Citric Acid → 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide

HRID 416468Notes

Reaction equation

HRID 416468 reaction equation
[Br:1][C:2]1[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:5]([C:15](O)=[O:16])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.ClC(N(C)C)=C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37].C(N(C(C)C)C(C)C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(OCC)(=O)C>[OH:37][C@@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:15]([C:5]1[C:4]([C:18]([F:20])([F:21])[F:19])=[N:3][C:2]([Br:1])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1)=[O:16]

Participants

8

Reactant 5

HCID 311Citric AcidHCID 81531DiisopropylethylamineHCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 735777(1R,2R)-2-AminocyclohexanolHCID 462210845-Bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid

Product 1

HCID 462210855-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amideYield 82.9%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a yellow suspension of 1.50 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid in 11 ml dichloromethane was added drop wise 0.608 g 1-chloro-N,N, 2-trimethylpropenylamine and the resulting the yellow solution was stirred at room temperature for 30 min. The resulting orange solution was added dropwise to a cooled (ice bath) solution of 0.522 g (1R,2R)-2-amino-cyclohexanol and 0.7868 g ethyldiisopropylamine in 10 ml ethyl acetate. This red solution was stirred at room temperature for 90 min. To the red solution was added 30 ml 10% aqueous citric acid solution. The layers were separated and the organic layer was purified by chromatography on silica gel with a gradient of heptane: ethyl acetate=1:1 to ethyl acetate to yield 1.56 g of the title compound as yellow crystals. MS (M−H) at 479.0 and 476.0.

Workup

  1. additionThe resulting orange solution was added dropwise to
  2. stirringThis red solution was stirred at room temperature for 90 min
  3. customThe layers were separated
  4. customthe organic layer was purified by chromatography on silica gel with a gradient of heptane

Sources & evidence

ORD record
ord-ac4c025389014761ae8146eccb6d4fd4
Source dataset
uspto-grants-2012_01
Patent number
US08088920B2

Reaction notes

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