FORM 2 THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION [See section 10, rule 13]
AN IMPROVED PROCESS FOR THE PREPARATION OF PALIPERIDONE PALMITATE
PIRAMAL ENTERPRISES LIMITED, a company incorporated under the Companies Act, 1956, of Piramal Tower, Ganpatrao Kadam Marg, Lower Parel, Mumbai - 400 013, State of Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 3-(2-(4-(6-fluorobenzo[d]isoxazoI-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl palmitate; commonly known as paliperidone palmitate (referred to as the compound (I)) containing dimer compound (referred to as 'PP-Dimer') as impurity less than 0.15%.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.
Paliperidone palmitate (the Compound (I)), is an atypical antipsychotic agent indicated for the
acute and maintenance treatment of schizophrenia in adults and marketed under the brand name
as INVEGA SUSTENNA® The compound is chemically known as 3-(2-(4-(6-
fluorobenzo[d]isoxazol-3-yl) piperidm-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-
pyrido[1,2-a]pyrimidin-9-yl palmitate, and is structurally represented as follows;

Paliperidone palmitate being an important antipsychotic agent; a number of processes for its preparation as well as for its intermediates are known in the art.

US patent No. 5,254,556 refers to the 3-piperidinyl-l,2-benzisoxazole compounds, wherein
generically as well as with analogous compounds, it describes a process for the synthesis of
Paliperidone comprising reaction of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-
4H-pyrido[l,2-a]pyrimidin-4-one with 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole
monohydrochloride in the presence of a base. The process further refers purification using column chromatography which subsequently results in low yield.
Published PCT application WO2008/021345 A2 and WO2008/024415 A2 describes a process
for the preparation of paliperidone consisting of reacting 3-(2-chloroethyl)-9-hydroxy-2-methyl-
6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one with 6-fluoro-3-(piperidin-4-
yl)benzo[d]isoxazole in the presence of sodium carbonate and potassium iodide in N,N-dimethylmethanamide (DMF) solvent to provide paliperidone in a purity of >90% and with 58% yield.
Also, published PCT application WO2009/016653 Al describes a process for the preparation of
paliperidone comprising of reacting 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-
4H-pyrido[l,2-a]pyrimidin-4-one with 6-fluoro-3-(piperidin-4-yI)benzo[d]isoxazole
monohydro chloride in the presence of potassium carbonate and potassium iodide in DMF solvent to provide crude paliperidone; which on further crystallization provides a pure product.
The published US patent application 2009/0209757A1 disclosed a process for preparing paliperidone palmitate containing less than 0.1% by HPLC of palmitic acid comprising firstly crystallization of palmitic acid from suitable solvent and subsequently purifying paliperidone palmitate.
Published PCT application WO2011/074017A1 refers to a process for the preparation of paliperidone comprising hydrolysis of 9-O-acylated Paliperidone.
In addition, to the afore discussed patent documents, there are a number of patent documents that describe a process for the preparation of Paliperidone and paliperidone palmitate (I). For instance, Published PCT application WO2010/082110A2, WO2013/080220 A2, WO

2013/046225 A2, published US patent application 2010/0311969A1, WO2012/035554A1 and published US patent application 2014/0200228A1 describe a process for the preparation of paliperidone and paliperidone palmitate.
It is evident from the discussion of the processes for the preparation of Paliperidone (IA) and paliperidone palmitate (I) described in the afore cited patent documents that the reported processes provide a product with low yield and purity, which requires purification by column chromatography or multiple crystallization steps. The prior art process also refers the use of various reagents and coupling agents which renders the process costlier and hence are not industrially feasible. In view of these drawbacks, there is a need to develop an industrially viable commercial process for the preparation of Paliperidone palmitate; which is a simple, efficient and cost-effective process and provides the desired compounds in improved yield and purity.
Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present invention does not involve use of any toxic and/or costly solvents, also does not involve use of costlier coupling agents and reagents. Moreover, the process does not require repetitive purification steps and column chromatography. Accordingly, the present invention provides a process for the preparation of Paliperidone palmitate, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to an improved process for the preparation of paliperidone palmitate (the compound (I)), comprising reacting the compound (II) (as described herein) with the compound (HI) (as described herein) in a mixture of organic solvents, a base and iodate salt to obtain paliperidone (IA); and converting it to paliperidone palmitate (I).
In another aspect, the present invention provides paliperidone palmitate containing less than about 0.15% by HPLC of the compound 'PP-Dimer' [3-(2-(4-(6-(4-(6-fluorobenzo[d]isoxazol-3-

yl)piperidin-l-yl)benzo[d]isoxazol-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl palmitate].
In another aspect, the present invention provides a novel compound 3-(2-(4-(6-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-l-yl)benzo[d]isoxazol-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl palmitate (the compound 'PP-Dimer').
In yet another aspect, the present invention relates to an improved process for the preparation of paliperidone palmitate (the compound (I)) containing less than about 0.15% by HPLC of the compound 'PP-Dimer1, comprising reacting the compound (II) (as described herein) with the compound (HI) (as described herein) in a mixture of organic solvents, a base and iodate salt to obtain paliperidone (IA); and converting it to paliperidone palmitate (I).
According to another aspect of the present invention, there is provided a process for the
preparation of compound 'PP-Dimer', comprising the steps of;
(i) treating the compound (III) with a base to obtain compound (Q),
(ii) reacting the compound (Q) with compound (II) in the presence of a base and a solvent or
mixture of solvents to obtain compound (M),
(iii) reacting the compound (M) with palmitic acid.
According to another aspect of the present invention, there is provided an improved process for the preparation of Paliperidone (IA), comprising reacting the compound (H) (as described herein) with the compound (HI) (as described herein) in a mixture of organic solvents, a base and iodate salt.
According to another aspect of the present invention, there is provided an improved process for the preparation of Paliperidone (IA), wherein the said compound (IA) is obtained in a yield of about 85% and purity of more than about 98% (HPLC).

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of paliperidone palmitate (the compound (I)) represented by the following formula,

comprising; reacting 3-(2-haloethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l ,2-a]pyrimidin-4-one (the compound (II)) represented by the following formula;

with 6-fluoro~3-(piperidin-4-yl)benzo[d]isoxazole (the compound (HI)) represented by the following formula;

in a mixture of organic solvents, a base and iodate salt to obtain paliperidone (IA); and optionally, converting it to paliperidone palmitate (I).
Accordingly, there is provided an improved process for the preparation of Paliperidone palmitate

(I) containing less than about 0.15% by HPLC of the compound 'PP-Dimer'; comprising the steps of:
(a) preparation of Paliperidone (the compound (IA)) represented by the following formula;

by reacting the compound (II) represented by the following formula;

with the compound (HI) represented by the following formula;

in a mixture of organic solvents, a base and iodate salt;
(b) converting the compound (IA) into Paliperidone palmitate (I).
In the context of the present invention, the term "optionally" when used in reference to any element; including a process step e.g. conversion of a compound; it is intended to mean that the subject element is subsequently converted, or alternatively, is not converted to a further compound. Both alternatives are intended to be within the scope of the present invention.

In the context of the present invention, the term "a mixture of organic solvents" means that the mixture of organic solvents consists of at least two solvents, or more solvents. All alternatives are intended to be within the scope of the present invention.
Accordingly, in an embodiment the present invention relates to a process for the preparation of Paliperidone palmitate (I) containing less than about 0.15% by HPLC of the compound 'PP-Dimer' represented by the following formula,

comprising the steps of;
(a) reacting the compound (IT) represented by the following formula;

with the compound (HI) represented by the following formula;

in the presence of a mixture of organic solvents consisting of an amide solvent and an ketone

solvent; a base and alkali metal iodide to obtain the paliperidone compound (IA); (b) reacting the paliperidone (IA) with Palmitic acid.
In an embodiment, the amide solvent contained in the mixture of organic solvents is selected from the group consisting of N,N-Dimethylmethanamide (DMF), N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethyIacetamide, N,N-dimethylpropionamide, N,N-dimethylbutyramide, N-methylpyrrolidone and N-ethylpyrrolidone; or a mixture thereof
In an embodiment, the amide solvent is N,N-Dimethylmethanamide (DMF).
In an embodiment, the ketone solvent contained in the mixture of organic solvents is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, diisoproyl ketone, methyJisopropyl ketone, methylphenyl ketone; or a mixture thereof
In an embodiment, the ketone solvent is acetone.
In an embodiment, the mixture of organic solvents consists of DMF and Acetone.
In an embodiment, the mixture of organic solvents comprises of an amide solvent and a ketone solvent in a ratio ranging from 1:1 to 10:10 as v/v (volume/volume). Preferably, the ratio of the amide solvent to the ketone solvent ranges from 1:1 to 10:5 as v/v (volume/volume).
In the context of the present invention, the term "ratio" when used with respect to any element e.g. solvent, it is intended to mean that the subject element consists of v/v (volume/volume) ratio ranging from 1:1 to 10:10 of the amide solvent to ketone solvent. All the possible permutation and combination alternatives of v/v ratio are intended to be within the scope of the present invention.
In an embodiment, the base is an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide.
In an embodiment, the inorganic base is sodium carbonate.

In an embodiment, the base is an organic base selected from the group consisting of triethylamine, tripropylamine, pyridine, quinolone, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, dimethylaminopyridine, dibutyl amine, tributyl amine and diisopropylamine.
In a specific embodiment, the process for the preparation of Paliperidone palmitate (I) containing less than about 0.15% by HPLC of the compound 'PP-Dimer' comprises the steps of;
(1) dissolving the compound (II) in an amide solvent;
(2) adding the compound (HI) to the reaction mixture of step (1);
(3) adding a base and a iodate salt to the reaction mixture of step (2);
(4) adding a ketone solvent to the reaction mixture of step (3) at temperature of about 30 °C;
(5) stirring the reaction mixture of the above step (4) at reflux temperature;
(6) cooling the reaction mixture of the above step (5) at temperature of about 5 °C;
(7) isolating the precipitated product (the compound (IA)) obtained in the step (6);
(8) dissolving the compound (IA) of the above step (7) in a solvent;
(9) adding palmitic acid and a base to the reaction mixture of step (8);
(10) isolating the product Paliperidone Palmitate (I).

The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme-I,

The amide solvent used in the step-(l) of the above process (as depicted in the Scheme-I) is selected from the group consisting of N,N-Dimethylmethanamide (DMF), N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethyIacetamide, N,N-dimethylpropionamide, N,N-dimethylbutyramide, N-methylpyrrolidone and N-ethylpyrrolidone; or a mixture thereof
In an embodiment, the amide solvent used in step-(l) of the above process (as depicted in the Scheme-I) is N,N-Dimethylmethanamide (DMF).
In an embodiment, the base used in the step-(3) of the above process (as depicted in the Scheme-I) is selected from an inorganic base or organic base.
The inorganic base used in the step-(3) of the above process (as depicted in the Scheme-I) is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide.
In an embodiment, the base used in the step (3) is sodium carbonate.
Alternatively, the organic base used in the step-(3) of the above process (as depicted in the Scheme-I) is selected from the group consisting of triethylamine, tripropylamine, pyridine, quinolone, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, dimethyl am inopyrid in e, dibutyl amine, tributyl amine and diisopropylamine.
The iodate salt used in the step-(3) of the above process (as depicted in the Scheme-I) is an alkali

metal iodide such as potassium iodide, sodium iodide.
The ketone solvent used in the step-(4) of the above process (as depicted in the Scheme-I) is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, diisoproyl ketone, methylisopropyl ketone, methylphenyl ketone; or a mixture thereof
In an embodiment, the ketone solvent used in step-(4) of the above process (as depicted in the Scheme-I) is acetone.
In an embodiment, the quantity of ketone solvent added in step (4) of the above process (as depicted in the Scheme -I) is in the v/v ratio with respect to amide solvent ranging from 1:1 to 10:10 as v/v (volume/volume).
The term 'temperature of about 30 °C referred to in the step (4) of the above process (as depicted in the Scheme-I) can range from 25 °C to 35 °C.
The term 'temperature of about 5 °C referred to in the step (6) of the above process (as depicted in the Scheme-I) can range from 0 °C to 10 °C.
The term 'isolating the precipitated product' referred to in the step (7) corresponds to the steps involving filtration, washing and drying.
The solvent used in the step-(8) of the above process (as depicted in the Scheme-I) for the washing of product is selected from an alcohol such as ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol; an ether such as ethyl ether or propylether; halogenated solvent such as dichloromethane (MDC), ethyl chloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,2 dichloropropane, 1,2-dichloro ethylene, 1,1,1 trichloroethane, 1,1,2 trichloroethane, trichloroethylene, trichloromethane, carbon tetrachloride, 1,1,2,2 tetrachloroethylene, isobutyl chloride, 1-chloropentane, ethyl bromide, propyl bromide, hexyl bromide, dibromoethane, dibromobutane and tetrabromoethane; aromatic hydrocarbon solvents such as toluene, benzene or xylene; and other solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or

d i methy lacetam ide.
The base used in the step-(9) of the above process (as depicted in the Scheme-I) is selected from inorganic base or organic base (as defined earlier).
The process of the present invention as illustrated in the above Scheme-I comprises reaction of 3-(2-haloethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one the compound (II) with 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole the compound (III) in the presence of an inorganic base selected from sodium carbonate or potassium carbonate and a iodate salt, in a mixture of an amide solvent such as DMF and ketone solvent such as acetone. The reaction mixture was heated to a reflux temperature for about 15 hours. The reaction mixture was cooled to 0-5 °C and filtered the precipitated product Paliperidone (IA) with about 85% yield and more than 98% HPLC purity. The compound (IA) was dissolved in halogenated solvent such as MDC and was treated with palmitic acid in the presence of triethylamine. The organic layer partitioned by the water and the organic layer evaporated by distillation to obtain crude paliperidone palmitate (I). The product was crystallized to obtain pure Paliperidone palmitate (I) with more than 99% HPLC purity and containing less than about 0.15% by HPLC of the compound 'PP-Dimer'.
It is evident from the processes reported in the prior art that the Paliperidone (IA) was obtained with low yield of about 58% and of poor quality with a purity of about 90%; whereas the process of the present invention provided the pure Paliperidone (IA) in a yield of about 85% and purity of more than about 98% (HPLC). This amounts to a significant advantage over the processes reported in the prior art.
In an embodiment, in the present invention there is provided an improved process for the preparation of Paliperidone (IA), wherein the said compound (IA) is obtained in a yield of about 85% and purity of more than about 98% (HPLC).
It is further evident from the processes reported in the prior art that the isolation of the pure Paliperidone palmitate (I) involves use of column chromatography or repetitive purification;

whereas the process of the present invention provided the pure desired product compound (I) without harsh and costly purification steps.
Advantageously, the above identified elements of the process of the instant invention effectively contribute to the reduction of overall cost of the process.
In an further embodiment, the present invention provides Paliperidone palmitate (I) containing less than about 0.15% by HPLC of the compound 'PP-Dimer' [3-(2-(4-(6-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-l-yl)benzo[d]isoxazol-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl palmitate].
In an another embodiment, the present invention provides a pharmaceutical composition consisting of Paliperidone palmitate (I) which has less than about 0.15% by HPLC of the compound 'PP-Dimer' [3-(2-(4~(6-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-l -yl)benzo[d]isoxazol-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro~4H-pyrido[l,2-a]pyrimidin-9-yl palmitate].
In another aspect, the present invention provides a compound 3~(2-(4-(6-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-l-yl)benzo[d]isoxazol-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl palmitate (the compound 'PP-Dimer').


Accordingly, in an embodiment the present invention relates' to a process for the preparation of 3-(2-(4-(6-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin:l-yl)benzo[d]isoxazol-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl palmitate (the compound 'PP-Dimer') represented by the following formula;

comprising the steps of;
(i) treating the compound (HI) represented by the following formula, with a base to obtain
compound (Q) represented by the following formula,

(ii) reacting the compound (Q) of the above step (i) with compound (H) represented by the following formula;


in the presence of a base, iodate salt and a solvent or mixture of solvents, to obtain compound (M);

(iii) reacting the compound (M) of the above step (ii) with palmitic acid.
In a specific embodiment, the process for the preparation of 3-(2-(4-(6-(4-(6-fluorobenzo[d]isoxazoI-3-yl)piperidin-l-yl)ben2o[d]isoxazol-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyndo[l,2-a]pyrimidin-9-yI palmitate (the compound 'PP-Dimer') comprises the steps of:
(xi) dissolving the compound (HI) in a solvent;
(xii) adding a base to the reaction mixture of step (xi);
(xiii) stirring the reaction mixture of step (xii) at temperature of about 120 °C;
(xiv) cooling the reaction mixture of the above step (xiii) to room temperature and isolating the compound (Q);
(xv) dissolving compound (Q) of step (xiv) in a solvent(s);

(xvi) adding a base and an iodate salt to the reaction mixture of step (xv),
(xvii) adding compound (II) to the reaction mixture of step (xvi) and stirring at a temperature of about 75 °C;
(xviii) cooling the reaction mixture of the above step (xvii) at temperature of about 5 °C and isolating the precipitated product compound (M);
(xix) dissolving the compound (M) of the above step (xviii) in a solvent;
(xx) adding palmitic acid and a base to the reaction mixture of step (xix);
(xxi) isolating the compound 'PP-Dimer'.
The process of the present invention as per yet another embodiment described above is illustrated in the following Scheme-II,


The solvent used in the step-(xi), step-(xv) and step-(xix) of the above process (as depicted in the
Scheme-II) is selected from dimethyl sulfoxide (DMSO); an amide solvent selected from the
group consisting of N,N-Dimethylmethanamide (DMF), N,N-diethylformamide, N,N-
dimethylacetamide, N,N-diethylacetamide, N,N-dimethylpropionamide, N,N-
dimethylbutyramide, N-methylpyrrolidone and N-ethylpyrrolidone; a ketone solvent selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, diisoproyl ketone, methylisopropyl ketone, methylphenyl ketone; an alcohol such as ethyl alcohol, n-propyl alcohol, isopropyJ alcohol, isobutyl alcohol and methanol; an ether such as ethyl ether or propylether; halogenated solvent such as dichlorom ethane (MDC), ethyl chloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,2 dichloropropane, 1,2-dichloro ethylene, 1,1,1 trichloroethane; 1,1,2 trichloroethane, trichloroethylene, trichloromethane, carbon tetrachloride, 1,1,2,2 tetrachloroethylene, isobutyl chloride, 1-chloropentane, ethyl bromide, propyl bromide, hexyl bromide, dibromoethane, dibromobutane and tetrabromoethane; aromatic hydrocarbon solvents such as toluene, benzene or xylene; and other solvents such as acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, dimethylacetamide, and/or a mixture thereof
The base used in the step (xii) of the above process (as depicted in the Scheme-II) is an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide.
The term 'temperature of about 120 °C referred to in the step (xiii) of the above process (as depicted in the Scheme-II) can range from 110 °C to 135 °C.
In an embodiment, the solvent used in the step (xv) of the above process (as depicted in the Scheme-II) is a mixture of solvent preferably selected from an amide solvent and a ketone solvent.
In an embodiment, the quantity of ketone solvent added in step (xv) of the above process (as depicted in the Scheme-II) is in the v/v ratio with respect to amide solvent ranging from 1:1 to 10:10 as v/v (volume/volume).

In an embodiment, the base used in the step (xvi) of the above process (as depicted in the Scheme-U) is selected from an inorganic base or organic base.
The inorganic base used in the step (xvi) of the above process (as depicted in the Scheme-U) is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide.
In an embodiment, the base used in the step (xvi) is sodium carbonate.
Alternatively, the organic base used in the step (xvi) of the above process (as depicted in the Scheme-U) is selected from the group consisting of triethylamine, tripropylamine, pyridine, quinolone, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, dimethylaminopyridine, dibutyl amine, tributyl amine and diisopropylamine.
The iodate salt used in the step (xvi) of the above process (as depicted in the Scheme-U) is an alkali metal iodide such as potassium iodide, sodium iodide.
The term 'temperature of about 75 °C referred to in the step (xvii) of the above process (as depicted in the Scheme-U) can range from 70 °C to 80 °C.
The term 'temperature of about 5 °C' referred to in the step (xviii) of the above process (as depicted in the Scheme-U) can range from 0 °C to 10 °C.
The base used in the step (xx) of the above process (as depicted in the Scheme-U) is selected from inorganic base or organic base (as defined earlier).
The term 'isolating the product' referred to in the above process steps correspond to the steps involving separation of organic phase, filtration, evaporation of solvent, washing and drying; precipitation, filtration of precipitated product.
The process of the present invention as illustrated in the above Scheme-U comprises treatment of 6-fluoro-3-(piperidin-4-yI)benzo[d]isoxazole (the compound (III)) with a base such as

potassium carbonate in solvent such as DMSO. The reaction mixture was heated to temperature about 125 °C. The compound was precipitated by addition of water and isolated compound (Q). The compound (Q) further reacted with 3-(2-haloethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one the compound (II) in the presence of an inorganic base selected from sodium carbonate or potassium carbonate and iodate salt, in a mixture of an amide solvent such as DMF and ketone solvent such as acetone. The reaction mixture was heated to a temperature about 75 °C for about 4 hours. The reaction mixture was cooled to 0-5 °C and filtered the precipitated compound (M). The compound (M) was dissolved in a halogenated solvent such as MDC and was treated with palmitic acid in the presence of triethylamine. The organic layer was partitioned by water and the organic layer was evaporated by distillation to obtain the compound 'PP-Dimer'.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. 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.
EXAMPLES
Example-1: Preparation of Paliperidone (the compound (IA))
Charged 45.0 mL of DMF in a flask followed by the addition of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (the compound (II)) (25.0 g) and 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (the compound (III)). To the reaction mixture was added potassium iodide (1.65 g), sodium carbonate (28.4 g) and acetone (100 mL). The reaction mixture was heated to a reflux temperature for about 15h. The reaction mixture was cooled to 0-5 °C and the precipitated solid was filtered and washed by acetone to yield the title compound (IA) (Yield: 85% with Purity (by HPLC): 98%)
Example-2: Preparation of Paliperidone Palmitate (I).
Charged 125 mL dichloromethane (MDC) in a flask followed by the addition of paliperidone (IA) (25.0 g), Palmitic acid (15.75 g), N,N-Dimethyl amino pyridine (DMAP) (0.71 g), Triethylamine (8.86 g) and pivaloyl chloride (10 g). The reaction mixture was stirred at room

temperature for about 10 h. To the reaction mixture was added water (75 mL) and separated the organic layer. The solvent was evaporated to provide the crude title compound (I) which on crystallization using IPA provided pure paliperidone palmitate (I) (HPLC purity: 99.5% containing amount of 'PP-Dimer' 0.08%).

Charged 200 mL of DMSO in a flask followed by the addition of the compound (HI) (50.0 g) and potassium carbonate (31.5 g). The reaction mixture was heated at a temperature of 125-130 °C for 5 h. The reaction mixture was cooled to room temperature and was added water (2000 mL) to it. The precipitated solid was filtered and washed by ethyl acetate (100 mL) to yield the title compound (Q).

Charged 30.0 mL of DMF in a flask followed by the addition of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one (the compound (II)) (3.0 g) and the Compound (Q). To the reaction mixture was added potassium iodide (0.5 g) and sodium carbonate (3.4 g). The reaction mixture was heated to a temperature about 75 °C for 4h. Acetone (60 mL) was added to the mixture at room temperature and cooled to 0-5 °C. The precipitated solid was filtered and washed by acetone (40 mL) to yield the title compound (M) as 6.3 g.

Charged 30 mL MDC in a flask followed by the addition of the compound (M) (5.0 g), Palmitic acid (2.22 g), N,N-Dimethyl amino pyridine (DMAP) (0.2 g), Triethylamine (3.2 g) and pivaloyl chloride (1.9 g). The reaction mixture was stirred at room temperature for 20 h. To the reaction mixture was added water (50 mL) and separated the organic layer. The solvent was evaporated to provide the title compound ('PP-Dimer') as 4.8 g.

We claim
1. A process for the preparation of paliperidone palmitate (I) of the following formula,

comprising, reacting the compound (II) of the following formula;

with 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (HI) of the following formula;

in a mixture of organic solvents, a base and iodate salt to obtain paliperidone (IA) of the following formula;

and optionally, converting it to paliperidone palmitate (I).
2. The process according to the claim 1, wherein the product Paliperidone palmitate (I) contains less than about 0.15% by HPLC of the compound 'PP-Dimer' of the following formula;
3. The process according to the claim 1, wherein the solvent is selected from the group consisting of an amide solvent such as N,N-Dimethylmethanamide (DMF), N,N-diethylformamide, N,N-dirnethylacetamide, N,N-diethylacetamide, N,N-dimethylpropionamide, N,N-dimethylbutyramide, N-methylpyrrolidone and N-ethylpyrrolidone; and a ketone solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diisoproyl ketone, methylisopropyl ketone, methylphenyl ketone; or a mixture thereof.
4. The process according to the claim 1, wherein the mixture of organic solvents comprises of an amide solvent and a ketone solvent in a ratio ranging from 1:1 to 10:10 as v/v (volume/volume).
5. A process for the preparation of 3-(2-(4-(6-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-l-yl)benzo[d]isoxazol-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl palmitate (the compound 'PP-Dimer') of the following formula;

comprising the steps of;
(i) treating the compound (HI) of the following formula, with a base to obtain compound
(Q) of the following formula,

(ii) reacting the compound (Q) of the above step (i) with compound (II) of the following formula;

in the presence of a base, iodate salt and a solvent or mixture of solvents, to obtain compound (M);


(iii) reacting the compound (M) of step (ii) with palmitic acid.
6. The process according to the claim 1 or claim 5, wherein the base is selected from an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide; or an organic base selected from the group consisting of triethylamine, tripropylamine, pyridine, quinolone, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, dimethylaminopyridine, dibutyl amine, tributyl amine and diisopropylamine.
7. The process according to the claim 1 or claim 5, wherein the iodate salt is an alkali metal iodide selected from the group consisting of potassium iodide and sodium iodide.
8. The process according to the claim 5, wherein the solvent is selected from the group consisting of an amide solvent, a ketone solvent, an alcohol solvent, an ether solvent, halogenated solvent, an aromatic hydrocarbon solvents and/or a mixture thereof
9. A compound 3-(2-(4-(6-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1 -yl)benzo[d]isoxazol-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl palmitate (the compound 'PP-Dimer') of the following formula,


10. Paliperidone palmitate (I) containing less than about 0.15% by HPLC of the compound 'PP-Dimer'.