(S)-2-(BOC-氨基)-4-碘丁酸甲酯

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (S)-2-tert-butoxycarbonylamino-4-iodobutyric acid methyl ester (0.200 g, 0.58 mmol), (2-methoxyethyl)-methylamine (0.062 g, 0.70 mmol), and triethylamine (0.41 mL, 2.9 mmol) in dioxane (1 mL) was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in dichloromethane (20 mL). The solution was washed with water (3×10 mL), brine (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure. The tan oil was chromatographed eluting with ether to provide 0.87 g of pale yellow oil (49% yield). The mixture was cooled to room temperature concentrated under reduced pressure dissolved in dichloromethane (20 mL) The solution was washed with water (3×10 mL), brine (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure The tan oil was chromatographed eluting with ether

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield). The mixture was then cooled to room temperature concentrated under reduced pressure partitioned between water (10 mL) and ether (40 mL) The layers were separated the organic layer was washed with water (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield). The mixture was then cooled to room temperature concentrated under reduced pressure partitioned between water (10 mL) and ether (40 mL) The layers were separated the organic layer was washed with water (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (S)-2-tert-butoxycarbonylamino-4-iodobutyric acid methyl ester (0.200 g, 0.58 mmol), (2-methoxyethyl)-methylamine (0.062 g, 0.70 mmol), and triethylamine (0.41 mL, 2.9 mmol) in dioxane (1 mL) was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in dichloromethane (20 mL). The solution was washed with water (3×10 mL), brine (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure. The tan oil was chromatographed eluting with ether to provide 0.87 g of pale yellow oil (49% yield). The mixture was cooled to room temperature concentrated under reduced pressure dissolved in dichloromethane (20 mL) The solution was washed with water (3×10 mL), brine (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure The tan oil was chromatographed eluting with ether

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (S)-2-tert-butoxycarbonylamino-4-iodobutyric acid methyl ester (0.200 g, 0.58 mmol), (2-methoxyethyl)-methylamine (0.062 g, 0.70 mmol), and triethylamine (0.41 mL, 2.9 mmol) in dioxane (1 mL) was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in dichloromethane (20 mL). The solution was washed with water (3×10 mL), brine (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure. The tan oil was chromatographed eluting with ether to provide 0.87 g of pale yellow oil (49% yield). The mixture was cooled to room temperature concentrated under reduced pressure dissolved in dichloromethane (20 mL) The solution was washed with water (3×10 mL), brine (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure The tan oil was chromatographed eluting with ether

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield). The mixture was then cooled to room temperature concentrated under reduced pressure partitioned between water (10 mL) and ether (40 mL) The layers were separated the organic layer was washed with water (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure

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

实验步骤: To a dry 2-5 mL microwave vial under N2 is added tert-butyl (5-formylthiazol-2-yl)carbamate (100 mg, 0.438 mmol) and anhydrous DMF (2.5 mL). The resulting dark solution stirred at room temp for 5 min, treated with sodium hydride (22.13 mg, 0.876 mmol), flushed with N2 for 15 min, then treated with material from Example 115 (301 mg, 0.876 mmol) and securely capped. The resulting dark solution is stirred at room temp for 30 min, then heated in a microwave heating unit for 15 min at 80° C. under high power. The reaction is diluted with ethyl acetate (200 mL), washed with water (6×25 mL), brine (1×25 mL), dried over Na2SO4, filtered, the solvent removed in vacuo and the resulting residue purified by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge using 100% CH2Cl2 to 75% EtOAc/CH2Cl2 over 11 column volumes to give 176.7 mg (91%) of the title compound as a thick oil, LC/MS (Condition A): ret. T=3.83 min, (M+Na) 466. flushed with N2 for 15 min securely capped The resulting dark solution is stirred at room temp for 30 min heated in a microwave heating unit for 15 min at 80° C. under high power washed with water (6×25 mL), brine (1×25 mL) dried over Na2SO4 filtered the solvent removed in vacuo the resulting residue purified by BIOTAGE® Silica gel chromatography on a 25 g Thompson Single Step silica cartridge

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

实验步骤: To an ice cold suspension of (S)-methyl 2-amino-4-bromobutanoate, 1.00 HCl (see WO2003/101948 A2, 4.42 g, 19.02 mmol) and N,N-diisopropylethylamine (9.97 mL, 57.1 mmol) in anhydrous THF (50 mL) is slowly added a solution of di-tert-butyldicarbonate (4.36 g, 19.97 mmol) in anhydrous THF (8 mL). The reaction is stirred for 18 h while warming to room temp. The solvent is removed in vacuo, and the residue is partitioned between EtOAc (450 mL) and aqueous saturated ammonium chloride (30 ml). The organic layer is washed with aqueous saturated sodium bicarbonate (1×30 mL), water (1×30 mL), brine (1×30 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue is dissolved in acetone (450 mL). treated with sodium iodide (14.25 g, 95.1 mmol) and the reaction is refluxed for 18 h. The reaction is cooled to room temp, filtered thru a ground glass frit and the solvent removed in vacuo. The residue is dissolved in EtOAc (450 mL), washed with water (3×40 mL), brine (1×40 mL), dried over Na2SO4, filtered, evaporated to dryness and purified by BIOTAGE® Silica gel chromatography on a 80 g Thompson Single Step silica cartridge using 100% CH2Cl2 over 10 column volumes to give 3.9 g (60%) of the title compound as a thick oil. LC/MS (Condition A): ret. T=3.40 min, (M+Na) 366. The solvent is removed in vacuo the residue is partitioned between EtOAc (450 mL) and aqueous saturated ammonium chloride (30 ml) The organic layer is washed with aqueous saturated sodium bicarbonate (1×30 mL), water (1×30 mL), brine (1×30 mL) dried over Na2SO4 filtered evaporated to dryness The residue is dissolved in acetone (450 mL) the reaction is refluxed for 18 h The reaction is cooled to room temp filtered thru a ground glass frit the solvent removed in vacuo The residue is dissolved in EtOAc (450 mL) washed with water (3×40 mL), brine (1×40 mL) dried over Na2SO4 filtered evaporated to dryness purified by BIOTAGE® Silica gel chromatography on a 80 g Thompson Single Step silica cartridge

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (S)-2-tert-butoxycarbonylamino-4-iodobutyric acid methyl ester (0.200 g, 0.58 mmol), (2-methoxyethyl)-methylamine (0.062 g, 0.70 mmol), and triethylamine (0.41 mL, 2.9 mmol) in dioxane (1 mL) was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in dichloromethane (20 mL). The solution was washed with water (3×10 mL), brine (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure. The tan oil was chromatographed eluting with ether to provide 0.87 g of pale yellow oil (49% yield). The mixture was cooled to room temperature concentrated under reduced pressure dissolved in dichloromethane (20 mL) The solution was washed with water (3×10 mL), brine (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure The tan oil was chromatographed eluting with ether

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield). The mixture was then cooled to room temperature concentrated under reduced pressure partitioned between water (10 mL) and ether (40 mL) The layers were separated the organic layer was washed with water (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (S)-2-tert-butoxycarbonylamino-4-iodobutyric acid methyl ester (0.200 g, 0.58 mmol), (2-methoxyethyl)-methylamine (0.062 g, 0.70 mmol), and triethylamine (0.41 mL, 2.9 mmol) in dioxane (1 mL) was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in dichloromethane (20 mL). The solution was washed with water (3×10 mL), brine (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure. The tan oil was chromatographed eluting with ether to provide 0.87 g of pale yellow oil (49% yield). The mixture was cooled to room temperature concentrated under reduced pressure dissolved in dichloromethane (20 mL) The solution was washed with water (3×10 mL), brine (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure The tan oil was chromatographed eluting with ether

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (S)-4-bromo-2-tert-butoxycarbonylaminobutyric acid methyl ester (1.19 g, 4.0 mmol) (Example 120, Steps A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 mL) was heated to 70° C. for 2 hours. The mixture was then cooled to room temperature, concentrated under reduced pressure and partitioned between water (10 mL) and ether (40 mL). The layers were separated and the organic layer was washed with water (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure to afford 1.26 g of the product (92% yield). The mixture was then cooled to room temperature concentrated under reduced pressure partitioned between water (10 mL) and ether (40 mL) The layers were separated the organic layer was washed with water (10 mL) dried over MgSO4 filtered through Celite concentrated under reduced pressure