WO2011073997A2

WO2011073997A2 - Process for preparing paliperidone and pharmaceutically acceptable salts thereof

Info

Publication number: WO2011073997A2
Application number: PCT/IN2010/000794
Authority: WO
Inventors: Shriprakash Dhar Dwivedi; Dhimant Jasubhai Patel; Rushikesh Udaykumar Roy; Mayur Ramnikbhai Patel
Original assignee: Cadila Healthcare Ltd
Current assignee: Zydus Lifesciences Ltd
Priority date: 2009-12-14
Filing date: 2010-12-08
Publication date: 2011-06-23
Anticipated expiration: 2012-06-14
Also published as: WO2011073997A3

Abstract

The present invention discloses the process for the preparation of paliperidone and its pharmaceutically acceptable salts comprising (a) condensing 2-amino-3-hydroxy- pyridine with 2-acetylbutyro lactone in the presence of an acid catalyst to isolate 9- hydroxy-3-(2-hydroxyethyl)-2-rnethyl-4H-pyrido[l, 2-a] pyrimidin-4-one; treating 9- hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l, 2-a] pyrimidin-4-one with a chlorinating agent; hydrogenating the product in the presence of one or more lewis acids to obtain 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one; and condensing3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2- methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one. The present invention also discloses processes for the preparation of intermediates useful in the preparation of paliperidone and its pharmaceutically acceptable salts.

Description

PROCESS FOR PREPARING PALIPERIDONE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

FIELD OF THE INVENTION:

The present invention relates to improved processes for the preparation of paliperidone and pharmaceutically acceptable salts thereof. The invention also relates to processes for the preparation of intermediates useful in the preparation of paliperidone and pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION:

Paliperidone is a 5-HT antagonist belonging to the chemical class of benzisoxazole derivatives and a racemic mixture having the structural Formula (I). Chemically, it is 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-l -piperidyl]ethyl]-7-hydroxy- 4-methyl-l,5-diazabicyclo[4.4.0]deca-3,5-dien-2-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. A process for the preparation of paliperidone is described in U.S. Patent No. 5, 158,952.

U.S. Patent No. 5,688,799 discloses a process for the synthesis of 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4- one.

U.S. Patent Publication No. 20070260061 discloses a process for preparing 9- hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one by reacting 2- amino-3-hydroxy pyridine with a slight excess of 2-acetyl-butyrolactone in an organic solvent such as 4-methyl-2-pentanol, a mixture of xylene and as 4-methyl-2-pentanol and chlorobenzene. The condensation reaction involves the use of alcoholic solvents for the work-up stage. Further, the application relates to . crystalline 9-hydroxy-3-(2- l hydroxyethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one having purity greater than 97% by weight and having less than 0.3% residual 2-acetylbutyrolcatone by weight.

U.S. Patent Publication No. 20080214809 provides a process for the preparation of 9-hydroxy-3-(2-chloroyethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one and 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l ,2-a]-pyrimidin-4- one. It discloses substantially isolated 9-hydroxy-3-(2-chloroyethyl)-2-methyl-4H- pyrido[l,2-a]pyrimidin-4-one containing less than about 26 ppm phosphorous.

PCT Publication No. WO 2008024415 discloses a process for the preparation of certain intermediates for the preparation of paliperidone. Further, it discloses two crystalline forms, viz. Form-I and Form-II of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9- hydroxy-2-methyl-4H-pyrrido[l ,2-a]-pyrimidin-4-one intermediate.

Organic Process Research and Development Vol. 9, No. 3, 2005, Pg 344-347 discloses a process for the preparation of crystalline 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one intermediate from hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2- a]pyrimidin-4-one by using Pd/C and methanol as the solvent for hydrogenation process. Finally, the hydrochloride salt of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9- hydroxy-2-methyl-4H-pyrrido[l ,2-a]-pyrimidin-4-one which is in residue form is converted into a crystalline form of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2- methyl-4H-pyrrido[l ,2-a]-pyrimidin-4-one by using potassium acetate as the base and water for crystallization.

U.S. Patent Publication No. 2008/0171876 Al discloses a process for obtaining pure paliperidone by purification from various solvents. The process involves dissolution or suspension of paliperidone containing impurity in a solvent and isolation of pure paliperidone.

PCT Publication No. WO 2009/010988 Al discloses a process for purification of paliperidone via formation of paliperidone hydrochloride salt, which is further converted to paliperidone by treatment with a base.

The processes described in the above patents/publications are lengthy, results in low yield and purity and are difficult to adopt for commercial scale production. Moreover, these processes use benzyl protected intermediate for the preparation of key intermediates of paliperidone. The processes also use mixture of organic solvents for the condensation of 2-amino-3 -hydroxy pyridine and 2-acetyl-butyrolactone. The processes disclosed in the literature use hazardous chemicals such as phosphorous oxychloride for the chlorination of the hydroxy intermediate.

SUMMARY OF THE INVENTION:

The present inventors have found that there is no need to use mixture of organic solvents for the condensation reaction between 2-amino-3-hydroxy pyridine and 2- acetyl-butyrolactone and use of hazardous chemicals such as phosphorous oxychloride for the chlorination of the hydroxy intermediate. The condensation reaction can be carried out in a single solvent system and using a safe reagent such as thionyl chloride for the chlorination.

Further, the inventors have also found that there is no need to use protected intermediates for the preparation of key intermediates and unprotected intermediates can be used without affecting the yield and purity. This significantly improves the process economics and commercial viability.

Accordingly, in one general aspect there is provided a process for the preparation of paliperidone. The process includes obtaining a solution or a suspension containing paliperidone; adding water and one or more halogenated solvents; separating the halogenated solvent layer containing paliperidone; additing a second solvent; optionally, removing the halogenated solvent; and isolating the paliperidone.

Embodiments of the process may include one or more of the following features. For example, the solution or suspension may be obtained by dissolving or suspending paliperidone in a suitable solvent. Alternatively, such a solution may be obtained directly from a reaction mixture in a process in which paliperidone is formed. The solvent containing paliperidone may be heated to obtain a solution. It can be heated from about 30 °C to about reflux temperature of the solvent used, for example from about 30 °C to about 100 °C.

The term "obtaining" includes dissolving, slurrying, stirring or a combination thereof.

The isolation may include filtration, filtration under vacuum, centrifugation, and decantation. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

The paliperidone obtained may be further purified by any process known in the art, which may optionally include crystallization and chromatographic purification. In another general aspect there is provided a process for the preparation of 9- hydrOxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of Formula (A),

(A) which is an intermediate in the preparation of paliperidone. The process includes reacting 2-amino-3-hydroxy pyridine and 2-acetyl-butyrolactone in the presence of a substituted or unsubstituted aromatic hydrocarbon solvent and an acid catalyst.

The process may produce a crystalline form of 9-hydroxy-3-(2-hydroxyethyl)- 2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (A).

In another general aspect there is provided a process for the preparation of 9- hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (B),

which is an intermediate in the preparation of paliperidone. The process includes chlorination of 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4- one in the presence of an organic solvent.

The process may produce a crystalline form of 9-hydroxyr3-(2-chloroethyl)-2- methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of Formula (B).

In another general aspect there is provided a process for the preparation of a hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyridb[l,2- a]pyrimidin-4-one, compound of Formula (C),

which is an intermediate in the preparation of paliperidone. The process includes reacting 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one in an organic solvent in the presence of an acid.

The process may produce a crystalline form of the hydrochloride salt of 9- hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (C).

In another general aspect, there is provided a process for the preparation of a crystalline form of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l ,2-a]-pyrimidin-4-one, compound of Formula (D),

which is a key intermediate in the preparation of paliperidone. The process includes hydrogenating the hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l,2-a]pyrimidin-4-one in an organic solvent with a suitable base. The process may produce a crystalline form of 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydfoxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one, compound of Formula (D).

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

BREIF DESCRIPTION OF THE DRAWINGS

FIGURE 1 is an X-ray powder diffraction pattern of crystalline 9-hydroxy-3-(2- hydroxyethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one.

FIGURE 2 is an X-ray powder diffraction pattern of crystalline 9-hydroxy-3-(2- chloroethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one.

FIGURE 3 is an X-ray powder diffraction pattern of crystalline hydrochloride salt of

9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one.

FIGURE 4 is an X-ray powder diffraction pattern of crystalline 3-(2-chloroethyl)-

6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one as per the reference example of Organic Process Research and Development Vol. 9, No. 3, 2005, Pg 344-347.

DETAILED DESCRIPTION OF THE INVENTION:

In one aspect there is provided a process for the preparation of paliperidone of Formula (I) or pharmaceutical acceptable salts thereof.

The process includes:

(i) condensing 2-amino-3- hydroxy-pyridine of Formula (II) with 2-acetylbutyro lactone of Formula (III) in a substituted or unsubstituted aromatic hydrocarbon solvent in the presence of an acid catalyst to isolate 9-hydroxy-3-(2-hydroxyethyl)-2-methyl- 4H-pyrido[l ,2-a] pyrimidin -4-one of Formula (A);

(A)

(ii) treating the 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin -4- one of Formula (A) with a chlorinating agent to obtain 9-hydroxy-3-(2-chloroethyl)-2- methyMH-pyrido[l ,2-a] pyrimidin -4-one hydrochloride of Formula (C);

(iii) hydrogenating the 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one of Formula (C) in the presence of one or more lewis acids to obtain 3- (2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4- one of Formula (D); and

(iv) condensing the 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l ,2-a]-pyrimidin-4-one of Formula (D) with 6-fluoro-3-(piperidinyl)-l ,2- benzisooxazole of Form

and isolating the paliperidone from reaction mass thereof.

In another aspect there is provided a process for the preparation of 9-hydroxy-3- (2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin -4-one of Formula (A). The process includes reacting 2-amino-3- hydroxy-pyridine of Formula (II) with 2- acetylbutyro lactone of Formula (III) in the presence of an acid catalyst in a substituted or unsubstituted aromatic hydrocarbon solvent.

In general, any acid catalyst which promotes the reaction can be used as a catalyst. For example, p-toluene sulfonic acid can be used as an acid catalyst. In general, the reaction can be carried out at ambient temperature to reflux temperature. For example, the reaction at step (i) may be carried out from about 100°C to about 160°C, for example at about 140- 145°C.

Examples of substituted or unsubstituted aromatic hydrocarbon solvents include toluene, xylene, chlorobenzene, ethyl benzene, 2,4-dichloro benzene, 4-chloro toluene and mixtures thereof.

Embodiments of the process may include one or more of the following features. For example, the 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin- 4-one of Formula (A) so obtained may be isolated using a suitable solvent. A suitable solvent include one or more of dimethylformamide, dimethylsulfoxde, dimethylacetamide, sulfolane, N-methyl pyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, C3-C6 ketones, or C3-C6 esters. In particular, dimethylformamide may be used for the isolation of compound (A).

In general, 2-amino-3- hydroxy-pyridine of Formula (II) may be reacted with 2- acetylbutyro lactone of Formula (III) in the presence of p-toluene sulfonic acid in xylene solvent at a reflux temperature. Dimethylformamide may be further added to the reaction mass and the compound (A) may be isolated by cooling and filtration.

The process may produce crystalline form of 9-hydroxy-3-(2-hydroxyethyl)-2- methyi-4H-pyrido[l,2-a]pyrimidin-4-one, compound of Formula (A). The crystalline form of 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of Formula (A) may be characterized by X-ray diffraction peaks at 9.7, 10.8, 13.2, 16.2, 18.5, 20.6, 21.9, 22.2, 23.6, 26.0, 27.2, 27.8, 28.2, 29.8 and 32.6 degree two-theta, ±0.2 two-theta.

In another aspect of the invention there is provided a process for the preparation of crystalline 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one hydrochloride compound of Formula (C). The process includes treating 9-hydroxy-3- (2-hydroxyethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin -4-one of Formula (A) with a chlorinating agent to obtain 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin -4-one hydrochloride of Formula (C)

Examples of the chlorinating agents which can be used include thionyl chloride, phosphorous pentachloride, phosphoryl chloride, phosphoryl bromide, phosphorous trichloride, and the like. In particular, thionyl chloride may be used as a chlorinating agent

The chlorination reaction may be carried out in the presence of one or more organic solvents. Examples of a suitable organic solvent for the reaction include toluene, xylene, dichloromethane, trichloromethane, dimethylformamide, dimethylsulfoxide, sulfolane, and n-methyl pyrrolidone.

The process may produce a crystalline form of hydrochloride salt of 9-hydroxy- 3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of Formula (C). The crystalline form of hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2- methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (C) may be characterized by X-ray diffraction peaks at 7.8, 13.3, 14.5, 16.6, 17.9, 19.4, 22.6, 23.4, 24.9, 25.8, 26.1, 26.7, 27.0, 28.4, 29.3, 30.1, 30.5, 32.6, 35.7, 37.2 and 38.1 degree two- theta, ±0.2 two-theta. In yet another aspect there is provided a process for the purification of 9-hydroxy-

3- (2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one hydrochloride of Formula (C). The process includes:

(i) obtaining a solution of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one hydrochloride in water or one or more organic solvents and treating with ethylenediaminetetraacetate;

(ii) basifying the solution to obtain 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l ,2-a] pyrimidin-4-one free base; and

(iii) treating the 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin-4- one free base with hydrochloric acid or hydrogen chloride gas in a suitable solvent to obtain pure 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one hydrochloride.

In general, 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin-

4- one hydrochloride of Formula (C) may be dissolved in water of one or more suitable organic solvents to obtain a solution. The solution may be treated with ethylenediaminetetraacetate. The solution may further be basified with one or more bases to obtain a free base of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin-4-one. Examples of bases which may be used include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethyl amine, and diisopropyl amine. In part^lar, sodium carbonate may be used as a base.

Embodiments of the process may include one or more of the following features. For example, the solution of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one hydrochloride in water may be treated with ethylenediaminetetraacetate and the solution may be filtered before treatment with a base. It may be further treated with sodium carbonate and the product may be isolated to provide 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (B).

The process may produce a crystalline form of 9-hydroxy-3-(2-chloroethyl)-2- methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (B). The crystalline form of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (B) may be characterized by X-ray diffraction peaks at 5.2, 10.4, 1 1.9, 13.0, 14.2, 14.9, 15.8, 18.1, 18.9, 19.6, 20.4, 20.8, 21.5, 22.1, 22.5, 23.6, 24.6, 25.0, 25.6, 26.1, 26.7, 27.6, 28.6, 29.9, 31.0, 32.7, 33.4, 35.9, 36.7 and 37.2 degree two-theta, ±0.2 two-theta.

The crystalline form of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2- a]pyrimidin-4-one, compound of Formula (B) may further be treated with hydrochloric acid in a suitable solvent or a solvent containing hydrogen chloride gas to obtain crystalline form of the hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l,2-a]pyrimidin-4-one, compound of Formula (C). Examples of the suitable solvents include one or more of Ci.₈ alcohols, C_3-7 esters, C_3-8 ethers, C_3-7 ketones, C6-i₂ aromatic hydrocarbons, acetonitrile, and water.

The crystalline form of hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2- methyl-4H-pyrido[l ,2-a]pyrimidin-4-one, compound of Formula (C) may be characterized by X-ray diffraction peaks at 7.8, 13.3, 14.5, 16.6, 17.9, 19.4, 22.6, 23.4, 24.9, 25.8, 26.1 , 26.7, 27.0, 28.4, 29.3, 30.1, 30.5, 32.6, 35.7, 37.2 and 38.1 degree two- theta, ±0.2 two-theta.

In another aspect of the invention there is provided a process for the preparation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one of Formula (D). The process includes:

(i) condensing 2-amino-3- hydroxy-pyridine of Formula (II) with 2-acetylbutyro lactone of Formula (III) to obtain 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H- pyrido[l,2-a] pyrimidin -4-one of Formula (A);

(ii) treating 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin -4-one of Formula (A) with a chlorinating agent to obtain 9-hydroxy-3-(2-chloroethyl)-2- methyl-4H-pyrido[l ,2-a] pyrimidin -4-one hydrochloride of Formula (C); and

(iii) hydrogenating 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin- 4-one hydrochloride of Formula (C) in the presence of a lewis acid to obtain 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4- one hydrochloride; and

(iv) converting 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l ,2-a]-pyrimidin-4-one hydrochloride to 3-(2-chloroethyl)-6,7,8,9-tetrahydro- 9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one of Formula (D).

In general, 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyI-4H- pyrrido[l ,2-a]-pyrimidin-4-one compound of Formula (D) may be obtained by hydrogenating the hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l,2-a]pyrimidin-4-one in an organic solvent in the presence of a lewis acid; adding a suitable base to reaction mass; and crystallizing with a suitable solvent and isolating the 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2- a]-pyrimidin-4-one.

The process may produce the crystalline form of 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l ,2-a]-pyrimidin-4-one compound of Formula (D).

Examples of a suitable hydrogenating agent may include Pd/C, Pt/C, mixture of Pd/C and ZnCl₂, and the like. The preferred hydrogenating agent is mixture of Pd/C and ZnCl₂.

Examples of Lewis acids include one or more of aluminum chloride, zinc chloride, ferric chloride, copper chloride, magnesium chloride.

A suitable organic solvent includes one or more of C1 -C5 alcohols. In particular, methanol may be used as an organic solvent.

Examples of a suitable base include one or more of potassium acetate, sodium acetate, liquid ammonia, etc. In particular, potassium acetate may be used as a base.

The term "suitable solvents" includes any solvent or solvent mixture in which paliperidone can be crystallized, including, for example, water, alcohols, ketones, and mixtures thereof. In particular, water may be used for crystallization.

In yet another aspect there is provided a process for the preparation of paliperidone or pharmaceutically acceptable salts thereof. The process includes:

(a) obtaining a solution or a suspension containing paliperidone;

(b) adding water and one or more halogenated solvents;

(c) separating the halogenated solvent layer containing paliperidone;

(d) adding a second solvent;

(e) optionally, removing the halogenated solvent; and

(f) isolating the paliperidone.

Embodiments of the process may include one or more of the following features. For example, the solution or suspension may be obtained by dissolving or suspending paliperidone in a suitable solvent. Alternatively, such a solution may be obtained directly from a reaction mixture in a process in which paliperidone is formed.

In general, 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]-pyrimidin-4-one may be reacted with 6-fluoro-3-(piperidinyl)-l ,2- benzisooxazole of Formula (F) in a first organic solvent in the presence of a base to obtain a reaction mass containing paliperidone. To the reaction mass, water and one or more halogenated solvents may be added and the halogenated solvent layer containing paliperidone may be separated. A second solvent may be added and halogenated solvent may be removed by distillation. The reaction mass may be cooled to crystallize paliperidone, filtered and isolated by conventional techniques.

Examples of the organic solvents include one or more of C]_-8 alcohols, C3-7 esters,

C_3- ethers, C3.7 ketones, C₆-i₂ aromatic hydrocarbons, acetonitrile, halogenated solvent, C_3-6 ketones, a mixture of a C₃-₆ ketone and water, N-methylpyrrolidone, C_3-6 amides, dimethylsulfoxide. In particular, methanol may be used as a solvent.

The reaction may preferably be carried out in the presence of a base in an organic solvent. The base which can be used in the condensation step may be selected from an inorganic base or an organic base The inorganic bases may include hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and lithium hydroxide; hydrides such as sodium hydride, potassium hydride, lithium hydride and calcium hydride; metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate; alkoxides such as tert-butoxide, isopropoxide, ethoxide, and methoxide. The organic bases may include triethyl amine, di-isopropyl amine, diisopropyl ethyl amine and the like. In particular, diisopropyl ethyl amine is used as a base.

The reaction can be carried out in the presence of a catalyst. Such catalyst can be potassium iodide, sodium iodide, phase transfer catalyst like quaternary ammonium salts like benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, tetraethylammonium bromide, didecyldimethylammonium chloride and domiphen bromide and the like. More particularly, potassium iodide is used as a catalyst.

Further, water and halogenated solvent are added to reaction mass containing paliperidone and extracted with a halogenated solvent. The halogenated solvent can be selected from methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform, chloro benzene etc. In particular, methylene dichloride is used.

Second solvent can be selected from C_3-6 ketones, a mixture of a C_3-6 ketone and water, N-methylpyrrolidone, C_3-6 amides, propylene glycol, dimethyl sulfoxide, dimethyl carbonate, C₁.4 alkyl alcohols, a mixture of a alkyl alcohol and water, acetonitrile, a mixture of acetonitrile and water, C_2-6 alkyl acetates, a mixture of a C₂.₆ alkyl acetate and water, cellosolve, dimethyl carbonate, polyethylene glycol methyl ether and C_2-8 ethers. Examples of C3-6 ketones include acetone, methyl ethyl ketone (MEK) and methyl iso-butyl ketone (MIBK). Examples of C_3-6 amides include dimethylacetamide and dimethylformamide. Examples of C_1-4 alkyl alcohols include methanol, ethanol, n- propanpl, isopropanol, n-butanol, isobutanol and 2-butanol. Examples of C_2-6 alkyl acetates include ethyl acetate, isopropyl acetate and isobutyl acetate. Examples of C_2-8 ethers include diethyl ether, methyl tet-butyl ether, dibutyl ether and polyethylene glycol (PGME). More particularly, a mixture of acetone and water is used as a solvent.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1: Preparation of crystalline 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H- pyrido[l ,2-a] pyrimidin -4-one, compound of Formula (A)

2-amino-3 -hydroxy pyridine (100 g, 0.90 mole) and xylene (1360 mL) were added to a four-neck two litre round bottom flask. The reaction mass was stirred for 5 mins. at about 25°C to 35°C. To the reaction mass, acetyl-butyro lactone (122.0 g, 0.95 mole) was added within 30 mins. at 25 °C to 35°C- Further, p-toluenesulfonic acid (5.2 g, 0.02 mole) was added and washed with xylene (162 mL). The reaction mass was heated at 140°C to 142°C and maintained for 20 hours. The reaction mass was cooled to 95°C to 100°C and dimethylformamide was added. Further, the reaction mass was cooled to 0°C to 5°C and washed with xylene to afford the title compound as crystalline 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin -4-one, compound of Formula (A) (HPLC Purity: 98.80%)

Example 2: Preparation of crystalline 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l ,2-a] pyrimidin -4-one, compound of Formula (B)

9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin -4-one (100 g, 0.45 mole) dichloromethane (100 mL) and dimethylformamide (1.6 g) were added to a four-neck two litre round bottom flask. Further, dichloromethane (300 mL) was added to the reaction mass at 25°C to 35°C and stirred for 30 mins. To the reaction mass, thionylchloride (92.0 g, 0.77 mole) was added within 1 hour and heated at 38°C to 43 °C and maintained for 20 hours. Further, dichloromethane was distilled out and again dichloromethane (400 mL) was added at 39°C to 45 °C and distilled out at atmospheric pressure at 38°C to 43°C. The reaction mass was degassed for 2 hours under vacuum below 60°C. The reaction mass was cooled to 35°C to 40°C and water (300 mL). To the reaction mass, HP-120 charcoal (10 g) was added and stirred for 1 hour at 35°C to 40°C. The reaction mass was filtered and washed with water (2 x 50 mL) and neutralized with ammonia to afford the tiltle compound as crystalline 9-, hydroxy-3-(2-chloroethyl)-2-rhethyl-4H-pyrido[l ,2-a] pyrimidin -4-one, compound of Formula (B).

Example 3: Preparation of crystalline 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l ,2-a] pyrimidin -4-one, compound of Formula (B) 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin -4-one

(100 g, 0.45 mole) toluene and dimethylformamide (1.6 g) were added to a four-neck two liter round bottom flask. Further, dichloromethane (300 ml) was added to the reaction mass at 25°C to 35°C and stirred for 30 mins. To the reaction mass, thionylchloride (92.0 g, 0.77 mole) was added within 1 hour and heated at 38°C to 43 °C and maintained for 20 hours. Further, the reaction mass was cooled to obtain 9- hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin-4-one hydrochloride salt. (HPLC purity: 97.02%).

9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin-4-one hydrochloride was added in 1000 ml water and 5gm of ethylenediaminetetracetate was added followed by the addition of HP-120 grade charcoal. The mass was filtered and treated with sodium carbonate solution to obtain 9-hydroxy-3-(2-chloroethyl)-2- methyl-4H-pyrido[l,2-a] pyrimidin-4-one. (HPLC purity: 99.7%)

Example 4: Preparation of crystalline hydrochloride salt of 9-hydroxy-3-(2- chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin -4-one, compound of Formula (C) 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin -4-one (100 g) and methanol (800 mL) were added and heated at 60°C to 65°C to get a clear solution and maintained for 30 mins. To the reaction mass, dry IPA/HC1 (95 g) was added to get a pH of 1 to 3. To the reaction mass, HP-120 charcoal (50 g) was added at 60°C to 65 °C and stirred for 1 hour. The reaction mass was filtered and washed with hot methanol (4 x 50 mL) at 60°C to 65°C. Further, the reaction mass was cooled to 0°C to 5°C and maintained for 2 hours. The reaction mass was filtered and washed with chilled methanol (2 x 25 mL) to afford the title compound as crystalline hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimi- din -4-one, compound of Formula (C). (HPLC Purity: 99.7%) Example 5: Preparation of crystalline 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy- 2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one compound of Formula (D)

Hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin -4-one (100 g, 0.36 mole) and methanol (1800 mL) was added at 25°C to 35°C. The reaction mass was heated at 35°C to 40°C to get a clear solution. Zinc chloride (10 g), 20% Pd/C (10%) (20 g) and methanol (200 mL) were added at 35°C to 40°C. The reaction mass was heated at 50°C to 55°C. To the reaction mass, hydrogen gas was purged for 6 to 12 hours at 50°C to 55°C. The reaction mass was cooled to 25°C to 35°C, filtered and washed with methanol (2 x 100 mL). The total methanol mother liquor obtained was treated with HP-120 charcoal (15 g) at 25°C to 35°C. The reaction mass was heated to 50°C to 55°C for 30 min. The reaction mass was filtered and washed with methanol (2 x 100 mL). Methanol was distilled out completely under vacuum below 65°C. The reaction mass was degassed for 2 hours under vacuum below 75°C. Water (365 mL) was added at 70°C to 75°C and stirred for 30 min. The reaction mass was cooled to 25°C to 35°C and potassium acetate solution (35.0 g potassium acetate + 375.0 ml water) was added within 1 to 1.5 hours and stirred for 30 min. Further, sodium carbonate solution (25.0 g sodium carbonate + 375.0 ml water) was added and stirred for 1 hour at 25°C to 35°C. The reaction mass was filtered and washed with water (2 x 50 mL) to afford the title compound as crystalline 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4- one compound of Formula (D) (HPLC purity 96.7%).

Example 6: Preparation of paliperidone

15.0 gm of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]-pyrimidin-4-one compound of Formula (D) and 15.0 gm of 6-fluoro-3- , (piperidinyl)-l ,2-benzisooxazole of Formula (E) were added in 150 ml of methanol. 16 gm of diisopropylethylamine was added to the reaction mass and heated to 50°C to 70°C till the completion of reaction. 120 ml of methylene dichloride and 75 ml of water was further added to the reaction mass and methylene dichloride layer containing paliperidone was separated. To the methylene dichloride layer, a mixture of acetone and water was added and stirred at room temperature. The methylene dichloride was removed from the reaction mass by distillation and the solution so obtained was cooled to 0 to 5°C to obtain crystalline paliperidone, which was isolated by filtration and dried till constant weight obtained.

Yield: 55%. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention

Claims

We Claim:

1. A process for the preparation of paliperidone of Formula (I) or pharmaceutical acceptable salts thereof, ,

(I)

the process comprising:

(i) condensing 2-amino-3- hydroxy-pyridine of Formula (II) with 2-acetylbutyro

10. lactone of Formula (III) in a substituted or unsubstituted aromatic hydrocarbon solvent in the presence of an acid catalyst to isolate 9-hydroxy-3-(2-hydroxyethyl)-2-methyl- 4H-pyrido[l ,2-a] pyrimidin -4-one of Formula (A);

(ii) treating the 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin -4- one of Formula (A) with a chlorinating agent to obtain 9-hydroxy-3-(2-chloroethyl)-2- methyl-4H-pyrido[l ,2-a] pyrimidin -4-one hydrochloride of Formula (C);

0

(iii) hydrogenating the 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one of Formula (C) in the presence of one or more lewis acids to obtain 3- (2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l ,2-a]-pyrimidin-4- one of Formula (D) ; and

(D)

(iv) condensing the 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l ,2-a]-pyrimidin-4-one of Formula (D) with 6-fluoro-3-(piperidinyl)-l,2- benzisooxazole of Formula

and isolating the paliperidone from reaction mass thereof. 2. The process as claimed in claim 1, wherein the lewis acid comprises one or more of aluminum chloride, zinc chloride, ferric chloride, copper chloride, or magnesium chloride.

3. The process as claimed 1, wherein the solvent comprises one or more of toluene, xylene, chlorobenzene, ethyl benzene, 2,4-dichloro benzene, 4-chloro toluene or^¬ mixtures thereof.

4. The process as claimed in claim 1 , wherein the catalyst is p-toluene sulfonic acid.

5. The process as claimed in claim 1, wherein the 9-hydroxy-3-(2-hydroxyethyl)-2- methyl-4H-pyrido[l,2-a] pyrimidin -4-one of Formula (A) is isolated using one or more solvents comprising dimethylformamide, dimethylsulfoxide, dimethylacetamide, sulfolane, N-methyl pyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, C3-C6 ketones, or C3-C₆ esters.

6. The process as claimed in claim 5, wherein the solvent is dimethylformamide or tetrahydrofuran.

7. The process as claimed in claim 1, wherein the chlorinating agent comprises one or more of oxaraly chloride, phosphorous oxychloride, phosphorus pentachloride, or thionyl chloride.

8. A process for the preparation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2- methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one of Formula (D), the process comprising hydrogenating 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin-4- one hydrochloride of Formula (C) in the presence of one or more lewis acids to obtain

3- (2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l ,2-a]-pyrimidin-

4- one of Formula (D).

(D) (C)

9. The process as claimed in claim 8, wherein the lewis acid comprises one or more of aluminum chloride, zinc chloride, ferric chloride, copper chloride, or magnesium chloride.

10. A process for the preparation of pure 9-hydroxy-3-(2-hydroxyethyl)-2-rnethyl-4H- pyrido[l ,2-a] pyrimidin -4-one of Formula (A) having purity more than 98% by HPLC, the process comprising:

(i) condensing 2-amino-3- hydroxy-pyridine of Formula (II) with 2-acetylbutyro lactone of Formula (III) in the presence of an acid catalyst in a substituted or unsubstituted aromatic hydrocarbon solvent to obtain 9-hydroxy-3-(2-hydroxyethyl)-2- methyl-4H-pyrido[l ,2-a] pyrimidin -4-one of Formula (A); and

(Π) (III)

(ii) isolating the 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l ,2-a] pyrimidin-4-one of Formula (A) by using one or more solvents comprising dimethylformamide, dimethylsulfoxde, dimethylacetamide, sulfolane, N-methyl pyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, C3-C6 ketones, or C₃-C₆ esters. 1 1. A process for the purification of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[l ,2-a] pyrimidin-4-one hydrochloride, the process comprising:

(i) obtaining a solution of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l ,2- a] pyrimidin-4-one hydrochloride in water or one or more organic solvents and treating with ethylenediaminetetraacetate;

(iii) treating the 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one free base with hydrochloric acid or hydrogen chloride gas in a suitable solvent to obtain pure 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one hydrochloride.

12. A process for the preparation of paliperidone or pharmaceutically acceptable salts thereof, the process comprising:

(a) obtaining a solution or a suspension containing paliperidone;

(b) adding water and one or more halogenated solvents;

(c) separating the halogenated solvent layer containing paliperidone;

(d) adding a second solvent;

(e.) optionally, removing the halogenated solvent; and

(f) isolating the paliperidone.

13. The process as claimed in claim 12, wherein the halogenated solvent comprises one or more of methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform, or chlorobenzene.

14. The process as claimed in claim 12, wherein the second solvent comprises one or more of C_3-6 ketones, a mixture of a C_3-6 ketone and water, N-methylpyrrolidone, C_3-6 amides, propylene glycol, dimethylsulfoxide, dimethyl carbonate, C1-4 alkyl alcohols, a mixture of a Ci_-4 alkyl alcohol and water, acetonitrile, a mixture of acetonitrile and water, C_2-6 alkyl acetates, a mixture of a C_2-6 alkyl acetate and water, cellosolve, polyethylene glycol methyl ether and C_2-8 ethers.

15. A crystalline form of 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[l ,2- a]pyrimidin-4-one of Formula (A) characterized by X-ray diffraction peaks at 9.7, 10.8,

13.2, 16.2, 18.5, 20.6, 21.9, 22.2, 23.6, 26.0, 27.2, 27.8, 28.2, 29.8 and 32.6 degrees two-theta ±0.2 degrees two-theta.

16. A crystalline form of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[l,2- a]pyfimidin-4-one of Formula (B) characterized by X-ray diffraction peaks at 5.2, 10.4, 1 1 .9, 13.0, 14.2, 14.9, 15.8, 18.1 , 18.9, 19.6, 20.4, 20.8, 21.5, 22.1, 22.5, 23.6, 24.6, 25.0, 25.6, 26.1 , 26.7, 27.6, 28.6, 29.9, 31.0, 32.7, 33.4, 35.9, 36.7 and 37.2 degree two-theta ±0.2 degrees two-theta.

17. A crystalline form of hydrochloride salt of 9-hydroxy-3-(2-chloroethyl)-2-methyl- 4H-pyrido[l ,2-a]pyrimidin-4-one of Formula (C) characterized by X-ray diffraction peaks at 7.8, 13.3, 14.5, 16.6, 17.9, 19.4, 22.6, 23.4, 24.9, 25.8, 26.1 , 26.7, 27.0, 28.4,

29.3, 30.1, 30.5, 32.6, 35.7, 37.2 and 38.1 degrees two-theta ±0.2 degrees two-theta.