1-chloro-4-dichlorophosphoryloxybenzene

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: 5'-O-Acetyl-3'-azido-3'-deoxythymidine was reacted with 5 equivalents of 1,2,4-triazole and two equivalents of 4-chlorophenyl dichlorophosphate in dry pyridine at ambient temperature for 10 days. Silica gel chromatography of the crude product using 1:1 EtOAc/hexane (v/v) followed by combination and evaporation of the appropriate fractions yielded an oil. Crystallization from EtOAc afforded the title compound as a solid 2.7 g (7.5 mMol; 60%); m.p.=143°-145° C. UV (nm): at pH 1λmax =324,245,215 (ε=9300, 10000, 20500), λmin =282,233 (ε=2100,8200); at pH 13λmax =276 (ε=6000), λmin =242 (ε=2000), H1NMR (DMSO-d6) δ9.34, 8.40(2s,2H, triazolyl), δ8.23(s,1H,H6), δ6.12(t, 1H, H1', J=6.16 Hz), β4.48-4.17(m, 4H, H3', H4', H5'), δ2.35(s, 3H, 5'-acetyl), δ2.07(s, 3H, 5CH3). followed by combination and evaporation of the appropriate fractions yielded an oil Crystallization from EtOAc

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

Procedure: 5'-O-Acetyl-3'-azido-3'-deoxythymidine was reacted with 5 equivalents of 1,2,4-triazole and two equivalents of 4-chlorophenyl dichlorophosphate in dry pyridine at ambient temperature for 10 days. Silica gel chromatography of the crude product using 1:1 EtOAc/hexane (v/v) followed by combination and evaporation of the appropriate fractions yielded an oil. Crystallization from EtOAc afforded the title compound as a solid 2.7 g (7.5 mMol; 60%); m.p.=143°-145° C. UV (nm): at pH 1λmax =324,245,215 (ε=9300, 10000, 20500), λmin =282,233 (ε=2100,8200); at pH 13λmax =276 (ε=6000), λmin =242 (ε=2000), H1NMR (DMSO-d6) δ9.34, 8.40(2s,2H, triazolyl), δ8.23(s,1H,H6), δ6.12(t, 1H, H1', J=6.16 Hz), β4.48-4.17(m, 4H, H3', H4', H5'), δ2.35(s, 3H, 5'-acetyl), δ2.07(s, 3H, 5CH3). followed by combination and evaporation of the appropriate fractions yielded an oil Crystallization from EtOAc

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

Procedure: 5'-O-Acetyl-3'-azido-3'-deoxythymidine was reacted with 5 equivalents of 1,2,4-triazole and two equivalents of 4-chlorophenyl dichlorophosphate in dry pyridine at ambient temperature for 10 days. Silica gel chromatography of the crude product using 1:1 EtOAc/hexane (v/v) followed by combination and evaporation of the appropriate fractions yielded an oil. Crystallization from EtOAc afforded the title compound as a solid 2.7 g (7.5 mMol; 60%); m.p.=143°-145° C. UV (nm): at pH 1λmax =324,245,215 (ε=9300, 10000, 20500), λmin =282,233 (ε=2100,8200); at pH 13λmax =276 (ε=6000), λmin =242 (ε=2000), H1NMR (DMSO-d6) δ9.34, 8.40(2s,2H, triazolyl), δ8.23(s,1H,H6), δ6.12(t, 1H, H1', J=6.16 Hz), β4.48-4.17(m, 4H, H3', H4', H5'), δ2.35(s, 3H, 5'-acetyl), δ2.07(s, 3H, 5CH3). followed by combination and evaporation of the appropriate fractions yielded an oil Crystallization from EtOAc

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

Procedure: To a solution of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-cyclopropylmethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carbonitrile (0.42 g) in pyridine (5 mL) were added 4-chlorophenyl phosphorodichloridate (0.5 mL) and 3-nitro-1,2,4 triazole (0.15 g). After heating (Tb=50° C.) for 3 h, the reaction was diluted with ethyl acetate. The organic solution was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was dissolved in THF (10 mL) and ethanolamine (1.0 mL). After 3 h, the reaction was concentrated. This residue was purified by flash chromatography using a FlashMaster™ yielding 0.22 g, ES (M+H)+=529. The organic solution was washed with saturated NaHCO3 and brine dried (Na2SO4) filtered concentrated The residue was dissolved in THF (10 mL) the reaction was concentrated This residue was purified by flash chromatography yielding 0.22 g, ES (M+H)+=529

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

Procedure: To a solution of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-cyclopropylmethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carbonitrile (0.42 g) in pyridine (5 mL) were added 4-chlorophenyl phosphorodichloridate (0.5 mL) and 3-nitro-1,2,4 triazole (0.15 g). After heating (Tb=50° C.) for 3 h, the reaction was diluted with ethyl acetate. The organic solution was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was dissolved in THF (10 mL) and ethanolamine (1.0 mL). After 3 h, the reaction was concentrated. This residue was purified by flash chromatography using a FlashMaster™ yielding 0.22 g, ES (M+H)+=529. The organic solution was washed with saturated NaHCO3 and brine dried (Na2SO4) filtered concentrated The residue was dissolved in THF (10 mL) the reaction was concentrated This residue was purified by flash chromatography yielding 0.22 g, ES (M+H)+=529

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

Procedure: To a solution of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-cyclopropylmethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carbonitrile (0.42 g) in pyridine (5 mL) were added 4-chlorophenyl phosphorodichloridate (0.5 mL) and 3-nitro-1,2,4 triazole (0.15 g). After heating (Tb=50° C.) for 3 h, the reaction was diluted with ethyl acetate. The organic solution was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was dissolved in THF (10 mL) and ethanolamine (1.0 mL). After 3 h, the reaction was concentrated. This residue was purified by flash chromatography using a FlashMaster™ yielding 0.22 g, ES (M+H)+=529. The organic solution was washed with saturated NaHCO3 and brine dried (Na2SO4) filtered concentrated The residue was dissolved in THF (10 mL) the reaction was concentrated This residue was purified by flash chromatography yielding 0.22 g, ES (M+H)+=529

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

Procedure: Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.090 M) of the commercially available 4-chlorophenyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1.1:1* mixture of diastereoisomers. 31P NMR (400 MHz, CDCl3): δ: 9.52 and 9.28*

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

Procedure: Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.090 M) of 4-chlorophenyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1:1* mixture of diastereoisomers.