Ammonium Chloride → (2S,3S)-2-(3,4-difluorophenyl)-3,5,5-trimethylmorpholin-2-ol

HRID 1399533Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1399533
[CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[F:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][C:17]=1[F:18].[NH4+].[Cl-]>C1COCC1>[F:11][C:12]1[CH:13]=[C:14]([C@:7]2([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C@H:2]2[CH3:1])[CH:15]=[CH:16][C:17]=1[F:18]

Komponenten

5

Edukt 3

HCID 25517Ammonium ChlorideHCID 46837646HCID 46837646, VerbindungHCID 178505835HCID 178505835, Verbindung

Produkt 1

HCID 46837784(2S,3S)-2-(3,4-difluorophenyl)-3,5,5-trimethylmorpholin-2-olAusbeute 25,8 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
-78 °C

Versuchsvorschrift

A solution of morpholin-2-one 15 (410 mg, 2.86 mmol) in anhydrous THF (2.9 mL, 1M) was cooled to −78° C. and treated with 3,4-difluorophenylmagnesium bromide (1.2 equiv., 3.43 mmol, 6.90 mL, 0.5 M solution in THF) under an N2 atmosphere. After stirring the reaction mixture at −78° C. under an inert atmosphere for 1.5 h, saturated aqueous solution of NH4Cl was added to the reaction vessel. The reaction mixture was allowed to warm to room temperature and extracted with ether (three times). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. Purification of the residue by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH—NH4OH (90:9:1) as the eluent gave 190 mg (25%) of 4m as a yellow solid: [α]22D +18.2° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.45-7.39 (m, 1H), 7.34-7.32 (m, 1H), 7.18-7.10 (m, 1H), 3.82 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.3 Hz), 3.18 (q, 1H, J=6.5 Hz), 1.38 (s, 3H), 1.08 (s, 3H), 0.78 (d, 3H, J=6.5 Hz); 13C NMR (CDCl3) δ 122.40, 122.31 116.74, 116.51, 115.8, 115.6, 96.5, 69.6, 53.4, 49.8, 27.3, 22.8, 16.5; LCMS (ESI) m/z 258.6, [(M+H)+, M=C13H17F2NO2].

Aufarbeitung

  1. temperatureto warm to room temperature
  2. extractionextracted with ether (three times)
  3. washThe combined organic extracts were washed (water, brine)
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated
  6. customPurification of the residue by column chromatography on silica gel

Quellen und Nachweise

ORD-Eintrag
ord-3f73679c45044b2d965d68eeeebfa398
Quelldatensatz
uspto-grants-2014_12
Patentnummer
US08906908B2

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