DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

PROCESS FOR THE PREPARATION OF LENVATINIB

INTRODUCTION
The present invention provides process for the preparation of Lenvatinib and its intermediates.
BACKGROUND OF THE INVENTION
Lenvatinib Mesylate, 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide has the following chemical formula.

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.
US 7,253,286 describes Lenvatinib or pharmaceutically acceptable salts thereof. US 7,612,208 describes crystalline forms of Lenvatinib Mesylate and process for their preparation. US 7,683,172 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.
US 7,253,286 describes preparation of Lenvatinib 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 85oC to produce Lenvatinib.
The present application provides the synthesis of Lenvatinib which is based on inexpensive, environmentally friendly solvents and an economical process that is better suited for industrial application.
Summary
The present invention provides an improved process for the preparation of Lenvatinib.
Detail description
The present invention provides an improved process for the preparation of Lenvatinib using inexpensive solvents such as dimethylformamide in place of dimethylsulfoxide and carrying out the reaction at room temperature instead of elevated temperature.

Examples
Example 1: Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide
4-Amino-3-Chloro Phenol Hydrochloride (5.697g), DMSO (50.0 mL) and Potassium Carbonate (5.83g,) were taken in a flask and cooled to 10-15oC. Sodium hydride (60%, 1.69g) was added to the above flask under nitrogen atmosphere and maintained at 15-20oC for 30 minutes. The temperature of the reaction mixture was raised to 25-30oC and 4-Chloro-7-methoxyquinoline-6-carboxamide (5g) was added. The reaction mixture was heated to 55-60oc for 22 hours under nitrogen atmosphere. After the completion of the reaction, the reaction mixture was filtered and filtrate was added to distilled water (500mL) to obtain solid. The obtained solid was dissolved in tetrahydrofuran (250 mL) and distilled under reduced pressure. The distilled product was slurred in n-hexane and filtered. The product is dried in vacuum at 40oC to obtain the title compound.
Yield: 66.11%; purity: 98.375%
Example 2: Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide
4-Amino-3-Chloro Phenol Hydrochloride (57.2 g), DMF (500 mL) and Potassium Carbonate (58.45 g,) were taken in a flask and cooled to 10-15oC. Sodium hydride (60%, 16.9g) was added to the above flask under nitrogen atmosphere and maintained at 15-20oC for 30 minutes. The temperature of the reaction mixture was raised to 25-30oC and 4-Chloro-7-methoxyquinoline-6-carboxamide (50g) was added. The reaction mixture was heated to 55-60oc for 22 hours under nitrogen atmosphere. After the completion of the reaction, the reaction mixture was filtered and filtrate was added to distilled water (5000mL) to obtain solid. The obtained solid was dissolved in tetrahydrofuran (3000 mL) and distilled under reduced pressure. The distilled product was slurred in n-hexane and filtered. The product is dried in vacuum at 40oC to obtain the title compound.
Yield: 78.44%; purity: 99.58%
Example 3: Phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl) carbamate
4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (10 g), pyridine (10 mL) and DMF (100 mL) were taken in a flask under nitrogen atmosphere and cooled to 10-15oC. Phenyl Chloroformate (3.93 mL) was added to the reaction mixture and maintained at 25-30oC for one hour. After completion of the reaction, reaction mass was diluted with distilled water and filtered to obtain the title compound.
Yield: 82.08%; purity: 96.74%
Example 4: Preparation of Lenvatinib
Phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)carbamate (10 g) and DMF (100 mL) were taken in a flask under nitrogen atmosphere and cooled to 10-15oC. Cyclopropylamine (2.55 mL) was added to the reaction mixture and maintained at 25-30oC for one hour. After the completion of the reaction, the reaction mass was diluted with 30% acetone-water mixture (200 mL) and filtered. The obtained material was dried under vacuum at 30oC for one hour and slurred in methanol (200 mL). The solid was filtered and dried in vacuum at 40oC for 30 minutes to obtain the title compound.
Yield: 60%; purity: 98.77%
Example 5: Preparation of Lenvatinib
4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (5.0 g), pyridine (5 mL) and DMF (50 mL) were taken in a flask under nitrogen atmosphere and cooled to 10-15oC. Phenyl Chloroformate (2.31 mL) was added to the reaction mixture and maintained at 25-30oC for 30 minutes. Cyclopropyl amine (1.7 mL) was added to the reaction mixture and maintained at 25-30oC for 72 hours. After completion of the reaction, reaction mass was diluted with distilled water and filtered. The filtered material was dried in vacuum at 40oC for 30 minutes and then slurred in methanol (75 mL) and filtered. The product was dried in vacuum at 40oC for 30 minutes to obtain the title compound.
Yield: 55%; purity: 97.4%
Example 6: Preparation of 4-chloro-7-methoxy-6-methoxycarbonylquinoline
7-methoxy-6-methoxycarbonyl-1,4-dihydroquinolin-4-one (5.0g) and Toluene (50 mL) were taken in a clean and dry flask at 25-35oC. Phosphoryl chloride (6.5g) was added to the above flask and heated to 85-90oC. After the completion of the reaction, the reaction mass was cooled to 25-35oC and de-mineralized water (50 mL) was added to the above flask. The aqueous and organic layers were separated and the pH of the aqueous layer was adjusted around to 10. After 1-2 hours the reaction mass was filtered and washed with de-mineralized water. The solid was dried at 40-45oC under reduced pressure to afford the title compound.
Yield: 4.6g.
Example 7: 4-chloro-7-methoxyquinoline-6-carboxamide
4-chloro-7-methoxy-6-methoxycarbonylquinoline (3.0g) and 25% Aqueous Ammonia solution (24mL) were taken in a clean and dry RBF at 25-35°C. Methanol (15mL) and Water (15mL) were added to the above flask and stirred till the completion of the reaction. The reaction mass was filtered and washed with n-Hexane and dried under reduced pressure at 45-50oC to afford the title compound.
Yield: 2.3g
,CLAIMS:1. A process for the preparation of Lenvatinib comprising the steps of:
a. reacting 4-Chloro-7-methoxyquinoline-6-carboxamide with 4-Amino-3-Chloro Phenol or salt thereof in presence of base and solvent at 55-60oC;
b. adding phenyl Chloroformate to the product obtained in step a. in the presence of base and solvent at 25-35oC;
c. adding cyclopropylamine to the product obtained in step b. in presence of dimethylformamide at 25-35oC;
d. optionally, purifying the crude product from methanol.
2. The process of claim 1, wherein in step a. the base used is selected from Potassium Carbonate, Sodium hydride or mixtures thereof.
3. The process of claim 1, wherein in step b. the base is pyridine and solvent is dimethylformamide.