4-Methylmorpholine → (3R)-6-Cyclohexyl-N-hydroxy-3-(3-{[3-(4-morpholinyl)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanamide

HRID 2182919Notes

Reaction equation

HRID 2182919 reaction equation
FC(F)(F)C(O)=O.[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([C:27]([N:29]3[CH2:32][CH:31]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:30]3)=[O:28])[N:23]=2)[CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:55][OH:56]>CN(C)C=O>[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([C:27]([N:29]3[CH2:32][CH:31]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[CH2:30]3)=[O:28])[N:23]=2)[CH2:18][C:19]([NH:55][OH:56])=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1

Participants

6

Reactant 4

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 443297Hydroxyamine hydrochlorideHCID 69778494(3R)-6-cyclohexyl-3-(3-{[3-(4-morpholinyl)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid trifluoroacetate

Product 1

HCID 10114766(3R)-6-Cyclohexyl-N-hydroxy-3-(3-{[3-(4-morpholinyl)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanamideYield 12.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

A solution of (3R)-6-cyclohexyl-3-(3-{[3-(4-morpholinyl)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid trifluoroacetate (Preparation 28) (1173 mg, 2.70 mmol) and N-methylmorpholine (327 μl, 2.97 mmol) in N,N-dimethylformamide (25 ml) was cooled to 0° C., treated dropwise with isobutyl chloroformate (386 μl, 2.97 mmol) and stirred under a nitrogen atmosphere at 0° C. for 45 minutes. Hydroxylamine hydrochloride (564 mg, 8.11 mmol) was then added followed by further N-methylmorpholine (891 μl, 8.11 mmol) and the mixture was stirred for 18 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue dissolved in a saturated aqueous solution of sodium carbonate. The pH of the solution was adjusted to 9 by dropwise addition of acetic acid. Water was added (75 ml) and the product was then extracted with ethyl acetate (×2). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:0.88 ammonia (90:10:1) then dichloromethane:methanol:0.88 ammonia (80:20:2). The product was further purified by HPLC to afford the title compound as a white solid (151 mg)

Workup

  1. stirringthe mixture was stirred for 18 hours
  2. temperatureto warm to room temperature over this time
  3. customThe solvent was removed under reduced pressure
  4. dissolutionthe residue dissolved in a saturated aqueous solution of sodium carbonate
  5. additionThe pH of the solution was adjusted to 9 by dropwise addition of acetic acid
  6. additionWater was added (75 ml)
  7. extractionthe product was then extracted with ethyl acetate (×2)
  8. washThe combined organic phases were washed with brine
  9. dry with materialdried over anhydrous sodium sulphate
  10. filtrationfiltered
  11. customthe solvent removed under reduced pressure
  12. customThe residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane
  13. customThe product was further purified by HPLC

Sources & evidence

ORD record
ord-662806a1399c477195606cfc48449e2e
Source dataset
uspto-grants-2005_05
Patent number
US06897306B2

Reaction notes

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