Pyridine → Piragliatin;RO 4389620

HRID 854816Notes

Reaction equation

HRID 854816 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](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[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]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]

Participants

8

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 78747AminopyrazineHCID 21958963HCID 21958963, compound

Product 1

HCID 10477292Piragliatin;RO 4389620Yield 28.5%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid (594.8 mg, 1.725 mmol) in methylene chloride (8.6 mL) and N,N-dimethylformamide (2 drops) cooled to 0° C. was treated with oxalyl chloride (226 μL, 2.587 mmol). The reaction mixture was stirred at 0° C. for 15 min and then stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to afford a red oil. This red oil was dissolved in tetrahydrofuran (4.03 mL), cooled to 0° C., and then slowly treated with a solution of 2-aminopyrazine (246.1 mg, 2.587 mmol) and pyridine (209 μL, 2.587 mmol) in tetrahydrofuran (4.3 mL). The resulting reaction mixture was stirred at 0° C. for 15 min and then stirred at 25° C. for 2 h. The reaction mixture was quenched with a 1N aqueous citric acid solution (20 mL) and then extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (2×100 mL) and a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (207.3 mg, 28%) as a pale yellow foam: mp 93-96° C. (foam to gel); (ES)+-HRMS m/e calcd for C19H20ClN3O4S (M+H)+422.0936. found 422.0938.

Workup

  1. stirringstirred at 25° C. for 2 h
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. customto afford a red oil
  4. temperaturecooled to 0° C.
  5. customThe resulting reaction mixture
  6. stirringwas stirred at 0° C. for 15 min
  7. stirringstirred at 25° C. for 2 h
  8. customThe reaction mixture was quenched with a 1N aqueous citric acid solution (20 mL)
  9. extractionextracted with ethyl acetate (2×100 mL)
  10. washThe combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (2×100 mL)
  11. dry with materiala saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0cbd0783f7044f96bde28b45a01e7752
Source dataset
uspto-grants-2007_08
Patent number
US07259166B2

Reaction notes

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