DESC:ECO-FRIENDLY PROCESS FOR THE PREPRATION OF HIGH PURITY SUNITINIB AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

FIELD OF THE INVENTION:
The present invention relates to an improved, economic and eco-friendly large-scale industrial process for the preparation of Sunitinib and pharmaceutically acceptable salt thereof. The present invention also relates to use of neat water for the preparation of highly pure Sunitinib with high yield.

BACKGROUND OF THE INVENTION:
Sunitinib (previously known as SU11248) is a kinase inhibitor indicated for (1) the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate; (2) the treatment of advanced renal cell carcinoma (RCC); (3) the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy; and (4) the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease.
Sunitinib (CAS ID: 557795-19-4) exists as yellow to orange powder and is a non-hygroscopic substance having no chiral center. Sunitinib is chemically known as N-(2-Diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. and is structurally represented as below:

Sunitinib Base [I]
Sunitinib malate (CAS ID: 341031-54-7) is structurally represented as below wherein Sunitinib base and Butanedioic acid is present in ratio of 1:1. Sunitinib malate is optically active due to malate part of the molecule.

Sunitinib Malate [II]

Sunitinib malate is the presently marketed salt in the formulation having brand name “SUTENT®” which was first approved by the United States Food and Drug Administration (USFDA) during January, 26, 2006. Primarily, it was approved by the USFDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). Sunitinib was the first cancer drug simultaneously approved for two different indications simultaneously. Studies have revealed that Sunitinib malate formulation is an oral, multi-targeted tyrosine kinase inhibitor (TKl) that targets and blocks the signaling pathways of multiple selected receptor tyrosine kinases (RTKs).
Sunitinib and Malate salt thereof are described in WO2001/060814 and its corresponding Indian product patent no. 209251 which is assigned to Sugen and Pharmacia & Upjohn. The reaction sequence may be schematically represented as follows in scheme-1:
Scheme-1: Process reported in WO2001/060814
Scheme-1 discloses the preparation of sunitinib by the condensation of 5-formyl-2,4-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide with 5-fluoro 2-oxindole in ethanol in presence of pyrrolidine. It may be important to note that by above claimed process final product yield is less than 70%. Hence, this process using above-mentioned reagents and solvents may produce high-cost product.
WO2003/070725 discloses reacting imidazole-amide derivative of formula-XI with N,N-Diethylaminoethylamine of formula- VI to get imine-amide derivative of formula-XII and its in-situ condensation with 5-Fluoro-2-oxindole of formula-IX in acetonitrile at 60° C for 18 hours affords Sunitinib base of formula-I.

Scheme-2: Process reported in WO2003/070725

Above patent has not reported purity of the final product which may point towards low purity Sunitinib was developed. The reaction sequence may be schematically represented in above scheme-2.
Indian patent application 2652/DEL/2010 discloses reacting 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid in the presence of hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) in tetrahydrofuran followed by addition of triethylamine and stirred for 5-6 hours at 25-30 °C. % yield of the final is not reported in the said Indian patent application may point towards low product yield which may not be viable at industrial scale due to production of high cost compound. The reaction sequence may be schematically represented as followed in scheme-3:

Scheme-3: Process reported in 2652/DEL/2010

CN103992308 discloses reacting 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid and anhydrous DMF at 0°C followed by the dropwise addition of dichloromethane solution of DCC under stirring. After the addition was completed, 4-dimethylaminopyridine (DMAP) and N, N-Diethylethylenediamine was reacted at room temperature. It may be important to note that the said patent has not reported purity of the final product which may point towards low purity Sunitinib was developed. The reaction sequence may be schematically represented in following scheme-4.

Scheme-4: Process reported in CN103992308

WO2004/012776 discloses reacting 5-Fluoro-1,3-dihydro-2H-indol-2-one under nitrogen with stirring to a suspension of N-[2-(diethylamino) ethyl]-5-[14C]formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide in the presence of ethanol. Further, after addition of pyrrolidine, the reaction mixture was refluxed for 30 minutes to produce the final product Sunitinib. This patent has reported yield of Sunitinib which is less than 75%. Due to low yield, this process may not be more adaptable at large-scale because it may produce costly final product. The reaction sequence may be schematically represented in following scheme-5.

Scheme-5: Process reported in WO2004/012776

CN106588888 discloses treating B5 with 5-fluoro Indole-2-one and KOH in DMF. This whole process is protected by argon and the reaction was stirred at room temperature for 3.5h. Water was added dropwise, stirred, and an orange-yellow solid precipitated out; filtered and dried to obtain an orange-yellow solid, namely B6. The reaction sequence may be schematically represented in following scheme-6.

Scheme-6: Process reported in CN106588888

Indian patent no. 278989 discloses reflux of 5-formyl-2,4- dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide with 5-Fluoro-2-oxindole and methanol followed by addition of potassium hydroxide by stirring at 25-30° C for 30 min. After completion of reaction, the product solution was filtered and washed with methanol to get the final product Sunitinib. The reaction sequence may be schematically represented in following scheme-7.

Scheme-7: Process reported in IN278989

Most of the prior art processes involves condensation of 5-formyl-2,4-1H-pyrrole-3-carboxylic acid-(2-diethylaminoethyl) amide with 5-fluoro-l,3-dihydro-indol-2-one for preparation of Sunitinib in the presence of reagents like pyrrolidine, inorganic or organic bases. Pyrrolidine is an expensive reagent, highly toxic causes skin irritation; also, other reagent used are highly corrosive in nature, reacts violently with water and produce toxic fumes of hydrogen chloride, thus uses of these reagents are unsuitable for industrial scale.
Inventors of the present invention have not found any of the prior-art wherein above- mentioned condensation is carried out using neat water. Water used in the process give many advantages which mainly include cost-effective final product and eco-friendly large-scale process. In addition, all the processes disclosed in prior art publications are time consuming and difficult to carry out as they involve many steps and also not suitable for synthesis of API because the final product is not obtained in desired purity as well as in desired quantity. In view of above, there is an unmet need to develop an industrially advantageous, cost effective as well as eco-friendly process for the preparation of Sunitinib and salt thereof.
Thus, the present invention fulfills the above need by providing a process for the preparation of Sunitinib wherein use of expensive and hazardous reagent such as pyrrolidine or another reagent is avoided. The inventors of the present invention have developed an alternative improved process but yet simple, efficient and industrially advantageous process for the preparation of Sunitinib with high yield and high purity. The present invention also entails an economical and eco-friendly large-scale industrial process for the preparation of Sunitinib. Furthermore, the present invention comprises the novel use of water as well as solvent to prepare Sunitinib base as well as Sunitinib Malate.

OBJECTIVE OF THE INVENTION:
The principal objective of present invention is to provide an industrially advantageous and cost-effective process for the synthesis of Sunitinib and pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide an industrially advantageous process for the preparation of Sunitinib which circumvent the use of expensive reagent such as pyrrolidine, sodium methoxide, piperidine.
Another object of the present invention is to provide an industrially advantageous process for the preparation of Sunitinib base which uses water as a solvent to give an eco-friendly process.
Yet another object of present invention is to provide an efficient process for the preparation of Sunitinib and salt thereof which yields final product with high purity in high yield.
One more object of the present invention is to provide an industrially advantageous process for the preparation of Sunitinib Malate which uses water as a solvent to give an eco-friendly process.
Another object of the present invention is to provide large-scale advantageous process for the preparation of Sunitinib malate with lesser step in shorter span to produce low-cost final product.
One more object of present invention is to provide use of methylene dichloride with 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride, 1-Hydroxy benzotriazole and triethylamine for the preparation of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide using 5-Formyl-2,4-dimethyl-1-H-pyrrole-3-carboxylic acid and N,N-Diethylethylenediamine.

SUMMARY OF THE INVENTION:
One aspect of the present invention relates to preparation of Sunitinib [I] comprising the reaction steps as below.
a) adding 5-Formyl-2,4-dimethyl-1-H-pyrrole-3-carboxylic acid of formula-[III] in methylene dichloride;
b) adding 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (EDC. HCl) and 1-Hydroxy benzotriazole (HOBt) followed by slowly addition of Triethylamine (TEA) into the reaction mixture of step-a;
c) adding N,N-Diethylethylenediamine of formula-[IV] to step-b;
d) washing the reaction mass of step-c with methylene dichloride to obtain compound of formula-[V];
e) adding 5-fluoroindolin-2-one of formula-[VI] followed by addition of water to the above reaction mass of step-d;
f) adding Potassium hydroxide to above reaction mass of step-e to produce Sunitinib base of formula-[I].

One more aspect of the present invention relates to preparation of Sunitinib malate [II] comprising the reaction steps as below.
a) adding 5-Formyl-2,4-dimethyl-1-H-pyrrole-3-carboxylic acid of formula-[III] in methylene dichloride;
b) adding 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (EDC. HCl) and 1-Hydroxy benzotriazole (HOBt) followed by slowly addition of Triethylamine (TEA) into the reaction mixture of step-a;
c) adding N,N-Diethylethylenediamine of formula-[IV] to step-b;
d) washing the reaction mass of step-c with 10N NaOH to obtain compound of formula-[V];
e) adding 5-fluoroindolin-2-one of formula-[VI] followed by addition of water to the above reaction mass of step-d;
f) adding Potassium hydroxide to above reaction mass of step-e to produce Sunitinib base of formula-[I];
g) adding malic acid to above reaction mass to afford Sunitinib malate of formula-[II] using suitable solvents like methanol, acetonitrile, ethyl acetate, water.

In another aspect of the present invention, the process of the present invention may be depicted as a whole in below scheme-8.

Scheme-8: Process of the present invention

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 shows an X-ray powder diffractogram of crystalline form-II of Sunitinib Malate.

DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention relates to an improved, economic and eco-friendly large-scale industrial process for the preparation of Sunitinib and pharmaceutically acceptable salt thereof.
One embodiment of the present invention provides a process for the preparation of Sunitinib of formula [I] by the condensation of formyl amide intermediate of formula [V] with indole intermediate of formula [VI] with using neat water.
Another embodiment of the present invention provides a process for the preparation of formyl amide intermediate of formula [V] by the condensation of carboxylic acid intermediate of formula [III] with diamine intermediate of formula [IV] with using methylene dichloride in combination with 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (EDC. HCl), Hydroxy benzotriazole (HOBt) and triethyl amine (TEA).
Yet another embodiment of the present invention provides a process for the preparation of Sunitinib malate of formula [II] by reacting Sunitinib of formula [I] with malic acid using appropriate reagents and solvents.
One embodiments of the present invention involve arranging a 3 L round bottom flask in water bath under nitrogen atmosphere. Charging 5-Formyl-2,4-dimethyl-1-H-pyrrole-3-carboxylic acid of formula-[III] at 25-30oC along with suitable solvent like methylene dichloride and stirred for 10-15 minutes. Then, suitable reagents are added which can include but not limited to 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (EDC. HCl) and 1-Hydroxy benzotriazole (HOBt) followed by slowly addition of Triethylamine (TEA) into the reaction mixture at 25-30oC. Reaction mixture now can be cooled to 20-25oC. Once the whole reaction mixture is reached at above temperature, N,N-Diethylethylenediamine of formula-[IV] is added into above reaction mixture at 20-25oC. Again, the temperature is raised to 25-30oC and stirred for 4 to 5 hr. After checking for completion of the reaction, reaction mass can be treated with activated charcoal, filtered and washed with methylene dichloride. Now, 10% sodium chloride solution can be added into the reaction mass followed by addition of 10 N sodium hydroxide to adjust pH at around 11.0-12.0 at 25-30oC and separate the layers. Again, charge methylene dichloride to the aqueous layer and stir for 15 min followed by separating layers. To the combined organic layers, saturated sodium bicarbonate solution is added and stirred for 30 min at 25-30oC, separated the layers followed by drying out the organic layer on sodium sulphate and distilling the same at 40-45oC. Now, ethyl acetate is charged into reaction mass and distilled out under vacuum, again charged ethyl acetate into the reaction mass and heated for 30 min to 60-65oC to get clear solution. The reaction mass is then gradually cooled to -5 to -10oC to afford the compound of formula-[V].

Another embodiment of the present invention involves purification of above formula-[V] by arranging 3 L RBF in water bath under nitrogen atmosphere. Charge crude formula-[V] at 25-30oC followed by addition of methylene dichloride at 25-30oC and stirred for 15 min to get clear solution. 25% sodium chloride solution can be charged into the above reaction mixture at 25-30oC and stirred for 15 min followed by adjusting pH at 8.5-8.7 using 10% acetic acid solution. Separate out layers. To the separated organic layer, 25% sodium chloride solution is added then again readjusting pH at 8.5-8.7 using 10% acetic acid solution and separated layers. Above obtained organic layer is then washed with 2% sodium hydroxide solution three times and dried over anhydrous sodium sulphate for 15 min. Distilled off solvent below 40oC under reduced pressure followed by charging of ethyl acetate and its removal under reduced pressure below 40oC. Again, charged ethyl acetate into reaction mass and heated to 60-65oC to get clear solution for 30 min. Gradually reaction mass is cooled to -5 to -10oC for 2 hr. Resulting product can be isolated from the resulting mixture by using suitable techniques such as filtration, centrifugation and the like.
In another embodiment of the present invention Formula-[V] obtained from above steps can be charged into 2 L assembly into bath tub with addition of formula-[VI] at 25-30oC followed by addition of water. Potassium hydroxide is then charged and the reaction mass was stirred at 25-30oC. Reaction mass was checked on TLC for completion of reaction after 30 min. Final product is then filtered off and wet cake is washed with water followed by suck drying for 30-45 min. To the above wet cake, methanol is charged and stirred it for 60 min. at 25-30oC. Reaction mass is then filtered off and washed with methanol and dried at 50-55oC to give crude sunitinib base which was then dissolved in methanol to obtain pure Sunitinib base.

One embodiments of the present invention include preparation of Sunitinib base. Product obtained from the reaction can be sunitinib free base or sunitinib salt depending upon the nature as well as on the quantity of condensing reagent used for the reaction. Whenever reaction is carried out using catalytic amount of condensing reagent like potassium hydroxide, the reaction mass can be optionally washed with a water to remove any extra basicity from the reaction mass.
The present invention also provides novel salts of sunitinib with a protic acid selected from malic acid, hydrochloric acid, hydrobromic acid, oxalic acid, lavulinic acid, salicylic acid, phosphoric acid, sulfuric acid, picric acid and the like, preferably sunitinib malate. Salts of sunitinib as described by the present invention can be amorphous or crystalline form I or form II. More preferably, obtained final product Sunitinib Malate is crystalline form-II.
One embodiments of the present invention include preparation of Sunitinib salts which can be direct product of condensation reaction or can be alternatively prepared by the reaction of sunitinib free base with a suitable acid.
According to another embodiment, present invention provides a process for the preparation of sunitinib salt by reaction of sunitinib free base with a suitable acid.
One embodiments of the present invention include process for preparation of Sunitinib malate that involves reaction of sunitinib in a suitable solvent with malic acid at a temperature of 25-30oC for 60 min. Suitable solvent used for the salt formation can be selected from methanol, acetonitrile, ethyl acetate, water with other solvents which are not limited to water, alcohols, esters, ketones, nitriles, ethers, chlorinated solvents, and the like or mixture thereof. Malic acid used for the reaction is preferably L-malic acid. Sufficient amount of malic acid can be added to the reaction mixture so that whole of the sunitinib reacts with malic acid. After completion of salt formation, sunitinib malate can be isolated using suitable techniques such as filtration, centrifugation and the like.

As per one embodiments of the present invention Sunitinib malate can be optionally purified to enhance purity and/or to remove impurity in the product. Any suitable purification method can be employed such as slurry wash, crystallization, base acid treatment and the like.
As per one more embodiment of the present invention, wherein suitable reagents and solvents are selected one or more from methylene dichloride, 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride, 1-Hydroxy benzotriazole, triethylamine, sodium chloride, sodium hydroxide, ethyl acetate, potassium hydroxide, methanol and purified water.

Examples:
Having described the invention with reference to certain preferred embodiments, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The following examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.

Example-1: Preparation of crude N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide [V]
5-Formyl-2,4-dimethyl-1-H-pyrrole-3-carboxylic acid of formula-[III] (100 gm) was charged at 25-30oC along with suitable reagent like methylene dichloride (1000 ml) and was stirred for 10-15 minutes. 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride (EDC. HCl) (172 gm) was then added to above reaction mass along with 1-Hydroxy benzotriazole (HOBt) (158 gm) followed by slowly addition of Triethylamine (TEA) into the reaction mixture at 25-30oC. Reaction mixture was cooled to 20-25oC. N,N-Diethylethylenediamine of formula-[IV] was then added into above reaction mixture at 20-25oC and again, the temperature was raised to 25-30oC and stirred for 4 to 5 hr. Above reaction mass was then washed with methylene dichloride (500 ml). 10% sodium chloride solution (1000 ml) was added into the reaction mass and pH was adjusted around 11.0-12.0 at 25-30oC using 10 N sodium hydroxide (300 ml). Methylene dichloride solution (500 ml) was then charged into reaction mass and stirred for 15 min followed by separating layers. To the organic layer saturated sodium bicarbonate (200 ml) was added and stirred for 30 min at 25-30oC followed by drying out the organic layer on sodium sulphate and distilling the same at 40-45oC. Finally, ethyl acetate (400 ml) was charged into reaction mass and distilled out under vacuum and heated for 30 min to 60-65oC to get clear solution. The reaction mass was then gradually cooled to -5 to -10oC and maintain for 2 hours at same temperature. Filtered the reaction mass at -5 to -10oC and washed with 100 ml pre-chilled ethyl acetate. Obtained wet material is dried at 45-50ºC under vacuum to afford the title compound (113 gm). Final yield was 78.18% with purity of 99.11%.

Example-2: Purification of crude N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide [V]
Methylene chloride (1110 ml) was then charged into crude form of formula-[V] (110 gm) as obtained in example-1at 25-30oC and stirred for 15 min to get clear solution. 25% sodium chloride solution (220 ml) was then charged into the above reaction mixture at 25-30oC and stirred for 15 min followed by adjusting pH at 8.5-8.7 using 10% acetic acid solution (~3 ml). Separated organic layer of above reaction mass was then washed with 2% sodium hydroxide solution (330 ml) for three times and dried over anhydrous sodium sulphate for 15 min. Ethyl acetate (440 ml) was then charged into reaction mass and distil out under vacuum and again charged ethyl acetate and heated to 60-65oC to get clear solution for 30 min. Gradually reaction mass was cooled to -5 to -10oC for 2 hr. Resulting product then was isolated from the resulting mixture by using any of the suitable techniques such as filtration, centrifugation and the like to afford the 83 gm title compound. Final yield was 75.4% with purity of 99.89%.

Example-3: Preparation of Sunitinib [I]
Pure compound of Formula-[V] (70 gm) as obtained from above example-2 was then charged into 2 L assembly into bath tub with addition of 5-fluoroindolin-2-one of formula-[VI] (41.86 gm) at 25-30oC followed by addition of water (1750 ml). Potassium hydroxide (7.40 gm) was then charged and the reaction mass was stirred at 25-30oC. Reaction mass was then checked on TLC for completion of reaction after 30 min. Final product was then filtered and the wet cake is washed with purified water (140 ml). To the above wet cake, methanol (840 ml) is charged and stirred it for 60 min. at 25-30oC. Reaction mass is then filtered off and washed with methanol and dried at 50-55oC to get the 96.3 gm title compound. Final yield was 91.7% with purity of 99.04%.

Example-4: Preparation of Sunitinib Malate [II]
Sunitinib base (5 gm) is slurried in ethyl acetate (100 ml) at 25-30oC. L-Malic acid is added to above reaction mixture and stirred it for 60 min. at 25-30oC. Filtered off the reaction mass and washed with ethyl acetate (10 ml) followed by drying at 40-45oC to get 6.6gm Sunitinib Malate Form-I. Final yield was 99.25% with purity of 99.76%.

Example-5: Purification of Sunitinib [I]
Methanol (1092 ml) was added into round-bottom flask at 25 to 30°C. Crude form of Sunitinib-[I] (91 gm) as obtained in example-3 was added into the flask and stirred the reaction mass for 15 minutes at 25-30°C. Reaction mass was heated to 45-50oC and stir for 45 min at same temperature. Gradually cooled the reaction mass to 25-30oC for 2 hr. Filtered off the resulting mixture to afford the 84 g title compound after drying at 45-50ºC under vacuum. Final yield was 92.3% with purity of 99.61%.

Example-6: Preparation of Sunitinib Malate [II]
Sunitinib base (70 gm) and Purified Water (700 ml) were charged into round-bottom flask at 25 to 30°C. Stir reaction mass for 10-15 minutes to get homogeneous slurry. L-Malic acid (23.52 gm) was added to above reaction mixture and heated to 55-60°C to get clear reaction mixture. Stirred reaction mass for 30 minutes at 55-60oC. Fine Filtered off the reaction mass and filtrate were charged in Lyophilizer for freeze drying for 48 h to get 87.3 gm Sunitinib Malate form-II. Final yield was 93.4% with purity of 99.82%.

Example-7: Preparation of Sunitinib Malate [II]
Sunitinib base (10 gm) and Purified Water (50 ml) were charged into round-bottom flask at 25 to 30°C. Stir reaction mass for 10-15 minutes to get homogeneous slurry. L-Malic acid (3.36 gm) was added to above reaction mixture and heated to 55-60°C to get clear reaction mixture. Stirred reaction mass for 30 minutes at 55-60oC. Distilled out water completely under vacuum at 50-60ºC to get 12.4 gm Sunitinib Malate form-II. Final yield was 93.23% with purity of 99.78%.

Example-8: Preparation of Sunitinib Malate [II]
Sunitinib base (10 gm) and Purified Water (50 ml) were charged into round-bottom flask at 25 to 30°C. Stir reaction mass for 10-15 minutes to get homogeneous slurry. L-Malic acid (3.36 gm) was added to above reaction mixture and heated to 55-60°C to get clear reaction mixture. Stirred reaction mass for 30 minutes at 55-60oC. Distilled out water completely under vacuum at 40-50ºC to get 12.3 gm Sunitinib Malate form-II. Final yield was 92.48% with purity of 99.82%.

The invention described herein comprises in various objects and their description as mentioned above, with respect to characteristics and processes adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.
,CLAIMS:We claim:

1. An improved eco-friendly process for the preparation of Sunitinib malate wherein,
a) Sunitinib base is prepared by reacting with N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide and 5-fluoroindolin-2-one using purified water;
b) Sunitinib base obtained in above step-a is reacted with L-malic acid in the presence of purified water to obtain Sunitinib Malate.

2. An improved eco-friendly process for the preparation of Sunitinib malate as claimed in claim 1, wherein sunitinib malate is prepared by following steps:
a) reacting 5-Formyl-2,4-dimethyl-1-H-pyrrole-3-carboxylic acid in suitable reagents and solvents followed by addition of N,N-Diethylethylenediamine to produce crude N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide;
b) purifying N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide using methylene chloride;
c) reacting N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide with 5-fluoroindolin-2-one using purified water to obtain Sunitinib base;
d) dissolving Sunitinib base in purified water or in other suitable solvent with malic acid to obtain sunitinib malate.

3. An improved eco-friendly process for the preparation of Sunitinib malate as claimed in claim 2, wherein suitable reagents and solvents are selected one or more from methylene dichloride, 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimide hydrochloride, 1-Hydroxy benzotriazole, triethylamine, sodium chloride, sodium hydroxide, ethyl acetate, potassium hydroxide, methanol and purified water.

4. An improved eco-friendly process for the preparation of Sunitinib malate as claimed in claim 1 and 2, wherein purified sunitinib base is prepared by following steps:
a) reacting N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide with 5-fluoroindolin-2-one using purified water to obtain crude Sunitinib base;
b) recrystallizing crude sunitinib base in methanol to obtain pure Sunitinib base.

5. An improved eco-friendly process for the preparation of Sunitinib malate as claimed in claim 1 and 4, wherein finally obtained Sunitinib malate is in crystalline form-II.

Dated this 20th day of April, 2021.