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[0143] A mixture of 44.8 mL of acetic anhydride and 19.2 mL of formic acid was heated in a 50-60 C oil bath temperature for 3 h and then cooled to rt to give formic-acetic anhydride, which was then slowly added to the solid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl and then stirred at rt for 8 h. Excess reagent was evaporated to give a residue, which was neutralized by very slow addition of sat. NaHC03 solution. Solution was extracted with DCM, dried and evaporated to provide ethyl imidazo[l,5-a]pyridine-8-carboxylate as a yellow solid (crude weight 2.7 g). MS: exact mass calculated for C10H10N2O2, 190.07; m/z found, 191 [M+H] +.
A mixture of 44.8 mL of acetic anhydride and 19.2 mL of formic acid was heated in a 50-60 C. oil bath temperature for 3 h and then cooled to rt to give formic-acetic anhydride, which was then slowly added to the solid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl and then stirred at rt for 8 h. Excess reagent was evaporated to give a residue, which was neutralized by very slow addition of sat. NaHCO3 solution. _Solution was extracted with DCM, dried and evaporated to provide ethyl imidazo[1,5-a]pyridine-8-carboxylate as a yellow solid (crude weight 2.7 g). MS: exact mass calculated for C10H10N2O2, 190.07; m/z found, 191 [M+H]+.
With potassium hydroxide; In methanol; for 0.5h;Heating / reflux;
Description 36 (8.67 g, 45.6 mmol) and KOH [1. OM in methanol] (91.2 ml, 91.2 mmol) were mixed together and heated to reflux for 30 minutes when HPLC indicated the reaction was complete. The mixture was cooled and evaporated to dryness. Water (50 ml) was then added, and the mixture acidified with 2N HC1 to give a yellow precipitate. The precipitate was filtered and washed successively with water, ethanol, and diethyl ether to give the title compound (3.1 g, 42%) as a yellow solid
Ethyl imidazo [1, 5-a] pyridine-8-carboxylate (J. Het. CLIEIIZ., 1993,473) (0.21 g) was dissolved in 1M KOH in methanol (5 ml) and the solution heated at reflux for 5 min. The mixture was then concentrated, diluted with water (2 ml) and acidified to pH 1 with 2N HCI. The resulting precipitate was collected by filtration to give imidazo [1, 5-a] pyridine-8-carboxylic acid (80 mg) as a yellow solid.
Acetic anhydride (38. 21 ml, 405 mmol) and formic acid (15.28 ml, 405 mmol) were mixed together at 60 C for 2 hours then allowed to cool to room temperature. To this mixture was added Description 35 (17.55 g, 81 mmol), and the resulting mixture stirred at room temperature for 1 hour, then heated at 35 C for 3 hours. The mixture was cooled to 5 C and neutralised with 0.88 ammonia solution and then extracted with dichloromethane (3 x). The combined dichloromethane layers were washed with water, saturated NACI, dried over NA2S04, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 2% MEOH in DCM + 0.5% NH40H to give the title compound (8.67 g, 56%).
[0144] To a cold solution of lithium aluminum hydride (1.62 g, 42,4 mmol, 4.0 eq) in THF (50 mL) was added the crude ethyl imidazo[l,5-a]pyridine-8-carboxylate (2.7 g, 14.2 mmol, 1.0 eq) and the reaction mixture was heated at reflux for 2 h. The reaction was cooled and water (1.7 mL), 15% NaOH (1.7 mL) and water (5.1 mL) were slowly added. Solution was diluted with excess EtOAc and stirred at rt for 30 min. The solution was filtered and the solid was washed with ethyl acetate. Organic layers were combined, dried and solvent was removed to give crude imidazo[l,5-a]pyridine-8-methanol, which was purified by column chromatography (EtOAc/ Hexane). MS: exact mass calculated for 148.06; m/z found, 149 [M+H] +.
With lithium aluminium tetrahydride; In tetrahydrofuran; for 2h;Reflux;
[0251] To a cold solution of lithium aluminum hydride (1.62 g, 42,4 mmol, 4.0 eq) in THF (50 mL) was added the crude <strong>[697739-12-1]ethyl imidazo[1,5-a]pyridine-8-carboxylate</strong> (2.7 g, 14.2 mmol, 1.0 eq) and the reaction mixture was heated at reflux for 2 h. The reaction was cooled and water (1.7 mL), 15% NaOH (1.7 mL) and water (5.1 mL) were slowly added. Solution was diluted withexcess EtOAc and stirred at rt for 30 mm. The solution was filtered and the solid was washed with ethyl acetate. Organic layers were combined, dried and solvent was removed to give crude imidazo[1,5-a]pyridine-8-methanol, which was purified by column chromatography (EtOAc/ Hexane). MS: exact mass calculated for C8H8N20, 148.06; m/z found, 149 [M+H]+ .
With lithium aluminium tetrahydride; In tetrahydrofuran; for 2h;Reflux;
Steps 5 and 6 :To a cold solution of lithium aluminum hydride (1.62 g, 42.4 mmol, 4.0 eq) in THF (50 mL) was added the crude <strong>[697739-12-1]ethyl imidazo[1,5-a]pyridine-8-carboxylate</strong> (2.7 g, 14.2 mmol, 1.0 eq) and the reaction mixture was heated at reflux for 2 h. The reaction was cooled and water (1.7 mL), 15% NaOH (1.7 mL) and water (5.1 mL) were slowly added. Solution was diluted with excess EtOAc and stirred at rt for 30 min. The solution was filtered and the solid was washed with ethyl acetate. Organic layers were combined, dried and solvent was removed to give crude imidazo[1,5-a]pyridine-8-methanol, which was purified by column chromatography (EtOAc/Hexane). MS: exact mass calculated for C8H8N2O, 148.06; m/z found, 149 [M+H]+.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 2h;
To a solution of 550 <strong>[697739-12-1]ethyl imidazo[1,5-a]pyridine-8-carboxylate</strong> (2 g, 10.52 mmol) in 166 THF (20 mL) was added 192 LiAlH4 (798 mg, 21.0 mmol) with stirring at 0 C. The resulting suspension was stirred at 20 C. for 2 hours. The reaction mixture was cooled to 0 C. and was quenched with 55 water (2 mL), then diluted with ethyl acetate (200 mL). The resulting suspension was filtered through a pad of A1203 and concentrated. The residue was purified by column silica gel chromatography (Gradient: 0-10%, 113 MeOH in 68 dichloromethane) to give 551 imidazo[1,5-a]pyridin-8-ylmethanol.
With acetic anhydride; formyl acetic anhydride; at 20℃; for 8h;
[0250] A mixture of 44.8 mL of acetic anhydride and 19.2 mL of formic acid was heated in a 50-60 C oil bath temperature for 3 h and then cooled to rt to give formic-acetic anhydride,which was then slowly added to the solid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl andthen stirred at rt for 8 h. Excess reagent was evaporated to give a residue, which was neutralizedby very slow addition of sat. NaHCO3 solution. Solution was extracted with DCM, dried and evaporated to provide ethyl imidazo[1,5-a]pyridine-8-carboxylate as a yellow solid (crude weight 2.7 g). MS: exact mass calculated for C10H10N202, 190.07; m/z found, 191 [M+H]+ .
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