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

Reaktionsgleichung

Reaktionsgleichung von HRID 2178703
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

Komponenten

5

Edukt 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

Produkt 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

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
40 °C

Versuchsvorschrift

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).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-997118d86f314cbca7c1af96003f8c67
Quelldatensatz
uspto-grants-2015_06
Patentnummer
US09067934B2

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