Pyridine → 3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methylsulfanyl-pyrazin-2-yl)-propionamide

HRID 719862Notes

Reaction equation

HRID 719862 reaction equation
[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:27][S:28][C:29]1[N:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=1.N1C=CC=CC=1>CN(C)C=O.C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:35][C:32]2[CH:31]=[N:30][C:29]([S:28][CH3:27])=[CH:34][N:33]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

7

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 21356244(R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acidHCID 218972225-(Methylthio)pyrazin-2-amine

Product 1

HCID 509085563-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methylsulfanyl-pyrazin-2-yl)-propionamideYield 51%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)-propionic acid (prepared as in Example 3, 1.21 g, 4.07 mmol) and N,N-dimethylformamide (5 drops) in methylene chloride (10 mL) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (0.53 mL, 6.10 mmol), and the resulting reaction mixture was stirred at 0° C. for 1 h. The solution was then concentrated in vacuo, and the orange-brown gel was dissolved in methylene chloride. The resulting solution was added dropwise via an addition funnel at 0° C. to a solution of 5-methylsulfanyl-pyrazin-2-ylamine (prepared as in Example 4, 0.58 g, 4.07 mmol) in methylene chloride (10 mL) and pyridine (0.36 mL, 4.48 mmol). The reaction mixture was stirred at 0° C. for 30 min and then was allowed to warm to 25° C. where it was stirred for 3 h. The reaction mixture was quenched with a 1N aqueous citric acid solution (10 mL) and was stirred for 15 min. The reaction was then diluted with ethyl acetate (75 mL) and a 1N aqueous citric acid solution (50 mL). The layers were separated, and the organic layer was then 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, 1/1 ethyl acetate/hexanes) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methylsulfanyl-pyrazin-2-yl)-propionamide (0.864 g, 51%) as a white foam: mp 71–77° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H25N3O3S2 (M+H)+ 420.1410, found 420.1415.

Workup

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

Sources & evidence

ORD record
ord-a9b937b2482547c9b2aa9dd479009049
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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