methyl 2-diethoxyphosphorylacetate

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

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

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

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

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

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

Procedure: 96 mg (2.0 mmoles) of 50% sodium hydride was suspended in 5 ml of dry benzene, and 841 mg (4.0 mmoles) of methyl diethylphosphonoacetate was added. The mixture was stirred for 10 minutes. 600 mg (1.91 mmoles) of 4(RS)-t-butyldimethylsilyloxy-2-(4-oxobutylthio)-2-cyclopentenone was dissolved in 10 ml of dry benzene. The solution was stirred under ice cooling. To the resulting solution was added the above reaction mixture. The mixture was stirred further for 15 minutes. The reaction mixture was washed with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The extract was dried over anhydrous dodium sulfate, and concentrated. The resulting oily product was chromatographed on a silica gel column using hexane/ethyl acetate (8/1) as an eluent to give 531 mg (yield 75%) of 4(RS)-t-butyldimethylsilyloxy-2-(5-methoxycarbonyl-trans-4-pentenylthio)-2-cyclopentenone. The solution was stirred under ice cooling To the resulting solution was added the above reaction mixture The mixture was stirred further for 15 minutes The reaction mixture was washed with a saturated aqueous solution of ammonium chloride extracted with ethyl acetate The extract was dried over anhydrous dodium sulfate concentrated The resulting oily product was chromatographed on a silica gel column

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

Procedure: To a −78° C. cooled stirred solution of oxalyl chloride (1 eq) in dichloromethane was added dimethyl sulfoxide (2 eq). After an additional 5 minutes, 2-Imidazo[4,5-b]pyridin-1-yl-2-methyl-propan-1-ol (1 eq) dissolved in dichloromethane was added to the cooled solution via cannula. The resulting heterogeneous mixture was stirred at −78° C. for 30 minutes, and triethylamine (5 eq) was added to produce a thick white slurry. After stirring at −78° C. for 15 minutes, the mixture was allowed to warm slowly to 0° C., diluted with dichloromethane, washed with NaCl(sat), dried over sodium sulfate, filtered and concentrated. Following this, to a solution of sodium hydride (1 eq) in THF was added methyl diethylphosphonoacetate (1 eq) at 0° C. The mixture was stirred at room temperature for 30 minutes and a solution of the latter concentrated residue dissolved in THF was added dropwise to the mixture. The solution was stirred for 1 hour at the same temperature and then poured into H2O, followed by an extraction with ethyl acetate. The organic layer was washed with NaCl(sat), dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 97% DCM, 3% MeOH and 0.1% TEA to yield 4-Imidazo[4,5-b]pyridin-1-yl-4-methyl-pent-2-enoic acid methyl ester (93%). MH+(246). was added to the cooled solution via cannula to produce a thick white slurry After stirring at −78° C. for 15 minutes to warm slowly to 0° C. washed with NaCl(sat) dried over sodium sulfate filtered concentrated The mixture was stirred at room temperature for 30 minutes was added dropwise to the mixture The solution was stirred for 1 hour at the same temperature followed by an extraction with ethyl acetate The organic layer was washed with NaCl(sat) dried over sodium sulfate filtered concentrated The crude product was purified by flash chromatography

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

Procedure: To a solution of sodium hydride (1.2 eq) in THF was added slowly methyl diethylphosphonoacetate (1.2 eq) at 0° C. under dry conditions and the mixture was stirred at room temperature for 30 minutes. A solution of 2-Methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionaldehyde (1 eq), in THF was added dropwise at room temperature and the mixture was stirred for 1 hour at the same temperature. The mixture was poured into H2O and the whole was extracted with ethyl acetate. The organic layer was washed with NaCl(sat), dried over sodium sulfate, filtered and concentrated. To a solution of the residue in ethyl acetate, was added Palladium, 10 wt. % on activated carbon and left stirring under 1 atm hydrogen overnight. After the catalyst was filtered off, the filtrate was purified by flash chromatography using a solvent gradient 97% DCM, 3% MeOH and 0.1% TEA to yield 4-Methyl-4-(4-pyridin-3-yl-imidazol-1-yl)pentanoic acid methyl ester (75%). MH+(274). the mixture was stirred for 1 hour at the same temperature the whole was extracted with ethyl acetate The organic layer was washed with NaCl(sat) dried over sodium sulfate filtered concentrated To a solution of the residue in ethyl acetate, was added Palladium, 10 wt. % on activated carbon left stirring under 1 atm hydrogen overnight After the catalyst was filtered off the filtrate was purified by flash chromatography

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

Procedure: A stirred suspension of sodium hydride (0.272 g; 60% w/v dispersion in mineral oil; 6.8 mmol) in tetrahydrofuran (100 mL) at 0° C. under nitrogen is treated, dropwise, with methyl (diethylphosphono)acetate (1.43 g) and stirred for 15 minutes. It is then treated with a solution of ethyl (RS)-4-(5-benzyloxy-2-formylphenoxy)-4-(2-methylphenyl)butanoate (1.96 g) in tetrahydrofuran (5 mL) in one portion, and the reaction mixture is stirred at ambient temperature for 15 minutes. The mixture is treated with water (100 mL) and extracted with ethyl acetate (3×100 mL), and the combined organic extracts are washed with brine (50 mL), dried over magnesium sulphate, and filtered and the solvent is removed in vacuo, to give ethyl (E)-(RS)-4-(2-methylphenyl)-4-[2-(2-methoxycarbonylethenyl)-5-benzyloxyphenoxy]butanoate, in the form of a yellow oil. is treated extracted with ethyl acetate (3×100 mL) the combined organic extracts are washed with brine (50 mL) dried over magnesium sulphate filtered the solvent is removed in vacuo

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

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

Procedure: 1.1 ml of methyl diethylphosphonoacetate dissolved in 10 ml of dimethoxyethane was added to 1.84 g of 11-oxo-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and 0.3 g of 64% by weight sodium hydride suspended in 20 ml of dimethoxyethane and the mixture was refluxed under heating for 5 hours. The solvent was removed from the reaction mixture, the residue was dissolved in ethyl acetate and the organic layer was washed with water and a saturated saline solution and then dried over anhydrous sodium sulfate. After the solvent was removed from the solution, the residue was applied to silica gel column chromatography to obtain 2.3 g of 11-methoxycarbonylmethylene-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine as a brown oily product. the mixture was refluxed under heating for 5 hours The solvent was removed from the reaction mixture the residue was dissolved in ethyl acetate the organic layer was washed with water a saturated saline solution and then dried over anhydrous sodium sulfate After the solvent was removed from the solution

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

Procedure: Methyl diethylphosphonoacetate (1.6 g, 7 5 mmol) and NaH (0.19 g, 7.5 mmol) in THF (25 mL) was added to 2-acetyl-6-methoxynaphthalene (1.5 g, 7.5 mmol) in THF (50 mL) at 23° C. under nitrogen. After refluxing for 20 hours, the reaction mixture was cooled, saturated NH4Cl added, and the mixture poured into water. The solution was extracted with ether and the organic extracts were dried (MgSO4) and the solvent evaporated. Chromatography (silica gel, ether/pentane) afforded methyl 3-(6-methoxy-2-naphthyl)-2-butenoate (0.75 g). This intermediate (0.51 g, 2 mmol) in methanol (50 mL) was hydrogenated with 20% Pd/C (50 mg) at 3 atm at 23° C. until the theoretical amount of hydrogen was taken up. Removal of solvent and catalyst gave the crude ester which was dissolved in isopropanol/water : 2/1 (40 mL). Lithium hydroxide (82 mg, 2 mmol) was added and the reaction mixture stirred at 23° C. for 1 hour. Saturated ammonium chloride was added and the mixture extracted with ethyl acetate. Removal of solvent followed by recrystallization from methanol/water gave 3-(6-methoxy-2-naphthyl) butyric acid (0.45 g). Bromine (3 mL of a 1M solution in CCl4, 3 mmol) was added slowly to the acid (0.37 g, 1.5 mmol) and PBr3 (0.4 g, 1.5 mmol) in CCl4 (20 mL) at 23° C. under nitrogen. The mixture was heated at 80° C. for 20 hours. The mixture was then cooled and poured into ice water. Extraction with benzene followed by drying (Na2SO4) and evaporation gave a crude residue which was distilled under reduced pressure (0.5 mm) to afford 2-bromo-3-(6-methoxy-2-naphthyl)butyrylbromide (0.55 g). 1H NMR(60 MHz, DMSO-d6): 1.30 (3H, d J=7 Hz), 3.80 (3H, s), 4.01 (1H, g, J=7 Hz), 4.20 (1H, d, J=7 Hz), 7.0-8.0 (6H, m); Mass Spectrum: 386(M+). After refluxing for 20 hours the reaction mixture was cooled The solution was extracted with ether the organic extracts were dried (MgSO4) the solvent evaporated