Maleic Acid → N2-(4-{4-amino-1-[1-(2,2-difluoroethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide, dimaleate salt

HRID 898016Notes

Reaction equation

HRID 898016 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH:39]([F:41])[F:40])[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]\[C:45]([OH:47])=[O:46]>C(OCC)(=O)C>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]\[C:45]([OH:47])=[O:46].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]\[C:45]([OH:47])=[O:46].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH:39]([F:40])[F:41])[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12

Participants

4

Reactant 2

HCID 444266Maleic AcidHCID 22347012N2-(4-{4-amino-1-[1-(2,2-difluoroethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide

Product 1

HCID 131725051N2-(4-{4-amino-1-[1-(2,2-difluoroethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide, dimaleate saltYield 68.5%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

N2-(4-{4-amino-1-[1-(2,2-difluoroethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide (227 mg, 0.405 mmol) was dissolved in hot ethyl acetate (25 mL). Maleic acid (94 mg, 0.810 mmol) in hot ethyl acetate (3 mL) was added. The reaction mixture was stirred at room temperature overnight. No precipitate was formed. After stirring at room temperature for 4 days, precipitate was formed at bottom of the flask. The solvent was decanted. The solid was washed with ethyl acetate and dried to give N2-(4-{4-amino-1-[1-(2,2-difluoroethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide, dimaleate salt (220 mg, 68%). 1H NMR (DMSO-d6) δ 2.05 (m, 2H), 2.40 (m, 2H), 2.84-3.32 (bm, 6H), 3.96 (s, 3H), 4.04 (s, 3H), 4.85 (m, 1H), 6.22 (s, 4H), 6.34 (t, J=56.07 Hz, 1H), 7.15 (m, 1H), 7.33 (m, 4H), 7.59 (d, J=8.45 Hz, 1H), 7.70 (d, J=7.94 Hz, 1H), 8.12 (d, J=8.19 Hz, 1H), 8.28 (s, 1H), 9.45 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 0.8 mL/min.): RT=3.32 min. MH+=561.3.

Workup

  1. customNo precipitate was formed
  2. stirringAfter stirring at room temperature for 4 days
  3. customprecipitate was formed at bottom of the flask
  4. customThe solvent was decanted
  5. washThe solid was washed with ethyl acetate
  6. customdried

Sources & evidence

ORD record
ord-ca3f639c0f4f4bb386b39c5d576f8995
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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