Citric Acid → (R)-5-(6-cyclohexyl-1-(hydroxyamino)-1-oxohexan-3-yl)-N-methyl-1,2,4-oxadiazole-3-carboxamide

HRID 2182910Notes

Reaction equation

HRID 2182910 reaction equation
[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:22][CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:41][NH2:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:22][CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:42][OH:41])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

8

Reactant 5

HCID 311Citric AcidHCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 2734666O-(Trimethylsilyl)hydroxylamineHCID 59909843(3R)-6-cyclohexyl-3-{3-[(methylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoic acid

Product 1

HCID 9902427(R)-5-(6-cyclohexyl-1-(hydroxyamino)-1-oxohexan-3-yl)-N-methyl-1,2,4-oxadiazole-3-carboxamideYield 43.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of (3R)-6-cyclohexyl-3-{3-[(methylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 8) (285 mg, 0.88 mmol) and N-methylmorpholine (110 μl, 1.00 mmol) in anhydrous tetrahydrofuran (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (130 μl, 1.00 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (130 μl, 1.06 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with aqueous citric acid solution (10% w/v, 10 ml) and stirred for 2 hours. This mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was then recrystallised from hexane:ethyl acetate to afford the title compound as a white solid (130 mg).

Workup

  1. stirringthe mixture was stirred for 18 hours
  2. stirringstirred for 2 hours
  3. extractionextracted with ethyl acetate (×3)
  4. washThe combined organic layers were washed sequentially with water and brine
  5. dry with materialdried over anhydrous sodium sulphate
  6. filtrationfiltered
  7. customthe solvent removed under reduced pressure
  8. customThe solid was then recrystallised from hexane

Sources & evidence

ORD record
ord-9ed1652f00c94c61875e4afa6fb023b6
Source dataset
uspto-grants-2005_05
Patent number
US06897306B2

Reaction notes

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