4-Methylmorpholine → (R)-5-(6-cyclohexyl-1-(hydroxyamino)-1-oxohexan-3-yl)-1,2,4-oxadiazole-3-carboxamide

HRID 2182908Notes

Reaction equation

HRID 2182908 reaction equation
[NH2:1][C:2]([C:4]1[N:8]=[C:7]([C@H:9]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][C:11](O)=[O:12])[O:6][N:5]=1)=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:40][NH2:41]>O1CCCC1.CO>[CH:17]1([CH2:16][CH2:15][CH2:14][C@@H:9]([C:7]2[O:6][N:5]=[C:4]([C:2]([NH2:1])=[O:3])[N:8]=2)[CH2:10][C:11]([NH:41][OH:40])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 2734666O-(Trimethylsilyl)hydroxylamineHCID 11426858(3R)-3-[3-(aminocarbonyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoic acid

Product 1

HCID 9818682(R)-5-(6-cyclohexyl-1-(hydroxyamino)-1-oxohexan-3-yl)-1,2,4-oxadiazole-3-carboxamideYield 70.8%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of (3R)-3-[3-(aminocarbonyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoic acid (Preparation 6) (6.00 g, 19.42 mmol) in anhydrous tetrahydrofuran (200 ml) was cooled to 0° C. then treated with N-methylmorpholine (2.40 ml, 22.0 mmol) and isobutyl chloroformate (2.8 ml, 22.0 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (7.0 ml, 60.0 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 methanol (50 ml) and stirred for a further 30 minutes. This mixture was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was recrystallised from isopropyl acetate (500 ml) to afford the title compound as a white solid (4.46 g). Chiral HPLC analysis indicated this material to be 87.6% ee. A sample of this material (2.9 g) was dissolved in ethyl acetate (450 ml) at reflux then allowed to cool. The precipitate was filtered off and the solvent was removed from the filtrate under reduced pressure to afford a white solid, which was then recrystallised from isopropyl acetate (120 ml) to afford the title compound (1.42 g). Chiral HPLC analysis showed this material to be 98.3% ee.

Workup

  1. stirringthe mixture was stirred for 18 hours
  2. stirringstirred for a further 30 minutes
  3. customThis mixture was partitioned between ethyl acetate and water
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over anhydrous sodium sulphate
  6. filtrationfiltered
  7. customthe solvent removed under reduced pressure
  8. customThe solid was recrystallised from isopropyl acetate (500 ml)

Sources & evidence

ORD record
ord-aec34912a87946ca86f3a606c87de4fa
Source dataset
uspto-grants-2005_05
Patent number
US06897306B2

Reaction notes

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