Cesium carbonate → HCID 178431666, compound

HRID 339877Notes

Reaction equation

HRID 339877 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:37])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[N:10][S:9]2(=[O:36])=[O:35])[CH:5]=[CH:6][CH:7]=1.[N:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C@@H:17]([NH:16][C:11]1[O:12][C:13]([CH3:14])([CH3:15])[C:8]([CH3:37])([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:42]3[CH:43]=[N:38][CH:39]=[N:40][CH:41]=3)[CH:3]=2)[S:9](=[O:36])(=[O:35])[N:10]=1)[CH2:18][CH2:19][OH:20]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 1784316875-(3-bromophenyl)-N-[(1S)-3-[tert-butyl(dimethyl)silyl]oxy-1-(2-fluorophenyl)propyl]-5,6,6-trimethyl-4,4-dioxo-1,4,3-oxathiazin-2-amine

Product 1

HCID 178431666HCID 178431666, compoundYield 34.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Under inert gas, 45 mg of [5-(3-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propyl]amine, 11 mg of pyrimidine-5-boronic acid and 96 mg of cesium carbonate were dissolved in a mixture of 1 ml of dioxane and 0.4 ml of water. After purging with argon for 10 minutes, 6 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium were added and the reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with water. The organic phase was dried using a diatomaceous earth cartridge (Varian Chem Elut®) and concentrated by rotary evaporation. To detach the protecting group, the residue was dissolved in 1.5 ml of methanol, 0.18 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 2.5 hours. After the removal of the solvent under reduced pressure, the crude product was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (12.6 mg) with a molecular weight of 498.6 g/mol (C25H27N4O4S); MS (ESI): m/e=499 (M+H+).

Workup

  1. customAfter purging with argon for 10 minutes
  2. addition6 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium were added
  3. temperatureto cool to room temperature
  4. additiondiluted with ethyl acetate
  5. washwashed with water
  6. customThe organic phase was dried
  7. concentrationconcentrated by rotary evaporation
  8. dissolutionthe residue was dissolved in 1.5 ml of methanol
  9. addition0.18 ml of concentrated hydrochloric acid was added
  10. stirringthe mixture was stirred at room temperature for 2.5 hours
  11. customAfter the removal of the solvent under reduced pressure
  12. customthe crude product was purified in a purification laboratory by means of preparative HPLC
  13. customthe acetonitrile was removed under reduced pressure
  14. extractionextracted with ethyl acetate
  15. dry with materialThe organic phase was dried over MgSO4
  16. concentrationconcentrated by rotary evaporation
  17. additionthe residue was taken up again in a mixture of acetonitrile and water

Sources & evidence

ORD record
ord-619972528a0f47d7a4257215f5a42ce8
Source dataset
uspto-grants-2014_11
Patent number
US08895547B2

Reaction notes

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