Hydrochloric Acid → 1-(4-Methylpiperazin-1-yl)-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)ethanone dihydrochloride

Participants

Reaction Conditions

Reaction Steps

A 1 dram vial was charged with 2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetic acid trifluoroacetate (prepared according to Example 26; 70 mg, 0.14 mmol), triethylamine (0.10 mL, 0.72 mmol) and THF (2 mL) and cooled to 0° C. Ethyl chloroformate (0.035 mL, 0.36 mmol) was added and the reaction mixture was stirred at 0° C. for 30 minutes. N-methylpiperazine (0.080 mL, 0.72 mmol) was added and the reaction mixture was warmed to room temperature and stirred at room temperature for 1.5 hours. The reaction was poured into water and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified over silica gel (10% methanol in EtOAc to 10% methanol in EtOAc with ammonia) to afford 1-(4-methylpiperazin-1-yl)-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)ethanone dihydrochloride (51.3 mg, 64.2% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.64 (bs, 2H), 8.00 (dd, 1H), 7.67 (d, 1H), 7.28 (m, 2H), 7.17 (m, 2H), 6.91 (m, 2H), 5.33 (s, 2H), 4.97 (d, 2H), 4.39 (m, 1H), 4.08 (m, 2H), 3.59 (m, 1H), 3.40 (m, 2H), 3.14 (m, 2H), 2.96 (m, 1H), 2.75 (s, 3H), 2.35 (s, 3H). Mass spectrum (apci) m/z=454.2 (M+H-2HCl).

Provenance & Evidence