Hydrochloric Acid → (6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-chloro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

HRID 58498Notes

Reaction equation

HRID 58498 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.Cl.[Br:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:33](C(OCC)=O)=[N:34][N:35]=2)[CH:32]=1.O.[OH-].[Li+].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C.C1COCC1.O>[Br:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:33]([C:14]([N:11]3[CH2:10][CH2:9][CH:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:21]([F:23])([F:24])[F:22])[CH2:13][CH2:12]3)=[O:15])=[N:34][N:35]=2)[CH:32]=1

Participants

11

Reactant 6

HCID 313Hydrochloric Acid2×HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 168937Lithium hydroxide, monohydrateHCID 65349616Ethyl 6-bromo-(1,2,4)triazolo(4,3-a)pyridine-3-carboxylateHCID 118483325Tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate

Product 1

HCID 118483453(6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-chloro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneYield 50.6%

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.302 g, 0.830 mmol) in dichloromethane (5 mL) was added HCl solution (2 M in ether, 5 mL). The mixture was stirred for 4 h and evaporated to afford a solid that was dissolved in DMF (8 mL). In a separate flask, to a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.224 g, 0.830 mmol) in THF (5 mL) was added a solution of lithium hydroxide hydrate (0.035 g, 0.830 mmol) in water (2 mL). The mixture was stirred for 20 min, acidified with 2 N HCl to PH 6 and evaporated to dryness. To this residue were added benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (0.550 g, 1.25 mmol), N,N-diisopropylethylamine (0.646 g, 5.00 mmol), and the DMF solution obtained from the first reaction. The mixture was stirred at ambient temperature for 16 h and poured into water. The mixture was extracted with ethyl acetate and the organic layer was washed with brine for three times, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-60% EtOAc in hexanes) to give (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-chloro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a solid (0.205 g, 50%): 1H NMR (300 MHz, CDCl3) δ9.38 (m, 1H), 7.79 (dd, J=9.6, 0.9 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.50 (dd, J=9.6, 1.7 Hz, 1H), 7.42 (d, J=1.4 Hz, 1H), 7.31 (dd, J=8.5, 1.3 Hz, 1H), 5.76-5.71 (m, 1H), 5.01-4.95 (m, 1H), 3.38-3.26 (m, 2H), 3.02-2.92 (m, 1H), 2.01-1.82 (m, 4H); MS (ESI+) m/z 489 [M+H]+.

Workup

  1. customevaporated
  2. customto afford a solid
  3. stirringThe mixture was stirred for 20 min
  4. customevaporated to dryness
  5. stirringThe mixture was stirred at ambient temperature for 16 h
  6. extractionThe mixture was extracted with ethyl acetate
  7. washthe organic layer was washed with brine for three times
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe resulting residue was chromatographed over silica gel (0-60% EtOAc in hexanes)

Sources & evidence

ORD record
ord-cfba3fb9a4d743aba78784d7f62ed585
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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