dibenzyl chloromethyl phosphate

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 N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyri din-1-yl)piperidine-1-carboxamide, potassium salt, [Burgey et al. U.S. Pat. No. 6,953,790 B2] (1.00 g, 1.65 mmol) in anhydrous, degassed DMF (200 mL) at ambient temperature was added dibenzyl chloromethyl phosphate [Mäntylä et al. Tetrahedron Lett. 2002, 43, 3793] (0.54 g, 1.65 mmol). The resulting mixture was stirred at ambient temperature for 4 h, filtered, and purified by preparative HPLC on a C18 reversed phase column, eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 0:100:0.1. The product-containing fractions were poured into saturated aqueous NaHCO3 and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=857.7 (M+1). 6,953,790 B2] (1.00 g, 1.65 mmol) in anhydrous, degassed DMF (200 mL) at ambient temperature filtered purified by preparative HPLC on a C18 eluting with a gradient of H2O The product-containing fractions were poured into saturated aqueous NaHCO3 extracted with EtOAc (2×50 mL) The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: To a 100 mL round bottom flask were added dibenzyl (chloromethyl) phosphate (1.632 g, 4.99 mmol), (S)-benzyl 2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-hydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate, Compound 2, (2.1 g, 3.33 mmol) and 25 mL acetonitrile. The mixture was cooled in an ice bath. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.745 mL, 4.99 mmol) was added, and the mixture was stirred in the ice bath for 30 minutes, then at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude was purified first by flash chromatography using a 120 g silica column (0-50% ethyl acetate in heptanes), followed by RP-HPLC (60-100% acetonitrile in 0.1% TFA/water on Phenonemex C18 5 u column) to afford Compound 3 as a colorless oil (247 mg, 8%). The mixture was cooled in an ice bath at room temperature overnight the mixture was extracted with ethyl acetate twice The combined organic layers were washed with water and brine dried over anhydrous sodium sulfate concentrated The crude was purified first by flash chromatography

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

Procedure: To a 100 mL round bottom flask were added dibenzyl (chloromethyl) phosphate (1.632 g, 4.99 mmol), (S)-benzyl 2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-hydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate, Compound 2, (2.1 g, 3.33 mmol) and 25 mL acetonitrile. The mixture was cooled in an ice bath. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.745 mL, 4.99 mmol) was added, and the mixture was stirred in the ice bath for 30 minutes, then at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude was purified first by flash chromatography using a 120 g silica column (0-50% ethyl acetate in heptanes), followed by RP-HPLC (60-100% acetonitrile in 0.1% TFA/water on Phenonemex C18 5 u column) to afford Compound 3 as a colorless oil (247 mg, 8%). The mixture was cooled in an ice bath at room temperature overnight the mixture was extracted with ethyl acetate twice The combined organic layers were washed with water and brine dried over anhydrous sodium sulfate concentrated The crude was purified first by flash chromatography

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

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

Procedure: (S)-5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)-2-methylpentanoic acid (Example 47, 50 mg, 0.090 mmol) and [dibenzyl chloromethyl phosphate (32.5 mg, 0.1 mmol) were stirred in DMF at RT LCMS-80% done at 1 hr Stirred at RT ON-95% done, trace SM and trace mono-de-benzylated side prod.(+) 714 Added 800 μL ACN and 200 μL water Purified on HPLC C18 20-100% ACN/water 1% NH4OH 40 mL/min over 10 min Conc. on vac at 30° C.—no degradation. To give (S)-((bis(benzyloxy)phosphoryl)oxy)methyl 5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-methylpentanoate Purified on HPLC 20-100% ACN/water 1% NH4OH 40 mL/min over 10 min Conc. on vac at 30° C.—no degradation

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

Procedure: To a stirred solution of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyri din-1-yl)piperidine-1-carboxamide, potassium salt, [Burgey et al. U.S. Pat. No. 6,953,790 B2] (1.00 g, 1.65 mmol) in anhydrous, degassed DMF (200 mL) at ambient temperature was added dibenzyl chloromethyl phosphate [Mäntylä et al. Tetrahedron Lett. 2002, 43, 3793] (0.54 g, 1.65 mmol). The resulting mixture was stirred at ambient temperature for 4 h, filtered, and purified by preparative HPLC on a C18 reversed phase column, eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 0:100:0.1. The product-containing fractions were poured into saturated aqueous NaHCO3 and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=857.7 (M+1). 6,953,790 B2] (1.00 g, 1.65 mmol) in anhydrous, degassed DMF (200 mL) at ambient temperature filtered purified by preparative HPLC on a C18 eluting with a gradient of H2O The product-containing fractions were poured into saturated aqueous NaHCO3 extracted with EtOAc (2×50 mL) The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: To a 100 mL round bottom flask were added dibenzyl (chloromethyl) phosphate (1.632 g, 4.99 mmol), (S)-benzyl 2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-hydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate, Compound 2, (2.1 g, 3.33 mmol) and 25 mL acetonitrile. The mixture was cooled in an ice bath. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.745 mL, 4.99 mmol) was added, and the mixture was stirred in the ice bath for 30 minutes, then at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude was purified first by flash chromatography using a 120 g silica column (0-50% ethyl acetate in heptanes), followed by RP-HPLC (60-100% acetonitrile in 0.1% TFA/water on Phenonemex C18 5 u column) to afford Compound 3 as a colorless oil (247 mg, 8%). The mixture was cooled in an ice bath at room temperature overnight the mixture was extracted with ethyl acetate twice The combined organic layers were washed with water and brine dried over anhydrous sodium sulfate concentrated The crude was purified first by flash chromatography