Potassium Carbonate → HCID 178427274, compound

HRID 897591Notes

Reaction equation

HRID 897591 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.F[C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([S:40][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[C:33]=1[C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:32]4[CH:39]=[CH:38][CH:37]=[C:36]([S:40][C:41]5[CH:42]=[CH:43][C:44]([CH3:47])=[CH:45][CH:46]=5)[C:33]=4[C:34]#[N:35])=[CH:13][CH:12]=3)[C:3]=12

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 27374012-Fluoro-6-(4-methylphenylthio)benzonitrileHCID 178481006HCID 178481006, compound

Product 1

HCID 178427274HCID 178427274, compoundYield 11%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

A solution of cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol (0.300 g, 0.736 mmol) in dimethylformamide (20 mL), was treated with 2-fluoro-6-[(4-methylphenyl)sulfanyl]benzonitrile (0.447 g, 1.84 mmol) and potassium carbonate (0.203, 1.47 mmol). The reaction mixture was stirred at 120° C. over night under a nitrogen atmosphere. Ethyl acetate (150 mL) and 1 N sodium hydroxide solution were added to the reaction solution. The layers were partitioned, and the organic layer was washed with 1 N sodium hydroxide solution (300 mL). The organic layer was washed with water and brine (400 mL each), dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash silica gel column chromatography using 10% methanol in dichloromethane as the mobile phase. The light brown solid was triturated with ethyl acetate and filtered to give 0.050 g (11%) cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(4-methylphenyl)sulfanyl]benzonitrile. A warm solution of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(4-methylphenyl)sulfanyl]benzonitrile (0.050 g, 0.079 mmol) in ethyl acetate/methanol was treated with a warm solution of maleic acid (0.028 g, 0.240 mmol) in ethyl acetate. A precipitate immediately formed and was filtered under a nitrogen atmosphere to give 0.028 g of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(4-methylphenyl)sulfanyl]benzonitrile tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.251 (s, 1H), 7.72-7.70 (d, 2H, J=8 Hz), 7.55-7.48 (m, 3H), 7.37-7.33 (m, 4H), 6.96-6.93 (d, 1H, J=12 Hz), 6.74-6.72 (d, 1H, J=8 Hz), 6.18 (s, 6H), 4.85 (m, 1H), 3.15-2.90 (m, 4H), 2.85-2.75 (m, 3H), 2.38 (s, 3H), 2.05-1.99 (m, 2H), 1.90-1.60 (m, 5H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 6.359 min (100%).

Workup

  1. customThe layers were partitioned
  2. washthe organic layer was washed with 1 N sodium hydroxide solution (300 mL)
  3. washThe organic layer was washed with water and brine (400 mL each)
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customThe crude product was purified by flash silica gel column chromatography
  8. customThe light brown solid was triturated with ethyl acetate
  9. filtrationfiltered

Sources & evidence

ORD record
ord-1471e8d7f3c94d8eac9ea0214064cbf6
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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