Diisopropylethylamine → (2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

HRID 1411341Notes

Reaction equation

HRID 1411341 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].C(N(CC)C(C)C)(C)C.OC(C(F)(F)F)=O.[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]([CH3:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([C:50](O)=[O:51])=[CH:46][N:45]=2)[CH2:39][C@@H:38]1[CH3:53])=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C>[C:30]([O:34][C:35]([N:37]1[CH2:42][C@@H:41]([CH3:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([C:50](=[O:51])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][C:10]([F:12])([F:11])[F:13])[CH:4]=3)=[CH:46][N:45]=2)[CH2:39][C@@H:38]1[CH3:53])=[O:36])([CH3:31])([CH3:32])[CH3:33]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 141291984-Bromo-3-(trifluoromethoxy)anilineHCID 42624899O-(6-Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphateHCID 131732217(2S,5R)-4-(5-carboxy-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester TFA

Product 1

HCID 67495662(2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl esterYield 36.5%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent2×

Conditions

Temperature
50 °C

Procedure

To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (190 mg, 0.74 mmol) and N,N-diisopropylethylamine (0.65 mL, 3.73 mmol; in N,N-dimethylacetamide (3 mL) was added a solution of (2S,5R)-4-(5-carboxy-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester TFA (330 mg, 0.74 mmol; Preparation 26) and HCTU (401 mg, 0.97 mmol) in N,N-dimethylacetamide (3 mL). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated by rotary evaporation, extracted with ethyl acetate/sat. sodium carbonate, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (0-50% ethyl acetate:hexanes) to provide the title compound (155 mg, yield 36%). (m/z): [M+H]+ calcd for C24H28BrF3N4O4 573.12, 575.12 found 575.5.

Workup

  1. concentrationThe reaction mixture was concentrated by rotary evaporation
  2. extractionextracted with ethyl acetate/
  3. dry with materialsodium carbonate, dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. custompurified by silica gel chromatography (0-50% ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-ac64829146ea4fe4b7f864a3d910d66c
Source dataset
uspto-grants-2014_12
Patent number
US08921372B2

Reaction notes

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