Process Research and Large-Scale Synthesis of a Novel 5,6-Dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine PDE-IV Inhibitor

Abstract

An efficient synthesis of the PDE IV inhibitor, 9H-cyclopentyl-7-ethyl-3-(thiophen-2-yl)-pyrazolo[3,4-c]-1,2,4-triazolo-5,6-dihydro-[4,3-a]pyridine 1 is described. Starting from commercially available γ-caprolactone, the synthesis was carried out in 10 steps. Key transformations were the selective O-methylation of diketone, 3-hydroxy-1-(4-methoxybenzyl)-4-propionyl-5,6-dihydro-1H-pyridin-2-one, with dimethyl sulfate and cesium carbonate in dimethylformamide, a one-pot pyrazole formation with subsequent acidic deprotection to provide lactam, 1-cyclopentyl-3-ethyl-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one, and finally the utilization of imidate, 1-cyclopentyl-7-ethoxy-3-ethyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine for the introduction of the triazole moiety. This process avoided the use of harsh reaction conditions, undesirable reagents and overcame the environmental concerns in the original synthesis.

Microwave Assistant One Pot Synthesis, Crystal Structure, Antifungal Activities and 3D‐QSAR of Novel 1,2,4‐Triazolo[4,3‐a]pyridines

“…In the literature (15)(16)(17), these methods often contain two steps: first, intermediates (hydrazide or hydrazone) were synthesized; then, fused 1,2,4-triazoleheterocycles were prepared via catalyst or catalyst free. The one pot cyclization reaction of hydrazide with substituted acid in POCl 3 under microwave irradiation led to novel 1,2,4-triazolo [4,3-a]pyridines.…”

Synthesis, crystal structure, herbicidal activities and 3D-QSAR study of some novel 1,2,4-triazolo[4,3-a ]pyridine derivatives

“…Fused heterocyclic compounds often display two heterocycle functions. It has been reported that 1,2,4‐triazolo[4,3‐ a ]pyridine possesses excellent biological activities . The incorporation of a pyridine ring into the triazole ring is considered to be a good way to produce novel active compounds.…”

Triazole‐Pyridine Dicarbonitrile Targets Phosphodiesterase 4 to Induce Cytotoxicity in Lung Carcinoma Cells

“…Furthermore, the antitumor potential of triazole conjugated pyridine has also been established in various malignancies . Some of the reports also indicated that triazolo‐pyridine conjugates target PDE4 to induce their biological effect . Specifically, synthesis of a PDE4 inhibitor, 5,6‐dihydro‐9 H ‐pyrazolo[3,4‐ c ]‐1,2,4‐triazolo[4,3‐ a ]pyridine was described .…”

“…[18][19][20][21] Some of the reports also indicated that triazolo-pyridine conjugates target PDE4 to induce their biological effect. [22,23] Specifically, synthesis of a PDE4 inhibitor, 5,6-dihydro-9H-pyrazolo [3,4-c]-1,2,4-triazolo[4,3-a]pyridine was described. [23] In another study, the substitution at the 3-position of 5,6-dihydro-(9H)-pyrazolo [3,4-c]-1,2,4-triazolo [4,3-a]pyridine tricycle led to a 2-thienyl analog (Tofimilast) which is a potent PDE4 inhibitor with low oral bioavailability.…”

“…[22,23] Specifically, synthesis of a PDE4 inhibitor, 5,6-dihydro-9H-pyrazolo [3,4-c]-1,2,4-triazolo[4,3-a]pyridine was described. [23] In another study, the substitution at the 3-position of 5,6-dihydro-(9H)-pyrazolo [3,4-c]-1,2,4-triazolo [4,3-a]pyridine tricycle led to a 2-thienyl analog (Tofimilast) which is a potent PDE4 inhibitor with low oral bioavailability. [24] Apart, there are limited number of reports on the preparation of triazolo pyridine dicarbonitriles and many of them employ the use of strong base, hazardous organic solvents, expensive catalysts and tedious laboratory procedures.…”