DESC:FIELD OF THE INVENTION:
The present invention relates to process for the preparation of pomalidomide or pharmaceutically acceptable salts thereof and to the solid forms comprising pomalidomide and a coformer.

BACKGROUND OF THE INVENTION:
Pomalidomide, which was previously referred to as CC-4047 is marketed under the brand name Pomalyst® by CELGENE. Pomalidomide is chemically termed as, 4- amino-2-(2,6-dioxopiperidin-3-yl)isoindole-l,3-dione and has the structural formula:

Formula I
Pomalidomide is a derivative of thalidomide that is anti-angiogenic. The efficacy of the drug is thought to be due to its ability to suppress the production of the immunomodulatory agent tumor necrosis factor-alpha (TNF-a), and therefore the compound has been referred to as immunomodulators (IMiDs). It is used in combination with dexamethasone (an anti-inflammatory medicine) to treat multiple myeloma (a cancer of the bone marrow). It blocks the development of tumour cells, prevents the growth of blood vessels within tumours and also stimulates some of the specialized cells of the immune system to attack the tumour cells. Specifically, pomalidomide inhibits proliferation and induces apoptosis of hematopoietic tumor cells. ld. Additionally, pomalidomide inhibits the proliferation of lenalidomide resistant multiple myeloma cell lines and synergizes with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide also inhibits angiogenesis by blocking the migration and adhesion of endothelial cells. Due to its diversified pharmacological properties, pomalidomide is useful in treating, preventing, and/or managing various diseases or disorders.
Pomalidomide and its process were first disclosed in US patent no. 5,635,517. According to the publication, crystalline solid of pomalidomide was obtained by a process comprising steps of reacting 4-nitrophthalic anhydride with a-amino glutarimide HCl and sodium acetate in glacial acetic acid under reflux for 17 hours to obtain 1,3-dioxo-2(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline followed by reduction with palladium carbon in the presence of 200 volumes of 1,4-dioxane at 50 psi for 6.5 hours to obtain a residual solid. The residual solid was recrystallized from 1,4-dioxane and ethyl acetate to obtain crystalline pomalidomide.

Several other processes for the preparation of pomalidomide have been reported, for e.g., in U.S. Patent 7,994,327; and Chinese patent Application Publication No. 103819454 A; the entireties of which are incorporated herein by reference.

While these methods are enabling and useful for preparing pomalidomide, alternative or improved methods for their preparation, particularly in manufacturing scale, are still needed.

Further, pomalidomide can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

The crystalline pomalidomide obtained by the process of the prior art, is designated as pomalidomide crystalline Form I. Crystalline Form I is characterized by peaks in the powder x-ray diffraction spectrum having 2? angle positions at about 12.1, 14.1, 16.8, 17.2, 18.5, 24.4, 25.8, 28.1 and 28.6 ± 0.2 degrees.

The patent application publication WO 2013/126326 discloses anhydrous crystalline Form A and amorphous form of pomalidomide.

The other crystalline forms and process of their preparation are also reported in CN103626738, CN104072476, CN104140413; the entireties of which are incorporated herein by reference.

The different solid forms of a pharmaceutically active ingredient can have different characteristics, and offer certain advantages, for example with regard to stability, solubility or bioavailability. Thus, the innovation of new solid forms allows for improving the characteristics of the pharmaceutical formulations of the active ingredients, since some forms are more adequate for one type of formulation, and other forms for other type of formulations. Furthermore, depending on the therapeutic indications, one or another pharmaceutical formulation may be preferred. It is hence of interest to have new solid forms of pomalidomide.

OBJECT OF THE INVENTION
The object of the present invention is to provide a process for commercial manufacture of pomalidomide or pharmaceutically acceptable salts thereof.

Yet another object of the present invention is to provide a process which is simple, economical and, suitable for industrial scale-up.

Yet another object of the present invention is to provide novel solid forms comprising pomalidomide and a coformer.

Yet another object of the present invention is to provide process for the preparation of novel solid forms comprising pomalidomide and a coformer.

SUMMARY OF THE INVENTION
According to a first aspect of the present invention, there is provided an improved process for preparing pomalidomide or pharmaceutically acceptable salts thereof.

In one aspect, the invention provides a process for preparing pomalidomide or pharmaceutically acceptable salts thereof, wherein the process comprises the step of;
a) reacting 3-nitro phthalic anhydride of formula IV or 3-nitrophthalic acid of formula V

with 2,6-dioxo piperidine-3-ammonium chloride of formula III

in the presence of a suitable base and solvent to yield 4-nitro-2-(2,6-dioxo piperidine -3-yl)isoindole-1,3-dione of formula II; and
.

b) reducing the 4-nitro-2-(2,6-dioxo piperidine -3-yl)isoindole-1,3-dione of formula II by catalytic transfer hydrogenation to obtain pomalidomide of formula I.

The base used in step a) is selected from inorganic base and organic base and the solvent is selected from polar and nonpolar solvent. In an embodiment, the solvent is present in about 10 volumes. In a further embodiment, the reaction time is from about 4 to about 6 hours. In a further embodiment, the efficiency is > 90%.

The reduction of 4-nitro-2-(2,6-dioxo piperidine -3-yl)isoindole-1,3-dione of formula II may be carried out in a solvent selected from protic and aprotic solvents. In an embodiment the solvent is present in about 12-15 volumes. In a further embodiment, the efficiency is > 85%. In a further embodiment, the genotoxic impurity level is reduced to < 0.01%.

In a second aspect, the present invention provides a novel solid form comprising pomalidomide or pharmaceutically acceptable salts (including solvates and hydrates), and a coformer. Also provided are methods of preparing, characterizing such a solid form and methods of treating or preventing proliferation of neoplastic cells.

In a further aspect of the present invention, there is provided a process for preparing novel solid form comprising pomalidomide or pharmaceutically acceptable salts (including solvates and hydrates), and a coformer. The processes of the present invention afford novel solid form comprising pomalidomide or pharmaceutically acceptable salts (including solvates and hydrates), and a co-former in high purity and high yield. Advantageously, they are environmentally friendly and suitable for preparation on a commercial scale.

The novel solid form comprising pomalidomide or pharmaceutically acceptable salts (including solvates and hydrates), and a coformer of the present invention possess certain physical and chemical properties which render them particularly suitable for pharmaceutical development, such as good solubility, permeability and bioavailability. In addition, they are suitable for bulk handling and formulation.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising pomalidomide as described above (including novel solid form) optionally comprising one or more pharmaceutically acceptable excipients.

In a further aspect of the present invention, there is provided a method for preparing a pharmaceutical composition comprising pomalidomide as described above (including novel solid form), optionally comprising one or more pharmaceutically acceptable excipients.

In a further aspect of the present invention, there is provided method for the prevention or treatment of TNFa production which method comprises administering pomalidomide as described above (including novel solid form) to a patient in need thereof.
In a further aspect of the present invention, there is provided novel pomalidomide as described above (including novel solid form) for use in the prevention or treatment of TNFa production.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the powder X-ray diffraction pattern of solid crystalline Form C comprising pomalidomide and hydrochloric acid.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the synthesis of pomalidomide or pharmaceutically acceptable salts thereof of formula I.

In one aspect, the present invention provides a process for preparing 4-nitro-2-(2,6-dioxo piperidine -3-yl)isoindole-1,3-dione of formula II by reaction of 3-nitro phthalic anhydride of formula IV or 3-nitro phthalic acid of formula V with 2,6-dioxo piperidine-3-ammonium chloride of formula III in the presence of a suitable base and a suitable solvent as shown in Scheme 1.

A suitable base used for the reaction may be an inorganic or organic base. The inorganic base may be selected from the group consisting of alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, lithium carbonate, barium carbonate, sodium bicarbonate or potassium bicarbonate; alkali or alkaline earth metal acetates such as sodium acetate, potassium acetate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide or barium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, lithium t-butoxide.

Organic bases may be aliphatic or aromatic and may be selected from, but not limited to triethyl amine, diisopropyl amine, dimethyl amine, pyridine, picoline, diethyl amine, piperidine, morpholine, piperazine, N,N-diisopropylethylamine.
The solvent may be selected from the group consisting of polar and non polar solvent. The polar solvent may be selected from the group consisting of acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), N-methyl pyrrolidone (NMP), acetic acid or dioxane. The non polar solvent may be selected from the group consisting of toluene or xylene. Preferably, the reaction is carried out in the acetic acid.

In US patent no. 5,635,517 the reaction is carried out in 17 volumes of acetic acid at reflux for several hours to complete the reaction. This longer duration of reaction produces many impurities and hence requires additional purification steps. In the process of the present invention, the reaction is carried out in less than 11 volumes of the solvent, instead of 17 volumes as reported in the prior art, thus avoiding the handling of a large quantity of solvent. The advantage is that the reaction time is reduced drastically to about 4 to about 6 hours from 17 hours stirring as reported in the prior art. This forms one aspect of the present invention.

In the present process, after completion of reaction, the product is easily isolated by simple filtration, thus avoiding extraction and concentration steps using second solvent as reported in the prior art. This process avoids handling a large quantity of solvent such as acetic acid, and it avoids subsequent extraction as reported in the prior art, and this forms second aspect of the present invention.

In the process of the present invention, the work up procedure may be simplified to give the product in high purity and to minimize the formation of impurities which are formed when one employs the work-up procedure given in the prior art. Thus increasing efficacy to more than 90% as against 65% as reported in the prior art, and this forms third aspect of the present invention.

In another aspect, the present invention is directed to an improved process for preparing pomalidomide or pharmaceutically acceptable salts thereof of formula I by reducing 4-nitro-2-(2,6-dioxo piperidine -3-yl)isoindole-1,3-dione of formula II as shown in Scheme 2.

Accordingly, 4-nitro-2-(2,6-dioxo piperidine-3-yl)isoindole-1,3-dione of formula II is reduced by catalytic transfer hydrogenation to pomalidomide of formula I.

In one embodiment catalytic transfer hydrogenation is carried out using formic acid in combination with a base and a metal catalysts.

A suitable base used for the reaction may be an organic base. The organic base may be selected from the group consisting of aliphatic or aromatic and may be selected from, but not limited to triethyl amine, diisopropyl amine, dimethyl amine, pyridine, picoline, diethyl amine, piperidine, morpholine , piperazine or N,N-diisopropylethylamine.

Suitably, a metal catalyst is selected from palladium, platinum, nickel and iron.

The reduction is preferably carried out at a temperature ranging from about 25°C to about the reflux temperature of the solvent used. Preferably, the reduction is performed at about 25°C to about 50°C in a suitable solvent selected from protic, aprotic or combination thereof. Preferably, the reduction is performed in aprotic solvent selected from DMF, DMSO, acetonitrile, tetrahydrofuran (THF), N-methylpyrrolidinone, dioxane and DMA.

In US patent no. 5,635,517 the reduction reaction is carried out in 200 volumes of 1,4-dioxane at 25-30°C for 6.5 hours to complete the reaction. In the process of the present invention, the reaction is carried out in less than 12 volumes of the solvent, instead of 200 volumes as reported in the prior art, thus avoiding the handling of a large quantity of solvent on industrial scale. The advantage is that the reaction time is reduced drastically to about 3 to about 5 hours from 6.5 hours stirring as reported in the prior art. This forms one aspect of the present invention.

In the present process, after completion of the reaction, the product is easily isolated by quenching the reaction mass in water followed by filtration, thus avoiding concentration steps as reported in the prior art. This process avoids handling a large quantity of solvent such as acetic acid, and it avoids subsequent concentration as reported in the prior art. Further, in the process of the present invention, the work up procedure may be simplified to give the product in high purity and to minimize the formation of impurities such as genotoxic impurities level < 0.01%, which are formed when one employs the work-up procedure given in the prior art. Thus increasing efficacy to more than 85% as against 80% as reported in the prior art, and this forms another aspect of the present invention.

In an alternative embodiment, the nitro reduction is carried out using non hydrogenation conditions in the presence of Fe/AcOH, Zn/AcOH, SnCl2/HCl, Fe/HCl or Fe/NH4Cl and an inert solvent. Suitably, the inert solvent employed is selected from alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol or polar aprotic solvents such as acetonitrile, DMF, DMSO or THF.

In yet another embodiment, the nitro reduction is carried out using a hydrogen donating compound such as ammonium formate or hydrazine hydrate in the presence of hydrogen transfer catalysts.

Suitably, the hydrogen donating compound is hydrazine hydrate.

Suitably, the hydrogen transfer catalyst is selected from FeCl3.6H20-activated carbon, Fe (Ill) oxide hydroxide or Fe (Ill) oxide, Zn-C, Fe-C, Pd-C, Pt-C, Raney Ni, graphite and clays.

In an embodiment, the reduction is conducted in refluxing alcoholic solvents or dioxane. A suitable alcoholic solvent is methanol.

In another embodiment, the nitro reduction is carried out using ammonium formate and a hydrogenation - dehydrogenation catalyst in the presence of an inert solvent.

Suitably, the hydrogenation-dehydrogenation catalyst comprises a noble metal catalyst such as palladium, ruthenium or rhodium supported on carbon, clay, silica or alumina.

Suitably, the inert solvent employed is selected from alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol or polar aprotic solvents such as acetonitrile, DMF, DMSO or THF.

In this embodiment, the reduction is carried out at a temperature ranging from about 25° C to about the reflux temperature of the solvent used.

Pomalidomide obtained according to the process of the present invention, may be further purified by acid/base treatment or by crystallization from solvents selected from polar solvents, non-polar solvents or mixture thereof, to obtain pharmaceutically acceptable grade pomalidomide of formula I.

In another aspect, the invention provides pharmaceutical composition comprising pomalidomide or pharmaceutically acceptable salt thereof prepared according to the process of the invention and optionally in association with one or more pharmaceutical carriers.

In another aspect, provided herein is a novel solid form comprising
(a) pomalidomide of formula I, or a pharmaceutically acceptable salts thereof (including solvates and hydrates); and (b) a co former.

In a preferred embodiment, provided herein is a solid form comprising (a) a free base of pomalidomide of formula I (including solvates and hydrates); and (b) a co former.

In an embodiment a free base of pomalidomide of formula I may be in hydrated or solvated form. Preferably pomalidomide of formula I is in the hydrated form.

As used herein, the term "hydrate" is understood as a substance that is formed by adding water molecules.

In an embodiment the ratio of API to water in the solid form may be stoichiometric or non-stoichiometric.

The skilled person will appreciate that the water molecules are absorbed, adsorbed or contained within a crystal lattice of the solid compounds, usually in defined stoichiometric ratio. The notation for a hydrated compound may be .nH2O, where n is the number of water molecules per formula unit of the compound. For example, in a hemihydrate, n is 0.5; in a monohydrate n is one; in a sesquihydrate, n is 1.5; in a dihydrate, n is 2; in a trihydrate, n is 3 and so on.

In preferred embodiment, the water content in pomalidomide may vary in ratio depending on the conditions applied. Conveniently, the amount of water in pomalidomide may range between 3.0 wt% to 7.0wt%. While the pomalidomide comprising about 3.0 wt% to 7.0wt% of water per molecule of pomalidomide represent the lower and upper ranges respectively; water content of the crystal form may vary within this range depending on the temperature of the crystal form.

The coformer is typically a non-toxic pharmaceutically acceptable coformer such as, for example, food additives, preservatives, pharmaceutical excipients, or other APIs known in the art.

In an embodiment, the ratio of API to co former may be stoichiometric or non-stoichiometric. In another embodiment, the ratio of API to coformer may vary depending on the conditions applied.

In one embodiment, the ratio of API to coformer is about 5:1,4:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 20 1 :2.5, 1:3, 1:4, or 1:5. In one embodiment, the ratio of API to coformer is about 1:1. In one embodiment, the solid form comprises more than one coformers. In another embodiment, the solid form comprises two coformers.

Preferably, the amount of coformer present in the solid form will be in the nonstoichiometric ratio.

In a preferred embodiment, the coformer is hydrochloric acid.

In an embodiment, the HCl content may vary in ratio depending on the conditions applied. Conveniently, the amount of HCl in pomalidomide may range between 10.0 wt% to 13 wt%. While the pomalidomide, comprising 10.0 wt% of HCl per molecule of pomalidomide and about 13 wt% molecule of HCl per molecule of pomalidomide, represent the lower and upper ranges respectively, HCl content of the crystal form may vary within this range depending on the temperature of the crystal form.

Depending on the crystallization and drying conditions, the solid form can be isolated in different polymorphic forms for e.g., crystal forms or amorphous forms. The solid form can be further isolated in solvated, unsolvated, or mixtures thereof.

Thus, in a preferred embodiment, provided herein is a solid form comprising (a) a free base of pomalidomide of formula I; and (b) hydrochloric acid. Preferably the solid form is in the hydrated form comprising (a) pomalidomide and (b) a hydrochloric acid. Preferably, the hydrated form is in the substantially crystalline form, which is herein and in the claims designated as “Form C” which is substantially non-hygroscopic and has good flow characteristics.

The crystalline “Form C” is relatively stable towards moisture and humidity, thereby representing a crystalline hydrated solid form comprising (a) a free base of pomalidomide of formula I; and (b) hydrochloric acid, thus enhancing the efficacy of the parent molecule in lower doses.

Thus, pomalidomide forms a crystalline hydrate with hydrochloric acid wherein the hydrochloric acid is present in the non-stoichiometric ratio ranging from 10.0 wt% to 13.0 wt%, and water is present in the non-stoichiometric ratio ranging from about 3.0 wt% to 7.0 wt% .

As polymorphic forms are reliably characterized by peak positions in the X-ray diffractogram, the crystalline Form C of the present invention have been characterized by powder X-ray diffraction spectroscopy which produces a fingerprint of the particular crystalline form. Measurements of 2? values are accurate to within ± 0.2 degrees. All the powder diffraction patterns were measured on a Rigaku Dmax 2200 advanced X-ray powder diffractometer with a cu-Ka radiation source

The crystalline Form C may have an XRD pattern with characteristics peaks at 15.182 and 21.401, ± 0.2 °2?. The XRD pattern may have further peaks at 13.782, 18.220, 19.079, 22.181, 24.759, 27.482, 30.598 and 33.579± 0.2 °2?. The XRD pattern may have still further peaks at 9.079, 10.380, 14.602, 16.559, 20.601, 20.880, 22.900, 25.558, 26.380, 26.641, 28.699, 29.520, 30.220, 31.042, 31.561, 32.698, 33.916, 35.082, 35.462, 36.437 and 37.400± 0.2 °2?.
In an embodiment, the crystalline Form C has substantially the same XRPD pattern with peaks at 2? values as depicted in Table 1.

Table 1: Table of values for the XRPD pattern depicted in Figure 1

Peak value (°2?) Relative Intensity [%]
9.079 15.5
10.380 13.0
13.782 34.4
14.602 10.5
15.182 87.3
16.559 23.0
18.220 61.6
19.079 37.0
20.601 22.4
20.880 18.2
21.401 100.0
22.181 45.7
22.900 13. 5
24.759 40.7
25.558 12.8
26.380 11.7
26.641 24.9
27.482 63.4
28.699 10.8
29.520 24.9
30.220 26.6
30.598 63.9
31.042 17.3
31.561 21.8
32.698 27.5
33.579 41.0
33.916 13.0
35.082 12.4
35.462 16.5
36.437 14.5
37.400 10.3

In another embodiment, crystalline Form C of the present invention is characterized by having an X-ray powder diffraction spectrum as shown in Figure 1.

It will be appreciated that other conventional analytical methods including, but not limited to, intrinsic dissolution profiles, IR, solid state NMR, Thermogravimetric analysis (TGA), Differential Scanning Calorimetric analysis (DSC), Dynamic Vapour Sorption analysis (DVS) and Raman spectroscopy may also be employed to characterize the crystalline Form C of the present invention.

In another aspect, the present invention provides a process for the preparation of crystalline Form C The pomalidomide base used in preparing the polymorph may be obtained by methods described in the prior art which are herein incorporated by reference in their entirety. The pomalidomide used as a starting material can be in any form, e.g. it can be in a reaction solution, suspension, crude or in anhydrous, hydrated or solvated form.

The crystalline Form C of the present invention may be prepared by mixing pomalidomide base of any form, or in a mixture of any forms, with hydrochloric acid solution. Hydrochloric acid may be present in the aqueous solution or non-aqueous solution. Preferably hydrochloric acid is in the aqueous solution. The reaction mass may be stirred for about 30 minutes to about 5 hours at a temperature of about 25°C to 60°C. The reaction is preferably performed at a temperature ranging from about 25°C to about 40°C. Preferably, the reaction is performed at a temperature ranging from about 25°C to about 30°C. Typically the reaction time ranges from about 1 to about 4 hours.

In an embodiment the term “mixing” is understood as suspending or dissolving pomalidomide in concentrated HCl solution.

The Form C produced in the reaction solution may be isolated by filtration and washed with polar aprotic solvent or polar protic solvents. The Form C may be mixed further with polar solvent or mixture of polar solvents and stirred for a prolonged time period at around room temperature. In an embodiment, the prolonged period is from about 30 minutes to about days, preferably from about 30 minutes to about 1 day, more preferably from about 30 minutes to about 2 hours.

In an embodiment the term “mixing” is understood as suspending or dissolving solid in a polar solvent or mixture of polar solvents.

The solvent employed in this process are polar aprotic solvents and polar protic solvents. In an embodiment polar aprotic solvents selected from THF, acetone, acetonitrile, 1, 4-dioxane, DMF, DMSO, and N-methyl-2-pyrrolidone. In an embodiment polar protic solvents selected from water and alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and t-butanol. In a preferred embodiment the solvent is selected from acetone, acetonitrile and isopropanol.

The precipitated Form C may be isolated by filtration, for example by either gravity or suction. The precipitate may be dried at 25-60°C and/or in vacuum to obtain Form C.

The novel crystalline Form C obtained according to the present invention is substantially free from other crystal and non-crystal forms of pomalidomide. "Substantially free" from other forms of pomalidomide shall be understood to mean that the polymorphs of pomalidomide contain less than 10%, preferably less than 5%, of any other forms of pomalidomide and less than 1% of other impurities or solvates. Thus, the crystalline Form C prepared according to the present invention contains less than 11% total impurities, preferably less than 6% total impurities. In a particularly preferred embodiment, the crystalline Form C prepared according to the present invention contains less than 1% total impurities.

The process of invention may be used as a method for purifying any form of pomalidomide, as well as for the preparation of the new polymorphic forms.

Pomalidomide has been found to be effective in the treatment for relapsed and refractory multiple myeloma.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising pomalidomide as described above (including crystalline Form C of pomalidomide) together with one or more pharmaceutically acceptable carriers, excipients or diluents. Any conventional technique may be used for the preparation of pharmaceutical compositions according to the invention.

The invention is further described by reference to the following examples, which set forth in detail certain aspects and embodiments of the preparation of compounds and compositions of the present invention. It will be apparent to those skilled in the art, that many modifications, both to materials and methods, can be practiced without departing from the purpose and intent of this invention. The examples that follow are not intended to limit the scope of the invention as described herein above or as claimed below.

Examples:-

Example 1
Preparation of 4-nitro-2-(2,6-dioxo piperidine -3-yl)isoindole-1,3-dione from 3-nitrophthalic anhydride
3-Nitrophthalic anhydride (100g, 0.517 moles) and sodium acetate (53 g, 0.64 moles) were stirred in acetic acid (1000 ml) for 10 minutes at room temperature. To the solution was added 2, 6-dioxo piperidine-3- ammonium chloride (90 g, 0.54 moles). The reaction mass was stirred and heated to 110 to 115 °C for 4-6 hours. The reaction mass was allowed to cool to the room temperature and stirred for 30 minutes. The solid was isolated by filtration and washed with water.
The solid was stirred in 5 volumes of water at 50 to 55°C for 30 minutes and then cooled to the room temperature. The reaction mass was filtered and the solid was dried to afford 145 g (97.5% of the titled compound.

Example 2
Preparation of 4-nitro-2-(2,6-dioxo piperidine -3-yl)isoindole-1,3-dione from 3-nitrophthalic acid
3-Nitrophthalic acid (15.0 g, 0.071 moles) and sodium acetate (7.3 g, 0.088 moles) were stirred in acetic acid (150 ml) for 10 minutes at room temperature. To the solution was added 2, 6-dioxo piperidine-3- ammonium chloride (12.85 g, 0.078 moles). The reaction mass was stirred and heated to 110 to 115 °C for 4-6 hours. The reaction mass was allowed to cool to the room temperature and stirred for 30 minutes. The solid was isolated by filtration and washed with water.
The solid was stirred in 5 volumes of water at 50 to 55°C for 30 minutes and then cooled to the room temperature. The reaction mass was filtered and the solid was dried to afford 18.5 g (90.7%) of the titled compound.

Example 3
Preparation of Pomalidomide
To a stirred mixture of formic acid (125 ml, 3.3 moles), triethylamine (125 ml, 0.89 moles) and 10% Pd/C wet (10 g) was added a solution of 4-nitro-2-(2,6-dioxo piperidine-3-yl)isoindole-1,3-dione(100 g, 0.33 moles) in DMF ( 1200 ml) at 20 to 25°C in 30 minutes. The reaction mass was further stirred at 25 to 30°C for 3 to 5 hours. The reaction mass was filtered over hyflo. To the clear filtrate was added water (1500 ml) at 25 to 30°C and stirred further for 30 minutes. The solid was isolated by filtration and washed with water.

The solid was stirred in 5 volumes of DMSO and heated to 50 to 55°C to obtain a clear solution. To the solution was added water (10 volumes). The reaction mass was further stirred for 30 minutes and then allowed to cool to the room temperature. The solid was isolated by filtration and slurried in water at 50 to 55°C. The separated solid was isolated by filtration, washed with water and dried to afford 80 g (89 %) of the titled compound.

Example 4
Preparation of Pomalidomide
To a stirred mixture of formic acid (18.6 ml, 0.49moles), triethylamine (18.6 ml, 0.13 moles) and 10% Pd/C wet (1.5 g) was added a solution of 4-nitro-2-(2, 6-dioxo piperidine -3-yl) isoindole-1, 3-dione (15.0 g, 0.049 moles) in DMF (180 ml) at 20 to 25°C in 30 minutes. The reaction mass was further stirred at 25 to 30°C for 3 to 5 hours. The reaction mass was filtered over hyflo. To the clear filtrate was added water (225 ml) at 25 to 30°C and stirred further for 30 minutes. The solid was isolated by filtration and washed with water.

The solid was stirred in 5 volumes of DMSO and heated to 50 to 55°C to obtain a clear solution. To the solution was added water (10 volumes). The reaction mass was further stirred for 30 minutes and then allowed to cool to the room temperature. The solid was isolated by filtration and slurried in water at 50 to 55°C. The separated solid was isolated by filtration, washed with water and dried to afford 12 g (89 %) of the titled compound.

Example 5
Preparation of crystalline Form C
Pomalidomide (5 g) was stirred in concentrated HCl (approx. 36%, 20 ml) at 25 to 30°C for about 1 hour. The reaction mass was filtered and washed with acetone.
The solid was stirred in 5 volumes of acetone 25 to 30°C for 30 minutes. The reaction mass was filtered, washed with acetone and the solid was dried to afford 4.5 g of crystalline Form C.

Example 6
Preparation of crystalline Form C
Pomalidomide (5 g) was stirred in concentrated HCl (approx. 36%, 20 ml) at 25 to 30°C for about 1 hour. The reaction mass was filtered and washed with acetonitrile.
The solid was stirred in 5 volumes of acetonitrile at 25 to 30°C for 30 minutes. The reaction mass was filtered, washed with acetonitrile and the solid was dried to afford 4.5 g of crystalline Form C.

Example 7
Preparation of crystalline Form C
Pomalidomide (5 g) was stirred in concentrated HCl (approx. 36%, 20 ml) at 25 to 30°C for about 1 hour. The reaction mass was filtered and washed with ethyl acetate.

The solid was stirred in 5 volumes of ethyl acetate at 25 to 30°C for 30 minutes. The reaction mass was filtered, washed with ethyl acetate and the solid was dried to afford 4.5 g of crystalline Form C. ,CLAIMS:1. A process for preparing pomalidomide or pharmaceutically acceptable salts thereof, wherein the process comprises the step of;
a) reacting 3-nitro phthalic anhydride of formula IV or 3-nitrophthalic acid of formula V

with 2,6-dioxo piperidine-3-ammonium chloride of formula III

in the presence of a suitable base and solvent to yield 4-nitro-2-(2,6-dioxo piperidine-3-yl) isoindole-1,3-dione of formula II;
.
b) reducing 4-nitro-2-(2,6-dioxo piperidine -3-yl)isoindole-1,3-dione of formula II by catalytic transfer hydrogenation to obtain pomalidomide of formula I.

2. The process as claimed in claim 1, where in the base is selected from inorganic base or organic base.

3. The process as claimed in claim 1, where in the solvent is selected from polar and non polar solvent.

4. The process as claimed in claim 3, where in less than 11 volumes of the solvent is used in the reaction.

5. The process as claimed in claim 2, where the inorganic base may be selected from the group consisting of alkali or alkaline earth metal carbonates selected from cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, lithium carbonate, barium carbonate, sodium bicarbonate or potassium bicarbonate; alkali or alkaline earth metal acetates selected from sodium acetate, potassium acetate; alkali or alkaline earth metal hydroxides selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide or barium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, lithium t-butoxide.

6. The process as claimed in claim 2, where the organic base can be aliphatic or aromatic selected from the group consisting of triethyl amine, diisopropyl amine, dimethyl amine, pyridine, picoline, diethyl amine, piperidine, morpholine, piperazine, N,N-diisopropylethylamine.
7. The process as claimed in claim 3, where the polar solvent may be selected from the group consisting of acetonitrile, DMF, DMSO, DMA, NMP, acetic acid or dioxane.

8. The process as claimed in claim 3, where the non polar solvent may be selected from the group consisting of toluene or xylene.

9. The process as claimed in claim 1, where in the catalytic transfer hydrogenation is carried out using formic acid in combination with a base and a metal catalyst in suitable solvent.

10. The process as claimed in claim 9, wherein the base used is an organic base which may be aliphatic or aromatic selected from the group consisting of triethyl amine, diisopropyl amine, dimethyl amine, pyridine, picoline, diethyl amine, piperidine, morpholine , piperazine or N,N-diisopropylethylamine.

11. The process as claimed in claim 9, wherein the metal catalyst is selected from palladium, platinum, nickel and iron.

12. The process as claimed in claim 9, wherein, the reduction is performed in aprotic solvent selected from DMF, DMSO, acetonitrile, THF, N-methylpyrrolidinone, dioxane and DMA.

13. The process as claimed in claim 12, wherein, less than 12 volumes of the solvent is used in the reaction.

14. The process as claimed in claim 1, wherein, the reduction is carried out using non hydrogenation conditions in the presence of Fe/AcOH, Zn/AcOH, SnCl2/HCl, Fe/HCl or Fe/NH4Cl and an inert solvent.

15. The process as claimed in claim 14, wherein, the inert solvent is selected from alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol or polar aprotic solvents such as acetonitrile, DMF, DMSO or THF.

16. The process as claimed in claim 1, wherein, the reduction is carried out using a hydrogen donating compound such as ammonium formate or hydrazine hydrate in the presence of hydrogen transfer catalysts.

17. The process as claimed in claim 16, wherein the hydrogen transfer catalyst is selected from FeCl3.6H20-activated carbon, Fe (Ill) oxide hydroxide or Fe (Ill) oxide, Zn-C, Fe-C, Pd-C, Pt-C, Raney Ni, graphite and clays.

18. The process as claimed in claim 16, wherein the solvent used is dioxane or alcoholic solvents such as methanol.

19. The process as claimed in claim 16, wherein the hydrogen donating compound is hydrazine hydrate.

20. The process as claimed in claim 1, wherein the reduction is carried out using ammonium formate and a hydrogenation - dehydrogenation catalyst in the presence of an inert solvent.

21. The process as claimed in claim 20, wherein the the hydrogenation-dehydrogenation catalyst used is selected from a noble metal catalyst such as palladium, ruthenium or rhodium supported on carbon, clay, silica or alumina.

22. The process as claimed in claim 20, wherein the inert solvent employed is selected from alcohol solvents such as methanol, ethanol, isopropyl alcohol, butanol or polar aprotic solvents such as acetonitrile, DMF, DMSO or THF.

23. Pomalidomide or pharmaceutically acceptable salt thereof prepared according to any of the preceding claims having Genotoxic impurity less than 0.01%.

24. Pharmaceutical composition comprising pomalidomide or pharmaceutically acceptable salt thereof prepared according to any of the preceding claims.