Maleic Acid → HCID 178488228, compound

HRID 897694Notes

Reaction equation

HRID 897694 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[CH2:19][C:20]([CH3:28])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49]>C(OCC)(=O)C.C(O)C>[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49].[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49].[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[CH2:19][C:20]([CH3:28])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH3:21])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12

Participants

5

Reactant 2

HCID 444266Maleic AcidHCID 178488226HCID 178488226, compound

Product 1

HCID 178488228HCID 178488228, compoundYield 85%

Reagents, catalysts & solvents 2

HCID 702EthanolCatalystHCID 8857Ethyl AcetateSolvent2×

Procedure

A solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.458 mmol) in pyridine (4 mL) at −5° C. was treated with a solution of 3-methyl-3-phenylbutanoyl chloride (0.101 g, 0.514 mmol) in dichloromethane (1 mL) drop-wise. The reaction mixture was stirred for 20 min at −5° C., then the dry ice/acetone bath was removed and the reaction mixture stirred at room temperature for 4 h. 1 N sodium hydroxide solution (5 mL) was added and the mixture stirred over night. Solvent was removed under reduced pressure. The crude solid was dried under high vacuum. Dichloromethane (10 mL) and 1 N sodium hydroxide solution (10 mL) were added. The layers were separated using an Empore extraction cartridge. The organic solvent was removed by blowing nitrogen over the top, to give 0.240 g (88%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-methyl-3-phenylbutanamide. A hot solution of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-methyl-3-phenylbutanamide (0.240 g, 0.402 mmol) in ethyl acetate and a few drops of ethanol was treated with a hot solution of maleic acid (0.140 g, 1.206 mmol) in ethyl acetate. The precipitated formed was filtered under nitrogen atmosphere, and dried on a lyophilizer to give 0.323 g trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-methyl-3-phenylbutanamide tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.807 (s, 1H), 8.226 (s, 1H), 8.109-8.088 (d, 1H, J=8.4 Hz), 7.489-7.470 (d, 2H, J=7.6 Hz), 7.345-7.306 (m, 2H), 7.213-7.134 (m, 3H), 6.151 (s, 5H), 4.680 (m, 1H), 3.836 (s, 3H), 3.3 (br. s., 7H), 2.655 (s, 3H), 2.541 (s, 4H), 2.085-1.989 (m, 6H), 1.574-1.551 (m, 2H), 1.431 (s, 6H); 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 5.407 min (99%).

Workup

  1. customThe precipitated formed
  2. filtrationwas filtered under nitrogen atmosphere
  3. customdried on a lyophilizer

Sources & evidence

ORD record
ord-336fb24e8e6243db999afbf5d4074616
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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