Reacción #72813

Ecuación de reacción

lithium hydroxide

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

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

potassium carbonate

→

desired product

Rendimiento 34.9%

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

Rendimiento 34.9%

Disolventes

tetrahydrofuran

water

N,N-Dimethylformamide

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroThe resulting reaction mixture
2. 2
   TemperaturaThe solution was cooled to room temperature
3. 3
   Extracciónextracted with EtOAc
4. 4
   LavadoThe combined organic phase was washed with brine
5. 5
   Concentraciónconcentrated
6. 6
   OtroThe residue was purified on a Biotage Isolera purification system
7. 7
   Lavadoeluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes
8. 8
   OtroThe expected compound was collected
9. 9
   Otroevaporated
10. 10
    Otroto yield a tan solid
11. 11
    workup.STIRRINGThe reaction was stirred at 50° C. for 2 h
12. 12
    TemperaturaThe reaction was cooled to room temperature
13. 13
    Otrothe organic solvent was removed in-vacuo
14. 14
    workup.ADDITIONThe solution was diluted with water (20 mL)
15. 15
    FiltraciónThe mixture was then filtered
16. 16
    Otrothe 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
    OtroThe appropriate fractions were collected
18. 18
    Otroevaporated

Procedimiento

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]+.

Fuente