2-morpholin-4-ylacetohydrazide

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in CH2Cl2:EtOAc (20 mL, 2:1) and cooled to −60° C. where 2-morpholinoacetohydrazide (0.23 g, 1.0 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.27 mL, 1.5 eq.) was added dropwise followed by DIPEA (0.96 mL, 2 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-morpholinoacetyl)acrylohydrazide (0.1 g, yield: 14%). was introduced dropwise The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) the desired compound started eluting from 3% methanol/dichloromethane) Fractions containing the desired compounds

反応条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 25 mL, 3-neck round-bottom flask, methyl 2-morpholinoacetate (0.25 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (0.087 g, 1.1 eq.) was introduced dropwise at RT and the reaction mixture was refluxed at 95° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 2-morpholinoacetohydrazide (0.23 g) which was used without further purification in the following step. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg)

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

実験手順: The title compound was prepared in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and 2-morpholinoaceto-hydrazide. The title compound was obtained as light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.45 (d, 1H), 8.90 (d, 1H), 8.36 (d, 1H), 8.01 (m, 2H), 7.83 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 3.65 (d, 4H), 3.26 (s, 2H), 2.57 (d, 4H), 2.41 (s, 3H). LCMS (method B): [MH]+=446.2, tR=1.37 min.

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(3-(difluoro(quinolin-6-yl)methyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (25 mg, 0.074 mmol) and 2-morpholinoacetohydrazide (12 mg, 0.075 mmol) were dissolved in MeOH and the pH of the reaction solution was adjusted to 5. The solution was then stirred at 45° C. for 3 hours. Solvent was evaporated and the crude product was purified on HPLC (neutralized to free base) to give the title compound as a white solid (18 mg, 50%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.02 (s, 1H), 8.55 (d, 1H), 8.43 (d, 2H), 8.17 (d, 1H), 8.01 (m, 2H), 7.65 (d, 1H), 3.59 (m, 4H), 2.13 (m, 4H). LCMS (method B): [MH]+=481.1, tR=1.66 min. Solvent was evaporated the crude product was purified on HPLC (neutralized to free base)

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(3-(difluoro(quinolin-6-yl)methyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (25 mg, 0.074 mmol) and 2-morpholinoacetohydrazide (12 mg, 0.075 mmol) were dissolved in MeOH and the pH of the reaction solution was adjusted to 5. The solution was then stirred at 45° C. for 3 hours. Solvent was evaporated and the crude product was purified on HPLC (neutralized to free base) to give the title compound as a white solid (18 mg, 50%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.02 (s, 1H), 8.55 (d, 1H), 8.43 (d, 2H), 8.17 (d, 1H), 8.01 (m, 2H), 7.65 (d, 1H), 3.59 (m, 4H), 2.13 (m, 4H). LCMS (method B): [MH]+=481.1, tR=1.66 min. Solvent was evaporated the crude product was purified on HPLC (neutralized to free base)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.33 g (4.7 mmol) of ethyl [2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate (Example 128A) and 740 mg (4.7 mmol) of 2-morpholin-4-ylacetohydrazide are dissolved in NMP (6 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 3 h. The reaction mixture is cooled to RT and ethyl acetate (100 ml) and water (50 ml) are added. The organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase dichloromethane/methanol 100:1 to 50:1). 1.25 g (70% of theory) of the product are obtained. The reaction mixture is cooled to RT The organic phase is separated off dried with magnesium sulphate concentrated The residue is chromatographed on silica gel (mobile phase dichloromethane/methanol 100:1 to 50:1) 1.25 g (70% of theory) of the product are obtained