An efficient synthesis of 2-amino-4-(4-fluoro-3-(2-fluoropyridin-3-yl)phenyl)-4-(4-methoxy-3-methylphenyl)-1-methyl-1H-imidazol-5(4H)-one, a potent BACE1 inhibitor

Ping Zhou,Michael Malamas,Albert J Robichaud,Christian V Stevens

doi:10.3998/ark.5550190.0011.609

Abstract

An efficient method has been developed for the synthesis of 2-amino-4-(4-fluoro-3-(2- fluoropyridin-3-yl)phenyl)-4-(4-methoxy-3-methylphenyl)-1-methyl-1H-imidazol-5(4H)-one, a potent BACE1 inhibitor for the potential treatment of Alzheimer's Disease. The new method features a Friedel-Crafts reaction between 3-bromo-4-fluorophenylacetic acid and 2- methoxytoluene followed by DMSO mediated α-oxidation of the resulting 1,2-diarylethanone to give an α-diketone. Subsequent aminohydantoin formation and Suzuki coupling led to the target molecule in greater than 70% overall yield.

Highlights

Alzheimer’s Disease (AD) is a neurodegenerative disease that leads to progressive decline in cognitive function and incapacitation and death.[1,2,3,4] The amyloid cascade is a leading hypothesis for the cause of AD
According to this hypothesis, processing of the amyloid precursor protein (APP) by β-secretase (β-site APP Cleaving Enzyme or BACE1) followed by γsecretase releases the putative Aβ peptide, which has been implicated in the neurodegeneration associated with the disease
We recently reported that 2-amino-4-(4-fluoro-3-(2-fluoropyridin-3-yl)phenyl)-4-(4methoxy-3-methylphenyl)-1-methyl-1H-imidazol-5(4H)-one 1 was a potent BACE1 inhibitor (BACE1 IC50 40 nM).[9]

Summary

Introduction

Alzheimer’s Disease (AD) is a neurodegenerative disease that leads to progressive decline in cognitive function and incapacitation and death.[1,2,3,4] The amyloid cascade is a leading hypothesis for the cause of AD. Based on the key role of BACE1 in the β-amyloid cascade, inhibition of BACE1 is considered a prominent therapeutic target for treating AD.[5,6,7,8] In this regard, we recently reported that 2-amino-4-(4-fluoro-3-(2-fluoropyridin-3-yl)phenyl)-4-(4methoxy-3-methylphenyl)-1-methyl-1H-imidazol-5(4H)-one 1 was a potent BACE1 inhibitor (BACE1 IC50 40 nM).[9]. We describe a new and efficient synthesis of the target compound using readily commercially available 3-bromo-4-fluorophenylacetic acid 2 and 2-methoxytoluene 3 as starting materials (Scheme 1). A new and efficient method has been developed for the synthesis of 2-amino-4(4-fluoro-3-(2-fluoropyridin-3-yl)phenyl)-4-(4-methoxy-3-methylphenyl)-1-methyl-1Himidazol-5(4H)-one, a potent BACE1 inhibitor for the potential treatment of Alzheimer’s disease. Subsequent aminohydantoin formation and Suzuki coupling led to the target molecule in 71% overall yield This new synthesis avoids multiple time consuming chromatographic separations, and shortens the reaction sequence from seven to four steps. The preparation of a variety of synthetically and/or biologically important compounds such as imidazoles,14 2thioxoimidazolidin-4-one and imidazolidine-2,4-diones,[15] quinoxalines,[16] and 1,2,3,4tetrahydroquinoxalines can be effected from these key intermediates.[17]

Experimental Section

Findings

Reference and Notes