Methyl chloroacetate → methyl (4-[4-(1-benzofuran-5-yl)phenyl]-3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetate

HRID 525140

Reaction equation

HRID 525140 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]([O:43][CH3:44])=[O:42]>CN(C)C=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:17](=[O:32])[N:18]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1

Participants

5

Reactant 3

HCID 7295Methyl chloroacetateHCID 11430Potassium CarbonateHCID 67376285Gsk2194069

Product 1

HCID 68261353methyl (4-[4-(1-benzofuran-5-yl)phenyl]-3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetateYield 57.7%

Reagents, catalysts & solvents 1

HCID 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 (55 mg, 0.128 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.3 eq) and methyl chloroacetate (25 mg, 0.227 mmol, 1.7 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 the reaction had gone to completion. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extracts 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; 20-55% 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 (37 mg, 57%). MS(ES)+ m/e 501.1 [M+H]+.

Workup

  1. customThe vial was capped
  2. custompurged with nitrogen gas
  3. temperatureThe reaction mixture was cooled to room temperature
  4. additionpoured into a mixture of dichloromethane and water
  5. customThe organic layer was separated
  6. washThe aqueous layer was washed with dichloromethane
  7. washwashed 3× with a dilute brine solution
  8. customThe organic layer was separated
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-55% acetonitrile w/0.1% TFA/water w/0.1% TFA)
  13. additionThe product fractions were neutralized with the addition of saturated aq sodium bicarbonate
  14. extractionextracted with dichloromethane
  15. dry with materialThe organic layer was dried over sodium sulfate
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-a2b3d73dcb7f43e9ae471e64b3c97ef3
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Linked notes

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