WO2019038779A1

WO2019038779A1 - A novel process for the preparation of an intermediate of alectinib

Info

Publication number: WO2019038779A1
Application number: PCT/IN2018/050501
Authority: WO
Inventors: Srinivasan APPAYE KALIYAPERUMAL; Shyam Sunder Reddy TALASANI; Nagalingam SAMATHAM; Srinivasa Krishna Murthy Konduri; Shankar Reddy BUDIDETI; Pulla Reddy Muddasani; Venkaiah Chowdary Nannapaneni
Original assignee: Natco Pharma Limited
Priority date: 2017-08-21
Filing date: 2018-07-31
Publication date: 2019-02-28

Abstract

The present invention provides a novel process for the preparation of 2-(4-Ethyl-3-iodophenyl)-2-methylpropanoic acid of Formula (I), (I) which is a key intermediate in the synthesis of Alectinib or its salt of Formula (II).

Description

A NOVEL PROCESS FOR THE PREPARATION OF AN

INTERMEDIATE OF ALECTINIB

FIELD OF THE INVENTION

The present invention relates to a novel process for preparation of an (2-(4- Ethyl-3-iodophenyl)-2-methylpropanoic acid of Formula (I).

Formula I

which is a key intermediate in the synthesis of Alectinib or its salt of Formula (II).

Formula II

BACKGROUND OF THE INVENTION

Alectinib is chemically known as 9-Ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl) piperidin-l-yl]- 1 l-oxo-6, 1 l-dihydro-5H-benzo[ ]carbazole-3-carbonitrile

Formula (II). Alectinib is a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) and RET. In nonclinical studies, Alectinib inhibited 232 ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT, 233 and decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating 234 mutations. Alectinib hydrochloride is used for the treatment of patient with anaplastic lymphoma kinase (ALK), metastatic non- small cell lung cancer (NSCLC) who have progressed on or are intolerant to Crizotinib and is marketed under the trade name Alecensa®. US Patent No. 9126931 discloses Alectinib and its pharmaceutically acceptable salts.

US9126931 and JP 4588121 disclose a process for the preparation of 2-(4-Ethyl-3- iodophenyl)-2-methylpropanoic acid of Formula (I) by reaction of 2-(4- Bromophenyl)-2-methylpropanoic acid (III) with potassium vinyltrifluoroborate in the presence of palladium acetate and K2CO3 in 1-propanol to produce 2-(4- Vinylphenyl)-2-methylpropanoic acid (IV), which under goes reduction in the presence of palladium/carbon in ethanol to produce 2-(4-Ethylphenyl)-2- methylpropanoic acid (V). Further, iodination of compound of Formula (V) in the presence of N-iodosuccinimide and cone, sulfuric acid in acetic acid to produce compound of Formula (I).

The synthetic procedure is illustrated in Scheme-I as below:

1) The main disadvantage with the above prior art process is that the usage of homogeneous palladium based catalyst (like palladium acetate, tetrakistriphenylphosphine palladium etc.) in Suzuki reaction and also involved metal based hydrogenation reaction.

As we know that Suzuki reaction required homogeneous catalyst which also mentioned in the prior art process there could be potential chances of toxic metal residues bound to the desired product and another drawback of metal based reaction always leads to formation of undesired products (like dehalogenation, homocoupling, debenzylation and de aromatization etc. products). Moreover heterogeneous and homogeneous palladium catalyst are very expensive.

The prior art process also reveals that Formula (I) was prepared by iodination of Formula (V) with n-iodosuccinamide (NIS) under acetic acid- sulphuric acid medium. The drawback of the mention condition is formation of diiodo substituted compound as main impurity which is propagating with respect to reaction time, equivalent of NIS and concentration of sulfuric acid used for the reaction. Removal of this impurity is difficult or it required repeated crystallization, which reduce the yield of 2-(4-Ethyl-3-iodophenyl)-2-methylpropanoic acid of Formula (I). To sum up, the above reported synthetic methods for the compound of Formula (I) are with harsh reaction conditions, complicated, risky and costly hence it may not suitable for industrial production which drive us to develop a simple and efficient synthesis of Formula (I).

Though Amos et al., (Journal of the American Chemical Society 1984, 106, 4001-4009) discloses a process for the preparation of 2-(4-Methylphenyl)-2- methylpropanoic acid (VII) by basic hydrolysis of methyl 2-(4-methylphenyl)-2- methylpropanoate (VI), which may not be useful for Alectinib preparation. The synthetic procedure is illustrated in Scheme-II as below:

Methyl 2-(4-methy¾)henyl)-2- SCHEME-II

2-(4-Methy¾)henyl)-2- methylpropanoate (VI) methylpropanoic acid (VII)

Hence, there exists a need to have simple, easy to handle and cost effective process for the preparation of 2-(4-Ethyl-3-iodophenyl)-2-methylpropanoic acid of Formula (I) with high chemical purity and higher yield. OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple and cost effective process for the preparation of 2-(4-Ethyl-3-iodophenyl)-2- methylpropanoic acid of Formula (I) which is a key intermediate for the preparation of Alectinib or its salt of Formula II with high purity and good yield on a commercial scale.

SUMMARY OF THE INVENTION

The present invention provides a novel process for the preparation of 2-(4- Eth l-3-iodophenyl)-2-methylpropanoic acid of Formula (I), comprising the steps

Formula I

a) hydrolysing the compound of Formula (VIII),

b) iodination of a compound of Formula (V) obtained in step a) to produce compound of Formula (I).

c) Optionally, purification of compound of formula (I) from hydrocarbon solvent. The present invention further provides a process for preparation of compound of formula V, comprising of:

Formula V

hydrolysing the compound of Formula (VIII),

Formula VIII

in presence of a base in a suitable solvent to produce compound of Formula (V).

The present invention further provides a process for preparation of compound of Formula VIII, comprising the steps of: a) reacting a compound (IX) of Ethylbenzene

Formula IX

with 2-bromo-2-methyl-propionyl bromide in presence of lewis acid selected from AICI3 in halogenated solvent selected from dichloromethane to produce compound of Formula X.

Formula X

b) reacting the compound of Formula (X) obtained in step a) with trimethyl orthformate and zinc bromide to produce compound of Formula VIII.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel process for the preparation of 2-(4-Ethyl-3- iodophenyl)-2-methylpropanoic acid of Formula (I), comprising the steps of: a) hydrolysing the compound of Formula (VIII), in presence of a base in a solvent to produce compound of formula (V).

b) iodination of a compound of Formula (V) obtained in step a to produce compound of Formula (I).

c) Optionally, purification of compound of formula (I) from hydrocarbon solvent.

The base used in hydrolysis step a) is organic or inorganic base. The inorganic base comprises sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof preferably sodium hydroxide and the organic base comprises diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine or mixtures thereof.

The solvent used in hydrolysis step a) is organic solvent, for example alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, ie/ -butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof preferably methanol; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane, or mixture thereof.

The reaction may be performed usually from 0^° C to a boiling point of an used solvent for 30 min to 48hours and then compound of formula (V) can be obtained by a usual procedure. The obtained compound (V) may be used in the next reaction directly or optionally after further purification.

The Iodinating agent used in step b) is iodine or n-iodosuccinimide, preferably n- iodo succinimide .

The acid agent used in step b) is inorganic acid or organic acid. The organic acid comprises methanesulfonic acid, ethanesulfonic acid and propanoic acid or mixture thereof, preferably methanesulfonic acid.

The solvent used in step b) is organic solvent, for example an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane, or mixture thereof, preferably acetonitrile.

The reaction may be performed from -30 C to 60^° C for 30 min to 48hours and then compound of formula (I) can be obtained by a usual procedure.

The hydrocarbons solvent used in purification step c) is pentane, hexane, n-heptane, mixture thereof.

In another embodiment of the present invention provides a process for preparation of compound of formula V, comprising step of: hydrolysing the compound of formula (VIII), in presence of a base in a suitable solvent to produce compound of formula (V). The base used in above hydrolysis step is organic or inorganic base. The inorganic base comprises sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof preferably sodium hydroxide and the organic base comprises diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine or mixtures thereof.

The solvent used in above hydrolysis step is organic solvent, for example alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, ie/ -butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof preferably methanol; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane, or mixture thereof.

The reaction may be performed usually from 0 C to a boiling point of an used solvent for 30 min to 48hours and then compound of formula (V) can be obtained by a usual procedure. The obtained compound (V) may be used in the next reaction directly or optionally after further purification.

In another embodiment of the present invention provides a process for preparation of compound of Formula VIII, comprising the steps of:

a) reacting a compound (IX) of Ethylbenzene with 2-Bromo-2-methyl- propionyl bromide in presence of lewis acid selected from AICI3 in halogenated solvent selected from dichloromethane to produce compound of (X).

b) reacting the compound of formula (X) obtained in step a) with trimethyl orthformate and zinc bromide or zinc oxide or lewis acid to produce compound of Formula VIII.

The above step a) may be performed usually from -30^° C to 0 C for 30 min to 48hours and then compound of formula (X) can be obtained by a usual procedure. The obtained compound (X) may be used in the next reaction directly or optionally after further purification.

The above step b) may be performed usually from -30^° to 120 C for 30 min to 10 hours and then compound of formula (VIII) can be obtained by a usual procedure. The obtained compound (VIII) may be used in the next reaction directly or optionally after further purification.

2-(4-Ethyl-3-iodophenyl)-2-methylpropanoic acid of Formula (I) prepared by the above process is converted to Alectinib or its salt by reacting with Mono-ie/ -butyl malonic acid in the presence of TEA and magnesium chloride in THF to produce ie/ -butyl 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid, which is further reacted with 4-fluoro-3-nitrobenzonitrile in the presence of sodium carbonate in DMF followed by sodium hydrosulfite and HQ/ NaOH in THF to produce Tert- butyl-6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-lH-indole-3-carboxylic acid. Condensation of obtained compound with 4-morpholin-4-yl piperidine in the presence of l,3-bis-(2,6-diisopropylphenyl)-imidazoyl-2-ylidene (allyl) palladium (II) chloride to produce Te/t-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl- piperidin-l-yl)phenyl)propan-2-yl)-lH-indole-3-carboxylic acid hydrochloric acid salt. Hydrolysis of obtained compound with TMSC1 in trifluoroethanol (TFE) and acetone to produce 6-Cyano-2-(2-(4-ethyl-3-(4-morpholin-4-yl-piperidin-l- yl)phenyl)propan-2-yl)-lH-indole-3-carboxylic acid, which is further cyclization with Ν,Ν-dimethylacetamide (DMA), acetic anhydride and DIPEA to produce Alectinib, which is further treated with 2N HC1 in methanol to produce Alectinib HC1.

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention. EXAMPLES:

EXAMPLE-01: PREPARATION OF 2-BROMO-l-(4-ETHYLPHENYL)-2- METHYL-PROPAN-1-ONE (X).

Into the RBF, a suspension of dichlomethane and AICI3 (1.0 moles.) was cooled to -IO C to that 2-bromo-2-methyl-propanyl bromide (a-Bromoisobutyryl bromide) (0.8 moles) was slowly added. Later Ethyl benzene (IX) (0.9 moles) was added to the reaction mass. The reaction was monitored by HPLC after completion of reaction, reaction mass was quenched with diluted HC1 at low temperature (<15^° C). Organic layer was washed with bicarbonate and DM water. The obtained organic layer was dried over sodium sulphate. After concentration under reduced pressure afforded titled compound as a liquid without further purification proceed for next step.

EXAMPLE-02a: PREPARATION OF METHYL 2-(4-ETHYLPHENYL)-2- METHYL-PROPANOATE (VIII).

Into the RBF, a solution of trimethylorthoformate and compound (X) obtained from example-01 and anhydrous ZnBr (0.08 moles) was added. The mixture was refluxed (-95^° C). The reaction was monitored by HPLC. After completion of reaction the reaction mass was filtered and evaporated under reduced pressure. The crude product was dissolved in toluene and washed with water after concentration under reduced pressure afforded title compound as syrupy liquid without any further purification proceed for next step.

EXAMPLE-02b: PREPARATION OF METHYL 2-(4-ETHYLPHENYL)-2- METHYL-PROPANOATE (VIII).

To the concentrated mass of ALB-1A (1.08 moles), trimethyl orthoformate (3 vol) and anhydrous zinc bromide (0.1079 moles) were added at 20-30°C and heated to reflux (-90 °C). The reaction was monitored by HPLC. Upon completion of reaction the reaction mass was concentrated and it was directly used as such for compound of formula (V). EXAMPLE-03a: PREPARATION OF 2-(4-ETHYLPHENYL)-2-METHYL- PROPANOIC ACID (V).

Into the RBF, a solution of compound (VIII) obtained from example-02 and methanol were added. To that solution of sodium hydroxide (1.3 moles) was added then mixture was refluxed. The reaction was monitored by HPLC. After completion of the reaction, the reaction mass was concentrated under reduced pressure and the crude material was suspended in water and washed with dichloromethane. Later, the obtained product was acetified with dilute HCl up to pH of 1-2 afforded title compound as Low melting solid.

Yield: Overall 80 % (Three step); Purity: 99.5 %

EXAMPLE-03b: PREPARATION OF 2-(4-ETHYLPHENYL)-2-METHYL- PROPANOIC ACID (V).

To the concentrated mass of compound of formula (VIII) (1.08 moles), aqueous sodium hydroxide (1.631 moles) solution and methanol were added. The mixture was heated to reflux. The reaction was monitored by HPLC. Upon completion of the reaction, the reaction mass was cooled and adjusted the pH to acidic and the resulting product was extracted with methylene chloride. Later the product was extracted with aq. sodium hydroxide solution. Sodium salt of acid was acidified with dil. HCl (pH ~2). The resulting solid product was filtered and recrystallized from the mixture of methanol-water to yield pure compound of formula (V) as white to light brown coloured powder.

EXAMPLE-04: PREPARATION OF (2-(4-ETHYL-3-IODOPHENYL)-2- METHYLPROPANOIC ACID (I).

Into the RBF a suspension of acetonitrile, compound (V) obtained from example - 03 (0.2 moles) and N-iodosuccinamide (0.2 moles) were taken and cooled to 15-25^° C. Then methanesulphonic acid (0.3 moles) was added slowly. The reaction was monitored by HPLC. After reaction completion, the reaction mass quenched with sodium hydrogen sulphate. The precipitated material was filtered and dried then recrystallized with n-Heptane afforded title compound as solid.

Yield: 85%; Purity: 99 % . EXAMPLE-05: PREPARATION OF tert-BUTYL 4-(4-ETHYL-3-IODO- PHENYL)-4-METHYL-3-OXO-PENTANOATE.

Mono-ie/ -butyl malonic acid (226.3 g; 1.41 moles) was dissolved in THF under nitrogen atmosphere at RT. The reaction mixture was cooled to 10-15° C triethylamine (318.1 g; 3.14 moles) was added slowly followed by magnesium chloride (157.11 g; 1.65 moles) was added and stirred for ~2h at 25-30° C. In a separate vessel, Compound (I) obtained in example-04 (250 g; 0.7858 moles) was dissolved in THF under N₂ atmosphere at RT and cooled to 10-15° C. N,N- carbonyldiimidazole (CDI; 153 g; 0.94 moles) was added lots wise and stirred for ~lh at 25-30° C. This solution was then added dropwise to the above magnesium chloride complex and stirred for ~6h at 60-65° C. After completion of the reaction by HPLC, cooled to RT, diluted with Ethyl acetate and dil. aqueous HC1. Layers were separated and organic layer was washed with dil. Aq. NaOH and -15% w/v brine solution. Finally organic layer was concentrated to dryness at < 60° C under vacuum to obtain the product as a light brown colour liquid. HPLC Purity: 88.26%.

EXAMPLE-06: PREPARATION OF rt-BUTYL 2-(4-CYANO-2-NITRO-

PHENYL)-4-(4-ETHYL-3-IODO-PHENYL)-4-METHYL-3-OXO-

PENTANOATE.

4-Fluoro-3-nitrobenzonitrile (182.6 g; 1.10 moles) was dissolved in DMF at 25- 30°C under nitrogen atmosphere and sodium carbonate (249.8 g; 2.36 moles) was added. The slurry was heated to 45-50° C and compound obtained in example- 05/DMF solution (327.12 g; 0.78 moles) was added in 30-60 min at 45-50° C. The reaction mass was maintained for ~8h at 45-50° C. After completion of the reaction by HPLC, reaction mass was diluted with ethyl acetate and water at < 50° C and stirred for 30-45 min. Layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with -10% w/v brine solution and concentrated under vacuum at < 55° C. Methanol was added to the concentrated residue and heated to 45-50° C and stirred for lh at 45-50° C. The obtained slurry was cooled to 25-30° C and maintained for lh at 25-30° C. The product was filtered and washed with methanol followed by water and then dried under vacuum to obtain the title product as a light yellow wet solid (369.2 g; 74.85% of theory on dried basis). HPLC Purity: 95.91%.

EXAMPLE-07: PREPARATION OF tert-BUTYL 6-CYANO-2-[l-(4- ETHYL-3-IODO-PHENYL)-l-METHYL-ETHYL]-lH-INDOLE-3- CARBOXYLATE.

Compound obtained in example-06 (325 g; 0.57 moles) was dissolved in THF at 15-30°C and water was added to reaction solution. Sodium hydrosulfite (402.40 g; 2.31 moles) was added in small lots over a period of ~1.5h at 25-35° C and stirred for ~3h. After completion of the reaction by HPLC, layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic layer was treated with dil. aqueous hydrochloric acid, dil. sodium hydroxide and -15% w/v brine solution at 25-30° C. Organic layer was treated with activated carbon and concentrated under vacuum at < 50° C. Toluene added and co-distilled under vacuum at 50-60° C. Methanol was added followed by heated to 40-45° C and stirred for ~lh at 40-45° C. Cooled to 5-10° C, stirred for ~lh, filtered and washed with cold methanol. The wet product again suspended in methanol, heated to 40- 45° C and stirred for ~lh. Cooled to 5-10° C, stirred for ~lh, filtered and washed with cold methanol. Product was dried at 55-60° C under vacuum to obtain the title product as a white solid (221 g; 74.35% of theory). HPLC Purity: 98.96%.

EXAMPLE-08: PREPARATION OF tert-BUTYL 6-CYANO-2-[l-[4-ETHYL-3- (MORPHOLINO-l-PIPERIDYL)PHENYL]-l-METHYL-ETHYL]-lH- INDOLE-3- CARBOXYLA TE.

Compound obtained in example-07 (200 g; 0.38 moles) and 4-morpholin-4-yl piperidine (79.43 g; 0.46 moles) were dissolved in THF under N₂ atmosphere at 20- 30° C. NaHMDS (2.0M) in THF (437 g; 1.02 moles) was added at 20-40° C followed by l,3-bis-(2,6-diisopropylphenyl)-imidazoyl-2-ylidene(allyl) palladium- ill) chloride (6.7 g; 0.01 moles) at 30-40° C. Heated the reaction mass to 40-45° C and stirred for ~lh. After completion of the reaction by HPLC, reaction mass was diluted with ethyl acetate and aqueous ammonium chloride solution. Separated the organic layer and extracted the aqueous layer with ethyl acetate. Combined organic layer was washed with brine solution, treated with activated carbon and concentrated under vacuum at < 45° C. Co-distilled with acetone under vacuum at < 45° C, resulting residues were dissolved in acetone and added Cone. HC1. The precipitated solid was filtered, washed with acetone and dried under vacuum at 65- 70° C to obtain the title compound as a light cream colored powder (171.9 g; 74.53% of theory). HPLC Purity: 99.25%.

EXAMPLE-09: PREPARATION OF 6-CYANO-2-[l-[4-ETHYL-3-(4- MORPHOLINO-l-PIPERIDYL)-PHENYL]-l-METHYL-ETHYL]-lH- INDOLE-3-CARBOXYLIC ACID.

Compound obtained in example-08 (150 g; 0.25 moles) was suspended in Trifluoroethanol at 20-30° C under nitrogen atmosphere and cooled to 5-10° C. Trimethylchlorosilane (68.66 g; 0.63 moles) added drop-wisely at 5-10° C and maintained for ~3h at 5-10° C. After completion of the reaction by HPLC, worked up the reaction by addition of acetone, dil. Aq. NaOH solution, -10% w/v Aq. K₂HP0₄ solution below 20°C sequentially. Stirred the product slurry for ~lh at 25- 30° C, filtered the product, washed with 1: 1; acetone: water mixture and dried under vacuum at 65-70° C to obtain the title product as an off-white colored powder (106.6 g; 84.21% of theory). HPLC Purity: 99.64%.

EXAMPLE-10: PREPARATION OF 9-ETHYL-6,ll-DIHYDRO-6,6-

DIMETHYL-8-[4-(4-MORPHOLINYL)-l-PIPERIDINYL]-ll-OXO-5H-

BENZO[6]CARBAZOLE-3-CARBONITRILE.

DMF was heated to 70-75° C, diisopropylethylamine (115.24 g; 0.89 moles), acetic anhydride (38.73 g; 0.38 moles) and compound obtained in example-09/DMF solution (95 g; 0.18 moles) were added at 65-75° C. Reaction mass was further heated to 85-90° C and stirred for ~lh. After completion of the reaction by HPLC, reaction mass was cooled to 25-30° C, methanol and water were added. The crystallized solid was filtered, washed with methanol and water mixture and dried under vacuum at 65-70° C to obtain the title compound as an off-white colored powder (76.9 g; 83.97% of theory). HPLC Purity: 99.65%. EXAMPLE-11: PREPARATION OF 9-ETHYL-6,ll-DIHYDRO-6,6- DIMETHYL-8-[4-(4-MORPHOLINYL)-l-PIPERIDINYL]-ll-OXO-5H- BENZO[6]CARBAZOLE-3-CARBONITRILE (ALECTINIB HYDROCHLORIDE).

Compound obtained in example- 10 (40 g; 0.08 moles) was suspended in methyl ethyl ketone at 20-30° C, acetic acid and water were added. Reaction mass was heated to 40-45° C, treated with activated carbon and added to the 2N HCl in methanol at 25-30° C. Stirred for ~lh at 25-30° C, filtered, washed with methanol and dried under vacuum at 75-80° C to obtain the title product as an off-white colored powder (36.3 g; 84.38% of theory). HPLC Purity: 99.87%.

Claims

CLAIM:

A process for the preparation of 2-(4-Ethyl-3-iodophenyl)-2-methylprop acid of Formula (I), comprising the steps of:

Formula I

a) hydrolysing the compound of formula (VIII),

Formula VIII

in presence of a base in a solvent to produce compound of formula (V).

Formula V

The process according to claim 1, wherein the base used in step-a is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixture thereof. The hydrocarbons solvent used in purification step c) is selected from pentane, hexane, n-heptane, mixture thereof.

The process according to claim 2, wherein the base used in step-(a) is preferably sodium hydroxide.

4. The process according to claim 1, wherein the iodination step b) is carried out in presence of an iodinating agent selected from iodine or n-iodosuccinimide, preferably n-iodosuccinimide; and an organic acid selected from methanesulfonic acid, ethanesulfonic acid and propanoic acid or mixture thereof, preferably methanesulfonic acid; in an aprotic polar solvent selected from dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof.

5. A process for preparing a compound of Formula V, comprising the step of:

Formula V

hydrolysing the compound of Formula (VIII),

Formula VIII

in presence of a base in a suitable solvent to produce compound of Formula V.

6. The process according to claim 5, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixture thereof. 7. The process according to claim 6, wherein the base is preferably sodium hydroxide.

8. The process according to claim 5, wherein the solvent is selected from alcohol and water or mixture thereof.

The process according to claim 1, wherein the compound of Formula VIII prepared by process comprising of:

a) reacting the compound (IX) of Ethylbenzene

Formula IX

with 2-bromo-2-methyl-propionyl bromide in presence of lewis acid selected from AlCb in halogenated solvent selected from dichloromethane to produce compound of Formula X.

Formula X

b) reacting the compound of Formula (X) obtained in step a) with

trimethylorthformate and zinc bromide to produce compound of FormulaVIII.

10. The process according to claim 1, wherein the compound of Formula (I) used in the preparation of Alectinib or its salt compound of formula (II).