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isoxazole-3,4-dicarboxylic acid 3-tert-butylamide 4-(methyl-pyridazin-4-yl-amide)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 20℃; for 16h;
600 mg (2.8 mmol) of S-tert-Butylcarbamoyl-isoxazole^-carboxylic acid were suspended in 20 ml. of toluene and two drops of dimethylformamide were added to the mixture. 0.26 ml. of thionylchloride (3.5 mmol) were added at room temperature and the reaction mixture was stirred at 65 0C for two hours. After removal of the solvent, toluene was added and the evaporation was repeated. The obtained residue was then dissolved in 10 ml. of dichloromethane and the solution was added dropwise to a solution containing 247 mg methyl-pyridazin-4-ylamine (2.3 mmol) and 0.43 ml triethyl amine (3.1 mmol) in 40 ml dichloromethane. The mixture was stirred at room temperature for 16 h and the solvent was removed under vaccum. The obtained residue was purified by flash column chromatography (silica, gradient elution cyclohexane? ethyl acetate? methanol) to give 180 mg (20%, 95% purity) of the title compound.
With triethylamine; In dichloromethane; at 20℃; for 16h;
400 mg (2.6 mmol) of 3-cyclopropyl-isoxazole-4-carboxylic acid were suspended in 10 ml. of toluene and one drop of dimethylformamide was added to the mixture. 0.24 ml. of thionylchloride (3.3 mmol) were added at room temperature and the reaction mixture was stirred at 65 0C for two hours. After removal of the solvent, toluene was added and the evaporation was repeated. The obtained residue was then dissolved in 5 ml. of dichloromethane and the solution was added dropwise to a so- lution containing 285 mg <strong>[16401-70-0]methyl-pyridazin-4-yl-amine</strong> (2.6 mmol) and 0.45 ml triethyl amine (3.3 mmol) in 5 ml dichloromethane. The mixture was stirred at room temperature for 16 h and the solvent was removed under vaccum. The obtained brown oil was purified by flash column chromatography (silica, gradient elution cyclohexane? ethyl acetate? methanol) to give 400 mg (60%, 95% purity) of the ti- tie compound.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
200 mg (1.2 mmol) of 2-chlorothiazole-4-carboxylic acid and 96.1 mg (0.9 mmol) of pyridazin-4-yl-amine were dissolved in 6 ml dimethyl formamide. 0.15 ml. (1.1 mmol) of triethyl amine followed by 382 mg (0.73 mmol) of 1 H-Benzotriazol-1- yloxytri-pyrrolidinophosphonium hexafluorophosphate (PyBOP) were added and the reaction mixture was stirred at room temperature for 16 h. Brine was added and the reaction mixture was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The obtained residue was purified by flash column chromatography (silica, gradient elution cyclohexane? ethyl ace- tate? methanol) to give 200 mg (61 %, 95% purity) of the title compound.
With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 20℃; for 96h;
1 -(2-Methoxyethyl)-N,5-dimethyl-N-pyridazin-4-yltriazole-4-carboxamide (example I II .7) 0-(7-Azabenzotriazol-1 -y)-N, N, Lambda , Lambda -tetramethyluronium hexafluorophosphat (HATU; 1 .23 g, 3.24 mmol, 3.00 eq) and N-methylmorpholine (0.71 ml, 0.66 g, 6.5 mmol, 6.0 eq) was added to a solution of 1 -(2-methoxyethyl)-5-methyltriazole-4- carboxylic acid (200 mg, 1 .08 mmol) and <strong>[16401-70-0]N-methylpyridazin-4-amine</strong> (1 18 mg, 1.08 mmol, 1 .00 eq) in DMF (2.5 ml) and the mixture was stirred at room temperature for 4 d. After removal of the solvent, the residue was dissolved in dichloromethane, washed twice with sat. aq. NaHCC sol. and once with brine and dried over Na2S04. Removal of the solvent under vacuum and chromatographic purification (CH:EtOAc) gave the title compound as a brown oil (200 mg, 64%, 95% purity).HPLC/MS: r.t. 1 .406 min, m/z [MH]+ 277.1
1-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl]-5-methyl-pyrazole-4-carboxylic acid[ No CAS ]
1-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl]-N,5-dimethyl-N-pyridazin-4-yl-pyrazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
140 mg
Preparation of 1 -[1 -(2,2-dimethyl-1 ,3-dioxolan-4-yl)ethyl]-N,5-dimethyl-N-pyridazin-4-yl- pyrazole-4-carboxamide [1-18] To a solution of 240mg 1 -[1 -(2,2-dimethyl-1 ,3-dioxolan-4-yl)ethyl]-5-methyl-pyrazole-4- carboxylic acid in 8ml THF were added 103mg <strong>[16401-70-0]N-methylpyridazin-4-amine</strong>, 152mg diisopropyl- ethylamine and 359mg 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate. The mixture was stirred at 20-25C for about 2 d, then another 180mg 1 -[Bis(dimethylamino)methylene]-1 /-/-1 ,2,3-triazolo[4,5-t)]pyridinium 3-oxid hexafluorophosphate and 1 19mg triethylamine were added. The mixture was stirred at 20-25C for another 3 days and concentrated under reduced pressure. Purification by flash chromatography (CH2CI2/MeOH) gave 140mg of the title compound (95% purity). HPLC-MS (Method 2): RT 0.725 min, m/z [MH]+ 346.4.
5-methyl-1-(1-spiro[2.2]pentan-5-ylethyl)pyrazole-4-carbonyl chloride[ No CAS ]
N,5-dimethyl-N-pyridazin-4-yl-1-(1-spiro[2.2]pentan-5-ylethyl)pyrazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
522 mg
With triethylamine; In tetrahydrofuran; at 0 - 25℃; for 20h;
A solution of 594 mg 5-methyl-1 -(1 -spiro[2.2]pentan-5-ylethyl)pyrazole-4-carbonyl chloride in 5 mL THF was added dropwise to a solution of 271 mg <strong>[16401-70-0]N-methylpyridazin-4-amine</strong> and 315 mg triethylamine in 30 mL THF at 0C. The mixture was stirred at 20-25C for about 20 h, the solvent was evaporated and the residue was diluted with 70 mL dichloromethane, washed with 2 10 mL water, dried over MgSC and evaporated. Purification by flash chromatography (CH2CI2/MeOH) gave 522mg of the title compound. HPLC-MS: RT 0.842 min, m/z [MH]+ 312.2
With triethylamine; HATU; In dichloromethane; at 20 - 25℃; for 72h;
Preparation of N ,5-d imethyl-1 -(4-oxocyclohexyl)-N-pyridazin-4-yl-pyrazole-4-carboxamide [1-2] A mixture of 200 mg 5-methyl-i -(4-oxocyclohexyl)pyrazole-4-carboxylic acid, 98 mg N-methyl35 pyridazin-4-amine, 684 mg HATU [O-(7-azabenzotriazol-i-yl)-N,N,N? ,N?-tetramethyluroniumhexafluorophosphate] and 228 mg triethylamine in 30 ml CH2CI2 was stirred at 20-25C for 3d, then evaporated. Purification by flash chromatography (CH2CI2/MeOH) gave 103mg of the title compound (37% purity). HPLC-MS: RT 0.653 mi m/z [MH] 314.2
1-(6-chloro-3-methyl-2-pyridyl)-5-methylpyrazole-4-carbonyl chloride[ No CAS ]
1-(6-chloro-3-methyl-2-pyridyl)-N,5-dimethyl-N-pyridazin-4-yl-pyrazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; triethylamine; In tetrahydrofuran; dichloromethane; at 20℃;
To a solution of <strong>[16401-70-0]N-methylpyridazin-4-amine</strong> (83 mg, 0.76 mmol), triethylamine (0.42 ml, 3.04 mmol)and a catalytic amount of DMAP in 15 ml THE was added a solution in CH2Cl2 (5 ml) of 1-(6-chloro-3-methyl-2-pyridyl)-5-methyl-pyrazole-4-carbonyl chloride (0.21 g, 0.76 mmol), prepared from thecorresponding acid (oxalyl chloride 5 eq., CH2Cl2, cat. DMF, 40C,5 h). The mixture was stirred at rtovernight. After evaporation of the solvents, the residue was taken up in ethyl acetate and washedwith a solution of sodium bicarbonate. After drying (MgSO4) and evaporating the organic phase, theresidue was purified by flash chromatography to give the title compound as white crystals. Mp: 190-4C, LCMS: 0.69 min, 343-5 (MH).
2-cyclopropyl-3-methylimidazole-4-carboxylic acid[ No CAS ]
2-cyclopropyl-N,3-dimethyl-N-pyridazin-4-yl-imidazole-4- carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40 mg
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; at 20 - 25℃;
To a solution of 166 mg of compound 1-3 in 30 mL THF at 20 to 25C was added 109 mg N- methyl-4-amino pyridazine, followed by 1 11 mg triethylamine and 380 mg HATU. The reaction mixture was stirred overnight before being concentrated in vacuo. The obtained residue was purified using column chromatography over silica gei (0->20% dichloromethane/methanol) to afford 40 mg of the title compound.