Field of the Invention

The present invention relates to intermediates of Mitogen-activated protein kinase kinase (MAP2K or MEK) inhibitors such as Selumetinib, Binimetinib and process for their preparation. The present invention also relates to the process for the preparation of MEK inhibitors such as Selumetinib and Binimetinib.

Background of the Invention

Selumetinib of Formula A, is chemically known as 5-[(4-Bromo-2- chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-l-methyl-lH -benzimidazole-6- carboxamide.

Formula A

Selumetinib is under clinical trials for various types of cancer such as KRAS- mutant advanced or metastatic non-small cell lung cancer, differentiated thyroid cancer, neurofibromatosis Type 1.

Binimetinib of Formula B, is chemically known as 5-[(4-Bromo-2- fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-l-methyl-lH -benzimidazole-6- carboxamide.

Formula B

Binimetinib is under clinical trials for various types of cancer such as BRAF- mutant melanoma and NRAS-mutant melanoma.

PCT Publication No. WO 03/077914 provides a process for the preparation of methyl 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-l-methyl-lH-benzi midazole-6- carboxylate (Formula 1, when R ¹ is (4-bromo-2-chlorophenyl)amino, R ² is methoxy). The process involves i) cyclization of 4,5-Diamino-2-(2-chloro-phenylamino)-3-fluoro-benzoic acid methyl ester with formamidine acetate to obtain Methyl 5-[(2-chlorophenyl)amino]-4- fluoro-lH-benzimidazole-6-carboxylate, ii) bromination of Methyl 5-[(2- chlorophenyl)amino]-4-fluoro- lH-benzimidazole-6-carboxylate with N- bromosuccinamide to obtain Methyl 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-lH- benzimidazole-6-carboxylate, and iii) reacting Methyl 5-[(4-bromo-2- chlorophenyl)amino]-4-fluoro-lH-benzimidazole-6-carboxylate with iodomethane in the presence of potassium carbonate in dimethylformamide followed by flash chromatography to isolate Methyl 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-l-methyl-lH- benzimidazole-6-carboxylate in 36% yield.

PCT Publication No. WO 2007/002157 provides a process for the preparation of Methyl 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-l-methyl-lH-benzi midazole-6- carboxylate (Formula 1, when R ¹ is (4-bromo-2-chlorophenyl)amino, R ² is methoxy). The process involves i) reduction of Methyl 2,4-diamino-3-fluoro-5-nitrobenzoate using Palladium/Carbon to obtain Methyl 2,4,5 -triamino-3-fluorobenzoate which is in-situ reacted with diethoxymethane in the presence of >-toluene sulfonic acid to obtain 6- Amino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester, and ii) reacting 6-Amino-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester with bromochloroiodobenzene using Palladium acetate/Xantphos/Cesium carbonate to obtain Methyl 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-l-methyl-lH-benzi midazole- 6-carboxylate in 66% yield.

PCT Publication Nos. WO 2007/076245 and WO 2009/036020 provide a process for the preparation of Methyl 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-l-methyl-lH- benzimidazole-6-carboxylate (Formula 1, when R ¹ is (4-bromo-2-chlorophenyl) amino, R ² is methoxy). The process involves i) cyclization of 4-Amino-3-fluoro-5-nitro-2- (phenylamino)-benzoic acid methyl ester using formic acid/palladium hydroxide/carbon to obtain Methyl 4-fluoro-5-(phenylamino)-lH-benzimidazole-6-carboxylate, ii) bromination of Methyl 4-fluoro-5-(phenylamino)-lH-benzimidazole-6-carboxylate with N- bromosuccinamide to obtain Methyl 5-[(4-bromophenyl)amino]-4-fluoro-lH- benzimidazole-6-carboxylate, and iii) chlorination of Methyl 5-[(4-bromophenyl)amino]- 4-fluoro-lH-benzimidazole-6-carboxylate with N-chlorosuccinamide to obtain Methyl 5- [(4-bromo-2-chlorophenyl)amino] -4-fluoro- lH-benzimidazole-6-carboxylate, and iv) treating Methyl 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-lH-benzimidazole- 6- carboxylate with iodomethane in the presence of potassium carbonate in

dimethylformamide followed by flash chromatography to isolate Methyl 5-[(4-bromo-2- chlorophenyl)amino]-4-fluoro-l-methyl-lH-benzimidazole-6-car boxylate in 36% yield.

PCT Publication No. WO 2013/0142182 provides a process for the preparation of 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoim idazole-5-carboxylic acid methyl ester (Formula 1, wherein R ¹ is (4-bromo-2-fluorophenyl)amino, R ² is methoxy). The process involves i) converting 4-Amino-3-fluoro-2-(2-fluoro- phenylamino)-5-nitro-benzoic acid methyl ester by reduction/cyclization and bromination to obtain 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3H-benzoimidazole-5 -carboxylic acid methyl ester, and ii) treating 6-(4-Bromo-2-fluoro-phenylamino)-7-fluoro-3H- benzoimidazole-5-carboxylic acid methyl ester with iodomethane in the presence of potassium carbonate in dimethylformamide followed by flash chromatography to isolate 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoim idazole-5-carboxylic acid methyl ester.

PCT Publication Nos. WO 03/077914 and WO 2007/076245 provide processes for the preparation of Selumetinib.

PCT Publication Nos. WO 03/077914, WO 2013/142182, and WO 2014063024 provide processes for the preparation of Binimetinib. The processes described in the prior arts for the preparation of compounds of Formula 1 (when R ¹ is (4-bromo-2-chlorophenyl)amino, (4-bromo-2-fluorophenyl)amino, R ² is methoxy) suffers from one or more of the disadvantages such as low yield, increased number of chemical reaction steps, difficulties in isolation of the products, flash chromatography, and use of hazardous and costly reagents such as Xanthphos.

Thus, there is a need in the art to develop a new process for the preparation of compounds of Formula 1 which is efficient and commercially feasible.

Summary of the Invention

The present invention provides a compound of Formula 1, which is a useful intermediate for the preparation of MEK inhibitors such as Selumetinib and Binimetinib.

Formula 1

wherein R ¹ is independently selected from the group consisting of fluoro, chloro, bromo, phenylamino, or (4-bromophenyl)amino; and R ² is independently selected from the group consisting of hydroxy, Ci-C6 alkoxy, 0-(2-vinyloxy-ethyl)-hydroxylamino, or O- (hydroxyethyl)-hydroxylamino .

The present inventors have also developed an improved process for the preparation of compound of Formula 1,

wherein R ¹ is independently selected from the group consisting of fluoro, chloro, bromo, phenylamino, (4-bromophenyl)amino, (4-bromo-2-chlorophenyl) amino, or (4-bromo-2- fluorophenyl) amino; and R ² is independently selected from the group consisting of hydroxy, C1-C6 alkoxy, 0-(2-vinyloxy-ethyl)-hydroxylamino, or O-(hydroxyethyl)- hydroxylamino.

The present invention provides an efficient and an industrially feasible process for the preparation of compounds of Formula 1 in a good yield and an excellent chemical purity with a reduced number of process steps. The present invention avoids the excess use of environmentally hazardous/costly reagent(s).

Detailed Description of the Invention

The term "solvent," as used herein, refers to any solvent or solvent mixtures, including, for example, water, aromatic hydrocarbons, esters, halogenated

hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof. Examples of aromatic hydrocarbons include toluene and xylene. Examples of esters include ethyl acetate, ^-propyl acetate, isopropyl acetate, and «-butyl acetate. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2- dichloroethane. Examples of ketones include acetone and methyl ethyl ketone.

Examples of ethers include diethyl ether and tetrahydrofuran. Examples of polar aprotic solvents include NN-dimethylformamide, NN-dimethylacetamide,

dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.

The term "C1-C6 alkoxy," as used herein, refers to a linear or a branched chain alkoxy group having C1-C6 carbon atoms which include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and fert-butoxy.

The term "C1-C6 dialkoxy," as used herein, refers to a linear or a branched chain dialkoxy group having C1-C6 carbon atoms which include, but are not limited to, dimethoxy, diethoxy, dipropoxy, diisopropoxy, dibutoxy, disec-butoxy, and ditert- butoxy.

A first aspect of the present invention provides a compound of Formula 1,

Formula 1 wherein R ¹ is independently selected from the group consisting of fluoro, chloro, bromo, phenylamino, or (4-bromophenyl)amino; and R ² is independently selected from the group consisting of hydroxy, C1-C6 alkoxy, 0-(2-vinyloxy-ethyl)-hydroxylamino, or O- (hydroxyethyl)-hydroxylamino .

The compound of Formula 1 is a suitable intermediate for the preparation of

Selumetinib and Binimetinib.

A second aspect of the present invention provides a process for the preparation of compound of Formula 1,

Formula 1

wherein R ¹ is independently selected from the group consisting of fluoro, chloro, bromo, phenylamino, (4-bromophenyl)amino, (4-bromo-2-chlorophenyl)amino, or (4-bromo-2- fluorophenyl)amino; and R ² is independently selected from the group consisting of hydroxy, C1-C6 alkoxy, 0-(2-vinyloxy-ethyl)-hydroxylamino, or O-(hydroxyethyl)- hydroxylamino comprising treating a compound of Formula 2 or a salt thereof,

Formula 2

wherein R ¹ and R ² are as defined above, with C1-C6 dialkoxymethane in the presence of an acid.

The compound of Formula 2 may be prepared by any methods known in the art, for example, the method described in PCT Publication No. WO 03/077914 or as described herein. The treatment of the compound of Formula 2 or a salt thereof with C1-C6 dialkoxymethane includes adding, slurrying, dissolving, stirring, or a combination thereof in the presence of a suitable solvent at a temperature of about 25°C to reflux temperature for a time period sufficient to complete the reaction.

Suitable C1-C6 dialkoxymethane is diethoxymethane or dimethoxymethane.

Suitable acid is selected from the group consisting of an inorganic acid or an organic acid. Examples of inorganic acid include hydrochloric acid and sulfuric acid. Examples of organic acid include sulfonic acid derivatives or carboxylic acids.

Examples of sulfonic acid derivatives include methane sulfonic acid, / toluene sulfonic acid, and benzene sulfonic acid. Examples of carboxylic acids include formic acid and acetic acid.

The compound of Formula 1 may optionally be isolated by cooling,

evaporation under vacuum, extraction, washing, crystallization, precipitation, filtration, filtration under vacuum, decantation, centrifugation, drying, or combinations thereof.

The isolated compound of Formula 1 may be purified by treating with suitable solvent(s) at a temperature of about 25 °C to reflux temperature. The treatment of the compound of Formula 1 with a suitable solvent includes adding, slurrying, dissolving, stirring, or a combination thereof.

The compound of Formula 1 when R ¹ is not (4-bromo-2-chlorophenyl)amino and/or R ² is not 0-(hydroxyethyl)-hydroxylamino can be further converted to

Selumetinib by any methods known in the art, for example, the method described in PCT Publication Nos. WO 03/077914 and WO 2007/076245.

The compound of Formula 1 when R ¹ is not (4-bromo-2-fluorophenyl)amino and/or R ² is not 0-(hydroxyethyl)-hydroxylamino can be converted to Binimetinib by any methods known in the art, for example, the method described in PCT Publication Nos. WO 03/077914, WO 2013/142182, and WO 2014063024.

While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Methods: The NMR spectrum was recorded using Bruker® (Maker), Ultrashield-400 MHz (Model).

The mass spectrum was recorded using ABSCIEX® (Maker), API-2000 (Model).

The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Example 1 : Preparation of Methyl 4.5-diamino-3-fluoro-2-(phenylamino)benzoate p- toluene sulfonate (salt of Formula 2)

Dry Palladium/Carbon (2.5%, 1.4 g) was added to a solution of Methyl 4-amino-3- fluoro-5-nitro-2-(phenylamino)benzoate (14 g) in methanol (70 mL) and tetrahydrofuran (140 mL) while maintaining the temperature at 30°C to 32°C. The reaction mixture was hydrogenated at 3.5 kg to 4.0 kg/cm ² hydrogen pressure for 5 hours at 30°C to 35°C. After completion of the reaction (monitored by Thin Layer Chromatography (TLC)), the reaction mixture was filtered through Hyflo® and washed with methanol (2 x 35 mL). The solvent was recovered under vacuum at 40°C to 45 °C to obtain a residue. Acetonitrile (140 mL) was added to the above residue followed by slow addition of a solution of p- toluene sulfonic acid monohydrate (10.4 g) in acetonitrile (56 mL) at 10°C to 20°C over a period of 15 minutes. The reaction mixture was then stirred for 30 minutes at 10°C to 20°C. The solid obtained was filtered under vacuum and washed with acetonitrile (2 x 35 mL). The wet material obtained was used as such in the next step.

Example 2: Preparation of Methyl 4-fluoro- l-methyl-5-(phenylamino)-lH-benzimidazole- 6-carboxylate (Formula 1)

>-Toluene sulfonic acid monohydrate (1.74 g) was added to a solution of Methyl

4,5-diamino-3-fluoro-2-(phenylamino)benzoate, /J>-toluene sulfonate (obtained from Example 1) in acetonitrile (210 mL) at 20°C to 25 °C. The reaction mixture was heated to 60°C to 65°C. A solution of diethoxymethane (9.55 g) in acetonitrile (14 mL) was added at 60°C to 65 °C over a period of 15 minutes. The reaction mixture was stirred for 2 hours at 60°C to 65°C. After completion of the reaction (monitored by TLC), the solvent was recovered under vacuum and cooled to 20°C to 25 °C. Aqueous sodium hydroxide solution (10%, 140 mL) was added to the reaction mixture and then stirred for 30 minutes. The solid obtained was filtered under vacuum and washed with deionized water (2 x 70 mL). Methanol (84 mL) was added to the wet solid and the reaction mixture was heated to 45 °C to 50°C. Water (56 mL) was added over a period of 10 minutes, and the reaction mixture was stirred for 10 minutes at 45°C to 50°C and then cooled to 20°C to 25°C. The reaction mixture was stirred for 30 minutes at 20°C to 25 °C. The solid obtained was filtered under vacuum and washed with a mixture of methanol: deionized water (28 mL, 1 : 1 ratio). The wet material was dried under vacuum at 35°C to 40°C for 14 hours to obtain the title compound.

Yield: 77.5%

¾ NMR (de-DMSO, 400 MHz): δ 3.78 (s, 3H), 3.89 (s, 3H), 6.64-6.67 (m, 2H), 6.67-6.68 (m, 1H), 7.12-7.16 (m, 2H), 7.96-7.99 (d, 2H), 8.39 (s, 1H).

Mass (m/z): 300.2 [m+l] ⁺

Example 3: Preparation of Methyl 5-r(4-bromophenyl)aminol-4-fluoro-l-methyl-lH- benzimidazole-6-carboxylate

N-Bromosuccinamide (8.04 g) was added to a solution of Methyl 4-fluoro-l- methyl-5-(phenylamino)-lH-benzimidazole-6-carboxylate (10 g; obtained from Example 2) in dimethylformamide (400 mL) at 15°C to 20°C over a period of 10 minutes. The reaction mixture was stirred for 1 hour at 15°C to 20°C. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 10°C to 15°C. A solution of sodium bisulfite (6.9 g) in deionized water (1600 mL) was added and then stirred for 30 minutes. The solid obtained was filtered under vacuum and then washed with deionized water (2 x 100 mL). Methanol (100 mL) was added to the wet solid and the reaction mixture was heated to 45 °C to 50°C. Water (100 mL) was added over a period of 10 minutes and the reaction mixture was stirred for 10 minutes at 45°C to 50°C and then cooled to 20°C to 25°C. The reaction mixture was stirred for 30 minutes at 20°C to 25°C. The solid obtained was filtered under vacuum and then washed with a mixture of methanol and deionized water (20 mL, 1 : 1 ratio). The wet solid was dried under vacuum at 35°C to 40°C for 14 hours to obtain the title compound.

Yield: 81.7% ¾ NMR (de-DMSO, 400 MHz): δ 3.79 (s, 3H), 3.99 (s, 3H), 6.61-6.63 (m, 2H), 7.26-7.28 (m, 2H), 7.99-8.02 (d, 2H), 8.41 (s, 1H).

Mass (m/z): 378.2, 380.1 [m, m+2] ⁺

Example 4: Preparation of Methyl 5-[(4-bromo-2-chlorophenynamino]-4-fluoro-l-methyl- lH-benzimidazole-6-carboxylate

N-Chlorosuccinimide (3.64 g) was added to a solution of Methyl 5-[(4- bromophenyl)amino]-4-fluoro-l -methyl- lH-benzimidazole-6-carboxy late (10 g; obtained from Example 3) in dimethylformamide (300 mL) at 15°C to 20°C. The reaction mixture was stirred for 42 hours at 15°C to 20°C. After completion of the reaction (monitored by TLC), a solution of sodium bisulfite (5.5 g in deionized water (2100 mL)) was added and stirred for 15 minutes at 20°C to 25°C. The solid obtained was filtered under vacuum and washed with deionized water (2 x 30 mL). Methyl fert-butyl ether (100 mL) was added to the wet solid and the reaction mixture was heated to 45 °C to 50°C, stirred for 15 minutes and then cooled to 20°C to 25°C. The reaction mixture was stirred for 30 minutes at 20°C to 25 °C. The solid obtained was filtered under vacuum, washed with methyl fert-butyl ether (10 mL), and then dried under vacuum at 35°C to 40°C for 14 hours to obtain the title compound.

Yield: 76.1%

¾ NMR (de-DMSO, 400 MHz): δ 3.83 (s, 3H), 3.93 (s, 3H), 6.42-6.45 (m, 1H), 7.27-7.30 (m, 1H), 7.63-7.64 (d, 1H), 8.10 (s, 1H), 8.14 (s, 1H), 8.46 (s, 1H).

Mass (m/z): 412.1, 414.1 [m, m+2] ⁺

Example 5: Preparation of 5-r(4-Bromo-2-chlorophenyl)aminol-4-fluoro-l-methyl-lH- benzimidazole-6-carboxylic acid

Deionized water (10 mL) was added to a solution of Methyl-5-[(4-bromo-2- chlorophenyl)-amino]-4-fluoro-l-methyl-lH-benzimidazole-6-ca rboxylate (2 g; obtained from Example 4) in tetrahydrofuran (20 mL) and the temperature was maintained at 25 °C to 30°C. A solution of sodium hydroxide (0.74 g) in deionized water (4 mL) was added gradually to the reaction mixture at 25°C to 30°C over a period of 10 minutes. The reaction mixture was stirred for 3 hours at 25 °C to 30°C. After completion of the reaction (monitored by TLC), tetrahydroiuran was recovered under vacuum at 40°C to 45°C and deionized water (20 mL) was added . The aqueous reaction mixture was washed with dichloromethane (2 x 20 mL). The reaction mixture was cooled to 5°C to 10°C and the pH of aqueous layer was adjusted to 1.3 with 50% aqueous hydrochloric acid solution and then stirred for 30 minutes at 5°C to 10°C. The solid obtained was filtered under vacuum and washed with deionized water (2 x 20 mL). The wet solid was dried under vacuum at 35°C to 40°C for 14 hours to obtain the title compound.

Yield: 88.5%

¾ NMR (de-DMSO, 400 MHz): δ 3.92 (s, 3H), 6.48-6.51 (m, 1H), 7.30-7.32 (m, 1H), 7.64-7.65 (d, 1H), 8.10 (s, 1H), 8.44 (s, 1H), 8.52 (s, 1H).

Mass (m/z): 400.1 [m+2] ⁺

Example 6: Preparation of 5-[(4-bromo-2-chlorophenyl)amino]-N-[2-(ethenyloxy)ethoxy]- 4-fluoro- 1 -methyl- lH-benzimidazole-6-carboxamide

N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.57 g) and

Hydroxybenzotriazole (1.25 g) were added to a solution of 5-[(4-Bromo-2- chlorophenyl)amino]-4-fluoro-l-methyl-lH-benzimidazole-6-car boxylic acid (2.0 g; obtained from Example 5) in dimethylformamide (20 mL) and the reaction mixture was stirred at 25°C to 30°C. Triethylamine (1.73 mL) was added to the reaction mixture slowly at 25°C to 30°C over a time period of 10 minutes. A solution of 0-[2-

(ethenyloxy)ethyl]hydroxylamine (0.97 g in dimethylformamide (2 mL)) was added to the reaction mixture and stirred at 25°C to 30°C for 24 hours. After completion of the reaction (monitored by TLC), deionized water (100 mL) was added and the reaction mixture was stirred for 1 hour at 20°C to 25°C to obtain a brown solid. The solid obtained was filtered under vacuum and washed with deionized water (2 x 20 mL). The wet material was dried under vacuum at 35°C to 40°C for 14 hours to obtain the title compound.

Yield: 70% Example 7: Preparation of 5-r(4-Bromo-2-chlorophenyl)aminol-4-fluoro-N-(2- hvdroxyethoxy)-l-methyl-lH-benzimidazole-6-carboxamide (Selumetinib)

Aqueous hydrochloric acid (IN, 1.2 mL hydrochloric acid in 12 mL deionized water) was added slowly to a solution of 5-[(4-Bromo-2-chlorophenyl)amino]-N-[2- (ethenyloxy)ethoxy]-4-fluoro-l -methyl- lH-benzimidazole-6-carboxamide (1.3 g; obtained from Example 6) in ethanol (30 mL) over a period of 10 minutes and the reaction mixture was stirred at 25 °C to 30°C for 24 hours. After completion of the reaction (monitored by TLC), ethanol was concentrated under vacuum. Ethyl acetate: tetrahydrofuran (3: 1, 45: 15 mL) was added and the organic layer was washed with saturated potassium carbonate solution (25 mL). The organic layer was separated and the aqueous layer was washed with ethyl acetate: tetrahydrofuran (45: 15 mL) solution. The organic layers were combined and dried over sodium sulphate and then concentrated under vacuum to obtain a crude compound as a brown solid (950 mg). The crude compound was further purified by column chromatography using 2% methanol/dichloromethane as an eluent to obtain the title compound.

Yield: 70%