DESCRIPTION :

The present invention provides a process for the preparation of Paliperidone Palmitate free from its impurities  which comprises reaction of paliperidone with palmitic acid followed by purification.

Paliperidone palmitate of Formula I is chemically known as (9RS)-3-[2-[4-(6-Fluoro-1 2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl4-oxo-6 7 8 9-tetrahydro-4H-pyrido[1 2-a]pyrimadin-9-yl hexadecanoate.

Formula I

U.S. Patent Nos. 5 158 952 and 5 254 556 (US ""556) discloses Paliperidone palmitate and process thereof. Further  U.S. patent No. 6 077 843 ("US ""843")  PCT Publication Nos. WO 99/25354 WO ""35) and WO 2009/089076 (WO ‘076) discloses other processes for the preparation of paliperidone palmitate. The proposed processes in the above prior art provide low yield and contains impurities  for example  unreacted starting materials  byproducts of the reaction and/or degradation products.

Therefore  there is a need in the art to develop an improved process for paliperidone palmitate  which provides high yield and reduce the formation of impurities  for example  dicyclohexyl urea (DCU)  excess palmitic acid  other fatty acid esters mainly myristate and stearate.
The inventors has developed simple  improved  robust and commercially viable process for Paliperidone palmitate having purity greater than or equal to 99.5 % by HPLC.

In an aspect of the present invention provides an improved process for the preparation of Paliperidone palmitate of Formula I

Formula I
which includes steps of 
a) reaction of paliperidone of Formula II

Formula II
with palmitic acid in presence N N""-dicyclohexylcarbodiimide  4-dimethylamino pyridine and chlorinated solvent; and
b) purification of paliperidone palmitate.

The reaction is performed in presence of chlorinated solvents such as dichloromethane  chloroform  chlorobenzene and the like.

The reaction may be conducted at a temperature of about 25 to about 60°C  for example  at a temperature of about 35 to about 45°C as per the solvent used.

After completion of the reaction  the reaction mixture is filtered to remove by products  for example DCU and then filtrate may be concentrated and/or subjected to isolation of solid by using suitable techniques  such as  recrystallization  anti-solvent technique  concentration and stripping of the solvent  slurry and the like. The solvent used for the isolation of solid is selected from ether such as diisopropyl ether  methyl tertiary butyl ether (MTBE) and the like. The isolation of solid may be performed using purification technique such as slurry at an ambient temperature  for example  above 35°C  preferably  at 45 to 60°C.

In an embodiment of the present invention relates to a purification of paliperidone palmitate free from its impurities comprises:
a) suspension of paliperidone palmitate in alcohol and isolation of solid; and
b) recrystallization of solid of step a) from chlorinated solvent followed by ketone solvent to afford paliperidone palmitate free of its impurities.

The step a) involves suspension of paliperidone palmitate in alcohol and then subjected to slurry for a sufficient time period and then isolated solid by using filtration to remove some of the impurities  especially  DCU. The step a) is performed in presence of alcohol  for example  methanol  ethanol  isopropanol  n-butanol and the like.

The step b) involves providing solution of paliperidone palmitate in a suitable chlorinated solvent  such as  dichloromethane  chloroform  dichloroethane  chlorobenzene and the like; and then recovering the solid.

The obtained solution in step b) is filtered to provide particle free solution and then concentrated completely to provide crude of paliperidone palmitate. Finally  the solid is recovered from the crude of paliperidone palmitate by using ketone solvent such as acetone  methyl ethyl ketone (MEK)  and the like.
The yield of Paliperidone palmitate obtained from the process of present invention can be more than or equal to 85%. The purity can be more than or equal to 99.5% determined by High-performance liquid chromatography (HPLC).

The process of present invention provides the content of starting material  i.e. palmitic acid  less than 0.1%. Further  the present process conditions provide paliperidone palmitate free of DCU  especially  less than 0.1%  preferably less than 0.05%. Furthermore  the present process conditions provide the content of other impurities  for example  paliperidone myristate and paliperidone stearate  less than 0.1%  especially less than or equal to 0.05% in paliperidone palmitate.

The present invention is further illustrated by the following example  which does 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 application.

EXAMPLES
Example –1
Paliperidone (100 gm)  dichloromethane (2.0 Liter)  palmitic acid (120 gm)  N N""-dicyclohexylcarbodiimide (75 gm) and 4-dimethylamino pyridine (8 gm) were charged. The reaction mixture was heated to 35-40°C and maintained for 3 hr. After completion of the reaction  the reaction mixture was cooled to 25-30°C and filtered. The filtrate was concentrated and residue obtained was suspended in methyl tertiary butyl ether (2.0 Liter) and maintained for 2 hr at 50-55 0C. Then cooled to room temperature and filtered. This is further purified in methanol (2.5 Liter)  followed by dichloromethane and methyl ethyl ketone solvent mixture to get pure Paliperidone Palmitate

Yield: > 85% yield.
Purity: 99.8% by HPLC.

Content of impurities:
DCU: 0.05% by HPLC
Palmitic acid: 0.1% by HPLC
Paliperidone myristate and paliperidone stearate: less than 0.05% by HPLC.

We Claim:

1. A process for the preparation of Paliperidone palmitate of Formula I comprising 

Formula I
a) reaction of paliperidone of Formula II

Formula II
with palmitic acid in presence N N""-dicyclohexylcarbodiimide  4-dimethylamino pyridine and chlorinated solvent; and

b) purification of paliperidone palmitate.

2. The process according to the claim 1  wherein said chlorinated solvent is selected from dichloromethane  chloroform and chlorobenzene.

3. The process according to the claim 1  wherein said reaction is conducted at a temperature of about 25 to about 60°C.

4. The process according to the claim 1  wherein said purification technique is selected from slurry  recrystallization  concentration and stripping of the solvent  and anti-solvent technique.

5. A purification of paliperidone palmitate free from its impurities comprises:
a) suspension of paliperidone palmitate in alcohol and isolation of solid; and
b) recrystallization of solid of step a) from chlorinated solvent followed by ketone solvent to afford paliperidone palmitate free of its impurities.

6. The process according to the claim 5  wherein said reaction is performed in presence of alcohol such as methanol  ethanol  isopropanol  n-butanol and the like.

7 The process according to the claim 5  wherein said step b) involves providing solution of paliperidone palmitate in a suitable chlorinated solvent and then recovering the solid.

8. The process according to the claim 7  wherein said recovery is performed in presence of ketone  such as methyl ethyl ketone.

9. The process of claim 5  wherein paliperidone palmitate having the content each one of impurity  such as  palmitic acid  dicyclohexyl urea  other fatty acid ester is less than 0.1% by high pressure liquid chromatography.

10. The purity of Paliperidone palmitate obtained from process of claim 5  is greater than about 99.8 % determined by high pressure liquid chromatography.

Dated this 7th day of June  2012 For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory