Claims:We Claim:
1) A process for the preparation of Cabozantinib (I) or its pharmaceutically acceptable salts

(I)
comprising the steps of:
e. reacting cyclopropane-1,1-dicarboxylic acid (1) in an organic solvent in presence

(1)

of base and thionyl chloride and 4-fluoro aniline (2) in an organic solvent at

(2)
temperature ranging between 0 to 30°C to get 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (3)

(3)

f. reacting 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (3) with 4-aminophenol in an organic solvent in presence of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) to get N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (4)

(4)

g. reacting N-(4-fluorophenyl)-N-(4-hydroxyphenyl) cyclopropane-1,1-dicarboxamide (4) with 4-chloro-6,7-dimethoxyquinoline (5) in the presence of an

(5)

organic solvent to get N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib (I)

(I)

h. optionally reacting N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib (I) with pharmaceutically acceptable acid in presence of organic solvent to get N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide pharmaceutically acceptable salt.

2) The process for the preparation of Cabozantinib (I) according to Claim – 1, wherein the base utilized in step a) is selected from inorganic base as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate or an organic base selected from triethylamine and pyridine.

3) The process for the preparation of Cabozantinib (I) according to Claim – 1, wherein the organic solvent is selected from ethylacetate, methanol, tetrahydrofuran, dimethylacetamide (DMA), chlorobenzene, dimethyl sulfoxide (DMSO) methylethylketone and water and/or mixtures thereof.

4) The process for the preparation of Cabozantinib (I) according to Claim – 1, wherein the step c) of reacting N-(4-fluorophenyl)-N-(4-hydroxyphenyl) cyclopropane-1,1-dicarboxamide (4) with 4-chloro-6,7-dimethoxyquinoline (5) is carried out using aqueous KOH and DMSO solvent or potassium tertiary butoxide in dimethyl acetamide (DMA) solvent.

5) The process for the preparation of Cabozantinib (I) according to Claim – 4, wherein the reacting N-(4-fluorophenyl)-N-(4-hydroxyphenyl) cyclopropane-1,1-dicarboxamide (4) in an organic solvent with 4-chloro-6,7-dimethoxyquinoline (5) is carried out at temperature ranging between 60-145°C for the time duration of 10-20 hours.

6) A process for the preparation of Cabozantinib (S)-malate salt

comprising reacting (S)-malic acid and cabozantinib (I) in presence of organic solvent at temperature ranging between 40-70°C to get N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt.

7) A process for the preparation of Cabozantinib malate salt according to claim 6, wherein organic solvent is selected from methylethyl ketone or MIBK.

8) A process for the preparation of Cabozantinib malate salt according to claim 6, wherein reaction is carried in heterogeneous phase using organic solvent is selected from methylethyl ketone or MIBK and water.

9) A process for the preparation of Cabozantinib malate salt according to claim 8, wherein heterogeneous phase of organic solvent and water has ratio of 5:1-2 (v/v).
, Description:FIELD OF THE INVENTION

The present invention relates to a commercially viable process for the preparation of Cabozantinib (I) which is useful in the treatment of patients with advanced renal cell carcinoma (RCC) and for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

BACKGROUND OF THE INVENTION
Cabozantinib is chemically described as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4¬ fluorophenyl)cyclopropane-1,1-dicarboxamide and is represented by structural formula I.

(I)

Cabozantinib Mesylate is a kinase inhibitor that selectively inhibits the tyrosine kinases c-Met and VEGFR2 and also inhibits AXL and RET. It is marked in the United States under the trade name CABOMETYX® and COMETRIQ® by Exelixis Inc. CABOMETYX® is approved by the FDA for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy and COMETRIQ® is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

Bannen, et. al in the patent US 7,579,473 B2 describes the quinazolines and quinolines which inhibit, regulate and/or modulate kinase receptor, particularly c-Met, KDR, c-Kit, flt-3 and flt-4, signal transduction pathways related to the changes in cellular activities and also provides methods for making such compounds and its compositions. It WO 2005030140 A2 disclosure, it also describes preparation of Cabozantinib by reacting 4-amino phenol and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid using EDCI in an organic solvent to produce N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide which upon reaction with trifluoromethanesulfonic acid 6, 7-dimethoxy-quinolin-4-yl ester using anhydrous 2, 6 – Lutidine to give N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib as given in the below Scheme.

Brown, et. al in the patent US 8,877,776 describes Cabozantinib malate salts and its crystalline and amorphous forms. In US 8,877,776 disclosure, it also describes preparation of Cabozantinib by reacting 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine and 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride under basic condition to get N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib and reacting this with malic acid to get Malate salts of Cabozantinib.
The route of synthesis of Cabozantinib as delineated in the disclosure as below:

Stefinovic, et. al in WO 2016150966 A1 describes the crystalline forms of Cabozantinib phosphate and Cabozantinib hydrochloride.

Jetti, et. al in the patent IN 2561/CHE/2014 describes the novel crystalline polymorph M1, M2, M3 and M4 of Cabozantinib (S)-malate and its process of the preparation.

Parthasaradhi Reddy, et. al in the patent IN 1967/CHE/2014 describes the novel crystalline form of Cabozantinib malate. It also describes the process for the preparation of Cabozantinib by reacting 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine and 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride under basic condition to get N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib as given in the scheme below.

Despite various prior disclosures of the processes for preparing Cabozantinib, they still suffer with one or more drawbacks including commercially non-viable processes, handling concerns in plant besides multistep impurities removal etc. Considering the therapeutic importance of Cabozantinib, there still exist needs to develop and provide an improved commercially viable process, which is robust and amenable to scale up resulting in improved quality characteristics of active pharmaceutical ingredient.

SUMMARY OF THE INVENTION
The invention disclosed in the specification relates to commercially viable process for preparation of anticancer compound Cabozantinib, which is presently approved for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy besides treatment of progressive, metastatic medullary thyroid cancer (MTC).
In one aspect according to the present invention, it relates to a new process for preparing Cabozantinib (I),

(I)

comprising the steps of:
a. reacting cyclopropane-1,1-dicarboxylic acid (1) in an organic solvent in presence

(1)
of base and thionyl chloride and 4-fluoro aniline (2) in an organic solvent at

(2)
temperature ranging between 0 to 30°C to get 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (3)

(3)
b. reacting 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (3) with 4-aminophenol in an organic solvent in presence of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) to get N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (4)

(4)
c. reacting N-(4-fluorophenyl)-N-(4-hydroxyphenyl) cyclopropane-1,1-dicarboxamide (4) with 4-chloro-6,7-dimethoxyquinoline (5) in the presence of an

(5)
organic solvent to get N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib (I)

(I)
d. optionally reacting N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib (I) with pharmaceutically acceptable acid in presence of organic solvent to get N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide pharmaceutically acceptable salt.
In yet another aspect, the present invention also relates to process for the preparation of pharmaceutically acceptable salts of Cabozantinib.
In yet further another aspect according to the present invention, it relates to a process for the purification of Cabozantinib (S)-malate, comprising:
i. combining Cabozantinib (S)-malate with methylethylketone solvent at temperature ranging between 50-60°C
ii. addition of activated charcoal to the reaction mixture of Cabozantinib (S)-malate and stirred at 50-60°C for 30-45 minutes
iii. filtering and cooling the solution of step (ii) and stirring for 20-24 hours to precipitate the solid and
iv. isolating the substantially pure Cabozantinib (S)-malate (I).
In yet further aspect, the present invention relates to substantially pure Cabozantinib (S)-malate (I) having purity greater than 99.8% and total impurities less than 0.2% by HPLC.

DETAILED DESCRIPTION OF THE INVENTION
In their endeavor for the present invention, it provides new commercially useful process for preparation of Cabozantinib (I).
In one embodiment according to the present invention, it provides process for preparing Cabozantinib (I),

(I)
Said process according to the present invention for the preparation of Cabozantinib (I) or its pharmaceutically acceptable salts, comprising the steps of:
a. reacting cyclopropane-1,1-dicarboxylic acid (1) in an organic solvent in presence

(1)
of base and thionyl chloride and 4-fluoro aniline (2) in an organic solvent at

(2)
temperature ranging between 0 to 30°C to get 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (3)

(3)
b. reacting 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (3) with 4-aminophenol in an organic solvent in presence of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) to get N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (4)

(4)
c. reacting N-(4-fluorophenyl)-N-(4-hydroxyphenyl) cyclopropane-1,1-dicarboxamide (4) with 4-chloro-6,7-dimethoxyquinoline (5) in the presence of an

(5)
organic solvent to get N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib (I)

(I)
d. optionally reacting N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib (I) with pharmaceutically acceptable acid in presence of organic solvent to get N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide pharmaceutically acceptable salt.

The individual steps of the process according to the present invention are detailed herein below; however more specifics are demonstrated by virtue of working examples given in the example section.
The process step (a) of reacting cyclopropane-1,1-dicarboxylic acid (1) with 4-fluoro aniline (2) is carried out in the presence of a base selected from the group consisting of inorganic base such as alkali metal hydroxide as potassium hydroxide, sodium hydroxide or an alkali metal carbonate as sodium carbonate, sodium bicarbonate and potassium carbonate or an organic base selected from triethylamine and pyridine.
In one of the specific embodiment, triethylamine was used.
The suitable organic solvents that can be used in step (a) are selected from ethylacetate, methanol, tetrahydrofuran, dimethylacetamide, chlorobenzene, dimethyl sulfoxide, methylethylketone and water and/or mixtures thereof in any proportion without limitation.
In particular embodiment of the present invention, tetrahydrofuran was used.
The process step (a) is performed at a temperature ranging between 0-10°C.
In one of the particular embodiment according to present invention, the process step (a) reaction was performed at temperature 0-5°C for a time duration of about 14-16 hours.
The mole ratios of reactants and the reagents used therein can be appropriate based on the resultant product and the side products or by products.

The organic solvents that can be used in the process step (b) are selected from ethylacetate, methanol, tetrahydrofuran, dimethylacetamide, chlorobenzene, dimethyl sulfoxide, methylethylketone and water and/or mixtures thereof in any proportion without limitation.
In one of the specific embodiment, dimethylacetamide (DMA) was used.
The process step (b) is performed at a temperature ranging between 0-30°C.
In one of the particular embodiment according to present invention, the process step (b) was performed at temperature 15-30°C for a time duration of about 14-16 hours.
The suitable organic solvents that can be used in the process step (c) are selected from ethylacetate, methanol, tetrahydrofuran, dimethylacetamide, chlorobenzene, dimethyl sulfoxide, methylethylketone and water and/or mixtures thereof in any proportion without limitation.
In one of the specific embodiment, chlorobenzene was used.
The process step (c) is performed at a temperature ranging between 60-145°C.
In one of the particular embodiment according to present invention, the process step (c) was performed at temperature 130-140°C for a time duration of about 16-20 hours using chlorobenzene as solvent.
In one particular embodiment according to present invention, the process step (c) was carried out using aqueous KOH and dimethyl sulfoxide (DMSO) solvent.
The process step (c) is performed at a temperature ranging between 60-90°C.
In one of the particular embodiment according to present invention, the process step (c) was performed at temperature 70-80°C for a time duration of about 16-20 hours using dimethyl sulfoxide solvent.
In yet another specific embodiment, the process step (c) was carried out using potassium tertiary butoxide and dimethylacetamide (DMA) solvent.
The process step (c) is performed at a temperature ranging between 90-120°C.
In one of the particular embodiment according to present invention, the process step (c) was performed at temperature 100-110°C for a time duration of about 16-20 hours using dimethylacetamide solvent.
The suitable organic solvents that can be used in the process step (d) is selected from ethylacetate, methanol, tetrahydrofuran, dimethylacetamide, chlorobenzene, dimethyl sulfoxide, methylethylketone and water and/or mixtures thereof in any proportion without limitation.
The suitable pharmaceutically acceptable acid that can be used in the process step (d) is (S)-malic acid.
In a particular embodiment according to present invention, the process step (d) was performed at temperature ranging between 40-70°C.
In one of the particular embodiment according to present invention, the process step (c) was performed at temperature 50-60°C for a time duration of about 3-4 hours.

In yet another embodiment, the present invention provides a process for the purification of Cabozantinib (S)-malate of Formula I, comprising:
i. combining Cabozantinib (S)-malate with methylethylketone solvent at temperature ranging between 50-60°C
ii. addition of activated charcoal to the reaction mixture of Cabozantinib (S)-malate and stirred at 50-60°C for 30-45 minutes
iii. filtering and cooling the solution of step (ii) and stirring for 20-24 hours to precipitate the solid and
iv. isolating the substantially pure Cabozantinib (S)-malate (I).
The step (i) of providing Cabozantinib (S)-malate solution, comprise adding / mixing crude / impure Cabozantinib (S)-malate obtained from any source into crystalline form at room temperature.
The solvent used for the dissolution of Cabozantinib (S)-malate in step (i) is selected from the group consisting of ketones as methylethylketone and MIBK or mixtures thereof or their aqueous mixtures.
The temperature required for dissolution can range from about 45-65°C.
The precipitation of solid in step (iii) is achieved but not limited to evaporation, cooling, drying, or by adding anti-solvent.
In yet another embodiment, the present invention provides substantially pure Cabozantinib (S)-malate having purity greater than 99.8% and total impurities less than 0.2% by HPLC
The term “substantially pure Cabozantinib (S)-malate” means that the Cabozantinib (S)-malate is at least 99% purity with less than 0.5 % of total impurities as measured by HPLC. More preferred is where the analytical purity is at least 99.5%; even further preferred is where the Cabozantinib may completely free of impurities.
The term “substantially pure Cabozantinib (S)-malate” refers to the total absence, or near total absence, of impurities, such as related-substance impurities. For example, when Cabozantinib (S)-malate is said to be substantially pure, there are either no detectable related-substance impurities, or if a single related-substance impurity is detected, it is present in an amount not greater than 0.1% by weight, or if multiple related-substance impurities are detected, they are present in aggregate in an amount not greater than 0.5% by weight.
In yet another embodiment according to present invention, the purity of substantially pure Cabozantinib (S)-malate more than 99.86%. In certain other worked lab processes, it was found to
The mole ratios of reactants and the reagents used therein can be appropriate based on the resultant product and the side products or byproducts.
For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
Advantageously, the process of present invention avoids the use of hazardous reagents thus making the process ecofriendly.
The reagents used herein the process of present invention are cheaper, commercially available and may not form impurities or side products unlike in the prior art processes.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
The processes reported for the preparation of Cabozantinib (I) in the art results in the formation of various impurities and byproducts leading to include additional purification steps intermittently at several stages thus resulting in very poor yields of the final product.
Advantageously, the process of present invention provides substantially pure Cabozantinib (I) with higher yields and purities by using novel intermediate process.
The present invention provides simple, ecofriendly, economical, reproducible, robust process for the preparation of Cabozantinib (I) which is well feasible on a commercial scale.
Advantageously, the process of present invention described herein has simple reaction steps, produces the intermediate surprisingly in high yields and purities than the processes reported in the literature and well amenable on commercial scale.
As used herein, the term "HPLC" refers to High-performance liquid chromatography. As used herein, the term "area % by HPLC" refers to the area in an HPLC chromatogram of one or more peaks compared to the total area of all peaks in the HPLC chromatogram expressed in percent of the total area.
Substantially pure Cabozantinib (S)-malate obtained by the process of present invention was analyzed by high performance liquid chromatography (HPLC) method with the conditions and instrument as given below,
Chromatographic conditions: The liquid chromatograph is equipped with a UV/PDA detector
HPLC Make: Agilent 1260 infinity
Column: Inertsil ODS-3V,
250 X 4.6 mm, 5.0?m
Wave length: 240nm.
Flow: 1.0mL/min.; Load: 20µL
Run time: 60 minutes. Column oven temperature: 25°C.
Concentration: 0.4mg/mL.
Diluent: Water : Acetonitrile
Ratio- (30:70 % v/v)

Buffer: Weigh about 1.36g of potassium dihydrogen phosphate and 1.0 ml of TEA in 1000 mL of Milli-Q-water, filter and degas through 0.45µ membrane filter.
Mobile phase-A: Buffer: Acetonitrile: Methanol (60:30:10) %v/v/v.
Mobile phase-B: Mixture of acetonitrile and water in the ratio of 900mL and 100mL.
Standard preparation: Weigh about 7.5mg of standard in 50mL V.F, dissolve in diluent and make up to mark with diluent.
System suitability solution: Transfer 1mL of above solution in 10 mL volumetric flask, mix well and make up to volume with diluent.
Sample preparation: Weigh about 7.5 mg of test sample in 50mL V.F, dissolve in diluent and make up to mark with diluent.
Procedure: Equilibrate the chromatographic system with mobile phase until stable baseline is observed. Then proceed for the analysis as per below mentioned sequence.
S.No. Name of the sample No. of injections
1. Blank 1 or 2
2. System suitability solution 1
3. Test solution 1
4. System suitability solution 1

Record the chromatograms for 60 min and measure the peak responses. Inhibit the peaks due to blank. The retention time for Cabozantinib (S)-malate peak is about 19 mins.
In another embodiment, the Cabozantinib (I) obtained by the processes of the present invention may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyloleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising Cabozantinib (I) obtained as per the process of present invention include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

Examples:
Example-1: Preparation of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (3):
To a stirred solution of cyclopropane-1,1-dicarboxylic acid (1) (20g, 0.1538 mol) in THF (120 mL) was added triethylamine (16 g, 0.1584 mol) at 0oC-5oC under inert atmosphere. The reaction mixture was stirred for 25-30 min and then thionyl chloride (18g, 0.1512 mol) was added at 0o-5oC. The reaction mixture was stirred for 3-4h at 0o-5oC and then 4-fluoro aniline (2) (18g, 0.1621 mol) in THF (50 mL) was added at 0o-5oC. The reaction mixture was warmed to room temperature and stirred for 14-16h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (200 mL) and organic layer washed with brine solution (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude solid. The solid was dissolved in methanol (80 mL) and water was added with stirring. The precipitated solid was filtered, washed with water and dried under vacuum to furnish 12g of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (3) as light brown solid. Yield: 12g (35%).
1H NMR (400 MHz, DMSO-d6): d 13.07 (br s, 1H), 10.58 (s, 1H), 7.64-7.60 (m, 2H), 7.16-7.11 (m, 2H), 1.40 (s, 4H). Mass (m/z): 221.9 (M-H).

Example-2: Preparation of N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (4):
To a stirred solution of 4-aminophenol (14.7 g, 0.134 mol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (3) (25 g, 0.112 mol) in DMA (150 mL) was added EDC. HCl (25.7 g, 0.134 mol) at room temperature. The reaction mixture was stirred at room temperature for 14-16h. After consumption of starting material, sat. aqueous NaHCO3 solution (1000 mL) was added to the reaction mixture at room temperature and stirred for 1h. The precipitated solid was filtered and washed with water (50 mL). The wet solid was dissolved in methanol (150 mL), treated with activated carbon and filtered through hyflo. Water was added to the filtrate and the precipitated solid stirred for 1h. The solid was filtered, washed with water (50 mL) and dried to afford 27g of N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide as an off-white solid. Yield: 27g (76.7%).
1H NMR (500 MHz, DMSO-d6): d 10.15 (s, 1H), 9.72 (s, 1H), 9.20 (s, 1H), 7.62 (q, J = 4.6 Hz, 2H), 7.35 (d, J = 9.0 Hz, 2H), 7.14 (t, J = 9.0 Hz, 2H), 6.68 (d, J = 9.0 Hz, 2H), 1.44 (d, J = 3.4 Hz, 4H). Mass (m/z): 313.11 (M-H).

Example-3: Preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Cabozantinib) (I):
To a stirred suspension of 4-chloro-6,7-dimethoxyquinoline (5) (3g, 0.0133 mol) in chlorobenzene (30 mL) was added N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (4) (6.2g, 0.0197 mol) at room temperature. The reaction mixture was heated to 140-145oC and stirred at the same temperature for 16-20h. The reaction mass was cooled and the solvent was removed under reduced pressure to obtain crude which was slurried in ethyl acetate to obtain N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib (I) (3.5g) as light brown solid. Yield: 3.5g (54%).
1H NMR (400 MHz, DMSO-d6): d 10.18 (s, 1 H), 10.05 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 7.76-7.72 (m, 2H), 7.68-7.62 (m, 2H), 7.50 (s, 1H), 7.39 (s, 1H), 7.28-7.21 (m, 2H), 7.18-7.12 (m, 2H), 6.44 (d, J = 5.5 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 1.47 (s, 4H). Mass (m/z): 502.0 (M+1)

Example – 4: Preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-2-hydroxysuccinate [Cabozantinib-(S)-malate]:
To a stirred suspension of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or Cabozantinib (I) (46g, 0.0918 mol) in methylethylketone (MEK) was added (S)-malic acid (17.2g, 0.1282 mol) at room temperature. The mixture was stirred for 5-10min, water (128 mL) was added and the reaction mixture was heated to 50-60oC. The reaction mixture was stirred at 50-60oC for 3-4h. Activated charcoal (4.6g) was added to the reaction mixture and stirred for 30-45min at 50-55oC. Filter the reaction mass through hyflo bed and washed with MEK (23 mL). Filtrate was concentrated under vacuum at 50-55oC upto 5-7 volumes of MEK remains in the flask. The crude material co-distilled with MEK (230 mL) twice upto 5-7 volumes of MEK remains in the flask. The remaining material cooled to 25-30oC and stirred for overnight. Filter the obtained solid, washed with MEK (138 mL) and dried the material to yield 43 g of N-(4-(6, 7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-2-hydroxysuccinate [Cabozantinib-(S)-malate] as an off-white solid. Yield: 43g (73.7%). Purity: 99.86% (Area % by HPLC).
1H NMR (400 MHz, DMSO-d6): d 10.17 (s, 1 H), 10.04 (s, 1H), 8.47 (d, J = 5.3 Hz, 1H), 7.78-7.74 (m, 2H), 7.66-7.62 (m, 2H), 7.50 (s, 1H), 7.39 (s, 1H), 7.26-7.21 (m, 2H), 7.18-7.12 (m, 2H), 6.44 (d, J = 5.3 Hz, 1H), ), 4.25 (dd, J = 7.7, 4.8 Hz, 1H), 3.94 (d, J = 6.5 Hz, 6H), 2.61 (dd, J = 15.7, 4.8 Hz, 1H), 2.46-2.40 (m, 1 H), 1.47 (s, 4H). Mass (m/z): 502.0 (M+1)

While the foregoing pages provide working example and detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.