Scalable Process Design for a PDE10A Inhibitor Consisting of Pyrazolopyrimidine and Quinoxaline as Key Units

Abstract

In this study, research and development for the synthetic process of a PDE10A inhibitor are described; in particular, an efficient regioselective construction of the quinoxaline unit, a cost-effective pyrazolo[1,5-a]pyrimidine formation, and a cost-saving approach in a nucleophilic aromatic substitution (S N Ar) reaction by introducing oxazolidinone as an electronwithdrawing group to a chloropyrazolo[1,5-a]pyrimidine core are key points. The newly developed process has been successfully scaled up to 40 kg. Furthermore, a one-pot tandem reaction from aminopyrazole to dichloropyrazolo[1,5a]pyrimidine by activating malonic acid with POCl 3 was discovered. The finding contributed to avoiding isolation of the hygroscopic pyrazolo[1,5-a]pyrimidin-5(4H)-one intermediate, which caused complicated filtration and drying processes observed in the first scale-up campaign.

Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions

“…Selective bromination of 3 with N-bromosuccinimide in dichloromethane afforded the bromo derivative 4 in 94% yield. The 3-bromo-7-(trifluoromethyl) pyrazolo [1,5-a]pyrimidin-5-one 4 served as a building block for the synthesis of 3,5-disubstituted 7-(trifluoromethyl)pyrazolo [1,5-a] a]pyrimidine derivatives were found to have an antiviral effect against the respiratory syncytial virus (RSV) [21] and hepatitis C virus [22], and are inhibitors of phosphodiesterase (PDE) 2A [23] and 10A [24][25][26], promising new targets for the treatment of cognitive disorders and schizophrenia, respectively. The incorporation of a fluorine atom into potential pharmaceutical substances has been successfully used as a key strategy for enhancing the activity of drugs or drug candidates [27,28].…”

“…Moreover, pyrazolo [1,5-a]pyrimidines are also known as antagonists of serotonin 5-HT6 receptors [15], and also act as inhibitors of histone lysine demethylase 4D (KDM4D) [16] as well as several kinases such as Pim kinase [17,18], threonine tyrosine kinase (TTK) [19], and cyclin-dependent kinases (CDKs) [20]. In addition, some pyrazolo [1,5-a]pyrimidine derivatives were found to have an antiviral effect against the respiratory syncytial virus (RSV) [21] and hepatitis C virus [22], and are inhibitors of phosphodiesterase (PDE) 2A [23] and 10A [24][25][26], promising new targets for the treatment of cognitive disorders and schizophrenia, respectively.…”

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

“…In this context, Yamagami and co-workers developed a method to produce the 5,7-dichloro-2-hetarylpyrazolo[1,5- a ]pyrimidine 3 via the cyclocondensation reaction of the 5-amino-3-hetarylpyrazole 1 with malonic acid ( 2 ) ( Scheme 1 ) [ 30 ]. In this approach, the addition of POCl 3 in the presence of a catalytic amount of pyridine produces an activated species of malonic acid phosphoric ester.…”