Hydrochloric Acid → HCID 118483535, compound

HRID 58502Notes

Reaction equation

HRID 58502 reaction equation
[Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][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:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=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 118483532Tert-butyl 4-(3-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate

Product 1

HCID 118483535HCID 118483535, compoundYield 49.3%

Reagents, catalysts & solvents 4

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

Procedure

To a solution of tert-butyl 4-(3-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.115 g, 0.316 mmol) in dichloromethane (3 mL) was added HCl (2 M in ether, 3 mL). The mixture was stirred for 3 h and evaporated to afford a solid that was dissolved in DMF (3 mL). In a separate flask, to a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.094 g, 0.348 mmol) in THF (3 mL) was added a solution of lithium hydroxide hydrate (0.015 g, 0.348 mmol) in water (1 mL). The mixture was stirred for 20 min, acidified with 2 N HCl to PH 6 and evaporated. To the residue were added benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexa-fluorophosphate (0.210 g, 0.474 mmol), N,N-diisopropylethylamine (0.163 g, 1.26 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-chloro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a solid (0.076 g, 49%): 1H NMR (300 MHz, CDCl3) δ9.36 (m, 1H), 7.78 (dd, J=9.6, 0.9 Hz, 1H), 7.50-7.34 (m, 4H), 5.73-5.68 (m, 1H), 5.00-4.94 (m, 1H), 3.52-3.28 (m, 2H), 2.97 (m, 1H), 2.01-1.74 (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
  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-3e3220b4e07242458fcae55ddaf51ce7
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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