2-diethoxyphosphorylacetamide

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

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

Procedure: To a solution of diethyl carbamoylmethylphosphonate (12.7 g) and potassium tert-butoxide (13.9 g) in tetrahydrofuran (400 ml) were added a solution of (2R,4R)-1-allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-{2-(4-formylimidazol-1-yl)ethyl}pyrrolidine (24 g) in tetrahydrofuran (50 ml) at 45° C. After stirring for 1 hour, to the reaction mixture were added water (3 ml). Evaporation of the solvent gave a residue, which was dissolved in a mixture of ethyl acetate (500 ml) and water (50 ml). The organic layer was separated, washed in turn with water (50 ml×2) and brine (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (500 ml) eluting with a mixture of dichloromethane and methanol (10:1) to give (2R,4R)-1-allyloxycarbonyl-4-tert-butyl-dimethylsilyloxy-2-[2-{4-(2-carbamoylethenyl)imidazol-1-yl}ethyl]pyrrolidine (13.87 g). Evaporation of the solvent gave a residue, which The organic layer was separated washed in turn with water (50 ml×2) and brine (50 ml×2) dried over magnesium sulfate Evaporation of the solvent gave an oil, which was chromatographed on silica gel (500 ml) eluting with a mixture of dichloromethane and methanol (10:1)

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

Procedure: This compound was prepared in an analogous manner to Example 27d with the replacement of 6-chloro-1-indanone and diethyl carbamoylmethylphosphonate with 7-fluoro-1-tetralone (7.76 g, 0.05 mol) and diethyl(cyclopropylcarbamoyl)methylphosphonate (11.1 g, 0.05 mol). Chromatography on Silica gel using ethyl acetate:hexanes (1:2) as eluent gave 4.38 g (37%) of (E)-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide, m.p., 122.8°-123.3° C.; NMR (DMSO-d6): d 8.00 (d, J=4.0 Hz, 1H), 7.32 (dd, J=11.2 Hz, 1H), 7.04-7.23 (m, 2H), 6.33 (s, 1H), 3.06 (m,2H), 2.69 (m, 3H), 1.70 (m, 2H), 0.66 (m, 2H), 0.40 (m, 2H); steady-state nOe: irradiation at 6.39 d, observed significant nOe at 7.32 d.

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

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

Procedure: To a solution of dimethyl sulfoxide (49.9 ml, 703 mmol) in methylene chloride (1.1 l) was added oxalyl chloride (32.1 ml, 376 mmol) at -70° C., and the reaction mixture stirred for 30 minutes, treated with a pre-cooled (-70° C.) solution of (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine(115.3 g, 251 mmol) in methylene chloride (400 ml), and stirred for 30 minutes. The mixture was treated with triethylamine (174.9 ml, 1.25 mol), stirred for 30 minutes, and stirred for additional 30 minutes after removing an ice-bath. The mixture was poured into water (500 ml), the organic layer washed with lM sodium dihydrogen phosphate (500 ml) and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. A solution of the obtained residue and 2-(diethylphosphono)acetamide (63.6 g, 326 mmol) in tetrahydrofuran (1.6 l) was treated with 60% sodium hydride (11 g, 275 mmol) under ice-cooling, and the reaction mixture stirred for 30 minutes, and concentrated. The residue was dissolved in ethyl acetate (1.5 l), washed successively with water (1 l and 500 ml) and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residual solid was collected by filtration after addition of diisopropyl ether (600 ml), recrystallized from a mixture of ethyl acetate (700 ml) and hexane (700 ml) to give the title compound (79.2 g), and the mother liquor was purified by flash column chromatography on silica gel (Wakogel® C-300, 400 ml, elution with ethyl acetate) to give a second crop (combined weight 89.4 g, 71.5% total yield). treated with stirred for 30 minutes stirred for 30 minutes stirred for additional 30 minutes after removing an ice-bath The mixture was poured into water (500 ml) the organic layer washed with lM sodium dihydrogen phosphate (500 ml) and saturated sodium bicarbonate dried over anhydrous sodium sulfate concentrated in vacuo cooling the reaction mixture stirred for 30 minutes concentrated The residue was dissolved in ethyl acetate (1.5 l) washed successively with water (1 l and 500 ml) and saturated aqueous sodium chloride dried over anhydrous sodium sulfate concentrated The residual solid was collected by filtration after addition of diisopropyl ether (600 ml) recrystallized from a mixture of ethyl acetate (700 ml) and hexane (700 ml)

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

Procedure: To a solution of dimethyl sulfoxide (49.9 ml, 703 mmol) in methylene chloride (1.1 l) was added oxalyl chloride (32.1 ml, 376 mmol) at -70° C., and the reaction mixture stirred for 30 minutes, treated with a pre-cooled (-70° C.) solution of (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine(115.3 g, 251 mmol) in methylene chloride (400 ml), and stirred for 30 minutes. The mixture was treated with triethylamine (174.9 ml, 1.25 mol), stirred for 30 minutes, and stirred for additional 30 minutes after removing an ice-bath. The mixture was poured into water (500 ml), the organic layer washed with lM sodium dihydrogen phosphate (500 ml) and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. A solution of the obtained residue and 2-(diethylphosphono)acetamide (63.6 g, 326 mmol) in tetrahydrofuran (1.6 l) was treated with 60% sodium hydride (11 g, 275 mmol) under ice-cooling, and the reaction mixture stirred for 30 minutes, and concentrated. The residue was dissolved in ethyl acetate (1.5 l), washed successively with water (1 l and 500 ml) and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residual solid was collected by filtration after addition of diisopropyl ether (600 ml), recrystallized from a mixture of ethyl acetate (700 ml) and hexane (700 ml) to give the title compound (79.2 g), and the mother liquor was purified by flash column chromatography on silica gel (Wakogel® C-300, 400 ml, elution with ethyl acetate) to give a second crop (combined weight 89.4 g, 71.5% total yield). treated with stirred for 30 minutes stirred for 30 minutes stirred for additional 30 minutes after removing an ice-bath The mixture was poured into water (500 ml) the organic layer washed with lM sodium dihydrogen phosphate (500 ml) and saturated sodium bicarbonate dried over anhydrous sodium sulfate concentrated in vacuo cooling the reaction mixture stirred for 30 minutes concentrated The residue was dissolved in ethyl acetate (1.5 l) washed successively with water (1 l and 500 ml) and saturated aqueous sodium chloride dried over anhydrous sodium sulfate concentrated The residual solid was collected by filtration after addition of diisopropyl ether (600 ml) recrystallized from a mixture of ethyl acetate (700 ml) and hexane (700 ml)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 400 ml of 25% aqueous ammonia is dissolved 100 g (0.446 mol) of ethyl diethylphosphonoacetate at an temperature of not higher than 10° C. The solution is allowed to stand overnight at an temperature of not higher than 15° C. and concentrated under reduced pressure. To the residue is added 25 ml of toluene and the water is azeotropically removed off under reduced pressure. To the residue is added 300 ml of toluene and 100 ml is azeotropically removed off under atmospheric pressure for complete dehydration. The residual solution is cooled and seed crystals are added at 50° C. for crystallization. After cooling to 5° C., the crystals are collected by filtration. The crystals are washed with 100 ml of toluene and dried in vacuo overnight to give 76.7 g of diethylphosphono-acetamide (a carbamoyl-containing Wittig reagent) (Yield 88.0%). of not higher than 15° C. and concentrated under reduced pressure To the residue is added 25 ml of toluene the water is azeotropically removed off under reduced pressure To the residue is added 300 ml of toluene and 100 ml is azeotropically removed off under atmospheric pressure for complete dehydration The residual solution is cooled seed crystals are added at 50° C. for crystallization the crystals are collected by filtration The crystals are washed with 100 ml of toluene dried in vacuo overnight

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

Procedure: To a solution of diethyl carbamoylmethylphosphonate (12.7 g) and potassium tert-butoxide (13.9 g) in tetrahydrofuran (400 ml) were added a solution of (2R,4R)-1-allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-{2-(4-formylimidazol-1-yl)ethyl}pyrrolidine (24 g) in tetrahydrofuran (50 ml) at 45° C. After stirring for 1 hour, to the reaction mixture were added water (3 ml). Evaporation of the solvent gave a residue, which was dissolved in a mixture of ethyl acetate (500 ml) and water (50 ml). The organic layer was separated, washed in turn with water (50 ml×2) and brine (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (500 ml) eluting with a mixture of dichloromethane and methanol (10:1) to give (2R,4R)-1-allyloxycarbonyl-4-tert-butyl-dimethylsilyloxy-2-[2-{4-(2-carbamoylethenyl)imidazol-1-yl}ethyl]pyrrolidine (13.87 g). Evaporation of the solvent gave a residue, which The organic layer was separated washed in turn with water (50 ml×2) and brine (50 ml×2) dried over magnesium sulfate Evaporation of the solvent gave an oil, which was chromatographed on silica gel (500 ml) eluting with a mixture of dichloromethane and methanol (10:1)

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

Procedure: This compound was prepared in an analogous manner to Example 27d with the replacement of 6-chloro-1-indanone and diethyl carbamoylmethylphosphonate with 7-fluoro-1-tetralone (7.76 g, 0.05 mol) and diethyl(cyclopropylcarbamoyl)methylphosphonate (11.1 g, 0.05 mol). Chromatography on Silica gel using ethyl acetate:hexanes (1:2) as eluent gave 4.38 g (37%) of (E)-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide, m.p., 122.8°-123.3° C.; NMR (DMSO-d6): d 8.00 (d, J=4.0 Hz, 1H), 7.32 (dd, J=11.2 Hz, 1H), 7.04-7.23 (m, 2H), 6.33 (s, 1H), 3.06 (m,2H), 2.69 (m, 3H), 1.70 (m, 2H), 0.66 (m, 2H), 0.40 (m, 2H); steady-state nOe: irradiation at 6.39 d, observed significant nOe at 7.32 d.