(R)-缩水甘油

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 250 ml rounded bottom flask was charged with triethylamine (3.3 g, 4.5 ml, 32 mmol), R-glycidol (2.0 g, 27 mmol)(Arco Company, Newton Square, PA) and dichloromethane (50 ml) then cooled to 0° C. A solution of 3-nitrobenzenesulfonyl chloride (6.0 g, 27 mmol) in dichloromethane (40 ml) was added dropwise over a 5-minute period to the glycidol solution and the reaction mixture was stirred at 0° C. under N2 for 3 hrs. The reaction mixture was poured into a separatory funnel and washed successively with 1N aqueous hydrochloric acid (90 ml), 5% aqueous sodium bicarbonate solution (90 ml), and saturated aqueous sodium chloride. The organic layer was separated, dried over anhydrous magnesium sulfate (10 g), filtered and concentrated in vacuo to yield (2S)-(+)-glycidyl-3-nitrobenzenesulfonate as a pale colored solid. Recrystallization from hexanes/EtOAc (1:1, 50 ml) provided 5.89 g (83%) of pure (2S)-(+)-glycidyl- 3-nitrobenzenesulfonate, m.p. 61°-63° C., [α]D +22.3° (c 0.41, chloroform), >95% optical purity. The reaction mixture was poured into a separatory funnel washed successively with 1N aqueous hydrochloric acid (90 ml), 5% aqueous sodium bicarbonate solution (90 ml), and saturated aqueous sodium chloride The organic layer was separated dried over anhydrous magnesium sulfate (10 g) filtered concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of (R)-glycidol (0.33 mL, 5.0 mmol) and morpholine (0.65 mL, 7.5 mmol, 1.5 equiv.) in abs. ethanol was heated in a microwave for 4 min. at 140 0° C., cooled to room temperature and concentrated at 70° C. under a 12 mBar vacuum to afford (2S)-3-(4-morpholinyl)-1,2-propanediol (0.91 g, 113%): 1H NMR (CDCl3) δ 2.37 (dd, J=3.9, 12.5 Hz, 1H), 2.41-2.48 (m, 2H), 2.57 (dd, J=9.7, 12.5 Hz, 1H), 3.51 (dd, J=4.3, 11.4 Hz, 1H), 3.66-3.79 (m, 5H), 3.81-3.87 (m, 1H). concentrated at 70° C. under a 12 mBar vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To an ice-cooled solution of (R)-glycidol (5.0 g, 0.068 m) and triethylamine (8.1 g, 0.080 m) in toluene (100 ml) was added, over 15 minutes, methanesulfonyl chloride (8.0 g, 0.070 ml) in toluene (25 ml). Stirring was continued with cooling for 1 hour. The solution was filtered and concentrated to give an 80-85% yield of the crude (S)-3-mesyloxy-1,2-epoxypropane; this material could be used without further purification. Distillation gave 7 (61%); bp 92°-95° C./0.1 mm; [α]D22 =23.7° (c=5.16, CH3OH); 1H NMR (CDCl3) 4.5 (1H, d of d, J=12, J=3), 4.1 (1H, d of d, J=12, J=6), 3.3 (1H, m), 3.1 (3H, s), 2.8 (2H, m). was added, over 15 minutes with cooling for 1 hour The solution was filtered concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To an ice-cooled solution of (R)-glycidol (5.0 g, 0.068 m) and triethylamine (8.1 g, 0.080 m) in toluene (100 ml) was added, over 15 minutes, methanesulfonyl chloride (8.0 g, 0.070 ml) in toluene (25 ml). Stirring was continued with cooling for 1 hour. The solution was filtered and concentrated to give an 80-85% yield of the crude (S)-3-mesyloxy-1,2-epoxypropane; this material could be used without further purification. Distillation gave 7 (61%); bp 92°-95° C./0.1 mm; [α]D22 =23.7° (c=5.16, CH3OH); 1H NMR (CDCl3) 4.5 (1H, d of d, J=12, J=3), 4.1 (1H, d of d, J=12, J=6), 3.3 (1H, m), 3.1 (3H, s), 2.8 (2H, m). was added, over 15 minutes with cooling for 1 hour The solution was filtered concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To pyridine (10.3 g, 0.13 m) in CH2Cl2 (300 ml) cooled to -23° in a dry ice/CCl4 bath was added trifluoromethanesulfonic anhydride (36.7 g, 0.13 m) in CH2Cl2 (100 ml) dropwise over 1/2 hour. While still cooling this mixture at -23°, (R)-glycidol (8.6 g, 0.116 m) in CH2Cl2 (100 ml) was added dropwise over 1/2 hour. After stirring for 5 minutes with cooling and 15 minutes without, an equal volume of hexane was added and the solids were filtered. Concentration of the solution at 30°/25 torr. left a residue which was distilled to give (S)-3-trifloxy-1,2-epoxypropane (40%); bp 35°-39°/0.2 mm; [α]D24 =14.7° (c=3.90, CHCl3); 1H NMR (CDCl3) 4.8 (1H, d of d, J=11, J=3 ), 4.4 (1H, d of d, J=11, J=3), 3.3 (1H, m), 2.9 (1H, t, J=4.5), 2.7 (1H, J=4.5, J=2). While still cooling this mixture at -23° was added the solids were filtered at 30° left a residue which was distilled

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To pyridine (10.3 g, 0.13 m) in CH2Cl2 (300 ml) cooled to -23° in a dry ice/CCl4 bath was added trifluoromethanesulfonic anhydride (36.7 g, 0.13 m) in CH2Cl2 (100 ml) dropwise over 1/2 hour. While still cooling this mixture at -23°, (R)-glycidol (8.6 g, 0.116 m) in CH2Cl2 (100 ml) was added dropwise over 1/2 hour. After stirring for 5 minutes with cooling and 15 minutes without, an equal volume of hexane was added and the solids were filtered. Concentration of the solution at 30°/25 torr. left a residue which was distilled to give (S)-3-trifloxy-1,2-epoxypropane (40%); bp 35°-39°/0.2 mm; [α]D24 =14.7° (c=3.90, CHCl3); 1H NMR (CDCl3) 4.8 (1H, d of d, J=11, J=3 ), 4.4 (1H, d of d, J=11, J=3), 3.3 (1H, m), 2.9 (1H, t, J=4.5), 2.7 (1H, J=4.5, J=2). While still cooling this mixture at -23° was added the solids were filtered at 30° left a residue which was distilled

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (5.06 g, 31.4 mmol) in THF (80 mL), PPh3 (9.06 g, 34.5 mmol) and (R)-glycidol (2.29 mL, 34.5 mmol) are added. The mixture is cooled to 0° C. before DEAD in toluene (15.8 mL, 34.5 mmol) is added. The mixture is stirred for 18 h while warming up to rt. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-ethyl-5-methyl-4-oxiranylmethoxy-benzonitrile (5.85 g) as a yellow oil; LC-MS: tR=0.96 min; [M+42]+=259.08. is added The solvent is evaporated the crude product is purified by CC on silica gel eluting with heptane:EA 7:3

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (5.06 g, 31.4 mmol) in THF (80 mL), PPh3 (9.06 g, 34.5 mmol) and (R)-glycidol (2.29 mL, 34.5 mmol) are added. The mixture is cooled to 0° C. before DEAD in toluene (15.8 mL, 34.5 mmol) is added. The mixture is stirred for 18 h while warming up to rt. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-ethyl-5-methyl-4-oxiranylmethoxy-benzonitrile (5.85 g) as a yellow oil; LC-MS: tR=0.96 min; [M+42]+=259.08. is added The solvent is evaporated the crude product is purified by CC on silica gel eluting with heptane:EA 7:3

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Reaction of cytosine (2.2 g, 19.8 mmol) with (R)-glycidol (88% ee, 1.51 ml, 22.8 mmol) in the presence of anhydrous potassium carbonate (40 mg, 0.289 mmol) in dry DMF (20 ml) at 72° C. for 5 hours, as described in Example 1, furnished the title compound (88% ee) in 43.1% yield.

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 5 L 3-neck round bottom flask was charged with trityl chloride (133.8 g, 0.48 mol) and methylene chloride (400 ml). It was cooled to 0° C. under N2 and treated with triethylamine (70.7 g, 0.70 mol). After an hour of stirring at 0° C., a solution of (R)-glycidol (88% ee, 37.03 g, 0.5 mol) in methylene chloride (100 ml) was added over 0.75 hour. The resulting solution was allowed to warm to ambient temperature and was stirred for 3 hours. It was then filtered, and the filtrate was washed with water (2×500 ml) and brine (2×500 ml). The organic phase was dried over MgSO4 and concentrated to a foam, which on crystallization from isopropyl alcohol gave the title compound (116.2 g, 76.5%) as an off-white powder. to warm to ambient temperature was stirred for 3 hours It was then filtered the filtrate was washed with water (2×500 ml) and brine (2×500 ml) The organic phase was dried over MgSO4 concentrated to a foam, which on crystallization from isopropyl alcohol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 132.6 μl (20 mmol) of (R)-glycidol was added to an ethanol solution (10 ml) containing 608.5 mg (2.0 mmol) of the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 38. The obtained mixture was stirred under heating to reflux overnight. The residue obtained by concentration of the reaction solution was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain 514.3 mg (68%) of 7-((S)-2,3-dihydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a light yellow amorphous substance. under heating to reflux overnight The residue obtained by concentration of the reaction solution was purified by silica gel column chromatography (methylene chloride:methanol=20:1)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-glycidol (5 g, 67.5 mmol) in dry dichloromethane containing triethylamine (10.3 ml, 74 mmol) cooled down to 0° C., was added a solution of tert-butyldimethylsilyl chloride (11.2 g, 74 mmol) in dry dichloromethane (30 ml). Then DMAP ( 0.33 g, 2.7 mmol) was added. The mixture was allowed to warm up to room temperature and stirred for 5 hours. The triethylammonium chloride crystals were filtered out and washed with dichloromethane (2×10 ml). The organic solution was washed with brine (2×50 ml) and dried over anhydrous sodium sulfate. The solution was concentrated and passed though a short silica gel column to remove polar impurities, and eluted with hexane/ethyl acetate (3:2). After removing the solvent, a colourless oil was collected and dried in vacuo to provide pure (S)-glycidyl-tert-butyldimethylsilyl ether (10.3 g, 81.2%). to warm up to room temperature The triethylammonium chloride crystals were filtered out washed with dichloromethane (2×10 ml) The organic solution was washed with brine (2×50 ml) dried over anhydrous sodium sulfate The solution was concentrated to remove polar impurities eluted with hexane/ethyl acetate (3:2) After removing the solvent a colourless oil was collected dried in vacuo