DESC:FIELD OF THE INVENTION
The present invention relates to the process for the preparation of crystalline Lenvatinib mesylate (I).

The present invention also relates to a novel thermodynamically stable crystalline form of Lenvatinib mesylate (I) designated as Crystalline Form SL.
BACKGROUND OF THE INVENTION
LENVIMA® is marketed product of Eisai, a kinase inhibitor, Lenvatinib mesylate salt of Lenvatinib is chemically named as 4-[3-chloro-4-(cyclopropylcarbamoylamino) phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate. The molecular formula for Lenvatinib mesylate is C21H19ClN4O4. CH4O3S.
LENVIMA, capsules for oral administration contain 4 mg or 10 mg of lenvatinib, equivalent to 4.90 mg or 12.25 mg of Lenvatinib mesylate, respectively. Lenvatinib mesylate is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1, VEGFR2, and VEGFR3. It is marked in the United States under the trade name LENVIMA® by Eisai, Inc. and is approved by the FDA for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.
Funahashi et al in US7253286B2 first discloses Lenvatinib and its preparation method by reacting 4-chloro-7- methoxyquinoline-6-carboxamide with 4-amino-3-chlorophenol under basic condition at 100oC to produce 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide, which upon N-Carbamate reaction with phenyl chloroformate, in dimethyl formamide at room temperature gave phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2- chlorophenylcarbamate followed by urea formation using cyclopropyl amine in dimethyl sulfoxide at 85°C to produce Lenvatinib, which follows the synthetic pathway as given in the Scheme-1:

Scheme - 1: Process as per US7253286B2
Matsushima et al in US7612208B2 discloses various crystalline forms (Form A, B, C, F, I, a, ß) of 4-[3-chloro-4-(cyclopropylcarbamoylamino) phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate and process for their preparation.
Chen et al in WO2016/184436A1 publication discloses Crystalline Form- M of Lenvatinib mesylate and process for its preparation. This patent application also discloses the use of acetonitrile for the crystallization of Lenvatinib mesylate Form-M and US20070117842A1 describes crystalline Form-A and Form-B of Lenvatinib Free base.
Naito et al in US7683172B2 describes a process for preparation of Lenvatinib by reacting the compound (A-l) with a compound (B)

wherein R1 represents hydrogen, C1-6 alkyl or C3-8 cycloalkyl, and wherein R2 represents hydrogen or methoxy; L represents a leaving group. The synthetic pathway of Lenvatinib as given in the Scheme-2:

Scheme -2: Process as per US7683172B2
CN112174886A discloses Preparation method of Lenvatinib mesylate crystal Form-X having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2?) of 22.84°±0.2°, 20.16°±0.2°, 9.46°±0.2°, 14.52°±0.2°, 24.86°±0.2°, 18.92°±0.2°, 26.82°±0.2°, 8.68°±0.2°, 10.32°±0.2°, CN110903239A discloses crystalline Form-6 of Lenvatinib mesylate.
Srinivasan et al in US11236050B2 discloses crystalline Form-N, N1, N2, S, L & L1 of Lenvatinib mesylate and process for their preparation.
As a result of much avid research in light of the various literature described above, there still exists the need of more economically viable and amenable to scale up processes for Lenvatinib mesylate. It is also apparent that need exists for a thermodynamically stable polymorphic crystalline form of Lenvatinib mesylate with high purity levels and devoid of impurities including potential genotoxic impurities.
As existence and possible numbers of polymorphic forms for any compound cannot be predicted and there are no specific or "standard" known procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, viz., by A. Goho, "Tricky Business," Science News, Vol. 166(8), August 2004.
The discovery of new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as storage stability, ease of handling, ease of processing, ease of purification, or may serve as desirable intermediate crystal forms that facilitate purification or conversion to other polymorphic forms.
New solid state forms of a pharmaceutically useful active compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. Regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances. Owing to these reasons, there exist need for additional solid state forms of Lenvatinib mesylate.
The present invention provides novel unique process resulting in a thermodynamically stable crystalline form of Lenvatinib mesylate designated as Form SL, which has been observed to process excellent physico-chemical properties besides high purity. The crystalline form of Lenvatinib mesylate of the present invention may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
SUMMARY OF THE INVENTION
The main aspect of the present invention relates to a process for the preparation of crystalline Lenvatinib mesylate of Formula (I).

Different aspects of the present application are summarized herein below individually.
In one aspect of the present application, the present invention relates to a process for preparation of compound of formula (I),

comprising the steps of:
a). condensing 4-chloro-7-methoxyquinoline-6-carboxamide of formula (III) with 4-amino-3-chlorophenol hydrochloride of formula (II), in the presence of an inorganic base and a first and second solvent to get 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide of formula (IV);

b). reacting 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline -6-carboxamide of formula (IV) as obtained in step a) with phenylchloroformate of formula (V) in the presence of organic base and a first solvent and an anti-solvent to isolate phenyl(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)carbamate of formula (VI);

c). condensation of phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl) oxy)-2-chlorophenyl)carbamate of formula (VI) with cyclopropylamine in presence of an organic base, first solvent and an anti-solvent to obtain 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide of formula (VII);

d). reacting 4-(3-chloro- 4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide of formula (VII) with methane sulphonic acid in 10 to 15 % aqueous solution of isopropyl alcohol to isolate crystalline form of formula (I) having purity greater than 99.7% (Area % by HPLC).

Another aspect of the present invention relates to an improved process for preparing crystalline Lenvatinib mesylate Form SL of formula (I), characterised by XRPD diffraction angle peaks at 5.9, 6.27. 11.63, 13.48, 14.06, 14.33, 17.75, 19.40, 28.45 and 33.75 ± 0.2° 2? comprising the steps of-
a). charging compound of formula (VII) to isopropyl alcohol at 25-30°C;
b). charging purified water ranging between 10-15% (v/v) with respect to
isopropyl alcohol in the reaction mass at 25-30°C under stirring;
c). adding methane sulphonic acid to the mixture of formula (VII) and aqueous solution of isopropyl alcohol;
d). stirring the reaction mass for 3-4 hrs at 25-30°C;
e). filtering the solid obtained in step-d);
f). washing the solid with isopropyl alcohol;
g). isolating crystalline Form SL of formula (I).
Further aspect of the present invention relates to a crystalline Lenvatinib mesylate Form SL of formula (I) characterised by XRPD diffraction angle peaks at 5.9, 6.27. 11.63, 13.48, 14.06, 14.33, 17.75, 19.40, 28.45 and 33.75 ± 0.2° 2? having a purity greater than 99.7% (Area % by HPLC) and having water content (by KF) not more than 1.2% w/w.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG 1: is an illustration of X-Ray powder Diffraction (XRPD) pattern of the crystalline Lenvatinib mesylate Form SL of formula (I).
FIG 2: is an illustration of a TGA thermogram of the crystalline Lenvatinib mesylate Form SL of formula (I).
FIG 3: is an illustration of a Differential Scanning Calorimetric (DSC) Curve of the crystalline Lenvatinib mesylate Form SL of formula (I).
FIG 4: is an illustration of a High Performance Liquid Chromatography Curve of the crystalline Lenvatinib mesylate Form SL of formula (I).
FIG 5: is an illustration of X-Ray powder Diffraction (XRPD) pattern of the crystalline Lenvatinib mesylate Form SL of formula (I) after four months stability.
FIG 6: is an illustration of a High Performance Liquid Chromatography Curve of the crystalline Lenvatinib mesylate Form SL of formula (I) after four months stability.
DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention relates to a process for preparation of crystalline Lenvatinib mesylate (I). The present invention deals with a simple and industrially amenable process for making the compound of formula (I), which exhibits various advantages over other processes known in the state of arts. The advantages are discussed on the relevant places of further description. Individual embodiments of the present invention are detailed herein below separately.
In one embodiment according to the present application, it provides a process for preparation of compound of formula (I) or a salt thereof,

comprising the steps of;
a). condensing 4-chloro-7-methoxyquinoline-6-carboxamide of formula (III) with 4-amino-3-chlorophenol hydrochloride of formula (II), in the presence of an inorganic base and a first and second solvent to get 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline -6-carboxamide of formula (IV);

b). reacting 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide of formula (IV) as obtained in step a) with phenylchloroformate of formula (V) in the presence of organic base and a first solvent followed by an anti-solvent to isolate phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl) carbamate of formula (VI);

c). condensation of phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl) oxy)-2-chlorophenyl)carbamate of formula (VI) with cyclopropylamine in presence of an organic base, first solvent followed by an anti-solvent to obtain 4-(3-chloro-4-(3-cyclopropylureido)phenoxy) -7-methoxyquinoline-6-carboxamide of formula (VII);

d). reacting 4-(3- chloro - 4 - (3-cyclopropylureido) phenoxy)-7- methoxyquinoline - 6 -carboxamide of formula (VII) with methane sulphonic acid in 10 to 15 % aqueous solution of isopropyl alcohol to isolate crystalline form of formula (I) having purity greater than 99.7% (Area % by HPLC).

Individual steps of the process according to the present invention are detailed herein below.
According to the present invention in step a) of the process for the preparation of Lenvatinib mesylate, wherein inorganic base used in step a) selected from sodium carbonate, potassium carbonate or cesium carbonate.
In a particular embodiment the inorganic base used in the reaction of step a) is cesium carbonate.
In a particular embodiment the second solvent used in step a) is toluene for the preparation of formula (I).
The organic base used in step b) and c) is selected from pyridine, triethylamine, diisopropylamine or DBU and more particularly it is selected as pyridine.
In a particular embodiment the inventors of the present invention found that the reaction time of 6 hours in step b) is controlling the impurity of compound of formula (IV), a type of genotoxic impurity in the final API. Inventors of the present invention found that reaction time drastically affects the purity of the final API w.r.t impurity in the form of compound of formula (IV).
The suitable anti-solvent used in step b) and c) are selected from dimethyl ketone, ethyl methyl ketone, isopropyl ketone, methyl isobutyl ketone or diethyl ketone and more particularly dimethyl ketone or acetone.
In a particular embodiment, acetone is used twice as a ketone solvent for further purification.
The product can be isolated by suitable methods such as filtration, washing with acetone and then dried.
The isolated product of step c) of the present invention is highly pure crystalline free base of 4-(3-chloro-4-(3-cyclopropylureido) phenoxy) -7-methoxyquinoline-6-carboxamide of formula (VII) having purity exceeding 99.7% (by HPLC).
The product obtained by the present invention is free of process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities.
All the known impurities from 1 to 6 are either not detected or below the detection level of limits.
S. No. Known impurities IUPAC Name
1.
4-[4-(carbamoylamine)-3-chlorophenoxy]-7-methoxyquinoline-6-carboxamide
2.
4-(3-chloro-4-[(methylcarbamoyl)amino]phenoxy)-7-methoxyquinoline-6-carboxamide

3.
4-(3-chloro-4-[(cyclopropylcarbamoyl)amino]phenoxy)-7-methoxyquinoline-6-carboxylic acid

4.
phenyl(4-[(6-carbamoyl-7- methoxyquinoline-4-yl)oxy]-2-chloro-phenyl)carbamate

5.
4-(3-chloro-4-[(cyclopropyl carbamoyl)amino]phenoxy)-N-(cyclo-propylcarbamoyl)- 7-methoxyquinoline-6-carboxamide
6.
1-(2-chloro-4-[(6-cyano-7-methoxyquinoline-4-yl)oxy]phenyl)-3-cyclopropylurea

In another embodiment, Lenvatinib mesylate obtained by the process according to the present invention is highly pure having purity greater than 99.7% and having total impurities of ~0.2%.
Inventors of the present application emphasised that the polymorphic form SL of Lenvatinib mesylate is devoid of any type of genotoxic impurity.
A cumbersome task w.r.t the genotoxic impurities were there in front of the inventors of the present application. Therefore in order to improvise the quality and yield of the final API and to reduce the genotoxic impurities of formula (A-1) and (I)

and other process related impurities; step c) proceeds from compound of formula (VI) to the formation and isolation of the free base of Lenvatinib as crude (I) having the purity ranging between 98-99% by HPLC followed by formation and isolation of Lenvatinib mesylate monohydrate as crude (II) in the presence of a mixture of 17-20% aqueous isopropyl alcohol and methane sulphonic acid and again as pure Lenvatinib Free base of compound of formula (VII) having purity of 99.7 (area % HPLC).
In a further embodiment in order to obtain the high purity Lenvatinib free base of formula (VII) having purity exceeding 99.7% by HPLC the treatment of crude (II) of monohydrate salt of Lenvatinib mesylate is performed in sodium carbonate.
To leach out the genotoxic impurities inventors of the instant invention have conducted a large number of experiments and therefore arrived on the conclusion that no further purification step is required to obtain the Lenvatinib mesylate polymorphic form SL with desirable purity (~99.7% by HPLC).
Further for the preparation of the crystalline form of compound of formula (I) in step d), reaction of high purity Lenvatinib free base of compound of formula (VII) is performed in the presence of a mixture of methane sulphonic acid in 10-15% aqueous solution of isopropyl alcohol.
The product can be isolated by suitable methods such as filtration, washing with acetone and then dried.
In another embodiment of the present invention, it provides a highly pure Lenvatinib mesylate of formula (I) having purity exceeding 99.7% by HPLC.
In yet further embodiment water not more than 1.2% w/w in the compound of formula (I) as it is an anhydrous form.
In another aspect the present invention provides a process for the preparation of crystalline Lenvatinib mesylate Form SL of compound of formula (I).
In one embodiment, crystalline form SL of compound of formula (I) may be prepared by a process that include the steps of-
a). charging compound of formula (VII) to isopropyl alcohol at 25-30°C;
b). charging purified water ranging between 10-15% (v/v) with respect to
isopropyl alcohol in the reaction mass at 25-30°C under stirring;
c). adding methane sulphonic acid to the mixture of formula (VII) and aqueous solution of isopropyl alcohol;
d). stirring the reaction mass for 3-4 hrs. at 25-30°C;
e). filtering the solid obtained in step-d);
f). washing the solid with isopropyl alcohol;
g). isolating crystalline Form SL of formula (I).
The Lenvatinib mesylate crystalline Form SL of formula (I) obtained according to the present invention shall be dried under vacuum for 8 hours at 40-65°C to attain water content not more than 1.2 % w/w.
In yet further another embodiment isolation of Lenvatinib and Lenvatinib mesylate may be carried out by filtration, solvent removal (extraction), layer separation, concentration, distillation or a combination thereof.
Process of the present invention avoids the formation of by products and process related impurities in the formation of highly pure and stable Lenvatinib mesylate.
Lenvatinib mesylate Form SL exhibits an X-ray powder diffraction (‘’XRPD’’) pattern having characteristic diffraction angle peaks expresses in 2? at approximately 5.9, 6.27. 11.63, 13.48, 14.06, 14.33, 17.75, 19.40, 28.45 and 33.75 ± 0.2° 2? and having the melting point ranging between 230 to 240°C.
FIG. 4 and FIG. 6 illustrate the High Performance Liquid Chromatography (‘’HPLC’’) of Lenvatinib mesylate Form SL obtained in the initial stage and after four month’s stability respectively. Figures reveal that the purity remains same and the polymorphic form “Form SL” is a highly pure form with purity exceeding 99.7% (%w/w by HPLC).
FIG. 1 and FIG. 5 illustrate the X-ray powder diffraction (‘’XRPD’’) pattern of Lenvatinib mesylate Form SL obtained in the initial stage and after four month’s stability respectively. Figures reveal that the crystalline nature of the material remains same and thermodynamic stable.
The compositions for parenteral administration can be suspensions, emulsions or an aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising Lenvatinib mesylate of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions derived from Lenvatinib mesylate of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
While the present invention has been described in terms of its specific embodiments, 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.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the below examples, which are provided by way for illustration purpose only and should not be construed as limiting the scope of the invention in any manner.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the present invention.
EXAMPLE:
STAGE –01-a) : Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxy- quinoline-6-carboxamide:

Charged dimethylsulphoxide (800ml) in round bottom flask at 25-30°C under stirring. Charged 4 -amino-3-chlorophenolhydrochloride (91.4 gm) at 25-30°C under stirring. Charged Cesium carbonate (413.0gm) in reaction mass at 25-30°C under stirring. Stirred the reaction mixture for 60 minutes at 25-30°C. Charged 4-chloro-7-methoxyquinoline-6-carboxamide (100gm) and flushed with dimethylsulphoxide (200ml) in reaction mass at 25-30°C under stirring. Raised the temperature of reaction mass to 70-75°C. Stirred the reaction mixture for 2 hrs at 70-75°C. After completion of reaction cooled the reaction mass to 25-30°C. Added water 1000 ml into the reaction mass at 70-75°C. Charged water 9000 ml into another round bottom flask to 25-30°C. Added both the reaction mass at 25-30°C under stirring. Stirred the reaction mass for 2 hrs at 25-30°C. Filtered and wash the cake with 2x100 ml water. Suck dried for 25-30 minutes and unload the material for drying. Dried the material under vacuum for 8hrs at 50-55°C. After complying the result of moisture unload the material.
Dry wt: 152.6 gm
Yield (w/w): 1.52
%Yield: 99.8
Charged Toluene (2000ml) in round bottom flask at 25-30°C under stirring. Charged 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (152.0 gm) at 25-30°C under stirring. Raised the temperature of reaction mass to 105-110°C.Stirred the reaction mixture for 30 minutes at 105-110°C. Cooled to 30-35°C. Stirred the reaction mass for 30 minutes at 30-35°C. Filtered and washed the cake with Toluene (2x100 ml). Suck dried for 25-30 minutes and unload the material for drying. Dried the material under vacuum for 8 hrs at 50-55°C. After complying the result of moisture unload the material.
Dry wt: 140 gm
Yield (w/w): 0.92
%Yield: 92.1
STAGE –01-b): Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxy- quinoline -6-carboxamide:

Charged Ethyl acetate (800 ml) in round bottom flask at 25-30°C under stirring. Charged 91.40 gm of 4-Amino-3-chlorophenol hydrochloride at 25-30°C under stirring. Charged purified water (200 ml) in the reaction mass at 25-30°C under stirring. Added freshly prepared sodium bicarbonate solution (dissolved 64.0 gm Sodium bicarbonate in 800 ml of water) in the reaction mass at 25-30°C under stirring. Stirred for 30 minutes at 25-30°C. Settled and separated the layer at 25-30°C and keep the first lot of organic layer aside. Charged aqueous layer into round bottom flask. Charged 200 ml of ethyl acetate at 25-30°C. Stirred for 30 minutes at 25-30°C. Settled and separated the layer at 25-30°C and keep the second lot of organic layer aside. Charged aqueous layer into round bottom flask. Charged 200 ml of ethyl acetate at 25-30°C. Stirred for 30 minutes at 25-30°C. Settled and separated the layer at 25-30°C and keep the third lot of organic layer aside. Combined all three lots of organic layers and distilled out solvent under vacuum completely. Charged 150 ml of toluene and distilled out under vacuum completely below 50°C and degas for 30 minutes at 45-50°C. Charged 400 ml of DMSO in round bottom flask at 25-30°C under stirring. Charged 206.5 g of Cesium carbonate in reaction mass at 25-30°C under stirring. Stirred reaction mixture for 60 minutes at 25-30°C. Charged 100 g of 4-chloro-7-methoxyquinoline-6-carboxamide and flushed with 100 ml of DMSO in the reaction mass at 25-30°C under stirring. Raised the temperature of reaction mass to 70-75°C. Stirred the reaction mixture for 2.0 hr at 70-75°C. After completion of reaction added water 1000 ml into the reaction mass at 75-60°C. Stirred reaction mixture for 60 minutes at 60-70°C. Charged Purified water 3000 ml into another round bottom flask to 25-30°C. Add the above prepared reaction mass to the charged purified water 26-30°C under stirring and flushed with water 500ml. Stirred the reaction mass for 2 hrs at 25-30°C. Filtered and washed the cake with 500 ml water. Suck dried for 25-30 minutes and unload the material for drying wet cake 195gm. Dried the material under vacuum for 8 hrs at 50-55°C.
Dry wt.: 150 gm.
Yield (w/w): 1.5
Charged 2000 ml of Toluene in round bottom flask at 25-30°C under stirring. Charged 150 gm of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide at 25-30°C under stirring. Raised the temperature of reaction mass up to reflux and distilled out solvent 105 ml. Maintained reaction mass in reflux for 3.0 hrs to remove water azeotropically. Cooled to 30-35°C. Stirred the reaction mass for 60 minutes at 30-35°C. Filtered and washed the cake with Toluene 2x100 ml. Suck dried for 25-30 minutes and unload the material for drying wet cake ~158 gm. Dried the wet material under vacuum for 8.0 hrs at 50-55°C and unload the material.
Dry wt.: 135 gm.
Yield (w/w): 1.35
STAGE-02: Preparation of phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl) oxy)-2-chlorophenyl) carbamate:

Charged 800 ml N, N dimethylformamide at 25-35°C into a clean, dry multineck round bottom flask. Charged 100 gm 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide at 25-35°C under stirring. Charged 80.60 gm Pyridine at 25-35°C. Charged 6.0 gm water at 25-35°C. Cooled the reaction mass to -5 to 5°C. Slowly added 148.10gm phenylchloroformate drop wise in 60 minutes. Stirred for 2 hrs at -5 to 5°C. After completion of the reaction added 2000 ml acetone into the reaction mass at 0-15°C under stirring. Raised the temperature to 25-30°C. Stirred the reaction mass for 2 hrs at 25-35°C. Filtered the solid and washed the solid with acetone (2x100 ml). Suck dried the cake for 25-30 minutes. Dried the material under vacuum in oven at 25-30°C to get the 170 gm wet cake.
Charged 1000 ml of N, N dimethylformamide at 25-35°C into clean, dried multi-neck round bottom flask. Charged wet cake 170 gm at 25-35°C under stirring. Stirred the reaction mass for 1 hr at 30-35°C. Added acetone 2000 ml into the reaction mass at 30-35°C under stirring. Stirred the reaction mass for 1 hr at 30-35°C. Filtered the solid and washed the solid with 2x100 ml acetone. Suck dried the cake for 25-30 minutes. Dried the material under vacuum in oven for 6 hrs at 50-55°C. After complying the result of LOD, unload the material.
Dry wt.: 110 gm.
Yield (w/w): 1.10
STAGE–03: Preparation of 4-(3-chloro-4-(3-cyclopropylureido) phenoxy)-7-methoxyquinoline-6-carboxamide:

Charged 600 ml N, N dimethyl formamide at 25-35°C into a clean, dry multineck round bottom flask. Charged 100 gm Phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl) oxy)-2-chlorophenyl) carbamate in the above round bottom flask at 25-30°C under stirring. Charged 39.20 gm Pyridine in the above round bottom flask at 25-30°C under stirring. Cooled the reaction mass to 0-5°C. Added cyclopropylamine 59.09 gm at 0-5°C. Stirred the reaction mass for 2-3 hrs at 0-5°C. After completion of the reaction raised the temperature of reaction mass to 25-30°C and stirred for 30 minutes at 25-30°C. Added the mixture of acetone and water 1450 and 50 ml respectively at 25-30°C. Stirred the reaction mass for 2.0 hrs at 25-30°C. Filtered the solid and washed with acetone 2 x 100 ml. Suck dried for 20-30 minutes to get the wet cake ~100 gm. Dried the material under vacuum for 8 hrs at 50-55°C to get crude 4-(3-chloro-4-(3-cyclopropylureido) phenoxy) -7- methoxyquinoline-6-carboxamide .
Dry weight = ~60 g (Crude-I).
Charged 2206.60 ml Isopropyl alcohol at 25-30°C in the 5.0 litres round bottom flask under stirring. Charged 566.40 gm water at 25-30°C in the 5.0 litres round bottom flask under stirring. Charged 59 gm 4-(3-chloro-4-(3-cyclopropylureido) phenoxy)-7-methoxyquinoline-6-carboxamide crude in the above round bottom flask at 25-30°C under stirring. Added freshly prepared methane sulphonic acid solution (dissolved 14.0 gm methane sulphonic acid in 59.0 ml. Isopropyl alcohol) at 25-30°C. Stirred the reaction mass for 30 minutes at 25-30°C to make the clear solution. Charged 11.8 gm activated carbon in the above round bottom flask at 25-30°C under stirring. Stirred the reaction mass for 30 minutes at 25-30°C. Filtered through hyflo bed and washed with mixture of isopropyl alcohol 94.4 ml and water 23.60 gm. Collected clear filtrate and filtered through 0.45 micron filter at 25-30°C. Collected clear filtrate and charged into round bottom flask. Cooled to 5 to 10°C. Stirred the reaction mass for 3-4 hrs at 5 to 10°C. Filtered the solid and washed with chilled Isopropyl alcohol 2 x 59 ml. Suck dried for 20-30 minutes wet cake ~80 g. Dried the wet material under vacuum for 8 hrs at 50-55°C.
Dry weight of Lenvatinib mesylate monohydrate = ~39 gm. (Crude-II).
Charged 456.0 ml methanol at 25-30°C in the 3.0 litres round bottom flask under stirring. Charged 38.0 gm crude-II at 25-30°C under stirring. Charged purified water 114.0 ml at 25-30°C under stirring. Added freshly prepared Sodium carbonate solution (dissolved 10.0 gm. Sodium carbonate in 38.0 ml water) at 25-30°C. Stirred the reaction mass for 3.0 hrs at 25-30°C. Filtered the solid and washed with purified water 152.0 ml. Suck dried under vacuum for 20-30 minutes. The wet solid washed with 76.0 ml of Acetone. Suck dried under vacuum for 20-30 minutes. Unload the wet cake ~47.0 gm. Dried the material under vacuum for 8 hrs at 50-55°C to get the free base of 4-[3-chloro-4-(cyclopropylcarbamoyl amino) phenoxy]-7-methoxyquinoline-6-carboxamide.
Dry wt.: 35 gm.
Yield (w/w): 0.35
STAGE–04: Preparation of Crystalline Form SL of 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline -6-carboxamide methanesulfonic acid (Lenvatinib mesylate)

4a). with 10% Aqueous Solution of Isopropyl alcohol:
Charged 1100 ml Isopropyl alcohol into 2.0 litres clean round bottom flask at 25-30°C under stirring. Charged 25.0 gm. 4-(3-chloro-4-(3-cyclopropylureido) phenoxy)-7-methoxyquinoline-6-carboxamide into above round bottom flask at 25-30°C under stirring. Charged 125.0 ml Purified water into above round bottom flask at 25-30°C under stirring. Added freshly prepared Methane sulphonic acid solution (5.90 gm of methanesulphonic acid in 25.0 ml of Isopropyl alcohol) into reaction mass at 25-30°C under stirring. Stirred the reaction mass for 3-4 hrs at 25-30°C. Filtered the solid and washed with isopropyl alcohol (2x50 ml). Suck dried for 20-30 minutes. Dried the material under vacuum for 24 hrs at 60-65°C. After complying the result of moisture content (not more than 1.2%) unload the material.
Dry wt.: 23.5gm.
Yield (w/w): 0.94
% Yield: 78.34
KF= 1.04%
4b). with 12% Aqueous Solution of Isopropyl alcohol:
Charged 1075 ml Isopropyl alcohol into 2.0 litres clean round bottom flask at 25-30°C under stirring. Charged 25.0 gm 4-(3-chloro-4-(3-cyclopropylureido) phenoxy)-7-methoxyquinoline-6-carboxamide into above round bottom flask at 25-30°C under stirring. Charged 150.0 ml purified water into above round bottom flask at 25-30°C under stirring. Added freshly prepared Methane sulphonic acid solution (5.90 gm of methane sulphonic acid in 25.0 ml of Isopropyl alcohol and cool to 25-30°C) into reaction mass at 25-30°C under stirring. Stirred the reaction mass for 3-4 hrs at 25-30°C. Filtered the solid and washed with isopropyl alcohol (2x50 ml). Suck dry for 20-30 minutes wet cake 30.5gm. Dried the material under vacuum for 24.0 hrs at 60-65°C. After complying the result of moisture content (not more than 1.2%) unload the material.
Dry wt.: 23.0gm.
Yield (w/w): 0.92
% Yield: 76.66
KF= 0.53%
4c). with 14% Aqueous Solution of Isopropyl alcohol:
Charged 1050 ml Isopropyl alcohol into 2.0 litres clean flask at 25-30°C under stirring. Charged 25.0 gm 4-(3-chloro-4-(3-cyclopropylureido) phenoxy)-7-methoxyquinoline-6-carboxamide into above round bottom flask at 25-30°C under stirring. Charged 175.0 ml Purified water into above round bottom flask at 25-30°C under stirring. Added freshly prepared Methane sulphonic acid solution (5.90 gm of methane sulphonic acid in 25.0ml of Isopropyl alcohol and cool to 25-30°C) into reaction mass at 25-30°C under stirring. Stirred the reaction mass for 3-4 hrs at 25-30°C. Filtered the solid and washed with isopropyl alcohol (2x50 ml). Suck dried for 20-30 minutes wet cake 25.50gm. Dried the material under vacuum for 24 hrs at 60-65°C. After complying the result of moisture content (not more than 1.2%) unload the material.
Dry wt: 20.0gm
Yield (w/w): 0.80
% Yield: 66.60
KF= 0.72%
The above mentioned examples, which are provided by way of illustration, should not be construed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities use etc.
,CLAIMS:We Claim:
1. A process for preparing of a crystalline Lenvatinib mesylate of formula (I),

Comprising the steps of:
a). condensing 4-chloro-7-methoxyquinoline-6-carboxamide of formula (III) with 4-amino-3-chlorophenol hydrochloride of formula (II), in the presence of an inorganic base and a first and second solvent to get 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline -6-carboxamide of formula (IV);

b). reacting 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline -6-carboxamide of formula (IV) as obtained in step a) with phenylchloroformate of formula (V) in the presence of organic base and a first solvent followed by an anti-solvent to isolate phenyl(4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl) carbamate of formula (VI);

c). condensation of phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl) oxy)-2-chlorophenyl) carbamate of formula (VI) with cyclopropylamine in presence of an organic base, first solvent followed by an anti-solvent to obtain 4-(3-chloro-4-(3-cyclopropylureido) phenoxy)-7-methoxyquinoline-6-carboxamide of formula (VII);

d). reacting 4-(3- chloro – 4 - (3-cyclopropylureido) phenoxy)-7- methoxyquinoline - 6 -carboxamide of formula (VII) with methane sulphonic acid in 10 to 15% aqueous solution of isopropyl alcohol to isolate crystalline form of compound formula (I) having purity greater than 99.7% (Area % by HPLC).

2. The process for the preparation of formula (I) as claimed in claim 1, wherein inorganic base used in step a) is selected from sodium carbonate, potassium carbonate or cesium carbonate.
3. The process for the preparation of formula (I) as claimed in claim 1, wherein the first solvent used in step a), b) and c) is selected from dimethylsulfoxide, dimethylformamide, water, acetonitrile, ethyl acetate, propyl acetate, isopropyl acetate, methylene dichloride, ethylene dichloride or mixture thereof.
4. The process for the preparation of formula (I) as claimed in claim 1, wherein second solvent used in step a) is toluene.
5. The process for the preparation of formula (I) as claimed in claim 1, wherein organic base used in step b) and c) is selected from pyridine, triethylamine, diisopropylamine or DBU.
6. The process for the preparation of formula (I) as claimed in claim 1, wherein anti-solvent used in step b) and c) is selected from dimethyl ketone, ethyl methyl ketone, isopropyl ketone, methyl isobutyl ketone, or diethyl ketone.
7. The crystalline Lenvatinib mesylate of formula (I) according to claim 1 wherein crystalline form described as Form SL is characterised by –
i). XRPD diffraction angel peaks at 5.9, 6.27. 11.63, 13.48, 14.06, 14.33, 17.75, 19.40, 28.45 and 33.75 ± 0.2° 2?;
ii). DSC thermogram having one exothermic peak ranging between 230 to 240°C;
8. The crystalline Lenvatinib mesylate of formula (I) according to claim 7 wherein crystalline form designated as Form SL is further characterised by percentage weight loss (TGA) upto less than 1.20% at temperature below 150°C and purity greater than 99.7% (Area % by HPLC).
9. Process for preparing crystalline Lenvatinib mesylate Form SL of formula (I), characterised by XRPD diffraction angel peaks at 5.9, 6.27. 11.63, 13.48, 14.06, 14.33, 17.75, 19.40, 28.45 and 33.75 ± 0.2° 2? comprising the steps of-
a). charging compound of formula (VII) to isopropyl alcohol at 25-30°C;
b). charging purified water ranging between 10-15% (v/v) with respect to
isopropyl alcohol in the reaction mass at 25-30°C under stirring;
c). adding methane sulphonic acid to the mixture of formula (VII) and aqueous solution of isopropyl alcohol;
d). stirring the reaction mass for 3-4 hrs at 25-30°C;
e). filtering the solid obtained in step-d);
f). washing the solid with isopropyl alcohol;
g). isolating crystalline Form SL of formula (I).
10. A crystalline Lenvatinib mesylate Form SL of formula (I) characterised by XRPD diffraction angel peaks at 5.9, 6.27. 11.63, 13.48, 14.06, 14.33, 17.75, 19.40, 28.45 and 33.75 ± 0.2° 2? having a purity greater than 99.7% (Area % by HPLC) and having water content (by KF) not more than 1.20% w/w.