1-Hydroxybenzotriazole → 5-(2-Fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide

HRID 1093755Notes

Reaction equation

HRID 1093755 reaction equation
CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1N[N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.FC1C=CC=CC=1C(=[O:34])C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH2:59][CH2:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([NH:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=2[Cl:76])[CH2:65][CH2:64]1)=[O:62]>CN(C=O)C.O>[Cl:76][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][C:70]=1[NH:69][CH:66]1[CH2:67][CH2:68][N:63]([C:61](=[O:62])[CH2:60][NH:59][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])[O:34][N:20]=2)=[O:24])[CH2:64][CH2:65]1

Participants

9

Reactant 6

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 96744o-FluoroacetophenoneHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 665917512-Amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone dihydrochlorideHCID 178524114HCID 178524114, compound

Product 1

HCID 578744785-(2-Fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amideYield 26.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

DIPEA (328 mg, 2.5 mmol) to a stirred solution of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (150 mg, 0.724 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from 2′fluoroacetophenone) in DMF (5 mL) followed by HOBt (100 mg, 0.76 mmol) and EDCI.HCl (140 mg, 0.76 mmol). After 2 minutes 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone dihydrochloride (220 mg, 0.724 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected. The solid was purified by recrystallisation from ethyl acetate The residue obtained was again purified by column chromatography (using 60-120 silica gel and 60% EtOAc in hexane as eluent) to afford 88 mg (26.6% Yield) of 5-(2-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 457, 91.47%. 1H NMR (300 MHz, DMSO-d6): δ8.75 (t, 1H), 8.0 (m, 1H), 7.6 (m, 1H), 7.38 (m, 2H), 7.1 (m, 3H), 6.82 (d, 1H), 6.6 (m, 1H), 4.8 (m, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.8 (d, 1H), 3.6 (m, 1H), 3.1 (t, 1H), 2.8 (t, 1H), 1.9 (t, 2H), 1.45 (m, 2H).

Workup

  1. customthe precipitate was collected
  2. customThe solid was purified by recrystallisation from ethyl acetate The residue
  3. customobtained
  4. customwas again purified by column chromatography (using 60-120 silica gel and 60% EtOAc in hexane as eluent)

Sources & evidence

ORD record
ord-8ea231cdd8364b5e86f080b2209e7415
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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