2-Chloro-6-fluorobenzyl bromide → 1-[1-(2-Chloro-6-fluorobenzyl)-1H-benzimidazol-4-yl]-5-hydroxy-2-methylpyridin-4(1H)-one

HRID 571066Notes

Reaction equation

HRID 571066 reaction equation
[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[C:14]([OH:16])[C:13](=[O:17])[CH:12]=[C:11]3[CH3:18])[C:4]=2[N:3]=[CH:2]1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22]Br>CN(C=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[C:14]([OH:16])[C:13](=[O:17])[CH:12]=[C:11]3[CH3:18])[C:4]=2[N:3]=[CH:2]1

Participants

4

Reactant 2

HCID 27736252-Chloro-6-fluorobenzyl bromide2×HCID 67420264HCID 67420264, compound

Product 1

HCID 699322271-[1-(2-Chloro-6-fluorobenzyl)-1H-benzimidazol-4-yl]-5-hydroxy-2-methylpyridin-4(1H)-one

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

1-(1H-Benzimidazol-4-yl)-5-hydroxy-2-methylpyridin-4(1H)-one (30 mg, 0.124 mmol) and 2-chloro-6-fluorobenzyl bromide (20 μl, 0.146 mmol) were combined in DMF (0.5 ml) then heated to 100° C. After 3 h LC/MS indicated the reaction was incomplete. The mixture was cooled to RT and 10 μL of 2-chloro-6-fluorobenzyl bromide was added. The mixture was heated to 100° C. After 1 hr the mixture was cooled to RT and purified directly by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-40% ACN/water over 20 min at 20 mL/min). Fractions containing the product were pooled then applied to a Phenomenex Strata-X—C ion exchange column. The column was washed with H2O and MeOH (discard) then with 10% concentrated NH4OH in MeOH (collect). The collected fraction was concentrated to give 1-[1-(2-Chloro-6-fluorobenzyl)-1H-benzimidazol-4-yl]-5-hydroxy-2-methylpyridin-4(1H)-one as an off-white solid. 1H NMR (500 MHz, d6-DMSO) δ 8.43 (s, 1 H), 7.66 (d, J=8.3 Hz, 1 H), 7.52-7.29 (m, 6 H), 6.24 (s, 1 H), 5.70 (s, 2 H), 1.90 (s, 3 H). HRMS (ESI) Calc (M+H)=384.0910. Found 384.0913.

Workup

  1. temperatureThe mixture was cooled to RT
  2. temperatureThe mixture was heated to 100° C
  3. temperatureAfter 1 hr the mixture was cooled to RT
  4. custompurified directly by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-40% ACN/water over 20 min at 20 mL/min)
  5. additionFractions containing the product
  6. washThe column was washed with H2O and MeOH (discard)
  7. concentrationThe collected fraction was concentrated

Sources & evidence

ORD record
ord-5a24b38a38974749900f9049f9c4ab31
Source dataset
uspto-grants-2015_05
Patent number
US09024032B2

Reaction notes

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