Reaction #72813

Reaction equation

lithium hydroxide

methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate

1-(bromomethyl)-3-chloro-2-methylbenzene

potassium carbonate

→

desired product

Yield 34.9%

1-[(3-chloro-2-methylphenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid

Yield 34.9%

Solvents

tetrahydrofuran

water

N,N-Dimethylformamide

Conditions

Workup

1. 1
   OtherThe resulting reaction mixture
2. 2
   TemperatureThe solution was cooled to room temperature
3. 3
   Extractionextracted with EtOAc
4. 4
   WashThe combined organic phase was washed with brine
5. 5
   Concentrationconcentrated
6. 6
   OtherThe residue was purified on a Biotage Isolera purification system
7. 7
   Washeluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes
8. 8
   OtherThe expected compound was collected
9. 9
   Otherevaporated
10. 10
    Otherto yield a tan solid
11. 11
    workup.STIRRINGThe reaction was stirred at 50° C. for 2 h
12. 12
    TemperatureThe reaction was cooled to room temperature
13. 13
    Otherthe organic solvent was removed in-vacuo
14. 14
    workup.ADDITIONThe solution was diluted with water (20 mL)
15. 15
    FiltrationThe mixture was then filtered
16. 16
    Otherthe yellow solid was purified by reversed phase with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (25-55%) over 10 minutes
17. 17
    OtherThe appropriate fractions were collected
18. 18
    Otherevaporated

Procedure

To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-chloro-2-methylbenzene (0.239 g, 1.090 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and extracted with EtOAc. The combined organic phase was washed with brine and concentrated. The residue was purified on a Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in-vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the yellow solid was purified by reversed phase with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (25-55%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (104.4 mg, 0.253 mmol, 34.9% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.48 (s, 3H) 2.85 (s, 3H) 3.13 (d, J=4.04 Hz, 4H) 3.78-3.90 (m, 4H) 5.58 (s, 2H) 6.37 (d, J=7.83 Hz, 1H) 6.89 (d, J=1.52 Hz, 1H) 7.04 (t, J=7.96 Hz, 1H) 7.37 (d, J=8.08 Hz, 1H) 7.52 (d, 1H). MS (ES+) m/e 399.8 [M+H]+.

Source