反应详情

温度

210 °C

5-Bromo-2-chloro-3-fluoropyridine (100 mg, 0.475 mmol), ethyl 4-methyl-piperidine-4-carboxylate hydrochloride (118 mg, 0.57 mmol), ethyldiisopropylamine (248 uL, 1.426 mmol) and 1-methyl-pyrrolidin-2-one (0.5 mL) were transferred to a microwave reaction vial. The vial was sealed and heated at 210° C. for 15 minutes. A further portion of ethyl 4-methyl-piperidine-4-carboxylate hydrochloride (118 mg, 0.57 mmol) was added and the reaction mixture heated for a further 15 min at 210° C. The reaction mixture was diluted with water (25 mL), the pH adjusted to 3 using 1 M HCl, before extraction with DCM (3×25 mL). The organic fractions were combined, dried (cotton wool plug) and concentrated in vacuo to give a crude brown oil. Flash chromatography on silica gel, eluting with DCM (0-100% gradient) in n-hexane gave an impure mixture which was further purified using flash chromatography on silica gel, eluting with 0-4% EtOAc gradient, 4% isocratic, then 4-10% EtOAc in n-hexane to obtain the desired product (75 mg, clear oil). 1H NMR (Acetone) δ 8.05 (dd, J=2.0, 1.1 Hz, 1H), 7.60 (dd, J=12.6, 2.0 Hz, 1H), 4.17 (q, J=7.1 Hz, 1H), 3.83-3.75 (m, 1H), 3.16-3.07 (m, 1H), 2.19-2.11 (m, 1H), 1.60-1.50 (m, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.22 (s, 3H). m/z 345.0, 346.9 [M+H]+.

1. customThe vial was sealed
2. temperaturethe reaction mixture heated for a further 15 min at 210° C
3. extractionthe pH adjusted to 3 using 1 M HCl, before extraction with DCM (3×25 mL)
4. customdried (cotton wool plug)
5. concentrationconcentrated in vacuo
6. customto give a crude brown oil
7. washFlash chromatography on silica gel, eluting with DCM (0-100% gradient) in n-hexane
8. customgave an impure mixture which
9. customwas further purified
10. washeluting with 0-4% EtOAc gradient, 4% isocratic