1-chloro-1-(1-chloroethoxy)ethane

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

Procedure: The epoxide of the cis-cinnamate is then regioselectively opened to produce 3-phenyl isoserinamide. This 3-phenyl isoserinamide is hydrolyzed to produce 3-phenyl-isoserine, which in turn is reacted with benzoyl chloride to form N-benzoyl-3-phenyl-isoserine. Next, the N-benzoyl-3-phenyl-isoserine is reacted with 1-chloroethyl ether and a tertiary amine in methylene chloride to form N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine. Then, N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine is reacted with the alcohol shown below: ##STR8## This resulting intermediate is converted to taxol by hydrolytically removing the 1-ethoxyethyl and triethylsilyl protecting groups.

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

Procedure: To a solution of 6-chloro-5-hydroxy-nicotinonitrile (1.12 g, 7.24 mmol) in DCM (15 mL) was added N,N-diisopropyl ethylamine (1.57 mL, 9.05 mmol) followed by the addition of chloro-methyl methylether (0.66 mL, 8.69 mmol) slowly at 0° C. After overnight at room temperature, the reaction mixture was washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (0.68 g, 50%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 5.42 (s, 2H), 3.40 (s, 3H); MS (ES) m/z: 199 (M+1)+. the reaction mixture was washed with saturated NaHCO3 (10 mL) and brine (10 mL) dried over Na2SO4 filtered concentrated to give yellow oil Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution

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

Procedure: To a solution of 6-chloro-5-hydroxy-nicotinonitrile (1.12 g, 7.24 mmol) in DCM (15 mL) was added N,N-diisopropyl ethylamine (1.57 mL, 9.05 mmol) followed by the addition of chloro-methyl methylether (0.66 mL, 8.69 mmol) slowly at 0° C. After overnight at room temperature, the reaction mixture was washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (0.68 g, 50%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 5.42 (s, 2H), 3.40 (s, 3H); MS (ES) m/z: 199 (M+1)+. the reaction mixture was washed with saturated NaHCO3 (10 mL) and brine (10 mL) dried over Na2SO4 filtered concentrated to give yellow oil Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution

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

Procedure: To a solution of 6-chloro-5-hydroxy-nicotinonitrile (1.12 g, 7.24 mmol) in DCM (15 mL) was added N,N-diisopropyl ethylamine (1.57 mL, 9.05 mmol) followed by the addition of chloro-methyl methylether (0.66 mL, 8.69 mmol) slowly at 0° C. After overnight at room temperature, the reaction mixture was washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (0.68 g, 50%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (d, J=2.0 Hz, 1 H), 8.14 (d, J=2.0 Hz, 1 H), 5.42 (s, 2 H), 3.40 (s, 3H); MS (ES) m/z: 199 (M+1)+. the reaction mixture was washed with saturated NaHCO3 (10 mL) and brine (10 mL) dried over Na2SO4 filtered concentrated to give yellow oil Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution

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

Procedure: The epoxide of the cis-cinnamate is then regioselectively opened to produce 3-phenyl isoserinamide. This 3-phenyl isoserinamide is hydrolyzed to produce 3-phenyl-isoserine, which in turn is reacted with benzoyl chloride to form N-benzoyl-3-phenyl-isoserine. Next, the N-benzoyl-3-phenyl-isoserine is reacted with 1-chloroethyl ether and a tertiary amine in methylene chloride to form N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine. Then, N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine is reacted with the alcohol shown below: ##STR8## This resulting intermediate is converted to taxol by hydrolytically removing the 1-ethoxyethyl and triethylsilyl protecting groups.

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

Procedure: To a solution of 6-chloro-5-hydroxy-nicotinonitrile (1.12 g, 7.24 mmol) in DCM (15 mL) was added N,N-diisopropyl ethylamine (1.57 mL, 9.05 mmol) followed by the addition of chloro-methyl methylether (0.66 mL, 8.69 mmol) slowly at 0° C. After overnight at room temperature, the reaction mixture was washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (0.68 g, 50%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 5.42 (s, 2H), 3.40 (s, 3H); MS (ES) m/z: 199 (M+1)+. the reaction mixture was washed with saturated NaHCO3 (10 mL) and brine (10 mL) dried over Na2SO4 filtered concentrated to give yellow oil Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution