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

HRID 58481Notes

Reaction equation

HRID 58481 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.Cl.Cl.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:31]([F:34])([F:33])[F:32])=[C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1.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(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:28]3[CH2:29][CH2:30][CH:25]([C:23]4[CH:24]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=4[C:31]([F:34])([F:32])[F:33])[CH2:26][CH2:27]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 65349616Ethyl 6-bromo-(1,2,4)triazolo(4,3-a)pyridine-3-carboxylateHCID 1184833134-(5-Fluoro-2-(trifluoromethyl)phenyl)piperidine Hydrochloride

Product 1

HCID 118483463(6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanoneYield 65%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (85 mg, 0.32 mmol) in THF (2.6 mL) was added a solution of LiOH monohydrate (15 mg, 0.35 mmol) in H2O (1.8 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (3.0 mL) under an atmosphere of N2. To this mixture was added 4-(5-fluoro-2-trifluoromethyl)phenylpiperidine hydrochloride (11, 89 mg, 0.32 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (280 mg, 0.63 mmol), and diisopropylethylamine (0.17 mL, 0.95 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL). The solution was extracted with EtOAc (3×20 mL). The combined organic layers were washed with a saturated brine solution (3×20 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) to provide to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (97 mg, 65%): 1H NMR (500 MHz, DMSO-d6) δ 9.16-9.14 (m, 1H), 7.98 (dd, J=10.0, 1.0 Hz, 1H), 7.77 (dd, J=8.5, 5.5 Hz, 1H), 7.72 (dd, J=9.5, 1.5 Hz, 1H), 7.52 (dd, J=11.0, 3.5 Hz, 1H), 7.29-7.23 (m, 1H), 5.31-5.24 (m, 1H), 4.76-4.70 (m, 1H), 3.42-3.32 (m, 1H), 3.27-3.19 (m, 1H), 3.06-2.96 (m, 1H), 1.98-1.75 (m, 4H).

Workup

  1. concentrationThe mixture was concentrated under reduced pressure
  2. additionThe obtained residue was diluted in DMF (3.0 mL) under an atmosphere of N2
  3. stirringThe mixture was stirred at ambient temperature for 18 h
  4. extractionThe solution was extracted with EtOAc (3×20 mL)
  5. washThe combined organic layers were washed with a saturated brine solution (3×20 mL)
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes)
  8. customto provide

Sources & evidence

ORD record
ord-caff4e4cd53d42a28c1b7b19c2aae09f
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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