N-methyl-2-pyrrolidone → Methyl 1-(5-bromo-3-fluoro-2-pyridyl)-4-methyl-piperidine-4-carboxylate

HRID 712233

반응식

HRID 712233 반응식
[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:11][C:12]1([C:18]([O:20][CH2:21]C)=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C.CN1CCCC1=O>O>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([N:15]2[CH2:16][CH2:17][C:12]([CH3:11])([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:14]2)=[N:6][CH:7]=1

참가 물질

6

반응물 4

HCID 13387N-methyl-2-pyrrolidoneHCID 81531DiisopropylethylamineHCID 27632855-Bromo-2-chloro-3-fluoropyridineHCID 19361804Ethyl 4-methylpiperidine-4-carboxylate hydrochloride2회

생성물 1

HCID 66977224Methyl 1-(5-bromo-3-fluoro-2-pyridyl)-4-methyl-piperidine-4-carboxylate수율 47.7%

시약·촉매·용매 1

HCID 962Water용매

반응 조건

온도
210 °C

실험 절차

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]+.

후처리

  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

출처 및 근거

ORD 기록
ord-5f116c3e6c0b4ac597573bc30b01e4b7
출처 데이터셋
uspto-grants-2015_11
특허 번호
US09181234B2

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