Hydrochloric Acid → 4-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide

HRID 245032Notes

Reaction equation

HRID 245032 reaction equation
[CH3:1][NH:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2([C:16]#N)[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[F:18].[N:20]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1)=[C:21]=[S:22].C[OH:36].Cl>CN(C=O)C.O>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([N:20]2[C:16](=[O:36])[C:11]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:19])=[C:5]([F:18])[CH:6]=3)[C:21]2=[S:22])=[CH:24][C:25]=1[C:31]([F:32])([F:34])[F:33])#[N:28].[CH3:1][NH:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11]3([CH2:15][CH2:14][CH2:13]3)[C:16](=[O:36])[N:20]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:32])([F:34])[F:33])[CH:24]=3)[C:21]2=[S:22])=[CH:6][C:5]=1[F:18])=[O:19]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 116155404-Isothiocyanato-2-(trifluoromethyl)benzonitrileHCID 59296600N-Methyl 2-fluoro-4-(1-cyanocyclopentyl)aminobenzamide2×

Product 2

HCID 119577564-[7-[4-cyano-3-(trifluoromethyl)phenyl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamideYield 7%HCID 159516244-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-4-oxo-2-thioxo-1,3-diazaspiro[4,4]nonan-1-yl)-2-fluoro-N-methylbenzamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of N-Methyl 2-fluoro-4-(1-cyanocyclopentyl)aminobenzamide (Formula 43) (57 mg, 0.22 mmol) and 4-isothiocyanato-2-trifluoromethyl benzonitrile (0.15 g, 0.65 mmol) in DMF (3 mL) was heated under microwave irradiation (open vessel) at 130° C. for 12 hours. To this mixture was added methanol (20 mL) and aq. 1 N HCl (5 mL). The second mixture was refluxed for 1.5 h. After being cooled to room temperature, the reaction mixture was poured into cold water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 95:5) to give 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]nonan-1-yl)-2-fluoro-N-methylbenzamide, RD162″ (Formula 44) (8 mg, 7%) as a pale yellowish solid. 1H NMR δ 8.28 (dd, 1H, J=8.4, 8.4 Hz), 7.98 (d, 1H, J=8.3 Hz), 7.96 (d, 1H, J=1.8 Hz), 7.84 (dd, 1H, J=8.3, 1.8 Hz), 7.27 (dd, 1H, J=8.4, 1.8 Hz), 7.17 (dd, 1H, J=11.7, 1.8 Hz), 6.67-6.77 (m, 1H), 3.07 (d, 3H, J=4.3 Hz), 2.32-2.41 (m, 2H), 2.13-2.21 (m, 2H), 1.85-1.96 (m, 2H), 1.49-1.59 (m, 2H).

Workup

  1. temperatureThe second mixture was refluxed for 1.5 h
  2. temperatureAfter being cooled to room temperature
  3. extractionextracted with ethyl acetate (50 mL)
  4. dry with materialThe organic layer was dried over MgSO4
  5. concentrationconcentrated
  6. customthe residue was purified with silica gel column chromatography (dichloromethane:acetone, 95:5)

Sources & evidence

ORD record
ord-a243175fdb5e4c8bbd67cf3b5071bb25
Source dataset
uspto-grants-2014_02
Patent number
US08658681B2

Reaction notes

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