Trifluoroacetic acid → 1-(3-(Dimethylphosphoryl)phenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

HRID 1026800Notes

Reaction equation

HRID 1026800 reaction equation
[CH3:1][P:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:50])[NH:13][C:14]2[CH:48]=[CH:47][C:17]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]4[CH:25]=[C:26]([C:28]5[N:33]=[CH:32][C:31]([CH2:34][N:35]([CH2:43][CH2:44][O:45][CH3:46])C(=O)OC(C)(C)C)=[CH:30][CH:29]=5)[S:27][C:20]=34)=[C:16]([F:49])[CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])=[O:3].FC(F)(F)C(O)=O>ClCCl>[CH3:4][P:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:13][C:14]2[CH:48]=[CH:47][C:17]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]4[CH:25]=[C:26]([C:28]5[CH:29]=[CH:30][C:31]([CH2:34][NH:35][CH2:43][CH2:44][O:45][CH3:46])=[CH:32][N:33]=5)[S:27][C:20]=34)=[C:16]([F:49])[CH:15]=2)=[O:50])[CH:8]=[CH:9][CH:10]=1)([CH3:1])=[O:3]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 67049417Tert-butyl(6-(7-(4-(3-(3-(dimethylphosphoryl)phenyl)ureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate

Product 1

HCID 670482601-(3-(Dimethylphosphoryl)phenyl)-3-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureaYield 38.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of compound 288 (230 mg, 0.32 mmol) in dichloromethane (7 mL) under nitrogen at room temperature was added trifluoroacetic acid (2.5 mL, 32 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was removed under reduced pressure and a saturated aqueous solution of sodium bicarbonate was added. The aqueous phase was extracted with ethyl acetate (3×), the combined organic layers were concentrated. The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; 25M column) to afford compound 289 as an off-white solid (75.3 mg, 0.122 mmol, 38.0%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.15 (s, 1H), 9.06 (s, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.92-7.83 (m, 2H), 7.76 (dd, J=13.2, 2.4 Hz, 1H), 7.67-7.62 (m, 1H), 7.49-7.42 (m, 2H), 7.41-7.33 (m, 1H), 7.32-7.26 (m, 1H), 6.67 (d, J=5.6 Hz, 1H), 3.78 (s, 2H), 3.54-3.34 (2H, hidden under water signal), 3.24 (s, 3H), 2.65 (t, J=5.6 Hz, 2H), 1.65 (d, J=13.2 Hz, 6H). MS (m/z): 620.4 (M+H).

Workup

  1. customThe solvent was removed under reduced pressure
  2. additiona saturated aqueous solution of sodium bicarbonate was added
  3. extractionThe aqueous phase was extracted with ethyl acetate (3×)
  4. concentrationthe combined organic layers were concentrated
  5. customThe residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; 25M column)

Sources & evidence

ORD record
ord-48e5cf7236bb4a839f2489e92f6a7eb3
Source dataset
uspto-grants-2014_05
Patent number
US08729268B2

Reaction notes

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