DESC:This application claims the benefit of priority of our Indian patent application numbers 201821004082 filed on 02nd February 2018 and 201821031142 filed on 20th August 2018 which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel process for the preparation of Cobimetinib. More particularly the present invention relates to the process for the preparation of Cobimetinib intermediate of Formula (IX) and Formula (VIII).

BACKGROUND OF THE INVENTION

Cobimetinib hemifumarate is chemically described as (S)-[3, 4-difluoro-2-(2-fluoro-4-iodophenylamino) phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl] methanone hemifumarate having the structural Formula (I).

Cobimetinib (COTELLIC) is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with Vemurafenib.
US 7,803,839 (IN 2771DEN2008) patent application discloses the process for the preparation of Cobimetinib as shown below in Scheme-1

Scheme-1
Due to the need of multiple chiral resolutions in the synthesis process, the synthesis steps are cumbersome and the yield is low, which limits the industrialization prospect of the synthesis method.
W02014/059422 (IN 2015DN03928) discloses another process for the preparation of Cobimetinib as shown in Scheme-2. In this route, the preparation of starting material in chirally pure form is difficult and the route requires use of unstable strong base lithium diisopropylamide and requires ultra-low temperature (-78 °C) and absolute dry anaerobic reaction conditions which limits the synthesis for industrial use.

Scheme-2

CN104725352A, WO2017/096996, CN106220607A discloses different process for the preparation of Cobimetinib.
The synthetic methods of Cobimetinib which is disclosed in prior arts are not useful at large scale because of the problems, such as rare raw materials, long synthesis steps, low yield, difficult resolution and serious environmental pollution. These unfavorable factors have restricted the industrialized production of Cobimetinib. Therefore, it would be desirable to provide a simplified process which is environment friendly and can also be carried out advantageously on an industrial scale and which supports an active compound in high yield and high purity in pharmaceutically acceptable quality.

SUMMARY OF THE INVENTION

In first aspect, the present invention relates to process for the preparation of compound of Formula (VIII);

wherein R, R’ is independently selected from hydrogen, carbobenzyloxy, benzyl, tert-butyloxycarbonyl, acetyl, benzoyl, nosyl, mesyl and tosyl, which comprises the steps of:
i) reacting a compound of Formula (III) with a grignard reagent in the presence of
titanium catalyst to obtain compound of Formula (IV);

wherein, R is methyl, ethyl, propyl and butyl;
ii) converting the compound of Formula (IV) to obtain compound of Formula (V);

wherein R is carbobenzyloxy, benzyl, tert-butyloxycarbonyl, acetyl, benzoyl,
nosyl, mesyl and tosyl.
iii) reacting a compound of compound of Formula (V) with metal halide to obtain
compound of Formula (VI);

iv) reacting a compound of Formula (VI) with oxidizing agent to obtain compound of Formula (VII); and

X is F, Cl, Br and I.
v) reacting a compound of Formula (VII) with protected or unprotected amine to obtain a compound of Formula (VIII);

In second aspect, the present invention relates to process for the preparation of compound of Formula (IX);

wherein R’ and R’’ is independently selected from C1-6 alkyl or R’ and R’’ together represents cyclic alkyl ring; R is hydrogen, carbobenzyloxy, benzyl, tert-butyloxycarbonyl, acetyl, benzoyl, nosyl, mesyl and tosyl the said process comprises reacting compound for Formula (VIII) with compound of Formula (X)

wherein, A and A’ is independently selected from C 1-6 alkyl, or A and A’ together represents cyclic alkyl group.
The present invention is shown schematically in Scheme-4:
Scheme-4
In another aspect of the present invention is to provide following novel compounds and their use in the preparation of Cobimetinib.

wherein R is R’ and R’’ is selected from the group comprising of hydrogen, nosyl, mesyl, tosyl, carbobenzyloxy, benzyl, tert-butyloxycarbonyl, alkyl, aryl, acyl, acetyl, benzoyl, or R’ and R’’ together represents a cyclic alkyl ring.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel process for the preparation of Cobimetinib. More particularly the present invention relates to the process for the preparation of Cobimetinib intermediate of Formula (IX) and Formula (VIII).Applicant found the novel route is robust, industrially viable and yield the compound in good quality and quantity.
In another embodiment of the present invention, compound of Formula (III) in step i) is reacted with grignard reagent in the presence of titanium catalyst and suitable solvent at the temperature range of 0 °C to 10 °C to obtain compound of Formula (IV).
Suitable grignard reagent as used here in step i) is selected from alkyl magnesium halide such as ethyl magnesium bromide, ethyl magnesium chloride, isopropyl magnesium chloride, methyl magnesium bromide, phenyl magnesium bromide and the like. More preferably, ethyl magnesium bromide.
Titanium catalyst as used here in above in step i) is selected from the group comprising titanium alkoxides such as Ti(OiPr)4, MeTi(OiPr)3, MeTi(OtBu)3, ClTi(OiPr)3, ClTi(OtBu)3, or Ti(OtBu)4, more preferably Ti(OiPr)4.
Suitable solvent as used here in above in step i) is selected from diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, hexane and 2-methyltetrahydrofuran. More preferably, tetrahydrofuran.
In another embodiment of the present invention, compound of Formula (V) in step ii) is obtained by reacting the compound of Formula (IV) with reagent like tosyl chloride, mesyl chloride, nosyl chloride or its anhydrides and the like.
In another embodiment the protecting groups used in the invention are interchanged during the course of reaction so as to get desired yield and purity. Suitable deprotection of protecting groups are known in the art such as treatment with acid, base or hydrogenation. For example the deprotection using hydrogenation is carried out in a suitable solvent and suitable base at a temperature range of -10 °C to 10 °C. Metal catalyst used for hydrogenation in in step ii) is selected from the group comprising of nickel, palladium, platinum, rhodium and the like. More preferably, palladium. Hydrogenation in step ii) is carried out in a solvent that does affect the course of the reaction like methanol at the temperature range of 25 °C to 40 °C and at hydrogen pressure between 1 kg/cm2 to 15 kg/cm2. More preferably, 1-2 kg/cm2.
In another embodiment suitable solvent as preferably used in step ii) is selected from water, dichloromethane, chloromethane, trichloromethane, ethylene dichloride and chlorobenzene.
In another embodiment suitable base as preferably used in step ii) is selected from triethyl amine, diisopropyl ethylamine, 4-dimethylamino pyridine, tri-n-propyl amine, tri-n-butyl amine, piperidine and pyridine.
In another embodiment of the present invention, compound of Formula (V) in step iii) is treated with metal halides in suitable solvent at the temperature range of 25 °C to 40 °C to obtain compound of Formula (VI).
Metal halides used in step iii) is selected from the group comprising of titanium tetrachloride, aluminum trichloride, tin chloride, ferric chloride, zinc chloride, magnesium bromide diethyl etherate, boron trifluoride ethyl ether and the like. More preferably, titanium tetrachloride and magnesium bromide diethyl etherate.
In another embodiment, suitable solvent as preferably used in step iii) is selected from water, dichloromethane, chloromethane, trichloromethane, ethylene dichloride and chlorobenzene.
In another embodiment of the present invention, compound of Formula (VI) in step iv) is treated with oxidizing agent in suitable solvent and suitable base at the temperature range of 25 °C to 40 °C to obtain compound of Formula (VII).
Oxidizing agent as used in step iv) is selected from a group comprising of permanganates (such as potassium permanganate or the like), meta-chloro per benzoic acid, peracetic acid, performic acid, sodium hypochlorite, hydrogen peroxide, tert-butyl hydrogen peroxide and cumene hydroperoxide. More preferably, meta-chloro per benzoic acid or hydrogen peroxide.
Suitable solvent as used in step iv) is selected from water, dichloromethane, chloromethane, trichloromethane, ethylene dichloride and chlorobenzene.
Suitable base as used in step iv) is selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate and potassium carbonate.
In another embodiment of the present invention, compound of Formula (VII) in step v) is treated with protected or unprotected amine and further deprotection of the nitrogen protecting group of piperidine ring to obtain compound of Formula (VIII) in the presence of suitable solvent and suitable base at the temperature range of 25 °C to 40 °C to obtain compound of formula (VIII).
Suitable solvent as used in step v) is selected from water, methanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2- pentanol, toluene, xylene, methylene dichloride, ethylene dichloride and chlorobenzene.
Suitable base as used in step v) is selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate and potassium carbonate.
Deprotection of the nitrogen protecting group of piperidine ring is achieved by thioglycolic acid, thiophenol, 1-dodecanethiol, thiols and hydrogen sulfides/hydrosulfides of alkali metals, under acidic conditions, basic conditions and hydrogenation.
In yet another embodiment, the present invention relates to process for the preparation of compound of Formula (IX);

wherein R’ and R’’ is independently selected from C 1-6 alkyl or R’ and R’’ together represents cyclic alkyl ring; R is hydrogen, carbobenzyloxy, benzyl, tert-butyloxycarbonyl, acetyl, benzoyl, nosyl, mesyl and tosyl comprises reacting compound for Formula (VIII) with compound of Formula (X)

wherein, A and A’ is independently selected from C 1-6 alkyl, C 1-6 alkyloxy, or A and A’ together represents cyclic alkyl group.
Compound of Formula (X) as used is selected from cyclopentanone, cyclopropanone, cyclobutanone, cyclohexanone acetone, MIBK, and cyclootanone.
Suitable solvent as used is selected from water, methanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2- pentanol, toluene, xylene, methylene dichloride, ethylene dichloride and chlorobenzene.
In yet another embodiment, the present invention relates to the process for the preparation of Cobimetinib hemifumarate of Formula (I) comprising the steps of:
a) reacting a compound of Formula (X) with benzotriazole in the presence of suitable solvent and optionally in suitable base to obtain compound of Formula (XXI);

b) reacting a compound of Formula (XXI) with the compound of Formula (IX) in the presence of suitable base and suitable solvent to obtain compound of Formula (XXII);

Wherein R is R’ and R’’ is same as defined in Scheme-4
c) deprotecting the compound of Formula (XXII) in the presence of suitable acid and suitable solvent to obtain Cobimetinib of Formula (XXIII); and

d) reacting a compound of Formula (XXIII) with fumaric acid in presence of suitable solvent to obtain Cobimetinib hemifumarate of Formula (I).
In another embodiment of the present invention, compound of Formula (X) in step a) is treated with benzotriazole in the presence of suitable solvent and optionally in suitable base at a temperature range of 0 - 15 °C to obtain compound of Formula (XXI).
Suitable solvent as used in step a) is selected from water, dichloromethane, chloromethane, trichloromethane, ethylene dichloride and chlorobenzene.
In another embodiment of the present invention, compound of Formula (XXI) in step b) is treated with compound of Formula (XI) in the presence of suitable solvent and optionally in suitable base at a temperature range of 25- 40 °C to obtain compound of Formula (XXII).
Suitable solvent as used in step b) is selected from water, acetonitrile and butyronitrile.
Coupling of compound of Formula (XXI) and compound of Formula (VIII) may be carried out in the presence or absence of coupling agent.
In another embodiment of the present invention, compound of Formula (XXII) in step c) is treated with in the presence of suitable acid and suitable solvent at a temperature range of 50- 80 °C to obtain compound of Formula (XXIII).
Suitable acid as used in step c) includes but not limited to hydrochloric acid, sulfuric acid, nitric acid, acetic acid, methane sulfonic acid, trifluoroacetic acid and p-toluene sulfonic acid. More preferably, p-toluene sulphonic acid.
Suitable solvent as used in step c) is selected from water, methanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol and 2- pentanol.
In another embodiment of the present invention, compound of Formula (XXIII) in step d) is treated with fumaric acid in the presence of suitable solvent at a temperature range of 25- 40 °C to obtain Cobimetinib Hemifumarate of compound of Formula(I).
Suitable solvent as used in step d) is selected from water, methanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol and 2- pentanol.
According to the present invention, the compound which is isolated from the reaction mass by techniques such as 1) addition of suitable anti solvent 2) cooling the reaction mass 3) distilling the solvent 4) evaporation 5) spray drying 6) lyophilization 7) freeze drying or by combination of any of the said method in any order.
In another embodiment, present invention provides following novel compounds and their use in the preparation of Cobimetinib.

wherein R is R’ and R’’ is selected from the group comprising of hydrogen, nosyl, mesyl, tosyl, carbobenzyloxy, benzyl, tert-butyloxycarbonyl, alkyl, aryl, acyl, acetyl, benzoyl, or R’ and R’’ together represents a cyclic alkyl ring.
In another embodiment of the present invention, Cobimetinib fumarate and its intermediate is purified by conventional methods known in the art such as chromatography, crystallization, distillation, salt formation and the like.
In another embodiment Cobimetinib hemifumarate used in the pharmaceutical compositions of the present invention, wherein 90 volume-percent of the particles (D90) have a size of less than or equal to about 500 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 200 microns, still more specifically less than or equal to about 100 microns, and most specifically less than or equal to about 15 microns
In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
Examples
Preparation of Starting material
Preparation of (S)-methyl piperidine-2-carboxylate hydrochloride
To a solution (S)-piperidine-2-carboxylic acid (250.0 g, 1.94 mol.) in methanol (2.5 L) thionyl chloride (345.6 g, 2.904 mol.) was added at 0°C. The mixture was stirred at room temperature overnight. The solvent was evaporated from reaction mixture and the obtained solid was purified from toluene to afford (S)-methyl piperidine-2-carboxylate hydrochloride. (337 g, Yield 97%).
Preparation of 1-benzyl 2-methyl (2S)-piperidine-1,2-dicarboxylate (Formula III; wherein R’ is carbobenzyloxy)
To a solution of (S)-methyl piperidine-2-carboxylate hydrochloride (134. 0 g, 0.746 mol.) in MDC (1000 mL, triethylamine (226.5g, 2.24 mol.) and 4-dimethylamino pyridine (9.11g, 0.0746 mol.) were added at room temperature. The resulting mixture was cooled to 0 °C. A solution of benzyl chloroformate (191 g 1.12) in toluene (193 mL) at 0°C was added to the reaction mixture and stirred at room temperature till completion of reaction. The reaction mixture was quenched with 1.0N HCl, washed with brine solution and the separated organic solution was concentrated to afford 1-benzyl 2-methyl (2S)-piperidine-1,2-dicarboxylate as a pale yellow oil. (Yield >90%).
Preparation of methyl (2S)-1-benzylpiperidine-2-carboxylate (Formula III; wherein R’ is benzyl)
To a solution of methyl pipecolinate hydrochloride (50 g, 0.278 mol.) in acetonitrile (500 mL), potassium carbonate (115 g, 3.0 eq.) potassium iodide (9.3 g, 0.2 eq.) and benzyl chloride (42.25 g, 1.2 eq.) were added at room temperature. The resulting mixture was stirred for 4 h and filtered. The filtrate was diluted with water and organic layer was separated. The organic layer was diluted with EtOAc and extracted with 1.0N HCl The aqueous layer was washed with hexanes, basified with Na2CO3 solution and extracted with EtOAc to afford methyl (2S)-1-benzylpiperidine-2-carboxylate as colorless oil. (Yield >85%).
Preparation of methyl (2S)-1-[(4-methylphenyl) sulfonyl] piperidine-2-carboxylate (Formula III; wherein R’ is 4-methylphenyl sulfonyl)
To a solution of (2S)-methyl-2-piperidinecarboxylate hydrochloride (250 g, 1.39 mol.) in dichloromethane (2.5 L) 4-methylbenzenesulphonyl chloride (398.1 g, 2.09 mol.) and 4-dimethylamino pyridine (17.0 g, 0.14 mol.) were added at room temperature. The resulting reaction mixture was cooled to 0 °C. Triethylamine (563.4 g, 5.57 mol.) was added to the reaction mixture dropwise at 0-15 °C. The mixture was diluted with water at room temperature. DMC layer was separated, washed with HCl and water. The organic layer was dried over sodium sulphate and evaporated to afford methyl (2S)-1-[(4-methylphenyl) sulfonyl] piperidine-2-carboxylate as off-white solid. (Yield >97%).

Example 1: Preparation of tert-butyl (2S)-2-(3-hydroxyazetidin-3-yl) piperidine-1-carboxylate
Step (i) Benzyl (2S)-2-(1-hydroxycyclopropyl) piperidine-1-carboxylate (Formula IV: where in R’ is carbobenzyloxy)
To a solution of 1-benzyl 2-methyl (2S)-piperidine-1, 2-dicarboxylate (100 g) in THF (1000 ml), titanium tetraisopropoxide (51.2 g) was added at room temperature. Reaction mixture was cooled to 0 -10 °C. Ethyl magnesium bromide solution (1081 ml) was added till the completion of reaction. After completion of reaction, pH of reaction mixture was adjusted to 3-4 by slowly adding solution of citric acid (200 g) in process water (1000ml).The reaction mixture was stirred for 1 hour at 0-10 °C and layers were separated. Aqueous layer was extracted with MTBE and organic layer was distilled under vacuum to obtain residue. MDC and process water were added to the residue. Layers were separated, organic layer was dried over sodium sulphate and distilled under vacuum to obtain benzyl (2S)-2-(1-hydroxycyclopropyl) piperidine-1-carboxylate as oil. (90-100 g).
Step (i) Benzyl (2S)-2-(1-hydroxycyclopropyl) piperidine-1-carboxylate (Formula IV: where in R’ is carbobenzyloxy)
To a solution of 1-benzyl 2-methyl (2S)-piperidine-1, 2-dicarboxylate (100 g) and titanium tetraisopropoxide (0.2 eq) in THF, ethyl magnesium bromide (3.0 eq.) in THF was added dropwise over 30 minutes at -5 to 5 °C. The reaction mixture was cooled to room temperature and stirred overnight. The solution was quenched with water, filtered and extracted with MDC. The combined solution was washed with water, and dried over magnesium sulphate, filtered and concentrated to obtain crude compound. Crude compound was re-crystallized to afford benzyl (2S)-2-(1-hydroxycyclopropyl) piperidine-1-carboxylate. (Yield > 80%).
Step (i) 1-[(2S)-1-benzylpiperidin-2-yl] cyclopropanol (Formula IV: where in R’ is benzyl)
To a solution of methyl (2S)-1-benzylpiperidine-2-carboxylate (100 g) and titanium tetraisopropoxide (0.5 eq) in THF, ethyl magnesium bromide (3.0 eq.) in THF was added dropwise over 30 minutes at -5 to 5 °C. The reaction mixture was cooled to room temperature and stirred overnight. The solution was quenched with water, filtered and extracted with MDC. The combined solution was washed with water, and dried over magnesium sulphate, filtered and concentrated to obtain crude compound. Crude compound was re-crystallized to afford to afford 1-[(2S)-1-benzylpiperidin-2-yl] cyclopropanol. (Yield >75%).
Step (i) 1-{(2S)-1-[(4-methylphenyl)sulfonyl]piperidin-2-yl}cyclopropanol (Formula IV: where in R’ is 4-methylphenyl sulfonyl)
To a solution of methyl (2S)-1-[(4-methylphenyl) sulfonyl] piperidine-2-carboxylate (100 g) and titanium tetraisopropoxide (0.5 eq) in THF, ethyl magnesium bromide (3.0 eq.) in THF was added dropwise over 30 minutes at -5 to 5 °C. The reaction mixture was cooled to room temperature. The solution was quenched with water, filtered and extracted with MDC. The combined solution was washed with water, and dried over magnesium sulphate, filtered and concentrated to obtain crude compound. Crude compound was re-crystallized to afford to afford 1-{(2S)-1-[(4-methylphenyl)sulfonyl]piperidin-2-yl}cyclopropanol (Yield >85%).
Step (ii) 1-[(2S)-piperidin-2-yl] cyclopropanol (Formula IVa)
To a solution of benzyl (2S)-2-(1-hydroxycyclopropyl) piperidine-1-carboxylate (100 g) in methanol (300 ml), 10% Pd/C (20 g) in methanol (200 ml) was added at 25-35 °C. Hydrogen gas with 1-2 Kg/cm2 pressure was purged till the completion of reaction. After the completion of reaction, hydrogen pressure was released and hyflo (20 g) was added to the reaction mixture. Reaction mixture was filtered through hyflo bed in methanol and washed with methanol. The obtained filtrate was distilled under vacuum to obtain residue. MTBE (70 ml) was added to the residue, cooled at -9 to -15°C and stirred for 1 hour under nitrogen. The reaction mixture was filtered and washed with MTBE and dried in VTD under vacuum to afford 1-[(2S)-piperidin-2-yl]cyclopropanol as solid.( 30-35 g).
Step (iii) 1-{(2S)-1-[(2-nitrophenyl) sulfonyl] piperidin-2-yl} cyclopropanol (Formula IV b: where in R’ is nosyl)
To a solution of 1-[(2S)-piperidin-2-yl] cyclopropanol (100 g) in MDC (1000 ml), 2-nosyl chloride (235.4 g) was added at room temperature. The reaction mixture was cooled to -5 to 5°C and DIPEA (274.4 g) was added below 5°C.The reaction mixture was heated and stirred at 25-35°C till the completion of reaction. After completion of reaction, solution of citric acid (100 g) in process water (1000ml) was added to the reaction mixture and stirred for 30 mins at 25-35°C. Layers were separated, organic layer was distilled under vacuum to obtain residue. IPA was added to residue and stirred for 30 mins at 25-35°C.The reaction mixture was filtered, washed with IPA and filtrate was distilled under vacuum to afford 1-{(2S)-1-[(2-nitrophenyl)sulfonyl]piperidin-2-yl}cyclopropanol as oil.140-150g.

Step (iv) 1-{(2S)-1-[(2-nitrophenyl) sulfonyl] piperidin-2-yl} cyclopropyl methanesulfonate (Formula V: where in R’ is nosyl and R is mesyl)
To a solution of 1-{(2S)-1-[(2-nitrophenyl)sulfonyl]piperidin-2-yl}cyclopropanol (100g) in MDC (1000 ml), 4-dimethylamino pyridine (3.75 g) and methane sulphonyl chloride (35.5ml, 52.6 g) was added at room temperature. The reaction mixture was cooled at -5 to 5 °C. TEA (92.8g, 129 ml) was added in to the reaction mixture below 5°C. Reaction mixture was heated and at stirred at 25-35°C till the completion of reaction. After completion of reaction, process water (500 ml) was added to the reaction mixture and layers were separated. Solution of HCl in process water was added to the reaction mixture and layers were separated. Solution of sodium bicarbonate in process water was added to the reaction mixture and layers were separated. Process water was added to the reaction mixture at room temperature and layers were separated. Organic layer was dried over sodium sulphate and solvent was distilled under vacuum to afford 1-{(2S)-1-[(2-nitrophenyl) sulfonyl] piperidin-2-yl} cyclopropyl methanesulfonate as oil.90-100 g.
Step (iv) Benzyl (2S)-2-{1-[(methylsulfonyl) oxy] cyclopropyl} piperidine-1-carboxylate (Formula V: where in R’ is carbobenzyloxy and R is methyl)
To a solution of benzyl (2S)-2-(1-hydroxycyclopropyl) piperidine-1-carboxylate (100 g, 0.363 mol.) in MDC (1000 ml), triethylamine (110.2 g, 1.089 mol) and 4-dimethylamino pyridine (4.43 g, 0.036 mol.) was added at room temperature. The reaction mixture was cooled at 0 °C. Methane sulphonyl chloride (62.38 g, 0.544 mol.) in MDC (1000 ml) was added to the reaction mixture. The resulting reaction mixture was stirred, quenched with H2O and organic layer was separated. The organic layer was washed with HCl and water dried over sodium sulphate and concentrated in vacuum to afford crude compound. Crude compound was re-crystallized from a mixture of cyclohexane and MTBE to obtain pure benzyl (2S)-2-{1-[(methylsulfonyl) oxy] cyclopropyl} piperidine-1-carboxylate as a pale yellow solid. (Yield >75%).
Step (iv) 1-[(2S)-1-benzylpiperidin-2-yl] cyclopropyl methanesulfonate (Formula V: where in R’ is benzyl and R is methyl)
To a solution of 1-[(2S)-1-benzylpiperidin-2-yl] cyclopropanol (100 g, 0.432 mol.) in MDC (500 ml), triethylamine (131.23 g, 1.296 mol.) and 4-dimethylamino pyridine (5.28 g, 0.0432 mol) was added at room temperature. The reaction mixture was cooled at 0 °C. Methane sulphonyl chloride (74.24 g, 0.648 mol.) was added dropwise to the reaction mixture. The reaction mixture was quenched with H2O, organic layer was separated and aqueous layer was extracted with MDC. The combined organic fractions was dried over sodium sulphate and concentrated in vacuum to afford crude compound. Crude compound was re-crystallized from a mixture of cyclohexane to obtain pure 1-[(2S)-1-benzylpiperidin-2-yl] cyclopropyl methanesulfonate as a pale yellow solid. (Yield >80%).
Step (iv) 1-{(2S)-1-[(4-methylphenyl)sulfonyl]piperidin-2-yl}cyclopropyl methanesulfonate (Formula V: where in R’ is 4-methylphenyl sulfonyl and R is methyl )
To a solution of 1-{(2S)-1-[(4-methylphenyl) sulfonyl] piperidin-2-yl} cyclopropanol (95 g, 0.321 mol.) in MDC (950 ml), triethylamine (97.44 g, 0.963 mol.) and 4-dimethylamino pyridine (3.92 g, 0.032 mol.) was added at room temperature. The reaction mixture was cooled at 0 °C. Methane sulphonyl chloride (55.19 g, 0.482 mol.) was added to the reaction mixture. The reaction mixture was stirred, quenched with H2O, organic layer was separated. The organic layer was washed with HCl and water. The organic layer was dried over sodium sulphate and concentrated in vacuum to afford crude compound. Crude compound was re-crystallized from a mixture of cyclohexane and MTBE to obtain pure 1-{(2S)-1-[(4-methylphenyl)sulfonyl]piperidin-2-yl}cyclopropyl methanesulfonate as a pale yellow solid. (Yield >85%).
Step (v) (2S)-2-(3-bromoprop-1-en-2-yl)-1-[(2-nitrophenyl) sulfonyl] piperidine (Formula VI: where in R’ is nosyl)
To a solution of magnesium turnings (18 g) in diethyl ether (1.0 L), 1, 2-dibromoethane (76.7 ml) was added at room temperature. The resulting reaction mixture was stirred and solvent was removed by distillation under vacuum. 1-{(2S)-1-[(2-nitrophenyl) sulfonyl] piperidin-2-yl} cyclopropyl methanesulfonate (100 g) in chloroform (900 ml) was added at room temperature. Reaction mixture was heated and stirred at 55-65°C till the completion of reaction. After completion of reaction, reaction mixture was cooled and process water (500 ml) was added to the reaction mixture below 30°C. Layers were separated and organic layer was distilled under vacuum to obtain residue. IPA (500 ml) was added to the residue below 50°C and reaction mixture was heated at 55-65°C to obtain clear solution. Slurry of Charcoal in methanol (50 ml) was added to the clear solution and stirred for 30 mins at 55-65°C.The reaction mixture was filtered and obtained filtrate was concentrated, cooled and stirred at 20-30°C. Reaction mixture was filtered, washed with IPA and dried in VTD under vacuum to afford (2S)-2-(3-bromoprop-1-en-2-yl)-1-[(2-nitrophenyl) sulfonyl] piperidine.70-80g.

Step (v) Benzyl (2S)-2-(3-bromoprop-1-en-2-yl) piperidine-1-carboxylate (Formula VI: where in R’ is carbobenzyloxy)
To a solution of Mg turnings (41.8 g, 1.72 mol.) in ether (1.0 L), 1, 2-dibromoethane (406.7 g, 2.165 mol.) was added at room temperature. The resulting reaction mixture was stirred and ether was removed by distillation. MgBr2•OEt2 was diluted with CHCl3 (500 mL) and a solution of benzyl (2S)-2-{1-[(methylsulfonyl) oxy] cyclopropyl} piperidine-1-carboxylate (100 g, 0.282 mol.) in CHCl3 (100 mL) was added at room temperature. The reaction mixture was stirred at reflux temperature and cooled to 0 °C. The reaction mixture was quenched with water and organic layer was separated, washed with water and dried over Na2SO4 and the solvent was distilled to obtain crude compound. The crude product was purified from cyclohexane to afford pure benzyl (2S)-2-(3-bromoprop-1-en-2-yl) piperidine-1-carboxylate. (Yield >90%).
Step (v) (2S)-1-benzyl-2-(3-bromoprop-1-en-2-yl) piperidine (Formula VI: where in R’ is benzyl)
To a solution of Mg turnings (47.87g 1.97 mol.) in ether (1.0 L), 1, 2-dibromoethane (465.9 g, 2.48 mol.) was at room temperature. The resulting reaction mixture was stirred and ether was removed by distillation. MgBr2•OEt2 was diluted with CHCl3 (500 mL) and a solution of 1-[(2S)-1-benzylpiperidin-2-yl] cyclopropyl methanesulfonate (100 g, 0.323 mol.) in CHCl3 ( 100 mL) was added at room temperature. The reaction mixture was stirred at reflux temperature and cooled to 0 °C. The reaction mixture was quenched with H2O and organic layer was separated, washed with water and dried over Na2SO4 and distilled out to obtain crude compound. The crude product was purified from cyclohexane to afford pure (2S)-1-benzyl-2-(3-bromoprop-1-en-2-yl) piperidine. (Yield >80%).
Step (v) (2S)-2-(3-bromoprop-1-en-2-yl)-1-[(4-methyl phenyl) sulfonyl] piperidine (Formula VI: where in R’ is 4-methylphenyl sulfonyl)
To a solution of Mg turnings (39.57 g, 1.628 mol in ether (1.0 L), 1, 2-dibromoethane (385 g, 2.05 mol.) was slowly added at room temperature. The resulting reaction mixture was stirred and ether was removed by distillation. MgBr2•OEt2 was diluted with CHCl3 (500 mL) and of 1-{(2S)-1-[(4-methylphenyl) sulfonyl] piperidin-2-yl} cyclopropyl methanesulfonate (100 g, 0.267 mol.) was added at room temperature. The reaction mixture was stirred at reflux temperature and cooled to 0 °C. The reaction mixture was quenched with H2O and organic layer was separated, washed with water and dried over Na2SO4 and distilled out to obtain crude compound. The crude product was purified from IPA to afford pure (2S)-2-(3-bromoprop-1-en-2-yl)-1-[(4-methylphenyl) sulfonyl] piperidine. (Yield >90%).
1H-NMR (300 MHz, DMSO): d 7.74(d, 2H, J = 9.0 Hz),7.42 (d, 2H, J = 9.0 Hz), 5.57(Brs, 1H), 5.17(Brs, 1H), 4.75 (Brs,1H), 4.17 (s, 2H), 3.65 (d, 1H, J = 15.0, 3.0 Hz), ), 2.93 (ddt, 1H, J = 24.0, 15.0, 3.0 Hz), 2.40 (s, 3H), 1.90 (d, 1H, J = 9.0 Hz), 0.99-1.40 (m, 5H); MS (ESI-TOF): m/z [M+2H]2+ calcd for C15H22BrNO2S: 360.3; found: 360.05.
Step (vi) (2S)-2-[2-(bromomethyl) oxiran-2-yl]-1-[(2-nitrophenyl) sulfonyl] piperidine (Formula VII: where in R’ is nosyl)
To a solution of water (1000 ml) and NaHCO3 (86.31 g) in DCM (800 ml), (2S)-2-(3-bromoprop-1-en-2-yl)-1-[(2-nitrophenyl) sulfonyl] piperidine (10.0 g) was added at room temperature. m-CPBA (221.64g) was added at room temperature till the completion of reaction. After the completion of reaction, 10 g hyflo was added and reaction mass was filtered. Hyflo bed was washed with MDC and layers were separated. Organic layer was washed with solution of sodium sulphite in water. Water and TEA was added to the reaction mixture and stirred for 10-15 mins. Layers were separated, organic layer was washed with water and distilled under vacuum to afford (2S)-2-[2-(bromomethyl) oxiran-2-yl]-1-[(2-nitrophenyl) sulfonyl] piperidine as oil.100-110g.
Step (vii) 1-benzyl-3-{(2S)-1-[(2-nitrophenyl) sulfonyl] piperidin-2-yl} azetidin -3-ol (Formula VIII: where in R’ is nosyl and R is benzyl)
To a solution of (2S)-2-[2-(bromomethyl)oxiran-2-yl]-1-[(2-nitrophenyl) sulfonyl] piperidine (1.2 g, 3.2 mmol.) in n-butanol (900 ml) and sodium bicarbonate (41.4 g), benzyl amine (39.5 g) was added at room temperature and stirred. The reaction mixture was heated at 110-120°C till the completion of reaction. After the completion of reaction, solvent was distilled under vacuum to obtain crude product. Crude product was purified by column chromatography using silica gel (60-120 mesh size) (MDC: methanol=95:5) to afford pure 1-benzyl-3-{(2S)-1-[(2-nitrophenyl) sulfonyl] piperidin-2-yl} azetidin -3-ol solid.50-65g.
Step (vii) 1-benzyl-3-{(2S)-1-[(4-methylphenyl) sulfonyl] piperidin-2-yl} azetidin -3-ol (Formula VIII: where in R’ is 4-methylphenyl sulfonyl and R is benzyl)
To a solution of (2S)-2-[2-(bromomethyl)oxiran-2-yl]-1-[(4-methylphenyl) sulfonyl] piperidine (1.2 g, 3.2 mmol.) in acetonitrile (24 mL) a solution of benzyl amine (0.41 g, 3.8 mmol.) in acetonitrile ( 24 mL) was added at reflux temperature. The reaction mixture was continued to reflux till the completion of reaction and allowed to cool slowly to room temperature. The reaction mixture was evaporated to obtain crude compound. Crude compound was re-crystallized from IPA to afford pure 1-benzyl-3-{(2S)-1-[(4-methylphenyl) sulfonyl] piperidin-2-yl} azetidin -3-ol as a white solid. (Yield >60%).

Step (viii) 1-benzyl-3-{(2S)-piperidin-2-yl} azetidin -3-ol (Formula VIII a: where in R’ is H and R is benzyl)
To a solution of 1-benzyl-3-{(2S)-1-[(2-nitrophenyl) sulfonyl] piperidin-2-yl} azetidin -3-ol (100g) in methanol (900 ml) and potassium carbonate (248 g), thioglycolic acid (85.4 g) was added at room temperature. The reaction mixture was stirred at 25-30°C till the completion of reaction. After the completion of reaction, reaction mixture was filtered, washed with methanol (200 ml) and solvent was distilled under vacuum to obtain residue. MDC (100 ml) was added to the residue and stirred for 30 minutes at 25-30°C. Reaction mixture was filtered, washed with MDC and solvent was distilled under vacuum to afford 1-benzyl-3-{(2S)-piperidin-2-yl} azetidin -3-ol as oil. (40-50g. Yield >70)
Step (viii) 1-benzyl-3-{(2S)-piperidin-2-yl} azetidin -3-ol (Formula VIII a: where in R’ is H and R is benzyl)
To a solution of vitride(800 ml) in 2 Methyl THF(500 ml) was added (2S)-2-[2-(bromomethyl)oxiran-2-yl]-1-[(4-methylphenyl)sulfonyl]piperidine (100 g,0.204) at 15°C. The reaction mixture was stirred at 45-65°C till the completion of reaction. After the completion of reaction, reaction mixture was quenched in a solution of sodium potassium tartrate. Organic layer was seperated and concentrated. Aqueous layer was extracted with MDC, added to the concentrated residue and washed with water. To the organic MDC layer, a solution of oxalic acid was added, stirred and layers were seperated. Aqueous layer was washed with MDC, basified with an aqueous solution of sodium hydroxide. The obtained product was extracted with MDC and evaporated to afford 85 g of 1-benzyl-3-{(2S)-piperidin-2-yl} azetidin -3-ol. (40 g, Yield >80)
Step (ix) tert-butyl (2S)-2-(3-hydroxy-1-benzylazetidin-3-yl) piperidine-1-carboxylate (Formula VIII b: where in R’ is tert-butyloxycarbonyl and R is benzyl)
To a solution of 1-benzyl-3-{(2S)-piperidin-2-yl} azetidin -3-ol (100g) in MDC (700 ml) and TEA (82g, 114 ml), solution of boc anhydride (132.9g, 140 ml) in MDC (200 ml) was added below 5°C. The reaction mixture was heated at 35-45°C till the completion of reaction. After the completion of reaction, water (500ml) was added to the reaction mixture at to 35-45°C and stirred for 15-20 mins. Layers were separated and organic layer was distilled under vacuum below 40°C to afford tert-butyl (2S)-2-(3-hydroxy-1-benzylazetidin-3-yl) piperidine-1-carboxylate as oil.80-90g.
Step (x) tert-butyl (2S)-2-(3-hydroxyazetidin-3-yl) piperidine-1-carboxylate
(VIII c: where in R’ is tert-butyloxycarbonyl, R is H)
To a solution of tert-butyl (2S)-2-(3-hydroxy-1-benzylazetidin-3-yl) piperidine-1-carboxylate (100 g) in methanol (300 ml), 10% Pd/C (10 g) in methanol (100 ml) was added at 25 to 35 °C. Hydrogen gas with 1-2 Kg/cm2 pressure was purged and reaction mixture was stirred at 25-35°C. After the completion of reaction, hydrogen pressure was released and hyflo (20 g) was added to the reaction mixture. Reaction mixture was filtered through hyflo bed in methanol and washed with methanol (200ml).Obtained filtrate was distilled under vacuum to obtain residue. MTBE (70 ml) was added to the residue, cooled at -9 to -15°C and stirred for 1 hour under nitrogen. Reaction mixture was filtered and washed with MTBE (20ml) at -9 to -15°C and dried in VTD under vacuum to afford tert-butyl (2S)-2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate as solid.( 50-55 g).
Step (x) 3-{(2S)-1-[(4-methylphenyl) sulfonyl] piperidin-2-yl} azetidin-3-ol (Formula VIII c: where in R’ is 4-methylphenyl sulfonyl, R is H)
A solution of 1-benzyl-3-{(2S)-1-[(4-methylphenyl)sulfonyl]piperidin-2-yl}azetidin -3-ol (2.0 g) in methanol (10.0 mL) was added to a solution of 10% palladium on carbon (200 mg) in methanol (10.0 mL) at room temperature. The mixture was stirred under hydrogen atmosphere for 10 h, catalyst was filtered off and the filtrate mixture was evaporated to dryness to afford 3-{(2S)-1-[(4-methylphenyl) sulfonyl] piperidin-2-yl} azetidin-3-ol as a white solid. (Yield >95%).

Example 2: Preparation of tetrahydro-5'H-dispiro[azetidine-3,1'-oxazolo[3,4-a]pyridine-3',1''-cyclopentane] (Formula IX: where in R’ and R’’ together form a cyclopentyl ring and R is H)
Steps (a) to (h) is same as examples of steps (i) to (viii) of Example-1

Step (i) 1-benzyltetrahydro-5'H-dispiro[azetidine-3,1'-oxazolo[3,4-a] pyridine-3',1''-cyclopentane] (Formula IXa: where in R’ and R’’ together form a cyclopentyl ring and is R is benzyl)
To a solution of 1-benzyl-3-{(2S)-piperidin-2-yl} azetidin -3-ol (100 g, 0.406 mol) in toluene (100 ml) cyclopentanone (1000 ml) followed by pyridinium p-toluenesulfonate (20.43 g, 0.081 mol) were added at 25°C. Reaction mixture was refluxed for 24 hrs. After completion of the reaction, reaction mixture was washed with water and by sodium bicarbonate. Seperated organic layer was dried over sodium sulphate ,concentrated and further recrystallized in mixture of MTBE and hexane to afford 1-benzyltetrahydro-5'H-dispiro[azetidine-3,1'-oxazolo[3,4-a] pyridine-3',1''-cyclopentane(89 g Yield >70%).
Step (j) tetrahydro-5'H-dispiro[azetidine-3,1'-oxazolo[3,4-a]pyridine-3',1''-cyclopentane] (Formula IX: where in R’ and R’’ together form a cyclopentyl ring is R is H)
To a solution of 1-benzyltetrahydro-5'H-dispiro[azetidine-3,1'-oxazolo[3,4-a] pyridine-3',1''-cyclopentane (100g, 0.32 mol.) in Methanol (1000 ml),10% Palladium/Carbon was added at 25 to 35 °C. The resulting solution was charged in to autoclave, 2.0 Kg hydrogen pressure was applied at 30°C and stirred for 24 hours. After completion of reaction, catalyst was filtered , organic mass was dried over sodium sulphate and concentrated to afford tetrahydro-5'H-dispiro[azetidine-3,1'-oxazolo[3,4-a]pyridine-3',1''-cyclopentane]. (36 g Yield > 50%).

Example 3: Preparation of 1H-benzotriazol-1-yl {3, 4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] phenyl} methanone
Step (i) 3, 4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] benzoic acid
To a solution of 2-fluoroaniline (161.5 g 0.681 mol.) and 2, 3, 4-trifluorobenzoic acid (100.0 g 0.567 mol.) in THF (700 mL), a solution of 1.0 M LiHMDS (1.7 L) in THF was added slowly over a period of 1.0 h at 0-5°C. The resulting reaction mixture was stirred for 3.0 hours at room temperature. The progress of reaction was monitored by HPLC and the reaction mixture was quenched by addition of 5 % aqueous HCl solution (900 mL) and ethyl acetate (1200 mL). The reaction mixture was stirred for 30 min at room temperature, organic layer was separated and concentrated to obtain crude compound. Crude compound was re-crystallized from cyclohexane and methanol (800 mL) to afford pure 3, 4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] benzoic acid. (38.3 g, 68% Yield).
Step (ii) 1H-benzotriazol-1-yl {3, 4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] phenyl} methanone
To a stirring solution of 1H-benzotriazole (4.5 g, 38 mmol.) in MDC (50 mL), thionylchloride (1.82 g, 15.3 mmol.) was added slowly to a cold at 5-10 °C. The resulting reaction mass was stirred for 0.5 hour at 5-10 °C. 3, 4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] benzoic acid (5 g, 12.7 mmol.) was added at 5-10 °C to the reaction mixture. The resulting suspension was stirred for 2.0 hours at room temperature and filtered. The filtrate was concentrated to obtain residue. The residue was re-crystallized from MTBE to afford 1H-benzotriazol-1-yl{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino] phenyl}methanone.(4.16 g Yield 67%). %). 1H-NMR (300 MHz, CDCl3): d 8.24 (dt, 1H, J = d, 9.0, 18.0 Hz), 8.15 (dt, 1H, J = d, 9.0, 18.0 Hz), 7.91 (Brs, 1H), 7.82 (ddt, 1H, 5.7, 3.6, 2.1 Hz), 7.714 (dt, 1H, J = 7.2, 0.9 Hz), 7.56 (dt, 1H, J = 7.2, 0.9 Hz), 7.28 (m, 2H) 7.01 (dt, 1H, J = 9.0, 7.2 Hz), 6.65 (dt, 1H, J = 9.0, 4.5 Hz).; MS (ESI-TOF): m/z [M-H]- calcd for C19H9F3IN4O: 493.0; found: 492.9.
Step (iii) (S)-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl) (tetrahydro-5'H-dispiro[azetidine-3,1'-oxazolo[3,4-a]pyridine-3',1''-cyclopentan]-1-yl)methanone
To a solution of tetrahydro-5'H-dispiro[azetidine-3,1'-oxazolo[3,4-a]pyridine-3',1''-cyclopentane] (100g, 0.167 mol.) in Acetonitrile (500 ml), 1H-benzotriazol-1-yl {3, 4-difluoro-2-[(2-fluoro-4-iodophenyl) amino] phenyl} methanone (111 g, 0.225 mol.) was added. Reaction mixture was stirred for 10 hours at 30°C. After completion of reaction the obtained solid was filtered and dried to afford (S)-(3,4-difluoro-2-((2-fluoro-4-iodophenyl) amino) phenyl) (tetrahydro-5'H-dispiro[azetidine-3,1'-oxazolo[3,4-a]pyridine-3',1''-cyclopentan]-1-yl)methanone. (190 g Yield > 70 %)

Step (iv) (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl]methanone (Cobimetinib)
To a solution of (S)-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(tetra hydro-5'H-dispiro[azetidine-3,1'-oxazolo[3,4-a]pyridine-3',1''-cyclopentan]-1-yl) methanone (100g, 0.45 mol.) in Methanol (1000 ml) and water (300 ml), Para Toluene sulphonic acid (144.2 g, 0.837 mol.) was added at room temperature. Reaction mixture was stirred at 60-80°C for 24-30 hours. After completion of reaction, reaction mixture was concentrated and MDC (500 ml) was added.Reaction mixture was basified with 20 % Potassium carbonate solution (250ml). Organic layer was separated and aqueous layer was extracted with MDC (500 ml). organic layers were combined and washed with water (300 ml).Organic layer was concentrated and obtained residue was purified in acetonitrile to afford Cobimetinib. (72 g Yield > 80 %)
Step (v) Cobimetinib hemifumarate
To a solution of Cobimetinib freebase (100g, 0.188 mol.) in a methanol (100 ml), Fumaric acid (14.2g, 0.122 mol.) was added at room temperature. The resulting reaction mixture was stirred for 15 mins, filtered through celite bed and celite bed was washed with Methanol (120 ml). Reaction mixture was stirred at 30°C for 20 hrs. Obtained Solid was filtered and dried to obtain Cobimetinib hemifumarate (88 g, > 80).
,CLAIMS:We Claim:

1. A process for the preparation of compound of Formula (VIII);

wherein R, R’ is independently selected from hydrogen, carbobenzyloxy, benzyl, tert-butyloxycarbonyl, acetyl, benzoyl, nosyl, mesyl and tosyl which comprises the steps of:
i) reacting a compound of Formula (III) with a grignard reagent in the presence of
titanium catalyst to obtain compound of Formula (IV);

wherein R is methyl, ethyl, propyl and butyl;
ii) converting the compound of Formula (IV) to obtain compound of Formula (V);

wherein R is carbobenzyloxy, benzyl, tert-butyloxycarbonyl, acetyl, benzoyl,
nosyl, mesyl and tosyl.
iii) reacting a compound of compound of Formula (V) with metal halide to obtain
compound of Formula (VI);

iv) reacting a compound of Formula (VI) with oxidizing agent to obtain compound of Formula (VII); and

X is F, Cl, Br and I.
v) reacting a compound of Formula (VII) with protected or unprotected amine to obtain a compound of Formula (VIII).

2. The process as claimed in claim 1, wherein the grignard reagent used in step i) is selected from ethyl magnesium bromide, ethyl magnesium chloride, isopropyl magnesium chloride, methyl magnesium bromide and phenyl magnesium bromide and titanium catalyst as used is selected from Ti(OiPr)4, MeTi(OiPr)3, MeTi(OtBu)3, CITi(OiPr)3, CITi(OtBu)3, or Ti(OtBu)4.

3. The process as claimed in claim 1, wherein the metal halide used in step iii) is selected from titanium tetrachloride, aluminum trichloride, tin chloride, ferric chloride, zinc chloride, magnesium bromide diethyl etherate and boron trifluoride ethyl ether.

4. The process as claimed in claim 1, wherein the oxidizing agent used in step iv) is selected from selected from potassium permanganate , meta-chloro per benzoic acid, peracetic acid, performic acid, sodium hypochlorite, hydrogen peroxide, tert-butyl hydrogen peroxide and cumene hydroperoxide.

5. A process for the preparation of compound of Formula (IX);

wherein R’ and R’’ is independently selected from C 1-6 alkyl or R’ and R’’ together represents cyclic alkyl ring; R is hydrogen, carbobenzyloxy, benzyl, tert-butyloxycarbonyl, acetyl, benzoyl, nosyl, mesyl and tosyl comprises reacting compound for Formula (VIII) with compound of Formula (X)

wherein, A and A’ is independently selected from C 1-6 alkyl, C 1-6 alkyloxy, or A and A’ together represents cyclic alkyl group.

6. The process as claimed in claim 5, wherein the compound of Formula (X) is selected from cyclopentanone, cyclopropanone, cyclobutanone, cyclohexanone acetone, MIBK, and cyclootanone.

7. A process for the preparation of Cobimetinib which comprises converting the compound of formula (VIII) as prepared in claim 1.

8. A process for the preparation of Cobimetinib which comprises converting the compound of formula (IX) as prepared in claim 5.

9. A process for the preparation of Cobimetinib which comprises converting the compound of formula (XXI) in to cobimetinib.

10. A compound having following Formula and its use in the preparation of Cobimetinib

wherein R is R’ and R’’ is selected from the group comprising of hydrogen, nosyl, mesyl, tosyl, carbobenzyloxy, benzyl, tert-butyloxycarbonyl, alkyl, aryl, acyl, acetyl, benzoyl, or R’ and R’’ together represents a cyclic alkyl ring.

Dated this 1st February 2019
Dr. S.Ganesan