DESC:FIELD OF INVENTION:
The present invention relates to a process for the preparation of N-[2-(diethyl amino) ethyl]-5-[(Z)-(5-fluoro-1, 2-dihydro-2-oxo-3H-indol-3-ylidene) methyl]-2, 4-dimethyl-1H-pyrrole-3-carboxamide or pharmaceutically acceptable salts thereof.

BACKGROUND OF INVENTION:
Sunitinib of formula I, is chemically known as N-[2-(diethyl amino) ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene) methyl]-2, 4-dimethyl-1H-pyrrole-3-carboxamide.

Formula I
Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that is approved as the malate salt (I) by the FDA for the treatment of renal cell carcinoma (RCC) and Imatinib-resistant gastrointestinal stromal tumor (GIST).

Sunitinib is marketed in the United States under the trade name SUTENT® by Pfizer, Inc.

Sunitinib was first disclosed in US6573293. In this patent 5-Fluoro-1, 3-dihydroindol-2-one was condensed with 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide at 78°C for 3 hours to give sunitinib.

The process as disclosed in US6573293 does not reveal the purity of intermediates and of sunitinib and also the experimental procedure for the preparation of sunitinib malate is not disclosed. The yield reported is very low and the separation of the impurities requires a crystallization process. These factors would in turn contribute to the poor recovery of the required intermediates.
WO2009/150523 discloses the preparation of sunitinib malate which comprises the preparation of the malate salt of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide in organic solvent, which is gummy solid, crystallized from n-butanol and then condensed with 5-fluoro-1,3-dihydroindol-2-one in the presence of an organic amine at higher temperature. The obtained malate salt of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide is brown colored gummy solid and has a low purity. Also the process involves many steps which would not be viable for an industrial scale up.

WO2012059941 discloses process for preparation of sunitinib malate which comprises condensing 5-fluoro-l,3-dihydroindol-2-one with 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, wherein 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethyl aminoethyl)amide is prepared by the amidation of 5-formyl-2,4-dimethyl-IH-pyrrole-3-carboxylic acid with ?,?-diethylaminoethylamine in the presence of a coupling agent and workup is done with alkali metal carbonate or bicarbonate. Overall yield is low and reported to be 77%.

The processes as disclosed in the prior art have a poor yield, the purity issues are persistent and also these processes would still pose problems from a commercial viability and industrial feasibility aspect .Hence there is still a need in the art to provide a commercially viable and improved process for preparation of sunitinib, which can overcome the problems associated with prior art.

OBJECTIVE OF THE INVENTION:
The object of the present invention is to provide improved process for the preparation of sunitinib or pharmaceutically acceptable salts thereof.

Another objective of the present invention is to provide a suitable purification and isolation process for intermediate, 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide.

Yet another objective of the present invention is to provide a suitable process for the preparation of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide.

Yet another object of the present invention is to provide a simple and economic process for the preparation of sunitinib which is suitable for industrial scale up.

SUMMARY OF THE INVENTION:
According to the first aspect of the present invention, there is provided a process for the purification of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide of formula II.

Second aspect of the present invention, provides a suitable process for the preparation of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide of formula II.

According to third aspect of the present invention, a process for the preparation of sunitinib or pharmaceutically acceptable salts thereof has been provided.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved process for the preparation of sunitinib or pharmaceutically acceptable salts thereof obtained through pure intermediate.

Accordingly, the present invention provides a simple process for the preparation of highly pure (>99.5 %) intermediate compound, 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide through acid-base treatment. The invention further provides use of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide for the preparation of “substantially pure sunitinib or pharmaceutically acceptable salts” thereof.

The process of the present invention is schematically represented as follows:

As used herein in the entire specification, the term “SUN acid” refers to 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid.

As used herein in the entire specification, the term “N, N-DEAEA” refers to N, N-diethyl ethylene diamine.

As used herein in the entire specification, the term “SUN amide” refers to 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide.

As used herein in the entire specification, the term “SUN Oxyindole” refers to 5-fluoro-1,3-dihydroindol-2-one.

As used herein in the entire specification, the term “substantially pure” refers to sunitinib free base having purity (measured by HPLC) above 99.5%, preferably above about 99. 7% and more preferably above about 99. 8%.

As used herein in the entire specification, the term “pure intermediate” refers to an intermediate having purity more than 99.5 %.
SUN amide of formula II is one of the key intermediate in the synthesis of sunitinib.

Accordingly, the present invention provides a process for the preparation and purification of SUN amide of formula II.

In one embodiment, SUN acid of formula III is coupled with N, N-DEAEA of formula IV using suitable coupling agent in a suitable base as depicted in step 1.

Suitable coupling agent employed in step 1 includes 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl), diisopropylcarbodiimide and dicyclohexylcarbodiimide (DCC).

The coupling agent can be used with or without catalyst such as 1-hydroxybenzotriazole monohydrate (HOBT.H2O).

The base employed is selected from organic base, such as triethylamine (TEA) and diisopropylethylamine (DIPEA), or any inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K2CO3), sodium carbonate (Na2CO3).

The reaction is carried out in a suitable solvent selected from the group comprising of organic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride (DCM or CH2Cl2), C1-C4 alcohols, esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone and the like.

The reaction is carried out at a temperature in the range of 0oC to 50oC preferably 25oC to 30oC.

After completion of the reaction, the reaction mixture is diluted with water and sodium chloride. The reaction mass is basified to the pH between 10 to 14 using suitable base.
The base employed in step 2 of the present invention is selected from organic base, such as triethylamine (TEA) and diisopropylethylamine (DIPEA), or any inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K2CO3), sodium carbonate (Na2CO3).

The organic layer is separated. An alcohol solvent may be added optionally, prior to the separation of the organic layer.

The organic layer is then washed with water, dried on suitable drying agent, optionally filtered on hyflo and distilled under vacuum to obtain SUN amide of formula II, which is further crystallized in suitable solvent, filtered, and dried under vacuum.

The temperature at which crystallization is carried out is in the range of -15oC to 30oC preferably in the range of -5°C to -10°C.

Alternatively SUN amide of formula II obtained by any process may be purified by the process of the present invention.

Another embodiment of the present invention provides an alternative process to purify SUN amide of formula II.

The purification process involves the following steps:
i. dissolving SUN amide of formula II in a suitable solvent;
ii. adding sodium chloride solution;
iii. adjusting pH to 5 to 8.5, using suitable acid;
iv. separating the organic layer;
v. optionally carrying out step ii, iii and iv;
vi. treating the organic layer with suitable base to adjust pH between 10 to 14;
vii. separating the organic layer , drying on suitable drying agent, optionally filtering on hyflo and distilling under vacuum to obtain SUN amide of formula II; and
viii. crystallizing SUN amide of formula II in suitable solvent, filtering, and drying under vacuum.
The solvents employed are selected from organic solvents such as methylene chloride (DCM or CH2CI2), chloroform, carbon tetrachloride, ethylene dichloride, esters such as methyl acetate, ethyl acetate, isopropyl acetate and the like).

The acid employed is selected from organic acid, such as formic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like.

The base employed is selected from organic base, such as triethylamine (TEA) and diisopropylethylamine (DIPEA), or any inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K2CO3), sodium carbonate (Na2CO3).

The temperature at which crystallization is carried out is in the range of -15oC to 30oC preferably -5°C to -10°C.

According to another aspect of the present invention, there is provided a substantially pure sunitinib free base or pharmaceutically acceptable salts thereof.

Yet another embodiment, the present invention provides a process for the preparation of substantially pure sunitinib or pharmaceutically acceptable salts thereof comprising converting SUN amide of formula II obtained by the following process
a) condensing SUN amide of formula II with SUN Oxyindole of formula V;

in presence of a suitable base, in a suitable solvent to form sunitinib base formula I;
b) converting sunitinib base to pharmaceutically acceptable salts.

Solvents employed in the preparation of sunitinib is selected from dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride (DCM or CH2CI2), C1-C4 alcohols, esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone and the like.
The base employed is selected from organic base, such as triethylamine (TEA) and diisopropylethylamine (DIPEA), pyrrolidine or any inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K2CO3), sodium carbonate (Na2CO3), lithium carbonate and lithium hydroxide.

Finally the sunitinib free base thus obtained by the process of the present invention is converted to pharmaceutically acceptable salts such as malate, tartrate, hydrochloride, sulfate, carbonate, lactate, maleate, succinate and the like.

Preferably, sunitinib free base is converted to malate salt by reacting with malic acid in suitable solvent.

Sunitinib malate obtained by the present invention has an overall yield of 94%.
The following examples are provided as illustration only, and are not intended to limit this invention in any way.

Examples:
Example: 1
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide
To a reaction mixture of 100.0 gm (0.0598 mole) of SUN Acid into 1000 ml of DMF at 25 to 30°C, charged 171.52 gm (0.0897 mole) of EDC HCl, and 119.31 gm (0.0788 mole) of HOBT monohydrate and stirred. Added 121.04 gm (0.1120 mole) of triethylamine at 10 to 15°C. The reaction mixture stirred at 25 to 30°C for 30 minutes. Added 83.39 gm of N, N-DEAEA (0.0712 mole) at 10 to 15°C Stirred for 4.0 hours at 25 to 30°C. Cooled the reaction mixture to 15°C and added water. Added 100.0 gm of solid sodium chloride and adjusted pH to 12.0 to 12.5 by 10% aqueous sodium hydroxide solution at 25 to 30°C. Added 10 volumes of MDC and 2.0 volumes of methanol. Stirred for 10 minutes, separated layers. Extracted the upper aqueous layer with 5 volumes of MDC and 1 volume of methanol. Organic layers combined and washed with water. Dried over anhydrous sodium sulphate. Distilled the MDC layer under vacuum below 40oC.
Added 4 volumes of ethyl acetate, stirred for 15 minutes at 40°C, cooled to 25 to 30°C, chilled to -10 to -5°C and stirred for 30 minutes at -10 to -5°C. Filtered the material and washed with 2 volumes of chilled ethyl acetate. Dried the material under vacuum at 55-65oC for 6 hours.
Dry weight is ~ 65.0 gm. HPLC purity 99.67%

Example: 2
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((2-diethylamino)ethyl)amide [Pure]
10 g of 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((2-diethylamino)ethyl)amide dissolved in 100 ml of MDC, at 25 to 30°C followed by 20 ml of 25% sodium chloride solution. The pH adjusted to 8.5 to 8.7 with 10% acetic acid solution, stirred for 10 to 15 minutes and separated the layers. The MDC layer treated with 20 ml of 25% sodium chloride solution. The pH adjusted to 8.5 to 8.7 with 10% acetic acid solution, stirred for 10 to 15 minutes and separated the layers. MDC layer washed with 30 ml of 2% NaOH solution [pH 12.0 to 13.5] thrice. MDC layer separated, dried over anhydrous sodium sulphate and distilled under vacuum. Added 20 ml of ethyl acetate, removed solvent under vacuum. Added 40 ml of ethyl acetate, chilled to -5 to -10°C, filtered, washed with 20 ml of chilled ethyl acetate and dried at 60 to 65°C under vacuum for 6 to 8 hours.
Dry weight is ~7.0 g. HPLC purity 99.76%

Example: 3
Preparation of sunitinib base
Stirred SUN Amide 100gm (0.0376 mole) and SUN Oxyindole 56.95gm (0.0376 mole) in 16 volumes of methanol. Added pyrrolidine 1.56 ml at 25 to 30°C. Heated to reflux at 60 to 65°C and maintained for 4 hours. Cooled to 25 to 30°C, stirred for 30 minutes, filtered the solid and washed with 2 volumes of methanol. Slurried the material in 10 volumes of water for 1 hour, filtered, washed with 2 volumes of water, dried under vacuum at 70 to 75°C for 12 hours.
Dry weight is ~ 120.0 gm. HPLC purity 99.76%

Example: 4
Preparation of Sunitinib L- malate

Sunitinib base 100 gm (0.025mole) added in a mixture of Isopropanol: water (1000ml) (9:1).Under stirring, added 33.62 gm (0.025mole) of L-malic acid in mixture of Isopropanol: water (400ml) (9:1) in 30 minutes. Heated the reaction mixture to 55 to 60°C for 30 minutes, cooled to 25 to 30°C and stirred for 30 minutes at 25 to 30°C. Filtered the solid and washed with 4 volumes of Isopropanol. Dried the solid under vacuum at 60 to 65°C for 10 - 12 hours.

Dry weight is ~ 120.0 gm. HPLC Purity 99.85%

Example: 5
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide

To a reaction mixture of 100.0 gm (0.0598 mole) of SUN Acid into 1000 ml of MDC at 25 to 30°C, charged 171.52 gm (0.0897 mole) of DCC, and 119.31 gm (0.0788 mole) of HOBT monohydrate and stirred. Added 121.04 gm (0.1120 mole) of triethylamine at 10 to 15°C. The reaction mixture stirred at 25 to 30°C for 30 minutes. The reaction mixture was further cooled to 10 to 15°C. Added 83.39 gm of N, N-DEAEA (0.0712 mole) at 10 to 15°C over a period of 20 to 30 minutes. Stirred for 16 hours at 25 to 30°C. On completion of reaction, the reaction mass was filtered and washed with MDC. The filtrate was charged in water and further pH was adjusted to 12.0 to 12.5 by 10% aqueous sodium hydroxide solution at 27±2°C. Stirred for 10 minutes, separated layers. Extracted the upper aqueous layer with 3x5 volumes of MDC. Combined organic layers were washed with 5.0 volume of 10% sodium bicarbonate solution and 5.0 volume of 10% sodium chloride solution. Distilled the MDC layer under vacuum below 40oC.
Added 4 volumes of ethyl acetate, cooled to 0 to -5°C and stirred for 30 minutes at 0 to -5°C. Filtered the material and washed with 2 volumes of chilled ethyl acetate. Dried the material under vacuum at 60±2°C for 8 hours.
Dry weight is ~ 95.0 gm. HPLC purity 99.67% ,CLAIMS:1. A process for preparation of substantially pure SUN amide of formula II [ 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide], an intermediate of sunitinib, comprising steps of :
i. dissolving SUN amide of formula II in a suitable solvent followed by addition of sodium chloride solution
ii. adjusting pH to 5 to 8.5, using suitable acid followed by separation of organic layer;
iii. treating the organic layer with suitable base to adjust pH 10 to 14;
iv. isolating the SUN amide from the organic layer and ;
v. crystallizing the SUN amide from suitable solvent.

2. The process according to claim 1, wherein the suitable solvent is selected from organic solvents such as methylene, chloroform, carbon tetrachloride, ethylene dichloride, esters such as methyl acetate, ethyl acetate, isopropyl acetate.

3. The process according to claim 1, wherein the suitable acid is selected from organic acid, such as formic acid, acetic acid or an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like.

4. The process according to claim 1, wherein the suitable base is selected from organic base, such as triethylamine (TEA) and diisopropylethylamine (DIPEA), or any inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K2CO3), sodium carbonate (Na2CO3).

5. The process according to claim 1, wherein the temperature at which crystallization is carried out is in the range of -15°C to 30°C, preferably -5°C to -10°C.

6. The process according to claim 1, wherein the SUN amide of formula II is obtained having purity >99.5 %, preferably >99. 7 %.

7. A process for the preparation of substantially pure sunitinib free base or pharmaceutically acceptable salts thereof comprising:
a. condensing substantially pure SUN amide of formula II prepared according to claim1

with SUN Oxyindole of formula V

in presence of a suitable base, in a suitable solvent to form sunitinib base; and
b. converting sunitinib base into its pharmaceutically acceptable salts.

8. The process according to claim 7, wherein the suitable solvent is selected from the group consisting of dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride (DCM or CH2CI2), C1-C4 alcohols, esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone.

9. The process according to claim 7, wherein the suitable base is selected from organic base, such as triethylamine (TEA) and diisopropylethylamine (DIPEA), pyrrolidine or any inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K2CO3), sodium carbonate (Na2CO3), lithium carbonate and lithium hydroxide.

10. The process according to claim 7, wherein, the sunitinib free base or pharmaceutically acceptable salt thereof is obtained having purity >99.5 %.

11. The process according to claim 7, wherein, the sunitinib free base or pharmaceutically acceptable salts thereof is obtained having purity >99.7 %.
12. The process according to claim 7, wherein, the sunitinib free base or pharmaceutically acceptable salts thereof is obtained having purity >99.8 %.

13. The process according to any one of the preceding claims 7 to 12, wherein the pharmaceutically acceptable salt of sunitinib is Sunitinib malate.