Diisopropylethylamine → 5-Bromo-N-((1RS,2SR)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide

HRID 598245Notes

Reaction equation

HRID 598245 reaction equation
[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:53][C@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]1[OH:60]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[OH:60])=[O:9]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 12228413(1R,2S)-2-aminocyclohexan-1-ol hydrochlorideHCID 863463205-Bromo-6-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)nicotinic acid

Product 1

HCID 866348035-Bromo-N-((1RS,2SR)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (94.0 g, 0.255 mol) in DMF (900 mL) was added with stirring TBTU (90.2 g, 0.28 mol), N,N-diisopropyl ethylamine (219 mL) and cis-2-aminocyclohexanol hydrochloride (42.6 g, 0.28 mol). The temperature rose to 35° C. After stirring was for 3 h the mixture was concentrated in high vacuo at 45° C. The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L). Organic phases were washed with water (2×1.5 L). The organic phases were combined, dried with MgSO4 and concentrated in vacuo to ˜800-900ml volume. The product precipitated and the mixture was stirred at 0° C. for about 30 min. Filtration, washing with ethyl acetate/n-heptane 1:1 (4×50 mL) and drying in vacuo at 40° C. for 18 h yielded the title compound (75.8 g as a white solid); MS (ISP) 465.0, 467.0 (M+H)+.

Workup

  1. customrose to 35° C
  2. concentrationthe mixture was concentrated in high vacuo at 45° C
  3. extractionThe residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L)
  4. washOrganic phases were washed with water (2×1.5 L)
  5. dry with materialdried with MgSO4
  6. concentrationconcentrated in vacuo to ˜800-900ml volume
  7. customThe product precipitated
  8. stirringthe mixture was stirred at 0° C. for about 30 min
  9. filtrationFiltration
  10. washwashing with ethyl acetate/n-heptane 1:1 (4×50 mL)
  11. customdrying in vacuo at 40° C. for 18 h

Sources & evidence

ORD record
ord-6cc3c6cca9fb458bb1dc12bfe17dd79c
Source dataset
uspto-grants-2011_03
Patent number
US07897621B2

Reaction notes

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