ethoxy-N,N-di(propan-2-yl)phosphonamidous acid

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3,3,3-trifluoropropionic acid (2.07 mmole) in DCM (10 mL), was added EDCI HCl (3.02 mmole) and HOBt (2.07 mmole). The solution was stirred at RT for 0.5 hour followed by addition of 3-hydrazinyl-6-(4-phenoxyphenyl)pyridazine A, prepared as disclosed in Example 3, (2.07 mmole) in 30 mL of DCM and EDIPA ((7.24 mmole). The coupling reaction will also work with 1,3-dicyclohexylcarbodiimide and DCM as a solvent or EDCI HCl and methanol as a solvent. The resulting reaction mixture was stirred at RT overnight. The mixture was diluted with saturated aqueous NaHCO3. The organic extract was washed with H2O and dried over Na2SO4 and then evaporated in vacuo. The crude product was purified with prep TLC eluting with 5% methanol and dichloromethane mixture to give B. prepared The coupling reaction The resulting reaction mixture was stirred at RT overnight The organic extract was washed with H2O dried over Na2SO4 evaporated in vacuo The crude product was purified with prep TLC eluting with 5% methanol and dichloromethane mixture to give B

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-4,4,4-Trifluorobut-2-enoic acid (25 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (16 μl, 0.18 mmol) and the solution was stirred at room temperature for 10 minutes. This solution was added to a solution of ethyl 2-(2-aminoethylamino)-5-methylamino-thiazole-4-carboxylate dihydrochloride (48 mg, 0.15 mmol) and EDIPA (132 μl, 0.75 mmol) in anhydrous dichloromethane (1.5 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 30 mg of a solid (0.071 mmol, 47%). the resulting mixture was stirred at room temperature overnight The reaction mixture was concentrated under reduced pressure the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ethyl 2-bromo-5-methylamino-thiazole-4-carboxylate (546 mg, 2.059 mmol) and tert-butyl N-(2-aminoethyl)carbamate (1.3 g, 8.11 mmol) were combined in anhydrous 1,4-dioxane (15 ml). EDIPA (3 ml, 17.2 mmol) was added and the mixture was heated in a sealed tube for 23 hours at 100° C. The mixture was cooled to room temperature and partitioned between DCM and a saturated solution of sodium bicarbonate. Layers were separated, the aqueous phase was extracted twice with DCM and the combined organic layers were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica, gradient of 30 to 100% ethyl acetate in heptane) to yield 185 mg (0.537 mmol, 26%) MS(ESI) m/z=345.2 [M+1]+. The mixture was cooled to room temperature partitioned between DCM Layers were separated the aqueous phase was extracted twice with DCM the combined organic layers were dried over sodium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography (silica, gradient of 30 to 100% ethyl acetate in heptane) to yield 185 mg (0.537 mmol, 26%) MS(ESI) m/z=345.2 [M+1]+

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-4,4,4-Trifluorobut-2-enoic acid (25 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (16 μl, 0.18 mmol) and the solution was stirred at room temperature for 10 minutes. This solution was added to a solution of N,N′-dimethyl-N-(5-methyl-3-pyridyl)ethane-1,2-diamine dihydrochloride (36 mg, 0.13 mmol) and EDIPA (132 μl, 0.75 mmol) in anhydrous dichloromethane (1.5 ml) and the resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 24 mg of a solid (0.08 mmol, 53%). the resulting mixture was stirred at room temperature for two hours The reaction mixture was concentrated under reduced pressure the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-4,4,4-Trifluorobut-2-enoic acid (25 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (16 μl, 0.18 mmol) and the solution was stirred at room temperature for 10 minutes. This solution was added to a solution of N,N′-dimethyl-N-(5-methyl-3-pyridyl)ethane-1,2-diamine dihydrochloride (36 mg, 0.13 mmol) and EDIPA (132 μl, 0.75 mmol) in anhydrous dichloromethane (1.5 ml) and the resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 24 mg of a solid (0.08 mmol, 53%). the resulting mixture was stirred at room temperature for two hours The reaction mixture was concentrated under reduced pressure the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 7-(4-methyl-2-pyridyl)-2,7-diazaspiro[4.5]decane dihydrochloride (40 mg, 0.13 mmol, half of the residue from step B) and EDIPA (125 μl, 0.8 mmol) in anhydrous dichloromethane (2 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 10 mg of a solid (0.028 mmol, 9% yield for two steps). the resulting mixture was stirred at room temperature overnight The reaction mixture was concentrated under reduced pressure the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (20 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-ethyl-N-(4-methyl-2-pyridyl)ethane-1,2-diamine dihydrochloride (38 mg, 0.15 mmol) and EDIPA (128 μl, 0.8 mmol) in anhydrous dichloromethane (2 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 29 mg of a solid (0.096 mmol, 64% yield). the resulting mixture was stirred at room temperature overnight The reaction mixture was concentrated under reduced pressure the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (23 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(4-methyl-5-nitro-2-pyridyl)ethane-1,2-diamine (29 mg, 0.15 mmol) and EDIPA (70 μl, 0.5 mmol) in anhydrous dichloromethane (2 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 2.4 mg of a solid (0.0076 mmol, 5% yield). the resulting mixture was stirred at room temperature overnight The reaction mixture was concentrated under reduced pressure the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-4,4,4-Trifluorobut-2-enoic acid (32 mg, 0.23 mmol) was dissolved in dichloromethane (0.5 ml containing one drop of dimethyl formamide), oxalyl chloride was added (23 μl, 0.23 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(4-methyl-5-nitro-2-pyridyl)ethane-1,2-diamine (29 mg, 0.15 mmol) and EDIPA (70 μl, 0.5 mmol) in anhydrous dichloromethane (2 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 2.4 mg of a solid (0.0076 mmol, 5% yield). the resulting mixture was stirred at room temperature overnight The reaction mixture was concentrated under reduced pressure the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-4,4,4-Trifluorobut-2-enoic acid (64 mg, 0.46 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (40 μl, 0.46 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 3-(4-methyl-2-pyridyl)propan-1-amine hydrochloride (56 mg, 0.3 mmol) and EDIPA (240 μl, 1.4 mmol) in anhydrous dichloromethane (5 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 47 mg of a solid (0.17 mmol, 58% yield) the resulting mixture was stirred at room temperature for one hour The reaction mixture was concentrated under reduced pressure the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-4,4,4-Trifluorobut-2-enoic acid (64 mg, 0.46 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (40 μl, 0.46 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 3-(4-methyl-2-pyridyl)propan-1-amine hydrochloride (56 mg, 0.3 mmol) and EDIPA (240 μl, 1.4 mmol) in anhydrous dichloromethane (5 ml) and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 47 mg of a solid (0.17 mmol, 58% yield) the resulting mixture was stirred at room temperature for one hour The reaction mixture was concentrated under reduced pressure the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-4,4,4-Trifluorobut-2-enoic acid (70 mg, 0.5 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (42 μl, 0.5 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(6-methylpyrazin-2-yl)ethane-1,2-diamine (38 mg, 0.25 mmol) and EDIPA (175 μl, 1 mmol) in a mixture of anhydrous dichloromethane (2 ml) and anhydrous dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 19.9 mg of a solid (0.07 mmol, 14.5% yield) the resulting mixture was stirred at room temperature overnight The reaction mixture was concentrated under reduced pressure the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile)