New Pathway For Preparation Of Aripiprazole

Aripiprazole is the latest atypical antipsychotic drug that possesses both,post-synaptic dopamine receptor antagonist and dopamine auto-receptoragonist. By having dual activity, it can treat schizophrenia with fewestside-effects.The new pathway for the synthesis of aripiprazole from cheap raw materials,cinnamic acid and 2,3-dichloroaniline is presented.Cinnamic acid was first converted to acid chloride, followed by aminolysis,Friedel-Crafts cyclization and hydrogenation to form the first key intermediate,carbostyril compound with overall yield of 37.36%.The hydrogen sulphate salt of 2,3-dichloroaniline was converted to thecorresponding Aryl Iodide in good yield of 81% by reacting with conc. H₂SO₄and NaNO₂ to form intermediate diazonium salt, which was further displacedby KI. 2,3-dichlorophenylpiperazine(phenylpiperazine compound), the 2nd keyintermediate, was obtained by reacting Aryl Iodide and piperazine in thepresence of CuI as catalyst, proline as ligand, K₂CO₃ as base and dimethylsulfoxide as solvent with yield of 20%. The method is simple, utilizes cheapcatalyst and ligand, insensitive to moisture, and it is easy to separate theproduct. 7-hydroxy-3,4-dihydro-2-(1H)-quinolinone (carbostyril compound) wasconverted into 7-(4-chlorobutoxy)-3,4-dihydro-2-(1H)-quinolinone with theyield of 79% and then coupled with phenylpiperazine compound to form finalproduct with yield of 72.5%. The overall yield from cinnamic acid was21.40% and the analytical test and physical properties were correct. Most ofmaterial, reagents and condition applied are simple, easy and cheap; severalsteps can undergo large-scale production.