DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
PROCESS FOR PREPARATION AND PURIFICATION OF POMALIDOMIDE

INTRODUCTION
The present invention is directed towards a process for the preparation and purification of pomalidomide.
Pomalidomide is a derivative of thalidomide that is anti-angiogenic and also acts as an immunomodulator. Pomalidomide is marketed under the brand name Pomalyst by Celgene. Pharmaceutical compositions of pomalidomide and its combination with other active agents such as dexamethasone are useful in the treatment of multiple myeloma. Pomalidomide is having the following structure of Formula I.

Formula I
US5635517B2 describes a process for preparation of pomalidomide wherein the process comprising: a) heating a mixture of 4-nitrophthalic anhydride, a-aminoglutarimide hydrochloride and sodium acetate in glacial acetic acid under reflux to give desired intermediate which is further recrystallized from methanol; and b) hydrogenating the intermediate obtained in step a) with 10% Pd/C in 1,4-dioxane to produce a residue of pomalidomide which was crystallized from dioxane/ ethyl acetate to give pomalidomide crystals.
US7994327B2 describes a process for preparation of pomalidomide wherein the process comprising: heating a mixture of 3-aminophthalic acid hydrochloride, 3-aminoglutarimide hydrochloride, acetonitrile, and acetic acid to reflux temperature for about 5 to 7 hours in presence of triethylamine to give a solid precipitate of pomalidomide.
US8785644B2 describes a process for preparation of pomalidomide wherein the process comprising: heating a mixture of N-(3-Aminophthaloyl)-glutamide, 1,1'-carbonyldiimidazole and acetonitrile under reflux for 4.5 hours to give pomalidomide.
Pomalidomide obtained by following the synthetic process described in US7994327B2 and US8785644B2 was further purified by recrystallizing the crude product in DMSO and water.
WO2014170909A2 describes a process for purification of pomalidomide crystalline Form I, wherein the process comprising: a) suspending pomalidomide in dimethylformamide, dimethylacetamide or dimethyl sulfoxide; b) heating the suspension obtained in step (a) above 70°C; c) adding anti-solvent to the solution obtained in step (b); and d) isolating pomalidomide crystalline Form I.
The processes disclosed in the prior art for the preparation of pomalidomide suffer from other drawbacks such as low purity, yield and lengthy workup which does not result in an industrially feasible process.
Hence, there is a need to provide simple, environment friendly, cost effective, industrially feasible process for the preparation of pomalidomide.

SUMMARY OF THE INVENTION
In a first aspect, the application provides a process for the purification of pomalidomide, wherein the process comprising:
a) Suspending pomalidomide in dimethyl sulfoxide or dimethyl formamide;
b) Heating the suspension to 30 – 65°C to obtain a clear solution;
c) Adding the anti-solvent to the solution of step b);
d) Isolating the Pomalidomide.
In a second aspect, the application provides a process for preparation of polymorphic Form A of pomalidomide, wherein the process comprising:
a) Suspending pomalidomide in dimethyl sulfoxide or dimethyl formamide;
b) Heating the suspension to 30 – 65°C to obtain a clear solution;
c) Adding the anti-solvent to the solution of step b);
d) Isolating the Pomalidomide.

DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the application provides a process for the purification of pomalidomide, wherein the process comprising:
a) Suspending pomalidomide in dimethyl sulfoxide or dimethyl formamide;
b) Heating the suspension to 30 – 65°C to obtain a clear solution;
c) Adding the anti-solvent to the solution of step b);
d) Isolating the Pomalidomide.
The starting material, Pomalidomide with undesired purity may be produced by any of the methods known in the art or as per the methods described in this patent application.
Suspending the Pomalidomide in step a) includes: a) direct use of a reaction mixture containing pomalidomide that is obtained in the course of its synthesis; or b) any physical form of pomalidomide can be utilized for providing the suspension of pomalidomide.
Suitable solvents which can be used for suspending pomalidomide are selected from dimethyl sulfoxide or dimethyl formamide. The solvent or a mixture of the solvents (by volume) can be taken in the ratio of 1:1 to 1: 50 to the weight of pomalidomide.
Step b) involves heating the suspension to 30 – 65°C to obtain a clear solution. The suspension can be constantly heated to a temperature range of 30 – 65°C to get the clear solution. The solution obtained in step b) may be maintained at the same temperature for about 5 minutes to 3 hours or longer. The volume of the solvent may vary depending upon the temperature maintained in order to get a clear solution.
The obtained solution may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
This step c) involves adding an anti-solvent to the solution obtained in step b). One or more anti-solvents are added to the solution obtained in Step b). The suitable anti-solvents which can be used include but are not limited to: alcohols such as methanol, isopropyl alcohols; ketones such as acetone, methyl isobutyl ketone; esters such as isopropyl alcohol, ethyl acetate; ethers such as isobutyl ether; hydrocarbons such as n-hexane, n-heptane, cyclohexane; water etc.
In one embodiment, the step c) involves addition of two anti-solvents such as methanol and water. In an embodiment of step c), the anti-solvent can be added in a slow and consistent manner. The solution of pomalidomide can be added to the anti-solvent or the anti-solvent can be added to the solution of pomalidomide. The anti-solvent addition to the solution of pomalidomide or vice-versa can be done at 25° – 65°C. After the addition of anti-solvent, optionally the reaction mass can be maintained for 5 minutes to 2 hours or longer.
In one embodiment, the above reaction mixture can be maintained at below 65°C. The reaction mass can be optionally cooled to 25 – 30°C and maintained at the same temperature for 30 minutes to 5 hours or longer.
The step d) involves isolating Pomalidomide. The crystalline Pomalidomide can be isolated any of the techniques known in the art such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the reaction mass, preferably by filtration. After the isolation, the wet product can be washed with the same anti-solvent or other anti-solvent described herein.
The resulting crystalline Pomalidomide in step d) may optionally be further dried. The crystalline Pomalidomide can be polymorph Form-A of pomalidomide. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 70°C, less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Pomalidomide is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or longer.
If the purity obtained after this purification steps is lower than the desired one, the isolated product may be subjected to the same purification process described above.
In a second aspect, the application provides a process for preparation of polymorphic Form A of pomalidomide, wherein the process comprising:
a) Suspending pomalidomide in dimethyl sulfoxide or dimethyl formamide;
b) Heating the suspension to 30 – 65°C to obtain a clear solution;
c) Adding the anti-solvent to the solution of step b);
d) Isolating the Pomalidomide.
In embodiments of the second aspect, the application provides same process conditions as in the embodiments of the first aspect.
The starting material, pomalidomide can be prepared by any known processes in the literature. For example, pomalidomide can produced in the following synthetic route, which is described in US5635517B2.

Scheme B
The inventors of the present application observed that during the hydrogenation of 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione, over hydrogenation may occur which in turn leading to the formation of an impurity, 7-amino-2-(2,6-dioxopiperidin-3-yl)-3a,4,5,6-tetrahydro-1H-isoindole-1,3(2H)-dione, designated as compound of Formula A.

Formula A
The impurity if formed to an undesired extent in this stage may require repeated purification steps such as repeated recrystallizations, column chromatography etc., to reduce this impurity to a desired level in the final pomalidomide. This leads to reduction in the overall yield and increase in cycle time, and increase in the cost of manufacturing. The inventors of the present application surprisingly found that, the formation of this impurity can be significantly reduced by following the below procedure. This procedure will lead to the formation of impurity to less than 0.15%. Further reduction in the Impurity A may also occur during the purification process.
This patent application also provides the process for the preparation of Impurity A, which will be useful as a standard to check the purity of pomalidomide.
The steps involved in the preparation of Pomalidomide and the preparation of the Impurity A are same. However, they differ in the conditions followed in the process for preparation and/ or in the purification. The steps involve:
a) Adding 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione, 1,4-dioxane, methanol and Pd/C into a hydrogenation vessel;
b) Conducting hydrogenation reaction;
c) Isolating the crude compound; and
d) Optionally purifying the product.
Differences between the process for preparation of pomalidomide and Impurity A of pomalidomide:
Steps Process for the reduction of -(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione Process for the preparation of Impurity A
Step – a
Adding 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione, 1,4-dioxane, methanol and Pd/C into a hydrogenation vessel Temperature: Room temperature
Solvent: 1,4-dioxane & Methanol
Hydrogenating agent: 10.0 % Pd/C (5.0 % w/w) Temperature: Room temperature
Solvent: 1,4-dioxane & Methanol
Hydrogenating agent: 10.0 % Pd/C (8.0 % w/w)
Step – b
Conducting hydrogenation reaction Temperature: 25°C - 35°C
Pressure: 0.5 kg/cm2 to 1.5 kg/ cm2
Maintenance: 12 - 16 hours Temperature: Above 50°C
Pressure: 2 kg/cm2 to 3 kg/ cm2 or higher
Maintenance: 30 - 35 hours or longer
Step – c
Isolating the crude compound By decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product or other isolating techniques or methods known in the art. By decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product or other isolating techniques or methods known in the art.
Step – d
Optionally purifying the product Temperature: 25°C – 65°C
Solvent: Dimethyl sulfoxide or Dimethyl formamide
Anti-solvent: Alcohols, Esters, Ethers, Hydrocarbons, Water etc. Super critical fluid chromatography.

In an embodiment, the application provides obtained crude pomalidomide or impurity A of pomalidomide can be purified by the methods followed in the first aspects or the methods known in the art.

DEFINITIONS
The term "about" when used in the application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 1 1 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The term "room temperature" when used in the application referring to a temperature of from about 18°C to about 30°C., preferably about 20°C to about 25°C.
The term "polymorph" when used in the application referring to polymorphs already described in the art or any other polymorphic forms of which will be developed in the art.
The term "purified," as described herein, refers to the purity of a given compound. For example, a compound is "purified" when the given compound is a major component of the composition, i.e., at least 50% w/w pure. Thus, "purified" embraces at least 50% w/w purity, at least 60% w/w purity, at least 70% purity, at least 80% purity, at least 85% purity, at least 90% purity, at least 92% purity, at least 94% purity, at least 96% purity, at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity, wherein "substantially pure" embraces at least 97% purity, at least 98% purity, at least 99% purity, at least 99.5% purity, and at least 99.9% purity.
The term “desired quality” as described herein, refers to the purity pomalidomide containing less than 0.15% of impurity having Formula A.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES
Example-1: Preparation of pomalidomide:
3-Nitrophthalic anhydride (800 g), 3-aminopiperidine-2,6-dione hydrochloride (681.4 g), sodium acetate (339.8 g) and acetic acid (8 L) were charged into Julabo at 27°C. The white colored heterogeneous reaction mixture was heated to 114°C - 115°C. The reaction mixture was stirred for about 18 hours. The obtained heterogeneous black reaction mass was cooled to 30°C temperature and transferred into a 100 L glass reactor. Water (8 L) was added to the reaction mixture and stirred at 28°C - 30°C for 1 hour. The reaction mixture was filtered and the obtained sediment was washed three times with water (3×12 L) followed by two times with methanol (2×8 L). The reaction mass was dried under suction.
The crude reaction mass (1.1 Kg) and dimethyl formamide (7.2 L) were charged into a 100 L glass reactor at 28°C. The reaction mixture was heated to 67°C to get a clear solution. Water (10.4 L) was slowly added into the solution in drop wise manner for one hour. The obtained heterogeneous reaction mass was slowly cooled to 29°C and stirred for 2 hours. The heterogeneous reaction mass was filtered and the sediment was washed with water for 3 times (3×5.2 L) followed by methanol for 2 times (2×8 L). The obtained compound was dried under suction followed drying under vacuum at 70°C for 4 hours.
Yield - 1030g (82.0%)
Purity by HPLC - 99.88%
The above solid compound (260 g), 1,4-dioxane (10.4 L), methanol (2.6 L) and 10% palladium on carbon (5 % w/w; 13 g) were charged into an autoclave vessel. The reaction mixture was stirred under pressure of 1 kg/cm2 at 26°C - 27°C in hydrogen atmosphere for about 3.5 hours. Nitrogen gas was flushed into the reaction mixture and stirred for 1 hour. The reaction mass was unloaded from the autoclave and washed with methanol (1.3 L).
A cetile (520 g) bed was prepared by using methanol (2.6 L). The reaction mass was filtered through the celite and washed methanol (2.6 L). Another cetile (520 g) bed was prepared by using methanol (2.6 L) and carbon bed (260g) was prepared by using methanol (2.6 L). The obtained filtrate was filtered through the celite washed with methanol (1.04 L) followed by filtered through charcoal and washed with methanol (1.04 L). The filtrate was distilled at below 50°C till 1-2 volumes. MIBK (1.3 L) was charged into the reaction mass and stirred for 1.5 hours at 26°C - 30°C. The reaction mass was filtered and washed the solid with MIBK (0.52 L). The obtained solid was dried under suction at 24°C for 30 minutes. Yield - 167g (71.3%)
Purity by HPLC - 99.42%
Impurity A - 0.04%

Example-2: Purification of pomalidomide from DMSO and Methanol:
Pomalidomide (4 g) and DMSO (16 mL) were charged in a round bottom flask and stirred at 27°C to obtain a partially clear solution. The partially clear solution was stirred at 55° - 60oC for 20 minutes to obtain a clear solution. Methanol (16 mL) was slowly added into the clear solution for 1 hour at 55° - 60°C and stirred the reaction mixture at for 1 hour at the same temperature to precipitate a solid. The reaction mass was cooled to 29°C and stirred for 1 hour. The reaction mass was filtered and the residue was washed with methanol (16 mL) , dried under suction for 30 minutes and dried under vacuum at 70°C for 12 hours to obtain a yellow colored solid.
Yield - 3.5g (87.5%)
Purity - 99.81%
Example-3: Purification of pomalidomide from DMF and Methanol:
Pomalidomide (4 g) and DMF (48 mL) were charged in a round bottom flask at 28°C to obtain a partially clear solution. The partially clear solution was stirred at 55° - 60oC for 30 minutes to obtain a clear solution. Methanol (48 mL) was slowly added into the clear solution and stirred at 55° - 60°C for 1 hour. The reaction mass was cooled to 27°C and stirred for 20 minutes. The reaction mass was filtered and the residue was washed twice with methanol (2×48 mL) , dried under suction and dried under vacuum at 70°C for 12 hours to obtain a solid.
Yield - 2.7g (67.5%)
Purity - 99.84%

Example-4: Purification of pomalidomide from DMF and water:
Pomalidomide (3 g; HPLC purity = 98.5%) and DMF (30 mL) were charged in a round bottom flask at 27°C to obtain a partially clear solution. The reaction mass was stirred for 2 hours at 55° - 60°C to obtain a clear solution. Water (30 mL) was slowly added into the clear solution and stirred at 58°C for 1 hour to precipitate a solid. The precipitated solid was cooled to 30°C and stirred for 30 minutes. The reaction mass was filtered and washed with water (30 mL), dried under suction and dried under vacuum at 65° - 70°C for 12 hours to obtain a yellow colored solid.
Yield - 2.8g (83.3%)
Purity by HPLC - 99.46%

Example-5: Purification of pomalidomide from DMSO and MIBK:
Crude pomalidomide (165 g; HPLC purity = 99.42%) and DMSO (825 mL) were charged in a four neck flask at 28°C to obtain a partly clear solution. The partly clear solution was stirred at 45° for 1 hour 10 minutes and filtered through 0.22µm filter paper. The filtered reaction mixture is transferred into a four neck round bottom flask. The reaction mixture is heated to 61° - 65°C. Methyl isobutyl ketone (MIBK; 3.3 L) was slowly added into the solution at 65°C for 2 hours. The reaction mixture was stirred at 61° - 64°C for about 15 hours. The reaction mixture is filtered at 64°C and dried at 70°C under vacuum. The obtained product matches with the Form-A of pomalidomide.
Yield - 108 g (65.45% (w/w))
Purity - 99.89 %
Impurity A - 0.03%

Example-6: Preparation of impurity of Formula A:
2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (10 g), dioxane (400 mL), methanol (100 mL) and 10% palladium on carbon (50% wet, 4 g) are charged into an autoclave reactor at 25° - 30°C. The reaction mass was first flushed thrice with nitrogen followed by hydrogen. The reaction mass was maintained at 55°C under pressure of 10 kg/cm2 for 15 hours. The reaction mass was again flushed with hydrogen at and maintained at 50° - 55°C under pressure of 20 kg/cm2 for another 15 hours. The reaction mass was cooled to 25-30°C. The reaction mass was unloaded from the vessel and washed with methanol (50 mL). The reaction mass was filtered through celite and washed with methanol (30 ml). The obtained filtrate was distilled under vacuum at 45° - 50°C. The obtained crude of impurity of Formula A was purified by super critical felid chromatography to produce purified impurity of Formula A.
The obtained crude of impurity of Formula A was purified through super critical fluid chromatography to produce purified impurity of Formula A.
Purity of Impurity A - 93.44%
,CLAIMS:1. A process for purifying Pomalidomide comprising:
a) Suspending pomalidomide in dimethyl sulfoxide or dimethyl formamide;
b) Heating the suspension to 30 – 65°C to obtain a clear solution;
c) Adding the anti-solvent to the solution of step b);
d) Isolating the Pomalidomide.
2. A process according to claim 1, wherein the anti-solvent used in step c) is Methyl isobutyl ketone.
3. A process for preparing Form-A of Pomalidomide comprising:
a) Suspending pomalidomide in dimethyl sulfoxide or dimethyl formamide;
b) Heating the suspension to 30 – 65°C to obtain a clear solution;
c) Adding the anti-solvent to the solution of step b);
d) Isolating the Pomalidomide.
4. A process according to claim 3, wherein the dimethyl sulfoxide or dimethyl formamide in step a) is added in the ratio of 1:1 to 1: 50 to the weight of pomalidomide.
5. A process according to any of the preceding claims wherein Pomalidomide obtained is having HPLC purity greater than 99.4%.
6. A pharmaceutical composition comprising Pomalidomide obtained according to any of the preceding claims.