3-(Trifluoromethyl)aniline → 1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid (3-trifluoromethyl-phenyl)-amide

HRID 907538Notes

Reaction equation

HRID 907538 reaction equation
[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[C:10]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]3)=[N:11][S:12][N:13]=2)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:56][C:57]([F:66])([F:65])[C:58]1[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=1>CCOC(C)=O.CN(C=O)C>[F:56][C:57]([F:65])([F:66])[C:58]1[CH:59]=[C:60]([NH:64][C:20]([CH:17]2[CH2:16][CH2:15][N:14]([C:10]3[C:9]([O:8][CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:13][S:12][N:11]=3)[CH2:19][CH2:18]2)=[O:22])[CH:61]=[CH:62][CH:63]=1

Participants

7

Reactant 4

HCID 73753-(Trifluoromethyl)anilineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 590139171-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid

Product 1

HCID 590137691-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid (3-trifluoromethyl-phenyl)-amideYield 25%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid (280 mg, 0.87 mmol), HATU (328 mg, 0.86 mmol), DMF (1.5 mL) and DIEA (0.5 mL, 3.87 mmol) were combined and vortexed until a homogeneous mixture was obtained. 3-Trifluoromethyl-phenylamine (0.109 mL, 0.87 mmol) was added and the resulting mixture stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3 (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (4:1 hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 100 mg (25%) of 1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylic acid (3-trifluoromethyl-phenyl)-amide as a white solid after lyophilization from H2O—AcCN. 1H NMR (CD3OD) 8.54 (d, 2H), 8.02 (s, 1H), 7.74 (d, 1H), 7.51-7.46 (m, 3H), 7.36 (d, 1H), 5.57 (s, 2H), 4.32 (m, 2H), 3.00 (m, 2H), 2.64 (m, 1H), 1.96-1.90 (m, 4H) ppm. LC-MS (MH+)=464.

Workup

  1. customwas obtained
  2. washwashed with sat'd NaHCO3 (3×), sat'd NaCl (1×)
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated in vacuo
  5. customThe crude product was purified by column chromatography (4:1 hexanes:EtOAc, followed by 1:1 hexanes:EtOAc)

Sources & evidence

ORD record
ord-72ec042a5b7b4b8c9f8788d007d9c122
Source dataset
uspto-grants-2011_09
Patent number
US08013156B2

Reaction notes

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