Hydrochloric Acid → 1-{2-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-3,3,3-trifluoro-propyl}-3-(3-trifluoromethyl-phenyl)-piperidine hydrochloride

HRID 1051395Notes

Reaction equation

HRID 1051395 reaction equation
[F:1][C:2]([F:26])([F:25])[CH:3]([CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:10]1)[CH2:4][C:5](O)=O.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl>CCOCC.CCCCCC.O1CCOCC1>[ClH:27].[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]2[O:33][C:5]([CH2:4][CH:3]([C:2]([F:26])([F:1])[F:25])[CH2:8][N:9]3[CH2:14][CH2:13][CH2:12][CH:11]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=4)[CH2:10]3)=[N:35][N:34]=2)=[CH:30][CH:29]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 108164-ChlorobenzohydrazideHCID 24813Phosphorus oxychlorideHCID 901035704,4,4-Trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanoic acid

Product 1

HCID 752021581-{2-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-3,3,3-trifluoro-propyl}-3-(3-trifluoromethyl-phenyl)-piperidine hydrochlorideYield 111%

Reagents, catalysts & solvents 2

HCID 312751,4-DioxaneSolventHCID 21584099Diethylether hexaneSolvent

Conditions

Temperature
110 °C

Procedure

To a round-bottomed flask (5 ml) was added 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)-piperidin-1-yl)methyl)butanoic acid (50 mg, 130 μmol), 4-chlorobenzohydrazide (22.3 mg, 130 μmol,) and POCl3 (1.64 g, 1 mL, 10.7 mmol). The reaction mixture was heated to reflux at 110° C. for 4 hr. The crude reaction mixture was allowed to cool to room temperature, poured into ice/water and made basic with a saturated solution of Na2CO3. The reaction mixture was extracted with ethyl acetate, washed with brine and H2O, dried over MgSO4, filtered and concentrated. The resultant residue was purified on a silica column (100% CH2Cl2 to 40% ethyl acetate/CH2Cl2 eluent) to give an oil. The oil was dissolved in ether/hexane, treated with 4N HCl in dioxane (0.2 ml) and concentrated to afford 40 mg (56%) of 1-{2-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-3,3,3-trifluoro-propyl}-3-(3-trifluoromethyl-phenyl)-piperidine hydrochloride as a white solid. MH+=518.

Workup

  1. temperatureThe reaction mixture was heated
  2. customThe crude reaction mixture
  3. temperatureto cool to room temperature
  4. extractionThe reaction mixture was extracted with ethyl acetate
  5. washwashed with brine and H2O
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe resultant residue was purified on a silica column (100% CH2Cl2 to 40% ethyl acetate/CH2Cl2 eluent)
  10. customto give an oil
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-b7ae0766c3144eceb6defe0d54165a9a
Source dataset
uspto-grants-2016_07
Patent number
US09388172B2

Reaction notes

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