Claims:We Claim:
1) A process for preparation ofhighly pure Pomalidomide of Formula(I)

(I)
comprising:
a) reacting 3-nitrophthalic anhydride of formula (II)

(II)
with aminopiperidine-2,6-dione hydrochloride of formula (III)

(II)

in presence of base to provide2-(2,6-dioxopiperidin-3-yl)-4-nitro-1,3-dione compound of Formula (IV);

(IV)
b) reducing 2-(2,6-dioxopiperidin-3-yl)-4-nitro-1,3-dione(IV) in presence of reducing agent to provide crude Pomalidomide (I);
c) treating crude Pomalidomide with dimethylglyoxime to yield highly pure Pomalidomide (I) free from residual metal content (i.e. Palladium)

2) A process for preparation of Pomalidomide, according to claim-1, wherein base used is selected from organic base such as triethylamine, diisoproylethylamine, tributyl amine, N,N-dimethyl aniline, pyridine, DBN, DBU, N-methyl piperazine or inorganic base such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide.
3) A process for preparation of Pomalidomide, according to claim 1, wherein reduction in step b) is carried out using a reducing agent selected from borane complexes; metals such as iron, tin, zinc; transition metals such as palladium-carbon, platinum oxide, Raney nickel.

4) A process for preparation of highly pure Pomalidomide of Formula(I) comprising:
a) treating Pomalidomide with a dimethyl sulphoxide solvent;
b) stir the contents; and
c) filtered the material to yield highly pure Pomalidomide

5) A process for preparation of highly pure Pomalidomide, according to claim-4, wherein Pomalidomide is treated with dimethyl sulphoxide at a temperature ranging from 25-30°C.

6) A process for preparation of highly pure Pomalidomide, according to claim-4, wherein the contents in step-b) are stirred for 15 minutes to 45 minutes.

7) A process for preparation of highly pure Pomalidomide, according to claim-4, wherein the Pomalidomide obtained is highly pure having a purity of greater than 99.7% .

8) Highly pure Pomalidomide having a purity of greater than 99.7% and total impurities collectively less than 0.3 % by HPLC.

9) Highly pure Pomalidomide according to claim-7, wherein highly pure Pomalidomide is free of andtotal impurities A to E collectively less than 0.3 % by HPLC.

Impurity-A

Impurity-B
Impurity-C

Impurity-D
Impurity-E

10) A process for the preparation of highly pure Pomalidomide (I) according to claim 1; wherein Pomalidomide obtained is used for the preparation of pharmaceutical composition with at least one or more pharmaceutically acceptable excipients.
, Description:FIELD OF THE INVENTION
The present invention relates to a process for preparation of compound of Formula (I).

(I)
The present invention further relates to a process for the preparation of highly pure Pomalidomide (I) useful in the treatment of cancer.

BACKGROUND OF THE INVENTION
Pomalidomide is marketed under the brand name POMALYST®, which is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including Lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy. It was approved by USFDA in 2013.Pomalidomide is an immunomodulatory antineoplastic agent, chemically known as (RS)-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione (I) and was marketed in the form of free base.

Pomalidomide is a yellow solid powder. The empirical formula for Pomalidomide is C13H11N3O4 and the gram molecular weight is 273.24. It has limited to low solubility into organic solvents and it has low solubility in all pH solutions (about 0.01 mg/mL). Pomalidomide has a chiral carbon atom which exists as a racemic mixture of the R(+) and S (-) enantiomers.

Pomalidomide is a generically disclosed and specifically disclosed in US 5635517 and disclosed a generalized process for the preparation of Pomalidomide.

US ‘517 and US 6316471 disclosed a process for the preparation of Pomalidomide starting form 4-nitrophthalic anhydride. The process is as demonstrated below.
Scheme-I:

US 7994327 disclose different processes for the preparation of Pomalidomide. The processes disclosed in this patent are as demonstrated below.
Scheme-II:

Scheme-III:

Scheme-IV:

Scheme-V:

Scheme-VI:

WO 2013126326 disclose crystalline Form A and amorphous forms of Pomalidomide.

IN 5409/CHE/2013 claims a process of purification of Pomalidomide comprises dissolving Pomalidomide in an organic solvent, adding an anti-solvent selected from and isolating substantially pure Pomalidomide. This patent publication further discloses crystalline Form of Pomalidomide.

Though, there are various disclosures as mentioned above for process for preparing Pomalidomide, however, formation of different impurities, which are often genotoxic or teratogenic in nature remained a major concern to be addressed till date. Plethora of literature available for genotoxic or teratogenic impurities presence and their possible direct impact on human health is reported in different APIs and products. Hence, owing to several difficulties in preparing a highly pure API, which could address genotoxic impurities concerns besides to remain economically viable and amenableto scale up, the present inventors have now developed an improved process for the preparation of highly pure Pomalidomide, using novel intermediates, which is not only industrially viable process, but also involves the use of environment friendly reagents and does not require tedious work up.

OBJECTIVE OF THE INVENTION
The main objective of the invention is to provide a process for the preparation of compound of Formula (I).

Yet another objective of the invention is to provide a process for the preparation of highly pure Pomalidomide.

Yet another objective of the invention is to provide Pomalidomide free of process related impurities.

SUMMARY OF THE INVENTION
The main aspect of the present invention relates to a process for preparation of highly pure Pomalidomide of Formula (I)

(I)
comprising:
a) reacting 3-nitrophthalic anhydride of formula (II)

(II)
with aminopiperidine-2,6-dione hydrochloride of formula (III)

(II)
in presence of base to provide 2-(2,6-dioxopiperidin-3-yl)-4-nitro compound of Formula (IV);

(IV)
b) reducing 2-(2,6-dioxopiperidin-3-yl)-4-nitro(IV) in presence of reducing agent to provide crude Pomalidomide (I);
c) treating crude Pomalidomide with dimethylglyoxime to yield highly pure Pomalidomide (I).

Another aspect of the present invention, it relates to a process for preparation of highly pure Pomalidomide of Formula (I) comprising:
a) treating Pomalidomide with a dimethyl sulphoxide solvent;
b) stir the contents; and
c) filtered the material to yield highly pure Pomalidomide

In yet another aspect the present invention relates to highly pure Pomalidomide having a purity of greater than 99.7% and total impurities collectively less than 0.3 % by HPLC.

DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of Pomalidomide (I) obtained according to the process of the present invention.
Fig. 2 is an example of Differential Scanning Calorimeter (“DSC”) pattern of Pomalidomide (I) obtained according to the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment according to the present invention , it provides to a process for preparation of highly pure Pomalidomide (I) comprising reacting 3-nitrophthalic anhydride of formula (II) with aminopiperidine-2,6-dione hydrochloride of formula (III) in presence of base selected from organic base such as triethylamine, diisoproylethylamine, tributyl amine, N,N-dimethyl aniline, pyridine, DBN, DBU, N-methyl piperazine or inorganic base such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide to provide 2-(2,6-dioxopiperidin-3-yl)-4-nitro compound of Formula (IV); and a solvent selected from solvent selected from amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidone; amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidone; alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dioxane; acetic acid, acetonitrile, water or mixtures at a temperature ranging from 80 to 120°C for a period of 18 hours to 24 hours to yield 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione.

The present inventors found that the use of sodium acetate in this reaction step appears to result inthe reaction to beincomplete and results in the formation of high content of impurities/by products in the formation of 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione, which are not et al feasible for the preparation of commercial level Pomalidomide.

The present inventors now developed a process for the preparation of highly pure 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione, which is free of process related impurities and is feasible in large scale reproduction.

The above obtained 2-(2,6-dioxopiperidin-3-yl)-4-nitro-1,3-dione(IV) undergo reduction, in presence of reducing agent selected from borane complexes; metals such as iron, tin, zinc; transition metals such as palladium-carbon, platinum oxide, Raney nickel; in the presence of hydrogen or hydrogen source, selected from ammonium formate, ammonium chloride, sodium dihydrogen phosphate and hydrazine at a temperature ranging from 25-30°Cto provide crude Pomalidomide (I)

The present inventors observed that the Pomalidomide obtained according to the prior art process contain high amount of metal content and are unable to meet the requirement of ICH guidelines.

The present inventors now developed a process for the preparation of highly pure Pomalidomide comprises of treating crude Pomalidomide obtained above with dimethylglyoxime to yield highly pure Pomalidomide (I). The present inventors found that pure Pomalidomide obtained after purification meets the requirements of ICH guidelines and free of any metal catalyst.

In another embodiment of the present invention, it further provides a process for the preparation of highly pure Pomalidomide
a) treating Pomalidomide with a dimethyl sulphoxide solvent;
b) stir the contents; and
c) filtered the material to yield highly pure Pomalidomide
The purification process comprises of treating crude Pomalidomide with a solvent selected from DMSO,DMFat a temperature ranging from 25-30°Cfor a period of 15 minutes to 45 minutes to get the clear solution. Filtered the contents through Celite bed, washed the Celite bed with a solvent selected from DMSO,DMFSlowly Added the filtered DMSO/DMF solution into the pre heated water at 75 -80oC under stirring and continued stirring for 1 hour -2 hours at 75-80oC.Filtered the solid and washed with DM water to yield highly pure Pomalidomide.

The present inventors surprisingly found that treating of crude Pomalidomide with DMSO solvent yields in a highly pure Pomalidomide having a purity of greater than 99.7 % free of process related impurities, collectively less than 0.3% by HPLC and are devoid of genotoxic/teratogenic impurities.

The specified process disclosed in the present invention yield in highly pure Pomalidomide having a purity of greater than 99.7% and total impurities collectively less than 0.3 % by HPLC.

In an another embodiment the present invention provides Pomalidomide having a purity of greater than 99.7% and total impurities collectively less than 0.3 % by HPLC.

In one of the particular embodiment of the present invention it provides Pomalidomide (I) having a purity of greater than 99.8% and total impurities collectively less than 0.2 % by HPLC.

In an another embodiment the present invention provides Pomalidomide(I) having a purity of greater than 99.9% and total impurities collectively less than 0.1 % by HPLC.

In an another embodiment the present invention provides Pomalidomide(I) having a purity of greater than 99.95% and total impurities collectively less than 0.05 % by HPLC.

ThePomalidomide produced by the process described in the present invention was substantially pure Pomalidomide contains the process related impurities A, B, C, D and E collectively below 0.3% and meeting the ICH guidelines and having a purity of greater than 99.7%.
Marketed form/Prior reported Process As per the present invention
Impurity Level A single impurity

was identified during the course of the review as being above the level for qualification. Pomalidomide contains process related impurities A, B, C, D and E collectively below 0.3% and meeting the ICH guidelines and having a purity of greater than 99.5%.
Metal content 800-900 ppm Not more than 10 ppm

In another embodiment the present invention related to highly pure Pomalidomide having a purity of greater than 99.7 % andtotal impurities A to E collectively less than 0.3 % by HPLC.

Impurity-A

Impurity-B
Impurity-C

Impurity-D
Impurity-E

In one of the embodiment, Pomalidomide obtained may be treated using a suitable organic solvent or the mixture thereof to obtained pure Pomalidomide, which is in crystalline / non-crystalline nature i.e., amorphous.

In another embodiment the purification is carried out using a solvent selected from selected from alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol; ketones such as acetone, ethylmethyl ketone, methylisobutyl ketone; ethers such as tetrahydrofuran; non-polar solvents selected from Toluene, Xylene, Benzene; solvents like dioxane, acetonitrile or mixture thereof at a temperature ranging from 40-90°C , preferably at 25-30°C to yield Pure Pomalidomide.

The process related impurities that appear in the impurity profile of the Pomalidomide may be substantially removed by the process of the present invention resulting in the formation pure Pomalidomide. The merit of the process according to the present invention resides in that - product obtained after drying is directly obtained as pure Pomalidomide. Said material is found to be adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.

A synthetic process for the preparation of Pomalidomide, obtained as per the present invention is demonstrated in Scheme-I

Scheme: Process for the preparation of Pomalidomide as per the present invention

In another embodiment, the Pomalidomide obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Pomalidomide obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from Pomalidomide of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES
Example 1
Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-nitro-1,3-dione
3-nitroPhthalic anhydride was charged in to a reaction flask containing Acetonitrile at25-30°C.2,6-dioxopiperidine-3-ammonium chloride was added slowly and then Acetic acid was added slowly for a period of 15 to 30 minutes at 25-30°C.Triethyl amine was added slowly for a period of 30 to 40 minutes at 25 to 30°C.Heatthecontents to 80 to 85°C and stirred the content s for 18 to 24hrs at 80 to 85°C. Filtered the mass through Celite and washed with Acetonitrile.Distill out the solvent completely under vacuum at 45 to 50°C. Water was charged in to the crude material at 25 to 30°C and stirred for 1 to 2 hoursfilteredthe solid and washed with Water and further purified with acetone to get the pure product.Dried the solid under vacuum at a temperature ranging between 45 to 50°C for a period of 5 hours to 7 hours.
Water content by KF: 2.0% w/w.
Dry weight: 200 gm.
HPLC Purity: ~99.5%

Example 2
Preparation of Pomalidomide
2-(2,6-dioxopiperidin-3-yl)-4-nitro-1,3-dione was charged in to reaction flask containing N.N-dimethyl formamide (250 ml) under stirring at 25 to 30°C. The obtained reaction mass was added in to an autoclave containing 10% Pd/Carbon (50% wet) at 25 - 30°C. Hydrogen pressure was applied (4-5.0 kg) to the reaction mixture at 25 - 30°C under stirring. Stirred the reaction mixture in auto clave for 2-3 hr at 25 -30°C. Filtered the reaction mass filtered through Celite (5.0 gram) and washed with DMF (13.0 ml). Dimethyl glyoxime (2.5 gm) was added slowly in to the reaction mass at room temperature under stirring and further stir for 90-120 mint at room temperature. Activated carbon (2.5 gram) was added under stirring and stir for 30-60 minutes. Filtered the reaction mass through Celite (5.0 gram) and washed with DMF(13.0 ml). The reaction mass was charged in to DM Water (900.0ml) at 15 to 20°C under stirring. Stirred the reaction mass for 90 -180 mint at 20 to 25°C.Filtered the solid and washed with DM water (50.0 ml). Suck dried for 1 hr and unloaded solid. The obtained wet cake was charged in to a reaction flask containing Methanol (250.0ml) at room temperature under stirring. The contents are heated to 40 - 45oC and stirred for 60 -90 min. Filtered the solid at 40 - 45oC (Hot filtration), washed with methanol (25.0 ml) and suck dried for 1hr at room temperature. Dried the solid under vacuum for 6-10 hours at 45-50oCto yield Pomalidomide.
Yield: 18.6.0 gm.
Chromatographic purity (By HPLC): 99.50-99.70%
Moisture content (By KF): 0.16%

Example 3
Purification of Pomalidomide
Crude Pomalidomide was charged in to a reaction flask containing DMSO (106.0ml) at 25-30°C.Stirred the contents for a period of15minutes to 30 minutes and then Activated carbon( 1.76 gm) was charged in to the reaction flask at room temperature under stirring. Stirred the reaction mass for a period of 20-45 minutes at 25-30°C and then filtered the material through Celite bed and washed the Celite bed with DMSO (8.0 ml). Slowly charged the filtered DMSO solution for a period of 15minutes to 30 minutes into the pre heated filtered DM water (714.0 ml) at 75 -80oC.Filtered the solid and washed with DM water (44.0 ml).Dried the solid under vacuum at temp 45 -50oC for 10 -12 hrs to yield highly pure Pomalidomide.
Dry weight: 12.5 gm.
Chromatographic purity (By HPLC): 99.70% -99.80%
Moisture content (By KF): 0.17%

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.