Pyridine → N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide

HRID 2214129Notes

Reaction equation

HRID 2214129 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:36]=[N:35][C:34]([Br:37])=[CH:33][N:32]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br:37][C:34]1[N:35]=[CH:36][C:31]([NH:30][C:13](=[O:14])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)=[N:32][CH:33]=1

Participants

9

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 5995392-Amino-5-bromopyrazineHCID 219589672-(3-Chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid

Product 1

HCID 10029482N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamideYield 50%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 311Citric AcidSolventHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 58, 267 mg, 0.75 mmol) in methylene chloride (10 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 (0.45 mL, 0.90 mmol). The reaction mixture was stirred at 25° C. for 30 min and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (10 mL) and was treated dropwise with a solution of 2-amino-5-bromopyrazine (261 mg, 1.50 mmol, prepared according to Tetrahedron 1988, 44, 2977–2983) in tetrahydrofuran (10 mL) and pyridine (0.30 mL, 3.75 mmol). The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then diluted with a 1N aqueous citric acid solution (25 mL) and then concentrated to remove tetrahydrofuran. The remaining aqueous residue was then extracted with a 3/2 solution of chloroform/methanol (2×25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 35/65 hexanes/ethyl acetate) afforded N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (193 mg, 50%) as a yellow foam: EI-HRMS m/e calcd for C20H21BrClN3O4S (M+H)+ 514.0198, found 514.0200.

Workup

  1. concentrationconcentrated in vacuo
  2. customto remove solvents and excess oxalyl chloride
  3. dissolutionThe resulting residue was re-dissolved in dry tetrahydrofuran (10 mL)
  4. customThe resulting reaction mixture
  5. stirringwas stirred at 25° C. for 2 h
  6. concentrationconcentrated
  7. customto remove tetrahydrofuran
  8. extractionThe remaining aqueous residue was then extracted with a 3/2 solution of chloroform/methanol (2×25 mL)
  9. dry with materialThe combined organic extracts were dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-039c37f30b654be6afe4e9642bc1dc96
Source dataset
uspto-grants-2006_09
Patent number
US07105671B2

Reaction notes

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