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

HRID 2214113Notes

Reaction equation

HRID 2214113 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][C:33]([Br:36])=[CH:32][N:31]=1.N1C=CC=CC=1>CN(C)C=O.C(Cl)Cl>[Br:36][C:33]1[N:34]=[CH:35][C:30]([NH:29][C:13](=[O:15])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)=[N:31][CH:32]=1

Participants

7

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 5995392-Amino-5-bromopyrazineHCID 21958963HCID 21958963, compound

Product 1

HCID 9983474N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionamideYield 41%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid (prepared as in Example 45, 1.05 g, 3.04 mmol) and N,N-dimethylformamide (5 drops) in methylene chloride (10 mL) cooled to 0° C. was treated with oxalyl chloride (0.39 mL, 4.57 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at 25° C. for 1 h. The solution was then concentrated in vacuo, and the orange-brown gel was dissolved in methylene chloride (5 mL). The resulting solution was added dropwise via an addition funnel at 0° C. to a solution of 2-amino-5-bromopyrazine (0.79 g, 4.57 mmol, prepared according to Tetrahedron 1988, 44, 2977–2983) in methylene chloride (5 mL) and pyridine (0.37 mL, 4.57 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at 25° C. for 3 h. The reaction mixture was quenched with a 1N aqueous citric acid solution (10 mL) and stirred for 15 min. The reaction was then diluted with a 1N aqueous citric acid solution (50 mL) and ethyl acetate (75 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 50% ethyl acetate/hexanes) afforded N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionamide (0.622 g, 41%) as a yellow-orange foam: mp 97–103° C. (foam to gel); (ES)+-HRMS m/e calcd for C19H19BrClN3O4S (M+H)+ 500.0041 found 500.0048.

Workup

  1. waitat 25° C. for 1 h
  2. concentrationThe solution was then concentrated in vacuo
  3. dissolutionthe orange-brown gel was dissolved in methylene chloride (5 mL)
  4. stirringThe reaction mixture was stirred at 0° C. for 30 min
  5. waitat 25° C. for 3 h
  6. customThe reaction mixture was quenched with a 1N aqueous citric acid solution (10 mL)
  7. stirringstirred for 15 min
  8. additionThe reaction was then diluted with a 1N aqueous citric acid solution (50 mL) and ethyl acetate (75 mL)
  9. washThe organic layer was washed with a saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL)
  10. dry with materiala saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-ca577807e5a643789696723aa9c87524
Source dataset
uspto-grants-2006_09
Patent number
US07105671B2

Reaction notes

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