Cesium carbonate → HCID 59312584, compound

HRID 1931556Notes

Reaction equation

HRID 1931556 reaction equation
[NH2:1][C@:2]([CH3:53])([CH:50]([CH3:52])[CH3:51])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[C:45](Br)[CH:44]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28].CC1(C)C(C)(C)OB([C:62]2[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=2)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[NH2:1][C@:2]([CH3:53])([CH:50]([CH3:52])[CH3:51])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([C:62]3[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=3)[CH:44]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 27346484-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 59312592HCID 59312592, compound

Product 1

HCID 59312584HCID 59312584, compoundYield 82.5%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
135 °C

Procedure

(1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3-dimethylbutyl]oxy]-14-[5-(2-bromo-4-pyridinyl)-1H-1,2,4-triazol-1-yl]-8-[(1R)-1,2-dimethylpropyl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 175, 10.1 mg, 0.011 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (29.2 mg, 0.142 mmol), palladium(II) acetate (1.8 mg, 8.02 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′biphenyl (4.3 mg, 9.02 μmol), cesium carbonate (46.1 mg, 0.141 mmol), and 1,4-dioxane (0.5 ml) were combined in a 0.5-2 ml microwave vial. The reaction mixture was purged with nitrogen before the vial was sealed. The reaction mixture was heated at 135° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered (0.45 μm syringe filter), diluted with methanol, and evaporated under reduced pressure to give a light brown residue. The residue was dissolved in methanol and purified using a single HPLC run on a 30×150 mm Sunfire Prep C18 OBD 10 μm column by eluting with acetonitrile/water+0.1% TFA. The total flow rate was 20 ml/min and the HPLC method employed a 17 minute 20%-100% acetonitrile/water gradient followed by a 2 minute acetonitrile flush. The product fractions were combined, the solvent was evaporated under reduced pressure, and the residue was lyophilized from ethanol and benzene to give the title compound (7.2 mg) as a white solid.

Workup

  1. customThe reaction mixture was purged with nitrogen before the vial
  2. customwas sealed
  3. filtrationThe reaction mixture was filtered
  4. filtration(0.45 μm syringe filter)
  5. additiondiluted with methanol
  6. customevaporated under reduced pressure
  7. customto give a light brown residue
  8. custompurified
  9. washby eluting with acetonitrile/water+0.1% TFA
  10. wait20%-100% acetonitrile/water gradient followed by a 2 minute
  11. customacetonitrile flush
  12. customthe solvent was evaporated under reduced pressure

Sources & evidence

ORD record
ord-80f2bdd120a94ce583255ac00a1a2ec9
Source dataset
uspto-grants-2012_05
Patent number
US08188085B2

Reaction notes

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