1H-Benzimidazole-1-methanol → HCID 178480962, compound

HRID 897968Notes

Reaction equation

HRID 897968 reaction equation
[N:1]1(C[OH:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:20]=[C:21]([C:22]3[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=3)[C:14]=12>C1COCC1>[C:26]([OH:27])(=[O:11])[CH3:25].[NH3:1].[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:20]=[C:21]([C:22]3[CH:29]=[CH:28][C:25]([CH:26]([C:2]4[NH:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[OH:27])=[CH:24][CH:23]=3)[C:14]=12

Participants

5

Reactant 2

HCID 1464891H-Benzimidazole-1-methanolHCID 178480963HCID 178480963, compound

Product 2

HCID 12432Ammonia acetateHCID 178480962HCID 178480962, compoundYield 0.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

n-Butylithum (1.34M, 3.0 mL, 4 mmol) was added slowly to a mixture of 1H-benzo[d]imidazol-1-ylmethanol (296 mg, 2.0 mmol) in THF (9.0 mL) at −78° C. The reaction mixture was allowed to warm up to −20° C. and kept at −20° C. for 30 minutes then cooled back to −78° C. cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzaldehyde (420 mg, 1 mmol) in THF (5 mL) was added slowly. After 20 minutes, the dry ice bath was removed and the reaction mixture was stirred at room temperature overnight. Saturated ammonium chloride solution was added followed by ether. The layers were separated and the aqueous layer was neutralized with sodium hydroxide (1.0N) and extracted with dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was first purified by flash column chromatography using dichloromethane/methanol (95:5 to 85:15) as mobile phase then by reverse phase preparative HPLC (Rainin HPLC, Column: Thermoquest, hyperprep HS C18, 8 um, 250×21.2 mm. Eluents: 5% B/A to 100% B/A in 25 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 21 mL/min.) to give cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(1H-benzo[d]imidazol-2-yl)methanol (2 mg, 0.4%). 1H NMR (CDCl3) δ 1.68 (m, 2H), 1.81 (m, 2H), 2.01 (m, 2H), 2.13 (m, 2H), 2.33 (s, 3H), 2.42 (m, 2H), 2.64 (m, 7H), 4.68 (bs, 3H), 4.93 (m, 1H), 5.77 (bs, 2H), 6.06 (s, 1H), 7.20 (m, 2H), 7.52 (m, 2H), 7.58 (m, 4H), 8.32 (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+=538.3, Rt=3.80 min.

Workup

  1. additionwas added slowly
  2. waitAfter 20 minutes
  3. customthe dry ice bath was removed
  4. additionSaturated ammonium chloride solution was added
  5. customThe layers were separated
  6. extractionextracted with dichloromethane
  7. washThe organic layer was washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. customevaporated
  11. customThe residue was first purified by flash column chromatography
  12. waitEluents: 5% B/A to 100% B/A in 25 min. (B

Sources & evidence

ORD record
ord-9628faf403ba4a389dfde7eb6eba3a2a
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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