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

HRID 2407521Notes

Reaction equation

HRID 2407521 reaction equation
[C:1]([C:3]1([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4]1)#N.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N:28]=[C:29]=[S:30])[C:23]#[N:24].C([OH:33])C.Cl>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[C:22]([C:23]#[N:24])[CH:25]=[CH:26][C:27]=1[N:28]1[C:1](=[O:33])[C:3]2([CH2:6][CH2:5][CH2:4]2)[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)[C:29]1=[S:30]

Participants

7

Reactant 4

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

Product 1

HCID 498413414-[7-(2-Chloro-4-cyano-phenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]-2-fluoro-N-methyl-benzamideYield 23%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 6a (388 mg, 2 mmol) and 3d (494 mg, 2 mmol) in DMF (10 mL) was heated under microwave irradiation at 110° C. for 12 h. To this mixture is added ethanol (10 mL) and HCl (2N, 5 mL). The resulting mixture was refluxed for 1 h. After being cooled to room temperature, the reaction mixture was poured into cold water and extracted with ethyl acetate (3×100 mL). Combined organic layers were dried over MgSO4, concentrated. The residue was purified by silica gel column chromatography using petroleum ether:ethyl acetate (1:1), to give the title compound (Example 1, 200 mg, 23% yield). 1H NMR (CDCl3, 500 MHz): δ 8.39 (1H, t, J=9.0 Hz), 7.89 (1H, s), 7.72 (1H, dd, m), 7.54 (1H, d, J=8.0 Hz), 7.26 (1H, m.br), 7.20 (1H, d, J=11 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), 1.69 (1H, m, br). MS (ES-API positive): 443 (M+H)+.

Workup

  1. temperatureThe resulting mixture was refluxed for 1 h
  2. temperatureAfter being cooled to room temperature
  3. extractionextracted with ethyl acetate (3×100 mL)
  4. dry with materialCombined organic layers were dried over MgSO4
  5. concentrationconcentrated
  6. customThe residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-4993856c53be45a88951a1e02934d1f2
Source dataset
uspto-grants-2014_08
Patent number
US08809550B2

Reaction notes

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