Preparation of triazolo[1,5-c]pyrimidines as potential antiasthma agents

Abstract

With the use of the human basophil histamine release assay, 5-aryl-2-amino[1,2,4]triazolo[1,5-c]pyrimidines were found to be active as mediator release inhibitors. These compounds were prepared by reacting arylamidines with sodium ethyl formylacetate or with ethyl propiolate to give pyrimidinones. Treatment with phosphorus oxychloride gave a chloropyrimidine, which was converted to a hydrazinopyrimidine with hydrazine. Cyclization, using cyanogen bromide, gave the triazolo[1,5-c]pyrimidines, after a Dimroth rearrangement. Following a structure-activity evaluation, the 5-[3-(trifluoromethyl)phenyl]-2-amino (8-10), 5-(3-bromophenyl)-2-amino (8-13), 5-[3-(difluoromethoxy)-phenyl]-2-amino (8-11), and 5-(4-pyridinyl)-2-amino (6-7) compounds were found to have the best activity. They were chosen for further pharmacological and toxicological study.

Synthesis and evaluation of 2-pyridinylpyrimidines as inhibitors of HIV-1 structural protein assembly

“…The commercially available 3-/4-cyanopyridines were first converted to corresponding amidines 1 and 2 by treatment with sodium methoxide and later with ammonium chloride. 21 The resulting amidines were either combined with the sodium salt of ethyl formylacetate, which was prepared by aldol condensation of ethyl acetate with ethyl formate, or with methyl acetoacetate to yield pyrimidinones 3-6. 21,22 Subsequent treatment 23 with phosphorus oxychloride yielded 4-chloropyrimidines 7-10, which were subjected to nucleophilic displacement of the chlorine atom by variously substituted anilines.…”

“…21 The resulting amidines were either combined with the sodium salt of ethyl formylacetate, which was prepared by aldol condensation of ethyl acetate with ethyl formate, or with methyl acetoacetate to yield pyrimidinones 3-6. 21,22 Subsequent treatment 23 with phosphorus oxychloride yielded 4-chloropyrimidines 7-10, which were subjected to nucleophilic displacement of the chlorine atom by variously substituted anilines. 7,24 To prepare the carboxamide series (13, 17, 20, 28-31, 39-44), a different synthetic approach was used.…”

“…In the third SAR round Table 3, we intended to explore the effect of a methyl group introduced at C-6 of the pyrimidine core, similar to what was done with the first series (see [16][17][18][19][20][21]. The inhibition activity of ethyl ester derivative 33 was unaffected by the addition of a methyl substituent.…”

Consecutive Reaction of Bis [2, 2, 2‐trifluoroethyl] phosphite. One‐pot Synthesis of Substituted 3‐Cyano‐β, γ‐unsaturated Nitriles with Exclusive or Predominant E‐Selectivity

“…In addition the cyan0 group is an important functional group for organic transformations. [4][5][6][7] Therefore, the development of an effective method for the preparation of the tide compounds would be valuable.…”

“One‐pot” synthesis of (Z)‐2‐aryl‐1‐(2‐cyanoethyl)ethenylphosphonates via hexamethylphosphoramide‐promoted sequential transformation

“…The cyano group is an important functional group in organic transformations, and cyano-containing compounds are useful intermediates for the synthesis of pyrimidines [6], tetrazole analogues [7], thiazole derivatives [8], and Z-oxazolines [9]. Therefore, the development of an effective method for the preparation of the title compounds would be valuable.…”