Hydrochloric Acid → 4-[7-(3,4-Dicyano-phenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]-2-fluoro-N-methyl-benzamide

HRID 2407523Notes

Reaction equation

HRID 2407523 reaction equation
Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]=[C:11]=[S:12])[C:5]#[N:6].[C:13]([C:15]1([NH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=2)[CH2:18][CH2:17][CH2:16]1)#N.C([OH:33])C.Cl.[CH3:35][N:36](C=O)C>>[C:35]([C:3]1[CH:2]=[C:9]([N:10]2[C:13](=[O:33])[C:15]3([CH2:16][CH2:17][CH2:18]3)[N:19]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[C:11]2=[S:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])#[N:36]

Participants

6

Reactant 5

HCID 313Hydrochloric AcidHCID 702EthanolHCID 6228DimethylformamideHCID 183163923-Chloro-4-isothiocyanato-benzonitrileHCID 441395204-[(1-Cyanocyclobutyl)amino]-2-fluoro-N-methylbenzamide

Product 1

HCID 498428344-[7-(3,4-Dicyano-phenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]-2-fluoro-N-methyl-benzamideYield 23%

Conditions

Temperature
110 °C

Procedure

A mixture of 3k (370 mg, 2 mmol, prepared by a method similar to the synthesis of 3d) and 6a (494 mg, 2 mmol) in DMF (10 mL) was heated under microwave irradiation at 110° C. for 12 h. To this mixture was added ethanol (10 mL) and aqueous HCl solution (2N, 5 mL). The resulting mixture was heated at reflux for 1 h. The solution was poured into ice-cold water and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was purified with silica gel column chromatography using petroleum ether:ethyl acetate (1:1), affording the title compound (Example 9, 200 mg, 23% yield). 1H NMR (CDCl3, 500 MHz): δ 8.39 (1H, t, J=9.0 Hz), 8.00 (1H, d, J=2.0 Hz), 7.90 (2H, m.br), 7.26 (1H, m.br), 7.18 (1H, dd, J=11.5, 2.0 Hz), 6.71 (1H, br s), 3.00 (3H, d, J=5 Hz), 2.70 (2H, m), 2.52 (2H, m), 2.26 (1H, m), 1.62 (1H, m, br). MS (ES-API positive): 434 (M+H)+.

Workup

  1. temperatureThe resulting mixture was heated
  2. temperatureat reflux for 1 h
  3. additionThe solution was poured into ice-cold water
  4. extractionextracted with ethyl acetate (3×30 mL)
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified with silica gel column chromatography

Sources & evidence

ORD record
ord-31b3ed20b3e846be95bba7d368f33aff
Source dataset
uspto-grants-2014_08
Patent number
US08809550B2

Reaction notes

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