WO2010122575A2

WO2010122575A2 - Process for the preparation of pure paliperidone

Info

Publication number: WO2010122575A2
Application number: PCT/IN2010/000244
Authority: WO
Inventors: Siva Rama Prasad Vellanki; Arabinda Sahu; Naveen Kumar Phaduri; Debashish Datta
Original assignee: Matrix Laboratories Ltd
Current assignee: Mylan Laboratories Ltd
Priority date: 2009-04-20
Filing date: 2010-04-16
Publication date: 2010-10-28
Anticipated expiration: 2011-10-20
Also published as: WO2010122575A3

Abstract

The present invention provides pure Paliperidone comprising less than about 0.1%, preferably less than about 0.05% of PLP keto impurity as well as purification processes for preparing thereof.

Description

PROCESS FOR THE PREPARATION OF PURE PALIPERIDONE FIELD OF THE INVENTION The present invention relates to process for the preparation of pure Paliperidone.

BACKGROUND OF THE INVENTION

Paliperidone (Invega) is a second generation antipsychotic drug developed by Janssen Pharmaceutica. Invega is an extended release formulation of Paliperidone that uses the Osmotic Release Oral Systems extended release system to allow for once-daily dosing. Chemically, Paliperidone is primary active metabolite of the existing antipsychotic Risperidone (Paliperidone is 9-hydroxyrisperidone, i.e., Risperidone with an extra hydroxyl group). Paliperidone chemical name is 3-[2-[4-(6-fluoro-l,2-benzisoxozol-3-yl)-l-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2- methyl-4H-pyrido[l,2-a] pyrimidin-4-one, which is structurally represented as Formula- 1

Formula-1

Paliperidone (as Invega) was approved by the FDA for treatment of schizophrenia on December 20, 2006. This agent will initially be marketed for the treatment of schizophrenia and then for bipolar mania.

Paliperidone claimed as a product in US 5,158,952 and process for the preparation of Paliperidone is disclosed, wherein 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H-pyrido[l,2-a]pyrimidin-4- one is reacted with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole mono hydrochloride in the presence of base in a solvent. After completion of the alkylation reaction methanol is removed by reduced pressure to give oily residue, which is dissolved in chloroform and washed with water. The organic layer is dried and concentrated under reduced pressure to get residue, which is subjected to column chromatographic purification using mixture of chloroform and methanol, evaporation of eluents to give residue, which is subjected to repeated crystallizations in different solvents like acetone and isopropyl alcohol to give Paliperidone having the melting point 179.8° C. This process is commercially not viable as it involves purification by column chromatography.

US 20080171876 [Assignee: Teva Pharmaceuticals] discloses two potential impurities remaining in the final Paliperidone Pharma sample namely, 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-l- oxypiperidin-l-yl]ethyl]-7-hydroxy-4-methyl-l,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one (PLP- NO) and 2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-carboxylicacid]-7-hydrox- y-2-methyl- 6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one-3-yl-ethyl ester (PLP-car) as shown below.

US '876 patent application discloses a process for removing the said impurities, wherein the process comprises the steps of: a) dissolving Paliperidone in solvent selected from C₃-₆ ketones, N- methylpyrrolidone, C3.6 amides, halogens, dimethyl sulfoxide, dimethyl carbonate, alcohols, acetonitrile, water or mixtures thereof, at high temperatures to form clear solution; b) cooling the clear solution; and c) isolating pure Paliperidone. US '876 patent application discloses that by following the above said process, PLP-NO levels can be reduced from 0.67% to 0.35% and from 0.41% to 0.2%.

US 2008/0281 100 [Assignee: Teva Pharmaceuticals] discloses another potential impurity characterized by HPLC with a relative retention time of about 1.27. The impurity obtained at 1.27 RRT has been designated as Impurity X. This patent application discloses a process for obtaining Paliperidone containing less than 0.02% of Impurity X, wherein the process comprises the steps of: a) suspending Paliperidone in acetone: water solvent mixture in 3:1 ratio; b) heating the Paliperidone suspension to higher temperatures such that clear solution is obtained; c) cooling the clear solution to ambient temperature; and d) isolating pure Paliperidone. US ' 100 patent application discloses that Paliperidone obtained by following the above said process contains impurity X and in less than 0.05% and less than 0.05% of PLP-car impurity.

Hence there exists a need in the art for an improved economical process for the preparation of pure Paliperidone with high yield and purity. OBJECT OF THE INVENTION

Principle object of the present invention is to provide Paliperidone containing less than about 0.1 % of PAL-keto impurity.

Another object of the present invention is to provide Paliperidone having a total purity of atleast about 99%.

Another object of the present invention is to provide process for preparing pure Paliperidone.

Yet another object of the present invention is to provide a pharmaceutical composition comprising Paliperidone, wherein the Paliperidone is having 3-{2-[-4-(6-fluoro-benzo[c(]isoxazole-3-yl]- ethyl}-2-methyl-7,8-dihydro-6H-pyrido[l,2-a]pyrimidine-4,9-dione[PAL-keto] impurity less than about 0.1 %.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide Paliperidone containing less than about 0.1 % of 3-{2-[-4-(6-fluoro-benzo[c0isoxazole-3-yl]-ethyl}-2-methyl-7,8-dihydro-6H-pyrido[l,2-a] pyrimidine-4,9-dione [PAL-keto] impurity.

Another aspect of the present invention is to provide Paliperidone having a total purity of atleast about 99%.

Yet another aspect of the present invention is to provide process for preparing pure Paliperidone, comprising the steps of a) suspending Paliperidone in an aprotic solvent to form slurry; b) optionally heating the slurry to 40-50°C; c) filtering the slurry; and d) isolating pure Paliperidone.

Yet another aspect of the present invention is to provide a pharmaceutical composition comprising Paliperidone, wherein the Paliperidone is having 3-{2-[-4-(6-fluoro-benzo|//]isoxazole-3-yl]- ethyl}-2-methyl-7,8-dihydro-6H-pyrido[l,2-a]pyrimidine-4,9-dione[PAL-keto] impurity less than about 0.1 %. DETAILED DESCRIPTION OF THE DRAWINGS

Figure 1: PXRD pattern of crystalline Paliperidone

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides pure Paliperidone comprising less than about 0.1%, preferably less than about 0.05% of PAL-keto impurity as well as purification process for preparing thereof.

As used herein, the term PAL refers to Paliperidone.

As used herein, the term PAL-Keto refers to 3-[2-[4-(6-fluoro-l,2-benzisoxozol-3-yl)-l- piperidinyl]-ethyl]-2-methyl-7,8-dihydro-6H-pyrido-[l,2-a] pyrimidin-4,9-dione.

As used herein, the term IPA refers to isopropyl alcohol.

As used herein, the term DMF refers to dimethyl formamide.

As used herein, the term NMPO refers to N-methyl pyrrolidone.

US 20080171876 and US 2008/0281100 patent applications disclose Paliperidone impurities namely, N-oxide, carbamate and impurity X. Surprisingly, the present inventors have found another potential impurity during the synthesis of Paliperidone designated as Paliperidone Keto as depicted in Formula II.

PAL-Keto

Formula II

In one embodiment, the present invention provides a process for preparing pure Paliperidone containing less than 0.1%, preferably less than about 0.05% of PAL-keto impurity. The term pure Paliperidone, as used herein refers to Paliperidone containing less than about 0.2% of PAL-keto impurity. Preferably the Paliperidone of the present invention contains less than about 0.1%, more preferably less than about 0.08% and most preferably less than about 0.05% of keto impurity.

According to the present invention, total purity of Paliperidone is atleast about 98%, preferably the total purity is atleast about 99%, most preferably more than 99.8%.

Another embodiment of the present invention is to provide process for the purification of Paliperidone as represented in Scheme- 1, wherein the process comprises the steps of a) suspending Paliperidone in a solvent to form slurry; b) heating the slurry to 40-50⁰C; c) filtering the slurry at hot; and d) isolating pure Paliperidone.

(Palipeπdone-Crude) (Palipeπdone-Pure)

SCHEME-I

According to the present invention, in the purification step, Paliperidone is suspended in a solvent selected from aprotic solvents such as N-methyl pyrrolidone, dimethyl sulfoxide, dimethyl acetamide and dimethyl formamide preferably N-methyl pyrrolidone and dimethyl formamide. The suspension so formed is heated to 30-60⁰C preferably 45-50⁰C. The slurry is then filtered at hot and washed to obtain Paliperidone.

In one embodiment, Paliperidone taken for purification is having at least 0.3% of keto impurity. Paliperidone obtained by the above purification process contains PAL- keto impurity in less than about 0.1% preferably 0.08 % more preferably 0.05%. The total purity of Paliperidone obtained by the above process is of atleast 99%, preferably 99.5% and most preferably more than 99.8%.

According to the present invention, mother liquor obtained from purification of Paliperidone as described above, can be treated further to recover Paliperidone, wherein, DM water is added to mother liquor and maintained at room temperature for about 4-8 hrs. The solid obtained is filtered and dried to obtain Paliperidone of >99% purity.

In another embodiment, Paliperidone free of keto impurity can be subjected to further recrystallisation in alcohol solvents such as ethanol, methanol, isopropyl alcohol preferably isopropyl alcohol to obtain crystalline Paliperidone as shown in Figure 3.

In another embodiment, the present invention provides a pharmaceutical composition that includes a therapeutically effective amount of pure Paliperidone and its salts prepared according to the processes of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.

The present invention provides a pharmaceutical composition comprising Paliperidone, wherein the Paliperidone is having 3-{2-[-4-(6-fiuoro-benzo[^isoxazole-3-yl]-ethyl}-2-methyl-7,8-dihydro- 6H-pyrido[l,2-a]pyrimidine-4,9-dione[PAL-keto] impurity less than about 0.1 %.

Accordingly, the pharmaceutical composition comprising pure Paliperidone or their pharmaceutically acceptable salts along with one or more pharmaceutically acceptable carriers of this invention may further be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions, and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. The compositions may be prepared by direct blending, dry granulation, or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Powder X-ray Diffraction (PXRD)

The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PΛNalytical, XΨert PRO powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the synthesis of Paliperidone. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Example 1

Preparation of 9-Benzyloxy-3-(2-chIoro-ethyI)-2-methyl-pyrido[l,2-a] pyrimidin - 4-one

2-Amino-3-benzyloxypyridine (lOOgm) was taken into an RB flask at RT (25-35° C). Toluene (1000 ml) was taken and added phosphorous oxychloride (310 gm) dropwise at RT. Contents were heated to 50°C and charged 2-acetyl-butyrolactone (128 gm). The reaction was maintained at 60- 65°C. After the completion of the reaction, contents were cooled and treated with DM water and extracted into methylene dichloride. After separation of the layers, organic layer was concentrated under reduced pressure. The residue was taken and added isopropyl alcohol (200 ml). The solid obtained was filtered and dried to yield benzyloxy-3-(2-chloro-ethyl)-2-methyl-pyrido[l,2-a] pyrimidin - 4-one.

Example 2

Preparation of 3-(2-Chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-pyrido[l,2-aJ pyrimidin-4-one

Benzyloxy-3-(2-chloroethyl)-2-methyl-pyrido[l,2-a] pyrimidin - 4-one (100 gm) obtained in Example 1 was treated with acetic acid (25 gm) and sulphuric acid (30 gm) in methanol. To this mass Palladium (10%) on charcoal (10% wet) was added and maintained under hydrogen pressure of 3-4 kg/cm² at 60-65°C. After completion of the reaction, reaction mass was filtered over hyflo to remove the carbon. Filtrate was subjected to sodium carbonate (120 gm) washings and isolated in methanol to yield 3-(2-Chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-pyrido[l,2- a]pyrimidin-4-one. Example 3

Preparation of 3-[2-[4-(6-Fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyI]-6,7,8,9-tetra hydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one

3-(2-Chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-pyrido[l,2-a]pyrimidin-4-one of example 2 was taken into an RB flask at RT. To this, acetonitrile (1100 ml) and sodium carbonate (132 gm) were added and contents were heated to 82°C. 6-Fluoro-3-piperidin-4-yl-benzo[</]isoxazole (93 gm) was added at RT and reaction was maintained at 60-65⁰C. Solid obtained was filtered and washed with acetonitrile. The wet material was subjected to slurry in isopropyl alcohol to yield crude Paliperidone.

Example 4

Purification of Paliperidone n-Methyl pyrrolidone (1500 ml) was taken into an RB flask at RT. Paliperidone obtained in example 3 was also added at RT. Contents were heated to 40-45⁰C and maintained for 30 min. Solid was filtered at 45°C and washed with NMPO (100ml). The obtained solid was further washed with isopropyl alcohol (100 ml) at 40-45⁰C. Solid was dried to get Paliperidone.

Example 5

Purification of Paliperidone

Paliperidone isolated as in example 3 was suspended in NMPO and maintained at different temperatures without going to clear solution and filtered at same temperature without cooling. Experiments with observations are tabulated below.

Example 6

Purification of Paliperidone

Paliperidone isolated as in example 3 was purified by suspending the solid in DMF and maintained at different temperatures without going to clear solution and filtered at same temperature without cooling. Experiments with observations are tabulated below.

Example 7

Recovery of crop from NMPO ML's

NMPO ML's (200 ml) from purification of Paliperidone obtained in example 4 or 5 or 6 was charged into flask. Water (1600 ml) was added drop wise at 25-30⁰C over 1-2 hrs with cooling. Mass was maintained at 25-35°C for 6 hrs. Solid was filtered and wash with water (5 ml) and IPA (5 ml). Wet solid was dried at 70-75°C to get 2^nd crop of Paliperidone with purity >99%.

Example 8

Recrystallisation of Paliperidone

Paliperidone (lOgm) obtained example 5 or 6 was taken into an RB flask at RT. Isopropyl alcohol (600ml) was added at RT and the contents were heated to reflux for obtaining a clear solution. The clear solution so formed was maintained at reflux for 30 min., filtered and washed with hot IPA. The filtrate was cooled slowly to RT and later to 0 ⁰C. Mass was maintained at 0-5 °C for 2 hrs. The solid obtained was filtered and washed with chilled IPA (100 ml) to yield pure Paliperidone.

Claims

We Claim:

1. A process for purifying Paliperidone, which comprises; suspending Paliperidone in an aprotic organic solvent to obtain purified Paliperidone, wherein the keto impurity content in purified Paliperidone is less than the keto impurity content in the starting Paliperidone. 5

2. A process according to claim 1, wherein the aprotic organic solvent is selected from N- methyl pyrrolidone and dimethyl formamide.

3. A process according to claim 1, wherein the keto content in the starting Paliperidone is P atleast 0.3 % and keto content in the purified Paliperidone is not more than 0.1%.

4. The process according to claim 1, wherein process for preparing pure Paliperidone, comprises: a) suspending Paliperidone in a solvent to form slurry; b) optionally heating the slurry to 40-50 °C; c) filtering the slurry; and d) isolating pure Paliperidone. 5

5. A process for recovery of Paliperidone comprising the steps of: a) adding water to Paliperidone mother liquor; and b) isolating Paliperidone.

6. Paliperidone obtained by any of the preceding claims 1 to 5, which contains keto impurity0 content less than 0.1 %.

7. Paliperidone containing 3-{2-[-4-(6-fluoro-benzo[</|isoxazole-3-yl]-ethyl}-2-methyl-7,8- dihydro-6H-pyrido[l,2-a]pyrimidine-4,9-dione[PAL-keto] impurity less than about 0.1 %. 5 8. Paliperidone according to claim 7, wherein Paliperidone contains 3-{2-[-4-(6-fluoro- benzo[ύ(]isoxazole-3-yl]-ethyl}-2-methyl-7,

8-dihydro-6H-pyrido[l,2-a]pyrimidine-4,9- dione[PAL-keto] impurity less than about 0.08 % preferably less than 0.05%.

9. A process for preparing crystalline Paliperidone, further comprising crystallizing purified0 Paliperidone obtained in claim 1, in an alcohol solvent and isolating crystalline

Paliperidone.

10. The process according to claim 9, wherein the alcohol solvent is selected from methanol, ethanol and isopropyl alcohol preferably isopropyl alcohol. 5

11. A pharmaceutical composition comprising Paliperidone, wherein the Paliperidone is having less than 0.1% of keto impurity.