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

HRID 58479Notes

Reaction equation

HRID 58479 reaction equation
[F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34](C(OCC)=O)=[N:35][N:36]=2)[CH:33]=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:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34]([C:15]([N:12]3[CH2:11][CH2:10][CH:9]([C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[C:3]=4[C:22]([F:24])([F:25])[F:23])[CH2:14][CH2:13]3)=[O:16])=[N:35][N:36]=2)[CH:33]=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 118483534Tert-butyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate

Product 1

HCID 118483396(6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl) methanoneYield 34.8%

Reagents, catalysts & solvents 4

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

Procedure

To a solution of tert-butyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.246 g, 0.675 mmol) in dichloromethane (5 mL) was added HCl (2 M in ether, 10 mL). The mixture was stirred for 6 h and evaporated to afford a solid that was dissolved in DMF (4 mL). In a separate flask, to a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.182 g, 0.675 mmol) in THF (5 mL) was added a solution of lithium hydroxide hydrate (0.028 g, 0.675 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 (0.448 g, 1.01 mmol), N,N-diisopropylethylamine (0.349 g, 2.70 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 (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-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as an off-white solid (0.115 g, 34%): 1H NMR (300 MHz, CDCl3) δ9.37 (m, 1H), 7.79 (dd, J=9.6, 0.9 Hz, 1H), 7.50 (dd, J=9.6, 1.7 Hz, 1H), 6.96 (d, J=9.7 Hz, 1H), 6.84-6.77 (m, 1H), 5.77-5.72 (m, 1H), 5.00-4.95 (m, 1H), 3.44-3.29 (m, 2H), 3.01-2.92 (m, 1H), 2.01-1.69 (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 (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-5d1659e012144c89a9101a85a55a3f64
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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