dibenzyl propanedioate

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: 3,5-dichloro-2,4,6-trifluoropyridine (25 g, 15.4 mL, 123.7 mmol) and dibenzyl malonate (35.8 g, 31.5 mL, 126 mmol, Aldrich) were dissolved in anhydrous DMF (240 mL) under nitrogen atmosphere. The mixture was then cooled in an ice bath. To a stirred mixture, was added 60% sodium hydride (10 g, 250 mmol) portionwise (2 g) for 2 hr. The mixture was then stirred in a water bath for ca. 17 hr. Glacial acetic acid was added and the mixture was partitioned between ether and water. Ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and dried in vacuo to give 62 g of dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate as a yellow oil. dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate (62 g) was then dissolved in dimethyl sulfoxide (DMSO) (120 mL) and stirred with water (10 mL) in an oil bath (130-140° C.) for 3 hr. After cooling to room temperature, water was added to the mixture and the product was extracted with ether (Sometimes addition of EA is necessary to dissolve product completely). The ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light yellow solid. The crude product was recrystallized from MC/Hexane three times to afford 30.9 g (75% for two steps) of benzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)acetate as a white solid. m.p. 98-101° C. 1H NMR (200 MHz, CDCl3) δ 4.11 (2H, s), 5.19 (2H, s), 7.30-7.38 (5H, m). The mixture was then cooled in an ice bath the mixture was partitioned between ether and water washed with water twice dried with anhydrous magnesium sulfate filtered dried in vacuo

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

Procedure: 3-Chloro-2,4,5,6-tetrafluoropyridine (33.1 g, 178 mmol) and dibenzyl malonate (44.5 ml, 178 mmol) were dissolved in anhydrous DMF (360 ml) under nitrogen atmosphere. The mixture (142) was then cooled in an ice bath. To a stirred mixture, was portionwise added 60% sodium hydride (15.68 g, 392 mmol) during 2.5 hr. The mixture was then stirred in a water bath for ca. 15 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution and the mixture was partitioned between ether and water. Ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as an yellow oil. The crude product was then dissolved in DMSO (200 ml) and stirred with water (3.2 ml) in an oil bath (130˜140° C.) for 3 hr. After cooling to room temperature, water was added to the mixture and the product was extracted with ether. The ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light brown oil. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (1:9)) to afford 41.9 g (74% for two steps) of (3-chloro-2,5,6-trifluoro-pyridin-4-yl)-acetic acid benzyl ester as a white solid. m.p. 87-92° C.; 1H NMR (200 MHz, CDCl3) δδ 3.96 (2H, d, J=1.6 Hz), 5.19 (2H, s), 7.30-7.39 (5H, m). during 2.5 hr the mixture was partitioned between ether and water washed with water twice dried with anhydrous magnesium sulfate filtered evaporated in vacuo to give a crude product as an yellow oil the product was extracted with ether The ether layer was washed with water twice dried with anhydrous magnesium sulfate filtered evaporated in vacuo to give a light brown oil The crude product was purified by silica gel column chromatography (eluent, ether:hexane (1:9))

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

Procedure: A solution of dibenzyl malonate (20 g) in anhydrous THF (200 ml) was treated at 0° C. with sodium hydride (60% dispersion in mineral oil, 3.1 g). The mixture was allowed to warm to room temperature and stirred for 30 minutes under nitrogen. The mixture was then treated with a solution of N-(3-bromopropyl)phthalimide (20.5 g) in THF (100 ml) and heated at reflux for 12 hours. The reaction was then cooled, filtered, and the filtrate evaporated in vacuo. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous ammonium chloride (150 ml). The organic layer was washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate in hexane to yield the title compound (17.5 g, 50%) as a white solid. heated at reflux for 12 hours The reaction was then cooled filtered the filtrate evaporated in vacuo The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous ammonium chloride (150 ml) The organic layer was washed with water (100 ml), brine (100 ml) dried (MgSO4) filtered the filtrate evaporated in vacuo The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate in hexane

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

Procedure: Sodium hydride (60% dispersion in mineral oil, 4.4 g) was added to a solution of dibenzyl malonate (29.5 g) in THF (300 ml) and the mixture was stirred at room temperature for 30 min, then a solution of 1-bromo-3-chloropropane (10 ml) in THF (30 ml) was added dropwise. The solution was heated at reflux for 18 h, then cooled and evaporated in vacuo. The oily residue was dissolved in hexane (500 ml) and washed with water and brine, then dried (MgSO4) and evaporated to give a colourless oil. This oil was dissolved in acetone (300 ml) and sodium iodide (20 g) was added. The solution was stirred at room temperature for 18 h, then evaporated and the residue partitioned between water and hexane. The layers were separated and the organic layer was dried (MgSO4) and evaporated to give a pale yellow oil which was dissolved in dry DMF. Potassium succinimide (15 g) was added and the mixture was heated at 80° C. for 18 h. The mixture was cooled, poured into water (500 ml) and extracted with diethyl ether (3×200 ml). The ether layers were combined, washed with water, dried and evaporated. The residue was purified by column chromatography, eluting with diethyl ether, to give the title compound (9.65 g, 23%) as a colourless oil. The solution was heated at reflux for 18 h cooled evaporated in vacuo The oily residue was dissolved in hexane (500 ml) washed with water and brine dried (MgSO4) evaporated to give a colourless oil The solution was stirred at room temperature for 18 h evaporated the residue partitioned between water and hexane The layers were separated the organic layer was dried (MgSO4) evaporated to give a pale yellow oil which the mixture was heated at 80° C. for 18 h The mixture was cooled extracted with diethyl ether (3×200 ml) washed with water dried evaporated The residue was purified by column chromatography eluting with diethyl ether

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

Procedure: Dibenzyl malonate (28.43 g, 0.1 mole) was added dropwise over 1 hour to a stirred suspension of sodium hydride (3.15 g, 80% dispersion in oil; 0.105 mole) in dry tetrahydrofuran (100 ml) under nitrogen, the temperature being allowed to rise to 40° C. 2-Methoxyethyl bromide (13.9 g, 0.1 mole) was added to the resulting clear solution, which was stirred at room temperature for two hours, and then refluxed overnight. Water was added, and the mixture extracted with methylene chloride. The organic extract on washing with water, drying (MgSO4) and evaporation under vacuum gave a crude liquid (30.94 g). Chromatography on silica gel (700 g) eluting with a mixture of ether and hexane (2:8 by volume) gave 2-methoxyethyl-malonic acid dibenzyl ester as a colourless liquid (15.6 g). This was dissolved in dioxan (150 ml) and a solution of potassium hydroxide (2.55 g, 45.44 mmole) in water (40 ml) added at 0° C. with stirring. The mixture was stirred overnight at room temperature and the solvent was evaporated under vacuum. Water was added and the mixture was extracted with ether to remove unreacted diester. The aqueous phase was then acidified with 2N hydrochloric acid (50 ml) and extracted with ether. The organic extract on washing with water, drying (MgSO4) and evaporation under vacuum gave the mono-ester as a colourless oil (8.95 g, 78%). to rise to 40° C refluxed overnight the mixture extracted with methylene chloride The organic extract on washing with water drying (MgSO4) and evaporation under vacuum gave a crude liquid (30.94 g) Chromatography on silica gel (700 g) eluting with a mixture of ether and hexane (2:8 by volume)

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

Procedure: Dibenzyl malonate (28.43 g, 0.1 mole) was added dropwise over 1 hour to a stirred suspension of sodium hydride (3.15 g, 80% dispersion in oil; 0.105 mole) in dry tetrahydrofuran (100 ml) under nitrogen, the temperature being allowed to rise to 40° C. 2-Methoxyethyl bromide (13.9 g, 0.1 mole) was added to the resulting clear solution, which was stirred at room temperature for two hours, and then refluxed overnight. Water was added, and the mixture extracted with methylene chloride. The organic extract on washing with water, drying (MgSO4) and evaporation under vacuum gave a crude liquid (30.94 g). Chromatography on silica gel (700 g) eluting with a mixture of ether and hexane (2:8 by volume) gave 2-methoxyethyl-malonic acid dibenzyl ester as a colourless liquid (15.6 g). This was dissolved in dioxan (150 ml) and a solution of potassium hydroxide (2.55 g, 45.44 mmole) in water (40 ml) added at 0° C. with stirring. The mixture was stirred overnight at room temperature and the solvent was evaporated under vacuum. Water was added and the mixture was extracted with ether to remove unreacted diester. The aqueous phase was then acidified with 2N hydrochloric acid (50 ml) and extracted with ether. The organic extract on washing with water, drying (MgSO4) and evaporation under vacuum gave the mono-ester as a colourless oil (8.95 g, 78%). to rise to 40° C refluxed overnight the mixture extracted with methylene chloride The organic extract on washing with water drying (MgSO4) and evaporation under vacuum gave a crude liquid (30.94 g) Chromatography on silica gel (700 g) eluting with a mixture of ether and hexane (2:8 by volume)

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

Procedure: To a solution of dibenzyl malonate (2.99 ml, 11.9 mmol) in DMF (41 ml) was added sodium hydride in portions. The cloudy grey mixture was stirred at room temperature for 20 min after which time a clear solution resulted. The solution was further stirred at 120° C. for 20 min before adding a solution of methyl 1-methyl-2,4-dioxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate (2.82 g, 11.9 mmol) in DMF (41 ml). The resulting yellow solution was stirred at 120° C. for 3 hrs. The reaction mixture was cooled to room temperature, 2N HCl and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc 3×, the combined organics were washed with H2O (1×) followed by sat. NaCl (2×). The organic phase was then dried over MgSO4, filtered and concentrated to give a yellow solid. Purification was performed by ISCO using 10% to 50% Hex/EtOAc gradient, 40 g column to give 300 mg of a yellow solid. resulted The solution was further stirred at 120° C. for 20 min The resulting yellow solution was stirred at 120° C. for 3 hrs The reaction mixture was cooled to room temperature the layers were separated The aqueous layer was extracted with EtOAc 3× the combined organics were washed with H2O (1×) The organic phase was then dried over MgSO4 filtered concentrated to give a yellow solid Purification