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

HRID 58483Notes

Reaction equation

HRID 58483 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.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]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:29]3[CH2:28][CH2:27][CH:26]([C:20]4[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=4[Cl:18])[CH2:31][CH2:30]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 1184835134-(2-Chloro-5-fluorophenyl)piperidine Hydrochloride

Product 1

HCID 118483329(6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-5-fluorophenyl) piperidin-1-yl)methanoneYield 42.3%

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 (73 mg, 0.27 mmol) in THF (2.2 mL) was added a solution of LiOH monohydrate (13 mg, 0.30 mmol) in H2O (1.5 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 (2.9 mL) under an atmosphere of N2. To this mixture was added 4-(2-chloro-5-fluorophenyl)piperidine hydrochloride (17, 68 mg, 0.27 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (240 mg, 0.54 mmol), and diisopropylethylamine (0.14 mL, 0.81 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-5-fluorophenyl) piperidin-1-yl)methanone as a white solid (50 mg, 42%): 1H NMR (500 MHz, DMSO-d6) δ 9.13-9.11 (m, 1H), 7.98 (dd, J=9.5, 1.0 Hz, 1H), 7.71 (dd, J=9.5, 1.5 Hz, 1H), 7.50 (dd, J=9.0, 5.5 Hz, 1H), 7.28 (dd, J=25, 3.0 Hz, 1H), 7.15-7.10 (m, 1H), 5.28-5.20 (m, 1H), 4.76-4.70 (m, 1H), 3.42-3.29 (m, 2H, overlaps with H2O), 3.07-2.98 (m, 1H), 1.96-1.65 (m, 4H).

Workup

  1. concentrationThe mixture was concentrated under reduced pressure
  2. additionThe obtained residue was diluted in DMF (2.9 mL) under an atmosphere of N2
  3. stirringThe mixture was stirred at ambient temperature for 18 h
  4. filtrationthe resulting precipitate was collected by filtration
  5. customThe obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-7a67f86abea04b3fa93fb8f36e40cf65
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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