Dimethylformamide → HCID 53372818, compound

HRID 515826Notes

Reaction equation

HRID 515826 reaction equation
[O:1]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:4](=[S:23])[N:3]1[C:24]1[CH:25]=[C:26]([C:32]([F:35])([F:34])[F:33])[C:27]([C:30]#[N:31])=[N:28][CH:29]=1.Br[CH:37]([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C1COCC1>[CH:37]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([N:5]3[C:4](=[S:23])[N:3]([C:24]4[CH:25]=[C:26]([C:32]([F:34])([F:33])[F:35])[C:27]([C:30]#[N:31])=[N:28][CH:29]=4)[C:2](=[O:1])[C:6]43[CH2:9][CH2:8][CH2:7]4)=[CH:11][CH:12]=2)[CH2:18][CH2:19]1)([CH3:39])[CH3:38]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 63582-BromopropaneHCID 10796Cesium carbonateHCID 53373087HCID 53373087, compound

Product 1

HCID 53372818HCID 53372818, compoundYield 9.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

To a solution of 5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (50 mg, 0.10 mmol) in anhydrous THF (1 mL) was added 2-bromopropane (20 μL, 0.20 mmol) followed by cesium carbonate (100 mg, 0.30 mmol). The reaction mixture was heated at 70° C. overnight. DMF (1 mL) was added to improve solubility and the reaction was heated at 85° C. for 3 h. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous was extracted further with EtOAc (2×) and the combined organics were washed with water, then brine. The organics were dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC provided 5 mg of 5-(5-(4-((1-isopropylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.04 (d, 1H), 8.30 (d, 1H), 7.13 (d, 2H), 6.99 (d, 2H), 4.37-4.26 (m, 1H), 2.81-2.33 (m, 10H), 2.25-1.74 (m, 5H), 1.00 (d, 6H). LCMS [M+1]+ 544.0.

Workup

  1. temperaturethe reaction was heated at 85° C. for 3 h
  2. temperatureThe mixture was cooled to room temperature
  3. custompartitioned between water and EtOAc
  4. extractionThe aqueous was extracted further with EtOAc (2×)
  5. washthe combined organics were washed with water
  6. dry with materialThe organics were dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by preparative HPLC

Sources & evidence

ORD record
ord-ebd1654b33594a6bab9c0625202d8b3f
Source dataset
uspto-grants-2015_08
Patent number
US09108944B2

Reaction notes

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