(1R)-1,2,3,4-tetrahydronaphthalen-1-amine

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

Procedure: To a solution of 3-Methyl-isoxazole-4-carboxylic acid (0.52 g, 4.06 mmol) in DCM (15 mL) and DMF (2 mL), was added HOBt (1.1 g, 8.14 mmol) and EDCI (0.896 g 4.67 mmol). The clear yellow solution was cooled to 0 C and allowed to stir under Ar for 15 minutes. To the solution was added (R)-1-Amino-1,2,3,4-tetrahydronaphthalene (0.73 mL, 5.04 mmol and the reaction mixture was allowed to slowly warm to ambient temperature and was stirred for overnight. Dilution with DCM (50 mL) was followed by aqueous extraction (NaHCO3 water, brine (50 mL), drying over MgSO4, filtration and removal of solvent in vacuo. Silica gel chromatography (0-25% Hexane:EtOAc) afforded the title compound (650 mg; 62.5%) as a sticky solid. 1H NMR (CDCl3) δ 1.88 (m, 3H), 2.12 (m, 1H), 2.51 (s, 3H), 2.81 (m, 2H), 5.32 (m, 1H), 5.99 (bd, 1H), 7.13 (m, 1H), 7.20 (m, 2H) 7.20 (m, 2H); 13C NMR (CDCl3) δ 11.22, 20.15, 29.41, 30.35, 47.93, 116.73, 126.72, 127.88, 128.88, 129.65, 136.25, 138.00, 158.45, 160.28. ESIMS: 257 (M+H) EA calc'd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. found C, 70.61; H, 6.11; N, 11.09. The clear yellow solution was cooled to 0 C was stirred for overnight Dilution with DCM (50 mL) was followed by aqueous extraction (NaHCO3 water, brine (50 mL) drying over MgSO4, filtration and removal of solvent in vacuo

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

Procedure: To a solution of furan-3-carboxylic acid (100 mg, 0.68 mmol), HOBt (240 mg, 1.78 mmol) and EDCI.HCl (196 mg, 1.03 mmol) in CH2Cl2 (8 mL) and DMF (1.5 mL) at 0° C., was added (R)-1,2,3,4-tetrahydronaphthalen-1-amine (160 μL, 1.06 mmol). The reaction was stirred at rt for 24 h, after which CH2Cl2 was added. The resulting solution was washed with saturated NaHCO3, H2O, brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from EtOH/H2O afforded (R)—N-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,5-dihydrofuran-3-carboxamide. 1H NMR (500 MHz, CDCl3): δ 1.89 (m, 3H), 2.12 (m, 1H), 2.84 (m, 2H), 5.35 (m, 1H), 5.96 (br d, 1H, J=7.75 Hz), 6.59 (dd, 1H, J=1.90, 0.86 Hz), 7.13 (m, 1H), 7.19 (m, 2H), 7.32 (m, 1H), 7.43 (t, 1H, J=1.73 Hz), 7.93 (m, 1H). MS (M+H, 242). The resulting solution was washed with saturated NaHCO3, H2O, brine dried over MgSO4 concentrated in vacuo Recrystallization from EtOH/H2O

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

Procedure: Following a procedure analogous to that for the synthesis of Compound D of Example 1, (S)-1-((benzyloxy)carbonyl)-4-oxopyrrolidine-2-carboxylic acid (Aldrich, 4.00 g, 15.2 mmol) and (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 2.23 mL, 15.2 mmol) were converted to the title compound (5.96 g, 100%). MS (ESI+) m/z 393.1 (M+H)+.

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

Procedure: To a solution of (2S,4S)-Boc-gamma-(Fmoc-amino)-proline (Chem-Impex, 6.00 g, 13.3 mmol) in DMF (20 mL) at 0° C. were added EDC (3.05 g, 15.9 mmol), HOAt (2.17 g, 15.9 mmol) and NMM (4.38 mL, 39.8 mmol). The reaction mixture was stirred at ice bath temperature for 20 min then treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 2.15 g, 14.6 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 1 h and cold water (100 mL) was added to the reaction mixture. The solid that formed was collected by filtration and washed with cold water (100 mL). The solid was dissolved in CH2Cl2 (200 mL) and the organic solution was washed with 5% aq. citric acid solution and brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash column chromatography (gradient elution from 10 to 30% EtOAc in CH2Cl2) provided the title compound (6.70 g, 87%) as a light tan solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=7.5 Hz, 2H), 7.67 (d, J=7.3 Hz, 2H), 7.42 (td, J=7.2, 4.0 Hz, 2H), 7.37-7.03 (m, 6H), 5.22 (br. s., 1H), 4.57-4.23 (m, 5H), 3.68-3.49 (m, 2H), 2.91-2.74 (m, 2H), 2.52 (d, J=13.4 Hz, 1H), 2.35-2.21 (m, 1H), 2.14 (d, J=5.1 Hz, 1H), 1.97-1.80 (m, 3H), 1.44 (s, 9H); MS (ESI+) m/z 582.2 (M+H)+. The reaction mixture was stirred at rt for 1 h The solid that formed was collected by filtration washed with cold water (100 mL) The solid was dissolved in CH2Cl2 (200 mL) the organic solution was washed with 5% aq. citric acid solution and brine dried over MgSO4 filtered The filtrate was concentrated in vacuo The residue was dissolved in CH2Cl2 purified by flash column chromatography (gradient elution from 10 to 30% EtOAc in CH2Cl2)

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

Procedure: To a 0° C. solution of (S)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1.32 g, 4.49 mmol) in DMF (30 mL) was added EDC (1.03 g, 5.39 mmol) followed by HOAt (0.73 g, 5.39 mmol). After 10 min, (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 0.66 mL, 4.49 mmol) and NMM (1.48 mL, 13.5 mmol) were added. The resulting reaction mixture was allowed to warm to room temperature over 4 h and then poured into a separatory funnel containing EtOAc and sat. aq. NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were washed with 1N HCl, 10% LiCl and sat. NaCl and then dried over MgSO4, filtered and concentrated in vacuo. The crude oil was then purified by flash chromatography (gradient elution from 0 to 70% EtOAc/hexanes) to afford the title compound (1.25 g, 2.96 mmol, 66% over 3 steps) as a light yellow foam. 1H NMR (CDCl3) δ 7.18-6.86 (m, 4H), 6.84-6.67 (m, 1H), 6.58-6.39 (m, 1H), 6.04-5.74 (m, 2H), 4.94 (d, J=5.7 Hz, 1H), 4.78-4.61 (m, 1H), 4.56-4.41 (m, 1H), 4.20 (d, J=15.6 Hz, 1H), 3.34 (d, J=13.4 Hz, 1H), 3.02 (d, J=12.1 Hz, 1H), 2.81-2.60 (m, 2H), 1.87-1.68 (m, 2H), 1.67-1.54 (m, 2H), 1.53-1.37 (m, 9H); MS (ESI+) m/z 423.2 (M+H)+. The resulting reaction mixture poured into a separatory funnel The aqueous layer was extracted with EtOAc (3×) the combined organic extracts were washed with 1N HCl, 10% LiCl and sat. NaCl dried over MgSO4 filtered concentrated in vacuo The crude oil was then purified by flash chromatography (gradient elution from 0 to 70% EtOAc/hexanes)

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

Procedure: The title compound of Example 2 was treated with LiOH using the general procedure C to hydrolyze the methyl ester. The resulting acid was coupled to (R)-tetrahydro-1-naphthylamine using the general procedure D to prepare the title compound of Example 3. 1H NMR (CDCl3): consistent with proposed structure.

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

Procedure: To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-((4-(methoxycarbonyl)benzyl)oxy)pyrrolidine-2-carboxylic acid (1.2 g, 3.2 mmol) in DMF (10 mL) was added EDC (0.91 g, 4.7 mmol) and 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol (0.43 g, 3.2 mmol). The reaction mixture was stirred at rt for 5 min and treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (0.54 g, 3.6 mmol) in DMF (5 mL) and 4-methylmorpholine (0.70 mL, 6.3 mmol). The reaction mixture was stirred at rt for 1 h and diluted with ethyl acetate and brine. The organic layer was separated and washed successively with aq. NaHCO3 solution, brine, and 1N HCl solution. The organics were dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (1.3 g, 81%). 1H NMR (CDCl3) δ 7.99 (d, J=8.4 Hz, 2H), 7.33 (d, J=6.8 Hz, 2H), 7.13-6.94 (m, 3H), 6.85-6.80 (m, 1H), 5.21-5.01 (m, 1H), 4.49-4.33 (m, 2H), 4.11 (d, J=3.1 Hz, 1H), 3.93 (s, 3H), 3.70-3.41 (m, 2H), 2.74 (d, J=3.3 Hz, 2H), 2.05 (s, 2H), 1.90-1.68 (m, 3H), 1.58 (s, 1H), 1.45 (s, 10H); MS(ESI+) m/z 509.5 (M+H)+. The reaction mixture was stirred at rt for 1 h The organic layer was separated washed successively with aq. NaHCO3 solution, brine, and 1N HCl solution The organics were dried over MgSO4 concentrated in vacuo The resulting residue was purified by flash chromatography (eluting with 20% EtOAc/DCM)

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

Procedure: To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-((4-(methoxycarbonyl)benzyl)oxy)pyrrolidine-2-carboxylic acid (1.2 g, 3.2 mmol) in DMF (10 mL) was added EDC (0.91 g, 4.7 mmol) and 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol (0.43 g, 3.2 mmol). The reaction mixture was stirred at rt for 5 min and treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (0.54 g, 3.6 mmol) in DMF (5 mL) and 4-methylmorpholine (0.70 mL, 6.3 mmol). The reaction mixture was stirred at rt for 1 h and diluted with ethyl acetate and brine. The organic layer was separated and washed successively with aq. NaHCO3 solution, brine, and 1N HCl solution. The organics were dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (1.3 g, 81%). 1H NMR (CDCl3) δ 7.99 (d, J=8.4 Hz, 2H), 7.33 (d, J=6.8 Hz, 2H), 7.13-6.94 (m, 3H), 6.85-6.80 (m, 1H), 5.21-5.01 (m, 1H), 4.49-4.33 (m, 2H), 4.11 (d, J=3.1 Hz, 1H), 3.93 (s, 3H), 3.70-3.41 (m, 2H), 2.74 (d, J=3.3 Hz, 2H), 2.05 (s, 2H), 1.90-1.68 (m, 3H), 1.58 (s, 1H), 1.45 (s, 10H); MS(ESI+) m/z 509.5 (M+H)+. The reaction mixture was stirred at rt for 1 h The organic layer was separated washed successively with aq. NaHCO3 solution, brine, and 1N HCl solution The organics were dried over MgSO4 concentrated in vacuo The resulting residue was purified by flash chromatography (eluting with 20% EtOAc/DCM)

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

Procedure: To a solution of (2S,4S)-Boc-4-(Fmoc-amino)-proline (Chem-Impex, 6.00 g, 13.3 mmol) in DMF (20 mL) at 0° C. were added EDC (3.05 g, 15.9 mmol), HOAt (2.17 g, 15.9 mmol) and NMM (4.38 mL, 39.8 mmol). The reaction mixture was stirred at ice bath temperature for 20 min then treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 2.15 g, 14.6 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 1 h and cold water (100 mL) was added to the reaction mixture. The solid that formed was collected by filtration and washed with cold water (100 mL). The solid was dissolved in CH2Cl2 (200 mL) and the organic solution was washed with 5% aq. citric acid solution and brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash column chromatography (gradient elution from 10 to 30% EtOAc in CH2Cl2) provided the title compound (6.70 g, 87%) as a light tan solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=7.5 Hz, 2H), 7.67 (d, J=7.3 Hz, 2H), 7.42 (td, J=7.2, 4.0 Hz, 2H), 7.37-7.03 (m, 6H), 5.22 (br. s., 1H), 4.57-4.23 (m, 5H), 3.68-3.49 (m, 2H), 2.91-2.74 (m, 2H), 2.52 (d, J=13.4 Hz, 1H), 2.35-2.21 (m, 1H), 2.14 (d, J=5.1 Hz, 1H), 1.97-1.80 (m, 3H), 1.44 (s, 9H); MS(ESI+) m/z 582.2 (M+H)+. The reaction mixture was stirred at rt for 1 h The solid that formed was collected by filtration washed with cold water (100 mL) The solid was dissolved in CH2Cl2 (200 mL) the organic solution was washed with 5% aq. citric acid solution and brine dried over MgSO4 filtered The filtrate was concentrated in vacuo The residue was dissolved in CH2Cl2 purified by flash column chromatography (gradient elution from 10 to 30% EtOAc in CH2Cl2)

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

Procedure: To a solution of (R)-1-(tert-butoxycarbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxylic acid (1.0 g, 3.9 mmol) in DMF (9 mL) at 0° C. was added EDC (1.3 g, 6.6 mmol) and 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol (0.53 g, 3.9 mmol). The resulting mixture was stirred for 5 minutes and treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 0.60 g, 4.1 mmol) in DMF (4 mL) and then DIEA (0.94 mL, 5.4 mmol). The reaction mixture was stirred at rt for 1.5 h and diluted with ethyl acetate and brine. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 (eluting with 20% EtOAc/hexane) to afford the title compound (1.25 g, 83%). 1H NMR (400 MHz, CDCl3) δ 7.22-7.02 (m, 4H), 5.22-4.61 (m, 2H), 3.16-2.65 (m, 3H), 2.52 (d, J=14.5 Hz, 1H), 2.12-1.95 (m, 1H), 1.88-1.76 (m, 3H), 1.52-1.28 (m, 11H), 0.43-0.16 (m, 6H); MS(ESI+) m/z 389.4 (M+H)+. The reaction mixture was stirred at rt for 1.5 h The organic layer was separated washed with brine dried over MgSO4 concentrated in vacuo The residue was purified by flash column chromatography on SiO2 (eluting with 20% EtOAc/hexane)

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

Procedure: To a solution of (R)-1-(tert-butoxycarbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxylic acid (1.0 g, 3.9 mmol) in DMF (9 mL) at 0° C. was added EDC (1.3 g, 6.6 mmol) and 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol (0.53 g, 3.9 mmol). The resulting mixture was stirred for 5 minutes and treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 0.60 g, 4.1 mmol) in DMF (4 mL) and then DIEA (0.94 mL, 5.4 mmol). The reaction mixture was stirred at rt for 1.5 h and diluted with ethyl acetate and brine. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 (eluting with 20% EtOAc/hexane) to afford the title compound (1.25 g, 83%). 1H NMR (400 MHz, CDCl3) δ 7.22-7.02 (m, 4H), 5.22-4.61 (m, 2H), 3.16-2.65 (m, 3H), 2.52 (d, J=14.5 Hz, 1H), 2.12-1.95 (m, 1H), 1.88-1.76 (m, 3H), 1.52-1.28 (m, 11H), 0.43-0.16 (m, 6H); MS(ESI+) m/z 389.4 (M+H)+. The reaction mixture was stirred at rt for 1.5 h The organic layer was separated washed with brine dried over MgSO4 concentrated in vacuo The residue was purified by flash column chromatography on SiO2 (eluting with 20% EtOAc/hexane)

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

Procedure: A solution of crude 21 (106 mg, 0.19 mmol) in NMP (5 mL) was cooled to 0° C. and treated with HATU (73 mg, 0.19 mmol) and DIPEA (0.1 mL, 0.57 mmol). After 10 min, (1R)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (0.05 mL, 0.35 mmol) in NMP (3 mL) was added. The reaction was allowed to warm to ambient temperature. After 16 h, the solution was diluted with EtOAc, washed successively with 1M HCl, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 22 which was used without further purification. Mass spectrum, m/z [688.5] (M+H)+. After 16 h washed successively with 1M HCl, brine dried over anhydrous Na2SO4 filtered concentrated