DESC:RELATED APPLICATION:
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 201921015257 filed on Apr. 16, 2019
FIELD OF THE INVENTION
The present application describes a process of preparation of benzimidazole compounds such as Binimetinib and Selumetinib. Further, present application provides intermediates for process of preparation of Binimetinib and Selumetinib.
BACKGROUND OF THE INVENTION
Binimetinib, is chemically known as 5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-l-methyl-lH-benzimidazole-6-carboxamide. Binimetinib is represented by the following chemical structure according to Formula I.

Binimetinib is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.
Selumetinib of Formula II, is chemically known as 5-[(4-Bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-l-methyl-lH-benzimidazole-6-carboxamide.

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 leukaemia-lymphoma.
Patents US 7,425,637 and US 9,156,795 provide processes for the preparation of Selumetinib; and Patents US 7,777,050, US 8,039,637, and US 9,238,627 provide processes for the preparation of Binimetinib. The process in US ‘050 is as shown in below scheme:

The known processes have one or more of the disadvantages such as low yield, increased number of chemical reaction steps, difficulties in isolation or separation of the products, flash chromatography, costly reagents and use of hazardous.
Since the compounds are potentially useful as therapeutics, there exists a need in the art for the development of an easy, cost-effective, and industrially advantageous process for the preparation of Binimitinib and Selumetinib which overcomes the difficulties of the prior art process.
SUMMARY OF THE INVENTION
The invention provides compound of compound of Formula-2 its use thereof in the preparation of Binimetinib and/or Selumetinib.

wherein X is any halogen, and R is selected from group consisting of hydroxy, C1-C6 alkoxy, arylalkyloxy such as benzyloxy, O-(2-vinyloxy-ethyl)-hydroxylamino, or O- (hydroxyethyl)-hydroxylamino.
The invention provides compound of compound of Formula-4 its use thereof in the preparation of Binimetinib and/or Selumetinib.

Wherein X is halogen and X1 is chloro or bromo.
DETAILED DESCRIPTION OF THE INVENTION
Benzimidazole compounds like Binimetinib and/or Selumetinib is prepared by using the compound of Formula-2

wherein, X is any halogen, and preferably selected from the group consisting of fluoro or chloro and R is selected from group consisting of hydroxy, C1-C6 alkoxy, arylalkyloxy such as benzyloxy, O-(2-vinyloxy-ethyl)-hydroxylamino, or O- (hydroxyethyl)-hydroxylamino.
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 tert-butoxy.
The compound of Formula-2 is prepared by treating compound of Formula-1 with C1-C6 dialkoxymethane in the presence of an acid.

C1-C6 dialkoxymethane is selected from diethoxymethane and dimethoxymethane.
The acid use in imidazole formation is selected from the group consisting of an inorganic acid or an organic acid. The inorganic acid includes but not limited to hydrochloric acid and sulfuric acid. The organic acid includes but not limited to sulfonic acid derivatives such as methane sulfonic acid, p-toluene sulfonic acid, and benzene sulfonic acid; or carboxylic acid such as formic acid and acetic acid.
The compound of Formula-2 is converted in to compound of Formula-3 using an appropriate halogenating agent such as NBS or NCS optionally in the presence of an acid like p-TsOH. The reaction may be effected in the presence of suitable organic solvent. For that matter any solvent that does not affect the course of the reaction can be used.

wherein X1 is bromo or chloro.
The reaction is represented by below scheme:

The compound of Formula-3, when R is not O-(hydroxyethyl)-hydroxylamino, is converted in to Binimetinib or Selumetinib according to the at least one of the suitable known processes in the art such as described in US 7,777,050, US 7,425,637 and US 9,1567,95, US 8039637, and US 9,238,627.
The compound of Formula-3, when R is OCH2CH3 is converted to Binimetinib or Selumetinib, by first converting the ethyl ester compound to acid compound as represented by below scheme, and then converting acid compound to Binimetinib or Selumetinib according to the at least one of the suitable known processes in the art as described above.

Benzimidazole compounds like Binimetinib and/or Selumetinib is also prepared by using Formula-4

Wherein X and X1 are as defined herein above.
The process of preparation of Binimetinib or Selumetinib comprising steps of:
a) treating the compound of Formula-3, wherein R is selected from group consisting of hydroxy, C1-C6 alkoxy, arylalkyloxy such as benzyloxy; with hydroxylamine or its salt such as hydroxylamine hydrochloride to obtain compound of Formula-4; and
b) converting the compound of Formula-4 into binimitinib.
The conversion of compound of Formula-4 into Binimetinib or Selumetinib according to step (b) is carried out by reacting the compound of Formula-4 with optionally protected ethylene glycol preferably under Mitsunobu conditions followed by removing the protecting groups if any in polar aprotic solvent.
The suitable reagent for the said Mitsunobu conditions includes triphenylphosphine, trialkylphosphines or phosphites, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), dibenzyl azodicarboxylate (DBAD), N,N,N',N'-tetramethylazodicarbonamide (TMAD), and dipiperidyl azodicarboxylate (DPAD), tosyl chloride, mesyl chloride and mixture thereof.
The polar aprotic solvent is selected from the group consisting of tetrahydrofuran, acetonitrile, dioxane, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidon, dimethoxymethane, methylene chloride, ethyl acetate and mixtures thereof.
The said reaction is represented by below scheme for Binimitinib:

Alternatively, Binimetinib or Selumetinib is prepared by treating compound of Formula-3, wherein R is C1-C6 alkoxy, preferably ethoxy or methoxy or tert-butoxy with O-(2-hydroxyethyl)hydroxylamine with or without formation of acid compound as intermediate. The said reaction is shown below:

Binimetinib or Selumetinib is also prepared by treating compound of Formula-3, wherein R is C1-C6 alkoxy, preferably ethoxy or methoxy or tert-butoxy with O-(2-hydroxyethyl)hydroxylamine compound protected with PG, without formation of acid compound.
The above reaction may proceed in solvent such as xylene, toluene, tetrahydrofuran, 2-methyl tetrahydrofuran, NMP, sulfolane, N,N-dimethylimidazolinone, cyclopentylmethyl ether, DMF, DMAc, NMP, tetramethylurea, tetramethyl guanidine, and pentamethyl guanidine.
The above reaction may proceed with or without use of base. The base can be organic or inorganic base.
The above reaction may proceed preferably under close conditions such as in autoclave under pressure at higher temperature.
The said reaction is shown below:

The protecting group PG is selected from alkyl groups, such as tertiary alkyls (e.g., tertiary C4-C7 alkyls such as t-butyl or tertiary amyl); alkenyl groups; tertiary aryl-alkyl groups, such as 1-methyl-1-phenylethyl (cumyl) or triphenylmethyl (trityl); groups that result in acetals, such as methoxymethyl, 1-ethoxyethyl, 2-tetrahydropyranyl or 2-tetrahydrofuranyl; and silyl groups, such as trimethylsilyl, triethylsilyl or tert-butyl-dimethyldilyl.
The protecting group PG may be removed using any suitable deprotecting agent and deprotection conditions and will vary with the choice of protecting group. The suitable deprotection agents may include, but are not limited to, an aqueous acid such as phosphoric acid, hydrochloric acid or sulfuric acid, non-aqueous acids such as hydrogen chloride acid.
Examples:
Example 1: Preparation of 4-amino-3-fluoro-2-(2-fluoro-phenylamino)-5-nitro-benzoic acid methyl ester
Mixture of 4-amino-2,3-difluoro-5-nitro-benzoic acid methyl ester (50 g), 2-fluoro-phenylamine (239.31 g) in xylenes (500 mL), was heated at 150-155°C till completion of reaction. After completion of reaction, the reaction mixture was cooled to room temperature and the precipitated product was filtered and then dried under vacuum at 50-55°C to obtain the title compound (54.5 g).
Example 2: Preparation of 4, 5-diamino-3-fluoro-2-(2-fluoro-phenylamino)-benzoic acid methyl ester (Formula-1, X=F, and R=OCH3)
4-Amino-3-fluoro-2-(2-fluoro-phenylamino)-5-nitro-benzoic acid methyl ester (10 g) in methanol (150 mL): THF (150 mL) mixture was hydrogenated using Pd/C (0.5 g) at 50-55°C till completion of reaction. After completion of reaction, hydrogen pressure was released and the reaction mixture was cooled to room temperature, filtered through hyflo to remove the catalyst. The filtered mass was distilled under vacuum at 45-50°C to obtain the title compound (8.3 g).
Example 3: Preparation of methyl 4-fluoro-5-[(2-fluorophenyl)amino]-1-methyl-lH-benzimidazole-6-carboxylate (Formula-2, X=F, and R=OCH3)
The solution of 4,5-diamino-3-fluoro-2-(2-fluoro-phenylamino)-benzoic acid methyl ester (1.8 g), diethoxymethane (1.83 g), p-toluene sulfonic acid monohydrate (1.28 g), water (0.01 mL) and acetonitrile (18 mL) were heated at 60-65°C till completion of reaction. After completion of reaction, pyridine was added into the reaction mixture and cooled to room temperature. The reaction mixture was stirred for 4-5 hours; the precipitated solid was filtered, and dried under vacuum at 45-50°c to obtain the title compound (0.8 g).
Example 4: Preparation of 6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (Formula-3, X=F, X1=Br and R=OCH3)
Mixture of methyl 4-fluoro-5-[(2-fluorophenyl)amino]-1-methyl-lH-benzimidazole-6-carboxylate (0.6), tetrahydrofuran (20 mL) and methanol (20 mL) cooled to -78° C under N2 atmosphere. p-toluene sulfonic acid monohydrate (0.54 g) was added followed by N-bromosuccinimide (0.37 g). After 10 minutes, the reaction mixture was warmed to room temperature. The reaction mixture was stirred till completion of reaction, followed by quenching with the addition of aqueous saturated sodium bisulfite solution and diluted with ethyl acetate and water. Layers were separated and the aqueous layer re-extracted using ethyl acetate. The combined organic layers were washed with brine solution and separated out both layers. Organic layer distilled out under vacuum at 45-50°C to obtain solid residue. The resulting solid residue was triturated with methylene chloride, filtered, and dried to obtain the title compound (0.5 g).
Example 6: Preparation of 6-(4-Bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid
To the solution of 6-(4-Bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (0.3 g) in THF (10 mL)/water (7.8 mL), 1M aqueous solution of NaOH (0.12 g) was added and stirred at room temperature. After completion of reaction, the solvent was distilled under vacuum at 50-55°C and cooled to room temperature. The reaction mixture, pH was adjusted to 1-2 by the addition of 1.0 M aqueous HC1 and the product was extracted with 1:1 tetrahydrofuran: ethyl acetate mixture. Organic layer distilled under vacuum at 45-50°C to obtain the title compound (0.2 g).
Example 6A: Preparation of 6-(4-Bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid
To the solution of 6-(4-Bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester (10 g) (said compound is prepared by following the example given in example 1-5 or by any other conventional methods) in THF (100mL)/water (100 mL), 1M aqueous solution of NaOH ( 20 g) was added and stirred at room temperature. After completion of reaction, the solvent was distilled under vacuum at 50-55°C and cooled to room temperature. The reaction mixture, pH was adjusted to 1-2 by the addition of 2.0 M aqueous HC1 and the product was extracted with 1:1 tetrahydrofuran: ethyl acetate mixture. Organic layer distilled under vacuum at 45-50°C to obtain the title compound.
Example 7: Preparation of 6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole -5-carboxylic acid (2-vinyloxy-ethoxy)-amide
6-(4-Bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (0.6), O-(2-vinyloxy-ethyl)-hydroxylamine (0.243 g), HOBt (0.27 g), triethylamine (0.07 g) and EDCI (0.39 g) were dissolved in dimethylformamide (20 mL) and stirred at room temperature till completion of reaction. After the completion of reaction, the reaction mixture was added with ethyl acetate, washed with water, and followed by saturated potassium carbonate aqueous solution. The organic layer washed with aqueous ammonium chloride solution and finally with aqueous sodium chloride solution. The organic layer was distilled under vacuum at 45-50°C to obtain the title compound (0.6 g).
Example 8: Preparation of Binimetinib
To the solution of 6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole -5-carboxylic acid (2-vinyloxy-ethoxy)-amide (0.6 g) in ethanol (13.76 mL), hydrochloric acid (6.42 mL, 1.0 M aqueous solution) was added and stirred for 24 hours. After the completion of reaction, the solvent was concentrated till dryness under vacuum at 45-50°C. Ethyl acetate: tetrahydrofuran was added to the residue and washed with aqueous saturated potassium carbonate solution. Aqueous layer re-extracted out using ethyl acetate: tetrahydrofuran mixture. The organic layer was distilled under vacuum at 45-50°C and isolated using ethyl acetate to obtain the title compound (0.2 g).
,CLAIMS:We Claim:
1. A process of preparation of Binimetinib or Selumetinib comprising steps of:
a. treating a compound of Formula (1) with C1-C6 dialkoxymethane in the presence of an acid to obtain a compound of Formula (2);

wherein X is halogen.
b. converting the compound Formula (2) to a compound Formula-3, using an halogenating agent selected from NBS or NCS;

wherein R is hydroxy, C1-C6 alkoxy, arylalkyloxy such as benzyloxy; X1 is bromo or chloro ;and X is a halogen.
c. treating the compound of Formula (3) with hydroxylamine or its salt to obtain compound of Formula (4); and

d. converting the compound of Formula-4 into binimetinib or Selumetinib.
2. The process as claimed in claim 1, wherein the C1-C6 dialkoxymethane is selected from diethoxymethane or dimethoxymethane.
3. The process as claimed in claim 1, wherein the acid is inorganic acid selected from hydrochloric acid or sulfuric acid; or organic acid selected from methane sulfonic acid, p-toluene sulfonic acid, benzene sulfonic acid, formic acid or acetic acid.
4. The process as claimed in claim 1, wherein step (d) is carried out by reacting the compound of Formula-4 with optionally protected ethylene glycol preferably under mitsunobu conditions followed by removing the protecting groups if any in polar aprotic solvent.
5. The process as claimed in claim 4, wherein the mitsunobu conditions is created by using mitsunobu reagents selected from triphenylphosphine, trialkylphosphines or phosphites, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), dibenzyl azodicarboxylate (DBAD), N,N,N',N'-tetramethylazodicarbonamide (TMAD), and dipiperidyl azodicarboxylate (DPAD), tosyl chloride, mesyl chloride and mixture thereof.
6. A compound of Formula (2),

wherein X is any halogen, and R is selected from group consisting of hydroxy, C1-C6 alkoxy, arylalkyloxy such as benzyloxy, O-(2-vinyloxy-ethyl)-hydroxylamino, or O- (hydroxyethyl)-hydroxylamino.
7. A compound of Formula (4)

Wherein X is halogen and X1 is chloro or bromo.