Tetrahydrofuran → (4-Hydroxy-4-trifluoromethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone

HRID 572285Notes

Reaction equation

HRID 572285 reaction equation
[CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[OH:19][C:20]1([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[OH:19][C:20]1([C:26]([F:29])([F:27])[F:28])[CH2:25][CH2:24][N:23]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:22][CH2:21]1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 8082PiperidineHCID 179513214-(Trifluoromethyl)-4-piperidinolHCID 252109975-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid

Product 1

HCID 25211283(4-Hydroxy-4-trifluoromethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanoneYield 49%

Reagents, catalysts & solvents 1

HCID 8471TriethylamineSolvent

Procedure

Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-hydroxy-4-trifluoromethyl-piperidine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperidine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried and then chromatographed on silica gel with EtOAc/hexanes (50%) as eluant to afford product as a colorless solid (53 mg, 49%). 1H NMR (DMSO-d6) 1.70-1.72 (m, 4H), 2.34 (d, J=1.8, 3H), 3.24 (br, 2H), 4.19 (br, 2H), 6.17 (s, 1H), 7.56 (d, J=4.0, 1H), 7.65 (d, J=4.0, 1H). 19F NMR −83.5, −63.1. LC/MS 6.40 min, [M+1]+ 429.

Workup

  1. customThe reaction mixture was evaporated to a solid
  2. customtriturated
  3. filtrationfiltered with the aid of water
  4. washwashed with a 1 N aqueous hydrochloric acid solution
  5. customdried
  6. customchromatographed on silica gel with EtOAc/hexanes (50%) as eluant

Sources & evidence

ORD record
ord-258459740c454863837eba4ec964233a
Source dataset
uspto-grants-2015_05
Patent number
US09029397B2

Reaction notes

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