An efficient synthesis of the novel triazoloquinazoline adenosine antagonist, CGS 15943

Abstract

An efficient synthesis of the novel triazoloquinazoline adenosine antagonist, CGS 15943, is reported in five steps in approximately 50% overall yield. A key reaction in the synthetic sequence is the double cyclization of an N‐(substituted‐2‐cyanophenyl)carbamate with a carboxylic acid hydrazide to afford a [1,2,4]triazolo‐[1,5‐c]quinazolin‐5(6H)‐one in high yield without either a Dimroth or “translocative” rearrangement occurring. Another key reaction is the condensation of a 2‐(1H‐1,2,4‐triazol‐5‐yl)benzenamine with cyanamide under acidic conditions to prepare a guanidine.

The Reaction of 2-(Acylamino)benzonitriles with Primary Aromatic Amines: A Convenient Synthesis of 2-Substituted 4-(Arylamino)quinazolines

“…The reaction of 1a with ethyl chloroformate was previously reported to lead to the desired product 2e 16 by combining a fivefold excess of the acylating agent with 2-aminobenzonitrile under reflux for six hours. Combining 2-aminobenzonitrile (1a) and ethyl chloroformate in a 1:2 molar ratio at room temperature in ethanol-water (entry 5) gave 2e in 88% isolated yield.…”

“…Cyanophenylcarbamate (2e)White solid; yield: 0.35 g (1.86 mmol, 88%); mp 100-102 °C (Lit 16. 104-105 °C).IR (Nujol): 3298, 2221, 1704, 1602, 1585, 1536 cm -1 .…”

Phenotypic Discovery of Triazolo[1,5-c]quinazolines as a First-In-Class Bone Morphogenetic Protein Amplifier Chemotype

“…To do this, a synthetic route was devised, which enabled access to a set of diversely substituted triazoloquinazolines and scaffold analogues from a unified reaction path (Scheme ). Starting from 2-aminobenzonitriles 2a–h , we modified and combined reported routes that eventually provided several branching points for further diversification. − Each intermediate of a four-step core sequence (i.e., from 2 over 3 , 4 , and 5 to 1 ) served as a starting material for distinct modifications, thereby expanding the diversity of this compound collection at multiple nodes. Employing this route, the original CGS-15943 ( 1a ) was prepared in good overall yields (49%, four steps).…”

“…An analytical sample was purified by silica gel flash chromatography [dichloromethane (DCM)/methanol 0 → 10%]. Note: The 1 H NMR spectral data differed slightly from the literature reported values …”

2-(Azolyl)anilines: methods of synthesis, cyclocondensations, and biological properties

“…9-Chloro-2-(furan-2-yl) [1,2,4]triazolo [1,5-c]quinazolin-5-amine (125) was obtained via condensation of 4-chloro-2-[5-(furan-2-yl)-1H-1,2,4-triazol-3-yl]aniline (62a) with cyanamide in the presence of sulfuric acid in isopropanol (Scheme 42). 50 The cited paper also describes the alternative synthesis of compound 125, using 5,9-dichloro-2-(furan-2-yl) [1,2,4]triazolo [1,5-c]quinazoline.…”