4-Fluoroaniline → N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 1676244Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1676244
[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.[F:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[O:48][C:49]1[CH:54]=[CH:53][N:52]=[C:51]2[CH:55]=[C:56]([I:58])[S:57][C:50]=12)N.C([O-])(O)=O.[Na+]>C1COCC1.O.CN(C=O)C>[F:40][C:41]1[CH:42]=[C:43]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:11]2([C:14]([NH2:31])=[O:16])[CH2:12][CH2:13]2)=[O:10])[CH:45]=[CH:46][C:47]=1[O:48][C:49]1[CH:54]=[CH:53][N:52]=[C:51]2[CH:55]=[C:56]([I:58])[S:57][C:50]=12

Komponenten

10

Edukt 6

HCID 97314-FluoroanilineHCID 65578Oxalyl chlorideHCID 690171,1-Cyclopropanedicarboxylic acidHCID 516892Sodium BicarbonateHCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 584749503-Fluoro-4-((2-iodothieno[3,2-b]pyridin-7-yl)oxy)aniline

Produkt 1

HCID 67347909N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideAusbeute 67 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 8028TetrahydrofuranLösungsmittel2×

Versuchsvorschrift

To a stirred mixture of 1-((4-fluorophenyl)carbamoyl)-cyclopropanecarboxylic acid (867 mg, 3.88 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 a catalytic amount of DMF (10 μL) in THF (10 mL) was added oxalyl dichloride (0.33 mL, 3.9 mmol) dropwise. After stirring at room temperature for 30 minutes, a solution of 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 600 mg, 1.55 mmol) in THF (2 mL) was added. After stirring for 1 hour at room temperature, the reaction was diluted into aqueous saturated NaHCO3 (50 mL) and water (50 mL). The product was extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated. The product was purified by Biotage 40S silica gel column eluting with 2:1 EtOAc/hexanes. The product was obtained as a fluff-y white solid (745 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.41 (d, J=6 Hz, 1H), 8.34 (s, 1H), 7.74 (m, 2H), 7.44 (m, 2H), 7.22 (m, 2H), 7.06 (m, 2H), 6.46 (d, J=6 Hz, 1H), 1.79 (m, 2H), 1.61 (m, 2H). LRMS (ESI pos) m/e 592 (M+1).

Aufarbeitung

  1. stirringAfter stirring for 1 hour at room temperature
  2. extractionThe product was extracted with EtOAc
  3. washwashed with brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe product was purified by Biotage 40S silica gel column
  8. washeluting with 2:1 EtOAc/hexanes

Quellen und Nachweise

ORD-Eintrag
ord-560744bc371b4aa3897597a4bf726f11
Quelldatensatz
uspto-grants-2011_08
Patentnummer
US08003662B2

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