Process for the preparation of 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid

Abstract

The invention relates to novel processes for the preparation of 2-(3-cyano-5- fluorophenyl)-2-methyl-propionic acid of the formula: (I). The 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid of the formula (I) is a versatile intermediate in the synthesis of active pharmaceutical ingredients.

Description

[0001] Case P39455 Process for the preparation of 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid The invention relates to a novel process for the preparation of the 2-(3-cyano-5- fluorophenyl)-2-methyl-propionic acid of the formula (I), or salts thereof, comprising reacting 3-bromo-5-fluorobenzonitrile of the formula (II) , according to process variant (a1) with a Grignard reagent and acetone to the 3-fluoro-5-(1-hydroxy-1-methyl- ethyl)benzonitrile of formula (III) 14.07.2025 , or, according to process variant (a2) with an isopropenylborolane in the presence of a Pd-catalyst or Ni-catalyst and a base, or according to process variant (a3) with an isopropenylmagnesium halogenide in the presence of a Pd-catalyst or Ni- catalyst and the optional presence of a Zn-salt, to the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV) , and (b) further carbonylating, either the 3-fluoro-5-(1-hydroxy-1-methyl- ethyl)benzonitrile of formula (III) or the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV) with carbon monoxide and formic acid and / or water, in the presence of an additional acid and an organic solvent to the 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid of the formula (I). The 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid of the formula (I) is a versatile intermediate in the synthesis of active pharmaceutical ingredients (API’s). For instance, they can provide certain functionality to compounds that modulate the glucagon-like peptide-1 receptor (GLP-1R) and the gastric inhibitory polypeptide receptor (GIPR) as described in the International Patent Publication WO 2022 / 241287. A process for the preparation of the 2-(2-fluoro-3-cyanophenyl)-derivative, which is a close analogue of the 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid of the formula I is described in the International Patent Publication WO 2022 / 241287. Schemes A and B below illustrate the process as disclosed in Schemes 13 and 14 for the corresponding (2-cyano-4-fluorophenyl) and (2-fluoro-4-cyanophenyl)-derivatives, respectively: Scheme B In analogous manner, the 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid of the formula I can be prepared starting from 2-(3-bromo-5-fluorophenyl)-acetic acid and following one of the process routes as shown in Schemes A and B. The processes require four process steps and the reaction conditions have been found not suitable for a process on technical scale. Object of the invention was to facilitate the synthesis and to find processes which are applicable on a larger scale. It was found that the object of the invention could be reached with the processes as outlined below. The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein. The term “alkyl” as used herein denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 12 carbon atoms. Typical examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl and pentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl or dodecyl and its isomers. The term “alkyl” as used herein also encompasses carbocycles. Examples for carbocycles include the monocyclic cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or the polycyclic adamantyl. The term”C1-4-alkyl” as used herein denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 4 carbon atoms. Typical examples include methyl, ethyl,n-propyl, i-propyl, n-butyl and i-butyl. Preferred C1-4-alkyl group is methyl.The term “alkenyl” as used herein encompasses a monovalent linear or branched hydrocarbon group of 2 to 6 carbon atoms which contains at least one double bond. Typical examples are allyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, pentenyl or hexenyl and its isomers. The term “halogen” encompasses fluorine, chlorine, iodine or bromine, preferably chlorine or bromine. The term “halogenide” accordingly signifies the respective salt of the halogens mentioned above. The term “salt” in the context of the present invention encompasses typical salts of carboxylic acids, which can be formed with inorganic bases such as with alkali hydroxide, like sodium hydroxide or with organic bases such as with amines, like ammonia. Step (a) Process variant (a1) Process variant (a1) requires the reaction of 3-bromo-5-fluorobenzonitrile of formula (II) with a Grignard reagent and acetone to the 3-fluoro-5-(1-hydroxy-1-methyl- ethyl)benzonitrile of formula (III) . The starting compound 3-bromo-5-fluorobenzonitrile (II) is commercially available. The Grignard reagent selected for this reaction is an organomagnesium halogenide, such as an alkylmagnesium halogenide, like isopropylmagnesium bromide or isopropylmagnesium chloride. Inert reaction conditions and the presence of a suitable organic solvent are key for the reaction. Preferred organic solvents are ethers, like diethyl ether or the more preferred tetrahydrofuran. The reaction temperature can be selected between -40 °C and 0 °C, preferably between -30 °C and -10 °C. Acetone is then added, usually in stoichiometric excess. Upon completion of the reaction, the reaction mixture can be quenched with a suitable proton source, ideally with an aqueous ammonium chloride solution. The resulting tertiary alcohol of formula (III) can be isolated from the organic phase of the reaction mixture in a manner well known for Grignard reactions and therefore familiar to the skilled in the art. Further purification can be accomplished by chromatography or crystallization of a solution of the tertiary alcohol in a suitable organic solvent, such as for instance in a mixture of n-heptane and ethyl acetate. Alternatively, distillation is a suitable option to purify the tertiary alcohol formula (III). Process variant (a2) Process variant (a2) requires the reaction of 3-bromo-5-fluorobenzonitrile of formula with an isopropenylborolane in the presence of a Pd-catalyst or Ni-catalyst and a base to the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV) . The reaction follows the reaction principles of the Suzuki coupling and accordingly requires conditions which are typical for this type of reaction. Suitable isopropenylborolane derivatives are 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (CAS RN: 126726-62-3) or potassium isopropenyltrifluoroborate (CAS RN: 395083-14-4). Suitable Pd-catalysts or Ni-catalysts can be selected from palladium or nickel complexes, wherein the palladium or nickel is coordinated for example with chloride or bromide or allyl, and phosphine and / or carbene ligands. The catalysts can also be formed from a Pd-precursor or Ni-precursor and a ligand in situ or ex situ. For instance, palladium can be coordinated with two chloride ligands [PdCl2(ligand)x], with one chloride and an allyl such as in [PdCl(crotyl)(ligand)] or [PdCl(allyl)(ligand)], or in dimeric form such as ligand [Pd(allyl)Cl]2. The palladium can also be cationic such as for example [Pd(allyl)(ligand)x]Cl or [Pd(allyl)(ligand)x]OTf. For instance, nickel can be coordinated with chloride, o-tolyl or mesityl and a ligand, such as [NiCl(oTol)(ligand)x]. Typical phosphine ligands are 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis- (di-tert-butylphosphino)-ferrocene (dtbpf), 4,5-bis-(diphenylphosphino)-9,9- dimethylxanthene (Xantphos), bis(di-tert-butyl)-4-dimethylaminophenylphosphine (AmPhos), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos), 2- dicyclohexylphosphino-2’,6’-dimethoxybiphenyl (SPhos), 2-(dicyclohexylphosphino)-3,6- dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (BrettPhos), tri-tert-butylphosphine (PtBu3), triphenylphosphine (PPh3), tricyclohexylphosphine (PCy3). The Pd-catalyst or Ni-catalyst is as a rule added in a catalytic amount of 0.1 mol% to 10 mol%, preferably of 0.2 mol% to 5.0 mol%. Pd-catalyzed Suzuki couplings as a rule take place in the presence of a base and an organic solvent. Preferred bases are alkali metal salts, such as carbonates, hydrogen carbonates, phosphates, hydrogen phosphates of sodium, potassium or cesium. Also usable are alkali metal salts of organic acids, for example potassium acetate. Typically, the base is added as an aqueous solution. The organic solvent ideally is a polar aprotic solvent selected from e.g. methyltetrahydrofuran, acetonitrile, toluene, ethyl acetate, tert-amyl alcohol or isopropyl acetate.The reaction temperature is dependent on the solvent, but is as a rule selected between 20 °C to 115 °C, preferably between 40 °C and 80 °C. Ni-catalyzed Suzuki couplings as a rule also take place in the presence of a base and an organic solvent. Preferred bases are inorganic bases such K2CO3or organic bases such as tertiary amine bases, like diisopropylethylamine (DIPEA).Suitable organic solvents can be selected from tert-amyl alcohol, EtOAc, MeTHF ortoluene. Water can be added as co-reagent and OH source. The reaction temperature is dependent on the solvent, but is as a rule selected between 20 °C to 115 °C, preferably between 40 °C and 80 °C. The resulting 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV) can be isolated from the organic phase of the reaction mixture in a manner well known to the skilled in the art. Further purification can be accomplished by chromatography or by distillation of the alkene of formula (IV). Process variant (a3) Process variant (a3) requires the reaction of 3-bromo-5-fluorobenzonitrile of formula with an isopropenylmagnesium halogenide in the presence of a Pd-catalyst or Ni- catalyst and the optional presence of a Zn-salt, to the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV) . The reaction follows the reaction principles of the Kumada coupling (without Zn-salt) or Negishi coupling (with Zn-salt) and accordingly requires conditions which are typical for this type of reactions. Suitable isopropenylmagnesium halogenide is the isopropenylmagnesium bromide. Suitable Pd-catalysts or Ni-catalysts can be selected from palladium or nickel complexes, wherein the palladium or nickel is coordinated for example with chloride or bromide or allyl, and phosphine and / or carbene ligands. The catalysts can also be formed from a Pd-precursor or Ni-precursor and a ligand in situ or ex situ. For instance, palladium can be coordinated with two chloride ligands [PdCl2(ligand)x], with one chloride and an allyl such as in [PdCl(crotyl)(ligand)] or [PdCl(allyl)(ligand)], or in dimeric form such as ligand [Pd(allyl)Cl]2. The palladium can also be cationic such as for example [Pd(allyl)(ligand)x]Cl or [Pd(allyl)(ligand)x]OTf. For instance, nickel can be coordinated with chloride, o-tolyl or mesityl and a ligand, such as [NiCl(oTol)(ligand)x]. Typical phosphine ligands are selected from the group consisting of 1,1′- bis(diphenylphosphino)ferrocene (dppf), 1,1′-bis-(di-tert-butylphosphino)-ferrocene (dtbpf), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), bis(di-tert-butyl)-4- dimethylaminophenylphosphine (AmPhos), 2-dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl (RuPhos), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′-biphenyl (BrettPhos), tri-tert-butylphosphine (PtBu3), bis[(2- diphenylphosphino)phenyl]ether (DPEphos), and 1-((1,3,5,7-tetramethyl-2,4,6-trioxa-8- phosphaadamantan-8-yl)-2-(1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantan-8- yl)benzene (PAd2-DalPhos). [PdCl2(Xantphos)] was found to be a preferred Pd-catalyst. The Pd-catalyst or Ni-catalyst is as a rule added in a catalytic amount of 0.1 mol% to 10 mol%, preferably of 0.2 mol% to 5.0 mol%. The Zn-salt is usually a Zn-halogenide, preferably Zn chloride. The reaction is preferably performed in an ether, like diethyl ether or more preferred in tetrahydrofuran. The reaction temperature is as a rule selected between 0 °C to 100 °C, preferably between 20 °C and 60 °C. The resulting 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV) can be isolated from the organic phase of the reaction mixture in a manner well known to the skilled in the art. Further purification can be accomplished by chromatography or by distillation of the alkene of formula (IV). Process variant comprising steps (c) and (d) In a further embodiment the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV) can be prepared by (c) reacting a C1-4-alkyl-3-cyano-5-fluorobenzoate of the formula (V) ,wherein R1is C1-4-alkyl, with a Grignard reagent to the 3-fluoro-5-(1-hydroxy-1-methyl-ethyl)benzonitrile of formula (III) , and (d) by subjecting the 3-fluoro-5-(1-hydroxy-1-methyl-ethyl)benzonitrile of formula (III) to dehydration with an acid. The starting compounds C1-4-alkyl-3-cyano-5-fluorobenzoates of the formula (VI) are commercially available. The methyl-3-cyano-5-fluorobenzoate (R1=methyl, formula (VIa) is preferred. The Grignard reagent selected for this reaction is an organo magnesium halogenide, such as an alkyl magnesium halogenide, preferably methyl magnesium bromide. Inert reaction conditions and the presence of a suitable organic solvent are key for the reaction. Preferred organic solvents are ethers, like tetrahydrofuran and methyl tetrahydrofuran or mixtures thereof. The reaction temperature can be selected between -40 °C and 10 °C, preferably between -30 °C and 0 °C. Upon completion of the reaction, the reaction mixture can be quenched with a suitable proton source, ideally with an aqueous ammonium chloride solution. The resulting tertiary alcohol of formula (III) can be isolated from the organic phase of the reaction mixture in a manner well known for Grignard reactions and therefore familiar to the skilled in the art. Further purification can be accomplished by chromatography or crystallization of a solution of the tertiary alcohol in a suitable organic solvent, such as for instance in a mixture of n-heptane and ethyl acetate or cyclopentyl methyl ether and n- heptane. Alternatively, the tertiary alcohol of formula (III) can also be purified by distillation. The subsequent dehydration can be conducted in the presence of an organic or inorganic acid or an acidic salt in an organic solvent. A suitable organic acid is p-toluenesulfonic acid. Alternatively inorganic acids like sulfuric acid, phosphoric acid or hydrochloric acid can be used. Suitable acidic salts can be selected from acidic salts of the previously mentioned inorganic acids. Monohydrogen sulfates such as the potassium monohydrogensulfate, was found to be a suitable representative. Suitable organic solvents can be selected from aprotic solvents, such as from toluene, dichloromethane, 1,2 dichloroethane or N-methylpyrrolidone. Typically, the reaction temperature applied is in the range of 80 °C to 150 °C. Usually the reaction is conducted at reflux temperature of the selected solvent. In a preferred embodiment the dehydration reaction is performed with p- toluenesulfonic acid in toluene under reflux conditions. Quantitative conversion can already be achieved within a short reaction time, usually within 3 to 10 minutes, when continuous flow methods are applied. Isolation and purification of the resulting 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV) can be achieved by distillation. Step (b) Step b) requires the carbonylation of, either the 3-fluoro-5-(1-hydroxy-1-methyl- ethyl)benzonitrile of formula (III) or the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV) with carbon monoxide and formic acid and / or water, in the presence of an additional acid and an organic solvent to the 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid of the formula (I). Carbonylation as a rule takes place under conditions which are typical for Koch-Haaf carbonylation reactions. The CO pressure ranges usually between 1 bar and 50 bar, preferably between 10 bar and 40 bar. Water and / or formic acid can be added in catalytic amounts or with a slight excess relating to the educts of formula (III) or (IV). If water and formic acid is added equivalent amounts are typically applied. The additional acid can be selected from strong acids, for example from strong organic acids. Preferred is trifluoromethanesulfonic acid. Suitable organic solvents are polar aprotic solvents like dichloromethane. The reaction temperature can be selected between 0°C and 40°C. In a preferred embodiment a solution containing the 3-fluoro-5-(1-hydroxy-1-methyl- ethyl)benzonitrile of formula (III) or the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV), dichloromethane and water or formic acid and trifluoromethanesulfonic acid is in parallel fed to an autoclave, which is then pressurized with CO and operated under the reaction conditions described above. Reaction completion can be measured by HPLC. Upon completion of the reaction the reaction mixture is quenched with water. The resulting 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid of the formula (I) can be isolated from the organic phase following methods known to the skilled in the art.

[0002] Examples Abbreviations: CPME cyclopropyl methyletherDCM dichloromethaneDIPEA diisopropyl ethylamineDMSO dimethylsulfoxideEtOAc ethyl acetateHPLC high pressure liquid chromatographyIPC in-process control analyticsIT internal temperatureiPrOAc iso-propyl acetateMeCN acetonitrileMeTHF 2-methyltetrahydrofuranrt room temperaturet-AmOH tert-amylalcoholTBME tert-butyl methyl etherTFA trifluoroacetic acidTfOH trifluoromethanesulfonic acidTHF tetrahydrofuranCompounds: I2-(3-Cyano-5-fluoro-phenyl)-2-methyl-propionic acidII 3-Bromo-5-fluoro-benzonitrileIII 3-Fluoro-5-(1-hydroxy-1-methyl-ethyl)benzonitrileIV 2-(3-Cyano-5-fluoro-phenyl)propeneV 5-Fluoro-benzonitrileVIa Methyl 3-cyano-5-fluorobenzoateExample 1 Preparation of 3-fluoro-5-(1-hydroxy-1-methyl-ethyl)benzonitrile (III) Under inert atmosphere, 3-bromo-5-fluoro-benzonitrile (II) (50.1 g, 250.0 mmol) wasdissolved in THF (750 mL). After cooling the reaction mixture to ^15°C, iPrMgCl.LiCl,(1.3M in THF, 274.3 g, 375.0 mmol) was added within 20 min. After 30 min stirring, acetone (87.1 g, 1.5 mol) was added within 20 min. After 10 min stirring, an aqueous NH4Cl solution (25wt%, 214.0 g, 400.0 mmol) was added within 50 min. Then, the mixture was warmed up from -15 to 20°C and the two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 andconcentrated to dryness to deliver crude (III) which was purified by column chromatography(EtOAc / n-heptane) to furnish pure (III) as a waxy white solid (16.5 g, 36.5%) with a HPLCpurity of 99.3 area-% (HPLC method A).1H-NMR (600 MHz, CDCl3) δ ppm 7.58 (dd, J=1.6, 1.4 Hz, 1H), 7.47 (ddd, J=9.9, 2.5, 1.6 Hz, 1H), 7.23 (ddd, J=7.7, 2.5, 1.4 Hz, 1H), 1.85 (s, 1H), 1.58 (s, 6H). HPLC method A: Stationary phase: XBridge C18, 3.5umm, 3.0 x 50 mm (Serial.Nr.:02293301814823); Eluent: Eluent A: Water with 0.05% TFA; eluent B:Methanol Timetable: Time (min) Eluent A% Eluent B%0 95 54 35 654.3 5 955 95 56.5 95 5Run time: 6.5 minFlow: 1 mL / minColumn oven temperature: 35 °CInjection volume: 1 ^LDetection: DAD 210 nmRetention Times: (V) (3.77 min), (III (4.29 min), (II) (5.03 min)Example 2 2.1. Preparation of 2-(3-cyano-5-fluoro-phenyl)-2-methyl-propionic acid (I) A 35-mL autoclave was charged with a solution of 3-fluoro-5-(1-hydroxy-1-methyl- ethyl)benzonitrile (III) (300.0 mg, 1.7 mmol) in DCM (2.1 mL), trifluoromethanesulfonic acid (1.2 g, 8.0 mmol) and water (15.0 mg, 0.8 mmol). The reaction mixture was pressurizedwith 30 bar of carbon monoxide gas and stirred at rt (>99% conversion, 36.8 area-% I, HPLCmethod B). The autoclave was vented, the reaction mixture cooled to 0-5°C and treated with 2 M NaOH to reach a pH value of 13. After DCM and water addition, the two phases were separated. The organic layer was washed with water and the combined aqueous phases combined, cooled to 0-5°C and treated with 2 N HCl to reach a pH value of 1. After DCM addition and phase separation, the aqueous layer was extracted with DCM. The combinedorganic phases were dried over Na2SO4 and concentrated to dryness to deliver crude I (164.0mg, 61.8 area-% purity (HPLC method B). The crude product was purified by columnchromatography (EtOAc / n-heptane) to furnish purified I (97 mg, 28%) as a white solid with aHPLC purity of 92 area-%.1H-NMR (400 MHz, DMSO-d6) δ ppm 12.73 (br, s, 1H), 7.76 (ddd, 1H), 7.68 (t, 1H), 7.57 (d, 1H), 1.51 (s, 6H). HPLC method B: Stationary phase: X-Bridge C18, AD-H 3.0 mm x 150 mm x 3.5 μm(PN186003028) Eluent: Eluent A: Water with 0.05% TFA; eluent B: MethanolRun time: 8.5 minTimetable: Time (min) Eluent A% Eluent B%0 50 504 5 958 5 958.5 50 50Flow: 1 mL / minColumn oven 35 °C temperature: Injection volume: 5 μLDetection: DAD 230 nmRetention Times: (III) (3.60 min), (I) (3.95 min), (IV) (4.76 min), (V) (3.46min), (II) (4.29 min)2.2. Preparation of 2-(3-cyano-5-fluoro-phenyl)-2-methyl-propionic acid (I) A 50-mL autoclave was charged with trifluoromethanesulfonic acid (12.1 g, 80.4 mmol), DCM (15.8 mL) and water (75.0 mg, 4.2 mmol). The autoclave was sealed and pressurized with 30 bar of carbon monoxide gas. Under stirring at 10°C, a solution of 3-fluoro-5-(1- hydroxy-1-methyl-ethyl)benzonitrile (III) (1.5 g, 8.4 mmol) in DCM (5.3 mL) was added with aid of an HPLC pump with a flow rate of 0.20 mL / min over a period of 30 min. Afterwards the feeding line was flushed with DCM (3 mL) and the combined washing andreaction solutions stirred for 1 h (>99% conversion, 86.9 area-% I, HPLC method B - seeExample 2.1). After the autoclave was vented, the reaction mixture was cooled to 0-5°C and dropped within 10 min to ice-cold water (30 mL). After DCM (10 mL) and water (10 mL) addition, the two phases were separated. The organic layer was dried over Na2SO4, filteredand evaporated to dryness to yield crude I (1.6 g) with 87.4 area-% purity. Aftercrystallization from iPrOAc / n-heptane, pure I was isolated as white crystals (1.1 g, 64%) witha HPLC purity of 98.8 area-% (HPLC method B – see Example 2.1). 2.3. Preparation of 2-(3-cyano-5-fluoro-phenyl)-2-methyl-propionic acid (I) A solution of 3-fluoro-5-(1-hydroxy-1-methyl-ethyl) benzonitrile (III) in dichloromethane (DCM) (0.32 M, 1.00 equiv) containing formic acid (0.20 equiv) and trifluoromethanesulfonic acid (neat, 9.60 equiv) was added in parallel at an internal temperature (IT) of 30°C into a continuously stirred tank reactor (CSTR) autoclave. The autoclave was pressurized with carbon monoxide to 40 bar, and the mean residence time in the CSTR was set to 20 minutes. The outflow from the CSTR autoclave was then directed through a plug flow reactor to address the broad residence time distribution in a single CSTR and to provide an additional residence time of approximately 2 minutes. The resulting mixture was depressurized and passed through a cyclone gas / liquid separator. The organic layer (biphasic: DCM / TfOH) was collected batch-wise into vigorously stirred water at IT = 5°C. The DCM phase, being the heavier phase and containing the product, was separated and the aqueous phase was discarded. The DCM phase was subsequently washed with water and then basified to a pH of 8.5-9.5 using aqueous NaHCO3. This step facilitated the extraction of the product into the aqueous phase, while the DCM layer was discarded. Anisole was then added to the aqueous product solution. This anisole / water mixture was acidified with citric acid to pH = 4-5 at an internal temperature of 45°C. The water phase was discarded, and the product was crystallized from anisole.2-(3-cyano-5-fluoro-phenyl)-2-methyl-propionic acid (I) was isolated as a yellowish solid in 70-75% yield and 99 a% HPLCpurity. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.73 (br, s, 1H), 7.76 (ddd, 1H), 7.68 (t, 1H), 7.57 (d, 1H), 1.51 (s, 6H). Example 3 3.1. Preparation of 2-(3-cyano-5-fluoro-phenyl)propene (IV) (Pd-catalyzed; with an isopropenyl borolane) Under inert atmosphere, 3-bromo-5-fluoro-benzonitrile (II) (3.0 g, 15.0 mmol) and [PdCl2(dppf)].CH2Cl2(245.0 mg, 0.3 mmol) were dissolved in MeTHF (18 mL) at rt. After the reaction mixture was stirred for 5 min, 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (3.3 g, 19.5 mmol) and a solution of cesium carbonate (9.8 g, 30.0 mmol) in water (6 mL) were added. The reaction mixture was stirred for 16 h at 60°C. The organic layer was separated, washed with a saturated, aqueous NaCl solution (20 mL), dried overNa2SO4 and concentrated to dryness to deliver crude (IV) (4.3 g, 91.0 area-%). The crudeproduct was purified by column chromatography (EtOAc / n-heptane and TBME / n-heptane) to furnish purified (IV) (1.8 g, 76%) as a white solid with 84.5 area-% purity (HPLC method B – see Example 2.1).1H-NMR (500 MHz, CDCl3,) δ ppm 7.53 (t, 1H), 7.32-7.45 (m, 1H), 7.22-7.25 (m, 1H), 5.45 (quin, 1H), 5.26 (quin, 1H), 2.14 (d, 3H).3.2. to 3.49. Preparation of 2-(3-cyano-5-fluoro-phenyl)propene (IV) (Pd-catalyzed; withan isopropenyl borolane) In analogy to Example 3.1, 3-bromo-5-fluoro-benzonitrile (II) (10.0 mg, 5.0 µmol) was converted with 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.7 µL, 7.5 µmol)into IV within 2 to 20 h at 60°C in the presence of the catalysts (0.02 eq), bases (2 eq),solvents (2 vol) and water (2 vol) as listed in Table 1. Table 1 Examples Catalyst Base Solvent TimeIV (h) (area-%)13.2 [PdCl2(dppf)].CH2Cl2 Cs2CO3 MeTHF 2 983.3 [PdCl2(dppf)].CH2Cl2 K3PO4 MeTHF 2 973.4 [PdCl2(dppf)].CH2Cl2 Cs2CO3 MeCN 2 973.5 [PdCl2(dppf)].CH2Cl2 K3PO4 MeCN 2 953.6 [PdCl2(dppf)].CH2Cl2 KOAc MeCN 20 763.7 [PdCl2(dppf)].CH2Cl2 Cs2CO3 iPrOAc 2 1003.8 [PdCl2(dppf)].CH2Cl2 K3PO4 iPrOAc 2 1003.9 [PdCl2(dtbpf)] Cs2CO3 MeTHF 2 943.10 [PdCl2(dtbpf)] K3PO4 MeTHF 2 943.11 [PdCl2(dtbpf)] Cs2CO3 MeCN 2 1003.12 [PdCl2(dtbpf)] K3PO4 MeCN 2 963.13 [PdCl2(dtbpf)] Cs2CO3 iPrOAc 2 963.14 [PdCl2(dtbpf)] K3PO4 iPrOAc 2 953.15 [PdCl2(dtbpf)] NaHCO3 iPrOAc 20 923.16 [PdCl2(Xantphos)] Cs2CO3 MeTHF 2 93Examples Catalyst Base Solvent TimeIV (h) (area-%)13.17 [PdCl2(Xantphos)] K3PO4 MeTHF 2 893.18 [PdCl2(Xantphos)] Cs2CO3 MeCN 2 983.19 [PdCl2(Xantphos)] K3PO4 MeCN 2 913.20 [PdCl2(Xantphos)] Cs2CO3 iPrOAc 2 1003.21 [PdCl2(Xantphos)] K3PO4 iPrOAc 2 913.22 [PdCl2(Xantphos)] NaHCO3 iPrOAc 20 1003.23 [PdCl2(AmPhos)2] Cs2CO3 MeTHF 2 973.24 [PdCl2(AmPhos)2] K3PO4 MeTHF 2 903.25 [PdCl2(AmPhos)2] KOAc MeTHF 20 873.26 [PdCl2(AmPhos)2] NaHCO3 MeTHF 4 923.27 [PdCl2(AmPhos)2] Cs2CO3 MeCN 2 933.28 [PdCl2(AmPhos)2] K3PO4 MeCN 2 923.29 [PdCl2(AmPhos)2] Cs2CO3 iPrOAc 2 933.30 [PdCl2(AmPhos)2] K3PO4 iPrOAc 2 923.31 [Pd(crotyl)Cl(RuPhos)] Cs2CO3 MeTHF 4 933.32 [Pd(crotyl)Cl(RuPhos)] K3PO4 MeTHF 2 873.33 [Pd(crotyl)Cl(RuPhos)] Cs2CO3 MeCN 2 98Examples Catalyst Base Solvent TimeIV (h) (area-%)13.34 [Pd(crotyl)Cl(RuPhos)] K3PO4 MeCN 2 903.35 [Pd(crotyl)Cl(RuPhos)] Cs2CO3 iPrOAc 2 973.36 [Pd(crotyl)Cl(RuPhos)] K3PO4 iPrOAc 2 903.37 [Pd(crotyl)Cl(BrettPhos)] Cs2CO3 MeTHF 4 883.38 [Pd(crotyl)Cl(BrettPhos)] K3PO4 MeTHF 2 893.39 [Pd(crotyl)Cl(BrettPhos)] Cs2CO3 MeCN 4 983.40 [Pd(crotyl)Cl(BrettPhos)] K3PO4 MeCN 2 893.41 [Pd(crotyl)Cl(BrettPhos)] Cs2CO3 iPrOAc 4 913.42 [Pd(crotyl)Cl(BrettPhos)] K3PO4 iPrOAc 4 913.43 [Pd(crotyl)Cl(PtBu3)] Cs2CO3 MeTHF 2 923.44 [Pd(crotyl)Cl(PtBu3)] K3PO4 MeTHF 2 963.45 [Pd(crotyl)Cl(PtBu3)] NaHCO3 MeTHF 4 743.46 [Pd(crotyl)Cl(PtBu3)] Cs2CO3 MeCN 2 1003.47 [Pd(crotyl)Cl(PtBu3)] K3PO4 MeCN 2 973.48 [Pd(crotyl)Cl(PtBu3)] Cs2CO3 iPrOAc 2 943.49 [Pd(crotyl)Cl(PtBu3)] K3PO4 iPrOAc 2 941determined by LC-MS3.50. Preparation of 2-(3-cyano-5-fluoro-phenyl)propene (IV) (Pd-catalyzed; with anisopropenyl borolane) MeTHF (450 mL) and a solution of K2CO3 (86.4 g, 625 mmol, 2.5 eq) in water (125 mL) were added to 3-bromo-5-fluorobenzonitrile (II) (50.0 g, 250 mmol) and potassium isopropenyltrifluoroborate (46.2 g, 312 mmol, 1.25 eq) and heated to 70 °C. [Pd(allyl)Cl]2 (229 mg, 625 µmol, 0.25 mol%) and RuPhos (642 mg, 1.37 mmol, 0.55 mol%) in MeTHF (50 mL) were added and stirred at 70 °C for 2.5 h. The reaction was cooled to RT and the organic phase was separated, washed with saturated aqueous NaCl solution (50 mL), dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Distillation under reduced pressure afforded the product as a colorless liquid. Yield: 40.3 g (95%).3.51. Preparation of 2-(3-cyano-5-fluoro-phenyl)propene (IV) (Pd-catalyzed; with anisopropenyl borolane) MeTHF (150 mL) was added to 3-bromo-5-fluorobenzonitrile (II) (20.0 g, 100 mmol) and heated to 75 °C. [PdCl2(AmPhos)2] (408 mg, 500 µmol, 0.5 mol%), 2-isopropenyl-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (24.5 mL, 125 mmol, 1.25 eq) and a solution of K2CO3 (34.6 g, 250 mmol, 2.5 eq) in water (50 mL) was added and stirred at 75 °C for 20 h. After this time, the reactor was cooled to RT and the reaction mixture analyzed, confirming >95% conversion and selectivity LCMS and NMR.3.52. Preparation of 2-(3-cyano-5-fluoro-phenyl)propene (IV) (Ni-catalyzed; with anisopropenyl borolane) tAmOH (20 mL) was added to 3-bromo-5-fluorobenzonitrile (II) (8.00 g, 40.0 mmol) and 2- isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.3 mL, 60 mmol, 1.5 eq) and heatedto 70 °C. DIPEA (13.9 mL, 80.0 mmol, 2.0 eq) and water (13.3 mL) were added. tAmOH (20mL) was added to [Ni(oTol)Cl(PPh3)2] (710 mg, 1.00 mmol, 2.5 mol%) and PCy3 (561 mg, 2.00 mmol, 5.0 mol%) and stirred at RT for 1 h before being added to the previous mixture and stirred 70 °C for 2 h. The reaction was cooled to RT, diluted with EtOAc (120 mL) and washed with water (40 mL), 5% aqueous HCl solution (40 mL) and saturated aqueous NaHCO3 solution (40 mL), dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Distillation under reduced pressure afforded the product as a colorless liquid. Yield: 5.53 g (86%).3.53. Preparation of 2-(3-cyano-5-fluoro-phenyl)propene (IV) (isopropenylmagnesiumhalogenide; Pd-catalyst) Under inert atmosphere, ZnCl2(1.9 M in MeTHF, 73.7 mL, 1.4 eq) was added to isopropenylmagnesium bromide (0.5 M in THF, 260 mL, 1.3 eq) and stirred at 25 °C for 1.5 h.3-bromo-5-fluoro-benzonitrile (II) (20 g, 100 mmol) and [PdCl2(Xantphos)] (756 mg, 1.00 mmol, 1 mol%) were added and stirred for 3 h at 40 °C. AcOH (5.72 mL, 100 mmol, 1.0 eq) was added and the solution was concentrated under reduced pressure.10% aq. K2CO3solution was added and extracted twice with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over MgSO4, filtered and the solvent was removed under reduced pressure. TBME was added followed by NORIT A SUPRA (5 g) and stirred for 30 min at 25 °C and filtered through Celite. Solvent removal under reduced pressure afforded crude (IV) (14.5 g, 90%) as a yellow oil with 95 area-% purity (HPLC method B – see Example 2.1). 3.54. – 3.80. Preparation of 2-(3-cyano-5-fluoro-phenyl)propene (IV) (isopropenylmagnesium halogenide; Pd-catalyst or Ni-catalyst) In analogy to Example 3.53, 3-bromo-5-fluoro-benzonitrile (II) (10.0 mg, 5.0 µmol) and catalysts (2.0 mol%) were dispensed in the solvent (100 µL) as listed in Table 2. Then either a stock solution prepared by adding ZnCl2(1.9 M in MeTHF, 35.5 µL, 6.75 µmol, 1.35 eq) to isopropenylmagnesium bromide (0.5 M in THF, 125 µL, 6.25 µmol, 1.25 eq) (indicated as “Negishi” - see Table 2), resp. only isopropenylmagnesium bromide (0.5 M in THF, 125 µL, 6.25 µmol, 1.25 eq; indicated as “Kumada” - see Table 2) was added. The reaction mixtures were stirred at 50 °C between 4 and 20h. Table 2 Example Catalyst Coupling Type Solvent TimeIV (h) (area-%)13.55 [PdCl2(Xantphos)] Negishi THF 4 983.56 [PdCl2(Xantphos)] Negishi CPME 4 983.57 [PdCl2(Xantphos)] Negishi PhMe 2 953.58 [PdCl2(Xantphos)] Kumada THF 20 383.59 [PdCl2(Xantphos)] Kumada CPME 20 573.60 [PdCl2(Xantphos)] Kumada PhMe 20 573.61 [PdCl2(DPPP)] Negishi THF 4 953.62 [PdCl2(DPPP)] Negishi CPME 4 943.63 [PdCl2(DPPP)] Negishi PhMe 20 913.64 [PdCl2(DTBPF)] Negishi THF 2 873.65 [PdCl2(DTBPF)] Negishi CPME 2 943.66 [PdCl2(DTBPF)] Negishi PhMe 2 913.67 [PdCl2(DTBPF)] Kumada THF 2 293.68 [PdCl2(DTBPF)] Kumada CPME 2 193.69 [PdCl2(DTBPF)] Kumada PhMe 2 233.70 [Pd(allyl)Cl(SPhos)] Negishi CPME 2 883.71 Pd PEPPSI IPr Negishi CPME 20 853.72 [PdCl2(PPh3)2] Negishi CPME 20 823.73 [Ni(Mes)Br(DPEphos)] Negishi THF 20 893.74 [Ni(Mes)Br(DPEphos)] Negishi CPME 20 913.75 [Ni(Mes)Br(DPEphos)] Negishi PhMe 20 793.76 [Ni(oTol)Cl(PAd2-DalPhos)] Negishi PhMe 20 673.77 [Ni(oTol)Cl(NHP-DalPhos)] Negishi PhMe 20 943.78 [Ni(oTol)Cl(PPh3)2] Negishi PhMe 20 863.79 [Ni(oTol)Cl(DPPF)] Negishi PhMe 20 793.80 [Ni(oTol)Cl(PAd-DalPhos)] Negishi PhMe 20 741 determined by LC-MS Example 4 4.1. Preparation of 2-(3-cyano-5-fluoro-phenyl)-2-methyl-propionic acid (I) A 50-mL autoclave was charged with trifluoromethanesulfonic acid (12.1 g, 80.4 mmol), DCM (15.8 mL) and water (201.3 mg, 11.2 mmol). The autoclave was sealed and pressurized with 30 bar of carbon monoxide gas. Under stirring at 10°C, a solution of 2-(3-cyano-5- fluoro-phenyl)propene (IV) (1.5 g, 9.3 mmol) in DCM (5.3 mL) was added with aid of an HPLC pump with a flow rate of 0.20 mL / min over a period of 30 min. Afterwards the feeding line was flushed with DCM (3 mL) and the combined washing and reaction solutions stirredfor 1 h (99% conversion, 87.5 area-% I, HPLC method B). After the autoclave was vented,the reaction mixture was cooled to 0-5°C and then dropped within 10 min to ice-cold water (30 mL). After DCM (10 mL) and water (10 mL) addition, the two phases were separated. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield crude (I) (1.6 g) with 87.2 area-% purity (HPLC method B – see Example 2.1). 4.2. Preparation of 2-(3-cyano-5-fluoro-phenyl)-2-methyl-propionic acid (I) A solution of 2-(3-cyano-5-fluoro-phenyl)propene (IV) in dichloromethane (DCM) (0.32 M, 1.00 equiv) containing formic acid (0.20 equiv) and trifluoromethanesulfonic acid (TfOH) (neat, 9.60 equiv) was added in parallel at an internal temperature (IT) of 30°C into a continuously stirred tank reactor (CSTR) autoclave. The autoclave was pressurized with carbon monoxide to 40 bar, and the mean residence time in the CSTR was set to 20 minutes. The outflow from the CSTR autoclave was then directed through a plug flow reactor to address the broad residence time distribution in a single CSTR and to provide an additional residence time of approximately 2 minutes. The resulting mixture was depressurized and passed through a cyclone gas / liquid separator. The organic layer (biphasic: DCM / TfOH) was collected batch-wise into vigorously stirred water at IT = 5°C. The DCM phase, being the heavier phase and containing the product, was separated and the aqueous phase was discarded. The DCM phase was subsequently washed with water and then basified to a pH of 8.5-9.5 using aqueous NaHCO3. This step facilitated the extraction of the product into the aqueous phase, while the DCM layer was discarded. Anisole was then added to the aqueous product solution. This anisole / water mixture was acidified with citric acid to pH = 4-5 at an internal temperature of 45°C. The water phase was discarded, and the product was crystallized from anisole.2-(3-cyano-5-fluoro-phenyl)-2-methyl-propionic acid (I) was isolated as a yellowish solid in 70-75 % yield and 99a% HPLCpurity. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.73 (br, s, 1H), 7.76 (ddd, J=1.3, 2.6, 8.5 Hz, 1H), 7.68 (t, J=1.5 Hz, 1H), 7.57 (d, J=10.3 Hz, 1H), 1.51 (s, 6H). Example 5 Preparation of 2-(3-cyano-5-fluoro-phenyl)propene (IV) following steps c) and d) 5.1. Preparation of 3-fluoro-5-(1-hydroxy-1-methyl-ethyl)benzonitrile Methyl 3-cyano-5-fluorobenzoate (VIa) (103.8 g, 1.00 equiv) is dissolved in THF (500 mL, 4.81 V). Methylmagnesium bromide in MeTHF (3.5 M, 526.3 g, 3.00 equiv) is used as a commercial solution. A batch reactor is charged with a minimal amount of THF to ensure proper stirring and accurate temperature measurement, then cooled to -20°C. Both reagent solutions are added in parallel to the stirred reactor over 3-5 hours, maintaining the internal temperature at IT = -20°C. Stirring continues at IT = -20°C until the starting material conversion is complete, as determined by HPLC. The temperature is then adjusted to IT = 0-5°C. The reaction mixture is quenched with aqueous ammonium chloride (20 wt%, 1490 g, 14.3 V) at IT = 0-5°C. The biphasic system is warmed to 25°C, the phases are separated, and the aqueous layer is discarded. The organic phase is washed with water (556 g, 5.56 V), the phases are separated, and the aqueous layer is discarded. Cyclopentyl methylether (CPME) (500 mL, 5V) is added and the mixture is concentrated to 2.0 V by distillation until a complete solvent swap to CPME is achieved, as confirmed by GC. The product-containing CPME phase is warmed to 40°C, and heptane (450 mL, 4.5 V) is added. The CPME / heptane (1 / 2) mixture is cooled from 40°C to 20°C (0.33°C / min) and stirring commenced for an additional hour. Clear filtration removes some precipitated impurities. More heptane (952 g, 14 V)) is added at 20°C, seeds crystals are added, and the mixture is then cooled to IT = -5°C (0.1°C / min). Solids are filtered and the product cake is washed with cold CPME / heptane (1:9 - vol / vol) and heptane. The solids are dried under vacuum (10 mbar, 25°C) to constant weight.3-fluoro-5-(1-hydroxy-1-methyl- ethyl)benzonitrile is isolated as a yellowish solid in 70-80% yield and 98 a% HPLC purity. 1H-NMR (600 MHz, CDCl3) δ ppm 7.58 (dd, J=1.6, 1.4 Hz, 1H), 7.47 (ddd, J=9.9, 2.5, 1.6 Hz, 1H), 7.23 (ddd, J=7.7, 2.5, 1.4 Hz, 1H), 1.85 (s, 1H), 1.58 (s, 6H). 5.2 Preparation of 2-(3-cyano-5-fluoro-phenyl)propene (IV) 3-Fluoro-5-(1-hydroxy-1-methyl-ethyl)benzonitrile (III) (0.6 g, 1.00 equiv) is dissolved in toluene (4.84 mL, 8 V) and p-toluenesulfonic acid monohydrate (0.2 equiv) is added. The mixture is heated to JT = 150°C for 5 minutes in a microwave device to obtain quantitativeconversion to the desired 2-(3-cyano-5-fluoro-phenyl)propene (IV), which is isolated bydistillation (170°C / 10 mbar), affording it in 80-90% yield with 99 % purity. 1H-NMR (500 MHz, CDCl3,) δ ppm 7.53 (t, J=1,5 Hz, 1H), 7.32-7.45 (m, 1H), 7.22-7.25 m, 1H), 5.45 (quin, J=0.8 Hz, 1H), 5.26 (quin, J= 1.4 Hz, 1H), 2.14 (d, J=2.3 Hz, 3H). 5.3 Preparation of 2-(3-cyano-5-fluoro-phenyl)propene (IV) 3-Fluoro-5-(1-hydroxy-1-methyl-ethyl)benzonitrile (III) (0.6 g, 1.00 equiv) is dissolved in toluene (4.84 mL, 8 V) and KHSO4(0.2 equiv) is added. The mixture is heated to JT = 150°C for 5 minutes in a microwave device to obtain quantitative conversion to the desired 2-(3-cyano-5-fluoro-phenyl)propene (IV), which is isolated by distillation (170°C / 10 mbar),affording it in 80-90% yield with 99 % purity. 1H-NMR (500 MHz, CDCl3,) δ ppm 7.53 (t, J=1,5 Hz, 1H), 7.32-7.45 (m, 1H), 7.22-7.25 m, 1H), 5.45 (quin, J=0.8 Hz, 1H), 5.26 (quin, J= 1.4 Hz, 1H), 2.14 (d, J=2.3 Hz, 3H). ***

Claims

1. Claims:

1. Process for the preparation of 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid of formula (I), or of salts thereof,comprising (a) reacting 3-bromo-5-fluorobenzonitrile of the formula (II), according to process variant (a1) with a Grignard reagent and acetone to the 3-fluoro-5-(1-hydroxy-1-methyl- ethyl)benzonitrile of formula (III), or according to process variant (a2), with an isopropenylborolane in the presence of a Pd-catalyst or Ni-catalyst and a base, according to process variant (a3)with an isopropenylmagnesium halogenide in the presence of a Pd-catalyst or Ni- catalyst and the optional presence of a Zn-salt, to the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV), and (b) further carbonylating, either the 3-fluoro-5-(1-hydroxy-1-methyl- ethyl)benzonitrile of formula (III) or the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV) with carbon monoxide and formic acid and / or water, in the presence of an additional acid and an organic solvent to the 2-(3-cyano-5-fluorophenyl)-2-methyl-propionic acid of the formula (I).

2. Process according to claim 1, wherein the Grignard reagent used in process variant (a1) is an organomagnesium halogenide.

3. Process according to claims 1 or 2, wherein the process variant (a1) is conducted in the presence of an organic solvent at a reaction temperature between -40 °C and 0 °C.

4. Process according to claim 1, wherein the isopropenylborolane used in process variant (a2) is 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or potassium isopropenyltrifluoroborate.

5. Process according to claims 1 or 4, wherein the Pd-catalyst or Ni-catalyst used in process variant (a2) is a palladium or nickel complex, wherein the palladium or nickel is coordinated with chloride or bromide or allyl, and phosphine and / or carbene ligands.

6. Process according to claims 1, 4 or 5, wherein the base used in process variant (a2) is an alkali metal salt.

7. Process according to claims 1 and 4 to 6, wherein the process variant (a2) is conducted in the presence of an organic solvent at a reaction temperature between 20 °C and 115 °C.

8. Process according to claim 1, wherein the Pd-catalyst or Ni-catalyst used in process variant (a3) is a palladium or nickel complex, wherein the palladium or nickel is coordinated with chloride or bromide or allyl, and phosphine and / or carbene ligands.

9. Process according to claim 1 or 8, wherein the Zn-salt used in process variant (a3) is a Zn-halogenide.

10. Process according to claims 1, 8 or 9, wherein the process variant (a3) is conducted in the presence of an organic solvent at a reaction temperature between 0 °C and 100 °C.

11. Process according to claim 1, wherein the additional acid used in step (b) is trifluoromethanesulfonic acid.

12. Process according to claims 1 or 11, wherein the carbonylation in step (b) is conducted at a CO pressure of 1 bar to 50 bar.

13. Process according to claims 1, 11 or 12, wherein, the carbonylation in step (b) is conducted at reaction temperatures between 0 °C and 40 °C.

14. Process according to claims 1 and 11 to 13, wherein the carbonylation in step (b) is conducted by feeding in parallel a solution containing the 3-fluoro-5-(1-hydroxy-1-methyl- ethyl)benzonitrile of formula (III) or the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV), dichloromethane, water and / or formic acid and trifluoromethanesulfonic acid to an autoclave, which is pressurized with CO.

15. Process according to claim 1, wherein the 2-(3-cyano-5-fluoro-phenyl)propene of formula (IV)is prepared by (c) reacting a C1-4-alkyl-3-cyano-5-fluorobenzoate of the formula (VI)wherein R1is C1-4-alkyl, with a Grignard reagent to the 3-fluoro-5-(1-hydroxy-1-methyl-ethyl)benzonitrile of formula (III), and (d) by subjecting the 3-fluoro-5-(1-hydroxy-1-methyl-ethyl)benzonitrile of formula (III) to dehydration with an acid.

16. Process according to claim 15, wherein the Grignard reagent in step c) is an organomagnesium halogenide.

17. Process according to claims 15 or 16, wherein the reaction in step c) is conducted in the presence of an organic solvent at a reaction temperature between -40 °C and 10 °C.

18. Process according to any one of claims 15 to 17, wherein the dehydration in step d) is conducted in the presence of an organic or inorganic acid or an acidic salt in an organic solvent at a reaction temperature between 80 °C and 150 °C.

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