FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

PROVISIONAL SPECIFICATION
(See section 10, rule 13)

“AN IMPROVED PROCESS FOR THE PREPARATION OF PALIPERIDONE”

FRICHEM PRIVATE LIMITED of 12, Concord, Bullock Road, Band Stand, Bandra West, Mumbai 400 050

The following specification particularly describes the invention.

An Improved process for the preparation of Paliperidone

Field of the Invention

The present invention relates to an improved process for the preparation of substantially pure Paliperidone.

Background of the Invention
Paliperidone, 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]-7-hydroxy-4-methyl-1,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one, is a 5-HT antagonist belonging to the chemical class of benzisoxazole derivatives and is present as a racemic mixture having the following structural formula:

Paliperidone

Paliperidone is a metabolite of Risperidone, marketed under the name, Invega®. Paliperidone is a psychotropic agent approved in the United States for the treatment of schizophrenia.

A process for the synthesis of Paliperidone is described in U.S. Patent no. 5,158,952. As disclosed in this patent, the Paliperidone is prepared via the intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[1,2-a]pyrimidi-4-one (CMHTP). The process includes the condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[1,2-a]pyrimidi-4-one (CMHTP) with 6-fluoro-3-piperidino-1,2-benisoxazol (FBIP) in presence of a secondary organic amine and an alcohol to get the crude Paliperidone. The obtained crude product is purified by column chromatography and then crystallized in acetone. The product obtained from first crystallization is under-go second re-crystallization using 2-propanol to get the pure Paliperidone with 21% yield.

Process for the synthesis of intermediates of Paliperidone is described also in U.S. Patent No. 5,688,799.

The processes described in the above publications have many disadvantages like long reaction time, recovery stages and poor quality along with low chemical yields, making their application in the industry very hard. Moreover, the product obtained from process as disclosed in prior art have a very high content of impurities such as N-oxide of Paliperidone as well as carboxylate of Paliperidone Hence, there is a need in the art for a new/improved process for preparing substantially pure Paliperidone, which is simple, cost effective, eco-friendly and commercially suitable process by over coming the problems encountered in the above prior art process..

Objective of the invention
An object of the invention is to produce an economically and industrially viable process for producing paliperidone.

Summary of the Invention
The present invention relates to an improved process for the preparation of substantially pure Paliperidone, by condensing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[1,2-a]pyrimidi-4-one (CMHTP) with 6-fluoro-3-piperidino-1,2-benisoxazol (FBIP) or salt thereof in presence of a tertiary organic amine as a base in solvent and optionally in presence of phase transfer catalyst/dimethylamino pyridine (DMAP).

Detailed description of the Invention
Accordingly, the present invention provides for a process for the preparation of Paliperidone comprising the condensing the 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[1,2-a]pyrimidi-4-one (CMHTP) (I) and 6-fluoro-3-piperidino-1,2-benisoxazol (FBIP) (II) or salt thereof in presence of tertiary organic amine as a base and solvent system to provide the crude Paliperidone (III) as depicted in scheme 1.

Scheme 1

Preferably, the solvents used herein is selected from the group consisting of but not limited to C1-6 alkanol, ketone, ester and ether. The above reaction can also be done in presence of phase transfer catalyst or dimethylamino pyridine (DMAP). The phase transfer catalyst used herein is selected from the group consisting of but not limited to suitable phase transfer catalyst such as, for example, a trialkylphenylmethylammonium, tetraalkylammonium, tetraalkylphosphonium, tetraarylphosphonium halide, hydroxide, hydrogen sulfate and the like catalysts.

The crude Paliperidone is further purified by treating it with alcohol or in a mixture of water and alcohol to get the substantially pure Paliperidone free from the N-oxide as well as carboxylate impurity.

Advantages
1. Eliminates the use of column chromatography
2. The process is free of impurities such as the N-oxide as well as carboxylate impurity.
3. Process is simple, reproducible, cost effective, eco-friendly, non-hazardous and hence can be well suited for large-scale production.

Dated this 28th day of July 2008 Omana Ramkrishnan
Of K & S Partners
Agent for the Applicant