Trifluoroacetic acid → 2-[5-[3-Amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]-5-(methylaminomethyl)phenol

HRID 78673

Reaktionsgleichung

Reaktionsgleichung von HRID 78673
[NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]([CH3:40])C(=O)OC(C)(C)C)=[CH:27][C:26]=3Cl)=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C1(C=CC(=[O:59])C=CC2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-].[K+].C(O)(C(F)(F)F)=O>O1CCOCC1.[Pd]>[NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][NH:32][CH3:40])=[CH:27][C:26]=3[OH:59])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1

Komponenten

8

Edukt 5

HCID 6422Trifluoroacetic acidHCID 14797Potassium Hydroxide2×HCID 95417Dibenzylidene acetone2×HCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphane2×HCID 59471991tert-butyl N-[[4-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]-3-chloro-phenyl]methyl]-N-methyl-carbamate

Produkt 1

HCID 1361172942-[5-[3-Amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]-5-(methylaminomethyl)phenolAusbeute 18 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 23938PalladiumKatalysator2×HCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a solution of tert-butyl N-[[4-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]-3-chloro-phenyl]methyl]-N-methyl-carbamate (130 mg, 0.2170 mmol) in dioxane (3 mL) was added of 1,5-diphenylpenta-1,4-dien-3-one; palladium (6.239 mg, 0.01085 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (13.82 mg, 0.03255 mmol) and potassium hydroxide (434.0 μL of 1 M, 0.4340 mmol). The resulting mixture was heated to 100° C. for 2 h. Additional 1,5-diphenylpenta-1,4-dien-3-one; palladium (6.239 mg, 0.01085 mmol), ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (13.82 mg, 0.03255 mmol) and potassium hydroxide (434.0 μL of 1 M, 0.4340 mmol) were added and the resulting mixture heated for a further 2 h at 100° C. The reaction mixture was evaporated to dryness and the residue purified by column chromatography on silica eluting with 20% EtOAc/ petroleum ether. Product fractions were combined and concentrated in vacuo. This mixture was dissolved in DCM (10 mL) and TFA (247.4 mg, 167.2 μL, 2.170 mmol) added. The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo to an oil. This was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The product fractions were collected and lypholised to give the product as a yellow solid (24.0 mg, 18% yield); 1H NMR (400.0 MHz, DMSO) d 1.31 (m, 6H), 2.80 (s, 3H), 3.43 (m, 1H), 4.27 (s, 2H), 7.23 (m, 1H), 7.30 (m, 1H), 8.04 (m, 2H), 8.19 (m, 1H), 8.41 (m, 2H) and 8.95 (s, 1H) ppm; MS (ES+) 481.2

Aufarbeitung

  1. temperaturethe resulting mixture heated for a further 2 h at 100° C
  2. customThe reaction mixture was evaporated to dryness
  3. customthe residue purified by column chromatography on silica eluting with 20% EtOAc/ petroleum ether
  4. concentrationconcentrated in vacuo
  5. dissolutionThis mixture was dissolved in DCM (10 mL)
  6. concentrationconcentrated in vacuo to an oil
  7. customThis was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]
  8. customThe product fractions were collected

Quellen und Nachweise

ORD-Eintrag
ord-7183b84e6b414271b48e4afd603efc5b
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08841308B2

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