Liquid-Phase Synthesis of Combinatorial Libraries Based on 7-Trifluoromethyl-Substituted Pyrazolo[1,5-a]Pyrimidine Scaffold

Abstract

The parallel solution-phase synthesis of more than 2200 7-trifluoromethyl-substituted pyrazolo[1,5-a]pyrimidine and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine carboxamides on a 50-100-mg scale has been accomplished. Key reactions include assembly of the pyrazolo[1,5-a]pyrimidine ring by condensation of 5-aminopyrazole derivatives with the corresponding trifluoromethyl-beta-diketones. The libraries from libraries were then obtained in good yields and purities using solution-phase acylation and reduction methodologies. Simple manual techniques for parallel reactions using special CombiSyn synthesizers were coupled with easy purification procedures (crystallization from the reaction mixtures) to give high-purity final products. The scope and limitations of the developed approach are discussed.

Recent developments in aminopyrazole chemistry

“…154 The condensation of 1,3,5-triketone 301 with 5-amino-3-methylpyrazole (300) afforded 302. Refluxing the latter in methanol afforded 303 155 (Scheme 84).…”

Highly regioselective synthesis of trifluoromethyl derivatives of pyrazolo[1,5-a]pyrimidines bearing fused cycloalkane rings using (2-ethoxycycloalkenyl)-2,2,2-trifluoroethanones

“…A conventional synthetic route to CF 3 -containing pyrazolo [1,5-a]pyrimidines involves the cyclocondensation of 5(3)-aminopyrazoles with 1,3-biselectrophiles [2,7,10,11]. Following this synthetic strategy the reaction of 5(3)-aminopyrazoles 1a-c,e with 2-(2,2,2-trifluoroacetyl)-1-cycloalkanones 2a,b in both acetic acid and dimethyl sulfoxide affords a mixture of regioisomeric compounds, such as dihydrotriazaindacenes (4a-c,e and 5a-c,e) formed in the reaction with 2-(2,2,2-trifluoroacetyl)-1-cyclopentanone 2a and tetrahydropyrazoloquinazolines (6b,c,e and 7b,c,e) derived from the reaction with 2-(2,2,2-trifluoroacetyl)-1-cyclohexanone 2b (Scheme 1, Table 1).…”

“…The synthetic routes for preparation of pyrazolo [1,5-a]pyrimidines involves the cyclocondensation of aminopyrazoles with 1,3-biselectrophiles such as 1,3-dicarbonyl compounds, a-acetylene and unsaturated ketones, alkoxymethylene carbonyl compounds, 1,3-enaminones [2,[6][7][8][9][10][11].…”

Identification of AP80978, a Novel Small-Molecule Inhibitor of Hepatitis C Virus Replication That Targets NS4B

“…Fig. 1B) was synthesized in two steps by using a procedure described by Dalinger et al (15). The pyrazolo [1,5-a]pyrimidine ring was assembled by condensation of 5-amino-4-chloro-1H-pyrazole-3-carboxylic acid with 4,4,4-trifluoro-1-(furan-2-yl)-butane-1,3-dione, and the pyrimidine ring was reduced stereoselectively with sodium borohydride in ethanol, yielding only one pair of diastereoisomers that corresponds to 2,4-syn isomers.…”