叔-正丁基-[(2R)-1-羟丙烷-2-基]氨基甲酸酯

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

实验步骤: To a solution of tert-butyl N-[(1R)-2-hydroxy-1-methyl-ethyl]carbamate (1.9 g, 10.8 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.0 g, 7.7 mmol), and PPh3 (6.1 g, 23.2 mmol) in THF (80 mL) cooled with an ice bath was added DIAD (3.0 mL, 15.5 mmol; in 28 mL of THF) dropwise over a 1 hour period. The reaction was then stirred for 24 h at room temperature. The mixture was diluted into ethyl acetate (50 mL) and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting material was suspended in 20% ethyl acetate in dioxane (1000 mL) and sonicate for 1 hr. The solid was collected by filtration to obtain 2.1 g (66%) of tert-butyl N-[(1R)-2-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)-1-methyl-ethyl]carbamate as a white solid. washed with water and brine The organic layer was dried (MgSO4) filtered concentrated sonicate for 1 hr The solid was collected by filtration

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-[(R)-N-tertobutyloxycarbonylamino]-1-propylamine was prepared by standard synthetic steps from (R)-2-(N-tert-butyloxycarbonylamino)-1-propanol by Mitsunobu reaction with phthalimide followed by reaction with hydrazine hydrate. This amine (0.52 g, 3.0 mmol) and 2-chlorobenzothiazole (0.76 g, 4.5 mmol) were dissolved in dioxan (20 ml) and triethylamine (0.83 ml, 6.0 mmol) was introduced. The reaction mixture was heated at 50° C. for 18 h, evaporated and purified by "flash" column chromatography, eluting with heptane/ethyl acetate (10:3) to provide the 2-[(R)-2-(N-tert-butyloxycarbonylamino)-1-propylamino]benzothiazole (0.09 g, 10%) as an oil, TLC Rf 0.31 [SiO2 ; hexane/ethyl acetate (10:3)]. evaporated purified by "flash" column chromatography eluting with heptane/ethyl acetate (10:3)

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

实验步骤: 740 mg of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate was dissolved in 30 mL of tetrahydrofuran in a nitrogen atmosphere, and 1.44 g of N-(2-chlorophenethyl)-2-nitrobenzenesulfonamide and 3.3 g of triphenylphosphine were added thereto. 2.5 mL of diisopropyl azodicarboxylate was added thereto at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue (intermediate) was dissolved in 20 mL of dichloromethane. To the solution, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane (30 mL×3). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 380 mg of the title compound as a pale yellow oil (23%). were added The reaction solution was concentrated under reduced pressure the obtained residue (intermediate) was dissolved in 20 mL of dichloromethane To the solution, 2 mL of trifluoroacetic acid was added the mixture was stirred at room temperature for 6 hours followed by extraction with dichloromethane (30 mL×3) The organic layer was dried over anhydrous sodium sulfate After filtration the filtrate was concentrated under reduced pressure The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1)

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

实验步骤: ((R)-2-Hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (0.5 g, 2.85 mmol) was dissolved in dichloromethane (14 ml) and stirred in an ice bath. N,N-diisopropylethylamine (0.75 ml, 4.28 mmol) and then methanesulfonyl chloride (0.27 ml, 3.4 mmol) were slowly added and the reaction was warmed to room temperature over 16 h. Ammonium chloride solution was added to the reaction and it was extracted two times with ethyl acetate. The combined organics were washed with sodium chloride solution and dried over sodium sulfate. Evaporation gave 0.73 g of methanesulfonic acid (R)-2-tert-butoxycarbonylamino-propyl ester as a waxy white solid. 1H NMR (CDCl3) δ: 4.51-4.68 (m, 1H), 4.19-4.28 (m, 1H), 4.11-4.18 (m, 1H), 3.90-4.04 (m, 1H), 3.03 (s, 3H), 1.24 (d, J=6.8 Hz, 3H). was extracted two times with ethyl acetate The combined organics were washed with sodium chloride solution dried over sodium sulfate Evaporation

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

实验步骤: ((R)-2-Hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (0.5 g, 2.85 mmol) was dissolved in dichloromethane (14 ml) and stirred in an ice bath. N,N-diisopropylethylamine (0.75 ml, 4.28 mmol) and then methanesulfonyl chloride (0.27 ml, 3.4 mmol) were slowly added and the reaction was warmed to room temperature over 16 h. Ammonium chloride solution was added to the reaction and it was extracted two times with ethyl acetate. The combined organics were washed with sodium chloride solution and dried over sodium sulfate. Evaporation gave 0.73 g of methanesulfonic acid (R)-2-tert-butoxycarbonylamino-propyl ester as a waxy white solid. 1H NMR (CDCl3) δ: 4.51-4.68 (m, 1H), 4.19-4.28 (m, 1H), 4.11-4.18 (m, 1H), 3.90-4.04 (m, 1H), 3.03 (s, 3H), 1.24 (d, J=6.8 Hz, 3H). was extracted two times with ethyl acetate The combined organics were washed with sodium chloride solution dried over sodium sulfate Evaporation

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

实验步骤: Diethylazodicarboxylate (328 μL, 2.09 mmol) in THF (1 mL) was added slowly to a solution of 2,6-difluoro-3-nitrophenol (243 mg, 1.39 mmol), ((R)-2-hydroxy-1-methyl-ethyl)carbamic acid tert-butyl ester (292 mg, 1.67 mmol) and triphenylphosphine (547 mg, 2.09 mmol) in THF (10 mL) at 0° C. The solution was stirred for 30 min at 0° C., then concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound as a pale yellow oil (333 mg, 72%). 1H NMR (CDCl3, 300 MHz): δ 7.82 (1H, ddd, J=13.0, 9.4, 5.3 Hz), 7.04 (1H, app. td, J=9.4, 2.2 Hz), 4.76 (1H, br s), 4.23-4.12 (2H, m), 4.07-3.95 (1H, m), 1.44 (9H, s), 1.34 (3H, d, J=6.8 Hz) concentrated in vacuo The residue was purified by flash chromatography (Si—PPC, gradient 0-30% EtOAc in cyclohexane)

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

实验步骤: Diethylazodicarboxylate (328 μL, 2.09 mmol) in THF (1 mL) was added slowly to a solution of 2,6-difluoro-3-nitrophenol (243 mg, 1.39 mmol), ((R)-2-hydroxy-1-methyl-ethyl)carbamic acid tert-butyl ester (292 mg, 1.67 mmol) and triphenylphosphine (547 mg, 2.09 mmol) in THF (10 mL) at 0° C. The solution was stirred for 30 min at 0° C., then concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound as a pale yellow oil (333 mg, 72%). 1H NMR (CDCl3, 300 MHz): δ 7.82 (1H, ddd, J=13.0, 9.4, 5.3 Hz), 7.04 (1H, app. td, J=9.4, 2.2 Hz), 4.76 (1H, br s), 4.23-4.12 (2H, m), 4.07-3.95 (1H, m), 1.44 (9H, s), 1.34 (3H, d, J=6.8 Hz) concentrated in vacuo The residue was purified by flash chromatography (Si—PPC, gradient 0-30% EtOAc in cyclohexane)

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

实验步骤: Following the procedure of example 47A, but replacing N-(tert-butoxycarbonyl)L-alaninol with N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with propionyl chloride, provided N-(tert-butoxycarbonyl)-O-propionyl-D-alaninol. This was followed the procedure described in example 47B to give the title compound.

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

实验步骤: Following the procedure of example 47A, but replacing N-(tert-butoxycarbonyl)-L-alaninol with N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with benzoyl chloride, provided N-(tert-butoxycarbonyl)-O-benzoyl-D-alaninol. This was followed the procedure described in example 47B to give the title compound.

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Bromophenol (0.2 g, 1.14 mmol), ((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (0.2 g, 1.14 mmol) and triphenylphosphine (0.45 g, 1.71 mmol) were dissolved in anhydrous toluene (10 ml) under an atmosphere of nitrogen. A solution of di-tert-butyl azodicarboxylate (0.39 g, 1.71 mmol) in toluene (5 ml) was added slowly ensuring that the temperature did not exceed 35° C. The reaction mixture was heated to 80° C. and stirred overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and subsequently washed with 1M HCl, water, brine then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by Flash Chromatography using 10% ethyl acetate/cyclohexane as the elutant gave the final product. Yield 80 mg, 21%. LCMS method: 2, RT: 6.17 min; MI: 330-332 [M+1]. did not exceed 35° C The solvent was removed in vacuo the residue was dissolved in ethyl acetate subsequently washed with 1M HCl, water, brine then dried over magnesium sulfate filtered concentrated in vacuo Purification by Flash Chromatography

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Bromophenol (0.2 g, 1.14 mmol), ((R)-2-hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (0.2 g, 1.14 mmol) and triphenylphosphine (0.45 g, 1.71 mmol) were dissolved in anhydrous toluene (10 ml) under an atmosphere of nitrogen. A solution of di-tert-butyl azodicarboxylate (0.39 g, 1.71 mmol) in toluene (5 ml) was added slowly ensuring that the temperature did not exceed 35° C. The reaction mixture was heated to 80° C. and stirred overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and subsequently washed with 1M HCl, water, brine then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by Flash Chromatography using 10% ethyl acetate/cyclohexane as the elutant gave the final product. Yield 80 mg, 21%. LCMS method: 2, RT: 6.17 min; MI: 330-332 [M+1]. did not exceed 35° C The solvent was removed in vacuo the residue was dissolved in ethyl acetate subsequently washed with 1M HCl, water, brine then dried over magnesium sulfate filtered concentrated in vacuo Purification by Flash Chromatography

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

实验步骤: A solution of Boc-D-Ala—OH (1.0 g, 5.28 mmol) in tetrahydrofuran (10 ml) was added dropwise to a stirred solution of BH3, 1 M in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred for a further hour at 0° C., then quenched with 10% acetic acid in methanol. After solvent evaporation, the crude product was dissolved in ethyl acetate and washed with 1M HCl, water and then 1M sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield 0.39 g, 42%: NMR 1H (300 MHz, CDCl3): 0.97 (d, 3H), 1.36 (s, 9H), 3.14 (m, 1H), 3.29 (m, 1H), 3.40 (m, 1H), 4.57 (m, 1H) quenched with 10% acetic acid in methanol After solvent evaporation the crude product was dissolved in ethyl acetate washed with 1M HCl, water The organic layer was dried over anhydrous magnesium sulfate filtered concentrated in vacuo