Réaction #166231

Équation de réaction

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

hydrochloric acid

→

title compound

Rendement 10.0%

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

Rendement 10.0%

Solvants

methanol

Conditions de réaction

Traitement

1. 1
   ConcentrationThe reaction mixture was concentrated in vacuo
2. 2
   workup.DISSOLUTIONthe resultant residue dissolved in TFA (2 mL)
3. 3
   TempératureThe reaction mixture was heated at 65° C. for 3 hours
4. 4
   Concentrationat 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
   Lavagewashed with aqueous saturated sodium bicarbonate solution (10 mL)
7. 7
   Extractionthe aqueous fraction extracted twice with ethyl acetate (2×10 mL)
8. 8
   LavageThe combined organic fractions were washed with brine (20 mL)
9. 9
   Séchagedried (MgSO4)
10. 10
    Concentrationconcentrated in vacuo
11. 11
    workup.DISSOLUTIONThe resultant product was dissolved in ethyl acetate (5 mL)
12. 12
    Lavagewashed with aqueous saturated sodium bicarbonate solution (10 mL)
13. 13
    ExtractionThe aqueous fraction was extracted twice with ethyl acetate (2×10 mL)
14. 14
    Lavagethe combined organics washed with brine (20 mL)
15. 15
    Séchagedried with MgSO4
16. 16
    Concentrationconcentrated in vacuo

Mode opératoire

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).

Source