Hydrochloric Acid → 4-[(2-Fluoro-4-Iodophenyl)amino]-N-(2-Hydroxyethoxy)-1h-Indazole-5-Carboxamide

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).

1. concentrationThe reaction mixture was concentrated in vacuo
2. dissolutionthe resultant residue dissolved in TFA (2 mL)
3. temperatureThe reaction mixture was heated at 65° C. for 3 hours
4. concentrationat 50° C. for 16 hours before being concentrated in vacuo
5. dissolutionThe resultant residue was dissolved in ethyl acetate (10 mL)
6. washwashed with aqueous saturated sodium bicarbonate solution (10 mL)
7. extractionthe aqueous fraction extracted twice with ethyl acetate (2×10 mL)
8. washThe combined organic fractions were washed with brine (20 mL)
9. dry with materialdried (MgSO4)
10. concentrationconcentrated in vacuo
11. dissolutionThe resultant product was dissolved in ethyl acetate (5 mL)
12. washwashed with aqueous saturated sodium bicarbonate solution (10 mL)
13. extractionThe aqueous fraction was extracted twice with ethyl acetate (2×10 mL)
14. washthe combined organics washed with brine (20 mL)
15. dry with materialdried with MgSO4
16. concentrationconcentrated in vacuo

ORD record

ord-3c0b87b34fee4273b413f50379f0fc60

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08841462B2