Field of invention:

The present invention relates to the process for the preparation of Lenalidomide and its intermediates thereof.

Background of the invention:

Lenalidomide is an immunomodulatory agent with antiangiogenic and antineoplastic properties. Lenalidomide is indicated for the treatment of myelodeyplastic syndromes and for the treatment of multiple myeloma. Lenalidomide is available in the market for the treatment of myelodysplastic syndromes and for the treatment of multiple myeloma. Lenalidomide is chemically known as 3-(4-amino-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula I.

U.S. Patent No. 5,635,517 and WO 98/03502 both describe a process for preparing lenalidomide using the 3-(4-nitro-l-oxo-l,3-dihydro-2//-isoindol-2yl)piperidine-2,6-dione of Formula II as an intermediate.

3-(4-Nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula II is prepared by reacting methyl 2-bromomethyl-3-mtrobenzoate of Formula III with 3-aminopiperidine-2,6-dione hydrochloride in the presence of N,N-dimethylformamide and triethylamine at reflux temperature for 6 hours.


3-(4-Nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of Formula II is reduced by hydrogenating with palladium-carbon in 1,4-dioxane at 50 psi to obtain lenalidomide.

WO 2006/028964 describes processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)-l-oxo-isoindolines. The process described therein for preparing lenalidomide involves the preparation of the nitro intermediate by first 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 compound is then hydrogenated with 10% Pd/C catalyst in methanol at 50 psi of hydrogen. The solid was slurried in hot ethyl acetate and dried, resulting in a yield of 51% lenalidomide.

IN 47/CHE/2006 discloses a process for the preparation of lenalidomide comprising hydrogenating 3-(4-Nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione using 10% Pd on carbon in a mixture of solvents comprising methanol and N,N-dimethylaformamide. This publication also discloses a process for the preparation of a-amino glutarimide hydrochloride of formula IV.

However, in the above process product obtained with less purity and very low yields.
WO 2009/114601 discloses a process for the preparation of lenalidomide comprising hydrogenating 3-(4-Nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione using 10% Pd on carbon in the presence of an acid and solvent mixture. However, this process is very lengthy and the product yield is also very low.

In view of the above prior art processes, there is a need to develop a simple process, which involves easier procedures having less number of purification steps with higher yields and high purity.

Summary of the invention:

The present invention relates to a process for the preparation of lenalidomide and its intermediates.

In an aspect, the present invention provides a telescopic process for the preparation of a-amino glutarimide of Formula IV, which is an intermediate for the preparation of lenalidomide, comprises the steps of:

a) Protection of the a-amino group of L-glutamine of Formula V using di-t-butyl
carbonate in the presence of a suitable solvent to give Boc-glutamine of Formula VI
and extraction with ethylacetate;

b) cyclodehydration of the Boc-L-glutamine to afford Boc-glutarimide of Formula VII in ethyl acetate as a solvent; and

c) deprotection of the Boc-glutarimide of Formula VII to afford a-amino glutarimide
hydrochloride of Formula IV in the presence of a suitable organic solvent.

In another aspect, the present invention provides a process for the preparation of lenalidomide, comprising:

a) reacting the methyl 2-bromomethyl-3-nitrobenzoate of Formula VIII with a-amino glutarimide hydrochloride of Formula IV in the presence of solvent to give 3-(4-Nitro-l-oxo-l,3-dihydro-2h-isoindol-2-yl)piperidine-2,6-dione of Formula II; and

b) hydrogenation of 3-(4-Nitro-l-oxo-l,3-dihydro-2h-isoindol-2-yl)piperidine-2,6-dione of Formula II in the presence of water.

Detailed description:

As set forth herein, aspects of the present invention provides an improved process for the preparation of lenalidomide and it's intermediate.

In one aspect, the present invention provides a process for the preparation of a-amino glutarimide hydrochloride of Formula IV, which is a useful intermediate for the preparation of lenalidomide.

The above process comprises:

a) Protecting the a-amino group of L-glutamine of Formula V using di-t-butyl carbonate in the presence of a suitable solvent to give Boc-glutamine of Formula VI and
extraction with ethylacetate;

b) cyclodehydration of the Boc-L-glutamine to afford Boc-glutarimide of Formula VII in ethyl acetate as a solvent; and

c) deprotection of the Boc-glutarimide of Formula VII to afford a-amino glutarimide hydrochloride of Formula IV in the presence of a suitable organic solvent.

The above process is a telescopic process in which the intermediates formed are not isolated and carried on to next step. Step a) can be carried out in an alkaline medium using a suitable base selected from metal alkoxides, metal hydroxides, metal carbonates and bicarbonates, preferably sodium hydroxide.

Solvents used in the step a) are selected from water and lower alcohols, preferably water. The reaction is carried out at room temperature. The reaction mixture is extracted with ethylacetate after the completion of the reaction.

Ethylacetate plays a key role in the above telescopic process, which doesn't involve isolation of the intermediates. In step a) after reaction completion of the reaction, the reaction mixture is extracted with ethylacetate and the ethylacetate layer is taken for the next step. In step b) ethylacetate layer plays a role of solvent for the cyclodehydration reaction. Taking ethylacetate to the step b) and using ethylacetate as a solvent improves the product yield very effectively.

In step b), ethylacetate layer is treated with suitable dehydrating agents which can be used for cyclocondensation reaction are selected from carbonyl diimidazole, dicyclohexyl carbodiimide, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide. Suitably this reaction is carried out in the presence or absence of a base catalyst, preferably 4-(dimethylamino pyridine). The reaction temperature for the step b) is about 0 to 100°C, preferably about 55 to 80°C.

In step c), involves deprotection of Boc-glutarimide of Formula VII to give a-amino glutarimide hydrochloride of Formula IV. Deprotection can be carried out in the presence of a suitable solvent selected from methanol, ethanol, propanol and isopropyl alcohol, preferably isopropyl alcohol. Deprotection is carried out under acidic conditions by adding suitable acids such as hydrochloric acid along with the solvent preferably isopropyl alcohol. The deprotection step is carried out at room temperature. After completion of the reaction, the reaction mixture is filtered and dried to give dry solid of a-amino glutarimide of Formula IV.

The a-amino glutarimide of Formula IV prepared according to the above process is having a purity of not less than 99% and yield of not less than 75%, which shows the advantage of the above telescopic process.

In the other aspect of the present invention provides a process for the preparation of lenalidomide, which comprises:

a) reacting the a-amino glutarimide hydrochloride of Formula IV with methyl 2-halomethyl-3-nitrobenzoate of Formula III in the presence of a solvent and sodium acetate as a base to afford the compound 3-(4-nitro-l-oxo-l,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione of Formula II; and

b) hydrogenation of 3-(4-nitro-l-oxo-l,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione of Formula II to form lenalidomide of Formula I in the presence of water.

In step a) condensation is carried out in the presence of solvent selected from N,N-dimethylforrmamide (DMF), N,N-dimethylacetamide, water and mixtures thereof. The reaction is carried out at temperature between 20-120°C.

In another embodiment of the present invention, the hydrogenation reaction is carried out in the presence of water without adding any acid. Hydrogenation is carried out using a catalytic amount of 10 % palladium on carbon.

In another embodiment of the present invention, hydrogen gas is bubbled through the reaction mixture without applying any pressure in the presence of water. While hydrogen gas bubbling, the reaction temperature is maintained at 30-35 °C.

In another embodiment of the present invention, after completion of the reaction, the reaction mixture is dissolved in an acid or base selected from HC1, MSA, alkali metal hydroxides, alkali metal carbonates or bicarbonates, preferably MSA or NaOH. Then the reaction mixture is isolated by adjusting the pH with an acid or base selected from HC1, MSA, alkali metal hydroxides, alkali metal carbonates or bicarbonates, preferably HC1 or sodium bicarbonate.

In another embodiment of the present invention, to isolate the product, the pH of the reaction mixture is adjusted with an acid include but are not limited to HC1, MSA...etc.

The product can be easily isolated from the Pd/C mixture after the pH adjustment with acid. After filtration and isolation the lenalidomide thus obtained is recrystallized using alcohols such as isopropyl alcohol.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided 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 a-amino glutarimide hydrochloride of Formula IV

100 ml of water and 6.4 g of sodium hydroxide were charged into a clean and dry reactor and stirred. Charge 10 g of L-glutamine and cool the reaction mixture to 0-5°C and add 22.5 g of Boc anhydride and stirred for 7h at room temperature. Check for the completion of reaction with Thin Layer Chromatography (TLC). After completion of the reaction, charge 50 ml ethyl acetate and separate the layers. Add 150 ml of aqueous HC1 drop wise to the reaction mass and adjust the pH of the reaction to 2-2.5 at 0-5°C for 30 min and saturate the reaction mass with sodium chloride. Extract the aqueous layer with 60 ml of ethyl acetate at 0-5 °C. The organic layer was filtered and washed with ethyl acetate and concentrated to 50ml under vacuum at 50-55°C. Charge 9.9 g of CDI to the reaction mass at 25-30°C over a period of 30-40 min. After the completion of the reaction, charge 50 ml of IP A and co-distilled under vacuum below 55°C. Cool the reaction mass to 25-30°C and charge 250 ml of IPA-HC1 and stir the reaction mixture for 18-20h at 25-30°C. Filter and dry the product under vacuum for 5-6h at 55-60°C using rotavapor.

Yield - 45-55 %

Example 2: Preparation of 3-("4-nitro-l-oxo-l,3 dihvdro-isoindol-2-vD-piperidine-2.6-dione of Formula II.

Charge 460 ml dimethylformamide, add 84.3 g of methyl 2-bromomethyl 3-nitro benzoate and 46 g of a-amino glutarimide hydrochloride. Add 230 ml of dimethylformamide under nitrogen atmosphere and stirred for 10 min at 25-30°C. Add 46 g of sodium acetate slowly to the reaction mass over a period of 30 min at 25-30°C under nitrogen atmosphere and stir the reaction mixture for 21 h. Add 690 ml of DM water slowly to the reaction mixture and stir for 30 min at 40-45°C. Filter and wash the product with DM water and dry the product under vacuum at 65-70°C.

Yield-60-70%

Example III: Preparation of lenalidomide of Formula I:

Charge 5 g of 3-(4-nitro-l-oxo-l,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione into a flask added 70 ml of water and stirred for 10 min at 25-30°C. Charge 0.5 g of Pd/C slurry and hydrogen gas was bubbled through the reaction mixture while stirring at 25-30°C for 6-8h. Cool the reaction mass to 10-15°C and adjust the pH of the reaction mass to 0.2-0.5 with methane sulfonic acid and stir for 10-15 min. Adjust the pH of the reaction mass with 7% sodium bicarbonate. Filter the product and wash with 50 ml of water and dry vacuum.

Yield -55-60%

We claim,
1. A process for the preparation of compound of Formula IV, comprising,

a) protecting the a-amino group of L-glutamine of Formula V using di-t-butyl carbonate in the presence of a suitable solvent to give Boc-glutamine of Formula VI;

b) extracting with ethylacetate and cyclodehydrating the Boc-L-glutamine of Formula VI to afford Boc-glutarimide of Formula VII in ethyl acetate as a solvent; and

c) deprotecting the Boc-glutarimide of Formula VII to afford a-amino glutarimide
hydrochloride of Formula IV in the presence of a suitable organic solvent.

2. A process according to the claiml, the process is a telescopic process in which the intermediates are not isolated.

3. A process according to the claim 1, in step a) the suitable solvent is selected from water and lower alcohols.

4. A process according to the claim 1, in step b) cyclodehydration reaction is carried out in the presence or absence of suitable dehydrating agents selected from carbonyl diimidazole, dicyclohexyl carbodiimide, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide.

5. A process according the claim 1, step c) is carried out in the presence of isopropyl alcohol and HC1.

6. A process for cyclodehydrating the Boc-L-glutamine of Formula VI to afford Boc-glutarimide of Formula VII in the presence of ethyl acetate as a solvent.

7. A process for the preparation of lenalidomide, comprising,

a) reacting the a-amino glutarimide hydrochloride of Formula IV with methyl 2-
halomethyl-3-nitrobenzoate of Formula III in the presence of a solvent and sodium
acetate as a base to afford the compound 3-(4-nitro-l-oxo-l,3 dihydro-isoindol-2-yl)-
piperidine-2,6-dione of Formula II; and

b) hydrogenating 3-(4-nitro-l-oxo-l,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione of Formula II to form lenalidomide of Formula I in the presence of water.

c) Adjusting the pH of the reaction mixture obtain in step b) with an acid or a base; and

d) Isolating the lenalidomide from the reaction mixture by adjusting the pH with an acid or a base.

8. A process according to claim 7, solvent used in in step a) is selected from N,N-dimethyl formamide, N,N-dimethylacetamide and water or mixtures thereof.

9. A process according to claim 7, in step b) hydrogenation is carried out in the presence of palladium on carbon.

10. A process according to claim 7, in steps b) and c), acid is selected from HC1, methane sulfonic acid, sulfuric acid and base is selected from metal hydroxides or metal carbonates or bicarbonates.