SELUMETINIB SULFATE

Field of the Invention

The present invention relates to an improved process for the preparation of Selumetinib sulfate of Formula-(I).

Background of the Invention

Selumetinib, chemical name is 5-[(4-bromo-2-chlorophenyl)amino-4-fluoro-A-(2- hydroxy ethoxy)- 1 -methyl- 1 H-bcnzi midazolc-6- formamide, developed by

AstraZeneca in the United Kingdom, is approved exclusively for the treatment of Neurofibromatosis type 1 (NF-1) in a limited age group Its therapeutic mechanism is mainly by regulating the level of key protein kinase MEK in the Ras-Raf-MEK- ERK pathway to inhibit B-Raf-mutated melanoma and K-Ras-mutated non- small cell lung cancer (NSCLC) growth of various tumours.

Selumetinib is under clinical trials for various types of cancer such as biliary cancer, colorectal cancer, gastric cancer, gastrointestinal stromal tumours, glioma, histiocytosis, neurofibromatoses, non-hodgkin's lymphoma, non-small cell lung cancer, Solid tumours, Thyroid cancer, Uveal melanoma, Astrocytoma, Kaposi's sarcoma, Precursor cell lymphoblastic leukemia-lymphoma.

US 7,425,637 discloses a process for the preparation of Selumetinib of Formula-(I) by the reaction of 4-Amino-2,3-difluoro-5-nitro-benzoic acid of Formual-II with TMS diazomethane in hexane solvent to produce 4-Amino-2,3-difluoro-5-nitro- benzoic acid methyl ester of Formual-III. Further, the obtained compound of Formual-III is reacted with aniline in xylene to produce 4-Amino-3-fluoro-5-nitro- 2-phenylamino-benzoic acid methyl ester of Formula-(IV) followed by cyclization in the presence of formic acid and Pd(OH)/C in ethanol to produce 7-Fluoro-6- phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester of Formual-(V). Further, the compound of Formual-(V) udergoes bromination in the presence of N- bromo succinimide in DMF to produce 6-(4-Bromo-phenylamino)-7-fluoro-3H- benzoimidazole-5-carboxylic acid methyl ester of Formual-(VI). After that the compound of Formual-(VI) udergoes chlorination in the presence of N- chloro succinimide in DMF to produce 6-(4-Bromo-2-chloro-phenylamino)-7- fluoro-3/7-bcnzoimidazolc-5-carboxylic acid methyl ester of Formula-(VII) followed by methylation in the presence of iodomethane and K2CO3 in DMF to produce 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3/Z- benzoimidazole-5-carboxylic acid methyl ester of Formual-(VIII) followed by hydrolysis in the presence of NaOH in 2:1 THF/water to produce 6-(4-Bromo-2- chloro-phenylamino)-7-fluoro-3-methyl-3H-benzo- imidazole-5-carboxylic acid of Formula-(IX). Further, the compound of Formula-(IX) is reacted with O-(2- vinyloxy-ethyl)-hydroxylamine in the presence of HOBt/ EDCF TEA in DMF to produce 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid (2-vinyloxyethoxy)-amide of Formula-(X) followed by treated with HC1 in ethanol to produce Selumetinib of Formula-(Ia). The synthetic scheme is depicted in below Scheme-I.

Scheme-I

US 9,156,795 provides processes for the preparation of Selumetinib sulfate salt of Formula- (I) by treatment of Selumetinib free base with sulfuric acid in THF/water to give Selumetinib sulfate salt of Formula- (I).

The synthetic scheme is depicted in below Scheme-II.

Selumetinibfree base (la) Selumetinib Sulfate salt (I)

Scheme-II It is observed from the literature related to selumetinib sulfate, the following common disadvantages are observed:

1. The overall yield of literature process is observed to be very low.

2. Cumbersome workup procedures during isolation intermediates and final product. 3. Requires flash chromatography purification for purification of intermediates. On higher scale production, flash chromatographic purification techniques are time consuming and not viable as it requires huge quantity of organic solvents. The output quantity would be very low and is not viable on commercial scale to meet the market demand.

Objective of the Invention

The main objective of the present invention is to provide a simple and cost- effective and commercially viable process for the preparation of Selumetinib sulfate of Formula-(I) with high purity and the good yield.

Summary of the Invention:

An improved process for the preparation of Selumetinib sulfate of Formula-

(I), comprising the steps of: a) reacting a compound of Formual-(II)

Formula-(II) with a compound of Formula-(XI) Formula- (XI) in the presence of a strong base in a suitable solvent to obtain compound of Formula-(XII), b) reducing the compound of Formula-(XII) in the presence of metal in acidic medium to obtain compound of Formula-(XIII), c) reacting the compound of Formula- (XIII) with diethoxymethane in the presence of acid medium in a suitable solvent to obtain compound of Formula-(IX). d) reacting the compound of Formula-(IX) with a compound of Formula-(XIV) Formula- XIV in presence of a base and amide coupling reagent in an organic solvent to obtain the compound of Formula-(XV), e) selectively deprotecting the compound of Formula-(XV) in the presence of an acid in a suitable solvent to obtain Selumetinib free base of Formula-(Ia). ) f) converting the compound of Formula-la into corresponding sulfate salt in the presence of sulfuric acid in a suitable solvent to obtain Selumetinib sulfate salt of Formula- (I).

Detailed Description of the Invention One embodiment of the present invention is to provide a process for the preparation of selumetinib sulfate of Formula-(I) comprising the steps of: a) reacting a compound of Formual-(II) with a compound of Formula-(XI) in the presence of a strong base in a suitable solvent to obtain compound of Formula-(XII); b) reducing the compound of Formula-(XII) in the presence of metal in acidic medium to obtain compound of Formula-(XIII); c) reacting the compound of Formula-(XIII) with diethoxymethane in the presence of an acid medium in a suitable solvent to obtain compound of Formula-(IX); d) reacting the compound of formula-(IX) with a compound of Formula- (XIV) in presence of a base and amide coupling reagent in an organic solvent to obtain the compound of Formula-(XV); e) selectively deprotecting the compound of Formula-(XV) in the presence of an acid in a suitable solvent to obtain Selumetinib free base of Formula-(Ia); f) converting the compound of Formula-(Ia) into corresponding sulfate salt in the presence of sulfuric acid in a suitable solvent to obtain Selumetinib sulfate salt of Formula- (I).

In step (a) of the present invention, wherein the strong base is selected from Lithium bis(trimethylsilyl)amide (LiHMDS), Lithium diisopropylamide (LDA), n-Butyl lithium (n-BuLi), LiNFh, NaNFh, and NaHMDS or any other equivalent base.

In step (a) of the present invention, wherein the suitable solvent is selected from THF, 1,4-Dioxane, Dimethoxy ethane and methyl tert-butyl ether, diisopropylether, dimethylformamide, DMAc, NMP, toluene, acetonitrile, dichloromethane or mixture thereof.

In step (a) of the present invention, the temperature at which reaction carried out at at -80° to 40°C, preferably 25-30°C.

In step (a) of the present invention, compound of Formula-(XII) is isolated from organic solvent selected from dimethyformamide, Tetrahydrofuran, or mixture thereof.

In step (b) of the present invention, wherein for reduction the metal is selected from zinc, iron, stannous, palladium, and Raney nickel or any other equivalent metal. In step (b) of the present invention, wherein the acid is selected from hydrochloric acid, ortho phosphoric acid or any other equivalent acid.

In step (b) of the present invention, wherein the solvent is selected from THF, 1,4- Dioxane, Dimethoxy ethane and methyl tert-butyl ether, diisopropylether, toluene, acetonitrile, dichloromethane or mixture thereof.

In step (b) of the present invention, the temperature at which reaction carried out at 0° to 70°C, preferably 10-35°C.

In step (b) of the present invention, the resulting product of Formula- (XIII) is isolated from organic solvent selected from dime thy formamide, alcohol solvents and water or mixture thereof.

In step (c) of the present invention, wherein the acid may be selected from methanesulfonic acid, p-toluenesulfonic acid, triflic acid, benzenesulfonic acid, trifluoroacetic acid, naphthalenesulfonic acid, sulphuric acid or any other suitable acid.

In step (c) of the present invention, wherein the suitable solvent is selected from water, THF, 1,4-Dioxane, Dimethoxy ethane and methyl tert-butyl ether, diisopropylether, ethyl acetate, toluene, acetonitrile, dichloromethane or mixture thereof.

In step (c) of the present invention, the temperature at which reaction carried out 0° to 75°C preferably 40-55°C.

In step (c) of the present invention, compound of Formula-(IX) is isolated from organic solvent selected from dimethyformamide, Tetrahydrofuran and water or mixture thereof.

In step (d) of the present invention, wherein the base is selected from triethylamine, diisopropylethylamine, DBU, NMP, pyridine, 2,6-lutidine, 2,4,6-collidine, DABCO, and DMAP or any other equivalent organic base. In step (d) of the present invention, wherein the amide coupling reagent is selected from coupling reagents such as EDC. HC1, HOBt, PyBOP, HBTU, HATU, TBTU, EDCI, DCC, CDI, DIC, T3P or any other suitable reagent.

In step (d) of the present invention, wherein the organic solvent is selected from dichloromethane, chloroform, toluene, ethylacetate, tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-dioxane, acetonitrile, DMF, DMAc, methyl THF, NMP, DMSO or mixture thereof.

In step (d) of the present invention, the temperature at which reaction carried out 0° to 50°C preferably 20-35°C.

In step (d) of the present invention, the resulting product of Formula- (XV) is isolated from organic solvent selected from dimethyformamide, alcohol solvents, ketone solvents and water or mixture thereof.

In step (e) of the present invention, wherein the acid is selected from organic or inorganic acid. The organic acid may be selected from methanesulfonic acid, trifluoroacetic acid, triflic acid, p-tolucncsulfonic acid, cyanuric acid or any other suitable organic acid. The inorganic acid may be selected from dilute or concentrated acids, hydrochloric acid, ortho phosphoric acid, hydrobromic acid, HBr in acetic acid, perchloric acid or ceric ammonium nitrate or any other suitable inorganic acid.

In step (e) of the present invention, wherein the suitable solvent is selected from water, alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, 3- pentanone Cyclopentanone, cyclohexanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ether comprises THF, 1,4-Dioxane, Dimethoxy ethane and methyl tert-butyl ether, diisopropyl ether, anisole; aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof.

In step (e) of the present invention, the temperature at which reaction carried out at -20° to 40°C preferably 20-35°C.

In step (e) of the present invention, compound of Formula-(Ia) is isolated from organic solvent selected from acetone and water or mixture thereof.

In step (f) of the present invention, wherein the solvent is selected from water, alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, 3- pentanone Cyclopentanone, cyclohexanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ether comprises THF, 1,4-Dioxane, Dimethoxy ethane and methyl tert-butyl ether, diisopropyl ether, anisole; aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof.

Optionally compound of formula (I) can be purified from solvent selected from water, alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, 3- pentanone Cyclopentanone, cyclohexanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ether comprises THF, 1,4-Dioxane, Dimethoxy ethane and methyl tert-butyl ether, diisopropyl ether, anisole; aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof. Advantages of the present invention:

1. The process of the present invention successfully adopts in- situ stage operation, simple work-up, isolation procedures and thereby improve the overall yield of Selumetinib sulfate of formula (I).

2. The process of the present invention does not require chromatographic purification techniques like column chromatography, preparative HPLC or preparative TLC in any stage of the process.

3. The process of the present invention does not require any halogenation reaction to overcome the halogenated impurities like dibromo, tribromo and dichloro.

4. The process of the present invention avoids positional isomer formations.

The following examples are provide for illustration purpose only and are not intended to limit the scope of invention.

EXAMPLE-1: PREPARATION OF 4-AMINO-2-(4-BROMO-2-CHLORO- ANILINO)-3-FLUORO-5-NITRO-BENZOIC ACID OF FORMULA-(XII) .

4-amino-2,3-difluoro-5-nitrobenzoic acid of Formula-(II) (125g) was dissolved in tetrahydrofuran (2500mL), and 4-Bromo-2-chloroaniline of Formula- (XI) (147.9g) was added to the reaction mixture at 25°C to 30°C and stirred for lOmin at same temperature. The reaction mass was cooled to -60°C to -55°C. Lithium bis(trimethylsilyl)amide (LiHMDS) in THF solution (1637mL) was slowly added to the above reaction mass mixture at -60°C to -55°C, and maintained for 3h at - 60°C to -55°C by stirring. The temperature of the reaction mixture was slowly raised to 25 to 30°C and stirred for 16h at 25°C to 30°C. Aq.THF solution (175mL) was added to the reaction mass at 25°C to 30°C, and 70% THF was distilled off from the reaction mass under reduced pressure. The reaction mass was cooled to - 10°C to -0°C and aq. methanol was added to the reaction mass between 0°C to 5°C and stirred for 30 min at 0-5°C. Conc.HCl was added to the reaction mass between 0°C to 5°C and stirred for 15 min at the same temperature. The temperature of the reaction mixture was slowly raised to 25°C to 30°C and stirred for 3h at 25-30°C. Th solid was filtered, washed with water and dried. The crude compound was recrystallized using dimethylformide and tetrahydrofuran and dried at 85°C to 90°C. Yield: 205 g. HPLC purity 99.9% .

EXAMPLE-2: PREPARATION OF 4,5-DIAMINO-2-(4-BROMO-2- CHLORO-ANILINO)-3-FLUORO-BENZOIC ACID OF FORMULA-(XIII) .

4-Amino-2-(4-bromo-2-chloro-anilino)-3-fluoro-5-nitro-ben zoic acid of Formula- (XII) (190g) was dissolved in mixture of 1,4-dioxane (1520ml) and tetrahydrofuran (380ml). Zinc dust (214.9g) was added to the reaction mixture at 25°C to 30°C and stirred for 15min at same temperature. The reaction mass was cooled to 15°C-25°C. Conc.HCl (391.8g) was slowly added to the reaction mixture at 15°C-20°C and stirred for 2h at same temperature. The reaction mixture was filtered through high- flo bed and washed with THF/ 1,4-dioxane (190ml). Water was added to the filtrate at 25°C to 30°C, and the reaction mixture was stirred for 2h at the same temperature. The precipitated solid was filtered and washed with water. The wet solid was basified using aq.bicarbonate solution at 25 °C -30°C and filtered, washed with water and dried to get the title compound. Yield: 155. g HPLC purity 98.85%

EXAMPLE-3: PREPARATION OF 5-[(4-BROMO-2-CHLOROPHENYL) AMINO]-4-FLUORO-l-METHYL-lH-BENZIMIDAZOLE-6-CARBOXYLIC ACID OF FORMULA-(IX) .

4,5-Diamino-2-(4-bromo-2-chloro-anilino)-3-fluoro-benzoic acid of For mu I a- (XIII) (140g) was suspended in mixture of acetonitrile (1260mL) and p- Toluenesulfonic acid (106.21g), at 25°C to 30°C and stirred for 15min at 25-30°C. The reaction mass was heated to 40-45°C and diethoxymethane (85.59g) was slowly added to the reaction mixture at 40 °C -45 °C and the reaction mixture was stirred for 4h at same temperature. Water (1400mL) was added to the reaction mixture at same temperature, and stirred for Ih at same temperature. The solid was filtered and washed with water. The solid was leached using DMF/methanol mixture, and dried at 85-90°C.Yield: 104g. HPLC purity 98.9% EXAMPLE-4: PREPARATION OF 6-(4-BROMO-2-CHLOROANILINO)-N- (2- -BUTOXYETHOXY)-7-FLUORO-3-METHYL-BENZIMIDAZOLE-5- CARBOXAMIDE OF FORMULA-(XV) .

5-[(4-Bromo-2-chlorophcnyl)amino]-4-fluoro- l -methyl- l /7-bcnzimidazolc-6- carboxylic acid of Formula-(IX) (115g) was dissolved in mixture of ethyl acetate (460mL), dimethylformide (230ml). The reaction mass was cooled to 0 to 5°C and □-(2-tert-Butoxyethyl) hydroxylamine of Formual-(XIV) was added followed by l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1) addition to the reaction mixture at 0-5°C. The solution of DMPA(52.9g) in DMF was slowly added to the reaction mixture at 0-5°C and stirred for 16h 25-30°C. The reaction mixture was quenched into water (4600ml) and stirred for 2h at 25-30°C. The mass was ffiltered and washed with water. The solid was leached using acetone and filtered. Yield: 113.7g, HPLC purity 99.52% .

EXAMPLE S: 5-[(4-BROMO-2-CHLOROPHENYL)AMINO]-4-FLUORO-A- (2-HYDROXYETHOXY)-l-METHYL-lH-BENZIMIDAZOLE-6- CARBOXAMIDE OF FORMULA-(Ia) .

6-(4-Bromo-2-chloroanilino)-N-(2-terZ-butoxy ethoxy)-7-fluoro-3-methyl- benzimidazole-5-carboxamide of Formula-(XV) (110g ) was dissolved in dichloromethane (450mL) and cooled to 0-5°C. The solution of trifluroacetic acid (366.1g) in dichloromethane was slowly added to the reaction mixture at 0-5°C. The reaction mass temperature was raised to 25-30°C and stirred for 5h at 25-30°C. Aq.NaOH solution was added to above reaction mass at 25-30°C. The precipitated solid was filtered and washed with water. The wet solid was leached using Aq. acetone at 25-30°C and dried at 50-55°C. Yield: 88.2g HPLC purity 99.75%

EXAMPLE-6: 5-[(4-BROMO-2-CHLOROPHENYL)AMINO-4-FLUORO-N- (2-HYDROXY-ETHOXY)-l-METHYL-lH-BENZIMIDAZOLE-6-

FORMAMIDE HYDROGEN SULFATE OF FORMULA ® (SELUMETINIB SULFATE).

5-[(4-Bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyet hoxy)-l -methyl- l/Z-benzimidazole-6-carboxamide of Formula-(Ia) (55g) was dissolved in mixture of acetone (1165mL) and DM water (13.75mL). The reaction mass was cooled to 0-5°C. Aq. sulphuric acid (12.95g sulphuric acid in 30.25 ml of water) was slowly added to the reaction mixture at 0-5°C. The temperature of the reaction mass was raised to 40-55°C and stirred for Ih followed by reaction mass was cooled to 25- 30°C and stirred for lOh. The solid was filtered, washed with acetone and dried at 30-35°C. Yield: 64.5g, HPLC purity 99.85%.