Claims:We Claim:
1) A process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts

(I)
comprising the steps of:
a. reacting 4-chloro-7-methoxyquinoline-6-carboxamide (IV)

(IV)

with 4-amino-3-chloro phenol (V)

(V)

in an organic solvent in presence of base at temperature ranging between 70-90°C to get 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (VI);

(VI)

b. reacting 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (VI) with 4-nitrophenyl cyclopropylcarbamate (III)

(III)

in an organic solvent in presence of base at temperature ranging between 40-90°C to get pure [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] (I);

(I)

c. optionally reacting [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] (I) with pharmaceutically acceptable acid in presence of organic solvent at temperature ranging between 50-85°C to get [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] pharmaceutically acceptable salt.

2) Substantially pure Lenvatinib (I) having purity greater than 99.5% and

d. DSC melting point ranging between 225°C to 235°C

e. TGA weight loss of less than 0.5% w/w

f. Total impurities less than 0.5% by HPLC.

3) The substantially pure Lenvatinib (I) according to Claim – 2, prepared by the process comprising the steps of:

a. combining Lenvatinib (I) with DMSO solvent in a ratio of 1:15-30 (w/v) at temperature ranging between 20-35°C

b. addition of organic solvent selected from isopropyl alcohol or acetone or ethyl acetate at 35-50°C

c. cooling the solution of step (b) and stirring for 15-16h to precipitate the solid and

d. isolating the substantially pure Lenvatinib (I).

4) The process for the preparation of Lenvatinib (I) according to Claim – 1, wherein the base is selected from inorganic base as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and potassium carbonate and organic base as triethylamine and pyridine.

5) The process for the preparation of Lenvatinib (I) according to Claim – 1, wherein the organic solvent is selected from dimethylsulphoxide, dimethylformamide, dichloromethane, acetonitrile, methanol, hexane, acetone and isopropylalcohol and/or mixtures thereof.

6) The process for the preparation of Lenvatinib (I) according to Claim – 1, wherein the pharmaceutically acceptable acid is selected from (L)-malic acid, citric acid, oxalic acid, methane sulfonic acid and phosphoric acid.

7) Novel pharmaceutically acceptable salts of Lenvatinib (I) are

(I-a) (I-b)

8) The process for the preparation of pharmaceutically acceptable salt (I-a) according to Claim – 5, comprises of treating the Lenvatinib (I) in an organic solvent with oxalic acid and isolating the oxalate salt of Lenvatinib (I-a).

9) The process for the preparation of pharmaceutically acceptable salt (I-b) according to Claim – 5, comprises of treating the Lenvatinib (I) in an organic solvent with (L)-malic acid and isolating the (L)-malate salt of Lenvatinib (I-b).

10) The process for the preparation of pharmaceutically acceptable salts (I-a) & (I- b) according to Claim – 5, wherein the reaction step is carried out at a temperature ranging between 50-85°C.

, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Lenvatinib (I) which is useful in the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.
The present invention also relates to novel pharmaceutically acceptable salts of Lenvatinib and its process of the preparation.

BACKGROUND OF THE INVENTION
Lenvatinib is chemically described as [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] and is represented by structural formula I.

(I)
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. LENVIMA® 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 the patent US 7,253,286 describes Lenvatinib or pharmaceutically acceptable salts thereof. In US 7,253,286 disclosure, it also describes preparation of Lenvatinib by reacting 4-chloro-7-methoxyquinoline-6-carboxamide with 4-amino-3-chlorophenol under basic condition to produce 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide, which upon N-Carbamate reaction with phenyl chloroformate, in dimethyl formamide gave phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-chlorophenylcarbamate followed by urea formation using Cyclopropyl amine in Dimethyl sulfoxide to produce Lenvatinib as per the scheme given below.

Matsushima, et al in US 7,612,208 describe various crystalline forms of Lenvatinib Mesylate and process for their preparation.
Naito, et al in US 7,683,172 describe a process for preparation of Lenvatinib by performing reaction of 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 route of synthesis of Lenvatinib as delineated in the disclosure as below:

Sakaguchi, et al in US 7,550,483 B2 disclose the process for preparing Lenvatinib by reacting 4-chloro-7-methoxyquinoline-6-carboxamide with 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea to produce Lenvatinib as depicted in the scheme below.

Oruganti, et. al in IN 201641011188 A1 describe the process for the preparation of Lenvatinib by reacting 4-chloro-7-methoxyquinoline-6-carboxamide with 4-amino-3-chlorophenol under basic condition to produce 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide, which upon N-Carbamate reaction with phenyl chloroformate, in dimethyl formamide gave phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-chlorophenylcarbamate followed by urea formation using Cyclopropyl amine in Dimethyl sulfoxide to produce Lenvatinib as per the scheme given below.

Despite various prior disclosures of the processes for preparing Lenvatinib, they still suffer with one or more drawbacks including commercially non-viable processes, handling concerns in plant besides multistep impurities removal etc. Considering the therapeutic importance of Lenvatinib, there still exist needs to develop and provide an improved commercially viable process, which is robust and amenable to scale up resulting in improved quality characteristics of active pharmaceutical ingredient.

SUMMARY OF THE INVENTION
The invention disclosed in the specification relates to improved process for preparation of anticancer compound Lenvatinib, which is presently approved for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer besides expanded indication for the use in combination with everolimus for the treatment of patients with advanced Renal cell Carcinoma (RCC) following one prior anti-angiogenic therapy.
In one aspect according to the present invention, it relates to a new process for preparing Lenvatinib (I),

(I)
comprising the steps of:
a. reacting 4-chloro-7-methoxyquinoline-6-carboxamide (IV)

(IV)

with 4-amino-3-chloro phenol (V)

(V)

in an organic solvent in presence of base at temperature ranging between 70-90°C to get 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (VI);

(VI)

b. reacting 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (VI) with 4-nitrophenyl cyclopropylcarbamate (III)

(III)

in an organic solvent in presence of base at temperature ranging between 40-90°C to get pure [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] (I);

(I)

c. optionally reacting [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] (I) with pharmaceutically acceptable acid in presence of organic solvent at temperature ranging between 50-85°C to get [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] pharmaceutically acceptable salt .
In another aspect, the present invention relates to novel pharmaceutically acceptable salts of Lenvatinib (I)

(I-a) (I-b)

In yet another aspect, the present invention also relates to process for the preparation of novel pharmaceutically acceptable salts of Lenvatinib (I-a) and (I-b).
In yet further another aspect according to the present invention, it relates to a process for the purification of Lenvatinib of Formula I, comprising:
i. combining Lenvatinib (I) with DMSO solvent in a ratio of 1:15-30 (w/v) at temperature ranging between 20-35°C
ii. addition of organic solvent selected from isopropyl alcohol or acetone or ethyl acetate at 35-50°C
iii. cooling the solution of step (ii) and stirring for 15-16h to precipitate the solid and
iv. isolating the substantially pure Lenvatinib (I).

In yet further aspect, the present invention relates to Substantially pure Lenvatinib (I) having purity greater than 99.5% and
a. DSC melting point ranging between 225°C to 235°C
b. TGA weight loss of less than 0.5% w/w
c. Total impurities less than 0.5% by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1: is an example of X-ray powder diffraction ("XRPD") pattern of Lenvatinib free base.
Fig. 2: is an example of Differential Scanning Calorimetry (DSC) thermogram of Lenvatinib free base.
Fig. 3: is an example of Thermogravimetric Analysis (TGA) of Lenvatinib free base.
Fig. 4: is an example of X-ray powder diffraction ("XRPD") pattern of Lenvatinib Oxalate salt (I-a).
Fig. 5: is an example of Differential Scanning Calorimetry (DSC) thermogram of Lenvatinib Oxalate salt (I-a).
Fig. 6: is an example of X-ray powder diffraction ("XRPD") pattern of Lenvatinib (L)-Malate salt (I-b).
Fig. 7: is an example of Differential Scanning Calorimetry (DSC) thermogram of Lenvatinib (L)-Malate salt (I-b).
Fig. 8: is an example of Thermogravimetric Analysis (TGA) of Lenvatinib (L)-Malate salt (I-b).
DETAILED DESCRIPTION OF THE INVENTION
In their endeavor for the present invention, it provides new commercially useful process for preparation of Lenvatinib (I) and its novel salts (I-a) and (I-b).
In one embodiment according to the present invention, it provides process for preparing Lenvatinib (I),

(I)

Said process according to the present invention for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts, comprising the steps of:
a) reacting 4-chloro-7-methoxyquinoline-6-carboxamide (IV)

(IV)

with 4-amino-3-chloro phenol (V)

(V)

in an organic solvent in presence of base at temperature ranging between 70-90°C to get 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (VI);

(VI)

b) reacting 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (VI) with 4-nitrophenyl cyclopropylcarbamate (III)

(III)

in an organic solvent in presence of base at temperature ranging between 40-90°C to get pure [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] (I);

(I)

c) optionally reacting [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] (I) with pharmaceutically acceptable acid in an organic solvent at temperature ranging between 50-85°C to get [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] pharmaceutically acceptable salt.
The individual steps of the process according to the present invention are detailed herein below; however more specifics are demonstrated by virtue of working examples given in the example section.
The process step (a) of reacting 4-chloro-7-methoxyquinoline-6-carboxamide (IV) with 4-amino-3-chloro phenol (V) is carried out in the presence of a base selected from the group consisting of inorganic base such as alkali metal hydroxide as potassium hydroxide, sodium hydroxide and an alkali metal carbonate as sodium carbonate, sodium bicarbonate, potassium carbonate and organic base as triethylamine and pyridine.
In one of the specific embodiment, potassium hydroxide was used.
The suitable organic solvents that can be used in step (a) are selected from the group comprising of polar aprotic solvent as dimethylsulphoxide, dimethylformamide and halocarbonated solvents as dichloromethane and alcohols as methanol, isopropylalcohol and nitriles as acetonitrile, hydrocarbon solvents as hexane and toluene, ketones as acetone and/or mixtures thereof in any proportion without limitation.
The process step (a) is performed at a temperature ranging between 60-90°C.
In one of the particular embodiment according to present invention, the process step (a) reaction was performed at temperature 70-80°C for a time duration of about 12-15 hours.
The mole ratios of reactants and the reagents used therein can be appropriate based on the resultant product and the side products or by products.

The organic solvents that can be used in the process step (b) is selected from the group consisting of polar aprotic solvents as dimethylsulphoxide, dimethylformamide and halocarbonated solvents as dichloromethane and alcohols as methanol, isopropylalcohol and nitriles as acetonitrile, hydrocarbon solvents as hexane and toluene, ketones as acetone and/or mixtures thereof in any proportion without limitation.
In one of the specific embodiment, dichloromethane was used.
The process step (b) is performed at a temperature ranging between 30-90°C.
In one of the particular embodiment according to present invention, the process step (b) was performed at temperature 40-45°C for a time duration of about 35-40h.
In a particular embodiment according to present invention, the process step (b) was performed at temperature 80-85°C for a time duration of about 21-25h.
The suitable organic solvents that can be used in the process step (c) is selected from the group consisting of polar aprotic solvents as dimethylsulphoxide, dimethylformamide and halocarbonated solvents as dichloromethane and alcohols as methanol, isopropylalcohol and acetonitrile, hydrocarbon solvents as hexane and toluene, acetone and/or mixtures thereof in any proportion without limitation.
In one of the specific embodiment, methanol or isopropylalcohol was used.
The suitable pharmaceutically acceptable acid that can be used in the process step (c) is selected from (L)-malic acid, citric acid, oxalic acid, methane sulfonic acid and phosphoric acid.
In a particular embodiment according to present invention, the process step (c) was performed at temperature ranging between 50-85°C.
In yet another embodiment, the present invention provides a process for the purification of Lenvatinib of Formula I, comprising:
i. combining Lenvatinib (I) with DMSO solvent in a ratio of 1:15-30 (w/v) at temperature ranging between 20-35°C
ii. addition of organic solvent selected from isopropyl alcohol or acetone or ethyl acetate at 35-50°C
iii. cooling the solution of step (ii) and stirring for 15-16h to precipitate the solid and
iv. isolating the substantially pure Lenvatinib (I).
The step (i) of providing Lenvatinib solution, comprise adding / mixing crude / impure Lenvatinib obtained from any source into crystalline form at room temperature.
The solvent used for the dissolution of Lenvatinib in step (i) is selected from the group consisting of alcohols as isopropylalcohol and ketones as acetone and polar aprotic solvents as dimethylsulphoxide and esters such as ethyl acetate or mixtures thereof or their aqueous mixtures.
The temperature required for dissolution can range from about 40-45°C.
The precipitation of solid in step (ii) is achieved but not limited to evaporation, cooling, drying, or by adding anti-solvent.
In yet another embodiment, the present invention provides substantially pure Lenvatinib (I) having purity greater than 99.5% and
a. DSC melting point ranging between 225°C to 235°C
b. TGA weight loss of less than 0.5% w/w
c. Total impurities less than 0.5% by HPLC
The term “substantially pure Lenvatinib” means that the Lenvatinib is at least 99% purity with less than 0.5 % of total impurities as measured by HPLC. More preferred is where the analytical purity is at least 99.5%; even further preferred is where the Lenvatinib may completely free of impurities.
The term “substantially pure Lenvatinib” refers to the total absence, or near total absence, of impurities, such as related-substance impurities. For example, when Lenvatinib is said to be substantially pure, there are either no detectable related-substance impurities, or if a single related-substance impurity is detected, it is present in an amount not greater than 0.1% by weight, or if multiple related-substance impurities are detected, they are present in aggregate in an amount not greater than 0.5% by weight.
In yet another embodiment according to present invention, the purity of substantially pure Lenvatinib was 99.55%. In certain other worked lab processes, it was found to
The mole ratios of reactants and the reagents used therein can be appropriate based on the resultant product and the side products or byproducts.
For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
Advantageously, the process of present invention avoids the use of hazardous reagents thus making the process ecofriendly.
The reagents used herein the process of present invention are cheaper, commercially available and may not form impurities or side products unlike in the prior art processes.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
The processes reported for the preparation of Lenvatinib (I) in the art results in the formation of various impurities and byproducts leading to include additional purification steps intermittently at several stages thus resulting in very poor yields of the final product.
Advantageously, the process of present invention provides substantially pure Lenvatinib (I) with higher yields and purities by using novel intermediate process.
The present invention provides simple, ecofriendly, economical, reproducible, robust process for the preparation of Lenvatinib (I) which is well feasible on a commercial scale.
Advantageously, the process of present invention described herein has simple reaction steps, produces the intermediate surprisingly in high yields and purities than the processes reported in the literature and well amenable on commercial scale.
As used herein, the term "HPLC" refers to High-performance liquid chromatography. As used herein, the term "area % by HPLC" refers to the area in an HPLC chromatogram of one or more peaks compared to the total area of all peaks in the HPLC chromatogram expressed in percent of the total area.
Substantially pure Lenvatinib (I) obtained by the process of present invention was analyzed by high performance liquid chromatography (HPLC) method with the conditions and instrument as given below,
Chromatographic conditions: The liquid chromatograph is equipped with a UV/PDA detector
HPLC Make: Agilent 1260 infinity
Column: Inertsil ODS-3V, 250 X 4.6 mm, 5.0?m
Wave length: 250nm.
Flow: 1.0mL/min.
Load: 10µL
Run time: 55minutes.
Column oven temperature: 40°C.
Concentration: 0.4mg/mL.
Diluent: Water : Methanol : Acetonitrile : (25:25:150 % v/v/v).
Mobile phase-A: Transfer about 1.0mL of H3PO4 (88%) in 1000 mL of Milli-Q-water Filter and degas through 0.45µ membrane filter.
Mobile phase-B: Mixture of acetonitrile and water in the ratio of 900mL and 100mL.
Standard preparation: Weigh 8.0mg of standard sample in 20mL volumetric flask, dissolve in diluent and make up to mark with diluent.
Sample preparation: Weigh 8.0mg of test sample in 20mL volumetric flask, dissolve in diluent and make up to mark with diluent.
Procedure: Equilibrate the chromatographic system with mobile phase until stable baseline is observed.
Then proceed for the analysis as per below mentioned sequence.
S.No. Name of the sample No. of injections
1. Blank 1 or 2
2. Standard solution 1
3. Test solution 1
4. Standard solution 1

Record the chromatograms for 55mins and measure the peak responses. Inhibit the peaks due to blank. The retention time for Lenvatinib peak is about 16mins.

In yet another embodiment, the present invention provides substantially pure Lenvatinib (I) characterized by X-ray powder diffraction pattern as depicted in fig.1 and differential scanning calorimetry (DSC) thermogram as depicted in fig.2.
Substantially pure Lenvatinib (I) obtained by the process of present invention was characterized by XRPD using the XRPD method and instrument details as given below,
Method of Analysis:
Instrument Used: Powder X-ray diffractometer
Make: Bruker AXS.
Model: D2 Phaser.
Scan type: Coupled two theta / theta
Two theta range: 3.0° – 40.0o.
Step size: 0.012 deg.
Time for step: 0.44 sec.
Generator KV: 30.
Generator mA: 10.
Detector: Lynx Eye (PSD electronic window -5°)
Rotation speed: 15 Rpm.
Total scan time: 25 min 34sec.
X- Ray source: Cu Ka (Wave length = 1.54 A°)
Substantially pure Lenvatinib (I) is obtained by the process of present invention was also characterized by Differential Scanning Calorimetry (DSC) using the method and instrument details as given below.
Method of analysis:
Equilibrate temperature: 30 °C.
Ramp rate: 5.00 °C / min.
End temperature: 300 °C.
Nitrogen Flow: 50mL/Min
Sample size: Approximately 2 mg.
Instrument: DSC Q500.
Model: Q100-1001.
Serial No: 0100-1001
Make: TA instruments – Waters.
Sample Preparation: Weigh approximately 2mg of sample by using hermetic or standard pans. Close the pans with hermetic or standard lids then place the pans in Pellet press and apply the pressure manually. Open the lid of the instrument and place the pan containing sample on sample cell and empty pan on reference cell and close the lid of the instrument.

In another embodiment, the present invention provides novel pharmaceutically acceptable salts of Lenvatinib (I).

(I-a) (I-b)

In yet another embodiment, the present invention also relates to process for the preparation of novel pharmaceutically acceptable salts of Lenvatinib (I-a) and (I-b).
The pharmaceutically acceptable salts of formula (I-a) & (I-b) are identified as novel and was isolated, characterized by NMR and MASS.
In another embodiment, the Lenvatinib (I) obtained by the processes of the present invention may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions or 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. ethyloleate, 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 (I) obtained as per the process of present invention 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.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
Examples
Example-1: Preparation of 4-nitrophenyl cyclopropylcarbamate (III):
To a stirred solution of nitrophenyl chloroformate (88.0g, 0.436 mol) in dichloromethane (1000 mL) was added cyclopropyl amine (25.0 g, 0.437 mol) at 0-5oC over a period of 50-60 min. The reaction mixture was warmed to room temperature and stirred for 24-26h. After consumption of starting material, the reaction mixture was filtered and washed with dichloromethane (100 mL). The filtrate was evaporated under reduced pressure to obtain the solid. The solid was slurried in hexane (500 mL), filtered and washed the cake with hexane (100 mL). Again the obtained solid was slurried in hexane (500 mL), filtered and washed with hexane (100 mL). The wet cake was dried to obtain 4-nitrophenyl cyclopropylcarbamate 3 (65 g) as an off white solid. Yield: 65.0g (66.7%)
1H NMR (500 MHz, DMSO-d6): d 8.29-8.20 (m, 3H), 7.40 (dd, J = 7.1, 2.0 Hz, 2H), 2.62-2.56 (m, 1H), 0.69-0.64 (m, 2H), 0.52-0.50 (m, 2H).

Example-2: Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (VI):
To a stirred solution of 4-chloro-7-methoxyquinoline-6-carboxamide (IV) (50g, 0.211 mol) in DMSO (250 mL) was added 4-amino-3-chloro phenol (V) (42.5 g, 0.296 mol) at room temperature. After 5-10 min, 50% KOH solution (50 mL) was added dropwise over a period of 30-40 min at room temperature. The reaction mixture was warmed to 70-80oC and stirred at the same temperature for 12-13h. After consumption of starting material, the reaction mass was cooled to room temperature and water (500 mL) was added to obtain the solid. The contents were stirred for 60 min at room temperature, filtered the solid, washed with water (150 mL) and dried to afford 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (VI) (54 g) as light brown solid. Yield: 54.0g (74.3%). Purity: 99.73 % (Area % by HPLC)
1H NMR (CDCl3, 400 MHz): d 9.27 (s, 1H), 8.64 (d, J = 5.3 Hz, 1H), 7.79 (brs, 1H), 7.52 (s, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 8.6, 2.6 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 6.46 (1 d, J = 5.3 Hz, 1H), 5.95 (brs, 1H), 4.12 (s, 3H), 4.11 (s, 2H); Mass (m/z): 343.9 (M+H)

Example-3: Preparation of Lenvatinib: [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] (I):
To a stirred solution of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (VI) (5g, 0.014 mol) in DCM (50 mL) was added 4-nitrophenyl cyclopropylcarbamate (III) (6.46g, 0.029 mol) followed by triethylamine (2.94g, 0.029 mol) at room temperature. The reaction mixture was warmed to 40-45oC and stirred at the same temperature for 35-40h. The reaction mixture was cooled to room temperature and stirred for 30min. Filtered the solid, washed with DCM (20 mL) and dried to afford Lenvatinib [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] (I) (2.8 g) as an off white solid. Yield: 2.8g (45.1%). Purity: 92.53% (Area % by HPLC).
1H NMR (DMSO-d6, 500 MHz): d 8.67 (d, J = 5.2 Hz, 1H), 8.66 (s, 1H), 8.28 (d, J = 9.1 Hz, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 7.50 (d, J = 2.8 Hz, 1H), 7.25 (dd, J = 9.1, 2.8 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 6.53 (d, J = 5.2 Hz, 1H), 4.04 (s, 3H), 2.62-2.56 (m, 1H), 0.70-0.64 (m, 2H), 0.46-0.40 (m, 2H); Mass (m/z): 427.74 (M+H)

Example – 4: Alternate process for Lenvatinib (I):
To a stirred solution of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (VI) (50g, 0.145 mol) in acetonitrile (500 mL) was added 4-nitrophenyl cyclopropylcarbamate (III) (63g, 0.278 mol) followed by pyridine (34.5g, 0.434 mol) at room temperature. The reaction mixture was heated to 80-85oC and stirred at the same temperature for 13h. Another lot 4-nitrophenyl cyclopropylcarbamate (III) (10g, 0.044 mol) was added and stirred for 7-8h at 80-85oC. The reaction mixture cooled to room temperature and filtered the reaction mass. The obtained solid washed with acetonitrile (100 mL) and crude solid dissolved in methanol: DCM (1:1, 1560 mL). The solution was warmed to 40-45oC, carbon (25g) was added and stirred for 1h at the same room temperature. Filtered the reaction mass and filtrate evaporated below 40oC under vacuum to furnish crude which was slurried in acetone (250 mL) and filtered to furnish Lenvatinib [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide] (I) (32 g). Yield: 32.0g (51.6%). Purity: 98.27% (Area % by HPLC).

Example-5: Purification of Lenvatinib using dimethyl sulfoxide and isopropyl alcohol:
To a stirred solution of Lenvatinib (32g, crude) in DMSO (640 mL) was added IPA (1600 mL) dropwise at 40-45oC. The suspension was cooled to room temperature and stirred for 15-16h. Filtered the solid, cake washed with water (50 mL) followed by acetone (100 mL). The wet cake dried at 50oC under vacuum to obtain Lenvatinib (23g) with 99.54% HPLC purity. Yield: 23g (71.8%). Purity: 99.54% (Area % by HPLC). mp 228.23°C.

Example-6: Purification of Lenvatinib using dimethyl sulfoxide and acetone:
To a stirred solution of Lenvatinib (7g, crude) in DMSO (140 mL) was added acetone (420 mL) dropwise at 40-45oC. The suspension was cooled to room temperature and stirred for 6 days. Filtered the solid, cake washed with water (20 mL) followed by acetone (20 mL). The wet cake dried at 50oC under vacuum to obtain Lenvatinib (1.7g) with 99.55% HPLC purity. Yield: 1.7g (24.2%). Purity: 99.55% (Area % by HPLC).

Example-7: Process for Lenvatinib oxalate: 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide oxalate (I-a):
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide (I) (5g, 0.011 mol) in acetone (200 mL) was added oxalic acid (1.27 g, 0.014 mol) at room temperature. The reaction mixture was heated to 60-65oC and stirred for 6-7h at the same temperature. The suspension was cooled to room temperature and stirred for 15-16h. The obtained solid was filtered, washed with acetone (30 mL) and dried to yield Lenvatinib oxalate [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide oxalate] (I-a) (5.8 g) as an light brown solid. Yield: 5.8g (95.8%). Purity: 99.26% (Area % by HPLC).
1H NMR (DMSO-d6, 500 MHz): d 8.71-8.68 (m, 1H), 8.67 (s, 1H), 8.28 (d, J = 9.1 Hz, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.73 (s, 1H), 7.52 (s, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.25 (dd, J = 9.5, 3.0 Hz, 1H), 7.19 (d, J = 3.0 Hz, 1H), 6.55 (d, J = 5.3 Hz, 1H), 4.03 (s, 3H), 2.61-2.56 (m, 1H), 0.70-0.64 (m, 2H), 0.46-0.40 (m, 2H); Mass (m/z): 427.15 (M+H). mp 171.89°C.

Example-8: Process for Lenvatinib (L)-malate: 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide (S)-2-hydroxysuccinate (I-b):
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide (I) (4g, 0.009 mol) in acetone (120 mL) was added (L)-malic acid (1.5g, 0.011 mol) at room temperature. The reaction mixture was heated to 60-65oC and stirred for 6-7h at the same temperature. The suspension was cooled to room temperature and stirred for 18-20h. The obtained solid filtered, washed with acetone (15 mL) and dried to give Lenvatinib (L)-malate [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide (S)-2-hydroxysuccinate] (I-b) (5 g) as an off white solid. Yield: 5.0g (95.2). Purity: 99.63% (Area % by HPLC).
1H NMR (DMSO-d6, 500 MHz): d 12.33 (broad, 1H), 8.67 (s, 1H), 8.66 (s, 1H), 8.27 (d, J = 9.1 Hz, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.48 (d, J = 3.0 Hz, 1H), 7.24 (dd, J = 9.0, 2.5 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.53 (d, J = 5.2 Hz, 1H), 4.28-4.23 (m, 1H), 4.03 (s, 3H), 2.64-2.56 (m, 2H), 2.57-2.40 (m, 1H), 0.70-0.64 (m, 2H), 0.46-0.40 (m, 2H); Mass (m/z): 426.9 (M+H). mp 160.46°C.

Example-9: Preparation of Lenvatinib mesylate: [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide methane sulfonate] (I-c):
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide (I) (1g, 0.002 mol) in methanol (20 mL) was added MSA (0.2g, 0.002 mol) at room temperature. The reaction mixture was heated to 60-65oC, the clear solution was cooled to room temperature and stirred for 15-16h. The obtained solid was filtered, washed with methanol (3 mL) and dried to furnish Lenvatinib mesylate [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide methane sulfonate] (I-c) (0.45 g) as an off white solid. Yield: 0.45g (37.5%). Purity: 95.19% (Area % by HPLC).
1H NMR (DMSO-d6, 500 MHz): d 8.98 (d, J = 6.5 Hz, 1H), 8.73 (s, 1H), 8.37 (d, J = 9.1 Hz, 1H), 8.07 (s, 1H), 7.97 (brs, 1H), 7.91 (brs, 1H), 7.64 (s, 2H), 7.36 (d, J = 9.1, 2.8 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 6.95 (d, J = 6.5 Hz, 1H), 4.09 (s, 3H), 2.62-2.56 (m, 1H), 2.35 (s, 3H), 0.71-0.60 (m, 2H), 0.47-0.41 (m, 2H).

Example-10: Alternate process for Lenvatinib mesylate (I-c):
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide (I) (5g, 0.011 mol) in IPA (50 mL) was added MSA (1.1g, 0.011 mol)] at room temperature. The reaction mixture was heated to 80-85oC and stirred at the same temperature for 7-8h. The reaction mass was cooled to room temperature and stirred for 15-18h. The obtained solid was filtered, washed with IPA (10 mL) and dried to yield Lenvatinib mesylate [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide methane sulfonate] (I-c) (5 g) as an off white solid. Yield: 5.0g (81.6%).

Example-11: Process for Lenvatinib citrate: 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide 2-hydroxypropane-1,2,3-tricarboxylate (I-d):
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide (I) (5g, 0.011 mol) in acetone (200 mL) was added citric acid (2.7g, 0.014 mol) at room temperature. The reaction mixture was heated to 60-65oC and stirred for 6-7h at the same temperature. The suspension was cooled to room temperature and stirred for 15-16h. The obtained solid was filtered, washed with acetone (20 mL) and dried to furnish Lenvatinib citrate [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide 2-hydroxypropane-1,2,3-tricarboxylate] (I-d) (6 g) as an off white solid. Yield: 6.0g (82.7%). Purity: 99.78% (Area % by HPLC).
1H NMR (DMSO-d6, 500 MHz): d 12.21 (broad, 1H), 8.67 (s, 1H), 8.66 (s, 1H), 8.28 (d, J = 9.0 Hz, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 7.49 (d, J = 3.0 Hz, 1H), 7.24 (dd, J = 9.0, 2.5 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.53 (d, J = 5.3 Hz, 1H), 4.03 (s, 3H), 2.73, 2.64 (ABq, J = 15.5 Hz, 4H), 2.61-2.56 (m, 1H), 0.70-0.64 (m, 2H), 0.46-0.40 (m, 2H); Mass (m/z): 426.9 (M+H).

Example-12: Process for Lenvatinib phosphate: 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide phosphate (I-e):
To a stirred suspension of 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide (I) (5g, 0.011 mol) in IPA (200 mL) was added phosphoric acid (1.37 g, 0.013 mol) at room temperature. The reaction mixture was heated to 80-85oC and stirred at the same temperature for 4-5h. The suspension was cooled to room temperature and stirred for 15-16h. The obtained solid filtered, washed with IPA (20 mL) and dried to obtain Lenvatinib phosphate [4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide phosphate] (I-e) (5.0 g) as an off white solid. Yield: 5.0g (81.9%). Purity: 99.57% (Area % by HPLC).
1H NMR (DMSO-d6, 500 MHz): d 8.67 (m, 1H), 8.66 (s, 1H), 8.27 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.52 (s, 1H), 7.49 (d, J = 3.0 Hz, 1H), 7.24 (dd, J = 9.0, 2.5 Hz, 1H), 7.19 (d, J = 3.0 Hz, 1H), 6.53 (d, J = 5.2 Hz, 1H), 4.03 (s, 3H), 2.62-2.56 (m, 1H), 0.69-0.64 (m, 2H), 0.45-0.40 (m, 2H); Mass (m/z): 426.9 (M+H).

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.