반응 #166231

반응 방정식

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

hydrochloric acid

→

title compound

수율 10.0%

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

수율 10.0%

용매

methanol

반응 조건

후처리

1. 1
   농축The reaction mixture was concentrated in vacuo
2. 2
   workup.DISSOLUTIONthe resultant residue dissolved in TFA (2 mL)
3. 3
   온도The reaction mixture was heated at 65° C. for 3 hours
4. 4
   농축at 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
   세척washed with aqueous saturated sodium bicarbonate solution (10 mL)
7. 7
   추출the aqueous fraction extracted twice with ethyl acetate (2×10 mL)
8. 8
   세척The combined organic fractions were washed with brine (20 mL)
9. 9
   건조dried (MgSO4)
10. 10
    농축concentrated in vacuo
11. 11
    workup.DISSOLUTIONThe resultant product was dissolved in ethyl acetate (5 mL)
12. 12
    세척washed with aqueous saturated sodium bicarbonate solution (10 mL)
13. 13
    추출The aqueous fraction was extracted twice with ethyl acetate (2×10 mL)
14. 14
    세척the combined organics washed with brine (20 mL)
15. 15
    건조dried with MgSO4
16. 16
    농축concentrated in vacuo

실험 절차

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).

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