu(I) precipitate, a base can be added to the second reaction mixture to eliminate halogen atoms from the intermediate product to form a compound of formula (I). The intermediate product undergoes an elimination reaction in the presence of a base, wherein halogen atoms are removed from the intermediate product, i.e., base-catalyzed elimination of halogen atoms, and a compound of formula (I) is obtained. The base used can be an inorganic base, an organic base, or a combination of inorganic and organic bases, preferably a combination of inorganic and organic bases. The elimination reaction is exothermic, therefore it is preferred to add the base and carry out the elimination reaction under cooling. According to a preferred embodiment, during the elimination of halogen atoms from the intermediate product, the second reaction mixture is maintained at a temperature of 15-40°C, preferably 20-35°C, more preferably 20-25°C.

[0081] A base may be added to the second reaction mixture in an amount (in moles) relative to the amount of the intermediate dissolved in the second reaction mixture, which is at least 0.9 equivalents, for example, in the range of 0.9 to 1.5, preferably 0.9 to 1.3 equivalents, most preferably about 1 equivalent; or at least 1 equivalent, or even at least 1.3 equivalents, but higher amounts are less preferred.

[0082] According to one embodiment of the invention, the base added to the second reaction mixture may be or comprises an inorganic base, preferably selected from the group consisting of alkali metal bicarbonates and carbonates and alkaline earth metal carbonates or any mixture 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 a preferred embodiment, sodium bicarbonate or sodium carbonate is used as the inorganic base.

[0083] According to one embodiment of the invention, the base added to the second reaction mixture may be or contains an organic base, preferably selected from trialkylamines, such as triethylamine, trimethylamine; N-methylmorpholine; N-methylpyrrolidine; N,N-diisopropylethylamine (Hünig base); 1,4-diazabicyclo[2.2.2]octane (DABCO); 1,8-diazabicyclo[5.4.0]undecane-7-ene (DBU); or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or any mixture thereof.

[0084] According to a preferred embodiment of the invention, the base may be a combination of an inorganic base and an organic base, as defined above. The base may comprise 0.8-0.95 equivalents, preferably 0.9-0.95 equivalents, of an inorganic base and 0.05-0.2 equivalents, preferably 0.05-0.1 equivalents, of an organic base, in molar equivalents. The inorganic base and the organic base may be added to the second reaction mixture, either separately but simultaneously, or separately and sequentially. Preferably, the inorganic base is added first, followed by the organic base.

[0085] The second reaction mixture may preferably contain water. Water may be introduced into the second reaction mixture either together with or after the addition of a base, preferably, for example, after the addition of an inorganic base and / or an organic base. The amount of water in the second reaction mixture may be 15-200 wt%, preferably 40-150 wt%, more preferably 55-100 wt%, based on the amount of inorganic base in the second reaction mixture. Effective stirring of the second reaction mixture during the elimination reaction prevents phase separation between water and the low-polarity solvent. The water content of the second reaction mixture enables phase transfer processes involving both organic and inorganic bases (if both are present), which improves the efficiency of base-catalyzed elimination reactions.

[0086] After the elimination reaction is complete, compound (I) is separated from the second reaction mixture. Typically, the precipitate contains both organic and inorganic salts, such as copper salts. The precipitate can be easily separated from the organic solvent phase, for example, by filtration. Compound (I) remains in the organic solvent phase of the second reaction mixture formed by a low-polarity solvent. The organic phase can be washed with a mixture of sodium chloride and an organic acid, such as acetic acid or citric acid. A relatively pure compound (I) can be obtained by removing the organic phase (e.g., by evaporation), wherein the compound (I) crystallizes, and a solid or semi-solid product is obtained.

[0087] The term "comprising," as used throughout this specification and claims, means "including or consisting of." This term indicates that it includes at least the features following the term and does not exclude the inclusion of other features not expressly mentioned. The term can also refer to an entity consisting solely of the features following the term.

[0088] experiment

[0089] Embodiments of the invention are described more closely in the following non-limiting examples.

[0090] Example 1

[0091] The following chemicals and reagents were used in the examples:

[0092] 4-Methylmorpholine, Sigma-Aldrich, purulum >98%

[0093] Methanesulfonic acid, Alfa Aesar, 98+%

[0094] Copper chloride (I), Alfa Aesar, 97%

[0095] Acrylonitrile, Ineos, 99.4%

[0096] Toluenesulfonyl chloride, Sigma-Aldrich, purulum > 98%.

[0097] The chemicals and solvents used—methanol (MeOH), toluene, ethyl acetate (EtOAc), sodium carbonate, acetic acid, and sodium chloride—were reagent grade and obtained from commercial sources.

[0098] Step I: Preparation of ligands (4-methylmorpholinium methanesulfonate, NMM*MsOH) for catalyst complexes

[0099] Under cooling with cold water / ice, 0.49 mol of methanesulfonic acid MsOH (20% methanol solution) was slowly added to a stirred solution of 0.5 mol of 4-methylmorpholine NMM (20% methanol solution). The temperature was maintained below 40°C during the addition. After the addition of MsOH was complete, the methanol was removed under reduced pressure using a rotary evaporator, yielding a pale yellow oily residue. 80 mL of toluene was added to the residue and evaporated using a rotary evaporator. Azeotropic drying was repeated with the same amount of toluene. Evaporation continued until the salt crystallized. 4-Methylmorpholine onyx methanesulfonate, NMM*MsOH, was formed in a quantitative yield.

[0100] Step II: Preparation of the pre-reaction mixture

[0101] Under a nitrogen atmosphere, 2.817 g CuCl (0.02756 mol), 8.337 g NMM*MsOH (0.04227 mol) prepared in step I, and 37.25 g acrylonitrile (0.702 mol) were charged into a 250 mL 1-necked round-bottom flask. The pre-reaction mixture was stirred for 0.5 hours at room temperature under a nitrogen atmosphere. Within 10–15 minutes, an almost transparent yellow-green solution of Cu(I)-complex with NMM and acrylonitrile was formed.

[0102] Step III: Preparation of the first reaction mixture and free radical addition reaction. 3-[(4-methylphenyl)sulfonyl]-2-chloropropane nitrile.

[0103] Add 52.0 g of toluenesulfonyl chloride (0.273 mol) in a batch to the pre-reaction mixture prepared in step II. Stir the resulting first reaction mixture under a nitrogen atmosphere for approximately 0.5 hours. Increase the temperature to 88 °C over 1 hour. Continue stirring and heating at 88 °C overnight. Cool the reaction flask to room temperature and analyze the obtained intermediate product by thin-layer chromatography (TLC) (ethyl acetate:hexane 1:5).

[0104] Step IV: Preparation of the second reaction mixture and elimination reaction.

[0105] Acrylonitrile was removed from the first reaction mixture obtained in step III under reduced pressure, and 40 ml of ethyl acetate was added in two portions and evaporated. This removed any possible trace amounts of acrylonitrile.

[0106] The intermediate product was dissolved in 150 g of ethyl acetate to form a second reaction mixture. A Cu(I)-containing precipitate formed during this stage and was separated from the liquid phase by filtration. The liquid phase, i.e., the second reaction mixture, was placed in a 500 mL round-bottom flask. 13.07 g of Na₂CO₃ was added with stirring at 27 °C. After the addition of 6.7 mL of deionized water, slow gas generation began, and the mixture temperature was 28 °C. A batch of 2.77 g of NMM (10 mol-% toluenesulfonyl chloride) was added. The temperature of the reaction mixture was 31 °C. Samples were taken at 0 min; 1 hour 10 min; 2 hours 30 min; 4 hours 5 min; 6 hours 15 min; and 22 hours 30 min for ultra-high performance liquid chromatography (UPLC) analysis. In the final sample, the content of E-3-[(4-methylphenyl)sulfonyl]-2-acrylonitrile was 13.7 wt% (79% theoretical yield), and no intermediate product was found.

[0107] Step V: Purification and isolation of the desired compound.

[0108] The yellow organic liquid phase was separated from the semi-solid precipitate formed during the elimination reaction by decantation. The precipitate was washed twice with 30 ml of ethyl acetate. The ethyl acetate solution was combined with the organic liquid phase. The combined organic phase was washed three times with 20 ml (each) of a washing solution containing 50 g NaCl, 30 g acetic acid, and 420 g deionized water, and once with 10 ml of deionized water. The washing was performed by stirring on a magnetic stirrer (500 rpm, 5 minutes).

[0109] After washing, the organic liquid phase was placed on a rotary evaporator and the ethyl acetate was evaporated to dryness. The reaction product crystallized during evaporation. 25 ml of methanol was added to the crystallized reaction product and the mixture was refluxed in a water bath for 0.5 hours, slowly cooled to room temperature, and then placed in a refrigerator overnight (6°C).

[0110] The filtered product was washed with 50 ml of cold methanol and dried under reduced pressure in a water bath (80-90℃).

[0111] Yield: 35.21g, 62.5% of theoretical value.

[0112] Example 2

[0113] Step I: Preparation of ligands (4-methylmorpholinium toluenesulfonate, NMM*TosOH) for catalyst complexes

[0114] Dissolve 5.37 g of toluenesulfonic acid (TosOH*H2O, approximately 0.028 mol) in 7 mL of MeOH. Add 2.93 g of N-methylmorpholine, and evaporate the resulting solution to dryness in a rotary evaporator using a water bath at 90-95 °C. Obtain a colorless crystalline salt in quantitative yield.

[0115] Step II: Preparation of the first reaction mixture and free radical addition reaction. 3-[(4-methylphenyl)sulfonyl]-2-chloropropane nitrile.

[0116] In a 50 ml round-bottom reaction flask, charge 265.2 mg CuCl (approximately 2.6 mmol), 1,1154 NMM*TosOH (approximately 4 mmol), 9.83 g toluenesulfonyl chloride, TosCl (approximately 0.05 mol), and 9.09 g acrylonitrile (approximately 0.1715 mol).

[0117] The resulting transparent, pale yellow-green reaction mixture was refluxed under N2 (T) set =88℃) and magnetically stirred for 16 hours.

[0118] Through H 1 NMR, CDCl3 measurements showed that approximately 60% of the TosCl conversion was achieved.

[0119] Unreacted acrylonitrile is evaporated using a rotary evaporator in a water bath at 50-80°C. An oily product is formed. Ethyl acetate (EtOAc) (20 ml) is added and evaporation is repeated to remove residual acetonitrile.

[0120] Step III: Preparation of the second reaction mixture and elimination reaction.

[0121] Dissolve the oily reaction product in 50 ml of EtOAc and transfer it to a 100 ml round-bottom reaction flask. Add 2.4 g of Na2CO3 (approximately 23 mmol), 4 ml of water, and 0.5 ml of N-methylmorpholine (approximately 5 mmol).

[0122] A pale yellow reaction mixture was obtained. No crystallization was observed in the organic solution. The reaction mixture was stirred overnight at room temperature.

[0123] The following morning, the organic phase was separated in a separatory funnel. The aqueous layer was washed twice with 15 ml of EtOAc. The combined organic phases were then washed twice with 10 ml of 1 wt% citric acid / 10 wt% NaCl.

[0124] Then, evaporate EtOAc using a rotary evaporator, add 10 ml of MeOH, and repeat the evaporation. Add 10 ml of MeOH, reflux the mixture without stirring, and slowly cool to room temperature.

[0125] The product was filtered, washed with 10 ml of cold MeOH, and dried under reduced pressure (30-40 mbar) at 60-75 °C. Colorless crystals were obtained.

[0126] Upon resolvation, the product was found to be 97.2% pure, with approximately 2.2% insoluble matter and 0.6% other impurities.

[0127] The purified product was analyzed by GC-MS. The sample purity was approximately 99.42% when using this analytical method.

[0128] Example 3 (Comparative)

[0129] Step I: Preparation of the first reaction mixture and free radical addition reaction. 3-[(4-methylphenyl)sulfonyl]-2-chloropropane nitrile.

[0130] In a 100 ml round-bottom reaction flask, add 101.5 mg CuCl (approximately 1 mmol), 214.1 mg triethylamine chloride Et3N*HCl (approximately 1.55 mmol), 19.19 g toluenesulfonyl chloride TosCl (approximately 0.1 mol), and 10.6 g acrylonitrile (approximately 0.2 mol).

[0131] The resulting transparent pale yellow reaction mixture was refluxed under N2 (T) set =88℃) and magnetically stirred for 16 hours.

[0132] Through H 1 NMR, CDCl3 measurements showed that approximately 75% of the TosCl conversion was achieved.

[0133] Unreacted acrylonitrile is evaporated using a rotary evaporator in a water bath at 50-80°C, forming an oily product. Ethyl acetate (EtOAc) (30 ml) is added, and evaporation is repeated to remove residual acetonitrile.

[0134] Step II: Preparation of the second reaction mixture and elimination reaction.

[0135] The reaction product was dissolved in 100 ml of EtOAc and transferred to a 250 ml round-bottom reaction flask. 4.77 g of Na₂CO₃ (approximately 45 mmol), 6 ml of water, and 1 ml of N-methylmorpholine (approximately 10 mmol) were added. A small amount of crystalline product was observed in the organic solution. The solution was almost colorless. The reaction mixture was stirred overnight at room temperature.

[0136] The following morning, the organic phase was separated in a separatory funnel. The aqueous layer was washed twice with 25 ml of EtOAc. The combined organic phases were washed twice with 10 ml of 1% wt citric acid / 10% wt NaCl. The EtOAc was evaporated, 10 ml of MeOH was added, and evaporation was repeated. 25 ml of MeOH was added, the mixture was refluxed without stirring, and slowly cooled to room temperature.

[0137] The product was filtered, washed with 10 ml of cold MeOH, and dried under reduced pressure (30-40 mbar) at 60-75 °C. Colorless crystals were obtained.

[0138] Upon resolvation, the product was found to be 95.3% pure, with approximately 4.4% insoluble matter and 0.3% other impurities.

[0139] in conclusion

[0140] Comparative Example 3 is based on a catalyst complex containing a relatively high amount of chloride as a counterion and lacking organosulfonate ions. This addition reaction yields an intermediate product in which the organic phase contains some crystalline precipitates not observed in the corresponding Example 2 of the invention. Upon washing and recrystallization, the elimination product of Comparative Example 3 was found to contain significantly more solids and other impurities.

[0141] It is possible that sulfonyl radical recombination products may appear in the comparative examples. This could be due to the use of Cl-based products. - The catalyst allows for the formation of polynuclear Cu-complexes with Cl-bridge atoms. Using an organic sulfonate anion as a balancing ion solves this problem and makes it possible to use high-loading catalysts and even more robust synthetic methods.

Claims

1. A method for preparing compounds of formula (I) (I) in R1, R2, and R3 independently represent hydrogen atoms; halogen atoms; hydroxyl groups; alkyl groups; hydroxyalkyl groups; haloalkyl groups; alkoxy groups having 1 to 4 carbon atoms; amino groups; amide groups or alkylamino groups having 1 to 10 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 ester group, or a carboxylic amide group; The method includes the following steps: (a) forming a first reaction mixture, the first reaction mixture comprising - Catalyst complexes comprising Cu(I) halide and ligands, wherein the ligands are selected from monodentate, bidentate or polydentate amine ligands; - Organic sulfonate balance ions, wherein the organic sulfonate ions include aryl sulfonate ions or alkyl sulfonate ions selected from methanesulfonate ions, ethanesulfonate ions, benzenesulfonate ions, 4-toluenesulfonate ions and xylenesulfonate ions; -A reactive solvent selected from (meth)acrylonitrile or (meth)acrylate alkyl esters; and -Arylsulfonyl halide reactants; (b) The reaction is carried out at an elevated temperature in the first reaction mixture to obtain an intermediate product; (c) Separate the unreacted reactive solvent from the first reaction mixture and dissolve the intermediate product in a low-polarity solvent to form a second reaction mixture; (d) A base is added to the second reaction mixture, wherein the intermediate product undergoes base-catalyzed elimination of halogen atoms from the intermediate product to form a compound of formula (I); and (e) Separate compound (I) from the second reaction mixture.

2. The method according to claim 1, characterized in that In step (d), the base is added to the second reaction mixture under cooling.

3. The method according to claim 1, characterized in that In step (d), the intermediate product is dissolved in a low-polarity solvent with a relative polarity of <0.4 to form a second reaction mixture.

4. A method according to claim 1, 2 or 3, characterised in that The low-polarity solvent is selected from ethyl acetate, butyl acetate, tetrahydrofuran, dioxane, and toluene.

5. The method according to claim 1, 2 or 3, characterized in that In step (b), the increased temperature of 80-95°C causes the reaction to proceed in the first reaction mixture.

6. The method according to claim 5, characterized in that In step (b), the increased temperature of 85-92°C causes the reaction to proceed in the first reaction mixture.

7. The method according to claim 1, 2 or 3, characterized by The reactive solvent separated from the first reaction mixture in step (c) is recycled back to step (a) to form the first reaction mixture.

8. The method according to claim 1, 2 or 3, characterized by In step (e), the second reaction mixture is maintained at a temperature of 15-40°C.

9. The method according to claim 8, characterized in that In step (e), the second reaction mixture is maintained at a temperature of 20-35°C.

10. The method according to claim 1, 2 or 3, characterized in that... In step (d), the base is added to the second reaction mixture in an amount of at least one equivalent relative to the amount of the intermediate dissolved in the second reaction mixture.

11. The method according to claim 1, 2 or 3, characterized by The base in step (d) contains an inorganic base.

12. The method according to claim 11, characterized by The base in step (d) comprises an inorganic base selected from alkali metal bicarbonates or carbonates or alkaline earth metal carbonates, or any mixture thereof.

13. The method according to claim 1, 2 or 3, characterized by The base in step (d) contains an organic base.

14. The method according to claim 13, characterized by The base in step (d) comprises an organic base selected from triethylamine, trimethylamine; N-methylmorpholine; N-methylpyrrolidine; N,N-diisopropylethylamine; 1,4-diazabicyclo[2.2.2]octane; 1,8-diazabicyclo[5.4.0]undecane-7-ene; or 1,5-diazabicyclo[4.3.0]non-5-ene.

15. The method according to claim 1, 2 or 3, characterized by The base in step (d) is a combination of an inorganic base and an organic base, the combination comprising 0.8-0.95 equivalents of an inorganic base and 0.05-0.2 equivalents of an organic base, in molar equivalents.

16. The method of claim 1, 2 or 3, characterized by The amount of Cu(I) halide in the first reaction mixture is 2.5-30 mol-%, calculated based on the amount of arylsulfonyl halides in the first reaction mixture.

17. The method of claim 16, characterized by The amount of Cu(I) halide in the first reaction mixture is 5-20 mol-%, calculated based on the amount of arylsulfonyl halides in the first reaction mixture.

18. The method of claim 17, characterized by The amount of Cu(I) halide in the first reaction mixture is 7.5-15 mol-%, calculated based on the amount of arylsulfonyl halides in the first reaction mixture.

19. The method of claim 1, 2 or 3, characterized by The amount of ligand in the first reaction mixture is 7-45 mol-%, calculated based on the amount of arylsulfonyl halide in the first reaction mixture.

20. The method of claim 19, characterized by The amount of ligand in the first reaction mixture is 10-30 mol-%, calculated based on the amount of arylsulfonyl halide in the first reaction mixture.

21. The method of claim 1, 2 or 3, characterized by In step (a), an arylsulfonyl halide is added in an amount of 0.2 to 0.5 equivalents relative to the amount of reactive solvent in the first reaction mixture to form the first reaction mixture.

22. The method of claim 21, characterized by In step (a), an arylsulfonyl halide is added in an amount of 0.3 to 0.5 equivalents relative to the amount of reactive solvent in the first reaction mixture to form the first reaction mixture.

23. The method of claim 1, 2 or 3, characterized by Step (a) includes: (i) forming a pre-reaction mixture, the pre-reaction mixture comprising - Catalyst complexes of Cu(I) and ligands; -Organic sulfonate ions; and -A reactive solvent selected from (meth)acrylonitrile or (meth)acrylate alkyl esters; and (ii) A certain amount of arylsulfonyl halide reactant is added to the pre-reaction mixture to form the first reaction mixture.

24. The method of claim 23, wherein The pre-reaction mixture is formed at a temperature of 15-40°C.

25. The method of claim 24, wherein The pre-reaction mixture is formed at a temperature of 20-30°C.

26. The method of claim 1, 2, or 3, characterized by The compound of formula (I) is 3-[(4-methylphenyl)sulfonyl]-2-acrylonitrile.

27. The method of claim 1, 2, or 3, characterized by Cu(I) halide is Cu(I) chloride.

28. The method of claim 27, wherein In the first reaction mixture, the molar amount of halide anions does not exceed the molar amount of Cu(I).

29. The method of claim 1, 2, or 3, characterized by It provides organic sulfonate ions as a salt.

30. The method of claim 29, wherein It provides organic sulfonate as an ammonium salt.

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