tert-butyl N-(2-formylphenyl)carbamate

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

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

Procedure: A 20% dispersion of pyridinium chlorochromate in basic alumina (50 g) was added to a solution of tert-butyl N-[2-(hydroxymethyl)phenyl]carbamate (11.0 g, 0.0493 mol) in anhydrous chloroform and the resulting suspension was stirred under an atmosphere of nitrogen at ambient temperature for 1 hour. Additional 16 g of a 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 45 min. At this point in time, additional 15 g of of 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 25 min. The resulting suspension was filtered through a silica gel pad, the filtrate was concentrated under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (2:98) as mobile phase to yield tert-butyl N-(2-formylphenyl)carbamate (8.67 g, 0.0392 mol) as a white solid. the stirring was continued for 45 min the stirring was continued for 25 min The resulting suspension was filtered through a silica gel pad the filtrate was concentrated under reduced pressure the residue purified by flash chromatography on silica

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

Procedure: A 20% dispersion of pyridinium chlorochromate in basic alumina (50 g) was added to a solution of tert-butyl N-[2-(hydroxymethyl)phenyl]carbamate (11.0 g, 0.0493 mol) in anhydrous chloroform and the resulting suspension was stirred under an atmosphere of nitrogen at ambient temperature for 1 hour. Additional 16 g of a 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 45 min. At this point in time, additional 15 g of of 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 25 min. The resulting suspension was filtered through a silica gel pad, the filtrate was concentrated under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (2:98) as mobile phase to yield tert-butyl N-(2-formylphenyl)carbamate (8.67 g, 0.0392 mol) as a white solid. the stirring was continued for 45 min the stirring was continued for 25 min The resulting suspension was filtered through a silica gel pad the filtrate was concentrated under reduced pressure the residue purified by flash chromatography on silica

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

Procedure: A 20% dispersion of pyridinium chlorochromate in basic alumina (50 g) was added to a solution of tert-butyl N-[2-(hydroxymethyl)phenyl]carbamate (11.0 g, 0.0493 mol) in anhydrous chloroform and the resulting suspension was stirred under an atmosphere of nitrogen at ambient temperature for 1 hour. Additional 16 g of a 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 45 min. At this point in time, additional 15 g of of 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 25 min. The resulting suspension was filtered through a silica gel pad, the filtrate was concentrated under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (2:98) as mobile phase to yield tert-butyl N-(2-formylphenyl)carbamate (8.67 g, 0.0392 mol) as a white solid. the stirring was continued for 45 min the stirring was continued for 25 min The resulting suspension was filtered through a silica gel pad the filtrate was concentrated under reduced pressure the residue purified by flash chromatography on silica

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

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with (2-Formyl-phenyl)-carbamic acid tert-butyl ester (8.8 g, 0.040 mol), 2-(4-Amino-2-methyl-phenyl)-propane-1,3-diamine (10.0 g, 0.056 mol), t-butanol (177 mL), and N,N-dimethylformamide (53 mL) and purged well with nitrogen. The mixture was stirred at 75° C. for at least 3 h. To the cooled mixture were added anhydrous potassium carbonate (16.6 g) and iodine (12.2 g). The batch was stirred at 80° C. for 10 h. The cooled mixture was filtered through a celite pad (4.4 g) and the filter cake was rinsed with methanol (177 mL). The filtrate and wash were diluted with toluene (88 mL) and concentrated to dryness under reduced pressure. The residue was stirred with aqueous 15 wt % sodium thiosulfate pentahydrate (88 mL) and saturated aqueous sodium chloride (44 mL) for 1 h at ambient temperature. The resulting mixture was extracted with CH2Cl2 (2×177 mL). The separated organic layer was dried over anhydrous magnesium sulfate (4.4 g), filtered, and concentrate to dryness in vacuo. The concentrate (20 g) was dissolved with methanol (20 mL) and loaded onto a KP-Sil samplet (34 g). The sample was allowed to dry before loading it into a Biotage KP-Sil SNAP cartridge (340 g). A Biotage unit was used to elute the cartridge with a ethyl acetate-hexane gradient (0% to 90%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure to provide the title compound as a yellow solid (1.6 g, 13% yield). purged well with nitrogen To the cooled mixture were added anhydrous potassium carbonate (16.6 g) and iodine (12.2 g) The batch was stirred at 80° C. for 10 h The cooled mixture was filtered through a celite pad (4.4 g) the filter cake was rinsed with methanol (177 mL) The filtrate and wash were diluted with toluene (88 mL) concentrated to dryness under reduced pressure The residue was stirred with aqueous 15 wt % sodium thiosulfate pentahydrate (88 mL) and saturated aqueous sodium chloride (44 mL) for 1 h at ambient temperature The resulting mixture was extracted with CH2Cl2 (2×177 mL) The separated organic layer was dried over anhydrous magnesium sulfate (4.4 g) filtered concentrate to dryness in vacuo The concentrate (20 g) was dissolved with methanol (20 mL) to dry to elute the cartridge with a ethyl acetate-hexane gradient (0% to 90%) Clean fractions were collected concentrated to dryness under reduced pressure

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with (2-formyl-phenyl)-carbamic acid tert-butyl ester (8.8 g, 0.040 mol), 2-(4-amino-3-methyl-phenyl)-propane-1,3-diamine (10.0 g, 0.056 mol), t-butanol (177 mL), and N,N-dimethylformamide (53 mL). The mixture was stirred at 70-80° C. for 3 h. To the stirred, cooled (40-50° C.) mixture were added anhydrous potassium carbonate (16.6 g) and iodine (20.3 g). The batch was then stirred at 80° C. for at least 5 h or until HPLC analysis showed that the reaction had proceeded to greater the 98% completion. The cooled reaction mixture was filtered through a celite pad (8.8 g) and the filter cake was rinsed with MeOH (110 mL). The filtrate and rinse were diluted with toluene (90 mL) and concentrated to dryness under reduced pressure. The residue was stirred with aqueous 20 wt % sodium thiosulfate pentahydrate (180 mL) for 1 h at ambient temperature. This mixture was extracted with CH2Cl2 (2×180 mL) and the separated organic layers were concentrated to dryness in vacuo. The concentrate (20 g) was dissolved with methanol (10 mL) and loaded onto a Biotage KP-Sil SNAP cartridge (100 g) that had been pre-equilibrated with 300 mL 5% v/v triethylamine in hexane. A Biotage unit was used to elute the cartridge with an ethyl acetate-hexane gradient (0% to 80%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure as quickly as possible to provide the title compound as a yellow solid (2.9 g 23% yield). To the stirred, cooled (40-50° C.) mixture The batch was then stirred at 80° C. for at least 5 h or until HPLC analysis The cooled reaction mixture was filtered through a celite pad (8.8 g) the filter cake was rinsed with MeOH (110 mL) The filtrate and rinse were diluted with toluene (90 mL) concentrated to dryness under reduced pressure The residue was stirred with aqueous 20 wt % sodium thiosulfate pentahydrate (180 mL) for 1 h at ambient temperature This mixture was extracted with CH2Cl2 (2×180 mL) the separated organic layers were concentrated to dryness in vacuo The concentrate (20 g) was dissolved with methanol (10 mL) to elute the cartridge with an ethyl acetate-hexane gradient (0% to 80%) Clean fractions were collected concentrated to dryness under reduced pressure as quickly as possible

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2-Hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (44.7 g, 0.200 mol), CH2Cl2 (625 mL) and manganese(IV) oxide (85%, 5 μm powder; 245.5 g, 2.400 mol) were introduced into a flask. The mixture was stirred at 40° C. for at least 4 h or until HPLC analysis showed that the reaction had proceeded to greater than 97% completion. The cooled mixture was filtered through a Celite pad (22 g) and the filter cake was rinsed with CH2Cl2 (625 mL). The filtrate and wash were concentrated in vacuo to dryness to afford the title compound as an oily yellow material (44 g, 99% yield). The cooled mixture was filtered through a Celite pad (22 g) the filter cake was rinsed with CH2Cl2 (625 mL) The filtrate and wash were concentrated in vacuo to dryness

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

Procedure: A mixture of 2-(4-aminophenyl)propane-1,3-diamine.3HCl (632 mg, 2.30 mmol) and powdered K2CO3 (3.18 g, 23.0 mmol) in 30 mL t-BuOH was heated at 83° C. for 45 min, then tert-butyl(2-formylphenyl)carbamate (560 mg, 2.53 mmol) was added. At 6.5 hours the reaction was allowed to partially cool, approximately 25 mg tert-butyl(2-formylphenyl)carbamate was added, then iodine (48 mg, 0.188 mmol) added, stirred 5 min at rt, and the heating resumed at 83° C. After 1.5 hours the temperature was lowered to 75° C. and the reaction continued an additional 15 hours. The reaction was partitioned between EtOAc and aqueous Na2CO3 solution plus Na2S2O3, the EtOAc layer washed with brine, dried with Na2SO4, and evaporated. The resulting solid was chromatographed eluting with CHCl3/MeOH to give the title compound as a yellow-tan solid (262 mg, 39%). 1H NMR (DMSO-d6) δ: 10.65 (br. s, 1H), 7.97 (dd, J=7.9, 1.5 Hz, 1H), 7.39-7.45 (m, 1H), 6.98-7.08 (m, 2H), 6.93-6.98 (m, 2H), 6.51-6.57 (m, 2H), 4.96 (br. s, 2H), 4.12-4.20 (m, 1H), 3.61-3.70 (m, 1H), 3.36-3.53 (m, 2H), 2.73-2.85 (m, 1H). to partially cool resumed at 83° C After 1.5 hours the temperature was lowered to 75° C. the reaction continued an additional 15 hours The reaction was partitioned between EtOAc and aqueous Na2CO3 solution plus Na2S2O3 the EtOAc layer washed with brine dried with Na2SO4 evaporated The resulting solid was chromatographed eluting with CHCl3/MeOH

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

Procedure: A 20% dispersion of pyridinium chlorochromate in basic alumina (50 g) was added to a solution of tert-butyl N-[2-(hydroxymethyl)phenyl]carbamate (11.0 g, 0.0493 mol) in anhydrous chloroform and the resulting suspension was stirred under an atmosphere of nitrogen at ambient temperature for 1 hour. Additional 16 g of a 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 45 min. At this point in time, additional 15 g of of 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 25 min. The resulting suspension was filtered through a silica gel pad, the filtrate was concentrated under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (2:98) as mobile phase to yield tert-butyl N-(2-formylphenyl)carbamate (8.67 g, 0.0392 mol) as a white solid. the stirring was continued for 45 min the stirring was continued for 25 min The resulting suspension was filtered through a silica gel pad the filtrate was concentrated under reduced pressure the residue purified by flash chromatography on silica

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

Procedure: A 20% dispersion of pyridinium chlorochromate in basic alumina (50 g) was added to a solution of tert-butyl N-[2-(hydroxymethyl)phenyl]carbamate (11.0 g, 0.0493 mol) in anhydrous chloroform and the resulting suspension was stirred under an atmosphere of nitrogen at ambient temperature for 1 hour. Additional 16 g of a 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 45 min. At this point in time, additional 15 g of of 20% dispersion of pyridinium chlorochromate in basic alumina was added and the stirring was continued for 25 min. The resulting suspension was filtered through a silica gel pad, the filtrate was concentrated under reduced pressure and the residue purified by flash chromatography on silica using ethyl acetate/n-heptane (2:98) as mobile phase to yield tert-butyl N-(2-formylphenyl)carbamate (8.67 g, 0.0392 mol) as a white solid. the stirring was continued for 45 min the stirring was continued for 25 min The resulting suspension was filtered through a silica gel pad the filtrate was concentrated under reduced pressure the residue purified by flash chromatography on silica