Process for preparing opicapone

Abstract

The present invention provides an industrially applicable process for preparing opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof. This process, which provides opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof with good yield and purity, avoids the use of dichloromethane which is a solvent which needs to be replaced by other solvents in industrial processes.

Description

[0001] PROCESS FOR PREPARING OPICAPONE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to an industrially applicable process for preparing opicapone or any pharmaceutically acceptable salt thereof with good yield and purity.

[0004] BACKGROUND OF THE INVENTION

[0005] Opicapone (compound of formula I) is the international commonly accepted nonproprietary name (INN) of 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine-1 -oxide, has empirical formula of C15H10CI2N4O6 and its molecular weight is 413.17 g / mol.

[0006] Opicapone (compound of formula I) is a catechol-O-methyltransferase (COMT) inhibitor indicated as adjunctive treatment to levodopa / carbidopa in patients with Parkinson’s disease (PD) experiencing “OFF" episodes, and it is approved by US FDA under brand name of ONGENTYS®.

[0007] Opicapone (compound of formula I) was first disclosed in US8168793B2. The process disclosed in US8168793B2 is shown in scheme 1 :

[0008] Scheme 1

[0009] This process has several drawbacks such as the fact that the cyclization reaction involves use of tetrabutylammonium fluoride (TBAF). Use of expensive TBAF leads to high cost in the production and is therefore uneconomical for industrial production. Moreover, its use is also incompatible with conventional glass-lined reactors, thus reducing the flexibility of multipurpose manufacturing plants. The process also involves the use of BBra that is hazardous, and it is carried out at -78 °C making the above reaction not safe and cumbersome on large scale. Further, this process involves chromatographic purification which makes the process tedious at commercial scale-up. Also, the use of dichloromethane is not recommended at industrial scale. Dichloromethane has a low boiling point, and it is classified as human carcinogen. Consequently, dichloromethane has a very low emission limit, so that it brings a lot of inconvenience when used at large scale, i.e., at industrial scale. Dichloromethane is a substance that should be handled under control conditions. In conclusion, dichloromethane is a solvent which must be replaced by other solvents when scaling up processes.

[0010] WO2019123066A1 discloses a similar process but using as starting material 3,4- dimethoxy-5-nitrobenzoic acid (see scheme 2):

[0011] Scheme 2

[0012] Although, according to this route of synthesis, some of the above-mentioned inconvenient reaction conditions and reactants are avoided, still dichloromethane is repeatedly used in the above process for preparing opicapone (compound of formula I), making this process not suitable at industrial scale.

[0013] US9126988B2 discloses a process for preparing opicapone (compound of formula I) which is shown in scheme 3:

[0014]

[0015] One disadvantage of this process is the very low yield (40%) of 4-hydroxy-3-methoxy-5- nitrobenzoic acid (compound of formula IV-b) prepared from vanillic acid, which in turn affects the overall yield of opicapone (compound of formula I). Another disadvantage is the use of dichloromethane in the oxidation step.

[0016] Scheme 4 depicts the process for preparing opicapone (compound of formula I) disclosed in EP3421456A1:

[0017] Scheme 4 Two conditions are disclosed in this patent application for the oxidation of 5-(3-(2,5- dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) to obtain opicapone (compound of formula I): the use of urea hydrogen peroxide and trifluoroacetic anhydride in dichloromethane, solvent which must be replaced by other solvents at industrial scale as explained before, and the use of hydrogen peroxide 35% in acetic acid.

[0018] The authors of the present invention have found that very poor, if not any, conversions, of opicapone (compound of formula I) are obtained by using the above conditions of hydrogen peroxide in acetic acid.

[0019] The oxidation of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) or of other protected intermediates involved in prior art processes (e.g., 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4- oxadiazol-5-yl)-2,3-dibenzyloxy-1 -nitrobenzene, 5-(3-(2,5-dichloro-4,6-dimethylpyridin- 3-yl)- 1 , 2, 4-oxadiazol-5-yl)-2,3-dimethoxy-1 -nitrobenzene or 4-(3-(2,5-dichloro-4,6- dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol) is performed with good yields using urea hydrogen peroxide and trifluoroacetic anhydride, but always using dichloromethane as solvent in the prior art.

[0020] A process which involves the oxidation of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) is also disclosed in WO2022180649A1 (see scheme 5), again using urea hydrogen peroxide and trifluoroacetic anhydride in dichloromethane as solvent:

[0021] Scheme 5 EP2027091A1 discloses the preparation of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) but it is silent regarding its oxidation for preparing opicapone (compound of formula I) (see scheme 6):

[0022] Scheme 6

[0023] Notwithstanding the previously disclosed ways of producing opicapone there is still the need for new synthesis routes which provide opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof in high quality and yields. More specifically, it is necessary to have a safe, cost effective, environmentally friendly and easy-to-operate synthetic process of opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof.

[0024] It is therefore an object of the present invention to provide a new route of synthesis for the production of opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same and the use of the pharmaceutical compositions for the treatment of central nervous disorders.

[0025] BRIEF SUMMARY OF THE INVENTION

[0026] The present invention relates to an improved process for the preparation of opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof which is suitable at industrial scale. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 : X-Ray Powder Diffractogram (XRPD) of opicapone (compound of formula I) as obtained in Examples 4d, 4e and 4f.

[0028] Figure 2: X-Ray Powder Diffractogram (XRPD) of 5-(3-(2,5-dichloro-4,6-dimethylpyridin- 3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1,2-diol (compound of formula II) as obtained in Examples 3a and 3b.

[0029] Figure 3: X-Ray Powder Diffractogram (XRPD) of 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide (compound of formula V) as obtained in Example 1.

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] An aspect of the present invention provides a process for preparing opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof, which comprises the oxidation of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4- oxadiazol-5-yl)-3-nitrobenzene-1,2-diol (compound of formula II), using a peroxyacid selected from the group consisting of peracetic acid, trifluoroperacetic acid, m-chloroperoxybenzoic acid and mixtures thereof, in a solvent selected from the list of solvents consisting of sulfolane, 1 ,2-dichlorobenzene, chlorobenzene, alkyl esters of acetic acid, such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate or isobutyl acetate, and mixtures thereof.

[0032] The authors of the present invention have surprisingly found that oxidation of 5-(3-(2,5- dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) using organic peroxides occurs in good yields and purity only in a reduced number of solvents, so that the replacement of the undesired dichloromethane at industrial scale is not trivial at all.

[0033] In an embodiment of the present invention, the peroxyacid used in the oxidation of 5-(3- (2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) to form opicapone (compound of formula I) is formed in situ by the reaction of a peroxide, selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, tert-butyl hydroperoxide and mixtures thereof, and the corresponding carboxylic acid, acyl halide or anhydride of the corresponding acids, namely acetic acid, trifluoroacetic acid or m-chlorobenzoic acid, preferably the corresponding carboxylic acid or the corresponding anhydride.

[0034] In a preferred embodiment of the present invention, the peroxyacid used in the oxidation of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2- diol (compound of formula II) to obtain opicapone (compound of formula I) is trifluoroperacetic acid.

[0035] In a preferred embodiment of the present invention, the peroxyacid used in the oxidation of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2- diol (compound of formula II) to obtain opicapone (compound of formula I) is trifluoroperacetic acid which is formed in situ by reacting urea hydrogen peroxide and trifluoroacetic anhydride.

[0036] In a preferred embodiment of the present invention, the oxidation of 5-(3-(2,5-dichloro- 4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) to form opicapone (compound of formula I), preferably using trifluoroperacetic acid, preferably formed in situ by reacting urea hydrogen peroxide and trifluoroacetic anhydride, takes place in a solvent which is sulfolane, ethyl acetate, 1 ,2- dichlorobenzene, chlorobenzene or mixtures thereof. In a preferred embodiment of the present invention, the oxidation of 5-(3-(2,5-dichloro-

[0037] 4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) to form opicapone (compound of formula I), preferably using trifluoroperacetic acid, preferably formed in situ by reacting urea hydrogen peroxide and trifluoroacetic anhydride, takes place in chlorobenzene.

[0038] In a preferred embodiment of the present invention, the oxidation of 5-(3-(2,5-dichloro-

[0039] 4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) to form opicapone (compound of formula I) takes place using a molar ratio of the oxidant, preferably trifluoroperacetic acid formed in situ by reacting urea hydrogen peroxide and trifluoroacetic anhydride, with respect to 5-(3-(2,5-dichloro-4,6- dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II), from 2 to 6, preferably from 2.5 to 5, more preferably about 3.

[0040] In a preferred embodiment of the present invention, the oxidation of 5-(3-(2,5-dichloro-

[0041] 4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) to form opicapone (compound of formula I) takes place at a temperature from 00C to 80 °C, preferably from 10 °C to 60 °C, more preferably from 20 °C to 50 °C.

[0042] In an embodiment of the present invention, the isolation of opicapone (compound of formula I) from the reaction mixture may involve the use of reducing agents in order to destroy the excess of oxidants used, i.e., peroxyacid used. Non-limiting examples of reducing agents which can be used in the isolation of opicapone (compound of formula I) include sodium bisulfite, sodium sulfite, sodium thiosulfate, potassium bisulfite, potassium sulfite and mixtures thereof, preferably sodium bisulfite. In another embodiment no reducing agents are used to destroy the excess of oxidants used in the preparation process.

[0043] 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2- diol (compound of formula II) used in the process of the present invention can be obtained by any process known in the art. In a preferred embodiment, 5-(3-(2,5-dichloro-

[0044] 4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) is prepared according to a process which comprises the following steps (see scheme 7):

[0045] Step a) causing compound of formula IV, wherein G is selected from a group consisting of a halogen such as chlorine, bromine or iodine; a hydroxyl group, a group -O-SO2-R and a group -O-CO-R, wherein R stands for C1-C4 alkyl, optionally substituted by a halogen such as fluorine, chlorine, bromine or iodine; phenyl or C1-C4 alkyl-phenyl, to react with 2,5-dichloro-N'-hydroxy-4,6-dimethylnicotinimidamide (compound of formula V) to obtain 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2-methoxy- 6-nitrophenol (compound of formula III), and

[0046] Step b) deprotecting 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2- methoxy-6-nitrophenol (compound of formula III) to yield 5-(3-(2,5-dichloro-4,6- dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II)

[0047] Scheme 7

[0048] In the step a) above, it is preferred that G is selected from the group consisting of a halogen such as chlorine, bromine or iodine; a group -O-SO2-R and a group -O-CO-R, wherein R stands for C1-C4 alkyl, optionally substituted by a halogen such as fluorine, chlorine, bromine or iodine; phenyl or C1-C4 alkyl-phenyl.

[0049] In a preferred embodiment of the present invention, in the step a) above, G is a halogen, more preferably a chlorine (compound of formula IV-a):

[0050] IV-a

[0051] 4-hydroxy-3-methoxy-5-nitrobenzoic chloride (compound of formula IV-a) can be prepared by reacting the corresponding acid (compound of formula IV-b)

[0052] IV-b with phosgene, phosphorous trichloride, phosphorous pentachloride, sulfuryl chloride, thionyl chloride or mixtures thereof, preferably by reacting with thionyl chloride.

[0053] The reaction between 4-hydroxy-3-methoxy-5-nitrobenzoic acid (compound of formula IV-b) and thionyl chloride preferably takes place in the presence of a solvent. Non-limiting examples of suitable solvents which can be used are: ethers such as tetra hydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; ketones such as methyl ethyl ketone, methyl isobutyl ketone or acetone; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or 1 ,2-dichlorobenzene; polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V-dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; hydrocarbon aromatic solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate or mixtures of two or more of the solvents listed. Particularly preferred solvents are polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V-dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; hydrocarbon aromatic solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene and esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate or mixtures thereof. The reaction between the compound of formula IV, wherein G is selected from the group consisting of a halogen such as chlorine, bromine or iodine; a group -O-SO2-R and a group -O-CO-R, wherein R stands for C1-C4 alkyl, optionally substituted by a halogen such as fluorine, chlorine, bromine or iodine; phenyl or C1-C4 alkyl-phenyl, preferably chlorine (compound of formula IV-a), and 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide (compound of formula V) takes place preferably in the presence of a solvent. Non-limiting examples of suitable solvents which can be used are: ethers such as tetra hydrofuran, dioxane, diisopropyl ether, diethyl ether, 2- methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; ketones such as methyl ethyl ketone, methyl isobutyl ketone or acetone; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or 1 ,2-dichlorobenzene; polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V-dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; hydrocarbon aromatic solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate or mixtures of two or more of the solvents listed. Particularly preferred solvents are hydrocarbon aromatic solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene, preferably toluene, or esters such as ethylacetate, methylacetate, propylacetate, iso-propylacetate, butylacetate or isobutylacetate or mixtures thereof, preferably isobutyl acetate.

[0054] The reaction between the compound of formula IV, wherein G is selected from the group consisting of a halogen such as chlorine, bromine or iodine; a group -O-SO2-R and a group -O-CO-R, wherein R stands for C1-C4 alkyl, optionally substituted by a halogen such as fluorine, chlorine, bromine or iodine; phenyl or C1-C4 alkyl-phenyl, preferably chlorine (compound of formula IV-a), and 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide (compound of formula V) takes place in the presence of a base, preferably an organic base. Non-limiting examples of organic bases are pyridine, triethylamine, trimethylamine, tripropylamine, / V, / V-diisopropylethylamine (DI PEA), / V- methylpiperidine, / V, / V-dimethylaminopyridine (DMAP), / V-methylpyrrolidine, 1 ,4- diazabicyclo[2.2.2]octane (DABCO), 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), preferably pyridine.

[0055] The reaction between the compound of formula IV, wherein G is selected from the group consisting of a halogen such as chlorine, bromine or iodine; a group -O-SO2-R and a group -O-CO-R, wherein R stands for C1-C4 alkyl, optionally substituted by a halogen such as fluorine, chlorine, bromine or iodine; phenyl or C1-C4 alkyl-phenyl, preferably chlorine (compound of formula IV-a), and 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide (compound of formula V) takes place at a temperature between 50 °C and reflux temperature, preferably between 70 °C and 120 °C.

[0056] The obtained 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2- methoxy-6-nitrophenol (compound of formula III) can be purified before being used in the subsequent reaction step by means of recrystallization or slurry in a solvent or mixtures of solvents. Non-limiting examples of suitable solvents which can be used are: alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol; ethers such as tetra hydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; ketones such as methyl ethyl ketone, methyl isobutyl ketone or acetone; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or 1 ,2-dichlorobenzene; polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V- dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; hydrocarbon aromatic solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate, water or mixtures of two or more of the solvents listed.

[0057] In a preferred embodiment of the present invention the obtained 4-(3-(2,5-dichloro-4,6- dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol (compound of formula III) is purified by recrystallization or slurry in an alcohol such as methanol, ethanol, propanol, isopropanol, tert-butanol; an ether such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; a hydrocarbon aromatic solvent such as toluene, benzene, o- xylene, m-xylene or p-xylene; acetonitrile or mixtures thereof, more preferably by recrystallization in a mixture of tetrahydrofuran and methanol or by slurry in ethanol or methanol or in mixtures of ethanol and toluene or by slurry in acetonitrile.

[0058] In the step a) disclosed hereinbefore, the 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide (compound of formula V) used can be formed by any of the processes disclosed in the prior art. Preferably, 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide (compound of formula V) used in the present invention is formed by the reaction of 2,5-dichloro-4,6-dimethylnicotinonitrile (compound of formula VI) with hydroxylamine.

[0059] VI

[0060] The reaction between 2,5-dichloro-4,6-dimethylnicotinonitrile (compound of formula VI) and hydroxylamine takes place preferably in the presence of a solvent. Non-limiting examples of suitable solvents which can be used are: alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol; ethers such as tetra hydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; ketones such as methyl ethyl ketone, methyl isobutyl ketone or acetone; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or 1 ,2-dichlorobenzene; polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V-dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; hydrocarbon aromatic solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate, water or mixtures of two or more of the solvents listed. In a preferred embodiment, the solvent used in the reaction between 2,5-dichloro-4,6-dimethylnicotinonitrile (compound of formula VI) and hydroxylamine is an alcohol such as methanol, ethanol, propanol, isopropanol, tert-butanol, water or mixtures thereof, more preferably mixtures of methanol and water.

[0061] The obtained 2,5-dichloro-N'-hydroxy-4,6-dimethylnicotinimidamide (compound of formula V) can be purified before being used in the subsequent reaction step by means of recrystallization or slurry in an organic solvent or mixtures of organic solvents. Nonlimiting examples of suitable solvents which can be used are: alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol; ethers such as tetra hydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; ketones such as methyl ethyl ketone, methyl isobutyl ketone or acetone; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or 1 ,2-dichlorobenzene; polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V-dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; hydrocarbon aromatic solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate, water or mixtures of two or more of the solvents listed. In a preferred embodiment, the obtained 2,5-dichloro-4,6-dimethylnicotinonitrile (compound of formula VI) is purified by slurry in an alcohol such as methanol, ethanol, propanol, isopropanol, tert-butanol, water or mixtures thereof, more preferably in mixtures of methanol and water.

[0062] The 2,5-dichloro-N'-hydroxy-4,6-dimethylnicotinimidamide (compound of formula V) obtained according to the process of the present invention can be amorphous, crystalline or a mixture of crystalline and amorphous forms. More specifically, the present invention provides a novel crystalline form of 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide (compound of formula V) which shows an X-Ray Powder Diffractogram (XRPD) that comprises characteristic peaks at an angle of refraction 2 theta (20) of 11.9, 15.2, 16.9, 24.1 and 30.0 (± 0.2), preferably at an angle of refraction 2 theta (20) of 10.7, 11.9, 15.2, 16.9, 19.4, 24.1 , 27.5 and 30.0 (± 0.2), more preferably at an angle of refraction 2 theta (20) of 10.7, 11.9, 15.2, 16.4, 16.9, 19.4, 20.7, 22.2, 22.8, 23.8, 24.1 , 25.0, 25.3, 27.5. 29.1 , 30.0, 31.6 and 34.3 (± 0.2), even more preferably an X-Ray Powder Diffractogram (XRPD) as shown in Figure 3, as measured in an X-ray diffractometer with Cu Ka radiation (1.54056 A).

[0063] In the step b) disclosed hereinbefore, 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4- oxadiazol-5-yl)-2-methoxy-6-nitrophenol (compound of formula III) is deprotected to obtain 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene- 1 ,2-diol (compound of formula II), preferably by using a Lewis acid and a base. Nonlimiting examples of Lewis acids are aluminum trichloride, lithium tetrafluoroborate, boron trifluoride diethyl etherate and mixtures thereof. Non-limiting examples of bases are pyridine, triethylamine, trimethylamine, tripropylamine, / V, / V-diisopropylethylamine (DI PEA), N-methylpiperidine, / V, / V-dimethylaminopyridine (DMAP), N-methylpyrrolidine, 1 ,4-diazabicyclo[2.2.2]octane (DABCO), 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU). In a preferred embodiment of the present invention the Lewis acid used is aluminum trichloride and the base is pyridine.

[0064] The reaction of deprotection of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4- oxadiazol-5-yl)-2-methoxy-6-nitrophenol (compound of formula III) to obtain 5-(3-(2,5- dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) takes place preferably in the presence of a solvent. Non-limiting examples of suitable solvents which can be used are: ethers such as tetra hydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; ketones such as methyl ethyl ketone, methyl isobutyl ketone or acetone; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or 1 ,2-dichlorobenzene; polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V-dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; hydrocarbon aromatic solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate, water or mixtures of two or more of the solvents listed. In a preferred embodiment, deprotection of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2- methoxy-6-nitrophenol (compound of formula III) to obtain 5-(3-(2,5-dichloro-4,6- dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) takes place in an ether solvent such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tertbutyl ether, more preferably in 2-methyltetrahydrofuran.

[0065] The reaction of deprotection of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4- oxadiazol-5-yl)-2-methoxy-6-nitrophenol (compound of formula III) to obtain 5-(3-(2,5- dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) takes place at a temperature between 50 °C and reflux temperature.

[0066] The obtained 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) can be purified before being used in the subsequent reaction step by means of recrystallization or slurry in a solvent or mixtures of solvents. Non-limiting examples of suitable solvents which can be used are: alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol; ethers such as tetra hydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; ketones such as methyl ethyl ketone, methyl isobutyl ketone or acetone; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or 1 ,2-dichlorobenzene; polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V- dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; hydrocarbon aromatic solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate, water or mixtures of two or more of the solvents listed. In a preferred embodiment, the obtained 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5- yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) is purified by slurry in an alcohol such as methanol, ethanol, propanol, isopropanol, tert-butanol; in acetonitrile, in water or mixtures thereof, more preferably 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4- oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) is purified by slurry in methanol or in acetonitrile.

[0067] The obtained 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) obtained according to the process of the present invention can be amorphous, crystalline or a mixture of a crystalline and amorphous forms. More specifically, the present invention provides a novel crystalline form of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) which shows an X-Ray Powder Diffractogram (XRPD) that comprises characteristic peaks at an angle of refraction 2 theta (20) of 5.6, 11.9, 13.8 and 19.3 (± 0.2), preferably at an angle of refraction 2 theta (20) of 5.6, 6.9, 11.1 , 11.9, 13.8, 16.8 and 19.3 (± 0.2), more preferably at an angle of refraction 2 theta (20) of 5.6, 6.9, 8.0, 9.6, 11.1 , 11.9, 13.8, 15.8, 16.8, 19.3, 19.6, 21.6 and 24.1 (± 0.2), even more preferably an X-Ray Powder Diffractogram (XRPD) as shown in Figure 2, as measured in an X-ray diffractometer with Cu Ka radiation (1.54056 A).

[0068] Opicapone (compound of formula I) obtained according to the process of the present invention can be purified by means of recrystallization or slurry in an organic solvent or mixtures of organic solvents. Non-limiting examples of suitable solvents which can be used are: alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol; ethers such as tetra hydrofuran, dioxane, diisopropyl ether, diethyl ether, 2- methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; ketones such as methyl ethyl ketone, methyl isobutyl ketone or acetone; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or 1 ,2-dichlorobenzene; polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V-dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; hydrocarbon aromatic solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate; water or mixtures of two or more of the solvents listed. In an embodiment of the present invention, opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising one or more polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V-dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide and one or more ethers such as tetra hydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether. In a preferred embodiment of the present invention, opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising dimethylsulfoxide, tetrahydrofuran and acetonitrile.

[0069] In a preferred embodiment of the present invention, opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising one or more polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V- dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; one or more ethers such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2- methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether and one or more alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol. In a more preferred embodiment of the present invention, opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising dimethylsulfoxide, tetrahydrofuran and methanol.

[0070] In a preferred embodiment of the present invention, opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising one or more polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V- dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide and one or more esters such as such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate. In a more preferred embodiment of the present invention, opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising dimethylsulfoxide, ethylacetate and acetonitrile.

[0071] In a preferred embodiment of the present invention, opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising one or more polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V- dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; one or more ethers such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2- methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether and one or more alcohols such as methanol, ethanol, propanol, isopropanol or tert-butanol. In a more preferred embodiment of the present invention, opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising dimethylsulfoxide, tetrahydrofuran and methanol.

[0072] Any of the purification steps hereinbefore disclosed can be repeated until having an amount of unreacted 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) of less than 0.15% (HPLC, %area).

[0073] Additionally, and after any of the hereinbefore disclosed purification processes, opicapone (compound of formula I) can be further purified by forming a slurry in an alcohol such as methanol, ethanol, propanol, isopropanol, tert-butanol, preferably methanol, or in a ketone such as methyl ethyl ketone, methyl isobutyl ketone or acetone, preferably acetone.

[0074] Opicapone (compound of formula I) as obtained according to the process of the present invention can be crystalline or amorphous or a mixture of crystalline and amorphous forms. In a preferred embodiment of the present invention, opicapone (compound of formula I) obtained according to the process of the present invention shows a X-Ray Powder Diffractogram (XRPD) that comprises characteristic peaks at an angle of refraction 2 theta (20) of 6.8, 12.1 , 13.4 and 18.2 (± 0.2), preferably at an angle of refraction 2 theta (20) of 6.8, 12.1 , 13.4, 18.2, 20.0, 24.0 and 24.4 (± 0.2), more preferably at an angle of refraction 2 theta (20) of 6.8, 7.2, 12.1 , 13.4, 18.2, 20.0, 24.0, 24.4, 25.4, 28.3, 28.7 and 30.4 (± 0.2) as measured in a X-ray diffractometer with Cu Ka radiation (1.54056 A). In a preferred embodiment of the present invention, opicapone (compound of formula I) prepared according to the process of the present invention shows an X-Ray Powder Diffractogram (XRPD) as shown in Figure 1.

[0075] Opicapone (compound of formula I) as obtained according to the process of the present invention may have a particle size distribution (PSD), defined as the equivalent circular diameter (ECD), characterized by: (i) a D value of less than about 4 pm, preferably of less than 3 pm; (ii) a D50 value of less than about 10 pm, preferably of less than 8 pm, more preferably of less than 7 pm, even more preferably of less than 6 pm; or (iii) a D90 value of less than 70 pm, preferably of less than 50 pm, more preferably of less than 20 pm; or a combination of (i), (ii) and / or (iii).

[0076] The skilled artisan knows that the results of PSD determination by one technique can be correlated with results from another technique on an empirical basis by routine experimentation. Preferably, in the present invention the PSD determination is performed by optical microscopy using a Morphologi G3 particle size analyzer from Malvern Panalytical.

[0077] Opicapone (compound of Formula I) with this particle size distribution can be obtained directly from the purification processes of the present invention or applying a subsequent step of reducing the particle size by any known process disclosed in the prior art such as pin milling, ball milling or jet milling.

[0078] Most aptly opicapone (compound of formula I) is unsalted. However, salts of the hydroxy phenolic groups with metal ions such as the alkali or alkaline earth metals are possible, particularly the sodium and potassium salts, as well as those of highly basic organic compounds such as guanidine or the like are possible. For example, sodium or potassium salts of opicapone (compound of formula I) can be prepared by reaction of opicapone (compound of formula I) with sodium or potassium carbonate, sodium or potassium hydroxide, sodium or potassium hydride or sodium or potassium alkoxide.

[0079] The process according to the present invention leads to opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof which is more than 95% (area%) pure when analyzed by a HPLC method for chromatographic purity, preferably more than 96.5% (area%) pure when analyzed by a HPLC method for chromatographic purity, more preferably more than 98.0% (area%) pure when analyzed by a HPLC method for chromatographic purity, even more preferably more than 99.0% (area%) pure when analyzed by a HPLC method for chromatographic purity.

[0080] The HPLC method for chromatographic purity according to the present invention comprises any HPLC method used to determine the purity of opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof. Preferably, the HPLC method for chromatographic purity comprises the HPLC method for chromatographic purity used in the present invention.

[0081] Another aspect of the present invention provides a pharmaceutical composition comprising opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations, preferably tablets or capsules. For the preparation of pharmaceutical compositions of opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof obtained according to the process of the present invention, inert pharmaceutically acceptable carriers are admixed with the active compounds. The pharmaceutically acceptable carriers may be solid or liquid. A solid carrier can be one or more substances which may also act as diluent, flavouring agent, solubiliser, lubricant, suspending agent, binder, glidant, or disintegrant.

[0082] Opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof obtained according to the process of the present invention or pharmaceutical compositions thereof may be used to treat some central and peripheral nervous system disorders, such as Parkinson's disease, mood disorders, restless legs syndrome, gastrointestinal disturbances, edema formation states and hypertension.

[0083] The term “about” when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range defined by the number ±10% of its value, preferably a range defined by the number ±5%, more preferably a range defined by the number ±2%, still more preferably a range defined by the number ±1 %. For example, “about 10” should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

[0084] Examples

[0085] XRPD Method of Analysis used for opicapone (compound of formula I) obtained in Example 4d.

[0086] The XRPD pattern was recorded on a Bruker D2 Phaser diffractometer equipped with a vertical goniometer under Bragg-Brentano geometry and a SSD160-2 position-sensitive detector with a 6-position sample changer and a horizontal sample holder rotating at 15 rpm. Cu Ka radiation (I = 1.54056 A) was obtained from a copper X-ray tube operated at 30 kV and 10 mA. The diffraction pattern was recorded including values of 20 that range from 3 to 50° with a sampling rate of 0.02° per second and a step time of 0.7 seconds per step. The powdered sample was placed on a low-background silicon sample holder and covered with Kapton foil. DIFFRAC MEASUREMENT CENTER software with EVA evaluation software (Bruker) was used to record the data and for a primary analysis of the diffraction pattern. The equipment was periodically calibrated using a corundum (AI2O3) reference sample. XRPD Method of Analysis used for 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide (compound of formula V) obtained in Example 1 and 5-(3-(2,5- dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) obtained in Example 3.

[0087] The XRPD pattern was recorded on a Siemens D5000 diffractometer equipped with two symmetrically mounted vertical goniometers (Bragg-Brentano geometry) with horizontal sample stages, a X-ray tube, a high voltage generator (working at 45 kV and 35 mA) and standard scintillation detectors. Ni-filtered Cu-anode source was used and diffracted radiation was further monochromatized with a graphite crystal to avoid fluorescence effects [ (Ka) = 1 .54056 A], The diffraction pattern was recorded including values of 20 that range from 2 to 50° with a sampling rate of 0.02° per second and a step time of 1 second per step. The powdered sample was pressed between two glass plates, forming a film. DIFFRAC Plus measurement software with EVA evaluation software (Bruker) was used to record the data and for a primary analysis of the diffraction pattern. The equipment was periodically calibrated using quartz and silicon.

[0088] HPLC Method of Analysis:

[0089] The chromatographic separation was carried out using a Kinetex biphenyl (150 x 4.6 mm x 2.6 pm), at 35 °C.

[0090] The mobile phase A was 10 mM potassium dihydrogenphosphate buffer at pH 2.0.

[0091] The mobile phase B was methanol / acetonitrile (40 / 60, v / v)

[0092] The chromatograph was programmed as follows: initial 3 min isocratic 65% mobile phase A; 3-20 min linear gradient to 30% phase A; 20-30 min isocratic 30% phase A; 30-32 min linear gradient to 65% phase A; 32-37 min isocratic 65% phase A.

[0093] The chromatograph was equipped with a UV detector (270 nm). The flow rate was 0.9 mL / min.

[0094] The samples had a concentration of 0.5 mg / mL and were prepared, for example, by dissolving 25 mg in 50 mL of diluent (diluent: dimethylsulfoxide / water / acetonitrile: 40 / 30 / 30, v / v / v).

[0095] The process described in the present invention is illustrated in examples below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention: Example 1 : 2,5-dichloro-N'-hydroxy-4,6-dimethylnicotinimidamide (compound of formula

[0096] V)

[0097] Under an argon atmosphere, 61 mL of hydroxylamine 50% aqueous solution (1 mol) were added to a suspension of 50.0 g of 2,5-dichloro-4,6-dimethylnicotinonitrile (compound of formula VI) (250 mmol) in 300 mL of methanol and 500 mL of water. The resulting suspension was heated at 60-70 °C under nitrogen atmosphere and stirred at least 10 hours at this temperature. The mixture was cooled down to 5 °C and the resulting solid was filtered. The solid was stirred in a mixture of 250 mL of methanol and 300 mL of water, filtered and dried under vacuum to yield 46.6 of 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide (compound of formula V) as a white powder (yield: 80%). X- Ray Powder Diffraction as shown in Figure 3.

[0098] Example 2a: 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2- methoxy-6-nitrophenol (compound of formula III)

[0099] 50.0 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (compound of formula IV-b, 225 mmol), 21.5 mL of thionyl chloride (300 mmol), 0.5 mL of dimethylformamide and 300 mL of toluene were stirred for 3 hours at 70-80 °C. Then, solvent was distilled under atmospheric pressure and 300 mL of heptane were added. The resulting suspension was cooled down to 0 °C, stirred 1 hour and filtered.

[0100] The obtained wet solid, 4-hydroxy-3-methoxy-5-nitrobenzoyl chloride (compound of formula IV-a), was added over a suspension of 55.2 g of 2,5-dichloro-N'-hydroxy-4,6- dimethylnicotinimidamide (compound of formula V) (235 mmol) in 650 mL of toluene at 10-20°C. The resulting mixture was stirred for 1 hour at 10-20 °C and 2 additional hours at 80-90 °C. Then, 36 mL of pyridine were added, and the reaction was stirred at reflux for 5 additional hours. Then, solvent was partially distilled under atmospheric pressure and 330 mL of ethanol were added. The resulting suspension was cooled down to 0 °C, stirred 1 hour and filtered to yield 76.1 g of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol (compound of formula III) as a yellow powder (yield: 84%).

[0101] Example 2b: 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2- methoxy-6-nitrophenol (compound of formula III)

[0102] 50.0 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (compound of formula IV-b, 225 mmol), 21.5 mL of thionyl chloride (300 mmol), 0.5 mL of dimethylformamide and 400 mL of isobutyl acetate were stirred for 5 hours at 60-70 °C. Solvent was distilled off under reduced pressure and additional 300 mL of isobutyl acetate were added to obtain a solution of 4-hydroxy-3-methoxy-5-nitrobenzoyl chloride (compound of formula IV-a).

[0103] The obtained solution was added over a suspension of 55.2 g of 2,5-dichloro-N'-hydroxy- 4,6-dimethylnicotinimidamide (compound of formula V) (235 mmol) in 260 mL of isobutyl acetate at 10-20 °C. The resulting mixture was stirred for 1 hour at 10-20 °C and 2 additional hours at 80-90 °C. Then, 36 mL of pyridine were added, and the reaction was stirred at 115 °C for 3 additional hours. Then, solvent was distilled under atmospheric pressure and 400 mL of methanol were added. The resulting suspension was filtered. The solid was dissolved in a mixture of tetrahydrofuran and methanol at reflux, the solution was stirred for 30 minutes at this temperature and then cooled down to 10 °C. The resulting suspension was stirred for 30 minutes, filtered, and dried under vacuum to yield 64.3 g 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2-methoxy- 6-nitrophenol (compound of formula III) as a yellow powder (yield: 71 %).

[0104] Example 2c: 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2- methoxy-6-nitrophenol (compound of formula III)

[0105] 50.0 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (compound IV, 235 mmol), 20.3 mL of thionyl chloride (284 mmol), 0.3 mL of dimethylformamide and 475 mL of isobutyl acetate were stirred 5 hours at 60-70 °C. Solvent was distilled off under reduced pressure and additional 200 mL of isobutyl acetate were added to obtain a solution of 4-hydroxy- 3-methoxy-5-nitrobenzoyl chloride (compound IV-a).

[0106] The obtained solution was added over a suspension of 57.7 g of 5-dichloro-N'-hydroxy- 4,6-dimethylnicotinimidamide (compound V) (246 mmol) in 475 mL of isobutyl acetate at 10-20 °C. The resulting mixture was stirred for 1 hour at 10-20 °C and 2 additional hours at 80-90 °C. Then, 38 mL of pyridine were added, and the reaction was stirred at 115 °C for 3 additional hours. Then, solvent was distilled under atmospheric pressure and 700 mL of acetonitrile were added. The resulting suspension was stirred 30 minutes, filtered, and dried under vacuum to yield 82.0 g of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol (compound III) as a yellow powder (yield: 85%)

[0107] Example 3a: 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) A mixture of 33.0 g of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)- 2-methoxy-6-nitrophenol (compound of formula III) (80 mmol) and 430 mL of 2- methyltetrahydrofuran was cooled to 0 °C. Over this suspension, 12.8 g of aluminum trichloride (96 mmol) and 17.8 mL of pyridine (220 mmol) were consecutively added. The reaction mixture was stirred for 5 hours at reflux. Then, it was cooled to 25 °C and 150 mL of HCI 4 M were added. Layers were separated and the organic layer was washed twice with brine. Reaction mixture was distilled under reduced pressure and 290 mL of acetonitrile were added. The resulting suspension was filtered. The obtained solid was stirred in 200 mL of methanol, filtered and dried under vacuum to yield 26.4 g of 5-(3- (2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) as a yellow powder (yield: 83%). X-Ray Powder Diffraction as shown in Figure 2.

[0108] Example 3b: 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II)

[0109] A mixture of 60.0 g of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)- 2-methoxy-6-nitrophenol (compound III) (146 mmol) and 750 mL of 2- methyltetrahydrofuran were cooled to 0 °C. Over this suspension, 24.3 g of aluminum trichloride (183 mmol) and 32 mL of pyridine (400 mmol) were consecutively added. The reaction mixture was stirred 5 hours at reflux. Then, it was cooled to 25 °C and 150 mL of HCI 4 M were added. Layers were separated and the organic layer was washed twice with brine. The organic solvent was distilled under reduced pressure and 290 mL of acetonitrile were added. The resulting suspension was filtered and dried under vacuum to yield 49.8 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound II) as a yellow powder (yield: 86%). X-Ray Powder Diffraction as shown in Figure 2.

[0110] Example 4a: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4-oxadiazol-3-yl)-4,6- dimethylpyridine-1 -oxide: opicapone (compound of formula I)

[0111] A mixture of 6.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) (15 mmol) and 80 mL of sulfolane were cooled to 10-15 °C. Over this solution, 5.5 g of urea hydrogen peroxide (56 mmol) were slowly added. The resulting mixture was stirred for 10 minutes and then 9.5 mL of trifluoracetic anhydride (68 mmol) were added portion wise. The reaction mixture was heated to 35-40°C and stirred at this temperature for 6 additional hours. Then, the mixture was cooled to 15 °C and 75 mL of Na2S20s aqueous solution were added. The resulting mixture was stirred for 3 hours at 15 °C and the resulting solid was filtered. Purity (HPLC, %area): 83.5%.

[0112] Example 4b: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4-oxadiazol-3-yl)-4,6- dimethylpyridine-1 -oxide: opicapone (compound of formula I)

[0113] A mixture of 6.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) (15 mmol) and 120 mL of ethyl acetate were cooled to 10-15°C. Over this solution, 5.5 g of urea hydrogen peroxide (56 mmol) were slowly added. The resulting mixture was stirred for 10 minutes and then 9.5 mL of trifluoracetic anhydride (68 mmol) were added portion wise. The reaction mixture was heated to 20-25°C and stirred at this temperature for 20 additional hours. Then, the mixture was cooled to 15 °C and 75 mL of Na2SOs 10% aqueous solution were added. The resulting mixture was stirred for 1 hour at 15 °C and the resulting solid was filtered. Purity (HPLC, %area): 77.42%.

[0114] Example 4c: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4-oxadiazol-3-yl)-4,6- dimethylpyridine-1 -oxide (compound of formula I)

[0115] A mixture of 3.6 g of urea hydrogen peroxide (37.8 mmol), 6.3 mL of trifluoracetic anhydride (45.3 mmol) and 45 mL of 1 ,2-dichlorobenzene was stirred at 0-5 °C. Over this suspension, 3.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5- yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) (7.5 mmol) were added portion wise. The reaction mixture was stirred for 20 hours at 20-25 °C and then 5 additional hours at 40 °C. Then, the mixture was cooled to 15 °C and 30 mL of Na2SOs 10% aqueous solution were added. The resulting mixture was stirred for 1 hour at 15 °C and the resulting solid was filtered. Purity (HPLC, %area): 78.35%

[0116] Example 4d: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4-oxadiazol-3-yl)-4,6- dimethylpyridine-1 -oxide (compound of formula I)

[0117] A mixture of 50.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)- 3-nitrobenzene-1 ,2-diol (compound of formula II) (126 mmol) and 450 mL of chlorobenzene was cooled to 10-15 °C. Over this solution, 36.6 g of urea hydrogen peroxide (378 mmol) were slowly added. The resulting mixture was stirred for 10 minutes and then 87.5 mL of trifluoracetic anhydride (630 mmol) were added portion wise. The reaction mixture was heated to 25-35 °C and stirred to this temperature for 4 additional hours. Then, the mixture was cooled to 15 °C and 75 mL of methanol and 400 mL of Na2SC>3 10% aqueous solution were added. The resulting suspension was stirred for 2 hours at 15 °C, filtered and washed with methanol. 76.5 g of wet 2,5-dichloro-3-(5-(3,4- dihydroxy-5-nitrophenyl)-1 ,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide (compound of formula I) were obtained. Purity (HPLC, %area): 94.9%.

[0118] Wet opicapone (compound of formula I) was stirred with 187 mL of dimethylsulfoxide and 187 mL of tetrahydrofuran. The obtained suspension was heated to 55±5 °C and a solution was obtained. The solution was filtered to remove insoluble particles, cooled down to 20-25 °C and 515 mL of methanol were added. The resulting mixture was stirred for at least 2 hours at 10-15 °C. The solid was filtered and washed with methanol. This purification can be repeated to decrease the content of unreacted 5-(3-(2,5-dichloro-4,6- dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) below 0.15% (HPLC, %area).

[0119] Then, wet product was suspended in methanol (450 mL) and warmed to reflux. The suspension was stirred under reflux for 1 hour, cooled to 25 °C, filtered and dried. After drying the obtained solid under vacuum, about 35 g of opicapone (compound of formula I) were obtained as a yellow powder. X-Ray Powder Diffraction as shown in Figure 1.

[0120] Example 4e: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4-oxadiazol-3-yl)-4,6- dimethylpyridine-1 -oxide (compound of formula I)

[0121] A mixture of 50.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)- 3-nitrobenzene-1 ,2-diol (compound II) (126 mmol) and 5000 mL of chlorobenzene were cooled to 10-15 °C. Over this solution, 36.6 g of urea hydrogen peroxide (377 mmol) were slowly added. The resulting mixture was stirred 10 minutes and then 61.2 mL of trifluoracetic anhydride (440 mmol) were added portion wise. The reaction mixture was heated to 25-35 °C and stirred at this temperature for 4 additional hours. Then, the mixture was cooled to 15 °C and 250 mL of water and 175 mL of acetonitrile were added. The resulting suspension was stirred 2 hours at 15 °C, filtered and washed with methanol. 49.4 g of dry equivalent 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine-1 -oxide (compound I) were obtained. Purity (HPLC): 95.2%,

[0122] Wet opicapone was stirred with 175 mL of dimethylsulfoxide and 50 mL of ethyl acetate. The obtained suspension was heated to 55±5 °C and a solution was obtained. 450 mL of ethyl acetate and 500 mL of acetonitrile were successively added at 55±5 °C. The resulting mixture was cooled and stirred for at least 2 hours at 10-15 °C. The solid was filtered and washed with acetonitrile. 34.0 g of dry equivalent 2,5-dichloro-3-(5-(3,4- dihydroxy-5-nitrophenyl)-1 ,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1 -oxide (compound I) were obtained. This purification can be repeated to decrease the content of unreacted 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2- diol below 0.15% (% area by HPLC).

[0123] Then, the wet product was suspended in methanol (450 mL) and heated to reflux. The suspension was stirred under reflux for 1 hour, cooled to 25 °C, and filtered. After drying the obtained solid under vacuum, about 35 g of opicapone (compound of formula I) were obtained as a yellow powder. X-Ray Powder Diffraction as shown in Figure 1.

[0124] Example 4f: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4-oxadiazol-3-yl)-4,6- dimethylpyridine-1 -oxide (compound of formula I)

[0125] A mixture of 50.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)- 3-nitrobenzene-1 ,2-diol (compound II) (126 mmol) and 5000 mL of chlorobenzene were cooled to 10-15 °C. Over this solution, 36.6 g of urea hydrogen peroxide (377 mmol) were slowly added. The resulting mixture was stirred 10 minutes and then 61.2 mL of trifluoracetic anhydride (440 mmol) were added portion wise. The reaction mixture was heated to 25-35 °C and stirred at this temperature for 4 additional hours. Then, the mixture was cooled to 15 °C and 250 mL of water and 175 mL of acetonitrile were added. The resulting suspension was stirred 2 hours at 15 °C, filtered and washed with methanol. 49.4 g of dry equivalent 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine 1 -oxide (compound I) were obtained.

[0126] Then, the wet product was dissolved in 136 mL of dimethylsulfoxide and 136 mL of tetrahydrofuran. The solution was heated at 40°C and filtered to remove insoluble particles. The filtered solution was added over 408 mL of methanol at 10-15°C. The resulting suspension was stirred for 8 hours at 10-15°C. The suspension was filtered and dried. After drying the obtained solid under vacuum, about 30 g of 2,5-dichloro-3-(5-(3,4- dihydroxy-5-nitrophenyl)-1 ,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide (compound I) were obtained as a yellow powder.

[0127] Then, the wet product was suspended in methanol (450 mL) and heated to reflux. The suspension was stirred under reflux for 1 hour, cooled to 25 °C, and filtered. After drying the obtained solid under vacuum, about 35 g of opicapone (compound of formula I) were obtained as a yellow powder. X-Ray Powder Diffraction as shown in Figure 1. PSD: D (ECD) = 2.22 pm, D50(ECD) = 6.01 pm and D95(ECD) = 13.59 pm

[0128] Comparative Example 1 : 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide (compound of formula I)

[0129] A mixture of 2.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) (5 mmol) and 16 mL of acetic acid were cooled to 10-15°C. Over this solution, 6.23 g of hydrogen peroxide 30% aqueous solution (50 mmol) were slowly added. The reaction mixture was heated to 20-25°C and stirred at this temperature for 20 additional hours. No reaction was observed.

[0130] Comparative Example 2: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide (compound of formula I)

[0131] A mixture of 1.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) (2.5 mmol) and 10 mL of n-heptane were cooled to 10-15°C. Over this solution, 0.98 g of urea hydrogen peroxide (10 mmol) were slowly added. The resulting mixture was stirred 10 minutes and then 0.7 mL of trifluoracetic anhydride (5.0 mmol) were added portion wise. The reaction mixture was heated to 25-30°C and stirred at this temperature for 20 additional hours. Then, the mixture was cooled to 15 °C and 75 mL of Na2SOs 10% aqueous solution were added. The resulting mixture was stirred for 1 hour at 15 °C and the resulting solid was filtered. Purity (HPLC, %area): 17.2%.

[0132] Comparative Example 3: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide (compound of formula I)

[0133] A mixture of 3.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) (7.5 mmol) and 30 mL of acetonitrile were cooled to 10-15°C. Over this solution, 3.6 g of urea hydrogen peroxide (38 mmol) were slowly added. The resulting mixture was stirred for 10 minutes and then 5.2 mL of trifluoracetic anhydride (38 mmol) were added portion wise. The reaction mixture was heated to 50-60°C and stirred at this temperature for 20 additional hours. Then, the mixture was cooled to 15 °C and 75 mL of Na2SOs 10% aqueous solution were added. The resulting mixture was stirred for 1 hour at 15 °C and the resulting solid was filtered. Purity (HPLC, %area): 40.9%. Comparative Example 4: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide (compound of formula I)

[0134] A mixture of 2.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) (5.0 mmol) and 16 mL of dimethylsulfoxide were cooled to 10-15°C. Over this solution, 1.95 g of urea hydrogen peroxide (20.1 mmol) were slowly added. The resulting mixture was stirred for 10 minutes and then 2.5 mL of trifluoracetic anhydride (17.6 mmol) were added portion wise. The reaction mixture was heated to 25-30°C and stirred at this temperature for 20 additional hours. No reaction was observed.

[0135] Comparative Example 5: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide (compound of formula I)

[0136] A mixture of 2.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) (5.0 mmol) and 16 mL of / V, / V- dimethylacetamide were cooled to 10-15°C. Over this solution, 1.95 g of urea hydrogen peroxide (20.1 mmol) were slowly added. The resulting mixture was stirred for 10 minutes and then 2.5 mL of trifluoracetic anhydride (17.6 mmol) were added portion wise. The reaction mixture was heated to 25-30 °C and stirred at this temperature for 20 additional hours. Then, the mixture was cooled to 15 °C and 75 mL of Na2SOs 10% aqueous solution were added. The resulting mixture was stirred for 1 hour at 15 °C and the resulting solid was filtered. Purity (HPLC, %area): 9.08%.

[0137] Comparative Example 6: 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1 ,2,4- oxadiazol-3-yl)-4,6-dimethylpyridine-1-oxide (compound of formula I)

[0138] A mixture of 2.0 g of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-3- nitrobenzene-1 ,2-diol (compound of formula II) (5.0 mmol) and 24 mL of tetra hydrofuran were cooled to 10-15°C. Overthis solution, 1.71 g of urea hydrogen peroxide (17.6 mmol) were slowly added. The resulting mixture was stirred for 10 minutes and then 1.75 mL of trifluoracetic anhydride (12.6 mmol) were added portion wise. The reaction mixture was heated to reflux and stirred at this temperature for 6 additional hours. Then, the mixture was cooled to 15 °C and 75 mL of Na2SOs 10% aqueous solution were added. The resulting mixture was stirred for 1 hour at 15 °C and the resulting solid was filtered. Purity (HPLC, %area): 19.33%.

Claims

CLAIMS1 . A process for preparing opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof,which comprises the oxidation of 5-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4- oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II),II using a peroxyacid selected from the group consisting of peracetic acid, trifluoroperacetic acid, m-chloroperoxybenzoic acid and mixtures thereof, in a solvent selected from the list of solvents consisting of sulfolane, 1 ,2-dichlorobenzene, chlorobenzene, alkyl esters of acetic acid, such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate or isobutyl acetate, and mixtures thereof.

2. The process according to claim 1 , wherein the peroxyacid is formed in situ by the reaction of a peroxide, selected from the group consisting of hydrogen peroxide, urea hydrogen peroxide, tert-butyl hydroperoxide and mixtures thereof, and a carboxylic acid, acyl halide or anhydride of the corresponding acids, namely acetic acid, trifluoroacetic acid or m-chlorobenzoic acid.

3. The process according to any one of claims 1 or 2 wherein the peroxyacid is trifluoroperacetic acid.

4. The process according to any one of claims 1 to 3, wherein the trifluoroperacetic acid is formed in situ by reacting urea hydrogen peroxide and trifluoroacetic anhydride.

5. The process according to any one of claims 1 to 4 wherein the solvent is sulfolane, ethyl acetate, 1 ,2-dichlorobenzene, chlorobenzene or mixtures thereof.

6. The process according to any one of claims 1 to 5, wherein 5-(3-(2,5-dichloro-4,6- dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II) is prepared according to a process which comprises the following steps:Step a) causing a compound of formula IV, wherein G is selected from a group consisting of a halogen such as chlorine, bromine or iodine; a hydroxyl group, a group -O-SO2-R and a group -O-CO-R, wherein R stands for C1-C4 alkyl, optionally substituted by a halogen such as fluorine, chlorine, bromine or iodine; phenyl or C1-C4 alkyl-phenyl, to react with 2,5-dichloro-N'-hydroxy-4,6-dimethylnicotinimidamide (compound of formula V) to obtain 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2-methoxy- 6-nitrophenol (compound of formula III), andStep b) deprotecting 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1 ,2,4-oxadiazol-5-yl)-2- methoxy-6-nitrophenol (compound of formula III) to yield 5-(3-(2,5-dichloro-4,6- dimethylpyridin-3-yl)- 1 ,2,4-oxadiazol-5-yl)-3-nitrobenzene-1 ,2-diol (compound of formula II)7. The process according to claim 6, wherein in step a), G of the compound of formula IV is selected from a group consisting of a halogen such as chlorine, bromine or iodine;a group -O-SO2-R and a group -O-CO-R, wherein R stands for C1-C4 alkyl, optionally substituted by a halogen such as fluorine, chlorine, bromine or iodine; phenyl or C1-C4 alkyl-phenyl.

8. The process according to claim 7, wherein G represents a chlorine atom and the compound of formula IV is:IV-a9. The process according to any one of claims 6 to 8, wherein 2,5-dichloro-N'-hydroxy- 4,6-dimethylnicotinimidamide (compound of formula V) is formed by the reaction of 2,5- dichloro-4,6-dimethylnicotinonitrile (compound of formula VI) with hydroxylamine.VI10. The process according to any one of claims 1 to 9, wherein opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising one or more polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, A / . / V- dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide; one or more ethers such as tetra hydrofuran, dioxane, diisopropyl ether, diethyl ether, 2- methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether and one or more alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol.

11. The process according to claim 10, wherein opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising dimethylsulfoxide, tetrahydrofuran and methanol.

12. The process according to any one of claims 1 to 9, wherein opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprisingone or more polar aprotic solvents such as / V, / V-dimethylformamide, acetonitrile, / V, / V- dimethylacetamide, / V-methyl-2-pyrrolidone or dimethylsulfoxide and one or more esters such as such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate.

13. The process according to claim 12, wherein opicapone (compound of formula I) is purified by means of crystallization from a mixture of solvents comprising dimethylsulfoxide, ethylacetate and acetonitrile.

14. The process according to any one of claims 10 to 13, wherein opicapone (compound of formula I) is further purified by means of a slurry in an alcohol such as methanol, ethanol, propanol, isopropanol or tert-butanol or in a ketone such as methyl ethyl ketone, methyl isobutyl ketone or acetone.

15. The process according to claim 14 wherein opicapone (compound of formula I) is further purified by means of a slurry in methanol or in acetone.

16. A process according to any one of claims 1 to 15, wherein the obtained opicapone (compound of formula I) or any pharmaceutically acceptable salt thereof is further mixed with one or more pharmaceutically acceptable excipient to form a pharmaceutical formulation.

17. The pharmaceutical formulation obtained by the process of claim 16 for use in the treatment of central and peripheral nervous system disorders, such as Parkinson's disease.

18. Method for the treatment of central and peripheral nervous system disorders, such as Parkinson's disease, wherein a pharmaceutical formulation obtained by the process of claim 16 is administered to a subject in need thereof.

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