Maleic Acid → N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide tris-maleate

HRID 897609Notes

Reaction equation

HRID 897609 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:31]3[CH2:36][CH2:35][N:34]([CH:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)[CH2:33][CH2:32]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)=[C:13]([O:29][CH3:30])[CH:12]=3)[C:3]=12.[C:44]([OH:51])(=[O:50])/[CH:45]=[CH:46]\[C:47]([OH:49])=[O:48]>C(OCC)(=O)C.C(O)C>[C:44]([OH:51])(=[O:50])/[CH:45]=[CH:46]\[C:47]([OH:49])=[O:48].[C:44]([OH:51])(=[O:50])/[CH:45]=[CH:46]\[C:47]([OH:49])=[O:48].[C:44]([OH:51])(=[O:50])/[CH:45]=[CH:46]\[C:47]([OH:49])=[O:48].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:31]3[CH2:36][CH2:35][N:34]([CH:37]4[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]4)[CH2:33][CH2:32]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)=[C:13]([O:29][CH3:30])[CH:12]=3)[C:3]=12

Participants

5

Reactant 2

HCID 444266Maleic AcidHCID 22347336N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide

Product 1

HCID 131724248N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide tris-maleateYield 90.2%

Reagents, catalysts & solvents 2

HCID 702EthanolCatalystHCID 8857Ethyl AcetateSolvent2×

Procedure

A suspension of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.398 g, 0.912 mmol) in pyridine (7 mL) at −5° C. was treated with a solution of 4-(dimethylamino)-1-benzenecarbonyl chloride (0.167 g, 0.912 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at −5° C. for 2.5 h, and the ice bath was removed. 1 N sodium hydroxide solution (10 mL) was added to the reaction mixture and stirred for 1 h. The organic layer was removed under reduced pressure, and dichloromethane (15 mL) was added. The layers were separated using an Empore extraction cartridge. The organic layer was removed under reduced pressure. The crude solid was purified two times by flash chromatography on silica gel using 12% (methanol with 5% ammonium hydroxide) in dichloromethane as eluent to give 0.284 g (53%) of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide. A hot solution of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide (0.284 g, 0.487 mmol) in ethyl acetate and a few drops of ethanol was treated with a hot solution of maleic acid (0.169 g, 1.46 mmol) in ethyl acetate. The precipitate formed was filtered under nitrogen and dried under high vacuum to give 0.409 g N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 9.054 (s, 1H), 8.278 (s, 1H), 8.215-8.194 (m, 1H), 7.851-7.828 (m, 2H), 7.312-7.308 (m, 1H), 7.288-7.263 (m, 1H), 6.794-6.772 (m, 2H), 6.096 (s, 6H), 5.10-5.00 (m, 1H), 3.951 (s, 3H), 3.538 (s, 4H), 3.061 (s, 8H), 2.215-2.183 (m, 4H), 1.90-1.81 (m, 2H); 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 4.496 min (98%)

Workup

  1. customThe precipitate formed
  2. filtrationwas filtered under nitrogen
  3. customdried under high vacuum

Sources & evidence

ORD record
ord-a86ac793b8f64741bb45034c9c0e0172
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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