Ethanol, 1-ethoxy-2,2,2-trifluoro- → N-(1-Ethoxy-2,2,2-trifluoroethyl)-3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine

HRID 2193759Notes

Reaction equation

HRID 2193759 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[CH2:25]([O:27][CH:28](O)[C:29]([F:32])([F:31])[F:30])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:25]([O:27][CH:28]([NH:24][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=4)[S:17][C:10]=23)=[C:2]([F:1])[CH:3]=1)[C:29]([F:32])([F:31])[F:30])[CH3:26]

Participants

5

Reactant 3

HCID 9897Ethanol, 1-ethoxy-2,2,2-trifluoro-HCID 521998p-Toluenesulfonic acid monohydrateHCID 594245073-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine

Product 1

HCID 58790399N-(1-Ethoxy-2,2,2-trifluoroethyl)-3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamineYield 68.7%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A mixture of 12 (Scheme 3) (500 mg, 1.47 mmol), trifluoroacetaldehyde ethyl hemiacetal (0.35 mL, 2.94 mmol) and 4-toluenesulfonic acid monohydrate (280 mg, 1.47 mmol) in ethanol (25 mL) was heated to reflux for 48 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane 5:95 to 8:92) to afford title compound 318 (470 mg, 1.01 mmol, 68% yield). NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (d, J=5.5 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.72 (d, J=0.8 Hz, 1H), 7.67 (s, 1H), 7.29 (t, J=9.2 Hz, 1H), 7.08-7.02 (m, 2H), 3.86 (dd, J=9.2, 2.0 Hz, 1H), 6.52 (d, J=5.5 Hz, 1H), 5.68 (qd, J=10.4, 5.2 Hz, 1H), 3.72 (s, 3H), 3.76-3.59 (m, 2H), 1.15 (t, J=7.0 Hz, 3H). LRMS (M+1) 467.0 (100%).

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 48 h
  3. concentrationThe reaction mixture was concentrated
  4. customthe residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane 5:95 to 8:92)

Sources & evidence

ORD record
ord-e58613b703344165ac60ffa3fedb882a
Source dataset
uspto-grants-2012_12
Patent number
US08329726B2

Reaction notes

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