DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Tivozanib hydrochloride hydrate compound of Formula-I.

Formula-I
BACKGROUND OF THE INVENTION
Tivozanib is a kinase inhibitor. Tivozanib hydrochloride, the active ingredient, has the chemical name 1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea hydrochloride hydrate.

Tivozanib Hydrochloride was approved by the US Food and Drug Administration (FDA) in March 2021, for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (RCC)., sold under the brand name Fotivda®.
US 6821987 discloses a process for the preparation of Tivozanib compound of Formula-Ia as illustrated in the Scheme-I below; first, 2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline compound of Formula-II is reacted with 3-amino-5-methylisoxazole compound of Formula-III in the presence of triphosgene and triethylamine in chloroform to obtain Tivozanib compound of Formula-I. Further, Tivozanib compound of Formula-I is purified by HPLC using chloroform/ acetone.

Scheme-I:

US 7166722 discloses a process for the preparation of Tivozanib hydrochloride hydrate compound of Formula-I as illustrated in the Scheme-II below; first, nitration of 3,4-Dimethoxyacetophenone compound of Formula-IV in the presence of nitric acid and sodium nitrite to obtain 3,4-dimethoxy-6-nitroacetophenone compound of Formula-V, which further undergoes nitro reduction in the presence of 5% palladium/carbon and a hydrogen gas in acetic acid and MeOH to obtain 2-amino-4,5-dimethoxyacetophenone compound of Formula-VI. Thereafter, compound of Formula-VI undergoes cyclization in the presence of Ethyl formate and sodium methoxide in THF to obtain 6,7-dimethoxy-4-quinolone hydrate compound of Formula-VII followed by chlorination in the presence of phosphorus oxychloride in toluene to obtain 4-chloro-6,7-dimethoxyquinoline compound of Formula-VIII. Further, the compound of Formula-VIII is reacted with 4-Amino-3-chlorophenol-HCl compound of Formula-IX in the presence of Potassium t-butoxide in N,N-dimethylacetamide to obtain 4-[(4-amino-3-chlorophenol)oxy]-6,7-dimethoxy- quinoline compound of Formula-II, which is further reacted with 3-amino-5-methylisoxazole compound of Formula-III in the presence of Phenyl chlorocarbonate and pyridine in N,N-dimethylacetamide to obtain Tivozanib compound of Formula-Ia.

Scheme-II:

US 7166722 also discloses crystalline Form I, Form-II and Form-III of Tivozanib mono hydrochloric acid salt of monohydrate.

There is still need for an improved, cost-effective, commercially scalable and environment-friendly process for the preparation of Tivozanib hydrochloride hydrate compound of Formula-I.

The objective of the Invention
The main objective of the present invention is to provide a simple, cost-effective process for the preparation of Tivozanib hydrochloride hydrate compound of Formula-I and its intermediate compounds of Formula-XI and Formula-II with high purity and overall yield.

Another objective of the present invention is to provide a process, which is simple, economical and suitable for industrial scale up.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of the Tivozanib hydrochloride hydrate compound of Formula-I,

Formula-I
comprising the steps of:
a) reacting 4-chloro-6,7-dimethoxyquinoline compound of Formula-VIII,

Formula-VIII
with 3-chloro-4-nitrophenol compound of Formula-X

Formula-X
in a suitable solvent to obtain 4-(3-chloro-4-nitrophenoxy)-6,7-dimethoxy- quinoline compound of Formula-XI

Formula-XI
b) reducing the compound of Formula-XI with zinc dust and ammonium chloride in a suitable solvent to obtain 4-[(4-amino-3-chlorophenol)oxy]-6,7-dimethoxyquinoline compound of Formula-II;

Formula-II
c) reacting 3-amino-5-methylisoxazole compound of Formula-III

Formula-III
with 1,1'-carbonyldiimidazole (CDI) in a suitable solvent to obtain N-(5-methylisoxazol-3-yl)imidazole-1-carboxamide compound of Formula-XII;

Formula-XII
d) reacting the compound of Formula-XII in situ with compound of Formula-II
in the presence of a suitable solvent to obtain Tivozanib compound of Formula-Ia;

Formula-Ia

e) treating the compound of Formula-Ia with hydrochloric acid in a suitable solvent to obtain the Tivozanib hydrochloride hydrate compound of Formula-I.

Another object of the present invention is crystalline Form-N of Tivozanib free base characterized in that its X-ray powder diffraction pattern has a 2theta value of 7.2±0.2°, 9.2±0.2°, 11.1±0.2°, 11.6°±0.2°, 12.5°±0.2°, 12.9°±0.2°, 14.3 15.3°±0.2°, 20.7°±0.2°, 21.2°±0.2°, 24.0°±0.2°, 24.8°±0.2° and 26.8°±0.2° there is a characteristic peak at 26.3°±0.2°.
Furthermore, the crystalline Form-N of Tivozanib free base is characterized in that its X-ray powder diffraction pattern is basically the same as that of FIG. 1.
Crystalline Form-N can be characterized by Differential Scanning Calorimetry (DSC) thermogram having endotherm at about 131.37±2°C and shown in Figure-2.
Description of the drawings:
Figure 1: Illustrates the XRPD diagram of crystalline Form-N of Tivozanib free base;
Figure 2: Illustrates the DSC chart of crystalline Form-N of Tivozanib free base.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of the Tivozanib hydrochloride hydrate compound of Formula-I, comprising the steps of:
a) reacting 4-chloro-6,7-dimethoxyquinoline compound of Formula-VIII, with 3-chloro-4-nitrophenol compound of Formula-X in a suitable solvent to obtain 4-(3-chloro-4-nitrophenoxy)-6,7-dimethoxy- quinoline compound of Formula-XI;
b) reducing the compound of Formula-XI with zinc dust and ammonium chloride in a suitable solvent to obtain 4-[(4-amino-3-chlorophenol)oxy]-6,7-dimethoxyquinoline compound of Formula-II;
c) reacting 3-amino-5-methylisoxazole compound of Formula-III with 1,1'-carbonyldiimidazole (CDI) in a suitable solvent to obtain N-(5-methylisoxazol-3-yl)imidazole-1-carboxamide compound of Formula-XII;
d) reacting the compound of Formula-XII in situ with compound of Formula-II in presence of a suitable solvent to obtain the Tivozanib compound of Formula-Ia;
e) Treating the compound of Formula-Ia with hydrochloric acid in a suitable solvent to obtain Tivozanib hydrochloride hydrate compound of Formula-I.

In step (a) of the present invention, wherein the solvent is selected from chlorobenzene, ortho-dichlorobenzene, toluene, xylenes, DMF, DMSO, DMAC, and/or a mixture thereof.

In step (a) of the present invention, the temperature at which the reaction is carried out is 110oC to 150°C for 24.0 to 25.0 hours, preferably 125oC to 130°C for 24.0 to 25.0 hours.

In step (a) of the present invention, the compound of Formula-XI is isolated from an organic solvent selected from Toluene, xylene, DMAC, DMSO, DMF, chlorobenzene, ortho-dichlorobenzene preferably chlorobenzene.

In step (b) of the present invention, wherein the solvent is selected from “alcohol solvents” such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and mixture thereof and/or THF and/or mixture thereof.

In step (b) of the present invention, the temperature at which the reaction is carried out is 50 oC to 70 oC for 2 to 4 hours, preferably 55oC to 60°C for 2.0 to 3.0 hours.
In step (b) of the present invention, compound of Formula-II is isolated from organic solvent selected from ethyl acetate, THF, methanol, ethanol, isopropanol, and/or mixture thereof.

In step (c) of the present invention, wherein the solvent is selected from “chlorinated solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, THF and toluene and/or mixture thereof.
In step (c) of the present invention, the temperature at which reaction is carried out is 25oC to 40°C for 3.0 to 8.0 hours, preferably 25°C-35oC & 35-40oC for 5 to 6 hours.
In step (c) of the present invention, the obtained compound of Formula-XII is directly used in the next reaction without isolation.
In step (d) of the present invention, wherein the solvent is selected from “chlorinated solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and/or mixture thereof.
In step (d) of the present invention, the temperature at which reaction is carried out is 25oC to 40°C for 5 to 10 hours, preferably 35°C to 40°C for 8.0 to 9.0 hours.
In step (d) of the present invention, Tivozanib compound of Formula-Ia is isolated from organic solvent selected from DMF, methanol, Acetone and/or mixture thereof.

In step (e) of the present invention, wherein the solvent is selected from “alcohol solvents” such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and mixture thereof and/or DMSO or water and/or mixture thereof. Preferably mixture of DMSO & Ethanol.
In step (e) of the present invention, the temperature at which the reaction is carried out is 30±5 ºC for 23-24hrs, preferably 30 to 32°C for 23 to 24 hours.

Another object of the present invention is crystalline Form-N of Tivozanib compound of Formula-Ia characterized in that its X-ray powder diffraction pattern has a 2? value of 7.2±0.2°, 9.2±0.2°, 11.1±0.2°, 11.6°±0.2°, 12.5°±0.2°, 12.9°±0.2°, 14.3±0.2°, 15.3°±0.2°, 20.7°±0.2°, 21.2°±0.2°, 24.0°±0.2°, 24.8°±0.2° and 26.8°±0.2°.
Furthermore, the crystalline Form-N of Tivozanib compound of Formula-Ia is characterized in that its X-ray powder diffraction pattern is basically the same as that of FIG. 1.
The DSC curve of the Crystalline Form-N of Tivozanib compound of Formula-Ia exhibits an endotherm at approximately 124.38°C. which is likely due to dehydration followed by an endotherm at approximately 231° C and shown in Figure-2.
Advantages of the present invention:
1. Crude tivozanib base material is purified by Acid-base purification method to control all the known and unknown impurities in a mixture of DMF and Methanol solvents;
2. Achieved purity of Tivozanib hydrochloride hydrate of Formula-I above 99.5% with 80% yield.

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
EXAMPLES:
EXAMPLE-1: Preparation of 4-(3-chloro-4-nitrophenoxy)-6,7-dimethoxy- quinoline compound of Formula-XI.
Chlorobenzene (1200 ml) was charged into 4 N RBF under stirring. 4-chloro-6,7-dimethoxyquinoline compound of Formula-VIII (200 g) and 3-chloro-4-nitrophenol compound of Formula-X (186.23 g) was further charged into the flask under stirring. The temperature of the reaction mass was raised to 125-130oC and maintained for 24-25 hrs. The reaction mass was cooled to 45-50°C after confirming the absence of starting material by HPLC, 10% NaOH solution (2000 ml) was added to the reaction mass under stirring and cooled to 25-35°C. The product was filtered on a Buchner funnel under vacuum and the wet cake was washed with 400 ml of DM water. The material was suction-dried for 20-30 min, and the wet material was unloaded. The weight of the obtained wet material was 325.0 g. The obtained wet material was recrystallized using mixture of Acetonitrile and DM water to obtain 4-(3-chloro-4-nitrophenoxy)-6,7-dimethoxyquinoline compound of Formula-XI (200.0g) with more than 99.5% purity.
Yield: 75%; Purity: 99.5% %

EXAMPLE-2: Preparation of 4-[(4-amino-3-chlorophenol)oxy]-6,7-dimetho- xyquinoline compound of Formula-II.
Methanol (2100 ml) and THF (2400 ml) were charged into 4 N RBF under stirring. 4-(3-chloro-4-nitrophenoxy)-6,7-dimethoxyquinoline compound of Formula-XI (150 g) was further charged into the flask under stirring. Zinc dust (244.7 g) and of Ammonium chloride (200.17g) were added to the reaction mass respectively under stirring at 25-35ºC. The temperature of reaction mass was raised to 55-60ºC and maintained for 2-3 hrs. The reaction mass was cooled to 50oC after conforming the absence of starting material by HPLC. The reaction mass was filtered on a Buchner funnel under vacuum in the hot condition and removed the catalyst. The wet cake was washed with 300 ml of THF. The obtained filtrate was transferred into 10 L 4 N RBF. The reaction mass was cooled to 25-35oC and aqueous ammonia solution was added to the reaction mass. The reaction mass was stirred for 20-30 min. DM water (2100 ml) was added to the reaction mass and stirred for 90-120 min.

The obtained product was filtered on a Buchner funnel under vacuum and washed with 300 ml of DM water (lot-II), suction dry for 20-30 min to obtain the wet material (150.0 g).
The above wet compound was purified from Ethylacetate to obtain 2-Chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]benzenamine 103 g with above 99.5%? purity.
Yield: 70%; Purity:99.5 %

EXAMPLE-3: Preparation of N-(5-methylisoxazol-3-yl)imidazole-1-carbox- amide compound of Formula-XII
Methylene chloride (825 ml) was charged into 4 N RBF under stirring. 3-amino-5-methylisoxazole compound of Formula-III (55 g) was further charged into the flask under stirring at 25-35ºC. 1,1'-carbonyldiimidazole (118.18 g) was added to the reaction mass under stirring. The temperature of reaction mass was maintained at 25-35ºC for 5-6 hrs. The reaction mass was filtered on a Buchner funnel under vacuum. The obtained wet cake was washed with Methylene chloride (110 ml) and suction dried for 5-10 min. Methylene chloride (550 ml) and obtained wet material were charged into 4 N RBF under stirred at 25-35ºC. The reaction mass was stirred for 30-45 min at 25-35°C and filtered on a Buchner funnel under vacuum. The obtained wet cake was washed with Methylene chloride (110 ml) and suction dried for 5-10 min. The wet material (90.0 g) was dried in vacuum oven at 25-35°C for 2-3 hrs. The weight of dry material is 82.0g. The dry material was directly used for the next stage.

EXAMPLE-4: Preparation of Tivozanib compound of Formula-Ia.
Methylene chloride (lot-I) (1275 ml) was charged into 4 N RBF under stirring. N-(5-methylisoxazol-3-yl)imidazole-1-carboxamide compound of Formula-XII (85 g) and 4-[(4-amino-3-chlorophenol)oxy]-6,7-dimethoxyquinoline compound of Formula-II (64.2 g) were further charged into the flask under stirring at 25-35ºC. The temperature of reaction mass was raised to 35-40ºC and maintained the reaction mass temperature at 35-40ºC for 8-9 hrs. DM water (850 ml) was added to the reaction mass at 35-41°C under stirring. The reaction mass was stirred for 45-60 min at 30-40°C. The reaction mass was filtered on a Buchner funnel under vacuum and washed with Methylene chloride (170 ml ) and suction dried for 20-30 min. The wet material was loaded into a dry petri dish. Wet weight:137 g. The wet material was dried in vacuum oven at 55-60°C for 7-8 hrs. The obtained dried material (105.0g) was purified by acid-base purification method using Conc HCl and aqueous sodium hydroxide solution followed by leaching with aqueous acetone to obtain N-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N'-(5-methyl-3-isoxazolyl)urea compound of Formula-Ia with 80% yield and above 99.5% purity.
Yield: 38.3 g (59.63%); Purity: 99.73%

EXAMPLE-5: Preparation of Tivozanib hydrochloride hydrate compound of Formula-I.
DMSO (420 ml) was charged into 4 N RBF under stirring. N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N'-(5-methyl-3-isoxazolyl)urea compound of Formula-Ia (70 g ) was further charged into the flask under stirring. The temperature of reaction mass was raised to 65-75ºC and maintained for 10-15 min. The reaction mass was filtered on a Buchner funnel followed by 0.45µm filter in hot conditions. The reaction mass was cooled to 25-35°C. Conc.HCl (16.95 g) was added to reaction mass at 25-35°C. Ethanol (490 ml) was added to the reaction mass at 25-35°C followed by DM water (980 ml ) was added to the reaction mass at 25-35°C. the reaction mass was maintained at 30±5°C for 23-24 hrs. The reaction mass was filtered on a Buchner funnel under vacuum and washed the wet cake with of 10% EtOH (140 ml) in water (v/v) followed by suction dried for 20-30 min. The obtained wet material (186.0 g) was dried in vacuum oven at 55-60°C for 17-18 hrs to obtain Tivozanib hydrochloride hydrate compound of Formula-I with 90% yield and above 99.5% purity.
,CLAIMS:We Claim:
1. A process for the preparation of Tivozanib hydrochloride hydrate compound of Formula-I,

Formula-I
comprising the steps of:
a) reacting 4-chloro-6,7-dimethoxyquinoline compound of Formula-VIII,

Formula-VIII
with 3-chloro-4-nitrophenol compound of Formula-X

Formula-X
in a suitable solvent to obtain 4-(3-chloro-4-nitro-phenoxy)-6,7-dimethoxy- quinoline compound of Formula-XI;

Formula-XI

b) reducing the compound of Formula-XI with zinc dust and ammonium chloride in a suitable solvent to obtain 4-[(4-amino-3-chlorophenol)oxy]-6,7-dimethoxyquinoline compound of Formula-II.

Formula-II
c) reacting 3-amino-5-methylisoxazole compound of Formula-III

Formula-III
with 1,1'-carbonyldiimidazole (CDI) in a suitable solvent to obtain N-(5-methylisoxazol-3-yl)imidazole-1-carboxamide compound of Formula-XII.

Formula-XII
d) reacting the compound of Formula-XII in situ with compound of Formula-II in the presence of a suitable solvent to obtain Tivozanib compound of Formula-Ia;

Formula-Ia

e) treating the compound of Formula-Ia with hydrochloric acid in a suitable solvent to obtain Tivozanib hydrochloride hydrate compound of Formula-I.
2. The process as claimed in claim 1, wherein, the suitable solvent used in step- (a) is selected from chlorobenzene, ortho-dichlorobenzene, toluene, xylenes, DMF, DMSO, DMAC, and/or mixture thereof,

3. The process as claimed in claim 1, wherein, the suitable solvent used in step- (b) is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol and THF and/or mixture thereof.

4. The process as claimed in claim 1, wherein, the suitable solvent used in step- (c) is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, THF and toluene and/or mixture thereof.

5. The process as claimed in claim 1, wherein, the suitable solvent used in step- (d) is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride and/or mixture thereof.

6. The process as claimed in claim 1, wherein, the suitable solvent used in step- (e) is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, DMSO or water and/or mixture thereof.

7. The process as claimed in claim 1, wherein, the Tivozanib compound of Formula-Ia obtained in step-(d) characterized by a PXRD pattern comprising the peaks at about 2? value of 11.6°±0.2°, 12.5°±0.2°, 12.9°±0.2°, 15.3°±0.2°, 20.7°±0.2°, 21.2°±0.2°, 24.0°±0.2°, 24.8°±0.2° and 26.8°±0.2°.