FIELD OF THE INVENTION
to make essentially free of impurities, predominantly the dimer impurity of formula (II)
The present invention is directed to a process for purification of 7- (4-bromobutoxy)-3,4-dihydrocarbostyril of formula (I),


The compound of formula I is an intermediate in the synthesis of aripiprazole of following formula:

BACKGROUND OF THE INVENTION
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy}-3,4-dihydro-2 (IH)-quinolinone [CAS no 129722-12-9] of formula (V) generically called aripiprazole, is used for treating schizophrenia (EP 0 367 141) and is also used as an antipsychotic agent [J. Med. Chem., Vol. 41, 99 658-667 (1998)].
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EP 0 367 141 discloses a process for preparing aripiprazole by reaction of carbostyril represented by the general formula (III)

wherein X, is a halogen atom or a group which can act as a substrate to carry out a nucleophilic substitution reaction, with the piperazine moiety represented by formula (IV)

The compound of formula III (wherein X, is bromine) is chemically known as 7- (4-bromobutoxy)-3,4-dihydrocarbostyril, represented by formula (I).

Reference example 6 of EP '141 gives condition for synthesis of 7- (4-bromobutoxy)-3,4-dihydrocarbostyril, wherein the purification of the crude product is carried outiby means of a silica gel chromatography (eluent: dichloromethane) and recrystallised from n-hexane-ethanol. Impurity present in the crude are not identified or mentioned in the patent.
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The present inventors reproduced the process of EP'141 and analyzed the product, and found that in spite of purification / recrystallisation, the product still contained the dimer impurity of formula II. Because of the low yield due to impurities and a tedious purification using column chromatography, the process described in the EP '141 is not economically viable for industrial application.
US 2006/0079689 A1 provides processes for synthesis of 7-(4-halobutoxy)-3,4-dihydro-(IH)-quinolinone, which is subsequently converted to aripiprazole. This application, for the first time discloses in detail the impurities associated with the crude 7-(4-halobutoxy)-3,4-dihydro- (IH)-quinolinone. The impurities identified in the application are:
a) 1,4-bis [3,4-dihydro-2 (1 H)-quinolinone-7-oxy] butane of formula (II)

b) N- (4-bromobutyl)-7-hydroxy-3, 4-dihydro-2 (1 H)-quinolinone c)N- (4-bromobutyl)-7-(4-butoxy)-3,4-dihydro-2 (1 H)-quinolinone.
The process described in US 2006/0079689 for preparation of the 7- (4-bromobutoxy)-3,4-dihydrocarbostyril comprises reaction of 7-hydroxy quinolinone with a 1,4-disubstituted butane, wherein the substitutions are from the group consisting of chlorine, bromine, iodine, and sulfonate; in a heterogeneous biphasic mixture containing water immiscible organic solvent, water soluble base with optional addition of water and a phase transfer catalyst.
This invention provides a process for purification of 7- (4-bromobutoxy)-3,4-dihydrocarbostyril by using various organic solvents like ethyl acetate, isopropyl acetate, toluene, xylene, chloroform, acetonitrile, acetone, methanol, isopropanol etc. The above method gives 7- (4-bromobutoxy)-3,4-dihydrocarbostyril containing dimer impurity of the range 1.5-6.1 % which is initially 4.5-15% in the reaction mixture.
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Another method for synthesis of 7- (4-bromobutoxy)-3,4-dihydrocarbostyril is described in Journal of Medicinal Chemistry, 1998, Vol. 41, No. 5, 658-667. The crude product obtained herein is crystallized from ethanol. The inventors of the present invention, when repeated the same process observed that the reaction hardly proceeds even after 22 hours of the reaction 82% of the reactant was recovered.
Thus there is need for a process to produce pure 7- (4-bromobutoxy)-3,4-dihydrocarbostyril, which will consecutively lead to pure and economical synthesis of Aripiprazole.
OBJECT OF THE INVENTION
Thus the object of the present invention is to provide a process for purification of 7- (4-bromobutoxy)-3,4-dihydrocarbostyril, an intermediate for synthesis of aripiprazole.
SUMMARY OF THE INVENTION
Accordingly, there is provided a process for the purification of 7- (4-bromobutoxy)-3,4-
dihydrocarbostyril, substantially free of dimer impurity, said process comprising the
steps:
i) providing a solution of crude 7- (4-bromobutoxy)-3,4- dihydrocarbostyril containing the
dimer impurity in an organic solvent selected halogenated hydrocarbon solvent, aromatic
hydrocarbon, alcohols, alkyl esters of CrC4 alkanoic acids, ethers, diethyl ester and
ketones
ii) converting to a salt by the addition of an inorganic acid,
iii) separation of 1,4-bis [3,4-dihydro-2 (1 H)-quinolinone-7-oxy] butane salt (dimer impurity salt) from the mixture.by based on the difference in at least one physical property of 7- (4-bromobutoxy)-3,4- dihydrocarbostyril salt and the salt of dimer impurity,
iv) liberating the 7- (4-bromobutoxy)-3,4- dihydrocarbostyril salt by treating with an inorganic base,
v) precipitating 7- (4-bromobutoxy)-3,4- dihydrocarbostyril by adding an anti-solvent
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DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for purification of 7- (4-bromobutoxy)-3,4-dihydrocarbostyril, which is an intermediate for synthesis of aripiprazole. The crude 7-(4-bromobutoxy)-3,4-dihydrocarbostyril was obtained as per an example of US 2006/0079689. The impurity characterized in the crude was the dimer 1,4-bis [3,4-dihydro-2 (1H)-quinolinone-7-oxy] butane of formula (II). The intermediate if not purified would lead to aripiprazole with higher impurity levels, which would require number of purification, resulting in the yield loss of the final product.

The 7-hydroxy 3,4-dihydrocarbostyril (VI) when reacts with 1,4-dibromo butane (VII) gives the 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (I), its bromo group further reacts with hydroxy group of another molecule of 7-hydroxy 3,4-dihydrocarbostyril to give 1,4-bis [3,4-dihydro-2(1H)-quinolinone-7-oxy] butane, i.e. the dimer impurity of formula (II).
As the formation of product increases in the reaction, the rate of formation of the dimer impurity also increases, it was difficult to control the formation of the impurity in the reaction, so a method for purification of the intermediate 7- (4-bromobutoxy)-3,4-dihydrocarbostyril (I), had to be developed.
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The purification of intermediate 7- (4-bromobutoxy)-3,4-dihydrocarbostyril (I) was done taking advantage of difference in physical properties of corresponding salts of 7- (4-bromobutoxy)-3,4-dihydrocarbostyril (I) and the dimer impurity (II)
The inventors found that when the reaction mixture containing 7- (4-bromobutoxy)-3,4-dihydrocarbostyril (I) and the dimer impurity was treated with an inorganic acid in an organic solvent, corresponding salt of 7- (4-bromobutoxy)-3,4-dihydrocarbostyril (I) remained in the solution whereas corresponding salt of the dimer impurity was insoluble in the said solvent and was precipitated . The salt of impurity was separated.
Organic solvent suitable for the purpose of the invention was selected from group of halogenated hydrocarbon solvent, aromatic hydrocarbon like toulene, alcohols like methanol , ethanol, alkyl esters of CVC4 alkanoic acids, ethers such as diisopropyl ether, diethyl ester and ketones such as acetone.
The inorganic acid suitable for the purpose of the invention was selected from the group of hydrochloric acid, sulphuric acid and the like.
7- (4-bromobutoxy)-3,4-dihydrocarbostyril (I) was liberated from its salt by treating with an inorganic base selected from potassium carbonate / bicarbonate or its equivalent. 7- (4-bromobutoxy)-3,4-dihydrocarbostyril (I) was isolated using antisolvent like hexane or cyclohexane.
7- (4-bromobutoxy)-3,4- dihydrocarbostyril (I) obtained has HPLC purity of at least 97 % and contains not more than 0.5 % of 1,4-bis [3,4-dihydro 2 (1H)-quinolinone-7-oxy] butane of formula (II).
The HPLC parameters were as follows:
Column: Agilent Zorbax XDB C-18 (4.6 X 150 mm), 5(xm
Flow rate : 1.5 mL/minute.
Detector: UV at 220 nm.
Buffer preparation :
A homogenous mixture of 0.2 % (v/v) triethylamine in HPLC grade water is prepared.
Mobile phase-A :
A homogenous mixture buffer and acetonitrile (95:5) is prepared. pH of the solution is
adjusted to 4.0 with phosphoric acid. Filtered and degased.
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Mobile phase-B :
A homogenous mixture buffer and acetonitrile (25:75) is prepared. pH of the solution is adjusted to 4.0 with phosphoric acid. Filtered and degased.
The invention is illustrated by the following non limiting examples :
Example 1
A mixture of 7-hydroxy 3,4-dihydrocarbostyril (50g, 0.306 mole, 1 eq.), anhydrous potassium carbonate (50.7 g, 0.367 mole, 1.2 eq.) in acetonitrile (750 ml) was heated under reflux for 2 hours, the hot reaction mixture cooled to 25-30°C.A mixture of dibromo butane (200g, 0.926 mole, 3.02 eq.), tetrabutylammonium iodide (2.2g, 0.006 mole, 0.02eq.) in acetonitrile (250 ml) was heated under reflux for 15 min, the above potassium salt of 7-hydroxy 3,4-dihydrocarbostyril added to it. The resultant mixture was heated under reflux for 2-4 hrs, monitored by HPLC till 7-hydroxy 3,4-dihydrocarbostyril is present less than 1.0%, (the reaction mixture contained 14-15 % of the dimer impurity), mixture was cooled to 25-30°C, filtered, residue washed with acetonitrile (250 ml), the filtrate was concentrated, dichloromethane (750 ml) was added to it, Hydrogen chloride gas was purged into it, the filtrate was monitored by HPLC for dimer content to be less than 0.5 %, carbon (5g) was added to the solution, filtered through celite bed .water (250 ml) was added to the filtrate, pH of the solution was adjusted to 6.8-7.5 using 20% potassium carbonate solution, the organic layer separated , washed with water (250 ml), washed with 20% brine solution (250 ml). The organic layer further concentrated, cyclohexane (500 ml) was added to it, stirred for 15 minutes, then cooled to 5-10°C, the solid was filtered, washed with cyclohexane (100 ml), dried under vacuum at 40-45°C, for 5-6 hours, to give 7-(4- Bromo butoxy)-3,4-dihydro carbostyril (62 g, yield 66%, purity by HPLC 97.4 %, dimer impurity 0.28%).
Example 2
A mixture of 7-hydroxy 3,4-dihydrocarbostyril (50g, 0.306 mole, 1 eq.), anhydrous potassium carbonate (50.7 g, 0.367 mole, 1.2 eq.) in acetonitrile (750 ml) was heated under reflux for 2 hours, the hot reaction mixture cooled to 25-30°C.A mixture of dibromo butane (200g, 0.926 mole, 3.02 eq.), tetrabutylammonium iodide (2.2g, 0.006 mole, 0.02eq.) in acetonitrile (250 ml) was heated under reflux for 15 min, the above potassium salt of 7-hydroxy 3,4-dihydrocarbostyril added to it. The resultant mixture heated under
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reflux for 2-4 hrs, monitored by HPLC till 7-hydroxy 3,4-dihydrocarbostyril is present less than 1.0%, (the reaction mixture contained 14-15 % of the dimer impurity), mixture was cooled to 25-30°C, filtered, residue washed with acetonitrile (250 ml), the filtrate was concentrated, dichloromethane (750 ml) was added to it, sulphuric acid (55g) was added to it, the filtrate was monitored by HPLC for dimer content to be less than 0.5 %, carbon (5g) was added to the solution, filtered through celite bed .water (250 ml)";vas added to the filtrate, pH of the solution was adjusted to 6.8-7.5 using 20% potassium carbonate solution, the organic layer separated , washed with water (250 ml), washed with 20% brihe solution (250 ml). The organic layer further concentrated, cyclohexane (500 ml) was added to it, stirred for 15 minutes, then cooled to 5-10°C, the solid was filtered, washed with cyclohexane (100 ml), dried under vacuum at 40-45°C, for 5-6 hours, to give 7-(4- Bromo butoxy)-3,4-dihydro carbostyril (52 g, yield 55%, purity by HPLC 98.05 %, dimer impurity 0.08%).
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We Claim:
1. A process for the purification of 7- (4-bromobutoxy)-3,4- dihydrocarbostyril,
substantially free of dimer impurity, said process comprising the steps:
i) providing a solution of crude 7- (4-bromobutoxy)-3,4- dihydrocarbostyril containing
the dimer impurity in an organic solvent selected from the group of halogenated
hydrocarbon solvent, aromatic hydrocarbon, alcohols, alkyl esters of CrC4 alkanoic
acids, ethers, diethyl ester and ketones
ii) converting to a salt by the addition of an inorganic acid,
iii) separation of 1,4-bis [3,4-dihydro-2 (1H)-quinolinone-7-oxy] butane salt (dimer
impurity salt) from the mixture, based on the difference in at least one physical
property of 7- (4-bromobutoxy)-3,4- dihydrocarbostyril salt and the salt of dimer
impurity,
iv) liberating the 7- (4-bromobutoxy)-3,4- dihydrocarbostyril salt by treating with an
inorganic base, v) precipitating 7- (4-bromobutoxy)-3,4- dihydrocarbostyril by adding an anti-solvent.
2. A process according to claim 1, wherein the separation of the salts is based on the
difference in solubility.
3. A process according to claim 1, wherein organic solvent used for providing the
solution of crude 7- (4-bromobutoxy)-3,4- dihydrocarbostyril is selected from
dichloromethane, toluene, methanol, ethanol, diisopropyl ether, acetone.
4. A processs as claimed in claim 3 wherein the organic solvent used for providing the
solution of crude 7- (4-bromobutoxy)-3,4- dihydrocarbostyril is dichloromethane.
5. A process according to claim 1, wherein inorganic acid is hydrochloric acid.
6. A process according to claim 1, wherein inorganic acid is sulphuric acid.
7. A process according to claim 1, wherein inorganic base used is potassium
carbonate.
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8. A process according to claim 1, wherein anti-solvent is cyclohexane or hexane.
9. A process according to claim 1 wherein 7- (4-bromobutoxy)-3,4- dihydrocarbostyril (I)
has purity of at Ieast97 % and contains not more than0.5 % of dimer impurity 1,4-bis
[3,4-dihydro 2 (1H)-quinolinone-7-oxy] butane of formula (II).