tert-butyl (3S)-3-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylate

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

実験手順: To a solution of methyltriphenylphosphonium bromide (2.07 g, 5.8 mmol) in THF (20 mL) at −78° C. is added KHMDS (11.0 mL, 5.5 mmol) and the mixture is stirred for 1.5 h. A solution of (S)-3-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.94 g, 3.6 mmol) in THF (10 mL) is added and the solution stirred at −78-C for 1.5 h before warming to RT. The reaction is quenched with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extracts are washed with 1N HCl (3×35 mL), brine (2×30 mL) and dried over Na2SO4. Purification by flash chromatography using a gradient of 0-15% EtOAc/hexane affords the title compound. the solution stirred at −78-C for 1.5 h The reaction is quenched with water (10 mL) extracted with EtOAc (2×30 mL) The organic extracts are washed with 1N HCl (3×35 mL), brine (2×30 mL) dried over Na2SO4 Purification by flash chromatography

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of oxalyl chloride (0.798 mL, 9.15 mmol) in CH2Cl2 (11 mL) at −78° C. is added DMSO (1.08 mL, 15.25 mmol) dropwise (evolution of gas observed) and the mixture stirred at −78° C. for 1.5 h. To this is added a solution of (S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.803 g, 3.05 mmol) in CH2Cl2 (9 mL) and the mixture is stirred at −78° C. for 1.5 h. Triethylamine (3.4 mL, 24.41 mmol) is added and the mixture is stirred for 10 min at −78° C. and then warmed to room temperature for 1.5 h. The mixture is extracted with EtOAc (2×30 mL), washed with 1N HCl (1×35 mL) and extracted again with EtOAc (1×30 mL). The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL), dried over Na2SO4 and concentrated to afford the title compound. the mixture is stirred at −78° C. for 1.5 h the mixture is stirred for 10 min at −78° C. warmed to room temperature for 1.5 h The mixture is extracted with EtOAc (2×30 mL) washed with 1N HCl (1×35 mL) extracted again with EtOAc (1×30 mL) The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL) dried over Na2SO4 concentrated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of oxalyl chloride (0.798 mL, 9.15 mmol) in CH2Cl2 (11 mL) at −78° C. is added DMSO (1.08 mL, 15.25 mmol) dropwise (evolution of gas observed) and the mixture stirred at −78° C. for 1.5 h. To this is added a solution of (S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.803 g, 3.05 mmol) in CH2Cl2 (9 mL) and the mixture is stirred at −78° C. for 1.5 h. Triethylamine (3.4 mL, 24.41 mmol) is added and the mixture is stirred for 10 min at −78° C. and then warmed to room temperature for 1.5 h. The mixture is extracted with EtOAc (2×30 mL), washed with 1N HCl (1×35 mL) and extracted again with EtOAc (1×30 mL). The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL), dried over Na2SO4 and concentrated to afford the title compound. the mixture is stirred at −78° C. for 1.5 h the mixture is stirred for 10 min at −78° C. warmed to room temperature for 1.5 h The mixture is extracted with EtOAc (2×30 mL) washed with 1N HCl (1×35 mL) extracted again with EtOAc (1×30 mL) The combined organic layers are washed with 1N HCl (2×30 mL) and brine (2×30 mL) dried over Na2SO4 concentrated

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

実験手順: Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (58 mg, 0.22 mmol) and 2-(piperazin-1-yl)ethanol (33 μL, 0.267 mmol) provided a crude oil which was used without purification in the preparation of Example 115. MS(ESI+) m/z 276.2 (M+H)+. provided a crude oil which was used without purification in the preparation of Example 115

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

実験手順: Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (58 mg, 0.22 mmol) and 2-(piperazin-1-yl)ethanol (33 μL, 0.267 mmol) provided a crude oil which was used without purification in the preparation of Example 115. MS(ESI+) m/z 276.2 (M+H)+. provided a crude oil which was used without purification in the preparation of Example 115

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

実験手順: Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (58 mg, 0.22 mmol) and 2-(methylamino)ethanol (21.4 μL, 0.27 mmol) provided a crude oil which was used without purification in the preparation of Example 114. MS(ESI+) m/z 221.1 (M+H)+. provided a crude oil which was used without purification in the preparation of Example 114

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

実験手順: Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (57 mg, 0.22 mmol) and 1-methylpiperazine (26 mg, 0.26 mmol) provided a crude oil which was used without purification in the preparation of Example 112. MS(ESI+) m/z 246.1 (M+H)+. provided a crude oil which was used without purification in the preparation of Example 112

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

実験手順: Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (57 mg, 0.22 mmol) and 1-methylpiperazine (26 mg, 0.26 mmol) provided a crude oil which was used without purification in the preparation of Example 112. MS(ESI+) m/z 246.1 (M+H)+. provided a crude oil which was used without purification in the preparation of Example 112

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

実験手順: Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (57 mg, 0.22 mmol) and pyrrolidine (16 mg, 0.22 mmol) provided a crude oil which was used without purification in preparation of Example 111. MS(ESI+) m/z 217.1 (M+H)+. provided a crude oil which was used without purification in preparation of Example 111

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

実験手順: Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (57 mg, 0.22 mmol) and piperidin-4-ol (26 mg, 0.26 mmol) provided a crude oil which was used without purification in the preparation of Example 110. MS(ESI+) m/z 247.2 (M+H)+. provided a crude oil which was used without purification in the preparation of Example 110

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

実験手順: Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (57 mg, 0.22 mmol) and piperidin-4-ol (26 mg, 0.26 mmol) provided a crude oil which was used without purification in the preparation of Example 110. MS(ESI+) m/z 247.2 (M+H)+. provided a crude oil which was used without purification in the preparation of Example 110

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

実験手順: Following a procedure analogous to that for the synthesis of Example 106, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (Aubry, S. et al., Tetrahedron Lett., 47:1319-1323 (2006)) (71 mg, 0.27 mmol) and morpholine (28 μL, 0.33 mmol) were converted to the title compound (80 mg, 89%). 1H NMR (CDCl3, mixture of rotamers) δ 7.24-7.20 (m, 4H), 4.85-4.66 (m, 1H), 4.54-4.42 (m, 1H), 4.30-4.17 (m, 1H), 3.67 (br s, 4H), 3.13-2.96 (m, 1H), 2.93-2.69 (m, 1H), 2.62-2.29 (m, 5H), 2.18-2.01 (m, 1H), 1.51 (s, 9H); MS(ESI+) m/z 333.2 (M+H)+.