ethyl 2-acetamido-3-oxobutanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 0.054 mmol of ammonia in ethanol was added dropwise to 0.054 mol of ethyl 2-acetamidoacetoacetate in 40 ml of ice cold ethanol over a period of 10 minutes. The reaction vessel was tightly capped and allowed to stir overnight at 23° C., after which the solvent was removed at reduced pressure to provide ethyl 2-acetamido-3-aminobut-2-enoate in a 3/1 ratio of two geometrical isomers. The reaction vessel was tightly capped after which the solvent was removed at reduced pressure

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

Procedure: A Parr flask was charged with 0.2 mol of ethyl 2-oximinoacetoacetate, 0.4 mol of acetic anhydride, 45 psi of hydrogen, and a mixture of 0.25 g of 5% palladium-on-carbon and 0.4 g of 10% palladium-on-carbon and shaken for about 22 hours. Work-up of the resultant reaction mixture provided a 92.3% yield of ethyl 2-acetamidoacetoacetate. Work-up of the resultant reaction mixture

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

Procedure: Ammonium acetate (185 mg, 2.4 mmol) was added to a solution of ethyl 2-(acetylamino)-3-oxobutanoate (90 mg, 0.48 mmol) in acetic acid (1.0 mL). The mixture was heated to reflux overnight. After cooling, the solvent was evaporated under reduced pressure and the residue was taken up in saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (0-4% 2M NH3 solution of MeOH in DCM) to give the title compound (54 mg, 67%) as a white solid. 1H NMR (400 MHz, CDCl3-d) δ ppm 4.30 (q, J=7.20 Hz, 2H) 2.44 (s, 3H) 2.38 (s, 3H) 1.34 (t, J=7.14 Hz, 3H). LCMS: m/z 169 (M+1). The mixture was heated to reflux overnight After cooling the solvent was evaporated under reduced pressure extracted with EtOAc The organic layer was dried over sodium sulfate concentrated The residue was purified by column chromatography (0-4% 2M NH3 solution of MeOH in DCM)

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

Procedure: 4-Methylmorpholine (0.41 mL, 3.7 mmol) was added dropwise via a syringe pump to a mixture of ethyl 2-amino-3-oxobutanoate hydrochloride (565 mg, 3.12 mmol) and acetic anhydride (0.35 mL, 3.7 mmol) in DMF (2 mL) and THF (4 mL) at RT under N2 over a period of 30 min. The reaction was stirred for 1 h and water was then added. It was extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate, HCl (1 N) and brine, dried over sodium sulfate and concentrated. The residue was purified by ISCO FC with 0-40% EtOAc in hexane to give the title compound (73 mg, 13%) as a light-yellow crystalline solid. 1H NMR (400 MHz, CDCl3-d) δ ppm 6.60 (s, 1H) 5.22 (d, J=6.59 Hz, 1H) 4.25 (q, J=6.90 Hz, 2H) 2.36 (s, 3H) 2.04 (s, 3H) 1.28 (t, J=7.14 Hz, 2H). It was extracted with EtOAc The organic layer was washed with saturated sodium bicarbonate, HCl (1 N) and brine dried over sodium sulfate concentrated The residue was purified by ISCO FC with 0-40% EtOAc in hexane

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

Procedure: To a solution of ethyl 2-acetamido-3-oxobutanoate (compound 10, 2.0 g, 10.6 mmol), aniline (compound 11b, 2.0 g, 21.3 mmol) in butyronitrile (15 mL) was added acetic acid (1.2 mL, 21.3 mmol) at room temperature. The reaction mixture was irradiated in a microwave reactor (Biotage Initiator™) for 40 minutes at 160° C. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (purification system, Gilson) to provide the title compound (340 mg, 14%) as a brown oil. The reaction mixture was irradiated in a microwave reactor (Biotage Initiator™) for 40 minutes at 160° C The mixture was concentrated under reduced pressure The crude product was purified by preparative HPLC (purification system, Gilson)

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

Procedure: To a solution of ethyl 2-acetamido-3-oxobutanoate (compound 10, 5.0 g, 26.7 mmol), aniline (compound 11a, 7.3 mL, 80.1 mmol) in butyronitrile (10 mL) was added trifluoroacetic acid (6.2 mL, 80.1 mmol) at room temperature. The reaction mixture was irradiated in a microwave reactor (Biotage Initiator™) for 40 minutes at 140° C. The mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with aqueous K2CO3. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage SP1™ FLASH Purification System was used for normal phase column chromatography with tetrahydrofuran and hexane) to provide the title compound (4.97 g, 76%) as a yellow solid. The reaction mixture was irradiated in a microwave reactor (Biotage Initiator™) for 40 minutes at 140° C The mixture was concentrated under reduced pressure The residue was diluted with CH2Cl2 washed with aqueous K2CO3 The organic layer was dried over anhydrous MgSO4 filtered concentrated in vacuo The crude product was purified by flash column chromatography (Biotage SP1™ FLASH Purification System was used for normal phase column chromatography with tetrahydrofuran and hexane)

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

Procedure: To a mixture of ethyl 2-(hydroxyimino)-3-oxobutanoate (compound 8, 9.32 g, 58.5 mmol), Pd/C (400 mg, palladium on carbon, 10 wt %, support activated carbon, wet, Degussa type E101 NE/W) in EtOH was added acetic anhydride (compound 9, 11.0 mL, 117.0 mmol) at room temperature. The reaction mixture was stirred at room temperature under H2 for 15 hrs. The palladium was filtered off (filter aid, Celite 521 AW), then the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage SP1™ FLASH Purification System was used for normal phase column chromatography with tetrahydrofuran and hexane) to provide the title compound (9.48 g, 86%) as a white solid. The palladium was filtered off (filter aid, Celite 521 AW) the filtrate was concentrated in vacuo The crude product was purified by flash column chromatography (Biotage SP1™ FLASH Purification System was used for normal phase column chromatography with tetrahydrofuran and hexane)

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

Procedure: 6-Hydrazino-N-[4-(trifluoromethyl)phenyl]nicotinamide (0.31 g) and ethyl 2-acetamido-3-oxobutanoate (0.24 g) were suspended in ethanol (25 mL), and the suspension was heated to reflux for 23 hours. The reaction solution was cooled to room temperature, and the obtained solid was collected by filtration and washed with ethanol. The solid was dried under reduced pressure to obtain the title compound (0.20 g) as a white solid (yield: 46%). the suspension was heated to reflux for 23 hours the obtained solid was collected by filtration washed with ethanol The solid was dried under reduced pressure