FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of pure Paliperidone of Formula I.

BACKGROUND OF THE INVENTION

Paliperidone is chemically known as 9(RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-1 -piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]-pyrimidin-4-one. Paliperidone is a metabolite of Risperidone and is marketed under the trade name, Invega®. Paliperidone is a psychotropic agent approved in the United States for the treatment of schizophrenia.

Paliperidone is described in US 5,158,952. The process is as shown below:

The reaction mixture containing paliperidone obtained according to the method of US '952 patent is subjected to evaporation and the oily residue is extracted with trichloromethane followed by water washings. The organic layer is dried, filtered and evaporated followed by column chromatographic purifications over silica gel using a mixture of trichloromethane and methanol. The pure fractions are collected and the eluent is evaporated. The resulting residue is crystallized from 2-propanone. After cooling, the precipitated product is filtered off, washed with a mixture of 2-propanol and 2,2'-oxybispropane, and recrystallized from 2-propanol to produce paliperidone. Paliperidone obtained by this process does not have satisfactory purity for pharmaceutical use. Unacceptable amounts of impurities were formed along with paliperidone. In addition, the process involves the additional step of column chromatographic purifications. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.
WO 2008/021346 discloses various methods for the purification of paliperidone, which are as given below:

A) Crystallization of Paliperidone by dissolving Paliperidone in a solvent selected
from the group consisting of C3-6 ketone or a mixture thereof with water, N-
methylpyrrolidone, C3-6 amides, halo-substituted C6-12 aromatic hydrocarbons,
propylene glycol, dimethyl sulfoxide, di-methyl carbonate, C1-4 alkyl alcohols, a
mixture of a C1-8 alkyl alcohol and water, acetonitrile or a mixture thereof with water,
C2-6 alkyl acetates or their mixture with, water, cellosolve, dimethyl carbonate,
polyethylene glycol methyl ether and C2-8 ethers and heating to allow complete
dissolution, followed by cooling.

B) Crystallization of Paliperidone by dissolving Paliperidone in a first solvent selected from the group consisting of dichloromethane, dioxane and C1-4 alkyl alcohols, and thereafter treating with an anti-solvent selected from the group consisting of C3-6
ketones, C3-6 ethers, acetonitrile, C3-7 straight and cyclic carbohydrates, C6-12 aromatic carbohydrates and water.

C) Crystallization of Paliperidone by slurrying Paliperidone in an organic solvent selected from C1-4 alkyl alcohols, C3.5 ketones and water.

D) Crystallization of Paliperidone by dissolving Paliperidone in a mixture of acetone and water, admixing the solution with finely powdered carbon, and filtrating the admixture to obtain pure Paliperidone.

Koen De Smet et al., (Organic Process Research & Development 2005, 9, 344-347) discloses a process to prepare 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one by hydrogenating hydrochloride salt of 3-(2-chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[l ,2-a]pyrimidine-4-one using Pd-C/H2 and thereafter isolated the formed crystals, which were filtered, washed with water and dried in a vacuum at 40°C. The present inventors found that the color of the obtained intermediate was not good, which was also affecting the color of the final drug substance.

US 2008/0214809 Al discloses a process to prepare Paliperidone, which is as shown below:

The present inventors have repeated the above process, and found that the final drug substance obtained by above process contains about 1.12% of diketo compound of Formula XI,

Based on the aforementioned drawbacks, the prior art processes may be unsuitable for preparation of Paliperidone in commercial scale operations. A need remains for an improved and commercially viable process for preparing pure Paliperidone of Formula I.
The inventors of the present invention have now developed an improved process for preparing highly pure Paliperidone of Formula I, which can be easily adopted for commercial scale preparation.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple and cost effective process for the preparation of pure Paliperidone.

Another objective of the present invention is to provide a process for the preparation of Paliperidone, which is simple, industrially applicable and economically viable.
Yet another objective of the present invention is to provide a process for the preparation of Paliperidone with improved color and which contain diketo compound less than 0.1%.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Paliperidone of Formula I,

which comprises:
a) purifying 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]-pyrimidin-
4-one hydrochloride of Formula X,
X
by dissolving in a solvent and precipitating by adding an anti-solvent,

b) hydrogenating the 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-
pyrimidin-4-one hydrochloride of Formula X to give 3-(2-chloroethyl)-6,7,8,9-
tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one of Formula
V,

c) purifying the 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one of Formula V,

d) condensing the product obtained in step (e) with 6-fluoro-3-piperidino-l,2-benzisoxazol hydrochloride of Formula VI,

in the presence of organic base and a solvent to give Paliperidone of Formula I, and e) optionally purifying the obtained Paliperidone of Formula I.
In another embodiment, the present invention relates to a process for preparing 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one hydrochloride of Formula X,
X

which comprises:

a) reacting 2-amino-3-hydroxy pyridine of Formula VIII
VIII with 3-acetyl-4,5-dihydro-3H-2-furanone of Formula III
III
in the presence of an acid and a solvent to give 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one of Formula IX,

b) chlorinating 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]-
pyrimidin-4-one of Formula IX with a chlorinating agent to give compound of
Formula X.
In yet another embodiment, the present invention relates to a process for purifying Paliperidone of Formula I, which comprises:

a) dissolving Paliperidone in a solvent in the presence of base, and
b) isolating the highly pure Paliperidone of Formula I,

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Paliperidone, which comprises purifying the 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one hydrochloride of Formula X, by dissolving in solvent selected from methanol and adding anti-solvent selected from diisopropylether to give 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]-pyrimidin-4-one hydrochloride of Formula X.

The hydrogenation of compound of Formula X is carried out using catalyst in methanol to give 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one of Formula V, which is isolated from water and purified by dissolving in mixture of acetone and cyclohexane and silica gel treatment followed by concentration to obtain a residue. The catalyst used for hydrogenation is selected from Palladium, Platinum or Raney Nickel. The obtained residue is dissolved in isopropyl alcohol followed by crystallization to isolate pure 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one of Formula V.
The condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one of Formula V with 6-fluoro-3-piperidino-l,2-benzisoxazol hydrochloride of Formula VI is carried out in the presence of organic base selected from triethylamine, diisopropylethylamine, diisopropylamine, tributylamine in alcoholic solvent selected from methanol, ethanol, isopropyl alcohol and mixture thereof followed by cooling to give Paliperidone of Formula I.

In another embodiment, the present invention relates to a process for preparing 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]-pyrimidin-4-one hydrochloride of Formula X, which comprises reacting 2-amino-3-hydroxy pyridine of Formula VIII with 3-acetyl-4,5-dihydro-3H-2-furanone of Formula III to give 3-(2-hydroxyethyl)-9- hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one of Formula IX, followed by chlorination to give compound of Formula X.

The condensation of compound of Formula VIII with compound of Formula IX is carried out in the presence of acid selected from hydrochloric acid, sulfuric acid, benzenesulfonic acid and p-toluenesulfonic acid and solvent selected from toluene, xylene, chlorobenzene and mixture thereof, at a temperature in the range of 120-150°C.

The chlorination of compound of formula IX is carried out using a chlorinating agent selected from thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, in the presence of dimethylformamide to give compound of Formula X.

The Paliperidone obtained by the present invention is in crystalline form.
In yet another embodiment the present invention provides purification methods for obtaining highly pure Paliperidone of Formula I.

Method -1

The purification process comprises:

a) treating Paliperidone in mixture of acetone and methanol, and

b) cooling to obtain highly pure Paliperidone of Formula I.

Method - II

The purification process comprises:

a) dissolving Paliperidone in mixture of methanol and dichloromethane,

b) treating with carbon,

c) removing dichloromethane by distillation, and

d) cooling the reaction mass to obtain highly pure Paliperidone of Formula I.

Method-III

The purification process comprises:

a) dissolving Paliperidone in a solvent in the presence of base, and

b) isolating the highly pure Paliperidone of Formula I,
wherein the base is selected from organic bases such as triethylamine, diethylamine, dimethylamine, diisopropylamine, N,N-diisopropylethylamine and mixtures thereof and more preferably triethylamine and the solvent is selected from solvent consisting of C3-7 branched or chained hydrocarbons, C2-7 chained or branched ethers, cyclic ethers, lower fatty acid esters, aliphatic ketone solvents, halogenated hydrocarbon solvents or nitrile solvents and mixture there of; isolation is carried by crystallization or precipitating by adding anti-solvents in which product is poorly soluble selected from the same group of solvents as mentioned above or by crystallization after removing of partial solvents.
The paliperidone obtained according to above process has an improved color and contains diketo compound of Formula XI less than 0.1 % of total drug substance.
The following examples illustrate the nature of the present invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE 1

PREPARATION OF 3-(2-HYDROXYETHYL)-9-HYDROXY-2-METHYL-4H-PYRIDO[l,2-A]-PYRIMIDIN-4-ONE

2-Amino-3-hydroxy pyridine (200 g), 3-acetyl-4,5-dihydro-3H-2-furanone (303.72 g) and p-toluene sulfonic acid monohydrate (2 g) were added in xylene (2000 ml) and heated to reflux and removed water by azeotropic distillation. After completion of reaction the reaction mass was cooled and filtered to afford the title compound. Yield: 260 g Chromatographic purity (by HPLC): 98.04%

EXAMPLE-2

PREPARATION OF 3-(2-CHLOROETHYL)-9-HYDROXY-2-METHYL-4H-PYRIDO[l,2-A]-PYRIMIDIN-4-ONE HYDROCHLORIDE

3-(2-Hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one (200 g) was suspended in dimethylformamide (800 ml) and thereafter thionyl chloride (84.8 ml, 138.2 g) was added in lh±20 min. The content was heated at 65-70°C till completion of reaction. The reaction mass was cooled to 50-55°C and added methanol (50 ml) and ethyl acetate (800 ml) at 50-55°C and further cooled to 23-30°C and filtered the product at 23-30°C to yield crude title compound.

PURIFICATION OF 3-(2-CHLOROETHYL)-9-HYDROXY-2-METHYL-4H-PYRIDO[l,2-A]-PYRIMIDIN-4-ONE HYDROCHLORIDE

Suspended above wet crude 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one hydrochloride in methanol (1400 ml) and heated to 63-65°C to obtain a clear solution, diisopropylether (2200 ml) was added to the reaction mass at 55-60°C and cooled the reaction mass to 20-25°C and filtered to give title compound. Yield: 180 g Chromatographic Purity (By HPLC): 99.91%

EXAMPLE-3

PREPARATION OF 3-(2-CHLOROETHYL)-6,7,8,9-TETRAHYDRO-9-HYDROXY-2-METHYL-4H-PYRIDO[l,2-A]PYRIMIDIN-4-ONE

3-(2-Chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one hydrochloride (32.8 g) was suspended in methanol (320 ml) and heated the content to 50-55°C to get a clear solution. Thereafter the content was cooled to 23-30°C and transferred into hydrogenator. 10% Palladium on carbon (6.4 g) was added and applied the hydrogen pressure (2-3 kg/cm2) and maintained at 23-30°C till completion of reaction. After completion of reaction, the catalyst (Pd/C) was filtered and concentrated the filtrate completely. DM water (117 ml) was added in to concentrated mass and precipitated the product by adding aqueous potassium acetate solution. The obtained product was filtered and dried to give crude of title compound.

Yield: 18.0g

Chromatographic Purity (By HPLC): 96.34%

PURIFICATION OF 3-(2-CHLOROETHYL)-6,7,8,9-TETRAHYDRO-9-HYDROXY-2-METHYL-4H-PYRIDO[l,2-A]PYRIMIDIN-4-ONE-CRUDE

Crude 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-
a]pyrimidin-4-one-Crude (18 g) was dissolved in acetone (210 ml) and cyclohexane (210 ml) followed by silica gel (90 g) addition. The content was filtered and washed with mixture of acetone and cyclohexane. Thereafter the filtrate was concentrated under vacuum completely and isopropyl alcohol (90 ml) was added to obtain a clear solution. Isopropyl alcohol (36 ml) was distilled out and thereafter the content was cooled to 0-5°C. The obtained product was filtered and dried to obtain title compound. Yield. 15 g Chromatographic Purity (By HPLC): 98.45

EXAMPLE-4

PREPARATION OF PALIPERIDONE

6-Fluoro-3-piperidino-l,2-benzisoxazol hydrochloride (36.46 g) was suspended into methanol (300 ml), followed by addition of triethylamine (47.5 g, 65.5 ml) and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (30 g) at 23-30°C. The content was heated to 63-65°C and maintained till completion of reaction. After completion of reaction, the reaction mass was cooled, filtered and dried to give title compound. Yield: 45 g Chromatographic Purity (By HPLC): 99.29%, Diketo compound: 0.21%

EXAMPLE-5

PURIFICATION OF PAUPERIDONE

Paliperidone (37.5 g) was suspended into dichloromethane (562.5ml) and methanol (900 ml) at 23-30°C. The content was heated to 48-50°C to obtain a clear solution. Clear solutions were treated with carbon, dichloromethane/methanol mixture was distilled at 40-66°C under normal pressure up to 550 ml solution remain in the reaction mass. Thereafter the mass was cooled, filtered and dried to obtain title compound. Yield: 30 g Chromatographic Purity (By HPLC): 99.71%, Diketo compound: 0.07%

EXAMPLE-6

PURIFICATION OF PALIPERIDONE

Paliperidone (37.5 g) was suspended into dichloromethane (562.5ml), triethylamine (12.3ml) and methanol (900 ml) at 23-30°C. The content was heated to 48-50°C to obtain a clear solution. Clear solutions were treats with carbon, dichloromethane/methanol mixture was distilled at 40-66°C under normal pressure up to 550 ml solution remain in the reaction mass. Thereafter the mass was cooled, filtered and dried to obtain title compound. Yield: 30 g Chromatographic Purity (By HPLC): 99.93%, Diketo compound: 0.07%

EXAMPLE-7

PURIFICATION OF PALIPERIDONE

Paliperidone (37.5 g) was suspended into acetone (37.5ml) and Methanol (375 ml) at 23-30°C The content was heated to 60-65°C and stirred at 60-65°C for 1-2 hrs and thereafter the reaction mass was cooled to 20-25 °C, filtered and dried to obtain title compound. Yield: 33.5 g

WE CLAIM:

1. A process for the preparation of Paliperidone of Formula I, which comprises:

a) purifying 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-
4-one hydrochloride of Formula X,

by dissolving in a solvent and precipitating by adding an anti-solvent,

b) hydrogenating the 3-(2-chloroethyI)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-
pyrimidin-4-one hydrochloride of Formula X to give 3-(2-chloroethyl)-6,7,8,9-
tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one of Formula
V.

c) purifying the 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-
pyrido[ 1,2-a]pyrimidin-4-one of Formula V,

d) condensing the product obtained in step (c) with 6-fluoro-3-piperidino-l,2-
benzisoxazol hydrochloride of Formula VI,

in the presence of organic base and a solvent to give Paliperidone of Formula I, and

e) optionally purifying the obtained Paliperidone of Formula I.

2. The process according to claim 1, step (a) is carried out by dissolving compound of Formula X in methanol and precipitating compound of Formula X by adding diisopropylether.

3. The process according to claim 1, step (b) is carried out in presence of catalyst selected from Palladium, Platinum and Raney Nickel in methanol solvent.

4. The process according to claim 1, wherein step (c) is carried out by dissolving compound of Formula V in mixture of acetone and cyclohexane and silica gel treatment.

5. The process according to claim 1, wherein step (d) is carried out in presence of organic base selected from triethylamine, diisopropylethylamine, diisopropylamine, tributylamine in a solvent selected from methanol, ethanol, isopropyl alcohol and mixture thereof.

6. The process according to claim 1, wherein 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one hydrochloride of Formula X is prepared by a process comprising:

a) reacting 2-amino-3 -hydroxy pyridine of Formula VIII

with 3-acetyl-4,5-dihydro-3H-2-furanone of Formula III

in the presence of an acid and a solvent to give 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one of Formula IX,

b) chlorinating 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyndo[l ,2-aJ-
pyrimidin-4-one of Formula IX with a chlorinating agent to give 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one hydrochloride of Formula X.

7. The process according to claim 6, wherein step (a) is carried out in presence of an acid selected from hydrochloric acid, sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid in a solvent selected from toluene, xylene, chlorobenzene and mixture thereof.

8. The process according to claim 6, wherein chlorinating agent is selected from thionyl chloride, phosphorous pentachloride, phosphorous oxychloride.

9. A process for the purification of Paliperidone of Formula I, comprising:

a) dissolving Paliperidone in a solvent selected from methanol, ethanol and mixture thereof in the presence of organic base selected from triethylamine, diethylamine, dimethylamine, diisopropylamine, N,N-diisopropylethylamine and mixtures thereof, and

b) isolating the highly pure Paliperidone of Formula I.

10. A process for the preparation of Paliperidone of Formula I substantially same as described herein.