METHOD FOR PREPARING ARYLVINYLSULPHONES

Abstract

The invention relates to a method of preparing arylvinylsulphones. The method comprises forming o a first reaction mixture comprising a catalyst complex of Cu(I)halide and a ligand, wherein the ligand is selected from mono-, bi- or polydentate amine ligands and further comprises an organic sulphonate; a reactive solvent selected from (meth)acrylonitrile or alkyl (meth)acrylate; and an aryl sulfonyl halide reactant. A reaction is allowed to proceed in the first reaction mixture at an elevated temperature, whereby an intermediate product is obtained. The unreacted reactive solvent is separated from the first reaction mixture, and the intermediate product is dissolved to a low polarity solvent to form a second reaction mixture. A base is added 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. Finally, the desired compound is separated from the second reaction mixture.

Claims

1-20. (canceled)

21. Method for preparing a compound of formula (I) ##STR00004## 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 1 to 4 carbon atoms; an amino group; an alkylamino group or an acylamido group 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 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.

22. Method according to claim 21, wherein the intermediate product is dissolved in step (d) into a low polarity solvent, which has a relative polarity of <0.4 to form the second reaction mixture, wherein the low polarity solvent may be selected from a group consisting of ethyl acetate, butyl acetate, tetrahydrofuran, dioxane and toluene.

23. Method according to claim 21, wherein the reaction in the first reaction mixture in step (c) is allowed to proceed at the elevated temperature of 80-95° C., preferably 85-92° C., more preferably 88-90° C.

24. Method according to claim 21, wherein the reactive solvent, which is separated from the first reaction mixture in step (c), is recycled back to step (a) for formation of first reaction mixture.

25. Method according to claim 21, wherein the second reaction mixture in step (e) is maintained in a temperature of 15-40° C., preferably 20-35° C., more preferably 20-25° C.

26. Method according to claim 21, wherein the base in step (d) comprises an inorganic base, preferably selected from bicarbonates or carbonates of alkali metals or carbonates of earth alkaline metals, or any mixtures thereof.

27. Method according to claim 21, wherein the base in step (d) comprises an organic base, preferably selected from trialkylamines, such as triethylamine, trimethylamine; N-methylmorpholine; N-methylpyrrolidine; N, N-diisopropylethylamine; 1,4-diazabicyclo[2.2.2]octane; 1,8-diazabicyclo[5.4.0]undec-7-ene; or 1,5-diazabicyclo-[4.3.0]non-5-ene.

28. Method according to claim 21, wherein the base in the step (d) is a combination of an inorganic base and an organic base, preferably comprising 0.8-0.95 equivalent of an inorganic base and 0.05-0.2 equivalent of an organic base, given as molar equivalents.

29. Method according to claim 21, wherein the amount of Cu(I)halide in the first reaction mixture is 2.5-30 mol-%, preferably 5-20 mol-%, more preferably 7.5-15 mol-%, calculated from the amount of the aryl sulphonyl halide in the first reaction mixture.

30. Method according to claim 21, wherein the organic sulphonate in step (a) comprises an aryl sulphonate or alkyl sulphonate which is preferably selected from a group of methanesulphonate, ethanesulphonate, benzenesulphonate, 4-toluenesulphonate, and xylenesulphonate.

31. Method according to claim 21, wherein the amount of the ligand in the first reaction mixture is 7-45 mol-%, preferably 10-30 mol-%, more preferably 12.5-22.5 mol-%, calculated from the amount of the aryl sulphonyl halide in the first reaction mixture and/or wherein aryl sulphonyl halide is added, to form the first reaction mixture in step (a), in amount of 0.2-0.5 equivalents, preferably 0.3-0.5 equivalents, more preferably 0.35-0.4 equivalents, relative to the amount of the reactive solvent in the first reaction mixture.

32. Method according to claim 21, wherein step (a) comprises (i) forming a pre-reaction mixture comprising a catalyst complex of the Cu(I) and the ligand; the organic sulphonate counterion; and a reactive solvent selected from (meth)acrylonitrile or alkyl (meth)acrylate; and (ii) adding an amount of aryl sulfonyl halide reactant to the pre-reaction mixture to form the first reaction mixture, wherein the pre-reaction mixture may be formed at a temperature of 15-40° C., preferably 20-30° C., more preferably 25-30° C.

33. Method according to claim 21, wherein the compound according to formula (I) is 3-[(4-methylphenyl)sulphonyl]-2-propenenitrile.

34. Method according to claim 21, wherein the Cu(I) is provided as a Cu(I) halide, preferably a Cu(I) chloride, wherein the molar amount of halide ions in the first reaction mixture may be no more than the molar amount of Cu(I).

35. Method according to claim 21, wherein the organic sulphonate is supplied as a salt, preferably an ammonium salt.

Description

EXPERIMENTAL

[0060] Embodiments of the invention are described more closely in the following non-limiting examples.

EXAMPLE 1

[0061] The following chemicals and reagents were used in the Example: [0062] 4-methylmorpholine, Sigma-Aldrich, purum >98% [0063] methanesulfonic acid, Alfa Aesar, 98+% [0064] copper(I) chloride, Alfa Aesar, 97% [0065] acrylonitrile, Ineos, 99.4% [0066] toluenesulfonyl chloride, Sigma-Aldrich, purum >98%.

[0067] 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.

Step I: Preparation of the Ligand (4-methylmorpholinium hydromethanesulfonate, NMM*MsOH) for the Catalyst Complex

[0068] 0.49 mol methanesulfonic acid, MsOH (20% solution in methanol) was added slowly to a stirred 0.5 mol solution of 4-methylmorpholine, NMM (20% solution in methanol) under cooling with cold water/ice. Temperature during the addition was kept under 40° C. After the addition of MsOH was completed, methanol was removed under reduced pressure on rotary evaporator and a yellowish oily residue was obtained. 80 ml 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. 4-methylmorpholinium hydromethanesulfonate, NMM*MsOH, was formed in quantitative yield.

Step II: Preparation of the Pre-Reaction Mixture

[0069] 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) was charged in a 250 ml 1-neck round-bottom flask under nitrogen atmosphere. The pre-reaction mixture was stirred 0.5 h at room temperature under nitrogen atmosphere. Almost clear yellow-greenish solution of Cu(I)-complex with NMM and acrylonitrile was formed in 10-15 minutes.

[0070] Step III: Preparation of the First Reaction Mixture and Radical Addition Reaction. 3-[(4-Methylphenyl)sulfonyl]-2-chloropropanenitrile.

[0071] 52.0 g toluenesulfonyl chloride (0.273 mol) was added in one portion to the pre-reaction mixture prepared in Step II. The obtained first reaction mixture was stirred about 0.5 h under nitrogen atmosphere. Temperature was raised to 88° C. during 1 h. Stirring and heating at 88° C. 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 1:5).

Step IV: Preparation of the Second Reaction Mixture and the Elimination Reaction.

[0072] Acrylonitrile was removed from the first reaction mixture obtained in Step III under reduced pressure and 40 ml ethyl acetate was added in two portion and evaporated. This removed possible traces of acrylonitrile.

[0073] The intermediate product was dissolved in 150 g 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 500 ml round-bottom flask. 13.07 g Na.sub.2CO.sub.3 was added under stirring, temperature 27° C. After addition of 6.7 ml of deionized water a slow gas evaluation started, temperature of the mixture was 28° C. 2.77 g NMM (10 mol-% of toluenesulfonyl chloride amount) was added in one portion. Temperature of the reaction mixture was 31° C. Samples for analysis with ultra performance liquid chromatography, UPLC were taken at time 0 min; 1 h 10 min; 2 h 30 min; 4 h 5 min; 6 h 15 min; 22 h 30 min. In the last sample , the content of E-3-[(4-methylphenyl)sulfonyl]-2-propenenitrile was 13.7 weight-% (79% yield from theoretical), no intermediate product was found.

Step V: Purification and Separation of the Desired Compound.

[0074] A yellow organic liquid phase was separated from semi-solid precipitate formed during elimination reaction by decanting. The precipitate was washed twice with 30 ml ethyl acetate. The ethyl acetate solutions were combined with the organic liquid phase. The combined organic phase was washed with three times with 20 ml (per time) washing solution comprising 50 g NaCl, 30 g acetic acid and 420 g deionized water and once with 10 ml DI-water. The washing was conducted by stirring on magnetic stirrer (500 rpm, 5 min).

[0075] 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. 25 ml methanol was added to the crystallized reaction product and refluxed 0.5 h on water bath, cooled slowly to room temperature, and placed into fridge overnight (6° C.).

[0076] The product was filtered, washed with 50 ml of cold methanol and dried under reduced pressure on water bath (80-90° C.).

[0077] Yield 35.21 g, 62.5% from theoretical.

EXAMPLE 2

[0078] Step I: Preparation of the Ligand (4-methylmorpholinium toluenesulfonate, NMM*TosOH) for the Catalyst Complex

[0079] 5,37 g of toluenesulphonic acid, TosOH*H.sub.2O, (about 0.028 mol) was dissolved in 7 ml of MeOH. 2,93g of N-methylmorpholine was added and resulted solution was evaporated to dry in a rotary evaporator with a water bath temperature of 90-95° C. A colourless crystalline salt was obtained at quantitative yield.

Step II: Preparation of the First Reaction Mixture and Radical Addition Reaction. 3-[(4-Methylphenyl)sulfonyl]-2-chloropropanenitrile.

[0080] In a 50m1 round bottom reaction flask was charged 265,2 mg CuCl (about 2,6mmol), 1,1154 NMM*TosOH (about 4 mmol), 9,83 g toluene sulphonyl chloride, TosCl, (about 0,05 mol) and 9,09 g acrylonitrile (about 0,1715 mol).

[0081] The resulted clear yellowish-green reaction mixture was refluxed (T.sub.set=88° C.) and magnetically stirred under N.sub.2 for 16 h.

[0082] A conversion of TosCI of about 60% was achieved as measured by H.sup.1 NMR, CDCl.sub.3.

[0083] Unreacted acrylonitrile was evaporated using a rotary evaporator with a water bath at a temperature of 50-80° C. An oily product was formed. Ethyl acetate, EtOAc, (20 ml) was added and evaporation was repeated to remove residual acetonitrile.

Step III: Preparation of the Second Reaction Mixture and the Elimination Reaction.

[0084] The oily reaction product was dissolved in 50 ml EtOAc and transferred into a 100 ml round bottom reaction flask. 2,4 g of Na.sub.2CO.sub.3 (about 23 mmol), 4 ml of water and 0,5 ml of N-methylmorpholine (about 5 mmol) were added.

[0085] A yellowish reaction mixture was obtained. No crystalline product was observed in organic solution. The reaction mixture was stirred overnight at room temperature.

[0086] Next morning the organic phase was separated in a separation funnel. The water layer was washed twice with 15 ml of EtOAc. Combined organic phases were washed twice with 10 ml 1 wt % citric acid/10 wt % NaCl.

[0087] EtOAc was then evaporated using a rotary evaporator, 10 ml MeOH added and evaporation repeated. 10 ml MeOH was added, the mixture was refluxed without mixing and cooled slowly to room temperature.

[0088] The product was filtered, washed with 10 ml of cold MeOH and dried at 60-75° C. under reduced pressure (30-40 mbar). Colorless crystals were obtained.

[0089] Upon redissolution it was found that the product was 97.2% pure, with approximately 2.2% insolubles and 0.6% other impurities.

[0090] The above pure product was analysed by GC-MS. The purity of the sample was about 99,42% using this analytical method.

EXAMPLE 3 (comparative)

[0091] Step I: Preparation of the first reaction mixture and radical addition reaction. 3-[(4-Methylphenyl)sulfonyl]-2-chloropropanenitrile.

[0092] In a 100 ml round bottom reaction flask was charged 101,5 mg CuCl (about 1 mmol), 214,1 mg triethylamine chloride, Et.sub.3N*HCl, (about 1,55 mmol), 19,19 g toluene sulphonyl chloride, TosCl, (about 0,1 mol) and 10,6 g acrylonitrile (about 0,2 mol).

[0093] The resulting clear yellowish reaction mixture was refluxed (T.sub.set=88° C.) and magneticallly stirred under N.sub.2 for 16 h.

[0094] A conversion of TosCl of about 75% was achieved as measured by H.sup.1 NMR, CDCl.sub.3.

[0095] Unreacted acrylonitrile was evaporated using a rotary evaporator with a water bath at a temperature of 50-80° C. An oily product was formed. Ethyl acetate, EtOAc, (30 ml) was added and evaporation was repeated to remove residual acetonitrile.

Step II: Preparation of the Second Reaction Mixture and the Elimination Reaction.

[0096] The reaction product was dissolved in 100 ml EtOAc and transferred into 250 ml round bottom reaction flask. 4,77 g of Na.sub.2CO.sub.3 (about 45 mmol), 6 ml of water and 1 ml of N-methylmorpholine (about 10 mmol) 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.

[0097] Next morning the organic phase was separated in the separation funnel. The water layer was washed twice with 25 ml of EtOAc. Combined organic phases were washed twice with 10 ml 1 wt % citric acid/10wt % NaCl. EtOAc was evaporated, 10 ml MeOH added and evaporation repeated. 25 ml MeOH was added, the mixture was refluxed without mixing and cooled slowly to room temperature.

[0098] The product was filtered, washed with 10 ml of cold MeOH and dried at 60-under reduced pressure (30-40mbar). Colorless crystals were obtained.

[0099] Upon redissolution it was found that the product was 95.3% pure, with approximately 4.4% insolubles and 0.3% other impurities.

Conclusion

[0100] Comparative Example 3 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 2 according to the invention. The elimination product of Comparative Example 3 was found to contain significantly more solids and other impurities after washing and recrystallisation.

[0101] It is possible that sulfonyl radical recombination products may arise in the Comparative Example. This may be the result of the use of a Cl.sup.− based catalyst where formation of polynuclear Cu-complexes with Cl-bridge atoms can arise. The use of organic sulfonates as counterions may resolve this issue and make possible uses of high loads of catalyst and even more robust synthesis methods.