Potassium Carbonate → HCID 178519256, compound

HRID 525236Notes

Reaction equation

HRID 525236 reaction equation
[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH:40]=[N:39][C:38]2=[O:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:35]5[CH:36]=[C:37]6[C:42](=[CH:43][CH:44]=5)[NH:41][CH:40]=[N:39][C:38]6=[O:45])=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 673768905-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-oneHCID 178518215HCID 178518215, compound

Product 1

HCID 178519256HCID 178519256, compoundYield 11%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.238 mmol) in 1,4-dioxane (1.5 mL) was treated with 6-bromo-4(1H)-quinazolinone (0.238 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)-dichloromethane adduct (10 mg) and 2M aq potassium carbonate (0.715 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over sodium sulfate, treated with Si-Thiol (Silicycle, 20 mg), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions from the HPLC were combined, adjusted to pH˜5 with the addition of saturated aq sodium bicarbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was then purified by flash chromatography (0-10% methanol/dichloromethane). The resulting product was suspended in water (0.5 mL) and was lyophilized to afford the title compound as an amorphous white solid (11%). MS(ES)+ m/e 475.1 [M+H]+.

Workup

  1. customThe reaction mixture was purged with nitrogen
  2. customsealed
  3. customirradiated in a microwave at 150° C. for 15 min
  4. additionwas diluted with water (50 mL)
  5. extractionwas extracted with dichloromethane
  6. dry with materialThe organic layer was dried over sodium sulfate
  7. additiontreated with Si-Thiol (Silicycle, 20 mg)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude residue was purified by reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA)
  11. additionadjusted to pH˜5 with the addition of saturated aq sodium bicarbonate
  12. extractionextracted with dichloromethane
  13. dry with materialThe organic layer was dried over magnesium sulfate
  14. filtrationfiltered
  15. concentrationconcentrated in vacuo
  16. customThe resulting product was then purified by flash chromatography (0-10% methanol/dichloromethane)

Sources & evidence

ORD record
ord-e0c08950360940a182716488becfc6a8
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Reaction notes

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