Trifluoroacetic acid → 3-(1-methyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-9H-carbazole-1-carboxamide

HRID 2410891Notes

Reaction equation

HRID 2410891 reaction equation
[C:1]([C:4]1[CH:5]=[C:6]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[N:35]([CH3:39])[N:34]=[CH:33]3)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)CCl>[CH3:39][N:35]1[C:36]2[C:32](=[CH:31][C:30]([C:6]3[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]4[NH:15][C:14]5[C:9]([C:8]=4[CH:7]=3)=[CH:10][CH:11]=[C:12]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:13]=5)=[CH:38][CH:37]=2)[CH:33]=[N:34]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 66605037tert-butyl 4-(8-carbamoyl-6-(1-methyl-1H-indazol-5-yl)-9H-carbazol-2-yl)piperazine-1-carboxylate

Product 1

HCID 666045803-(1-methyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-9H-carbazole-1-carboxamideYield 92.2%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

The crude product from Example 413B [168 mg, contains ˜0.16 mmol tert-butyl 4-(8-carbamoyl-6-(1-methyl-1H-indazol-5-yl)-9H-carbazol-2-yl)piperazine-1-carboxylate was suspended in ClCH2CH2Cl (20 ml). Addition of TFA (2 ml, 26.0 mmol) resulted in complete dissolution. The reaction mixture was stirred at room temperature for 2.5 hours, then evaporated to dryness. The product was purified by prep HPLC to give 62.6 mg 3-(1-methyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-9H-carbazole-1-carboxamide. The “free base product” was suspended in MeOH. Addition of 1.0 equiv. HCl (147 ul of a 1.00 M aq. solution) resulted in complete dissolution. Evaporate to dryness gave 67.8 mg 3-(1-methyl-1H-indazol-5-yl)-7-(piperazin-1-yl)-9H-carbazole-1-carboxamide as its mono-HCl salt. MS (ESI) m/e+=425. HPLC retention time 5.82 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA), then isocratic at 100% B. 1H NMR (CD3OD) δ ppm 8.46 (d, 1H, J=1.5), 8.17 (d, 1H, J=1.7), 8.13 (b, 1H), 8.11-8.07 (m, 2H), 7.91 (dd, 1H, J=1.8, 8.8), 7.67 (d, 1H, J=8.8), 7.23 (d, 1H, J=2.0), 7.03 (dd, 1H, J=8.5, 2.0), 4.12 (s, 3H), 3.56-3.52 (m, 4H), 3.47-3.43 (m, 4H).

Workup

  1. customresulted in complete dissolution
  2. customevaporated to dryness
  3. customThe product was purified by prep HPLC

Sources & evidence

ORD record
ord-f4f1c6d780314dcfab743b6c117efc76
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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