Claims:CLAIMS

1. A process for preparing Aripiprazole of Formula (I) in one step, comprising:

reacting 1-(2,3-dichlorophenyl)piperazine or an acid addition salt thereof of Formula (Va) with a compound of Formula (IIIa), wherein X and Y are leaving groups;
followed by reaction with 7-Hydroxy-4,5-dihydrocarboxystyryl of Formula (II) to produce Aripiprazole.

2. The process according to claim 1, wherein 1-(2,3-dichlorophenyl)piperazine or an acid addition salt thereof of Formula (Va) is sequentially reacted before addition of 7-Hydroxy-4,5-dihydrocarboxystyryl of Formula (II).

3. The process according to claim 1, wherein reaction is carried out in the presence of suitable base and solvent.

4. The process according to claim 3, wherein suitable base comprises of inorganic base comprising of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or combination thereof.

5. The process according to claim 3, wherein suitable solvent comprises of mixture of polar aprotic solvent with ketonic solvent.

6. The process according to claim 5, comprising using dimethyl sulfoxide, dimethyl formamide, 1-methyl-2-pyrrolidinone or hexamethylphosphoramide is used as polar aprotic solvent.

7. The process according to claim 5, comprising using methyl ethyl ketone or methyl isobutyl ketone as ketonic solvent.

8. The process according to claim 1, comprises further step of azeotropic removal of water formed during the reaction.

Dated this the 14th day of March 2018

Signature: ___________________
Name: (Meghana H. Damani)
Applicant’s Agent , Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone of Formula (I) also known as Aripiprazole. The process of present invention is carried out in step at a commercially viable scale. Thus, making the production highly efficient, economic and technically advanced.

BACKGROUND OF THE INVENTION
7-[4-[4-(2,3-Dichlorophenyl)-l-piperazinyl]butoxy]-3,4-dihydro-2(lH)-quinolinone, INN Aripiprazole, is psychotherapic drug developed by Otsuka. Aripiprazole is approved specifically for the treatment of schizophrenia and bipolar disorder. Aripiprazole is marketed as oral tablets under the trade name of Ability®. Aripiprazole mediates its antipsychotic effects primarily by partial agonism at the D2 receptor. In addition to partial agonist activity at the D2 receptor, aripiprazole is also a partial agonist at the 5-HT1A receptor, and like the other atypical antipsychotics, aripiprazole displays an antagonist profile at the 5-HT2A receptor. Aripiprazole has moderate affinity for histamine and alpha adrenergic receptors, and no appreciable affinity for cholinergic muscarinic receptors.

Aripiprazole was generically disclosed in US 4,734,416, and specifically disclosed in US 5,006,528. Several succeeding patent(s)/application(s) have disclosed process of synthesis and manufacturing Aripiprazole using different route of synthesis and intermediates. Out of these, two routes for synthesis of aripiprazole have been widely used in industry. These routes are shown in Scheme-1 and 2 respectively.

Scheme-1 comprises of reacting 7-hydroxy-4,5-dihydrocarbostyryl of Formula (II) with a 1,4-dibromobutane of Formula (III) in a suitable solvent to obtain a 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone of Formula (IV) and in the next step reacting compound of Formula (IV) with 1-(2,3- dichlorophenyl) piperazine hydrochloride of formula (V) in a suitable solvent to obtain Aripiprazole of Formula (I).

The major drawback of practicing route of Scheme-1 is formation of dimer impurity of Formula (VII). The dimer impurity is formed in first step and difficult to separate from compound of Formula (IV) by conventional purification techniques. Thus, it gets carried forward in the next step of condensation with compound of Formula (V) and is observed as an impurity in final product which is difficult to remove by crystallization process affecting the purity of final product. Overall the operational steps must be added making process unsuitable for commercial scale-up.


Scheme-2 comprises of reacting 1-(2,3- dichlorophenyl) piperazine hydrochloride of Formula (V) with a 1,4-dibromobutane of Formula (III) in presence of a suitable base and solvent to obtain a quaternary spiro ammonium salt of Formula (VI) that is reacted in next step with 7-hydroxy-4,5-dihydrocarbostyryl of Formula (I) in the presence of a suitable base and solvent to obtain Aripiprazole of Formula (I).

Disadvantages associated with route of Scheme-2 is prolonged reaction time up to 15 hours in first step to obtain spiro intermediate of Formula (VI). Further, the spiro intermediate is contaminated with inorganic salts like potassium carbonate, bicarbonate, chloride and bromide with the ratio of organic/inorganic salts being 40/60 (w/w). Thus, leading to decrease in yield and further requirement of purification step. The reaction of purified compound of formula (VI) with compound of formula (II) in second step requires approximately 18 hours and obtained Aripiprazole needs additional purification by crystallization method. Thus, overall the process becomes lengthy and requires additional procedural steps making it commercially non-viable.

In order to overcome the practical problems associated with the prior art, there is a need to develop a process for preparing Aripiprazole that is superior in terms of technology and the quality of product obtained.

SUMMARY OF THE INVENTION
The present invention provides process for preparation of compound of Formula (I) or a salt, solvate including a hydrate, stereoisomer, or polymorph thereof.

In one embodiment, compound of Formula (I) is prepared in one step from compound of Formula (II), (IIIa) and (Va).

In another embodiment, compound of Formula (I) is prepared in one step comprising reacting sequentially compound of Formula (Va) before adding compound of Formula (II).

In yet another embodiment, compound of Formula (I) is prepared in one step from compound of Formula (II), (IIIa) and (Va), in presence of suitable solvent and base.

In yet another embodiment, compound of Formula (I) is prepared in one step from compound of Formula (II), (IIIa) and (Va), comprising step of azeotropic distillation.

The processes can be understood by referring the accompanied detailed description.

DETAIL DESCRIPTION OF THE INVENTION
The term ‘Aripiprazole’ as used herein includes Aripiprazole, its pharmaceutically acceptable salts, solvates including hydrates, polymorphs, isomers and related compounds.

The term ‘in one step’ unless otherwise specified is intended to include reaction carried out in single reaction vessel without having to isolate and purify the intermediates formed during the reaction sequence.

In accordance with the present invention there is provided a process for preparing Aripiprazole of Formula (I) in one step, comprising:

reacting 1-(2,3-dichlorophenyl)piperazine or an acid addition salt thereof of Formula (Va) with a compound of Formula (IIIa), wherein X and Y are leaving groups;
followed by reaction with 7-Hydroxy-4,5-dihydrocarboxystyryl of Formula (II) to produce Aripiprazole.

X and Y as defined herein may either be the same or different and are preferably selected from the group comprising halogens. Preferred examples of halogens include chlorine, bromine and iodine.

A preferred embodiment of the present invention provides a process for preparing Aripiprazole of Formula (I), wherein 1-(2,3-dichlorophenyl)piperazine or an acid addition salt thereof of Formula (Va) is sequentially reacted before addition of 7-Hydroxy-4,5-dihydrocarboxystyryl of Formula (II).

The reaction of present invention is carried out in the presence of suitable base and solvent.

In a preferred embodiment suitable base comprises of inorganic base preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or combination thereof.

In other preferred embodiment suitable solvent comprises of mixture of polar aprotic solvent with ketonic solvent. Preferred polar aprotic solvents are selected from dimethyl sulfoxide, dimethyl formamide, 1-methyl-2-pyrrolidinone, hexamethylphosphoramide or mixtures thereof. Preferred ketonic solvent comprises of methyl ethyl ketone or methyl isobutyl ketone.

In one preferred embodiment of the present invention 1-(2,3-dichlorophenyl)piperazine or an acid addition salt thereof of Formula (Va) is reacted with compound of Formula (IIIa) in the presence of suitable base and polar aprotic solvent for stipulated period of 3 to 6 hours. Further, ketonic solvent and 7-Hydroxy-4,5-dihydrocarboxystyryl of Formula (II) are added to the reaction system and refluxed for another 6 to 12 hours or till the reaction is complete. The reaction is carried out at elevated temperature to facilitate the removal of water formed during the reaction.

In one preferred embodiment of the present invention 1-(2,3-dichlorophenyl)piperazine or an acid addition salt thereof of Formula (Va) is reacted with compound of Formula (IIIa) in the presence of suitable base and mixture of polar aprotic solvent and ketonic solvent for stipulated period of 3 to 6 hours. Further, 7-Hydroxy-4,5-dihydrocarboxystyryl of Formula (II) is added to the reaction system and refluxed for another 6 to 12 hours or till the reaction is complete. The reaction is carried out at temperature in range of 80? to 140? to facilitate the removal of water formed during the reaction.

The most preferred embodiment of the present invention comprises step of azeotropic removal of water formed during the reaction using conventional methods.

After completion of the reaction the reaction mixture may be worked up and if required the obtained product may be purified by techniques known perse or by methods described in the accompanying examples.

Advantages of present invention:
- Single step reaction, thus reducing the number of operational steps.
- No requirement of isolation of intermediates and its purification.
- Lower reaction times, thus making the process easily scalable.

The inventors of the present invention have successfully carried out the reaction on commercial quantities. The invention is further illustrated by the following non-limiting examples.

Examples:
Example 1: To a suspension of 1-(2,3- dichlorophenyl) piperazine hydrochloride (12 kg) and potassium carbonate (14.88 kg) in dimethyl formamide (25.80 l.) was added 1,4-dibromobutane (9.6 kg). The resulting mixture was heated to 90-95°C for 6 hr. To the suspension added methyl isobutyl ketone (86.40 l.), 7-hydroxy-4,5-dihydrocarbostyryl (6.6 kg) and potassium carbonate (16.92 kg). The resulting mixture was refluxed for 12 hrs. The water generated in the reaction was removed by azeotropic distillation. The reaction temperature was brought down to 60-65°C and methyl isobutyl ketone (60 l.) was distilled under vacuum. Water (86.40 l.) and hexanes (86.40 l.) were added, and the suspension stirred for 30 min. The medium was filtered, and the filter cake washed with water (42 l.) and suctioned. The wet filter cake was dried under vacuum and then re-crystallized in the mixture of alcoholic and chlorinated solvent (120 l.), to yield aripiprazole as a white powder (13 kg).

Example 2: To a suspension of 1-(2,3- dichlorophenyl) piperazine hydrochloride (100 g) and potassium carbonate (265 g), methyl isobutyl ketone (720 ml) and dimethyl formamide (215 ml) was added 1,4-dibromobutane (80 g). The resulting mixture was heated to 90-95°C for 6 hr. To the suspension added 7-hydroxy-4,5-dihydrocarbostyryl (55 g). The resulting mixture was refluxed for 12 hrs. The water generated in the reaction was removed by azeotropic distillation. The reaction temperature was brought down to 60-65°C and methyl isobutyl ketone (500 ml) was distilled under vacuum. Water (720 ml) and hexanes (720 ml) were added, and the suspension stirred for 30 min. The medium was filtered, and the filter cake washed with 350 ml water and suctioned. The wet filter cake was dried under vacuum and then re-crystallized in the mixture of alcoholic and chlorinated solvent (1000 ml), to yield aripiprazole as a white powder (105 g).

Example 3: To a suspension of 1-(2,3- dichlorophenyl) piperazine hydrochloride (100 g) and potassium carbonate (124 g) in dimethyl sulfoxide (215 ml) was added 1,4-dibromobutane (80 g). The resulting mixture was heated to 90-95°C for 6 hr. To the suspension added methyl isobutyl ketone (720 ml), 7-hydroxy-4,5-dihydrocarbostyryl (55 g) and potassium carbonate (141 g). The resulting mixture was refluxed for 12 hrs. The water generated in the reaction was removed by azeotropic distillation. The reaction temperature was brought down to 60-65°C and methyl isobutyl ketone (500 ml) was distilled under vacuum. Water (720 ml) and hexanes (720 ml) were added, and the suspension stirred for 30 min. The medium was filtered, and the filter cake washed with 350 ml water and suctioned. The wet filter cake was dried under vacuum and then re-crystallized in the mixture of alcoholic and chlorinated solvent (1000 ml), to yield aripiprazole as a white powder (102 g).

Example 4: To a suspension of 1-(2,3- dichlorophenyl) piperazine hydrochloride (100 g) and potassium carbonate (124 g) in 1-methyl-2-pyrrolidinone (215 ml) was added 1,4-dibromobutane (80 g). The resulting mixture was heated to 90-95°C for 6 hr. To the suspension added methyl isobutyl ketone (720 ml), 7-hydroxy-4,5-dihydrocarbostyryl (55 g) and potassium carbonate (141 g). The resulting mixture was refluxed for 12 hrs. The water generated in the reaction was removed by azeotropic distillation. The reaction temperature was brought down to 60-65°C and methyl isobutyl ketone (500 ml) was distilled under vacuum. Water (720 ml) and hexanes (720 ml) were added, and the suspension stirred for 30 min. The medium was filtered, and the filter cake washed with 350 ml water and suctioned. The wet filter cake was dried under vacuum and then re-crystallized in the mixture of alcoholic and chlorinated solvent (1000 ml), to yield aripiprazole as a white powder (80 g).

It is appreciated that various modifications to the inventive concepts may be apparent to those skilled in the art without departing from the spirit and scope of the invention.