DESC:“AN IMPROVED PROCESS FOR THE PREPARATION OF POMALIDOMIDE”

FIELD OF THE INVENTION:
The present invention relates to an improved and economic industrial process for the preparation of Pomalidomide with high yield. The present invention also relates to method and novel use of a reagent for preparing Pomalidomide.

BACKGROUND OF THE INVENTION:
Pomalidomide is an aminoisoindoline aromatic-ring containing compound acting as an immunomodulatory agent with antineoplastic activity.
Pomalidomide is chemically known as (RS)-4-Amino-2-(2, 6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione and is structurally represented as below:

POMALIDOMIDE
Pomalidomide is indicated for the patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Multiple myeloma almost always starts out as a relatively benign condition called monoclonal gammopathy of undetermined significance (MGUS)
Pomalidomide is disclosed in US5635517 and is marketed by Celgene Corporation. As hard capsules containing pomalidomide. Initially, Pomalidomide is approved by USFDA during 2013 as POMALYST® capsule 1 mg, 2mg, 3mg and 4 mg. However, recommended daily dose of pomalidomide is 4 mg once daily orally on days 1-21 of repeated 28-day cycles until disease progression. POMALYST® capsule is reported to contain excipients like mannitol, Pregelatinized starch and sodium stearyl fumarate.
WO1998/003502 discloses a process for preparation of (RS)-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3¬-dione (pomalidomide). The said patent application disclosed preparation of pomalidomide by reacting 4-nitrophthalic anhydride and O-aminoglutarimide hydrochloride and sodium acetate in glacial acetic acid. The mixture was concentrated in vacuo and the residue was stirred with methylene chloride. Further the aqueous layer was separated, extracted with methylene chloride to give 1,3-dioxo-2-(2, 6-dioxopiperidin-3-yl)-5-nitroisoindoline). Further steps included mixing of 1,3-dioxo-2-(2, 6-dioxopiperidin-3-yl)-5-nitroisoindoline and 10% Pd/C in 1, 4-dioxane at 50 psi for 6.5 hours. The catalyst was filtered through celite and the filtrate concentrated in vacuo to give 4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3¬-Dione (pomalidomide). The shortcomings of the prior art included use of pyriphoric catalyst like Palladium, under pressurized conditions for the reaction to be carried out.
WO2014/170909 discloses a process for the preparation of pomalidomide where in dimethylformamide was added to 3-(4-nitro-l-oxoisoindolin-2-yl)piperidine-2,6-dione and then stirred for 30 minutes at room temperature to obtain a clear solution. To that solution was added 10% palladium carbon and then applied 4 Kg of hydrogen pressure at room temperature and it was filtered through hi-flow bed and then concentrated to obtain pomalidomide. Further the purification of pomalidomide was carried by suspended in dimethyl sulfoxide and then heated to reflux to obtain a pure pomalidomide. The prior art included drawbacks such as use of catalyst like Palladium and Raney Nickle under pressurized conditions in an SS reactor.
WO2015/075694 discloses a process for the preparation of pomalidomide where in 3-nitrophthalic acid in Acetonitrile was added with 1,1-carbonyldiimidazole (CDI) under nitrogen atmosphere at ambient temperature. To this mixture, 3-aminopiperidine 2,6-dione hydrochloride was added to obtain to obtain 3-nitrophthalidomide. Catalyst palladium on carbon was added to a stirred solution of 3-nitrophthalidomide in N,N-dimethyl formamide maintained under nitrogen. Hydrogen gas was bubbled through the reaction mixture at atmospheric pressure and was separated by filtration of the reaction mixture on celite bed to obtain Pomalidomide.
WO2015/078543 discloses a process for the preparation of pomalidomide where in glacial acetic acid and anhydrous sodium acetate were added to of 4-nitroisobenzofuran-l,3-dione and 3- aminopiperidine-2,6-dione hydrochloride to give 4-nitro-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione.futher these is added to 1,4-dioxane and 10% Pd/C to obtain 90% pomalidomide. The purification of Pomalidomide is carried out by adding dimethylsulfoxide. The shortcomings of the prior art included less purity and the use of catalyst such as Raney nickel.
US20170260157 discloses a process for the preparation of pomalidomide wherein glacial acetic acid and a-amino glutarimide hydrochloride with Sodium acetate anhydrous in 3-nitro phthalic anhydride is reacted to obtain 2-(2, 6-dioxopiperidin-3-yl)-4-nitroisoindoline-1, 3-dione. Further 1, 4- dioxane and 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-l,3-dione were mixed and Raney nickel was added to get 4-amino-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (pomlidomide)The purification was carried out in the presence of 1,4-dioxane and ethyl acetate.
WO2017/221261 disclosed process for the preparation of pomalidomide wherein 3-nitrophthalic acid with acetic anhydride is reacted in presence of toluene to get 4- nitrophthalic anhydride. Further 4-nitrophthalic anhydride with 3-aminoglutarimide hydrochloride is added in presence of tri ethylamine and acetic acid solvent to get 2-(2, 6-dioxo-3-piperidyl)-4-nitroisoindoline-1, 3-dione. It was reduced in presence of Pd/C and dimethyl formamide solvent to get pomalidomide
The inventors of the present invention have developed an alternative improved process for the preparation of pomalidomide with high yield. The present invention also entails an economical industrial process for the preparation of pomalidomide. Furthermore, the present invention comprises the use of a novel reagent as well to prepare pomlidomide.

SUMMARY OF THE INVENTION:
One aspect of the present invention relates to preparation of Pomalidomide comprising the reaction steps as below.
a) reacting 3-nitrophthalic anhydride with a-amino glutarimide. HCl and sodium acetate in glacial acetic acid to obtain 1,3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-nitroisoindoline;
b) reacting 1,3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-nitroisoindoline as in step-1 in the presence of 1, 4-Dioxane, sodium dithionite and cesium carbonate with tertrabutyl ammonium bromide to obtain 4-Amino-2-(2, 6-dioxo-piperidin-3-yl)-isoindoline-1, 3-dione (Pomalidomide);
c) purification of Pomalidomide as produced in step-b) by addition of dimethyl sulfoxide, acetone and methanol to obtain pure Pomalidomide.
The present invention is depicted as below.


DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved process for the preparation of pomalidomide, wherein 3-nitrophthalic anhydride in a suitable solvent (i.e. sodium acetate and glacial acetic acid), is reacted with a-amino glutarimide. HCl to yield 1, 3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-nitroisoindoline. 1,3-dioxo-2-(2,6dioxopiperidine-3-yl)-5-nitro isoindoline is reacted in the presence of 1,4-dioxane, sodium dithionite and cesium carbonate with tertrabutyl ammonium bromide to obtain 4-amino-2-(2, 6-dioxo-piperidin-3-yl)-isoindoline-1,3¬-dione. Purification of Crude pomalidomide is carried out by addition of dimethyl sulfoxide, acetone and methanol to obtain Pure Pomalidomide.

One embodiment of the present invention relates to preparation of pure pomalidomide comprising the steps as below.
a) reacting 3-nitrophthalic anhydride (I) with a-amino glutarimide. HCl (II) and sodium acetate in glacial acetic acid to obtain1,3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-nitroisoindoline (III);
b) reacting 1,3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-nitroisoindolin (III) e as in step-1 in the presence of 1, 4-dioxane, sodium dithionite and cesium carbonate with tertrabutyl ammonium bromide to obtain crude 4-amino-2-(2, 6-dioxo-piperidin-3-yl)-isoindoline-1, 3¬-dione (Pomalidomide);
c) purification of crude Pomalidomide as produced in step-b) by addition of dimethyl sulfoxide, acetone and methanol to obtain pure Pomalidomide.

Other embodiment of the present invention relates method and novel use of sodium dithionite and cesium carbonate with tertrabutyl ammonium bromide to prepare Pomalidomide (I)

Additional embodiment of the present invention relates to purification of pomalidomide.

According to the present invention, 3-nitrophthalic anhydride was added with a-amino glutarimide. HCl and sodium acetate in glacial acetic acid to obtain 1,3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-nitroisoindoline. 1,3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-nitro isoindoline was reacted in the presence of 1,4-Dioxane, sodium dithionite and Cesium carbonate with tertrabutyl ammonium bromide to yield 4-amino-2-(2, 6-dioxo-piperidin-3-yl)-isoindoline-1,3-dione. Purification of 4-amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline -1, 3¬-dione was carried out by addition of dimethyl sulfoxide, acetone and methanol.

Advantages of the improved method as described by the examples:
1. Do not required pressure reactor
2. Do not use pyriphoric catalyst like Palladium or Raney-Ni,
3. Can be carried out in normal SS reactor and scalable
4. Providing high purity and good yield.
5. Reduced reaction time compare to pressure reaction.

The following examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.

Example-1: Preparation of 1, 3-dioxo-2-(2, 6-dioxopiperidine-3-yl)-5-nitroisoindoline
(III):
A mixture of 3-nitrophthalic anhydride (I) (100 g, 0.520 mmol), a-amino glutarimide. HCl (II) (85 g, 0.520 mmol) and sodium acetate (45 g, 0.540 mmol) in glacial acetic acid (750 ml) was heated under reflux for 24 h, the mixture was concentrated in vacuum and the residue was suspended with (1000 x 5 ml) water at RT and filtered solid wash with water (20 ml x 5), isolated wet cake was dry in vacuum tray drier at 55–60°C to give 120 g (76.4%) of 1,3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-nitroisoindoline (III) as crystalline brown solid with purity greater then 99.2%.

Example-2: Preparation of 4-Amino-2-(2, 6-dioxo-piperidin-3-yl)-isoindoline-1, 3-dione Pomalidomide crude:
A mixture of 1,3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-nitroisoindoline (100 g, 0.329 mmol), 1,4-dioxane (5.0 l), sodium dithionite (275 g, 1.579 mmol), cesium carbonate (33 g, 0.101 mmol), tertrabutyl ammonium bromide (10 g, 0.031 mmol), purified water (1311 ml) was heated at 68-73°C for 4 to 5 h, mixture was cool to 40-45°C and concentrated in vacuum and the residue was suspended with (1200 ml) water at RT and filtered solid wash with (300ml) water, wet cake was purified using mixture of 1,4-dioxan and methanol 1:3 (4 l) at 60-70°C, further purify in mixture of 1,4-dioxan and ethanol 1:3 (4 l) at same temperature, then wet cake was dissolved in dimethyl sulfoxide at 25-30°C and solid was isolated using addition of water as an anti-solvent, filtered wet cake was suspended in water (1000 ml) at 50-55°C and then cool to RT, filtered wet cake was dried in vacuum tray drier at 50-55°C to give 44 g (48.8%) of 4-amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3¬-dione as yellow solid powder with purity greater than 99.2%

Example-3: Purification of Crude Pomalidomide:
10 g of Crude Pomalidomide of example 2 was dissolved in the presence of dimethyl sulfoxide (DMSO) 50 ml. The reaction mass was heated up to 65-70°C, stirred and maintained for 30 min at 65-70°C. The reaction mass was cooled up to 30-35°C, and acetone 50 ml was added at 30-35°C and maintained for 30 min at 30-35°C. Methanol (50 ml) was added slowly, after addition of methanol stirred and maintained for 2-3 h at 30-35°C. The solid was filtered and washed with mixture of acetone and methanol (30 ml: 30 ml). Dried wet cake was put under vacuum in vacuum tray drier at 60-65°C.
,CLAIMS:WE CLAIM:

1. An improved process for preparation of Pomlidomide comprising:
(a) reacting of 3-nitrophthalic anhydride (I) with a-amino glutarimide. HCl (II) to obtain 1,3-dioxo-2-(2, 6-dioxopiperidine-3-yl)-5-nitroisoindoline (III) in the presence of solvent;
(b) reacting 1,3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-nitroisoindoline (III) with cesium carbonate and sodium dithionite in the presence of solvents to obtain Pomalidomide crude;

(c) Purification of crude pomalidomide in the presence of solvent and water to obtain Pure pomalidomide.
.
2. The improved process for preparation Pomalidomide as claimed in claim 1, wherein step A contains solvents such as sodium acetate and glacial acetic acid.

3. The improved process for preparation Pomalidomide as claimed in claim 1, wherein step B contains solvents such as 1,4 dioxane and tertrabutyl ammonium bromide.

4. The improved process for preparation pure Pomalidomide as claimed in claim 1, wherein step C contains solvents for purification such as 1,4 dioxane, Purified water and a solvent.

5. The improved process for preparation pure Pomalidomide as claimed in claim 4, wherein step C contains solvents for purification such as DMSO with 1,4 dioxane and purified water.