1-trityloxybut-3-en-2-ol

反応条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a reactor with 1-(trityloxy)but-3-en-2-ol (41.6 g, 0.111 mol, 1.0 equiv.) was charged toluene (146 mL). The resulting solution was cooled to 0-5° C. and tetra-n-butylammonium hydrogen sulfate (7.52 g, 0.0222 mol, 0.20 equiv.) was charged. 4-(Chloroacetyl)morpholine (18.1 g, 0.111 mol, 1.00 equiv.) was added at 0-5° C. Sodium hydroxide (50% wt. in water; 88.6 g, 1.10 mol, 10 equiv.) was cooled to 15° C. and charged to the reaction mixture with T<10° C. The reaction mixture was stirred for 1 hr at T<15° C. and monitored for consumption of 1-(trityloxy)but-3-en-2-ol (target>99%). To the reaction mixture was charged 2-methoxy-2-methylpropane (146 mL) and water (146 mL) with T<20° C. The organics were washed with 18% aq. NaCl (73 mL) and sat. aq NH4Cl (21 mL). The organics were filtered over Celite (10.4 g) to remove particulates and rinsed with 2-methoxy-2-methylpropane (83 mL). The solvents were evaporated under vacuum T<30° C. to afford a white solid on standing (55.0 g, 98.7% yield accounting for residual solvents). 1H NMR (500 MHz, CDCl3) δ ppm 7.46-7.41 (m, 6H), 7.32-7.25 (m, 6H), 7.25-7.18 (m, 3H), 5.79-5.68 (m, 1H), 5.28 (d, J=17.0 Hz, 1H), 5.26 (d, J=10.1 Hz, 1H), 4.20 (d, J=12.7 Hz, 1H), 4.10 (d, J=12.7 Hz, 1H), 3.97-3.88 (m, 1H), 3.69-3.47 (m, 8H), 3.25 (dd, J=9.9, 6.5 Hz, 1H), 3.17 (dd, J=9.9, 4.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 167.84, 143.84, 134.84, 128.67, 127.78, 127.04, 119.06, 86.73, 81.07, 68.78, 66.78, 66.34, 45.94, 42.16. charged to the reaction mixture with T<10° C monitored for consumption of 1-(trityloxy)but-3-en-2-ol (target>99%) To the reaction mixture was charged 2-methoxy-2-methylpropane (146 mL) and water (146 mL) with T<20° C The organics were washed with 18% aq. NaCl (73 mL) and sat. aq NH4Cl (21 mL) The organics were filtered over Celite (10.4 g) to remove particulates rinsed with 2-methoxy-2-methylpropane (83 mL) The solvents were evaporated under vacuum T<30° C. to afford a white solid

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of tetrabutylammonium hydrogen sulfate (367 g, 1.08 mol, 0.1 equiv.) in toluene (4.63 kg) under nitrogen atmosphere was prepared and cooled down to 0° C. 50% aq. NaOH solution (9.09 kg) was slowly added with the temperature kept under 50° C. Crude mixture from Step 4-(2) (3.95 kg of 1-(trityloxy)but-3-en-2-ol in toluene, total weight 6.34 kg) was slowly added with temperature kept under 15° C. The reaction mixture was stirred for 15 min. tert-Butyl bromoacetate (1.01 kg, 5.19 mol, 0.43 equiv.) was added leading to the formation of a slurry. Water (1 kg) was added then tert-butyl bromoacetate (1.55 kg, 7.95 mol, 0.66 equiv) while maintaining temperature below 30° C. The reaction was left to stir overnight. The reaction was followed by TLC (Rf 0.60 in Heptane/EtOAc 20%). Water (9.72 kg) and 2-methoxy-2-methylpropane (10.4 kg) were added then the reaction mixture was successively washed with water (3.90 kg) and with saturated aq NaCl solution (0.63 kg). The organic phase was then concentrated under reduced pressure to generate a crude mixture (4.70 kg). 1H NMR (500 MHz, CDCl3) δ ppm 7.47 (dt, J=7.9, 3.9 Hz, 6H), 7.27-7.19 (m, 6H), 7.14 (dd, J=14.2, 6.9 Hz, 3H), 5.81-5.70 (m, 1H), 5.28 (d, J=17.2 Hz, 1H), 5.21 (d, J=9.9 Hz, 1H), 4.10-3.94 (m, 3H), 3.34 (dt, J=17.7, 8.8 Hz, 1H), 3.18 (dd, J=9.6, 5.3 Hz, 1H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 169.48, 143.95, 135.69, 128.69, 127.67, 126.86, 118.47, 86.62, 81.07, 80.74, 66.75, 66.41, 28.05. was prepared kept under 50° C kept under 15° C was added The reaction was left the reaction mixture was successively washed with water (3.90 kg) and with saturated aq NaCl solution (0.63 kg) The organic phase was then concentrated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of tetrabutylammonium hydrogen sulfate (367 g, 1.08 mol, 0.1 equiv.) in toluene (4.63 kg) under nitrogen atmosphere was prepared and cooled down to 0° C. 50% aq. NaOH solution (9.09 kg) was slowly added with the temperature kept under 50° C. Crude mixture from Step 4-(2) (3.95 kg of 1-(trityloxy)but-3-en-2-ol in toluene, total weight 6.34 kg) was slowly added with temperature kept under 15° C. The reaction mixture was stirred for 15 min. tert-Butyl bromoacetate (1.01 kg, 5.19 mol, 0.43 equiv.) was added leading to the formation of a slurry. Water (1 kg) was added then tert-butyl bromoacetate (1.55 kg, 7.95 mol, 0.66 equiv) while maintaining temperature below 30° C. The reaction was left to stir overnight. The reaction was followed by TLC (Rf 0.60 in Heptane/EtOAc 20%). Water (9.72 kg) and 2-methoxy-2-methylpropane (10.4 kg) were added then the reaction mixture was successively washed with water (3.90 kg) and with saturated aq NaCl solution (0.63 kg). The organic phase was then concentrated under reduced pressure to generate a crude mixture (4.70 kg). 1H NMR (500 MHz, CDCl3) δ ppm 7.47 (dt, J=7.9, 3.9 Hz, 6H), 7.27-7.19 (m, 6H), 7.14 (dd, J=14.2, 6.9 Hz, 3H), 5.81-5.70 (m, 1H), 5.28 (d, J=17.2 Hz, 1H), 5.21 (d, J=9.9 Hz, 1H), 4.10-3.94 (m, 3H), 3.34 (dt, J=17.7, 8.8 Hz, 1H), 3.18 (dd, J=9.6, 5.3 Hz, 1H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 169.48, 143.95, 135.69, 128.69, 127.67, 126.86, 118.47, 86.62, 81.07, 80.74, 66.75, 66.41, 28.05. was prepared kept under 50° C kept under 15° C was added The reaction was left the reaction mixture was successively washed with water (3.90 kg) and with saturated aq NaCl solution (0.63 kg) The organic phase was then concentrated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of triphenylmethyl chloride (3.31 kg, 11.87 mol, 0.99 equiv) in toluene (6.74 kg) at RT, was added but-3-ene-1,2-diol (1.06 kg, 12.02 mol, 1.0 equiv.). The reaction mixture was cooled down to 0° C. Triethylamine (2.72 kg, 26.91 mol, 2.24 equiv.) was slowly added to the reaction mixture while maintaining temperature below 5° C., followed by 4-dimethylaminopyridine (8.38 g, 0.068 mol, 5.71 mmol). The reaction mixture was allowed to warm up to 10° C. then heated to 40° C. The reaction mixture was stirred at 40° C. overnight. The reaction was followed by TLC (Rf 0.45 in Heptane/EtOAc 20%). The reaction mixture was cooled down to 26.5° C., filtered and the solids were rinsed with toluene (2.72 kg). The filtrate was successively washed with 28% aq. NH4Cl solution (3.38 kg) and saturated aq NaCl solution (1.26 kg). The organic phase was then concentrated under reduced pressure to afford an oil as a crude mixture 3.95 kg). 1H NMR (500 MHz, DMSO) δ ppm 7.42 (dd, J=8.3, 1.0 Hz, 6H), 7.33 (dd, J=10.5, 4.8 Hz, 6H), 7.30-7.19 (m, 3H), 5.94-5.83 (m, 1H), 5.25 (td, J=17.3, 1.8 Hz, 1H), 5.08 (td, J=10.9, 1.8 Hz, 1H), 2.99 (dd, J=8.9, 6.3 Hz, 1H), 2.84 (dd, J=8.9, 5.7 Hz, 1H); 13C NMR (125 MHz, DMSO) δ 144.35, 140.07, 128.78, 128.26, 127.39, 115.04, 86.25, 70.88, 68.27. while maintaining temperature below 5° C. to warm up to 10° C. then heated to 40° C The reaction mixture was cooled down to 26.5° C. filtered the solids were rinsed with toluene (2.72 kg) The filtrate was successively washed with 28% aq. NH4Cl solution (3.38 kg) and saturated aq NaCl solution (1.26 kg) The organic phase was then concentrated under reduced pressure

反応条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a reactor with 1-(trityloxy)but-3-en-2-ol (41.6 g, 0.111 mol, 1.0 equiv.) was charged toluene (146 mL). The resulting solution was cooled to 0-5° C. and tetra-n-butylammonium hydrogen sulfate (7.52 g, 0.0222 mol, 0.20 equiv.) was charged. 4-(Chloroacetyl)morpholine (18.1 g, 0.111 mol, 1.00 equiv.) was added at 0-5° C. Sodium hydroxide (50% wt. in water; 88.6 g, 1.10 mol, 10 equiv.) was cooled to 15° C. and charged to the reaction mixture with T<10° C. The reaction mixture was stirred for 1 hr at T<15° C. and monitored for consumption of 1-(trityloxy)but-3-en-2-ol (target>99%). To the reaction mixture was charged 2-methoxy-2-methylpropane (146 mL) and water (146 mL) with T<20° C. The organics were washed with 18% aq. NaCl (73 mL) and sat. aq NH4Cl (21 mL). The organics were filtered over Celite (10.4 g) to remove particulates and rinsed with 2-methoxy-2-methylpropane (83 mL). The solvents were evaporated under vacuum T<30° C. to afford a white solid on standing (55.0 g, 98.7% yield accounting for residual solvents). 1H NMR (500 MHz, CDCl3) δ ppm 7.46-7.41 (m, 6H), 7.32-7.25 (m, 6H), 7.25-7.18 (m, 3H), 5.79-5.68 (m, 1H), 5.28 (d, J=17.0 Hz, 1H), 5.26 (d, J=10.1 Hz, 1H), 4.20 (d, J=12.7 Hz, 1H), 4.10 (d, J=12.7 Hz, 1H), 3.97-3.88 (m, 1H), 3.69-3.47 (m, 8H), 3.25 (dd, J=9.9, 6.5 Hz, 1H), 3.17 (dd, J=9.9, 4.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 167.84, 143.84, 134.84, 128.67, 127.78, 127.04, 119.06, 86.73, 81.07, 68.78, 66.78, 66.34, 45.94, 42.16. charged to the reaction mixture with T<10° C monitored for consumption of 1-(trityloxy)but-3-en-2-ol (target>99%) To the reaction mixture was charged 2-methoxy-2-methylpropane (146 mL) and water (146 mL) with T<20° C The organics were washed with 18% aq. NaCl (73 mL) and sat. aq NH4Cl (21 mL) The organics were filtered over Celite (10.4 g) to remove particulates rinsed with 2-methoxy-2-methylpropane (83 mL) The solvents were evaporated under vacuum T<30° C. to afford a white solid

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of tetrabutylammonium hydrogen sulfate (367 g, 1.08 mol, 0.1 equiv.) in toluene (4.63 kg) under nitrogen atmosphere was prepared and cooled down to 0° C. 50% aq. NaOH solution (9.09 kg) was slowly added with the temperature kept under 50° C. Crude mixture from Step 4-(2) (3.95 kg of 1-(trityloxy)but-3-en-2-ol in toluene, total weight 6.34 kg) was slowly added with temperature kept under 15° C. The reaction mixture was stirred for 15 min. tert-Butyl bromoacetate (1.01 kg, 5.19 mol, 0.43 equiv.) was added leading to the formation of a slurry. Water (1 kg) was added then tert-butyl bromoacetate (1.55 kg, 7.95 mol, 0.66 equiv) while maintaining temperature below 30° C. The reaction was left to stir overnight. The reaction was followed by TLC (Rf 0.60 in Heptane/EtOAc 20%). Water (9.72 kg) and 2-methoxy-2-methylpropane (10.4 kg) were added then the reaction mixture was successively washed with water (3.90 kg) and with saturated aq NaCl solution (0.63 kg). The organic phase was then concentrated under reduced pressure to generate a crude mixture (4.70 kg). 1H NMR (500 MHz, CDCl3) δ ppm 7.47 (dt, J=7.9, 3.9 Hz, 6H), 7.27-7.19 (m, 6H), 7.14 (dd, J=14.2, 6.9 Hz, 3H), 5.81-5.70 (m, 1H), 5.28 (d, J=17.2 Hz, 1H), 5.21 (d, J=9.9 Hz, 1H), 4.10-3.94 (m, 3H), 3.34 (dt, J=17.7, 8.8 Hz, 1H), 3.18 (dd, J=9.6, 5.3 Hz, 1H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 169.48, 143.95, 135.69, 128.69, 127.67, 126.86, 118.47, 86.62, 81.07, 80.74, 66.75, 66.41, 28.05. was prepared kept under 50° C kept under 15° C was added The reaction was left the reaction mixture was successively washed with water (3.90 kg) and with saturated aq NaCl solution (0.63 kg) The organic phase was then concentrated under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of triphenylmethyl chloride (3.31 kg, 11.87 mol, 0.99 equiv) in toluene (6.74 kg) at RT, was added but-3-ene-1,2-diol (1.06 kg, 12.02 mol, 1.0 equiv.). The reaction mixture was cooled down to 0° C. Triethylamine (2.72 kg, 26.91 mol, 2.24 equiv.) was slowly added to the reaction mixture while maintaining temperature below 5° C., followed by 4-dimethylaminopyridine (8.38 g, 0.068 mol, 5.71 mmol). The reaction mixture was allowed to warm up to 10° C. then heated to 40° C. The reaction mixture was stirred at 40° C. overnight. The reaction was followed by TLC (Rf 0.45 in Heptane/EtOAc 20%). The reaction mixture was cooled down to 26.5° C., filtered and the solids were rinsed with toluene (2.72 kg). The filtrate was successively washed with 28% aq. NH4Cl solution (3.38 kg) and saturated aq NaCl solution (1.26 kg). The organic phase was then concentrated under reduced pressure to afford an oil as a crude mixture 3.95 kg). 1H NMR (500 MHz, DMSO) δ ppm 7.42 (dd, J=8.3, 1.0 Hz, 6H), 7.33 (dd, J=10.5, 4.8 Hz, 6H), 7.30-7.19 (m, 3H), 5.94-5.83 (m, 1H), 5.25 (td, J=17.3, 1.8 Hz, 1H), 5.08 (td, J=10.9, 1.8 Hz, 1H), 2.99 (dd, J=8.9, 6.3 Hz, 1H), 2.84 (dd, J=8.9, 5.7 Hz, 1H); 13C NMR (125 MHz, DMSO) δ 144.35, 140.07, 128.78, 128.26, 127.39, 115.04, 86.25, 70.88, 68.27. while maintaining temperature below 5° C. to warm up to 10° C. then heated to 40° C The reaction mixture was cooled down to 26.5° C. filtered the solids were rinsed with toluene (2.72 kg) The filtrate was successively washed with 28% aq. NH4Cl solution (3.38 kg) and saturated aq NaCl solution (1.26 kg) The organic phase was then concentrated under reduced pressure