WO2007094009A1

WO2007094009A1 - A novel process for preparation of aripiprazole and its intermediates

Info

Publication number: WO2007094009A1
Application number: PCT/IN2006/000362
Authority: WO
Inventors: Arul Ramakrishnan; V. Damle Subhash; G. Panchal Dharmesh
Original assignee: Unichem Laboratories Limited
Priority date: 2006-02-15
Filing date: 2006-09-12
Publication date: 2007-08-23
Also published as: EP1984352A1

Abstract

A process for the preparation of 7-hydroxy-3,4-dihydro carbostyril (II) by intramolecular Fridel-Craft alkylation of N-(3-methoxyphenyl)-3-chloropropionamide (I) in which an equivalent of N-(3-methoxyphenyl)-3-chloropropionamide (I) is contacted with a Lewis acid (e.g. aluminium chloride) in dimethyl acetamide (DMA), at an elevated temperature of from about 120°C to about 160°C, is provided. The process produces 7-hydroxy-3,4- dihydro carbostyril (II) in high yield and a high state of purity such that it may be used in subsequent .reaction towards the preparation of aripiprazole (IV). Thus 7-hydroxy-3,4- dihydro carbostyril (II) was treated with l-bromo-4-chlorobutane under phase transfer catalyst (PTC) conditions using solvents like acetone or n-butanol at temperature ranging 25°C to 45°C to afford 7-(4-chlorobutoxy)-3,4-dihydro carbostyril (III). The PTC conditions described in this patent afford 7-(4-chlorobutoxy)-3,4-dihydro carbostyril (III) in high purity and high yield with the corresponding dimmer formation is considerably low as compared with the other literature methods of preparing 7-(4-chlorobutoxy)-3,4- dihydro carbostyril (III). Compound (III) was treated with l-(2,3-dichlorophenyl)piperazine, at temperature ranging from 50°C to 100°C, and sodium iodide, potassium carbonate, dimethyl formamide (DMF) as a solvent to afford aripiprazole in high purity and high yield.

Description

TITLE - A NOVEL PROCESS FOR PREPARATION OF ARIPIPRAZOLE

AND ITS INTERMEDIATES

FIELD OF INVENTION

The present invention provides a novel process for the preparation of psychotropic drug aripiprazole and its intermediate.

BACKGROUND OF THE INVENTION

7-[4-[4-(2,3-Dichloro,phenyl)-l-piperazinyl]butoxy]-3,4-dihydro-2(7//)-quinolinone, having formula (IV),

(IV) is called aripiprazole, which is useful for the treatment of schizophrenia. In the available prior art aripiprazole is prepared by a reaction of carbostyril compound having formula (III)

(III) with a piperazine compound represented by the following formula,

in the presence of an inorganic or organic base in an organic solvent.

Compound 7-(4-chlorobutoxy)-3,4-dihydro carbostyril (III), is prepared from the reaction of carbostyril compound having formula (II),

(H) with l-bromo-4-chlorobutane in the presence of an inorganic base, in an organic or inorganic solvent.

An article J. Chinese Chem. Soc, 47, (2000), 155-162 describes the preparation of 7- hydroxy-3,4-dihydro carbostyril (II), It states that the only 4% of the product is obtained by carrying out intramolecular Fridel-Craft alkylation in chlorobenzene as a solvent.

US patent number 5^006,528 discloses a process for the preparation of aripiprazole by condensation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with l-(2,3- dichlorophenyl)piperazine using triethylamine as a base, acetonitrile as a solvent and sodium iodide as a reaction accelerator.

The synthesis of aripiprazole intermediate viz. 7-(4-bromobutoxy)-3,4-dihydrocarbostyril using solvent as dimethylformamide and potassium carbonate as a base, is disclosed in J.

Med Chem., 41, (1998), 658-667. Also the same paper describes a process for the preparation of aripiprazole by condensation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with l-(2,3-dichlorophenyl)piperazine using triethylamine as a base, acetonitrile as a solvent and sodium iodide as a reaction accelerator.

WO patent number Q63162 discloses a process for the preparation of aripiprazole by

1 condensation of (4-chlorobutoxy)-3,4-dihydrocarbostyril with l-(2,3- dichlorophenyl)piperazine monohydrochloride using potassium carbonate as a base and water a solvent.

WO patent number 099152 discloses a process for the preparation of aripiprazole by condensation of a spiro compound viz. 8-(2,3-dichlorophenyl)-8-aza-5- azoniaspiro[4,5]decane bromide with 7-hydroxy-4,5-dihydrocarbostyril in presence of methyl isobutylketone:dimethyl formamide as a solvent system at reflux temperature. However most of the synthetic process used for the preparation of aripiprazole suffers from the drawbacks like lesser yield, use of tedious work ups, formation of impurities etc. Further the corresponding impurity formation, during the synthetic process described in this patent, is also considerably low.

SUMMARY OF THE INVENTION

This invention relates to a process for preparing 7-hydroxy-3,4-dihydro carbostyril (II) by intramolecular Fridel-Craft alkylation of N-(3-methoxyphenyl)-3-chloropropionamide (I). The process consist of contacting N-(3-methoxyphenyl)-3-chloropropionamide (I) with a' Lewis acid (e.g. aluminium chloride) in an organic aprotic solvent like dimethyl acetamide (DMA), at an elevated temperature from about 12O⁰C to about 16O⁰C, is provided. The process produces 7-hydroxy-3,4-dihydro carbostyril (II) in high yield and high purity.

The invention also relates to the use of the 7-hydroxy-3, 4-dihydro carbostyril (II) prepared by the process according to the invention for producing aripiprazole, in high yield and high purity.

The invention further relates to a process for preparation of 7-(4-chlorobutoxy)-3,4- dihydro carbostyril (III) by reacting 7-hydroxy-3, 4-dihydro carbostyril (II) with 1-bromo- 4-chlorobutane in the presence of a base and a phase transfer catalyst (PTC) at room temperature in high yield and high purity.

The invention further relates to a process for preparation of aripiprazole with high purity and high yield, by reacting 7-(4-chlorobutoxy)-3, 4-dihydro carbostyril (III) with l-(2,3- dichlorophenyl)piperazine at temperature ranging from 5O⁰C to. 100⁰C and sodium iodide, potassium carbonate and DMF as a solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of aripiprazole which comprise: a) intramolecular Fridel-Craft alkylation of N-(3-methoxyphenyl)-3- chloropropionamide (I) to give 7-hydroxy-3, 4-dihydro carbostyril (II); b) further reaction of 7-hydroxy-3, 4-dihydro carbostyril (II) with l-bromo-4- chlorobutane i^i the presence of a base and a phase transfer catalyst (PTC) at room temperature to give 7-(4-chlorobutoxy)-3, 4-dihydro carbostyril (III); c) further reaction of 7-(4-chlorobutoxy) -3,4-dihydro carbostyril (III) with 1 -(2, 3 - dichlorophenyl)piperazine in presence of sodium iodide, potassium carbonate and DMF as a solvent at temperature 50-100 ⁰C.

The preparation of 7-hydroxy-3, 4-dihydro carbostyril (II) from N-(3-methoxyphenyl)-3- chloropropionamide (I) involves a ring closure and a demethylation of the phenol group. This is achieved by using Lewis acids as a catalyst like aluminum chloride, aluminum tribromide, ferric chloride, ferric bromide, titanium tetrachloride, tin tetra chloride and boron trifluoride preferably aluminium chloride. The catalyst is taken in 3 to 5 molar equivalents preferably 4 molar equivalents.

The reaction is conducted at high concentration in a diluent selected from the group consisting of dimethyl sulfoxide, high boiling amines and high boiling N,N-disubstituted amides. Suitable amides and amines have boiling point in excess of 150 C, so that the reaction may be conducted at ambient pressure without significant loss of the diluent by evaporation. The most preferred diluent is DMA.

The preparation of 7-hydroxy-3,4-dihydro carbostyril (II) comprises:

Contacting an equivalent of N-(3-methoxyphenyl)-3-chloropropionamide (I) with about 3 to about 5 equivalents of a Lewis acid catalyst in a paraffin free diluent selected from the group consisting of dimethyl sulfoxide, N,N-disubstituted amides and amines having boiling point of 15O⁰C, or above; the diluent being present in an amount of from about 1 to about 1.3 equivalents with respect to the N-(3-methoxyphenyl)-3-chloroρropionamide

(I), at an elevated temperature of from about 15O⁰C to about 22O⁰C, for a period of time sufficient to cause substantially all of the N-(3-methoxyphenyl)-3-chloropropionamide (I) to cyclize and demethylate, resulting in the formation of a Lewis acid salt of 7-hydroxy-

3,4-dihydro carbostyril (II) and thereafter:

Decomposing the Lewis acid salt of 7-hydroxy-3,4-dihydro carbostyril (II), and isolating

7-hydroxy-3,4-dihydro carbostyril (II).

The workup for the preparation of 7-hydroxy-3, 4-dihydro carbostyril (II) is further made simpler from the scale-up point of view, by adding toluene to the reaction mixture, at about 100⁰C.

The obtained 7-hydroxy-3, 4-dihydro carbostyril (II) is reacted with l-bromo-4- chlorobutane to obtain 7-(4-chlorobutoxy)-3, 4-dihydro carbostyril (III), in presence of a alkali metal carbonate base selecting from the group comprising lithium carbonate, sodium carbonate, potassium carbonate preferably powdered potassium carbonate in presence of PTC selected from the group consisting polyethylene glycol or Aliquat-336.

Preferably, the PTC is a polyethylene glycol-400. The solvent used for this PTC catalyzed reaction was acetone, C₃-Cs alcohols, acetonitrile, methyl ethyl ketone and methyl isobutyl ketone preferably acetone. It uses 1.5 to 3.5 equivalents of l-bromo-4- chlorobutane preferably 3,0 equivalents. The reaction is carried out in a temperature range from -10⁰C to 35⁰C, preferably from O⁰C to 3O⁰C₃ particularly from 25-3O⁰C. The reaction is complete in 10-20 hours, preferably in 15-18 hours, particularly in 16-17 hours.

The obtained 7-(4-chlorobutoxy)-3,4-dihydro carbostyril (III) is reacted with l-(2,3- dichlorophenyl)piperazine in DMF, postassium carbonate, and sodium iodide conventionally.

N-(3-methoxyphenyl)ⁱ-3-chloropropionamide (I) which is a starting material for the preparation of 7-hydroxy-3,4-dihydro carbostyril (II), can be prepared by acylation of m-anisidine with 3-chloropropionyl chloride. m-Anisidine is dissolved in a sufficient amount of toluene to produces an approximately 3 to 5 M solution, more preferably about 4M solution. Between 1 and 2 equivalents, more preferably about 1.5 equivalents of sodium bicarbonate are suspended in the m-anisidine solution, and the resulting suspension is stirred while an approximately . 1 to 1.2 equivalent amount of 3- chloropropionyl chloride is added dropwise to the stirred suspension. The addition may be conducted at reduced to ambient temperature and the temperature may be allowed to rise, but should not be allowed to exceed 7O⁰C. After completion of the addition, temperature of the reaction is maintained between room temperature and the reflux temperature of toluene, most preferably to about 6O⁰C, for a time sufficient for the reaction to be complete. Progress of the reaction may be monitored by thin layer chromatography (TLC). After the reaction is complete, the reaction mixture is quenched with water or aqueous mineral acid and N-(3-methoxyphenyl)-3-chloropropionamide (I) is isolated from the resulting suspension by filtration, decantation and the like, preferably filtration.

The invention can be illustrated by the following examples, which is for illustration purpose only and is not intended to limit the scope of the invention in any way.

Examples:

Example (A):

Preparation of N-(3-methoxyphenyl)-3-chloropropionamide (I): m-Anisidine (200gm, 1.62moles) and sodium bicarbonate (205gm, 2.44moles) were added to toluene (2,00ml) in a three necked flask. A solution of 3-chloropropionyl chloride (207.5gm, 1.63 moles) in toluene (400ml) was added dropwise over a period of hour to the reaction mixture and the temperature of the reaction mixture was allowed to rise to 4O⁰C. After completion of the addition, the reaction mixture was heated to 60-65 ⁰C for about one hour. The reaction was monitored by TLC (eluent: n-hexane: ethyl acetate (60:40)). The mixture was cooled to ambient temperature and 10% aqueous HCl solution (1000ml) was added dropwise to reaction mixture in one hour, and stirred for 30min. The reaction mixture was filtered and the collected solid was washed with water (1000ml) and then toluene (250ml). The resulting product was dried at 60-65 ⁰C. The product N-(3-methoxyphenyl)-3-chloropropionamide (I) was obtained. (318.5gm; 91%) in >99.5% purity by HPLC analysis.

¹H (CDCl₃): 2.8 (t, 2H)₃ 3.7 (t, 3H), 3.9 (t, 2H), 6.6 (d, IH), 7.2 (m, 2H), 7.3 (s, IH) and 10.1 (s, IH)

Example (B):

Preparation of 7-hydroxy-3, 4-dihydro carbostyril (II):

A three necked flask was charged with N-(3-methoxyphenyl)-3-chloropropionamide

(lOOgm) and N,N-dimethyl acetamide (55ml). The mixture was stirred for 15min. Then 4 equivalents of aluminum chloride was charged lot wise (249gm), over a period of 45 min.

The temperature of the reaction mixture was raised slowly to 140-150 ⁰C. After 2 hours, the reaction mixture was monitored by TLC (eluent: n-hexane: ethyl acetate (60:40)). The mixture was cooled to 100 ⁰C and slowly toluene (500ml) was added to reaction mixture.

The reaction mixture was further cooled to 10-15 ⁰C, and slowly chilled water (1000ml) was added. The reaction mixture was stirred further one hour. The solid was filtered and washed with water (300ml) and then with toluene (200ml). The resulting solid was dried at 50-55⁰C to obtain 7-hydroxy-3, 4-dihydro carbostyril (II) (62.5gm, 82%).

¹H (CDCl₃): 2.4 (t, 2H), 2.7 (t, 2H), 6.3 (m, 2H), 6.9 (d, IH), 9.3 (s, IH) and 10.0 (s, IH) Example (C):

1

Preparation of 7-(4-cMorobutoxy)-3,4-dihydro carbostyril (III):

The three necked flask was charged with 7-hydroxy-3, 4-dihydro carbostyril (II) (50gm, 0.306moles) in acetone: water mixture (400ml: 25ml). To this mixture was successively added potassium carbonate (50,8gm, 0,367moles), PEG-400 (61.2gm) and stirred at ambient temperature for one hour. The l-bromo-4-chlorobutane (157ml, 0.918moles) was added to mixture over a period of 10 min. Reaction mixture was then stirred at ambient temperature for 15-16 hours. The progress of the reaction was monitored by TLC (eluent: chloroform: methanol (90:10)). Reaction mixture was filtered and the inorganics were washed with acetone (100ml). The solvent was removed under the reduced pressure below 40 ⁰C. The thick oily residue obtained was stirred with n-hexane (500ml) and water (500ml), at 10-15 ⁰C, for a period of 45 min.

The solid was filtered, washed with water (500ml) and then with n-hexane (500ml). The resulting solid was dried at 65-70 ⁰C to obtain 7-(4-chlorobutoxy)-3, 4-dihydro carbostyril (III) (72.7gm, 94 %).

¹H (CDCl₃): 1.9 (m, 4H), 2.5 (m, 2H), 2.8 (m, 2H), 3.6 (m, 2H), 3.9 (m, 2H), 6.3 (s, IH), 6.4 (d, IH), 7.0 (d, IH) and 9.3 (s, IH)

Example (D):

Preparation of 7-[4-[4-(2,3-Dichlorophenyl)-l-piperazinyl]butoxy]-3,4-dihydro-2(lH)- quinolinone:

The three necked flask was charged with 7-(4-chlorobutoxy)-3, 4-dihydro carbostyril (III) (50gm, 0.19SmOIeS)Un N,N-dimethyl formamide (250ml) along with sodium iodide (37.1gm, 0.247moles). The reaction mixture was heated to 70-80 ⁰C for over a period of one hour. Solid potassium • carbonate (17.1gm, 0.124moles) and l-(2,3- dichlorophenyl)piperazine (45.7gm, 0.198moles) dissolved in N, N-dimethyl formamide (150ml) were added successively, at 70-80 ⁰C. The reaction mixture was stirred further four hours at 70-80 ⁰C. The progress of the reaction was monitored by TLC (eluent: chloroform: methanol (90:10)). To the reaction mixture water (800ml) was added. Reaction mixture was then further cooled to 30-35 ⁰C and filtered. The resultant was filtered and washed with water (1000ml) and then with ethanol: hexane (25ml; 225ml)

(83 gm, 94%). The solid was recrystallized from ethanol, to obtain, 7-[4-[4-(2,3-

Dichlorophenyl)-l-piperazinyl]butoxy]-3,4-dihydro-2(lH)-quinolinone.

¹H (CDCl₃): 1.5-1.7 (m, 4H), 2.3-2.5 (m, 8H), 2.7 (m, 2H), 3.3 (m, 2H), 3.9 (m, 2H), 6.4

(m, 2H), 7.0 (m, IH), 7.1 (s, IH), 7.3 (m, 2H) and 9.9 (s, IH),

Claims

We claim:

1. A process for the preparation of aripiprazole comprising: a) preparation of N-(3-methoxyphenyl)-3-chloropropionamide (I) by the reaction of m-anisidine and 3-chloropropionyl chloride in presence of sodium bicarbonate and toluene; b) preparation of 7-hydroxy-3,4-dihydro carbostyril (II) by reacting the obtained N- (3-methoxyphenyl)-3-chloropropionamide (I) 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 ⁰C or above, at an elevated temperature of from about 120 ⁰C to about 160 ⁰C c) preparation of 7-(4-chlorobutoxy)-3,4-dihydro carbostyril (III) by reaction of 7- hydroxy-3,4-dihydro carbostyril (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-dihydro carbostyril (III) with l-(2,3- dichlorophenyl)piperazine to give aripiprazole

2. A Process as claimed in claim 1, wherein the alkali metal carbonate in (c) is selected from the group comprising lithium carbonate, sodium carbonate, potassium carbonate preferably potassium carbonate.

3. A Process as claimed in claim 1, wherein the alkali metal carbonate used in (c) is 1 to 2 equivalents preferably 1.2 equivalent based on 7-hydroxy-3,4-dihydro carbostyril (II)

4. A Process as claimed in claim 1, wherein the PTC used in (c) is either Polyethylene glycol or Aliquat-336 preferably polyethylene glycol-400

5. A Process as claimed in claim 1, wherein the solvents used in (c) for the PTC reaction were acetone, C₃-Cg alcohols, acetonitrile, methyl ethyl ketone and methyl isobutyl ketone preferably acetone.

6. A Process as claimed in claim 1, wherein l-chloro-4-bromobutaneused in (c) is in the range of 1.5 to 3.5 equivalents preferably 3.0 equivalents based on 7-hydroxy-3,4- dihydro carbostyril (II)

7. A Process as claimed in claim 1, wherein the reaction in (c) is carried out in the range of -10 to 35° C, preferably 25-30° C A process for the preparation of 7-(4-chlorobutoxy)-3,4-dihydro carbostyril (III) by reaction of 7-hydroxy-3,4-dihydro carbostyril (II) with l-chloro-4-bromobutane in the presence of an alkali metal carbonate and a PTC.