Diisopropylethylamine → 1,1-dimethylethyl (2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)carbamate

HRID 1875016Notes

Reaction equation

HRID 1875016 reaction equation
CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]([O:49][C:50]([NH:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[NH:58][C:57]([C:62](O)=[O:63])=[CH:56]2)=[O:51])([CH3:48])[CH3:47].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:62]([C:57]2[NH:58][C:59]3[C:55]([CH:56]=2)=[CH:54][C:53]([NH:52][C:50](=[O:51])[O:49][C:46]([CH3:47])([CH3:45])[CH3:48])=[CH:61][CH:60]=3)=[O:63])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 158871475-(((tert-butoxy)carbonyl)amino)-1H-indole-2-carboxylic acidHCID 594513923-{[3-(Aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile

Product 1

HCID 594514661,1-dimethylethyl (2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)carbamateYield 49.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

HATU (2.75 g, 7.23 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.50 g, 4.82 mmol), 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (1.33 g, 4.82 mmol) and diisopropylethylamine (1.26 mL, 7.23 mmol) in DMF (10 mL). The mixture was stirred at RT overnight. The reaction mixture was extracted with EtOAc and water and the organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography (5-50% EtOAc:hexane) to give an off-white solid which was triturated with EtOAc:hexane, filtered and dried to afford the title compound (1.36 g, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 9.07 (br. s., 1H), 8.95 (t, 1H), 7.78 (s, 1H), 7.71 (br. s., 1H), 7.41-7.55 (m, 3H), 7.36 (t, 1H), 7.21-7.30 (m, 1H), 7.15 (d, 1H), 7.03 (s, 1H), 4.37-4.68 (m, 2H), 1.44 (s, 9H). ES-LCMS: m/z 569 (M+H).

Workup

  1. extractionThe reaction mixture was extracted with EtOAc and water
  2. washthe organic layer was washed with water
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified by silica gel flash chromatography (5-50% EtOAc:hexane)
  6. customto give an off-white solid which
  7. customwas triturated with EtOAc
  8. filtrationhexane, filtered
  9. customdried

Sources & evidence

ORD record
ord-31e0db3f08b84aeb831a470632f45764
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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