Cesium carbonate → 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzonitrile

HRID 515188Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 515188
[C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][C:4]=1OS(C(F)(F)F)(=O)=O)#[N:2].[F:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[CH:7]=[C:8]([CH3:9])[C:3]=2[C:1]#[N:2])[CH2:26]1

Komponenten

7

Edukt 3

HCID 10796Cesium carbonateHCID 27591633-FluoropyrrolidineHCID 86699756Trifluoro-methanesulfonic acid (2-cyano-3-methyl-5-morpholin-4-yl-phenyl)ester

Produkt 1

HCID 866997552-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzonitrileAusbeute 50,8 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 167845palladium(II) acetateKatalysatorHCID 634876Binap, (A+-)-KatalysatorHCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

A solution of affording trifluoro-methanesulfonic acid (2-cyano-3-methyl-5-morpholin-4-yl-phenyl)ester (0.43 g, 1.22 mmol), (3R)-3-fluoro-pyrrolidin (0.19 g, 1.47 mmol) and caesium carbonate (1.6 g, 4.92 mmol) in tetrahydrofuran (25 ml) is degassed and flushed with Argon for 30 min followed by the addition of palladium(II) acetate (6.0 mg, 0.03 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (23 mg, 0.04 mmol). The resulting mixture is stirred at 90° C. for 16 h. After completion of the reaction (monitored by TLC), the mixture is poured onto water (30 ml) and extracted with ethyl acetate (3×50 ml).The combined organic layers are washed with water (2×20 ml), brine (2×20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (silica gel, 15% ethyl acetate/hexane) affording 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzonitrile (0.18 g, 0.62 mmol, 50%).

Aufarbeitung

  1. customflushed with Argon for 30 min
  2. customAfter completion of the reaction (monitored by TLC)
  3. additionthe mixture is poured onto water (30 ml)
  4. extractionextracted with ethyl acetate (3×50 ml).The combined organic layers
  5. washare washed with water (2×20 ml), brine (2×20 ml)
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated in vacuo
  8. customThe crude product is purified by flash column chromatography (silica gel, 15% ethyl acetate/hexane)

Quellen und Nachweise

ORD-Eintrag
ord-d2af3348a5234bbf9c3d523c757a7708
Quelldatensatz
uspto-grants-2015_08
Patentnummer
US09108936B2

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