Hydrochloric Acid → (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(1-hydroxyethyl)pyrazin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide

HRID 2192958Notes

Reaction equation

HRID 2192958 reaction equation
[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17]([OH:19])=O)[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[N:35]=[CH:36][C:37]([CH:40]([OH:42])[CH3:41])=[N:38][CH:39]=1.[OH-].[Na+].Cl>ClCCl.CN(C=O)C.O.N1C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][CH:21]3[CH2:22][CH2:23][O:26][CH2:24][CH2:25]3)[C:17]([NH:33][C:34]3[CH:39]=[N:38][C:37]([CH:40]([OH:42])[CH3:41])=[CH:36][N:35]=3)=[O:19])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 65578Oxalyl chlorideHCID 552840111-(5-Aminopyrazin-2-yl)ethanolHCID 59570882(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoic acid

Product 1

HCID 59570991(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(1-hydroxyethyl)pyrazin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamideYield 64%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1049PyridineSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propionic acid (200 mg) in dichloromethane (10 mL) were sequentially added a solution of oxalyl chloride in 0.5 M dichloromethane (1.3 mL) and DMF (16 μL) under ice-cooling, followed by stirring for 30 minutes under ice-cooling. Thereafter, 1-(5-aminopyrazin-2-yl)ethanol (81 mg) and pyridine (0.09 mL) were added thereto under ice-cooling, followed by stirring for 3 hours. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. To a solution of the oily substance obtained by concentration in methanol (4 mL) was added 1 M aqueous sodium hydroxide solution (1 mL) at room temperature, followed by stirring at room temperature for 1 hour. To the reaction mixture was added 1 M hydrochloric acid to adjust the pH to 3, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (wetting with hexane:ethyl acetate=1:1, chloroform:methanol=1:0-10:1) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(1-hydroxyethyl)pyrazin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (170 mg) as a white amorphous substance.

Workup

  1. temperaturecooling
  2. temperaturecooling
  3. temperatureunder ice-cooling
  4. stirringby stirring for 3 hours
  5. temperaturecooling
  6. extractionfollowed by extraction with ethyl acetate
  7. washThe organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine
  8. dry with materialdried over anhydrous magnesium sulfate
  9. customTo a solution of the oily substance obtained by concentration in methanol (4 mL)
  10. stirringby stirring at room temperature for 1 hour
  11. extractionfollowed by extraction with ethyl acetate
  12. washThe organic layer was sequentially washed with 1 M aqueous sodium hydroxide solution and saturated brine
  13. dry with materialdried over anhydrous magnesium sulfate
  14. customThe crude product obtained by concentration
  15. customwas purified by silica gel column chromatography (wetting with hexane:ethyl acetate=1:1, chloroform:methanol=1:0-10:1)

Sources & evidence

ORD record
ord-93416ea9e2c141669ea5ab2b12125625
Source dataset
uspto-grants-2012_12
Patent number
US08329707B2

Reaction notes

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