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

Temperature

80 °C

A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (527 mg, 1.56 mmol) in ethanol (20 ml) was treated with triethylamine (508 mg, 5.02 mmol) and glycine t-butyl ester hydrochloride (743 mg, 4.43 mmol) and the resulting solution was heated at 80° C. under a nitrogen atmosphere for 30 hours. The solvent was removed under reduced pressure and the residue was dissolved in hydrochloric acid (1M, 20 ml) then extracted with ethyl acetate (×2). The combined organic layers were 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 dichloromethane: ethyl acetate (1:1) then dichloromethane: methanol (19:1). This residue (430 mg, 1.02 mmol) was dissolved in dichloromethane (10 ml), cooled to 0° C. and treated sequentially with N-methylmorpholine (130 μl, 1.20 mmol) and isobutyl chloroformate (150 μl, 1.20 mmol). This mixture was stirred at 0° C. under a nitrogen atmosphere for 1 hour, then treated with O-(trimethylsilyl)hydroxylamine (160 μl, 1.30 mmol). The mixture was stirred for 17 hours being allowed to warm to room temperature over this time. The mixture was diluted with dichloromethane, washed with aqueous citric acid solution (10% w/v), dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane (10 ml), treated with trifluoroacetic acid (10 ml) and the solution was stirred for 2.5 hours at room temperature. The solvent was removed under reduced pressure and the residue azeotroped from toluene (×2). The residue was purified by HPLCb to afford the title compound as a white solid (350 mg).

1. customThe solvent was removed under reduced pressure
2. dissolutionthe residue was dissolved in hydrochloric acid (1M, 20 ml)
3. extractionthen extracted with ethyl acetate (×2)
4. dry with materialThe combined organic layers were dried over anhydrous sodium sulphate
5. filtrationfiltered
6. customthe solvent removed under reduced pressure
7. customThe residue was purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate (1:1)
8. temperaturecooled to 0° C.
9. stirringThe mixture was stirred for 17 hours
10. temperatureto warm to room temperature over this time
11. washwashed with aqueous citric acid solution (10% w/v)
12. dry with materialdried over anhydrous magnesium sulphate
13. filtrationfiltered
14. customthe solvent removed under reduced pressure
15. dissolutionThe residue was dissolved in dichloromethane (10 ml)
16. additiontreated with trifluoroacetic acid (10 ml)
17. stirringthe solution was stirred for 2.5 hours at room temperature
18. customThe solvent was removed under reduced pressure
19. customthe residue azeotroped from toluene (×2)
20. customThe residue was purified by HPLCb

ORD record

ord-4b28d782586e4cd49707039bf86db546

Source dataset

uspto-grants-2002_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06448278B2