Field of invention:

The present invention relates to a process for the preparation of malic acid salt of Sunitinib. Background of the invention:

Sunitinib is chemically described as N-[2-(diemylammo)erayl]-5-[(Z)-(5-fIuoro- 1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide as represented by Formula I.

Sunitinib malate of formula I is a small molecule inhibitor of multiple receptor kinases involved in cancer, including vascular endothelial growth factor receptors, platelet derived growth factor receptors and the KIT receptor. It has been recently approved by the US FDA for the treatment of Gastro Intestinal Stromal Tumors (GIST) and Advanced Renal Cell Carcinoma (RCC). Studies revealed that Sunitinib malate (SUTENT®) is an oral, multi-targeted tyrosine kinase inhibitor (TK1) that targets and blocks the signaling pathways of multiple selected receptor tyrosine kinases (RTKs).

Sunitinib exists as yellow to orange powder. Sunitinib is a non-hygroscopic substance and has no chiral center; however the final substance is optically active due to malate part of the molecule.

Sunitinib base is having the chemical name N-[2- (diethylamino)ethyl]-5-[(Z)-(5-fluoro- 1,2-dihydro-2-oxo-3H-indol-3-ylidine) methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide is also known as SU1 1248 and similar pyrrole derivatives are first disclosed in WOO 1/060814. Its equivalent patent is US 6573293.

US patent No. 7,125,905 describes a process for the preparation of sunitinib base, which involves reacting a mixture of N-[2- (diemylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide of Formula II and 5-fluoro-l,3-dihydro-2H-indol-2-one of Formula III in the presence of ethanol and pyrrolidine at 78°C.

US Publication Nos. 2003/0069298 and 2007/0191458 describe the preparation of crystal Forms I and II of L-malic acid salt of sunitinib from sunitinib base. PCT Publication No. WO 2009/067686 describes processes for preparing crystalline forms of racemic sunitinib malate, sunitinib hemi-L-malate and compositions containing sunitinib base and L- or racemic malic acid salt of sunitinib base.

WO 2009/150523 describes a process for the preparation of L-malic acid salt of sunitinib, wherein the process involves preparation of L-malic acid salt of N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide of Formula II and reacting the salt with 5-fluoro-l,3-dihydro-2H-indol-2-one of Formula III to obtain L- malic acid salt of sunitinib with 75.1% yield.

WO 2011/114246 describes processes for the preparation of L-malic acid salt of sunitinib, wherein the process involves preparation of L-malic acid salt of sunitinib without isolation of its free base.

Summary of the invention:

The present invention provides an efficient process for the preparation of L-malic acid salt of sunitinib of formula I.

The present process does not involve the isolation of sunitinib base from the reaction mixture and it can be directly converted into sunitinib malate. The reaction is carried out at room temperature and the malic acid salt of sunitinib obtained by the present process has higher purity and yield.

Detailed description of the invention:

The aforesaid patent describes a process for the preparation of Sunitinib as shown in Scheme-1 below:

In one aspect of the present invention is provided a process for the preparation of Malic acid salt of sunitinib, wherein the process comprises:

a) treating the N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-
carboxamide (I) with a solvent at 25-30°C;

b) adding 5-fluoro-l,3-dihydro-2H-indol-2-one (III) at 25-30°C in the presence of a
solvent and a base to obtain sunitinib base and

c) adding L-malic acid to the above reaction mixture after completion of the reaction to give malic acid salt of sunitinib.

wherein the above process is carried out without isolation of sunitinib free base.

N-[2-(diethylammo)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (II) and 5-fluoro-l,3-dihydro-2H-indol-2-one (III) are prepared according to the method disclosed in WO 01/060814.

The above process comprising treating N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (II) with the solvent and adding 5-fluoro-l,3-dihydro-2H-indol-2-one (III) in the presence of base to give sunitinib free base, which is not isolated. The solvent is selected from water, dichloromethane. The base can be an organic base or an inorganic base. Organic base is selected from amine preferably pyrrolidine. Inorganic base is selected form metal hydroxides, metal carbonates or bicarbonates. Metal hydroxides are selected from KOH, NaOH, LiOH and Ba(OH)2, preferably KOH. Metal carbonates are selected from carbonates of potassium, sodium, lithium and barium, preferably potassium carbonate. Metal bicarbonates are selected form bicarbonates of potassium, sodium, lithium and barium, preferably potassium bicarbonate. Then malic acid is added to the reaction mixture after completion of the reaction which can be monitored by Thin Layer Chromatography (TLC). Malic acid may be L-malic acid or D-malic acid, preferably L-malic acid. The malic acid salt of sunitinib may be isolated by filtration, solvent removal, solvent precipitation or combination thereof. The solvent is same as mentioned above. When the water is used as solvent the solvent removal can be done by using an antisolvent selected from acetone.

In a preferred embodiment of the present aspect of the invention, inventors have found that when dichloromethane is used as a solvent the total reaction can be carried out at 25-30°C, which also can be considered as an advantage of the present invention. However, when water is used as a solvent, the reaction mixture is heated after addition of malic acid and the temperature is maintained at 90-95°C for one hour.

In another aspect of the present invention provides a process for the in situ preparation of sunitinib malate in the absence of base, which comprises:

a) treating the N-[2-diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-
carboxamide (I) with a solvent at 25-30°C;

b) refluxing the reaction mixture for 20 hrs;

c) cooling to room temperature, adding L-malic acid and THF to the above reaction mixture after completion of the reaction to give malic acid salt of sunitinib and stirring for 1 hr at room temparature; and
d) filtering, washing the product with THF and dried to obtain L-malic acid salt of sunitinib.

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

EXAMPLES

Example 1: Preparation of L-malic acid salt of sunitinib using PCM:

A mixture of N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (0.5 g) and dichloromethane (10 ml) were stirred and 5-Fluoro-l,3-dihydro-2H-indol-2-one (0.27 g) and pyrrolidine (0.05 ml) were added and the reaction mixture was stirred at 25-30°C (room temperature) for 4 hours. Check for the completion of reaction with Thin Layer Chromatography (TLC). L-Malic acid (0.25 g) was added to the reaction mixture and the reaction mixture was stirred for 10 hours. Then the solid is filtered and washed with dichloromethane (2 ml). The product is dried Under vacuum at 50-55°C.

Yield: 70%

Example 2: Preparationof L-malic acid salt of sunitinib using water:

A mixture of N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (0.5 g) and DM water (12 ml) were stirred. 5-Fluoro-l,3-dihydro-2H-indol-2-one (0.27 g) and

KOH (0.05 g) were added and the reaction mixture was stirred at 25-30°C (room temperature) for 4 hours. Check for the completion of reaction with Thin Layer Chromatography (TLC). L-Malic acid (0.5 g) was added to the reaction mixture and the reaction mixture was stirred. Heat the reaction mixture at 90-95°C (internal temperature) for 1-2 hours. The reaction mixture was cooled to room temperature and acetone (50 ml) is added to get a precipitate of sunitinib malate. Further, reaction mixture is cooled to 5-10°C. Then the solid is washed with DM water followed by acetone at 25-30°C, filtered the product and dried under vacuum at 50-55°C.

Yield: 80%

Example 3: Preparation of L-malic acid salt of sunitinib using THF:

A mixture of N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (0.2 g) and THF (2 ml) were stirred. 5-Fluoro-l,3-dihydro-2H-indol-2-one (0.12 g) added and refluxing the reaction mixture at 70-75°C for 20 hours. Check for the completion of reaction with Thin Layer Chromatography (TLC). Cooling the reaction mixture to room temperature and L-Malic acid (0.11 g) and THF (10 ml) were added to the reaction mixture and the reaction mixture was stirred for 1 hr. Filter the product and dried to give L-malic acid salt of Sunitinib.

Yield: 87.5%

We claim,

1. One pot process for the preparation of malic acid salt of sunitinib, which comprises:
a) treating the N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-
carboxamide (II) with a solvent at 25-30°C;

FORMULA II FORMULA III

b) adding 5-fluoro-l,3-dihydro-2H-indol-2-one (III) at 25-30°C in the presence of a solvent and a base to obtain sunitinib base;

c) optionally adding acetone as an antisolvent; and

d) adding L-malic acid to the above reaction mixture after completion of the reaction to give malic acid salt of sunitinib.

2. A process according to the claim 1, the solvent used in step (a) is dichloromethane or water.

3. A process according to claim 1, wherein the base is an organic base or an inorganic base.

4. A process according to claim 3, wherein the organic base is pyrrolidine.

5. A process according to claim 3, wherein the inorganic base is selected from metal hydroxide or metal carbonate or metal bicarbonate.

6. A process according to claim 3, wherein the inorganic base is selected from KOH, NaOH, LiOH, BaOH, K2CO3, Na2CO3) Li2CO3, BaCO3) KHCO) NaHCO3j LiHCO3, Ba(HCO3)2.

7. A process for the preparation of malic acid salt of sunitinib, which comprises:

a) treating the N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-
carboxamide (II) with dichloromethane at 25-30°C;

I
b) adding 5-fluoro-l,3-dihydro-2H-indol-2-one (III) at 25-30°C in the presence of a dichloromethane and pyrrolidine to obtain sunitinib base;

c) adding L-malic acid to the above reaction mixture after completion of the reaction; and

d) washing the solid obtained in step c) with dichloromethane to give malic acid salt of sunitinib.

8. A process according the claim 7, wherein the sunitinib base formed in step b) is not
isolated.

9. A process for the preparation of malic acid salt of sunitinib, which comprises:

a) treating the N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-
carboxamide (II) with DM water at 25-30°C;

b) adding 5-fluoro-l,3-dihydro-2H-indol-2-one (III) at 25-30°C in the presence of a DM water and KOH to obtain sunitinib base;

c) adding L-malic acid to the above reaction mixture after completion of the reaction;

d) heating the reaction mixture to the temperature ranges from 90-95°C for 1-2 hours;

e) cooling the reaction mixture to the room temperature and adding acetone as an antisolvent; and

f) washing the solid obtained in the step e) with DM water followed by acetone to give malic acid salt of sunitinib.

10. A process according the claim 9, wherein the sunitinib base formed in step b) is not isolated.