tert-butyl N-(3-aminophenyl)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:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-1-fluoro-2-nitrobenzene (6.0 g, 27 mmol, Aldrich, Cat. No. 539112) and tert-butyl (3-aminophenyl)carbamate (6.7 g, 32 mmol, Aldrich, Cat. No. 53175) in N-methylpyrrolidinone (30 mL) was heated at 150° C. overnight. The solution was cooled to room temperature (r.t.) and quenched with NaHCO3 aqueous solution, then extracted with ethyl acetate twice. The combined organic phases were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired compound (10.1 g, 91%). LCMS (M+H)+: m/z=408.0. quenched with NaHCO3 aqueous solution extracted with ethyl acetate twice The combined organic phases were washed with brine dried over MgSO4 After filtration the filtrate was concentrated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) was dissolved in a mixture of MeOH (2 ml) and H2O (0.2 ml). 3-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and the mixture was refluxed for 40 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis[3-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 7.96 (d, 1H, J=4.1 Hz), 7.83 (m, 1H), 7.60 (m, 1H), 7.34-7.42 (m, 2H), 7.15-7.19 (m, 2H), 7.06 (t, 1H, J=8.2 Hz), 6.93 (d, 1H, J=8.2 Hz), 1.43 (s, 9H), 1.40 (s, 9H); LCMS: purity: 93.2%; MS (m/e): 511.06 (M+, 100). The mixture was cooled to 22° C. concentrated to dryness under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,6-Dichloropyrimidine (1.5 g, 10 mmol), tert-butyl 3-aminophenylcarbamate (2.1 g, 10 mmol) and triethylamine (2.2 g, 20 mmol) were mixed in ethanol (20 mL), heated at 80° C. for 16 hr. The reaction mixture was cooled to RT and solvent was removed in vacuo. The gummy crude product was mixed with 20 mL of DCM and was stirred at RT to give an off-white solid, which was filtered and dried under vacuum (1.6 g, 5 mmol). MS (m/z): MH+=321, 323. The reaction mixture was cooled to RT solvent was removed in vacuo The gummy crude product was mixed with 20 mL of DCM to give an off-white solid, which was filtered dried under vacuum (1.6 g, 5 mmol)

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

Procedure: A solution of (3-amino-phenyl)-carbamic acid tert-butyl ester (1 g, 4.8 mmol), benzaldehyde (0.54 ml, 5.3 mmol) and acetic acid (0.41 ml, 7.2 mmol) in dry tetrahydrofuran (30 ml) were stirred at room temperature for 2 hrs. Sodium borohydride (0.172 g, 4.5 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (50 ml) and extracted with dichloromethane (3×50 ml). The combined organics were dried (magnesium sulphate), concentrated in vacuo and the crude residue purified by flash column chromatography (SiO2) eluting with ethyl acetate to afford the title compound as an off white solid (1.27 g, 89%) HPLC retention time 6.4 min. Mass spectrum (ES+) m/z 198 (M+H-BOC) The reaction mixture was quenched with water (50 ml) extracted with dichloromethane (3×50 ml) The combined organics were dried (magnesium sulphate) concentrated in vacuo the crude residue purified by flash column chromatography (SiO2) eluting with ethyl acetate

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

Procedure: A solution of (3-Amino-phenyl)-carbamic acid tert-butyl ester (0.5 g, 2.4 mmol) and 1-Chloro-2-isocyanato-ethane (0.25 ml, 2.9 mmol) in dry tetrahydrofuran (20 ml) were stirred at room temperature overnight. Reaction was quenched with water (50 ml) then extracted with dichloromethane (3×50 ml). Combined organics dried (magnesium sulphate) and concentrated in vacuo. The crude residue was purified by column chromatography (eluent 10% ethylacetate in dichloromethane) to afford the title compound (1 g). HPLC retention time 7.45 min. Mass spectrum (ES+) m/z 314 (M+H) Reaction was quenched with water (50 ml) then extracted with dichloromethane (3×50 ml) Combined organics dried (magnesium sulphate) concentrated in vacuo The crude residue was purified by column chromatography (eluent 10% ethylacetate in dichloromethane)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,6-Dichloropyrimidine (1.5 g, 10 mmol), tert-butyl 3-aminophenylcarbamate (2.1 g, 10 mmol) and triethylamine (2.2 g, 20 mmol) were mixed in ethanol (20 mL), heated at 80° C. for 16 hr. The reaction mixture was cooled to RT and solvent was removed in vacuo. The gummy crude product was mixed with 20 mL of DCM and was stirred at RT to give an off-white solid, which was filtered and dried under vacuum (1.6 g, 5 mmol). MS (m/z): MH+=321, 323. The reaction mixture was cooled to RT solvent was removed in vacuo The gummy crude product was mixed with 20 mL of DCM to give an off-white solid, which was filtered dried under vacuum (1.6 g, 5 mmol)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,6-Dichloropyrimidine (1.5 g, 10 mmol), tert-butyl 3-aminophenylcarbamate (2.1 g, 10 mmol) and triethylamine (2.2 g, 20 mmol) were mixed in ethanol (20 mL), heated at 80° C. for 16 hr. The reaction mixture was cooled to RT and solvent was removed in vacuo. The gummy crude product was mixed with 20 mL of DCM and was stirred at RT to give an off-white solid, which was filtered and dried under vacuum (1.6 g, 5 mmol). MS (m/z): MH+=321, 323. The reaction mixture was cooled to RT solvent was removed in vacuo The gummy crude product was mixed with 20 mL of DCM to give an off-white solid, which was filtered dried under vacuum (1.6 g, 5 mmol)

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

Procedure: By using 1-nitro-2-naphthyl trifluoromethanesulfonate (5.94 g, 18.5 mmol), and tert-butyl(3-aminophenyl)carbamate, the title compound (1.02 g, yield 17%) was obtained as brown crystals in the same manner as that of Example 1, (1), (2) and (3).

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,6-Dichloropyrimidine (1.5 g, 10 mmol), tert-butyl 3-aminophenylcarbamate (2.1 g, 10 mmol) and triethylamine (2.2 g, 20 mmol) were mixed in ethanol (20 mL), heated at 80° C. for 16 hr. The reaction mixture was cooled to RT and solvent was removed in vacuo. The gummy crude product was mixed with 20 mL of DCM and was stirred at RT to give an off-white solid, which was filtered and dried under vacuum (1.6 g, 5 mmol). MS (m/z): MH+=321, 323. The reaction mixture was cooled to RT solvent was removed in vacuo The gummy crude product was mixed with 20 mL of DCM to give an off-white solid, which was filtered dried under vacuum (1.6 g, 5 mmol)

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

Procedure: To a mixture of the (3-aminophenyl)carbamic acid tert-butyl ester (100 mg, 0.48 mmol) and 2-mercaptonicotinic acid (81 mg, 0.52 mmol) in DMF (5 mL) was added EEDQ (154 mg, 0.63 mmol). The mixture was stirred at ambient temperature for 15 h, was diluted with water and extracted with ethyl acetate (3×25 mL). The combined extracts were washed with water and brine and dried over magnesium sulfate. The residue was taken up in a small quantity of ethyl acetate (3 mL) and was briefly heated at reflux (1 minute). The mixture was cooled and the resulting solids collected via vacuum filtration on a fritted glass funnel. This afforded 90 mg of a solid which was not purified or characterized, but carried on directly. The material was dissolved in NMP (5 mL) and was treated with ethyl bromoacetate (32 μL, 0.29 mmol) and DIPEA (90 μL, 0.52 mmol). The resulting mixture was stirred for 10 minutes and was poured into water. The resulting mixture was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with water and brine. Filtration and concentration in vacuo afforded a residue which was purified via radial chromatography (1 mm plate, 10% ethyl acetate/hexanes) to give 41 mg (36%) of [5-(3-tert-butoxycarbonylamino-phenylcarbamoyl)pyrdin-2-ylsulfanyl]acetic acid ethyl ester as a solid: 1H NMR (300 MHz, acetone-d6) δ 9.63 (bs, 1H), 8.99 (m, 1H), 8.45 (bs, 1H), 8.18 (m, 1H), 8.01 (s, 1H), 7.58 (m, 1H), 7.40 (m, 1H), 7.20 (m, 2H), 4.13 (m, 2H), 4.07 (s, 2H), 1.47 (s, 9H), 1.19 (m, 1H); MS (EI) m/z 430.06 (M−H)−. extracted with ethyl acetate (3×25 mL) The combined extracts were washed with water and brine dried over magnesium sulfate was briefly heated at reflux (1 minute) The mixture was cooled the resulting solids collected via vacuum filtration on a fritted glass funnel This afforded 90 mg of a solid which was not purified The material was dissolved in NMP (5 mL) The resulting mixture was stirred for 10 minutes The resulting mixture was extracted with ethyl acetate (3×50 mL) the combined extracts were washed with water and brine Filtration and concentration in vacuo afforded a residue which was purified via radial chromatography (1 mm plate, 10% ethyl acetate/hexanes)