Hydrochloric Acid → 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-an-5-yl)-2-fluorophenyl)-n,n-dimethylbutanamide

HRID 1192874Notes

Reaction equation

HRID 1192874 reaction equation
C([C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:9]([F:21])[CH:8]=1)([CH3:5])[CH3:4])#N.[N:22]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=1)=[C:23]=[S:24].[CH3:37][OH:38].Cl.[CH3:40]N(C=O)C>O>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:22]2[C:37](=[O:38])[C:3]3([CH2:4][CH2:40][CH2:5]3)[N:6]([C:7]3[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[C:9]([F:21])[CH:8]=3)[C:23]2=[S:24])=[CH:26][C:27]=1[C:33]([F:34])([F:36])[F:35])#[N:30]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 887MethanolHCID 6228DimethylformamideHCID 116155404-Isothiocyanato-2-(trifluoromethyl)benzonitrileHCID 687328064-(4-(2-Cyanopropan-2-ylamino)-2-fluorophenyl)-N,N-dimethylbutanamide

Product 1

HCID 252684844-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-an-5-yl)-2-fluorophenyl)-n,n-dimethylbutanamideYield 65%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 4-(4-(2-Cyanopropan-2-ylamino)-2-fluorophenyl)-N,N-dimethylbutanamide (75) (7 mg, 0.02 mmol) and 4-isothiocyanato-2-trifluoromethylbenzonitrile (96) (12 mg, 0.05 mmol) in DMF (1 mL) was heated to 80° C. using microwave for 16 h. To this mixture was added methanol (3 mL) and aq. 1 N HCl (3 mL). The second mixture was refluxed for 1.5 h. After being cooled to room temperature, the reaction mixture was poured into cold water (30 mL) and extracted with ethyl acetate (30 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-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-an-5-yl)-2-fluorophenyl)-N,N-dimethylbutanamide (74) [ND-8] (8 mg, 65%) as a pale yellowish solid: 1H NMR δ 7.98 (d, 1H, J=8.2 Hz) 7.97 (d, 1H, J=2.1 Hz), 7.84 (dd, 1H, J=8.2, 2.1 Hz), 7.46 (dd, 1H, J=8.0, 8.0 Hz), 7.05 (dd, 1H, J=8.0, 2.2 Hz), 7.02 (dd, 1H, J=9.6, 2.2 Hz), 3.01 (s, 3H), 2.97 (s, 3H), 2.80 (t, 2H, J=7.8 Hz) 2.63-2.71 (m, 2H), 2.52-2.62 (m, 2H), 2.42 (t, 2H, J=7.4 Hz) 2.20-2.31 (m, 1H), 2.00-2.08 (m, 2H), 1.65-1.75 (m, 1H); 13C NMR δ 179.9, 174.7 (2 C's), 161.3 (d, J=248 Hz), 137.0, 135.2, 134.1 (d, J=10.3 Hz), 133.6 (q, J=33.3 Hz), 132.1, 131.9 (d, J=5.7 Hz), 131.2 (d, J=16.2 Hz), 127.1, 125.7 (d, J=4.3 Hz), 121.9 (q, J=272 Hz), 117.2 (d, J=25.1 Hz), 114.8, 110.2, 67.5, 37.2, 35.5, 32.7, 31.6, 28.5, 25.2, 13.7.

Workup

  1. customfor 16 h
  2. temperatureThe second mixture was refluxed for 1.5 h
  3. temperatureAfter being cooled to room temperature
  4. extractionextracted with ethyl acetate (30 mL)
  5. dry with materialThe organic layer was dried over MgSO4
  6. concentrationconcentrated
  7. customthe residue was purified with silica gel column chromatography (dichloromethane:acetone, 95:5)

Sources & evidence

ORD record
ord-c6e8b5b1d72240d0b8ec24da2d3a3389
Source dataset
uspto-grants-2014_03
Patent number
US08680291B2

Reaction notes

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