Reaktion #166231

Reaktionsgleichung

4-(2-fluoro-4-iodophenylamino)-1-(toluene-4-sulfonyl)-1H-indazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide

hydrochloric acid

→

title compound

Ausbeute 10.0%

4-(2-Fluoro-4-iodo-phenylamino)-1H-indazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide

Ausbeute 10.0%

Lösungsmittel

methanol

Reaktionsbedingungen

Aufarbeitung

1. 1
   EinengenThe reaction mixture was concentrated in vacuo
2. 2
   workup.DISSOLUTIONthe resultant residue dissolved in TFA (2 mL)
3. 3
   TemperaturThe reaction mixture was heated at 65° C. for 3 hours
4. 4
   Einengenat 50° C. for 16 hours before being concentrated in vacuo
5. 5
   workup.DISSOLUTIONThe resultant residue was dissolved in ethyl acetate (10 mL)
6. 6
   Waschenwashed with aqueous saturated sodium bicarbonate solution (10 mL)
7. 7
   Extraktionthe aqueous fraction extracted twice with ethyl acetate (2×10 mL)
8. 8
   WaschenThe combined organic fractions were washed with brine (20 mL)
9. 9
   Trocknendried (MgSO4)
10. 10
    Einengenconcentrated in vacuo
11. 11
    workup.DISSOLUTIONThe resultant product was dissolved in ethyl acetate (5 mL)
12. 12
    Waschenwashed with aqueous saturated sodium bicarbonate solution (10 mL)
13. 13
    ExtraktionThe aqueous fraction was extracted twice with ethyl acetate (2×10 mL)
14. 14
    Waschenthe combined organics washed with brine (20 mL)
15. 15
    Trocknendried with MgSO4
16. 16
    Einengenconcentrated in vacuo

Vorschrift

To a solution of 4-(2-fluoro-4-iodophenylamino)-1-(toluene-4-sulfonyl)-1H-indazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide (200 mg, 0.31 mmol) in methanol (3 mL) was added hydrochloric acid (1 mL, 1 N) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resultant residue dissolved in TFA (2 mL). The reaction mixture was heated at 65° C. for 3 hours then at 50° C. for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (gradient 10-95% acetonitrile/water+0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The resultant product was dissolved in ethyl acetate (5 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The aqueous fraction was extracted twice with ethyl acetate (2×10 mL) and the combined organics washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo to yield the title compound as a white solid (14 mg, 10%). LCMS (Method A): RT=8.31 min, [M+H]+=457. 1H NMR (DMSO-d6, 400 MHz): 13.19 (1 H, s), 11.60 (1H, s), 9.93 (1H, s), 7.66 (1 H, dd, J=10.31, 1.93 Hz), 7.46 (1H, d, J=8.70 Hz), 7.42 (1H, d, J=8.56 Hz), 7.23 (1H, s), 7.01 (1H, d, J=8.77 Hz), 6.91 (1H, t, J=8.64 Hz), 4.68 (1H, s), 3.85 (2H, t, J=4.92 Hz), 3.60-3.52 (2H, m).

Quelle