9H-fluoren-9-ylmethyl N-(2,2-dimethoxyethylsulfamoyl)carbamate

Conditions: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (10.00 g, 29.23 mmol) in DCM (160 mL) was added methanesulfonic acid (MeSO3H, 8.46 g, 88.04 mmol) and triethylsilane (Et3SiH, 8.37 g, 71.96 mmol) at ambient temperature over 10 minutes to give a slurry. Solid 9H-fluoren-9-ylmethyl{[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (12.25 g, 30.14 mmol) was added portionwise (1 g/3-4 min; over 1 h) while maintaining the internal temperature at less than about 20° C. using a water bath. After the addition, the resulting mixture was stirred at about 13 to 22° C. for 3 days. Additional triethylsilane (Et3SiH, 0.1755 g, 1.51 mmol) and 9H-fluoren-9-ylmethyl{[(2,2-dimethoxyethy)amino]sulfonyl}carbamate (0.3082 g, 0.76 mmol) were added and the resulting mixture was stirred at ambient temperature for an additional 23 h. Isopropyl alcohol (IPA, 15 mL) was added and the resulting mixture was stirred at ambient temperature for 1 h. Heptane (100 mL) was added and the mixture was stirred at ambient temperature for an additional 2 h. The solids were collected by filtration, washed with IPA/heptane (1/5; 2×30 mL) and heptane (2×30 mL), and dried under vacuum to afford 9H-fluoren-9-ylmethyl ({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate as a white solid (18.30 g, 91.1% yield). 1H NMR (500 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.07 (dd, J=6.2, 2.5 Hz, 1H), 7.90 (t, J=5.6 Hz, 1H), 7.88 (d, J=7.6 Hz, 2H), 7.72 (d, J=7.0 Hz, 2H), 7.71 (ddd, J=8.9, 4.3, 2.6 Hz, 1H), 7.57 (dd, J=8.7, 8.7 Hz, 1H), 7.40 (t, J=7.4 Hz, 2H), 7.31 (td, J=7.4, 1.0 Hz, 2H), 6.55 (t, J=6.0 Hz, 1H), 4.35 (d, J=7.3 Hz, 2H), 4.25 (t, J=7.2 Hz, 1H), 3.39 (q, J=6.4 Hz, 2H), 3.15 (q, J=6.3 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 159.03 (d, J=248.7 Hz), 156.61 (s), 155.22 (s), 151.55 (s), 148.67 (s), 143.29 (s), 140.68 (s), 133.82 (s), 133.39 (s), 130.05 (d, J=8.5 Hz), 128.54 (d, J=3.2 Hz), 127.73 (s), 127.07 (s), 125.24 (s), 120.11 (s), 117.42 (d, J=24.0 Hz), 108.19 (d, J=22.5 Hz), 66.70 (s), 46.17 (s), 43.34 (s), 40.79 (s) ppm; 19F NMR (376 MHz, DMSO-d6) δ −103.99-−107.39 (m) ppm. to give a slurry while maintaining the internal temperature at less than about 20° C. After the addition the resulting mixture was stirred at ambient temperature for an additional 23 h the resulting mixture was stirred at ambient temperature for 1 h the mixture was stirred at ambient temperature for an additional 2 h The solids were collected by filtration washed with IPA/heptane (1/5; 2×30 mL) and heptane (2×30 mL) dried under vacuum

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into an oven dried 2 L 4-neck round bottom flask was charged 9-fluorenylmethanol (50.0 g, 255 mmol) and anhydrous DCM (382 mL) at room temperature. The resulting slurry was cooled in an ice-bath to about 0-5° C. A solution of chlorosulfonyl isocyanate (CSI, 23.0 mL, 264 mmol) in anhydrous DCM (127 mL) was added dropwise to the slurry through an addition funnel over 22 minutes, maintaining the reaction mixture temperature at <5° C. The resulting mixture was stirred at 0-5° C. for 1.75 h, producing a thick white slurry. A solution of aminoacetaldehyde dimethyl acetal (27.9 mL, 255 mmol) in anhydrous DCM (382 mL) and 4-methylmorpholine (84.0 mL, 764 mmol) were added to the mixture at about 0-5° C. over 71 minutes. The resulting reaction mixture was then stirred in the ice bath for 1.5 hours. When HPLC showed the reaction was complete, the reaction mixture was acidified by the dropwise addition of a 1.0 M phosphoric acid (H3PO4, aq., 640 mL) over 22 minutes to pH 1-2. Water (300 mL), EtOAc (2150 mL) and heptane (250 mL) were then added and the resulting mixture was stirred for 10 minutes. The two phases were separated and the organic phase was washed sequentially with water (500 mL), heptane (300 mL) and water (2×500 mL) and dried over MgSO4. The filtrate was concentrated under vacuum to dryness. The resulting solids were redissolved in EtOAc (600 mL) at 65° C. and the warm solution was filtered into a clean 3 L round bottom flask. The filtrate was cooled to room temperature and stirred for 2.5 h before heptane (1200 mL) was then added via an addition funnel over 80 min. After stirring overnight at room temperature, the mixture was then cooled in an ice bath for 1 h. The resulting solids were collected by filtration, washed with 25% EtOAc/heptane (250 mL), and dried overnight at about 40-45° C. under vacuum to afford 9H-fluoren-9-ylmethyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (91.3 g, 88% yield) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.98-7.85 (m, 3H), 7.76 (d, J=7.5 Hz, 2H), 7.43 (t, J=7.2 Hz, 2H), 7.33 (td, J=7.4, 1.1 Hz, 2H), 4.44-4.33 (m, 3H), 4.33-4.22 (m, 1H), 3.23 (s, 6H), 2.99 (t, J=5.8 Hz, 2H) ppm. Into an oven dried 2 L 4-neck round bottom flask maintaining the reaction mixture temperature at <5° C producing a thick white slurry The resulting reaction mixture the resulting mixture was stirred for 10 minutes The two phases were separated the organic phase was washed sequentially with water (500 mL), heptane (300 mL) and water (2×500 mL) dried over MgSO4 The filtrate was concentrated under vacuum to dryness The resulting solids were redissolved in EtOAc (600 mL) at 65° C. the warm solution was filtered into a clean 3 L round bottom flask The filtrate was cooled to room temperature stirred for 2.5 h before heptane (1200 mL) was then added via an addition funnel over 80 min After stirring overnight at room temperature the mixture was then cooled in an ice bath for 1 h The resulting solids were collected by filtration washed with 25% EtOAc/heptane (250 mL) dried overnight at about 40-45° C. under vacuum

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into an oven dried 2 L 4-neck round bottom flask was charged 9-fluorenylmethanol (50.0 g, 255 mmol) and anhydrous DCM (382 mL) at room temperature. The resulting slurry was cooled in an ice-bath to about 0-5° C. A solution of chlorosulfonyl isocyanate (CSI, 23.0 mL, 264 mmol) in anhydrous DCM (127 mL) was added dropwise to the slurry through an addition funnel over 22 minutes, maintaining the reaction mixture temperature at <5° C. The resulting mixture was stirred at 0-5° C. for 1.75 h, producing a thick white slurry. A solution of aminoacetaldehyde dimethyl acetal (27.9 mL, 255 mmol) in anhydrous DCM (382 mL) and 4-methylmorpholine (84.0 mL, 764 mmol) were added to the mixture at about 0-5° C. over 71 minutes. The resulting reaction mixture was then stirred in the ice bath for 1.5 hours. When HPLC showed the reaction was complete, the reaction mixture was acidified by the dropwise addition of a 1.0 M phosphoric acid (H3PO4, aq., 640 mL) over 22 minutes to pH 1-2. Water (300 mL), EtOAc (2150 mL) and heptane (250 mL) were then added and the resulting mixture was stirred for 10 minutes. The two phases were separated and the organic phase was washed sequentially with water (500 mL), heptane (300 mL) and water (2×500 mL) and dried over MgSO4. The filtrate was concentrated under vacuum to dryness. The resulting solids were redissolved in EtOAc (600 mL) at 65° C. and the warm solution was filtered into a clean 3 L round bottom flask. The filtrate was cooled to room temperature and stirred for 2.5 h before heptane (1200 mL) was then added via an addition funnel over 80 min. After stirring overnight at room temperature, the mixture was then cooled in an ice bath for 1 h. The resulting solids were collected by filtration, washed with 25% EtOAc/heptane (250 mL), and dried overnight at about 40-45° C. under vacuum to afford 9H-fluoren-9-ylmethyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (91.3 g, 88% yield) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.98-7.85 (m, 3H), 7.76 (d, J=7.5 Hz, 2H), 7.43 (t, J=7.2 Hz, 2H), 7.33 (td, J=7.4, 1.1 Hz, 2H), 4.44-4.33 (m, 3H), 4.33-4.22 (m, 1H), 3.23 (s, 6H), 2.99 (t, J=5.8 Hz, 2H) ppm. Into an oven dried 2 L 4-neck round bottom flask maintaining the reaction mixture temperature at <5° C producing a thick white slurry The resulting reaction mixture the resulting mixture was stirred for 10 minutes The two phases were separated the organic phase was washed sequentially with water (500 mL), heptane (300 mL) and water (2×500 mL) dried over MgSO4 The filtrate was concentrated under vacuum to dryness The resulting solids were redissolved in EtOAc (600 mL) at 65° C. the warm solution was filtered into a clean 3 L round bottom flask The filtrate was cooled to room temperature stirred for 2.5 h before heptane (1200 mL) was then added via an addition funnel over 80 min After stirring overnight at room temperature the mixture was then cooled in an ice bath for 1 h The resulting solids were collected by filtration washed with 25% EtOAc/heptane (250 mL) dried overnight at about 40-45° C. under vacuum

Conditions: temp:17.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (10.00 g, 29.23 mmol) in DCM (160 mL) was added methanesulfonic acid (MeSO3H, 8.46 g, 88.04 mmol) and triethylsilane (Et3SiH, 8.37 g, 71.96 mmol) at ambient temperature over 10 minutes to give a slurry. Solid 9H-fluoren-9-ylmethyl{[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (12.25 g, 30.14 mmol) was added portionwise (1 g/3-4 min; over 1 h) while maintaining the internal temperature at less than about 20° C. using a water bath. After the addition, the resulting mixture was stirred at about 13 to 22° C. for 3 days. Additional triethylsilane (Et3SiH, 0.1755 g, 1.51 mmol) and 9H-fluoren-9-ylmethyl{[(2,2-dimethoxyethy)amino]sulfonyl}carbamate (0.3082 g, 0.76 mmol) were added and the resulting mixture was stirred at ambient temperature for an additional 23 h. Isopropyl alcohol (IPA, 15 mL) was added and the resulting mixture was stirred at ambient temperature for 1 h. Heptane (100 mL) was added and the mixture was stirred at ambient temperature for an additional 2 h. The solids were collected by filtration, washed with IPA/heptane (1/5; 2×30 mL) and heptane (2×30 mL), and dried under vacuum to afford 9H-fluoren-9-ylmethyl ({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate as a white solid (18.30 g, 91.1% yield). 1H NMR (500 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.07 (dd, J=6.2, 2.5 Hz, 1H), 7.90 (t, J=5.6 Hz, 1H), 7.88 (d, J=7.6 Hz, 2H), 7.72 (d, J=7.0 Hz, 2H), 7.71 (ddd, J=8.9, 4.3, 2.6 Hz, 1H), 7.57 (dd, J=8.7, 8.7 Hz, 1H), 7.40 (t, J=7.4 Hz, 2H), 7.31 (td, J=7.4, 1.0 Hz, 2H), 6.55 (t, J=6.0 Hz, 1H), 4.35 (d, J=7.3 Hz, 2H), 4.25 (t, J=7.2 Hz, 1H), 3.39 (q, J=6.4 Hz, 2H), 3.15 (q, J=6.3 Hz, 2H); 13C NMR (126 MHz, DMSO-d6) δ 159.03 (d, J=248.7 Hz), 156.61 (s), 155.22 (s), 151.55 (s), 148.67 (s), 143.29 (s), 140.68 (s), 133.82 (s), 133.39 (s), 130.05 (d, J=8.5 Hz), 128.54 (d, J=3.2 Hz), 127.73 (s), 127.07 (s), 125.24 (s), 120.11 (s), 117.42 (d, J=24.0 Hz), 108.19 (d, J=22.5 Hz), 66.70 (s), 46.17 (s), 43.34 (s), 40.79 (s) ppm; 19F NMR (376 MHz, DMSO-d6) δ −103.99-−107.39 (m) ppm. to give a slurry while maintaining the internal temperature at less than about 20° C. After the addition the resulting mixture was stirred at ambient temperature for an additional 23 h the resulting mixture was stirred at ambient temperature for 1 h the mixture was stirred at ambient temperature for an additional 2 h The solids were collected by filtration washed with IPA/heptane (1/5; 2×30 mL) and heptane (2×30 mL) dried under vacuum

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into an oven dried 2 L 4-neck round bottom flask was charged 9-fluorenylmethanol (50.0 g, 255 mmol) and anhydrous DCM (382 mL) at room temperature. The resulting slurry was cooled in an ice-bath to about 0-5° C. A solution of chlorosulfonyl isocyanate (CSI, 23.0 mL, 264 mmol) in anhydrous DCM (127 mL) was added dropwise to the slurry through an addition funnel over 22 minutes, maintaining the reaction mixture temperature at <5° C. The resulting mixture was stirred at 0-5° C. for 1.75 h, producing a thick white slurry. A solution of aminoacetaldehyde dimethyl acetal (27.9 mL, 255 mmol) in anhydrous DCM (382 mL) and 4-methylmorpholine (84.0 mL, 764 mmol) were added to the mixture at about 0-5° C. over 71 minutes. The resulting reaction mixture was then stirred in the ice bath for 1.5 hours. When HPLC showed the reaction was complete, the reaction mixture was acidified by the dropwise addition of a 1.0 M phosphoric acid (H3PO4, aq., 640 mL) over 22 minutes to pH 1-2. Water (300 mL), EtOAc (2150 mL) and heptane (250 mL) were then added and the resulting mixture was stirred for 10 minutes. The two phases were separated and the organic phase was washed sequentially with water (500 mL), heptane (300 mL) and water (2×500 mL) and dried over MgSO4. The filtrate was concentrated under vacuum to dryness. The resulting solids were redissolved in EtOAc (600 mL) at 65° C. and the warm solution was filtered into a clean 3 L round bottom flask. The filtrate was cooled to room temperature and stirred for 2.5 h before heptane (1200 mL) was then added via an addition funnel over 80 min. After stirring overnight at room temperature, the mixture was then cooled in an ice bath for 1 h. The resulting solids were collected by filtration, washed with 25% EtOAc/heptane (250 mL), and dried overnight at about 40-45° C. under vacuum to afford 9H-fluoren-9-ylmethyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (91.3 g, 88% yield) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.98-7.85 (m, 3H), 7.76 (d, J=7.5 Hz, 2H), 7.43 (t, J=7.2 Hz, 2H), 7.33 (td, J=7.4, 1.1 Hz, 2H), 4.44-4.33 (m, 3H), 4.33-4.22 (m, 1H), 3.23 (s, 6H), 2.99 (t, J=5.8 Hz, 2H) ppm. Into an oven dried 2 L 4-neck round bottom flask maintaining the reaction mixture temperature at <5° C producing a thick white slurry The resulting reaction mixture the resulting mixture was stirred for 10 minutes The two phases were separated the organic phase was washed sequentially with water (500 mL), heptane (300 mL) and water (2×500 mL) dried over MgSO4 The filtrate was concentrated under vacuum to dryness The resulting solids were redissolved in EtOAc (600 mL) at 65° C. the warm solution was filtered into a clean 3 L round bottom flask The filtrate was cooled to room temperature stirred for 2.5 h before heptane (1200 mL) was then added via an addition funnel over 80 min After stirring overnight at room temperature the mixture was then cooled in an ice bath for 1 h The resulting solids were collected by filtration washed with 25% EtOAc/heptane (250 mL) dried overnight at about 40-45° C. under vacuum