DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF TAFAMIDIS MEGLUMINE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATERMARK BUILDING,
PLOT NO.11, SURVEY NO.9,
KONDAPUR, HITECH CITY,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the nature of this invention and the manner in which is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Tafamidis meglumine and its intermediates.

BACKGROUND OF THE INVENTION
Tafamidis is chemically known as 2-(3,5-dichlorophenyl)-1,3-benzoxazole -6-carboxylic acid, as shown below a Compound of Formula (1). Tafamidis approved as free base and meglumine salt as shown below a Compound of Formula (2). Tafamidis and Tafamidis meglumine are marketed under the brand name of VYNDAMAXTM and VYNDAQEL® respectively. VYNDAQEL and VYNDAMAX are indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

Formula 1

Formula 2

Tafamidis (1) along with pharmaceutically acceptable salts, disclosed first time in US 7214695, which is hereby incorporated by reference. US ‘695 patent discloses a process for the preparation of Tafamidis, wherein 4-amino-3-hydroxybenzoic acid of a Compound of Formula (3) is reacted with 3,5-dichlorobenzoyl chloride of a Compound of Formula (4) in presence of pyridine in THF to produce Amide Intermediate a Compound of Formula (5). Which is in-situ treatment with p-toluenesulfonic acid monohydrate in xylene and quenched with NaOH then acidified with HCl and then dried. The resulting residue was dissolved in a mixture of MeOH:Benzene and treated with TMS-CHN2 in hexanes at 25° C and the residue was chromatographed to afford the desired Tafamidis methyl ester of a Compound of Formula (6). The Tafamidis methyl ester (6) was dissolved in a mixture of THF:MeOH:H2O and treated with LiOH.H2O. Upon completion, the mixture was acidified to pH 2 with 1 N HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by preparative thin layer chromatography to give the product Tafamidis of a Compound of Formula (1).
The process as shown in Scheme-I below:

Scheme-I
It is recognized that this procedure is especially problematic for large-scale operations with few disadvantages, like use of highly toxic trimethylsilyldiazomethane (TMS-CHN2); unnecessary step of esterification and hydrolysis and the use of excess amount of p-toluenesulfonic acid and strong base pyridine.

US 9249112 reported Tafamidis meglumine salt (2) and process for the preparation thereof by treating Tafamidis with N-methyl-D-glucamine in isopropanol – water. US ‘112 also discloses Tafamidis meglumine crystalline Form M; Liquid Crystalline Form B, and Amorphous Form A.

US 9770441 reported a process for the preparation of Tafamidis, wherein 4-amino-3-hydroxybenzoic acid of a Compound of Formula (3) is reacted with 3,5-dichlorobenzoyl chloride of a Compound of Formula (4) in presence of triethylamine in THF followed by isolation using ethanol to produce Amide Intermediate of a Compound of Formula (5). Which is treatment with methanesulfonic acid in presence of triethylamine in toluene followed by isolation using isopropyl alcohol to produce Tafamidis (1).
The process as shown in Scheme-II below:

Scheme-II
However, the above route suffered with high temperature or many additives which limit large-scale industrial applications. Also in the above process, cyclization takes longer hours in toluene and isolated from ethanol gives less purity of amide intermediate (5).

WO 2019175263 reported a process for the preparation of Tafamidis, wherein 4-Amino-3-hydroxybenzoic acid of a Compound of Formula (3) is reacted with 3,5-dichlorobenzoyl chloride of a Compound of Formula (4) in presence of pyridine or trimethylamine in THF followed by purification using 1-butanol to produce Amide Intermediate of a Compound of Formula (5). This compound (5) treated with p-toluenesulfonic acid and acetic acid in water followed by isolation using acetic acid to produce Tafamidis (1).
The process as shown in Scheme-III below:

Scheme-III
It is recognized that this procedure is not suitable for large-scale operations with some disadvantages, like distillation of larger volume of acetic acid and the use of excess strong base pyridine and finally lower yield of Tafamidis and amide intermediates.

Chemical Communications 2012, 48, 8964, reported a process for the preparation of Tafamidis, wherein methyl 1,3-benzoxazole-6-carboxylate (A) condensed with 1,3-dichlorobenzene (B) using Pd(OAc)2, CuBr2, O2, K3PO4 and pivalic acid in DMA at 140°C, giving Tafamidis methylester (6). The Tafamidis methyl ester (6) was dissolved in a mixture of THF:MeOH:H2O and treated with LiOH.H2O to produce Tafamidis (1).
The process as shown in Scheme-IV below:

Scheme-IV
However, this route suffered from high temperature or many additives which limit large-scale industrial applications. It is recognized that this procedure is not suitable for large-scale operations with some disadvantages, like use of expensive palladium acetate and use of toxic copper (II) bromide.

Chemistry - A European Journal, 2011, 17(36), 10113-10122, reported a process for the preparation of Tafamidis, wherein benzoxazole amide (C) is treated with 1,3-dichloro-5-iodobenzene (D) giving Tafamidis amide compound (E) and subsequent hydrolysis of the amide using HF/pyridine provided Tafamidis (1).
The process as shown in Scheme-V below:

Scheme-V
However, the above coupling did not proceed at all and these routes suffered from high temperature or many additives which limit large-scale industrial applications. And also use of expensive nickel complex and use of high corrosive HF acid is not industrially effective.

Considering the importance of Tafamidis (1) and Tafamidis meglumine (2), there is always a need for an alternative and improved preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.

Moreover the prior art processes do not disclose preparation of pure Tafamidis and Tafamidis meglumine, substantially free from impurities. The removal of the impurities form the final API is very essential as the compound is known to have impurities.

In view of this, our inventors have developed the present invention; it has now surprisingly been found that the pure Tafamidis and Tafamidis meglumine have numerous advantages over the reported processes.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is an improved process for the preparation of Tafamidis and Tafamidis meglumine and its intermediates with high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides an improved process for the preparation of Tafamidis (1):

Formula 1
which comprises:
(i) reducing 3-hydroxy-4-nitro benzoic acid of a compound of Formula (7);

Formula 7
to produce 4-amino-3-hydroxybenzoic acid of a compound of Formula (3);

Formula 3

(ii) isolating 4-amino-3-hydroxybenzoic acid of a Compound of Formula (3) from an ester solvent;
(iii) converting a Compound of Formula (3) to Tafamidis of a Compound of Formula (1).

In another embodiment, the present invention provides an improved process for the preparation of Tafamidis (1):

Formula 1
which comprises:
(i) reacting 4-amino-3-hydroxybenzoic acid of a compound of Formula (3);

Formula 3
with a compound of Formula (4A);

Formula 4A
wherein X is a leaving group;
to produce Amide Intermediate of a compound of Formula (5);

Formula 5

(ii) isolating Amide Intermediate of a compound of Formula (5) from an ester solvent or mixture of ester and water solvent;
(iii) cyclisation of an Amide intermediate compound of Formula (5) to produce Tafamidis (1); and
(iv) optionally, conversion of Tafamidis of a Compound of Formula (1) to Tafamidis meglumine salt (2);

Formula 2.

In another embodiment, the present invention provides an improved process for the preparation of Tafamidis meglumine salt (2):

Formula 2
which comprises:
(a) cyclisation of an Amide Intermediate of a compound of Formula (5);

Formula 5

in the presence of an acid, base and in xylene solvent to produce Tafamidis (1); and

Formula 1

(b) optionally, conversion of Tafamidis (1) to Tafamidis meglumine salt of a (2).

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides an improved process for the preparation of Tafamidis of a Compound of Formula (1):

Formula 1
which comprises:
(i) reducing 3-hydroxy-4-nitro benzoic acid of a compound of Formula (7);

Formula 7

to produce 4-amino-3-hydroxybenzoic acid of a compound of Formula (3);

Formula 3

(ii) isolating 4-amino-3-hydroxybenzoic acid of a compound of Formula (3) from an ester solvent;
(iii) reacting 4-amino-3-hydroxybenzoic acid of a compound of Formula (3) with a compound of Formula (4A);

Formula 4A
wherein X is a leaving group;
to produce Amide Intermediate of a compound of Formula (5);

Formula 5
(iv) isolating Amide Intermediate of a compound of Formula (5) from an ester solvent or mixture of water and ester solvent;
(v) cyclisation of an Amide Intermediate compound of Formula (5) to produce Tafamidis (1); and
(vi) optionally, conversion of Tafamidis (1) to Tafamidis meglumine salt (2);

Formula 2.

In still another embodiment, step (i) is carried out using a reducing agent and a solvent.

In still another embodiment, reducing agent comprises Palladium-Carbon (Pd-C), Fe, Sn, Zn in acidic media, sodium borohydride (NaBH4), Lithium borohydride (LiBH4), diborane, Sodium aluminium hydride (NaAlH4), hydrazine hydrate, sodium dithionate (Na2S2O4), sodium sulfide, ammonium sulfide, sodium cyanoborohydride (NaBH3CN), hydrogenation catalysts comprises rhodium, raney cobalt, raney iron, lithium aluminum hydride (LiAlH4), sodium amalgam, borane-tetrahydrofuran complex, and in combination with hydrogen.

In still another embodiment, solvent comprises ethanol, methanol, ethyl acetate, isopropyl alcohol, n-butanol, petroleum ether, diispropyl ether, methyl tert-butyl ether, diethyl ether and/or mixtures thereof.

In another embodiment, ester solvent used is step (ii) for isolating 4-amino-3-hydroxybenzoic acid of a compound of Formula (3) comprises ethyl acetate, isopropyl acetate, methyl acetate, methyl benzoate, butyl acetate, benzyl acetate, butyl butyrate, butyl propanoate, ethyl benzoate, ethyl butyrate, ethyl hexanoate, ethyl formate, ethyl heptanoate, ethyl isovalerate, ethyl lactate, ethyl pentanoate, isobutyl acetate, isobutyl formate, isoamyl acetate, and/or mixtures thereof.
The advantage of using ester solvent in step (ii) is ~15% of higher yield is obtained for isolation of product from ester solvent than alcohol / methanol solvent.

In still another embodiment, after adding suitable solvent and reducing agent in step (i) hydrogen gas (5-7 Kg/cm2) was passed to reaction mass and maintained for 2 h at 20-30°C and further stirred the reaction mixture up to 30 minutes, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure.
In still another embodiment, in step (iii) reaction, wherein X is selected from hydroxyl, flurone, chloro or bromo.

In still another embodiment, step (iii) reaction is carried out in the presence of a base and a solvent.

In still another embodiment, the base is organic or inorganic base. The inorganic base comprises potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. The organic base comprises alkali metal acetate such as potassium acetate, sodium acetate; diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and mixtures thereof.

In still another embodiment, the solvent used in the reaction step comprises polar protic solvent or polar aprotic solvent or non-polar solvent and/or mixtures thereof.

In another embodiment, polar protic solvent comprises water, methanol, ethanol, isopropyl alcohol, n-butanol, and/or mixtures thereof; polar aprotic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methylpyrrolidoneand/or mixtures thereof; and non-polar solvents comprises hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methylene chloride (CH2Cl2) and/or mixtures thereof.

In one more embodiment, the step (iii) reaction is carried out at room temperature depending upon the solvent used in the reaction for a time period of 2-5 hours.

In still another embodiment, the reaction mixture was stirred at ambient temperature for 10 h, refluxed for 1 h, concentrated in vacuo after completion of the reaction heating the reaction mixture to 40-100°C, preferably to 40°C and placed for isolation.

In still another embodiment, ester solvent used is step (iv) for isolating Amide Intermediate of a compound of Formula (5) comprises ethyl acetate, isopropyl acetate, methyl acetate, methyl benzoate, butyl acetate, benzyl acetate, butyl butyrate, butyl propanoate, ethyl benzoate, ethyl butyrate, ethyl hexanoate, ethyl formate, ethyl heptanoate, ethyl isovalerate, ethyl lactate, ethyl pentanoate, isobutyl acetate, isobutyl formate, isoamyl acetate, and/or mixtures thereof.

In still another embodiment, the reaction is carried out using ester solvent-water mixture.

The advantage of using ester solvent OR ester solvent-water mixture is high purity obtained in step (iv) for isolation of product specifically from ester solvent-water mixture.

In still another embodiment, after adding suitable ester solvent and water the reaction mass and maintained for 2 h at 20-30°C. Filtering the reaction mixture and dried at 60-65°C under vacuum.

In still another embodiment, step (v) cyclisation reaction is carried out in the presence of an acid, base and a solvent.

In still another embodiment, an acid comprises, p-toluenesulfonic acid and/or methanesulfonic acid.

In still another embodiment, the base is organic or inorganic base. The inorganic base comprises potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. The organic base comprises alkali metal acetate such as potassium acetate, sodium acetate; diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and mixtures thereof.

In still another embodiment, the solvent used in the cyclisation step is non-polar solvent comprises o-Xylene or m-Xylene or p-Xylene.

The advantage of using non-polar solvent like o-Xylene in step (v), reaction will complete in 2 h in case of using o-Xylene, whereas toluene solvent it will take about 18 h for completion of reaction.

In still another embodiment, after adding suitable acid and a base heating the reaction mixture up to reflux temperature and removed water azeotropically by maintaining temperature at 140-145°C for 2 hr. The reaction mass was cooled to 60°C and concentrated under reduced pressure. To the concentrated mass, isopropanol was added and stirred for 2 hr at 20-30°C. The product was filtered and washed isopropanol.

In still another embodiment, Tafamidis meglumine salt (2) was prepared by treating Tafamidis (1) with N-methyl-D-glucamine in isopropanol – water.

In another embodiment, purification of Tafamidis meglumine salt (2) by conventional methods like crystallization using a solvent selected from isopropanol.
In another embodiment, the present invention provides Tafamidis meglumine salt obtained is in crystalline form.
The state of such crystalline form can be investigated using known analytical methods, e.g. by Powder X-Ray Diffraction (PXRD) Methods or by Differential Scanning Calorimetry (DSC) or by Infrared (IR) spectroscopy.
As used herein, the term "reduced pressure" refers to a pressure below 50 mmHg.
Drying may be suitably carried out in a tray dryer, vacuum oven, Buchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer. The drying may be carried out at temperature of less than 100°C, or less than about 70°C, or any other suitable temperature. The drying may be carried out under reduced pressure, that is, less than standard atmospheric pressure or at atmospheric pressure or any other suitable pressure. The drying may take place over a period of about 30 minutes to about 12 hours, or any other suitable time period.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
EXAMPLES:
EXAMPLE 1:
PREPARATION OF 3-HYDROXY-4-NITROBENZOIC ACID
3-Hydroxybenzoic acid (300 g) was suspended in acetic acid (600 ml) at 20-30°C. Concentrated nitric acid (254 g) was added to this suspension slowly over a period of ~ 6 h at 20-30°C. The reaction mass was stirred for 1 h at 20-30°C. The product was collected by filtration and washed with water (3×500 ml). The wet material was dissolved in methanol (1200 ml) at reflux temperature. The resulting solution was cooled to -15°C to -10°C, filtered and washed with chilled methanol (60 ml) and dried at 50-55°C under vacuum to give 3-hydroxy-4-nitrobenzoic acid (72 g).
Yield : 0.24 w/w
HPLC purity : 98.73 %
PREPARATION OF 4-AMINO-3-HYDROXYBENZOIC ACID
3-Hydroxy-4-nitrobenzoic acid (150 g) was added to methanol (1500 ml). Palladium on charcoal paste (5%w/w, 4.5 g) was added to the reaction mixture. Hydrogen gas (5-7 Kg/cm2) was passed to reaction mass and maintained for 2 h at 20-30°C. After completion of reaction, the hydrogen gas was displaced with nitrogen gas. The catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. Ethyl acetate (300 ml) was added to the resulting solid, at 25-40°C. The slurry was cooled to -10°C to -5°C and stirred for 2hr at -10°C to -5°C. The product was filtered and washed with chilled ethyl acetate (75 ml) and dried at 60-65°C under vacuum to give 4-amino-3-hydroxybenzoic acid (115.5 g).
Yield : 0.77 w/w
HPLC purity : 99.9 %
PREPARATION OF 4-(3,5-DICHLOROBENZAMIDO)-3-HYDROXYBENZOIC ACID (AMIDE INTERMEDIATE)
4-Amino-3-hydroxybenzoic acid (100 g) was dissolved in a mixture of tetrahydrofuran (1900 ml) and water (200 ml) at 20-30°C. 3,5-dichlorobenzoyl chloride (164.3 g) solution in tetrahydrofuran (190 ml) was added to the reaction mass at 20-30°C and continued stirring for 1 hr at 20-30°C. Thereafter, triethylamine (72.6 g) was added to the reaction mass at 20-30°C and concentrated at 40°C under reduced pressure. To the concentrated mass, ethyl acetate (1000 ml) and water (600 ml) were charged and stirred for 2 h at 20-30°C. The slurry was filtered and washed with ethyl acetate (200 ml), dried at 60-65°C under vacuum to give 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid (200 g).
Yield : 2.0 w/w
HPLC purity : 99.0 %
PREPARATION OF TAFAMIDIS
4-(3,5-Dichlorobenzamido)-3-hydroxybenzoic acid (50 g) was suspended in o-xylene (500 ml) at 20-30°C. Triethylamine (17 g) and methanesulphonic acid (23.5 g) were added to the reaction mass at 20-30°C. The reaction mass was heated to reflux temperature and removed water azeotropically by maintaining temperature at 140-145°C for 2 hr. The reaction mass was cooled to 60°C and concentrated under reduced pressure. Isopropanol (250 ml) was added to the concentrated mass, and stirred for 2 hr at 20-30°C. The product was filtered and washed isopropanol (2×50 ml), dried at 60-65°C to give Tafamidis (43 g).
Yield : 0.86 w/w
HPLC Purity : 99.79 %
PREPARATION OF TAFAMIDIS MEGLUMINE
Tafamidis (25 g) was suspended in isopropanol (500 ml) at 20-30°C. N-methyl D-glucamine (16.6 g) and water (137.5 ml) were added to above suspension at 20-30°C. The slurry was heated to 70-75°C and stirred for 30 min. The resulting solution was filtered through 0.45µ filter and washed with hot isopropanol (12.5 ml). Thereafter, the filtrate was cooled to 10-15°C and stirred for 2 hr. The precipitated product was filtered and washed with isopropanol (25 ml), dried at 60-65°C to give Tafamidis meglumine (35 g).
Yield : 1.4 w/w
HPLC purity : 99.9 % ,CLAIMS:WE CLAIM:
1. An improved process for the preparation of Tafamidis (1):

1
which process comprises the steps of:
(i) reacting 4-amino-3-hydroxybenzoic acid of a compound of Formula (3);

Formula 3
with a compound of Formula (4A);

Formula 4A
wherein X is a leaving group;
to produce Amide Intermediate of a compound of Formula (5);

Formula 5
(ii) isolating Amide Intermediate of a compound of Formula (5) from an ester solvent or mixture of ester and water solvent;
(iii) cyclisation of an Amide intermediate compound of Formula (5) to produce Tafamidis (1); and
(iv) optionally, conversion of Tafamidis (1) to Tafamidis meglumine salt (2);

2.

2. The process as claimed in claim 1, wherein the X is a leaving group comprises hydroxyl, fluro, chloro and/or bromo.
3. The process as claimed in claim 1, step (i) is carried out in the presence of a base and a solvent.
4. The process as claimed in claim 1 and claim 3, the base comprises potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, potassium acetate, sodium acetate; diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, and/or mixtures thereof and solvent comprises water, methanol, ethanol, isopropyl alcohol, n-butanol, dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methylpyrrolidone, hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methylene chloride (CH2Cl2) and/or mixtures thereof.
5. An improved process for the preparation of Tafamidis (1):

1
which comprises:
(i) reducing 3-hydroxy-4-nitro benzoic acid of a compound of Formula (7) in presence of a reducing agent;

Formula 7
to produce 4-amino-3-hydroxybenzoic acid of a compound of Formula (3);

Formula 3
(ii) isolating 4-amino-3-hydroxybenzoic acid of a compound of Formula (3) from an ester solvent;
(iii) converting a Compound of Formula (3) to Tafamidis (1).

6. The process as claimed in claim 5, the reducing agent in step (i) comprises Palladium-Carbon (Pd-C), Fe, Sn, Zn in acidic media, sodium borohydride (NaBH4), Lithium borohydride (LiBH4), diborane, Sodium aluminium hydride (NaAlH4), hydrazine hydrate, sodium dithionate (Na2S2O4), sodium sulfide, ammonium sulfide, sodium cyanoborohydride (NaBH3CN), hydrogenation catalysts comprises rhodium, raney cobalt, raney iron, lithium aluminum hydride (LiAlH4), sodium amalgam, borane-tetrahydrofuran complex, and/or in combination with hydrogen.
7. The process as claimed in claim 1 and claim 5, the ester solvent comprises ethyl acetate, isopropyl acetate, methyl acetate, methyl benzoate, butyl acetate, benzyl acetate, butyl butyrate, butyl propanoate, ethyl benzoate, ethyl butyrate, ethyl hexanoate, ethyl formate, ethyl heptanoate, ethyl isovalerate, ethyl lactate, ethyl pentanoate, isobutyl acetate, isobutyl formate, isoamyl acetate, and/or mixtures thereof.

8. An improved process for the preparation of Tafamidis meglumine salt (2):

2
which comprises:
(a) cyclisation of an Amide Intermediate of a compound of Formula (5);

Formula 5

in the presence of a sulfonic acid, base and in an aromatic solvent to produce Tafamidis (1); and

1

(b) optionally, conversion of Tafamidis (1) to Tafamidis meglumine salt (2).

9. The process as claimed in claim 8, the base comprises diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethylamine, pyridine, and/or mixtures thereof.

10. The process as claimed in claim 8, the aromatic solvent comprises o-Xylene, m-Xylene, p-Xylene and/or mixtures thereof.