tert-butyl 7-amino-4,4-dimethyl-1,3-dihydroisoquinoline-2-carboxylate

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: To a solution of 2-[1-(2-methylamino-pyrimidin-4-yl)-ethylamino]-benzoic acid (Step B, 800 mg, 2.94 mmol) in CH2Cl2 (40 mL) was added 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (812 mg, 2.94 mmol), TBTU (1.0 g, 3.23 mmol), and DIEA (1.5 mL, 8.81 mmol). The reaction was stirred at RT under N2 for 20 h. The reaction was quenched with sat. NH4Cl, washed with water, brine, dried over MgSO4, and evaporated in vacuo. The crude solid was purified by chromatography on silica gel. Elution with Hexanes:acetone mixture (80:20) gave final compound. MS m/z: 531.2 (M+H). Calc'd. for C30H37N6O3-531.66. The reaction was quenched with sat. NH4Cl washed with water, brine dried over MgSO4 evaporated in vacuo The crude solid was purified by chromatography on silica gel Elution with Hexanes

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

Procedure: A mixture of 2-[(2-methylamino-pyrimidin-4-ylmethyl)-amino]-benzoic acid (Step C, 0.31 g, 1.20 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.33 g, 1.20 mmol), TBTU (0.43 g, 1.32 mmol), and DIEA (0.31 mL, 1.80 mmol) in 10 mL of DMF was stirred at RT for 2 h. The mixture was partitioned between EtOAc and Na2CO3 (aq). The organic layer was washed with water, brine, dried with MgSO4, filtered, condensed, and the residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2). The titled compound was obtained as a light yellowish solid. MS (ES+): 517.4 (M+H)+. Calc'd for C29H36N6O3-516.63 The mixture was partitioned between EtOAc and Na2CO3 (aq) The organic layer was washed with water, brine dried with MgSO4 filtered condensed the residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2)

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

Procedure: A mixture of 2-[(2-methylamino-pyrimidin-4-ylmethyl)-amino]-benzoic acid (Step C, 0.31 g, 1.20 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.33 g, 1.20 mmol), TBTU (0.43 g, 1.32 mmol), and DIEA (0.31 mL, 1.80 mmol) in 10 mL of DMF was stirred at RT for 2 h. The mixture was partitioned between EtOAc and Na2CO3 (aq). The organic layer was washed with water, brine, dried with MgSO4, filtered, condensed, and the residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2). The titled compound was obtained as a light yellowish solid. MS (ES+): 517.4 (M+H)+. Calc'd for C29H36N6O3-516.63 The mixture was partitioned between EtOAc and Na2CO3 (aq) The organic layer was washed with water, brine dried with MgSO4 filtered condensed the residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 14.60 mmol), 2-amino-benzoic acid (2.0 g, 14.60 mmol), TBTU (5.2 g, 16.06 mmol) and DIEA (2.7 mL, 16.06 mmol) in 5 mL of DMF was heated (50° C.) for 12 h in a sealed tube. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (SiO2, 20% EtOAc/hexane) to afford a pinkish solid. MS (ES+): 396.0 (M+H)+. Calc'd for C23H29N3O3: 395.49. The aqueous layer was extracted with EtOAc The combined organic layers were dried over Na2SO4 filtered concentrated under vacuum The crude material was purified by flash chromatography (SiO2, 20% EtOAc/hexane) to afford a pinkish solid

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 14.60 mmol), 2-amino-benzoic acid (2.0 g, 14.60 mmol), TBTU (5.2 g, 16.06 mmol) and DIEA (2.7 mL, 16.06 mmol) in DMF (5 mL) was heated (50° C.) for 12 h in a sealed tube. The mixture was diluted with EtOAc and water. The aqueous layer extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 20% EtOAc/hexane) to afford a pinkish solid. MS (ES+): 396.0 (M+H)+. Calc'd for C23H29N3O3-395.49. The aqueous layer extracted with EtOAc The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo The crude material was purified by flash chromatography (SiO2, 20% EtOAc/hexane) to afford a pinkish solid

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 14.60 mmol), 2-amino-benzoic acid (2.0 g, 14.60 mmol), TBTU (5.2 g, 16.06 mmol) and DIEA (2.7 mL, 16.06 mmol) in DMF (5 mL) was heated (50° C.) for 12 h in a sealed tube. The mixture was diluted with EtOAc and water. The aqueous layer extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 20% EtOAc/hexane) to afford a pinkish solid. MS (ES+): 396.0 (M+H)+. Calc'd for C23H29N3O3-395.49. The aqueous layer extracted with EtOAc The combined organic layers were dried over Na2SO4 filtered concentrated in vacuo The crude material was purified by flash chromatography (SiO2, 20% EtOAc/hexane) to afford a pinkish solid

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

Procedure: A mixture of 2-[(7-fluoro-1H-indol-3-ylmethyl)-amino]-benzoic acid (Step A, 200 mg, 0.70 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (194 mg, 0.70 mmol), TBTU (247 mg, 0.80 mmol), and DIEA (0.25 mL, 1.4 mmol) in CH2Cl2 (5 mL) was stirred at RT under N2 atmosphere for 16 h. The mixture was diluted with CH2Cl2 (5 mL) and extracted with water (2×10 mL). The crude material was purified with flash chromatography (SiO2, 15% EtOAc/hexane) to give a yellow solid. MS (ES+) 543.1. (M+H)+. Calc'd for C32H35FN4O3-542.24. extracted with water (2×10 mL) The crude material was purified with flash chromatography (SiO2, 15% EtOAc/hexane) to give a yellow solid

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

Procedure: A mixture of 2-[(7-fluoro-1H-indol-3-ylmethyl)-amino]-benzoic acid (Step A, 200 mg, 0.70 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (194 mg, 0.70 mmol), TBTU (247 mg, 0.80 mmol), and DIEA (0.25 mL, 1.4 mmol) in CH2Cl2 (5 mL) was stirred at RT under N2 atmosphere for 16 h. The mixture was diluted with CH2Cl2 (5 mL) and extracted with water (2×10 mL). The crude material was purified with flash chromatography (SiO2, 15% EtOAc/hexane) to give a yellow solid. MS (ES+) 543.1. (M+H)+. Calc'd for C32H35FN4O3-542.24. extracted with water (2×10 mL) The crude material was purified with flash chromatography (SiO2, 15% EtOAc/hexane) to give a yellow solid

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

Procedure: A mixture of 2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-benzoic acid (Step A, 516 mg, 2.0 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol), TBTU (0.706 g, 2.2 mmol), and DIEA (0.7 mL) in 30 mL of CH2Cl2 was stirred at RT for 2 h, then diluted with more CH2Cl2. The organic layer was washed with water, brine, dried with MgSO4, filtered, and condensed. The residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2), to obtain the titled compound as oil. MS (ES+): 526 (M+H)+. Calc'd for C31H35N5O3-525.27. The organic layer was washed with water, brine dried with MgSO4 filtered condensed The residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2)