FIELD OF INVENTION

The present invention relates to an improved process for the preparation of Blonanserin.

BACKGROUND OF THE INVENTION

Schizophrenia is a serious mental illness characterized with delusion, hallucinations as well as asociality, alogia and anhedonia.

Blonanserin, 2-(4-ethylpiperazin-l-yl)-4-(4-fluorophenyl)-5,6,7,8,9,10-
hexahydrocycloocta[b] pyridine is an atypical antipsychotic which was disclosed in US 5,021,421. Blonanserin exhibit potent binding property to serotonin (S2) and dopamine (D2) receptors, thereby increasing the effect on concentration of brain monoamine metabolites. Blonanserin is used to improve the effect for positive symptoms such as hallucination, delusion etc and negative symptoms such as emotional withdrawal, apatheia etc occurring in schizophrenia.

Blonanserin is commercially available as LONASEN immediate release tablets 2mg, 4mg and 8mg and powder 2% strengths in Japan and South Korea.

Blonanserin CAS No [132810-10-7] having the following structure of formula I

Formula I

could be produced through many synthetic routes.

US 5,021,421 disclose the preparation of Blonanserin as shown below.

The condensation of cyclooctanone with 3-(4-fluorophenyl)-3-oxopropanenitrile by heating with polyphosphoric acid at 120°C gives 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2(lH)-one which is converted to 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine by treatment with refluxing POCI3 (or) phenyl phosphonic dichloride. The reaction of 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine with 7V-ethylpiperazine at 170°C affords blonanserin of formula I.

A general short coming of the prior-art methods residues in that processes proposed involve apart from applying column chromatography, additional isolation steps, which are acknowledge to decrease yield and rendering the process cumbersome.

In view of the short comings of the prior art an object of the present invention residues in providing an alternative process for obtaining blonanserin which may be rapidly carried out, is economical and provides the desired compound in high purity.

OBJECT OF THE INVENTION

The main object of the present invention is to provide a process for the preparation of blonanserin with high purity.

Another embodiment of the invention provides a process for the preparation blonanserin intermediate compounds.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Blonanserin.

The main aspect of the present invention provides a process for the preparation of Blonanserin which comprises

a) Conversion of compound of Formula II

Formula II

by using sulphuric acid or in combination with trifluoroacetic acid to give an amide of Formula III

Formula III

b) Followed by condensation of Formula III with cyclooctanone to give
compound of formula IV

Formula IV

c) Then reacting compound of formula IV with PBr3 to give compound of
formula V

Formula V

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes a process for the preparation of Blonanserin intermediates through the conversion of compound of formula II to an amide of formula III followed by condensation of formula III with cyclooctanone to yield compound of formula IV which in turn is reacted with PBr3 to give compound of formula V.

Normally in the prior art cyclization of cyclooctanone and 3-(4-fluorophenyl)-3-oxopropanenitrile to give 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cycloocta[b] pyridin-2(lH)-one is achieved by using polyphosphoric acid. The inventors have found the cyclization requires large excess of PPA and which in turn generates lot of effluent making the environment hazardous.

The conversion of compound of formula II to give an amide of formula III is performed using sulphuric acid or in combination with trifluoroacetic acid. The mixture was stirred at ambient temperature followed by heating to 65-70°C for 14-16 hrs. After completion of the reaction, the reaction mass is quenched into ice cold water followed by neutralization with 50% sodium hydroxide solution. The obtained aqueous layer was extracted with ethyl acetate and solvent evaporated to get a semi solid residue which was triturated with ethyl alcohol to obtain compound of formula III.

The compound of formula III on condensation with cyclooctanone gives compound of formula IV.

Normally in prior-art, the conversion of 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctafb]pyridin-2(l H)-one to 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine is achieved by employing phenyl phosphonic dichloride and also with POCI3 which are not economical. Hence, the inventors have surprisingly found that the same conversion can be accomplished with cheaply and commercially available reagents like PBr3.

The obtained compound of formula IV is subsequently converted to compound of formula V by employing PBr3. The reaction is conducted as neat.

To 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2(lH)-one (IV), phosphorous tribromide is added and the reaction is heated to 170-180°C for 3 hrs.

After completion of the reaction as ascertained by TLC, the reaction mass was quenched into ice-cooled water and extracted with methylene dichloride. The organic layer was evaporated to dryness and isolated by addition of n-hexane resulting in 2-bromo-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b] pyridine i.e. compound of formula V.

The obtained compound of formula V is condensed with iV-ethyl piperazine to give blonanserin. The above condensation leading to the formation of blonanserin is achieved as per the methods reported in the prior-art.

The obtained blonanserin is recrystallized from ethanol and subsequently by ethyl acetate to give blonanserin of pharmaceutical grade.

EXAMPLES

1. Preparation of 3-(4-fluorophenyl)-3-oxopropanamide

To a mixture of Sulfuric acid (368.0 g) and Trifluoro acetic acid (74.0 g), 3-(4-fluorophenyl)-3-oxopropanenitrile (50.Og) was added and the resultant reaction mixture was stirred at RT for around 15 min and then for 14-16 hrs at 65-70°C. On completion of reaction by TLC, the reaction mass was quenched into iced water (750.0 g), neutralized with sodium hydroxide solution (50%) and extracted with ethyl acetate. The ethyl acetate layer was concentrated to obtain a semi solid residue which was triturated with ethyl alcohol to obtain a solid having purity by HPLC >99.3%.

Yield in g : 25.0

2. Preparation of 3-(4-fluorophenyl)-3-oxopropanamide

To 3-(4-fluorophenyl)-3-oxopropanenitrile (50.0 g), Sulfuric acid (368.0 g) was added and the resultant reaction mixture was stirred at RT for around 15 min and then for 14-16 hrs at 65-70°C. On completion of reaction by TLC, the reaction mass was quenched into iced water (750.0 g) neutralized with sodium hydroxide solution (50%) and extracted with ethyl acetate. The ethyl acetate layer was concentrated to obtain a semi solid residue which was triturated with ethyl alcohol to obtain a solid having purity by HPLC >99.3%.

Yield in g : 23.0

3. Preparation of 2-bromo-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta
[b] pyridine

To 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2(lH)-one
(15.0 g), Phosphorus tri bromide (43.2 g) was added and maintained for 3 hrs at 170-180°C. On completion of the reaction, reaction mass was quenched into iced water and extracted into methylene dichloride. Obtained organic layer was distilled out and solid isolated by addition of n-hexane to obtain 2-bromo-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta [b] pyridine having purity by HPLC >90%.

4. Preparation of 2-(4-ethylpiperazin-l-yl)-4-(4-fluorophenyi)-5,6,7,8,9,10-
hexahydrocycloocta[b]pyridine (Blonanserin)

To 2-bromo-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (9.0 g), N-Ethyl piperizine (13.2 g) and Potassium iodide (4.2g) were added. Heated at 165°C and stirred for 6 hrs. On completion of the reaction by TLC, the reaction mass was cooled and poured into mixture of water (1.0 Lit) and Ethyl acetate (180.0 mL). Both the layers were separated and organic layer was extracted with 5M HCI (2x67.5 mL). The pH of aqueous layer was adjusted to 8.0-8.5 with potassium carbonated solution (50%) and extracted with Ethyl acetate. Combined organic layer was concentrated and solid isolated in Ethanol.

Recrystallize the solid from ethanol followed by ethyl acetate to get pure Blonanserin.

CLAIMS

1. A process for the preparation of Blonanserin which comprises

a) Conversion of compound of Formula II

Formula II

by using sulphuric acid or in combination with trifluoroacetic acid to give an amide of Formula III

Formula III

b) Followed by condensation of Formula III with cyclooctanone to give
compound of formula IV

Formula IV

c) Then reacting compound of formula IV with PBr3 to give compound of
formula V

Formula V

2. The process according to claim 1, wherein the compound of formula V is converted to blonanserin of formula I.

3. The process according to claim 2, wherein the obtained blonanserin is recrystalised from ethanol and subsequently by ethyl acetate.