Reaktion #72813

Reaktionsgleichung

lithium hydroxide

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

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

potassium carbonate

→

desired product

Ausbeute 34.9%

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

Ausbeute 34.9%

Lösungsmittel

tetrahydrofuran

water

N,N-Dimethylformamide

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe resulting reaction mixture
2. 2
   TemperaturThe solution was cooled to room temperature
3. 3
   Extraktionextracted with EtOAc
4. 4
   WaschenThe combined organic phase was washed with brine
5. 5
   Einengenconcentrated
6. 6
   SonstigeThe residue was purified on a Biotage Isolera purification system
7. 7
   Wascheneluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes
8. 8
   SonstigeThe expected compound was collected
9. 9
   Sonstigeevaporated
10. 10
    Sonstigeto yield a tan solid
11. 11
    workup.STIRRINGThe reaction was stirred at 50° C. for 2 h
12. 12
    TemperaturThe reaction was cooled to room temperature
13. 13
    Sonstigethe 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
    Sonstigethe 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
    SonstigeThe appropriate fractions were collected
18. 18
    Sonstigeevaporated

Vorschrift

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]+.

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