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

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 dichloride (1.14 g, 9 mmol) in dichloromethane (30 mL) was added dimethyl sulfoxide (1.4 g, 18 mmol) at −78° C. After stirring at −78° C. for 20 min, to the mixture was added a solution of (R)-tert-butyl3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (2), 1.32 g, 5 mmol) in dichloromethane (30 mL) and stirred at −78° C. for 30 to 45 min. Then triethylamine (36 mmol) was added and the reaction mixture was warmed up to rt over 2 h. Saturated sodium carbonate solution was added and extracted with dichloromethane. The solvent was removed and the crude mixture was purified by silica gel Flash chromatography to give the title compound: 1.2 g (90% yield). 1H NMR (CDCl3, 500 MHz) δ 1.48 (9H, d, J=35 Hz), 3.06-3.62 (2H, m), 4.45-4.81 (3H, m), 7.09-7.19 (4H, m), 9.48 (1H, d, J=25 Hz). stirred at −78° C. for 30 to 45 min the reaction mixture was warmed up to rt over 2 h extracted with dichloromethane The solvent was removed the crude mixture was purified by silica gel 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 dichloride (1.14 g, 9 mmol) in dichloromethane (30 mL) was added dimethyl sulfoxide (1.4 g, 18 mmol) at −78° C. After stirring at −78° C. for 20 min, to the mixture was added a solution of (R)-tert-butyl3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (2), 1.32 g, 5 mmol) in dichloromethane (30 mL) and stirred at −78° C. for 30 to 45 min. Then triethylamine (36 mmol) was added and the reaction mixture was warmed up to rt over 2 h. Saturated sodium carbonate solution was added and extracted with dichloromethane. The solvent was removed and the crude mixture was purified by silica gel Flash chromatography to give the title compound: 1.2 g (90% yield). 1H NMR (CDCl3, 500 MHz) δ 1.48 (9H, d, J=35 Hz), 3.06-3.62 (2H, m), 4.45-4.81 (3H, m), 7.09-7.19 (4H, m), 9.48 (1H, d, J=25 Hz). stirred at −78° C. for 30 to 45 min the reaction mixture was warmed up to rt over 2 h extracted with dichloromethane The solvent was removed the crude mixture was purified by silica gel Flash chromatography

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.4 g of tert-butyl (3R)-3-{[methoxy(methyl)-amino]carbonyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate are dissolved in 31 ml of diethyl ether under N2. The reaction medium is placed at 0° C. and 0.98 g of lithium aluminium hydride is carefully added. The mixture is stirred at 0° C. for 45 min. After hydrolysis with an aqueous potassium sulphate solution, extraction is carried out with diethyl ether until the aqueous phase is completely depleted. The organic phases are washed with a 3N aqueous hydrochloric acid solution, with a saturated aqueous sodium hydrogen carbonate solution, then with H2O, and finally with a saturated aqueous sodium chloride solution. Drying over MgSO4 and concentration to dryness are carried out. 3.5 g of tert-butyl (3R)-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate are obtained, which product is subsequently used as it is. is placed at 0° C. After hydrolysis with an aqueous potassium sulphate solution, extraction The organic phases are washed with a 3N aqueous hydrochloric acid solution, with a saturated aqueous sodium hydrogen carbonate solution Drying over MgSO4 and concentration to dryness

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Lithium aluminum hydride (1 M in THF, 5.3 ml, 5.3 mmol) was added to a solution of (3R)-tert-butyl 3-(methoxy(methyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.7 g, 5.0 mmol theory) in ether (16 ml) stirring at 0° C. under nitrogen. After stirring at 0° C. for 1 h, the reaction was slowly quenched with water (0.40 ml). Sodium hydroxide (1N, 0.80 ml) followed by water (0.60 ml) were then added and the resultant gelatinous precipitate was filtered through Celite® rinsing with ether and THF. The filtrate was evaporated and the residue transferred to a separatory funnel with EtOAc. Washing with brine and drying with MgSO4 afforded crude product (1.3 g, 100% yield) which was used in the next step without further purification. After stirring at 0° C. for 1 h the reaction was slowly quenched with water (0.40 ml) were then added the resultant gelatinous precipitate was filtered through Celite® rinsing with ether and THF The filtrate was evaporated the residue transferred to a separatory funnel with EtOAc Washing with brine drying with MgSO4

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

実験手順: Sodium triacetoxyborohydride (3.1 g, 15 mm) was added to a mixture of (3R)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.3 g, 5.0 mmol theory), 2,4-dimethoxybenzylamine (0.77 ml, 5.5 mmol), and dry 4 A sieves in 1,2-dichloroethane (25 ml) stirring at ambient temperature. After stirring at ambient temperature overnight the reaction solution was transferred to a separatory funnel with EtOAc and saturated NaHCO3. Extraction with EtOAc (2×), washing the combined organic layers with brine and drying over MgSO4 afforded 1.6 g of crude product. Flash chromatography (SiO2, 1 to 10% 2N N3 in MeOH/CH2Cl2) gave pure product (1.3 g, 63% yield over the previous 3 steps). MS (ESI) 413 (M+H). dry 4 A sieves in 1,2-dichloroethane (25 ml) After stirring at ambient temperature overnight the reaction solution was transferred to a separatory funnel with EtOAc and saturated NaHCO3 Extraction with EtOAc (2×) washing the combined organic layers with brine drying over MgSO4 afforded 1.6 g of crude product

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Lithium aluminum hydride (1 M in THF, 5.3 ml, 5.3 mmol) was added to a solution of (3R)-tert-butyl 3-(methoxy(methyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.7 g, 5.0 mmol theory) in ether (16 ml) stirring at 0° C. under nitrogen. After stirring at 0° C. for 1 h, the reaction was slowly quenched with water (0.40 ml). Sodium hydroxide (1N, 0.80 ml) followed by water (0.60 ml) were then added and the resultant gelatinous precipitate was filtered through Celite® rinsing with ether and THF. The filtrate was evaporated and the residue transferred to a separatory funnel with EtOAc. Washing with brine and drying with MgSO4 afforded crude product (1.3 g, 100% yield) which was used in the next step without further purification. After stirring at 0° C. for 1 h the reaction was slowly quenched with water (0.40 ml) were then added the resultant gelatinous precipitate was filtered through Celite® rinsing with ether and THF The filtrate was evaporated the residue transferred to a separatory funnel with EtOAc Washing with brine drying with MgSO4

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 dichloride (1.14 g, 9 mmol) in dichloromethane (30 mL) was added dimethyl sulfoxide (1.4 g, 18 mmol) at −78° C. After stirring at −78° C. for 20 min, to the mixture was added a solution of (R)-tert-butyl3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (2), 1.32 g, 5 mmol) in dichloromethane (30 mL) and stirred at −78° C. for 30 to 45 min. Then triethylamine (36 mmol) was added and the reaction mixture was warmed up to rt over 2 h. Saturated sodium carbonate solution was added and extracted with dichloromethane. The solvent was removed and the crude mixture was purified by silica gel Flash chromatography to give the title compound: 1.2 g (90% yield). 1H NMR (CDCl3, 500 MHz) δ 1.48 (9H, d, J=35 Hz), 3.06-3.62 (2H, m), 4.45-4.81 (3H, m), 7.09-7.19 (4H, m), 9.48 (1H, d, J=25 Hz). stirred at −78° C. for 30 to 45 min the reaction mixture was warmed up to rt over 2 h extracted with dichloromethane The solvent was removed the crude mixture was purified by silica gel Flash chromatography