Claims:1. An improved process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. condensing 4-chloro-7-methoxyquinoline-6-carbonitrile of formula (II)

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


in the presence of base to produce 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV);

b. conversion of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV) in the presence of peroxide, and a base to provide 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V);

c. condensation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V) with phenylhaloformate or 3-phenylpropanoic acid esters in presence of base to produce phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenylcarbamate (VI); and

d. condensing phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenyl carbamate (VI) with cyclopropylamine to produce Lenvatinib (I).

2. An improved process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts according to claim 1, wherein base used in step a) or step b) or step c) are selected from organic base such as methylamine, triethylamine, diisoproylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate; wherein acid esters is used in step-c) is selected from 3-phenylpropanoic acid methyl ester, 3-phenylpropanoic acid ethyl ester, 3-phenylpropanoic acid isopropyl ester, phenyl 3-phenylpropanoate.

3. A process for the preparation of Lenvatinib according to claim 1, wherein the solvent comprises one or more of water, alcohol, ketone, ester, halogenated hydrocarbon, polar aprotic solvent, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or mixtures thereof. The process as claimed in claim 1, wherein the alcohol is selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; the ketone is selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone; the ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and N-methyl- pyrrolidone.

4. An improved process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. condensing 4-chloro-7-methoxyquinoline-6-carbonitrile of formula (II)

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


in presence of base to produce 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV);

b. conversion of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV) to Lenvatinib or its pharmaceutically acceptable salts.

5. An improved process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts according to claim 4, wherein base used in step a) or step b) or step c) are selected from organic base such as methylamine, triethylamine, diisoproylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate.

6. A process for the preparation of Lenvatinib according to claim 1, wherein the solvent comprises one or more of water, alcohol is selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; the ketone is selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone; the ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and N-methyl- pyrrolidone.

7. An improved process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a) conversion 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV)

in presence of peroxide and a base to provide 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V);

b) conversion of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V) to Lenvatinib or its pharmaceutically acceptable salts

8. An improved process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts according to claim 7, wherein base used in step a) or step b) or step c) are selected from organic base such as methylamine, triethylamine, diisoproylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate; wherein acid is used in step-b) is selected from organic acid such as organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, alkyl/aryl sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, the inorganic acid is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; wherein acid esters is used in step-c) is selected from 3-phenylpropanoic acid methyl ester, 3-phenylpropanoic acid ethyl ester, 3-phenylpropanoic acid isopropyl ester, phenyl 3-phenylpropanoate.

9. A process for the preparation of Lenvatinib according to claim 8, wherein the solvent comprises one or more of alcohol, ketone, ester, halogenated hydrocarbon, polar aprotic solvent, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or mixtures thereof. The process as claimed in claim 1, wherein the alcohol is selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; the ketone is selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone; the ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and N-methyl- pyrrolidone.

10. Use of Lenvatinib and its pharmaceutical acceptable salts obtained according to any of the preceding claims in the preparation of pharmaceutical composition.
, Description:FIELD OF THE INVENTION
The present invention provides an improved process for preparation of Lenvatinib Mesylate (Formula I) and its pharmaceutically acceptable salts thereof, which is useful as kinase inhibitor.

BACKGROUND OF THE INVENTION
Lenvatinib is chemically known as 4-[3­chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate. Lenvatinib is a kinase inhibitor, which is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, and it is approved by USFDA February 13, 2015 under the brand name Lenvima®.

Lenvima is marketed in the form of crystalline mesylate salt, which is a white, non-hygroscopic, crystalline powder with empirical formula C21H19ClN4O4 • CH4O3S and molecular weight 522.96. It is slightly soluble in water and practically insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of Lenvatinib mesylate is 5.05 at 25°C and partition coefficient (log P value) is 3.30.

Lenvatinib and its pharmaceutical acceptable salts are first disclosed in US 7,253,286 B2 and process for the preparation involves reacting 4-amino-2-chlorobenzonitrile reacted with MeONa to yield 4-amino-2-methoxybenzonitrile, which is condensed with 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione to yield 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene) methyl)amino)-2-methoxybenzonitrile. The obtained is cyclized in presence of Dowtherm to produce 7-Methoxy-4-oxo-1,4-dihydroquinoline-6-carbonitrile, which undergoes hydrolysis to produce 7-Methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid. The obtained acid is halogenated to yield 4-chloro-6-methoxyquinoline-7-carbonyl chloride, which is aminated in presence of ammonia to produce 4-chloro-7-methoxyquinoline-6-carboxamide. The obtained carboxamide is condensed with 4-amino-3-chlorophenol in presence of NaH / DMSO to yield 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide, which is followed by condensation with phenyl chloroformate to yield phenyl (4-((7-carbamoyl-6-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)carbamate, which is then finally condensed with cyclopropanamine in presence of DMSO to yield Lenvatinib.

The above process is schematically represented as below:

Tomohiro et al in US 7612208 B2 discloses a process for the preparation of Lenvatinib mesylate comprising condensation of 4-amino-3-chlorophenol reacted with phenyl chloroformate to yield phenyl (2-chloro-4-hydroxyphenyl) carbamate, which is then condensed with cyclopropylamine to yield 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea. The obtained is reacted is then reacted with 4-chloro-7-methoxyquinoline-6-carboxamide to yield Lenvatinib, which is further converted to Mesylate salt by treating Methanesulphonic acid. Furthermore this patent also discloses crystalline forms of Lenvatinib and its pharmaceutically acceptable salts.

The above process is schematically shown as below

Nakamura et al in WO 2016/031841 disclosed a process for the preparation of Lenvatinib and its pharmaceutically acceptable salts comprising condensation of 4-chloro-7-methoxyquinoline-6-carboxamide with 4-amino-3-chlorophenol to yield 4-chloro-7-methoxyquinoline-6-carboxamide or its salt, which is followed by condensation with compound of formula (A) or (B) in presence of base to yield carbonate compound, which is then condensed with cyclopropylamine in the presence of hydrous organic acid to yield Lenvatinib or its salt.

CN 104876864 B disclosed a process for the preparation of Lenvatinib comprising protection of 4-amino-3-chlorophenol using Boc anhydride to yield tert-butyl (2-chloro-4-hydroxyphenyl) carbamate followed by condensation with 4-chloro-7-methoxyquinoline-6-carboxamide in presence of Cs2CO3 and DMSO to produce tert-butyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)carbamate is deprotected in the presence of 2N HCl in MeOH to produce hydrochloride salt of 4-chloro-7-methoxyquinoline-6-carboxamide, which is further condensed with cyclopropylamine in the presence of CDI / TEA and DCM to produce Lenvatinib.

Further review of the available literature regarding Lenvatinib mesylate discloses various other processes for its preparation. However, due to one or more drawbacks with respect to the production of side products, the use of expensive coupling reagents, less than desirable yields, and the need for multiple reaction steps, most of them are not particularly convenient and economical for industrial scale up.

Hence, there is an unmet need to develop improved, cost effective and industrially amenable processes for the preparation of Lenvatinib mesylate involving less number of steps and providing higher yield of end product with better purity.

Therefore, inventors of the present application provide a simple high yielding process for preparation of highly pure Lenvatinib, which overcomes the disadvantages associated with prior disclosed literature methods.

OBJECTIVE OF THE INVENTION
The main objective of the invention is to provide an improved process for the preparation of Lenvatinib and its pharmaceutically acceptable salts.

Yet another object of the present invention is to provide an improved process for the preparation of Lenvatinib intermediates.

SUMMARY OF THE INVENTION
The main aspect of the present invention relates to an improved process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. condensing 4-chloro-7-methoxyquinoline-6-carbonitrile of formula (II)

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


in the presence of base to produce 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV);

b. conversion of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV) in the presence of oxidizing agent and a base to provide 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V);

c. condensation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V) with phenylhaloformate or 3-phenylpropanoic acid esters in presence of base to produce phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenylcarbamate (VI); and

d. condensing phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenyl carbamate (VI) with cyclopropylamine to produce Lenvatinib (I).

Another aspect of the present invention relates to an improved process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. condensing 4-chloro-7-methoxyquinoline-6-carbonitrile of formula (II)

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

in presence of base to produce 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV);

b. conversion of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV) to Lenvatinib or its pharmaceutically acceptable salts.

Further aspect of the present invention relates to an improved process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a) conversion 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV)

in presence of oxidizing agent and a base to provide 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V);

b) conversion of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V) to Lenvatinib or its pharmaceutically acceptable salts

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved, commercially viable and industrially –advantageous process for the preparation of Lenvatinib and its pharmaceutically acceptable salts thereof.

In one embodiment, the present invention relates an improved process for the preparation of Lenvatinib (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. condensing 4-chloro-7-methoxyquinoline-6-carbonitrile of formula (II)

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

in the presence of base to produce 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV);

b. conversion of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV) in the presence of oxidizing agent and a base to provide 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V);

c. condensation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V) with phenylhaloformate or 3-phenylpropanoic acid esters in presence of base to produce phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenylcarbamate (VI); and

d. condensing phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenyl carbamate (VI) with cyclopropylamine to produce Lenvatinib (I).

In one embodiment the present invention relates to a process for the preparation of Lenvatinib and its pharmaceutically acceptable salts comprising, condensation of 4-chloro-7-methoxyquinoline-6-carbonitrile of formula (II) or its salts selected from hydrochloride and the like thereof with 4-amino-3-chloro phenol (III) in presence of base selected from organic base such as methylamine, triethylamine, diisoproylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate; a solvent selected from comprises one or more of alcohol, ketone, ester, halogenated hydrocarbon, polar aprotic solvent, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or mixtures thereof. The process as claimed in claim 1, wherein the alcohol is selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; the ketone is selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone; the ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and N-methyl- pyrrolidone; at a temperature ranging from 70-90 °C for a period of 12 hours to 14 hours to obtain compound of formula (IV). The reaction mixture was allowed to cooled to 25-30 °C and the obtained solid was filtered. The solid was washed with water and suck dried. The obtained product may dried under vacuum to obtained 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile

According to the present invention, the said methods should in particular be more industrially scalable, allow the desired compounds to be obtained with high yields, and use cheaper reagents which are simpler to handle and industrial applicable.

On the other hand, the prior art process does not suggest the particular process for the preparation of Lenvatinib. Further, the prior art processes involves the use of excess solvents and reagents, further involves distillation of solvent and purifications, which leads in the decomposition of product and lowering the quantity of yield.

To overcome the above disadvantage the inventors of the present invention developed a process, which is industrially liable, viable and environmental friendly.

The above obtained pure 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile is converted to Lenvatinib or its pharmaceutically acceptable salts using any of the prior art processes / process, which are feasible for a person skilled in the art.

The above obtained 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV) is converted to 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V) comprising dissolving 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV) and a base selected from such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate; in a suitable solvent selected from solvent comprises one or more of water, alcohol is selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; the ketone is selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone; the ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and N-methyl- pyrrolidone; at a temperature ranging from 0 -50°C, to the obtained solution an oxidizing agent has been added selected from Hydrogen peroxide, Urea Hydrogen peroxide was added dropwise for a period of 30 minutes to 2 hours at a temperature ranging from 0-50°C. The obtained reaction mass was stirred for 2 to 4 hours at same temperature. The obtained reaction mixture was added to water and the precipitated solid was filtered to obtain pure 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide.

The above conversion from 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (IV) to 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V) may also carried out in presence or absence of oxidizing agents and in presence of acids selected from Hydrochloric acid, sulfuric acid, trifluoro acetic acid, nitric acid etc.

The prior art processes involves conversion of nitrile intermediate to acid, which follows conversion to its aid halide and finally to an amide. However, the present inventors now developed a process for the preparation of amide in a single step, which is industrially feasible and environmental friendly.

The prior art processes involves the use of excess solvents and reagents, further involves distillation of solvent and purifications, which leads in the formation of additional impurities in the product and also lowers the quantity of yield.

The present process yields in 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide, which is highly pure and free of these process related impurities and higher yields compared to prior art processes.

The above obtained pure 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide is converted to Lenvatinib or its pharmaceutically acceptable salts using any of the prior art processes / process, which are feasible for a person skilled in the art.

The present inventors further converted above obtained pure 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide to Lenvatinib or its pharmaceutically acceptable salts comprises condensation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (V) with phenylhaloformate or any other carbamates like alkyl carbamates, phenyl carbamates, imidazole carbamates ; in presence of base to produce phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenylcarbamate (VI); and selected from organic base such as methylamine, triethylamine, diisoproylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate; at a temperature ranging from 0-5° C and stirred for two hours to 4 hours at 25-30° C. The precipitated reaction solid was filtered and followed by water and saturated sodium bicarbonate solution through pH adjustments. The solid was filtered and washed with water and suck dry for 1 hour to get 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenyl carbamate

The above obtained 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenyl carbamate was further converted to Lenvatinib by condensation with cyclopropylamine, in presence of a solvent selected from one or more of alcohol, ketone, ester, halogenated hydrocarbon, polar aprotic solvent, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or mixtures thereof. The process as claimed in claim 1, wherein the alcohol is selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, and 2-pentanol; the ketone is selected from acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone; the ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; and the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and N-methyl- pyrrolidone; at temperature ranging from 5-100 °C for 2 hours to 4 hours. After completion of the reaction, Lenvatinib was isolated using any of the known techniques.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-65°C for a time ranging from 12 to 16 hours depending upon the physical attributes of the end product obtained i.e. Pure Lenvatinib or its pharmaceutically acceptable salts mainly mesylate salt obtained according to the present invention is having purity greater than 99.5%.

The obtained pure Lenvatinib or its pharmaceutically acceptable salts having purity greater than 99.5% and substantially free from process related impurities:

The process related impurities that appear in the impurity profile of the Lenvatinib may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:

The process related impurities that appear in the impurity profile of the Lenvatinib (I) or its pharmaceutically acceptable salts may be substantially removed by the process of the present invention resulting in the formation of Lenvatinib (I) or its pharmaceutically acceptable salts of high purity.

The merit of the process according to the present invention resides in that product isolated after drying is directly obtained as pure Lenvatinib or its pharmaceutically acceptable salts (I). Said material is found devoid of any other crystal lattice and is adequately stable to handle and store for longer time (alteast up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics. Lenvatinib or its pharmaceutically acceptable salts (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99.5 % w/w, and found to be stable at different ICH conditions.

In another embodiment, the Lenvatinib or its pharmaceutically acceptable salts (I) obtained by the processes of the present application 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. 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 or its pharmaceutically acceptable salts (I) obtained as per the present application process- 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 or its pharmaceutically acceptable salts (I) 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.

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 invention.
EXAMPLES
Example-1:
Preparation of 4-Chloro-7-Methoxyquinoline-6-carbonitrile Hydrochloride:
1,4-dihydro-7-methoxy-4-oxoquinoline-6-carbonitrile (150 gm, 0.75 mol), thionyl Chloride (3750.0 ml, 51.69 mol) and dimethylformamide (5.0 ml, 0.065 mol) were charged into a round bottom flask at 25-30° C. Stir the reaction mass and allow to refluxed for 2 hours. The solvent from the reaction mixture was distilled out under vacuum below 70° C to get to get brown color solid. Toluene (2 × 150 ml) was added to solid and distilled out the solvent under vacuum to get brown color solid. n-heptane was added to the solid material and stirred for 1 hour at 25-30° C. The wet solid was filtered and dried under vacuum to obtain title compound.
Purity: 91.75%
Yield: 185.0-gm

Example-2:
Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile:
Charged 4-amino-3-chloro phenol (258.0 gm, 1.80 mol) and acetonitrile (5550.0 ml) in to reaction flask and added K2CO3 (416.25 gm 3.01 mol) at 25-30 °C. The reaction mixture was stirred for 15 min at 25-30° C and addition of 4-chloro-7-methoxyquinoline-6-carbonitrile hydrochloride (185.0 gm, 0.726 mol) to reaction mixture and heated to reflux for 12-14 hours. The reaction mixture was allowed to 25-30 °C and filtered to solid. The solid material was dissolved in DM water (1850.0 ml) and stirred for 1 hour at 25-30 ° C. The solid was filtered and washed with water (185.0 ml) and dried to get 192.0 gm of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile.
Purity: 87.97%
Yield: 192.0-gm

Example-3:
Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide:
4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6- carbonitrile (110 gm, 0.337 mol), KOH (27.5 gm, 0.49 mol) and 25% Methanol in DMSO (2860.0 ml) stirred at 0-5 °C. 30% Hydrogen Peroxide (110.0 ml) was added to the reaction mixture in 1-2 hours at 0-5 °C and stirred for two hour at 0-5 °C. Reaction mixture was added to the DM water (9000.0 ml) at 25-30 °C and stirred for 1 hr. The precipitated solid was filtered to obtain 90.0 gm of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide.
Purity: 97.63%
Yield: 90.0-gm

Example-4
Preparation of phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenyl carbamate:
4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile (50.0 gm, 0.145 mol) and dimethylformamide (5.0 ml, 0.052 mol) were taken in dichloromethane (2000.0 ml) and cooled to 0-5° C and allow to stir for few minutes, slow addition of phenyl chloroformate (75.0 ml 0.598 mol) was added to the reaction mixture in 1-2 hours at 0-5° C and stirred for two hours at 25-30° C. The precipitated reaction solid was filtered and followed by water (500.0 ml) and saturated sodium bicarbonate solution through pH adjustments. The solid was filtered and washed with water (50.0 ml) and suck dry for 1 hour to get 58.0 gm of title compound.
Purity: 95.64%
Yield: 58.0gm (Practical)
Example-6
Preparation of Lenvatinib
phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-chlorophenyl carbamate (50.0 gm, 0.107 mol) and cyclopropylamine (7.5 ml, 0.107 mol) were added to the mixture of dimethylsulfoxide (750 ml) and acetonitrile (1750.0 ml) and stirred at 50-55 °C for 2 hrs. acetonitrile was distilled out under vacuum to obtain residue. DM Water (2250 ml) was added to residue in 30 min. The precipitated solid was filtered and suck dry for 1 hour to get 38.0 gm of 1-(4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-chlorophenyl)-3-cyclopropylurea or Lenvatinib (I) .
Purity: 98.71%
Yield: 38.0-gm

Example-8
Preparation of Lenvatinib Mesylate
To a mixture of Acetic acid (200.0 mL) and iso-propyl alcohol (200.0 mL) was added 1-(4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-chlorophenyl)-3-cyclopropylurea (20.0 g, 0.0467 mol) obtained in Example 6 and the reaction mixture was stirred at 10-15° C for 30 min. To the reaction mass Methane sulfonic acid (6.25 mL, 0.065 mol) was added and stirred at 25-30 °C for 1 hours and added ethyl acetate (200 mL) to obtain solid which was further dried to obtain titled crystals.
Purity: 99.85%
Yield: 18.5-gm