1-Hydroxybenzotriazole → 5-(4-Hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide

HRID 1093760Notes

Reaction equation

HRID 1093760 reaction equation
CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)=[CH:13][CH:12]=1.C(OC1C=C(C(=O)C)C=CC=1)C1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:65][CH2:66][C:67]([N:69]1[CH2:74][CH2:73][CH:72]([O:75][C:76]2[CH:81]=[CH:80][CH:79]=[C:78]([C:82]([F:85])([F:84])[F:83])[CH:77]=2)[CH2:71][CH2:70]1)=[O:68]>CN(C=O)C.O>[O:68]=[C:67]([N:69]1[CH2:70][CH2:71][CH:72]([O:75][C:76]2[CH:81]=[CH:80][CH:79]=[C:78]([C:82]([F:85])([F:83])[F:84])[CH:77]=2)[CH2:73][CH2:74]1)[CH2:66][NH:65][C:22]([C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=2)[O:21][N:20]=1)=[O:24]

Participants

9

Reactant 6

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 986891-(3-(Phenylmethoxy)phenyl)ethan-1-oneHCID 10909835-(4-Hydroxyphenyl)isoxazole-3-carboxylic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 665915472-Amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride

Product 1

HCID 1361706625-(4-Hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amideYield 51.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

DIPEA (133 mg, 1.03 mmol) was added to a stirred solution of 5-(4-hydroxy-phenyl)-isoxazole-3-carboxylic acid (61 mg, 0.294 mmol) (prepared by the method used for the synthesis of Intermediate 25, starting from 3′benzyloxyacetophenone) in DMF (2 mL) followed by HOBt (41.7 mg, 0.308 mmol) and EDCI.HCl (59 mg, 0.308 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (99 mg, 0.294 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from 110% EtOAc in hexane afforded 74 mg (51.3% Yield) of 5-(4-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 490, 90.53%. 1H NMR (300 MHz, DMSO-d6): δ10.2 (s, 1H), 8.6 (s, 1H), 7.78 (d, 2H), 7.5 (t, 1H), 7.3 (t, 3H), 7.16 (s, 1H), 6.9 (m, 2H), 4.7 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).

Workup

  1. customprepared by the method
  2. additionwas added to the reaction mixture
  3. extractionextracted with ethyl acetate
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customPurification
  7. customby recrystallisation from 110% EtOAc in hexane

Sources & evidence

ORD record
ord-5d8e2ad444094b5a9a7c65f130355639
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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