1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 5-Phenyl-isoxazole-3-carboxylic acid {2-[3-(2,5-difluoro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amide

HRID 1093866Notes

Reaction equation

HRID 1093866 reaction equation
CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[O:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[F:50][C:51]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>CN(C=O)C>[F:50][C:51]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:52]=1[O:53][CH:54]1[CH2:58][CH2:57][N:56]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[O:41][N:40]=2)=[O:43])[CH2:55]1

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 433543392-[(5-Phenyl-1,2-oxazol-3-yl)formamido]acetic acidHCID 450755433-(2,5-Difluorophenoxy)pyrrolidine hydrochloride

Product 1

HCID 578743835-Phenyl-isoxazole-3-carboxylic acid {2-[3-(2,5-difluoro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amideYield 35.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

DIPEA (153.5 mg, 1.2 mmol) followed by HOBt (44.1 mg, 0.32 mmol) and EDCI (113.8 mg, 0.59 mmol) were added to a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (73.4 mg, 0.29 mmol) in DMF (2 mL). After 2 minutes of stirring, 3-(2,5-difluoro-phenoxy)-pyrrolidine hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (70 mg, 0.29 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. Purification by column chromatography (using silica gel 60-120 and 50% EtOAc in hexane) afforded 45 mg (35.4% Yield) of 5-phenyl-isoxazole-3-carboxylic acid {2-[3-(2,5-difluoro-phenoxy)-pyrrolidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 428, 91.77%. 1H NMR (300 MHz, DMSO-d6): δ 8.8-8.68 (m, 1H), 8.0-7.9 (m, 2H), 7.6-7.5 (m, 3H), 7.4 (s, 1H), 7.34-7.2 (m, 2H), 6.9-6.75 (m, 1H), 5.3-5.0 (m, 2H), 4.2-4.0 (m, 2H), 3.9 (m, 1H), 3.8-3.7 (m, 1H), 3.7-3.5 (m, 2H), 2.3-2.2 (m, 1H), 2.1 (m, 1H).

Workup

  1. additionwas added
  2. stirringthe resulting mixture was stirred at ambient temperature overnight
  3. customThe reaction mixture was partitioned between ethyl acetate and water
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customPurification by column chromatography (using silica gel 60-120 and 50% EtOAc in hexane)

Sources & evidence

ORD record
ord-6c0f835c515449548a152f17b729f981
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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