(R)-4-(2-羟乙基)-2,2-二甲基-1,3-二氧戊环

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

实验步骤: The title compound was prepared using the procedure described for Example 2K by using (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (4.28 mL, 30 mmol), CH2Cl2 (100 mL), 2-hydroxyisoindolin-1,3-dione (4.9 g, 30 mmol), triphenylphosphine (11.8 g, 45 mmol), diisopropylazodicarboxylate (8.8 ml, 45 mmol) and hydrazine hydrate (6.0 mL, 60 mmol) to afford 2.1 g (43%, over two steps) of (R)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (2×) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 3H), 1.18 (s, 3H), 1.53-1.71 (m, 2H), 3.53 (m, 2H), 3.79-3.89 (m, 1H), 3.89-4.01 (m, 1H), 4.63-4.81 (m, 1H). MS (ES) [M+H] calculated for C7H16NO3, 162.11. found 162.0. The title compound was prepared

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

实验步骤: The title compound was prepared using the procedure described for Example 2K by using (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (4.28 mL, 30 mmol), CH2Cl2 (100 mL), 2-hydroxyisoindolin-1,3-dione (4.9 g, 30 mmol), triphenylphosphine (11.8 g, 45 mmol), diisopropylazodicarboxylate (8.8 ml, 45 mmol) and hydrazine hydrate (6.0 mL, 60 mmol) to afford 2.1 g (43%, over two steps) of (R)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (2×) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 3H), 1.18 (s, 3H), 1.53-1.71 (m, 2H), 3.53 (m, 2H), 3.79-3.89 (m, 1H), 3.89-4.01 (m, 1H), 4.63-4.81 (m, 1H). MS (ES) [M+H] calculated for C7H16NO3, 162.11. found 162.0. The title compound was prepared

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

实验步骤: To a solution of 1.0 g of methyl 2-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)acetate in 29 ml of diethyl ether, 110 mg of lithium aluminum hydride was added under cooling with ice, followed by 12 hours' stirring at the same temperature. Sodium sulfate decahydrate was added to the reaction liquid which was then stirred for 30 minutes and filtered with Celite. Distilling the solvent off under reduced pressure, 782 mg of the title compound was obtained. under cooling with ice was then stirred for 30 minutes filtered with Celite Distilling the solvent off under reduced pressure

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

实验步骤: To (R)-2,2-dimethyl-1,3-dioxolane-4-ethanol (2.12 g) in 10 mL dioxane was added sodium hydride (0.656 g) at 0° C. The resulting mixture was stirred for 10 minutes, and then 4-Chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 3.213 mmol) was added. The reaction mixture was heated to reflux for one hour, then cooled to room temperature. Water (150 mL) and ethyl acetate (300 mL) was added, and the layers separated. The aqueous layer was washed four times with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (20% to 30% EtOAc in hexanes) to yield 1.03 g of 3-(2-Chloro-phenyl)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=407. Mp.=119.5-122.3° C. The reaction mixture was heated to reflux for one hour the layers separated The aqueous layer was washed four times with ethyl acetate the combined organic layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography (20% to 30% EtOAc in hexanes)

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

实验步骤: A mixture of (R)-(+)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml, 2724 mmol) and p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) was stirred at room temperature for 16.5 hours. To the reaction mixture, triethylamine was added and the mixture was concentrated. The crude product was purified by silica gel column chromatography (silica gel, elution solvent: heptane/ethyl acetate=1/0→1/1→1/3 gradient). Desired fractions were concentrated to obtain the title compound (29.9 g, 72.3% yield) as a colorless oil. the mixture was concentrated The crude product was purified by silica gel column chromatography (silica gel, elution solvent: heptane/ethyl acetate=1/0→1/1→1/3 gradient) Desired fractions were concentrated

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

实验步骤: To (R)-2,2-dimethyl-1,3-dioxolane-4-ethanol (2.12 g) in 10 mL dioxane was added sodium hydride (0.656 g) at 0° C. The resulting mixture was stirred for 10 minutes, and then 4-Chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 3.213 mmol) was added. The reaction mixture was heated to reflux for one hour, then cooled to room temperature. Water (150 mL) and ethyl acetate (300 mL) was added, and the layers separated. The aqueous layer was washed four times with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (20% to 30% EtOAc in hexanes) to yield 1.03 g of 3-(2-Chloro-phenyl)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=407. Mp.=119.5-122.3° C. The reaction mixture was heated to reflux for one hour the layers separated The aqueous layer was washed four times with ethyl acetate the combined organic layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography (20% to 30% EtOAc in hexanes)

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

实验步骤: A mixture of (R)-(+)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml, 2724 mmol) and p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) was stirred at room temperature for 16.5 hours. To the reaction mixture, triethylamine was added and the mixture was concentrated. The crude product was purified by silica gel column chromatography (silica gel, elution solvent: heptane/ethyl acetate=1/0→1/1→1/3 gradient). Desired fractions were concentrated to obtain the title compound (29.9 g, 72.3% yield) as a colorless oil. the mixture was concentrated The crude product was purified by silica gel column chromatography (silica gel, elution solvent: heptane/ethyl acetate=1/0→1/1→1/3 gradient) Desired fractions were concentrated

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flask cooled to −78° C. under N2 was added 2-butyne gas via syringe needle until approximately ˜3 mL of liquid had condensed in the flask. THF (120 mL) was then added followed by DMPU (18.9 ml, 156 mmol). The flask was purged with N2 and n-butyllithium (2.5M hexanes, 18.7 ml, 46.9 mmol) was added via syringe over 5 min and stirred for an additional 15 min at which time (R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (10.0 g, 39.1 mmol) was added as a solution in THF (30 mL) [preparation of enantiopure (R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane from commercially available (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol was performed using the procedure described by: Taber. D. F.; Xu, M.; Hartnett, J. C. J. Am. Chem. Soc. 2002, 124, 13121]. The reaction was slowly warmed to rt and stirred a total of 3 h. The mixture was quenched with sat. NH4Cl, and extracted with Et2O (2×). The organics were washed with H2O, and brine, dried over MgSO4, filtered, and concentrated. The material was purified by silica gel chromatography (5% EtOAc in hexanes gradient to 15% EtOAc in hexanes) to give (R)-4-(hex-3-ynyl)-2,2-dimethyl-1,3-dioxolane as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.19 (1H, m), 4.08 (1H, dd, J=8.0, 6.0 Hz), 3.58 (1H, dd, J=7.6, 6.8 Hz), 2.26 (2H, m), 2.15 (2H, qt, J=5.2, 2.4 Hz), 1.81 (1H, m), 1.68 (1H, m), 1.40 (3H, s), 1.36 (3H, s), 1.11 (3H, t, J=7.6 Hz). condensed in the flask was added via syringe over 5 min The reaction was slowly warmed to rt The mixture was quenched with sat. NH4Cl extracted with Et2O (2×) The organics were washed with H2O, and brine dried over MgSO4 filtered concentrated The material was purified by silica gel chromatography (5% EtOAc in hexanes gradient to 15% EtOAc in hexanes)

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

实验步骤: To (R)-2,2-dimethyl-1,3-dioxolane-4-ethanol (2.12 g) in 10 mL dioxane was added sodium hydride (0.656 g) at 0° C. The resulting mixture was stired for 10 minutes, and then 4-Chloro-3-(2-chloro-phenyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 3.213 mmol) was added. The reaction mixture was heated to reflux for one hour, then cooled to room temperature. Water (150 mL) and ethyl acetate (300 mL) was added, and the layers separated. The aqueous layer was washed four times with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (20% to 30% EtOAc in hexanes) to yield 1.03 g of 3-(2-Chloro-phenyl)4-(2,2-dimethyl-[1,3]dioxolan 4-ylmethoxy)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=407. Mp.=119.5-122.3° C. The reaction mixture was heated to reflux for one hour the layers separated The aqueous layer was washed four times with ethyl acetate the combined organic layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography (20% to 30% EtOAc in hexanes)

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

实验步骤: The title compound was prepared using the procedure described for Example 2K by using (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (4.28 mL, 30 mmol), CH2Cl2 (100 mL), 2-hydroxyisoindoline-1,3-dione (4.9 g, 30 mmol), triphenylphosphine (11.8 g, 45 mmol), diisopropylazodicarboxylate (8.8 ml, 45 mmol) and hydrazine hydrate (6.0 mL, 60 mmol) to afford 2.1 g (43%, over two steps) of (R)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (2X) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 3H), 1.18 (s, 3H), 1.53-1.71 (m, 2H), 3.53 (m, 2H), 3.79-3.89 (m, 1H), 3.89-4.01 (m, 1H), 4.63-4.81 (m, 1H). MS (ES) [M+H] calculated for C2H16NO3, 162.11; found 162.0. The title compound was prepared

反应条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The mixture of [2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (80 mg, 0.13 mmol), methanesulfonic acid 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (437 mg, 1.95 mmol, prepared from 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol and methanesulfonyl chloride in the present of triethylamine) and diisopropylethylamine (110 uL, 0.65 mmol) in dry dimethylformamide (3 mL) was heated in the microwave at 180° C. for 20 min. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (5×) and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the crude residue by flash column chromatography (silica gel, eluting with ethyl acetate and hexane) gave rac-[(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-{4-[2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-piperazin-1-yl}-methanone (45 mg). Upon cooling to room temperature washed with water (5×) and brine The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure Purification of the crude residue by flash column chromatography (silica gel, eluting with ethyl acetate and hexane)

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

实验步骤: Triphenyl phosphine (5.94 g, 22.65 mmol) and imidazole (22.65 mmol) were dissolved in a mixed solution (120 ml) of diethyl ether-acetonitrile (3:1). Iodine (5.75 g, 22.65 mmol) was added thereto under cooling on ice and the mixture was stirred at room temperature for 30 minutes. The solution was cooled on ice again, (4R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (3.0 mmol, 20.59 mmol) was added thereto and the mixture was stirred at room temperature for 24 hours. A saturated sodium thiosulfate aqueous solution was added to the reaction solution under cooling on ice and stirred for a while, the solution was extracted with diethyl ether and the extract was washed with saturated sodium chloride solution. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 3.20 g (61%) of the title compound in the form of a yellowish oily product. under cooling on ice The solution was cooled on ice again the mixture was stirred at room temperature for 24 hours under cooling on ice stirred for a while the solution was extracted with diethyl ether the extract was washed with saturated sodium chloride solution The solvent was removed under reduced pressure the residue was purified by silica gel column chromatography (hexane/ethyl acetate)