FIELD OF INVENTION

[001] The present invention relates to an improved process for the preparation of Aripiprazole, which is used as an antipsychotic and antidepressant.

BACKGROUND OF INVENTION

[002] Aripiprazole is an antipsychotic and antidepressant which is useful for treating schizophrenia, bipolar disorder, and clinical depression. Prior art search revealed a few methods of synthesizing the said compound.

[003] Many processes to synthesize Aripiprazole in the prior art use various starting materials such as carbostyrils, quinolinones, piperazines and amides.

[004] WO2007148191 discloses a process for the preparation of Aripiprazole. The present invention also relates to a process for the preparation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril by reacting 7-hydroxy-3,4- dihydrocarbostyril with 1,4-dichlorobutane, in presence of inorganic base and solvent dimethylacetamide. The Intermediate obtained is treated with l-(2,3-dichlorophenyl)piperazine in presence of a base and alkali iodide in dimethylacetamide to obtain Aripiprazole.

[005] WO2008146156 discloses a process for the preparation of Aripiprazole wherein 7.Hydroxy-3,4-dihydro-2(lH)-quinolinone is treated with 1,4- dibromobutane in presence of base selected from potassium

carbonate and tetrahydrofuran among others to produce 7-(4-bromobutoxy)-3,4-dihydro-2(lH)-quinolinone, which is further treated with silica gel in a solvent to produce pure 7-(4-bromobutoxy)-3,4-dihydro-2(1H) quinolinone. The pure form is then treated with N-(2,3-dichlorophenyl) piperazine in presence of alkali iodide in a solvent to produce Aripiprazole.

[006] WO/2006/038220 discloses a process for the preparation of Aripiprazole which comprises (i) reacting 6-hydroxy-l-indanone with 1,4-dihalobutane in the presence of a base and a solvent to form an intermediate 6-(4-halo butoxy)-indan-l-one, (ii) reacting the intermediate with l-(2,3-clichlorophenyl)-piperazine to get another intermediate 6-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy]-indan-l-one and (iii) reacting the resulting compound with sodium azide.

[007] WO/2004/099152 discloses a process for the preparation of Aripiprazole which comprises (a) reacting dichlorophenylpiperazine (DCPP) or an acid addition salt thereof with a compound of formula XC4H8Y or XC4H6Y to produce a quaternary spiro ammonium salt having a cation of the general formula wherein X and Y are leaving groups; and (b) reacting the quaternary spiro ammonium salt with 7 hydroxydihydrocarboxystyryl (HCS) to produce said carbostyril
derivative having the general formula

[008] WO/2007/094009 discloses a process for the preparation of
Aripiprazole comprising: a) preparation of N-(3-methoxyphenyl)-3- chloropropionamide by the reaction of m-anisidine and 3-chloropropionyl
chloride in presence of sodium bicarbonate and toluene; b) preparation of
7-hydroxy-3,4-dihydrocarbostyril by reacting the obtained N-(3-
methoxyphenyl)-3-chloropropionamide with about 3 to 5 equivalents of a
Lewis acid calalyst in a paraffin free diluent, amines or N,N disubstituted
amides having a boiling point of 150°C or above, at an elevated
temperature of from about 120°C to about 160°C c) preparation of 7-(4-
chlorobutoxy)-3,4-dihydrocarbostyril by reaction of 7-hydroxy-3,4-
dihydrocarbostyril (II) with l-chloro-4-bromobutane in the presence of an
alkali metal carbonate and a PTC, for about 15-18 hours; d) reaction of 7-
(4-chlorobutoxy)-3,4-dihydrocarbostyril with l-(2,3-
dichlorophenyl)piperazine to give aripiprazole.

[009] The present invention provides a process for the preparation of Aripiprazole with 3-(4-hydroxy-2-nitrophenyl) propanoic acid as the starting material.

OBJECT OF INVENTION

[0010] The primary objective of the present invention is to provide a process for the preparation of Aripiprazole.

STATEMENT OF INVENTION

[0011] The invention provides a process for the preparation of
Aripiprazole. The process includes converting 3-(2-nitro-4-
hydroxyphenyl)propanonic acid to methyl[3-(4-Hydroxy-2-
nitrophenyl)]propanoate which inturn is reacted with 1,4-dibromobutane to produce methyl 3-[(4-bromobutoxy)-2-nitrophenyl]propanoate. methyl 3-[(4-bromobutoxy)-2-nitrophenyl]propanoate so obtained is further reacted with l-(2,3-dichlorophenyl)piperazine to produce methyl 3-[{4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy}-2-nitrophenyl]propanoate. Methyl 3 - [ {4- [4-(2,3 -dichlorophenyl)piperazin-1 -yl]butoxy} -2-nitrophenyl]propanoate is then reduced to produce methyl 3-[2-amino-{4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy}phenyl]propanoate. Thereafter, methyl 3-[2-amino-{4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy}phenyl]propanoate is refluxed to produce Aripiprazole.

[0012] These and other aspects of the embodiments herein will be better appreciated and understood when considered in conjunction with the following description. It should be understood, however, that the following
descriptions, while indicating preferred embodiments and numerous specific details thereof, are given by way of illustration and not of limitation. Many changes and modifications may be made within the scope of the embodiments herein without departing from the spirit thereof, and the embodiments herein include all such modifications.

DETAILED DESCRIPTION OF INVENTION

[0013] The embodiments herein and the various features and advantageous details thereof are explained in greater depth with reference to the non-limiting embodiments that are detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

[0014] The present invention relates to a process of preparation of Aripiprazole of Formula (I).
Formula (I)

[0015] As per one of the embodiments of the invention, the process of preparation of Aripiprazole starts with 3-(2-nitro-4-hydroxyphenyl)propanonic acid of Formula (II) as the starting compound.

Formula (II)

The starting compound 3-(2-nitro-4-hydroxyphenyl)propanonic acid is converted to its methyl ester form, i.e. methyl[3-(4-Hydroxy-2- nitrophenyl)]propanoate of Formula (III) in presence of methanol and sulphuric acid. Ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol or any C1-C6 alcohol; and cone, sulphuric acid, methanesulphonic acid, p-
toluenesulphonic acid or a catalyst suitable for esterification can also be used to prepare the appropriate alkyl ester.
Formula (III)

[0016] The phenolic hydroxyl group of the methyl ester of Formula (III) so obtained is mono-O-alkylated by reacting it with 1,4-dibromobutane in the presence of a base such as anhydrous potassium carbonate, anhydrous sodium carbonate, sodium hydride or potassium t-butoxide in a refluxing aprotic solvent such as tetrahydrofuran (THF),

Dimethylformamide (DMF), Dichloromethane (DCM), Ethyl acetate,
Acetone, Acetonitrile (MeCN), Dimethyl sulfoxide (DMSO) or dimethyl
acetamide; to produce methyl 3-[(4-bromobutoxy)-2-
nitrophenyljpropanoate of Formula (IV).

Formula (IV)

[0017] The primary bromide of the compound of Formula (IV) is displaced by N-(2,3-dichlorophenyl)piperazine at the unsubstituted nitrogen to produce methyl 3-[{4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy}-2-nitrophenyljpropanoate of Formula (V) in the presence of a base such as anhydrous potassium carbonate, anhydrous sodium carbonate or potassium t-butoxide in a refluxing aprotic solvent such as tetrahydrofuran (THF),
Dimethylformamide (DMF), Dichloromethane (DCM), Ethyl acetate,
Acetone, Acetonitrile (MeCN), Dimethyl sulfoxide (DMSO) or dimethylacetamiuc.

[0018] The nitro group in the compound of Formula (V) so obtained is reduced with Raney Nickel and hydrogen to produce methyl 3-[2-amino-{4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy}phenyl]propanoate of Formula (VI).

Formula (VI)

[0019] The amino ester compound of Formula (VI) so obtained is refluxed in toluene, xylene, mesitylene, 1,2,4-trimethylbenzene or any other suitable aromatic hydrocarbon to give Aripiprazole.

[0020] The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXAMPLE Stage -1
Scheme:
Procedure:

[0021] A 5L 3-necked round bottom flask fitted with a water cooled condenser, an overhead stirrer and a thermometer pocket; is charged with 3-(2-nitro-4-hydroxyphenyl)propanonic acid (lOOg), methanol (1L) and cone. H2S04 (5ml). The mixture is refluxed for 12 hours. Product formation (100%) is confirmed by Thin Layer Chromatography (TLC). Thereafter, methanol is removed from the reaction mixture and the reaction mixture is cooled at room temperature (RT). Ethyl acetate (1L) is added to the cooled reaction mixture, the organic layer is washed with water and dried over anhydrous sodium sulphate. The solvent is removed by distillation to get lOOg of product.

Stage - 2

Scheme

Procedure:

[0022] A 5L 3-necked round bottom flask fitted with a water cooled condenser, an overhead stirrer and a thermometer pocket, is charged with methyl 3-(4-hydroxyphenyl-2-nitro)propanoate (l00g, 0.444moles, leq), 1,4-dibromobutane (672g, 3.11moles, 8eq), potassium carbonate (429g, 3.11moles, 8eq) and THF(IL). The mixture is heated at 60°C for 20 hours and starting material consumption and product formation is confirmed by TLC. Reaction mixture is filtered to remove solid K2CO3, It is then distilled at 70°C to remove THF, thereafter distilled at 120°C (high vacuum) to remove excess 1,4-dibromobutane. 143g (90% yield) of yellow brown colour product is present in the round bottom flask.

Stage - 3
Scheme:
Procedure:

[0023] A 5L 3-necked round bottom flask fitted with a water cooled condenser, an overhead stirrer and a thermometer pocket; is charged with methyl 3-[(4-bromobutoxy)-2-nitrophenyl]propanoate (l00g, 0.277moles, leq), l-(2,3-dichlorophenyl)piperazine (63g, 0.278moles, leq), potassium carbonate (268g, 1.946moles, 7eq) and DMF(IL). The mixture is heated at 50°C for 24 hours and completion of the reaction is confirmed by TLC. The reaction mixture is then filtered to remove K2CO3; DMF is then distilled out by high vacuum to get 125g of product (89% yield).

Stage - 4
Scheme:
Procedure:

[0024] A 5L autoclave is charged with methyl 3-[(4-(l-(2,3-dichloropiperazine)) butoxy-2-bitrophneyl) propanoate (lOOg), toluene (IL) and Raney nickel(l0g). The mixture is then pressurized with hydrogen gas at 6kg/cm at room temperature. The reaction is continued until hydrogen uptake stops (Approx. 12 hours). Once complete consumption of starting material is confirmed by TLC, the catalyst is filtered, the toluene layer washed with water, and the resultant is taken to the next stage.

Stage - 5
Scheme:
Procedure:

[0025] A 5L 3-necked round bottom flask fitted with a water cooled condenser, an overhead stirrer and a thermometer pocket; is charged with the product from the previous step and IL of toluene. The mixture is then refluxed until the starting material is converted into product. The reaction is
monitored by IR. After completion of the reaction, the reaction mixture is decolourized with charcoal, filtered, then toluene is distilled out. This residue is recrystallized from methanol (two times).

[0026] The foregoing description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.

STATEMENT OF CLAIMS

We Claim:
1. A process for the preparation of Aripiprazole, the process comprising:

(a) reacting 3-(2-nitro-4-hydroxyphenyl)propanonic acid with a C1-C6 alcohol in the presence of a catalyst to produce methyl[3-(4-Hydroxy-2-nitrophenyl)]propanoate;

(b) mono-O-alkylating phenolic hydroxyl group of methyl[3-(4-Hydroxy-2-nitrophenyl)]propanoate with 1,4-dibromobutane to in the presence of a base and a polar aprotic solvent to produce methyl 3-[(4-bromobutoxy)-2-nitrophenyl]propanoate;

(c) displacing the primary bromide of methyl 3-[(4-bromobutoxy)-2-nitrophenyljpropanoate with l-(2,3-dichlorophenyl)piperazine at the unsubstituted nitrogen in the presence of a base and a polar aprotic solvent to produce methyl 3-[{4-[4-(2,3-dichlorophenyl)piperazin-
1 -ylbutoxy} -2-nitrophenyl]propanoate;

(d) reducing the nitro group of methyl 3-[{4-[4-(2,3 dichlorophenyl)piperazin-l-yl]butoxy}-2-nitrophenyl]propanoate with raney nickel in the presence of hydrogen to produce methyl 3- [2-amino-{4-[4-(2,3-dichlorophenyl)piperazin-l- yl]butoxy}phenyl]propanoate; and

(e) refluxing methyl 3-[2-amino-{4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy}phenyl]propanoate in an aromatic hydrocarbon to produce Aripiprazole.

2. The process for the preparation of Aripiprazole as claimed in claim 1, wherein the C1-C6 alcohol of step (a) is selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, n-pentanol and n-hexanol.

3. The process for the preparation of Aripiprazole as claimed in claim 1, wherein the catalyst of step (a) is selected from the group consisting of sulphuric acid, methanesulphonic acid and p-toluenesulphonic acid

4. The process for the preparation of Aripiprazole as claimed in claim 1, wherein the base of step (b) is selected from the group consisting of anhydrous potassium carbonate, anhydrous sodium carbonate, sodium hydride and potassium t-butoxide.

5. The process for the preparation of Aripiprazole as claimed in claim 1, wherein the polar aprotic solvent of step (b) is selected from the group consisting of tetrahydrofuran (THF), Dimethylformamide (DMF),

Dichloromethane (DCM), Ethyl acetate, Acetone, Acetonitrile (MeCN), Dimethyl sulfoxide (DMSO) and dimethyl acetamide.

6. The process for the preparation of Aripiprazole as claimed in claim 1, wherein the base of step (c) is selected from the group consisting of anhydrous potassium carbonate, sodium carbonate and potassium t-butoxide.

7. The process for the preparation of Aripiprazole as claimed in claim 1, wherein the polar aprotic solvent of step (c) is selected from the group consisting of tetrahydrofuran (THF), Dimethylformamide (DMF), Dichloromethane (DCM), Ethyl acetate, Acetone, Acetonitrile (MeCN), Dimethyl sulfoxide (DMSO) and dimethyl acetamide.

8. The process for the preparation of Aripiprazole as claimed in claim 1, wherein the aromatic hydrocarbon of step (e) is selected from the group consisting of toluene, xylene, mesitylene and 1,2,4-trimethylbenzene.

9. The process for the preparation of Aripiprazole as claimed in claim 1, wherein the boiling point of the aromatic hydrocarbon of step (e) is I the range of 100°C-150°C.