6-BroMopyrazolo[1,5-a]pyridine synthesis

Yield:1264193-11-4 50%

Reaction Conditions:

Stage #1:ethyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate with sulfuric acid;water for 18 h;Reflux;
Stage #2: with sodium hydroxide in water; pH=7

Steps:

4.1.2. Synthesis of pyrazolo[1,5-a]pyridine-3-carbaldehydes 4
General procedure: These were made by decarboxylation/Vilsmeier or hydrolysis/reduction/reoxidation as detailed below, unless otherwise stated.Decarboxylation was carried out by refluxing a solution of the ester (1 equiv) in 40% aqueous H₂SO₄ (3 mL) for 18 h. The solution was then cooled in ice and neutralised to pH 7 with 6 M NaOH, then extracted twice with CH₂Cl₂. The combined extracts were dried (Na₂SO₄) and the solvent removed in vacuo to leave the decarboxylated material. The pyrazolo[1,5-a]pyridine was then reacted under Vilsmeier conditions in dry DMF (2 mL) with POCl₃ (3 equiv) at 0 °C under an atmosphere of N₂. The reaction mixture was then warmed to room temperature and stirred for 2 h. The solution was poured onto ice, basified to pH 10 with 1 M NaOH, stirred for 1 h then extracted twice with CH₂Cl₂. The combined extracts were washed twice with water, dried (Na₂SO₄) and the solvent removed in vacuo to leave the aldehyde.Alternatively, the ester was hydrolysed by refluxing a solution of the ester (1 equiv) in 1 M NaOH (3 equiv) and EtOH (5 mL) for 6 h. The EtOH was removed in vacuo, and then the aqueous residue acidified to pH 1 with 1 M HCl. The precipitated carboxylic acid was filtered off, washed with water and dried. The carboxylic acid was reduced by adding CDI (1.5 equiv) to a suspension of carboxylic acid (1 equiv) in dry THF (10 mL) under an atmosphere of N₂. After stirring for 18 h, the resulting solution was added dropwise to a solution of NaBH₄ (5 equiv) in H₂O (10 mL) and stirred for 30 min. The reaction was then quenched by the addition of 1 M HCl and stirred for a further 30 min. The solution was neutralised with saturated aqueous NaHCO₃ and extracted twice with CH₂Cl₂. The combined organic layers were dried (Na₂SO₄) and the solvent removed in vacuo. Chromatography (eluting with a hexanes: EtOAc gradient) gave the alcohol. Reoxidation was carried out by stirring a suspension of the pyrazolo[1,5-a]pyridine-3-methanol (1 equiv) and MnO₂ (10 equiv) in CH₂Cl₂ (2 mL) at room temperature for 4 days. The reaction mixture was then filtered through celite, washed with CH₂Cl₂, and the solvent removed from the filtrate in vacuo to leave the aldehyde.

References:

Kendall, Jackie D.;O'Connor, Patrick D.;Marshall, Andrew J.;Frédérick, Raphaël;Marshall, Elaine S.;Lill, Claire L.;Lee, Woo-Jeong;Kolekar, Sharada;Chao, Mindy;Malik, Alisha;Yu, Shuqiao;Chaussade, Claire;Buchanan, Christina;Rewcastle, Gordon W.;Baguley, Bruce C.;Flanagan, Jack U.;Jamieson, Stephen M.F.;Denny, William A.;Shepherd, Peter R. [Bioorganic and Medicinal Chemistry,2012,vol. 20,# 1,p. 69 - 85] Location in patent:experimental part

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