DESC:“AN IMPROVED PROCESS FOR THE PREPARATION OF LENVATINIB”

FIELD OF THE INVENTION:
The present invention relates to an improved and economic industrial process for the preparation of amorphous form of Lenvatinib mesylate with reduced processing steps, high yield and stability. The present invention also relates to process for the preparation and purification of Lenvatinib wherein the process is simple with easily available solvents and reagents.

BACKGROUND OF THE INVENTION:
Lenvatinib is a kinase inhibitor having mechanism of action as a receptor tyrosine kinase inhibitor. It is a nitrogenous aromatic-ring containing compound with potential antineoplastic activity that is used in treatment of advanced, metastatic medullary thyroid cancer and refractory renal cell carcinoma. Lenvatinib is also used in combination with Everolimus to treat adults with advanced renal cell carcinoma (RCC) type of kidney cancer.
Lenvatinib is chemically known as 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide and is structurally represented as below:

Lenvatinib mesylate is a methanesulfonate salt obtained by reaction of Lenvatinib with methanesulfonic acid. Lenvatinib mesylate is indicated for the patients with progressive, locally recurrent or metastatic differentiated thyroid cancer (DTC) that can no longer be treated with radioactive iodine.
According to the National Cancer Institute, there are over 56,000 new cases of thyroid cancer in the US each year. Females are more likely to have thyroid cancer at a ratio of 3:1. Approximately 1.2 percent of all men and women will be diagnosed with thyroid cancer during the course of their lifetime.
There are three main histologic types of thyroid carcinoma: differentiated, medullary and anaplastic. Differentiated thyroid cancer (DTC), a common thyroid cancer, arises from follicular epithelial cells and accounts around 90% to 95% of total thyroid cancer cases. Lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Lenvatinib is first disclosed in US7253286 and is marketed by EISAI INC. as oral hypromellose hard capsules containing Lenvatinib as mesylate (methanesulfonate) salt in polymorphic ‘Type C’ crystals. Initially, Lenvatinib is approved by USFDA during 2015 as LENVIMA® capsule 4 mg and 10 mg. However, recommended daily dose of Lenvatinib is 24 mg once orally. LENVIMA® capsule is reported to contain excipients like calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and talc.

US7612208 discloses polymorphic ‘Form A’ and polymorphic ‘Form B’ of Lenvatinib, and process for preparation thereof. The said patent application discloses preparation of Lenvatinib crystalline polymorph (part-3) by reacting 1-(2-chloro-4-hydroxypenyl)-3-cyclopropylurea (II) with 7-methoxy-4-chloro-quinoline-6-carboxamide (III). As per the said patent, 1-(2-chloro-4-hydroxypenyl)-3-cyclopropylurea is prepared by part-1 and 7-methoxy-4-chloro-quinoline-6-carboxamide prepared by part-2. These processes are described herein as below (Scheme-1).

WO2005/044788 discloses process for the preparation of Lenvatinib wherein the condensation reaction is performed between 1-(2-chloro-4-hydroxypenyl)-3-cyclopropylurea (II) with 7-methoxy-4-chloro-quinoline-6-carboxamide (III) in dimethylsulfoxide, in the presence of cesium carbonate or potassium t-butoxide.
WO2006/137474 discloses an amorphous form of Lenvatinib methanesulfonate and ethanesulfonate salt. Further, the said patent application also discloses preparation of these amorphous salts of Lenvatinib by dissolving their corresponding crystalline form salts in an alcohol and water followed by filtration and lyophilization.
WO2014/098176 discloses an amorphous form of Lenvatinib. The said patent application also discloses preparation of an amorphous form of Lenvatinib by dissolving Lenvatinib crystals in solvents selected from the group consisting of water, an alcohol (C1-6), an ether, acetonitrile or a combination thereof followed by freeze-drying of the said solution.
WO2016/184436 discloses a new crystal form of Lenvatinib mesylate salt (Form M) and process for the preparation thereof. The said process of preparation involves crystallization of Lenvatinib ‘Form M’ crystals from Lenvatinib using solvent acetonitrile.
WO2018/122780 relates to a crystalline form of Lenvatinib mesylate, processes for the preparation of crystalline form and pharmaceutical compositions thereof. The crystalline form of Lenvatinib mesylate designated as Form VN1. This patent further discloses a process for the preparation of amorphous form of Lenvatinib mesylate which is methyl isobutyl ketone solvate of Lenvatinib mesylate.
The inventors of the present invention have developed an alternative improved process for the preparation of amorphous form of Lenvatinib mesylate with reduced processing steps, high yield and stability. The present invention also represents the process for the preparation and purification of Lenvatinib wherein the process is simple with easily available solvents and reagents. Hence, it is less costly alternative compare to processes as disclosed in prior arts for preparation of Lenvatinib.

OBJECTIVE OF THE INVENTION:
The main object of the present invention is to provide an improved process for the preparation of amorphous form of Lenvatinib mesylate with high yield and stability.
Another object of the present invention is to provide an economical industrial process for the preparation of Lenvatinib mesylate with the reduced processing steps.
Another object of the present invention is to provide the preparation and purification process of Lenvatinib mesylate with the easily available solvents and reagents.
Another object of the present invention is to provide the preparation of amorphous form of Lenvatinib mesylate that has excellent physicochemical properties.
One more object of the present invention is to provide the processes for the preparation of polymorphic forms DRC-1 and DRC-2 for Lenvatinib mesylate.
Another object of the present invention is to provide amorphous form of Lenvatinib mesylate that may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION:
The present invention relates to an improved process for preparation of amorphous form of Lenvatinib, wherein 4-amino-3-chlorophenol and 4-chloro-7-methoxyquinoline-6-carboxamide in suitable solvents form 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (III); that is reacted with phenylchloroformate to form Intermediate –II. Intermediate –II reacts with cyclopropylamine solution to yield Lenvatinib base. Then after, Lenvatinib base is converted to obtain Lenvatinib mesylate.
The present invention also provides novel forms of Lenvatinib mesylate designated as Form DRC-1 and Form DRC-2.
In another aspect, the present invention provides novel form of Lenvatinib mesylate designated as Form DRC-1, characterized by X-ray powder diffraction (XRD) pattern having peaks at about 10.84, 18.00, 19.40, 23.88, 25.86, 27.21, 28.68, 30.88, 43.26 and 46.89 ± 0.20 degrees 2-theta.
In another aspect, the present invention provides novel form of Lenvatinib mesylate designated as Form DRC-2, characterized by X-ray powder diffraction pattern having peaks at about 4.58, 6.17, 8.05, 9.15, 9.84, 10.58, 12.34, 13.66, 14.26, 15.24, 16.53, 17.17, 18.34, 19.11, 20.85, 21.23, 22.63, 24.84, 25.64, 26.26, 27.37, 28.34, 29.53, 30.69, 32.88, 35.04, 37.62, 38.57, 43.02 and 45.72 ± 0.20 degrees 2-theta.
One aspect of the present invention relates to preparation of amorphous form of Lenvatinib comprising the reaction steps as below:
a) dissolving 4-amino-3-chlorophenol with 4-chloro-7-methoxyquinoline-6-carboxamide in suitable solvents for formation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide;
b) adding phenyl chloroformate into 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide along with suitable solvents to form intermediate - II;
c) adding cyclopropylamine into mass obtained in step b) comprising intermediate - II to obtain Lenvatinib base (crude);
d) purifying Lenvatinib base (crude) prepared in step c) by adding methanol, activated charcoal and sodium carbonate to obtain pure Lenvatinib base (V).
e) reacting Lenvatinib base (V) as prepared in step d) with methanesulphonic acid to obtain amorphous Lenvatinib mesylate (I).
In another aspect of the present invention relates to preparation of crystalline form DRC-1 of Lenvatinib comprising addition of Tetrahydrofuran (THF) to Lenvatinib base (V) followed by addition of methanesulfonic acid to crystallize out crystalline form DRC-1 of Lenvatinib mesylate (I).
In one more aspect of the present invention relates to preparation of crystalline form DRC-1 of Lenvatinib comprising addition of tertiary butanol to Lenvatinib base (V) followed by addition of methanesulfonic acid to crystallize out crystalline form DRC-2 of Lenvatinib mesylate (I).

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 shows an X-ray powder diffractogram of novel form of Lenvatinib mesylate Form DRC-1.
Figure 2 shows an X-ray powder diffractogram of novel form of Lenvatinib mesylate Form DRC-2.
Figure 3 shows an X-ray powder diffractogram of amorphous form of Lenvatinib mesylate
Figure 4 shows Differential Scanning Calorimetry (DSC) of amorphous form of Lenvatinib mesylate

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved process for preparation of Lenvatinib, wherein 4-amino-3-chlorophenol and 4-chloro-7-methoxyquinoline-6-carboxamide (II) in suitable solvents form 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (III); that is reacted with phenylchloroformate to form Intermediate–II (IV). Intermediate –II reacts with cyclopropylamine solution to yield Lenvatinib base. Lenvatinib base obtained in crude form is purified with acid in pure form. Then after, Lenvatinib base (V) is converted to obtain Lenvatinib mesylate (I).
The present invention also provides novel forms of Lenvatinib mesylate designated as Form DRC-1 and Form DRC-2.
In one embodiment of the present invention provides novel form of Lenvatinib mesylate designated as Form DRC-1, characterized by X-ray powder diffraction pattern having peaks at about 10.84, 18.00, 19.40, 23.88, 25.86, 27.21, 28.68, 30.88, 43.26 and 46.89 ± 0.20 degrees 2-theta.
In another embodiment of the present invention provides novel form of Lenvatinib mesylate designated as Form DRC-2, characterized by X-ray powder diffraction pattern having peaks at about 4.58, 6.17, 8.05, 9.15, 9.84, 10.58, 12.34, 13.66, 14.26, 15.24, 16.53, 17.17, 18.34, 19.11, 20.85, 21.23, 22.63, 24.84, 25.64, 26.26, 27.37, 28.34, 29.53, 30.69, 32.88, 35.04, 37.62, 38.57, 43.02 and 45.72 ± 0.20 degrees 2-theta.
In another embodiment of the present invention, the suitable organic solvents are selected from methanol, ethanol, isopropyl alcohol, dimethylformamide, acetonitrile and acetone.
In other embodiment of the present invention, the hydrocarbon solvents are selected from toluene, xylene, hexane and benzene.
One embodiment of the present invention relates to preparation of Lenvatinib mesylate (I) comprising the steps as below.
a) dissolving 4-amino-3-chlorophenol with 4-chloro-7-methoxyquinoline-6-carboxamide (II) in suitable solvents for formation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (III);
b) adding phenyl chloroformate into 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (III) along with suitable solvents to form intermediate - II (IV);
c) adding cyclopropyl amine into mass comprising intermediate - II (IV) to obtain Lenvatinib base (crude);
d) purifying Lenvatinib base (crude) prepared in step c) with concentrated HCl, activated charcoal and sodium carbonate solution to obtain pure Lenvatinib base (V);
e) reacting Lenvatinib base (V) as prepared in above step with methanesulphonic acid to obtain Lenvatinib mesylate (I).

The present invention is follows as below in Scheme-2.

Scheme -2

One embodiment of the present invention relates to formation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (III) by dissolving 4-amino-3-chlorophenol with 4-chloro-7-methoxyquinoline-6-carboxamide (II) in suitable solvents selected from potassium hydroxide (KOH), toluene, water heated at 100-115°C. Then, addition of DMF and potassium iodide (KI) into reaction mass at 60°C leads to formation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (III).
Another embodiment of the present invention relates to use of phenylchloroformate for the preparation of intermediate-II (IV); wherein prepared 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (III) is reacted with phenylchloroformate in dimethylformamide (DMF) and pyridine at 5-25°C to yield intermediate -II (IV).
Another embodiment of the present invention relates to purification of Lenvatinib base (crude) with concentrated HCl, activated charcoal and sodium carbonate to obtain pure Lenvatinib base.
Additional embodiment of the present invention relates to a method of preparation of Lenvatinib mesylate in amorphous form by reacting Lenvatinib base (V) with methanesulfonic acid, methanol, ethanol and water to yield amorphous Lenvatinib mesylate (I).
In another embodiment of the present invention relates to preparation of crystalline form DRC-1 of Lenvatinib comprising addition of Tetrahydrofuran (THF) to Lenvatinib base (V) followed by addition of methanesulfonic acid to crystallize out crystalline form DRC-1 of Lenvatinib mesylate (I).
In one more embodiment of the present invention relates to preparation of crystalline form DRC-1 of Lenvatinib comprising addition of tertiary butanol to Lenvatinib base (V) followed by addition of methanesulfonic acid to crystallize out crystalline form DRC-2 of Lenvatinib mesylate (I).
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES:

Example-1: Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide
Toluene (250ml) was added into round-bottom flask at 25 to 30°C. 4-amino-3-chlorophenol (50gm) was added into the flask and stirred the reaction mass for 30 minutes at 25-30°C. Then, potassium hydroxide solution (29.25gm in 35.5ml purified water) was added in the reaction mass and heated the reaction mass to get temperature 110-115°C. Removed water by azeotropic distillation at 110-115°C followed by distilled out toluene atmospherically with stripping of toluene (50ml) to get solid residue. Then, DMF was added into reaction mass at 25-30ºC and stirred the reaction mass for 10 minutes at 25-30ºC to get clear reaction mass. In the said reaction, 4-chloro-7-methoxyquinoline-6-carboxamide (45.3gm) was gradually added at room temperature and the resulted mixture was stirred at 55-60ºC for 6 hr after adding potassium iodide (11.75gm). Conversion was checked by TLC till completion of the reaction. Cooled the reaction mass to 25-30ºC and slowly added into purified water (4000ml) at 0-5ºC. Slowly added dilute HCL solution (15ml in 150ml purified water) to get pH 7.0-8.0. Filtered the reaction mass followed by washing with purified water (200ml) to obtain 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (63.6gm). Final yield was 96.65% with purity of 95.52%.

Example-2: Purification of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide
Purified water (675ml) was added into round-bottom flask at 25 to 30°C. Then, sodium hydroxide (15.7gm) was added into the flask and stirred the reaction mass for 15 minutes at 25-30°C. Charged 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (135gm) into the reaction mass at 25-30ºC followed by charging of ethyl acetate (540ml) and n-heptanes (270ml). Resulted mixture was stirred for 30-45 minutes at room temperature. Filtered the reaction mass and washed with purified water (3 x 135ml) to get pure 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (113gm).
Final yield was 83.70% with purity of 97.81%.

Example-3: Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide
Toluene (1000ml) was added into round-bottom flask at 25 to 30°C. 4-amino-3-chlorophenol (200gm) was added into the flask and stirred the reaction mass for 30 minutes at 25-30°C. Then, potassium hydroxide solution (117gm in 145ml purified water) was added in the reaction mass and heated the reaction mass to get temperature 110-115°C. Removed water by azeotropic distillation at 110-115°C followed by distilled out toluene atmospherically with stripping of toluene (200ml) to get solid residue. Then, DMF (800ml) was added into reaction mass at 25-30ºC and stirred the reaction mass for 10 minutes at 25-30ºC to get clear reaction mass. In the said reaction, 4-chloro-7-methoxyquinoline-6-carboxamide (181.2gm) was gradually added at room temperature and the resulted mixture was stirred at 55-60ºC for 6 hours after adding potassium iodide (47.2gm). Conversion was checked by TLC till completion of the reaction. Cool the reaction mass to 25-30ºC and slowly added into mixture of Acetone (2400ml) and purified water (5600ml) at 10-15ºC. Stir reaction mass for 45 minutes at 10-15ºC for complete precipitation. Slowly added dilute HCL solution (70ml in 210ml purified water) to get pH 7.0-8.0. Then after, filtered the reaction mass followed by wash with mixture of purified water (280ml) and acetone (120ml) to obtain 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (259.3gm) after drying with bounded ~5% moisture. Obtained material was again added into round-bottom flask at 25 to 30°C with Toluene (2280ml). Heat reaction mass to 110-115ºC to remove water by azeotropic distillation. Cool the reaction mass to 60-65ºC and distilled out toluene under vacuum till 3 volume reaction mass remain inside with respect to batch size. Further cool reaction mixture to 25-30ºC and stir for 2.0 hrs at same temperature. Filter the reaction mass and washed with Toluene (228ml). Obtained wet material was dried under vacuum at 50-55ºC to get 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (248.5gm) after drying with moisture below 0.5%.
Final yield was 94.58% with purity of 97.86%.

Example-4: Preparation of Intermediate-II
DMF (1000ml) was added into round-bottom flask at 25 to 30°C. 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (100gm) was added in to flask at room temperature followed by stirring the reaction mass for 10-15 minutes at 25-30°C. Pyridine (69gm) was added into reaction mass at 0-5°C. In the said reaction, phenyl chloroformate (68.25gm) was slowly added at 0-5 °C in 15-20 minutes. Raised the temperature of reaction mass to 25-30°C and stirred reaction mass for 5 hours at room temperature. Conversion was checked by TLC till completion of the reaction. Reaction mass was slowly added into purified water (20000ml) at 0-5ºC and stirred for 2 hours at same temperature. Filtered the reaction mass and washed with purified water (400ml) to obtain Intermediate –II (132gm). Final yield was 97.83% with purity of 93.14%.

Example-5: Preparation of Lenvatinib base (crude)
DMF (250ml) was added into round-bottom flask at 25 to 30°C. 4-(4-Amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (50gm) was added in to flask at room temperature and stirred the reaction mass for 15-20 minutes at 25-30°C. Then, cyclopropyl amine (7.4gm) was added into the reaction mass at 10-15°C in 15-20 minutes. After stirring the reaction mass for 10-15 minutes at 10-15ºC, temperature was raised up to 25-30°C and stirred for 3 hours at same temperature. Conversion was checked by TLC till completion of the reaction. Reaction mass was slowly added into purified water (7500ml) at 0-5ºC. Filtered the reaction mass followed by wash with purified water (400ml) to obtain Lenvatinib crude base (37.2gm). Final yield was 80.85% with purity of 95.39%.

Example-6: Preparation of Lenvatinib base (crude)
In another embodiment, DMF (1080ml) was added into round-bottom flask at 25 to 30°C. 4-(4-Amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (108gm) was added in to flask at room temperature and stirred the reaction mass for 15-20 minutes at 25-30°C. Pyridine (124.74gm) was added into reaction mass at 0-5°C. In the said reaction, phenyl chloroformate (58.88gm) was slowly added at 0-5 °C in 15-20 minutes. Stirred the reaction mixture for 2 hours at 0-5ºC. Conversion was checked by TLC till completion of the reaction. Cyclopropylamine (62.76gm) was slowly added into reaction mass at 5-10ºC in 10-15 minutes and stirred the reaction mass for 2 hours at 5-10ºC. Conversion was checked by TLC till completion of the reaction. The reaction mass was slowly added into mixture of purified water (7560ml) and acetone (3240ml) at 5-10ºC. Stirred the reaction mass for 2 hours for complete precipitation. Filtered the reaction mass and washed with mixture of purified water (151.2ml) and acetone (64.5ml) to obtain lenvatinib crude base (109gm). Final yield was 81.27% with purity of 97.71%.

Example-7: Purification of Lenvatinib base
In another embodiment, methanol (6000ml) was added into the round-bottom flask containing Lenvatinib crude base (100gm) at 25-30ºC and stirred for 10-15 minutes at 25-30ºC. Then, slowly HCl solution (34.2gm 28-30% HCl diluted with 34.2ml purified water) was added into reaction mass. Stirred the reaction mass for 10-15 minutes for homogeneous solution. Heat the reaction mass to 35-40°C. Activated charcoal (5gm) was added into the reaction mass and stirred the reaction mass for 60 min at 35-40°C. The resultant mass was filtered through hyflo and washed with methanol (twice with 100ml). Distilled out methanol (3000ml) under vacuum below 40ºC. Sodium carbonate solution (19gm sodium carbonate in 170 ml of purified water) was slowly added into reaction mass at 25-30ºC to get pH 7.5-8.0. Purified water (1000ml) was added into reaction mass and stirred for 1 hour at 25-30ºC. Filtered reaction mass and washed with purified water (200ml). Obtained wet cake was dried under vacuum at 40-45ºC to get pure Lenvatinib base. Final yield was 92.00% with purity of 99.81%.

Example-8: Purification of Lenvatinib base
In another embodiment, methanol (5700ml) was added into the round-bottom flask containing Lenvatinib crude base (95gm) at 25-30ºC and stirred for 10-15 minutes at 25-30ºC. Then, methane sulfonic acid solution (21gm in 190ml methanol) was added slowly into reaction mass and stirred the reaction mass for 30 minutes at 25-30ºC. Activated charcoal (9.5gm) was added into reaction mass and stirred for 1 hour at 25-30ºC. The resultant mass was filtered through hyflo and washed with methanol (190ml). Distilled out methanol (4750ml) under vacuum at room temperature. Cooled the reaction mass to 0-5ºC and maintained for 1 hour at same temperature. Filtered the reaction mass washed with methanol (95ml) to get wet cake. Charged wet cake into RBF followed by charging of methanol (1425ml) and stirred for 10-15 minutes. Sodium carbonate solution (13gm in 115ml purified water) was slowly added into reaction mass at 25-30ºC to get pH 7.5-8.0. Purified water (950ml) was added into reaction mass and stirred for 1 hour at 25-30ºC. Filtered the reaction mass and washed with purified water (190ml). Obtained wet cake was dried under vacuum at 40-45ºC to get pure Lenvatinib base (69gm). Final yield was 79.63% with purity of 99.68%.

Example-9: Preparation of Lenvatinib mesylate amorphous monohydrate
Methanol (300 ml) was added into the round-bottom flask containing Lenvatinib base (30gm) at 25-30ºC and stirred for 30 minutes at 25-30ºC. Methane sulfonic acid solution (6.75gm in 60ml methanol) was slowly added in to above reaction mass in 10-15 minutes at room temperature. The said reaction mass was stirred at room temperature for 4 hours to obtain off white slurry followed by filtration. Obtained wet cake (29.8gm) was washed with methanol (30ml, twice). The said wet cake (29.8gm) was charged in to glass assembly with purified water (596ml) at room temperature and reaction mass was stirred for 2 hours to get clear gummy mass. Ethanol (596ml) was added to the obtained reaction mass for 2 hours at room temperature to get yellow mass. The reaction mass was transferred in to buchi round bottom flask at room temperature. Solvent was distilled out in rota vapour under reduced pressure below 35°C. The obtained material was dried in vacuum tray dryer below 35°C for 12 hours to afford the title compound (34.1gm). Final yield was 92.9% with purity of 99.58%.

Example-10: Preparation of Lenvatinib mesylate amorphous monohydrate
In another embodiment, methanol (1800ml) was added into the round-bottom flask containing Lenvatinib base (30gm) at 25-30ºC and stirred for 30 minutes at 25-30ºC. Methane sulfonic acid solution (6.62gm in 60ml methanol) was added slowly into reaction mass and stirred the reaction mass for 30 minutes at 25-30ºC. Activated charcoal (3.0gm) was added into reaction mass and stirred for 1 hour at 25-30ºC. The resultant mass was filtered through hyflo and washed with methanol (60ml). Distilled out methanol (1500ml) under vacuum at room temperature. Cooled the reaction mass to 0-5ºC and maintained for 1 hour at same temperature. Filtered the reaction mass and gave slurry washed with methanol (150ml) to get wet cake. Wet cake was charged into RBF (Full form ?) followed by charging of purified water (600ml) and stirred for 2 hours at 25-30ºC to get thick gummy mass. Then, ethanol (600ml) was added into the reaction mass and stirred for 2 hours at 25-30ºC to get clear yellow mass. The resultant mass was distilled off under vacuum at room temperature followed by dried in vacuum tray dryer (VTD) below 35ºC for 12 hours to obtain pure amorphous Lenvatinib mesylate monohydrate (32.9gm). Final yield was 89.52% with purity of 99.32%.

Example-11: Preparation of Lenvatinib mesylate amorphous
In another embodiment, methanol (7500ml) was added into the round-bottom flask containing Lenvatinib base (125gm) at 25-30ºC and stirred for 30 minutes at 25-30ºC. Methane sulfonic acid solution (27.58gm in 250ml methanol) was added slowly into reaction mass and stirred the reaction mass for 30 minutes at 25-30ºC. Activated charcoal (12.5gm) was added into reaction mass and stirred for 1 hour at 25-30ºC. The resultant mass was filtered through hyflo and washed with methanol (250ml). Distilled out methanol (6250ml) under vacuum at room temperature. Cooled the reaction mass to 0-5ºC and maintained for 1 hour at same temperature. Filtered the reaction mass and gave slurry wash with methanol (625ml) to get wet cake. Wet cake was charged into RBF followed by charging of purified water (600ml) and stirred for 2 hours at 25-30ºC to get thick gummy mass. The resultant gummy mass was dried in vacuum tray dryer (VTD) below 35ºC for 24 hours to obtained pure Lenvatinib mesylate amorphous monohydrate (126.2gm). Final yield was 82.41% with purity of 99.50%.

Example-12: Preparation of Lenvatinib mesylate polymorph DRC-1:
Tetrahydrofuran (50ml) was added into round-bottom flask at 25 to 30°C. Lenvatinib Base (5gm) was added into the flask and stirred the reaction mass for 30 minutes at 25-30°C. Slowly add methanesulfonic acid solution (1.10gm methanesulfonic acid in 5ml Tetrahydrofuran) into reaction mass at 25-30ºC in 10-15 minutes. Stir the reaction mixture for 2 hours at 25-30ºC. Filter the reaction mixture at 25-30ºC and wash with 5ml Tetrahydrofuran (Twice). Obtained wet material was dried at 35-40ºC under vacuum for 12 hours to get 5.95gm Lenvatinib Mesylate form DRC-1.

Example-13: Preparation of Lenvatinib mesylate polymorph DRC-2:
Tertiary butanol (100ml) was added into round-bottom flask at 30-35°C. Lenvatinib Base (5gm) was added into the flask and stirred the reaction mass for 30 minutes at 30-35°C. Slowly add methanesulfonic acid solution (1.10gm methanesulfonic acid in 5ml Tertiary butanol at 30ºC) into reaction mass at 30-35ºC in 10-15 minutes. Stir the reaction mixture for 2 hours at 30-35ºC. Filter the reaction mixture at 30-35ºC and wash with 10ml Tertiary butanol (Twice). Obtained wet material was dried at 40-45ºC under vacuum for 12 hours to get 6.01gm Lenvatinib Mesylate form DRC-2.

Example-14: Stability study of Lenvatinib mesylate polymorph DRC-1:
Polymorph DRC-1 prepared as per the example-12 was placed under stability study at 2° to 8° C. Surprisingly, the inventors of the present invention found it very stable over a period of 6 months. In addition, total impurity generation was also minimal. This shows a robust development of process for a novel polymorph. Following is the data for stability studies of DRC-1 polymorph.

Table-1: Lenvatinib mesylate polymorphic form DRC-1
Test Parameter Initial 1 month 2 months 3 months 6 months
% Assay 99.48 99.19 99.38 99.14 99.43
Total Impurities 0.70 1.05 0.79 0.93 0.73

The invention described herein comprises in various objects and their description as mentioned above, with respect to characteristics and processes adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.
,CLAIMS:We Claim:

1. An improved process for the preparation of Lenvatinib mesylate polymorph DRC-1 comprising following steps:
a. conversion of 4-amino-3-chlorophenol (IV) in the presence of hydrocarbon solvent to potassium salt of 4-amino-3-chlorophenol;
b. coupling of potassium salt of 4-amino-3-chlorophenol with 4-chloro-7-methoxyquinoline-6-carboxamide (II) to prepare 4-(4-amino-3-chlorophenoxy) -7-methoxy quinoline-6-carboxamide (III) in the presence of suitable organic solvents;
c. coupling of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (III) with phenyl chloroformate in the presence of suitable organic solvents to prepare phenyl[4-[(6-carbamoyl-7-methoxyquinolin-4-yl)oxy]-2-chlorophenyl]carbamate (IV);
d. reacting phenyl[4-[(6-carbamoyl-7-methoxyquinolin-4-yl)oxy]-2-chloro phenyl]carbamate (IV) with cyclopropylamine to prepare Lenvatinib base (V);
e. dissolving Lenvatinib base (V) in tetrahydrofuran in the presence of methanesulfonic acid to prepare polymorphic form DRC-1 of Lenvatinib mesylate (I).

2. An improved process for the preparation of Lenvatinib mesylate polymorph DRC-2 comprising following steps:
a. conversion of 4-amino-3-chlorophenol (IV) in the presence of hydrocarbon solvent to potassium salt of 4-amino-3-chlorophenol;
b. coupling of potassium salt of 4-amino-3-chlorophenol with 4-chloro-7-methoxyquinoline-6-carboxamide (II) to prepare 4-(4-amino-3-chlorophenoxy) -7-methoxy quinoline-6-carboxamide (III) in the presence of suitable organic solvents;
c. coupling of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (III) with phenyl chloroformate in the presence of suitable organic solvents to prepare phenyl[4-[(6-carbamoyl-7-methoxyquinolin-4-yl)oxy]-2-chlorophenyl]carbamate (IV);
d. reacting phenyl[4-[(6-carbamoyl-7-methoxyquinolin-4-yl)oxy]-2-chloro phenyl]carbamate (IV) with cyclopropylamine to prepare Lenvatinib base (V);
e. dissolving Lenvatinib base (V) in tertiary butanol in the presence of methanesulfonic acid to prepare polymorphic form DRC-2 of Lenvatinib mesylate (I).

3. An improved process for the preparation of amorphous form of Lenvatinib mesylate comprising following steps:
a. conversion of 4-amino-3-chlorophenol (IV) in the presence of hydrocarbon solvent to potassium salt of 4-amino-3-chlorophenol;
b. coupling of potassium salt of 4-amino-3-chlorophenol with 4-chloro-7-methoxyquinoline-6-carboxamide (II) to prepare 4-(4-amino-3-chlorophenoxy)-7-methoxy quinoline-6-carboxamide (III) in the presence of suitable organic solvents;
c. coupling of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (III) with phenyl chloroformate in the presence of suitable organic solvents to prepare phenyl[4-[(6-carbamoyl-7-methoxyquinolin-4-yl)oxy]-2-chlorophenyl]carbamate (IV);
d. reacting phenyl[4-[(6-carbamoyl-7-methoxyquinolin-4-yl)oxy]-2-chloro phenyl]carbamate (IV) with cyclopropylamine to prepare Lenvatinib base (V);
e. dissolving Lenvatinib base (V) in methanol or ethanol in the presence of methanesulfonic acid to prepare polymorphic form DRC-2 of Lenvatinib mesylate (I).

4. An improved process for the preparation of Lenvatinib mesylate as claimed in claim 1 to 3, wherein the suitable organic solvents are selected from methanol, ethanol, isopropyl alcohol, dimethylformamide, acetonitrile and acetone.

5. An improved process for the preparation of Lenvatinib mesylate as claimed in claim 1 to 3, wherein the hydrocarbon solvents are selected from toluene, xylene, hexane and benzene.

6. An improved process for the preparation of Lenvatinib mesylate as claimed in claim 1 to 3, wherein the potassium salt of 4-amino-3-chlorophenol is prepared from 4-amino-3-chlorophenol in the presence of potassium hydroxide and toluene.

7. A polymorphic form of Lenvatinib mesylate DRC-1 comprising of major peaks in X-ray diffraction (XRD) at about 2-theta values of 10.84, 19.40, 23.88 and 25.86 ± 0.20 degrees.

8. A polymorphic form of Lenvatinib mesylate DRC-2 comprising of major peaks in X-ray diffraction (XRD) at about 2-theta values of 4.58, 6.17, 9.15 and 10.58 ± 0.20 degrees.

9. An oral pharmaceutical composition of Lenvatinib mesylate comprising polymorphic form DRC-1 or DRC-2 or amorphous form as prepared in claim-1 to 3 and one or more pharmaceutically acceptable excipients.