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

HRID 1279771Notes

Reaction equation

HRID 1279771 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][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].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:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[O:26][CH3:25])=[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 812922-MethoxybenzylamineHCID 2734666O-(Trimethylsilyl)hydroxylamineHCID 59909750(3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid

Product 1

HCID 102254805-{(1R)-4-Cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-N-(2-methoxybenzyl)-1,2,4-oxadiazole-3-carboxamideYield 21.4%

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 2-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 anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. This residue (672 mg) was then dissolved in dichloromethane (15 ml), cooled to 0° C. and treated sequentially with N-methylmorpholine (180 μl, 1.64 mmol) and isobutyl chloroformate (210 g, 1.63 mmol). This mixture was stirred at 0° C. under a nitrogen atmosphere for 1 hour, then treated with O-(trimethylsilyl)hydroxylamine (220 μl, 1.80 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 (5 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 (140 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 anhydrous magnesium sulphate
  5. filtrationfiltered
  6. customthe solvent removed under reduced pressure
  7. dissolutionThis residue (672 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-810a1855391649868a7c52f56efcdfef
Source dataset
uspto-grants-2002_09
Patent number
US06448278B2

Reaction notes

Loading…