ethyl 2-diethoxyphosphoryl-2-fluoroacetate

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: To a stirred solution of tert-butyl 3-(2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-formyl-4-pyridinyl)-1-piperidinecarboxylate (0.500 g, 5 0.851 mmol), triethyl-2-fluoro-2-phosphonoacetate (0.350 mL, 1.701 mmol) and anhydrous lithium chloride (0.072 g, 1.701 mmol) in acetonitrile (20 mL) was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.250 mL, 1.701 mmol). The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue (liquid) was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1-1/1) to give tert-butyl 3-(2-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-6-fluoro-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate as a form (0.261 g, 49%). concentrated under reduced pressure The residue was extracted with ethyl acetate and water The separated organic phase was washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The resulting residue (liquid) was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1-1/1)

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

Procedure: 382 mg (9.5 mmol) of sodium hydride are added to a solution of 1.9 mL (9.5 mmol) of commercial triethyl 2-fluoro-2-phosphonoacetate in 10 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 40 minutes. A solution of 803 mg of 3′-methylaminobiphenyl-4-carbaldehyde prepared as described in Example 5b (3.8 mmol) in 8 mL of tetrahydrofuran is then added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction medium is poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and the residue (2.2 g) is purified by chromatography on a column of silica eluted with an 85/15 heptane/ethyl acetate mixture. 936 mg (82%) of ethyl 2-fluoro-3-(3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of a yellow oil. is then added dropwise The reaction mixture is stirred at room temperature overnight extracted with ethyl acetate washed with water dried over sodium sulfate The solvent is evaporated off the residue (2.2 g) is purified by chromatography on a column of silica eluted with an 85/15 heptane/ethyl acetate mixture

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

Procedure: Compound 9 was prepared using the methods described in Scheme AE. Intermediate AE1 was prepared as follows. Lithium chloride (0.39 g) was added to a solution cooled to 0° C. of triethyl-2-fluoro-2-phophonoacetate (1.84 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.15 mL) in acetonitrile (6 mL). The mixture was stirred until the lithium chloride was dissolved to form a homogeneous solution. N-Boc-piperidine-4-carboxaldehyde (1.61 g) in acetonitrile (2.0 mL) was added to the mixture and stirred for 24 h at room temperature. The reaction was quenched with saturated ammonium chloride (20 mL), diluted with ethyl acetate (150 mL), and washed with saturated sodium chloride (50 mL). The organic layer was dried (magnesium sulfate) and evaporated to yield 2.27 g of (E)-ethyl 2-fluoro-3-(N-Boc-piperdin-4-yl)propenoate (AE1). AE1 was carried forward as shown in Scheme AA to afford 9. Compound 9 was isolated as white flakes: mp 147-150° C.; MS m/e 515 (MH+). Anal. calcd. for C25H31FN6O5•2.3 HCl•1.6 H2O (627.25): C, 47.88; H, 5.87; N, 13.40; Cl, 13.00. Found: C, 48.26; H, 6.02; N, 12.90; Cl, 12.74. Intermediate AE1 was prepared was dissolved to form a homogeneous solution The reaction was quenched with saturated ammonium chloride (20 mL) diluted with ethyl acetate (150 mL) washed with saturated sodium chloride (50 mL) The organic layer was dried (magnesium sulfate) evaporated

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

Procedure: 450 mg (60%, 12 mmol) of sodium hydride was suspended in 10 ml of N,N-dimethylformamide. 3.3.g (14 mmol) of ethyl 2-fluoro-diethylphosphonoacetate was dropped into the suspension under cooling with ice. The obtained mixture was stirred under cooling with ice for 30 minutes, followed by the addition of 2.0 g (9.2 mmol) of 1-[1-(1-methylethyl)-1,2,3,4-tetrahydro-quinolin-6-yl)ethanone. The obtained mixture was stirred under cooling with ice for one hour, followed by the addition of an aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography to give 2.3 g of the title compound as a colorless oil. under cooling with ice under cooling with ice for 30 minutes The obtained mixture was stirred under cooling with ice for one hour The obtained mixture was extracted with ethyl acetate the organic phase was washed with a saturated aqueous solution of common salt dried over anhydrous magnesium sulfate concentrated in a vacuum The residue was purified by silica gel column chromatography

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (60 wt. %, 83.6 g, 2.09 mol) was added to a mixture of triethyl 2-fluoro-2-phosphonoacetate (506 g, 2.09 mol) and THF (3.0 l) with ice-cooling, and the mixture was stirred for 2 hours. A THF (600 ml) solution of 3-quinuclidinone (238 g, 1.90 mol) was added and the mixture was stirred at room temperature for 5 days. Water (500 ml) was added to the reaction mixture and the mixture was concentrated under a reduced pressure. Water (2.5 l) was added to the residue, and then the reaction product was extracted with chloroform (1.5 l×2). The extract was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. THF (1.0 l) was added to the resulting yellow oily material, and then a borane-THF complex (1.0M THF solution, 2.1 l, 2.1 mol) was added dropwise with ice-cooling spending 2.5 hours. After additional 0.5 hour of stirring, water (400 ml) was added to the reaction mixture and the mixture was concentrated under a reduced pressure. Ethyl acetate was added to the resulting residue, the mixture was washed with water and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure. The resulting residue was washed with hexane (400 ml) and dried under a reduced pressure. Ethanol (2.8 l) was added to the resulting brown solid (402 g) and then, while heating at 50° C., sodium hydride (60 wt. %, 4.24 g, 106 mmol) was added, and the mixture was stirred for 7 hours. After spontaneous cooling, acetic acid (5.4 ml) was added to the reaction mixture, and the mixture was concentrated under a reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure. Ethanol (1.2 l) was added to the resulting brown solid, and the mixture was stirred for 20 minutes. The insoluble matter was removed by filtration and then the resulting filtrate was concentrated under a reduced pressure to give the title compound (304 g, E/Z mixture) as a brown oil. cooling the mixture was stirred at room temperature for 5 days the mixture was concentrated under a reduced pressure Water (2.5 l) was added to the residue the reaction product was extracted with chloroform (1.5 l×2) The extract was washed with saturated sodium chloride aqueous solution dried over anhydrous magnesium sulfate concentrated under a reduced pressure THF (1.0 l) was added to the resulting yellow oily material cooling spending 2.5 hours After additional 0.5 hour of stirring the mixture was concentrated under a reduced pressure Ethyl acetate was added to the resulting residue the mixture was washed with water and saturated sodium chloride aqueous solution in that order dried over anhydrous magnesium sulfate concentrated under a reduced pressure The resulting residue was washed with hexane (400 ml) dried under a reduced pressure Ethanol (2.8 l) was added to the resulting brown solid (402 g) the mixture was stirred for 7 hours the mixture was concentrated under a reduced pressure Ethyl acetate was added to the residue the mixture was washed with water and saturated sodium chloride aqueous solution in that order dried over anhydrous magnesium sulfate concentrated under a reduced pressure Ethanol (1.2 l) was added to the resulting brown solid the mixture was stirred for 20 minutes The insoluble matter was removed by filtration the resulting filtrate was concentrated under a reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 45.31 g (826 mmol) of propargyl alcohol and 0.94 g (4.1 mmol of tetraethyl titanate were added to 10.00 g (41.3 mmol) of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate, and heated under reflux at 100° C. for 10 hours. Subsequently, ethanol and propargyl alcohol were evaporated away under reduced pressure at a temperature falling within a range of from 70° C. to 100° C., taking 10 hours, and then the residue was cooled down to room temperature. 0.18 g of water was added to the reaction liquid, the formed precipitate was filtered away, and the filtrate was purified through silica gel column chromatography (ethyl acetate/hexane=1/1 for elution) to give 8.96 g (yield 86%) of the intended 2-propynyl 2-(diethoxyphosphoryl)-2-fluoroacetate. The obtained 2-propynyl 2-(diethoxyphosphoryl)-2-fluoroacetate was analyzed through 1H-NMR to confirm the structure thereof. The results are shown below. heated Subsequently, ethanol and propargyl alcohol were evaporated away under reduced pressure at a temperature falling within a range of from 70° C. to 100° C. the residue was cooled down to room temperature 0.18 g of water was added to the reaction liquid the formed precipitate was filtered away the filtrate was purified through silica gel column chromatography (ethyl acetate/hexane=1/1 for elution)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.00 g (24.0 mmol) of triethyl phosphite and 4.45 g (24.0 mmol) of ethyl bromofluoroacetate (purchased from PCR Inc. Gainesville, Fla.) was heated to 150° C. for 4 h under argon. The contents of the flask were cooled to RT and then distilled under vacuum (0.5 mm Hg) to provide 4.5 g (77%) of title compound as a colorless oil. The contents of the flask were cooled to RT distilled under vacuum (0.5 mm Hg)