THEREOF FIELD OF THE INVENTION

The present invention provides a process for the preparation of Lenvatinib or its salts thereof.

BACKGROUND OF THE INVENTION

Lenvatinib Mesylate, 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7- methoxy-6-quinolinecarboxamide has the following chemical formula (Formula I).

Formula I

Lenvatinib Mesylate is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFRl, 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 Form A, B, C, F and I of Lenvatinib Mesylate and processes for their preparation.

US20070117842A1 describes crystalline Form A and Form B of Lenvatinib Free base.

WO 2016/184436 Al describes Crystalline Form M of Lenvatinib Mesylate and process for its preparation. WO '436 discloses the use of acetonitrile for the crystallization of Lenvatinib Mesylate Form M.

Our co-pending application IN 201641044843 discloses crystalline form VN1 of Lenvatinib Mesylate

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 R ¹ represents hydrogen, C _1-6 alkyl or C3-8 cycloalkyl, and wherein R ² 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 100°C to produce 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide , which upon N-Carbamate reaction with phenyl chloroformate, in dimethyl formamide at room temperature gave phenyl 4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2- chlorophenylcarbamate followed by urea formation using Cyclopropyl amine in Dimethyl sulfoxide at 85°C to produce Lenvatinib.

Despite the existence of processes for the preparation of Lenvatinib and its intermediates, there remains a need for providing a novel solution that would decrease the consumption of time and labor and it is of particular importance to develop methods that would allow for the increase in yields and purity of particular steps, which in turn would favor an increase of the yield of the whole technology.

SUMMARY OF THE INVENTION

In an aspect, the present invention provides a crystalline form of Lenvatinib, characterized by X-ray powder diffraction pattern having peaks at about 4.13, 10.38, 12.41, 14.04 16.59, 17.36, 19.06, 20.03, 20.92, 21.70, 22.41, 23.53, 26.75, 28.04, 29.20, 29.44 + 0.20 degrees 2-theta.

In an aspect, the present invention provides a process for the preparation of Lenvatinib, which is characterized by the PXRD pattern as shown in figure 1. In another aspect, the present invention provides process for the preparation of Lenvatinib or its salts.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 illustrates an X-ray powder diffractogram of Lenvatinib.

DETAILED DESCRIPTION OF THE INVENTION

In an aspect, the present invention provides a crystalline form of Lenvatinib, characterized by X-ray powder diffraction pattern having peaks at about 4.13, 10.38, 12.41, 14.04 16.59, 17.36, 19.06, 20.03, 20.92, 21.70, 22.41, 23.53, 26.75, 28.04, 29.20, 29.44 + 0.20 degrees 2-theta.

In an aspect, the present invention provides a process for the preparation of Lenvatinib, which is characterized by the PXRD pattern as shown in figure 1.

In an aspect, the present invention provides a process for the preparation of Lenvatinib of formula VIII,

Formula VIII

comprising:

a) halogenating the compound of formula II,

Formula II

with a halogenating agent to obtain a compound of formula III,

Formula III

wherein X is halogen;

b) amidation of compound of formula III to obtain a compound of formula IV,

Formula IV

wherein X is halogen;

c) coupling the compound of formula IV with a compound of formula V thereof,

d) reacting the compound of formula VI with phenylchloroformate to obtain compound of formula VII,

Formula VII

e) reacting the compound of formula VII with cyclopropyl amine to obtain the compound of Formula VIII

Formula VIII

Optionally, the compound of formula VIII is converted to pharmaceutically acceptable salt or salts thereof.

In step a) halogenating the compound of formula II is carried out in a solvent medium chosen from phosphorus oxychloride, thionyl chloride, toluene, tetrahydrofuran, dimethylformamide or the like and the reaction temperature may vary from about room temperature to about reflux temperature of the solvent, and the reaction time may vary from about 10 minutes to about 30 hours. The halogenating agent is selected from phosphorus oxychloride, thionyl chloride or the like. The obtained compound may be carried to the next step without isolation or can be isolated and purified before proceeding to the next step. The isolated compound may optionally be washed after isolation with a suitable solvent such as: water; an alcohol like methanol; a ketone like acetone, methyl isobutyl ketone; a nitrile like acetonitrile; a halogenated hydrocarbon like dichloromethane; any mixtures thereof. The isolated compound may optionally be dried by conventional techniques such as rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof at temperatures such as about 35°C to about 70°C, or higher for about 1 to about 20 hours, or longer.

In step b) the amidation of the compound of formula III to obtain compound of formula IV is using aqueous ammonia and may be carried out in a solvent medium selected from tetrahydrofuran, toluene, dimethylformamide, methanol or the like. The reaction temperature may vary from about room temperature to about reflux temperature of the solvent. The reaction time may vary from about 10 minutes to about 30 hours. The obtained compound may be carried to the step next without isolation or can be isolated and purified before proceeding to the next step. The isolated compound may optionally be washed after isolation with a suitable solvent such as: water; an alcohol like methanol; a ketone like acetone; a nitrile like acetonitrile; a halogenated hydrocarbon like dichloromethane; any mixtures thereof. The isolated compound may optionally be dried by conventional techniques such as rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof at temperatures such as about 35°C to about 70°C, or higher for about 1 to about 20 hours, or longer.

In step c), coupling the compound of formula IV with a compound of formula V or salt thereof, may be carried out in a solvent medium such as 1-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, toluene, dimethylformamide; Dimethylactamide or the like. A base such as sodium hydride, potassium hydroxide, pyridine, triethylamine may be used for the reaction. The reaction temperature may vary from about room temperature to about reflux temperature of the solvent. The reaction time may vary from about 10 minutes to about 30 hours. The obtained compound may be carried to the next step without isolation or can be isolated and purified before proceeding to the next step. The isolated compound may optionally be washed after isolation with a suitable solvent such as: water; an alcohol like methanol, ethanol or 2-propanol; a ketone like acetone, MIBK; a nitrile like acetonitrile; a halogenated hydrocarbon like dichloro methane; any mixtures thereof. The isolated compound may optionally be dried by conventional techniques such as rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof at temperatures such as about 35°C to about 70°C, or higher for about 1 to about 20 hours, or longer.

In step d) the reaction may be conducted using a base such as pyridine or corresponding pyridine bases such as DMAP. The reaction solvent used may be dimethylsulfoxide, dimethylformamide, dimethylacetamide, NMP, tetrahydrofuran or the like. The reaction temperature may vary from about -40°C to about reflux temperature of the solvent. The reaction time may vary from about 10 minutes to about 30 hours. The obtained compound may be carried to the next step without isolation or can be isolated and purified before proceeding to the next step. The isolated compound may optionally be washed after isolation with a suitable solvent such as: water; an alcohol like methanol; a ketone like acetone; a nitrile like acetonitrile; a halogenated hydrocarbon like dichloro methane; any mixtures thereof. The isolated compound may optionally be recrystallized in a suitable solvent such as water; an alcohol like methanol; a ketone like acetone; a nitrile like acetonitrile; a halogenated hydrocarbon like dichloro methane; any mixtures thereof and can optionally be dried by conventional techniques such as rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof at temperatures such as about 35°C to about 70°C, or higher for about 1 to about 20 hours, or longer.

In step e) the reaction may be conducted using a base such as triethylamine. The reaction solvent used may be dimethylsulfoxide, dimethylformamide, dimethylacetamide or the like. The reaction temperature may vary from about -10 oC to about reflux temperature of the solvent. The reaction time may vary from about 10 minutes to about 30 hours. The obtained compound may be carried to the step next without isolation or can be isolated and purified before proceeding to the next step. The isolated compound may optionally be washed after isolation with a suitable solvent such as: water; an alcohol like methanol; a ketone like acetone; a nitrile like acetonitrile; a halogenated hydrocarbon like dichloro methane; any mixtures thereof. The isolated compound may optionally be recrystallized in a suitable solvent such as water; an alcohol like methanol; a ketone like acetone; a nitrile like acetonitrile; a halogenated hydrocarbon like dichloro methane; any mixtures thereof and can optionally be dried by conventional techniques such as rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof at temperatures such as about 35°C to about 70°C, or higher for about 1 to about 20 hours, or longer.

In an embodiment, the compound of formula VIII is reacted with methanesulfonic acid to form methanesulfonic acid salt of Lenvatinib of formula I

Formula I

In above embodiment, the reaction solvent used is methyl isobutyl ketone, dimethylacetamide or the like. The reaction temperature may vary from about 10 oC to about reflux temperature of the solvent. The reaction time may vary from about 10 minutes to about 30 hours. The isolated compound may optionally be washed with methyl isobutyl ketone or dimethylacetamide and can optionally be dried by conventional techniques such as rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof at temperatures such as about 35°C to about 70°C, or higher for about 1 to about 20 hours, or longer.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise.

The terms "about," the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

The term "optional" or "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the present application in any manner.

The following examples further illustrate the invention but should not be construed in any way limiting its scope.

Chromatographic Conditions and Parameters: Analytical Column Description: YMC Triart C18, 150 mm x 4.6 mm, 3.0μιη, Column Temperature: 30°C, Flow rate: 1.0 mL/min, Injection volume: 10 μί, Detection wave length: 241 nm & 272 nm, Diluent: Acetonitrile: Water 8:2 ratio

EXAMPLES

Example 1: Preparation of Methyl 4-chloro-7-methoxyquinoline-6-carboxylate.

10.0 g of methyl 7-methoxy-4-oxo-l, 4-dihydroquinoline-6-carboxylate, 90 mL of toluene and 8.2 g of phosphoryl chloride were taken in a flask at 25-30oC and heated to 90-95oC for 3-4 hours. The reaction was cooled to 25-30oC and 100 mL of demineralized water was added to the above reaction mass. The organic layer was washed with 50 mL of demineralized water and to this 41 mL of 20% sodium hydroxide solution was added. The resulting compound was filtered, washed and dried under reduced pressure to obtain the title compound.

Yield: 94.53 %; HPLC purity: 99.61%

Example 2: Preparation of 4-chloro-7-methoxyquinoline-6-carboxamide.

55.0 g of methyl 4-chloro-7-methoxyquinoline-6-carboxylate, 330 mL of methanol and 660 mL of 25% aqueous ammonia solution were taken in a flask at 25-30oC and stirred for 10-12 hours. 275 mL of demineralized water was added to the above reaction solution and filtered.

The filtered mass was washed with 165 mL of 15% methanolic solution and dried at 50-

55oCunder reduced pressure to obtain the title compound.

Yield: 88.97%; HPLC Purity: 99.41%

Example 3: Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide 9.89 g of 4-amino-3-chlorophenol hydrochloride and 100 mL of 1-methylpyrrolidone were taken in a flask and cooled to 2-8oC. 8.3 g of potassium hydroxide dissolved in 10 mL of water was added to the above flask. 10. Og of 4-chloro-7-methoxyquinoline-6-carboxamide was added to the above flask and the contents were heated to 80-85oC and maintained for 8 hours. 400 mL of 10% 1-propanol solution was added to the above flask and stirred. The contents were filtered and washed with 50 mL of 10% 1-propanol solution. The filtered compound was dried under reduced pressure at 56oC to obtain the title compound. The title compound was taken in a flask along with 88 mL of dimethylacetamide and heated to 60- 65oC. The seed compound 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6- carboxamide was added followed by addition of 88 mL of 1-propanol. The contents were cooled to 25-30oC and maintained for 3-4 hours. The contents were filtered and washed with 20 mL of 1-propanol. The filtered compound was dried under reduced pressure 76oC to obtain 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide .

Yield: 64.01%; HPLC purity: 99.8%

Example 4: Preparation of phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2- chlorophenyDcarbamate. 25. Og of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide , 6.33g of pyridine and 375 mL of dimethylformamide were taken in a flask at 25-30oC and stirred. The contents were cooled to -15 to -lOoC and 12.52g of phenylchloro formate was slowly added. The cooling was removed and 1875 mL of demineralized water was slowly added to the above flask at OoC. The contents were maintained for 1-2 hours at 20-25oC and filtered and washed with demineralized water (250 mL). The filtered compound was dried at 53oC under reduced pressure to obtain the title compound.

Yield: 81.9%; HPLC purity: 97.48%

Example 5: Preparation of Lenvatinib.

10. Og of phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl) carbamate and 100 mL of dimethylacetamide were taken in a flask at 25-30oC and cooled to 5-lOoC. 2.46g of cyclopropylamine was added to the above flask and stirred for 10-20 minutes. 200 mL of methyl isobutyl ketone was added to the above contents at 5-10oC and maintained for 4-5 hours. The contents were filtered at 5-10oC and dried at 52oC under reduced pressure to obtain the title compound. The PXRD pattern of the lenvatinib is as shown in figure 1.

Yield: 67.39 %; HPLC purity: 99.77%

Example 6: Preparation of Lenvatinib Mesylate.

10. Og of 4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-methoxyquinoli ne-6-carboxamide and 150 mL of dimethylacetamide were taken in an flask at 25-30oC and heated to 60-65oC to obtain a clear solution. 2.25g of methanesulfonic acid was taken in 20 mL of methyl isobutyl ketone and added to the above solution at 25-30oC. Another 280 mL of methyl isobutyl ketone was added to the above reaction mass and stirred at 25-30oC for 2-3 hours. The reaction mass was filtered and washed with methyl isobutyl ketone and dried under reduced pressure at 55oC to obtain the title compound.

Yield: 86.5%; HPLC purity: 99.83%

Example 7: Preparation of Lenvatinib Mesylate.

100.0 g of phenyl (4-((6-carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl) carbamate and 800 mL of dimethylacetamide were taken in a flask at 25-30oC. 14.77 g of cyclopropylamine taken in 100 mL of dimethylacetamide was added to the above flask at 25°C. The contents of the above flask were stirred at 25-30oC for 1-2 hours. 2000 mL of methyl isobutyl ketone was added to the above flask and the reaction mass was maintained for 8-10 hours. The contents were filtered and washed with 500 mL of methyl isobutyl ketone. The filtered compound was dried at 70-80°C for 8-10 hours. The dried material was taken in fresh flask along with 890 mL of diemethylacetamide and heated to 70-80oC for 30- 60 minutes. The contents were then cooled to 40-50°C and 1780 mL of methyl isobutyl ketone was added. The reaction mass was maintained for 3-4 hours at 40-50°C and then cooled to 25-30oC. The reaction mass was filtered and washed with methyl isobutyl ketone and then dried for 8-10 hours at 70-80 °C. The dried material was taken in a fresh flask along with 720 mL of dimethylacetamide and heated to 60-70°C for 30-60 minutes. The reaction mass was cooled to 25-30oC and 24.76 g of methanesulfonic acid taken in 100 mL of methyl isobutyl ketone was added to reaction mass and stirred for 1-2 hours. 1350 mL of methyl isobutyl ketone was further added and stirred for 3-4 hours. The reaction mass was filtered under nitrogen atmosphere and dried at 50oC under reduced pressure to afford the title compound.