DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Cabozantinib and salts thereof. The present invention also relates to a process for the preparation of Cabozantinib intermediates.
BACKGROUND OF THE INVENTION
Cabozantinib-S-malate is a kinase inhibitor indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer and advanced renal cell carcinoma in people who have received prior anti-angiogenic therapy. Cabozantinib is marketed under the trade name of COMETRIQ® by Exelixis, Inc. COMETRIQ® is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer. The chemical name of Cabozantinib is N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide. Its structural Formula is the following Formula (I)

(Formula I)
US 7,579,473 B2 (hereinafter referred to as the US '473 patent) discloses Cabozantinib or its pharmaceutical acceptable salt thereof. Further it discloses process for prepration of Cabozantinib. According to the process, Cabozantinib was prepared by the condensation of 4-aminophenol with 1-(4-fluoro-phenylcarbamoyl)-cyclopropane carboxylic acid in presence of EDCI in DMA to form cyclopropane-1,1-dicarboxylic acid (4-fluorophenyl)-amide(4-hydroxy-phenyl)-amide. Further, reacting it with trifluoro methanesulfonic acid 6,7-dimethoxy-quinolin-4-yl ester in presence of anhydrous 2,6- lutidine to give Cabozantinib. The crude compound is purified using column chromatography.
The synthetic process disclosed in US’473 is schematically represented as below.

Scheme I
US 8,877, 776 B2 discloses Cabozantinib malate salt and its solid crystalline Form N-1, Form N-2. It also discloses amorphous form of Cabozantinib L-malate. Further it describes preparation of Cabozantinib by reacting 4(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine and 1-(4-fluorophenylcarbomoyl)-cyclopropanecarbonyl chloride under basic condition to get cabozantinib, which is reacted with malic acid to get Cabozantinib malate.
The synthetic route of Cabozantinib malate as describe in the disclosure as below in scheme-2.

Scheme 2
Considering the importance of Cabozantinib in the pharmaceutical field, there is a need that remains for an improved and commercially viable process of preparing pure Cabozantinib malate.

SUMMARY OF THE INVENTION
The main aspect of the invention is to provide an improved process for preparation of Cabozantinib as per below scheme 3.

Scheme 3
One more aspect is to provide an improved process of preparation of Cabozantinib, comprising the steps of:
a) reacting compound of Formula (II) with 4-aminophenol to get compound of Formula (III); and
b) reacting compound of Formula (III) with compound of Formula (IV) to get compound of Formula (I).
Another aspect of this invention is to provide an improved process of preparation of compound of Formula (IV), comprising the steps of reacting cyclopropane-1, 1-dicarboxylic acid with 4-fluoroaniline to get compound of Formula (IV).

DETAILED DESCRIPTION OF THE INVENTION
An embodiment is to provide an improved process of preparation of Cabozantinib, comprising the steps of:
a) reacting compound of Formula (II) with 4-aminophenol to get compound of Formula (III); and
b) reacting compound of Formula (III) with compound of Formula (IV) to get compound of Formula (I).
In one embodiment of the present invention, step (a) may be carried out by reacting compound of Formula (II) with 4-aminophenol to get compound
of Formula (III). The reaction may be carried out in presence of inorganic base selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), ammonium hydroxide (NH4OH), sodium hydride (NaH), Potassium hydride (KH) and the like. Alternatively an organic base may also be employed. The reaction may be carried out in the presence of catalyst selected from sodium bromide (NaBr), Sodium iodide (NaI), potassium iodide (KI), potassium bromide (KBr) and the like. The reaction may be carried out in the presence of inert organic solvent including but not limited to N, N-dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N’-dimethyl acetamide (DMAc), N-methyl pyrrolidine (NMP), acetonitrile (ACN), toluene, xylene, methyltertbutylether (MTBE), diethylether, cyclopentyl methyl ether, dichloromethane (DCM), 1,2-dichloroethane, ethyl acetate, isopropyl acetate, acetone, and mixtures thereof. In particular embodiment of the present invention, combination of sodium hydroxide as a base, N, N-dimethyl sulfoxide (DMSO) as a solvent and NaBr as a catalyst used for step (a). The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Preferably, the reaction step (a) may be carried out at 95+5 °C temperature.
In one embodiment, compound of Formula (III) may be isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification.
In one more embodiment of the present invention, the compound of formula (IV) may be prepared by reacting cyclopropane-1,1-dicarboxylic acid with 4-fluoroaniline. The reaction may be carried out in presence of chlorinating agent, organic base and organic solvent. The chlorinating agent selected from thionyl chloride or oxalyl chloride and the like. The reaction may be carried out in the presence of organic base such as triethyl amine, diisopropyl ethyl amine, diethylamine, tributyl amine and n-butyl amine; or inorganic base is selected from the group consisting of sodium bicarbonate and potassium bicarbonate. More preferable organic base is triethyl amine. The reaction may be carried out in the presence of an inert organic solvent including but not limited to ether solvents such as methyltertbutylether (MTBE), diethylether, cyclopentyl methyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), ethyl acetate, isopropyl acetate, acetone, toluene, xylene and the like. Further, obtained acid chloride in-situ reacts with 4-fluoroaniline to form compound of Formula (IV); The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Preferably, the compound of Formula (IV) formation may be carried out at 30 + 3 °C temperature.
In one embodiment, compound of Formula (IV) may be isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification. Preferably, compound of formula (IV) is isolated from MTBE.
In another embodiment of the present invention, step (b) may be carried out by reacting compound of Formula (III) and compound of Formula (IV) using coupling reagent such as O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU) , O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-Azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N’,N’-dimethylamino)propylcarbodiimide hydrochloride (EDC) and the like. Preferable coupling reagent is HBTU. The reaction may be carried out in the presence of catalyst such as 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU), diethanolamine (DEA), 1- hydroxybenzotriazole (HOBt), 7-aza-l-hydroxybenzotriazole (HOAt), N-Hydroxysuccinimide (HOSu). Preferable catalyst used for the step (C) is 4- dimethylaminopyridine(DMAP). The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as dimethylformamide (DMF), N,N’-dimethyl acetamide (DMAc), N-methyl pyrrolidine (NMP), acetonitrile (ACN), tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), dichloromethane (DCM), 1,2-dichloroethane, toluene, xylene and mixtures thereof. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Preferably, compound of Formula (I) formation may be carried out 25±5°C temperature.
In one embodiment, compound of Formula (I) may be isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification.
In another embodiment of the present invention, compound of Formula (I) can be converted into malate salt by reacting compound of Formula (I) with malic acid . The reaction may be carried out in the presence of an inert organic solvent including but not limited to alcoholic solvent such as ethanol methanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol and mixtures thereof. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Preferably, salt formation may be carried out 55±5°C temperature.
Further, obtained malate salt may optionally be purified if require by any known technique in the art. In another embodiment, malate salt may be crystallized in inert organic solvent such as methanol, ethanol, and isopropanol.
In one embodiment, the present invention provides a process for the preparation of compound of Formula (I) as represented schematically in scheme 4 as shown below.

Scheme 4
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material like N-acetyl-L-cysteine, SilaMetS thiol to remove metallic impurity, color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples:
Example-1: Preparation of 4-[(6,7-dimethoxyquinolin-4-yl)oxy] aniline.
4-chloro-6,7-dimethoxyquinoline (100 g, 1 eq. mole), 4-aminophenol (97.59 g, 0.8942 eq. mole), sodium hydroxide (35.77g) and sodium bromide (92.0 g) were added to dimethylsulphoxide (950 ml) at room temperature and stirred at 95-100°C. After completion of reaction, reaction mass was cooled to room temperature, water was added and the obtained solid was filtered to get 4-[(6,7-dimethoxyquinolin-4-yl)oxy] aniline. (Yield-91%)

Example-2: Preparation of 4-[(6,7-dimethoxyquinolin-4-yl)oxy] aniline.
4-chloro-6,7-dimethoxyquinoline (100 g, 1 eq. mole), 4-aminophenol (97.59 g, 0.8942 eq. mole), sodium hydroxide (35.77g) and sodium Iodide (67.06g) were added in to dimethylsulphoxide (950 ml) at room temperature and stirred at 95-100°C. After completion of reaction, reaction mass was cooled to room temperature, water was added and the obtained solid was filtered to get 4-[(6,7-dimethoxyquinolin-4-yl)oxy] aniline. (Yield-60.60%)

Example-3: Preparation of 1-[(4-fluorophenyl) carbamoyl] cyclopropanecarboxylic acid.
Cyclopropane-1, 1-dicarboxylic acid (100 g, 1 eq. mole) was added to methyl tert butyl ether (800 ml) at 30-35°C followed by triethylamine (79.0gm)) and thionyl chloride (89.0gm). The reaction mass was stirred at room temperature for 55-60 minutes. A solution of 4-fluoroaniline (104.0gm) in methyl tert butyl ether (300ml) was added to the reaction mixture and stirred the reaction mixture until completion of the reaction. After completion of reaction, the reaction mass was worked-up using aqueous sodium carbonate, pH adjustment of aqueous layer with conc. HCl & Filtered & dried to get 1-[(4-fluorophenyl) carbamoyl] cyclopropanecarboxylic acid. (Yield- 66.5%)

Example-4: Preparation of 1-[(4-fluorophenyl) carbamoyl] cyclopropanecarboxylic acid.
Cyclopropane-1, 1-dicarboxylic acid (100 g, 1 eq. mole) was added to THF (500 ml) at 30-35°C followed by triethylamine (79.0gm) and thionyl chloride (89.0gm). The reaction mass was stirred for at room temperature 55-60 minutes. A solution of 4-fluoroaniline (104.0gm) in THF (500ml) was added to the reaction mixture and stirred the reaction mixture until completion of the reaction. After completion of reaction, the reaction mass was worked-up using aqueous sodium carbonate, pH of Aqueous layer adjusted with conc. HCl followed by filtration to get 1-[(4-fluorophenyl) carbamoyl] cyclopropanecarboxylic acid. (Yield- 60.1%)

Example-5: Preparation of N-(4-((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl)-N’-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (Cabozantinib free base)
1-[(4-fluorophenyl) carbamoyl] cyclopropanecarboxylic acid (82.85 g) was added in dimethylformamide (400ml) at room temperature followed by addition of HBTU (140.77 g), 4-[(6,7-dimethoxyquinolin-4-yl) oxy]aniline (100 g) and DMAP (123.67 g) at room temperature and stirred. After completion of the reaction, water was added to reaction mass and the obtained residue was filtered to get N-(4-((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl)-N’-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide. (Yield-98%)

Example-6: Preparation of N-(4-((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl)-N’-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, (2S)-hydroxyl butanedioate (Cabozantinib-S- Malate)
N-(4-((6, 7-dimethoxyquinolin-4-yl) oxy) phenyl)-N’-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (100.0gm) was dissolved in methanol (2300ml) at 50-55 °C. A solution of L-malic acid (53.47) in methanol (200ml) was added into the reaction mass and stirred at 50-55 °C for 30 minutes with carbon treatment. After filtering carbon, reaction mass was cooled to room temperature and solid was filtered. Wet solid was dissolved in methanol (1200ml) at reflux temperature, gradually cooled to room temperature, filtered and dried to get pure Cabozantinib-S- malate salt. (Yield-68%)

Example-7: Preparation of 1, 2-dimethoxybenzene
Dimethyl sulphate was added to solution of catechol and potassium carbonate in acetone at room temperature and stirred at room temperature till reaction complies, followed by filtration and concentration of filtrate. The obtained mass was cooled, diluted with water and MDC, organic layer was separated and concentrated under vacuum to get 1, 2-dimethoxybenzene.

Example-8: Preparation of 1-(3, 4-dimethoxyphenyl) ethan-1-one
Aluminum chloride was added lot wise to a solution of 1, 2-dimethoxybenzene in MDC at -10°C, stirred for 30 mins, followed by addition of acetyl chloride and further stirred till completion of reaction. After the completion of reaction, reaction mass was added into cooled water, stirred for 30 minutes, organic layer separated and concentrated under vacuum to get 1-(3,4-dimethoxyphenyl)ethan-1-one.

Example-9: Preparation of 1-(4, 5-dimethoxy-2-nitrophenyl) ethan-1-one
Nitric acid was gradually added to solution of 1-(3, 4-dimethoxyphenyl) ethan-1-one was added in MDC at -10 °C and reaction mass was stirred till completion of reaction. After the completion of reaction, reaction mass was added into cooled water, stirred for 30 minutes, organic layer separated and concentrated under vacuum to crude compound. Crude compound was dissolved in ethyl acetate at 60°C, followed by slow addition of cyclohexane, isolation by filtration at room temperature, washing with cyclohexane and dried to obtain 1-(4, 5-dimethoxy-2-nitrophenyl) ethan-1-one.

Example-10: Preparation of 1-(2-amino-4,5-dimethoxyphenyl)ethan-1-one.
Zinc dust was added to a solution of 1-(4, 5-dimethoxy-2-nitrophenyl) ethan-1-one in methanol at room temperature followed by addition of ammonium acetate solution in water. Resulting reaction mass was stirred at room temperature till completion of reaction, filtered through Hyflo bed and concentrated the filtrate. The obtained reaction mass was partitioned between water and dichloromethane followed by concentrating organic layer to get crude compound. Crude compound was dissolved in ethyl acetate at 60°C, followed by slow addition of cyclohexane, isolation by filtration at room temperature, washing with cyclohexane and dried to obtain 1-(4, 5-dimethoxy-2-nitrophenyl) ethan-1-one.

Example-11: Preparation of 6,7- dimethoxyquinolin-4-ol
Sodium tert-butoxide was added to a solution of 1-(4, 5-dimethoxy-2-nitrophenyl) ethan-1-one in dichloromethane at room temperature followed by ethyl formate and stirred at room temperature. After completion of reaction, water was added to reaction mass, organic layer was separated followed by pH adjustment of aqueous layer with conc. HCl pH (~7.0-8.0). The obtained precipitate was filtered, washed with process water and dried to obtain 6, 7- dimethoxyquinolin-4-ol.

Example-12: Preparation of 4-chloro-6, 7-dimethoxyquinoline
Phosphorus oxychloride was added to a solution of 6, 7- dimethoxyquinolin-4-ol was added in dimethylformamide at 55°C and stirred at 100° C and stirred till completion of reaction. After completion of reaction, reaction mass was added into chilled water, pH adjusted with sodium carbonate, filtered, washed with water and dried to get 4-chloro-6, 7-dimethoxyquinoline.

Example-13: Preparation of cyclopropane-1,1-dicarboxylic acid
Mixture of diethyl malonate, tetrabutylammonium bromide, dibromoethane were added to sodium hydroxide solution in water at room temperature and the reaction mass was stirred till completion of reaction. The reaction mass was partitioned with ethyl acetate and water followed by layer separation and distillation to obtain diethyl cyclopropane-1,1-dicarboxylic acid.
Mixture of diethyl cyclopropane-1,1-dicarboxylic acid, water and sodium hydroxide at room temperature was stirred till completion of reaction. Reaction mass pH was adjusted below 2.0 with Conc. HCl, extracted with n-butanol followed by layer separation, distillation. The obtained residue was stirred with toluene followed by distilling out toluene. The obtained residue was further stirred with cyclohexane at room temperature followed by filtration and dried to obtain cyclopropane-1,1-dicarboxylic acid.

Dated this: 22th March, 2023 Dr. S. Ganesan
Alembic Pharmaceutical Ltd.
,CLAIMS:We claim:
1. An improved process for the preparation of Cabozantinib-S- malate, comprising the steps of:
a) reacting compound of Formula (II) with 4-aminophenol in presence of a suitable base in a suitable solvent and in presence of suitable catalyst to get compound of Formula (III);

b) reacting compound of Formula (III) with compound of Formula (IV) to get compound of Formula (I); and

c) treating the compound of formula (I) with L-malic acid in methanol, optionally, followed by purifying the obtained compound in methanol to provide cabozantinib (S)-malate compound of formula- la.

2. The process as claimed in claim- 1, wherein the suitable base used in step-a) is selected from group of sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), ammonium hydroxide (NH4OH), sodium hydride (NaH) and potassium hydride (KH).

3. The process as claimed in claim- 1, wherein, in the suitable solvent used in step-a) is selected from group of N, N-dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N’-dimethyl acetamide (DMAc), N-methyl pyrrolidine (NMP), acetonitrile (ACN), toluene, xylene, methyltertbutylether (MTBE), diethylether, cyclopentyl methyl ether, dichloromethane (DCM), 1,2-dichloroethane, ethyl acetate, isopropyl acetate, acetone, and mixtures thereof.

4. The process as claimed in claim- 1, wherein the suitable catalyst used in step-a) is selected from group of sodium bromide (NaBr), sodium iodide (NaI), potassium iodide (KI) and potassium bromide (KBr).

5. The process as claimed in claim- 1, wherein the compound of Formula (IV) used in step (b) is prepared by reacting cyclopropane-1, 1-dicarboxylic acid with 4-fluoroaniline in presence of thionyl chloride, triethyl amine and inert organic solvent to get compound of Formula (IV).

6. The process as claimed in claim- 5, wherein an inert organic solvent used is selected from the group of ether solvents such as methyltertbutylether (MTBE), diethylether, cyclopentyl methyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), and mixtures thereof.

Dated this: 22th March, 2023 Dr. S. Ganesan
Alembic Pharmaceutical Ltd.