Cesium carbonate → (S)-2,2-Difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)-1-(2-(5-((pyridazin-4-yloxy)methyl)isoxazol-3-yl)pyrrolidin-1-yl)ethanone

HRID 710068

Reaction equation

HRID 710068 reaction equation
[F:1][C:2]([F:28])([C:17]1([OH:27])[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[CH:14]=[C:13]([CH2:15][OH:16])[O:12][N:11]=1)=[O:4].Br.Br[C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1P(C(C)(C)C)C(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:28][C:2]([F:1])([C:17]1([OH:27])[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH2:22]1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[CH:14]=[C:13]([CH2:15][O:16][C:31]2[CH:36]=[CH:35][N:34]=[N:33][CH:32]=2)[O:12][N:11]=1)=[O:4]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 2734941(1,1'-Binaphthalen)-2-yldi-tert-butylphosphineHCID 534079064-Bromopyridazine hydrobromideHCID 86706747(S)-2,2-Difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)-1-(2-(5-(hydroxymethyl)isoxazol-3-yl)pyrrolidin-1-yl)ethanone

Product 1

HCID 86706781(S)-2,2-Difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)-1-(2-(5-((pyridazin-4-yloxy)methyl)isoxazol-3-yl)pyrrolidin-1-yl)ethanoneYield 16.7%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A sealed tube was charged with a mixture prepared by adding toluene (2 ml) to Compound 18 (30 mg), 4-bromopyridazine hydrobromide (22 mg), Pd(OAc)2 (2 mg), Cs2CO3 (37 mg), and [1,1′-binaphthalen]-2-yldi-tert-butylphosphine (3 mg) and the mixture was stirred at 100° C. for 4 hours. After cooling the reaction mixture to room temperature, NH silica gel was added, followed by stirring for a while. After separating the silica gel by filtration, the silica gel was washed with chloroform and the solvent was distilled off; the resulting residue was purified by reverse-phase preparative HPLC to give the titled compound (6.0 mg, colorless oil.)

Workup

  1. additionA sealed tube was charged with a mixture
  2. customprepared
  3. temperatureAfter cooling the reaction mixture to room temperature
  4. additionNH silica gel was added
  5. stirringby stirring for a while
  6. customAfter separating the silica gel
  7. filtrationby filtration
  8. washthe silica gel was washed with chloroform
  9. distillationthe solvent was distilled off
  10. customthe resulting residue was purified by reverse-phase preparative HPLC

Sources & evidence

ORD record
ord-a77022a34471403ea39f5d751aafaa39
Source dataset
uspto-grants-2015_11
Patent number
US09181229B2

Linked notes

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