WO2011030213A1

WO2011030213A1 - Improved process for the preparation of 7.(4-bromobutoxy) 3,4-dihydrocarbostyril, a precursor of aripiprazole

Info

Publication number: WO2011030213A1
Application number: PCT/IB2010/002276
Authority: WO
Inventors: Jayant Srivastava; Vijay Shankar Gupta; Bharat Vithalbhal Varu; Parmod Kumar; Dharam Vir
Original assignee: Jubilant Organosys Limited
Priority date: 2009-09-14
Filing date: 2010-09-14
Publication date: 2011-03-17
Also published as: WO2011030213A8

Abstract

Disclosed herein is an improved process for the preparation of 7-(4-bromobutoxy) 3,4-dihydrocarbostyril, a key intermediate used in the preparation of Aripiprazole.

Description

IMPROVED PROCESS FOR THE PREPARATION OF 7-(4-BROMOBUTOXY) 3,4-DIHYDROCARBOSTYRIL, A PRECURSOR OF ARIPIPRAZOLE

Field of the Invention

The present invention relates to an improved process for the preparation of 7-(4- bromobutoxy) 3,4-dihydrocarbostyril, a key intermediate used in the preparation of Aripiprazole.

Background of the Invention

7-[4-[4-(2,3-Dichlorophenyl)-l-piperazinyl]butoxy]-3,4- dihydrocarbostyril(Aripiprazole) of the Formula I is an atypical antipsychotic agent useful for the treatment of schizophrenia.

H

Formula I

Schizophrenia is a common type of psychosis characterized by the symptoms like delusions, hallucination, excitations and the like. Schizophrenia generally occurs between the age of 16-25 years and affects one percent individuals worldwide. It is considered as more prevalent than Alzheimer's disease, multiple sclerosis, insulin- dependent diabetes and muscular dystrophy. Schizophrenia is the most common type of psychosis caused by an excessive neurotransmission activity of the dopaminergic nervous system in the central nervous system.

A number of drugs, having the activities for blocking the neurotransmission of dopaminergic receptor in the central nervous system such as chlorpromazine, haloperidol and sulpiride have been developed. However, many of these drugs are considered not effective for improving the negative symptoms, which are observed in the chronic period of schizophrenia.

l 7-[4-[4-(2,3-Dichlorophenyl) -1 -piperazinyl] butoxy]-3,4-dihydrocarbostyril (Aripiprazole) represented by Formula I is generically disclosed in US 4,734,416 and specifically in US 5,006,528 patents.

US 5,006,528 discloses process for the preparation of Aripiprazole in two steps. The first step comprises synthesis of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (7-BBQ) by alkylating the hydroxy group of 7-hydroxy-3,4-dihydrocarbostyril (7-HQ) with 1 ,4-dibromobutane using potassium carbonate in water at reflux temperature for 3 hours to obtain 7-BBQ in 68% yield. The resulting 7-BBQ is further reacted with 1- (2,3-dichlorophenyl)-piperazine to obtain Aripiprazole. It has been observed that during the preparation of 7-BBQ, water is difficult to remove from the reaction mixture and the resulting product is contaminated with large amount of impurity mainly dimer impurity of Formula IV in more than 10%, which is difficult to remove in the final Aripiprazole product.

Formula IV

Another method for preparing 7-BBQ is described in J. Med. Chem. 1998, 41 , 658- 667, wherein 7-BBQ is obtained by reaction of 7-HQ with 3 molar equivalent of 1,4- dibromobutane in dimethylformamide in the presence of potassium carbonate. The reaction is conducted by mixing the said reagents for four hours at 60°C to obtain reaction product, which was diluted with water, followed by extraction with ethyl acetate. The organic layers were separated, washed and evaporated to dryness under vacuum. Recrystallization from ethanol gave pure 7-(4-bromobutoxy)-3,4- dihydrocarbostyril in 78% yield. The main drawback of the said process is the use of dimethylformamide, which is not only harmful by inhalation but also acts as carcinogen and its long-term exposure may result in kidney or liver damage. Moreover, 7-BBQ obtained by the said process involves the formation of dimer impurity in the range of 5-8%, which causes low yield and affect the purity of 7-BBQ as well as final Aripiprazole product. Similarly, US 7,361 ,756 discloses the process for the preparation of 7-BBQ by mixing 7HQ and dibromobutane and at least one base to form a reaction mixture, heated the said mixture at temperature between 50-140°C, cooled the reaction mixture and isolated 7-BBQ from the reaction mixture. US '756 also disclose the use of phase transfer catalyst during the reaction. The main drawback of the process disclosed in the US'756 patent is the preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (7- BBQ) at high reaction temperature (140°C or above), which not only increases the formation of dimer impurity but also difficult to handle on the commercial scale, thus make the process tedious and uneconomical. Further the inventor of the present invention observed that once the dimer impurity is formed during the preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, it is difficult to remove completely even after multiple purifications. This not only increases the number of operational steps, but also increases the production cost and makes the process unsuitable and unviable on commercial scale.

WO2008146156 A2 discloses a process for the preparation of 7-[4-[4-(2,3- dichlorophenyl)- 1 -piperazinyl]butoxy]-3 ,4-dihydro-2-(l H)-quinolinone by reacting 7- hydroxy-3,4-dihydro-2(lH)-quinolinone with 1 ,4-dibromobutane in the presence of base and solvent at temperature 75-100°C to form 7-[4-bromobutoxy]-3,4-dihydro- 2(l H)-quinolinone, treating the resulting compound with silica gel in a solvent to produce pure 7-[4-bromobutoxy]-3,4-dihydro-2(lH)-quinolinone, reacting the resulting compound with l-(2,3-dichlorophenyl)piperazine or its salt to produce Aripiprazole. The main drawback is 7-[4-bromobutoxy]-3,4-dihydro-2(lH)- quinolinone prepared by the said process is contaminated by 5 to 10% dimer impurity, thus removal of said dimer impurity require extra purification step. This not only increases the number of steps, but also increases the production cost on commercial scale.

The process disclosed in the prior arts have several limitations like high reaction temperature above 140°C during the preparation of 7-(4-bromobutoxy)-3,4- dihydrocarbostyrii (7-BBQ), use of carcinogenic solvents like dimethylformamide, multiple purification step, which makes the process unsuitable on commercial scale. Object and Summary of the Invention

It is an object of the present invention to improve upon limitations in the prior art by providing a commercially viable and environment friendly process, for the preparation of intermediate 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of formula II with less dimer content, utilizing mild reaction conditions and producing aripiprazole in high yield and purity.

In accordance with an embodiment of the present invention, there is provided an improved process for producing 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of Formula II

Formula II

comprising reacting 7-hydroxy-3,4-dihydrocarbostyril (7-HQ) of Formula III with 1 ,4-dibromobutane in presence of base in an organic solvent, wherein the reaction is performed at a temperature 45°C or below.

Formula III

In accordance with another preferred embodiment of the present invention, there is provided an improved process for producing 7-[4-[4-(2,3-dichlorophenyl)-l- piperazinyl]butoxy]-3,4-dihydrocarbostyril (Aripiprazole) of Formula I having dimer content less than 0.1%

Formula I

comprising reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of Formula II

Formula II

with l-(2,3-dichlorophenyl)piperazine or its salt in the presence of base and solvent and in the absence of phase transfer catalyst.

DETAILED DESCRIPTION OF THE INVENTION

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

According to the one embodiment of the present invention, there is provided an improved process for the preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of Formula II

Formula II

comprising reacting 7-hydroxy-3 4-dihydrocarbostyril (7-HQ) of Formula III

Formula III

with 1 ,4-dibromobutane in presence of a base in an organic solvent at temperature 45°C or below.

According to the present invention, the reaction of 7-hydroxy-3,4-dihydrocarbostyril (7-HQ) of Formula III with 1 ,4-dibromobutane is carried out in presence of a base in an organic solvent, at temperature 45°C or below in order to reduce the formation of dimer impurity. Further, the base can be selected from organic or inorganic. The organic base can be selected from diethylamine, triethylamine, pyridine, diisopropylamine, diisopropylethyl amine and the like. The inorganic base can be selected from alkali metal or alkaline earth metal carbonate, bicarbonates, hydroxide, alkoxides, hydride and the like or mixture thereof.

The solvent used herein can be selected from lower alcohols, nitriles, ethers, esters, chlorinated hydrocarbons, ketone, and the like and mixture thereof. Preferably, the solvent is selected from methanol, ethanol, propanol, butanol, acetonitrile, propionitrile tetrahydrofuran, ethyl acetate, propyl acetate, butyl acetate, dichloromethane, 1 ,2-dichloroethane, chloroform, acetone, or mixture thereof.

The reaction can optionally be carried out in presence of phase transfer catalyst, wherein the phase transfer catalyst is selected from quaternary ammonium and phosphonium compound, crown ethers or polyethylene glycols. Few examples of the phase transfer catalyst, but are not limited to tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, benzyl tributylammonium chloride, benzyl triethylammonium chloride, tetramethylammonium chloride, tetrabutylphosphonium chloride, dibenzo- 18-crown-6, PEG-200 or PEG-400, preferably tetrabutylammonium iodide and tetrabutylammonium bromide. The phase transfer catalyst can be present in an amount of about 0.1 to about 5 mole equivalent with respect to the 7-hydroxy-3,4- dihydrocarbostyril. Preferably, the phase transfer catalyst is present in an amount of about 0.1 to about 1 mole equivalent with respect to the 7-hydroxy-3,4- dihydrocarbostyril.

The reaction is carried at temperature 45°C or below, preferably between 20-45°C more preferably between 25-45°C. The reaction time depends on the scale and the mixing procedure as is commonly known to the person skilled in the art. Typically the reaction time is from about 20 to about 50 hours.

After the completion of the reaction, the reaction mixture is cooled to room temperature, filtered, followed by distillation of filtrate. The resultant mass was cooled to room temperature and non-polar solvent such as cyclohexane was added, as a result solid was precipitated off, which was filtered, washed with water and dried to obtain 7-(4-bromobutoxy)_^3,4-dihydrocarbostyril, having low dimer content.

According to another embodiment of the present invention, there is provided an improved process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)-l- piperazinyl]butox -3,4-dihydrocarbostyril (Aripiprazole) of Formula I,

H

Formula I

comprising reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of Formula II, having low dimer content

Formula II

with l-(2,3-dichlorophenyl)piperazine or its salt in the presence of a base and solvent and in the absence of phase transfer catalyst. The base can be selected from organic or inorganic. The inorganic base can be selected from alkali metal or alkaline earth metal carbonate, bicarbonates, hydroxide, alkoxides, hydride and the like or mixture thereof. Preferably, the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, sodium alkoxide, potassium alkoxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate and the like. The organic base can be selected from diethylamine, triethylamine, pyridine, diisopropylamine, diisopropylethyl amine and the like. The solvent used herein can be selected from lower alcohols, nitriles, esters, chlorinated solvents, ketone, amides, sulfoxides and the like or mixture thereof. Preferably the solvent is selected from methanol, ethanol, propanol, butanol, acetonitrile, propionitrile, ethyl acetate, propyl acetate, butyl acetate, dichloromethane, chloroform, dimethylsulphoxide, dimethylformamide or mixture thereof. The reaction is carried at temperature of about 35-90°C, preferably between 75-85°C more preferably between 80-85°C for 5 to 10 hours, preferably between 6-8 hours.

The aripiprazole so obtained is crystallized employing the suitable solvent such aliphatic alcohol and water, wherein alcohol is selected from methanol, ethanol, propanol, butanol and the like to obtain pure aripiprazole having dimer impurity content less than 0.1 %, preferably less than 0.05%.

The present invention is further described in greater detail as illustrated in the non- limiting examples. It should be understood that variation and modification of the process are possible within the ambit of the invention broadly disclosed herein.

Example 1

Preparation of 7-(4-bromobutoxy)-3,4-dihvdrocarbostyril

7-Hydroxy-3,4-dihydrocarbostyril (60gm) and potassium carbonate (76.3 gm) were taken in acetonitrile (1200ml) at room temperature. To this tetra butyl ammonium iodide (13.7 gm) and 1 ,4-dibromobutane (238.5gm) were added and heated at 40- 45°C for 24 hours. Reaction mass was cooled upto room temperature and was filtered off. The resulting filtrate was distilled off under vacuum. The resultant mass was cooled to 25-30°C and cyclohexane (300 ml) was added under stirring. The resulting solid was filtered off and was dried. The resulting solid was taken in water and was stirred for few minutes. The solid was filtered and dried under vacuum at 55-60°C for 20 hours to obtain title compound.

Yield: 73-75%; Purity: 93-95%

Example 2

Preparation of 7-(4-bromobutoxyV3,4-dihvdrocarbostyril

7-Hydroxy-3,4-dihydrocarbostyril (5 gm) and potassium carbonate (6.35gm) were taken in acetonitrile (100ml) at room temperature. To this tetra butyl ammonium iodide (1.13 gm) and 1 ,4-dibromobutane (19.8 gm) were added and heated at 25-30°C for 30 hours. Reaction mass was filtered off and wash with acetonitrile. The resulting filtrate was distilled off under vacuum. The resultant mass was cooled to 25-30°C, cyclohexane (25 ml) was added and was stirred. The resulting solid was filtered off and to the solid mass, water was added under stirring. The solid was filtered and dried under vacuum at 55-60°C for 16 hours to obtain title compound.

Yield: 42-43%; Purity: 90.2%

Example 3

Preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril

7-Hydroxy-3,4-dihydrocarbostyril (25gm) and potassium carbonate (31.7 gm) were taken in the ethanol (500 ml) at ambient temperature. To this tetra butyl ammonium iodide (5.6 gm) and 1 ,4-dibromobutane (99.3gm) were added and heated at 42-43°C for 40 hours. Reaction mass was cooled upto room temperature and was filtered off. The resulting filtrate was distilled off under vacuum. The resultant mass was then cooled to room temperature. Cyclohexane was added under stirring and the resulting solid was filtered off. To the resulting solid, water was added and was stirred. The solid was filtered and dried under vacuum at 50-55°C for 16 hours to obtain title compound.

Yield: 70-72%; Purity: 86%

Example 4

Step-2 Preparation of pure 7- 4-[4-(2.3-dichlorophenylVl-piperazinyl1butoxyl-3,4- dihydrocarbostyril

7-(4-Bromobutoxy)-l ,2,3,4-tetrahydroquinolin-2-one (50 gm) was taken in acetonitrile (500 ml) at 25-30°C. To this potassium carbonate (67.2 gm) and l-(2,3- dichlorophenyl) piperazine hydrochloride (44.9gm) were added under stirring. The reaction mixture was refluxed at 80-85°C for 8 hours. The reaction mass was cooled to room temperature, filtered and the resulting solid was washed with acetonitrile. To the resulting solid, water was added and was stirred. The solid was filtered off, washed with water and dried under vacuum at 75-80°C for 15 hrs. The resulting crude aripiprazole was crystallized from isopropyl alcohol and water to obtain title compound. Yield: 75-80%; Dimer Impurity: <0.1%

Certain modification and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

Claims

We claim:

1. An improved process for producing 7-(4-bromobutoxy)-3,4- dihydrocarbostyril of Formula II

Formula II

comprising reacting 7-hydroxy-3,4-dihydrocarbostyril (7-HQ) of Formula III with 1 ,4-dibromobutane in presence of a base in an organic solvent a temperature 45°C or below.

Formula III

2. The process according to claim 1, wherein the reaction is performed at a temperature 20 to 45°C.

3. The process according to claim 1, wherein the base is selected from organic or inorganic.

4. The process according to claim 2, wherein the organic base is selected from the group comprising of diethylamine, triethylamine, diisopropylamine, diisopropylethyl amine and pyridine.

5. The process according to claim 1, wherein the inorganic base is selected from the group comprising of alkali metal or alkaline earth metal carbonate, bicarbonates, hydroxide, alkoxide, hydride.

6. The process according to claim 1, wherein the solvent is selected from the group comprising of lower alcohols, nitriles, ethers, esters, ketone, chlorinated hydrocarbon, or mixture thereof.

7. The process according to claim 5, wherein the solvent is selected from methanol, ethanol, propanol, butanol, acetonitrile, propionitrile, tetrahydrofuran, ethyl acetate, propyl acetate, butyl acetate, acetone, dichloromethane, chloroform, or mixture thereof.

8. The process according to claim 1, wherein the reaction is carried out optionally in presence of a phase transfer catalyst.

9. The process according to claim 8, wherein the phase transfer catalyst is selected from the group comprising of quaternary ammonium and phosphonium compounds, crown ethers or polyethylene glycols.

10. The process according to claim 9, wherein the phase^' transfer catalyst is selected from the group comprising of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, benzyl tributylammonium chloride, benzyl triethylammonium chloride, tetramethylammonium chloride, tetrabutylphosphonium chloride, dibenzo- 18-crown-6, PEG-200 or PEG-400.

1 1. A process for producing 7-[4-[4-(2,3-dichlorophenyl)-l- piperazinyl]butoxy]-3,4-dihydrocarbostyril (Aripiprazole) of Formula I having dimer impurity less than 0.1%

Formula I further comprising reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of Formula II, as obtained from claim 1 ;

Formula II

12. The process according to claim 11, wherein the salt of 1 -(2,3- dichlorophenyl)piperazine is selected from hydrochloride.

13. The process according to claim 11, wherein the base is selected from organic and inorganic.

14. The process according to claim 13, wherein the inorganic base is selected from alkali metal and alkaline earth metal carbonate, bicarbonates, hydroxide, alkoxide, hydride.

15. The process according to claim 13, wherein the organic base is selected from the group comprising of diethylamine, triethylamine, diisopropylamine, diisopropylethyl amine and pyridine.

16. The process according to claim 11, wherein the solvent is selected from lower alcohols, nitriles, esters, chlorinated solvent, ketone, amides, sulfoxide and the like or mixture thereof.

17. The process according to claim 16, wherein the solvent is selected from methanol, ethanol, propanol, acetonitrile, propionitrile, ethyl acetate, propyl acetate, butyl acetate, dichloromethane, chloroform, acetone, dimethylsulphoxide, dimethylformamide or mixture thereof.

18. The process according to claim 11, wherein the reaction is carried at temperature between 35_^90°C.

19. The process according to claim 1 1, wherein the 7-[4-[4-(2,3- dichlorophenyl)-l-piperazinyl]butoxy]-3,4-dihydrocarbostyril (Aripiprazole) of Formula I is purified using aliphatic alcohol and water.

20. The process according to claim 19, wherein alcohol is selected from methanol, ethanol, propanol and butanol.