Piperidine → tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate

HRID 1529992Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1529992
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=O.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:36][C@@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12

Komponenten

5

Edukt 3

HCID 8082PiperidineHCID 2734674tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate2×HCID 71015721(2R)-2-((4-Amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo(3,4-d)pyrimidin-1-yl)methyl)-beta-oxo-1-pyrrolidinepropanenitrile

Produkt 1

HCID 86714560tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylateAusbeute 57 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 702EthanolLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a sealed tube was added 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (507 mg, 1.07 mmol), tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (0.2, mL, 1.1 mmol), piperidine (0.05 mL, 0.54 mmol) and ethanol (3 mL). The tube was capped and heated to 100° C. for 16 hrs. The reaction was not complete so an additional amount of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (732 mg, 3 eq) was added and heating was continued for 4 hrs at 110° C. The reaction was cooled and concentrated then dissolved in DCM (50 mL) and washed with water (50 mL) and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting material was purified by Isolera (250 g column; 2%-3% MeOH/DCM) to provide 403 mg (57%) of tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate as a solid.

Aufarbeitung

  1. customThe tube was capped
  2. additionwas added
  3. temperatureheating
  4. temperatureThe reaction was cooled
  5. concentrationconcentrated
  6. dissolutionthen dissolved in DCM (50 mL)
  7. washwashed with water (50 mL) and brine
  8. dry with materialThe organic layer was dried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe resulting material was purified by Isolera (250 g column; 2%-3% MeOH/DCM)

Quellen und Nachweise

ORD-Eintrag
ord-3ad042517cbd4169bbe4b99398e2fde7
Quelldatensatz
uspto-grants-2015_07
Patentnummer
US09090621B2

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