Field of the Invention:
The present invention relates to novel crystalline form of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate compound of formula-1a.
H V7 H

Formula-1a The present invention also relates to novel crystalline forms of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
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 has been approved by the US FDA as COMETRIQ for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib chemically known as N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.
WO2005030140 A1 first disclosed Cabozantinib and process for its preparation.
WO2010083414 A1 discloses amorphous forms of Cabozantinib L- and D-malate as well as the N-1 and N-2 polymorphs of crystalline Cabozantinib L- and D-malate and process for its preparation.
Brief description of the Invention:
The first aspect of the present invention is to provide novel crystalline form of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, herein after designated as form-M and process for its preparation.
The second aspect of the present invention is to provide an improved process for the

like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), 2,6-lutidine, lithium diisopropylamide.
The "hydrochloric acid source" used herein the present invention is selected from hydrochloric acid gas, aqueous hydrochloric acid, ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid, diethylether- hydrochloric acid, and trimethylchlorosilane, ethanolic-HCl, methanolic-HCl.
The first aspect of the present invention provides a crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, characterized by its powder x-ray diffraction pattern having peaks at 6.4, 7.8, 8.6, 9.5, 10.4, 10.8, 12.0, 12.7, 13.4, 14.7, 16.0, 17.2, 17.5, 18.6, 20.2, 20.8, 21.5, 22.1, 22.7, 23.2, 24.1, 26.5, 26.8 and 27.2 ± 0.2 degrees two theta as depicted in figure-1.
Further the first aspect of the present invention also provides a process for the preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, comprising of:
a) Adding a suitable solvent to N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt of compound of formula-1b,
b) stirring the reaction mixture for 3 hours at 25-30°C,
c) filtering the reaction mixture and drying to get crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.

Wherein, in step-a) the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures thereof.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, comprising of:
a) Adding isopropanol to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluoro phenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt of compound of formula-1b,
b) stirring the reaction mixture for 3 hours at 25-30°C,
c) filtering the reaction mixture and drying to get crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
The second aspect of the present invention provides an improved process for the
preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclo
propane-1,1-dicarboxamide (S)-malate compound of formula-1a, comprising of the following steps:
a) Reacting 1-((4-fluorophenyl)carbamoyl)cyclopropane carboxylic acid compound of formula-2 with chlorinating agent in a suitable solvent to provide 1-(4-fluorophenyl carbamoyl)cyclopropanecarbonyl chloride compound of formula-3,
b) reacting the compound of formula-3 in-situ with 4-(6,7-dimethoxyquinolin-4-yloxy) aniline compound of formula-4 in the presence of a suitable base in a suitable solvent to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclo propane-1,1-dicarboxamide compound of formula-1,
c) treating the compound of formula-1 in-situ with a suitable hydrochloric acid source in a suitable solvent to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b,
d) purifying the compound of formula-1b using a suitable solvent,

e) treating the compound of formula-1b with a suitable base in a suitable solvent to
provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclo
propane-1,1-dicarboxamide compound of formula-1, which is treated with (L)-malic acid in a suitable solvent to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate compound of formula-1a.
Wherein, in step-a) the suitable chlorinating agent is selected from pivaloyl chloride, hionyl chloride, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus richloride, phosphorus pentachloride; in step-b) & step-e) the suitable base is selected from norganic or organic bases; in step-c) the suitable hydrochloric acid source is same as defined bove; in step-a) to step-e) the suitable solvent is selected from chloro solvents, alcohol olvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether olvents, ketone solvents, polar solvents such as water or mixtures thereof.
The preferred embodiment of the present invention provides an improved process for he preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclo ropane-1,1-dicarboxamide (S)-malate compound of formula-1a, comprising of the following teps:
a) Reacting 1-((4-fluorophenyl)carbamoyl)cyclopropane carboxylic acid compound of formula-2 with thionyl chloride in tetrahydrofuran to provide 1-(4-fluorophenyl carbamoyl)cyclopropanecarbonyl chloride compound of formula-3,
b) reacting the compound of formula-3 in-situ with 4-(6,7-dimethoxyquinolin-4-yloxy) aniline compound of formula-4 in the presence of potassium carbonate in a mixture of water and tetrahydrofuran to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide compound of formula-1,
c) treating the compound of formula-1 in-situ with aqueous hydrochloric acid to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b,
d) purifying the compound of formula-1b using isopropanol and then followed by using dimethyl sulfoxide and ethyl acetate,

e) treating the compound of formula-1b with aqueous sodium carbonate solution to
provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclo
propane-1,1-dicarboxamide compound of formula-1, which is treated with (L)-malic acid in a mixture of tetrahydrofuran, water and methyl isobutyl ketone to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate compound of formula-1a.
US7579473 B2 involves purification of crude Cabozantinib by preparative column chromatography which is expensive, tedious, time consuming and inevitably decrease yield of the product. Hence this process is not suitable for commercial scale. Therefore, there is an unmet need to develop a purification process which can be performed at industrial scale.
The present invention have overcame the problems associated with the prior art, by simply converting the crude Cabozantinib into its acid addition salt and then treating the acid addition salt of Cabozantinib with a suitable base to provide Cabozantinib free base compound of formula-1 with enhanced purity.
N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-
dicarboxamide (S)-malate compound of formula-1a obtained according to the present
invention is having 1-((4-((6,7-dimethoxyquinolin-4-yloxy)phenyl)carbamoyl)cyclopropane
carboxylic acid {M-Acid Impurity}; 1-((4-fluorophenyl)carbamoyl)cyclopropane carboxylic
acid {Acid Impurity}; N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-di
carboxamide {Hydroxy Impurity}; N-(4-((6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-phenyl cyclopropane-1,1-dicarboxamide {Desfluoro Impurity}; N-(4-((6,7-dimethoxyquinolin-4-yl oxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-dicarboxamide {2-Fluoro Impurity}; 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)-6,7-dimethoxyquinoline 1-oxide {N-Oxide Impurity}; N-(4-((6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(3-fluoro phenyl)cyclopropane-1,1-dicarboxamide {3-Fluoro Impurity}; and N-(4-((6,7-dimethoxy quinolin-4-yloxy)phenyl)-6,7-dimethoxyquinolin-4-amine {Dimer Impurity} less than 0.05% as measured by HPLC.


The third aspect of the present invention provides a crystalline form-S of N-(4-(6,7-imethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide ydrochloric acid salt compound of formula-1b, characterized by its powder x-ray diffraction attern having peaks at 5.1, 6.5, 7.9, 8.6, 9.7, 10.5, 12.8, 13.4, 15.2, 16.1, 17.2, 17.9, 18.5, 9.1, 19.4, 20.4, 20.9, 22.0, 23.0, 23.7, 24.8, 26.8, 28.4, 29.1, 29.8 and 40.6 ± 0.2 degrees two heta as depicted in figure-2.
The another embodiment of the present invention provides a process for the reparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-luorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, omprising of the following steps:

a) Adding a suitable solvent to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride compound of formula-1b,
b) stirring the reaction mixture,
c) filtering the reaction mixture,
d) adding a suitable solvent to the filtrate obtained in step-c),
e) stirring the reaction mixture,
f) filtering the precipitated solid and drying to get the crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
Wherein, in step-a) and step-d) the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures thereof.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, comprising of the following steps:
a) Adding dimethylsulfoxide to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride compound of formula-1b,
b) stirring the reaction mixture,
c) filtering the reaction mixture,
d) adding ethyl acetate to the filtrate obtained in step-c),
e) stirring the reaction mixture,
f) filtering the precipitated solid and drying to get the crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
The fourth aspect of the present invention provides a crystalline form-N of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloric acid salt compound of formula-1b, characterized by its powder x-ray diffraction

pattern having peaks at 4.0, 5.1, 6.3, 7.5, 8.0, 8.6, 9.4, 10.5, 11.2, 11.8, 12.6, 13.3, 13.5, 15.0, 15.3, 16.0, 16.3, 17.5, 17.9, 18.9, 19.9, 20.5, 21.2, 22.3, 22.7, 23.2, 23.8, 25.8, 26.4 and 27.4 ± 0.2 degrees two theta as depicted in figure-3.
The another embodiment of the present invention provides a process for the preparation of crystalline form-N of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, comprising of:
a) Adding a suitable solvent to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt of compound of formula-1b,
b) stirring the reaction mixture for 5 hours,
c) filtering the reaction mixture and drying to get crystalline form-N of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
Wherein, in step-a) the suitable solvent is same as defined in step-a) of the third aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, comprising of:
a) Adding isopropanol to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluoro phenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt of compound of formula-1b,
b) stirring the reaction mixture 5 hours,
c) filtering the reaction mixture and drying to get crystalline form-N of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
The fourth aspect of the present invention provides a crystalline form-R of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, characterized by its powder x-ray diffraction

pattern having peaks at 8.5, 9.3, 10.5, 11.6, 11.8, 12.1, 12.5, 12.9, 13.2, 13.7, 14.5, 15.5, 16.1, 16.8, 17.2, 17.6, 17.8, 19.3, 19.7, 20.0, 20.4, 21.3, 21.8, 22.2, 22.7, 23.2, 23.7, 24.0, 25.2, 25.7, 25.9, 27.0, 27.4, 27.6, 28.5, 30.0, 30.6, 31.9 and 32.3 ±0.2 degrees two theta as depicted in figure-4.
The another embodiment of the present invention provides a process for the preparation of crystalline form-R of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, comprising of the following steps:
a) Adding a suitable solvent to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide compound of formula-1,
b) adding suitable hydrochloric acid salt to the reaction mixture,
c) stirring the reaction mixture,
d) filtering the reaction mixture,
e) adding a suitable solvent to the compound obtained in step-d),
f) stirring the reaction mixture,
g) filtering the reaction mixture and drying to get the crystalline form-R of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
Wherein, in step-a) and step-e) the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures thereof; in step-b) the suitable hydrochloric acid source is same as defined in step-(c) of the second aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-R of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, comprising of the following steps:
a) Adding a mixture of tetrahydrofuran and ethyl acetate to N-(4-(6,7-dimethoxy
quinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
compound of formula-1,

b) adding aqueous hydrochloric acid salt to the reaction mixture,
c) stirring the reaction mixture,
d) filtering the reaction mixture,
e) adding isopropanol to the compound obtained in step-d),
f) stirring the reaction mixture,
g) filtering the reaction mixture and drying to get the crystalline form-R of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
The crude compound of formula-1 was treated with a suitable acid selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, p-toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid to provide its corresponding acid addition salt of compound of formula-1 and further neutralizing the acid addition salt of compound of formula-1 with a suitable base in a suitable solvent to provide pure compound of formula-1.
The sixth aspect of the present invention provides novel crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a, characterized by its powder x-ray diffraction pattern having peaks at 7.0, 7.4, 7.8, 9.4, 11.0, 11.4, 11.9, 12.6, 13.6, 14.0, 15.4, 15.6, 16.1, 17.2, 18.4, 19.2, 19.9, 21.1, 21.8, 22.1, 22.4, 23.1, 24.0, 24.2, 25.8, 26.2, 27.1, 27.6, 28.9, 29.3, 29.9, 30.1, 31.6, 32.5, 33.8, 35.3, 36.8, 37.6 and 39.9 ±0.2 degrees two theta as depicted in figure-5.
The another embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a, comprising of the following steps:
a) Adding a suitable solvent to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-

fluorophenyl)cyclopropane-1,1-dicarboxamide compound of formula-1,
b) heating the reaction mixture to a suitable temperature,
c) adding (L)-malic acid to the reaction mixture,
d) stirring the reaction mixture,
e) cooling the reaction mixture to a suitable temperature and stirring the reaction mixture,
f) filtering the precipitated solid and drying to get the crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a.
Wherein, in step-a) the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures thereof; in step-b) the suitable temperature is ranging from 30°C to reflux temperature of the solvent used in the reaction; in step-e) the suitable temperature is ranging from -50°C to 0°C.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a, comprising of the following steps:
a) Adding xylene to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide compound of formula-1,
b) heating the reaction mixture to 70-75°C,
c) adding (L)-malic acid to the reaction mixture,
d) stirring the reaction mixture,
e) cooling the reaction mixture to -50°C and stirring the reaction mixture,
f) filtering the precipitated solid and drying to get the crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a.
The another preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a, comprising of the following steps:

a) Adding n-heptane to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluoro phenyl)cyclopropane-1,1-dicarboxamide compound of formula-1,
b) heating the reaction mixture to 65-70°C,
c) adding (L)-malic acid to the reaction mixture,
d) stirring the reaction mixture,
e) cooling the reaction mixture to -50°C and stirring the reaction mixture,
f) filtering the precipitated solid and drying to get the crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a. The another preferred embodiment of the present invention provides a process for the
preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-luorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a, comprising of the following steps:
a) Adding methyl tert-butyl ether to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide compound of formula-1,
b) heating the reaction mixture to 50-55°C,
c) adding (L)-malic acid to the reaction mixture,
d) stirring the reaction mixture,
e) cooling the reaction mixture to -50°C and stirring the reaction mixture,
f) filtering the precipitated solid and drying to get the crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a. The preferred embodiment of the present invention provides a process for the
preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-luorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a, comprising of the following steps:
a) Adding toluene to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide compound of formula-1,
b) heating the reaction mixture to 70-75°C,
c) adding (L)-malic acid to the reaction mixture,

d) stirring the reaction mixture,
e) cooling the reaction mixture to -50°C and stirring the reaction mixture,
f) filtering the precipitated solid and drying to get the crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a.
N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate salt compound of formula-1a and hydrochloride salt compound of formula-1b respectively produced according to the present invention are useful in the preparation of pharmaceutical formulation.
N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate compound of formula-1a obtained according to the present invention is having particle size distribution D90 < 100 μm.
N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide compound of formula-1a and formula-1b produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The invention also encompasses pharmaceutical compositions comprising compound of formula-1 or salts thereof of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
P-XRD Method of Analysis: PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Kα radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. PSD method of Analysis: Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
The process described in the present invention was demonstrated in examples

illustrated below. These examples are provided as illustration only and therefore should not be
construed as limitation of the scope of the invention.
The process of the present invention can be represented schematically as follows:

Examples
Example-1: Preparation of crystalline form-M of Cabozantinib hydrochloride salt:
Thionyl chloride (180.4 gms) was slowly added to the mixture of 1-((4-fluorophenyl) carbamoyl)cyclopropane carboxylic acid (112.9 gms) and tetrahydrofuran (600 ml) at 25-30°C and stirred for 5 hours at the same temperature. The reaction mixture was slowly added to a pre-cooled mixture of 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (100 gms), aqueous potassium carbonate solution (418.5 gms of potassium carbonate in 600 ml of water) and

tetrahydrofuran (600 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Both the organic and aqueous layers were separated and water was added to the aqueous layer at 25-30°C. Extracted the aqueous layer with ethyl acetate. Combine the organic layers. Aqueous hydrochloric acid solution (75 ml of HCl in 725 ml of water) was added to the organic layer at 25-30°C and stirred the reaction mixture for 3 hours at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and ethyl acetate, To the obtained compound, isopropanol (22.0 lts) was added at 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 152 gms; Chloride content: 7.0%. The P-XRD pattern of the obtained compound was depicted in figure-1.
Example-2: Preparation of crystalline form-S of Cabozantinib hydrochloride salt:
Dimethyl sulfoxide (700 ml) was added to the obtained compound in example-1 at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the reaction mixture. Ethyl acetate (2.1 lts) was added to the obtained filtrate at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.
Yield: 169.3 gms; M.R: 185-190°C; Chloride content: 7.3%; Purity by HPLC: 99.83%. The P-XRD pattern of the obtained compound was depicted in figure-2.
Example-3: Preparation of Cabozantinib (S)-malate (Formula-1a):
A mixture of water (840 ml) and N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride (120 gms) was stirred for 10 minutes at 25-30°C. Aqueous sodium carbonate solution was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Tetrahydrofuran (900 ml) and ethyl acetate (900 ml) were added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted twice with tetrahydrofuran and ethyl acetate mixture. Combined the organic layers and washed with aqueous sodium chloride solution. Carbon powder was added to the organic layer at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with tetrahydrofuran. Distilled off the solvent completely from the obtained filtrate under reduced pressure and co-distilled

with tetrahydrofuran. To the obtained compound, tetrahydrofuran (1300 ml) and water (14 ml) were added at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 15 minutes at the same temperature. The reaction mixture was slowly added to a solution of L-malic acid (34.5 gms) and methyl isobutyl ketone (3.0 lts) and seeding crystals of at 25-30°C and stirred the reaction mixture for 3 hours at the same temperature. Filtered the reaction mixture and washed with methyl isobutyl ketone. To the obtained compound, methyl isobutylketone was added at 25-30°C and stirred for 3 hours at the same temperature. Filtered the reaction mixture, washed with methyl isobutylketone and dried to get the title compound. Yield: 113.2 gms; M.R: 182-187°C; Purity by HPLC: 99.98%.
M-Acid impurity: Not detected; Acid impurity: Not detected; Hydroxy impurity: Not detected; Desfluoro impurity: 0.04%; 2-fluoro impurity: Not detected; 3-fluoro impurity: Not detected; N-oxide impurity: Not detected and HIUI: 0.05%.
Before micronization: Particle size distribution: D90: 47.97 µm; D50: 8.82 µm; D10: 3.26 µm. After micronization: Particle size distribution: D90: 15.5 µm; D50: 7.4 µm; D10: 2.8 µm.
Example-4: Preparation of crystalline form-N of Cabozantinib hydrochloride salt:
Aqueous hydrochloric acid solution was added to N-(4-(6,7-dimethoxy quinolin-4-yl oxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide compound of formula-1 (163 gm) at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and ethyl acetate, To the obtained compound, isopropanol (2.2 lts) was added at 25-30°C and stirred for 5 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 152 gms; Chloride content: 6.4%. The P-XRD pattern of the obtained compound was depicted in figure-3.
Example-5: Preparation of crystalline form-R of Cabozantinib hydrochloride salt:
Tetrahydrofuran (1080 ml) and ethyl acetate (720 ml) was added to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (150 gms) at 25-30°C. Aqueous hydrochloric acid (67.5 ml of hydrochloric acid in 900 ml of water) was added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Filtered the reaction mixture and washed with a mixture of ethyl acetate and tetrahydrofuran. Washed the obtained compound with water and isopropanol. To the obtained

compound, isopropanol (2.0 lts) was added at 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 149.02 gms; M.R: 240-245°C; Chloride content: 6.3%; Purity by HPLC: 99.80%. The P-XRD pattern of the obtained compound was depicted in figure-4.
Example-6: Preparation of crystalline form-M of Cabozantinib (S)-malate salt:
A mixture of toluene (50 ml) and N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (5 gms) was stirred for 10 minutes at 25-30°C. Heated the reaction mixture to 70-75°C. L-malic acid (1.6 gms) was added to the reaction mixture at 70-75°C and stirred for 60 minutes at the same temperature. Cooled the reaction mixture to -50°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 4.0 gms; Malate content: 23.6%. The P-XRD pattern of the obtained compound was depicted in figure-5.
Example-7: Preparation of crystalline form-M of Cabozantinib (S)-malate salt:
A mixture of xylene (50 ml) and N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (5 gms) was stirred for 10 minutes at 25-30°C. Heated the reaction mixture to 70-75°C. L-malic acid (1.6 gms) was added to the reaction mixture at 70-75°C and stirred for 60 minutes at the same temperature. Cooled the reaction mixture to -50°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 4.5 gms; Malate content: 22.8%. The P-XRD pattern of the obtained compound was depicted in figure-5.
Example-8: Preparation of crystalline form-M of Cabozantinib (S)-malate salt:
A mixture of n-heptane (20 ml) and N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (2 gms) was stirred for 10 minutes at 25-30°C. Heated the reaction mixture to 70-75°C. L-malic acid (0.64 gms) was added to the reaction mixture at 70-75°C and stirred for 60 minutes at the same temperature. Cooled the reaction mixture to -50°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 1.2 gms; Malate content: 22.8%. The P-XRD pattern of the obtained compound was depicted in figure-5.
Example-9: Preparation of crystalline form-M of Cabozantinib (S)-malate salt:

A mixture of methyl tert-butyl ether (20 ml) and N-(4-(6,7-dimethoxyquinolin-4-yl oxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (2 gms) was stirred for 10 minutes at 25-30°C. Heated the reaction mixture to 50-55°C. L-malic acid (0.64 gms) was added to the reaction mixture at 50-55°C and stirred for 60 minutes at the same temperature. Cooled the reaction mixture to -50°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 1.2 gms; Malate content: 23.1%. The P-XRD pattern of the obtained compound was depicted in figure-5.
Example-10: Preparation of crystalline form-M of Cabozantinib (S)-malate salt:
A mixture of xylene (250 ml) and N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (25 gms) was stirred for 10 minutes at 25-30°C. Heated the reaction mixture to 70-75°C. L-malic acid (8.5 gms) was added to the reaction mixture at 70-75°C and stirred for 60 minutes at the same temperature. Cooled the reaction mixture to -50°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 24 gms. The P-XRD pattern of the obtained compound was depicted in figure-5.

We Claim:
1. A process for the preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate compound of formula-1a,
comprising of the following steps:
a) Reacting 1-((4-fluorophenyl)carbamoyl)cyclopropane carboxylic acid compound of formula-2 with chlorinating agent in a suitable solvent to provide 1-(4-fluorophenyl carbamoyl)cyclopropanecarbonylchloride compound of formula-3,
b) reacting the compound of formula-3 in-situ with 4-(6,7-dimethoxyquinolin-4-yloxy) aniline compound of formula-4 in the presence of a suitable base in a suitable solvent to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclo propane- 1,1-dicarboxamide compound of formula-1,
c) treating the compound of formula-1 in-situ with a suitable hydrochloric acid source in a suitable solvent to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b,
d) optionally purifying the compound of formula-1b using a suitable solvent,
e) treating the compound of formula-1b with a suitable base in a suitable solvent to provide N-(4-[(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclo propane-1,1-dicarboxamide compound of formula-1 which on in-situ treating with (L)-malic acid in a suitable solvent to provide N-(4-(6,7-dimethoxyquinolin-4-yl oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide (S)-malate compound of formula-1a.
2. The process as claimed in claim 2, wherein, in step-a) the suitable chlorinating agent is
selected from pivaloyl chloride, thionyl chloride, sulfuryl chloride, phosphorusoxy
chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride; in step-b) &
step-e) the suitable base is selected from inorganic or organic bases; in step-c) the
suitable hydrochloric acid source is selected from hydrochloric acid gas, aqueous
hydrochloric acid, ethanolic-HCl, methanolic-HCl, ethyl acetate-hydrochloric acid,
isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid, diethylether-
hydrochloric acid, and trimethyl chloro silane; in step-a) to step-e) the suitable solvent is

selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures thereof.
. A process for the preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (S)-malate compound of formula-1a, comprising of the following steps:
a) Reacting 1-((4-fluorophenyl)carbamoyl)cyclopropane carboxylic acid compound of formula-2 with thionyl chloride in tetrahydrofuran to provide 1-(4-fluorophenyl carbamoyl)cyclopropanecarbonylchloride compound of formula-3,
b) reacting the compound of formula-3 in-situ with 4-(6,7-dimethoxyquinolin-4-yloxy) aniline compound of formula-4 in the presence of potassium carbonate in a mixture of water and tetrahydrofuran to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide compound of formula-1,
c) treating the compound of formula-1 in-situ with aqueous hydrochloric acid to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b,
d) purifying the compound of formula-1b using isopropanol and then followed by using dimethyl sulfoxide and ethyl acetate,
e) treating the compound of formula-1b with aqueous sodium carbonate solution to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclo propane-1,1-dicarboxamide compound of formula-1 which on in-situ treating with (L)-malic acid in a mixture of tetrahydrofuran, water and methyl isobutyl ketone to provide N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclo propane-1,1-dicarboxamide (S)-malate compound of formula-1a.
. Crystalline forms of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide hydrochloride salt, which includes:
a) Crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluoro phenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, characterized by its powder x-ray diffraction pattern having peaks at 6.4, 7.8, 8.6, 9.5,

10.4, 10.8, 12.0, 12.7, 13.4, 14.7, 16.0, 17.2, 17.5, 18.6, 20.2, 20.8, 21.5, 22.1, 22.7, 23.2, 24.1, 26.5, 26.8 and 27.2 ± 0.2 degrees two theta as depicted in figure-1.
) Crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluoro phenyl)cyclopropane-1,1-dicarboxamide hydrochloric acid salt compound of formula-1b, characterized by its powder x-ray diffraction pattern having peaks at 5.1, 6.5, 7.9, 8.6, 9.7, 10.5, 12.8, 13.4, 15.2, 16.1, 17.2, 17.9, 18.5, 19.1, 19.4, 20.4, 20.9, 22.0, 23.0, 23.7, 24.8, 26.8, 28.4, 29.1, 29.8 and 40.6 ± 0.2 degrees two theta as depicted in figure-2.
) Crystalline form-N of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluoro phenyl)cyclopropane-1,1-dicarboxamide hydrochloric acid salt compound of formula-1b, characterized by its powder x-ray diffraction pattern having peaks at 4.0, 5.1, 6.3, 7.5, 8.0, 8.6, 9.4, 10.5, 11.2, 11.8, 12.6, 13.3, 13.5, 15.0, 15.3, 16.0, 16.3, 17.5, 17.9, 18.9, 19.9, 20.5, 21.2, 22.3, 22.7, 23.2, 23.8, 25.8, 26.4 and 27.4 ± 0.2 degrees two theta as depicted in figure-3.
) Crystalline form-R of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluoro phenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, characterized by its powder x-ray diffraction pattern having peaks at 8.5, 9.3, 10.5,
11.6, 11.8, 12.1, 12.5, 12.9, 13.2, 13.7, 14.5, 15.5, 16.1, 16.8, 17.2, 17.6, 17.8, 19.3,
19.6, 20.0, 20.4, 21.3, 21.8, 22.2, 22.7, 23.2, 23.7, 24.0, 25.2, 25.7, 25.9, 27.0, 27.4, 27.6, 28.5, 30.0, 30.6, 31.9 and 32.3 ±0.2 degrees two theta as depicted in figure-4.
rystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluoro henyl)cyclopropane-1,1-dicarboxamide (S)-malate compound of formula-1a, haracterized by its powder x-ray diffraction pattern having peaks at 7.0, 7.4, 7.8, 9.4, 1.0, 11.4, 11.9, 12.6, 13.6, 14.0, 15.4, 15.6, 16.1, 17.2, 18.4, 19.2, 19.9, 21.1, 21.8, 22.1, 2.4, 23.1, 24.0, 24.2, 25.8, 26.2, 27.1, 27.6, 28.9, 29.3, 29.9, 30.1, 31.6, 32.5, 33.8, 35.3, 6.8, 37.6 and 39.9 ±0.2 degrees two theta as depicted in figure-5.
process for the preparation of crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yl xy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt ompound of formula-1b, comprising of:

a) Adding isopropanol to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluoro phenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt of compound of formula-1b,
b) stirring the reaction mixture for 3 hours at 25-30°C,
c) filtering the reaction mixture and drying to get crystalline form-M of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
A process for the preparation of crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yl oxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, comprising of the following steps:
a) Adding a suitable solvent selected from alcohol solvents, ketone solvents, polar aprotic solvents, polar solvents like water or mixture thereof to N-(4-(6,7-dimethoxy quinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride compound of formula-1b,
b) stirring the reaction mixture and filtering the reaction mixture,
c) adding ester solvent to the filtrate obtained in step-b),
d) stirring the reaction mixture and filtering the precipitated solid to get the crystalline form-S of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclo propane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
A process for the preparation of crystalline form-N of N-(4-(6,7-dimethoxyquinolin-4-yl oxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, comprising of:
a) Adding isopropanol to N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluoro phenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt of compound of formula-1b,
b) stirring the reaction mixture for 5 hours and filtering the reaction mixture to get crystalline form-N of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluoro phenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.

9. A process for the preparation of crystalline form-R of N-(4-(6,7-dimethoxyquinolin-4-yl oxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide hydrochloride salt compound of formula-1b, comprising of the following steps:
a) Adding a suitable solvent selected from ether solvents, chloro solvents, ester solvents,
5 ketone solvents, hydrocarbon solvents, polar solvents like water or mixtures thereof to
N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide compound of formula-1,
b) adding aqueous hydrochloric acid to the reaction mixture,
c) stirring the reaction mixture and filtering the reaction mixture, 10 d) adding alcohol solvent to the compound obtained in step-c),
e) stirring the reaction mixture and filtering the reaction mixture to get the crystalline form-R of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclo propane-1,1-dicarboxamide hydrochloride salt compound of formula-1b.
15 10. A process for the purification of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide compound of formula-1, comprising of treating the compound of formula-1 with a suitable acid in a suitable solvent to provide its corresponding acid addition salt of compound of formula-1 and further neutralizing the acid addition salt of compound of formula-1 with a suitable base in a suitable solvent
20 to provide pure compound of formula-1.
Dated this day of December 2017.
25 Authorized Signatory
(Srinivasan Thirumalai Rajan)
MSN Laboratories Private Limited,
R&D Center
30 *********
26