Field of the invention:

The present invention provides acid-addition salts of (9RS)-3-[2-[4-(6-fiuoro-l,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a] pyrimidin-9-yl hexadecanoate compound represented by the following structural formula-1, their polymorphs and processes for their preparation.

Formula-1 The present invention also provides a process for the preparation of (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.

Background of the invention:

(9RS)-3-[2-[4-(6-Fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate is developed by Janssen Pharmaceutica. It is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. This drug is marketed under the brand name Invega sustenna in USA and Xeplion in Europe.

US5254556A patent disclosed the 3-piperidinyl-l,2-benzisoxazole compounds and process for their preparation. This patent disclosed the synthesis of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-9-yl hexadecanoate in analogous manner, which involves the condensation of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one with palmitoyl chloride in presence of sodium hydroxide in a mixture of dichloromethane and water to provide (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate as a residue, which is purified by column chromatography over silica gel using a mixture of chloroform and methanol as eluent.

Brief description of the invention:
The first aspect of the present invention is to provide acid addition salts of (9RS)-3-[2-[4-(6-fiuoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate having the general formula-2.

The second aspect of the present invention is to provide hydrochloride salt of (9RS)-3-[2-[4-(6-fiuoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate in crystalline form.

The third aspect of the present invention is to provide hydrobromide salt of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate in crystalline form.

The fourth aspect of the present invention is to provide nitrate salt of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate in crystalline form.

The fifth aspect of the present invention is to provide hydrogen sulfate salt of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate in crystalline form.

The sixth aspect of the present invention is to provide a process for the purification of palmitic acid.

The seventh aspect of the present invention is to provide a process for the preparation of pure (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.

The eighth aspect of the present invention is to provide another process for the preparation of pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l ,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.

The ninth aspect of the present invention is to provide a process for the purification of (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.

The tenth aspect of the present invention is to provide a process for the preparation of acid-addition salt compounds of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate having the general formula-2.

Brief Description of the Drawings:

Figure-1: Illustrates the PXRD pattern of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)
piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl
hexadecanoate compound of formula-1 of the present invention.

Figure-2: Illustrates the PXRD pattern of crystalline form-M of (9RS)-3-[2-[4-(6-fluoro-l,2-
benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]
pyrimidin-9-yl hexadecanoate hydrochloride salt.

Figure-3: Illustrates the DSC thermogram of crystalline form-M of (9RS)-3-[2-[4-(6-fiuoro-
l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido
[l,2-a]pyrimidin-9-yl hexadecanoate hydrochloride salt.

Figure-4: Illustrates the PXRD pattern of crystalline form-S of (9RS)-3-[2-[4-(6-fluoro-l,2-
benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]
pyrimidin-9-yl hexadecanoate hydrobromide salt.

Figure-5: Illustrates the PXRD pattern of crystalline form-N of (9RS)-3-[2-[4-(6-fluoro-l,2-
benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]
pyrimidin-9-yl hexadecanoate nitrate salt.

Figure-6: Illustrates the PXRD pattern of crystalline form-L of (9RS)-3-[2-[4-(6-fluoro-l,2-
benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]
pyrimidin-9-yl hexadecanoate hydrogen sulfate salt.

Detailed description of the invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethylether, diethylether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, dioxane, acetonitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; and/or their mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tertbutoxide and the like; "alkali metal phosphates" such as disodium hydrogen phosphate, dipotassium hydrogen phosphate and "organic bases" like diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-pyrrolidino pyridine, 4-dimethylaminopyridine (DMAP) and the like.

The first aspect of the present invention provides acid addition salts of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate having the general formula-2.

Formula-2 Wherein the term "Acid" represents inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, 2-oxopropionic acid (pyruvic acid), hexanoic acid, methane sulfonic acid, ethane sulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzene sulfonic acid, 4-methylbenzene sulfonic acid, naphthalene-l,5-disulfonic acid, oxalic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 2,3 or 4-amino benzoic acid, 4-hydroxybenzoic acid, 2-acetoxybenzoic acid, 2,4,6-trimethyl benzoic acid, succinic acid, mandelic acid, acetyl mandelic acid, lactic acid, stearic acid, carbonic acid, glutamic acid, gluconic acid, glycolic acid, malonic acid, aspartic acid, phthalic acid, cinnamic acid, 4-hydroxy cinnamic acid, salicylic acid, acetyl salicylic acid, orotic acid, oleic acid, nicotinic acid and their hydrates or solvates thereof.

The second aspect of the present invention provides hydrochloride salt of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate in crystalline form herein designated as crystalline form-M, which is characterized by its X-Ray powder diffraction pattern having peaks at about 3.1, 6.2, 9.3, 12.8, 13.5, 18.8, 20.4, 20.7, 21.1, 21.5, 21.9, 23.9, 24.3 ± 0.2 degrees of 29 values. The crystalline form-M is further characterized by the PXRD pattern as illustrated in figure-2 and the differential scanning calorimetric (DSC) thermogram as illustrated in figure-3.

The third aspect of the present invention provides hydrobromide salt of (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate in crystalline form herein designated as crystalline form-S, which is characterized by its X-Ray powder diffraction pattern having peaks at about 3.1, 9.4, 10.2, 11.8, 12.7, 13.4, 15.8, 16.9, 18.9, 19.8, 20.6, 20.9, 21.6, 21.9, 24.3, 25.1, 27.1, 28.4, 29.8, 38.4, 42.3 ± 0.2 degrees of 29 values. The crystalline form-S is further characterized by the PXRD pattern as illustrated in figure-4.

The fourth aspect of the present invention provides nitrate salt of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate in crystalline form herein designated as crystalline form-N, which is characterized by its X-Ray powder diffraction pattern having peaks at about 3.4, 5.2, 6.9, 10.4, 12.2, 13.9, 18.2, 19.3, 21.2, 22.6, 23.3, 27.0, 27.5 ± 0.2 degrees of 29 values. The crystalline form-N is further characterized by the PXRD pattern as illustrated in figure-5.

The fifth aspect of the present invention provides hydrogen sulfate salt of (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate in crystalline form herein designated as crystalline form-L, which is characterized by its X-Ray powder diffraction pattern having peaks at about 3.2, 3.3, 6.7, 8.3, 10.0, 11.6, 13.3, 14.5, 19.2, 19.5, 20.3, 21.0, 21.7, 25.3, 27.3 ± 0.2 degrees of 26 values. The crystalline form-L is further characterized by the PXRD pattern as illustrated in figure-6.

Commercially available palmitic acid is contaminated with many other saturated and unsaturated fatty acids such as lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, oleic acid, heptadecanoic acid and stearic acid. When, such impure palmitic acid is used in the esterification of Paliperidone, the presence of these unwanted acids leads to the formation of Paliperidone palmitate contaminated with the corresponding fatty acid ester impurities which are difficult to remove in the final stage. Hence before going to use in the esterification process, the palmitic acid should be purified by processes such as recrystallization from a suitable solvent.

Usage of pure palmitic acid which is free of other fatty acids, in the esterification of Paliperidone consequently produces pure Paliperidone palmitate free of other fatty acid ester impurities.

The sixth aspect of the present invention provides a process for the purification of palmitic acid, comprising of;

a) Adding palmitic acid to a suitable solvent,
b) heating the reaction mixture,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) stirring the reaction mixture,
f) filtering the compound followed by washing with a suitable solvent to provide pure palmitic acid.

Wherein, the suitable solvent used in step-a) and step-f) can be selected from alcoholic solvents and ether solvents.

A preferred embodiment of the present invention provides a process for the purification of palmitic acid, comprising of;

a) Adding palmitic acid to isopropyl alcohol,
b) heating the reaction mixture,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) stirring the reaction mixture,
f) filtering the compound followed by washing with isopropyl alcohol to provide pure palmitic acid.

The commercially available palmitic acid generally contains 0.5-1% of other fatty acid impurities. The purification/recrystallization of the palmitic acid from the suitable solvent leads to reducing the all other fatty acid impurities to minimum levels or not detected levels and provide highly pure palmitic acid.
The seventh aspect of the present invention provides a process for the preparation of pure (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1, comprising of;

a) Purification of palmitic acid from a suitable solvent,

b) esterification of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one compound of formula-3 with palmitic acid obtained in step-a) in presence of a suitable base and a suitable coupling agent in a suitable solvent to provide (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1,

c) treating the compound of formula-1 with a suitable acid in a suitable solvent to provide its corresponding acid-addition salt compound of general formula-2,

d) treating the compound of general formula-2 with a suitable base in a suitable solvent to provide pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl -4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.
Wherein, in step-a) the suitable solvent can be selected from alcoholic solvents, ether solvents and/or their mixtures thereof;

in step-b) the suitable base can be selected from organic bases, alkali metal hydroxides and alkali metal alkoxides; the suitable coupling agent is N,N'-dicyclohexylcarbodiimide; and the suitable solvent is selected from chloro solvents, polar solvents, ketone solvents, polar-aprotic solvents and/or their mixtures thereof;

In step-c) the suitable acid is same as defined in the first aspect of the present invention and in step-d) the suitable base can be selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates, preferably sodium bicarbonate;

In step-c) and step-d) the suitable solvent can be selected form chloro solvents, alcoholic solvents, ketone solvents, ether solvents, polar solvents and/or their mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1, comprising of;

a) Purification of palmitic acid from isopropyl alcohol,

b) esterification of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one compound of formula-3 with palmitic acid obtained in step-a) in presence of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide in dichloromethane to provide (9RS)-3-[2-[4-(6-fiuoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1,
c) treating the compound of formula-1 with aq.hydrochloric acid to provide its hydrochloride salt compound of formula-2a,

Formula-2a

d) treating the compound of formula-2a with sodium bicarbonate in dichloromethane to provide pure (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.

The (RS)-3-[2-[4-(6-fluoro-l ,2-benzisoxazol-3-yl)-l -piperidinyl]ethyl]-6,7,8,9-
tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one compound of formula-3 utilized in step-b) of the seventh aspect of the present invention can be synthesized by any of the processes known in the art.

The eighth aspect of the present invention provides a process for the preparation of pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1, comprising of;

a) Esterification of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one compound of formula-3 with palmitic acid in presence of a suitable base and a suitable coupling agent in a suitable solvent to provide (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1,

b) treating the compound of formula-1 with a suitable acid in a suitable solvent to provide its corresponding acid-addition salt compound of general formula-2,

c) treating the compound of general formula-2 with a suitable base in a suitable solvent to provide pure (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.

Wherein the suitable acid, the suitable base, the suitable coupling agent and the suitable solvents are same as defined for the seventh aspect of the present invention.

A preferred embodiment of the present invention provides a process for the preparation of pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1, comprising of;

a) Esterification of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one compound of formula-3 with palmitic acid in presence of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide in dichloromethane to provide (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1,

b) treating the compound of formula-1 with aq.hydrochloric acid to provide its
hydrochloride salt compound of formula-2 a,

c) treating the compound of formula-2a with sodium bicarbonate in dichloromethane to
provide pure (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-
methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate
compound of formula-1.

The acid-addition salt compounds of general formula-2 of the present invention are useful in the preparation of pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.
The ninth aspect of the present invention provides a process for the purification of (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1, comprising of;

a) Converting the (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1 into its acid-addition salt compounds of general formula-2 by treating it with a suitable acid in a suitable solvent,
b) treating the acid-addition salt obtained in step-a) with a suitable base in a suitable solvent to provide pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.

Wherein, in step-a) and step-b) the suitable acid, the suitable base and the suitable solvent are same as defined for step-c) and step-d) of the seventh aspect of present invention.

The tenth aspect of the present invention provides a process for the preparation of acid-addition salt compounds of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate having the general formula-2, comprising of treating the (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a] pyrimidin-9-yl hexadecanoate compound of formula-1 with a suitable acid in a suitable solvent selected from chloro solvents, alcoholic solvents, ketone solvents, ether solvents, hydrocarbon solvents, ester solvents, polar solvents, polar-aprotic solvents and/or their mixtures.

The PXRD analysis of the crystalline compounds of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10° per minute.

The particle size distribution of (9RS)-3-[2-[4-(6-Fluoro-l,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1 is measured using Malvern Mastersizer 2000 instrument.

(9RS)-3-[2-[4-(6-Fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1 produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.

The (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1 of the present invention was analyzed by HPLC under the following conditions; Apparatus: A liquid chromatograph equipped with variable wavelength UV-detector; Column: Xterra RP 8, 250x4.6 mm, 5 urn or equalent; Flow rate: 2.0 mL/min; Wavelength: 210 irai; Column temperature: 50°C; Injection volume: lOuL; Run time: 60 min; Diluent: Dichloromethane:Acetonitrile (3:7 v/v); Elution: Isocratic; Buffer: Dissolve 1.36 gm of potassium dihydrogen orthophosphate anhydrous and 3.48 gm of dipotassium hydrogen . orthophosphate anhydrous in 1000 mL milli-Q-water, filter this solution through 0.22 um nylon membrane filter paper;

Mobile phase-A: Buffer; Mobile phase-B: Acetonitrile:water (90:10 v/v); Mobile phase composition: Mobile phase-A: Mobile phase-B (30:70 v/v).

The present invention is schematically represented as follows.

Synthetic scheme:

Wherein the term "Acid" is as defined in the description.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:
Example-1: Purification of palmitic acid

A mixture of palmitic acid (100 gm) and isopropyl alcohol (200 ml) was heated to 55-60°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 15-20°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get pure palmitic acid. Yield: 92.0 gm; Purity by GC: 99.8%.

Example-2: Preparation of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yI)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimiidin-9-yl hexadecanoate hydrochloride (Formula-2a)
Palmitic acid (39 gm) and 4-dimethylaminopyridine (7.1 gm) were added to a mixture of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (50 gm) and dichloromethane (300 ml) at 25-30°C and stirred for 20 min at the same temperature. A solution of N,N'-dicyclohexylcarbodiimide (36.2 gm) in dichloromethane (200 ml) was slowly added to the reaction mixture at 5-10°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 90 min at the same temperature. Filtered the reaction mixture, dil.hydrochloric acid was added to the filtrate at 5-10°C and stirred for 60 min at the same temperature. Filtered the precipitated solid and washed with dichloromethane to get the title compound. The PXRD of the obtained compound is shown in figure-2. Yield: 65.0 gm.

Example-3: Preparation of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate (Formula-1)
Dichloromethane (500 ml) was added to (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate hydrochloride (65 gm) at 25-3 0°C and stirred for 10 min at the same temperature. Sodium bicarbonate solution was added to the reaction mixture at 25-30°C and both the organic and aqueous layers were separated. Washed the organic layer with water and distilled off the solvent completely from the organic layer under atmospheric pressure. Isopropyl alcohol (900 ml) followed by dichloromethane (200 ml) were added to the obtained compound. Heated the reaction mixture to reflux temperature and stirred for 30 min at the same temperature. Carbon (15 gm) was added to the reaction mixture at reflux temperature and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with isopropyl alcohol. Cooled the filtrate to 20-25°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound. Yield: 60.0 gm; Purity by HPLC: 99.95%.

Example-4: Preparation of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yI hexadecanoate (Formula-1)
Palmitic acid (20 gm) and 4-dimethylaminopyridine (3.6 gm) were added to a mixture of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (25 gm) and dichloromethane (150 ml) at 25-30°C and stirred for 20 min at the same temperature. A solution of N,N'-dicyclohexylcarbodiimide (18 gm) in dichloromethane (100 ml) was slowly added to the reaction mixture at 5-10°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 90 min at the same temperature. Filtered the reaction mixture, dil.HCl was added to the filtrate at 5-10°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, dichloromethane (250 ml) was added at 25-30°C and stirred for 10 min at the same temperature. Aqueous sodium bicarbonate solution was added to the reaction mixture at 25-30°C and both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer under atmospheric pressure. Isopropyl alcohol (450 ml) followed by dichloromethane (100 ml) were added to the obtained compound. Heated the reaction mixture to reflux temperature and stirred for 30 min at the same temperature. Carbon (7.5 gm) was added to the reaction mixture at reflux temperature and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with isopropyl alcohol. Cooled the filtrate to 20-25°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound. The PXRD of the obtained compound is shown in figure-1.; Yield: 31.0 gm; Purity by HPLC: 99.95%.
Particle size distribution: D(0.1) is 2.52 μm; D(0.5) is 8.61 urn; D(0.9) is 22.62 urn.

Example-5: Purification of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate (Formula-1)
(9RS)-3 -[2-[4-(6-fluoro-1,2-benzisoxazol-3 -yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate (10 gm) and dichloromethane (100 ml) were charged into a clean and dry RBF at 25-30°C and stirred for 10 min at the same temperature. Dil.hydrochloric acid was added to the reaction mixture at 5-10°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, dichloromethane (110 ml) and aqueous sodium bicarbonate solution were added to it and stirred for 15 min. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer under atmospheric pressure and isopropyl alcohol (180 ml) followed by dichloromethane (40 ml) were added. Heated the reaction mixture to reflux temperature and stirred for 30 min at the same temperature. Carbon (10 gm) was added to the reaction mixture at reflux temperature and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with isopropyl alcohol. Cooled the filtrate to 20-25°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the pure title compound. Yield: 9.6 gm; Purity by HPLC: 99.95%.

Example-6: Preparation of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate hydrobromide
(9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate (10 gm) and dichloromethane (110 ml) were charged into a clean and dry RBF at 25-30°C and cooled the reaction mixture to 0-5°C. Aq.HBr solution was added to the reaction mixture at 0-5°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with dichloromethane and dried to get the title compound. The PXRD of the obtained compound is shown in figure-4. Yield: 8.0 gm; M.R: 185-190°C.

Example-7: Preparation of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate hydrobromide
(9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate (10 gm) and dichloromethane (110 ml) were charged into a clean and dry RBF at 25-3 0°C. Aq.HBr solution was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with dichloromethane and dried to get the title compound. Yield: 7.9 gm; M.R: 185-190°C.
Example-8: Preparation of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [ 1,2-a] pyrimidin-9-yl hexadecanoate nitrate salt
(9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate (10 gm) and dichloromethane (100 ml) were charged into a clean and dry RBF at 25-30°C. Nitric acid (1.0 gm) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with dichloromethane and dried to get the title compound. The PXRD of the obtained compound is shown in figure-5. Yield: 7.0 gm; M.R: 108-114°C.

Example-9: Preparation of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate nitrate salt
(9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate (10 gm) and dichloromethane (100 ml) were charged into a clean and dry RBF at 25-30°C. Cooled the reaction mixture to 0-5°C, nitric acid (1.0 gm) was added and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with dichloromethane and dried to get the title compound. Yield: 7.0 gm; M.R: 108-114°C.

Example-10: Preparation of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyI]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate hydrogen sulfate salt
(9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate (10 gm) and acetone (100 ml) were charged into a clean and dry RBF at 25-30°C. Sulfuric acid (1.0 gm) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. The PXRD of the obtained compound is shown in figure-6. Yield: 7.3 gm; M.R: 123-128°C.

Example-11: Preparation of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate phosphate salt
(9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl] ethyl] -2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate (10 gm) and dichloromethane (110 ml) were charged into a clean and dry RBF at 25-30°C. Phosphoric acid (1.0 gm) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with dichloromethane and dried to get the title compound. Yield: 7.1 gm.

We Claim:

1. Acid addition salts of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate having the general formula-2.

Fonnula-2 Wherein "Acid" represents inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, 2-oxopropionic acid (pyruvic acid), hexanoic acid, methane sulfonic acid, ethane sulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzene sulfonic acid, 4-methylbenzene sulfonic acid, naphthalene-1,5-disulfonic acid, oxalic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 2,3 or 4-amino benzoic acid, 4-hydroxybenzoic acid, 4-chloro benzoic acid, 2-acetoxybenzoic acid, 2,4,6-trimethyl benzoic acid, succinic acid, mandelic acid, acetyl mandelic acid, lactic acid, stearic acid, carbonic acid, glutamic acid, gluconic acid, glycolic acid, malonic acid, aspartic acid, phthalic acid, cinnamic acid, 4-hydroxy cinnamic acid, salicylic acid, acetyl salicylic acid, orotic acid, oleic acid, nicotinic acid and their hydrates or solvates thereof.

2. Crystalline acid-addition salts of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidine-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate having the general formula-2, wherein the acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.

3. Crystalline forms of acid-addition salts of (9RS)-3-[2-[4-(6-fluoro-l ,2-benzisoxazol-3-yl) piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate, wherein;
a) crystalline form-M of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate hydrochloride salt is characterized by its PXRD pattern having peaks at about 3.1, 6.2, 9.3, 12.5, 13.5, 18.8, 20.4, 20.7, 21.1, 21.5, 21.9, 23.9, 24.3 ± 0.2 degrees of 29 values,

b) crystalline form-S of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate hydrobromide salt is characterized by its PXRD pattern having peaks at about 3.1, 9.4, 10.2, 11.8, 12.7, 13.4, 15.8, 16.9, 18.9, 19.8, 20.6, 20.9, 21.6, 21.9, 24.3, 25.1, 27.1, 28.4, 29.8, 38.4, 42.3 ± 0.2 degrees of 29 values,

c) crystalline form-N of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate nitrate salt is characterized by its PXRD pattern having peaks at about 3.4, 5.2, 6.9, 10.4, 12.2, 13.9, 18.2, 19.3, 21.2, 22.6, 23.3, 27.0, 27.5 ± 0.2 degrees of 29 values,

d) crystalline form-L of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl] ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate hydrogen sulfate salt is characterized by its PXRD pattern having peaks at about 3.2, 3.3, 6.7, 8.3, 10.0, 11.6, 13.3, 14.5, 19.2, 19.5, 20.3, 21.0, 21.7, 25.3,27.3 ± 0.2 degrees of 29 values.

4. A process for the purification of palmitic acid comprising of;

a) Adding palmitic acid to a suitable alcoholic solvent or ether solvent, preferably isopropyl alcohol,
b) heating the reaction mixture,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) stirring the reaction mixture,
f) filtering the compound followed by washing with isopropyl alcohol to provide pure palmitic acid.

5. A process for the preparation of acid-addition salts of (9RS)-3-[2-[4-(6-fluoro-l,2-
benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido
[l,2-a]pyriimdin-9-yl hexadecanoate having the general formvila-2, comprising of treating
the (9RS)-3-[2-[4-(6-fiuoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-
6,7,8,9-tetrahydro-4H-pyrido [l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1 with a suitable acid in a suitable solvent selected from chloro solvents, alcoholic solvents, ketone solvents, ether solvents, hydrocarbon solvents, ester solvents, polar solvents, polar-aprotic solvents and/or their mixtures.

6. A process for the preparation of pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1, comprising of;

a) Purification of palmitic acid from a suitable alcoholic solvent,

b) esterification of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one compound of formula-3 with palmitic acid obtained in step-a) in presence of a suitable base selected from organic bases, alkali metal hydroxides, alkali metal alkoxides and a suitable coupling agent such as N,N'-dicyclohexylcarbodiimide in a suitable solvent selected from chloro solvents, polar solvents, ether solvents to provide (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1,

c) treating the compound of formula-1 with a suitable acid in a suitable solvent selected from chloro solvents, alcoholic solvents, ketone solvents, ether solvents, polar solvents and/or their mixtures to provide its corresponding acid-addition salt compound of general formula-2,

d) treating the compound of general formula-2 with a suitable base selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals in a suitable solvent selected from chloro solvents, alcoholic solvents, ketone solvents, ether solvents, polar solvents and/or their mixtures to provide pure (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.

7. A process for the preparation of pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1, comprising of;

a) Purification of palmitic acid from isopropyl alcohol,

b) esterification of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [ 1,2-a]pyrimidin-4-one compound of formula-3 with palmitic acid obtained in step-a) in presence of 4-dimethylamino

pyridine and N,N'-dicyclohexylcarbodiimide in dichloromethane to provide (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1,

c) treating the compound of formula-1 with aq.hydrochloric acid to provide its hydrochloride salt compound of formula-2a,

d) treating the compound of formula-2a with sodium bicarbonate in dichloromethane to provide pure (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.

8. A process for the preparation of pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)
piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl
hexadecanoate compound of formula-1, comprising of;

a) Esterification of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one compound of formula-3 with palmitic acid in presence of a suitable base and a suitable coupling agent in a suitable solvent to provide (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1,

b) treating the compound of formula-1 with a suitable acid in a suitable solvent to provide its corresponding acid-addition salt compound of general formula-2,

c) treating the compound of general formula-2 with a suitable base in a suitable solvent to provide pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.

9. A process for the preparation of pure (9RS)-3-[2-[4-(6-fiuoro-l,2-benzisoxazol-3-yl)
piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl
hexadecanoate compound of formula-1, comprising of;

a) Esterification of (RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one compound of formula-3 with palmitic acid in presence of 4-dimethylamino pyridine and N,N'-dicyclohexylcarbodiimide in dichloromethane to provide (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido

[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1,

b) treating the compound of formula-1 with aq.hydrochloric acid to provide its hydrochloride salt compound of formula-2a,

c) treating the compound of formula-2a with sodium bicarbonate in dichloromethane to provide pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.
10. A process for the purification of (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1, comprising of;

a) Converting the (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1 into its acid-addition salt by treating it with a suitable acid in a suitable solvent selected from chloro solvents, alcoholic solvents, ketone solvents, ether solvents, polar solvents and/or their mixtures,

b) treating the acid-addition salt obtained in step-a) with a suitable base selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates to provide pure (9RS)-3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-l-yl]emyl]-2-memyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-9-yl hexadecanoate compound of formula-1.
c)