PROCESS FOR PREPARING LENALIDOMIDE
INTRODUCTION TO THE INVENTION
The present invention relates to a process for the preparation of lenalidomide and intermediates thereof.
Lenalidomide is chemically known as 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione (hereinafter referred to by the adopted name "lenalidomide") and is structurally represented by Formula I.

Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic and antineoplastic properties. It is commercially marketed under the brand name REVLIMID™ in the form capsules having strength 5 mg, 10 mg, 15 mg and 25 mg.
U.S. Patent No. 5,635,517 discloses substituted 1-oxo-2- (2, 6-dioxopiperidin-3-yl) isoindolines derivatives, pharmaceutical compositions containing these compounds and their use in the treatment of cancer. It also discloses a process for the preparation of these compounds.
U.S. Patent No. 6,281,230 discloses lenalidomide, a process for the preparation of lenalidomide and its use in the treatment of inflammatory disease or autoimmune disease in a mammal.
U.S. Patent Application Publication No. 2006/0052609 discloses a process for the preparation of lenalidomide. The process uses a benzyloxy carbonyl group for protecting the amino group of glutamic acid. The deprotection of the amino group requires lengthy processes such as reduction using palladium on carbon (Pd/C).
All of the above processes describe bromination of methyl 2-methyl-3-nitrobenzoate, using light or 1,1'-azobis-(cyclohexanecarbonitrile) as the free radical

initiator, which is a slow process. The process also involves flash chromatographic purification of various intermediates during the process. All these factors make the process less economic and difficult to be scaled up.
The foregoing processes suffer from serious disadvantages such as low yields of lenalidomide and use of excess amount of expensive reagents, rendering the processes not suitable for industrial scale manufacturing.
Thus there is a need to develop a process, which involves easier procedures, simple reagents and less number of purification steps at various stages of the process.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of lenalidomide and intermediates thereof.
In one aspect, the present invention provides a process for the preparation of 2-bromomethyl-3-nitrobenzoic acid methyl ester of Formula VIII, an intermediate useful in the preparation of lenalidomide of Formula I.
The process comprises reaction of methyl 2-methyl-3-nitrobenzoate of Formula VII with a brominating agent in the presence of 2,2'-azobisisobutyronitrile as a catalyst to afford 2-bromomethyl-3-nitrobenzoic acid methyl ester of Formula VIII.
In a second aspect the present invention relates to a process for the preparation of a-amino glutarimide hydrochloride of Formula V, an intermediate useful in the preparation of lenalidomide, comprising the steps of:
a) protection of the a-amino group of L-glutamine of Formula II using a protecting reagent such as di-t-butyl carbonate in presence of a suitable organic solvent to form Boc-glutamine of Formula III;
b) cyclodehydration of the Boc-L-glutamine of Formula III to afford Boc-glutarimide of Formula IV in the presence of a suitable solvent; and
c) deprotection of the Boc-glutarimide of Formula IV to afford a-amino glutarimide hydrochloride of Formula V in the presence of a suitable organic solvent.
In a third aspect the present invention provides a process for the preparation of lenalidomide, comprising:

\) reaction or tne compound methyl 2-halomethyl-3-nitrobenzoate of Formula VIII with the compound a-amino glutarimide hydrochloride of Formula V in the presence of a solvent such as acetonitrile to afford the compound 3-(4-nitro-1-oxo-1, 3 dihydro-isoindol-2-yl)-piperidine-2, 6-dione of Formula VI; and
ii) hydrogenation of 3-(4-nitro-1-oxo-1, 3 dihydro-isoindol-2-yl)-piperidine-2, 6-dione of Formula VI to form lenalidomide of Formula I in the presence of a mixture of solvents comprising methanol and dimethylformamide.
In another aspect, the present invention provides substantially pure intermediates for the preparation of lenalidomide, including: a-amino glutarimide hydrochloride of Formula V; methyl-2-halomethyl-3-nitrobenzoate of Formula VIII; and 3-(4-nitro-1-oxo-1, 3 dihydro-isoindol-2-yl)-piperidine-2, 6-dione of Formula VI.
BRIEF DESCRIPTION OF THE DRAWING Fig. 1 is a schematic representation of a process for preparing lenalidomide.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of lenalidomide
and intermediates thereof.
In one aspect, the present invention provides a process for the preparation of 2-
bromomethyl-3-nitrobenzoic acid methyl ester of Formula VIII, which is useful in the
preparation of lenalidomide of Formula I.
The process comprises the reaction of methyl 2-methyl-3-nitrobenzoate of
Formula VII with a brominating agent in the presence of 2,2'-azobisisobutyronitrile as a
catalyst to afford 2-bromomethyl-3-nitrobenzoic acid methyl ester of Formula VIII.

Suitable reagents which can be used for bromination include but are not limited to N-bromosuccinimide (NBS), anhydrous bromine gas, aqueous hydrobromic acid

Dromide, bromine in acetic acid, bromine/dimethylsulphoxide complex, pyridinium hydrobromide perbromide, and the like.
Suitable free radical initiators that can be also used in the bromintiaon include but are not limited to 2,2'-azobisisobutyronitrile (AIBN), benzoyl peroxide, hydrogen peroxide and the like.
In an embodiment, the present invention involves the use of AIBN as the free radical initiator in the catalytic amount of about 0.02 to about 0.2 molar equivalents per molar equivalent of methyl 2-methyl-3-nitrobenzoate of Formula VII.
In an embodiment, the bromination reaction of the present invention can be carried out in the presence of: chlorinated aromatic hydrocarbons such as chlorobezene, o-dichlorobenzene, 1,3,5-trichlorobenzene and the like; chlorinated aliphatic hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like; ether solvents such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; inorganic acids such as hydrochloric acid, sulphuric acid, hydrobromic acid and the like; organic acids such as acetic acid, oxalic acid, formic acid, para-toluene sulfonic acid, trifluoroacetic acid and the like; and mixtures thereof.
An additional embodiment of the invention includes a bromination reaction, involving the addition of the brominating agent and the free radical initiator in portions instead of adding them all at a single time. The reagents can be added in equal portions or the quantity of the portions may be unequal. The entire quantity of the reagents may be added in about 2 or more, or 5 or more, portions.
The process for preparing the compound of Formula VIII can be carried out suitably at temperatures from about 20°C to about 140 °C or from about 80°C to about 90 °C.
In an embodiment, the addition of brominating agent and the free radical initiator can be completed in times from about 30 minutes to about 25 hours, or longer.
The methyl 2-bromomethyl-3-nitrobenzoate of Formula VIII obtained by the process of present invention typically has a purity of not less than about 95%, or about 99%, by high performance liquid chromatography (HPLC).

in a second aspect, the present invention relates to a process for the preparation of a-amino glutarimide hydrochloride of Formula V, an intermediate useful in the preparation of lenalidomide, comprising in the steps of:
a) protection of the a-amino group of L-glutamine of Formula II using a protecting
reagent such as di-t-butyl dicarbonate (also called "Boc anhydride") in the presence of a
suitable organic solvent to form Boc-glutamine of Formula III, where Boc is a t-butoxy
carbonyl group;
b) cyclodehydration of the Boc-L-glutamine of Formula III to afford Boc-
glutarimide of Formula IV in the presence of a suitable solvent; and
c) deprotection of the Boc-glutarimide of Formula IV to afford a-amino glutarimide
hydrochloride of Formula V in the presence of a suitable organic solvent.
Step a) involves pr imine of Formula II
using protecting reagent such as di-t-butyl dicarbonate in the presence of a suitable organic solvent to form Boc-glutamine of Formula III.

Suitable protecting groups, which are also suitable for the protection of the amino group include but are not limited to formyl, a lower alkanoyl group which is branched in the 1- or a-position to the carbonyl group, for example pivolyl, or a lower alkanoyl group which is substituted in the position alpha to the carbonyl group, for example trifluoroacetyl, and the like.
The protected Boc-L-glutamine differs from L-glutamine in that the amino group of the glutamine bears a blocking N-Boc substituent. The protected L-glutamine can be converted back to L-glutamine by a simple deprotection step. The protecting group blocks the amino group from participating in, interfering, or competing during the cyclodehydration reaction.
The reaction of step a) can be carried out in an alkaline medium using a suitable base. Suitable bases include but are not limited to alkoxides such as: sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertiary-butoxide, potassium tertiary-butoxide, sodium secondary-butoxide, sodium tertiary-butoxide and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate; and the like or mixtures thereof.
Suitable solvents that can be used in the formation of the compound of Formula III include but are not limited to water and alcoholic solvents like methanol, ethanol, isopropyl alcohol, n-propanol, and the like.
After the completion of the reaction, the acidification of the reaction mixture can be accomplished using acids to extract reaction mixture into a suitable organic solvent and then the solid can be isolated by adding an anti-solvent.
Acids such as hydrochloric acid, sulphuric acid, and the like, and organic acids such as acetic acid, para-toluene sulfonic acid, oxalic acid, tartaric acid, formic acid, and the like or mixtures thereof can be used.
Suitable organic solvents useful for extracting the compound include but are not limited to: esters such as ethyl acetate, ethyl aceto acetate, and the like; and aromatic solvents such as toluene, ethyl benzene, xylene and the like.

Anti-solvents which can be used in the isolation of solid include bui are not limited to hydrocarbons such as n-heptane, cyclohexane, n-hexane and the like, or mixtures thereof or their combinations with water in various proportions.
Step b) involves cyclodehydration of the Boc-L-glutamine of Formula III to afford Boc-glutarimide of Formula IV in the presence of a suitable solvent.
Suitable solvents which can be used for the cyclodehydration reaction include: nitrile solvents such as acetonitrile, propionitrile and the like; ethers such as diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran (THF) and the like; dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide; and mixtures thereof in various proportions.
Suitable dehydrating agents that can be used for the cyclocondensation reaction include carbodiimides such as carbonyl diimidazole, dicyclohexyl carbodiimide, or a water-soluble carbodiimide such as N-(3-dimethylaminopropyl)-N-ethyl carbodiimide.
Suitably the reaction is performed in the presence of a base catalyst. Suitable base catalysts, which can be used, include but are not limited to 4-(dimethylamino pyridine) and the like.
The process for preparing the compound of Formula IV of step b) can be carried out suitably at temperatures from about -10 to about 100 °C, or from about 55 to about 75 °C.
The reaction mixture can be optionally treated with activated charcoal to enhance the color of the compound followed by filtration through a medium such as through a flux calcined diatomaceous earth (Hyflow) bed to remove the carbon.
Step c) involves deprotection of the Boc-glutarimide of Formula IV to afford a-amino glutarimide hydrochloride of Formula V in the presence of a suitable organic solvent.
Deprotection can be carried out under mild conditions using, for example, about a one to ten fold molar excess (based on the moles of the protected L-glutamine) of a mineral acid.
Suitable acids which can be used for the acidifying include but are not limited to: inorganic acids such as hydrochloric acid, sulphuric acid; organic acids such as acetic

auiu, oxanc acid, tartaric acid, formic acid, para-toluene sulfonic acid and the like; and combinations thereof.
The deprotection step can be carried out in a solution, or in an aqueous suspension with or without the addition of an organic solvent.
Suitable solvents which can be used to carry out the deprotection include, but are not limited to: halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like; alcohols such as methanol, ethanol, isopropyl alcohol, t-propanol, n-butanol and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ether solvents such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene, heptane, hexane and the like; and mixtures thereof.
The deprotection step can be carried out at a temperature of about 20 °C to about 100 °C, or to about 45 to about 65 °C.
After completion of the reaction, the reaction mixture can be concentrated by evaporating solvent and the solid can be isolated by stirring for about 30 minutes to about 3 hours or more at low temperatures of about -10 to about 35 °C.
The invention provides a-amino glutarimide hydrochloride of Formula V having a purity of not less than about 95%, or about 99%, by HPLC,
In a third aspect the present invention provides a process for the preparation of lenalidomide, comprising:
i) reaction of the compound methyl 2-halomethyl-3-nitrobenzoate of Formula VIII with the compound ct-amino glutarimide hydrochloride of Formula V in the presence of the solvent acetonitrile to afford the compound 3-(4-nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione of Formula VI; and


ii) hydrogenation of 3-(4-nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione of Formula VI to form lenalidomide of Formula I in the presence of a mixture of solvents comprising methanol and dimethylformamide.
Step i) involves reaction of the compound methyl 2-halomethyl-3-nitrobenzoate of Formula VIII with the compound a-amino glutarimide hydrochloride of Formula V in the presence of the solvent acetonitrile to afford the compound 3-(4-nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione of Formula VI.
Suitable solvents which can be used in the condensation reaction include, but are not limited to: ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ether solvents such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 1,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene, heptane, hexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); N,N-dimethylacetamide; water; and mixtures thereof in various proportions.
Suitable temperatures for conducting the reaction range from about 20 °C to about 160 °C, or about 25 °C to about 60 °C.
The condensation reaction is conducted in a slightly basic medium. The basic medium can be provided using mild bases such as, but not limited to: alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate and the like; and organic bases such as triethylamine, diethylisopropylamine, diisopropyl ethyl amine and the like.
In another embodiment of the invention, addition of the base to the reaction mass is done in portions. The reagents can be added in equal portions or the size of the portions may be different. The entire quantity of the reagents may be added in about 2 to about 5 or more portions. The time between additions of the portions may be from 30 minutes to about 3 hours, or more.
3-(4-nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione of Formula VI obtained by the process of the present invention has a purity of not less than about 95%, or about 99%, by HPLC.

Step ii) involves hydrogenation of 3-(4-nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione of Formula VI to form lenalidomide of Formula I in the presence of a mixture of solvents comprising methanol and dimethylformamide.
In an embodiment of the invention the hydrogenation reaction is carried out using a catalytic amount of 10 % palladium on carbon. The quantity of palladium on carbon is from about 5 to about 30 % w/w with respect to the compound 3-(4-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione of Formula VI.
The hydrogenation reaction can also be conducted using different catalysts such as but without limitation thereto: noble metal catalysts such as platinum, nickel, iridium, ruthenium, and the like in the presence of carbon or another support; a transition metal catalyst in combination with an acid such as iron/HCI, Zn/HCI, Sn/HCI, Zn/acetic acid, or Zn/ammonium formate; Raney nickel; and the like.
Suitably the volume of solvent mixture comprising methanol and N,N-dimethylformamide can range from about 10 times to about 40 times the weight of the compound of Formula VI.
The quantity of N,N-dimethylformamide, which is used in the hydrogenation reaction, is in the range of about 1 to about 6 times the quantity of methanol.
Suitable temperatures for conducting the reaction range from about 20 °C to about 60 °C, or about 25 °C to about 35 °C.
After completing the reaction, the reaction mixture can be concentrated to a minimum volume and the solid can be isolated by adding an anti-solvent such as water.
The concentration of the reaction mixture can be terminated when the concentration of lenalidomide becomes about 0.01 to about 0.05 g/ml.
The lenalidomide thus obtained may optionally be further purified by recrystallization or slurrying in a suitable solvent.
Suitable solvents which can be used for the recrystallization or slurrying of the compound include, but are not limited to: water; alcoholic solvents like methanol, ethanol, isopropyl alcohol and the like; ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbon solvents such as toluene, xylene, heptane, hexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; and mixtures thereof in various proportions, or aqueous mixtures thereof.

Lenalidomide prepared by the process of present invention may be further purified by recrystallizing from water.
Lenalidomide of Formula I, provided by the process of this invention, has a purity by high performance liquid chromatography ("HPLC") greater than or equal to about 99.5 %. It contains less than 0.15%, or less than 0.1 %, of 3-(4-methylamino-1-oxo-2,3-dihydro-1H-2-isoindolyl)-2,6-piperidinedione compound of Formula IX.



Using these parameters, the relative retention time for the compound having Formula IX is about 2.26, when the retention time for lenalidomide is assigned a value of 1.
The dried product can optionally be milled to get the required particle size. Milling or micronization can be performed prior to drying, or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities.
In an embodiment, lenalidomide obtained by the process of present invention has a particle size of D9o less than about 500 microns, or about 300 microns, or about 100 microns, D50 less than 300 microns, or about 100 microns, or about 25 microns, and D10 less than 100 microns, or about 50 microns, or about 10.
The D10, D5o and D90 values are useful ways for indicating a particle size distribution. D90 refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value given. Likewise D50 and D10 refer to the values for the particle size for which 50 volume percent, and 10 volume percent, respectively, of the particles have a size smaller than the value given. Methods for determining D10, D50 and D90 include laser light diffraction, such as using equipment from Malvern Instruments Ltd. (Malvern, Worcestershire, United Kingdom). There is no specific lower limit for any of the D values.
Lenalidomide obtained from present invention has a bulk density of less than 0.5 g/ml or less than 0.4 g/ml before tapping, and a bulk density of less than about 0.7 g/ml or less than about 0.6 g/ml after tapping. The bulk densities are determined using Test

616 "Bulk Density and Tapped Density," United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005, in method 2.
Lenalidomide obtained from the present invention has a single point surface area less than about 0.4 m2/g,or less than about 0.3 m2/g.
The process of the present invention is simple, inexpensive, eco-friendly, commercially suitable and reproducible on an industrial scale.
Certain aspects and embodiments of the processes of the present invention will be explained in more detail with reference to the following examples, which are providec by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES
EXAMPLE 1: PREPARATION OF Boc-L-GLUTAMINE OF FORMULA III
25 L of demineralized water and 2 Kg of sodium hydroxide were charged into a clean and dry reactor and stirred for 10 minutes. The solution was cooled to 27.5 °C anc 5 Kg of L-glutamine was charged into the above reactor. The obtained reaction mixture was stirred for 5 minutes and then 11.2 Kg of Boc anhydride was added. The reaction mixture was stirred for 24 hours at 27.5 °C. After the completion of the reaction, the reaction mixture was washed with 2x25 L of toluene to remove starting materials. The aqueous layer was acidified to a pH of 2.36 using 48 L of 1 N hydrochloric acid solution and 20 Kg of sodium sulfate was added to the aqueous layer. The aqueous layer was then extracted with 3^50 L of ethyl acetate. The ethyl acetate layer was concentrated under vacuum of 600 mm Hg at 49.2 °C until 23 L of solvent remained and then the solution was cooled to 27 °C. 75 L of n-heptane was charged into the above reaction solution and stirred for 4 hours at 27 °C. the obtained suspension was filtered and suction dried for 30 minutes. Finally the solid was dried for 4 hours at 51 °C to afford 4.88 Kg of the title compound having purity by HPLC 99.68 %.
EXAMPLE 2: PREPARATION OF Boc-GLUTARIMIDE OF FORMULA IV
A mixture of 4.88 Kg of Boc-L-glutamine and 24.5 L of tetrahydrofuran were charged into a reactor and stirred at 28 °C for 10 minutes. 4.7 Kg of N,N-carbonyl-di-

imidazole and 10 g of dimethyl amino pyridine were added to the reaction solution and stirred at 28 °C for 1 hour, 50 minutes. The temperature of the reaction mixture was raised to about 66 °C followed by stirring for 23 hours. After the completion of the reaction, the reaction mixture was cooled to 4 °C and maintained at 4 °C for 4 hours, 45 minutes. The separated solid was filtered and the solid was washed with 11 L of THF and the solid was dried at 50 °C for 30 minutes to afford 2.7 Kg of the title compound with a purity by HPLC 99.74 %. After completion of the drying, the solid was dissolved in 200 L of a (1:1) methanol and ethyl acetate mixture and 0.25 Kg of charcoal was charged. The suspension was heated to 65 °C and stirred for 2 hours at 65 °C. then was filtered under hot conditions at 65 °C through a flux calcined diatomaceous earth (Hyflow) bed and the filtrate was concentrated at 65 °C under vacuum of 600 mm Hg until 5.4 L of solvent remained. The obtained suspension was cooled to 5 °C and filtered, and the solid was dried at 50 °C to get 2.45 Kg of title compound having a purity by HPLC: 99.74 %.
EXAMPLE 3: PREPARATION OF a-AMINO GLUTARIMIDE HYDROCHLORIDE OF FORMULA V
24 L of 18 % HCI in isopropanol and 2.4 Kg of Boc-amino glutarimide were charged into clean and dry reactor. The reaction mixture was stirred for 10.5 hours at 27.5 °C. After completion of the reaction, the reaction mixture was concentrated under a vacuum of 600 mm Hg at 55.8 °C until 12 L of solvent remained. The reaction mixture was cooled to 30 °C and stirred for 3 hours. The obtained suspension was filtered and the wet solid washed with 5 L of isopropyl alcohol and then the solid was dried under a vacuum of 600 mm Hg at 49 °C for 4 hours to afford 1.65 Kg of title compound with a purity by HPLC 99.74 %.
EXAMPLE 4: PREPARATION OF METHYL 2-BROMOMETHYL 3-NITRO BENZOATE OF FORMULA VIII
2.5 Kg of methyl 2-methyl-3-nitro benzoate of Formula VII and 37.5 L of chlorobenzene were charged into a container at 28 °C. The mixture was stirred for 15

minutes to get a clear solution. 3.4 Kg of N-bromosuccinimide, 42 g of 2,2'-azobisisobutyronitrile, and 200 ml of acetic acid were added to above solution. The temperature of the mixture was raised to 90 °C followed by stirring for 6 hours. The reaction mixture was cooled to 29.1 °C. Another 1.13 Kg of N-bromosuccinimide, 42 g of 2,2'-azobisisobutyronitrile, and 50 ml of acetic acid were added to the reaction mixture and again the reaction mixture was heated to 90 °C followed by stirring for about 18 hours. After the completion of the reaction, the reaction mixture was cooled to about 10 °C followed by stirring for about 1 hour. The reaction mixture was filtered and the filtrate was concentrated under vacuum at 59 °C until 5 L of solvent remained. The concentrated filtrate was cooled to 28 °C and 25 L of n-hexane was added followed by stirring for 3 hours. The suspension was filtered and the solid suction dried for 30 minutes. Finally the solid was dried at 39.3 °C for 3 hours to obtain 2.2 Kg of the title compound with a purity by HPLC of 96.4 %.
EXAMPLE 5: PREPARATION OF 3-(4-NITRO-1 -OXO-1, 3 DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2, 6-DIONE OF FORMULA VI
2.2 Kg of methyl 2-bromomethyl 3-nitro benzoate was dissolved in 22 L of acetonitrile and taken into a glass container. 1.32 Kg of a-amino glutarimide hydrochloride was added to the reaction solution at 28 °C and stirred for 10 minutes. 0.56 L of triethyl amine was added under a nitrogen atmosphere. The reaction mass was then heated to a temperature of 31 °C and stirred at 55 °C for 2 hours. Another 0.56 L of triethyl amine was added to the reaction mixture and stirred at 56 °C for 2 hours. Another 0.56 L of triethylamine was added to the reaction mixture and stirring was continued at 56 °C for 2 hours. Then another 0.56 L of triethylamine was added to the reaction mixture and stirred at 50 °C for 18 hours. After the completion of the reaction, the reaction mixture was cooled to 28 °C. 7 L of demineralized water was added to the reaction mixture and the reaction mixture was stirred at 28 °C for 2 hours. The reaction mixture was filtered and the solid was vacuum dried for 2 hours. The solid was dried at 45 °C under vacuum of 600 mm Hg for 8 hours, 20 minutes to afford 2 Kg of the title compound with a purity by HPLC of 99.07 %.

EXAMPLE 6: PREPARATION OF LENALIDOMIDE OF FORMULA I
100 g of 3-(4-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione of Formula VI was charged into a clean and dry round bottom flask and was slurried with 2.5 L of 50% dimethylformamide in methanol at 28 °C. 10 g of 10% palladium on carbon was charged followed by transferring the reaction suspension into an autoclave. 30 psi of dry hydrogen gas pressure was applied to the reaction suspension at about 28 °C for 1 hour. After the completion of the reaction, the reaction mixture was filtered through a Hyflow bed. The Hyflow bed was washed with 100 ml of dimethylformamide. The combined filtrate was taken into a Buchi Rotavapor flask and distilled under high vacuum of 600 mm Hg until 200 ml of solvent remained. 2 L of demineralized water was added followed by stirring for 2 hours. The separated solid was filtered and suction dried under a vacuum of 600 mm Hg for 30 minutes to yield 32 g of the title compound with a purity by HPLC of 99.68%.
EXAMPLE 7: PURIFICATION OF LENALIDOMIDE OF FORMULA I
30 g of the lenalidomide, obtained from a preparation similar to that of Example 6, was taken into a round bottom flask and 300 ml of demineralized water was added. The mixture was heated to 75 °C followed by stirring for about 6 hours. The separated solid was filtered in the hot condition at a temperature of 60° C and the solid was washed with preheated water (temperature 60 °C). The wet solid was dried under a vacuum of 550 mm Hg at a temperature of about 35 °C for about 4 hours to afford 25 g of the title compound with a purity by HPLC of 99.91 %.
EXAMPLE 8: ISOLATION OF 3-(4-METHYLAMINO-1-OXO-2>DIHYDRO-1H-2-ISOINDOLYL)-2,6-PIPERIDINEDIONE COMPOUND OF FORMULA IX
A glass column was packed with 70 g of silica (230-400 mesh size) using dichloromethane. 3.5 g of lenalidomide (having a purity of about 97 % and containing 2.76 % of the compound of Formula IX) was adsorbed on 2 g of silica (230-400 mesh size) and then placed onto the bed in the column. The column was eluted with 3 %

methanol in dichloromethane (4 L) to separate the impurity. The obtained impurity-containing fractions were concentrated to afford 100 mg of the title compound.
1H NMR (400 MHz, DMSO-d6, 5 in ppm): 2.78 8 (3H, d), 5.7 5 (NH.q), 6.71 5 (1H, d), 7.31 5 (1H, t), 6.94 5 (1H, d), 4.12 (Ha,d), 4.22 5(Hb, d), 5.10 5 (1H, dd), 11 5 (NH, s), 2.62 5 (Ha.m), 2.92 (Hb, m), 2.03 8 (Ha, m), 2.30 8 (Hb, m) in ppm.
MASS: m/z 273.

CLAIMS:
1. A process for brominating a compound having a formula:

comprising reacting with a brominating agent in the presence of a catalytic amount of 2,2'-azobisisobutyronitrile.
2. The process of claim 1, wherein a brominating agent comprises N-bromosuccinimide.
3. The process of either of claims 1 or 2, wherein reacting is conducted in a solvent comprising a chlorinated aromatic hydrocarbon.
4. A process for preparing lenalidomide, comprising reacting a compound
having a formula:
o

with a compound having a formula:

to form a compound having a formula:

the reaction being conducted in a solvent comprising acetonitrile.

5. The process of claim 4, wherein a compound having a formula:

is prepared by a process comprising reacting a compound having a formula:

with a brominating agent in the presence of a catalytic amount of 2,2'-azobisisobutyronitrile.
6. The process of claim 5, wherein reacting is conducted in a solvent comprising a chlorinated aromatic hydrocarbon.
7. The process of any one of claims 4-6, wherein a compound having a formula:
is further hydrogenated to form lenalidomide.
8. The process of claim 7, wherein hydrogenation is conducted in a solvent comprising methanol and dimethylformamide.
9. Lenalidomide containing less than about 0.15 percent by weight of a compound having the formula: