Claims:
1. An improved process for the preparation of Lenalidomide comprising;
a) Hydrogenating 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2,6-dione using 10% Pd/C in N,N-Dimethylacetamide (DMAc) as a solvent to obtain 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
b) Isolating Lenalidomide either by partial or complete distillation of the N,N- Dimethylacetamide (DMAc) solvent; and
c) Precipitating Lenalidomide by the addition of suitable organic solvent(s) as anti-solvent.
2. The process as claimed in claim 1, wherein the organic solvent is selected from the group consisting of Toluene, n-Heptane, Acetone, IPA, Methanol, Ethanol and DCM etc.
3. The process as claimed in claim 1, wherein the organic solvent is Toluene.
4. The process as claimed in claim 1, wherein the hydrogenation of 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2,6-dione is conducted at a pressure 50- 100PSI.
5. The process as claimed in claim 1, wherein the hydrogenation of 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2,6-dione is conducted at a pressure 50- 100PSI for 3-9Hrs.
6. A process for preparation of Lenalidomide polymorphic Form A which process comprises;
a) Dissolving Lenalidomide prepared according to the process of claim 1, in methanol at reflux temperature followed by addition of charcoal;
b) Filtering the hot solution through celite bed and reducing the volume to half of the volume of the filtrate by concentration; and
c) Stirring the concentrated filtrate at 0-5° C for 2Hrs and followed by drying the product at 60° C to isolate Lenalidomide crystalline polymorphic Form A.
7. A process for preparation of Lenalidomide polymorphic Form B which process comprises;
a) Dissolving Lenalidomide prepared according to the process of claim 1, in water: IPA, in 1:2 ratio at reflux temperature followed by addition of charcoal;
b) Filtering the hot solution through celite bed and reducing the volume to one fourth of the volume of the filtrate by concentration; and
c) Cooled the reaction mixture to room temperature to isolate solid; and
d) Heating the solid at 70-75°C till moisture of the product reduced to 3-4% to isolate Lenalidomide polymorphic Form B.

, Description:Technical field:
The present invention relates to an improved process for the preparation of Lenalidomide and preparation of crystalline polymorphic forms thereof. More particularly, the invention relates to preparation of Lenalidomide with high yields and purity and towards the preparation of crystalline polymorphic Form A and Form B.

Background and prior art:
Lenalidomide chemically known as 3-(4-amino-l-oxoisoindolin-2-yl) piperidine-2,6- dione, is a non-polypeptide compound which decrease the levels of TNF [alpha]. It was approved by US FDA in 2005 for patients and it is commercially sold as REVLIMID by Celgene.

TNF[alpha] is a candidate inducing angiogenesis in inflammation, wound repair, and tumor growth. TNF [alpha] production also has been associated with cancerous conditions, particularly induced tumors. It also plays a role in the area of chronic pulmonary inflammatory diseases. The deposition of silica particles leads to silicosis, a disease of progressive respiratory failure caused by a fibrocystic reaction. Lenalidomide inhibits tumor angiogenesis, tumor secreted cytokines and tumor proliferation through the induction of apoptosis. Lenalidomide has also shown efficacy in the class of hematological disorders known as myelodysplasia syndromes (MDS).

Lenalidomide and its process are disclosed in U.S. patent no. 5,635,517. The process for synthesis of Lenalidomide includes reacting methyl 2- bromomethyl-3-nitrobenzoate with 2,6 dioxopiperidin-3 -ammonium chloride in presence of DMF and triethylamine to obtain 3-(4-nitro-l-oxo-l,3-dihydroisoindol-2-yl)-piepridine-2,6-dione and hydrogenating the nitro intermediate, 3-(l-oxo-4-nitro-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, at 50 psi pressure using 10% Pd/C catalyst in 1 ,4-dioxane. The residue is crystallized from ethyl acetate and further from dioxane /ethyl acetate mixture to yield about 36% of the Lenalidomide
WO2006/028964 describes the preparation of Lenalidomide which involves the preparation of the nitro intermediate which comprises coupling of an L-glutamine methyl ester with methyl-2- bromomethyl -3 -nitro benzoate in acetonitrile and cyclising the resultant N-(l-oxo -4-nitro-isoindol-2-yl)-L-glutamine methyl ester. The nitro intermediate is then reduced with Pd/C in methanol followed by cyclisation under acidic conditions to yield 51 % of Lenalidomide.

WO 2009/114601 discloses improved processes for the preparation of substantially pure Lenalidomide by reacting methyl 2-halomethyl-3-nitrobenzoate with a-amino glutarimide hydrochloride in the presence of triethylamine and N-methylpyrrolidone (NMP) or acetonitrile solvent to obtain 3-(4-nitro-l-oxo- l,3-dihydroisoindol-2-yl)-piepridine-2,6- dione and then hydrogenating with palladium carbon in presence of methanol and methanesulfonic acid to obtain methane sulfonate salt in 80% yield which is further hydrolysed to obtain Lenalidomide in 93% yield. However, the overall yield of Lenalidomide obtained by this process is in the range of 50 to 52%.

Indian Application No. 047/CHE/2006 discloses a process for preparation of Lenalidomide which comprises hydrogenating 3-(4-nitro-l -oxo-1,3- dihydroisoindol-2-yl)-piperidine-2,6-dione using 10% Pd on carbon in a mixture of solvents comprising methanol and N,N-dimethylformamide to provide Lenalidomide.

WO 2010/100476 discloses catalytic reduction of 3-(l-oxo-4-nitro-l ,3-dihydro-isoindol-2-yl)-piepridine-2,6-dione with palladium carbon preferably in acetonitrile and methanol to obtain Lenalidomide which is isolated as hydrochloride salt by treatment with HCl. The hydrochloride salt of Lenalidomide is further hydrolysed with triethylaine to obtain Lenalidomide in 70% yield.

As is evident from the above, the prior art processes suffer from low yield and purity of Lenalidomide due to the use of large amount of solvents; use of mixtures of solvents and additional chemicals such as acids; makes the processes commercially expensive.

In the light of the foregoing, there remains a need in the art to provide an improved process for the preparation of Lenalidomide with high yield and purity.

Summary of the invention:
In line with the above, the present invention provides an improved process for the preparation of Lenalidomide in which the process comprises;
a) Hydrogenating 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2,6-dione using 10% Pd/C in N,N-dimethylacetamide (DMAc) as a solvent to obtain 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione, and
b) Isolating Lenalidomide by partial or complete distillation of the N,N-dimethylacetamide (DMAc); and
c) Precipitating Lenalidomide by the addition of suitable organic solvent(s).

The organic solvent that can be used as an anti-solvent to precipitate Lenalidomide is selected from the group consisting of Toluene, n-Heptane, Acetone, IPA, Methanol, Ethanol and DCM etc.

In another aspect, the invention provides a process for preparation of Lenalidomide polymorphic Form A which process comprises;
a) Dissolving Lenalidomide in methanol at reflux temperature followed by addition of charcoal;
b) Filtering the hot solution through celite bed and reducing the volume to half of the volume of the filtrate by concentration; and
c) Stirring the concentrated filtrate at 0-5° C for 2Hrs and followed by drying the product at 60° C to isolate Lenalidomide polymorphic Form A.

In another aspect, the invention provides process for preparation of Lenalidomide polymorphic Form B which process comprises;
a) Dissolving Lenalidomide in water: IPA in 1:2 ratio at reflux temperature followed by addition of charcoal;
b) Filtering the hot solution through celite bed and reducing the volume to one fourth of the volume of the filtrate by concentration; and
c) Cooled the reaction mixture to room temperature to isolate solid;
d) Heating the solid at 70-75°C for 4-6Hrs till moisture of the product reduced to 3-4% to isolate Lenalidomide polymorphic Form B.

Description of drawings:
Figure 1 depicts PXRD of the crystalline Lenalidomide polymorphic Form A obtained as per example 2.
Figure 2 depicts PXRD of the crystalline Lenalidomide polymorphic Form B obtained as per example 3.

Detailed description:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Accordingly, the present invention provides an improved process for the preparation of Lenalidomide which process comprises;
a) Hydrogenating 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2,6-dione using 10% Pd/C in N,N-dimethylacetamide (DMAc) as a solvent to obtain 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
b) Isolating Lenalidomide by partial or complete distillation of the N,N-dimethylacetamide (DMAc) solvent; and
c) Precipitating Lenalidomide by the addition of suitable organic solvent(s).

In accordance with the above process, 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione was taken into N,N-dimethylacetamide (DMAc) and hydrogenated using 10% Pd/C for 6 to 10Hrs. After the completion of the reaction, the catalyst was filtered off and the solvent was concentrated to maximum extent to obtain a residue. Use of DMAc in the hydrogenation reaction increases the isolated yield. Although, DMAc facilitates the precipitation of Lenalidomide, from the reaction mixture, however, distillation of solvent is more preferred as it improves the overall yield and purity of Lenalidomide upon addition of a suitable organic solvent.

Therefore, after the completion of the reaction DMAc was distilled either partially or completely to obtain a residue. To this residue, a suitable organic solvent as anti-solvent was added and stirred to obtain a solid. The solid was collected by filtration to obtain with Lenalidomide with yield and purity of more than 99%.

The organic solvent that can be used as an anti-solvent to precipitate Lenalidomide is selected from the group consisting of Toluene, n-Heptane, Acetone, IPA, Methanol, Ethanol and DCM etc. In one preferred embodiment, the organic solvent is toluene.

The hydrogenation of 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2,6-dione is conducted at a pressure 50- 100PSI.

The hydrogenation of 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2,6-dione is conducted at a pressure 50- 100PSI for 3-9Hrs.

The inventive ness in the process for preparation of Lenalidomide lies in the choice of solvent i.e., N,N-dimethylacetamide (DMAc) as reaction solvent for the reduction of 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione, as the same facilitates complete and faster reduction of nitro group in about 3 to 9 hrs to results in Lenalidomide in greater yields. The addition of an organic solvent to the concentrate obtained after the evaporation of dimethylacetamide (DMAc) results in Lenalidomide with more than 98% yield and 99%purity.

Lenalidomide thus obtained was further used for the preparation of Lenalidomide Polymorphic Form A and Form B.

In another embodiment, the invention provides a process for preparation of Lenalidomide polymorphic Form A which process comprises;
a) Dissolving Lenalidomide in methanol at reflux temperature followed by addition of charcoal;
b) Filtering the hot solution through celite bed and reducing the volume to half of the volume of the filtrate by concentration; and
c) Stirring the concentrated filtrate at 0-5° C for 2Hrs and followed by drying the product at 60° C to isolate Lenalidomide crystalline polymorphic Form A.

The process for preparation of polymorphic Form A using methanol is cost-effective over the reported processes in the prior art, as the process is simple and avoids costly solvents

According to this embodiment, Lenalidomide thus obtained was dissolved in Methanol at reflux temperature and further charcoal was added. The hot solution thus obtained was filtered through celite bed and concentrated to half of the original volume. The concentrated filtrate thus obtained was stirred at 0-5° C for 2Hrs and collected the solid by filtration. Finally, the product was dried in oven at 60-70° C 3-6Hrs and isolated the crystalline product with >99.5% purity. The PXRD confirmed that the product matches with Form A (Fig.1).

In another embodiment, the invention provides a process for preparation of Lenalidomide polymorphic Form B which process comprises;
a) Dissolving Lenalidomide in water: IPA, in 1:2 ratio at reflux temperature followed by addition of charcoal;
b) Filtering the hot solution through celite bed and reducing the volume to one fourth of the volume of the filtrate by concentration; and
c) Cooled the reaction mixture to room temperature to isolate solid; and
d) Heating the solid at 70-75°C till moisture of the product reduced to 3-4% to isolate Lenalidomide polymorphic Form B.

According to this embodiment, Lenalidomide obtained according to the process of the present invention taken into water: IPA in 1:2 and the mixture was heated to reflux at 85-90 °C and Charcoal was added. The hot solution was filtered and concentrated to ~25% of the original volume and cooled the filtrate to room temperature and filtered the solid. The solid was heated in an oven at 70-75°C for 4-6Hrs till moisture of the product reduced to 3-4%. The product thus obtained as per PXRD confirmed as Form B. (Fig 2).

The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.

Examples:

Example 1
Synthesis of Lenalidomide:
3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60gm) taken into N,N-dimethylacetamide (DMAc) (240mL, 4V). It was hydrogenated using 10% Pd/C at 100PSI for 6Hrs. Catalyst was filtered off and the solvent was concentrated to maximum extent. Toluene (900mL, 15V) was added to the residue and stirred. Obtained solid collocated by filtration. 53gm of Lenalidomide was isolated.
Yield: 98%
Purity: 99.6%

Example 2
3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60gm) taken into N,N-dimethylacetamide (DMAc) (240mL, 4V). It was hydrogenated using 10% Pd/C at 100PSI for 6Hrs. The Catalyst was filtered off. The solvent was divided into few equal portions. The solvent was concentrated and different anti solvents was added to precipitate Lenalidomide in higher yields and purity. Details are given in following table.
Sr. No. Anti-solvent Quantity Temperature Time Purity Yield
1 n-Heptane 90mL RT Overnight 99.8% 96%
2 Acetone 90mL RT Overnight 99.5% 98%
3 IPA 120mL RT Overnight 99.4% 94%
4 Methanol 120mL RT Overnight 99.6% 94%
5 DCM 90mL RT Overnight 99.3% 93%

Example 3
Preparation of Form A:
Lenalidomide (53gms) taken into Methanol (120 Volumes) at reflux temperature and charcoal (~10gms) was added. The hot solution was filtered through celite bed and concentrated to half of the original volume. The concentrate was stirred at 0-5° C for 2Hrs and collected the crystalline solid by filtration. Finally, the solid was dried in oven at 60-70° C and isolated with >99.5% purity. The PXRD of the crystalline solid was confirmed to polymorphic Form A (Fig.1).
Yield: 43gm, 81%
Purity: 99.8%

Example 4
Preparation of Form B:
Lenalidomide (50gm) taken into Water: IPA in a ratio of 1:2 (30 Volumes) and the mixture was heated to reflux at 85-90 °C and Charcoal (12gm) was added. The hot solution was filtered and concentrated to ~25% of the original volume. The filtrate thus obtained was cooled to room temperature and filtered the crystalline solid product. The solid was heated in an oven at 70-75°C for 4-6Hrs till moisture of the product reduced to 3-4%. The PXRD of the crystalline solid was confirmed to polymorphic Form B. (Fig 2).
Yield: 47gm, 87%,
Purity: 99.8%