Toluene → HCID 118207444, Verbindung

HRID 716078Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 716078
O[C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.COCCN(S(F)(F)[F:32])CCOC.C1(C)C=CC=CC=1.[Cl-].[NH4+]>C(#N)C>[F:32][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1

Komponenten

6

Edukt 4

HCID 1140TolueneHCID 25517Ammonium ChlorideHCID 2734690(Bis(2-methoxyethyl)amino)sulfur trifluorideHCID 24820608Tert-butyl (3S,4S)-3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate2×

Produkt 1

HCID 118207444HCID 118207444, VerbindungAusbeute 75 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6342AcetonitrileLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

A solution of (3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (15.5 g, 61.4 mmol, intermediate D) in 270 mL of acteonitrile was chilled to 0° C. To the stirred solution was added bis(2-methoxyethyl)aminosulfur trifluoride 50% solution in toluene (Deoxo-fluor, 58.4 mL, 159 mmol) dropwise via addition funnel over 65 min. After the addition, the reaction mixture was stirred for 30 min at 0° C. and then allowed to come to rt and stirred for an additional 2 h. A saturated ammonium chloride solution (150 mL) was then added, and the mixture was extracted with two 150 mL portions of DCM. The organic layers were combined, dried over sodium sulfate, and concentrated to afford the crude product. The product was purified by silica gel chromatography (1.5 kg of silica) eluting with a gradient of 0-15% acetone in hexanes to afford 11.9 g (75%) of the desired (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate. LC/MS RT (conditions B)=3.295 min, (M+H with loss of t-butyl and elimination of fluorine)+=220.0. 1H NMR (400 MHz, chloroform-d) δ 7.15 (d, J=8.6 Hz, 2H), 6.83 (dt, J=8.6, 2.0 Hz, 2H), 4.59-4.48 (m, 1H), 4.47-4.37 (m, 1H), 4.23-4.12 (m, 1H), 2.88-2.68 (m, 3H), 1.96-1.84 (m, 1H), 1.80-1.66 (m, 1H), 1.51 (s, 9H).

Aufarbeitung

  1. additiondropwise via addition funnel over 65 min
  2. additionAfter the addition
  3. customto come to rt
  4. stirringstirred for an additional 2 h
  5. extractionthe mixture was extracted with two 150 mL portions of DCM
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. customto afford the crude product
  9. customThe product was purified by silica gel chromatography (1.5 kg of silica)
  10. washeluting with a gradient of 0-15% acetone in hexanes

Quellen und Nachweise

ORD-Eintrag
ord-9594f2c3b7f245bb868a7784b3cd9d9d
Quelldatensatz
uspto-grants-2015_11
Patentnummer
US09187506B2

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