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

HRID 58487Notes

Reaction equation

HRID 58487 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=O)=[N:10][N:11]=2)[CH:8]=1.Cl.Cl.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:22]=[C:23]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=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>[F:38][C:20]([F:19])([F:37])[C:21]1[CH:22]=[C:23]([CH:31]2[CH2:36][CH2:35][N:34]([C:12]([C:9]3[N:7]4[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]4=[N:11][N:10]=3)=[O:14])[CH2:33][CH2:32]2)[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 450739294-(3,5-Bis(trifluoromethyl)phenyl)piperidine HydrochlorideHCID 118483439Ethyl 6-methoxy-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate

Product 1

HCID 118483520(4-(3,5-Bis(trifluoromethyl)phenyl)piperidin-1-yl)(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl) methanoneYield 56.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of ethyl 6-methoxy-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (66 mg, 0.30 mmol) in THF (2.5 mL) was added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (1.6 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 (3.3 mL) under an atmosphere of N2. To this mixture was added 4-(3,5-bis(trifluoromethyl)phenyl)piperidine hydrochloride (20, 100 mg, 0.30 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (266 mg, 0.60 mmol), and diisopropylethylamine (0.16 mL, 0.90 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were washed with a saturated brine solution (3×30 ml) and concentrated under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 24 g Redisep column, 0% to 2% MeOH in CH2Cl2 with 0.1% NH4OH in CH2Cl2). The obtained residue was dissolved in CH2Cl2 (10 mL) and hexanes (100 mL). The solution was partially concentrated and the resulting solids were collected by filtration to provide (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl) methanone as an off-white solid (80 mg, 56%): mp 146-149° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=2.0 Hz, 1H), 8.03 (s, 2H), 7.95-7.89 (m, 2H), 7.38 (dd, J=10, 2.5 Hz, 1H), 5.40-5.33 (m, 1H), 4.81-4.73 (m, 1H), 3.85 (s, 3H), 3.39-3.31 (m, 1H, overlaps with H2O), 3.26-3.16 (m, 1H), 3.02-2.93 (m, 1H), 2.03-1.77 (m, 4H); ESI MS m/z 473 [M+H]+.

Workup

  1. concentrationThe mixture was concentrated under reduced pressure
  2. additionThe obtained residue was diluted in DMF (3.3 mL) under an atmosphere of N2
  3. stirringThe mixture was stirred at ambient temperature for 18 h
  4. extractionextracted with EtOAc (4×30 mL)
  5. washThe combined organic extracts were washed with a saturated brine solution (3×30 ml)
  6. concentrationconcentrated under reduced pressure
  7. customThe obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 24 g Redisep column, 0% to 2% MeOH in CH2Cl2 with 0.1% NH4OH in CH2Cl2)
  8. dissolutionThe obtained residue was dissolved in CH2Cl2 (10 mL)
  9. concentrationThe solution was partially concentrated
  10. filtrationthe resulting solids were collected by filtration

Sources & evidence

ORD record
ord-04dd500d3ff84e3cac4d52ce5d9af78a
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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