Dimethylcarbamoyl Chloride → 5-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one

HRID 515415Notes

Reaction equation

HRID 515415 reaction equation
CN(C)[C:3](Cl)=[O:4].[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23]([NH:25][NH2:26])=[O:24])[CH2:19][CH2:18]1>N1C=CC=CC=1>[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[O:24][C:3](=[O:4])[NH:26][N:25]=2)[CH2:19][CH2:18]1

Participants

4

Reactant 2

HCID 6598Dimethylcarbamoyl ChlorideHCID 896487191-(2-Fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide

Product 1

HCID 896509215-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-oneYield 40%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
85 °C

Procedure

To a stirred solution of 3,4-difluoro nitrobenzene (1b, 3.5 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(2-fluoro-4-nitrophenyl)-4-piperidine carboxylate (3b, 5.33 g, 86%). To a stirred solution of ester (3b, 5.0 g, 18 mmol) in ethanol, NH2NH2.H2O (2.25 g, 45 mmol) is added and refluxed for 12 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(2-fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide (4b, 4.62 g, 91%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4b, 3.38 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.47 g, 40%). Nitro compound (5b, 1.23 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodi imide)) (0.19 g, 1 mmol) and amine compound (7e, 0.28 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8e, 333 mg, 80%).

Workup

  1. customAfter completion of the reaction
  2. temperaturethe reaction mixture is cooled
  3. filtrationfiltered
  4. customThe residue is recrystallized from water

Sources & evidence

ORD record
ord-3584da80e45e4ad9a4aa49c2192fdd61
Source dataset
uspto-grants-2015_08
Patent number
US09108960B2

Reaction notes

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