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To 3,4-dimethyl-lH-pyrazole-5-carboxylic acid 6 (35 mg, 0.25 mmol) in dimethylacetamide (4 mL) was added benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.12 g, 0.23 mmol), followed by N,N-diisopropylethylamine (0.2 ml, 1.16 mmol). The suspension was stirred at room temperature for 30 minutes. To this suspension was added 2-(4- fluorophenyl)pyrazolo[l,5-a]pyrimidin-6-amine (35) (22 mg, 0.1 mmol, brownish solid). The reaction mixture was stirred at room temperature overnight and poured into water. The precipitate was collected and purified by column chromatography to provide compound (P-2072) as a pale yellow solid (5 mg, 15%). MS ESI [M+H+]+ = 351.95. The data from the Eta NMR spectrum were consistent with the structure of the compound.
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;
To a solution of 3-(4-fluorophenyl)-lH-pyrazolo[3,4-Z?]pyridin- 5-amine 39 (0.150 g, 0.657 mmol) in N,N-dimethylformamide (3.87 mL) was added a mixture of triethylamine (0.102 mL, 0.723 mmol), 3,4-dimethyl- lH-pyrazole-5-carboxylic acid (0.101 g, 0.723 mmol) and 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.250 g, 0.657 mmol) and stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with acetate. The organic layer was separated and concentrated under reduced pressure and the resulting residue was dissolved in a minimal amount of dichloromethane and was purified by chromatography eluting with 0-10% methanol/dichloromethane and trituration with methyl tert-buiyl ether /heptane to give compound (P-2041) (0.100 g, 0.285 mmol, 43.4 % yield) as a light yellow solid. MS ESI [M+H+]+ = 351.3. The data from the lH NMR spectrum were consistent with the structure of the compound.
To 3,4-dimethyl- lH-pyrazole-5-carboxylic acid 6 (50 mg, 0.36 mmol) in dimethylacetamide (3 mL) was added benzotriazol- 1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate (200 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 30 minutes and added 2-(3-fluoroprop-l-ynyl)-lH-pyrrolo[2,3-Z?]pyridin- 5-amine hydrochloride 45 (12 mg, 0.05 mmol) and Nu,Nu-diisopropylethylamine (1 mL) and further stirred at room temperature for three hours. The reaction mixture was then purified by chromatography eluting with a gradient of ethyl acetate and hexanes to provide compound (P-2063) (2.2 mg, 13%). MS ESI [M+H+]+ = 312.1. The data from the lH NMR spectrum were consistent with the structure of the compound.
To a 20 mL scintillation vial were added 3,4-dimethyl-lH-pyrazole-5-carboxylic acid 6 (0.6 g, 4.28 mmol) and benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (2.4 g, 4.61 mmol) in dimethylacetamide (4 mL) to form a reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes to give solution A. To another 20 mL scintillation vial were added 2- chloropyrimidin-5-amine 47 (0.75 g, 5.79 mmol) and N,N-diisopropylethylamine (0.1 mL) to form a mixture. The mixture was heated at 60 C to form solution B. The activated acid (solution A) was then added to the amine (solution B). The reaction mixture was stirred at 60 C overnight and cooled down to room temperature. Water was added to the reaction mixture to form a precipitate, which was collected to provide compound 48 (323 mg, 30%). MS ESI [M+H+]+ = 251.8.
A mixture of 3,4-dimethyl- lH-pyrazole-5-carboxylic acid 6 (0.1 1 g, 0.78 mmol) and benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.5 g, 0.96 mmol) in dimethylacetamide (4 mL) was stirred for 30 minutes. To the mixture was added 2-(4- fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-amine 5 (0.12 g, 0.53 mmol), followed by N,N- diisopropylethylamine (O. lmL). The reaction was stirred at room temperature overnight. To the reaction mixture was added acetonitrile and water and the precipitate was collected, washed with ethyl acetate and methanol. It was dried under vacuum to provide compound (P-2024) (85 mg, 46%). MS ESI [M+H+]+ = 350.1. The data from the lH NMR spectrum was consistent with the structure of the compound.
With 4-methyl-morpholine; In toluene; at -20 - 20℃;
To 4,5-dimethyl-lH-pyrazole-3-carboxylic acid 6 (69.3 mg, 0.49 mmol) in N-methylmorpholine (2 mL) at -20C was added isopropyl carbonochloridate 127 (0.5 ml, 1.0 M in toluene, 0.5 mmol) dropwise. The mixture was stirred at -20C for 10 minutes. To this mixture was then added 2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-amin 5 (105 mg, 0.46 mmol) N-methylmorpholine (2 mL). The reaction mixture was stirred -20C for 20 minutes and was allowed to warm up to room temperature. It was then stirred at room temperature overnight. Solvent was removed and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layers were collected, washed with brine, and dried under sodium sulfate. After removal of drying agent and solvent, the residue was purified by column chromatography to provide compound 128 (32 mg, 15.9%). MS ESI [M+H+]+ = 435.90. lH NMR and MS were consistent with the desired product.
To 4,5-dimethyl-lH- pyrazole-3-carboxylic acid 6 (0.02 g, 0.17 mmol) in acetonitrile (3 mL) was added benzotriazol- 1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate (0.1 g, 0.19 mmol). The reaction mixture was stirred at room temperature for one hour, and then was added [4-(5-amino-lH-pyirolo[2,3-Z?]pyridin-2-yl)-3,6- dihydro-2H-pyridin-l-yl]-cyclopropyl-methanone hydrochloride 56 (0.05 g, 0.16 mmol) and triethylamine (0.03 ml, 0.19 mmol), and stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After solvent was removed, the residue was triturated with ethyl acetate. The solid was collected, washed with methanol and water to provide compound 57 as a white solid (5 mg, 7%). MS ESI [M+H]+ = 404.9. The data from the lH NMR spectrum were consistent with the structure of the compound.
A solution of 3,4-dimethyl-lH-pyrazole-5-carboxylic acid 6 (0.81 g, 5.79 mmol) and benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (3.01 g, 5.79 mmol) in dimethylacetamide (20 ml) was stirred at room temperature for one hour. To the reaction mixture was added 2-iodo-lH-pyrrolo[2,3-Z?]pyridin-5-amine 58 (0.5 g, 1.93 mmol), followed by N,N- diisopropylethylamine (0.67 ml, 3.86 mmol). The reaction mixture was stirred at room temperature for 3 hours, then added dropwise into iced water (200 mL). The resulting suspension was stirred overnight. The solid was collected by filtration, washed with water, and triturated with methanol to provide compound 59 (1.4 g, 96%). MS ESI [M+H+]+ = 382.05. The compound was used for subsequent reaction without purification.
To 3,4-dimethyl-lH-pyrazole-5-carboxylic acid 6 (0.2 g, 1.43 mmol) in acetonitrile (20 mL) was added o-benzotriazole-N,N,N',N'-tetramethyl-uronium- hexafluorophosphate (0.55 g, 1.45 mmol), followed N,N-diisopropylethylamine (0.5 ml, 2.89 mmol). The suspension was stirred at room temperature for 2 hours to yield a clear solution. To the clear solution was added l-(benzenesulfonyl)-2-iodo-pyrrolo[2,3-Z7]pyridin-5-amine hydrochloride 67 (0.4 g, 0.92 mmol) in tetrahydrofuran (1 mL). The reaction mixture was stirred at 40 C overnight. The reaction mixture was concentrated and the residue was partitioned with ethyl acetate, washed with brine and dried with sodium sulfate. Solvent was removed and the residue was purified by flash chromatography on silica gel to provide product 68 as a pale yellow solid (0.1 g, 21%). MS(ESI) [M+H+]+ = 522.0. The data from the lH NMR spectrum were consistent with the structure of the compound.
To a 20 mL scintillation vial were added 3,4-dimethyl-lH-pyrazole- 5-carboxylic acid 6 (0.1 g, 0.71 mmol), benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.36 g, 0.7 mmol) and dimethylacetamide (2mL). The reaction mixture was stirred at room temperature for one hour. To the mixture was added 2-pyrazol-l-yl-lH-pyrrolo[2,3-Z?]pyridin-5- amine hydrochloride 75 (0.13 g, 0.39 mmol) in dimethylacetamide (1 mL) followed by N, N- diisopropylethylamine (1.5 ml, 8.67 mmol). The reaction mixture was stirred at room temperature for two hours and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of methanol and dichloromethane to provide a product, which was further titrated with a mixture of ethyl acetate and hexanes to provide compound 76 (5 mg, 4%). MS ESI [M+H+]+ = 322.3. The data from the lH NMR spectrum were consistent with the structure of the compound.
To a scintillation were added 3,4-dimethyl- lH-pyrazole-5-carboxylic acid 6 (0.03 g, 0.21 mmol) and (0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (0.1 g, 0.26 mmol) in dimethylacetamide (3 ml). The reaction mixture was stirred at room temperature for one hour. To this mixture were then added 2-phenylthiazolo[5,4-b]pyridin-6-amine 104 (30 mg, 0.13 mmol) and triethylamine (0.04 ml, 0.26 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate and washed with brine. The organic layer was dried with sodium sulfate. After removal of solvent, the residue was purified by reverse phase column chromatography to provide compound (P-2144) as a fluffy white solid (6.3 mg, 13.7%). MS (ESI) [M+H+]+ = 349.85. lB NMR and mass spectroscopy data were consistent with the desired product.
To a scintillation vial were added 3,4-dimethyl-lH-pyrazole-5- carboxylic acid 6 (44 mg, 0.32 mmol) and (0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (0.15 g, 0.39 mmol) in dimethylacetamide (3 ml). The reaction mixture was stirred at room temperature for one hour, then added 2-(2-fluorophenyl)-3H-imidazo[4,5-b]pyridin-6-amine 109 (45 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.07 ml, 0.39 mmol). The mixture was stirred at room temperature overnight, quenched with water, extracted with ethyl acetate, and washed with brine. The organic layer was collected and dried with sodium sulfate. After removal of solvent, the residue was purified by column chromatography and further triturated with methanol to afford compound (P-2152) as an off-white solid (22 mg, 30%). MS (ESI) [M+H+]+ = 351.1. Eta NMR and mass spectroscopy data were consistent with the desired product.
To 4,5-dimethyl-lH- pyrazole-3-carboxylic acid 6 (30 mg, 0.21 mmol) in N,N-dimethylamide (4 mL) was added benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.1 15 g, 0.22 mmol), followed by N,N- diisopropylethylamine (0.1 ml, 0.58 mmol). The suspension was stirred at room temperature for 60 minutes. To this suspension was added tert-butyl 4-[3-(5-amino-lH-pyrazolo[3,4-b]pyridin-3- yl)phenyl]piperazine- 1 -carboxylate 114 (46 mg, 0.12 mmol) in Nu,Nu-dimethylamide (1 mL). The reaction mixture was stirred at room temperature for two days, then quenched with water and extracted with ethyl acetate. The organic layer was collected, washed with brine and dried under sodium sulfate. After removal of drying agent and solvent, the residue was purified by column chromatography and preparative HPLC to provide compound 115 as a white solid (12 mg, 10%). MS(ESI) [M+H+]+ = 517.4. The data from the lH NMR spectrum was consistent with the structure of the compound.
2-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine hydrochloride[ No CAS ]
[ 89831-40-3 ]
[ 1616385-50-2 ]
Yield
Reaction Conditions
Operation in experiment
5 mg
To a solution of 3,4-dimethyl-lH-pyrazole-5-carboxylic acid 6 (0.03 g, 0.21 mmol) in dimethylacetamide (2 mL) was added benzotriazol- 1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate (0.1 1 g, 0.21 mmol) and the mixture was stirred at room temperature for 30 minutes. 2-(4-Fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-amine hydrochloride 5 (16 mg, 0.06 mmol) was added, followed by N,N-diisopropylethylamine (0.5 ml, 2.89 mmol). The reaction mixture was stirred at room temperature for an hour and purified by preparative HPLC to provide compound (P-2034) ( 5 mg, 21%). MS ESI [M+H+]+ = 350.15. lH NMR and mass spectroscopy data were consistent with the desired product.
To 3,4-dimethyl- lH-pyrazole-5- carboxylic acid 6 (1 eq.) in an appropriate amount of solvent such as dimethylacetamide, tetrahydrofuran, acetonitrile, or Nu,Nu-dimethylformamide are added benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (1 eq.) or o-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (1 eq.) and N-hydroxybenzotriazole (1 eq.), followed by Nu,Nu-diisopropylethylamine (1 eq.) or triethylamine (1 eq.). The mixture is stirred at room temperature from 30 minutes to a few hours. To this mixture is added 2-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)- lH-pyrrolo[2,3-b]pyridin-5-amine 132 (1 eq.) and Nu,Nu-diisopropylethylamine (1 eq.) or triethylamine (1 eq.). The reaction mixture is stirred at room temperature from one hour to 2-3 days. Heating can be used to if needed. The reaction mixture is partitioned between an organic solvent (including, but not limiting to, hexanes, benzene, ethyl acetate, and dichloromethane) and water. The organic layer is collected and dried over sodium sulfate. After removal of drying agent and solvent, the residue is purified by chromatography to produce compound 133.
A solution of compound 6 (0.09 g, 0.67 mmol) and benzotriazol- 1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate (0.35 g, 0.67 mmol) in dimethylacetamide (4 mL) was stirred at room temperature for 30 minutes. To this mixture was added 2-phenyl-lH-pyrrolo[2,3- Z?]pyridin-5-amine (16) (0.08 g, 0.38 mmol) followed by diisopropylethylamine (0.1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was added dropwise to water and the suspension was stirred for 1 hour. The solid was filtered and was purified by preparative HPLC to give compound (P-2007) as white solid (46 mg, 36%). MS ESI [M+H+]+ = 332.2. 1H NMR spectrum was consistent with the structure of the compound.
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