Field of invention:

The present invention relates to the process for the preparation of polymorph I of sorafenib tosylate.

Background of the invention:

Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis. Sorafenib, marketed as Nexavar® by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received "Fast Track" designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer). It is a small molecular inhibitor of RAF kinase, PDGF (platelet-derived growth factor), VEGF receptor2 and 3 and c Kit the receptor for stem cell factor.

Sorafenib Tosylate of formula I and other pharmaceutically acceptable salts of 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide are mentioned in WO 00/42012, WO 03/068228 and WO 03/047579.

The compound 4- {4-[({[4-chloro-3-(trifluoromethyl)
phenyl]amino}carbonyl)amino]phenoxy} -N-methylpyridine-2-carboxamide of formula II is described in WO 00/42012.

Bayer Pharmaceutical Corporation has reported for the first time a process for the preparation of sorafenib base and its analogues in WO 00/42012.

Bankston et al.in Organic Process Research & Development, 2002, 6, 777-781 discloses a process for the preparation of sorafenib Tosylate, which involves reacting 2-picolinic acid with thionyl chloride in a solvent inert towards thionyl chloride without using dimethylformamide to form acid chloride salt. This acid salt on further reaction with aqueous solution of methylamine or gaseous methyl amine gives amide derivative, this on reacted with 4-aminophenol with addition of carbonate salt in the presence of base to yield 4-(4-aminophenoxy)-N-methylpicolinamide-4-(4-aminophenoxy)-N-methylpicolinamide when reacted with 4-chloro-3-(trifluoromethyl) phenyl isocyanate in a non-chlorinated organic solvent, inert towards Isocyanate gives sorafenib. Sorafenib by admixing with p-toluenesulfonic acid in a polar solvent gives sorafenib Tosylate.

WO 2006/034796 discloses a process for the preparation of sorafenib Tosylate, which involves reacting 4-(4-aminophenoxy)-N-methylpicolinarnide with 4-chloro-3(trifluoromethyl)phenyl isocyanate in a non-chlorinated organic solvent, gives sorafenib base. By admixing the sorafenib with p-toluene sulfonic acid in polar solvent, water is added to the reaction mixture and, if appropriate, a clarifying filtration is conducted, if required seeding added to give sorafenib tosylate.

WO 2006/034797 discloses a process for the preparation of Polymorph I of sorafenib tosylate, which involves the preparation of polymorph II of sorafenib tosylate and further conversion to Polymorph I of sorafenib tosylate.

WO 2011/036647 discloses a process for the preparation of Polymorph I of sorafenib tosylate, which involves the addition of p-toluenesulfonic acid to sorafenib in the presence of water.

Summary of the invention:

Different aspects of the present application are summarized herein below individually.

In one aspect of the present application, the present invention provides a process of preparation of crystalline sorafenib tosylate of formula (I)

Comprising the steps of

A. reacting 4-(4-ammophenoxy)-N-methylpicolinamide (III) with 4-chloro-3-
(trifluoromethyl) phenylisocyanate (IV) in toluene gives sorafenib.

B. sorafenib (II) by admixing with p-toluenesulfonicacid in t-Butanol gives sorafenib
tosylate (I) without seeding.

In another aspect of the present invention provides process for the preparation of crystalline Polymorph I of sorafenib tosylate comprising reacting sorafenib tosylate methanol solvate with mixture of polyethylene glycol and ethyl acetate.

Description:

As set forth herein, aspects of the present invention provides a process for preparation of sorafenib tosylate, its purification process, to give substantially pure product as well as crystalline polymorphic form designated as Form I.

In one embodiment of the present application provides a process for the preparation of 4-(4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide 4-methylbenzene sulfonate of formula (I) or sorafenib tosylate.

Comprising the steps of-

A. reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3-
(trifluoromethyl)phenylisocyanate (IV) in toluene gives sorafenib.

The process of reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with commercially available 4-chloro-3-(trifluoromethyl)phenylisocyanate (IV) to give sorafenib is effected at a temperature above 15°C and below 60°C, for example at a temperature of 20°C to 60°C, more preferably at 30°C to 60°C. Preference is given to initially charging the compound of the formula (III) at a temperature of 20°C to 60°C, more preferably at from 30°C to 50°C, in toluene, and to admixing with the compound of the formula (IV), if appropriate dissolved or suspended in toluene, in such a way that the reaction temperature does not exceed 70°C, preferably 60°C. If appropriate, the crude product of the compound of the formula (II) is used in the following stage dissolved or suspended in a suitable solvent, preferably toluene. The compound of the formula (II) is isolated preferably by crystallization from the reaction mixture, by cooling the reaction mixture, for example, to a temperature of 0 to 30°C, more preferably to a temperature of 10-25°C. The compound of the formula (IV) is used in an amount of from 0.9 to 4 mol, preferably from 1 to 4 mol, for 1 mole of the compound of the formula (III). The concentration of the compound of the formula (IV) in the reaction mixture is from 4 to 40 percent by weight, preferably from 3 to 30 percent by weight. The conventional methods for isolating the product may include but are not limited to filtering (with or without vacuum), optionally washing with suitable solvent and drying.

B. Sorafenib (II) by admixing with p-toluenesulfonicacid in the presence of t-butanol
gives sorafenib tosylate (I) without seeding.

Treating sorafenib (II) with p-toluenesulfonicacid in tert-butanol may be carried out at temperatures ranging about 30 to 100°C. A suitable proportion of tert-butanol solvent may be desired to get kinetic controlled reaction and preferably about 20 to 100 times the volume of the tert-butanol solvent may be utilized with respect to total amount of compound of formula-II utilized. In order to improve the purity of the compound of the formula (I) enabled a clarifying filtration, obtained compound of the formula (I) without seeding.

The process of treating sorafenib (II) with p-toluenesulfonicacid comprising the reaction about equi-molar amounts, however, an excess of molar proportion of p-toluenesulfonicacid may be utilized to get reaction kinetics remain in the control of the desired reaction time, minimal or no impurities formation and any other relevant factor in order to achieve the maximum output of compound of formula I. Preferable molar ratio of p-toluenesulfonicacid for the reaction may range from 1 mole to 3 moles per mole of compound of formula II.

Addition of p-toluenesulfonicacid may be suitably carried out at temperatures ranging from 30 to 100°C, which may further comprise the temperature elevation upto about 85 °C or preferably reflux temperature of the reaction mass for a suitable time duration.

In this process, sorafenib tosylate is having PXRD of polymorphic Form I of sorafenib tosylate is obtained without isolating the polymorphic Form II of sorafenib tosylate.

The compound of formula-I may be isolated by conventional methods and optionally may be dried suitably. The conventional methods for isolating the product may include but are not limited to cooling the reaction mass, wherever required neutralizing , maintaining , filtering (with or without vacuum), optionally washing with suitable solvent and drying.

In another embodiment of the present invention, it provides a process for the preparation of sorafenib tosylate polymorphic Form I of Sorafenib tosylate from sorafenib tosylate methanol solvate using mixture of polyethylene glycol and ethyl acetate. Here, sorafenib tosylate methanol solvate is prepared according the process given in US 2009/0192200 Al.

In another embodiment of the present invention, it provides a process for the preparation of sorafenib base comprising reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3-(trifluoromethyl) phenylisocyanate (IV) in the presence of chlorobenzene to give sorafenib free base.

Brief description of the drawings:

Figure I: PXRD of crystalline Form I of sorafenib tosylate obtained according to the process given in example II.

Figure II: DSC of crystalline Form I of sorafenib tosylate obtained according to the process given in example II.

Figure III: PXRD of crystalline Form I of sorafenib tosylate obtained according to the process given in example III.

Figure IV: DSC of crystalline Form I of sorafenib tosylate obtained according to the process given in example III.

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 sorafenib
Charge 150 ml of toluene at ambient temperature in round bottom flask. Add 20 g of 4-(4-aminophenoxy)-N-methylpicolinamide and stirred for about 20-25 minutes. Add 4-chloro-3-trifluoromethylisocyanate dissolved in toluene and maintained for about 3-6 hrs. (This time may be more, however, depending upon impurity profile compliance). Filter the reaction mass followed by washing with 40-50 ml toluene finally washed with IN HC1 and isolating the product after drying.

Yield - 78 %

Example 2: Preparation of crystalline Form I of sorafenib tosylate

Charge 400 ml of tert-butanol at ambient temperature in round bottom flask. Add 10gm of sorafenib crude and stirred for about 20-25 minutes. Raise the temperature up to about 80 to 85°C and maintained for about 1-2 hrs. (This time may be more, however, depending upon homogenous solution). Slowly add p-toluenesulfonicacid dissolved in 100 ml tert-butanol maintained for about 1 hr. Cool the reaction mass up to 30-35°C and stir for about 2 hrs at 30-35'C. Filter the reaction mass followed by washing with 10 -20 ml tert-butanol and isolating the product after drying.

Yield - 85 %

HPLC purity - 99.7 to 99.9%

Example 3: Preparation of crystalline Form I of sorafenib tosylate

To the solution of polyethylene glycol added sorafenib tosylate methanol solvate (1.5g) at 50°C. Ethyl acetate (75 ml) is added to the reaction mixture. Stir for 24 hrs at room temperature. Filter the solid and drying at 60°C to give crystals of sorafenib tosylate.

Example 4: Preparation of sorafenib:

Charge 150 ml of chlorobenzene at ambient temperature in round bottom flask. Add 20 g of 4-(4-aminophenoxy)-N-methylpicolinamide and stirred for about 20-25 minutes. Add 4-chloro-3-trifluoromethylisocyanate dissolved in toluene and maintained for about 3-6 hrs. (This time may be more, however, depending upon impurity profile compliance). Filter the reaction mass followed by washing with 40-50 ml chlorobenzene and isolate the product after drying.

We claim,

1. A process for the preparation of Sorafenib tosylate, which comprises:

a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (IV) in toluene gives sorafenib.

b) sorafenib (II) by admixing with p-toluenesulfonicacid in the presence of t-butanol gives sorafenib tosylate (I) without seeding.

2. A process according to the claim 1, wherein the process doesn't involve seeding of sorafenib tosylate.

3. A process for the preparation of crystalline Form I of sorafenib tosylate, which comprises:

a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3-
(trifluoromethyl)phenylisocyanate (IV) in toluene gives Sorafenib.

b) sorafenib (II) by admixing with p-toluenesulfonicacid in the presence of t-butanol gives crystalline Form I of sorafenib tosylate (I) without seeding.


4. A process according to claim 3, wherein the crystalline Form I of sorafenib tosylate obtained is free of Form II and Form III.

5. A process for the preparation of crystalline sorafenib tosylate, which comprises:

a) reacting sorafenib tosylate methanol solvate with polyethylene glycol at 50°C;

b) adding ethyl acetate to the reaction mixture;

c) stir the reaction mixture for 24 hrs; and

d) filtering and drying the product to give crystals of sorafenib tosylate.

6. A process according to the claim 5, wherein the crystalline sorafenib tosylate is Form I of sorafenib tosylate.