Maleic Acid → HCID 178427275, compound

HRID 432302Notes

Reaction equation

HRID 432302 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:34]3[CH2:39][CH2:38][C@@H:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)[CH2:36][CH2:35]3)[N:9]=[C:10]([C:11]3[CH:33]=[CH:32][C:14]([O:15][C:16]4[CH:23]=[CH:22][CH:21]=[C:20]([S:24][C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)[C:17]=4[C:18]#[N:19])=[CH:13][CH:12]=3)[C:3]=12.[C:47]([OH:54])(=[O:53])/[CH:48]=[CH:49]\[C:50]([OH:52])=[O:51]>C(OCC)(=O)C.CO.C(OCC)(=O)C>[C:47]([OH:54])(=[O:53])/[CH:48]=[CH:49]\[C:50]([OH:52])=[O:51].[C:47]([OH:54])(=[O:53])/[CH:48]=[CH:49]\[C:50]([OH:52])=[O:51].[C:47]([OH:54])(=[O:53])/[CH:48]=[CH:49]\[C:50]([OH:52])=[O:51].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:34]3[CH2:39][CH2:38][C@@H:37]([N:40]4[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]4)[CH2:36][CH2:35]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:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=5)[C:17]=4[C:18]#[N:19])=[CH:32][CH:33]=3)[C:3]=12

Participants

5

Reactant 2

HCID 444266Maleic AcidHCID 178427274HCID 178427274, compound

Product 1

HCID 178427275HCID 178427275, compoundYield 36.2%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 21584119Ethylacetate methanolSolvent

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. customA precipitate immediately formed
  2. filtrationwas filtered under a nitrogen atmosphere

Sources & evidence

ORD record
ord-ed48a1527b4a4b38a121cfb31dca7659
Source dataset
uspto-grants-2003_12
Patent number
US06660744B1

Reaction notes

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