Oxalyl chloride → Mk-0736

HRID 1784514Notes

Reaction equation

HRID 1784514 reaction equation
[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([NH:19][CH3:20])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[F:27][C:28]([F:41])([F:40])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1NN=[N:37][N:36]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]3[N:19]([CH3:20])[C:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[C:28]([F:27])([F:41])[F:40])=[N:36][N:37]=3)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2]

Participants

6

Reactant 3

HCID 65578Oxalyl chlorideHCID 207550394-[3-(ethylsulfonyl)propyl]-N-methylbicyclo[2.2.2]octane-1-carboxamideHCID 178506136HCID 178506136, compound

Product 1

HCID 22591684Mk-0736

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Procedure

Methyl amide 11-9 (0.470 g, 1.56 mmol) was dissolved in anhydrous methylene chloride (5 mL) and treated with oxalyl chloride (2M in methylene chloride, 1.56 mL, 3.12 mmol) and DMF (2 drops). The solution was stirred at room temperature for 1 h, then solvent removed by evaporation under reduced pressure. The residue was redissolved in anhydrous toluene (7 mL) and treated with 5[2-(trifluoromethyl)phenyl]1H-tetrazole (368 mg, 1.72 mmol). The mixture was refluxed for 18 h. The reaction was cooled to room temperature and the precipitate was filtered and washed to give 300 mg of crude product as the HCl salt. The salt was taken up in methylene chloride/1N HCl and the aqueous layer was washed with two additional portions of methylene chloride. The organic layers were combined and evaporated and the residue was chromatographed by flash silica gel chromatography. Elution was carried out with a gradient ranging from 0 to 5% methanol/methylene chloride. The appropriate fractions were combined and evaporated to give 3-{4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]oct-1-yl}4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole (11-10) as a white powder. MS (ESI+)=470.4 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.87 (1H, m), 7.72 (2H, m), 7.56 (1H, m), 3.49 (3H, s), 3.05 (2H, q, J=7.2 Hz), 2.96 (2H,m), 2.18 (6H, m), 1.86 (2H, m), 1.62 (6H, m), 1.46 (3H, t, J=7.3 Hz), 1.36 (2H, m) ppm.

Workup

  1. customsolvent removed by evaporation under reduced pressure
  2. dissolutionThe residue was redissolved in anhydrous toluene (7 mL)
  3. temperatureThe mixture was refluxed for 18 h
  4. temperatureThe reaction was cooled to room temperature
  5. filtrationthe precipitate was filtered
  6. washwashed
  7. customto give 300 mg of crude product as the HCl salt
  8. washthe aqueous layer was washed with two additional portions of methylene chloride
  9. customevaporated
  10. customthe residue was chromatographed by flash silica gel chromatography
  11. washElution
  12. customevaporated

Sources & evidence

ORD record
ord-9dbb478b35b94176bb360da1ffb6b9df
Source dataset
uspto-grants-2009_03
Patent number
US07504402B2

Reaction notes

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