反应详情

温度

106 °C

Combine 4-(3-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 30, 100 mg, 0.342 mmol), dioxane (2 mL) and polymer bound morpholine resin (205 mg, 0.513 mmol) and add 2-chloro-6-fluoro-benzoyl chloride (0.048 mL, 0.376 mmol), shake (in a J-KEM® block) and heat at 106° C. After 2 hr., dilute with methanol (5 mL) and add tris-amine resin (100 mg), shake in a rotary evaporator overnight, filter, concentrate and use directly in the next step. Combine methanol (5 mL) and acetyl chloride (2.5 mL) and stir at 0° C. After 1 hr., add a solution of 4-[3-(2-chloro-6-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester in methanol (2 mL) and stir at room temperature. After 30 min., concentrate under reduced pressure, dissolve the residue in ethyl acetate (10 mL), wash with NaHCO3 (sat. aq., 10 mL), dry the organic layers over magnesium sulfate, filter and concentrate under reduced pressure to give 100 mg (84%, 2 steps) of the titled compound as the free base. Following a method similar to Example 2 gives the title compound as the hydrochloride salt (130 mg, off-white solid). Mp: 139-42° C.; mass spectrum (free base, ion spray): m/z=311.2 (M+1); 1H NMR (free base, CDCl3): 8.19 (bs, N—H), 7.41 (t, J=2.1 Hz, 1H), 7.35-7.29 (m, 1H), 7.26-7.20 (m, 2H), 7.07-7.02 (m, 2H), 6.70 (dd, J=2.3 Hz, 8.4 Hz, 1H), 4.43-4.36 (m, 1H), 3.11-3.04 (m, 2H), 2.74-2.67 (m, 2H), 2.50 (bs, N—H), 2.04-1.95 (m, 2H), 1.72-1.62 (m, 2H).

1. customin a rotary evaporator overnight
2. filtrationfilter
3. concentrationconcentrate
4. waitAfter 1 hr
5. addition, add a solution of 4-[3-(2-chloro-6-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester in methanol (2 mL)
6. stirringstir at room temperature
7. waitAfter 30 min.
8. concentrationconcentrate under reduced pressure
9. dissolutiondissolve the residue in ethyl acetate (10 mL)
10. washwash with NaHCO3 (sat. aq., 10 mL)
11. dry with materialdry the organic layers over magnesium sulfate
12. filtrationfilter
13. concentrationconcentrate under reduced pressure