Development of a Commercially Scalable Process for the Preparation of Dehydroaripiprizole (Active Metabolite of Aripiprazole)

Dharmesh G. Panchal , Yashwant S. Surve, R.S. Lokhande

School of Basic science, Department of Chemistry. Jaipur National University, Jaipur

*Corresponding Author E-mail: yashwantsurveresearch@gmail.com

ABSTRACT:

Novel commercially scalable process for the green Synthesis of the Dehydroaripiprazole has been developed using phase transfer catalysis. This phase transfer process can be utilized for the synthesis of the Dehydroaripiprazole has advantages over previously reported methods.

KEYWORDS: Active Metabolite, Dehydroaripiprazole, Phase transfer catalysis, Hydrotopes

INTRODUCTION:

Aripiprazole chemically known as 7-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one is an anti-psychotic drug^1,2 used in the treatment of psychosis including schizophrenia.³ Aripiprazole was developed by Otsuka Pharmaceutical Co. Ltd. Schizophrenia is a most common type of psychosis caused by an excessive neurotransmission activity of the dopaminergic nervous system in the CNS. Aripiprazole, a carbostyril derivative, functions as a partial agonist^4-7 at the dopamine D2 and serotonin 5 HT1A receptors and as an antagonist at serotonin 5-HT2A receptor. It is a novel antipsychotic agent which is an agonist of dopamine (DA) auto receptors and an antagonist of postsynaptic DA receptors. Similar activity is shown by it's metabolite Dehydroaripiprazole. Dehydroaripiprazole shows structural similarity with aripiprazole and hence the drug activity is also similar.⁸ Although process for the preparation of dehydroaripiprazole is just mentioned on the lines of preparation of aripiprazole in product patent and subsequently no further references are available as a whole for Dehydroaripiprazole.

Furthermore it is reported mainly as impurity10 and not considered as a future drug target, hence method for routine preparation of the same is not covered as a whole under any single literature. So here we report new scalable process for the synthesis of Dehydroaripiprazole using phase transfer catalysis. PTC is newer synthesis methods which can be called as green synthesis. the reported method can be useful for the synthesis of the Dehydroaripiprazole for the metabolite profiling as well as for ADME predictions.

EXPERIMENTAL:

Solvents and reagents were obtained from commercial sources and used without purifications. The IR spectra (ν max cm-1) were recorded in solid state KBr dispersion using a FTIR (Perkin Elmer FTIR operating range 400-4000 cm-1 with a resolution of 5 cm-1). The 1H NMR spectra was recorded on a Joel 400 MHz instrument. We have synthesized all these compounds as described in this experimental section.

Preparation of 7- (4-chlorobutoxy)quinolin-2(1H)-one:

Method -I

A mixture of Acetone (100mL), PEG 400 ( 12.2 gm), 7-hydroxyquinoline-2(1H)-one (10 g), Potassium Carbonate (10.17 g), 1-bromo-4-chlorobutane(9.0 g), water (5ml) was stirred at 30-35°C, maintained at this temperature for 20-24 h. After completion of reaction, mass is filtered to remove insoluble. filtrate is subjected to solvent evaporation, residue is partitioned between water: Hexane (1 : 1) at 25-30°C. Product is precipitated and stirs the mass for 30 minute. Filter and dry to get pure 7- (4-chlorobutoxy)quinolin-2(1H)-one Weight: 15.0 g (Yield: 93 %); HPLC purity: 96.46% Off White Solid to pale yellow crystalline solid.

Method-II

A aqueous hydrotopes cumene sodium sulfonate (100mL), 7-hydroxyquinoline-2(1H)-one (10 g), Sodium hydroxide (3.2 g), 1-bromo-4-chlorobutane(9.0 g), was stirred at 30-35°C, maintained at this temperature for 9 hrs. After completion of reaction, mass is filtered, washed with deminaralised water, Product recrystallised from hexane. Filter and dry to get pure 7- (4-chlorobutoxy)quinolin-2(1H)-one

Preparation of crude 7- (4-(4-(2,3-dichlorophenyl)- piperazin-1-yl) butoxy)- quinolin- 2(1H)-one:

Method-I

A mixture of Water (100mL), 7-(4- chlorobutoxy)-quinoline-2(1H)-one (10 g), Potassium Carbonate (6.60 g), 1-(2,3-dichloro phenyl) piperazine hydrochloride (8.5 g) were heated to 90-95°C. Reaction mass maintained at this temperature for 3-4 h. After completion of reaction, mass is cooled to 50-55°C. Maintain at this temperature for further 30 minute. Reaction mass is filtered to remove insoluble, if any. Clear filtrate, cool to 25-30°C and ectracted with ethylacetate. Product is precipitated and stirs the mass for 30 minute. Filter and dry to get crude 7-(4-(4-(2,3-dichlorophenyl) piperazin-1-yl) butoxy) - quinolin- 2(1H)-one. Weight: 16.0 g (Yield: 88.0 %); HPLC purity: 97.5%

Method-II

A mixture of Dimethylformamide (80mL), 7-(4- chlorobutoxy)-quinoline-2(1H)-one (10 g), Sodium carbonate (6.60 g),sodium iodide (3.0 g) 1-(2,3-dichloro phenyl) piperazine hydrochloride (8.5 g) were heated to 80-85°C. Reaction mass maintained at this temperature for 3-4 h. After completion of reaction, mass is cooled to 50-55°C and water was added. Precipitation observed. cool to 5-10°C and. Filtered and dry to get crude 7-(4-(4-(2,3-dichlorophenyl) piperazin-1-yl) butoxy) - quinolin- 2(1H)-one. Weight: 15.0 g (Yield: 86.0 %); HPLC purity: 98.1% Off White Solid-cream colored solid.

Preparation of Pure 7- (4-(4-(2,3-dichlorophenyl)- piperazin-1-yl) butoxy)- quinolin- 2(1H)-one:

Crude product (10.0) was dissolved in 150 ml of ethanol at reflux temperature, upon cooling to 5-10 °C pure product was filtered off. Same procedure was repeated one more time to get pure Dehydroaripiprazole. Weight: 7.0 g (Yield: 70.0 %); HPLC purity: 99.7% , Mass (M+1) = 446.2

NMR : - 1.83 (4H,dq, Aliphatic chain CH2-¬), 2.55 (2H,t,Aliphatic), 2.71 (4H,d,Aliphatic), 3.10 (4H,s,piperazine), 4.09 (2H,t, Aliphatic), 6.52 (1H,d,Alkene), 6.79 (2H,dt,Aromatic), 6.94(1H,dd,Alkene), 7.12 (2H,t,Aromatic), 7.42 (1H,d,Aromatic), 7.70(1H,d, Aromatic), 12.11 (1H,s, Amide-NH)

RESULTS AND DISCUSSION:

Aripiprazole was synthesized by the known literature synthetic procedure.1 and subsequently the same is mentioned for dehydroaripiprazole. One key starting material, 7-hydroxy-3, 4-dihydroquinolin-2(1H)- one was reacted with 1,4-dibromobutane in water and then purified over column to get 7-(4-bromobutoxy)-3,4- dihydroquinoline-2(1H)-one. 7-(4-bromobutoxy)-3, 4-dihydroquinoline-2(1H)-one is reacted with second key starting material 1-(2, 3-dichloro phenyl) piperazine hydrochloride in presence of Acetonitrile, sodium iodide, sodium Carbonate to form Aripiprazole (Scheme 1).

Figure No 1: Figure Showing Synthetic Scheme of Aripiprazole

One of the drawbacks of the above mentioned procedure is the isolation of intermediate through column chromatography, likely most reason for carrying out column chromatography may the formation of dimmer impurity, this can form due similar reactivity of the reagent (1,4-dibromobutane) and secondly the reaction conditions. Based on the above synthetic scheme, shortfalls predicted and other literature reference following scheme was predicted for the preparation of Dehydroaripiprazole.

Figure No 2: Figure Showing Synthetic Scheme of Dehydroaripiprazole

In the scheme mentioned above, 7-hydroxy carbostyril is reacted with dihalobutane derivative in different reaction conditions to give intermediate, which is subsequently free of dimer impurity and no column purification is required for the same. This intermediate is in turn reacted with dichloro-piperazine derivative again under phase transfer conditions to give Dehydroaripiprazole.

In the very first aspect, looking at the phenolic nature of the hydroxy group attached to the carbostyril ring, it indicates the reaction can be carried out at much lower temperature than that mentioned in the literature, preferably using phase transfer conditions and reducing the reactivity of the dihaloderivative (preferred 1-bromo-4-chlorobutane instead of 1,4-dibromobutane).

Firstly reactions were carried out using two different phase transfer catalyst in different solvents under different reaction conditions (moles ratio of dihaloderivative and reaction Temperature). (Table-1)

Also the reaction was carried out using hydrotopes like cumene sodium sulphonate and xylene sodium sulphonate. (Table-2)

Table no 1: Table showing Effects of PTC reagents on the Reaction Yield

PTC Moles	Temp °C		Time	Reaction Solvent	Dihaloderivative (Moles)
PTC Used was Aliquat 336
0.5	50-55		40 hrs	n-butanol	3
0.3	40-45		90 hrs	n-butanol	3
0.5	30-32		64 hrs	Acetone	3
0.2	45-50		25 hrs	Methyl isobutyl Ketone	3
0.2	40-45		24 hrs	n-butanol	2
0.2	30-32		19 hrs	DMF	1.2
0.2	50-55		40 hrs	n-butanol	1.2
PTC Used was PEG 400
1.0	40-45	5 hrs		n-butanol	3
0.5	40-45	7 hrs		n-butanol	3
0.5	40-45	9 hrs		n-butanol	3
0.5	40-45	24 hrs		Ethyl methyl Ketone	3
0.5	30-32	16 hrs		Acetone	3
0.5	30-32	24 hrs		n-butanol	3
0.5	30-32	16 hrs		Acetone	3
0.5	30-32	10 hrs		Acetonitrile	3

Table-2:

Conc of hydrotrope	Temp °C	Time	Yield	Dihaloderivative (Moles)
Hydrotrope Used was Cumene sodium sulphonate
0.2	30-32	9 hrs	30 %	3
0.5	30-32	9 hrs	50 %	3
1.0	30-32	9 hrs	65 %	3
Hydrotrope Used was Xylene sodium sulphonate
0.2	30-32	9 hrs	25 %	3
0.5	30-32	9 hrs	47 %	3
1.0	30-32	9 hrs	62 %	3

In reactions using hydrotropes since the by product is acid, which in turn neutralizes in hydrotropic reaction media, hence constant basicity is maintained during the course of the reaction.

In all of the above reaction the formation of dimer impurity was not avoided completely, however the formation was controlled to around 1-2 %. The product was isolated after proper work-up, by directly adding water/hexane mixture or can be purified by dissovling in isopropanol and precipitating out using hexane. The product isolated by any of the method was pure enough to be utilized for the next stage.

After the intermediate formation, the subsequent reaction was carried out in line with literature of aripiprazole with 1(2,3-dichlorophenyl)piperazine with sodium iodide as intiator, potassium carbonate as base and DMF or acetonitrile as reaction solvent. Product so obtained was further crystallized with ethanol to give pure form of Dehydroaripiprazole.

Another method for the formation of Dehydroaripiprazole was also devised, wherein the reaction is carried out in water, in presence of base and hydrochloride salt of the piperazine derivative to afford crude Dehydroaripiprazole, which was further purified to give pure dehydroaripiprazole.

CONCLUSIONS:

Addressed here is a scalable process for the synthesis of dehydroaripiprazole, wherein greener methodologies are applied for the preparation of intermediates and final product.

ACKNOWLEDGEMENTS:

The authors are thankful to the management of Jaipur National University for providing necessary facilities to carry out this research work. The authors are also thankful to the colleagues of the synthetic research and analytical research department for their cooperation.

REFERENCES:

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Received on 09.05.2015 Modified on 15.06.2015

Accepted on 25.07.2015 © AJRC All right reserved

Asian J. Research Chem. 8(8): August 2015; Page 503-506

DOI: 10.5958/0974-4150.2015.00079.6