bis(2,3,4,5,6-pentafluorophenyl) carbonate

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

実験手順: To a 100 mL round bottom flask, 1,1,1-tris(hydroxymethyl)ethane (2.0 g, 16.7 mmol) was combined with bis(pentafluorophenyl)carbonate (15.1 g, 38.3 mmol, 2.3 eq.) and cesium fluoride (0.76 g, 5.0 mmol, 0.3 eq.) in anhydrous tetrahydrofuran (THF) (11.9 mL) and stirred for four hours at room temperature. Initially the reaction was heterogeneous, but after one hour the reaction formed a clear homogeneous solution. The reaction was concentrated in vacuo (100 mm Hg, 30° C.) and the residue was dissolved in methylene chloride (˜50 mL). Upon standing (˜10 min), the pentafluorophenol byproduct precipitated from solution and was recovered by filtration. The mother liquor was washed with aqueous sodium bicarbonate (3×50 mL) until the pH of aqueous layer was ˜8 and then with brine (1×50 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solution was concentrated to give the crude product that was purified by recrystallization. The crude product was dissolved in ethyl acetate (24 mL) at 65° C. n-Hexane (35 mL) was added at the same temperature, and the resulting solution was allowed to cool to room temperature. After stirring the solution overnight, the white crystalline product TMCPFP was separated by filtration (4.0 g, 67% yield). m.p. 130-131° C. 1H NMR (CDCl3, 400 Hz) 1.22 (s, 3H), 4.23 (d, 2H, J=11 Hz), 4.37 (s, 2H), 4.38 (d, 2H, J=11 Hz). 19F NMR (CDCl3, 376 Hz) −154.3˜−154.3 (m, 2F), −157.8 (t, 1F, J=22 Hz), −162.6˜−162.7 (m, 2F). 13C NMR (CDCl3, 100 Hz) 16.8, 32.6, 70.3, 73.0, 125.4, 137.9, 140.1, 141.3, 147.4, 151.1. after one hour the reaction formed a clear homogeneous solution The reaction was concentrated in vacuo (100 mm Hg, 30° C.) the residue was dissolved in methylene chloride (˜50 mL) (˜10 min) the pentafluorophenol byproduct precipitated from solution was recovered by filtration The mother liquor was washed with aqueous sodium bicarbonate (3×50 mL) until the pH of aqueous layer The organic layer was separated dried over anhydrous sodium sulfate The solution was concentrated

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

実験手順: To a 100 mL round bottom flask, 1,1,1-tris(hydroxymethyl)ethane (2.0 g, 16.7 mmol) was combined with bis(pentafluorophenyl)carbonate (15.1 g, 38.3 mmol, 2.3 eq.) and cesium fluoride (0.76 g, 5.0 mmol, 0.3 eq.) in anhydrous tetrahydrofuran (THF) (11.9 mL) and stirred for four hours at room temperature. Initially the reaction was heterogeneous, but after one hour the reaction formed a clear homogeneous solution. The reaction was concentrated in vacuo (100 mm Hg, 30° C.) and the residue was dissolved in methylene chloride (˜50 mL). Upon standing (˜10 min), the pentafluorophenol byproduct precipitated from solution and was recovered by filtration. The mother liquor was washed with aqueous sodium bicarbonate (3×50 mL) until the pH of aqueous layer was ˜8 and then with brine (1×50 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solution was concentrated to give the crude product that was purified by recrystallization. The crude product was dissolved in ethyl acetate (24 mL) at 65° C. n-Hexane (35 mL) was added at the same temperature, and the resulting solution was allowed to cool to room temperature. After stirring the solution overnight, the white crystalline product TMCPFP was separated by filtration (4.0 g, 67% yield). m.p. 130-131° C. 1H NMR (CDCl3, 400 Hz) 1.22 (s, 3H), 4.23 (d, 2H, J=11 Hz), 4.37 (s, 2H), 4.38 (d, 2H, J=11 Hz). 19F NMR (CDCl3, 376 Hz) −154.3˜−154.3 (m, 2F), −157.8 (t, 1F, J=22 Hz), −162.6˜−162.7 (m, 2F). 13C NMR (CDCl3, 100 Hz) 16.8, 32.6, 70.3, 73.0, 125.4, 137.9, 140.1, 141.3, 147.4, 151.1. after one hour the reaction formed a clear homogeneous solution The reaction was concentrated in vacuo (100 mm Hg, 30° C.) the residue was dissolved in methylene chloride (˜50 mL) (˜10 min) the pentafluorophenol byproduct precipitated from solution was recovered by filtration The mother liquor was washed with aqueous sodium bicarbonate (3×50 mL) until the pH of aqueous layer The organic layer was separated dried over anhydrous sodium sulfate The solution was concentrated

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

実験手順: A solution of 2-ethyl-6-methyl-pyridin-4-ylamine (1.33 g, 9.8 mmol) in THF (25 mL) is slowly added to a solution of bis(pentafluorophenyl)carbonate (3.99 g, 10.1 mmol) in THF (10 mL). The mixture is stirred at r.t. for 48 h and the solution of title compound is used as stock solution for subsequent coupling reactions.

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

実験手順: A solution of 2,6-dimethyl-pyridin-4-ylamine (Example C1.2., 1.23 g, 10 mmol) in THF (30 mL) is slowly added to a cooled (−10° C.) solution of bis(pentafluorophenyl)carbonate (3.94 g, 10 mmol) in THF (10 mL). The mixture is stirred at r.t. for 48 h and the solution of title compound is used as stock solution for subsequent coupling reactions.

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

実験手順: A solution of 2,6-dimethyl-pyridin-4-ylamine (Example C1.2., 1.23 g, 10 mmol) in THF (30 mL) is slowly added to a cooled (−10° C.) solution of bis(pentafluorophenyl)carbonate (3.94 g, 10 mmol) in THF (10 mL). The mixture is stirred at r.t. for 48 h and the solution of title compound is used as stock solution for subsequent coupling reactions.

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

実験手順: A solution of 2,6-dimethyl-pyridin-4-ylamine (Example C1.2., 1.23 g, 10 mmol) in THF (30 mL) is slowly added to a cooled (−10° C.) solution of bis(pentafluorophenyl)carbonate (3.94 g, 10 mmol) in THF (10 mL). The mixture is stirred at r.t. for 48 h and the solution of title compound is used as stock solution for subsequent coupling reactions.

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

実験手順: To a 100 mL round bottom flask, 1,1,1-tris(hydroxymethyl)ethane (2.0 g, 16.7 mmol) was combined with bis(pentafluorophenyl)carbonate (15.1 g, 38.3 mmol, 2.3 eq.) and cesium fluoride (0.76 g, 5.0 mmol, 0.3 eq.) in anhydrous tetrahydrofuran (THF) (11.9 mL) and stirred for four hours at room temperature. Initially the reaction was heterogeneous, but after one hour the reaction formed a clear homogeneous solution. The reaction was concentrated in vacuo (100 mm Hg, 30° C.) and the residue was dissolved in methylene chloride (˜50 mL). Upon standing (˜10 min), the pentafluorophenol byproduct precipitated from solution and was recovered by filtration. The mother liquor was washed with aqueous sodium bicarbonate (3×50 mL) until the pH of aqueous layer was ˜8 and then with brine (1×50 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solution was concentrated to give the crude product that was purified by recrystallization. The crude product was dissolved in ethyl acetate (24 mL) at 65° C. n-Hexane (35 mL) was added at the same temperature, and the resulting solution was allowed to cool to room temperature. After stirring the solution overnight, the white crystalline product TMCPFP was separated by filtration (4.0 g, 67% yield). m.p. 130-131° C. 1H NMR (CDCl3, 400 Hz) 1.22 (s, 3H), 4.23 (d, 2H, J=11 Hz), 4.37 (s, 2H), 4.38 (d, 2H, J=11 Hz). 19F NMR (CDCl3, 376 Hz) −154.3˜−154.3 (m, 2F), −157.8 (t, 1F, J=22 Hz), −162.6˜−162.7 (m, 2F). 13C NMR (CDCl3, 100 Hz) 16.8, 32.6, 70.3, 73.0, 125.4, 137.9, 140.1, 141.3, 147.4, 151.1. after one hour the reaction formed a clear homogeneous solution The reaction was concentrated in vacuo (100 mm Hg, 30° C.) the residue was dissolved in methylene chloride (˜50 mL) (˜10 min) the pentafluorophenol byproduct precipitated from solution was recovered by filtration The mother liquor was washed with aqueous sodium bicarbonate (3×50 mL) until the pH of aqueous layer The organic layer was separated dried over anhydrous sodium sulfate The solution was concentrated

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

実験手順: To a 100 mL round bottom flask, 1,1,1-tris(hydroxymethyl)ethane (2.0 g, 16.7 mmol) was combined with bis(pentafluorophenyl)carbonate (15.1 g, 38.3 mmol, 2.3 eq.) and cesium fluoride (0.76 g, 5.0 mmol, 0.3 eq.) in anhydrous tetrahydrofuran (THF) (11.9 mL) and stirred for four hours at room temperature. Initially the reaction was heterogeneous, but after one hour the reaction formed a clear homogeneous solution. The reaction was concentrated in vacuo (100 mm Hg, 30° C.) and the residue was dissolved in methylene chloride (˜50 mL). Upon standing (˜10 min), the pentafluorophenol byproduct precipitated from solution and was recovered by filtration. The mother liquor was washed with aqueous sodium bicarbonate (3×50 mL) until the pH of aqueous layer was ˜8 and then with brine (1×50 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solution was concentrated to give the crude product that was purified by recrystallization. The crude product was dissolved in ethyl acetate (24 mL) at 65° C. n-Hexane (35 mL) was added at the same temperature, and the resulting solution was allowed to cool to room temperature. After stirring the solution overnight, the white crystalline product TMCPFP was separated by filtration (4.0 g, 67% yield). m.p. 130-131° C. 1H NMR (CDCl3, 400 Hz) 1.22 (s, 3H), 4.23 (d, 2H, J=11 Hz), 4.37 (s, 2H), 4.38 (d, 2H, J=11 Hz). 19F NMR (CDCl3, 376 Hz) −154.3-154.3 (m, 2F), −157.8 (t, 1F, J=22 Hz), −162.6˜-162.7 (m, 2F). 13C NMR (CDCl3, 100 Hz) 16.8, 32.6, 70.3, 73.0, 125.4, 137.9, 140.1, 141.3, 147.4, 151.1. after one hour the reaction formed a clear homogeneous solution The reaction was concentrated in vacuo (100 mm Hg, 30° C.) the residue was dissolved in methylene chloride (˜50 mL) (˜10 min) the pentafluorophenol byproduct precipitated from solution was recovered by filtration The mother liquor was washed with aqueous sodium bicarbonate (3×50 mL) until the pH of aqueous layer The organic layer was separated dried over anhydrous sodium sulfate The solution was concentrated

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

実験手順: Cyclizations of the above diols were also attempted using ethyl chloroformate, and bis(pentafluorophenyl) carbonate (PFC). Table 7 summarizes the results.

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

実験手順: 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270 mL of dichloromethane and then stirred at 25˜30° C. for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2 mol) of bis(pentafluorophenyl)carbonate was added to the reaction solution to form a suspended reaction solution, and then the suspended reaction solution was stirred at 25˜30° C. for 3˜4 hours. After confirming the completion of a reaction using thin layer chromatography (TLC), the reaction solution was concentrated under reduced pressure. Subsequently, oily matter obtained by adding 1270 mL of ethyl acetate to the reaction solution was dissolved, and then 209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the reaction solution and stirred at 25˜30° C. for 4˜5 hours. After confirming the completion of a reaction using high performance liquid chromatography (HPLC), the reaction solution was concentrated under reduced pressure. Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution to adjust the pH of the reaction solution to 1˜2. Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product. Then, an aqueous layer was extracted from the reaction solution using 1270 mL of dichloromethane, and then the reaction solution was concentrated under reduced pressure. Then, 1270 mL of water was added to the reaction solution, the pH of the reaction solution was adjusted to 9˜10 using ammonium hydroxide, and then an aqueous layer was further extracted from the reaction solution using 1270 mL of toluene. Subsequently, 1270 mL of acetone and 118.1 g (1.0 mol) of succinic acid were added to the reaction solution, stirred at 55˜60° C. for 30 minutes, further stirred at 10˜15° C. for 2 hours, and then filtered to obtain a reaction product. Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone, and then dried in vacuum at 40° C. to obtain 384.9 g (80.1%) of solifenacin succinate. to obtain a reaction solution to form a suspended reaction solution the suspended reaction solution was stirred at 25˜30° C. for 3˜4 hours the reaction solution was concentrated under reduced pressure Subsequently, oily matter obtained was dissolved stirred at 25˜30° C. for 4˜5 hours the reaction solution was concentrated under reduced pressure Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product Then, an aqueous layer was extracted from the reaction solution the reaction solution was concentrated under reduced pressure Then, 1270 mL of water was added to the reaction solution an aqueous layer was further extracted from the reaction solution stirred at 55˜60° C. for 30 minutes further stirred at 10˜15° C. for 2 hours filtered to obtain a reaction product Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone dried in vacuum at 40° C.

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

実験手順: 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270 mL of dichloromethane and then stirred at 25˜30° C. for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2 mol) of bis(pentafluorophenyl)carbonate was added to the reaction solution to form a suspended reaction solution, and then the suspended reaction solution was stirred at 25˜30° C. for 3˜4 hours. After confirming the completion of a reaction using thin layer chromatography (TLC), the reaction solution was concentrated under reduced pressure. Subsequently, oily matter obtained by adding 1270 mL of isopropanol to the reaction solution was dissolved, and then 209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the reaction solution and stirred at 25˜30° C. for 4˜5 hours. After confirming the completion of a reaction using high performance liquid chromatography (HPLC), the reaction solution was concentrated under reduced pressure. Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution to adjust the pH of the reaction solution to 1˜2. Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product. Then, an aqueous layer was extracted from the reaction solution using 1270 mL of dichloromethane, and then the reaction solution was concentrated under reduced pressure. Then, 1270 mL of water was added to the reaction solution, the pH of the reaction solution was adjusted to 9˜10 using ammonium hydroxide, and then an aqueous layer was further extracted from the reaction solution using 1270 mL of toluene. Subsequently, 1270 mL of acetone and 118.1 g (1.0 mol) of succinic acid were added to the reaction solution, stirred at 55˜60° C. for 30 minutes, further stirred at 10˜15° C. for 2 hours, and then filtered to obtain a reaction product. Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone, and then dried in vacuum at 40° C. to obtain 386.4 g (80.4%) of solifenacin succinate. to obtain a reaction solution to form a suspended reaction solution the suspended reaction solution was stirred at 25˜30° C. for 3˜4 hours the reaction solution was concentrated under reduced pressure Subsequently, oily matter obtained was dissolved stirred at 25˜30° C. for 4˜5 hours the reaction solution was concentrated under reduced pressure Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product Then, an aqueous layer was extracted from the reaction solution the reaction solution was concentrated under reduced pressure Then, 1270 mL of water was added to the reaction solution an aqueous layer was further extracted from the reaction solution stirred at 55˜60° C. for 30 minutes further stirred at 10˜15° C. for 2 hours filtered to obtain a reaction product Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone dried in vacuum at 40° C.

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

実験手順: 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270 mL of dichloromethane and then stirred at 25˜30° C. for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2 mol) of bis(pentafluorophenyl)carbonate was added to the reaction solution to form a suspended reaction solution, and then the suspended reaction solution was stirred at 25˜30° C. for 3˜4 hours. After confirming the completion of a reaction using thin layer chromatography (TLC), 209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the reaction solution, and then stirred at 25˜30° C. for 4˜5 hours. After confirming the completion of a reaction using high performance liquid chromatography (HPLC), the reaction solution was concentrated under reduced pressure. Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution to adjust the pH of the reaction solution to 1˜2. Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product. Then, an aqueous layer was extracted from the reaction solution using 1270 mL of dichloromethane, and then the reaction solution was concentrated under reduced pressure. Then, 1270 mL of water was added to the reaction solution, the pH of the reaction solution was adjusted to 9˜10 using ammonium hydroxide, and then an aqueous layer was further extracted from the reaction solution using 1270 mL of toluene. Subsequently, 1270 mL of acetone and 118.1 g (1.0 mol) of succinic acid were added to the reaction solution, stirred at 55˜60° C. for 30 minutes, further stirred at 10˜15° C. for 2 hours, and then filtered to obtain a reaction product. Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone, and then dried in vacuum at 40° C. to obtain 381.5 g (79.4%) of solifenacin succinate. to obtain a reaction solution to form a suspended reaction solution the suspended reaction solution was stirred at 25˜30° C. for 3˜4 hours was added to the reaction solution stirred at 25˜30° C. for 4˜5 hours the reaction solution was concentrated under reduced pressure Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product Then, an aqueous layer was extracted from the reaction solution the reaction solution was concentrated under reduced pressure Then, 1270 mL of water was added to the reaction solution an aqueous layer was further extracted from the reaction solution stirred at 55˜60° C. for 30 minutes further stirred at 10˜15° C. for 2 hours filtered to obtain a reaction product Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone dried in vacuum at 40° C.