1-Cyclopropyl-1,3-butanedione

PREPARATION 176 1 -Cyclopropylbutane-1 , 3-dione Sodium hydride (60percent dispersion in oil, 0.95 g, 23.8 mmol) was washed several times with pentane and then suspended in 18 ml tetrahydrofuran under nitrogen. Ethyl acetate (2.3 ml, 23.5 mmol) and 2 drops of ethanol were added. A solution of cyclopropyl methyl ketone (1 .0 g, 1 1 .9 mmol) dissolved in 5 ml tetrahydrofuran was added drop-wise with stirring, maintaining the reaction temperature below 20 °C with an ice-bath. 18-Crown-6 (63 mg, 0.25 mmol) was added and the mixture was stirred at 40 °C for 4 h. The mixture was evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous phase was washed with ether. The aqueous was then acidified to pH 2 with 2N hydrochloric acid. The aqueous was extracted three times with ether and the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 0.7 g (5.5 mmol, 47percent) of the title compound. Purity 100percent. Preparation of PREPARATION 176 1 -Cyclopropylbutane-1 , 3-dione Sodium hydride (60percent dispersion in oil, 0.95 g, 23.8 mmol) was washed several times with pentane and then suspended in 18 ml tetrahydrofuran under nitrogen. Ethyl acetate (2.3 ml, 23.5 mmol) and 2 drops of ethanol were added. A solution of cyclopropyl methyl ketone (1 .0 g, 1 1 .9 mmol) dissolved in 5 ml tetrahydrofuran was added drop-wise with stirring, maintaining the reaction temperature below 20 °C with an ice-bath. 18-Crown-6 (63 mg, 0.25 mmol) was added and the mixture was stirred at 40 °C for 4 h. The mixture was evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous phase was washed with ether. The aqueous was then acidified to pH 2 with 2N hydrochloric acid. The aqueous was extracted three times with ether and the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 0.7 g (5.5 mmol, 47percent) of the title compound. Purity 100percent. 1 H NMR (400 MHz, CHLOROFORM-c/) mixture of keto and enol tautomers Keto form delta ppm 0.83 - 0.99 (m, 2 H), 1 .07 - 1 .17 (m, 2 H), 1 .55 - 1 .71 (m, 1 H), 2.25 (s, 3 H), 3.69 (s, 2 H). Enol form delta ppm 0.83 - 0.99 (m, 2 H), 1 .07 - 1 .17 (m, 2 H), 1 .55 - 1 .71 (m, 1 H), 2.02 (s, 3 H), 5.61 (s, 1 H). UPLC/MS (3 min) retention time 0.69, 1 .33 min. LRMS: m/z 127 (M+1 ).  Sodium hydride (60percent dispersion in oil, 1.9 g, 47.5 mmol) was washed several times with pentane and then suspended in 35 ml   tetrahydrofuran under nitrogen.   Ethyl acetate (4.7 ml, 48 mmol) and 2 drops of   ethanol were added. A solution of   cyclopropyl methyl ketone (2.0 g, 23.8 mmol) dissolved in 10 ml tetrahydrofuran was added drop-wise with stirring, maintaining the reaction temperature below 20 ºC with an ice-bath. 18-Crown-6 (130 mg, 0.49 mmol) was added and the mixture was stirred at 40 ºC for 3 h. The mixture was evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous phase was extracted with ether. The aqueous was then acidified to pH 2 with 5N hydrochloric acid. The aqueous was further extracted three times with ether and the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 3.1 g of the crude   title compound.1H NMR (400 MHz, CHLOROFORM-d) ) delta ppm 0.88 - 0.95 (m, 2 H), 1.07 - 1.14 (m, 2 H), 1.56 - 1.68 (m, 1 H), 2.02 (s, 3 H), 3.70 (s, 2 H).UPLC/MS (3 min) retention time 1.33 min.LRMS: m/z 127 (M+1).Sodium hydride (60percent dispersion in oil, 1 .9 g, 47.5 mmol) was washed several times with pentane and then suspended in 35 ml tetrahydrofuran under nitrogen. Ethyl acetate (4.7 ml, 48 mmol) and 2 drops of ethanol were added. A solution of cyclopropyl methyl ketone (2.0 g, 23.8 mmol) dissolved in 10 ml tetrahydrofuran was added drop- wise with stirring, maintaining the reaction temperature below 20 °C with an ice-bath. 18-Crown-6 (130 mg, 0.49 mmol) was added and the mixture was stirred at 40 °C for 3 h. The mixture was evaporated under reduced pressure and the residue was partitioned between ether and water. The aqueous phase was extracted with ether. The aqueous was then acidified to pH 2 with 5N hydrochloric acid. The aqueous was further extracted three times with ether and the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 3.1 g of the crude title compound. 1 H NMR (400 MHz, CHLOROFORM-d) ) delta ppm 0.88 - 0.95 (m, 2 H), 1 .07 - 1 .14 (m, 2 H), 1 .56 - 1 .68 (m, 1 H), 2.02 (s, 3 H), 3.70 (s, 2 H). UPLC/MS (3 min) retention time 1 .33 min. LRMS: m/z 127 (M+1 ).ntermediate 163-(Aminomethyl)-6-c lopropyl-4-methyl-2(lH)-pyridinoneStep 1l-Cyclopropyl-l, 3-butanedioneTo a a stirring solution of THF (100 mL) was suspended potassium tert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone (3.27mL, 33 mmol) and ethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at 35 °C, via addition funnel over a 25 min period. The contents were heated and stirred at 60 °C. After 3 h, the contents were removed from heating, and allowed to stir with cooling to roomtemperature. The reaction mixture was carefully diluted with 30 mL 2N HCl and stirred for 10 min. The mixture was extracted with diethyl ether (3 x 50 mL), and the combined organic layers washed with brine (1 x 50 mL). The organic layer was dried over MgSC^, filtered, and concentrated in vacuo. The crude oil was chromatographed on silica gel (eluent: 0 to 15percent EtOAc in hexanes) with good separation to afford the desired product as a light yellow colored oil, 3.9 g in -75percent purity (residual solvent), for an overall yield of 70percent. 1H NMR (400 MHz, CHLOROFORM- ) ' ppm 0.89 - 0.96 (m, 2 H), 1.09-1.15 (m, 2 H), 1.59-1.69 (m, 1H), 2.04 (s, 3H), 5.63 (s, 1 H), 15.5 - 16.0 (br s, 1H).To a stirring solution ofTHF (100 mL) was added potassium tert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone (3 .27 mL, 33 mmol) andethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at 35 °C, via addition funnel over a 25min period. The contents were heated and stirred at 60 °C. After 3 h, the contents wereremoved from heating, and allowed to cool to room temperature. The reaction mixture wascarefully diluted with 30 mL 2 N HCl and stirred for 10 min The mixture was extracted with diethyl ether (3 x 50 mL), and the combined organic layers washed with brine (1 x 50mL). The organic layer was dried over MgS04, filtered, and concentrated in vacuo.Purification by chromatography on silica gel (eluent: 0 to 15percent EtOAc in hexanes) withgood separation afforded General procedure: To a freshly prepared sodium methylate solution in methanol and THF ethyl trifluoroacetate (1.2 equiv) was added under stirring at 0° followed by addition of ketone 2 (1.0 equiv). The reaction mixture was allowed to stir for additional 3-24 h until the starting materials were consumed, as determined by thin-layer chromatography (TLC). Then the solvent was removed under reduced pressure and the residue was acidified with hydrochloric acid (1 N), followed by extracted with acetic ether. The combined organic layers were dried (MgSO4), Fitered and the filtrate was concentrated under reduced pressure. The crude product was puried by column chromatography. Yield: 40-90percent. For some cases, the crude products can be straight used for step c without the column chromatography procedure.To a stirring solution of THF (100 mL) was added potassium tert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone (3.27 mL, 33 mmol) and ethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at 35° C., via addition funnel over a 25 min period. The contents were heated and stirred at 60° C. After 3 h, the contents were removed from heating, and allowed to cool to room temperature. The reaction mixture was carefully diluted with 30 mL 2 N HCl and stirred for 10 min. The mixture was extracted with diethyl ether (3×50 mL), and the combined organic layers washed with brine (1×50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (eluent: 0 to 15percent EtOAc in hexanes) with good separation afforded