Field of the Invention

The present invention relates to a process for the preparation of Paliperidone of formula (I) and/or salts and esters thereof

Background of the Invention

Paliperidone is primary active metabolite of atypical antipsychotic Drug Risperidone. Chemically Paliperidone is 9-hydroxyrisperidone. The chemical name of Paliperperidone is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H pyrido[1,2-a]pyrimidine-4-one. Paliperidone is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. It is sold in US under brand name of Invega. It is approved for the acute and maintenance treatment of schizophrenia.

Paliperidone and its process for preparation is first disclosed in US patent no. 5,158,952. The process for synthesis of Paliperidone as exemplified in this patent is as follows:

The process for the preparation of compound of formula (III) i.e. 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one comprises of reactiong compound of formula (V) i.e. 3-(phenylmethoxy)-2-pyridinamine and compound of formula (VI) i.e. 3-acetyl-4,5-dihydro-2(3H)-furanone in the presence of phosphoryl chloride to give compound of formula (IV) i.e. 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one, which is further hydrogenated in presence of 10% palladium-on-charcoal in methanol to give compound of formula (III). Compound of formula (III) is further reacted with compound of formula (II) i.e. 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride to obtain Paliperidone of formula (I).

The process for preparation of compound of formula (III) abbreviated as CMHTP disclosed in US patent application no. 20080214809 is shown in the synthetic scheme as follows:

The process involves formation of CMHTP through CMHP intermediate i.e. 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one.

The disadvantage of prior art process is that during hydrogenation of compound of formula (IV) undesired impurities are formed.

These process impurities are difficult to separate and thus are carried forward in the final step. This results into decrease in yield and purity of Paliperidone of formula (I).

The ICH Q3A(R1) guidance for API manufacturers requires that process impurities should be maintained below set limits by controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.

It is therefore important to control the impurity level at the intermediate stage to get the final API which comply the set regulatory standards of various countries. Hence, inventors of present invention have directed their efforts to minimize formation of undesired impurities. They have established that if hydrogenation of compound of formula (IV) is carried out in the presence of halogen substituted aromatic hydrocarbon e.g. 4-chlorotoluene, 4-bromotoluene, 2,4-dichlorotoluene and the like or mixtures thereof, it reduces formation of undesired impurities. Therefore, the quality and the purity of final product are increased.

Objects of the Invention

It is the primary object of the present invention to provide a process for the preparation of compound of formula (III).

Another object of the present invention is to provide a process for the preparation of Paliperidone of formula (I).

Yet another object of the present invention is to provide halogen substituted aromatic hydrocarbon for hydrogenation of compound of formula (III) which results in materially superior quality of Paliperidone of formula (I).

Summary of the Invention

An aspect of present invention provides a process for the preparation of compound of formula (III) comprising of hydrogenating compound of formula (IV) in the presence of halogen substituted aromatic hydrocarbon and optionally in the presence of another solvent.

Another aspect of the present invention provides a process for the preparation of Paliperidone of formula (I) and/or salts or esters thereof comprising a step of compound of hydrogenating compound of formula (IV) in the presence of halogen substituted aromatic hydrocarbon and optionally in the presence of another solvent to obtain compound of formula (III).

Yet another aspect of the present invention provides a process for the preparation of Paliperidone of formula (I) and/or salts and esters thereof comprising steps of:
(a) hydrogenating compound of formula (IV) in the presence of halogen substituted aromatic hydrocarbon and optionally in the presence of another solvent to obtain compound of formula (III)
(b) converting compound of formula (III) to Paliperidone of formula (I) and/or salts and esters thereof.

Detailed Description of the Invention

The process of present invention can be represented by synthetic scheme as follows: