Sodium hydride → HCID 59375166, compound

HRID 1811119Notes

Reaction equation

HRID 1811119 reaction equation
[NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Br[CH2:46][CH2:47][CH2:48][C:49](Cl)=[O:50].[H-].[Na+]>C1COCC1.C(Cl)Cl.CCOC(C)=O.O>[CH3:35][C:20]1[C:21]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:34])=[CH:22][CH:23]=[CH:24][C:19]=1[C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([CH2:2][N:1]4[CH2:46][CH2:47][CH2:48][C:49]4=[O:50])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1

Participants

9

Reactant 4

HCID 24758Sodium hydrideHCID 702254-Bromobutyryl chlorideHCID 81531DiisopropylethylamineHCID 59375043HCID 59375043, compound

Product 1

HCID 59375166HCID 59375166, compoundYield 4.3%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

A solution of 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 80 mg, 0.087 mmol) in THF (3 mL) was treated with DIEA (0.030 mL, 0.174 mmol) and a solution of 4-bromobutanoyl chloride (10 μL, 0.087 mmol) in DCM (1 mL) and the mixture was stirred at rt for 35 min. The reaction mixture was diluted with EtOAc, washed with NaHCO3 (aq) and brine, and dried and concentrated. The residue was dissolved in THF (6 mL) and treated with sodium hydride (60% oil dispersion, 24.32 mg, 0.608 mmol). The resulting mixture was stirred at 50° C. for 2 h, then was diluted with water and extracted with EtOAc. The organic phase was dried and concentrated, and the residue was purified by preparative HPLC to provide 4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-7-((2-oxopyrrolidin-1-yl)methyl)-9H-carbazole-1-carboxamide as a white solid (2 mg, 3%). 1H NMR (400 MHz, DMSO-d6) δ 11.44 (1 H, s), 8.11 (1 H, br. s.), 7.95 (1 H, d, J=7.9 Hz), 7.73 (1 H, d, J=7.5 Hz), 7.62 (2 H, d, J=3.7 Hz), 7.46-7.57 (3 H, m), 7.42 (2 H, t, J=7.7 Hz), 7.23-7.29 (1 H, m), 6.90-6.99 (2 H, m), 6.74 (1 H, dd, J=8.1, 1.5 Hz), 4.79-5.00 (2 H, m), 4.25-4.51 (2 H, m), 3.11-3.22 (2 H, m), 2.19-2.29 (2 H, m), 1.80-1.93 (2 H, m), 1.77 (3 H, s). Mass spectrum m/z 529.2 (M+H)+.

Workup

  1. washwashed with NaHCO3 (aq) and brine
  2. customdried
  3. concentrationconcentrated
  4. dissolutionThe residue was dissolved in THF (6 mL)
  5. extractionextracted with EtOAc
  6. customThe organic phase was dried
  7. concentrationconcentrated
  8. customthe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-10bb025aeee44bfdb0041b21213f06db
Source dataset
uspto-grants-2013_01
Patent number
US08362065B2

Reaction notes

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