Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphane → 1,1-dimethylethyl 4-((2-((9-cyclopentyl-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1,3-thiazol-4-yl)carbonyl)-1-piperazinecarboxylate

HRID 79117Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 79117
[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC([O-])(C)C.[Na+].Br[C:27]1[S:28][CH:29]=[C:30]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)=[O:33])[N:31]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:27]4[S:28][CH:29]=[C:30]([C:32]([N:34]5[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]5)=[O:33])[N:31]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1

Komponenten

9

Edukt 4

HCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphane2×HCID 23676156Sodium t-butoxide2×HCID 582995859-Cyclopentyl-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-amineHCID 58299784Tert-butyl 4-(2-bromothiazole-4-carbonyl)piperazine-1-carboxylate2×

Produkt 1

HCID 582999641,1-dimethylethyl 4-((2-((9-cyclopentyl-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1,3-thiazol-4-yl)carbonyl)-1-piperazinecarboxylateAusbeute 57,7 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysator2×HCID 962WaterLösungsmittelHCID 1140TolueneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

Compound 4 (0.075 g, 0.30 mmol) was combined with sodium 2-methylpropan-2-olate (0.085 g, 0.89 mmol) and compound 72 (0.14 g, 0.38 mmol) in toluene (2 mL). This mixture was degassed by bubbling nitrogen through this solution for ˜2 min followed by the addition of Pd2(dba)3 (0.014 g, 0.015 mmol) and t-Butyl-XPhos (0.025 g, 0.059 mmol). The reaction was heated overnight at 60° C. Additional compound 72, 0.28 g, 0.76 mmol), Pd2(dba)3 (25 mg), t-Butyl-XPhos (54 mg), and the sodium 2-methylpropan-2-olate (0.085 g, 0.89 mmol) were added to the reaction which was heated overnight at 100° C. The reaction was cooled to 20° C. and poured into a separation funnel, with ethyl acetate and water. The layers were partitioned and the aqueous layer was washed with ethyl acetate. The combined organic fractions were dried over MgSO4 and concentrated. The product was purified by flash column chromatography, eluting with a gradient of DCM-6% methanol/0.3% NH4OH/DCM to yield compound 74 (95 mg) as a brown film. LCMS-ESI (POS), M/Z, M+1: Found 549.3.

Aufarbeitung

  1. customThis mixture was degassed
  2. customby bubbling nitrogen through this solution for ˜2 min
  3. temperaturewas heated overnight at 100° C
  4. temperatureThe reaction was cooled to 20° C.
  5. customThe layers were partitioned
  6. washthe aqueous layer was washed with ethyl acetate
  7. dry with materialThe combined organic fractions were dried over MgSO4
  8. concentrationconcentrated
  9. customThe product was purified by flash column chromatography
  10. washeluting with a gradient of DCM-6% methanol/0.3% NH4OH/DCM

Quellen und Nachweise

ORD-Eintrag
ord-a2ff19afe194443399156c5428e7ed28
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08841312B2

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