DESC:Field of the invention:
The present invention relates to an improved process for the preparation of 4-[3-chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate compound of formula-1a. The said compound of formula-1a is represented by the following structural formula:

Formula-1a

Background of the Invention:
The 4-[3-chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate is commonly known as Lenvatinib mesylate.
Lenvatinib is an anti-cancer drug for the treatment of certain kinds of thyroid cancer, and potentially for other cancers as well. It was developed by Eisai Co. and acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2 and VEGFR3 kinases. The Lenvatinib is marketed under the trade name as Lenvima and its dosage form is capsule.
US7253286 has first disclosed the Lenvatinib and its process for the preparation. The said process provides Lenvatinib with low yield, hence not suitable for commercial level process.
Further, US7683172 disclosed an alternate process for the preparation of Lenvatinib. The said process involves the usage of cesium carbonate as a base and dimethyl sulfoxide as a solvent to provide Lenvatinib. Whereas, the usage of cesium carbonate as a base required high temperature and prolonged period of time to complete the reaction thereby increase the cost of the production.
In view of the above, there is a need to develop an alternate process for the preparation of Lenvatinib with the usage of low cost reagents and solvents, low temperatures and less reaction time which shall be suitable for the commercial scale process.
The present invention relates to an improved process for the preparation of Lenvatinib by the usage of potassium tertiary pentoxide as a base and dimethyl sulfoxide as a solvent to provide Lenvatinib with high purity and less reaction time when compare to the prior reported processes.

Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of Lenvatinib compound of formula-1.
The second aspect of the present invention is to provide an improved process for the preparation of Lenvatinib Mesylate compound of formula-1a.

Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, monoglyme, diglyme and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane/Methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, potassium tertiary pentoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 2-picoline, 3-picoline, 4-picoline, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.

The first aspect of the present invention is to provide an improved process for the preparation of Lenvatinib compound of formula-1, comprising of:
a) Reacting 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl-urea (Formula-2) with 4-chloro-7-methoxy-quinoline-6-carboxamide (Formula-3) in presence of a suitable base in a suitable solvent to provide Lenvatinib compound of formula-1,

b) optionally, purifying the compound of formula-1 with a suitable solvent to provide pure Lenvatinib compound of formula-1.
Wherein,
In step-a), the suitable base is selected from alkali metal alkoxides such as sodium
tert.butoxide, potassium tertiary pentoxide, lithium tert.butoxide, preferably potassium tertiary pentoxide. And the suitable solvent is selected from polar-aprotic solvent such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP);
In step-b), the suitable solvent is selected from ether solvents, chloro solvents, ester
solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents such as water or mixtures thereof.

In a preferred embodiment of the present invention provides an improved process for the preparation of Lenvatinib compound of formula-1, comprising of:
a) Reacting 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl-urea (Formula-2) with 4-chloro-7-methoxy-quinoline-6-carboxamide (Formula-3) in presence of potassium tertiary pentoxide in dimethylsulfoxide provides Lenvatinib compound of formula-1,
b) purifying the compound of formula-1 with dimethyl sulfoxide and acetonitrile provides pure Lenvatinib compound of formula-1.

The second aspect of the present invention is to provide an improved process for the preparation of Lenvatinib Mesylate compound of formula-1a, comprising of treating Lenvatinib with methanesulfonic acid in a suitable solvent to provide Lenvatinib Mesylate compound of Formula-1a.
Wherein the suitable solvent is selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents such as water or mixtures thereof.

In a preferred embodiment of the present invention provides an improved process for the preparation of Lenvatinib Mesylate compound of formula-1a, comprising of treating Lenvatinib with methane sulfonic acid in a mixture of methanol and acetone provides Lenvatinib Mesylate compound of Formula-1a.

The compound of Formula-2 and Formula-3 used in the present invention can be prepared from the process known in the art.

The present invention is schematically represented in Scheme-I

Scheme-I:

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples:

Exampe-1: Process for the preparation of Lenvatinib (Formula-1)
Dimethylsulfoxide (300 ml), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl-urea (28.73 g) (Formula-2) and 4-chloro-7-methoxy-quinoline-6-carboxamide (25.0 g) (Formula-3) were charged into RB flask under nitrogen atmosphere. Potassium tert-pentoxide solution 2.0M in tetrahydrofuran (63 ml) was added to the reaction mixture and stirred for 30 min at 25-30°C. Reaction mass temperature was raised to 55±5°C and stirred for 6 h. 33% of acetone in water (125 ml) and water (250 ml) were added to the reaction mass for 1h. Cooled the reaction mass to 40-45°C and stirred for 2h. Filtered the mass and washed the wet compound with 33% acetone in water followed by DM water and acetone to get the title compound as wet cake. Further, drying the compound to get the title compound. Dry wt: 32.69 g (72.3%)

Exampe-2: Process for the purification of Lenvatinib (Formula-1)
Dimethylsulfoxide (300 ml) was added to the compound obtained in example-1 (65.0 g) and raised the temperature of the reaction mixture to 55±5°C until dissolution. Treating the reaction mixture with charcoal (5 g) and filtering the reaction mixture. Acetonitrile (1050 ml) was added to the reaction mixture at 55±5°C. Cooled the reaction mixture to 40-45°C and stirred for 2h. Filtered the mass, washed with acetonitrile and drying to get the title compound. Yield: 25.6 g (56.7 %); Purity: > 99% by HPLC.

Exampe-3: Process for the preparation of Lenvatinib Mesylate (Formula-1a)
Lenvatinib (25.0g), methanesulfonic acid (6.19 g), methanol (75 ml) and acetone (425 ml) were charged into RB flask under nitrogen atmosphere. Stirred the reaction mixture at 25-30°C for 20h. Filtered the mass, washed with methanol and acetone and drying to get the title compound. Yield: 29g (95 %). Purity more than 99.5% by HPLC.
Exampe-4: Process for the preparation of Lenvatinib (Formula-1)
Dimethylsulfoxide (600 ml), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl-urea (57.46 g) (Formula-2) and 4-chloro-7-methoxy-quinoline-6-carboxamide (50 g) (Formula-3) were charged into RB flask under nitrogen atmosphere at 25-30°C. Raised the reaction mass temperature to 40-45°C. Potassium tert-pentoxide solution 2.0M in tetrahydrofuran (63 ml) was added to the reaction mixture. Again raised the reaction mass temperature to 50-55°C and stirred for 10 hrs. Cooled the reaction mass temperature to 40-45°C. 33% of acetone in water (500 ml) and water (500 ml) were added to the reaction mass and stirred at 40-45°C for 2h. Filtered the mass and washed the wet compound with 33% acetone in water followed by DM water and acetone to get the title compound as wet cake. Further, drying the compound to get the title compound. Dry wt: 62 g.

Exampe-5: Process for the purification of Lenvatinib (Formula-1)
Dimethylsulfoxide (600 ml) was added to the compound obtained in example-4 (62.0 g) and raised the temperature of the reaction mixture to 55±5°C until dissolution. Filtered the mass and washed the dimethylsulfoxide. Raised the reaction mass temperature to 55±5°C. Acetonitrile (2310 ml) was added to the reaction mixture at 55±5°C. Cooled the reaction mixture to 40-45°C and stirred for 2h. Filtered the mass, washed with acetonitrile and drying to get the title compound. Yield: 52 g; Purity: > 99% by HPLC.

Exampe-6: Process for the preparation of Lenvatinib Mesylate (Formula-1a)
Lenvatinib (25.0g), methanesulfonic acid (6.76 g), methanol (500 ml) were charged into RB flask under nitrogen atmosphere. Stirred the reaction mixture at 25-30°C for 13h. Filtered the mass, washed with methanol and drying to get the title compound. Yield: 30g (98.2 %). Purity more than 99.5% by HPLC.
,CLAIMS:We Claim:

1. An improved process for the preparation of Lenvatinib mesylate compound of formula-1a, comprising of:
a) Reacting 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl-urea (Formula-2) with 4-chloro-7-methoxy-quinoline-6-carboxamide (Formula-3) in presence of potassium tertiary pentoxide in dimethylsulfoxide provides Lenvatinib compound of formula-1,

b) optionally, purifying the compound of formula-1 with a suitable solvent to provide pure Lenvatinib compound of formula-1,
c) treating Lenvatinib with methane sulfonic acid in a suitable solvent provides Lenvatinib Mesylate compound of Formula-1a.

2. The process as claimed in claim-1, wherein,
In step-(b) the suitable solvent is selected from polar-aprotic solvents and nitrile
solvents or mixture thereof.
In step-(c) the suitable solvent is selected from alcohol solvents.

3. The process as claimed in claim-1, wherein the preparation of Lenvatinib mesylate compound of formula-1a, comprising of:
a) Reacting 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl-urea (Formula-2) with 4-chloro-7-methoxy-quinoline-6-carboxamide (Formula-3) in presence of potassium tertiary pentoxide in dimethylsulfoxide provides Lenvatinib compound of formula-1,
b) purifying the compound of formula-1 with dimethyl sulfoxide and acetonitrile to provide pure Lenvatinib compound of formula-1,
c) treating Lenvatinib with methane sulfonic acid in methanol provides Lenvatinib mesylate compound of Formula-1a.

4. A process for the preparation of Lenvatinib compound of formula-1, comprising of reacting 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropyl-urea (Formula-2) with 4-chloro-7-methoxy-quinoline-6-carboxamide (Formula-3) in presence of potassium tertiary pentoxide in dimethylsulfoxide provides Lenvatinib compound of formula-1.

5. The process as claimed in claims 1-3, the obtained Lenvatinib mesylate compound of Formula-1a having purity more than 99.5 % by HPLC.