methyl 3-bromo-2-oxobutanoate

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

Procedure: 5.83 g of 3-amino-6-chloropyridazine was suspended in 70 ml of ethanol; 9.75 g of methyl 3-bromo-2-oxobutyrate and 8.6 ml of N-ethyldiisopropylamine were added, followed by thermal refluxing for 5 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was ajusted to pH 7 by the addition of an aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; ethyl acetate was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl acetate and dried to yield 3.9 g of the title compound. refluxing for 5 hours After cooling the mixture was concentrated under reduced pressure the residue was ajusted to pH 7 by the addition of an aqueous solution of sodium hydrogen carbonate extracted with ethyl acetate-tetrahydrofuran (1:1) the extract was washed with saline dried with magnesium sulfate The dry product was concentrated under reduced pressure ethyl acetate was added to the residue the crystal precipitated was collected by filtration washed with ethyl acetate dried

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

Procedure: Ethoxycarbonylmethylene triphenyl phosphorane (33.8 g) in dry THF (200 ml) was treated with isopropyl isothiocyanate (10.1 g) at 65° C. for 16 h under nitrogen. The mixture was cooled to −78° C. and methyl 3-bromo-2-oxo-butanoate (19.5 g) was added. The reaction was allowed to warm slowly to room temperature. After 24 h at room temperature more methyl 3-bromo-2-oxo-butanoate (2.8 g) was added and the mixture was warmed to 60° C. for 16 h. The cooled reaction was poured into water (1.5 L) and extracted into ether. Drying and evaporation gave an oil which was chromatographed (SiO2/10:1 isohexane-ethyl acetate then 5:1 isohexane-ethyl acetate) to afford the subtitle compound (23.5 g). to warm slowly to room temperature the mixture was warmed to 60° C. for 16 h The cooled reaction extracted into ether Drying evaporation gave an oil which was chromatographed (SiO2/10:1 isohexane-ethyl acetate

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

Procedure: Ethoxycarbonylmethylene triphenyl phosphorane (33.8 g) in dry THF (200 ml) was treated with isopropyl isothiocyanate (10.1 g) at 65° C. for 16 h under nitrogen. The mixture was cooled to −78° C. and methyl 3-bromo-2-oxo-butanoate was added. The reaction was allowed to warm slowly to room temperature. After 24 h at room temperature more methyl 3-bromo-2-oxo-butanoate (2.8 g) was added and the mixture was warmed to 60° C. for 16 h. The cooled reaction was poured into water (1.5 L) and extracted into ether. Drying and evaporation gave an oil which was chromatographed (SiO2/10:1 isohexane-ethyl acetate then 5:1 isohexane-ethyl acetate) to afford the sub-title compound (23.5 g). to warm slowly to room temperature the mixture was warmed to 60° C. for 16 h The cooled reaction extracted into ether Drying evaporation gave an oil which was chromatographed (SiO2/10:1 isohexane-ethyl acetate

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

Procedure: To a stirred solution of 30 g of 2-amino-3-pivaloylaminopyridine in 300 ml of dry tetrahydrofuran are added dropwise under argon 40 g of 3-bromo-2-oxobutanoic acid methylester. The brown solution is stirred at ambient temperature for 3 d. The resulting suspension is poured onto a mixture of icewater and ethyl acetate and the mixture is neutralised by adding 10 M sodium hydroxide solution. The organic phase is separated and the aqueous layer extracted two times with ethyl acetate. The combined organic phases are washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the blue coloured residue purified by column chromatography on silica gel to yield 35 g (78%) of a light brown solid (m.p. 132° C.). The organic phase is separated the aqueous layer extracted two times with ethyl acetate The combined organic phases are washed with water dried over anhydrous sodium sulfate The solvent is removed in vacuo the blue coloured residue purified by column chromatography on silica gel

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

Procedure: To a solution of methyl 3-bromo-2-oxobutanoate (8.26 g, 42.4 mmol) in DME (33 mL) at room temperature was added 2-amino-5-chloropyridine (5.45 g, 42.4 mmol). The reaction mixture was stirred at room temperature for 20 h. The solid was collected by filtration, washed with EtOAc (2×), and dried under high vacuum to give methyl 3-(5-chloro-2-iminopyridin-1(2H)-yl)-2-oxobutanoate hydrobromide (8.51 g, 26.3 mmol, 62% yield) as a white solid. The solid was collected by filtration washed with EtOAc (2×) dried under high vacuum

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

Procedure: To a solution of methyl 2-oxobutanoate (6.92 g, 59.6 mmol) in DCM (60 mL) at 0° C. was added bromine (3.10 mL, 60.3 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, diluted with EtOAc, washed with saturated NaHCO3 (2×), water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The product, methyl 3-bromo-2-oxobutanoate, (8.26 g, 42.4 mmol, 71% yield) was used in the next step without further purification. washed with saturated NaHCO3 (2×), water (1×), brine (1×) dried over MgSO4 filtered concentrated

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

Procedure: To a solution of methyl 2-oxobutanoate (6.92 g, 59.6 mmol) in DCM (60 mL) at 0° C. was added bromine (3.10 mL, 60.3 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, diluted with EtOAc, washed with saturated NaHCO3 (2×), water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The product, methyl 3-bromo-2-oxobutanoate, (8.26 g, 42.4 mmol, 71% yield) was used in the next step without further purification. washed with saturated NaHCO3 (2×), water (1×), brine (1×) dried over MgSO4 filtered concentrated

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

Procedure: A mixture of methyl 3-bromo-2-oxobutanoate (4.6 g) and 2-methylpropanethioamide (2.5 g) in THF (100 mL) was heated at reflux for 18 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography using 17% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.7 g. was heated at reflux for 18 hours The solvent was evaporated under reduced pressure The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution the organic layer was dried over sodium sulphate filtered the solvent evaporated under reduced pressure The residue was purified by flash silica chromatography Pure fractions were evaporated to dryness

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

Procedure: A mixture of methyl 3-bromo-2-oxobutanoate (4.6 g) and 2-methylpropanethioamide (2.5 g) in THF (100 mL) was heated at reflux for 18 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography using 17% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.7 g. was heated at reflux for 18 hours The solvent was evaporated under reduced pressure The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution the organic layer was dried over sodium sulphate filtered the solvent evaporated under reduced pressure The residue was purified by flash silica chromatography Pure fractions were evaporated to dryness

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

Procedure: An ethanol suspension (400 mL) of methyl 3-bromo-2-oxobutyrate (46.6 g) and 2-amino-5-nitropyridine (33.3 g) was stirred at 90° C. for 24 hours. The precipitated solid was taken out through filtration, and the obtained solid was suspended in ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution, and purified through silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain methyl 3-methyl-6-nitroimidazo[1,2-a]pyridine-2-carboxylate (13.0 g) as a yellow crystal. The precipitated solid was taken out through filtration washed with aqueous saturated sodium hydrogencarbonate solution purified through silica gel column chromatography (hexane/ethyl acetate=2/1)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 3-bromo-2-oxobutanoate (320 mg, 1.642 mmol) was added to a suspension of N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B, 435 mg, 1.094 mmol) in EtOH (10 ml) and the reaction mixture was heated at 65° C. for 2 h. The solvent was removed in vacuo and the residue purified by silica gel chromatography (2-10% MeOH/dichloromethane) to give methyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-5-methylthiazole-4-carboxylate (380 mg, 70% yield) as yellow solid. The solvent was removed in vacuo the residue purified by silica gel chromatography (2-10% MeOH/dichloromethane)

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

Procedure: To a solution of (triphenylphosphoranylidene)-acetic acid ethyl ester (15 g) in anhydrous tetrahydrofuran (100 ml) was added isothiocyanato-cyclopropane (4.4 g) and the mixture was refluxed under a nitrogen atmosphere for 20 hr. After allowing to cool to ambient temperature the reaction mixture was cooled to −78° C. and then a solution of 3-bromo-2-oxo-butanoic acid methyl ester (8.7 g) in anhydrous tetrahydrofuran (10 ml) was added. The resulting mixture was allowed to warm to ambient temperature and then refluxed for 20 hr., then ambient temperature for 2 days. The reaction was poured into water and extracted with diethyl ether. The collected organic extract was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with i-hexane/ethyl acetate (95:5) then triturated with i-hexane/diethyl ether (8:2) to give the sub-title compound as a solid (7.5 g). the mixture was refluxed under a nitrogen atmosphere for 20 hr was cooled to −78° C. to warm to ambient temperature refluxed for 20 hr extracted with diethyl ether The collected organic extract was dried over magnesium sulfate filtered evaporated under reduced pressure The residue was purified by column chromatography over silica eluting with i-hexane/ethyl acetate (95:5) then triturated with i-hexane/diethyl ether (8:2)