Sodium hydride → tert-butyl (9aR)-3-(3-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

HRID 1501983

Reaktionsgleichung

Reaktionsgleichung von HRID 1501983
[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([OH:27])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]2[CH2:25]O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[H-].[Na+].S(N1C=CN=C1)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]2[O:27][CH2:25][C@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]

Komponenten

5

Edukt 3

HCID 24758Sodium hydrideHCID 752191-(p-Toluenesulfonyl)imidazoleHCID 86727047tert-butyl (3R)-4-[2-(3-cyano-4-fluorophenyl)-2-hydroxyethyl]-3-(hydroxymethyl)piperazine-1-carboxylate

Produkt 1

HCID 86727048tert-butyl (9aR)-3-(3-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

A solution of tert-butyl (3R)-4-[2-(3-cyano-4-fluorophenyl)-2-hydroxyethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (5.0 g, 13.2 mmol) in 100 mL of THF was stirred at 0° C. for 10 min, and then NaH (60%) (1.32 g, 33.0 mmol) was added at 0° C. The resulting white suspension was stirred vigorously at 0° C. for 5 min, then at r.t for 1 h. The reaction suspension was then recooled to 0° C., N-Tosylimidazole was added and the resulting solution was stirred for a further 10 min at 0° C. before being warmed again to r.t and stirred for 1 h. The reaction solution was then cooled once more to 0° C., and excess sodium hydride was carefully quenched by the slow addition of sat. NH4Cl solution. The resulting biphasic solution was partitioned between sat. NH4Cl and EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified with silica gel column chromatography to give the title compound: 1H-NMR (300 MHz, CDCl3) δ 7.76˜7.79 (m, 1H), 7.49˜7.58 (m, 1H), 7.11˜7.15 (m, 1H), 7.16˜7.12 (m, 1H), 3.86˜4.06 (m, 2H), 3.33˜3.48 (m, 1H), 3.08˜3.17 (m, 1H), 2.80˜2.94 (m, 2H), 2.64˜2.74 (m, 2H), 2.29˜2.46 (m, 2H), 2.09˜2.20 (m, 1H), 1.40 (d, J=3.0 Hz, 9H);

Aufarbeitung

  1. waitat r.t for 1 h
  2. customwas then recooled to 0° C.
  3. stirringthe resulting solution was stirred for a further 10 min at 0° C.
  4. temperaturebefore being warmed again
  5. stirringstirred for 1 h
  6. temperatureThe reaction solution was then cooled once more to 0° C.
  7. customexcess sodium hydride was carefully quenched by the slow addition of sat. NH4Cl solution
  8. customThe resulting biphasic solution was partitioned between sat. NH4Cl and EtOAc
  9. washThe organic layer was washed with water and brine
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated in vacuum
  12. customThe residue was purified with silica gel column chromatography

Quellen und Nachweise

ORD-Eintrag
ord-4cf2b82a14d84dc5be700a14de0abffa
Quelldatensatz
uspto-grants-2015_12
Patentnummer
US09206199B2

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