Hydrochloric Acid → 4-(3-(isoquinolin-1-ylamino)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide

HRID 1811092Notes

Reaction equation

HRID 1811092 reaction equation
[NH2:1][C:2]1[C:3]([CH3:33])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1.Cl>C(O)(C)C.O1CCOCC1>[C:35]1([NH:1][C:2]2[C:3]([CH3:33])=[C:4]([C:8]3[C:20]4[C:19]5[C:14](=[CH:15][C:16]([C:21]([N:23]6[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]6)=[O:22])=[CH:17][CH:18]=5)[NH:13][C:12]=4[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1

Participants

6

Reactant 3

HCID 313Hydrochloric Acid2×HCID 140539Isoquinoline, 1-chloro-HCID 468338134-(3-amino-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide

Product 1

HCID 593749994-(3-(isoquinolin-1-ylamino)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamideYield 35.6%

Reagents, catalysts & solvents 2

HCID 312751,4-DioxaneCatalyst2×HCID 3776IsopropanolSolvent

Conditions

Temperature
140 °C

Procedure

A suspension of 4-(3-amino-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-2, 35 mg, 0.079 mmol) and 1-chloroisoquinoline (19.45 mg, 0.119 mmol) in isopropanol (0.5 mL) was treated with 4M hydrogen chloride in 1,4-dioxane (3 drops) and the mixture was heated in a sealed tube by microwave irradiation at 140° C. for 45 min. Additional 4 M hydrogen chloride in 1,4-dioxane (1 drop) was added and the mixture was again heated in a sealed tube by microwave irradiation at 140° C. for 60 min. The mixture was concentrated and the residue was purified by preparative HPLC. The appropriate effluent fractions were concentrated and the residue was partitioned between NaHCO3 (aq) and EtOAc, and the aqueous phase was extracted twice more with EtOAc. The combined organic phases were dried and concentrated to provide 4-(3-(isoquinolin-1-ylamino)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a white solid (16 mg, 32%). 1H NMR (400 MHz, methanol-d4) δ 8.28 (1H, d, J=8.3 Hz), 7.91 (1H, d, J=7.8 Hz), 7.72 (1H, d, J=6.1 Hz), 7.66 (1H, d, J=8.3 Hz), 7.56-7.61 (2H, m), 7.48 (1H, ddd, J=8.0, 7.2, 0.8 Hz), 7.44 (1H, d, J=7.5 Hz), 7.34 (1H, t, J=7.8 Hz), 7.22 (1H, d, J=8.0 Hz), 7.14 (1H, d, J=6.7 Hz), 7.06 (1H, d, J=7.8 Hz), 6.97 (1H, d, J=6.1 Hz), 6.94 (1H, dd, J=8.2, 1.5 Hz), 3.71 (2H, br. s.), 3.42 (2H, br. s.), 2.45 (2H, br. s.), 2.32 (2H, br. s.), 2.23 (3H, s), 1.81 (3H, s). Mass spectrum m/z 569.4 (M+H)+.

Workup

  1. temperaturethe mixture was again heated in a sealed tube by microwave irradiation at 140° C. for 60 min
  2. concentrationThe mixture was concentrated
  3. customthe residue was purified by preparative HPLC
  4. concentrationThe appropriate effluent fractions were concentrated
  5. customthe residue was partitioned between NaHCO3 (aq) and EtOAc
  6. extractionthe aqueous phase was extracted twice more with EtOAc
  7. customThe combined organic phases were dried
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-240c00516bd54af7bbedee0466d1f7f9
Source dataset
uspto-grants-2013_01
Patent number
US08362065B2

Reaction notes

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