Tris(hydroxymethyl)aminomethane → N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide

HRID 907576Notes

Reaction equation

HRID 907576 reaction equation
FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]2[C:17]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1.C(O)C(N)(CO)CO.C(N(CC)CC)C.[F:43][C:44]([F:59])([F:58])[C:45]1[CH:46]=[C:47]([N:55]=[C:56]=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>O1CCCC1>[F:43][C:44]([F:58])([F:59])[C:45]1[CH:46]=[C:47]([NH:55][C:56]([N:25]2[CH2:26][CH2:27][N:22]([C:17]3[C:16]([O:15][CH2:14][C:11]4[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=4)=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:23][CH2:24]2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:52])[F:53])[CH:50]=1

Participants

6

Reactant 4

HCID 6503Tris(hydroxymethyl)aminomethaneHCID 8471TriethylamineHCID 27333143,5-Bis(trifluoromethyl)phenyl isocyanateHCID 67388278HCID 67388278, compound

Product 1

HCID 10436864N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamideYield 3.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

The crude 1-[3-(Pyridin-4-ylmethoxy)pyridin-2-yl]-piperazine trifluoroacetic acid salt (˜500 mg) was dissolved in 25 mL of tetrahydrofuran along with 2 g of trisamine resin. The suspension was stirred for 1 hr and the resin was removed by filtration. The filtrate was concentrated under vacuum. The free-based material was dissolved in 5 mL of dichloromethane. To this solution was added triethylamine (150 μL, 1.08 mmol) and 3,5-bis(trifluoromethyl)phenyl isocyanate (150 μL, 0.864 mmol). The reaction was stirred at room temperature for 1 hr. The reaction mixture was concentrated under vacuum and re-dissolved in 25 mL ethyl acetate. The reaction mixture was washed 3 times each with 25 mL portions of water, 0.05 M HCl and saturated aqueous sodium chloride. The organic fraction was dried with magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography with a gradient of 0% to 10% methanol in ethyl acetate with 5% triethylamine, giving N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide (14 mg). 1H NMR (DMSO-d6) δ 9.24 (s, 1H), 8.60 (d, 2H), 8.22 (s, 2H), 7.84 (d, 1H), 7.58 (s, 1H), 7.46 (d, 2H), 7.33 (d, 1H), 6.92 (dd, 1H), 5.23 (s, 2H), 3.62-3.68 (m, 4H) 3.37-3.41 (m, 4H) ppm.

Workup

  1. customthe resin was removed by filtration
  2. concentrationThe filtrate was concentrated under vacuum
  3. dissolutionThe free-based material was dissolved in 5 mL of dichloromethane
  4. stirringThe reaction was stirred at room temperature for 1 hr
  5. concentrationThe reaction mixture was concentrated under vacuum
  6. dissolutionre-dissolved in 25 mL ethyl acetate
  7. washThe reaction mixture was washed 3 times each with 25 mL portions of water, 0.05 M HCl and saturated aqueous sodium chloride
  8. dry with materialThe organic fraction was dried with magnesium sulfate
  9. concentrationconcentrated under vacuum
  10. customThe residue was purified by flash chromatography with a gradient of 0% to 10% methanol in ethyl acetate with 5% triethylamine

Sources & evidence

ORD record
ord-3fadfb3224ef408e9ee3bfac53de5168
Source dataset
uspto-grants-2011_09
Patent number
US08013156B2

Reaction notes

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