Triphenylphosphine → 3-[(1-{3-Cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-fluoropiperidin-4-yl)oxy]-5-fluorobenzonitrile

HRID 575507

Reaktionsgleichung

Reaktionsgleichung von HRID 575507
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([OH:29])[CH:28]=1)[C:24]#[N:25].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:46][CH:47]1[CH:52](O)[CH2:51][CH2:50][N:49]([CH2:54][CH:55]([N:59]2[CH:63]=[C:62]([C:64]3[C:65]4[CH:72]=[CH:71][N:70](COCC[Si](C)(C)C)[C:66]=4[N:67]=[CH:68][N:69]=3)[CH:61]=[N:60]2)[CH2:56][C:57]#[N:58])[CH2:48]1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C(Cl)Cl>[C:57]([CH2:56][CH:55]([N:59]1[CH:63]=[C:62]([C:64]2[C:65]3[CH:72]=[CH:71][NH:70][C:66]=3[N:67]=[CH:68][N:69]=2)[CH:61]=[N:60]1)[CH2:54][N:49]1[CH2:50][CH2:51][CH:52]([O:29][C:27]2[CH:26]=[C:23]([CH:22]=[C:21]([F:20])[CH:28]=2)[C:24]#[N:25])[CH:47]([F:46])[CH2:48]1)#[N:58]

Komponenten

7

Edukt 5

HCID 11776Triphenylphosphine2×HCID 97268Di-tert-butyl azodicarboxylateHCID 5387121Dibenzyl azodicarboxylateHCID 219499203-Fluoro-5-hydroxybenzonitrileHCID 696752434-(3-Fluoro-4-hydroxypiperidin-1-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

Produkt 1

HCID 696749183-[(1-{3-Cyano-2-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-fluoropiperidin-4-yl)oxy]-5-fluorobenzonitrileAusbeute 37,2 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel2×

Versuchsvorschrift

To a mixture of resin of triphenylphosphine (63.8 mg, 0.133 mmol) and 3-fluoro-5-hydroxybenzonitrile (12.5 mg, 0.0910 mmol) in methylene chloride (0.6 mL) was added di-tert-butyl azodicarboxylate (22.3 mg, 0.0970 mmol) (DBAD). The mixture was stirred for 15 minutes before adding a solution of 4-(3-fluoro-4-hydroxypiperidin-1-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (30.3 mg, 0.0606 mmol) (diastereomer 2) in methylene chloride (0.2 mL). The reaction was stirred overnight at room temperature then another portion of resin of triphenylphosphine and DBAD was added and the solution was stirred for 6 hours, then the solvent was evaporated. The vial and resin were washed with DCM and filtered. The filtrates were washed with 10% aq. NaOH. The organic was dried over MgSO4, filtered, and concentrated. The crude was diluted with methanol and purified with preparative LCMS (Sunfire C18 column eluting with a gradient MeCN/H2O containing 0.1% TFA at 30 mL/min) to give the desired product (11 mg, 29%). The product was synthesized from diastereomer 1 using same procedure in 14% yield. LCMS (M+H)+: 619.3.

Aufarbeitung

  1. stirringThe reaction was stirred overnight at room temperature
  2. stirringthe solution was stirred for 6 hours
  3. customthe solvent was evaporated
  4. washThe vial and resin were washed with DCM
  5. filtrationfiltered
  6. washThe filtrates were washed with 10% aq. NaOH
  7. dry with materialThe organic was dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. additionThe crude was diluted with methanol
  11. custompurified with preparative LCMS (Sunfire C18 column
  12. washeluting with a gradient MeCN/H2O containing 0.1% TFA at 30 mL/min)

Quellen und Nachweise

ORD-Eintrag
ord-605fb0c8fa744b39816ac57b3fe4e274
Quelldatensatz
uspto-grants-2015_05
Patentnummer
US09034884B2

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