ethyl 3-hydrazinyl-3-oxopropanoate

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

Procedure: To a mixture of hydrazinocarbonylacetic acid ethyl ester (1.0 g, 6.84 mmol) and diisopropypethylamine (1.77 g, 13.69 mmol) in THF (7 mL) is added a solution of propionyl chloride (633 mg, 6.84 mmol) in THF (2 mL) dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to furnish 3-oxo-3-(N′-propionylhydrazino)-propionic acid ethyl ester. 1H-NMR (400 MHz, CDCl3); δ ppm 1.21 (t, 3H), 1.30 (t, 3H), 2.31 (q, 2H), 3.43 (s, 2H), 4.23 (q, 2H), 8.27 (s, 1H), 9.63 (s, 1H). is washed with aqueous 1M HCl and brine The organic phase is dried over magnesium sulfate the solvent is removed under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-{2-[1-cyclohexyl-2-(ethyloxy)-2-oxoethylidene]hydrazino}-3-oxopropanoate. A solution of diethyl oxylate (4.1 mL, 30.0 mmol) in THF (50 mL) was cooled to −78° C. Cyclohexyl magnesium bromide (1.0M solution in THF, 36 mL, 36.0 mmol) was dropwise added and the solution stirred under a nitrogen atmosphere for 1.5 h at −78° C. The reaction was brought to 0° C. and quenched with 6N HCl. Et2O and H2O were added and the layers separated. The aqueous phase was backextracted with Et2O several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The resulting residue was dissolved in EtOH (20 mL) and partitioned between two microwave vials. Ethyl-3-hydrazino-3-oxopropionate (2.41 g, 18.0 mmol) and catalytic AcOH (0.2 mL, 3.50 mmol) were added to each vial. The reactions were heated in the microwave at 150° C. for 1 h. The reactions were cooled and combined in a round bottom flask. The solvent was removed under reduced pressure and the resulting residue was azeotroped with Toluene several times. The product was purified by column chromatography (SiO2, 10-30% EtOAc/Hexanes) to give the title compound (1.93 g, 21% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44-11.78 (m, 1H) 3.99-4.34 (m, 4H) 3.44-3.67 (m, 2H) 2.52-2.63 (m, 1H) 1.52-1.84 (m, 5H) 1.04-1.37 (m, 11H). was brought to 0° C. quenched with 6N HCl Et2O and H2O were added the layers separated The combined organic layers were washed with Brine dried (MgSO4) filtered concentrated The resulting residue was dissolved in EtOH (20 mL) partitioned between two microwave vials The reactions were heated in the microwave at 150° C. for 1 h The reactions were cooled combined in a round bottom flask The solvent was removed under reduced pressure the resulting residue was azeotroped with Toluene several times The product was purified by column chromatography (SiO2, 10-30% EtOAc/Hexanes)

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

Procedure: Ethyl 3-{2-[2-(ethyloxy)-2-oxo-1-phenylethylidene]hydrazino}-3-oxopropanoate. A mixture of ethyl 3-hydrazino-3-oxopropionate (1.46 g, 10.0 mmol), ethyl benzoylformate (2.14 g, 12.0 mmol), acetic acid (0.5 mL, 8.3 mmol) and dichloromethane (10 mL) was stirred at room temperature with excess anhydrous magnesium sulfate for 20 h, then filtered and the cake washed with ethyl acetate. The filtrate was evaporated under reduced pressure, azeotroped 3 times with toluene and chromatographed (silica gel, 10-3-% ethyl acetate/hexane) to give the title compound (0.773 g, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, J=7.07 Hz, 3H) 1.30 (t, J=7.07 Hz, 3H) 3.74 (s, 2H) 4.08 (q, J=7.07 Hz, 2H) 4.40 (q, J=7.18 Hz, 2H) 7.42-7.49 (m, 3H) 7.55-7.59 (m, 2H) 11.57 (s, 1H). filtered the cake washed with ethyl acetate The filtrate was evaporated under reduced pressure azeotroped 3 times with toluene chromatographed (silica gel, 10-3-% ethyl acetate/hexane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-{2-[1-cyclohexyl-2-(ethyloxy)-2-oxoethylidene]hydrazino}-3-oxopropanoate. A solution of diethyl oxylate (4.1 mL, 30.0 mmol) in THF (50 mL) was cooled to −78° C. Cyclohexyl magnesium bromide (1.0M solution in THF, 36 mL, 36.0 mmol) was dropwise added and the solution stirred under a nitrogen atmosphere for 1.5 h at −78° C. The reaction was brought to 0° C. and quenched with 6N HCl. Et2O and H2O were added and the layers separated. The aqueous phase was backextracted with Et2O several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The resulting residue was dissolved in EtOH (20 mL) and partitioned between two microwave vials. Ethyl-3-hydrazino-3-oxopropionate (2.41 g, 18.0 mmol) and catalytic AcOH (0.2 mL, 3.50 mmol) were added to each vial. The reactions were heated in the microwave at 150° C. for 1 h. The reactions were cooled and combined in a round bottom flask. The solvent was removed under reduced pressure and the resulting residue was azeotroped with Toluene several times. The product was purified by column chromatography (SiO2, 10-30% EtOAc/Hexanes) to give the title compound (1.93 g, 21% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44-11.78 (m, 1H) 3.99-4.34 (m, 4H) 3.44-3.67 (m, 2H) 2.52-2.63 (m, 1H) 1.52-1.84 (m, 5H) 1.04-1.37 (m, 11H). was brought to 0° C. quenched with 6N HCl Et2O and H2O were added the layers separated The combined organic layers were washed with Brine dried (MgSO4) filtered concentrated The resulting residue was dissolved in EtOH (20 mL) partitioned between two microwave vials The reactions were heated in the microwave at 150° C. for 1 h The reactions were cooled combined in a round bottom flask The solvent was removed under reduced pressure the resulting residue was azeotroped with Toluene several times The product was purified by column chromatography (SiO2, 10-30% EtOAc/Hexanes)

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

Procedure: Ethyl 3-{2-[2-(ethyloxy)-2-oxo-1-phenylethylidene]hydrazino}-3-oxopropanoate. A mixture of ethyl 3-hydrazino-3-oxopropionate (1.46 g, 10.0 mmol), ethyl benzoylformate (2.14 g, 12.0 mmol), acetic acid (0.5 mL, 8.3 mmol) and dichloromethane (10 mL) was stirred at room temperature with excess anhydrous magnesium sulfate for 20 h, then filtered and the cake washed with ethyl acetate. The filtrate was evaporated under reduced pressure, azeotroped 3 times with toluene and chromatographed (silica gel, 10-3-% ethyl acetate/hexane) to give the title compound (0.773 g, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, J=7.07 Hz, 3H) 1.30 (t, J=7.07 Hz, 3H) 3.74 (s, 2H) 4.08 (q, J=7.07 Hz, 2H) 4.40 (q, J=7.18 Hz, 2H) 7.42-7.49 (m, 3H) 7.55-7.59 (m, 2H) 11.57 (s, 1H). filtered the cake washed with ethyl acetate The filtrate was evaporated under reduced pressure azeotroped 3 times with toluene chromatographed (silica gel, 10-3-% ethyl acetate/hexane)

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

Procedure: 100 mg (0.249 mmol) of the compound from Example 44A and 40 mg (0.273 mmol) of ethyl 3-hydrazinyl-3-oxopropanoate were reacted according to the General Method 4. Yield: 9 mg (6% of theory).

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

Procedure: To a mixture of hydrazinocarbonylacetic acid ethyl ester (1.0 g, 6.84 mmol) and diisopropypethylamine (1.77 g, 13.69 mmol) in THF (7 mL) is added a solution of propionyl chloride (633 mg, 6.84 mmol) in THF (2 mL) dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to furnish 3-oxo-3-(N′-propionylhydrazino)-propionic acid ethyl ester. 1H-NMR (400 MHz, CDCl3); δ ppm 1.21 (t, 3H), 1.30 (t, 3H), 2.31 (q, 2H), 3.43 (s, 2H), 4.23 (q, 2H), 8.27 (s, 1H), 9.63 (s, 1H). is washed with aqueous 1M HCl and brine The organic phase is dried over magnesium sulfate the solvent is removed under reduced pressure