Cesium carbonate → N-(3-Fluoro-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide

HRID 2117086Notes

Reaction equation

HRID 2117086 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:24]1[C:25]2[S:32][CH:31]=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>[Cu]Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][C:24]1[C:25]2[S:32][CH:31]=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 707002,2,6,6-Tetramethyl-3,5-heptanedioneHCID 27358214-Chlorothieno[3,2-d]pyrimidineHCID 44203043N1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide

Product 1

HCID 58798989N-(3-Fluoro-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide

Reagents, catalysts & solvents 1

HCID 62652Cuprous chlorideCatalyst

Conditions

Temperature
120 °C

Procedure

N1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide (46 mg, 0.15 mmol), 4-chlorothieno[3,2-d]pyrimidine (17 mg, 0.10 mmol), cesium carbonate (49 mg, 0.15 mmol), and copper(I) chloride (10 mg, 0.10 mmol) were placed in a test tube. The tube was sealed, flushed with nitrogen, charged with 1-methyl-2-pyrrolidinone (0.3 mL) followed by 2,2,6,6-tetramethyl-3,5-heptanedione (4.0 μL, 0.02 mmol). The reaction was stirred at 120° C. for 2 h. The reaction mixture was purified by preparative HPLC. The appropriate fraction was concentrated to remove methanol and the resulting aqueous solution was made basic with saturated NaHCO3 solution (5 mL). The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the desired product as a colorless oil. Lyophilization with methanol/water gave the title compound (23 mg, 52%) as a white solid. 1H NMR (CD3OD) δ 8.54 (s, 1H), 8.21 (d, 1H, J=5.5 Hz), 7.69 (dd, 1H, J=12.4, 2.0 Hz), 7.49 (m, 3H), 7.27 (m, 2H), 6.96 (t, 2H, J=8.9 Hz), 3.47 (s, 2H); MS(ESI+) m/z 441.1 (M+H)+.

Workup

  1. customThe tube was sealed
  2. customflushed with nitrogen
  3. additioncharged with 1-methyl-2-pyrrolidinone (0.3 mL)
  4. customThe reaction mixture was purified by preparative HPLC
  5. concentrationThe appropriate fraction was concentrated
  6. customto remove methanol
  7. extractionThe aqueous solution was extracted with EtOAc (3×10 mL)
  8. dry with materialthe combined organic extracts were dried over anhydrous Na2SO4
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-96b5ac609d144980863d1837ee87c6df
Source dataset
uspto-grants-2008_10
Patent number
US07439246B2

Reaction notes

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