DESC:AN IMPROVED PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE INTERMEDIATES

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 7-(4-halobutoxy)-3,4-dihydro-2(1H)-quinolinone, an intermediate of Aripiprazole.
BACKGROUND OF THE INVENTION
Aripiprazole is chemically described as, 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one and is structurally represented by Formula I:

is used for the treatment of Schizophrenia.
Several synthetic methods of aripiprazole preparation are described in U.S. Pat. No. 5,006,528 (hereinafter the ‘528 patent), including the method described in the scheme 1.

According to this synthetic method aripiprazole is prepared in two steps. The first step comprises alkylating the hydroxy group of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone of formula (II) with 1,4-dibromobutane to obtain 7-(4-bromobutoxy)-3,4-dihydroquinolinone of formula (III). A mixture of potassium carbonate, 7-hydroxy-3,4-dihydro-2(1H)-quinolinone 1,4-dibromobutane in water is refluxed for 3 hours. The reaction mixture thus obtained is extracted with dichloromethane, dried with anhydrous magnesium sulfate, and the solvent is removed by evaporation. The residue is purified by means of a silica gel column chromatography (eluent:dichloromethane), eluent evaporation and recrystallization from a mixture of ethanol and n-hexane to obtain 7-(4-bromobutoxy)-3,4-dihydroquinolinone in low yield.
But this synthetic procedure described in the ‘528 patent yields relatively large amounts of impurities along with 7-(4-bromobutoxy)-3,4-dihydroquinolinone. Among these impurities, the following dimer impurity is of major concern: 1,4-bis(3,4-dihydro-2(1H)-quinolinone-7-oxybutane.
Another process for preparing Aripiprazole is described in PCT publication No. WO 2004/063162 A1 which is described in Scheme 2 below:

In this process, the N-alkylation of 1-(2,3-dichlorophenyl)piperazine (IV) is carried out with 7-(4-chlorobutoxy)-3,4-dihydro-(1H)-quinolinone of formula V in water in the presence of an inorganic base. A mixture of 7-(4-chlorobutoxy)-3,4-dihydro-(1H)-quinolinone and 1-(2,3-dichlorophenyl)piperazine mono hydrochloride and potassium carbonate in water is heated with stirring at 90-95° C. for 4 hours. Then, the reaction mixture is cooled to about 40°C, and the obtained crystals are collected by filtration. The crystals are washed with water and dissolved in ethyl acetate (9 vol.), and an azeotropic mixture of water-ethyl acetate (about 3 vol.) is distilled out. The remaining solution is cooled to 0-5° C, and the crystals are collected by filtration and dried to obtain aripiprazole.
In U.S. Patent Application No. US 2006/0079689 A1 (hereinafter the ‘689 application), processes are provided for preparing the carbostyril intermediate 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone and aripiprazole thereof. According to the ‘689 application the purification of 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone or 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone is carried out by slurrying process, which is liable in some cases to be less convenient for large scale preparation.

Therefore, there is still a need in the art for an improved low-cost process for the preparation of purified carbostyril compounds such as 7-(4-halobutoxy)-3,4-dihydro-2(1H)-quinolinone, which will be suitable for large-scale preparation, in terms of simplicity, chemical yield and purity of the product.
The process of the present invention has advantages of simple, easy handling and increased productivity which afford a significantly greater yield and completely avoids formation of dimer impurity. The process is also industrially scalable; cost effective which makes it highly suitable for industrial scale.
SUMMARY OF THE INVENTION
In the first embodiment the present application provides a process for the preparation of 7-(4-halobutoxy)-3,4-dihydro-2(1H)-quinolinone of formula A, comprising:
reacting a compound of formula B with a halogenation reagent

wherein, Y is a leaving group selected from the group consisting of C1-C4 alkanesulfonyloxy group or the arylsulfonyloxy group and X is a halogen selected from the group consisting of chloro, bromo and iodo.
In the second embodiment the present application provides a process for the preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone of formula (III), comprising:
reacting 7-(4-methanesulfonyloxybutoxy)-3,4-dihydro-2(1H)-quinolinone with tetra-n-butylammonium bromide (TBAB)

DETAILED DESCRIPTION OF THE INVENTION
In the aspects of the first embodiment, the present application provides a process for the preparation of compound of formula A, comprising:
reacting a compound of formula B with a halogenation reagent,

wherein, X and Y are as defined above.
The reaction of compound of formula B with halogenation reagent may be performed in a suitable solvent. The solvents includes but not limited to water, alcohol solvent such as methanol, ethanol, propanol, 2-propanol, n-butanol and the like; ether solvent such as tetrahydrofuran, diethyl ether and the like; aromatic hydrocarbon solvent such as benzene, toluene and the like; aliphatic hydrocarbon solvent such as heptane, hexane and the like; chlorinated hydrocarbon solvent such as dichloromethane and the like and the mixtures thereof. Specifically, the solvent is an aromatic hydrocarbon solvent. More specifically, the solvent may be toluene.
The halogenation reagent can be selected from the group comprising thionylchloride, oxalylchloride, hydrochloricacid, N-chlorosuccinimide, trimethylsilyl chloride, bromine, posphoroustribromide, borontribromide, tetra-n-butylammonium bromide, N-bromosuccinimide, 1,3-Dibromo-5,5-dimethylhydantoin, iodine, potassium iodide and N-iodosuccinimide.
The reaction of compound of formula B with halogenation reagent may be carried out for about 30 minutes to about 36 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out for about 1 hour to about 24 hours at about 60 °C to about room temperature. The resulting compound of formula A may be isolated from the reaction mass by any method known in the art.
In the aspects of the second embodiment, the present application provides a process for the preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone of formula (III), comprising:
reacting 7-(4-methanesulfonyloxybutoxy)-3,4-dihydro-2(1H)-quinolinone with tetra-n-butylammonium bromide (TBAB)

The reaction of 7-(4-methanesulfonyloxybutoxy)-3,4-dihydro-2(1H)-quinolinone with tetra-n-butylammonium bromide (TBAB) may be performed in a suitable solvent. The solvents includes but not limited to water, alcohol solvent such as methanol, ethanol, propanol, 2-propanol, n-butanol and the like; ether solvent such as tetrahydrofuran, diethyl ether and the like; aromatic hydrocarbon solvent such as benzene, toluene and the like; aliphatic hydrocarbon solvent such as heptane, hexane and the like; chlorinated hydrocarbon solvent such as dichloromethane and the like and the mixtures thereof. Specifically, the solvent is an aromatic hydrocarbon solvent. More specifically, the solvent may be toluene.
The reaction of 7-(4-methanesulfonyloxybutoxy)-3,4-dihydro-2(1H)-quinolinone with tetra-n-butylammonium bromide (TBAB) may be carried out for about 30 minutes to about 36 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out for about 1 hour to about 24 hours at about 60 °C to about room temperature. The resulting compound, 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone of formula (III) may be isolated from the reaction mass by any method known in the art.
The compounds of formula B and VI used as starting materials may be prepared by any of the methods known in the literature.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, "generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skilled in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.
The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours. For example the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period. The reaction time normally depends on the amount of Hydrogen pressure applied. The hydrogen pressure applied may vary from 1 kg/cm2 to 30 kg/cm2.
The isolation may be effected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique.
Suitable temperatures for isolation may be less than about 120 °C, less than about 80 °C, less than about 60 °C, less than about 40 °C, less than about 30 °C, less than about 20 °C, less than about 10°C, less than about 0 °C, less than about -10 °C, less than about -40 °C or any other suitable temperatures.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.
EXAMPLES
Example 1: Preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone
A round bottom flask was charged with toluene (300 ml), 7-(4-methanesulfonyloxybutoxy)-3,4-dihydro-2(1H)-quinolinone (20 gm) and tetra-n-butylammonium bromide (20.5 gm) at room temperature. The temperature of the reaction mass was raised to 90 oC and maintained for 4-5 hours. Then the reaction mass was cooled to 50-55 oC, water (60 ml) was charged and stirred well. The layers were separated and toluene layer was taken into a round bottom flask and the distilled under vacuum at 70 oC. To the round bottom flask isopropyl alcohol (100 ml) was added and cooled to room temperature. Stirred for 1 hour at this temperature and filtered. The solid was washed with isopropyl alcohol (20 ml) and dried to give titled compound.
Yield: 16 gm
Example 2: Preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone
A round bottom flask was charged with toluene (750 ml), 7-(4-methanesulfonyloxybutoxy)-3,4-dihydro-2(1H)-quinolinone (50 gm) and tetra-n-butylammonium bromide (51.25 gm) at room temperature. The temperature of the reaction mass was raised to 90 oC and maintained for 4-5 hours. Then the reaction mass was cooled to 50-55 oC, water (150 ml) was charged and stirred well. The layers were separated and toluene layer was taken into a round bottom flask and the distilled under vacuum at 70 oC. To the round bottom flask isopropyl alcohol (250 ml) was added and cooled to room temperature. Stirred for 1 hour at this temperature and filtered. The solid was washed with isopropyl alcohol (50 ml) and dried to give titled compound.
Yield: 41.5 gm ,CLAIMS:1) A process for the preparation of 7-(4-halobutoxy)-3,4-dihydro-2(1H)-quinolinone of formula A, comprising:
reacting a compound of formula B with a halogenation reagent

wherein, Y is a leaving group selected from the group consisting of C1-C4 alkanesulfonyloxy group or the arylsulfonyloxy group and X is a halogen selected from the group consisting of chloro, bromo and iodo.

2) The process according to claim 1, wherein the halogenation reagent is selected from the group comprising thionylchloride, oxalylchloride, hydrochloricacid, N-chlorosuccinimide, trimethylsilyl chloride, bromine, posphoroustribromide, borontribromide, tetra-n-butylammonium bromide, N-bromosuccinimide, 1,3-Dibromo-5,5-dimethylhydantoin, iodine, potassium iodide and N-iodosuccinimide..

3) A process for the preparation of 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone of formula (III), comprising:
reacting 7-(4-methanesulfonyloxybutoxy)-3,4-dihydro-2(1H)-quinolinone with tetra-n-butylammonium bromide (TBAB)