Claims:Claims:

1) A process for the preparation of highly pure Lenalidomide (I), comprising the steps of:

(I)

a) reacting 3-Amino piperidine-2,6-Dione or its salt with

(III)

Methyl-2-(Bromomethyl)-3-Nitrobenzoateof Formula (IV)

(III)

to yield 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione of Formula II

(II)

b) selective hydrogenating compound of formula IIat a hydrogen pressure ranging between 40-60 PSI in presence of sulfonic acid;
c) maintaining the reaction mass at a pH ranging between 5-7 using organic acid or itssalt; and
d) isolating the pure Lenalidomide.

2) A process for the preparation of highly pure Lenalidomide (I) according to claim 1, wherein sulfonic acid selected from methane sulfonic acid, Para toluene sulfonic acid, per fluoro octane sulfonic acid.

3) A process for the preparation of highly pure Lenalidomide (I) according to claim 1, wherein selective hydrogenation is carried out in presence of a hydrogenation catalyst selected from iron, tin, zinc, palladium, platinum, palladium-carbon, platinum oxide, Raney nickel, samarium, rhodium and ruthenium.
4) A process for the preparation of highly pure Lenalidomide (I) according to claim 1, wherein organic acid is selected from mono carboxylic acid such as formic acid, C2-C5 carboxylic acids selected from acetic acid, propanoic acid, butyric acid, valeric acid; di-carboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, maleic acid, fumaric acid, glutaconic acid, traumatic acid, muconic acid, pthalic acid, isopthalic acid, terepthalic acid; tri-carboxylic acid such as citric acid, triethyl amine citric acid salt, isocitric acid, aconitic acid, propane-1,2,3-tricarboxylic acid (tricarballylic acid, carballylic acid).

5) A process for the preparation of highly pure Lenalidomide (I), comprises of:
a) adding an organic solvent, an organic acid to the crude Lenalidomide
b) maintaining the reaction mass at a pH ranging between 5-7 using organic acid or its salt; and
c) Isolating the pure Lenalidomide

6) A process for the preparation of highly pure Lenalidomide (I) according to claim 4, wherein solvent is selected from alcohol such as methanol, ethanol, isopropanol, n-butanol; C2-C5 ester solvent or mixtures thereof.

7) A process for the preparation of highly pure Lenalidomide (I) according to claim 5; wherein Lenalidomide obtained is having purity at least 99.8% by HPLC and moisture content less than 0.3 % w/w (by KF method)

8) A process for the preparation of highly pure Lenalidomide (I) according to claim 5; wherein Lenalidomide obtained is having purity at least 99.8% by HPLC and genotic impurities less than 10 ppm

9) A process for the preparation of highly pure Lenalidomide (I) according to claim 5; wherein Lenalidomide obtained is having purity at least 99.8% and impurities A, B and C

(A)

(B)

(C)

10) A process for the preparation of highly pure Lenalidomide (I) according to claim 5; wherein Lenalidomide obtained is used for the preparation of pharmaceutical composition and at least one or more pharmaceutically acceptable excipients.
, Description:FIELD OF THE INVENTION
The present invention relates to process for the preparation of highly pure Lenalidomide (I).

(I)

The present invention further relates to a pharmaceutical compositions comprising highly pure Lenalidomideuseful in the treatment of cancer.

BACKGROUND OF THE INVENTION
Lenalidomide is an immunomodulatory agent with anti-angiogenic and antineoplastic properties. Lenalidomide is chemically known as 3-(4-amino-l-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula I.

(I)

Lenalidomide has been used for the treatment of both inflammatory disorders and cancers for the past manyyears. Itis a thalidomide analogue used in the treatment of multiple cancers and is sold under the trade name REVLIMID® by Celgene.

REVLIMID is indicated for the treatment of patients with- i) Multiple myeloma (MM), in combination with dexamethasone, in patients who have received at least one prior therapy; ii) Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities; iii) Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included Bortezomib. Lenalidomide is off-white to pale-yellow solid powder known to exist as a stable hemihydrate form, which is also used in preparing commercially available solid oral dosage form.

Lenalidomide and its process wasdisclosed initially in U.S. patent no. 5,635,517. Further various polymorphic forms of Lenalidomide have been disclosed in US 2005/0096351 Al by Jaworsky et al. Polymorphic forms of Lenalidomide were disclosed in this application designated as Form-A, Form-B, Form-C, Form-D, Form-E, Form-F, Form-G and Form-H. It was reported in this patent application that the polymorphic Form-A is anhydrous form and polymorphic Form-B is hemi hydrate. Polymorphic Form-C is disclosed to be a hemi- solvate of acetone and Form-D is solvated with water and acetonitrile. Form-E is apparently dihydrate and Form-F is an unsolvated material obtained by dehydration of Form-E. Form-G is also an unsolvated material obtained by slurring Form-B and Form-E in THF solvent. Form-H is a crystalline solid hydrated with about 0.26 moles of water. Lenalidomide Form-B has been described to be the preferred polymorphic form which has been used in the formulation of API into drug product.

Amorphous polymorphic form of Lenalidomide and its methanesulfonic acid salt have been reported in patent application WO 2009/114601 A2. Further strong acid addition salts of Lenalidomide and their polymorphic forms are disclosed in patent application WO 2009/111948 Al. Konakanchi et al in WO2011/111053 A1 have disclosed anhydrous Lenalidomide Form I.

Lenalidomide being an important anticancer therapeutic agent, additional and improved ways of preparing Lenalidomide and its polymorphs may be of immense value to pharmaceutical science and the healthcare of cancer patients. Further exploring new forms of pharmaceutically active / useful compounds such as Lenalidomide may provide an opportunity to improve the drug performance characteristics of such products. Hence, there exists a need for the further development of new stable crystalline form of Lenalidomide and economically viable processes for its preparation, which may be commercially up scalable, safer for handling, less time consuming and with better and consistent quality parameters.

The inventors of this application have developed a commercially viable process which provides a stable polymorphic crystalline form of Lenalidomide, which is highly pure, non-hygroscopic and has easy handling properties. The process of this invention provides the crystalline Lenalidomide in a substantially pure form, which is without any detectable impurities/ contamination of any other previously known crystalline forms of Lenalidomide.

OBJECTIVE OF THE INVENTION
The main objective of the invention relates to a process for the preparation of highly pure Lenalidomide (I).
Another objective of the invention relates to a process for the preparation of highly pure Lenalidomide (I) having purity at least 99.8%.

SUMMARY OF THE INVENTION
Among the main aspect of the present invention, it relates to a process for the preparation of highly pure Lenalidomide (I), comprising the steps of:

(I)

a) reacting 3-Amino piperidine-2,6-Dione or its salt with

(II)

Methyl-2-(Bromomethyl)-3-Nitrobenzoate of Formula (IV)

(III)

to yield 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione of Formula II

(II)

b) selective hydrogenating compound of formula IIat a hydrogen pressure ranging between 40-60 PSI in presence of sulfonic acid;
c) maintaining the reaction mass at a pH ranging between 5-7 using organic acidsalt; and
d) isolating the pure Lenalidomide.

Another aspect of the invention relates to a process for the preparation of highly pure Lenalidomide (I), comprises of:
a) adding an organic solvent, an organic acid to the crude Lenalidomide
b) maintaining the reaction mass at a pH ranging between 5-7 using organic acid or a salt of it; and
c) isolating the highly pure Lenalidomide

In another aspect of the present invention relates to a process for the preparation of highly pure Lenalidomide (I) having purity of at least 99.8% and devoid of impurities A, B and C

(A); and/or

(B); and/or

(C)
In a further aspect, the present application also relates to a pharmaceutical composition comprising highly pure Lenalidomide of the present application and at least one or more pharmaceutically acceptable excipients. Such composition may besubstantially free of any other previously known crystalline forms of Lenalidomide. Further, particular aspects of the invention are detailed in the description and working example part of the specification..

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of crystalline Lenalidomide
Fig. 2 is an example of a Differential Scanning Calorimetry (“DSC”) curve of crystalline Lenalidomide
Fig. 3 is an example of a Thermo gravimetric analysis (“TGA”) curve of crystalline Lenalidomide

DETAILED DESCRIPTION OF THE INVNETION
As set forth herein, embodiments of the present invention relate to a reproducible and efficient process for preparation of highly pure Lenalidomide (I) in high yield. Highly pure Lenalidomide obtained by the process of the present invention is found to be substantially pure and stable.

The present invention provides to a process for the preparation of highly pure Lenalidomide (I), comprising reacting 3-Amino piperidine-2,6-Dione or its salt with Methyl-2-(Bromomethyl)-3-Nitrobenzoate(IV) in presence of a solvent selected from formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidone,Acetonitrile,water,water miscible solvents such as alcohol C1-5, C3-7 ketones, DMSO or mixture thereofat a temperature ranging from 25-30°C under Nitrogen atmosphere. To the obtained reaction mass organic base selected from methyl amine, pyridine, imidazole, benzimadazole, triethylamine, was added at a temperature ranging between 25-30°C. Stirred the reaction mass for 18 hours to 21 hours at 25-30°C, water was added slowly to the reaction mass, filtered the precipitated product and slurry was washed with water and followed by an alcohol solvent such as methanol, ethanol, propanol, isopropanol, n-butanol to yield wet material, which was dried at 60-65°C under vacuum for 10-12 hours to yield 3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione of Formula II.

3-(4-nitro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione obtained above was dissolved in a solvent selected from methanoland acid selected from methanesulfonic acidto provide a reaction mass. The obtained reaction mass may be degassed by using Nitrogen gas purging for suitable duration of time. The reaction mixture obtained is subjected to hydrogenation in presence of hydrogenation catalyst selected from iron, tin, zinc, palladium, platinum, palladium-carbon, platinum oxide, Raney nickel, samarium, rhodium and ruthenium for about 1 hour to 3 hours.The obtained reaction mixture was filtered through celite bed. Filtrate was treated with Dimethylglyoxime with charcoal for 20 minutes to 30 minutes. The reaction mixture was filtered through celite bed. Filtrate was neutralized with a solution of organic acid or their salt.Hereacid are selected from mono carboxylic acid such as formic acid, C2-C5 carboxylic acids selected from acetic acid, propanoic acid, butyric acid, valeric acid; di-carboxylic acid such as oxalic acid, malonicacid, succinic acid, glutaric acid, adipic acid, pimelic acid, maleic acid, fumaric acid, glutaconic acid, traumatic acid, muconic acid, pthalicacid, isopthalic acid, terepthalic acid; tri-carboxylic acid such as citric acid, triethyl amine citric acid salt, isocitric acid, aconitic acid, propane-1,2,3-tricarboxylic acid (tricarballylic acid, carballylic acid) and Base selected for making such acid salts are either organic or inorganic base such as triethylamine in Methanol ata temperature ranging from 25-30°C. Cooled the precipitated product to a temperature of about 10-15°C and stirred the reaction mass for an about 2-3 hours at a temperature ranging between 10-15°C.Filtered the product and washed with Methanol. Wet material slurry washed with methanol. Obtained wet material was dried at 60-65°C under vacuum (110-60 mm of Hg) for about 12-15 hours.

The present inventors found that the methanol formed during the process was sensitive for degradation during the workup of the reaction and by adding acid salt during workup helps in controlling the formation of degradation impurities and were controlled the formation of impurity.

The present inventors further found that the Lenalidomide obtained as per the present process is free of Genotoxic impurities and are below 10 ppm.

In view of this, the present inventors overcome the prior-art problems and developed an improved process for the preparation of Lenalidomide, using industrially feasible and viable process, with the use of industrially friendly solvents and reagents, which does not include tedious work up.

In another embodiment of the present invention further provides to a process for the preparation of highly pure Lenalidomide (I), comprises of:
a) adding an organic solvent, an organic acid to the crude Lenalidomide;
b) maintaining the reaction mass at a pH ranging between 5-7 using organic acid/or its salt; and
c) Isolating the pure Lenalidomide.

Filtered the reaction mass under vacuum and given washing with a C1-C4 alcoholic such as methanol, ethanol, isopropanol, n-butanol; C2-C5 ester solvent or mixtures thereof. The wet solid material is then dried at a temperature of 50-65 °C, wherein drying may be optionally carried out under reduced pressure conditions. Drying may be carried out for time duration ranging from 3-20 hrs depending upon achieving the anhydrous end-product as crystalline Lenalidomide.

The wet solid material is then dried at a temperature of 50-65 °C, wherein drying may be optionally carried out under reduced pressure conditions. Drying may be carried out for time duration ranging from 3-20 hrs depending upon achieving the anhydrous end-product as crystalline Lenalidomide.

Drying may be also be performed by any conventional process. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-65°C for time ranging from 3 to 20hrs depending upon the physical attributes of the end product obtained i.e. achieving the anhydrous end-product as crystalline Lenalidomide.

In another embodiment the present invention provides a process for the preparation of highly pure Lenalidomide (I)obtained is having purity at least 99.8% by HPLC and moisture content less than 0.3 % w/w (by KF method)

In another embodiment the present invention provides to a process for the preparation of highly pure Lenalidomide (I) having purity at least 99.8% and impurities A, B and Care well control within the ICH limits.

(A)

(B)

(C)

In an another embodiment of the invention, the present invention provides crystalline Lenalidomide, which is characterized by-
i. X-ray powder diffraction pattern comprising of at least seven peaks selected from 7.9, 11.4, 14.4, 14.9, 15.9, 16.3, 17.4, 17.7, 20.2, 20.7, 23.9, 24.2, 25.3, 26.1, 28.4± 0.2°2?;
ii. DSC isotherm having an endothermic peak at 265-270°C;
iii. HPLC purity of at least 99.8% ;
iv. Moisture content less than 0.3 % (by KF method).

Crystalline Lenalidomide, is a non-hygroscopic crystalline solid, which is further characterized by-
i. X-ray powder diffraction pattern comprising of at least seven peaks selected from 7.9, 11.4, 14.4, 14.9, 15.9, 16.3, 17.4, 17.7, 20.2, 20.7, 23.9, 24.2, 25.3, 26.1, 28.4± 0.2°2?;
ii. DSC isotherm having an endothermic peak at 265-270°C.

Process of recovering the crystalline Lenalidomide may further comprise processes but not limited to conventional processes including scrapping and if required filtering from slurry which may be carried out at room temperature for the suitable durations to retain the crystalline Lenalidomide.

The process related impurities that appear in the impurity profile of Lenalidomide may be substantially removed by the process of the present invention resulting in the formation of crystalline Lenalidomide of high purity, without involving any cumbersome processes. The merit of the process according to the present invention resides in that - product isolated after drying is directly obtained as crystalline Lenalidomide.

The crystalline Lenalidomide described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis. The samples of crystalline Lenalidomide were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 Å and lynx Eye detector. DSC was done on a Perkin Elmer Pyris 7.0 instrument. Illustrative examples of analytical data for the crystalline Lenalidomide obtained in the examples are set forth in the Figs. 1-2.

Another embodiment of the present invention provides crystalline Lenalidomide obtained by the process according to the present invention. Lenalidomide is found adequately stable to handle and store for longer time without any significant or measurable change in its morphology and physicochemical characteristics. Crystalline Lenalidomide obtained according to the process of the present invention is substantially pure i.e. it is found to have final API HPLC purity of more than 99.8 % w/w, with moisture content of not more than 0.3% (by KF method).

The crystalline Lenalidomide as obtained by the process of the present invention is without any detectable impurities/ contamination of any other previously known crystalline forms of Lenalidomide. This stable form thus, offers various advantages in terms of storage, shelf life, solubility, safety profile, improved physical and/or chemical properties.

In a further embodiment according to this specification, the invention also relates to a composition containing Crystalline Lenalidomide, which is substantially free of any other known forms of Lenalidomide.

In another embodiment the present inventors found that the Lenalidomide obtained as per the present invention is having highly HPLC purity of at least 99.8 % and moisture content less than 0.3 % (by KF method).

The Crystalline Lenalidomide obtained by the process 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, glycerin, propylene glycol or liquid paraffin.

In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with crystalline Lenalidomide, while retaining the crystalline nature of the premix.

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 crystalline Lenalidomide according to the present application include, but are 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 of crystalline Lenalidomide of the present application may also comprise to include the pharmaceutically acceptable carriers 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 -01
PROCESS FOR PREPARATION OF 3-(4-NITRO-1-OXOISOINDOLIN-2-YL) PIPERIDINE-2, 6-DIONE
Charge 80.0 g of 3-Amino piperidine-2,6-Dione Hydrochloride to a solution of 146.6 g of Methyl-2-(Bromomethyl)-3-Nitrobenzoate in 1200mL of N,N-Dimethylformamide at 25-30°C under Nitrogen atmosphere. 108.23g of Triethylamine was added lot wise to the reaction mass at 25-30°C under Nitrogen atmosphere. Stirred the reaction mass for 18-21 h at 25-30°C, 1200 mL of water was added to the reaction mass, filtered the precipitated product and slurry washed with 800 mL of DM water and followed by 800mL methanol. Wet material was dried at 60-65°C under vacuum for 10-12 hours.
Yield: 128.3 g
HPLC purity: 99.94 %
Loss of drying: 0.34%

EXAMPLE-02: PROCESS FOR PREPARATION OF HIGHLY PURE LENALIDOMIDE
In a 5.0 L autoclave,Charged100.0g of 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2, 6-dioneslurry mass in Methanol (3.0 L) and 49.8 g of Methanesulfonic acid under stirring at 25-30°C. 10.0g of 10% Pd/C (50% wet) was charged to the reaction mass. The reaction mixture was maintained at 30-40 PSI Hydrogen pressure for about 4-6 hours. On completion of the reaction as confirmed by HPLC, the reaction mixture was filtered through celite bed. Filtrate was again hydrogenated over 1.0g of 10% Pd/C (50% wet)the reaction mixture was maintained at 30-40 PSI Hydrogen pressure for about 1-2 hours,the reaction mixture was filtered through celite bed. Filtrate was treated with 5.0g of Dimethylglyoxime with charcoal for 20 minutes;the reaction mixture was filtered through celite bed. Filtrate was neutralized with a solution of citric acid (49.81 g) and Triethylamine (78.71g) in 200.0 mL of Methanol at 25-30°C. Cooled the precipitated product to 10-15°C and stirred the reaction mass for 2-3 hours at 10-15°C.Filtered the product and washed with 200 mL of Methanol at 25-30°C. Wet material slurry washed with 1.0L of methanol. Obtained wet material was dried at 60-65°C under vacuum (110-60 mm of Hg) for about 12-15 hours.
Yield: 68.0 g
HPLC purity: 99.86 %
Moisture Content: 0.18% (by KF)

EXAMPLE-03
PURIFICATION OF LENALIDOMIDE
Charge 300mL of Methanol, 10.0g of Crude Lenalidomide into 500mL Round bottom flask and Charge Methanesulfonic acid (3.71g) to reaction mass. Reaction mass was neutralized with a solution of citric acid (3.71 g) and Triethylamine (5.85g) in 20.0 mL of Methanol at 25-30°C. Cooled the precipitated product to 10-15°C and stirred the reaction mass for 2-3 hours at 10-15°C.Filtered the product and washed with 20 mL of Methanol at 25-30°C. Wet material slurry washed with 100.0 mL of methanol. Obtained wet material was dried at 60-65°C under vacuum (110-60 mm of Hg) for about 12-15 hours.
Yield: 8.4 g
HPLC purity: 99.96 %
Moisture Content: 0.21%

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.