FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A PROCESS FOR PREPARING PALIPERIDONE PALMITATE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: D-4, M.I.D.C INDUSTRIAL AREA, CHIKALTHANA,
AURANGABAD- 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation of Paliperidone palmitate using an organic base.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides a process for the preparation of Paliperidone Palmitate, which comprises reaction of paliperidone with palmitoyl chloride in presence of an organic base.
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.

U.S. Patent Nos. 5,158,952 and 5,254,556 ("US '556") disclose Paliperidone palmitate and process thereof. Further, U.S. patent No. 6,077,843 ("US '843"), PCT Publication Nos. WO 99/25354 ("WO '354") 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. The present inventors developed simple, improved, robust and commercially viable process for Paliperidone palmitate by using an organic base.


which comprises reaction of paliperidone of Formula II

In an aspect of the present invention provides an improved process for the preparation of Paliperidone palmitate of Formula I
with palmitoyl chloride in presence of an organic base.
The organic base includes but are not limited to alkyl amine such as triethyl amine, methyl amine, diisopropylamine and the like; imidazole, benzimidazole, pyridine, piperidine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide and the like.
The reaction is performed in presence of solvent includes but are not limited to halogenated solvents such as dichloromethane, chloroform, chlorobenzene and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone and the like; esters such as ethyl acetate, 2-methoxyethyl acetate and the like; hydrocarbon such as hexane, heptane, cyclohexane, toluene and the like; nitrile such as acetonitrile, propionitrile and the like, dimethyl formamide and dimethyl acetamide.

The reaction optionally performed in presence of reaction initiator such as dimethylaminopyridine (DMAP).
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 may be subjected to isolation of solid by using suitable techniques, such as, recrystallization, anti-solvent technique, 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 yield of Paliperidone palmitate obtained from the process of present invention can be more than or equal to 70%. The purity can be more than or equal to 99% determined by High-performance liquid chromatography (HPLC).
The process of present invention provides the content of starting material, i.e. Paliperidone, less than 0.1%. Further, the use of organic base and specific temperature avoid and/or reduce the formation of starting material from paliperidone palmitate ester.
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
A three neck 1 L round bottom flask fitted with mechanical stirrer, thermometer pocket, reflux condenser, guard tube arranged in water bath. Paliperidone (20

gm), dichloromethane (600 ml), triethyl amine (23 ml) and DMAP (0.5 gm) were charged. A solution of palmitoyl chloride (28.4 ml/100 ml of DCM) was added at 25-30°C. After addition, temperature of reaction mixture was raised to 35-40°C and maintained for 4 hr. After completion of the reaction, the reaction mixture was cooled to 25-30°C. The organic layer was concentrated under vacuum to get residue. The crude was suspended in MTBE (430 ml) and isolated as crude Paliperidone palmitate. This was purified in isopropyl alcohol (215 ml) to get Paliperidone palmitate (20 gm).
Purity >99% by HPLC. Paliperidone: 0.05% by HPLC

We Claim:

which comprises reaction of paliperidone of Formula II

1. An improved process for the preparation of Paliperidone palmitate of Formula I
with palmitoyl chloride in presence of organic base.
2. The process according to the claim 1, wherein said organic base is selected from alkyl amine.
3. The process according to the claim 1, wherein said organic base is selected from alkyl amine such as methylamine, triethyl amine and diisopropyl amine; pyridine, piperidine and the like.
4. The process according to the claim 1, wherein said reaction is performed at a temperature of about 25 to about 45°C.

5. The process according to the claim 1, wherein said reaction is performed in presence of solvent.
6. The process according to the claim 5, wherein said solvent is selected from halogenated solvent such as dichloromethane, chloroform, chlorobenzene and the like;
7. The process according to the claim 1, wherein said reaction is performed in presence of reaction initiator such as dimethylaminopyridine (DMAP).
8. The process of claim 1, wherein palipeiridone is less than 0.1% in the Paliperidone palmitate.
9. The purity of Paliperidone palmitate obtained from process of claim 1, is greater than about 99% determined by high pressure liquid chromatography (HPLC).