Hydrochloric Acid → 1-(1-benzothien-7-ylmethyl)-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid

Temperature

80 °C

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 7-(bromomethyl)-1-benzothiophene (0.247 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. An additional amount of 7-(bromomethyl)-1-benzothiophene (0.247 g, 1.090 mmol) was added and 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 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 found to be incomplete so the solution was neutralized with 1M HCl and evaporated. The residue was dissolved in 5 mL of methanol and treated with 1N NaOH for 2 h at 50° C., which resulted in a complete reaction. 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 isolated. The aqueous layer was found to contain a significant amount of product and was evaporated. Both solid and residue were purified by reversed phase chromatography with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-45%) over 10 minutes. The appropriate fractions were collected and evaporated to the desired product (27.9 mg, 0.068 mmol, 9.42% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (s, 3H) 3.14-3.21 (m, 4H) 3.71-3.76 (m, 4H) 6.01 (s, 2H) 7.06 (d, J=7.07 Hz, 1H) 7.36-7.44 (m, 1H) 7.56-7.62 (m, 2H) 7.71 (d, J=2.27 Hz, 1H) 7.83 (d, J=5.31 Hz, 1H) 7.92 (d, 1H). MS (ES+) m/e 408.1 [M+H]+.

1. customThe resulting reaction mixture
2. stirringmixture was stirred for 3 h at 80° C
3. temperatureThe solution was cooled to room temperature
4. extractionextracted with EtOAc
5. washThe combined organic phase was washed with brine
6. concentrationconcentrated
7. customThe residue was purified on Biotage Isolera purification system
8. washeluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes
9. customThe expected compound was collected
10. customevaporated
11. customto yield a tan solid
12. customevaporated
13. dissolutionThe residue was dissolved in 5 mL of methanol
14. additiontreated with 1N NaOH for 2 h at 50° C.
15. customwhich resulted in a complete reaction
16. temperatureThe reaction was cooled to room temperature
17. customthe organic solvent was removed in vacuo
18. additionThe solution was diluted with water (20 mL)
19. filtrationThe mixture was then filtered
20. customthe yellow solid was isolated
21. customwas evaporated
22. customBoth solid and residue were purified by reversed phase chromatography with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-45%) over 10 minutes
23. customThe appropriate fractions were collected

ORD record

ord-cbfb3e86ef4e4b7db47ff5da38d96683

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08541411B2