tert-butyl N-(3-hydroxy-2-methylpropyl)carbamate

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

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

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

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

Procedure: Using methods substantially equivalent to those described in Example 21-C, ethyl-2-(3-tert-butoxycarbonylamino-2-methylpropoxy)-4-fluorobenzoate was prepared from ethyl-2,4-difluorobenzoate and 2-methyl-3-tert-butoxycarbonylaminopropanol. The impure material was saponified using methods substantially equivalent to those described in Example 21-D to give 2-(3-tert-butoxycarbonylamino-2-methylpropoxy)-4-fluoro-benzoic acid (554 mg, 1.69 mmol, 7% for 2 steps after RPHPLC purification).

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

Procedure: The tert-butyl N-(2-methylallyl)carbamate (213 mg, 1.24 mmol) was diluted with THF (12 mL) and the mixture was cooled to 0° C. Borane-dimethylsulfide complex (0.9 mL, 1.8 mmol) was added. After 1.5 hours, the reaction was cooled to −40° C. and 1 N NaOH (5 mL) and 30% hydrogen peroxide (5 mL) were carefully added. After 15 minutes, the reaction was warmed slowly until the frozen mixture melted. Ethyl acetate (100 mL) was then added, and the mixture was washed with brine (3×10 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 20 g silica, 10% EtOAc/CH2Cl2 through 15% EtOAc/CH2Cl2) to give the desired product (209 mg, 1.10 mmol, 89%). Borane-dimethylsulfide complex (0.9 mL, 1.8 mmol) was added the reaction was cooled to −40° C. After 15 minutes the reaction was warmed slowly until the frozen mixture the mixture was washed with brine (3×10 mL) The combined aqueous layers were extracted with ethyl acetate (100 mL) dried over sodium sulfate filtered concentrated The crude residue was purified by flash column chromatography (about 20 g silica, 10% EtOAc/CH2Cl2 through 15% EtOAc/CH2Cl2)

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

Procedure: To a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 1.9 g, 7.4 mmol), tert-butyl (3-hydroxy-2-methylpropyl)carbamate (2.8 g, 14.8 mmol) and triphenylphosphine (4.9 g, 18.5 mmol) in THF (35 mL) at 0° C. is added diisopropyl azodicarboxylate (3.8 mL, 18.5 mmol). The mixture is stirred for 16 h at room temperature and then the solvent is removed. The residue is filtered through a pad of silica (300 g, 240-400 mesh) using 30% EtOAc in heptane to afford of mixture of the title compound and diethyl 1H-indole-2,6-dicarboxylate (3.2 g) which is used in the next step without further purification. the solvent is removed The residue is filtered through a pad of silica (300 g, 240-400 mesh)

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

Procedure: Using methods substantially equivalent to those described in Example 21-C, ethyl-2-(3-tert-butoxycarbonylamino-2-methylpropoxy)-4-fluorobenzoate was prepared from ethyl-2,4-difluorobenzoate and 2-methyl-3-tert-butoxycarbonylaminopropanol. The impure material was saponified using methods substantially equivalent to those described in Example 21-D to give 2-(3-tert-butoxycarbonylamino-2-methylpropoxy)-4-fluoro-benzoic acid (554 mg, 1.69 mmol, 7% for 2 steps after RPHPLC purification).

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

Procedure: The tert-butyl N-(2-methylallyl)carbamate (213 mg, 1.24 mmol) was diluted with THF (12 mL) and the mixture was cooled to 0° C. Borane-dimethylsulfide complex (0.9 mL, 1.8 mmol) was added. After 1.5 hours, the reaction was cooled to −40° C. and 1 N NaOH (5 mL) and 30% hydrogen peroxide (5 mL) were carefully added. After 15 minutes, the reaction was warmed slowly until the frozen mixture melted. Ethyl acetate (100 mL) was then added, and the mixture was washed with brine (3×10 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography (about 20 g silica, 10% EtOAc/CH2Cl2 through 15% EtOAc/CH2Cl2) to give the desired product (209 mg, 1.10 mmol, 89%). Borane-dimethylsulfide complex (0.9 mL, 1.8 mmol) was added the reaction was cooled to −40° C. After 15 minutes the reaction was warmed slowly until the frozen mixture the mixture was washed with brine (3×10 mL) The combined aqueous layers were extracted with ethyl acetate (100 mL) dried over sodium sulfate filtered concentrated The crude residue was purified by flash column chromatography (about 20 g silica, 10% EtOAc/CH2Cl2 through 15% EtOAc/CH2Cl2)