WO2007093870A2

WO2007093870A2 - A process for the preparation of risperidone

Info

Publication number: WO2007093870A2
Application number: PCT/IB2007/000289
Authority: WO
Inventors: Venkata Sasidhar Balla; Sampathkumar Upparapalli; Loganathan Veluppillai; Lakshmi Sivalingam; Mahender Rao Siripragada
Original assignee: Orchid Chemicals & Pharmaceuticals Limited
Priority date: 2006-02-15
Filing date: 2007-02-08
Publication date: 2007-08-23
Also published as: WO2007093870A3

Abstract

The present invention relates to an improved process for the preparation of Risperidone of formula (I) by condensing 6-fluoro-3- (4-piperidinyl)-l, 2- benzisoxazole with 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one in water and water immiscible solvents under basic conditions in the presence of a catalyst. This invention also relates to a method for purification of crude Risperidone by removing an impurity specifically named as 9-hydroxy Risperidone to undetectable level using acid chlorides and an organic base in a suitable solvent.

Description

A PROCESS FOR THE PREPARATION OF RISPERIDONE

Field of the Invention

The present invention relates to an improved process for the preparation of

Risperidone of formula (I) by condensing 6-fluoro-3- (4-piperidinyl)-l, 2- benzisoxazole with 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one in water and water immiscible solvents under basic conditions in the presence of a catalyst. This invention also relates to a method for purification of crude Risperidone by removing an impurity specifically named as 9-hydroxy Risperidone to undetectable level using acid chlorides and an organic base in a suitable solvent.

(I)

Background of the Invention

Risperidone, which is chemically known as 3-[2-[4-(6-fluoro-l,2-benzisoxazol- 3-yl) piperidin-l-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a] pyrimidin-4- one having following structural formula is useful as an anti-psychotic agent and it is marketed as Risperdal ® by Johnson & Johnson.

(I)

U.S. Pat. No. 4,804,663 (Janssen Pharmaceutica) is an innovator patent and describes a synthesis of Risperidone, which may be prepared by condensation of the following two intermediates, 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole (Compound A) and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4- one monohydrochloride (Compound II) in dimethylformamide (DMF) in basic conditions (Na₂CO₃ or K₂CO₃) with catalytic amount of potassium iodide (KI). The crude Risperidone was crystallized using a mixture of dimethylformamide and isopropanol to get pure Risperidone with an overall yield of 46 %.

(A) (H) (I)

PCT application WO 2004 / 009591 (Aurobindo Pharma Ltd.) claims the process for the preparation of Risperidone, which comprises reacting 3-(2-chloroethyl)- 6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[l,2-a] pyrimidin-4-one monohydrochloride (II) with 4-(2,4-difluorobenzoyl) piperidine oxime (III) to form the compound (IV) and insitu cyclisation of (IV) to form Risperidone (I) in a solvent selected from the group consisting of acetonitrile, N,N-dimetylformamide, methyl isobutyl ketone in a base such as anhydrous powdered potassium carbonate or sodium carbonate in presence of potassium iodide as catalyst at the temperature in the range of 75° C to 110° C.

PCT application WO 2005 / 030772 (Jubilant Organosys Ltd.) claims the process for the preparation of Risperidone of formula (I) by condensing the 6-fluoro-3- (4-piperidinyl)-l,2-benzisoxazole monohydrochloride of formula (B) with 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2,a]pyrimidin-4-one monohydrochloride of formula (II). The condensation reaction was carried out in the presence of a base (condensing agent) in a solvent medium of water, one or more water-miscible solvents or a mixture of water and one or more water-miscible solvents. The reaction sequence is as follows:

This PCT application also mention that the sequence of addition of the reactants and reagent is very important in the condensation step, according to this application the base (condensing agent) was dissolved or suspended in a solvent medium, and the hydrochloride salt of the compound of Formula (II) was added. The hydrochloride salt of the compound of Formula (B) was dissolved in a solvent medium as described above and added to the reaction mixture.

Most of the prior art processes are suffering from many disadvantages like involving multiple operations, recovery stages and poor quality. Moreover, the product obtained by these processes is suffering from many impurities. Among the impurities, 9-hydroxyrisperidone impurity is very common and difficult to remove. The 9- hydroxyrisperidone is generically known as Paliperidone, which is claimed in U. S. Patent No. 5,158,952 and has following structural formula:

According to the Drug Metabolism and Disposition (2001), 29 (10), 1263-1268, Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of Risperidone to 9-hydroxyrisperidone by the enzyme CYP2D6.

With reference to the above-discussed procedures none of the prior art references disclosed or claimed the use of water and water immiscible solvent mixture as biphasic solvent system in the condensation reaction of preparation of compound of formula (I). In the purification of the compound of formula (I), acid chlorides such as benzoyl chloride and an organic base such as triethylamine in a suitable solvent are used to eliminate the impurity 9-hydroxy Risperidone to undetectable level. We focused our research to develop an improved and efficient process for the preparation of the compound of formula (I) in substantially good yield and high chemical purity.

Objectives of the Invention

The main objective of the present invention is to provide a method for the preparation of compound of formula (I) in good yield and high chemical purity in particular free from 9-hydroxy Risperidone.

Another objective of the present invention is to provide a process for the preparation of compound of formula (I), which would be easy to implement on commercial scale and economically viable.

Summary of the Invention

Accordingly, the present invention provides a process for the preparation of

Risperidone of formula (I) comprising the steps of;

(I) (1) preparing the 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one base of formula (IV) from 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro- 2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride of formula (II) in a solvent mixture of water and water immiscible solvent in presence of an inorganic base and catalytic amount of potassium iodide;

<^IV> (II)

(2) preparing the 6-fluoro-3-(4-piperidinyl)-l , 2-benzisoxazole base of formula (V) from 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazoIe monohydrochloride of formula

(III) in a solvent mixture of water and water immiscible solvent using an inorganic base;

(V) (III)

(3) preparing the crude Risperidone by condensing 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole base of formula (V) with 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2- methyl-4H-pyrido [1,2-a] pyrimidin-4-one base of formula (IV) in water and water immiscible biphasic solvent mixture using an inorganic base and catalytic amount of potassium iodide;

(4) isolating the crude Risperidone;

(5) treating crude Risperidone with acid chloride in the presence of an organic base using water miscible solvent;

(6) isolating the Risperidone of formula (I); (7) optionally purifying Risperidone using water miscible solvents. The process is shown in the scheme given below:

(II) (IH)

NaOH / MIBK / Water

Na₂CO₃

KI ■ Aqueous layer

Water / MIBK

(IV) in (V) in MIBK layer

MIBK / Water / KI / Na₂CO₃

Description of the Invention

In an embodiment of the present invention, wherein water immiscible solvent is selected from the group comprising of methyl ethyl ketone, methyl propyl ketone, methyl isopropyl ketone, methyl vinyl ketone, methyl isobutyl ketone and the like; most preferably methyl isobutyl ketone.

In another embodiment of the present invention, wherein inorganic base is alkali carbonate or alkali hydroxide. Alkali carbonate is selected from the group comprising of sodium carbonate, potassium carbonate and the like, most preferably sodium carbonate and Alkali hydroxide is selected from the group comprising of sodium hydroxide, potassium hydroxide and the like, most preferably sodium hydroxide.

In another embodiment of the present invention, wherein water miscible solvent is selected from the group comprising of methanol, ethanol, propanol, isopropanol, acetone, acetonitirle, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide and mixtures thereof.

In another embodiment of the present invention wherein, the said preparation is carried out at temperature in the range of 10⁰C to the reflux temperature, more preferably the steps (1) & (2) are performed at a temperature in the range of 20 to 40⁰C and steps (3), (5) & (7) are carried out at a temperature in the range of 60 to 90⁰C.

In another embodiment of the present invention, wherein organic base is selected from the group comprising of triethylamine, diethylamine, pyridine, N,N-diethyl methylamine, N,N-diethyl aniline, N,N-diethylethylenediamine, N,N- diisopropylethylamine, dimethylaminopyridine, diisopropylethylamine, N- methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4-methylpyridine, most preferably triethylamine.

In another embodiment of the present invention, wherein acid chloride is selected from group comprising of acetyl chloride, benzoyl chloride, pivolyl chloride and the like, most preferably benzoyl chloride.

The starting material of this invention is prepared according to the literature available in the prior art.

The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.

Example 1: Preparation of Risperidone

Water (300 mL), methyl isobutyl ketone (400 mL) and 6-fluoro-3-(4- piperidinyl)-l, 2-benzisoxazole monohydrochloride (97.5 g) were taken in a reaction vessel and NaOH solution (30.40 g in 300 mL water) was slowly added, stirred the reaction mass for 5 to 10 min. the organic layer separated and washed with water (150 mL). Water (300 mL), methyl isobutyl ketone (200 mL) were taken in another reaction vessel and 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride (100 g) and KI (5.0 g) were added to the reaction vessel. Sodium carbonate (100.70 g) was slowly added to the reaction mass and then methyl isobutyl ketone layer of 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole base was added to the reaction mass and then the contents were heated up to 85 to 90⁰C and maintained up to 8 hrs. Cooled the reaction mass to room temperature and stirred at room temperature for 4 hrs. Water (300 mL) was added and stirred for 10 min., filtered the solid and washed with water (200 mL) followed by methyl isobutyl ketone (200 mL) to get the Crude Risperidone, which was taken in another reaction vessel and isopropyl alcohol (1800 mL) was added and the solution was heated to 70 to 8O⁰C to get a clear solution. Carbon (10 g) was added to the solution and stirred for 20 to30 min., filtered the carbon through highflo. washed the bed with isopropyl alcohol (300 mL) and distilled the filtrate up to residual volume 7 times the 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyriniidin-4-one monohydrochloride quantity. Heated the suspension to 70 to 8O⁰C to get the clear solution and dimethylformamide (70 mL) was added. Cooled the reaction mass to room temperature' and stirred at room temperature for 3 to 6 hrs., filtered the solid, washed with isopropyl alcohol (100 mL) and dried the solid at 60 to70°C for 2 hrs. Micronized the material and dried at 80 to 85⁰C for 12 hrs to get Risperidone. (80 g) having HPLC Purity more than 99.70 %.

Example 2: Purification of Risperidone Risperidone crude (20 g) and N,N-dimethylformamide (160 mL) followed by triethylamine (1.48 gm) were added in a reaction vessel and were heated to 60 ⁰C to 65⁰C to get a clear solution to which benzoyl chloride (1.37 g) was added. The reaction mixture was stirred at the same temperature for 1 hr and then to room temperature to obtain the solid material, which was stirred for 3 hrs at 10⁰C to 15⁰C, filtered and washed with isopropyl alcohol to get solid which is dried at 60⁰C to 65°C for 6 hrs to get highly pure Risperidone having HPLC purity more than 99.70%.

Example 3: Preparation of Risperidone Water (300 mL), methyl isobutyf ketone (400 mL) and 6-fluoro-3-(4- piperidinyl)-l, 2-benzisoxazole monohydrochloride (97.5 g) were taken in a reaction vessel and NaOH solution (30.40 g in 300 mL water) was slowly added, stirred the reaction mass for 5 to 10 min., the organic layer was separated and washed with water (150 mL). Water (300 mL), methyl isobutyl ketone (200 mL) were taken in another reaction vessel and 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride (100 g), potassium iodide (5.0 g) were added to the reaction vessel. Sodium carbonate (100.70 g) slowly added in to the reaction mass and then methyl isobutyl ketone layer of 6-fluoro-3-(4-piρeridinyl)-l, 2-benzisoxazole base was added to the reaction mass and then heated the contents up to 85 to 90⁰C and maintained up to 8 hrs. Cooled the reaction mass to room temperature and stirred at room temperature for 4 hrs. Water (300 mL) was added and stirred for 10 min. filtered the solid and washed with water (200 mL) followed by methyl isobutyl ketone (200 mL) to get the solid which is dried at 60 to70°C under vacuum for 2 hrs to get crude Risperidone 80g.

Example 4; Purification of Risperidone:

Risperidone crude (20 g) and N,N-dimethylformamide (16OmL) followed by triethylamine (1.48 g) were added in a reaction vessel and were heated to 60 ⁰C to 65⁰C to get a clear solution to which benzoyl chloride (1.37 g) was added. The reaction mixture was stirred at the same temperature for 1 hr and then to room temperature to obtain the solid material, which was stirred for 3 hrs at 10-15⁰C, filtered and washed with isopropyl alcohol to get crude Risperidone which is taken in another reaction vessel and isopropyl alcohol (120 mL) and N,N-dimethylformamide (3.2 mL) added and heated the solution to 70 to 80⁰C to get a clear solution. Carbon (2 g) was added to the solution and stirred for 20 to30 min., filtered the carbon through highflo, washed the bed with isopropyl alcohol (40 mL) and heated the suspension to 70 to 80⁰C to get the clear solution. Cooled the reaction mass to 10 to 15⁰C and stirred for 3 hrs., filtered the solid, washed with isopropyl alcohol (40 mL) and dried the solid at 60 to70°C for 2 hrs. Micronized the material and dried at 80 to 85°C for 12 hrs to get Risperidone. (13.5 g) having HPLC Purity more than 99.70 %.

Claims

We claim:

(I) A process for the preparation of Risperidone of formula (I), comprising the steps of;

(I)

(a) preparing the 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one base of formula (IV) from 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro- 2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride of formula (II) in a solvent mixture of water and water immiscible solvent in presence of an inorganic base and catalytic amount of potassium iodide;

(IV) (II)

(b) preparing the 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole base of formula (V) from 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazoIe monohydrochloride of formula (III) in a solvent mixture of water and water immiscible solvent using an inorganic base;

(c) preparing the crude Risperidone by condensing 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole base of formula (V) with 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2- methyl-4H-pyrido [1,2-a] pyrimidin-4-one base of formula (IV) in water and water immiscible biphasic solvent mixture using an inorganic base and catalytic amount of potassium iodide; (d) isolating the crude Risperidone;

(e) treating crude Risperidone with acid chloride in the presence of an organic base using water miscible solvent;

(f) isolating the Risperidone of formula (I), and (g) optionally purifying Risperidone using water miscible solvents.

(2) A process as claimed in claim I₉ wherein water immiscible solvent is selected from the group comprising of methyl ethyl ketone, methyl propyl ketone, methyl isopropyl ketone, methyl vinyl ketone, methyl isobutyl ketone and the like, most preferably methyl isobutyl ketone.

(3) A process as claimed in claim 1, wherein the inorganic base is alkali carbonate or alkali hydroxide.

(4) A process as claimed in claim 3, wherein the alkali carbonate is selected from the group comprising of sodium carbonate, potassium carbonate and the like, most preferably sodium carbonate.

(5) A process as claimed in claim 3, wherein the alkali hydroxide is selected from the group comprising of sodium hydroxide, potassium hydroxide and the like, most preferably sodium hydroxide.

(6) A process as claimed in claim I₉ wherein water miscible solvent is selected from the group comprising of methanol, ethanol, propanol, isopropanol, acetone, acetonitirle, N,N-dimethyl formamide, dimethyl sulfoxide, N,N-dimethylformamide, dimethylacetamide and mixtures thereof.

(7) A process as claimed in claim I₉ wherein the said preparation is carried out at temperature in the range of 10⁰C to the reflux temperature.

(8) A process as claimed in claim 1, wherein the steps (a) & (b) are performed at a temperature in the range of 20 to 44O⁰C and steps (c), (e) & (g) are carried out at a temperature in the range of 60 to 90⁰C .

(9) A process as claimed in claim 1, wherein the said acid chloride is selected from group comprising of acetyl chloride, benzoyl chloride, pivolyl chloride and the like, most preferably benzoyl chloride.

(10) A process as claimed in claim 1, wherein the organic base is selected from the group comprising of triethylamine, N,N-diethyl methylamine, N,N-diethyl aniline, N,N-diethylethylenediamine, N,N-diisopropylethylamine, dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4- methylpyridine, pyridine, diethylamine, most preferably triethyl amine.