Maleic Acid → HCID 178481003, compound

HRID 897594Notes

Reaction equation

HRID 897594 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:33]3[CH2:38][CH2:37][C@@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:32]=[CH:31][C:14]([O:15][C:16]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[C:17]=4[C:18]#[N:19])=[CH:13][CH:12]=3)[C:3]=12.[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]\[C:49]([OH:51])=[O:50]>C(O)C>[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]\[C:49]([OH:51])=[O:50].[C:46]([OH:53])(=[O:52])/[CH:47]=[CH:48]\[C:49]([OH:51])=[O:50].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:33]3[CH2:38][CH2:37][C@@H:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[C:17]=4[C:18]#[N:19])=[CH:31][CH:32]=3)[C:3]=12

Participants

4

Reactant 2

HCID 444266Maleic AcidHCID 178481002HCID 178481002, compound

Product 1

HCID 178481003HCID 178481003, compoundYield 83.4%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

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-(2-pyridylsulfanyl)benzonitrile (0.424 g, 1.84 mmol) and potassium carbonate (0.203, 1.47 mmol). The reaction mixture was stirred at 120° C. for 2 h under a nitrogen atmosphere. Ethyl acetate (125 mL) and 1 N sodium hydroxide solution (50 mL) were added to the reaction mixture. 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 (250 mL each), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The solid was triturated with ethyl acetate to yield 0.310 g (68%) of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)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-(2-pyridylsulfanyl)benzonitrile (0.310 g, 0.502 mmol) in ethanol was treated with a warm solution maleic acid (0.175 g, 1.503 mmol) in ethanol. A precipitate formed upon cooling and was filtered under a nitrogen atmosphere to give 0.356 g of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)benzonitrile bis-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.47-8.46 (d, 1H, J=4 Hz), 8.26 (s, 1H), 7.79-7.72 (m, 4H), 7.53-7.51 (d, 1H, J=8 Hz), 7.38-7.34 (m, 3H), 7.28-7.24 (m, 2H), 6.14 (s, 4H), 4.85 (m, 1H), 3.60-3.10 (m, 7H), 3.1-2.85 (m, 2H), 2.71-2.67 (m, 2H), 2.32-2.27 (m, 3H), 2.05-1.99 (m, 2H), 1.78-1.71 (m, 4H); 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 5.196 min (98%).

Workup

  1. customA precipitate formed
  2. temperatureupon cooling
  3. filtrationwas filtered under a nitrogen atmosphere

Sources & evidence

ORD record
ord-76055812e49a4432bbff1b4d7d3c4a4a
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

Loading…