Hydrochloride methanol → 5-(8-Oxo-5-(4-(piperazin-1-yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

HRID 515812Notes

Reaction equation

HRID 515812 reaction equation
[C:1]([C:3]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4]1)#N.[N:27]([C:30]1[CH:31]=[C:32]([C:38]([F:41])([F:40])[F:39])[C:33]([C:36]#[N:37])=[N:34][CH:35]=1)=[C:28]=[S:29].Cl.C[OH:44]>CC(N(C)C)=O.CCOC(C)=O>[O:44]=[C:1]1[C:3]2([CH2:6][CH2:5][CH2:4]2)[N:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[C:28](=[S:29])[N:27]1[C:30]1[CH:31]=[C:32]([C:38]([F:41])([F:39])[F:40])[C:33]([C:36]#[N:37])=[N:34][CH:35]=1

Participants

6

Reactant 3

HCID 21893726Hydrochloride methanolHCID 250199805-Isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile2×HCID 67132054Tert-butyl 4-(4-(1-cyanocyclobutylamino)phenyl)piperazine-1-carboxylate2×

Product 1

HCID 866834705-(8-Oxo-5-(4-(piperazin-1-yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of tert-butyl 4-(4-(1-cyanocyclobutylamino)phenyl)piperazine-1-carboxylate (Intermediate 86, 0.25 g, 0.70 mmol) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (Intermediate 10, 241 mg, 1.05 mmol) in DMA (5 mL) was heated to 80° C. for 12 h. 2M HCl/MeOH=1/1 (10 mL) was added then and the resulting mixture was heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water (3×), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by Prep-HPLC (20% acetonitrile in water) to afford 75 mg of 5-(8-oxo-5-(4-(piperazin-1-yl)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile. 1H NMR (DMSO-d6, 300 MHz) δ 9.26 (s, 1H), 9.19 (m, 1H), 8.74 (m, 1H), 7.25 (d, 2H), 7.15 (d, 2H), 3.48 (m, 4H), 3.22 (m, 4H), 2.60-2.49 (m, 2H), 2.48-2.40 (m, 2H), 1.95 (m, 1H), 1.63 (m, 1H). LCMS [M+H]+ 487.1.

Workup

  1. temperaturethe resulting mixture was heated at 100° C. for 2 h
  2. temperatureThe reaction mixture was cooled to room temperature
  3. washThe organic layer was washed with water (3×)
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by Prep-HPLC (20% acetonitrile in water)

Sources & evidence

ORD record
ord-d43dd54e9f5946d9bba2be7fe024e356
Source dataset
uspto-grants-2015_08
Patent number
US09108944B2

Reaction notes

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