2,6-Lutidine → 2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-pyran-2-yl)-propionamide

HRID 2214042Notes

Reaction equation

HRID 2214042 reaction equation
[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12](O)=[O:13])=[CH:7][C:6]=1[C:22]([F:25])([F:24])[F:23])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12]([NH:32][C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)=[O:13])=[CH:7][C:6]=1[C:22]([F:23])([F:25])[F:24])(=[O:3])=[O:4]

Participants

9

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 78747AminopyrazineHCID 21958991HCID 21958991, compound

Product 1

HCID 219589992-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-pyran-2-yl)-propionamideYield 22%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (prepared as in Example 12, 50 mg, 0.13 mmol) in methylene chloride (1 mL) was treated with N,N-dimethylformamide (3 drops) and then cooled to 0° C. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.08 mL, 0.156 mmol). The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to 25° C., and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (1 mL) and was treated dropwise with a solution of 2-aminopyrazine (15 mg, 0156 mmol) in tetrahydrofuran (1 mL) and 2,6-lutidine (0.02 mL, 0.157 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (50 mL) and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 7/3 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-pyran-2-yl)-propionamide (13 mg, 22%) as a colorless gum: EI-HRMS m/e calcd for C20H22F3N3O4S (M+Na)+ 480.1175 found 480.1177.

Workup

  1. temperatureto warm to 25° C.
  2. concentrationconcentrated in vacuo
  3. customto remove solvents and excess oxalyl chloride
  4. dissolutionThe resulting residue was re-dissolved in dry tetrahydrofuran (1 mL)
  5. customThe resulting reaction mixture
  6. stirringwas stirred at 25° C. for 16 h
  7. extractionextracted with methylene chloride (3×50 mL)
  8. dry with materialThe combined organic layers were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-feff9383dd7a4101a401f6c2afa8885e
Source dataset
uspto-grants-2006_09
Patent number
US07105671B2

Reaction notes

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