DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of Cabozantinib S-malate using propanephosphonic acid anhydride as condensing agent in the reaction of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline compound of Formula IV and 1-[(4-fluorophenyl)carbamoyl]cyclopropane carboxylic acid compound of Formula V.

BACKGROUND OF THE INVENTION
Cabozantinib is an inhibitor of tyrosine kinase, chemically known as N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Formula I
represented by structural Formula:

-

Formula I

Cabozantinib is a kinase inhibitor indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC) and also indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy. Cabozantinib was approved by USFDA and marketed by Exelixis Inc under the brand name Cometriq® and Cabometyx®.
Cometriq® (Cabozantinib) capsules are supplied as printed hard gelatin capsules containing Cabozantinib (S)-malate equivalent to 20 mg or 80 mg Cabozantinib. Cabometyx® (Cabozantinib) tablets are supplied as film-coated tablets containing 20 mg, 40 mg, or 60 mg of Cabozantinib, which is equivalent to 25 mg, 51 mg, or 76 mg of Cabozantinib (S)-malate, respectively.

Cabozantinib and pharmaceutically acceptable salts were disclosed in U.S. Patent No. 7,579,473 (herein after referred as ‘473). US ‘473 describes a process for the preparation of Cabozantinib, the synthetic process is represented schematically as follows:

The process disclosed in US’473 involves the use of column chromatography for purification of Cabozantinib, which is expensive and time consuming process, and condensation reaction is carried out at higher temperature and provides Cabozantinib with low yield (for example 44 %). Hence the process is not suitable for commercial scale for industrial production.

U.S. Pat. No. 8,877,776 B2 discloses Cabozantinib (S)-malate salt and its processes of preparation thereof, the synthetic process is represented schematically as follows:

This process involves the usage of oxalyl chloride in the condensation of acid and amine intermediates to prepare Cabozantinib.

The use oxalyl chloride, which is irritant, has great pollution to the environment, generates more number of impurities, and hence difficult to handle at industrial production. One of such major impurity formed during preparation of Cabozantinib due to use of oxalyl chloride is represented structurally as follows:

-

Impurity I

Further the present inventors use of thionyl chloride in place of oxalyl chloride can also results in the formation of impurities such as Dimer impurity (Impurity II) and Desmethyl impurity (Impurity III) which are represented as follows:

-

Impurity II

Further thionyl chloride with pungent odour, can easily cause equipment corrosion. The chemical properties of the acid chloride are relatively active, resulting in heavier odours on site, which are not conducive to large-scale Industrial production. Further the use of thionyl chloride or oxalyl chloride, results in significant a yield loss due to purification.

Further the HCl generated during the condensation reaction using thionyl chloride/ oxalyl chloride may results in the formation of impurity which is represented structurally as follows:

-

Impurity IV

Further use of DMF as a catalyst along with thionyl chloride /oxalyl chloride may form by-product dimethylcarbamoyl chloride, which is human carcinogen.

Chinese patent publication CN 109836381 A discloses the synthesis of Cabozantinib, it involves the condensation of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine with l-(4-fluoro-phenyl carbamoyl)-cyclopropanecarboxylic acid using condensing agents in presence of an organic base and a polar organic solvent, wherein condensing agents selected from 2-(7-benzotriazideoxide)azole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU) and organic base is selected from triethylamine, N,N-diisopropylethylamine (DIEA). The reaction solvent is preferably one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone. This is represented schematically as follows:

This scheme involves usage of condensing agents such as HATU, HBTU, which are potent immune sensitizers. They may cause both skin and respiratory sensitization in the form of rashes and lesions (dermatitis) and coughing, sneezing, and throat-closing (anaphylaxis) reactions. Peptide condensing agents can modify human proteins, which is the most likely mechanism through which they cause immune sensitization. Hence, the said process is not suitable for commercial scale. Moreover the process results in formation of Cabozantinib with low purity.

US patent number US 11,498,902 B2 (herein after referred as ‘902) discloses the synthesis of Cabozantinib in examples 3 & 4, which is represented schematically as follows:.

This process involves the use of condensing agent such as EDC.HC1, and the obtained compound is purified by methanol and results in the formation of Cabozantinib with low purity. This condensing agent EDC.HC1, which is one of the potential genotoxic agents. The condensing agents also lead to the formation of by-products/impurities.

This publication also discloses PyBOP, PyBrOP, COMU as additional condensing agents which are also expensive and lead to impurities. In addition, the benzotriazole motif has been reported to exhibit explosive properties, making scale-up and work at high temperatures difficult

Chinese patent publication CN 110903240 discloses a process for preparation of Cabozantinib in examples 7 & 8, which is shown below:
Scheme I:

Scheme II:

which results in the formation of low pure Cabozantinib, even after purification using ethanol and water.

The prior art processes either use the acid chloride method or employ the condensation reagents for preparation of Cabozantinib via condensing of l-(4-fluoro-phenylcarbamoyl)-cyclopropane carboxylic acid or its corresponding acid chloride with 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine.

Disadvantages of methods involving usage of acid chloride:
• Involves use of either thionyl chloride or oxalyl chloride, which results in the formation of impurities such as Impurities I-IV
• results in formation of low pure Cabozantinib, which in-turn results in low yield due to extra purifications
• oxalyl chloride is irritant and environment pollutant hence not suitable for industrial application
• Thionyl chloride with its pungent odour, is carcinogenic and can easily cause equipment corrosion.
• Involves two steps reaction to complete the reaction.
• Results in the formation of dimethylcarbamoyl chloride, which is carcinogenic.

Disadvantages of usage of condensation reagents by acid-amine condensing method:
• DCC, HATU, HBTU and TBTU, which may cause allergic reactions, and therefore may arise Storage and handling problems.
• EDC.HCl is one of the potential genotoxic agent
• Condensing agents dicyclohexylcarbodiimide may results in the formation by product such as dicyclohexylurea which is insoluble in commonly used organic solvents makes the work –up process difficult
• Results in low pure Cabozantinib
• Safety parameters required for the highly sensitizing carbodiimide reagents,
• Explosion prone benzotriazole derivatives require specific attention.

It is therefore, needed to develop a process for preparing Cabozantinib by eliminating the steps of usage of acid chloride route or by usage of above mentioned condensation agents and provides a process is simple, reproducible and is well suited for industrial scale.

OBJECTIVES OF THE INVENTION

The object of the present invention to provide an improved process for preparation Cabozantinib, which avoids the usage of expensive and tedious column chromatography techniques.

Another object of the present invention to provide an improved process for preparation Cabozantinib, which avoids genotoxic and allergents.

Another object of the present invention to provide an improved process for preparation Cabozantinib, which involves the use of environmental friendly reagent.

Another object of the present invention to provide an improved process for preparation of Cabozantinib, which involves use of propanephosphonic acid anhydride, due to the solubility of its by products in water renders the process in easy work up and easy handling of the reagent on large scale

Another object of the present invention to provide an improved process for preparation of Cabozantinib involves the use of low toxicity, low allergenic potential, and non-inflammabilitity reagent.

Another object of the present invention to provide a safe, simpler & economical process for the preparation of Cabozantinib with high yield & purity.

SUMMARY OF THE INVENTION

The present invention relates to a process for preparation of Cabozantinib compound of Formula I,

-

Formula I

which comprises: condensing of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline compound of Formula IV

-

Formula IV
and 1-[(4-fluorophenyl)carbamoyl]cyclopropane carboxylic acid compound of Formula V

-
Formula V
in presence of condensing agent, a base in a suitable solvent, wherein condensing agent is propanephosphonic acid anhydride.

In another embodiment of the present invention provides a process for preparation of Cabozantinib S-malate, which comprises:
a) Chlorinating the 6,7-dimethoxy-quinoline-4-ol compound of Formula II

-

Formula II

with chlorinating agent in a solvent to provide 4-chloro-6,7-dimethoxy-quinoline compound of Formula III,

-

Formula III
b) reacting the compound of Formula III with 4-aminophenol in presence of base in a suitable solvent to provide 4-[(6,7-dimethoxy-4-quinolyl)oxy] aniline compound of Formula IV,

-

Formula IV
c) condensing of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline compound of Formula IV and 1-[(4-fluorophenyl)carbamoyl]cyclopropane carboxylic acid compound of Formula V

-
Formula V

in presence of condensing agent such as propanephosphonic acid anhydride, base in a suitable solvent provides Cabozantinib compound of Formula I,

-

Formula I
and;
d) converting Cabozantinib into its malate compound of Formula Ia.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for preparation of Cabozantinib compound of Formula I, which comprises: condensing of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline compound of Formula IV and 1-[(4-fluorophenyl)carbamoyl]cyclopropane carboxylic acid compound of Formula V in presence of condensing agent, a base in a suitable solvent, wherein condensing agent is propanephosphonic acid anhydride.

In another embodiment of the present invention the suitable solvent is dimethylformamide, dichloromethane, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, butyl acetate.

In another embodiment of the present invention the base is organic base such as triethyl amine and diisopropylethylamine.

In another embodiment of the present invention the reaction is carried out at a temperature 15-100°C, preferably at 25-35°C, for about 5-20 hours, preferably 8-10 hours.

In another embodiment of the present invention involves the use of propanephosphonic acid anhydride, which is green condensing reagent of low toxicity, low allergenic potential, and non-inflammabilitity and the molar ratio of propanephosphonic acid anhydride w,r,to 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline compound of Formula IV from about 0.1 to 2 mol%; preferably 0.942 mol %.
The main advantage of propanephosphonic acid anhydride in the condensation reaction, the bi- products of the condensation reaction are soluble in water and do not offer any difficulty in the workup. propanephosphonic acid anhydride possesses good solubility in common organic solvents and its remnants are highly soluble in aqueous solution, thus their complete removal can be achieved by simple aqueous washes.

In another embodiment of the present invention provides a process for preparation of Cabozantinib or its S-malate salt, which comprises: a) Chlorinating the 6,7-dimethoxy-quinoline-4-ol compound of Formula II with chlorinating agent in a solvent to provide 4-chloro-6,7-dimethoxy-quinoline compound of Formula III, b) reacting the compound of Formula III with 4-aminophenol in presence of base in a suitable solvent to provide 4-[(6,7-dimethoxy-4-quinolyl)oxy] aniline compound of Formula IV, c) condensing of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline compound of Formula IV and 1-[(4-fluorophenyl)carbamoyl]cyclopropane carboxylic acid compound of Formula V in presence of condensing agent such as propanephosphonic acid anhydride in presence of a base in a suitable solvent provides Cabozantinib compound of Formula I, and d) Optionally, converting Cabozantinib into its S-malate compound of Formula Ia.

In an another embodiment, the preparation of Cabozantinib or its S-malate salt, wherein in step-b) the chlorinating reagent is phosphorous oxychloride, the solvent is a mixture of toluene and dimethylformamide; step b) the base is sodium tert-butoxide or potassium tert-butoxide in dimethylformamide or dimethylacetamide; step c) the solvent is methylene dichloride; the base is organic base selected from triethylamine, diisopropyl ethylamine; step d) the conversion of Cabozantinib to its S-malate salt using L-malic acid in a solvent, wherein solvent is a mixture of methylene dichloride and methanol.

The details of the invention are given in the examples provided-below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

Examples:
Reference example 1: Preparation of Cabozantinib using oxalyl chloride in condensation step
Step 1) A stirred suspension of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (10.3 g, 0.043mol) and DMF (0.3 mL, 0.004mol) in THF (50 mL) was cooled in an ice-water bath. Oxalyl chloride (4.7 mL, 0.055 mol) was added slowly to the suspension to keep the reaction temperature below 10°C. When the addition was complete, the reaction mixture was stirred at room temperature for another 2 h. The solution was concentrated under vacuum to give 1-((4-fluorophenyl) carbamoyl)
cyclopropane-1-carbonyl chloride as a light yellow soild, which was used directly at the next step.

Step 2) To a stirred suspension of 4-((6,7-Dimethoxyquinolin-4-yl)oxy)aniline (8.4 g, 0.028 mol) in THF (80 mL) was added a solution of K2CO3 (8.3 g, 0.06 mol) in water (40 mL). The mixture was stirred at room temperature for 2 h. Then the carbonyl chloride 10 (0.043 mol) was added at room temperature and the reaction solution was stirred for 3 h. The stirring was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. To the remaining upper organic phase was added water (100 mL). Then the mixture was stirred at 15°C for 10 h. The solid was precipitated. The product was filtered and washed with a mixture of 2:1 (v/v) water/THF (20mL X 2). The crude product was dried at 60°C for 4 h. The dried product was then taken up in EtOAc: EtOH ¼ 1:1 (v:v) (50 mL) and heated to reflux for 30 min, then cooled to room temperature for 1 h, the resulting solid was filtered off and washed with EtOAc (20mL x 2), dried at 50°C for 3 h to afford 1 (11.5 g, 82%) as an off-white solid. purity by HPLC: 99.1%.

Reference example 2: Preparation of Cabozantinib using thionyl chloride in condensation step
A mixture of 1-[(4-fluorophenyl)carbamoyl]cyclopropane carboxylic acid (89.9 g), thionyl chloride (80.2 g), Tetrahydrofuran (500 ml), Dimethylformamide (5 ml) and stirred for 3 hours at 25-35°C. After the reaction was completed, the reaction mixture was added to a mixture of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 g), potassium carbonate (265.8 g), Tetrahydrofuran (1000 ml), water (500 ml) at 25-35°C and stirred for 1 hour. After the reaction was completed, the reaction mixture was treated with Carbon, filtered the reaction mixture, water was added to the filtrate obtained and stirred for 2 hours at 25-35°C. Filtered the reaction mixture and then dried to crude compound. Methanol (3000 ml) was added to the crude compound, heated to 65-70°C and stirred for 1 hour. Cooled the reaction mixture to 25-35°C and stirred for 2 hours. Filtered the solid and then dried to get pure title compound. Yield : 120 g. Purity by HPLC: 99.54 %; Dimer impurity: 0.08 % by HPLC

Reference example 3: Preparation of Cabozantinib in presence of HATU
1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (200 g, 0.90 mol), 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (340 g, 0.90 mol), DIEA (50 ml) and N-methylpyrrolidone (4 L) were added to the reaction flask, and 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (220 g, 0.74 mol) was added thereto with stirring, and the mixture was stirred at 70 ° C. The reaction is carried out for 3 to 4 hours. Water (8 L) was added to the reaction solution, and the mixture was stirred and crystallized at 10 to 20 ° C for 1 to 2 hours, filtered, and the filter cake was vacuum dried at 40 to 50 ° C for 23 to 24 hours to obtain 340 g of a white solid, yield 91.6%, HPLC purity 99.3. %

Reference example 4: Preparation of Cabozantinib in presence of HBTU
1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (200 g, 0.90 mol), O-benzotriazole-tetramethylurea hexafluorophosphate (307 g, 0.81 mol), DIEA (50 ml) N,N-dimethylacetamide (3 L) was added to the reaction flask, and 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (220 g, 0.74 mol) was added thereto with stirring, and the reaction was stirred at 70 ° C for 3 to 4 hours. Water (6 L) was added to the reaction mixture, and the mixture was stirred and crystallized at 10 to 20 ° C for 1 to 2 hours, filtered, and the filter cake was vacuum dried at 40 to 50 ° C for 23 to 24 hours to obtain 334 g of a white solid, yield 90.1%, HPLC purity 98.5. %.

Reference example 5: Preparation of Cabozantinib using EDC. HCl as condensing agent

100 L the reaction kettle of L, add 25kg of dichloromethane and 1.3kg of DMF, add 2.8kg of intermediate, 2.65kg of EDC hydrochloride, and 2.5kg of N, N-diisopropylethylamine. (4-amino phenoxy)-6,7-dimethoxyquinoline in dichloromethane (3.9kg dissolved in 25kg dichloromethane), the reaction is completed, washed with 2N hydrochloric acid 4.7kg, the organic layer is concentrated to recover dichloromethane Methane, residual ethanol and water were recrystallized and centrifuged and filtered to obtain 5.1 kg of Cabozantinib free base with a yield of 81.6% and a purity of 97.3%.

Reference example 6: Preparation of Cabozantinib using EDC. HCl as condensing agent
Step a) process for preparation of Cabozantinib
4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline hydrochloride (50 g) and dichloromethane (MDC) (750 mL) were charged into 4N RB flask under nitrogen atmosphere and stirred for 5 min at 25-30° C. The 1-[(4-fluorophenyl)carbamoyl]cyclopropanecarboxylic acid (36.87 g), dimethylaminopyridine (DMAP) (29.35 g) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl) (46 g) were added to the reaction mixture and stirred for 5 h at the same temperature. Water (750 mL) was added to the reaction mixture and further stirred for 2 h at 25-30° C. Filtered, washed the compound with water followed by MDC to get the title compound.
Step b) Process for the purification of Cabozantinib
Cabozantinib obtained in step a) and methanol (700 mL) were charged in 4N RB flask and stirred for 10 min at 25-30° C. Heated the reaction mixture to 60-65° C. and stirred for 30 min. Cooled the reaction mixture to 25-30° C. followed by methanol (350 mL) was added to the reaction mixture and stirred for 3 h at the same temperature. Filtered the compound and washed with methanol and dried to get the title compound. Yield: 56.91 g. Purity by HPLC: 99.45%.

Reference example 7: Preparation of Cabozantinib using DCC as condensing agent
100 L the reaction kettle of L, add 25 kg of dichloromethane and 1.3 kg of DMF, add 2.8 kg of 1-[(4-fluorophenyl)carbamoyl]cyclopropane carboxylic acid, DCC 3.36 kg, DMAP 0.16 kg, N, N-diisopropylethylamine 2.6 kg, dropwise add under room temperature stirring 4-(4-Aminophenoxy)-6,7-dimethoxyquinoline in dichloromethane (3.9kg dissolved in 25kg dichloromethane), the reaction is completed, washed with 2N hydrochloric acid 4.7kg, the organic layer is concentrated and recovered Chloromethane, residual ethanol and water were recrystallized, and centrifugal filtered to obtain 4.4 kg of Cabozantinib free base, with a yield of 70% and a purity of 95.2%.

Example 1: Preparation of 4-chloro-6,7-dimethoxyquinoline compound
A mixture of 6,7-dimethoxyquinoline-4-ol (100 g), POCl3 (149.5 g), toluene (1000 ml) and dimethylformamide (50 ml) was heated to 100-105°C and stirred for 5 hours. After the reaction was completed, distilled of the solvent, water was added to reaction mixture and cooled to 20-25°C. pH of the reaction mixture was adjusted using sodium hydroxide solution at 20-25°C and stirred for 2 hours. Filtered the solid and then dried to get title compound. Yield: 90 g.

Example 2: Preparation of 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline compound of Formula IV
Dimethyl acetamide (400 ml) followed by sodium tert-butoxide (85.8 g) were added to 4-chloro-6,7-domethoxyquinoline (100 g) at 25-35°C and stirred for 10 minutes. A solution of 4-aminophenol (73.1 g) in dimethylacetamide (600 ml) was added to the reaction mixture at 25-35°C. The reaction mixture was heated to 105-110°C and stirred for 22 hours. After the reaction was completed, water was added to reaction mixture at 25-35°C and stirred for 2 hours. Filtered the solid and then dried to get title compound. Yield: 110 g.

Example 3: Process for preparation of Cabozantinib compound of Formula I
A mixture of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline compound of Formula IV (100 g), 1-[(4-fluorophenyl)carbamoyl]cyclopropane carboxylic acid compound of Formula V (75 g) and methylene dichloride (1000 ml) was cooled to 0-10°C. N-ethyl diisopropyl ethylamine (130 g) followed by 50% propanephosphonic acid anhydride solution in ethyl acetate (300 ml) were added to reaction mixture at 0-10°C. The temperature of the reaction mixture was raised to 25-35°C and stirred for 10 hours. After completion of the reaction, water was added to reaction mixture and both

the layers were separated. The organic layer was separated and distilled off the solvent from organic layer and then cooled to 25-35°C. Methanol (500 ml) was added at 25-35°C and stirred for 2 hours. Filtered the compound, co-distilled with methylene dichloride and methanol and then cooled to 25-35°C. Methanol (500 ml) was added at 25-35°C and stirred for 2 hours. Filtered and then dried to get the title compound.

Yield: 105 grams; Purity by HPLC: 99.9 %; Dimer impurity: 0.03 % by HPLC.

Example 4: Process for preparation of Cabozantinib S-malate compound of Formula Ia
A mixture of Cabozantinib (60 g), methylene chloride (600 ml), methanol (600 ml) was stirred for 10 minutes at 25-30°C. L-malic acid (15.24 g) was added to the reaction mixture at 25-30°C and stirred for 4 hours. The reaction mixture was treated with carbon, filtered the reaction mixture and the obtained filterate was spray dried to get Cabozantinib malate compound of Formula Ia. Yield: 56 g.

Example 5: Comparison of HPLC purity profiles of Cabozantinib of present invention with prior art processes:

Reagents in condensation
Step thionyl chloride Oxalyl chloride HATU HBTU
EDC.HCl DCC Present invention
Purity of Cabozantinib
(by HPLC) 99.54 % 99.1%.
99.3 % 98.5% 97.3 %
99.45 %
(After purification) 95.2%. 99.9 %

,CLAIMS:We claim:
1. A process for preparation of Cabozantinib compound of Formula I,

-

Formula I

which comprises: condensing of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline compound of Formula IV

-

Formula IV
and 1-[(4-fluorophenyl)carbamoyl]cyclopropane carboxylic acid compound of Formula V

-
Formula V
in presence of condensing agent, a base in a suitable solvent, wherein condensing agent is propanephosphonic acid anhydride.

2. The process as claimed in claim 1, wherein suitable solvent is Dimethylformamide, Dichloromethane, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, butyl acetate.

3. The process as claimed in claim 1, wherein the base is organic base such as triethyl amine and diisopropylethylamine.

4. A process for preparation of Cabozantinib S-malate, which comprises:
a) Chlorinating the 6,7-dimethoxy-quinoline-4-ol compound of Formula II

-

Formula II

with chlorinating agent in a solvent to provide 4-chloro-6,7-dimethoxy-quinoline compound of Formula III,

-

Formula III
b) reacting the compound of Formula III with 4-aminophenol in presence of base in a suitable solvent to provide 4-[(6,7-dimethoxy-4-quinolyl)oxy] aniline compound of Formula IV,

-

Formula IV
c) condensing of 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline compound of Formula IV and 1-[(4-fluorophenyl)carbamoyl]cyclopropane carboxylic acid compound of Formula V

-
Formula V

as claimed in claim 1, provides Cabozantinib compound of Formula I,

-

Formula I
and;
d) converting Cabozantinib into its malate compound of Formula Ia.
5. The process as claimed in claim 4, wherein in step-a) the chlorinating reagent is phosphorous oxychloride, the solvent is a mixture of toluene and dimethylformamide; step b) the base is sodium tert-butoxide or potassium tert-butoxide in dimethylformamide or dimethylacetamide; step c) the solvent is methylene dichloride; the base is organic base selected from triethylamine, diisopropyl ethylamine; step d) the conversion of Cabozantinib to its S-malate salt using L-malic acid in a solvent, wherein solvent is a mixture of methylene dichloride and methanol.