Trifluoroacetic acid → 5-{(1R)-4-Cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-N-(4-methoxybenzyl)-1,2,4-oxadiazole-3-carboxamide

HRID 1279772Notes

Reaction equation

HRID 1279772 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]([O:22]CC)=O)[N:16]=2)[CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:52][NH2:53].FC(F)(F)C(O)=O>C(O)C.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:32][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[O:22])[N:16]=2)[CH2:11][C:12]([NH:53][OH:52])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

9

Reactant 6

HCID 6422Trifluoroacetic acidHCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 754524-MethoxybenzylamineHCID 2734666O-(Trimethylsilyl)hydroxylamineHCID 59909750(3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid

Product 1

HCID 101607195-{(1R)-4-Cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-N-(4-methoxybenzyl)-1,2,4-oxadiazole-3-carboxamideYield 11.3%

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent2×HCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (500 mg, 1.47 mmol) in ethanol (13 ml) was treated with a solution of 4-methoxybenzylamine (1.00 g, 7.35 mmol) in ethanol (2 ml) and the resulting solution was heated at 80° C. under a nitrogen atmosphere for 10 hours. The solvent was removed under reduced pressure and the residue was dissolved in hydrochloric acid (1M, 10 ml) then extracted with ethyl acetate (×2). The combined organic layers were dried over an hydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. This residue (578 mg) was then dissolved in dichloromethane (15 ml), cooled to 0° C. and treated sequentially with N-methylmorpholine (160 μl, 1.45 mmol) and isobutyl chioroformate (190 μl, 1.47 mmol). This mixture was stirred at 0° under a nitrogen atmosphere for 1 hour, then treated with O-(trimethylsilyl)hydroxylamine (195 μl, 1.60 mmol) and stirring continued for 10 minutes at 0° then for 17 hours at room temperature. The mixture was then treated with trifluoroacetic acid:water (ml, 9:1) and the solution stirred for 30 minutes. The solvent was removed under reduced pressure and the residue azeotroped from toluene (×2). The residue was purified by HPLCa to afford the title compound as a foam (74 mg).

Workup

  1. customThe solvent was removed under reduced pressure
  2. dissolutionthe residue was dissolved in hydrochloric acid (1M, 10 ml)
  3. extractionthen extracted with ethyl acetate (×2)
  4. dry with materialThe combined organic layers were dried over an hydrous magnesium sulphate
  5. filtrationfiltered
  6. customthe solvent removed under reduced pressure
  7. dissolutionThis residue (578 mg) was then dissolved in dichloromethane (15 ml)
  8. temperaturecooled to 0° C.
  9. stirringstirring
  10. waitcontinued for 10 minutes at 0°
  11. waitfor 17 hours at room temperature
  12. customThe solvent was removed under reduced pressure
  13. customthe residue azeotroped from toluene (×2)
  14. customThe residue was purified by HPLCa

Sources & evidence

ORD record
ord-0481f01a549a4e94bc37fc9689381f11
Source dataset
uspto-grants-2002_09
Patent number
US06448278B2

Reaction notes

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