Hydrochloric Acid → (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(hydroxymethyl)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide

HRID 2192950Notes

Reaction equation

HRID 2192950 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.[Si]([O:40][CH2:41][C:42]1[N:43]=[CH:44][C:45]([NH2:48])=[N:46][CH:47]=1)(C(C)(C)C)(C)C.Cl>ClCCl.O.C1COCC1.N1C=CC=CC=1.CN(C=O)C>[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]([NH:48][C:45]3[CH:44]=[N:43][C:42]([CH2:41][OH:40])=[CH:47][N:46]=3)=[O:19])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1

Participants

10

Reactant 4

HCID 313Hydrochloric AcidHCID 65578Oxalyl chlorideHCID 59570882(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoic acidHCID 595709715-(((tert-Butyldimethylsilyl)oxy)methyl)pyrazin-2-amine

Product 1

HCID 44198880(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(hydroxymethyl)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamideYield 42%

Reagents, catalysts & solvents 5

HCID 962WaterSolvent2×HCID 1049PyridineSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoic acid (252 mg) in dichloromethane (2.5 mL) were added oxalyl chloride (68 μL) and DMF (104 μL) under ice-cooling, followed by stirring for 20 minutes. Thereafter, pyridine (65 μL) and 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrazin-2-amine (240 mg) were added thereto under ice-cooling, followed by stirring for 20 minutes under ice-cooling. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:chloroform=20:80). Further, it was purified by preparative TLC using the same solvent system to obtain a white amorphous substance (200 mg). A mixture of the obtained amorphous substance, 2 M hydrochloric acid (1 mL), and THF (1 mL) was stirred at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(hydroxymethyl)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide (136 mg) as a white amorphous substance.

Workup

  1. temperaturecooling
  2. temperatureunder ice-cooling
  3. stirringby stirring for 20 minutes under ice-
  4. temperaturecooling
  5. extractionfollowed by extraction with ethyl acetate
  6. washThe organic layer was washed with saturated brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. customThe solvent was evaporated
  9. customthe obtained residue was purified by silica gel column chromatography (ethyl acetate:chloroform=20:80)
  10. customFurther, it was purified by preparative TLC
  11. customto obtain a white amorphous substance (200 mg)
  12. stirringwas stirred at room temperature for 2 hours
  13. extractionfollowed by extraction with ethyl acetate
  14. washThe organic layer was washed with saturated brine
  15. dry with materialdried over anhydrous sodium sulfate
  16. customThe solvent was evaporated
  17. customthe obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50)

Sources & evidence

ORD record
ord-80e85410e0d347fe94dbbc45a0db4efc
Source dataset
uspto-grants-2012_12
Patent number
US08329707B2

Reaction notes

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