methyl 4-bromo-3-methylbutanoate

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

実験手順: 80 g. of the methyl half ester of 3-methylglutaric acid (Linstead, lunt and Weedon, J. Chem. Soc. 1950, 3331) was converted to methyl 4-bromo-3-methylbutyrate as described by Marks and Polgar, J. Chem. Soc. 1955, 3854. The bromoester (51 g.) was reduced with sodium bis (2-methoxyethoxy)aluminum hydride in a mixture of toluene and ether yielding 43 g. of 4-bromo-3-methylbutyraldehyde. The aldehyde and 49 g. of 5-chlorosalicylhydroxamic acid were condensed by the method described in Example 1 and the product was ring-closed with 10 percent aqueous sodium hydroxide to give 8-chloro-3-methyl-2,3,4,4a-tetrahydro-10H-1,2-oxazino(3,2-b) (1,3)benzoxazin-10-one which melted at 121- 140° C. after recrystallization from ethanol. condensed by the method

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

実験手順: 80 g. of the methyl half ester of 3-methylglutaric acid (Linstead, lunt and Weedon, J. Chem. Soc. 1950, 3331) was converted to methyl 4-bromo-3-methylbutyrate as described by Marks and Polgar, J. Chem. Soc. 1955, 3854. The bromoester (51 g.) was reduced with sodium bis (2-methoxyethoxy)aluminum hydride in a mixture of toluene and ether yielding 43 g. of 4-bromo-3-methylbutyraldehyde. The aldehyde and 49 g. of 5-chlorosalicylhydroxamic acid were condensed by the method described in Example 1 and the product was ring-closed with 10 percent aqueous sodium hydroxide to give 8-chloro-3-methyl-2,3,4,4a-tetrahydro-10H-1,2-oxazino(3,2-b) (1,3)benzoxazin-10-one which melted at 121- 140° C. after recrystallization from ethanol. condensed by the method

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-methoxy-4-nitrophenol (0.207 mg. 1.23 mmole) {Aldrich}, methyl 4-bromo-3-methylbutyrate(0.25 g. 1.35 mmole) and potassium carbonate (0.19 g. 1.35 mmole) in DMF (10 mL.) was heated and stirred at 80° C. for 8 hours. After cooling, the inorganics were filtered off, and the filtrate evaporated to dryness. The residue was dissolved in dichloromethane and washed twice with water. After drying (MgSO4) the solvent was evaporated off to yield an oil. The oil was purified by chromatography (Varian Megabondelut silica column) using a gradient of 100% dichloromethane to 20% ethyl acetate/dichloromethane to give methyl 3-methyl-4-(2-methoxy-5-nitrophenoxy)butyrate as an oil (90 mg. 29%) ms 284(M+) was heated After cooling the inorganics were filtered off the filtrate evaporated to dryness The residue was dissolved in dichloromethane washed twice with water After drying (MgSO4) the solvent was evaporated off to yield an oil The oil was purified by chromatography (Varian Megabondelut silica column)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-methoxy-4-nitrophenol (0.207 mg. 1.23 mmole) {Aldrich}, methyl 4-bromo-3-methylbutyrate(0.25 g. 1.35 mmole) and potassium carbonate (0.19 g. 1.35 mmole) in DMF (10 mL.) was heated and stirred at 80° C. for 8 hours. After cooling, the inorganics were filtered off, and the filtrate evaporated to dryness. The residue was dissolved in dichloromethane and washed twice with water. After drying (MgSO4) the solvent was evaporated off to yield an oil. The oil was purified by chromatography (Varian Megabondelut silica column) using a gradient of 100% dichloromethane to 20% ethyl acetate/dichloromethane to give methyl 3-methyl-4-(2-methoxy-5-nitrophenoxy)butyrate as an oil (90 mg. 29%) ms 284(M+) was heated After cooling the inorganics were filtered off the filtrate evaporated to dryness The residue was dissolved in dichloromethane washed twice with water After drying (MgSO4) the solvent was evaporated off to yield an oil The oil was purified by chromatography (Varian Megabondelut silica column)

反応条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 3-methylglutarate(37 g; 231 mmol) was added to 1M NaOH (231 mL; 231 mmol) causing the solution to warm slightly. This solution was added to a solution of silver nitrate (39.2 g; 231 mmol) in water (184 mL) at 60° C. A fine white precipitate formed immediately. The mixture was cooled and stirred in an ice bath for 1 h before being filtered, washed with water, acetone and ether and partially dried on the filter. The solid was then dried over night at 80° C. in a vacuum oven to give the silver salt of the methyl 3-methylglutarate(49 g, 79%) as a pale brown solid. The silver salt of the methyl 3-methylglutarate (49 g; 184 mmol) was suspended in carbon tetrachloride (245 mL) and bromine (9.5 mL) slowly added. The reaction mixture warmed to ≈30° C. during this process and effervescence was seen. The reaction mixture was maintained at this temperature by the rate of addition of bromine. After the final addition of bromine the viscous mixture was stirred for 0.5 h before being heated at reflux for 1 h. After cooling, the pale yellow precipitate was removed by filtration and the filtrate washed with 1M aqueous sodium thiosulphate, brine, dried (phase separation paper) and concentrated under reduced pressure. This gave a pale yellow oil which contained 15% of methyl 3-methylglutarate as an impurity by 1H NMR. This was removed by taking the oil up in dichloromethane (DCM) and washing with 1M NaOH. Drying and concentration as above gave (±) methyl 4-bromo-3-methylbutyrate (25 g, 70%) as a pale yellow oil. before being heated at reflux for 1 h After cooling the pale yellow precipitate was removed by filtration the filtrate washed with 1M aqueous sodium thiosulphate, brine dried (phase separation paper) concentrated under reduced pressure This gave a pale yellow oil which This was removed washing with 1M NaOH Drying concentration

反応条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 3-methylglutarate(37 g; 231 mmol) was added to 1M NaOH (231 mL; 231 mmol) causing the solution to warm slightly. This solution was added to a solution of silver nitrate (39.2 g; 231 mmol) in water (184 mL) at 60° C. A fine white precipitate formed immediately. The mixture was cooled and stirred in an ice bath for 1 h before being filtered, washed with water, acetone and ether and partially dried on the filter. The solid was then dried over night at 80° C. in a vacuum oven to give the silver salt of the methyl 3-methylglutarate(49 g, 79%) as a pale brown solid. The silver salt of the methyl 3-methylglutarate (49 g; 184 mmol) was suspended in carbon tetrachloride (245 mL) and bromine (9.5 mL) slowly added. The reaction mixture warmed to ≈30° C. during this process and effervescence was seen. The reaction mixture was maintained at this temperature by the rate of addition of bromine. After the final addition of bromine the viscous mixture was stirred for 0.5 h before being heated at reflux for 1 h. After cooling, the pale yellow precipitate was removed by filtration and the filtrate washed with 1M aqueous sodium thiosulphate, brine, dried (phase separation paper) and concentrated under reduced pressure. This gave a pale yellow oil which contained 15% of methyl 3-methylglutarate as an impurity by 1H NMR. This was removed by taking the oil up in dichloromethane (DCM) and washing with 1M NaOH. Drying and concentration as above gave (±) methyl 4-bromo-3-methylbutyrate (25 g, 70%) as a pale yellow oil. before being heated at reflux for 1 h After cooling the pale yellow precipitate was removed by filtration the filtrate washed with 1M aqueous sodium thiosulphate, brine dried (phase separation paper) concentrated under reduced pressure This gave a pale yellow oil which This was removed washing with 1M NaOH Drying concentration

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 analogously to 5-(3-fluorophenyl)-10-hydroxy-1,3,8-trimethyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (Intermediate La) by replacing Methyl 4-bromo-3-methylbutanoate (Intermediate T) with methyl 4-bromo-2-methylbutanoate (Intermediate S).

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 analogously to 3-(1,3-dimethyl-2,4,10-trioxo-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile (Example 9 steps 1-7) by replacing 3-bromobenzonitrile (step 3) with 1-bromo-3-fluorobenzene (commercially available) and methyl 4-bromobutanoate (Step 5) with methyl 4-bromo-3-methylbutanoate (Intermediate T).