Water → HCID 178480951, compound

HRID 2056142Notes

Reaction equation

HRID 2056142 reaction equation
C[O-].[Na+].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH2:24][CH2:23]3)[N:12]=[C:13]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)[C:6]=12.C1(C)C=CC(S([CH2:44][N+:45]#[C-:46])(=O)=O)=CC=1.O>CO>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C@@H:25]2[CH2:26][CH2:27][C@H:22]([N:11]3[C:7]4=[N:8][CH:9]=[N:10][C:5]([NH2:4])=[C:6]4[C:13]([C:14]4[CH:21]=[CH:20][C:17]([C:18]5[O:19][CH:46]=[N:45][CH:44]=5)=[CH:16][CH:15]=4)=[N:12]3)[CH2:23][CH2:24]2)[CH2:33][CH2:32]1

Participants

6

Reactant 4

HCID 962WaterHCID 161915Tosylmethyl isocyanideHCID 10942334Sodium MethoxideHCID 20817053HCID 20817053, compound

Product 1

HCID 178480951HCID 178480951, compoundYield 27.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Sodium methoxide (130 mg, 2.41 mmol) was added in portions to a mixture of 4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzaldehyde (300 mg, 0.715 mmol) in methanol (20 mL). After 5 minutes, (p-tolylsulfonyl)methyl isocyanide (tosmic) (167 mg, 0.858 mmol) was added in portions. The solution was heated at reflux for 5 hours. Water (10 mL) was added while it was still hot. After cooling on ice for 5 minutes, the solid was filtered and washed with a mixture of methanol/water (50/50, 2 mL) then dried. The filtrate was evaporated to remove organic solvent and the solid was collected and washed with water. The combined solid was first purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase then re-crystallized twice from DMF to give cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(1,3-oxazol-5-yl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 27%). 1H NMR (DMSO-d6) δ 1.61 (m, 2H), 1.71 (m, 2H), 2.10 (m, 2H), 2.15 (s, 3H), 2.44 (m, 1H), 4.82 (m, 1H), 7.78 (m, 3H), 7.79 (m, 2H), 8.24 (s, 1H), 8.51 (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.): MH+=459.2, Rt 0.72 nm.

Workup

  1. temperatureThe solution was heated
  2. temperatureat reflux for 5 hours
  3. temperatureAfter cooling on ice for 5 minutes
  4. filtrationthe solid was filtered
  5. washwashed with a mixture of methanol/water (50/50, 2 mL)
  6. customthen dried
  7. customThe filtrate was evaporated
  8. customto remove organic solvent
  9. customthe solid was collected
  10. washwashed with water
  11. customThe combined solid was first purified by flash column chromatography
  12. customthen re-crystallized twice from DMF

Sources & evidence

ORD record
ord-ac1c9d7acf7d4ae9b397e9dc9dd67ded
Source dataset
uspto-grants-2008_02
Patent number
US07332497B2

Reaction notes

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