Field of the invention:

The present invention relates to an improved process for the preparation of Sunitinib malate. More particularly, the invention relates to a process that provides Sunitinib malate having high purity.

Background of the invention:

Sunitinib malate has chemically named N-(2-(diethylamino)ethyl)-5-((Z)-(5-fluoro-1,2- dihydro-2-oxo-3H-indol-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide, 2(S)- hydroxybutanedioic acid salt (1:1) and represented by the formula-1. Sunitinib malate is a tyrosine kinase inhibitor (TKI) that targets and blocks the signaling pathways of multiple selected receptor tyrosine kinases (RTKs). It is therefore useful for the treatment of cancer and tumors. It is currently marketed for the treatment of metastatic malignant gastrointestinal stromal tumor (GIST) and advanced and/ or metastatic renal cell carcinoma (MRCC).

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Sunitinib, its antiviral activity and its use in pharmaceutical product are first discloses in US 6573293. This patent also discloses the process for the preparation of Sunitinib, wherein 5- fluorooxindole was condensed with 5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2- diethylaminoethyl)amide in presence of piperidine (or pyrrolidine) in ethanol at 90-100°C (Scheme-1).

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US 7119209 and US 20050171357 discloses a process for the preparation of Sunitinib by condensation of 4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde with N,N-diethylethylenediamine and 5-fluorooxindole in acetonitrile in presence of triethylamine for 18 h at 60°C in 85% yield (Scheme-2).

US 20060009510 discloses a process for the preparation of Sunitinib by formulation of 2, 4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide with chloromethylene- dimethylammonium chloride in acetonitrile followed by reaction with 5-fluorooxindole containing pulverized KOH (Scheme-3).

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US 7125905 claims specifically Sunitinib malate and its use in pharmaceutical composition. Further, W02009150523 discloses a process for the preparation of Sunitinib malate by reacting the L-(-)-malic acid salt of N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-l/-/-pyrrole- 3-carboxamide with 5-fluorooxindole in the presence of pyrrolidine in n-butanol at 70-80°C (Scheme-4).

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US7435832 discloses a process for the preparation of anhydrous crystal Sunitinib Form I by combining malic acid, Sunitinib base and a solvent. Further, W02009104021, W02010004339, W02010011834 and W02010076805 discloses the various process for the preparation of Sunitinib malate Form I.

Sunitinib obtained by the processes described in the art is not satisfactory from purity point of view. We have repeated the Sunitinib synthetic procedures as described in the prior art mentioned above and found that relatively large amounts of impurities were obtained along with Sunitinib.

In a specific run, we have found that Sunitinib prepared by the product patent procedure was having purity less than 99% and containing above 0.15% of the each individual impurity measured by High Performance Liquid Chromatography (HPLC), which needs repeated crystallizations in different solvents to get desired quality of the final product resulting in poor yields.

In order to overcome the problems associated with the prior art, the inventors have found improved process for the preparation of Sunitinib base and its salts. The invention resulted in a high purity, high quantitative yield, relatively less reaction time, simpler and cost effective process for the preparation of Sunitinib and its salts, in particular, Sunitinib malate. Also, described are the Sunitinib analogs compound of formula-2 to compound of formula-6 and process for their preparation. The novel Sunitinib analogs compound of formula-3 and compound of formula-4 may be present as impurities in Sunitinib and its salts.

Summary of the Invention:

The main aspect of the present invention is to provide an improved process for the preparation of Sunitinib, solvates or its pharmaceutically acceptable salts having substantially free of N, N-dimethyl amide analog represented by compound of formula-2, N, N-diethyl amide analog represented by compound of formula-3, N-ethyl amide analog represented by compound of formula-4, N-desethylsunitinib represented by compound of formula-5 and Sunitinib N-oxide represented by compound of formula-6 impurities.
Picture (4,5,6)

Yet another aspect of the present invention is to provide an improved process for the preparation of Sunitinib or its salts, particularly, Sunitinib malate represented by the compound of formula-1 having the structurally related impurities less than 0.1% comprising the steps of:

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a) dissolving the compound of formula-7 in a mixture of acetonitrile and methanol;

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b) adding a compound of formula-8;

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c) adding an organic amine to the reaction mixture;

d) isolating the Sunitinib base;

e) optionally purifying the isolated Sunitinib base;

f) reacting the Sunitinib base with L-malic acid; and

g) isolating the precipitated Sunitinib malate.

Yet another aspect of the present invention is to provide a novel compound N, N-diethyl amide analog represented by compound of formula-3.
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Yet another aspect of the present invention is to provide a novel compound N-ethyl amide analog represented by compound of formula-4.

Formula-4

Yet another aspect of the present invention is to provide Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-2 is less than 0.1%.

Yet another aspect of the present invention is to provide Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-3 is less than 0.1%.

Yet another aspect of the present invention is to provide Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-4 is less than 0.1%.

Yet another aspect of the present invention is to provide Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-5 is less than 0.1%.

Yet another aspect of the present invention is to provide Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-6 is less than 0.1%.

Detailed Description of the Invention:

The main aspect of the present invention is to provide an improved process for the preparation of Sunitinib, solvates or its pharmaceutically acceptable salts having substantially free of N, N-dimethyl amide analog represented by compound of formula-2, N, N-diethyl amide analog represented by compound of formula-3, N-ethyl amide analog represented by compound of formula-4, N-desethylsunitinib represented by compound of formula-5 and Sunitinib N-oxide represented by compound of formula-6 impurities.

Sunitinib, solvates or its pharmaceutically acceptable salts having substantially freed of impurities means the content of any individual impurity is less than 0.1 %.

One embodiment of the present invention is to provide a process for the preparation of Sunitinib malate as depicted in the following scheme-6 below.

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Yet another embodiment of the present invention is to provide an improved process for the preparation of Sunitinib or its salts, particularly, Sunitinib malate represented by the compound of formula-1 having the structurally related impurities less than 0.1% comprising the steps of:

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a) dissolving the compound of formula-7 in a mixture of acetonitrile and methanol;

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b) adding compound of formula-8;

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Formula-8

c) adding an organic amine to the reaction mixture;

d) isolating the Sunitinib base;

e) optionally purifying the isolated Sunitinib base;

f) reacting the Sunitinib base with L-malic acid; and

g) isolating the precipitated Sunitinib malate.

According to the present invention, the compound of formula-7 is dissolving in an organic solvent or mixture of solvents at ambient temperature, reacting with compound of formula-8 in presence of an organic amine and isolating Sunitinib base. The Sunitinib base may purify in a solvent or mixture of solvents at 65-70°C. The Sunitinib base is reacted with L-malic acid in an organic solvent at elevated temperature and thus isolating Sunitinib malate.

The structurally related impurities selected from N, N-dimethyl amide analog represented by compound of formula-2,N, N-diethyl amide analog represented by compound of formula-3, N-ethyl amide analog represented by compound of formula-4, N-desethylsunitinib represented by compound of formula-5, Sunitinib N-oxide represented by compound of formula-6 or any similar structure.

The organic amine is selected from 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU), piperidine, pyrrolidine, Hunig's base, N, N-dimethylaminopyridine (DMAP) or N, N-dimethylaniline (DMA).

The organic solvent used for the purification of the base is selected from acetonitrile, methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 2-butanol, ethyl acetate or mixture thereof.

The organic solvent used for the preparation of Sunitinib malate is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, water or mixture thereof. The elevated temperature for the formation of Sunitinib malate is in the range of 30- 70°C.

Yet another embodiment of the present invention is to provide a novel compound N, N- diethyl amide analog represented by compound of formula-3, solvate, isomer, tautomer or it's pharmaceutically acceptable salts thereof:

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Yet another embodiment of the present invention is to provide a novel compound N-e thyl amide analog represented by compound of formula 4, solvate, isomer, tautomer or it's pharmaceutically acceptable salts thereof:

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Yet another embodiment of the present invention is to provide Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-2 is less than 0.1%.

Yet another embodiment of the present invention is to provide Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-3 is less than 0.1%.

Yet another embodiment of the present invention is to provide Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-4 is less than 0.1%.

Yet another embodiment of the present invention is to provide Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-5 is less than 0.1%.

Yet another embodiment of the present is to provide Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-6 is less than 0.1%.

Yet another embodiment of the present invention is to provide Sunitinib, or its pharmaceutically acceptable salts having a chemical purity above 99%, preferably about 99.8%.

Yet another embodiment of the present invention is to provide a pharmaceutical composition comprising: (a) a therapeutically effective amount of Sunitinib, solvates or its pharmaceutically acceptable salts; and (b) at least one pharmaceutically acceptable
carrier.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the in any way.

Examples

Example-1:- Preparation of Sunitinib base

To a mixture of acetonitrile (1680 mL) and methanol (1120 mL), compound of formula-7 (70 g, 264 mmol) and compound of formula-8 (40 g, 264 mmol) were added at ambient temperature and stirred for 15-20 min. to get a clear solution. The reaction mass was filtered, added DBU (13 g, 85 mmol) to the filtrate and then stirred for 5h. The progress of the reaction was monitored by HPLC. After completion of the reaction, the obtained solid was filtered, washed with acetonitrile and suck dried for 1h. The wet cake was dried in vacuum oven at 50-55°C for 10h. The resultant solid was purified with acetonitrile. The obtained solid was optionally grinded in jet mill to get uniform solid and its HPLC purity is 99.67%.

Example-2:- Preparation of Sunitinib malate

Sunitinib base (30 g, 75.4 mmol) was suspended in a filtered n-butanol (480 mL) and heated to 45-50°C. To this slurry, a clear solution of L-malic acid (10.1 g, 75.4 mmol) in water (120 mL) was added. The obtained clear solution was maintained for 30 min. The reaction mass was cooled to ambient temperature and maintained for 1h. The separated solid was filtered, washed with methanol (90 mL) and suck dried for 1h. The wet cake was dried in vacuum oven at 50-55°C for 10h. The obtained salt was further purified on slurry wash with methanol and dried in vacuum oven at 50-55°C to get the Sunitinib malate in yield 80% with HPLC purity- 99.8%.

The crystalline form of the Sunitinib malate obtained by above method was shown to be Form I as reported in US 7435832B2 by XRPD.

Example-3: Preparation of N, N-dimethyl amide analog (formula-2)

To a stirred solution of 5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2 g, 12 mmol) in THF (20 mL) at ambient temperature, hydroxybenzotriazole (HOBT, 2.43 g, 18 mmol) and 1- ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCI, 3.44 g, 18 mmol) were added and maintained for 15 min. The reaction mass was cooled to 0-5°C, slowly TEA (2.43 g, 24 mmol) was added under stirring and maintained for 30-45 min. The obtained solid (TEA.HCI) was filtered off. The filtrate was cooled to 0-5°C and N, N-dimethylamine (1.35 g, 30 mmol) was added slowly. After completion of the reaction, reaction mass was warmed up to ambient temperature and maintained for 1h. The reaction mass was concentrated under reduced pressure at 40°C and water (50 mL) was added to the obtained residue to get a clear solution. A basic solution of compound of formula-8 (4.52 g (30 mmol) in water (25 mL) containing KOH (3.35 g, 60 mmol)) was added to the above aqueous phase and stirred for 1h. The yellow solid obtained was filtered, washed with water (50 mL) and suck dried for 1h. The wet cake was dried under vacuum for 20h. The obtained compound has been purified by treating with acetone (100 mL) at 40-45°C to get the title compound in 4.5 g with HPLC-99.3%.

1H-NMR (DMSO-d6, 300 MHz)- δ 2.41 (s, 3H, CH3), 2.43 (s, 3H, CH3), 2.65 (s, 6H, 2 x NCH3), 6.86 - 6.84 (m, 1H, Ar-H), 6.93 - 6.89 (m, 1H, Ar-H), 7.72 (s, 1H, =CH), 7.75 - 7.78(m, 1H, Ar-H), 10.91 (s, D2O exchangeable, 1H, NH), 13.62 (bs, D2O exchangeable, 1H, NH).

13C-NMR (DMSO-D6, 75 MHz) - 5 13.28, 15.07, 37.50, 38.11, 105.77 & 106.11 (d, JCF = 25.7 Hz), 109.96 & 110.07 (d, JCF = 8.1 Hz), 112.19 & 112.51 (d, JCF = 24.9 Hz), 114.47 & 114.50 (d, JCF = 234.4 Hz), 121.09, 124.95, 125.78, 127.14 & 127.26 (d, JCF = 234.4 Hz), 130.27 (d, JCF = 9.7 Hz), 134.50, 136.38, 156.70 & 159.80 (d, JCF = 234.4 Hz), 164.48, 169.59. DIP MS: m/z (%) 328 (M+1)+.

Example-4: Preparation of N, M-diethyl amide analog (formula-3)

To a stirred solution of 5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2 g, 12 mmol) in THF (20 mL) at ambient temperature, added HOBT (2.43 g, 18 mmol) and EDC.HCI (3.44 g, 18 mmol) and continued stirring for 15 min. at the same temperature. The reaction mass was cooled to 0-5°C, slowly TEA (2.43 g, 24 mmol) was added under stirring and maintained for 30-45 min. The separated solid (TEA.HCI) was filtered off. The filtrate was cooled to 0-5°C and N, N-diethylamine (2.19 g, 30 mmol) was added slowly. After completion of the reaction, reaction mass was warmed up to ambient temperature and maintained for 1h. The reaction mass was concentrated under reduced pressure at 40°C and water (20 mL) was added to the obtained residue to get a clear solution. A basic solution of compound of formula-8 (1.81 g (12 mmol) in water (10 mL) containing KOH (1.34 g, 24 mmol)) was added to the aqueous phase and stirred for 1h. The obtained yellow solid was filtered, washed with water (20 mL) and suck dried for 1h. The wet cake was dried under vacuum for 20h. Further purity has been achieved by treatment with acetone (40 mL) at 40-45°C to obtain the title compound in 57% yield with HPLC purity-99.2%.

1H-NMR (DMSO-d6, 300 MHz)- δ 1.10 (t, 6H, 2 x NCH2CH3), 2.41 (s, 3H, CH3), 2.43 (s, 3H, CHj), 3.20 (q, 2H, NCH2), 3.23 (q, 2H, NCH2), 6.86 - 6.84 (m, 1H, Ar-H), 6.93 - 6.89 (m, 1H, Ar-H), 7.72 (s, 1H, =CH), 7.75 - 7.78 (m, 1H, Ar-H), 10.91 (s, DzO exchangeable, 1H, NH), 13.62 (bs, D20 exchangeable, 1H, NH).
13C-NMR (DMSO-c/6, 75 MHz)-5 10.50, 10.52, 13.28, 15.07, 33.52, 33.57, 105.77 & 106.11 (d, JCF = 25.7 Hz), 109.96 & 110.07 (d, JCF = 8.1 Hz), 112.19 & 112.51 (d, JCF = 24.9 Hz), 114.47 & 114.50 (d, JCF = 234.4 Hz), 121.09, 124.95, 125.78, 127.14 & 127.26 (d, JCF = 234.4 Hz), 130.27 (d, JCF = 9.7 Hz), 134.50, 136.38, 156.70 & 159.80 (d, JCF = 234.4 Hz), 164.48, 169.59. DIP MS: m/z (%) 356 (M+1)+.

Example-5 - Preparation of N-Ethyl amide analog (formua-4)

To a stirred solution of 5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 30 mmol) in THF (50 mL) at ambient temperature, HOBT (6.08 g, 45 mmol) and EDC.HCI (8.6 g, 45 mmol) were added and maintained for 15 min. The reaction mass was cooled to 0-5°C, slowly TEA (6.06 g, 60 mmol) was added under stirring and maintained for 30-45 min. The separated solid (TEA.HCI) was filtered off. The filtrate was cooled to 0-5°C and N- ethylamine (3.38 g, 75 mmol) was added slowly. After completion of the reaction, reaction mass was warmed up to ambient temperature and maintained for 1h. The reaction mass was concentrated under reduced pressure at 40°C and water (50 mL) was added to the obtained residue to get a clear solution. A basic solution of compound of formula-8 (4.53 g (30 mmol) in water (25 mL) containing KOH (3.36 g, 60 mmol)) was added to the aqueous phase and stirred for 1 h. The obtained yellow solid was filtered, washed with water (50 mL) and suck dried for 1h. The wet cake was dried under vacuum for 20h. Further purity has been achieved by the treatment of above obtained solid with acetone (50 mL) at 40-45°C to obtain the title compound in 50% yield with HPLC Purity-99.2%.

1H-NMR (DMSO-d6, 300 MHz)- δ 1.10 (t, 3H, -CH2CH3), 2.41 (s, 3H, -CH3), 2.43 (s, 3H, - CH3), 2.43 (q, 2H, -CH,CHO. 6.86- 6.84 (m, 1H, Ar-H), 6.93- 6.89 (m, 1H, Ar-H), 7.64- 7.67 (broad t, DZO exchangeable,1H, NH), 7.72 (s, 1H, =CH), 7.75- 7.78 (m, 1H, Ar-H), 10.91 (s, D2O exchangeable, 1H, NH), 13.62 (bs, D2O exchangeable, 1H, NH). 13C-NMR (DMSO-C/6, 75 MHz) - 5 10.52, 13.28, 15.07, 33.57, 105.77 & 106.11 (d, JCF = 25.7 Hz), 109.96 & 110.07 (d, JCF = 8.1 Hz), 112.19 & 112.51 (d, JCF =24.9 Hz), 114.47 & 114.50 (d, JCF =234.4 Hz), 121.09, 124.95, 125.78, 127.14 & 127.26 (d, JCF =234.4 Hz), 130.27 (d, JCF = 9.7 Hz), 134.50, 136.38, 156.70 & 159.80 (d, JCF =234.4 Hz), 164.48, 169.59. DIP MS: m/z (%) 328 (M+1)+.

Example-6- Preparation of N-desethylsunitinib (formula-5)

To a stirred solution of 5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 30 mmol) in THF (50 mL) at ambient temperature, HOBT (6.08 g, 45 mmol) and EDC.HCI (8.6 g, 45 mmol) were added and maintained for 15 min. The reaction mass was cooled to 0-5°C and slowly TEA (6.06 g, 60 mmol) was added under stirring and maintained for 30-45 min. The separated solid (TEA.HCI) was filtered off. The filtrate was cooled to 0-5°C and N- ethylethylenediamine (6.6 g, 75 mmol) at 0-5°C. After completion of the reaction, reaction mass was warmed up to ambient temperature and maintained for 1h. The reaction mass was concentrated under reduced pressure at 40°C and water (50 mL) was added to the obtained residue to get a clear solution. A basic solution of compound of formula-8 (4.53 g (30 mmol) in water (25 mL) containing KOH (3.36 g, 60 mmol)) was added to the aqueous phase and stirred for 1h. The obtained yellow solid was filtered, washed with water (50 mL) and suck dried for 1h. The wet cake was dried under vacuum for 20h. Further purity has been achieved by the treatment with acetone (100 mL) at 40-45°C to obtain the title compound in 80% yield with HPLC Purity-99.4%.

1H-NMR (DMSO-d6, 300 MHz)- δ 1.01 (t, 3H, -CH2CH3), 2.51 (m, 2H, CH2), 2.66 (t, 2H, CH2), 3.26- 3.32 (q, 2H, CH2CH3), 6.84- 6.89 (m, 1H, Ar-H), 6.90- 6.93 (m, 1H, Ar-H), 7.54- 7.57 (m, D20 exchangeable, 1H, NH), 7.71 (s, 1H, =CH), 7.74- 7.78 (m, 1H, Ar-H), 10.98 (bs, D2Oexchangeable, 1H, NH), 13.71 (s, D2O exchangeable, 1H, NH). 13C-NMR (DMSO-d6, 75 MHz) - 5 10.56, 13.32, 15.30, 40.33, 43.27, 48.69, 105.76 & 106.10 (d, JCF = 25.7 Hz), 110.05 &110.17 (d, JCF = 8.1 Hz), 112.25 & 112.57 (d, JCF =24.9 Hz), 114.68, 120.95, 124.89, 125.85, 127.16 & 127.29 (d, JCF = 9.7 Hz), 130.24, 134.69, 136.48, 156.72 & 159.82 (d, JCF =234.4 Hz), 164.81, 169.68. DIP MS: m/z(%) 371 (M+1)+.

Example-7 - Preparation of Sunitinib N-oxide impurity (formula-6)

To a stirred suspension of Sunitinib base (2 g, 5 mmol) in methanol (4 mL) at 0-5°C was added the solution of 30% H2O2 (0.96 g, 7.5 mmol) in methanol (5 mL). After completion of the addition, temperature of the reaction mass was allowed to ambient temperature (25- 30°C) and stirred for 50h. The solvent was evaporated under reduced pressure at 35-40°C. The obtained residue was recrystallized from methanol (10 mL) to isolate Sunitinib N-oxide in 65% yield with HPLC Purity-98%.

1H-NMR (DMSO-d6, 300 MHz)- δ 0.95- 1.00 (t, 6H, 2 x CH,CH,). 2.42- 2.44 (m, 6H, 3 x CH2), 2.43 (s, 3H), 2.45 (s, 3H), 3.25- 3.31 (m, 2H, CH2), 6.82- 6.86 (m, 1H, Ar-H), 6.90- 6.93 (m, 1H, Ar-H), 7.42- 7.46 (m, D2O exchangeable, 1H, NH), 7.72 (s,1H, =CH), 7.75- 7.78 (m, 1H, Ar-H), 10.92 (s, D2O exchangeable, 1H, NH), 13.68 (s, D20 exchangeable, 1H, NH). 13C-NMR (DMSO-d6, 75 MHz) - 5 9.7 (2C), 10.9, 13.4, 35.0, 46.8 (2), 50.6, 105.76 & 106.10 (d, JCF= 25.7 Hz), 109.99 & 110.10 (d, JCF = 8.1 Hz), 112.29 & 112.61 (d, JCF =24.9 Hz), 115.0, 119.9, 124.9, 125.9, 127.14 & 127.26 (d, JCF =234.4 Hz), 130.3 (d, JCF = 9.7 Hz), 134.5, 136.9, 156.17 & 158.3 (d, JCF =234.4 Hz), 165.3, 169.5. DIP MS: m/z (%) 415 (M+1)+.

We claim:

1) An improved process for the preparation of Sunitinib malate (formua-1) having the structurally related impurities less than 0.1% comprising the steps of:

Formula1


a) dissolving the compound of formula-7 in a mixture of acetonitrile and methanol;

Formula-7

b) adding compound of formula-8;

Formula-8

c) adding an organic amine to the reaction mixture;

d) isolating the Sunitinib base;

e) optionally purifying the isolated Sunitinib base;

f) reacting the Sunitinib base with L-malic acid; and

g) isolating the precipitated Sunitinib malate.

2) The process according to claim 1, wherein said structurally related impurities selected from N, N-dimethyl amide analog represented by compound of formula-2,N, N-diethyl amide analog represented by compound of formula-3, N-ethyl amide analog represented by compound of formula-4, N-desethylsunitinib represented by compound of formula-5, Sunitinib N-oxide represented by compound of formula-6 or any similar structure.

3) The process according to claim 1, wherein said solvent used in step e) is selected from acetonitrile, methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 2-butanol, ethyl acetate or mixture thereof.

4) The process according to claim 1, wherein said organic amine is selected from 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), piperidine, pyrrolidine, Hunig's base, N, N-dimethylaminopyridine (DMAP) or N, N-dimethylaniline (DMA).

5) The process according to claim 1, wherein said organic solvent used for the preparation of Sunitinib malate is selected from methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, isobutyl alcohol, water or mixture thereof.

6) A compound of formula-3 or solvate, isomer, tautomer or it's pharmaceutically acceptable salts thereof:

Formula-3

7) A compound of formula-4 or solvate, isomer, tautomer or it's pharmaceutically acceptable salts thereof:

Formula-4

8) Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-2 is less than 0.1%.

9) Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-3 is less than 0.1%.

10) Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-4 is less than 0.1%.

11) Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-5 is less than 0.1%.

12) Sunitinib, solvates or its pharmaceutically acceptable salts having the compound of formula-6 is less than 0.1%.

13) Sunitinib, solvates or its pharmaceutically acceptable salts so prepared having the HPLC purity of about 99.8%.

14) A pharmaceutical composition comprising: (a) a therapeutically effective amount of Sunitinib, solvates or its pharmaceutically acceptable salts; and (b) at least one pharmaceutically acceptable carrier.