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Citric Acid → (2S)-3-cyclobutoxy-N-(5-methylpyrazin-2-yl)-2-(1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide

HRID 1098011
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1098011
[H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:29]=[CH:30][C:23]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:3]1([O:7][CH2:8][C@H:9]([O:20][C:22]2[N:27]=[CH:26][N:25]=[C:24]3[N:28]([C:31]4[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=4)[N:29]=[CH:30][C:23]=23)[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

6

Edukt 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 575045064-chloro-1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine2×HCID 57504623HCID 57504623, Verbindung

Produkt 1

HCID 59279464(2S)-3-cyclobutoxy-N-(5-methylpyrazin-2-yl)-2-(1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide
Ausbeute 41,6 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

Sodium hydride (19.54 mg, 0.49 mmol) was added to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (102 mg, 0.41 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate V5) (100 mg, 0.41 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 5% MeOH in DCM to afford the product (78 mg, 41.6%). 1H NMR (400 MHz, DMSO) δ 1.23-1.36 (m, 1H), 1.38-1.51 (m, 1H), 1.60-1.75 (m, 2H), 1.96-2.07 (m, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 3.71-3.87 (m, 2H), 3.89-3.98 (m, 1H), 5.71-5.78 (m, 1H), 7.28-7.34 (m, 1H), 7.75 (d, 1H), 8.15 (s, 1H), 8.39 (s, 1H), 8.45-8.51 (m, 2H), 8.93 (s, 1H), 11.01 (s, 1H), m/z (ESI+) (M+H)+=461.48; HPLC tR=1.75 min

Aufarbeitung

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour
  3. customthe majority of the THF removed in vacuo
  4. additionThe reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with ethyl acetate (2×50 mL)
  7. washThe combined organics were washed with saturated brine (25 mL)
  8. dry with materialdried (MgSO4)
  9. customevaporated
  10. customThe crude product was purified by flash silica chromatography
  11. washeluting with 0 to 5% MeOH in DCM

Quellen und Nachweise

ORD-Eintrag
ord-42787f34b76c4b0a8e2479458f0bc85a
Quelldatensatz
uspto-grants-2012_03
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08143263B2

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