Sodium Carbonate → N2-(4-{4-amino-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide

HRID 898020Notes

Reaction equation

HRID 898020 reaction equation
I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[NH:39][C:40]([C:42]1[N:43]([CH3:51])[C:44]2[C:49]([CH:50]=1)=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:3]=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([NH:39][C:40]([C:42]4[N:43]([CH3:51])[C:44]5[C:49]([CH:50]=4)=[CH:48][CH:47]=[CH:46][CH:45]=5)=[O:41])=[C:24]([O:23][CH3:22])[CH:29]=3)[C:10]=12

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 223466583-iodo-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amineHCID 22347095N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide

Product 1

HCID 22347393N2-(4-{4-amino-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamideYield 30%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 3-iodo-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.188 g, 0.469 mmol) in ethylene glycol dimethyl ether (16 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.209 g, 0.516 mmol), tetrakis(triphenylphosphine)palladium (0.033 g, 0.028 mmol), and a solution of sodium carbonate (0.119 g, 1.13 mmol) in water (8 mL). The reaction mixture was stirred for 4.5 h at 80° C. The organic solvent was removed under reduced pressure and ethyl acetate (200 mL) was added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (400 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 20% methanol in dichloromethane to 50% methanol in dichloromethane. The column afforded 0.078 g (30%) of pure N2-(4-{4-amino-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.442 (s, 1H), 8.258 (s, 1H), 8.122-8.1076 (d, 1H, J=8.16 Hz), 7.719-7.6991 (d, 1H, J=7.96 Hz), 7.6005-7.5793 (d, 1H, J=8.48 Hz), 7.349-7.294 (m, 4H), 7.172-7.135 (t, 1H), 4.405-4.371 (m, 2H), 4.04 (s, 3H), 3.958 (s, 3H), 3.291 (m, 2H), 2.5 (m, 3H), 2.45-2.337 (m, 5H), 2.30-2.10 (m, 3H), 2.022-2.005 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.05 min (100%), MH+ 554.3.

Workup

  1. customThe organic solvent was removed under reduced pressure and ethyl acetate (200 mL)
  2. additionwas added
  3. customThe layers were partitioned
  4. extractionthe aqueous layer was extracted with ethyl acetate (400 mL)
  5. dry with materialThe combined organic layers were dried over magnesium sulfate
  6. filtrationfiltered
  7. customevaporated under reduced pressure
  8. customThe crude material was purified by flash chromatography on silica gel using a step-wise gradient of 20% methanol in dichloromethane to 50% methanol in dichloromethane

Sources & evidence

ORD record
ord-6240fc8a5bf14bf781fd714fa79e255a
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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