Ethyl glyoxylate hydrate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-n-propyl-4-(2-aminoethyl)-1-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methylimidazole (21.95 g) and tetrahydrofuran (200 ml) is added a solution of ethyl glyoxylate hydrate (4.25 g) in tetrahydrofuran (20 ml) at 5° C. The mixture is stirred overnight at room temperature and refluxed for 30 minutes. To a mixture is added a 8% hydrogen chloride-ethanol solution (100 ml) at room temperature. The reaction mixture is stirred for 30 minutes, and evaporated to remove the solvent. The residue is dissolved in chloroform and washed successively with saturated sodium hydrogen carbonate solution and brine. The organic layer is dried and evaporated to remove the solvent. The crude residue is treated with a mixture of oxalic acid and ethanol to give ethyl 2-n-propyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate oxalate (10.84 g). refluxed for 30 minutes The reaction mixture is stirred for 30 minutes evaporated to remove the solvent The residue is dissolved in chloroform washed successively with saturated sodium hydrogen carbonate solution and brine The organic layer is dried evaporated to remove the solvent The crude residue is treated with a mixture of oxalic acid and ethanol

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (320 mg, 0.66 mmol) in ethanol (20 mL) was added 50% ethyl 2-oxoacetate hydrate (268 mg, 1.31 mmol), AcOH (0.1 mL, 1.75 mmol) and NaBH3CN (83 mg, 1.32 mmol). The resulting solution was stirred at 60° C. for 12 h and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 2% MeOH in DCM. The crude product (100 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=55:75 within 12 min; Detector, UV 254 nm. 25.3 mg product was obtained. This resulted in 25.3 mg (7%) of ethyl 2-(4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]piperidin-1-yl)acetate as an off-white solid. LCMS (Method 20) [M+H]+=574.2, RT=2.70 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.36 (s, 1H), 8.69-8.67 (m, 2H), 8.36 (s, 1H), 7.63-7.25 (m, 5H), 4.25-4.23 (m, 1H), 4.13-4.10 (m, 2H), 3.28-3.27 (m, 2H), 3.01-2.98 (m, 2H), 2.42-2.40 (m, 2H), 2.12-1.98 (m, 4H), 1.25-1.20 (m, 3H). concentrated under vacuum The crude product (100 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1) mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=55:75 within 12 min

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-n-propyl-4-(2-aminoethyl)-1-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methylimidazole (21.95 g) and tetrahydrofuran (200 ml) is added a solution of ethyl glyoxylate hydrate (4.25 g) in tetrahydrofuran (20 ml) at 5° C. The mixture is stirred overnight at room temperature and refluxed for 30 minutes. To a mixture is added a 8% hydrogen chloride-ethanol solution (100 ml) at room temperature. The reaction mixture is stirred for 30 minutes, and evaporated to remove the solvent. The residue is dissolved in chloroform and washed successively with saturated sodium hydrogen carbonate solution and brine. The organic layer is dried and evaporated to remove the solvent. The crude residue is treated with a mixture of oxalic acid and ethanol to give ethyl 2-n-propyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate oxalate (10.84 g). refluxed for 30 minutes The reaction mixture is stirred for 30 minutes evaporated to remove the solvent The residue is dissolved in chloroform washed successively with saturated sodium hydrogen carbonate solution and brine The organic layer is dried evaporated to remove the solvent The crude residue is treated with a mixture of oxalic acid and ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-n-propyl-4-(2-aminoethyl)-1-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methylimidazole (21.95 g) and tetrahydrofuran (200 ml) is added a solution of ethyl glyoxylate hydrate (4.25 g) in tetrahydrofuran (20 ml) at 5° C. The mixture is stirred overnight at room temperature and refluxed for 30 minutes. To a mixture is added a 8% hydrogen chloride-ethanol solution (100 ml) at room temperature. The reaction mixture is stirred for 30 minutes, and evaporated to remove the solvent. The residue is dissolved in chloroform and washed successively with saturated sodium hydrogen carbonate solution and brine. The organic layer is dried and evaporated to remove the solvent. The crude residue is treated with a mixture of oxalic acid and ethanol to give ethyl 2-n-propyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate oxalate (10.84 g). refluxed for 30 minutes The reaction mixture is stirred for 30 minutes evaporated to remove the solvent The residue is dissolved in chloroform washed successively with saturated sodium hydrogen carbonate solution and brine The organic layer is dried evaporated to remove the solvent The crude residue is treated with a mixture of oxalic acid and ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-n-propyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole (6.92 g), ethyl glyoxylate hydrate (1.30 g) and tetrahydrofuran (70 ml) is stirred overnight at room temperature. The mixture is evaporated, and the residue is purified by silica gel column chromatography (solvent; chloroform/ethanol) to give ethyl 2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.32 g) as a foam. The mixture is evaporated the residue is purified by silica gel column chromatography (solvent; chloroform/ethanol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-ethyl-4-(2-aminoethyl)-1-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methylimidazole (5.30 g) in tetrahydrofuran (40 ml) is added ethyl glyoxylate hydrate (1.67 g). The reaction mixture is stirred overnight at room temperature and then refluxed for two hours. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.90 g) as a yellow oil. refluxed for two hours The solvent is evaporated the residue is purified by silica gel column chromatography (solvent; chloroform/methanol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Ethyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole (7.48 g) is dissolved in tetrahydrofuran (60 ml) to which is added ethyl glyoxylate hydrate (1.56 g). The reaction mixture is stirred overnight at room temperature and then refluxed for one hour. The solution is evaporated and the residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(1-trityl- 1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.54 g) as a foam, characterized as its oxalate. refluxed for one hour The solution is evaporated the residue is purified by silica gel column chromatography (solvent; chloroform/methanol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-n-propyl-4-(2-aminoethyl)-1-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methylimidazole (10.0 g) and tetrahydrofuran (100 ml) is added a solution of ethyl glyoxylate hydrate (2.90 g) in tetrahydrofuran at room temperature. The reaction mixture is stirred overnight, refluxed for 30 minutes, and evaporated. The residue is dissolved in chloroform and the solution is washed with 2% hydrochloric acid solution, a saturated sodium hydrogen carbonate solution and brine. The organic layer is dried and evaporated. The crude product is crystallized with oxalic acid from ethanol-ether to give ethyl 2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate oxalate (8.45 g). refluxed for 30 minutes evaporated The residue is dissolved in chloroform the solution is washed with 2% hydrochloric acid solution The organic layer is dried evaporated The crude product is crystallized with oxalic acid from ethanol-ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-n-Propyl-5-(2-aminoethyl)-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole (1.01g) is dissolved in tetrahydrofuran (10 ml), and thereto is added ethyl glyoxylate hydrate (195 mg), and the mixture is stirred at room temperature overnight. The mixture is heated at 50° C. for 30 minutes, and after cooling, 7% hydrochloric acid-methanol solution (3 ml) and chloroform (10 ml) are added to the mixture, which is refluxed for 20 minutes. The mixture is evaporated under reduced pressure to remove the solvent, and the resulting residue is dissolved in chloroform (30 ml). To the mixture are added acetic anhydride (290 mg) and a solution of sodium hydrogen carbonate (1.2 g) in water (20 ml), and the mixture is stirred at room temperature overnight. The mixture is acidified with citric acid, and extracted with chloroform. The extract is washed with water, dried, and evaporated. To the residue are added fumaric acid (100 mg) and ethanol (35 ml), and the mixture is refluxed for 5 hours. Then, the reaction mixture is evaporated under reduced pressure, and the residue is recrystallized from methanol/ether to give ethyl 2-n-propyl-5-acetyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate 1/2 fumarate (728 mg). The mixture is heated at 50° C. for 30 minutes after cooling is refluxed for 20 minutes The mixture is evaporated under reduced pressure to remove the solvent the resulting residue is dissolved in chloroform (30 ml) To the mixture are added acetic anhydride (290 mg) a solution of sodium hydrogen carbonate (1.2 g) in water (20 ml), and the mixture is stirred at room temperature overnight extracted with chloroform The extract is washed with water dried evaporated To the residue are added fumaric acid (100 mg) and ethanol (35 ml) the mixture is refluxed for 5 hours Then, the reaction mixture is evaporated under reduced pressure the residue is recrystallized from methanol/ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-n-propyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole (6.92 g), ethyl glyoxylate hydrate (1.30 g) and tetrahydrofuran (70 ml) is stirred overnight at room temperature. The mixture is evaporated, and the residue is purified by silica gel column chromatography (solvent; chloroform/ethanol) to give ethyl 2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.32 g) as a foam. The mixture is evaporated the residue is purified by silica gel column chromatography (solvent; chloroform/ethanol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-ethyl-4-(2-aminoethyl)-1-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methylimidazole (5.30 g) in tetrahydrofuran (40 ml) is added ethyl glyoxylate hydrate (1.67 g). The reaction mixture is stirred overnight at room temperature and then refluxed for two hours. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.90 g) as a yellow oil. refluxed for two hours The solvent is evaporated the residue is purified by silica gel column chromatography (solvent; chloroform/methanol)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Ethyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole (7.48 g) is dissolved in tetrahydrofuran (60 ml) to which is added ethyl glyoxylate hydrate (1.56 g). The reaction mixture is stirred overnight at room temperature and then refluxed for one hour. The solution is evaporated and the residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-[2'-(1-trityl- 1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.54 g) as a foam, characterized as its oxalate. refluxed for one hour The solution is evaporated the residue is purified by silica gel column chromatography (solvent; chloroform/methanol)