Dichloromethane → HCID 53371707, compound

HRID 525153Notes

Reaction equation

HRID 525153 reaction equation
[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41]([CH3:44])([OH:43])[CH3:42].ClCCl>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[CH2:23]5)=[N:19][N:18]([CH2:40][C:41]([OH:43])([CH3:44])[CH3:42])[C:17]4=[O:32])=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 684091-Chloro-2-methylpropan-2-olHCID 67376285Gsk2194069

Product 1

HCID 53371707HCID 53371707, compoundYield 48%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.233 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (100 mg, 0.724 mmol, 3.1 eq) and 1-chloro-2-methyl-2-propanol (50 mg, 0.461 mmol, 2 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed no reaction. The solution was then irradiated in the microwave at 185° C. for 60 min. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-55% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (56 mg, 48%). MS(ES)+ m/e 501.1 [M+H]+.

Workup

  1. customThe vial was capped
  2. custompurged with nitrogen gas
  3. customno reaction
  4. customThe solution was then irradiated in the microwave at 185° C. for 60 min
  5. customThe organic layer was separated
  6. washThe aqueous layer was washed with dichloromethane
  7. extractionThe organic extractions
  8. washwashed 3× with a dilute brine solution
  9. customThe organic layer was separated
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customThe crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-55% acetonitrile w/0.1% TFA/water w/0.1% TFA)
  14. additionThe product fractions were neutralized with the addition of saturated aq sodium bicarbonate
  15. extractionextracted with dichloromethane
  16. dry with materialThe organic layer was dried over sodium sulfate
  17. filtrationfiltered
  18. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-823988c5cd284d22a6e7b92cf8f3a350
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Reaction notes

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