Cesium carbonate → HCID 86670377, Verbindung

HRID 1972516Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1972516
Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[Si]([O:39][CH2:40][CH2:41][C:42]#[C:43][B-](F)(F)F)(C(C)(C)C)(C)C.[K+].COC(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:43]#[C:42][CH2:41][CH2:40][OH:39])[CH2:9][CH2:10]1)(=[O:16])=[O:15]

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 15413tert-Butyl methyl etherHCID 23676307Potassium (4-{[tert-butyl(dimethyl)silyl]oxy}but-1-yn-1-yl)(trifluoro)borate(1-)HCID 86670331HCID 86670331, Verbindung

Produkt 1

HCID 86670377HCID 86670377, VerbindungAusbeute 23,9 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
135 °C

Versuchsvorschrift

2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (95 mg, 0.17 mmol, Example 69), potassium (4-(tert-butyldimethylsilyloxy)but-1-ynyl)trifluoroborate (75 mg, 0.26 mmol, ASDI, Newark, Del.), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (14 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), and cesium carbonate (182 mg, 0.56 mmol) were combined in toluene (1.5 mL) and water (0.2 mL). The reaction mixture was purged with nitrogen gas for several minutes and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 135° C. for 30 min. The reaction mixture was filtered through a pad of Celite® (diatomaceous earth) eluting with CH2Cl2 and the filtrate was concentrated in vacuo. The residue was suspended in 1N HCl (5 mL) and stirred at room temperature for 30 min. The mixture was partitioned between CH2Cl2 (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The layers were separated, the organic material was dried (Na2SO4), filtered, and concentrated. This crude material was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (30% to 100% over 10 min) to provide 4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-1-ol (22 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.11 (dd, J=1.27, 4.99 Hz, 1H), 7.71 (dd, J=1.37, 3.72 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J=8.61 Hz, 1H), 7.35 (dd, J=3.81, 4.99 Hz, 1H), 7.08 (d, J=8.80 Hz, 1H), 4.88 (t, J=5.38 Hz, 1H), 3.50-3.59 (m, 2H), 3.27-3.32 (m, 4H), 3.08-3.15 (m, 4H) 2.56 (t, J=6.70 Hz, 2H); m/z (ESI, +ve ion) 543.1 (M+H)+. GK-GKRP IC50 (Binding)=0.656 μM. GK-GKRP EC50 (LC MS/MS-2)=0.895 μM.

Aufarbeitung

  1. customThe reaction mixture was purged with nitrogen gas for several minutes
  2. filtrationThe reaction mixture was filtered through a pad of Celite® (diatomaceous earth)
  3. washeluting with CH2Cl2
  4. concentrationthe filtrate was concentrated in vacuo
  5. stirringstirred at room temperature for 30 min
  6. customThe mixture was partitioned between CH2Cl2 (5 mL) and saturated aqueous sodium bicarbonate (5 mL)
  7. customThe layers were separated
  8. dry with materialthe organic material was dried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. washeluting with 0.1% TFA in CH3CN/H2O (30% to 100% over 10 min)

Quellen und Nachweise

ORD-Eintrag
ord-1547c714bbd54288af83a895e22f2beb
Quelldatensatz
uspto-grants-2013_04
Patentnummer
US08431563B2

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