Cesium carbonate → HCID 86670377, compound

HRID 1972516Notes

Reaction equation

HRID 1972516 reaction equation
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]

Participants

7

Reactant 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, compound

Product 1

HCID 86670377HCID 86670377, compoundYield 23.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
135 °C

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-1547c714bbd54288af83a895e22f2beb
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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