chloromethyl propan-2-yl carbonate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Propan-2-ol (785 mg, 13.19 mmol) was added to a solution of chloromethyl chloroformate (1.7 g, 13.19 mmol) in dry ethyl ether (20 mL). The reaction mixture was cooled to 0° C. Pyridine (1.043 g, 13.19 mmol) was added dropwise with stirring. Thereafter, the reaction mixture was stirred at room temperature for 20 hours. The heterogenous mixture was filtered and the filtrate was washed with citric acid 1% (2×20 mL), NaHCO3 1% (2×20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give desired compound (1.71 g, 85%). 1H NMR (CDCl3) δ: 5.69 (s, 2H, ClCH2O), 4.92 (sept, J=6.26 Hz, 1H, OCH(CH3)2), 1.30 (d, J=6.27 Hz, 6H, OCH(CH3)2). 13C NMR (CDCl3) δ: 152.68, 73.60, 71.95, 21.52 (2C). Thereafter, the reaction mixture was stirred at room temperature for 20 hours The heterogenous mixture was filtered the filtrate was washed with citric acid 1% (2×20 mL), NaHCO3 1% (2×20 mL) and brine (20 mL) The organic layer was dried over Na2SO4 filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following a procedure similar to that described in Preparation 22(ii), but using 1.06 g of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid [prepared as described in Preparation 22(i)] and 0.83 g of isopropoxycarbonyloxymethyl chloride, 1.22 g of the title compound, melting at 144°-146° C., were obtained.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following a procedure similar to that described in Preparation 22(ii), but using 1.06 g of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid [prepared as described in Preparation 22(i)] and 0.83 g of isopropoxycarbonyloxymethyl chloride, 1.22 g of the title compound, melting at 144°-146° C., were obtained.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold solution (approximately 10° C.) of chloromethylchloroformate (65 mL) in diethyl ether (1.4 L) was added isopropanol (56 mL) followed by a dropwise addition of pyridine (60 mL). After the addition the cold bath was removed and the reaction mixture was stirred for 18 h. The reaction mixture was poured into a separation funnel containing cold water (100 mL). The ether layer was separated and washed with water (100 mL×2) and then dried over Na2SO4. Evaporation of the solvent furnished the chloromethyl isopropyl carbonate (107 g, 95%). Chloromethyl isobutyl carbonate, chloromethyl neopentyl carbonate, chloromethyl tert butyl carbonate and chloromethyl 3-pentyl carbonate are prepared in a similar manner. After the addition the cold bath was removed The reaction mixture was poured into a separation funnel containing cold water (100 mL) The ether layer was separated washed with water (100 mL×2) dried over Na2SO4 Evaporation of the solvent

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol) and KOH (46 mg, 0.82 mmol) in DMF (1.5 mL) was added a solution of chloromethyl isopropyl carbonate (62 mg, 0.41 mmol) in DMF (0.5 mL) over 30 min. The reaction mixture was stirred at 10° C. for 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (105 mg, 43%). The title compound was characterized by LC-MS and 1H NMR as shown below: filtered The filtrate was concentrated in vacuo the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1)

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol) and KOH (46 mg, 0.82 mmol) in DMF (1.5 mL) was added a solution of chloromethyl isopropyl carbonate (62 mg, 0.41 mmol) in DMF (0.5 mL) over 30 min. The reaction mixture was stirred at 10° C. for 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (105 mg, 43%). The title compound was characterized by LC-MS and 1H NMR as shown below: filtered The filtrate was concentrated in vacuo the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared according to the procedure as described in Example 26 step 1 using a solution of chloromethyl chloroformate (10 g, 78.2 mmol) in DCM (200 mL), a mixture of i-PrOH (6.6 mL, 86.2 mmol) and pyridine (7.5 mL, 93.2 mmol) in DCM (50 mL). The title compound was obtained as colorless oil (9.63 g, 81.0%) and was used in the next step without further purification. The title compound was characterized by 1H NMR as shown below: The title compound was prepared

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Propanol (73.14 mmole, 5.6 mL) was added to a solution of chloromethyl chloroformate (73.85 mmole, 6.5 mL) in ether (100 mL). The reaction mixture was cooled to 0° C. and pyridine (74.18 mmole, 6 mL) was dropwise added with stirring. Thereafter, the reaction mixture was stirred at ambient temperature for 20 hours. The formed solids were filtered and the filtrate was washed with citric acid (1% aqueous), water, sodium bicarbonate solution (1%) and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 10.26 g (92%) of a colorless oil. MS (ES+): m/e 152 (M+H). Thereafter, the reaction mixture was stirred at ambient temperature for 20 hours The formed solids were filtered the filtrate was washed with citric acid (1% aqueous), water, sodium bicarbonate solution (1%) and brine The organic layer was dried over magnesium sulfate filtered evaporated to dryness

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold solution (approximately 10° C.) of chloromethylchloroformate (65 mL) in diethyl ether (1.4 L) was added isopropanol (56 mL) followed by a dropwise addition of pyridine (60 mL). After the addition the cold bath was removed and the reaction mixture was stirred for 18 h. The reaction mixture was poured into a separation funnel containing cold water (100 mL). The ether layer was separated and washed with water (100 mL×2) and then dried over Na2SO4. Evaporation of the solvent furnished the chloromethyl isopropyl carbonate (107 g, 95%). Chloromethyl isobutyl carbonate, chloromethyl neopentyl carbonate, chloromethyl tert butyl carbonate and chloromethyl 3-pentyl carbonate are prepared in a similar manner. After the addition the cold bath was removed The reaction mixture was poured into a separation funnel containing cold water (100 mL) The ether layer was separated washed with water (100 mL×2) dried over Na2SO4 Evaporation of the solvent

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of chloromethyl isopropyl carbonate (15.6 mg, 102 μmol) and NaI (15.3 mg, 102 μmol) in acetone (0.7 mL, 10 mmol) was stirred at 65° C. for 1 hour, then added (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (20.0 mg, 36.4 μmol) that had been dissolved in acetone (0.4 mL, 5 mmol) at room temperature and treated with cesium carbonate (13.0 mg, 40 μmol). The resulting mixture was then heated at 40° C. for 1 hour. DIPEA (0.2 mL, 1 mmol) was added and heating continued for 1 hour. The mixture was cooled to room temperature and concentrated. The residue was partitioned between EtOAc (10.0 mL) and water (2.0 mL). The organic layer was washed with saturated aqueous NaHCO3 (3.0 mL), saturated aqueous NaCl (3.0 mL), dried over Na2SO4, filtered, and concentrated. Zinc 90.8 mg, 1.4 mmol) and AcOH (0.5 mL, 9 mmol) were added and the resulting mixture was stirred at room temperature for 1 hour. The solids were washed with AcOH (1.0 mL) then filtered. The filtrates were combined and purified by reverse phase preparative HPLC to yield the title compound (3.8 mg). MS m/z [M+H]+ calc'd for C25H26ClN3O9, 548.14. found 548.5. The resulting mixture was then heated at 40° C. for 1 hour heating continued for 1 hour The mixture was cooled to room temperature concentrated The residue was partitioned between EtOAc (10.0 mL) and water (2.0 mL) The organic layer was washed with saturated aqueous NaHCO3 (3.0 mL), saturated aqueous NaCl (3.0 mL) dried over Na2SO4 filtered concentrated the resulting mixture was stirred at room temperature for 1 hour The solids were washed with AcOH (1.0 mL) then filtered purified by reverse phase preparative HPLC