(2R)-2-(恶烷-2-酰氧基)丙-1-醇

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

实验步骤: A solution of 2-O-tetrahydropyranyl-(R)-propane-1,2-diol(67.2 g, 0.42 mol) in pyridine (600 ml) was placed in a 2 l round-bottom flask with magnetic stirring rod and 500 ml dropping funnel with a side-tubing, protected by calcium chloride tube. 4-Dimethylaminopyridine (2 g) was added, the flask was placed in an ice-water cooling bath and a solution of p-toluenesulfonyl chloride (91 g, 0.477 mol) in pyridine (300 ml) was added over 1 hour under stirring. The mixture was stirred under ice-cooling for additional 3 hours and left to stand overnight in a refrigerator at 4° C. Water (20 ml) was then added to the mixture and, after standing for 1 hour, pyridine (approx. 300 ml) was distilled off in vacuo. The residue was diluted by ethyl acetate (2.5 l) and shaken with water (300 ml). After separation of the lower aqueous layer, the organic phase was washed with water (two 300 ml portions), evaporated in vacuo and the residue co-evaporated with toluene (four 250-ml-portions) in vacuo. The remaining amber oil was purified by chromatography over silica gel (eluting with chloroform) to afford 122 g (0.39 mol, 93%) of (R)-2-O-tetrahydropyranyl-1-O-p-toluenesulfonylpropane-1,2 diol as a thick colorless oil, RF 0.60 (TLC, chloroform). This product was stored at +4° C. for several months without obvious decomposition. For C15H22OS (MW 314,4) calculated: C,57.30; H,7.05; S,10.20. Found: C,57.15; H,7.22; S,10.52. protected by calcium chloride tube the flask was placed in an ice-water cooling bath The mixture was stirred under ice- cooling for additional 3 hours left after standing for 1 hour pyridine (approx. 300 ml) was distilled off in vacuo The residue was diluted by ethyl acetate (2.5 l) shaken with water (300 ml) After separation of the lower aqueous layer the organic phase was washed with water (two 300 ml portions) evaporated in vacuo The remaining amber oil was purified by chromatography over silica gel (eluting with chloroform)

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

实验步骤: To an ice-cooled suspension of 720 mg of sodium hydride (60%) in 12 ml of anhydrous toluene was added dropwise a solution of 2.88 g of 2-O-tetrahydropyranyl-(R)-propane-1,2-diol (IIIR, Rc=THP) in 12 ml of anhydrous toluene, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 10 minutes. The mixture was added dropwise to a solution of 2.66 g of 2,3,4-trifluoronitrobenzene in 12 ml of anhydrous toluene with stirring under cooling with ice. The mixture was stirred at an external temperature of 5° C. for 24 hours. To the mixture were added ice-water and benzene, and the resulting mixture was shaken. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield 2,3-difluoro-6-nitro-{[(R)-2-(tetrahydropyran-2-yl)oxypropyl]oxy}benzene (IR, Xa=Xb=F, Rc=THP) in quantitative yield. This compound was dissolved in 38 ml of anhydrous ethanol and to this was added 450 mg of pyridinium tosylate. The mixture was heated under refluxing for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed successively with 1 N hydrochloric acid, a 5% sodium bicarbonate aqueous solution and water, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 3.20 g of the oily titled compound. with stirring under cooling with ice The mixture was stirred at an external temperature of 5° C. for 24 hours the resulting mixture was shaken The organic layer was separated dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure

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

实验步骤: To an ice-cooled suspension of 720 mg of sodium hydride (60%) in 12 ml of anhydrous toluene was added dropwise a solution of 2.88 g of 2-O-tetrahydropyranyl-(R)-propane-1,2-diol (IIIR, Rc=THP) in 12 ml of anhydrous toluene, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 10 minutes. The mixture was added dropwise to a solution of 2.66 g of 2,3,4-trifluoronitrobenzene in 12 ml of anhydrous toluene with stirring under cooling with ice. The mixture was stirred at an external temperature of 5° C. for 24 hours. To the mixture were added ice-water and benzene, and the resulting mixture was shaken. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield 2,3-difluoro-6-nitro-{[(R)-2-(tetrahydropyran-2-yl)oxypropyl]oxy}benzene (IR, Xa=Xb=F, Rc=THP) in quantitative yield. This compound was dissolved in 38 ml of anhydrous ethanol and to this was added 450 mg of pyridinium tosylate. The mixture was heated under refluxing for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed successively with 1 N hydrochloric acid, a 5% sodium bicarbonate aqueous solution and water, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 3.20 g of the oily titled compound. with stirring under cooling with ice The mixture was stirred at an external temperature of 5° C. for 24 hours the resulting mixture was shaken The organic layer was separated dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure

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

实验步骤: A solution of 2-O-tetrahydropyrany-(R)-propane-1,2-diol(67.2 g, 0.42 mol) in pyridine (600 ml) was placed in a 2 l round-bottom flask with magnetic stirring rod and 500 ml dropping funnel with a side-tubing, protected by calcium chloride tube. 4-Dimethylaminopyridine (2 g) was added, the flask was placed in an ice-water cooling bath and a solution of p-toluenesulfonyl chloride (91 g, 0.477 mol) in pyridine (300 ml) was added over 1 hour under stirring. The mixture was stirred under ice-cooling for additional 3 hours and left to stand overnight in a refrigerator at 4° C. Water (20 ml) was then added to the mixture and, after standing for 1 hour, pyridine (approx. 300 ml) was distilled off in vacuo. The residue was diluted by ethyl acetate (2.5 l) and shaken with water (300 ml). After separation of the lower aqueous layer, the organic phase was washed with water (two 300 ml portions), evaporated in vacuo and the residue co-evaporated with toluene (four 250-ml-portions) in vacuo. The remaining amber oil was purified by chromatography over silica gel (eluting with chloroform) to afford 122 g (0.39 mol, 93%) of (R)-2-O-tetrahydropyrany-1-O-p-toluenesulfonylpropane-1,2 diol as a thick colorless oil, RF 0.60 (TLC, chloroform). This product was stored at +4° C. for several months without obvious decomposition. For C15H22OS (MW 314,4) calculated: C,57.30; H,7.05; S,10.20. Found: C,57.15; H,7.22; S,10.52. protected by calcium chloride tube the flask was placed in an ice-water cooling bath The mixture was stirred under ice- cooling for additional 3 hours left after standing for 1 hour pyridine (approx. 300 ml) was distilled off in vacuo The residue was diluted by ethyl acetate (2.5 l) shaken with water (300 ml) After separation of the lower aqueous layer the organic phase was washed with water (two 300 ml portions) evaporated in vacuo The remaining amber oil was purified by chromatography over silica gel (eluting with chloroform)

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

实验步骤: To a stirred mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (80 mg) and (R)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol (100 μL) in dry DMF (1 mL) was added NaH (40 mg, dispersion in mineral oil) and the mixture was stirred at room temperature for 1 h. Then, water (10 mL) was added and the reaction mixture stirred for 10 minutes. The precipitated solid was filtered and dissolved in 1:1 mixture of methanol and DCM (5 mL). To this was added 2 M solution of hydrochloric acid in methanol (1 mL) and stirred at room temperature for 2 h. After air drying, the product was purified by column chromatography (12 g pre-packed silica gel column cartridge) using DCM and 2N ammonia in methanol to afford 6-((R)-2-hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (37 mg). LCMS (m/z): 532. 1H NMR (400 MHz, DMSO-d6): δ 12.5 and 11.5 (1H, brs) 8.85 (1H, s) 8.15 (1H, d) 7.92 (1H, brs) 7.87-7.93 (3H, m) 7.55-7.63 (2H, m) 7.08 (1H, d) 5.01 (1H, d) 4.17 (2H, d) 4.03-4.07 (1H, m) 1.18 (3H, d). the reaction mixture stirred for 10 minutes The precipitated solid was filtered dissolved in 1:1 mixture of methanol and DCM (5 mL) To this was added 2 M solution of hydrochloric acid in methanol (1 mL) stirred at room temperature for 2 h After air drying the product was purified by column chromatography (12 g pre-packed silica gel column cartridge)

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

实验步骤: To a stirred solution of (R)-2-hydroxy-propionic acid methyl ester (10 g) and 3,4-dihydro-2H-pyran (15 mL) in DCM (400 mL) was added camphorsulfonic acid (50 mg) (exothermic reaction). The reaction mixture was stirred at ambient temperature for 2 hours, and washed with saturated bicarbonate solution (20 mL). The organic layer was dried, filtered and concentrated to obtain crude (R)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester, which was used as is in the next step. To a stirred suspension of LAH (4 g) in anhydrous ether (400 mL) at 0-5° C. was added (R)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester dropwise over 30 minute period. After completion of the addition, the cold bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was cooled to 0-5° C., and ethyl acetate was added dropwise to quench excess LAH, which was followed by the addition of saturated sodium sulfate solution and solid sodium sulfate. The resulting mixture was stirred at room temperature for 1 hour, the solid was filtered off, and the solid was washed with ether. The combined organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by column chromatography using a silica gel stationary phase (pre-treated with 0.1 triethylamine in hexanes) and hexanes in ethyl acetate to get (R)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol. 1H NMR (400 MHz, CDCl3): δ 4.51-4.75 (1H, m) 3.76-4.02 (2H, m) 3.42-3.62 (3H, m) 1.67-1.90 (2H, m) 1.46-1.63 (4 h, m) 1.10-1.24 (3H, m). After completion of the addition the cold bath was removed The resulting mixture was cooled to 0-5° C. ethyl acetate was added dropwise to quench excess LAH, which was followed by the addition of saturated sodium sulfate solution and solid sodium sulfate The resulting mixture was stirred at room temperature for 1 hour the solid was filtered off the solid was washed with ether The combined organic layer was dried over Na2SO4 filtered concentrated the residue was purified by column chromatography

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

实验步骤: (2R)-2-tetrahydropyranyloxy-1-hydroxypropane (60 g, 0.37 mol) was dropwise added to a suspension of sodium hydride (60%) (22 g) in THF (100 ml) under ice cooling. After completion of the dropwise addition, a solution of benzyl bromide (70 g) in DMF (300 ml) was dropwise added, followed by agitating the mixture at room temperature for 6 hours, pouring it into water (500 ml), extracting with toluene (300 ml), washing the resulting organic layer with water, concentrating it, dissolving the concentrate in ethanol (300 ml), adding 6N-hydrochloric acid (20 ml), agitating the mixture at 20° C. for 2 hours, distilling off ethanol, adding toluene (300 ml), washing the resulting organic layer with an alkali and then with water and distilling it under reduced pressure to obtain (R)-1-benzyloxy-2-propanol (b.p. 105°-107° C./5 mmHg) (28 g). After completion of the dropwise addition extracting with toluene (300 ml) washing the resulting organic layer with water concentrating it dissolving the concentrate in ethanol (300 ml) adding 6N-hydrochloric acid (20 ml) agitating the mixture at 20° C. for 2 hours distilling off ethanol adding toluene (300 ml) washing the resulting organic layer with an alkali and then with water distilling it under reduced pressure

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

实验步骤: A solution of 2-O-tetrahydropyranyl-(R)-propane-1,2-diol(67.2 g, 0.42 mol) in pyridine (600 ml) was placed in a 2 l round-bottom flask with magnetic stirring rod and 500 ml dropping funnel with a side-tubing, protected by calcium chloride tube. 4-Dimethylaminopyridine (2 g) was added, the flask was placed in an ice-water cooling bath and a solution of p-toluenesulfonyl chloride (91 g, 0.477 mol) in pyridine (300 ml) was added over 1 hour under stirring. The mixture was stirred under ice-cooling for additional 3 hours and left to stand overnight in a refrigerator at 4° C. Water (20 ml) was then added to the mixture and, after standing for 1 hour, pyridine (approx. 300 ml) was distilled off in vacuo. The residue was diluted by ethyl acetate (2.5 l) and shaken with water (300 ml). After separation of the lower aqueous layer, the organic phase was washed with water (two 300 ml portions), evaporated in vacuo and the residue co-evaporated with toluene (four 250-ml-portions) in vacuo. The remaining amber oil was purified by chromatography over silica gel (eluting with chloroform) to afford 122 g (0.39 mol, 93%) of (R)-2-O-tetrahydropyranyl-1-O-p-toluenesulfonylpropane-1,2 diol as a thick colorless oil, RF 0.60 (TLC, chloroform). This product was stored at +4° C. for several months without obvious decomposition. For C15H22OS (MW 314,4) calculated: C,57.30; H,7.05; S,10.20. Found: C,57.15; H,7.22; S,10.52. protected by calcium chloride tube the flask was placed in an ice-water cooling bath The mixture was stirred under ice- cooling for additional 3 hours left after standing for 1 hour pyridine (approx. 300 ml) was distilled off in vacuo The residue was diluted by ethyl acetate (2.5 l) shaken with water (300 ml) After separation of the lower aqueous layer the organic phase was washed with water (two 300 ml portions) evaporated in vacuo The remaining amber oil was purified by chromatography over silica gel (eluting with chloroform)

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

实验步骤: To an ice-cooled suspension of 720 mg of sodium hydride (60%) in 12 ml of anhydrous toluene was added dropwise a solution of 2.88 g of 2-O-tetrahydropyranyl-(R)-propane-1,2-diol (IIIR, Rc=THP) in 12 ml of anhydrous toluene, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 10 minutes. The mixture was added dropwise to a solution of 2.66 g of 2,3,4-trifluoronitrobenzene in 12 ml of anhydrous toluene with stirring under cooling with ice. The mixture was stirred at an external temperature of 5° C. for 24 hours. To the mixture were added ice-water and benzene, and the resulting mixture was shaken. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield 2,3-difluoro-6-nitro-{[(R)-2-(tetrahydropyran-2-yl)oxypropyl]oxy}benzene (IR, Xa=Xb=F, Rc=THP) in quantitative yield. This compound was dissolved in 38 ml of anhydrous ethanol and to this was added 450 mg of pyridinium tosylate. The mixture was heated under refluxing for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed successively with 1 N hydrochloric acid, a 5% sodium bicarbonate aqueous solution and water, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 3.20 g of the oily titled compound. with stirring under cooling with ice The mixture was stirred at an external temperature of 5° C. for 24 hours the resulting mixture was shaken The organic layer was separated dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure

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

实验步骤: A solution of 2-O-tetrahydropyrany-(R)-propane-1,2-diol(67.2 g, 0.42 mol) in pyridine (600 ml) was placed in a 2 l round-bottom flask with magnetic stirring rod and 500 ml dropping funnel with a side-tubing, protected by calcium chloride tube. 4-Dimethylaminopyridine (2 g) was added, the flask was placed in an ice-water cooling bath and a solution of p-toluenesulfonyl chloride (91 g, 0.477 mol) in pyridine (300 ml) was added over 1 hour under stirring. The mixture was stirred under ice-cooling for additional 3 hours and left to stand overnight in a refrigerator at 4° C. Water (20 ml) was then added to the mixture and, after standing for 1 hour, pyridine (approx. 300 ml) was distilled off in vacuo. The residue was diluted by ethyl acetate (2.5 l) and shaken with water (300 ml). After separation of the lower aqueous layer, the organic phase was washed with water (two 300 ml portions), evaporated in vacuo and the residue co-evaporated with toluene (four 250-ml-portions) in vacuo. The remaining amber oil was purified by chromatography over silica gel (eluting with chloroform) to afford 122 g (0.39 mol, 93%) of (R)-2-O-tetrahydropyrany-1-O-p-toluenesulfonylpropane-1,2 diol as a thick colorless oil, RF 0.60 (TLC, chloroform). This product was stored at +4° C. for several months without obvious decomposition. For C15H22OS (MW 314,4) calculated: C,57.30; H,7.05; S,10.20. Found: C,57.15; H,7.22; S,10.52. protected by calcium chloride tube the flask was placed in an ice-water cooling bath The mixture was stirred under ice- cooling for additional 3 hours left after standing for 1 hour pyridine (approx. 300 ml) was distilled off in vacuo The residue was diluted by ethyl acetate (2.5 l) shaken with water (300 ml) After separation of the lower aqueous layer the organic phase was washed with water (two 300 ml portions) evaporated in vacuo The remaining amber oil was purified by chromatography over silica gel (eluting with chloroform)