1-Hydroxybenzotriazole → 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid methyl ester

HRID 1726727

Reaction equation

HRID 1726727 reaction equation
C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:16]=[C:15]([C:17]([O-:19])=O)[CH:14]=[CH:13][C:12]=1[C:20]([O:22][CH3:23])=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:49]1[C:57]2[CH:56]=[CH:55][CH:54]=[C:53]([CH2:58][NH2:59])[C:52]=2[CH:51]=[CH:50]1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[Br:10][C:11]1[CH:16]=[C:15]([C:17]([NH:59][CH2:58][C:53]2[CH:54]=[CH:55][CH:56]=[C:57]3[C:52]=2[CH:51]=[CH:50][NH:49]3)=[O:19])[CH:14]=[CH:13][C:12]=1[C:20]([O:22][CH3:23])=[O:21]

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 226614481H-indole-4-methanamine hydrochlorideHCID 857711401,4-Benzenedicarboxylic acid, 2-bromo-, 1-methyl ester

Product 1

HCID 235607692-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid methyl esterYield 70%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Diisopropylethylamine (2.3 mL, 13.2 mmol) was added dropwise to a solution of 2-bromo-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 2; 861 mg, 3.32 mmol), HBTU (1.39 g, 3.65 mmol), 1H-indole-4-methanamine hydrochloride salt (Example 11; 528 mg, 3.98 mmol), and HOBT (493 mg, 3.65 mmol) in N,N-dimethylformamide (6.5 mL) at 0° C. The solution warmed to room temperature and stirred for 24 h. The solvent was concentrated under vacuum to remove most of the N,N-dimethylformamide. The residue was diluted with ethyl acetate (50 mL) and washed with 1 M HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, evaporated and flash chromatographed (silica, 25-35% ethyl acetate/petroleum ether) to give 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid, methyl ester (900 mg, 70%) as an off-white solid.

Workup

  1. concentrationThe solvent was concentrated under vacuum
  2. customto remove most of the N,N-dimethylformamide
  3. additionThe residue was diluted with ethyl acetate (50 mL)
  4. washwashed with 1 M HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL)
  5. dry with materialThe organic layer was dried (MgSO4)
  6. filtrationfiltered
  7. customevaporated
  8. customflash chromatographed (silica, 25-35% ethyl acetate/petroleum ether)

Sources & evidence

ORD record
ord-6eff55a90b4547f190ac3275c0dfdad6
Source dataset
uspto-grants-2009_02
Patent number
US07491741B2

Linked notes

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