Triethylamine → CarbaMic acid, N-[(1R)-1-[3-[6-(trifluoroMethyl)-1H-benziMidazol-2-yl]-5-isoxazolyl]ethyl]-, 1,1-diMethylethyl ester

HRID 2403144Notes

Reaction equation

HRID 2403144 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[O:15][N:14]=[C:13]([C:16](O)=O)[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC(C)C)=O.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:37]=[C:38]([NH2:43])[C:39]([NH2:42])=[CH:40][CH:41]=1>C1COCC1.O>[F:34][C:35]([F:44])([F:45])[C:36]1[CH:41]=[CH:40][C:39]2[N:42]=[C:16]([C:13]3[CH:12]=[C:11]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[O:15][N:14]=3)[NH:43][C:38]=2[CH:37]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 62365Isobutyl chloroformateHCID 5208224-Trifluoromethyl-1,2-phenylenediamineHCID 573555205-{(1R)-1-[(tert-Butoxycarbonyl)amino]ethyl}-1,2-oxazole-3-carboxylic acid

Product 1

HCID 136088227CarbaMic acid, N-[(1R)-1-[3-[6-(trifluoroMethyl)-1H-benziMidazol-2-yl]-5-isoxazolyl]ethyl]-, 1,1-diMethylethyl esterYield 88.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of (R)-5-(1-(tert-butoxycarbonylamino)ethyl)-isoxazole-3-carboxylic acid (55 g, 0.215 mol) and Et3N (36 mL, 0.26 mol) in THF (2 L) was added dropwise isobutyl chloroformate (33 mL, 0.26 mol) at −20° C. The reaction mixture was stirred for 1 hr, and a solution of 4-(trifluoromethyl)benzene-1,2-diamine (45.4 g, 0.26 mol) in THF was added. After stifling for 2 h at −20° C., the mixture was allowed to warm up to RT and stirred for another 2 hr. Water was added to quench the reaction and the reaction mixture was evaporated under reduced pressure to remove THF. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The residue was re-dissolved in acetic acid (250 mL) and stirred for 2 hr at 90° C. The solution was concentrated under vacuum and partitioned with ethyl acetate and water. The organic layer was separated, washed with water, Na2CO3 solution and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography to afford compound N.7, (R)-tert-butyl 1-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)isoxazol-5-yl)ethylcarbamate (75.7 g, 88.8%). 1H NMR (DMSO-d6) δ7.8 (m, 4H), 6.9 (s, 1H), 4.91 (m, 1H), 1.46 (d, 3H), 1.39 (s, 9H).

Workup

  1. waitAfter stifling for 2 h at −20° C.
  2. stirringstirred for another 2 hr
  3. customto quench
  4. customthe reaction
  5. customthe reaction mixture was evaporated under reduced pressure
  6. customto remove THF
  7. extractionThe aqueous layer was extracted with ethyl acetate (2×)
  8. washThe combined organic layers were washed with water
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. dissolutionThe residue was re-dissolved in acetic acid (250 mL)
  13. stirringstirred for 2 hr at 90° C
  14. concentrationThe solution was concentrated under vacuum
  15. custompartitioned with ethyl acetate and water
  16. customThe organic layer was separated
  17. washwashed with water, Na2CO3 solution and brine
  18. dry with materialdried over Na2SO4
  19. filtrationfiltered
  20. concentrationconcentrated
  21. customThe crude product was purified by column chromatography

Sources & evidence

ORD record
ord-6d3eabe6d4cf4dd1b4ab3ad30bf0f218
Source dataset
uspto-grants-2014_08
Patent number
US08802657B2

Reaction notes

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