WO2013005229A1 - Process for lenalidomide - Google Patents

Abstract

The present invention provides an improved process for the preparation of 3-(benzyloxycarbonylamino)piperidine-2,6-dione. The present invention also provides an improved process for the preparation of 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. The present invention further provides a process for the preparation of lenalidomide crystalline Form H1.

Description

PROCESS FOR LENALIDOMIDE

This application claims the benefit of Indian Patent Application 2297/CHE/2011, filed on July 05, 201 1, which is incorporated herein by reference.

Filed of the Invention

The present invention provides an improved process for the preparation of 3- (benzyloxycarbonylamino)piperidine-2,6-dione. The present invention also provides an improved process for the preparation of 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dione. The present invention further provides a process for the preparation of lenalidomide crystalline Form HI .

Background of the Invention

Lenalidomide is chemically, 3-(4-amino-l,3-dihydro-l-oxo-2H-isoindol-2-yl)- 2,6-piperidinedione and has the structural formula:

Lenalidomide, a thalidomide analogue, was initially intended for use as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic modality. Lenalidomide has also shown efficacy in the hematological disorders known as the myelodysplastic syndromes. Lenalidomide is currently marketed under the trade name REVLIMID® by Celgene.

Lenalidomide and its process were disclosed in U.S. patent no. 5,635,517.

According to the patent, lenalidomide can be prepared by reacting methyl 2- bromomethyl-3-nitrobenzoate with 3-aminopiperidine-2,6-dione hydrochloride in the presence of Ν,Ν-dimethylformamide and triethylamine to obtain 3-(4-nitro-l -oxo-l,3- dihydroisoindol-2-yl)-piepridine-2,6-dione and then hydrogenating with palladium carbon in 1,4-dioxane. Process for the preparation of 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dione was reported in Journal of Bioorganic & Medicinal Chemistry Letters 9 (1999) 1625-1630 by reacting 2-(bromomethyl)-3-nirobenzoic acid methyl ester with 3-amino-piperidine-2,6-dione hydrochloride in the presence of triethylamine and dimethylformamide. According to the journal also reported as a process for the preparation of 3-(benzyloxycarbonylamino)piperidine-2,6-dione, can be prepared by reacting carbonyl diimidazole with N-(benzyloxycarbonyl)glutamine in teterahydrofuran at reflux.

PCT publication no. WO 2009/1 14601 disclosed improved processes for the preparation of substantially pure lenalidomide. According to the publication, can be prepared by reacting methyl 2-bromomethyl-3-nitrobenzoate with a-amino glutarimide hydrochloride in the presence of triethylamine and acetonitrile 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 methanesulfonic acid and methanol.

PCT publication no. WO 2010/100476 ('476 patent) disclosed a process for the preparation of lenalidomide. According to the publication, lenalidomide can be prepared by catalytic reduction of 3-(l-oxo-4-nitro-l ,3-dihydro-isoindol-2-yl)-piepridine-2,6-dione with palladium carbon in acetonitrile and methanol.

According to the '476 patent also disclosed a process for the preparation of 3-(l- oxo-4-nitro-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, can be prepared by reacting

3-amino-piperidine-2,6-dione hydrochloride with methyl 2-bromomethyl-3-nitro- benzoate in N,N-dimethylformamide.

PCT publication no. WO 201 1/027326 ('326 patent) disclosed a process for the preparation of 3-(4-nitro- 1 -oxo- 1 ,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. According to the '326 patent, 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-

2,6-dione can be prepared by reacting methyl 2-bromomethyl-3-nitrobenzoate with 3- aminopiperidine-2,6-dione in the presence of N,N-dimethylformamide.

According to the '326 patent also disclosed a process for the preparation of lenalidomide, can be prepared by reducing the 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol- 2-yl)piperidine-2,6-dione with palladium carbon in N,N-dimethylformamide. An unpublished application, IN 899/CHE/2011 assigned to Hetero research foundation discloses a lenalidomide crystalline Form HI .

We have found an improved process for the preparation of 3- (benzyloxycarbonylamino)piperidine-2,6-dione. The process of the invention ensures that 3-(benzyloxycarbonylamino)piperidine-2,6-dione is obtained at faster rate with higher yields.

We have also found an improved process for the preparation of 3-(4-nitro-l-oxo- l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione.

It has been found that the 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dione produced according to the prior art procedures result in low yields. According to the present invention 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dione can be obtained in higher yields than the prior art processes.

We have also found a process for the preparation of lenalidomide crystalline Form

HI .

Thus, one object of the present invention is to provide an improved process for the preparation of 3-(benzyloxycarbonylamino)piperidine-2,6-dione.

Another object of the present invention is to provide an improved process for the preparation of 3-(4-nitro-l -oxo-1 ,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione.

Another object of the present invention is to provide a process for the preparation of lenalidomide crystalline Form HI .

Summary of the Invention

In one aspect, the present invention provides an improved process for the preparation of 3-(benzyloxycarbonylamino)piperidine-2,6-dione, which comprises:

a) reacting carbonyl diimidazole with N-(benzyloxycarbonyl)glutamine in teterahydrofuran;

b) heating the contents obtained in step (a) at above 60°C;

c) removing the solvent from the reaction mass obtained in step (b) to obtain a residual mass;

d) slurring the residual mass obtained in step (c) with water and methanol; and e) isolating the 3-(benzyloxycarbonylamino)piperidine-2,6-dione. In another aspect, the present invention provides an improved process for the preparation of 3-(4-nitro- 1 -oxo- 1 ,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, which comprises:

a) reducing the 3-(benzyloxycarbonylamino)piperidine-2,6-dione with palladium carbon in an alcoholic solvent;

b) concentrating the reaction mass to obtain a crystalline solid;

c) adding a mixture of dirriethylformamide, triethylamine and 2-(bromomethyl)- 3-nirobenzoic acid methyl ester to the crystalline solid obtained in step (b); d) maintaining the reaction mass;

e) isolating the solid;

f) adding alcoholic solvent to the solid obtained in step (e); and

g) isolating the 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6- dione.

Yet in another aspect, the present invention provides a process for the preparation of lenalidomide crystalline Form HI, which comprises:

a) reducing the 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6- dione with palladium carbon in the presence of an acetic acid;

b) concentrating the reaction mass to obtain a residual mass;

c) slurring the residual mass obtained in step (b) with water;

d) isolating the solid;

e) suspending the solid obtained in step (d) in N-methylpyrrolidone;

f) heating the suspension obtained in step (e) at about 50 to 70°C;

g) cooling the solution obtained in step (f) at about 15 to 45°C;

h) adding solvent to the solution at about 15 to 45°C;

i) separating the solid;

j) slurring the isolated solid obtained in step (i) with hydrocarbon solvent; and k) isolating lenalidomide crystalline Form Hi.

Detailed Description of the Invention

The term "room temperature" refers to temperature at about 25 to 35°C. According to one aspect of the present invention, there is provided an improved process for the preparation of 3-(benzyloxycarbonylamino)piperidine-2,6-dione, which comprises:

a) reacting carbonyl diimidazole with N-(benzyloxycarbonyl)glutamine in teterahydrofuran ;

b) heating the contents obtained in step (a) at above 60°C;

c) removing the solvent from the reaction mass obtained in step (b) to obtain a residual mass;

d) slurring the residual mass obtained in step (c) with water and methanol; and e) isolating the 3-(benzyloxycarbonylamino)piperidine-2,6-dione.

The reaction in step (b) may preferably be heated at about 65 to 70°C.

Removal of the solvent in step (c) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distilled off.

The step (d) may conveniently be carried out at room temperature.

The isolation of 3-(benzyloxycarbonylamino)piperidine-2,6-dione in step (e) may be carried out by the methods known such as filtration or centrifugation.

According to another aspect of the present invention, there is provided an improved process for the preparation of 3-(4-nitro-l-oxo-l ,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dione, which comprises:

a) reducing the 3-(benzyloxycarbonylamino)piperidine-2,6-dione with palladium carbon in an alcoholic solvent;

b) concentrating the reaction mass to obtain a crystalline solid;

c) adding a mixture of dimethylformamide, triethylamine and 2-(bromomethyl)- 3-nirobenzoic acid methyl ester to the crystalline solid obtained in step (b); d) maintaining the reaction mass;

e) isolating the solid;

f) adding alcoholic solvent to the solid obtained in step (e); and

g) isolating the 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6- dione. The alcoholic solvent used in step (a) and (f) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol and n-butanol. More preferably the alcoholic solvent is methanol.

Preferably the reaction mass is concentrated in step (b) by distilling off the solvent. The distilling off the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.

The step (d) may conveniently be carried out at room temperature.

The isolation of solid in step (e) may be collected by the method known such as centrifugation or filtration.

The step (f) may preferably be carried out at room temperature.

3-(4-Nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione may be isolated in step (g) by the methods known such as filtration or centrifugation.

According to another aspect of the present invention, there is provided a process for the preparation of lenalidomide crystalline Form HI , which comprises:

a) reducing the 3-(4-nitro-l -oxo-l ,3-dihydro-2H-isoindol-2-yl)piperidine-2,6- dione with palladium carbon in the presence of an acetic acid;

b) concentrating the reaction mass to obtain a residual mass;

c) slurring the residual mass obtained in step (b) with water;

d) isolating the solid;

e) suspending the solid obtained in step (d) in N-methylpyrrolidone;

f) heating the suspension obtained in step (e) at about 50 to 70°C;

g) cooling the solution obtained in step (f) at about 15 to 45°C;

h) adding solvent to the solution at about 15 to 45°C;

i) separating the solid;

j) slurring the isolated solid obtained in step (i) with hydrocarbon solvent; and k) isolating lenalidomide crystalline Form HI .

Preferably the reaction mass is concentrated in step (b) by distilling off the solvent. The distilling off the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off. The separation of the precipitated solid in step (d) may be carried by the methods known in the art such as filtration or centrifugation.

The reaction in step (f may preferably be heated at about 55 to 65°C.

The solution in step (g) may preferably be cooled at about 25 to 35°C.

The solvent used in step (h) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, tetrahydrofuran, 1,4- dioxane, methyl tert-butyl ether, diisopropyl ether and diethyl ether. More preferably the solvents are ethanol, ethyl acetate and methyl tert-butyl ether.

The separation of the precipitated solid in step (i) may be carried by the methods known in the art such as filtration or centrifugation.

The hydrocarbon solvent used in step (j) may preferably be a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene, and more preferably the hydrocarbon solvent is toluene.

The temperature at which slurrying in step (j) is done is not critical and the slurrying may conveniently be carried out at about 50°C to 1 10°C.

Lenalidomide crystalline Form HI may be isolated in step (k) by the methods known such as filtration or centrifugation.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

Examples

Example 1:

Preparation of 2-(bromomethyl)-3-nirobenzoic acid methyl ester

2-Methyl-3-nitrobenzoic acid methyl ester (100 gm) was suspended in carbon tetrachloride (500 ml) and then added N-bromosuccinimide (160 gm) and 2,2- azobisisobutyronitrile (5 gm) at room temperature. The contents were heated to 80°C and maintained for 24 hours at 80°C. Water (1000 ml) and chloroform (200 ml) were added to the solution and then the layers were separated. The organic layer was washed with water and sodium chloride (10%) and then dried with sodium sulfate. The solvent was distilled off under vacuum and then co-distilled with n-hexane to obtain a residual solid. To the residual solid obtained was added n-hexane (100 ml) and stirred for 30 minutes. The separated solid was filtered and dried to obtain 130 gm of 2-(bromomethyl)-3- nirobenzoic acid methyl ester. Example 2:

Preparation of 3-(benzyloxycarbonylamino)piperidine-2,6-dione

Tetrahydrofuran (2500 ml) was added to N-(benzyloxycarbonyl)glutamine (500 gm) under stirring and then added carbonyl diimidazole (400 gm) slowly for 30 minutes at room temperature. The contents were heated to 65 to 70°C and maintained for 2 hours. The reaction mass was then cooled to 45°C and the solvent was distilled off under vacuum to obtain a residual mass. To the residual mass was added water (2200 ml) and methanol (50 ml) at room temperature. The reaction mass was stirred for 2 hours at room temperature and filtered. The solid obtained was washed with water and dried to obtain 390 gm of 3-(benzyloxycarbonylamino)piperidine-2,6-dione.

Example 3:

Preparation of 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione

3-(Benzyloxycarbonylamino)piperidine-2,6-dione (100 gm), methanol (1000 ml) and 10% palladium carbon (15 gm) were added and then applied hydrogen pressure at room temperature. The reaction mass was maintained for 2 hours and filtered over on celyte bed. The solvent was distilled off under vacuum from the filtrate thus obtained to obtain a crystalline solid. To the crystalline solid was added a mixture of dimethylformamide (400 ml), triethylamine (100 ml) and 2-(bromomethyl)-3-nirobenzoic acid methyl ester (100 gm) as obtained in example 1. The reaction mass was stirred for 6 hours at room temperature, filtered and then dried to obtain a solid. The solid obtained was dissolved in methanol (250 ml) and stirred for 1 hour at room temperature. The solid obtained was collected by filtration and dried to obtain 77 gm of 3-(4-nitro-l-oxo-l,3- dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. Example 4:

Preparation of lenalidomide crystalline Form HI

3-(4-Nitro-l -oxo-1 ,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (200 gm), acetic acid and palladium carbon in hydrogenation were added and then applied hydrogen pressure. The reaction mass was stirred for 4 hours and filtered over celyte bed. The solvent was distilled off under vacuum at below 50°C from the filtrate thus obtained to obtain a residual mass. To the residual mass was added water (750 ml) and stirred for 5 minutes. The contents were then cooled to 10°C and the pH of the reaction mass was adjusted to 7.0 to 7.5 with ammonia. The reaction mass was stirred for 2 hours at 15°C, filtered and then dried to obtain a solid. To the solid was added N-methylpyrrolidone (480 ml) at room temperature and then heated to 60°C to obtain a solution. The solution was then cooled to 40°C and then added ethanol (800 ml). The reaction mass was stirred for 1 hour at room temperature, filtered and dried to obtain a solid. To the solid was added toluene (180 ml) and then heated to 90 to 95°C. The reaction mass was maintained for 1 hour at 90 to 95°C and then cooled to room temperature. The reaction mass was stirred for 1 hour at room temperature and filtered. The solid obtained was dried under vacuum at 100°C for 48 hours to obtain 48 gm of lenalidomide crystalline Form HI (Purity of High Performance Liquid Chromatography: 99.95%)

Claims

We claim:

1. A process for the preparation of 3-(benzyloxycarbonylamino)piperidine-2,6-dione, which comprises:

a. reacting carbonyl diimidazole with N-(benzyloxycarbonyl)glutamine in teterahydrofuran;

b. heating the contents obtained in step (a) at above 60°C;

c. removing the solvent from the reaction mass obtained in step (b) to obtain a residual mass;

d. slurring the residual mass obtained in step (c) with water and methanol; and e. isolating the 3_:(benzyloxycarbonyiamino)piperidine-2,6-dione.

2. The process as claimed in claim 1, wherein the reaction in step (b) is heated at about 65 to 70°C.

3. A process for the preparation of 3-(4-nitro-l-oxo-l ,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dione, which comprises:

a. reducing the 3-(benzyloxycarbonylamino)piperidine-2,6-dione with palladium carbon in an alcoholic solvent;

b. concentrating the reaction mass to obtain a crystalline solid;

c. adding a mixture of dimethylformamide, triethylamine and 2-(bromomethyl)- 3-nirobenzoic acid methyl ester to the crystalline solid obtained in step (b); d. maintaining the reaction mass;

e. isolating the solid;

f. adding alcoholic solvent to the solid obtained in step (e); and

g. isolating the 3-(4-nitro-l -oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6- dione.

4. The process as claimed in claim 3, wherein the alcoholic solvent used in step (a) and (f) is a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol and n-butanol.

5. The process as claimed in claim 4, wherein the alcoholic solvent is methanol.

6. A process for the preparation of lenalidomide crystalline Form HI, which comprises: a. reducing the 3-(4-nitro-l-oxo-l,3-dihydro-2H-isoindol-2-yl)piperidine-2,6- dione with palladium carbon in the presence of an acetic acid; b. concentrating the reaction mass to obtain a residual mass;

c. slurring the residual mass obtained in step (b) with water;

d. isolating the solid;

e. suspending the solid obtained in step (d) in N-methylpyrrolidone;

f. heating the suspension obtained in step (e) at about 50 to 70°C;

g. cooling the solution obtained in step (f) at about 15 to 45°C;

h. adding solvent to the solution at about 15 to 45°C;

i. separating the solid;

j. slurring the isolated solid obtained in step (i) with hydrocarbon solvent; and k. isolating lenalidomide crystalline Form HI.

7. The process as claimed in claim 6, wherein the solvent used in step (h) is a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, tetrahydrofuran, 1 ,4-dioxane, methyl tert-butyl ether, diisopropyl ether and diethyl ether.

8. The process as claimed in claim 7, wherein the solvents are ethanol, ethyl acetate and methyl tert-butyl ether.

9. The process as claimed in claim 6, wherein the hydrocarbon solvent used in step (j) is a solvent or mixture of solvents selected from cyclohexane, hexane, n-heptane, benzene, toluene and xylene.

10. The process as claimed in claim 9, wherein the hydrocarbon solvent is toluene.