Practical application of the palladium-catalyzed amination in phenylpiperazine synthesis: An efficient synthesis of a metabolite of the antipsychotic agent aripiprazole

doi:10.1016/S0040-4020(98)00175-6

Tetrahedron

Volume 54, Issue 19, 7 May 1998, Pages 4811-4818

https://doi.org/10.1016/S0040-4020(98)00175-6 Get rights and content

Abstract

A metabolite of Aripiprazole (1), 7-[4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone (2), was prepared by the coupling reaction of 1-(4-benzyloxy-2,3-dichlorophenyl)-piperazine (11) with 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (16). The palladium-catalyzed amination of contiguous tri- and tetra-substituted benzenes with piperazine derivatives was investigated. The key intermediate 11 was efficiently prepared using the palladium-catalyzed amination of phenyl bromide 15 with piperazine.

A hydroxylated metabolite 2 of Aripiprazole (1) was prepared by the coupling reaction of 11 with 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (16). The palladium-catalyzed amination of contiguous tri- and tetra-substituted benzenes with piperazine derivatives was investigated. The key intermediate 11 and 2,3-dichlorophenylpiperazine (13a) were efficiently prepared using the palladium-catalyzed amination of phenyl bromides 15 and 12a with piperazine, respectively.

References (25)

J.P. Wolfe et al.
Tetrahedron
(1996)
J. Louie et al.
Tetrahedron Lett.
(1995)
J.P. Wolfe et al.
Tetrahedron Lett.
(1997)
J. .Ahman et al.
Tetrahedron Lett.
(1997)
J.P. Wolfe et al.
Tetrahedron Lett.
(1997)
Y. Oshiro et al.
J. Med. Chem.
(1998)
Chem. Abstr.
(1960)
Chem. Abstr.
(1961)
A.S. Guram et al.
Angew. Chem. Int. Ed. Engl.
(1995)

J.P. Wolfe et al.

J. Am. Chem. Soc.

(1996)

S. Wagaw et al.

J. Org. Chem.

(1996)

Cited by (48)

Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H- benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: Design, synthesis, and structure-activity relationships
2010, Bioorganic and Medicinal Chemistry
Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure–activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.
Potent, selective, and orally active adenosine A<inf>2A</inf> receptor antagonists: Arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines
2007, Bioorganic and Medicinal Chemistry Letters
Antagonism of the adenosine A_2A receptor offers great promise in the treatment of Parkinson’s disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A_2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11 h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.
Aripiprazole and its human metabolite are partial agonists at the human dopamine D<inf>2</inf> receptor, but the rodent metabolite displays antagonist properties
2006, European Journal of Pharmacology
Aripiprazole is a novel antipsychotic drug, which displays partial agonist activity at the dopamine D₂ receptor. Aripiprazole has been extensively studied pre-clinically, both in vitro and in vivo, and these results have been correlated with clinical findings. However, aripiprazole is metabolised differently in rats and man and these metabolites may contribute to the profile of aripiprazole observed in vivo. We have therefore studied the interaction of aripiprazole and its principal rat and human metabolites in both in vitro models of dopamine hD₂ receptor function and affinity, and of in vivo models of dopamine rat D₂ receptor function. The human metabolite displayed similar levels of partial agonist activity to aripiprazole at the dopamine hD₂ receptor and displayed similar behavioural profile to aripiprazole in vivo, suggesting that in man the metabolite may maintain the effects of aripiprazole. In contrast, the rat metabolite displayed antagonist activity both in vitro and in vivo. Thus care must be taken in ascribing effects seen in vivo with aripiprazole in rats to dopamine D₂ receptor partial agonist activity in man, and that care must also be taken in extrapolating effects seen in rats to man, particularly from long-term studies.
Mercury chloride assisted cyclization toward benzimidazoles by focused microwave irradiation
2005, Tetrahedron Letters
An efficient, microwave-assisted method for the mercury chloride mediated synthesis of 1,2-disubstituted benzimidazoles has been developed. Biologically interesting benzimidazoles were readily assembled utilizing S_NAr reactions, reduction, and followed with mercury(II) mediated cyclization under microwave irradiation. The desired products were then liberated from the soluble matrix in excellent yield and purity after cleavage.
Solid-phase synthesis of benzimidazole libraries biased for RNA targets
2003, Tetrahedron Letters
An efficient and highly versatile synthesis of two libraries 1(x,y) and 2-Ar(x,y,z) or 2-R²(x,y,w) based on the privileged benzimidazole scaffold is described. Our design is aimed at obtaining molecules, biased for binding to RNA targets, by incorporating functionalities, which are frequently found in natural RNA-ligands. The library construction was realized with the use of SPOS in high average yields and purity. Monitoring and quantitation of intermediates and final products were performed by the use of NMR spectroscopy using DMFu as an internal standard.
Synthetic study on the unique dimeric arylpiperazine: Access to the minor contaminant of aripiprazole
2003, Bioorganic and Medicinal Chemistry Letters

View all citing articles on Scopus

View full text

Practical application of the palladium-catalyzed amination in phenylpiperazine synthesis: An efficient synthesis of a metabolite of the antipsychotic agent aripiprazole

Abstract

Tetrahedron

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

Tetrahedron Lett.

J. Med. Chem.

Chem. Abstr.

Chem. Abstr.

Angew. Chem. Int. Ed. Engl.

J. Am. Chem. Soc.

J. Org. Chem.