tert-butyl N-[2-(4-aminophenyl)ethyl]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:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]-carboxamide (570 mg, 2.15 mmol, Step A), iron powder (602 mg, 10.75 mmol) and NH4Cl (82 mg, 1.5 mmol) in EtOH (6 mL) and H2O (6 ml) was stirred for 4 h at 80° C. Filtration and concentration gave the crude compound, which was used in next step without further purification. Filtration and concentration

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

Procedure: 960 mg of t-butyl 2-(4-aminophenyl)ethylcarbamate and (2-benzylaminothiazol-4-yl)acetic acid were subjected to an amidation reaction to obtain 500 mg of t-butyl [2-[4-[2-(2-benzylaminothiazol-4-yl)acetylamino]phenyl]ethyl]carbamate.

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

Procedure: To a solution of N-(tert-butoxycarbonyl)-4-nitrophenethyl-2-amine from Example 2 (24.2 g, 96.7 mmol) in a mixture of ethanol (150 mL) and THF (50 mL) was added 5% Pd/C (4.0 g). This solution was placed on a Parr Hydrogenator under 40 psig of hydrogen gas and shaken for 5 hours. The reaction mixture was filtered and evaporated to leave a colorless oil. This oil was taken up into hot hexane/ethyl acetate and allowed to crystallized overnight. The solid was collected via vacuum filtration and placed under high vacuum for eight hours. 19.31 g of the title compound, as a white solid, was obtained. The reaction mixture was filtered evaporated to leave a colorless oil to crystallized overnight The solid was collected via vacuum filtration placed under high vacuum for eight hours

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

Procedure: A mixture of tert-butyl 2-(4-aminophenyl)ethylcarbamate (709 mg, 3 mmol) and 2-naphthylmethyl propanimidothioate hydrobromide (930 mg, 3 mmol) in ethanol (10 mL) was stirred for overnight at ambient temperature. Then, the volatile components were removed by evaporation and the residue was partitioned between diethyl ether (10 mL) and water (10 mL). The aqueous phase was washed with diethyl ether (3×10 mL) and basified by NaOH to pH 10. The aqueous phase was extracted with chloroform (20×4) and the combined extract was dried (MgSO4). Concentration of the organic solvent afforded 831 mg (95%) of the title compound as a colorless powder. MS (ESI) m/z 292 [M+H]+. Then, the volatile components were removed by evaporation the residue was partitioned between diethyl ether (10 mL) and water (10 mL) The aqueous phase was washed with diethyl ether (3×10 mL) The aqueous phase was extracted with chloroform (20×4) the combined extract was dried (MgSO4)

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

Procedure: [2-(4-Amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.0 g, 2.76 mmol), benzyl acetoacetate (0.796 g, 4.14 mmol) and toluenesulfonic acid (0.026 g, 0.138 mmol) were refluxed in toluene at 125° C. 3 hours. The reaction was then cooled, evaporated to dryness, the crude redissolved in EtOAc and dried over anhydrous Na2SO4. Filtration under vacuum followed by purification on SiO2 (30% EtOAc/hexane) gave 1.055 g (71%) of the desired (E)-3-[4-(2-tert-butoxycarbonylamino-ethyl)-2-methyl-phenylamino]-but-2-enoicacid benzyl ester. 1HNMR (400 MHz, DMSO): δ 1.32 (s, 9H), 1.81 (s, 3H, olefineCH3),2.63 (t, J=2.96 Hz, 2H), 3.12 (q, J=6.03 Hz, 2H), 4.77 (s, 1H, olefineH), 5.07 (s, 2H), 6.83 (b, ArH), 7.20-7.35 (m, 6H, ArH), 7.70 (s, 1H, ArH), 10.05 (s, ArNH). MS(APCI−) m/z 535.2(M−1). 3 hours The reaction was then cooled evaporated to dryness the crude redissolved in EtOAc dried over anhydrous Na2SO4 Filtration under vacuum followed by purification on SiO2 (30% EtOAc/hexane)

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

Procedure: [2-(4-Amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.0 g, 2.76 mmol), benzyl acetoacetate (0.796 g, 4.14 mmol) and toluenesulfonic acid (0.026 g, 0.138 mmol) were refluxed in toluene at 125° C. 3 hours. The reaction was then cooled, evaporated to dryness, the crude redissolved in EtOAc and dried over anhydrous Na2SO4. Filtration under vacuum followed by purification on SiO2 (30% EtOAc/hexane) gave 1.055 g (71%) of the desired (E)-3-[4-(2-tert-butoxycarbonylamino-ethyl)-2-methyl-phenylamino]-but-2-enoicacid benzyl ester. 1HNMR (400 MHz, DMSO): δ 1.32 (s, 9H), 1.81 (s, 3H, olefineCH3),2.63 (t, J=2.96 Hz, 2H), 3.12 (q, J=6.03 Hz, 2H), 4.77 (s, 1H, olefineH), 5.07 (s, 2H), 6.83 (b, ArH), 7.20-7.35 (m, 6H, ArH), 7.70 (s, 1H, ArH), 10.05 (s, ArNH). MS(APCI−) m/z 535.2(M−1). 3 hours The reaction was then cooled evaporated to dryness the crude redissolved in EtOAc dried over anhydrous Na2SO4 Filtration under vacuum followed by purification on SiO2 (30% EtOAc/hexane)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(N-Boc-2-aminoethyl)aniline 28 (10 g, 42.34 mmole), benzaldehyde (4.52 mL, 44.47 mmole), and molecular sieves 4A (10 g) in toluene (100 mL) was refluxed at 95° C. for 15 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a colorless oil. The oil was dissolved in MeOH (150 mL) and AcOH (0.5 mL) and NaCNBH3 (2.79 g, 44.4 mmole) were added. The reaction mixture was stirred at 0° C. for 1 h and at rt for 2 h and then concentrated in vacuo to give a pale yellow oily residue. Purification by flash silica column chromatography: 1/1 hexane/EtOAc gave N-benzyl-4-(N-Boc-2-aminoethyl)aniline 41 as colorless oil (11.5 g, 83%). Rf=0.75 in 1/1 hexane/EtOAc. H1-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.38-7.2 (m, 5H), 6.87-6.84 (d, 2H), 6.58-6.55 (d, 2H), 4.27 (s, 2H), 3.2-3.15 (m, 2H), 2.6-2.56 (t, 2H), 1.41 (s, 9H); ESMS (C20H26N2O2): calcd. 326.4, obsd. 328 [M+H]+. The reaction mixture was filtered the filtrate was concentrated in vacuo to give a colorless oil concentrated in vacuo to give a pale yellow oily residue Purification by flash silica column chromatography

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

Procedure: 4-(N-Boc-2-aminoethyl)aniline 28 (1.25 g, 5.29 mmole) was dissolved in methanol (30 mL), followed by addition of phenyl glyoxal 24 (0.708 g, 5.28 mmole). The reaction mixture was stirred for 1 h at rt, prior to addition of NaCNBH3 (0.665 g, 10.6 mmole). The final mixture was stirred for 12 h at rt, concentrated, and purified by flash silica column chromatography (2 to 5% MeOH/CH2Cl2) to give N-(2-phenyl-2-hydroxyethyl)-4-(N-Boc-2-aminoethyl)-aniline as a pale yellow oil (1.71 g, 91%): Rf=0.18 in 5% MeOH/CH2Cl2. 1H-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.4-7.25 (m, 5H), 7.0-6.95 (d, 2H), 6.63-6.60 (d, 2H), 4.85-4.79 (dd, 1H), 3.3-3.21 (t, 2H), 3.2-3.15 (m, 2H), 2.64-2.5 (t, 2H), 1.42 (s, 9H). concentrated purified by flash silica column chromatography (2 to 5% MeOH/CH2Cl2)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(N-Boc-2-aminoethyl)aniline 28 (10 g, 42.34 mmole), benzaldehyde (4.52 mL, 44.47 mmole), and molecular sieves 4A (10 g) in toluene (100 mL) was refluxed at 95° C. for 15 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a colorless oil. The oil was dissolved in MeOH (150 mL) and AcOH (0.5 mL) and NaCNBH3 (2.79 g, 44.4 mmole) were added. The reaction mixture was stirred at 0° C. for 1 h and at rt for 2 h and then concentrated in vacuo to give a pale yellow oily residue. Purification by flash silica column chromatography: 1/1 hexane/EtOAc gave N-benzyl-4-(N-Boc-2-aminoethyl)aniline 41 as colorless oil (11.5 g, 83%). Rf=0.75 in 1/1 hexane/EtOAc. H1-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.38-7.2 (m, 5H), 6.87-6.84 (d, 2H), 6.58-6.55 (d, 2H), 4.27 (s, 2H), 3.2-3.15 (m, 2H), 2.6-2.56 (t, 2H), 1.41 (s, 9H); ESMS (C20H26N2O2): calcd. 326.4. obsd. 328 [M+H]+. The reaction mixture was filtered the filtrate was concentrated in vacuo to give a colorless oil concentrated in vacuo to give a pale yellow oily residue Purification by flash silica column chromatography