Brexpiprazole (OPC-34712) is a novel D2 dopamine partial agonist investigational product currently in clinical trials for the treatment of depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Although it failed Stage 2 trials for ADHD, it has been designed to provide improved efficacy and tolerability (e.g., less akathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).
The drug is being developed by Otsuka, and is considered to be a successor of its top-selling antipsychotic agent aripiprazole (brand names: Abilify, Aripiprex). Otsuka's US patent on aripiprazole expired on October 20, 2014; however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.
Scheme 1
Condensation of 2,6-dichlorobenzaldehyde (I) with rhodanine (II) in the presence of NaOAc in refluxing AcOH gives 5-(2,6-dichlorobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (III), which is treated with NaOH to provide 3-(2,6-dichlorophenyl)-2-mercapto-2(Z)-propenoic acid (IV). Cyclization of intermediate (IV) by means of KOH in refluxing H2O yields 3-(2,6- dichlorophenyl-2-mercapto-2(Z)-propenoic acid potassium salt, which is then hydrolyzed with HCl to obtain 4-chloro-1-benzothiophene-2-carboxylic acid (V). Alternatively, condensation of 2,6-dichlorobenzaldehyde (I) with thioglycolic acid (VI) in the presence of KOH in refluxing H2O, followed by hydrolysis of the obtained potassium salt, with HCl produces 4-chloro-1-benzothiophene-2-carboxylic acid (V), which can also be obtained by the reaction of (5Z)-5-(2,6-dichlorobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (II) with NaOH in H2O and HCl. Decarboxylation of 4-chloro-1-benzothiophene-2-carboxylic acid (V) either with DMI and DBU at 160-195°C or by means of quinoline and Cu at 145-155°C affords 4-chloro-1-benzothiophene (VII). Condensation of 4-chloro-1-benzothiophene (VII) with piparazine (VIII) in the presence of t-BuONa, Pd(OAc)2 and using variety of catalyst such as XPhos, (t-Bu)3P+Ph4B-, JohnPhos, (A), (B), (C), (D), (E) or (F) in refluxing xylene and subsequent treatment with HCl in i-PrOH furnishes 1-(1-benzothien-4-yl)piperazine hydrochloride (X) (1). Alternatively, condensation of 4-bromo-1-benzothiophene (IX) with piperazine (VIII) in the presence of t-BuONa, BINAP and Pd2dba3 in toluene and subsequent treatment with HCl in MeOH provides furnishes 1-(1-benzothien-4-yl)piperazine hydrochloride (X) (2). Condensation of 7-hydroxy-2(1H)-quinolinone (XI) with 1-bromo-4-chlorobutane (XII) (1,2) in the presence of either K2CO3 in refluxing DMF (1) or KOH in refluxing MeOH (2) gives the desired ether (XIII), which is then condensed with piperazine derivative (X) in the presence of K2CO3 (1,2) and KI (1) or NaI (2) in DMF at 80-100°C to yield the target brexpiprazole (1,2).
Scheme 2
Condensation of 4-chloro-1-benzothiophene (VII) with piparazine (VIII) in the presence of t-BuONa and catalyst (A), (B), (C) or (D) in refluxing xylene and subsequent treatment with HCl in i-PrOH furnishes 1-(1-benzothien-4-yl)piperazine hydrochloride (IX) (1).
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