4-Fluoroaniline → HCID 67349569, compound

HRID 1676265Notes

Reaction equation

HRID 1676265 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1(C(O)=O)(C(O)=O)CC1.FC1C=CC([NH2:31])=CC=1.C(Cl)(=O)C(Cl)=O.[I:40][C:41]1[S:49][C:48]2[C:43](=[N:44][CH:45]=[CH:46][C:47]=2[O:50][C:51]2[CH:56]=[CH:55][C:54](N)=[CH:53][CH:52]=2)[CH:42]=1.C([O-])(O)=O.[Na+]>C1COCC1.O.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:54]2[CH:55]=[CH:56][C:51]([O:50][C:47]3[CH:46]=[CH:45][N:44]=[C:43]4[CH:42]=[C:41]([I:40])[S:49][C:48]=34)=[CH:52][CH:53]=2)[C:9]([C:11]2([C:14]([NH2:31])=[O:16])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1

Participants

10

Reactant 6

HCID 97314-FluoroanilineHCID 65578Oxalyl chlorideHCID 690171,1-Cyclopropanedicarboxylic acidHCID 516892Sodium BicarbonateHCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 67347064HCID 67347064, compound

Product 1

HCID 67349569HCID 67349569, compound

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A 100 mL, single-neck, round-bottomed flask was charged with 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (0.2773 g, 1.243 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the methods described in WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836), and THF (10 mL). Catalytic DMF (10 microliters) was added to the reaction mixture. While stirring oxalyl dichloride (0.1067 mL, 1.243 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. 4-(2-Iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (example 72, Step A 0.500 g, 0.8284 mmol) in THF (2 mL) was added, and the reaction mixture was stirred for 1 hour, water (50 mL) and saturated NaHCO3 (50 mL) were added. The reaction mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified on a Biotage 40S column (2:1 EtOAc/Hexane). The product was a beige solid (155 mg, 29%). 1H NMR (CDCl3, 400 MHz) δ 9.37 (s, 1H), 8.59 (s, 1H), 8.41 (d, J=6 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J=9 Hz, 2H), 7.46 (m, 2H), 7.15 (d, J=9 Hz, 2H), 7.06 (t, J=9 Hz, 2H), 6.51 (d, J=6 Hz, 1H), 1.71 (m, 4H). LRMS (ESI pos) m/e 574 (M+1).

Workup

  1. additionwas added dropwise
  2. stirringthe reaction mixture was stirred for 1 hour
  3. extractionThe reaction mixture was extracted with EtOAc
  4. washthe organic layer was washed with brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified on a Biotage 40S column (2:1 EtOAc/Hexane)

Sources & evidence

ORD record
ord-35ed02323af246978fac16456bd6da82
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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