[2-(4-chlorophenoxy)phenyl]methanamine

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

Procedure: A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-cyclohexanecarbonylpiperidin-4-one (89.5 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}cyclohexylmethanone (116 mg, 63%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=10.18 min, m/z 429.46 (36), 427.44 (M++H, 100). HPLC tr=4.43 min (93.94%) 1H NMR (270 MHz, CDCl3) δ 1.12-1.79 (15H, m, 7CH2+NH), 2.44 (1H, m, CHCO), 2.64 (2H, m, CH2), 2.99 (1H, m, CHNH), 3.80 (2H, m, CH2NH), 3.82 (1H, m, ½CH2), 4.39 (1H, br d, J=13.3 Hz, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.12 (1H, td, ArH), 7.22 (1H, m, ArH), 7.25 (2H, AA′BB′, ArH) and 7.39 (1H, dd, J=7.3, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 25.97, 29.40, 29.59, 32.29, 33.40, 40.32 (CH2), 40.54 (CH), 43.91, 45.65 (CH2), 54.00 (CH), 118.94, 119.61, 124.54, 127.96, 128.70, 129.84, 130.57, 131.84, 154.35, 156.38 (ArC), and 174.48 (C═O). were consumed (30 min) Then, it was quenched with saturated NaHCO3 solution the aqueous layer was washed with DCM (2×20 mL) the combined organic layers were dried (MgSO4) filtered evaporated to dryness

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

Procedure: A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and N-benzoyl-4-piperidone (87 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCN to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}phenylmethanone (152 mg, 84%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.19 min, m/z 423.35 (36), 421.34 (M++H, 100). HPLC tr=4.04 min (98.05%) 1H NMR (270 MHz, CDCl3) δ 1.24-1.44 (3H, m, CH2+NH), 1.76 (1H, m, ½CH2), 1.91 (1H, m, ½CH2), 2.72 (1H, hept, CHNH), 2.96 (1H, m, ½CH2), 3.80 (2H, m, CH2NH), 4.46 (1H, m, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.12 (1H, td, ArH), 7.23 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.33-7.41 (6H, m, ArH). 13C NMR (270 MHz, CDCl3) δ 32.26, 33.09, 40.78, 45.67, 46.29 (CH2), 53.81 (CH), 118.95, 119.63, 124.57, 126.86, 127.97, 128.54, 128.75, 129.58, 129.85, 130.58, 131.78, 136.33, 154.35, 156.38 (ArC), and 170.00 (C═O). were consumed (30 min) Then, it was quenched with saturated NaHCO3 solution the aqueous layer was washed with DCM (2×20 mL) the combined organic layers were dried (MgSO4) filtered evaporated to dryness

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

Procedure: A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-cyclopentanecarbonylpiperidin-4-one (83.5 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave {4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}cyclopentylmethanone (144 mg, 81%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.42 min, m/z 415.36 (36), 413.40 (M++H, 100). HPLC tr=6.82 min (98.32%) 1H NMR (270 MHz, CDCl3) δ 1.23 (2H, m, CH2), 1.52 (2H, m, CH2), 1.60-1.90 (9H, m, 4CH2+NH), 2.66 (2H, m, CH2), 2.85 (1H, quin, J=7.9 Hz, CHCO), 3.00 (1H, m, CHNH), 3.79 (2H, m, CH2), 3.85 (1H, m, ½CH2), 4.40 (1H, m, ½CH2), 6.83 (2H, AA′BB′, ArH), 6.87 (1H, m, ArH), 7.12 (1H, td, ArH), 7.23 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.38 (1H, dd, J=7.4, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 26.12, 30.09, 32.29, 32.24, 40.55 (CH2), 41.19 (CH), 44.04, 45.65 (CH2), 54.00 (CH), 118.93, 119.62, 124.54, 127.95, 128.70, 129.84, 130.58, 131.83, 154.34, 156.38 (ArC), and 174.37 (C═O). were consumed (30 min) Then it was quenched with saturated NaHCO3 solution the aqueous layer was washed with DCM (2×20 mL) the combined organic layers were dried (MgSO4) filtered evaporated to dryness

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

Procedure: A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-isobutyrylpiperidin-4-one (78.4 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}-2-methylpropan-1-one (129 mg, 78%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.18 min, m/z 389.48 (36), 387.46 (M++H, 100). HPLC tr=3.65 min 97.72%) 1H NMR (270 MHz, CDCl3) δ 1.079 (3H, d, J=6.7 Hz, CH3), δ 1.082 (3H, d, J=6.7 Hz, CH3), 1.23 (2H, m, CH2), 1.45 (br s, NH), 1.83 (2H, m, CH2), 2.70 (2H, m, H2), 2.77 (1H, hept, J=6.7 Hz, CHMe2), 3.01 (1H, m, CHNH), 3.80 (2H, m, CH2), 3.83 (1H, m, ½CH2), 4.41 (1H, br d, J=13.4 Hz, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.87 (1H, m, ArH), 7.12 (1H, td, ArH), 7.24 (1H, m, ArH), 7.25 (2H, AA′BB′, ArH) and 7.39 (1H, dd, J=7.4, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 19.46, 19.65 (CH2), 30.13 (CH), 32.39, 33.30, 40.43, 43.95, 45.67 (CH2), 53.97 (CH), 118.94, 119.61, 124.54, 127.96, 128.72, 129.84, 130.58, 131.80, 154.35, 156.37 (ArC), and 175.30 (C═O). were consumed (30 min) Then, it was quenched with saturated NaHCO3 solution the aqueous layer was washed with DCM (2×20 mL) the combined organic layers were dried (MgSO4) filtered evaporated to dryness

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

Procedure: A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-(3-methylbutyryl)piperidin-4-one (78.4 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}-3-methylbutan-1-one (114 mg, 66%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.36 min, m/z 403.46 (35), 401.44 (M++H, 100). HPLC tr=3.39 min (96.55%) 1H NMR (270 MHz, CDCl3) δ 0.92 (6H, d, J=6.4 Hz, 2CH3), 1.23 (2H, m, CH2), 1.46 (br s, NH), 1.82 (2H, br d, J=12.9 Hz, CH2), 2.05 (1H, hept, J=6.4 Hz, CHMe2), 2.19 (2H, m, CH2), 2.65 (2H, m, CH2), 2.99 (1H, m, CHNH), 3.77 (1H, m, ½CH2), 3.79 (2H, s, CH2NH), 4.40 (1H, br d, J=13.3 Hz, ½CH2), 6.81-6.87 (3H, m, ArH), 7.11 (1H, td, ArH), 7.19-7.25 (3H, m, ArH) and 7.38 (1H, dd, J=7.2, 1.5 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 22.80 (CH2), 22.90 (CH3), 25.93 (CH), 32.30, 33.15, 40.23, 42.24, 44.44, 45.65 (CH2), 53.87 (CH), 118.93, 119.62, 124.54, 127.94, 128.71, 129.83, 130.58, 131.79, 154.34, 156.37 (ArC), and 170.91 (C═O). were consumed (30 min) Then, it was quenched with saturated NaHCO3 solution the aqueous layer was washed with DCM (2×20 mL) the combined organic layers were dried (MgSO4) filtered evaporated to dryness

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

Procedure: A solution of 2-(4-chlorophenoxy)benzylamine (AMR01073, 100 mg, 0.428 mmol), 1-acetylpiperidone (121 mg, 0.856 mmol) and acetic acid (0.13 mL, 2.14 mmol) in DCE (2 mL) was treated with NaBH(OAc)3 (227 mg, 1.07 mmol) and stirred under microwave irradiation for 15 min at 100° C. The reaction mixture was diluted with DCM (10 mL) and quenched with saturated NaHCO3 solution. The aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using AcOEt to AcOEt/MeOH 9:1 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}ethanone (124 mg, 81%) as a colorless oil. Rf: 0.14 (AcOEt/MeOH 9:1) LC/MS (APCI) tr=4.79 min, m/z 361.46 (35), 359.51 (M++H, 100). HPLC tr=3.04 min (97.37%) 1H NMR (270 MHz, CDCl3) δ 1.25 (2H, m, CH2), 1.68 (br s, NH), 1.79 (2H, m, CH2), 2.05 (3H, S, CH3), 2.67 (2H, m, CH2), 3.02 (1H, m, CH), 3.70 (1H, m, ½CH2), 3.82 (2H, s, CH2), 4.33 (1H, m, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.11 (1H, m, ArH), 7.21 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.38 (1H, dd, J=7.2, 1.5 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 21.10 (CH3), 31.49, 32.32, 39.64, 44.47, 45.05 (CH2), 53.21 (CH), 118.49, 119.04, 124.04, 127.51, 128.30, 129.36, 130.14, 131.02, 153.89, 155.80 (ArC), and 168.42 (C═O). quenched with saturated NaHCO3 solution The aqueous layer was washed with DCM (2×20 mL) the combined organic layers were dried (MgSO4) filtered evaporated to dryness

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

Procedure: AMR01073 To an ice cooled solution of 2-(4-chlorophenoxy)benzonitrile (AMR01071, 200 mg, 8.75 mmol) in dry THF (10 mL) was added a solution of LiAlH4 (THF 1M, 1.75 mL) under nitrogen. After stirring at room temperature for 3 h, the reaction mixture was cooled again and quenched with the minimum amount of saturated NH4Cl solution. The insoluble material was removed by filtration, and washed with DCM. The filtrate was dried (MgSO4) and the solvent evaporated to give 2-(4-chlorophenoxy)benzylamine (AMR01073, 203 mg, 100%) as an oil, which was used in the next step without further purification. AMR01076 Following the same procedure, from AMR01071 (1.5 g, 6.53 mmol) and LiAlH4 solution (THF 1M, 13 mL) in dry THF (30 mL), 2-(4-chlorophenoxy)benzylamine (AMR0106, 1.38 g, 90%) was obtained as an oil. Rf: 0.35 (DCM/MeOH 9:1) 1H NMR (270 MHz, CDCl3) δ 1.42 (2H, br s, NH2), 3.84 (2H, s, CH2), 6.84-6.90 (3H, m, ArH), 7.13 (1H, m, ArH), 7.21 (1H, dd, J=7.6, 2.0 Hz, ArH), 7.26 (2H, AA′BB′, ArH) and 7.38 (1H, td, J=7.4, 1.7 Hz, ArH). LC/MS (APCI) tr=1.40 min, m/z 236.38 (34), 234.36 (M++H, 100), 217.29 (M+—NH3, 35). the reaction mixture was cooled again quenched with the minimum amount of saturated NH4Cl solution The insoluble material was removed by filtration washed with DCM The filtrate was dried (MgSO4) the solvent evaporated