Methanol → tert-Butyl 4-(4-((4-(2-(3-oxoisoindolin-4-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate

HRID 1485196Notes

Reaction equation

HRID 1485196 reaction equation
[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)[CH2:4][NH:3]1.[H][H].CO>CN(C=O)C.[OH-].[OH-].[Pd+2].CCOC(C)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)=[CH:28][CH:29]=3)[N:14]=2)[CH2:4][NH:3]1

Participants

7

Reactant 3

HCID 887MethanolHCID 86675721tert-Butyl 4-(4-((4-((3-oxoisoindolin-4-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylateHCID 178418361HCID 178418361, compound

Product 1

HCID 86675720tert-Butyl 4-(4-((4-(2-(3-oxoisoindolin-4-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylateYield 56%

Reagents, catalysts & solvents 3

HCID 9942167Palladium hydroxideCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

tert-Butyl 4-(4-((4-((3-oxoisoindolin-4-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I62) (0.149 g, 0.258 mmol) was dissolved in dry DMF (6 mL) under an atmosphere of nitrogen. 20% Pearlman's catalyst (0.090 g) in EtOAc (6 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours at room temperature. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a yellow solid which was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I63) (0.084 g, 56% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.98 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 7.62-7.55 (m, 2H), 7.44 (t, J=7.4 Hz, 1H), 7.38 (d, J=7.3 Hz, 1H), 7.17 (brd, J=6.0 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 3.56 (t, J=7.6 Hz, 2H), 3.51-3.41 (m, 4H), 3.12 (t, J=7.5 Hz, 2H), 3.08-2.98 (m, 4H), 1.42 (s, 9H). LCMS Method A: rt 5.86 min; m/z 583.5 [M+H]+.

Workup

  1. customThe reaction was sealed with a balloon
  2. customThe catalyst was removed by filtration through Celite, which
  3. washwas washed with EtOAc (5×10 mL)
  4. customThe solvent was removed in vacuo
  5. customto give a yellow solid which
  6. customwas purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

Sources & evidence

ORD record
ord-0455c2213313479ab82779fdcbb7b6d1
Source dataset
uspto-grants-2016_08
Patent number
US09421205B2

Reaction notes

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