Pyridine → (2R)-N-{5-[2-(benzyloxy)ethoxy]pyrazin-2-yl}-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamide

HRID 2192944Notes

Reaction equation

HRID 2192944 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](O)=[O:18])[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.[CH2:33]([O:40][CH2:41][CH2:42][O:43][C:44]1[N:45]=[CH:46][C:47]([NH2:50])=[N:48][CH:49]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.CN(C=O)C.O>[CH2:33]([O:40][CH2:41][CH2:42][O:43][C:44]1[N:45]=[CH:46][C:47]([NH:50][C:17](=[O:18])[C@@H:16]([C:6]2[CH:7]=[CH:8][C:9]([S:10]([CH:13]3[CH2:15][CH2:14]3)(=[O:12])=[O:11])=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=2)[CH2:20][C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]2)=[N:48][CH:49]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1

Participants

8

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 59570882(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoic acidHCID 595709315-[2-(Benzyloxy)ethoxy]pyrazin-2-amine

Product 1

HCID 68670548(2R)-N-{5-[2-(benzyloxy)ethoxy]pyrazin-2-yl}-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamideYield 90.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propionic acid (120 mg) in dichloromethane (5 mL) was sequentially added a solution of 0.5 M oxalyl chloride in dichloromethane (0.77 mL) and DMF (10 μL) under ice-cooling, followed by stirring under ice-cooling for 1 hour. Thereafter, 5-[2-(benzyloxy)ethoxy]pyrazin-2-amine (86 mg) and pyridine (0.05 mL) were added thereto under ice-cooling, followed by stirring for 2 hours under ice-cooling. 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 then dried over anhydrous magnesium sulfate. The oily substance obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-1:1) to obtain (2R)—N-{5-[2-(benzyloxy)ethoxy]pyrazin-2-yl}-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamide (175 mg) as a pale yellow amorphous substance. To a solution of the obtained (2R)—N-{5-[2-(benzyloxy)ethoxy]pyrazin-2-yl}-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanamide (175 mg) in methanol (10 mL) was added 10% palladium carbon (50 mg). Under a hydrogen atmosphere, it was stirred at room temperature at 4 atm for 7 hours. The reaction mixture was filtered through Celite and concentrated. To a solution of the obtained oily substance in THF (10 mL) was added 1 M hydrochloric acid (10 mL) at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The oily substance 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-(2-hydroxyethoxy)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide (103 mg) as a pale yellow amorphous substance.

Workup

  1. temperaturecooling
  2. temperaturecooling for 1 hour
  3. temperatureunder ice-cooling
  4. stirringby stirring for 2 hours under ice-
  5. temperaturecooling
  6. temperaturecooling
  7. extractionfollowed by extraction with ethyl acetate
  8. washThe organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine
  9. dry with materialdried over anhydrous magnesium sulfate
  10. customThe oily substance obtained by concentration
  11. customwas purified by silica gel column chromatography (hexane:ethyl acetate=5:1-1:1)

Sources & evidence

ORD record
ord-24a275fa437040f9b546de7e2f3e19ea
Source dataset
uspto-grants-2012_12
Patent number
US08329707B2

Reaction notes

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