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Stage #1: With borane-THF In tetrahydrofuran at 25℃; for 16 h; Inert atmosphere Stage #2: With sodium carbonate In tetrahydrofuran; water for 0.25 h;
Example 16 Preparation of intermediate 6-bromomethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (D-1) To a solution of 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester (12.50 g, 45.08 mmol) in dry THF (125.0 mL), under nitrogen at 25° C., is added via syringe borane THF complex (99.17 mL, 99.17 mmol) The mixture is stirred at 25° C. for 16 h then water (10.0 mL) is slowly added followed by 2.0 M Na2CO3 (15.0 mL). This mixture is stirred for 15 min and then is diluted with EtOAc and the organic layers are collected. The organics are rinsed with 1M HCl, dried over MgSO4, and concentrated under reduced pressure to afford an oil. The oil is purified by silica gel chromatography to yield D-1-1 (11.8 g, 99.3percent yield), as a white solid. To a solution of alcohol, D-1-1, (9.50 g, 36.1 mmol) and N,N-diisopropylethylamine (9.43 mL, 54.1 mmol) in dichloromethane (200.0 mL) is added triphenylphosphine dibromide (23.79 g, 54.11 mmol) at 0° C. The reaction is stirred for 1 h then concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography to yield D-1 (8.74 g, 74percent yield), as a white solid.
11.78 g
Stage #1: With borane-THF In tetrahydrofuran at 25℃; for 16 h; Inert atmosphere Stage #2: With water; sodium carbonate In tetrahydrofuran for 0.25 h;
Preparation of intermediate 6-bromomethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4-19) Compound 4-17 (12.50 g, 45.08 mmol) is dissolved in dry THF (125.0 mL) under nitrogen at 25° C. Borane THF complex (99.17 mL, 99.17 mmol) is added via syringe and the mixture is stirred at 25° C. for 16 h. Water (10.0 mL) is slowly added and then 2.0 M Na2CO3 (15.0 mL). This mixture is stirred for 15 min and then is diluted with EtOAc and the organic layers are collected. The organics are rinsed with 1.0 M HCl, dried over MgSO4, and concentrated in vacuo to afford an oil. The oil is purified by silica gel chromatography using a gradient of 10-80percent EtOAc in heptane to yield the desired product, 4-18 (11.78 g), as a white solid.
2 g
With borane-THF In tetrahydrofuran at 20℃; for 3 h; Sealed tube; Inert atmosphere
Borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M, 15.87 mL, 15.87 mmol) was added dropwise to a stirred solution of 2-(tert-butoxycarbonyl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylic acid (2.0 g, 7.21 mmol) in tetrahydrofuran (50 mL) at ambient temperature under argon in a sealed flask. After stirring for 3 hours, the mixture was carefully quenched with water and sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate (x2) and the combined extracts were washed with brine, dried (anhydrous Na2SO4) and evaporated to give tert-butyl 6- (hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.0 g). LCMS m/z = 207.9 [M+H–isobutylene]+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
Intermediate 25: 1 ,1-Dimethylethyl 6-[(1 /-/-pyrazol-4-ylamino)carbonyl1-3,4-dihydro- 2(1 HVisoalphauinolinecarboxylate; To a solution of 1 H-pyrazol-4-amine (1.87 g, 22.5 mmol), N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (5.18 g, 27 mmol), 1-hydroxybenzotriazole hydrate (3.65 g, 27 mmol) and triethylamine (6.3 ml_, 45 mmol) in DMF was added 2- [(I J-dimethylethyOoxylcarbonylJ-i ^^^-tetrahydro-theta-isoquinolinecarboxylic acid (5.62 g, 20.3 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure, the residue was dissolved in MeOH and potassium hydroxide (5.04 g, 90 mmol), water (100 ml.) was added and the mixture was heated at 500C for 15 min. The MeOH was evaporated under reduced pressure and the solid which crystallized was filtered and recrystallized from acetonitrile to give the title compound as a solid (3.7 g, 48%). LC/MS: m/z 341 (M-H)+, Rt: 2.80 min.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 50℃; for 6h;
A solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (296 mg, 1.07 mmol), HATU (406 mg, 1.07 mmol), DIPEA (0.41 ml_, 2.36 mmol ) and ethyl 2-amino-4-methyl-1 ,3-thiazole-5-carboxylate (199 mg, 1.07 mmol) in DMF (5 ml.) was stirred at 500C for 6 hours. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic phase was then washed with dilute HCI, with a solution of sodium bicarbonate, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was dissolved in a mixture of ethanol (1.5 ml.) and water (2 ml.) and sodium hydroxide was added (86 mg, 2.15 mmol) and the reaction mixture was heated at 500C for 4 hours. The reaction was then cooled, acidified with dilute HCI and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue obtained was used directly in the next step without further purification.
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