DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of tivozanib or a pharmaceutically acceptable salt or a hydrate thereof. Particularly, the present invention relates to a process for the preparation of tivozanib hydrochloride or a hydrate thereof. The present invention also provides a process for the purification of tivozanib or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
The chemical name of tivozanib hydrochloride is 1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea hydrochloride, which is represented by the compound of formula I (the compound I). The free base, tivozanib represented by the compound of formula II (the compound II) is described in U.S. Pat. No. 6,821,987.

I II

Tivozanib hydrochloride (the compound I) is indicated for the treatment of advanced renal cell carcinoma (RCC), and is marketed in the USA as FOTIVDA® in capsule dosage form for oral administration.
Various processes for the preparation of tivozanib hydrochloride are reported in the art.
U.S. Pat. No. 6,821,987 discloses a process for the preparation of tivozanib free base (referred to herein as a compound of formula II or the compound II), wherein 2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline is treated with triphosgene in chloroform in the presence of triethylamine followed by treatment with 3-amino-5-methylisoxazole to obtain tivozanib (the compound II).
U.S. Pat. No. 7,166,722 discloses a process for the preparation of tivozanib (the compound II) wherein 3-amino-5-methylisoxazole is treated with phenyl chloroformate in N,N-dimethylacetamide in the presence of pyridine resulting in the formation of phenyl(5-methylisoxazol-3-yl)carbamate, which without isolation is treated with 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline to obtain tivozanib (the compound II).
There are certain disadvantages associated with the processes for the preparation of tivozanib or salts thereof, reported in the art, for instance, the process involving use of hazardous chemicals such as triphosgene is not recommended for use at commercial scale. There are other reported processes for the preparation of tivozanib that result in the formation of undesired by-products or impurities which affect the quality of the product.
It is a known fact that providing drug substances having high purity is considered a critical aspect in the pharmaceutical industry, particularly for ensuring the safety, efficacy and consistency of the pharmaceutical composition containing the drug substance.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of tivozanib (the compound II) or a pharmaceutically acceptable salt thereof represented by the following formula IA (the compound IA) or a hydrate thereof;

IA
wherein X is selected from the group consisting of HCl, HBr, HF, H2SO4, and H3PO4;
comprising the steps of:
(a) reacting 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III);

III
with an isolated 5-methylisoxazol-3-yl carbamate compound represented by the compound of formula IV (the compound IV);

IV
wherein R1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl; wherein the benzyl and phenyl are unsubstituted or substituted with Cl, Br or F;
to obtain tivozanib represented by the compound of formula II (the compound II);

II
(b) optionally, treating tivozanib (the compound II) with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, and phosphoric acid in a solvent to provide the corresponding pharmaceutically acceptable salt of tivozanib (the compound IA) or its hydrate.
Particularly, the present invention provides a process for the preparation of tivozanib represented by the compound of formula II (the compound II);

II
comprising:
reacting 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III);

III
with an isolated 5-methylisoxazol-3-yl carbamate compound represented by the compound of formula IV (the compound IV);

IV
wherein R1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl; wherein the benzyl and phenyl are unsubstituted or substituted with Cl, Br or F;
in a solvent, and at a temperature ranging from about 25°C to about 140°C to obtain tivozanib (the compound II); and
wherein tivozanib (the compound II) is substantially free of a dimer impurity represented by the compound of formula C (the Impurity C),

C
The present invention further provides a process for the preparation of a pharmaceutically acceptable salt of tivozanib represented by the following formula IA (the compound IA) or a hydrate thereof;

IA
wherein X is selected from the group consisting of HCl, HBr, HF, H2SO4, and H3PO4;
comprising the step of treating tivozanib (the compound II) with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, and phosphoric acid in a solvent to provide the corresponding pharmaceutically acceptable salt of tivozanib (the compound IA) or its hydrate;
wherein the pharmaceutically acceptable salt of tivozanib is substantially free of the dimer impurity (the Impurity C).
The present invention also provides a process for the preparation of 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III),

III
The present invention further provides tivozanib (the compound II), or a pharmaceutically acceptable salt (the compound IA) or a hydrate thereof, having chemical purity of at least 99% wherein the content of each of the compound of formulae A, B, C and D (as described herein) is from about 0.01% to about 0.5% w/w as measured by HPLC (High performance liquid chromatography).
Further, the present invention relates to a compound selected from the group consisting of the compounds of formulae A, B and C (as described herein).

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of tivozanib (the compound II) or a pharmaceutically acceptable salt represented by the compound of formula IA (the compound IA) or a hydrate thereof;

IX
wherein X is selected from the group consisting of HCl, HBr, HF, H2SO4, and H3PO4;
comprising the steps of:
a) reacting 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III);

III
with an isolated 5-methylisoxazol-3-ylcarbamate compound represented by the compound of formula IV (the compound IV);

IV
wherein R1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl; wherein the benzyl and phenyl are unsubstituted or substituted with Cl, Br or F;
to obtain tivozanib represented by the compound of formula II (the compound II); and

II
(b) optionally, treating tivozanib, the compound II with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, and phosphoric acid, in a solvent to provide the corresponding pharmaceutically acceptable salt of tivozanib (the compound IA) or its hydrate.
Particularly, the present invention provides a process for the preparation of tivozanib represented by the compound of formula II (the compound II);

II
comprising:
reacting 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III);

III
with an isolated 5-methylisoxazol-3-yl carbamate compound represented by the compound of formula IV (the compound IV);

IV
wherein R1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted with Cl, Br or F;
in a solvent, and at a temperature ranging from about 25°C to about 140°C to obtain tivozanib (the compound II); and
wherein tivozanib (the compound II) is substantially free of a dimer impurity represented by the compound of formula C (the Impurity C).

C
The term “isolated” as used herein in reference to 5-methylisoxazol-3-yl carbamate compound (the compound IV) means that the 5-methylisoxazol-3-yl carbamate compound is physically separated from the reaction mixture wherein it is formed.
The term “substantially free” as used herein, unless otherwise defined, indicates presence of the impurities selected from Impurity A, Impurity B, Impurity C or Impurity D in a range from about 0.01% to about 0.5% w/w (as measured by HPLC) in the target compound (e.g. tivozanib, pharmaceutically acceptable salt of tivozanib, the compound III etc.). For instance, the statement, “wherein tivozanib (the compound II) is substantially free of the dimer impurity C” means that the content of dimer impurity C in tivozanib (the compound II) obtained by the present invention is in a range from about 0.01% to about 0.5% w/w.
As used herein, the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.
In an embodiment, the solvent used in the reaction of the compound III with the isolated compound IV is selected from a hydrocarbon solvent, a chlorinated solvent, a nitrile solvent, an ester solvent, an ether, a ketone, a polar aprotic solvent, an alcohol, or a mixture thereof, and wherein the hydrocarbon solvent is selected from toluene, xylene, benzene, chlorobenzene, cyclohexane, or a mixture thereof; the chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform, or a mixture thereof; the nitrile solvent is selected from acetonitrile, propionitrile, butyronitrile, or a mixture thereof; the ester solvent is selected from ethyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, or a mixture thereof; the ether is selected from diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or a mixture thereof; the ketone is selected from acetone, cyclohexanone, methyl ethyl ketone, isobutyl ketone, or a mixture thereof; the polar aprotic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, or a mixture thereof; and the alcohol is selected from methanol, ethanol, n-propanol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, isobutyl alcohol; or a mixture thereof.
In an embodiment, the solvent used in the reaction of the compound III with the isolated compound IV is a hydrocarbon solvent selected from toluene, xylene, benzene, chlorobenzene, cyclohexane; or a mixture thereof.
In an embodiment, the reaction of the compound III with the isolated compound IV is carried out at a temperature ranging from about 40? to about 110?.
The compound of formula III (the compound III) is a key intermediate in the preparation of tivozanib (the compound II) and its pharmaceutically acceptable salts (the compound IA) or hydrate thereof.
In one embodiment, the compound of formula III (the compound III);

III
is prepared by a process comprising:
reacting 4-chloro-6,7-dimethoxy quinoline represented by a compound of formula VII (the compound VII);

VII
with 4-amino-3-chlorophenol represented by a compound of formula VIII (the compound VIII);

VIII
in a solvent and in the presence of a base; and wherein the base is used in a molar equivalent of about 0.8 to about 1.8 with respect to the compound VII, to provide 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (the compound III);
wherein the compound III is substantially free of an impurity represented by the compound of formula A (the Impurity A);

A
In an embodiment, in the preparation of the compound III, the solvent used is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, cyclopentyl methyl ether, or a mixture thereof.
In an embodiment, in the reaction of the compound VII with the compound VIII, the base is used in a molar equivalent of about 1.2 to about 1.7 with respect to the compound VII.
In an embodiment, in the preparation of the compound III, the base used in the reaction of the compound VII with the compound VIII is selected from potassium tertiary butoxide, sodium tertiary butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or sodamide.
In an embodiment, the base used in the reaction of the compound VII with the compound VIII is selected from potassium tertiary butoxide or sodium tertiary butoxide.
In another embodiment, in the preparation of the compound III, the reaction of the compound VII with the compound VIII is carried out at a temperature ranging from about 50°C to about 150°C.
In one embodiment, the compound of formula IV (the compound IV) used in the preparation of tivozanib (the compound II);

IV
wherein R1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted with Cl, Br or F;
is prepared by reacting 5-methylisoxazol-3-amine represented by the compound of formula V (the compound V) with a haloformate represented by the compound of formula VI (the compound VI);

V VI
wherein in the compound of formula VI, X is Cl, Br, I or F, and R1 is as defined above; in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, dichloroethane, benzene, toluene, xylene or cyclohexane.
In an embodiment, the compound VI is selected from group consisting of phenyl chloroformate, chlorophenyl chloroformate, bromophenyl chloroformate, fluorophenyl chloroformate, benzyl chloroformate, methyl chloroformate, ethyl chloroformate, 2,2,2-trichloroethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate, isobutyl chloroformate, tertiary butyl chloroformate, methyl fluoroformate, and ethyl fluoroformate.
In an embodiment, the compound VI is selected from phenyl chloroformate, methyl chloroformate, or ethyl chloroformate.
In an embodiment, in the preparation of the compound IV, the reaction of the compound V with the compound VI is carried out in the presence of an organic base selected from pyridine, lutidine, N,N-dimethylaniline, trimethylamine, triethylamine, N-ethyldiisopropylamine, piperidine, 4-N,N-dimethylaminopyridine, N,N-dimethylaniline, imidazole, or N-methyl imidazole.
As used herein, reference to “lutidine” encompasses 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine and 3,5-lutidine.
In another embodiment, in the preparation of tivozanib (the compound II), the isolated 5-methylisoxazol-3-yl carbamate (the compound IV) is used in an amount of about 6.5 to about 7.5 molar equivalent with respect to 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (the compound III).
In an embodiment, in the preparation of tivozanib (the compound II), the pH of the isolated 5-methylisoxazol-3-yl carbamate (the compound IV) ranges from 4 to 7.

In an embodiment, the present invention further provides a process for the preparation of a pharmaceutically acceptable salt of tivozanib represented by the following formula IA (the compound IA) or a hydrate thereof;

IA
wherein X is selected from the group consisting of HCl, HBr, HF, H2SO4, and H3PO4;
comprising the step of treating tivozanib (the compound II) with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, and phosphoric acid, in a polar aprotic solvent to provide the corresponding pharmaceutically acceptable salt of tivozanib (the compound IA) or its hydrate; and
wherein the pharmaceutically acceptable salt of tivozanib (the compound IA) is substantially free of the dimer impurity (the Impurity C).
The term “pharmaceutically acceptable salt” as used herein may be used interchangeably with the term “salt”, and includes the salts selected from the group consisting of hydrochloride, hydrobromide, hydrofluoride, hydrogen sulfate and phosphate salts of tivozanib.
In an embodiment, the polar aprotic solvent used in the process for the preparation of the pharmaceutically acceptable salt of tivozanib (the compound IA) or its hydrate, is selected from N,N-dimethylformamide or N,N-dimethylacetamide.
In an embodiment, in the process for the preparation of the pharmaceutically acceptable salt of tivozanib (the compound IA) or its hydrate, the acid is used in the form of an aqueous solution or in the form of a solution in an organic solvent selected from methanol, ethanol, isopropyl alcohol or n-butanol.
In another embodiment, the preparation of the compound IA or its hydrate is carried out at a temperature ranging from about 25°C to about 80°C.
In an embodiment, the present invention relates to a process for the preparation of tivozanib hydrochloride represented by the compound of formula I (the compound I);

I
comprising treating tivozanib (the compound II) with hydrochloric acid in a polar aprotic solvent to provide tivozanib hydrochloride (the compound I) or its hydrate; and
wherein the tivozanib hydrochloride (the compound I) or its hydrate is substantially free of the dimer impurity (the Impurity C).
The polar aprotic solvent used in the process for the preparation of the tivozanib hydrochloride (the compound I) is as described supra.
In an embodiment, in the process for the preparation of tivozanib hydrochloride (the compound I) or a hydrate thereof, the hydrochloric acid is used in the form of an aqueous solution or in the form of a solution in an organic solvent selected from methanol, ethanol, isopropyl alcohol or n-butanol.
In an embodiment, the present invention relates to a process for the preparation of tivozanib (the compound II); comprising the steps of:
A. reacting 4-chloro-6,7-dimethoxy quinoline represented by a compound of formula VII (the compound VII) with 4-amino-3-chlorophenol represented by a compound of formula VIII (the compound VIII) in a solvent and in the presence of a base,

VII VIII
wherein the base is used in a molar equivalent of about 0.8 to about 1.8 with respect to the compound VII to provide 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (the compound III);
B. reacting 5-methylisoxazol-3-amine (the compound V) with a haloformate (the compound VI) in a solvent in the presence of an organic base to provide the compound IV, which is isolated; and
C. reacting 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (the compound III) obtained in the step (A) with the isolated 5-methylisoxazol-3-yl carbamate (the compound IV) obtained in the step (B) in a solvent, and at a temperature ranging from about 25°C to about 140°C to provide tivozanib (the compound II);
wherein the compound III obtained in the step (A) is substantially free of an impurity represented by the compound of formula A (the Impurity A);

A
and wherein tivozanib (the compound II) is substantially free of a dimer impurity represented by the compound of formula C (the Impurity C);

C
In an embodiment, in the step (A), the base is used in a molar equivalent of about 1.2 to about 1.7 with respect to the compound VII.
In an embodiment, the solvent and the base used in the reaction step (A) are as described supra in reference to the process for the preparation of the compound III.
In another embodiment, the reaction in the step (A) is carried out at a temperature ranging from about 50°C to about 150°C.
In an embodiment, the solvent and the organic base used in the reaction step (B) are as described supra in reference to the process for the preparation of the compound IV.
In an embodiment, the solvent used the step (C) is as described supra in reference to the process for the preparation of tivozanib (the compound II).
In an embodiment, the reaction of the compound III with the isolated compound IV is carried out at a temperature ranging from about 40? to about 110?.
In an aspect, the present invention provides a process for the purification of tivozanib (compound II) comprising treating tivozanib with a solvent selected from an alcohol, an ester solvent, or a hydrocarbon solvent.
In an embodiment, the solvent used for purification is selected from an alcohol, which is selected from methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, sec-butyl alcohol, tert-butyl alcohol, and isobutyl alcohol; an ester, which is selected from ethyl acetate, butyl acetate, isopropyl acetate, and isobutyl acetate; or a hydrocarbon solvent, which is selected from benzene, toluene, xylene, cyclohexane and a mixture thereof.
It is a known fact that it is not always straightforward to remove impurities formed in the process for the preparation of a drug substance. The present inventors have found a method for the removal of the impurities (as described herein) which are formed in the process for preparation of tivozanib or its pharmaceutically acceptable salts, and its removal was found to be difficult. Particularly, the present inventors have found that the dimer impurity (the Impurity C) is more difficult to remove, and the present process of purification efficiently removes this impurity.
In another aspect, the present invention provides a process for the purification of tivozanib (the compound II) comprising the steps of:
(i) treating tivozanib (the compound II) with an aqueous solution of a metal sulfate or a metal halide in a solvent; and
(ii) isolating the pure tivozanib (the compound II) as obtained in the step (i).
The tivozanib free base (the compound II) used in the process for the purification of the present invention can be obtained by any process for its preparation known in the art. For instance, tivozanib base prepared by following the process described in U.S. Pat. No. 6,821,987 can be purified using the purification process of the present invention.
In an embodiment, the pure tivozanib (the compound II) obtained by the purification process of the present invention is optionally converted to its corresponding pharmaceutically acceptable salt (the compound IA) or a hydrate thereof as per the process described herein above.
As used herein, the term “pure”, unless otherwise defined, means that tivazanib (the compound II) or its pharmaceutically acceptable salt (the compound IA) has purity of at least 99%.
In an embodiment, the solvent used in the step (i) of the process for the purification of tivozanib (compound II) is an alcohol selected from methanol, ethanol, propanol, isopropyl alcohol, n-butanol, sec-butyl alcohol, tert-butyl alcohol, or isobutyl alcohol; or a hydrocarbon solvent selected from benzene, toluene, xylene, cyclohexane or a mixture thereof.
In another embodiment, in the step (i) of the purification process, tivozanib (compound II) is treated with the aqueous solution of metal sulfate or a metal halide, which is prepared without using any organic solvent, at a temperature ranging from about 20°C to about 100°C.
In an embodiment, the metal sulfate used in step (i) of the purification process is selected from copper sulfate pentahydrate or zinc sulfate heptahydrate.
In an embodiment, the metal halide used in step (i) of the purification process is selected from zinc chloride, zinc bromide, zinc iodide, copper chloride, copper bromide or copper iodide.
In an embodiment, the metal halide is selected from zinc chloride, zinc bromide or zinc iodide.
In an aspect, the present invention relates to a compound selected from the group consisting of the compounds of formulae A, B, and C;

A B
wherein, R1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted with Cl, Br or F;

C

The inventors of the present invention have identified the compounds of formulae A, B and C as three major impurities that are formed in the process for the preparation of tivozanib (the compound II) or pharmaceutically acceptable salt (the compound IA) or a hydrate thereof.
Further, the inventors of the present invention have also identified the following compound of formula D, which is also formed as an impurity in the process for the preparation of tivozanib (the compound II) or pharmaceutically acceptable salt (the compound IA) or a hydrate thereof.

D
The compounds of formulae A, B, C and D that are formed as impurities in the process for the preparation of tivozanib (the compound II) or a pharmaceutically acceptable salt (the compound IA) or a hydrate thereof are designated as Impurity A, Impurity B, Impurity C and Impurity D respectively.
In an embodiment, the Impurity B is a compound represented by the compound of formula B, wherein R1 is phenyl, which is unsubstituted or substituted with Cl, Br or F.
In yet another embodiment, the present invention provides tivozanib (compound II) or its pharmaceutically acceptable salt (the compound IA) or a hydrate thereof having chemical purity of at least 99% as measured by HPLC.
In yet another embodiment, the present invention provides tivozanib (compound II) or its pharmaceutically acceptable salt (the compound IA) or a hydrate thereof having chemical purity of at least 99.5% wherein the content of each of the Impurity A, B, C and D ranges from about 0.01% to about 0.5 % w/w as measured by HPLC.
In an embodiment, the present invention provides tivozanib (compound II) or its pharmaceutically acceptable salt (the compound IA) or a hydrate thereof obtained by the process of the present invention, wherein the having chemical purity of at least 99.5% wherein the content of each of the Impurity A, B, C and D ranges from about 0.01% to about 0.5 % w/w as measured by HPLC.
In an embodiment, the present invention provides a process for the preparation of tivozanib hydrochloride (the compound I) or a hydrate thereof; having chemical purity of at least 99% wherein the content of each of the Impurity A, B, C and D ranges from about 0.01% to about 0.5% w/w as measured by HPLC.
In another embodiment, the present invention provides a process for the preparation of hydrochloride salt of tivozanib i.e. tivozanib hydrochloride (the compound I) or a hydrate thereof; having chemical purity of about 99.5% wherein the content of each of the Impurity A, B, C and D ranges from about 0.01% to about 0.3 % w/w as measured by HPLC.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examples:
General Method:
1. HPLC method:
High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting chemical purity:
Column: Zorbax Eclipse XDB C8, 150 x 4.6mm, 5µm
Column Temperature: 35°C
Mobile phase:
Mobile Phase A: Buffer: Methanol (95:5 v/v)
Mobile Phase B: Methanol: ACN: Water (55:35:10, v/v)
Time (min) % Mobile Phase A % Mobile Phase B
0.01 100 00
05 100 00
20 50 50
30 20 80
45 20 80
45.1 100 00
50 100 00

Diluent: 0.1% O-Phosphoric acid: Methanol (70:30, v/v)
Flow Rate: 1.0 mL/minute
Detection: UV 225 nm
Injection Volume: 10?L
Example 1: Preparation of 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (Compound III):
In a clean and dry flask under nitrogen atmosphere, solution of 4-amino-3-chlorophenol (compound VIII, 50 g) in N,N-dimethylacetamide (335 ml) was cooled at a temperature of 0-5°C. Potassium tertiary butoxide (38.2 g, 1.63 mole equivalent) was added to the reaction mass in portions at a temperature of 0-5°C. The resulting reaction mass was stirred for 2 hours at a temperature of 0-5°C. 4-chloro-6,7-dimethoxyquinoline (compound VII, 46.72 g) was added to the reaction mass. The reaction mass was heated to 110-115°C, and stirred for 4 hours at the same temperature. Cooled the reaction mass to a temperature of 0-10°C. Added 650 ml of purified water and 650 ml of methanol to the reaction mass. The reaction mass was warmed to a temperature of 20-35 °C, and stirred for 2 hours. The reaction mass was filtered and washed with water (50 ml). To the wet material obtained, was added water (650 ml), stirred for 1 hour and filtered. Wet material was dried in vacuum oven at a temperature of 45-50°C.
Yield: 59 g
Purity: 97.98%
Impurity A: ? 0.50% (as measured by HPLC)

Example 2: Preparation of 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (Compound III):
In a clean and dry flask under nitrogen atmosphere, solution of 4-amino-3-chlorophenol (compound VIII, 100 g) in N,N-dimethyl acetamide (670 ml) was cooled at a temperature of 0-5°C. Potassium tertiary butoxide (77.73 g, 1.66 mole equivalent) was added to the reaction mass in portions at a temperature of 0-10°C. The resulting reaction mass was stirred for 2 hours at a temperature of 0-10°C. 4-chloro-6,7-dimethoxyquinoline (compound VII, 93.46 g) was added to the reaction mass. The reaction mass was heated to 110-115°C, and stirred for 4 hours at the same temperature. Cooled the reaction mass to a temperature of 0-15°C. Added 1300 ml of purified water and 1300 ml of methanol to the reaction mass. Reaction mass was warmed to a temperature of 20-30 °C, and stirred for 3 hours. The reaction mass was filtered and washed thrice with water (300 ml). Wet material was dried in vacuum oven at a temperature of 50-55°C.
Yield: 85 g
Purity: 98.7%
Impurity A: 0.24% (as measured by HPLC)
Comparative Example 2A: Preparation of 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (Compound III)
(using Potassium tertiary butoxide in excess moles (3.49 mole equivalent))
In a clean and dry flask under nitrogen atmosphere, solution of 4-amino-3-chlorophenol (compound VIII, 9.62 g) in N,N-dimethyl acetamide (80 ml) was cooled at a temperature of 0-5°C. Potassium tertiary butoxide (17.55 g, 3.49 mole equivalent) was added to the reaction mass in portions at a temperature of 0-5°C. The resulting reaction mass was stirred for 2 hours at a temperature of 0-5°C. 4-chloro-6,7-dimethoxyquinoline (compound VII, 10 g) was added to the reaction mass. The reaction mass was heated to 110-115°C, and stirred for 5 hours at the same temperature. Cooled the reaction mass to a temperature of 0-15°C. Added 84 ml of purified water and 84 ml of methanol to the reaction mass. Reaction mass was warmed to a temperature of 20-25°C, and stirred for 3 hours. The reaction mass was filtered and washed thrice with water (30 ml). Wet material was dried in vacuum oven at a temperature of 50-55°C.
Yield: 5 g
Purity: 85.73%
Impurity A: 11.95% (as measured by HPLC)

Example 3: Preparation of Phenyl carbamate of 5-methyl-1,2-oxazol-3-amine (Compound IV):
In a clean and dry flask, 5-methyl-1,2-oxazol-3-amine (compound V, 50 g) was added with N,N-dimethyl acetamide (500ml) and pyridine (164.2 g). The reaction mass was cooled to 0-10°C. Phenyl chloroformate (Compound VI, 65.86 g) was added to the reaction mass over a period of 30 minutes. The reaction mass was stirred for 30 minutes at a temperature of 0-10°C. Reaction mass was warmed to a temperature of 20-25°C and stirred for 4 hours. Reaction mass was cooled to a temperature of 0-10°C and water (1.0 Lit) was added slowly. Reaction mass was warmed to a temperature of 20-30°C and stirred for 2 hours. The solid obtained was filtered and dried in vacuum oven at a temperature of 45-50°C to get crude phenyl (5-methylisoxazol-3-yl)carbamate.
To the crude material obtained was added with 10% aq. Sodium bicarbonate solution & stirred for 2hr. Reaction mass was filtered and the wet material was further stirred with 3 N aqueous Hydrochloric acid solution. Reaction mass was filtered & washed with water (100 ml). The wet material was dried in vacuum oven for 12 hours at 45-50°C.
Yield: 62g
Purity: 99.5% (as measured by HPLC)

Example 4: Preparation of Phenyl carbamate of 5-methyl-1,2-oxazol-3-amine (Compound IV):
In a clean and dry flask, 5-methyl-1,2-oxazol-3-amine (compound V, 100g) was added with N,N-dimethyl acetamide (700ml) and pyridine (322.41 g). The reaction mass was cooled to 0-10°C. Phenyl chloroformate (Compound VI, 175.5 g) was added to the reaction mass over a period of 30 minutes. The reaction mass was stirred for 30 minutes at a temperature of 0-10°C. Reaction mass was warmed to a temperature of 20-25°C and stirred for 4 hours. Reaction mass was cooled to a temperature of 0-10°C and water (1.4 Lit) was added slowly. Reaction mass was warmed to a temperature of 20-30°C and stirred for 2 hours. The solid obtained was filtered, washed thrice with water (200 ml) and dried in vacuum oven at a temperature of 50-55°C to get crude phenyl (5-methylisoxazol-3-yl)carbamate.
To the crude material obtained was added with 3 N aqueous Hydrochloric acid solution (1200 ml). Reaction mass was filtered & washed thrice with water (300ml). The wet material was dried in vacuum oven for 12 hours at 50-55°C. The dried material was checked for pH 4.0 to 7.5.
Yield: 180 g
Purity: 99.77% (as measured by HPLC)

Example 5: Preparation 1-(2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea (Tivozanib, compound II)
In a clean and dry flask, 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (compound III, 5 g) was added with toluene (100 ml). Phenyl carbamate of 5-methyl-1,2-oxazol-3amine (compound IV, 22.98 g) was added to the reaction mass and reaction mass was heated to 75-80°C. Reaction mass was stirred for 12-14 hours at 75-80°C. Reaction mass was cooled to 20-25°C and was filtered to obtain the wet material. The wet material was dried in vacuum oven at 45-50°C to obtain crude 1-(2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl) urea (Tivozanib, compound II).
Yield: 28 g

Purification: Crude (Tivozanib, compound II) (7.0 g) was mixed with solution of ethyl acetate and ethanol (50:50; 35 ml) and heated to a temperature of 70-75°C for 20 hours. Reaction mass was cooled to 20-25°C. The reaction mass was filtered to obtain wet solid which was dried in vacuum oven at 45-50°C.
Yield: 0.63g
Purity: 99.30%, (as measured by HPLC)
Dimer Impurity (Impurity C): Below Detection Level (as measured by HPLC)
Impurity D: 0.28% (as measured by HPLC)

Example 6: Preparation 1-(2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea (Tivozanib, compound II)
In a clean and dry flask, 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (compound III, 100 g) was added with Toluene (2000 ml). Phenyl carbamate of 5-methyl-1,2-oxazol-3amine (compound IV, 461.88 g) was added to the reaction mass and reaction mass was heated to 75-80°C. Reaction mass was stirred for 10-14 hours at 75-80°C. Reaction mass was cooled to 20-25°C and was filtered to obtain the wet material. The wet material was dried in vacuum oven at 60-65°C to obtain crude 1-(2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl) urea (Tivozanib, compound II).
Yield: 380g
Dimer Impurity (Impurity C): 0.02% (as measured by HPLC)

Purification: Crude (Tivozanib, compound II) (350.0 g) was mixed with solution of ethyl acetate and ethanol (50:50; 3500 ml) and heated to 70-75°C for 15 minutes. Reaction mass was cooled to 15-20°C. Reaction mass was stirred for 10-14 hours at 15-20°C. Reaction mass was filtered to obtain wet solid which was washed twice with ethyl acetate and ethanol (50:50; 175 ml), and dried in vacuum oven at 50-55°C.
Yield: 60 g
Purity: 99.83%,
Dimer Impurity (Impurity C): Below Detection Level (as measured by HPLC)
Impurity D: Below Detection Level (as measured by HPLC)

Comparative Example for preparation of Tivozanib (compound II), using basic phenyl carbamate of 5-methyl-1,2-oxazol-3amine (compound IV):
In a clean and dry flask, 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (compound III, 5 g) was added with N,N-dimethyl acetamide (100 ml) and pyridine (2.3 g). Phenyl carbamate of 5-methyl-1,2-oxazol-3amine (compound IV, 16.4 g), having pH 8.4, was added to the reaction mass. Reaction mass was stirred for 10-14 hours at 20-30°C. Reaction mass was added with another two lots of Phenyl carbamate of 5-methyl-1,2-oxazol-3amine (compound IV, 1.64 g), having pH 8.4. Reaction mass was stirred for 2 hours at 20-30°C. Reaction mass was added with water (200 ml) and methanol (100 ml) and was stirred for 30 minutes. Reaction mass was filtered and washed with water (50 ml) to obtain the wet material. The wet material was dried in vacuum oven at 50-55°C to obtain 1-(2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl) urea (Tivozanib, compound II).
Yield: 10g
Dimer Impurity (Impurity C): 67.21% (as measured by HPLC)

Example 7: Preparation of Tivozanib hydrochloride monohydrate (compound I):
In a clean flask, solution of Tivozanib (compound II, 0.6 g) in N,N-dimethylformamide (4.2 ml) was heated to 60°C. Reaction mass was maintained at 60°C for 2 hours. The Reaction mass was cooled to 20-25°C and added with concentrated Hydrochloric acid (0.6ml) followed by addition of ethanol (16.8 ml) and water (1.68 ml) under stirring. The reaction mass was stirred for 30 minutes at 20-30°C and was further cooled to 0-5°C. Reaction mass was stirred for 12 hours at 0-5°C. The solid obtained was filtered and dried under vacuum at 45-50°C.
Yield: 0.46 g
Purity: 99.89%,
Dimer Impurity (Impurity C): Not detected (as measured by HPLC)

Example 8: Preparation of Tivozanib hydrochloride monohydrate (compound I):
In a clean flask, solution of Tivozanib (compound II, 100 g) in N,N-dimethylformamide (2400 ml) was heated to 60°C. Reaction mass was maintained at 60°C for 2 hours. The Reaction mass was cooled to 20-30°C and added with concentrated hydrochloric acid (100 ml) followed by ethanol (8600 ml) and water (864 ml) under stirring. The reaction mass was stirred for 60 minutes at 20-30°C and was further cooled to 0-5°C. Reaction mass was stirred for 15 hours at 0-5°C. The solid obtained was filtered, washed twice with mixture of ethanol and water (80:20, 100 ml) and dried under vacuum at 45-50°C.
Yield: 80 g
Purity: 99.95%,
Dimer Impurity (Impurity C): Not detected. (as measured by HPLC)
Impurity D: Below Detection Level. (as measured by HPLC)

Example 9: Purification of Tivozanib (Compound II)
In a clean flask solution of copper sulfate pentahydrate (0.55g) in water (12 ml) was added with crude Tivozanib (compound II, 1 g). Reaction mass was stirred at 20-30°C for 30 minutes. Reaction mass was added with ethanol (12ml) and was stirred at 75-80°C for 3 hours. The Reaction mass was cooled to 20-25°C. The solid obtained was filtered and dried under vacuum at 45-50°C for 12 hours.
Yield: 0.43g
Purity: 99.91%, (as measured by HPLC)
Dimer Impurity (Impurity C): Not detected (as measured by HPLC)

Example 10: Purification of Tivozanib (Compound II)
In a clean flask, a solution of Zinc sulfate heptahydrate (0.65g) in water (12 ml) was added to crude tivozanib (compound II, 1 g). The resulting reaction mass was stirred at a temperature of 20-30°C for 30 minutes. To the reaction mass, was added ethanol (12ml) and stirred at a temperature of 75-80°C for 3hours. The reaction mass was cooled to 20-25°C. The solid obtained was filtered and dried under vacuum at a temperature of 45-50°C for 12 hours.
Yield: 0.48 g
Purity: 99.78%, (as measured by HPLC)
Dimer Impurity (Impurity C): Not detected (as measured by HPLC)
Example: 11 The stability data of the Tivozanib hydrochloride monohydrate
Tivozanib hydrochloride monohydrate prepared by the process of present invention was subjected to stability studies at 25? ± 2?/ 60% ± 5% RH and at 40? ± 2?/ 75% ± 5% RH respectively for 3 months. Results of the stability studies are presented in the following Table 1.
Table 1
Impurity Time Period
Initial 3 Month at 25? ± 2?/ 60% ± 5% RH 3 Month at 40? ± 2?/ 75% ± 5% RH
Impurity A ND ND ND
Impurity B ND ND ND
Impurity C 0.05 ND ND
Impurity D BDL BDL ND
In the above table, RH- Relative humidity and ND – Not detected and BDL- Below detection limit.
,CLAIMS:We claim:
1. A process for the preparation of tivozanib represented by the compound of formula II (the compound II);

II
comprising:
reacting 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III);

III
with an isolated 5-methylisoxazol-3-yl carbamate compound represented by the compound of formula IV (the compound IV);

IV
wherein R1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted with Cl, Br or F;
in a solvent, and at a temperature ranging from about 25°C to about 140°C to obtain tivozanib; and
wherein tivozanib (the compound II) is substantially free of a dimer impurity represented by the compound of formula C (the Impurity C);

C
2. The process as claimed in claim 1, wherein the process further comprises the step of treating tivozanib (the compound II) with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, and phosphoric acid in a polar aprotic solvent selected from N,N-dimethylformamide or N,N-dimethylacetamide to provide the pharmaceutically acceptable salt of tivozanib (the compound IA) or its hydrate;

IA
wherein X is selected from the group consisting of HCl, HBr, HF, H2SO4, and H3PO4; wherein the pharmaceutically acceptable salt of tivozanib (the compound IA) is substantially free of the dimer impurity (the Impurity C).
3. The process as claimed in claim 1, wherein the solvent used in the reaction of the compound III with the isolated compound IV is a hydrocarbon solvent selected from toluene, xylene, benzene, chlorobenzene, cyclohexane or a mixture thereof.
4. The process as claimed in claim 1 or claim 3, wherein the isolated compound IV is used in an amount of about 6.5 to about 7.5 molar equivalent with respect to the compound III.
5. The process as claimed in claim 1, claim 3 or claim 4, wherein pH of the isolated compound IV ranges from 4 to 7.
6. The process as claimed in claim 1, wherein the compound of formula III (the compound III);

III
is prepared by a process comprising:
reacting 4-chloro-6,7-dimethoxy quinoline represented by a compound of formula VII (the compound VII);

VII
with 4-amino-3-chlorophenol represented by a compound of formula VIII (the compound VIII);

VIII
in a solvent and in the presence of a base, and wherein the base is used in a molar equivalent of about 0.8 to about 1.8 with respect to the compound VII to provide 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (the compound III);
wherein the compound III is substantially free of an impurity represented by the compound of formula A (the Impurity A);

A
7. The process as claimed in claim 6, wherein the base is selected from potassium tertiary butoxide, sodium tertiary butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or sodamide.
8. A process for the purification of tivozanib (the compound II) comprising the steps of:
(i) treating tivozanib (the compound II) with an aqueous solution of a metal sulfate or a metal halide in a solvent; and
(ii) isolating the pure tivozanib (the compound II) as obtained in the step (i).
9. The process as claimed in claim 8, wherein the metal sulfate is selected from copper sulfate pentahydrate or zinc sulfate heptahydrate; and the metal halide is selected from zinc chloride, zinc bromide, zinc iodide, copper chloride, copper bromide or copper iodide.
10. A compound selected from the group consisting of the compounds of formula A, B and C;

A B
wherein, R1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl, wherein the benzyl and phenyl is unsubstituted or substituted with Cl, Br or F;

C