1-(2-aminoethyl)piperidin-4-ol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)ethyl]-amide (50.0 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 1-(2-amino-ethyl)-piperidin-4-ol (72.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 421. 1H NMR (DMSO-d6, 400 MHz): δ 8.00 (1H, m), 7.80-7.77 (1H, m), 7.65 (1H, m), 7.41-7.39 (1H, m), 7.26-7.24 (1H, m), 3.90 (1H, m), 3.75-3.72 (2H, t), 3.69 (3H, s), 3.37 (1H, m), 3.18 (2H, m), 2.07-2.02 (2H, m), 1.83-1.78 (2H, m), 1.32-1.29 (2H, m), 0.90-0.87 (2H, m), 2 —NH and —OH proton signals were not observed.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 102 mg of 2-{1 (S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one (Example 105e) and 0.5 g of N-(2-aminoethyl)-4-hydroxypiperidine are stirred for 2 hours at 80° C. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1). The title compound is obtained:Rf (dichloromethane/methanol=4:1)=0.16. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 102 mg of 2-{1 (S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one (Example 105e) and 0.5 g of N-(2-aminoethyl)-4-hydroxypiperidine are stirred for 2 hours at 80° C. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1). The title compound is obtained:Rf (dichloromethane/methanol=4:1)=0.16. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (90.5 mg) was coupled with 1-(2-amino-ethyl)-piperidin-4-ol (54 mg, 1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF (0.3 mL) at rt for overnight to give 69.8 mg (57%) of the titled compound as a yellow solid.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 102 mg of 2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one (Example 105e) and 0.5 g of N-(2-aminoethyl)-4-hydroxypiperidine are stirred for 2 hours at 80° C. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1). The title compound is obtained: Rf (dichloromethane/methanol=4:1)=0.16. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 102 mg of 2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one (Example 105e) and 0.5 g of N-(2-aminoethyl)-4-hydroxypiperidine are stirred for 2 hours at 80° C. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1). The title compound is obtained: Rf (dichloromethane/methanol=4:1)=0.16. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)ethyl]-amide (50.0 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 1-(2-amino-ethyl)-piperidin-4-ol (72.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 421. 1H NMR (DMSO-d6, 400 MHz): δ 8.00 (1H, m), 7.80-7.77 (1H, m), 7.65 (1H, m), 7.41-7.39 (1H, m), 7.26-7.24 (1H, m), 3.90 (1H, m), 3.75-3.72 (2H, t), 3.69 (3H, s), 3.37 (1H, m), 3.18 (2H, m), 2.07-2.02 (2H, m), 1.83-1.78 (2H, m), 1.32-1.29 (2H, m), 0.90-0.87 (2H, m), 2 —NH and —OH proton signals were not observed.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)ethyl]-amide (50.0 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 1-(2-amino-ethyl)-piperidin-4-ol (72.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 421. 1H NMR (DMSO-d6, 400 MHz): δ 8.00 (1H, m), 7.80-7.77 (1H, m), 7.65 (1H, m), 7.41-7.39 (1H, m), 7.26-7.24 (1H, m), 3.90 (1H, m), 3.75-3.72 (2H, t), 3.69 (3H, s), 3.37 (1H, m), 3.18 (2H, m), 2.07-2.02 (2H, m), 1.83-1.78 (2H, m), 1.32-1.29 (2H, m), 0.90-0.87 (2H, m), 2 —NH and —OH proton signals were not observed.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 102 mg of 2-{1 (S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one (Example 105e) and 0.5 g of N-(2-aminoethyl)-4-hydroxypiperidine are stirred for 2 hours at 80° C. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1). The title compound is obtained:Rf (dichloromethane/methanol=4:1)=0.16. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The method follows that of S6 using 4-hydroxy-piperidin-1-yl-acetonitrile (18.97 g, 0.136 mol), LiAlH4 (15.48 g, 0.408 mol) and dry THF (150 mL). The title compound (8.56 g, 44%) was afforded as a straw-coloured oil after kugelrohr distillation (178° C., 0.05 mbar). δH(250 MHz; CDCl3); 1.55 (m, 2H, 1×CHCH2CH2 and 1×CH2CH2CH), 1.85 (m, 2H, 1×CHCH2CH2 and 1×CH2CH2CH), 2-2.25 (m, 5H, NCH2CH2, NCH2CH2 and OH), 2.38 (t, 2H, H2NCH2CH2N), 2.72 (t, 4H, H2NCH2CH2N, NH2) and 3.65 (m, 1H, CH2CHOH); δC(62.9 MHz; CDCl3); 34.56, 38.98, 51.35, 60.84 and 67.64; FAB MS, m/z(M+H)+ 145; IR υmax/cm−1; 3375 (broad), 1600, 1460, 1370, 1290 and 1070.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The method follows that of S6 using 4-hydroxy-piperidin-1-yl-acetonitrile (18.97 g, 0.136 mol), LiAlH4 (15.48 g, 0.408 mol) and dry THF (150 mL). The title compound (8.56 g, 44%) was afforded as a straw-coloured oil after kugelrohr distillation (178° C., 0.05 mbar). δH(250 MHz; CDCl3); 1.55 (m, 2H, 1×CHCH2CH2 and 1×CH2CH2CH), 1.85 (m, 2H, 1×CHCH2CH2 and 1×CH2CH2CH), 2-2.25 (m, 5H, NCH2CH2, NCH2CH2 and OH), 2.38 (t, 2H, H2NCH2CH2N), 2.72 (t, 4H, H2NCH2CH2N, NH2) and 3.65 (m, 1H, CH2CHOH); δC(62.9 MHz; CDCl3); 34.56, 38.98, 51.35, 60.84 and 67.64; FAB MS, m/z(M+H)+ 145; IR υmax/cm−1; 3375 (broad), 1600, 1460, 1370, 1290 and 1070.