AND ITS PURIFICATION" CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from Indian patent applications 5409/CHE/2013 filed on Nov. 25, 2013 and 424/CHE/2014 filed on Jan, 30, 2014, the contents of which are incorporated by reference in their entirety. FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of pomalidomide and its purification.

BACKGROUND OF THE INVENTION :

Pomalidomide is chemically known as (RS)-4-amino-2-(2,6-dioxo-piperidin-3-yl)- isoindoline-l,3-dione and structurally represented as below:

Pomalidomide is an immunomodulatory- antineoplastic agent. Pomalidomide is marketed with the brand name POMALYST®. It is indicated for the treatment of relapsed and refractor}' multiple myeloma.

Several references disclose methods for the preparation and purification of pomalidomide. For example, U.S. Pat. Nos. 5,635,517; 6,335,349; and 7,994,327 (which are all hereby incorporated by reference) disclose processes for the preparation of pomalidomide. Additionally, Chinese Pat. No. 103288797 (which is hereby incorporated by reference) also discloses a process for the purification of pomalidomide. The present disclosure provides an improved process for the preparation of pomalidomide with a purity greater than about 99%. The process also results in a high yield, is simple, cost effective, and feasible for large scale production.

SUMMARY OF THE INVENTION:

A first aspect of the present disclosure provides a process for the preparation of pomalidomide that may include the steps of: a) reacting nitro phthalic acid with 3-amino-piperidine-2,,6-dione or its salt in the presence of a coupling agent and a suitable solvent to obtain 3-(3- nitrophthalimido)-piperidine-2,6-dione,

diona b) reducing 3-(3-nitrophthalimido)-piperidme-2,6-dione in the presence of a solvent and catalyst to obtain pomalidomide.

3-(3-niirophtha!imido)-piperidine Pomalidomide

-2,6-dione

In one embodiment, the present disclosure provides a process for the purification of pomalidomide that may include the steps of:

a) dissolving pomalidomide in a sulfoxide compound solvent, b) adding a second solvent,

c) adding an anti-solvent, and

d) isolating substantially pure pomaiidomide. Another aspect of the present disclosure provides a process for the preparation of thalidomide comprising the steps of reacting phthalic acid with 3-amino-piperidine-2,6- dione or its salt to give 2-(2,6-dioxopiperidin-3-yl)-isoindole-l,3-dione, commonly known as thalidomide. BRIEF DESCRTTION OF THE DRAWING:

Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein: Figure 1 is an X-ray powder diffractogram of pomaiidomide prepared and purified according to the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION: It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The present invention encompasses novel synthetic schemes for the synthesis of pomaiidomide and thalidomide. These schemes provide an improved, efficient method for the synthesis of pomaiidomide at a high yield and purity.

More specifically, the present disclosure relates to an improved process for the preparation of pomaiidomide. In one embodiment, the present disclosure provides a process for the preparation of pomalidomide that may include the following steps:

a) reacting nitre-substituted phthalic acid with 3-amino~piperidine-2,6-dione or its salt in the presence of a coupling agent and a solvent to obtain 3-(3-

diona b) reducing 3-(3-nitrophthalimido)-piperidine-2,6-dione in the presence of a solvent

3 {3- itrophth !itT!ido)-piperidin& Pomalidomide

-2,6-dione

According to the present disclosure, nitrophthalic acid with 3-amino-piperidine-2,6-dione or its salt is converted to 3-(3-nitrophthalimido)-piperidine-2,6-dione in the presence of a coupling agent and a solvent per step (a) above. The reaction may be performed at about 25°C to about 80°C for about 5 to 18 hours. Within the context of the present disclosure, the coupling agent may include, as examples, 1 ,1-carbonyldiimadazole, dicyclohexylcarbodiimide, diisopropylcarbodiirnide, 2~chloro~4,6~dimethoxy- 1,3,5- triazine (CDMT), dimethyl arainopyri dine, and mixtures thereof. One of skill in the art will readily recognize additional compounds that may be useful in activating the carboxylic acid groups of nitrophthalic acid so that 3-amino-piperidine-2,6-dione hydrochloride may react and create the pyrrolidine ring to couple together nitrophthalic acid and the 3-amino-piperidine-2,6-dione. The solvent may include, as examples, nitriles (such as acetonitrile and propionitrile), acid amides (such as N,N- dimethylformamide and dimethylacetainide), and cyclic ethers (such as ieirahydroftsran and 1,4-dioxane). Again, one of skill in the art will recognize other solvents that may be suitable for use in this reaction. According to the present disclosure, 3-(3-nitrophthalimido)-piperidine-2,6-dione is then reacted at ambient temperature for about 5 6 hours in the presence of a solvent and catalyst to obtain pomalidomide, per step (b) above. Within the context of the present disclosure, the catalyst may be, for example, palladium on carbon, Raney nickel or reducing agents such as iron-hydrochloric acid, zinc-acetic acid, zinc ammonium chloride, bubbled hydrogen (per Example 3 below), and sodium dithionite. One skilled in the art may recognize a variety of other compounds that may be useful reducing agents for use in this step of the reaction disclosed herein. The solvent used in this particular step of the process may be, for example, an acid amide (such as , -dimethylforrnamide and Ν,Ν-dimethyl acetamide), dimethyl sulfoxide, a nitrite (such as acetonitrile or propionitrile), or aliphatic alcohols (such as methanol, isopropanoi and mixtures thereof). Again, one skilled in the art may recognize a variety of other solvents that may be useful in performing this reaction.

Another aspect of the present disclosure provides a process for the preparation of thalidomide, wherein phthalic acid is reacted with 3-ammo-piperidine-2,6-dione or its salt in the presence of a coupling agent and solvent to give 2-(2,6~dioxopiperidin-3~yl)~ isoindole-l ,3-dione (thalidomide). Within the context of this disclosure, the coupling agents may include, as examples, 1,1-carbonyidiimadazole, dicyelohexylcarbodiimide, diisopropylcarbodiimide, 2-chloro-4,6-dimethoxy- 1 ,3,5-triazine (CDMT), dimethylaminopyridine, and mixtures thereof. One of skill in the art will readily recognize additional compounds that may be useful in activating the carboxylic acid groups of nitrophthalic acid so that 3-amino-piperidine~2,6-dione hydrochloride may react and create the pyrrolidine ring to couple together phthalic acid and the 3-amino- piperidine-2,6-dione. The solvent may include, as examples, nitrites (such as acetonitrile and propionitrile), acid amides (such as Ν,Ν-dimethylfonnamide and dimethyl acetamide), and cyclic ethers (such as tetrahydrofuran and 1,4-dioxane), Again, one of skill in the art will recognize other solvents that may be suitable for use in this reaction.

Another aspect of the present disclosure is to provide a process for the purification of pomalidomide which may include the following steps:

a) dissol ving pomalidomide in an organic solvent or mixture of solvents, b) adding an anti-solvent, and

c) isolating substantially pure pomalidomide. According to the present disclosure, pomalidomide is dissolved in an organic solvent. Within the context of the current invention, the organic solvent used in step (a) is used may include, for example, dimethyl sulfoxide, diethyl sulfoxide, di-n-propyl sulfoxide, di-or tetra-n-butyl sulfone sitlfoxide, acetone, methyl isobutyl ketone, or mixtitres thereof. According to the present disclosure, anti-solvent is then added to the pomalidornide/organic solvent solution. Within the context of the present specification, an anti-solvent is a fluid in which the product is insoluble, thus permitting more facile isolation of the product. For the present invention, useful anti-solvents may include alcohols, ethers, water, or mixtures thereof. Suitable alcohols include methanol, ethanol, n-propanol, isopropanol, and n-butanol. Suitable ethers include diethyl ether, tert-butyl methyl ether, and diisopropyl ether.

Another embodiment of the present disclosure is to provide another process for the purification of pomalidomide which may include the following steps:

a) dissolving pomalidomide in a sulfoxide compound solvent,

b) adding a second solvent,

c) adding an anti-solvent, and

d) isolating substantially pure pomalidomide.

According to the present invention, pomalidomide is dissolved in a sulfoxide compound solvent. This sulfoxide compound may include, for example, dimethyl sulfoxide, diethyl sulfoxide, di-n-propyl sulfoxide, or di- or tetra-n-butyl sulfone. Next, a second solvent is added. Examples of a useful second solvent include acetone and methyl isobutyl ketone. Next, an anti-solvent may be added to precipitate substantially pure pomalidomide. Examples of suitable anti-solvents include alcohols such as methanol and ethanol, ethers, water, or mixtures thereof.

Within the context of the current invention, the final pomalidomide product prepared by the processes described herein may yield a product with a purity greater than about 99.7% as measured by HPLC. Individual identified chemical impurities in the final pomalidomide product may be present at quantities less than about 0.10%.

A crystalline form of pomalidomide, prepared and purified according to the processes disclosed in the present invention, may be characterized by powder X-ray diffraction (PXRD), and have a PXRD pattern as shown in Fig. 1 and having peaks at 12.1, 13.9, 17.1 , 18.3, 24.2, 25.4, 27.9 ± 0.2 2Θ.

The pomalidomide as synthesized and purified by the methods disclosed herein may be useful in generating pharmaceutical dosage forms suitable for administration to patients in need thereof. The dosage form may be an oral dosage form and in some embodiments, the oral dosage form may be a capsule. The capsule may include appropriate excipients including rnannitol, pre-gelatinized starch, and sodium stearyl fumarate. Such formulations may be useful in the treatment of multiple myeloma. Formulations of pomalidomide are particularly useful for patients having multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within sixty days of completion of the last therapy.

Tn view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

Examples;

Example 1: Synthesis of l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-nitro-isoindoline- dione (3-nitrophthalidomide)

To the stirred mixture of 3-nitrophthalic acid (25.0 g or 0.12 mole) in acetonitrile (175 ml) was added 1 , 1 -carbonyldiimi dazole (CD1) (42,3 g or 0.26 mole) under nitrogen atmosphere at ambient temperature. To this mixture, 3-aminopiperidine 2,6-dione hydrochloride (19.5g or 0.12 mole) was added, and the reaction mixture was heated to 75 to 80 °C until the reaction was completed as monitored by TLC. After completion of the reaction, the solvent was distilled out under reduced pressure. Water (375 ml) was added to the reaction mass, and the reaction mass was slowly cooled at 0 to 5 °C while stirring. The isolated solid was filtered, washed with water, then by methanol, and suck dried. Finally the isolated solid was dried at 55 to 60 °C under vacuum until constant weight to obtain 3-nitrophthalidomide. Yield: 28.2 g, 78.5% (molar) (HPLC purity -99.5%).

Example 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-isoindole-1 -dione

(Thalidomide)

1,1-carbonyldiimidazole (21.5 g or 0.13 mole) was added to a stirred mixture of phthalic acid (10.0 g. or 0.06 mole) in acetonitrile (100 ml) maintained under nitrogen at ambient temperature. To this mixture, 3-aminopiperidine 2,6-dione hydrochloride (9.9 g or 0.06 mole) was added, and the reaction mixture was stirred at 25 to 30 °C until the reaction was completed as monitored by TLC. After completion of the reaction, the solvent was distilled out under reduced pressure. Water (100 ml) was added to the reaction mass and the reaction mass was slowly cooled at 0 to 5 °C while stirring. The isolated solid was filtered, washed with water, then by methanol, and suck dried. Finally the isolated sold was dried at 55 to 60 °C under vacuum until constant weight to get thalidomide. Yield: 1 1.6 g, 75.2% (molar). Purity by HPLC 99.13%

Example 3: Synthesis of 4-amino-2-(2,6-dioxopiperidin-3-yl)-isoindoIine-l,3-(lione (Pomalidomide)

Catalyst palladium (10%) on carbon (0.5 g. or 5% w/w of substrate ) was added to a stirred solution of 3-nitrophthalidomide (10 g or 0.033 mole) (Example 1 ) in N,N- dimethyl formamide (100 ml) maintained under nitrogen. Hydrogen gas was bubbled through the reaction mixture at atmospheric pressure. After completion of hydrogenation reaction, as monitored by TLC, hydrogen bubbling was stopped and the catalyst was separated by filtration of the reaction mixture on celite bed. The filtrate was distilled at 60 to 65 °C under reduced pressure until half of the solvent was removed. The solution was then cooled at ambient temperature and methanol (50 ml) was added while stirring. The solid obtained was filtered, washed with methanol (50 ml), and suck dried to obtain pomalidomide 8.2 g (90% molar yield) having HPLC purity > 99.0%.

Example 4: Pomalidomide Purification Process

In a reaction vessel, crude (RS) 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindole-l ,3- dione (pomalidomide, l g) was dissolved in dimethylsulfoxide (40 ml) by heating at 60 to 65 °C. The solution was cooled to 25 to 30 °C. To this solution, acetone (40 ml) was added while stirring. After completion of acetone addition, the solution was stirred for 30 minutes and then methanol (40 ml) was added at slow rate while stirring at 25 to 30 °C. The resulting mixture was allowed to stir for one to two hours. The isolated solid was filtered, washed with a methanol-acetone mixture (1 : 1 v/v, 10 ml) and suck dried. Finally, the material was dried by vacuum at 55 to 60 °C to get pure pomalidomide (8 g, 80% yield) with HPLC purity greater than 99.7%. All known individual chemical impurities were present at quantities less than 0.10 %).