tert-butyl N-[4-(4-aminophenyl)butyl]carbamate

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-[4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (4.5 g, 17 mmol) and 2-bromoethylamine hydrobromide (1.75 g, 8.5 mmol) in toluene was stirred at 100° C. for 3 days. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 8:1:0.1, v/v) to give 660 (1.47 g, 56%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.51 (m, 4H), 2.48 (t, 2H), 2.85 (t, 2H), 3.03 (t, 2H), 3.17 (m, 2H), 6.59 (d, 2H), 6.94 (d, 2H). m/z (ESI) 308 [C17H29lN3O2+H]. The solvent was removed under reduced pressure the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 8:1:0.1

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-[4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (4.5 g, 17 mmol) and 2-bromoethylamine hydrobromide (1.75 g, 8.5 mmol) in toluene was stirred at 100° C. for 3 days. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 8:1:0.1, v/v) to give 660 (1.47 g, 56%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.51 (m, 4H), 2.48 (t, 2H), 2.85 (t, 2H), 3.03 (t, 2H), 3.17 (m, 2H), 6.59 (d, 2H), 6.94 (d, 2H). m/z (ESI) 308 [C17H29lN3O2+H]. The solvent was removed under reduced pressure the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 8:1:0.1

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

Procedure: A solution of [4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (1.7 g, 6.43 mmol), 4-bromo-n-butyric acid ethyl ester (1.88 g, 9.64 mmol), 4-methylmorpholine (1.0 mL, 9.64 mmol), and DMF (10 mL) was stirred at 85° C. for 3 hours under a nitrogen atmosphere. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 4:1, hexanes/ethyl acetate, v/v) to provide 420 (0.44 g, 18%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.23 (t, 3H), 1.47 (s, 9H), 1.55 (m, 4H), 1.96 (m, 2H), 2.43 (t, 2H), 2.51 (t, 2H), 3.19 (m, 4H), 4.14 (q, 2H), 6.54 (d, 2H), 7.00 (d, 2H). m/z (ESI) 379. The solvent was evaporated in vacuo The residue was purified by flash chromatography (silica gel, 4:1, hexanes/ethyl acetate, v/v)

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

Procedure: A solution of [4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (1.7 g, 6.43 mmol), 4-bromo-n-butyric acid ethyl ester (1.88 g, 9.64 mmol), 4-methylmorpholine (1.0 mL, 9.64 mmol), and DMF (10 mL) was stirred at 85° C. for 3 hours under a nitrogen atmosphere. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 4:1, hexanes/ethyl acetate, v/v) to provide 420 (0.44 g, 18%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.23 (t, 3H), 1.47 (s, 9H), 1.55 (m, 4H), 1.96 (m, 2H), 2.43 (t, 2H), 2.51 (t, 2H), 3.19 (m, 4H), 4.14 (q, 2H), 6.54 (d, 2H), 7.00 (d, 2H). m/z (ESI) 379. The solvent was evaporated in vacuo The residue was purified by flash chromatography (silica gel, 4:1, hexanes/ethyl acetate, v/v)

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

Procedure: A mixture of [4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (0.8 g, 3.03 mmol), 2-bromoacetamide (0.46 g, 3.33 mmol), triethylamine (0.2 mL, 3.33 mmol), and DMF (30 mL) was stirred at 80° C. for 20 hours. TLC indicated that the reaction was not complete. Silver carbonate (0.92 g, 3.33 mmol) was thus added. The reaction was further stirred at 80° C. for 24 hours. The reaction mixture was passed through a silica plug. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3:1 ethyl acetate/dichloromethane, v/v) to provide 390 (0.20 g, 22%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.55 (m, 4H), 2.50 (t, 2H), 3.03 (t, 2H), 3.70 (s, 2H), 6.52 (d, 211), 7.00 (d, 2H). The reaction was further stirred at 80° C. for 24 hours The solvent was evaporated in vacuo The residue was purified by flash chromatography (silica gel, 3:1 ethyl acetate/dichloromethane, v/v)

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

Procedure: A mixture of [4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (0.8 g, 3.03 mmol), 2-bromoacetamide (0.46 g, 3.33 mmol), triethylamine (0.2 mL, 3.33 mmol), and DMF (30 mL) was stirred at 80° C. for 20 hours. TLC indicated that the reaction was not complete. Silver carbonate (0.92 g, 3.33 mmol) was thus added. The reaction was further stirred at 80° C. for 24 hours. The reaction mixture was passed through a silica plug. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3:1 ethyl acetate/dichloromethane, v/v) to provide 390 (0.20 g, 22%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.55 (m, 4H), 2.50 (t, 2H), 3.03 (t, 2H), 3.70 (s, 2H), 6.52 (d, 211), 7.00 (d, 2H). The reaction was further stirred at 80° C. for 24 hours The solvent was evaporated in vacuo The residue was purified by flash chromatography (silica gel, 3:1 ethyl acetate/dichloromethane, v/v)

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

Procedure: Compound 52 (0.16 g, 0.605 mmol) was dissolved in anhydrous THF (5 mL). To the clear solution were sequentially added triethylamine (0.18 mL, 1.21 mmol) and 4-dimethylaminopyridine (15 mg, 0.121 mmol). The mixture was cooled to about −10° C. for 15 min by a methanol-ice bath. To the cold solution was slowly added methanesulfonyl chloride (51 μL). The solution was further stirred at the temperature (about −10° C.) for an additional 30 min, then allowed to slowly warm up to room temperature by removing the cooling bath. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0-35%) and hexanes (100-65%), to afford 0.212 g (83%) of the product 53 as a white solid. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.52-1.70 (m, 4H), 2.68 (t, J=7.4 Hz, 2H), 3.13-3.18 (m, 2H), 3.40 (s, 6H), 4.53 (br s, 1H), 7.27 (s, 4H). m/z (APCI)=321 [C17H28N2O6S2−Boc+H]+. to slowly warm up to room temperature by removing the cooling bath The reaction mixture was concentrated under reduced pressure The residue was chromatographed over silica gel eluting with a mixture of ethyl acetate (0-35%) and hexanes (100-65%)

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

Procedure: Compound 52 (0.16 g, 0.605 mmol) was dissolved in anhydrous THF (5 mL). To the clear solution were sequentially added triethylamine (0.18 mL, 1.21 mmol) and 4-dimethylaminopyridine (15 mg, 0.121 mmol). The mixture was cooled to about −10° C. for 15 min by a methanol-ice bath. To the cold solution was slowly added methanesulfonyl chloride (51 μL). The solution was further stirred at the temperature (about −10° C.) for an additional 30 min, then allowed to slowly warm up to room temperature by removing the cooling bath. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0-35%) and hexanes (100-65%), to afford 0.212 g (83%) of the product 53 as a white solid. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.52-1.70 (m, 4H), 2.68 (t, J=7.4 Hz, 2H), 3.13-3.18 (m, 2H), 3.40 (s, 6H), 4.53 (br s, 1H), 7.27 (s, 4H). m/z (APCI)=321 [C17H28N2O6S2−Boc+H]+. to slowly warm up to room temperature by removing the cooling bath The reaction mixture was concentrated under reduced pressure The residue was chromatographed over silica gel eluting with a mixture of ethyl acetate (0-35%) and hexanes (100-65%)

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

Procedure: To a solution of compound 51 (2.01 g, 6.923 mmol) in ethanol (50 mL) was added 10% palladium on carbon (737 mg, wet) in one portion under argon protection. The flask was evacuated and re-filled with argon three times (to remove oxygen), and the mixture stirred at room temperature overnight under one atmosphere of hydrogen. The reaction system was then purged with nitrogen, and the catalyst was vacuum filtered and washed with ethanol (2×5 mL). The filtrate and washings were combined and concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0-25%) and hexanes (100-75%), to afford 1.75 g (96%) of the product 52 as a colorless viscous oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.47-1.64 (m, 4H), 2.50 (t, J=7.1 Hz, 2H), 3.08-3.14 (m, 2H), 3.57 (br s, 2H), 4.55 (br s, 1H), 6.62 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H). m/z (APCI)=265 [C15H24N2O2+H]+. The flask was evacuated re-filled with argon three times (to remove oxygen) The reaction system was then purged with nitrogen filtered washed with ethanol (2×5 mL) concentrated under reduced pressure The residue was chromatographed over silica gel eluting with a mixture of ethyl acetate (0-25%) and hexanes (100-75%)

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

Procedure: To a solution of compound 51 (2.01 g, 6.923 mmol) in ethanol (50 mL) was added 10% palladium on carbon (737 mg, wet) in one portion under argon protection. The flask was evacuated and re-filled with argon three times (to remove oxygen), and the mixture stirred at room temperature overnight under one atmosphere of hydrogen. The reaction system was then purged with nitrogen, and the catalyst was vacuum filtered and washed with ethanol (2×5 mL). The filtrate and washings were combined and concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0-25%) and hexanes (100-75%), to afford 1.75 g (96%) of the product 52 as a colorless viscous oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.47-1.64 (m, 4H), 2.50 (t, J=7.1 Hz, 2H), 3.08-3.14 (m, 2H), 3.57 (br s, 2H), 4.55 (br s, 1H), 6.62 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H). m/z (APCI)=265 [C15H24N2O2+H]+. The flask was evacuated re-filled with argon three times (to remove oxygen) The reaction system was then purged with nitrogen filtered washed with ethanol (2×5 mL) concentrated under reduced pressure The residue was chromatographed over silica gel eluting with a mixture of ethyl acetate (0-25%) and hexanes (100-75%)

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

Procedure: Compound 52 (0.16 g, 0.605 mmol) was dissolved in anhydrous THF (5 mL). To the clear solution were sequentially added triethylamine (0.18 mL, 1.21 mmol) and 4-dimethylaminopyridine (15 mg, 0.121 mmol). The mixture was cooled to about −10° C. for 15 min by a methanol-ice bath. To the cold solution was slowly added methanesulfonyl chloride (51 μL). The solution was further stirred at the temperature (about −10° C.) for an additional 30 min, then allowed to slowly warm up to room temperature by removing the cooling bath. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0-35%) and hexanes (100-65%), to afford 0.212 g (83%) of the product 53 as a white solid. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.52-1.70 (m, 4H), 2.68 (t, J=7.4 Hz, 2H), 3.13-3.18 (m, 2H), 3.40 (s, 6H), 4.53 (br s, 1H), 7.27 (s, 4H). m/z (APCI)=321 [C17H28N2O6S2-Boc+H]+. to slowly warm up to room temperature by removing the cooling bath The reaction mixture was concentrated under reduced pressure The residue was chromatographed over silica gel eluting with a mixture of ethyl acetate (0-35%) and hexanes (100-65%)

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

Procedure: To a solution of compound 51 (2.01 g, 6.923 mmol) in ethanol (50 mL) was added 10% palladium on carbon (737 mg, wet) in one portion under argon protection. The flask was evacuated and re-filled with argon three times (to remove oxygen), and the mixture stirred at room temperature overnight under one atmosphere of hydrogen. The reaction system was then purged with nitrogen, and the catalyst was vacuum filtered and washed with ethanol (2×5 mL). The filtrate and washings were combined and concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0-25%) and hexanes (100-75%), to afford 1.75 g (96%) of the product 52 as a colorless viscous oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.47-1.64 (m, 4H), 2.50 (t, J=7.1 Hz, 2H), 3.08-3.14 (m, 2H), 3.57 (br s, 2H), 4.55 (br s, 1H), 6.62 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H). m/z (APCI)=265 [C15H24N2O2+H]+. The flask was evacuated re-filled with argon three times (to remove oxygen) The reaction system was then purged with nitrogen filtered washed with ethanol (2×5 mL) concentrated under reduced pressure The residue was chromatographed over silica gel eluting with a mixture of ethyl acetate (0-25%) and hexanes (100-75%)