1,4-Diazabicyclo(2.2.2)octane--trimethylalumane (1/2) → N-{(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-yl}-1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide

HRID 2178703

반응식

HRID 2178703 반응식
C[Al](C)C.C[Al](C)C.C1N2CCN(CC2)C1.[Cl:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C@@H:24]([NH2:26])[CH3:25])=[C:20]([C:29]([CH3:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH:19]=1.[CH3:36][C:37]1[N:38]=[CH:39][N:40]([C:42]2[C:51](=[O:52])[N:50]3[C:45]([C:46](=[O:53])[O:47][CH2:48][CH2:49]3)=[CH:44][CH:43]=2)[CH:41]=1>O1CCCC1>[Cl:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C@@H:24]([NH:26][C:46]([C:45]2[N:50]([CH2:49][CH2:48][OH:47])[C:51](=[O:52])[C:42]([N:40]3[CH:41]=[C:37]([CH3:36])[N:38]=[CH:39]3)=[CH:43][CH:44]=2)=[O:53])[CH3:25])=[C:20]([C:29]([CH3:34])([CH3:35])[C:30]([F:31])([F:32])[F:33])[CH:19]=1

참가 물질

5

반응물 3

HCID 166883661,4-Diazabicyclo(2.2.2)octane--trimethylalumane (1/2)HCID 683801743,4-Dihydro-7-(4-methyl-1H-imidazol-1-yl)pyrido[2,1-c][1,4]oxazine-1,6-dioneHCID 68380483(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-amine

생성물 1

HCID 68379824N-{(2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-yl}-1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

반응 조건

온도
40 °C

실험 절차

Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (97%, 398 mg, 1.51 mmol) was added portion-wise over 5 minutes to a solution of (2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-amine (C50) (400 mg, 1.51 mmol) in tetrahydrofuran (8 mL), and the reaction mixture was heated to 40° C. for 45 minutes. 7-(4-Methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (P14) (555 mg, 2.26 mmol) was then added portion-wise over a period of approximately 5 minutes, and the reaction mixture was heated to 70° C. for 6 hours, whereupon it was cooled to 0° C. and slowly quenched with aqueous hydrochloric acid (1 M, 1 mL). After addition of water, the mixture was extracted three times with dichloromethane; the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the product as a pale yellow solid, which was used in the next step without additional purification. Yield: 690 mg, 1.28 mmol, 85%. LCMS m/z 541.3, 543.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.41 (d, J=6.8 Hz, 3H), 1.69 (br s, 6H), 2.23 (d, J=1.0 Hz, 3H), 3.85 (t, J=5.8 Hz, 2H), 4.05 (dd, half of ABX pattern, J=9.6, 5.4 Hz, 1H), 4.14 (dd, half of ABX pattern, J=9.6, 6.6 Hz, 1H), 4.41 (t, J=5.8 Hz, 2H), 4.48-4.57 (m, 1H), 6.54 (d, J=7.5 Hz, 1H), 7.10 (d, J=8.9 Hz, 1H), 7.24-7.26 (m, 1H), 7.31 (dd, J=8.8, 2.6 Hz, 1H), 7.37-7.40 (m, 1H), 7.67 (d, J=7.5 Hz, 1H), 8.19 (d, J=1.4 Hz, 1H).

후처리

  1. temperaturethe reaction mixture was heated to 70° C. for 6 hours, whereupon it
  2. temperaturewas cooled to 0° C.
  3. customslowly quenched with aqueous hydrochloric acid (1 M, 1 mL)
  4. additionAfter addition of water
  5. extractionthe mixture was extracted three times with dichloromethane
  6. dry with materialthe combined organic layers were dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure

출처 및 근거

ORD 기록
ord-997118d86f314cbca7c1af96003f8c67
출처 데이터셋
uspto-grants-2015_06
특허 번호
US09067934B2

연결된 노트

불러오는 중…