반응 #72842

반응 방정식

lithium hydroxide

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

2-methyl-5-(trifluoromethyl)benzyl bromide

potassium carbonate

→

product

수율 25.4%

2-methyl-1-{[2-methyl-5-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid

수율 25.4%

용매

tetrahydrofuran

water

N,N-Dimethylformamide

반응 조건

후처리

1. 1
   기타The resulting reaction mixture
2. 2
   온도The solution was cooled to room temperature
3. 3
   추출was extracted with EtOAc
4. 4
   세척The combined organic phase was washed with Brine
5. 5
   농축concentrated
6. 6
   기타The residue was purified on Biotage Isolera purification system
7. 7
   세척eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes
8. 8
   기타The expected compound was collected
9. 9
   기타evaporated
10. 10
    기타to yield a tan solid
11. 11
    workup.STIRRINGThe reaction was stirred at 50° C. for 2 h
12. 12
    온도The reaction was cooled to room temperature
13. 13
    기타the organic solvent was removed in vacuo
14. 14
    workup.ADDITIONThe solution was diluted with water (20 mL)
15. 15
    여과The mixture was then filtered
16. 16
    기타the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (25-55%) over 10 minutes
17. 17
    기타The appropriate fractions were collected
18. 18
    기타evaporated

실험 절차

To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.3 g, 1.090 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 2-methyl-5-(trifluoromethyl)benzyl bromide (0.552 g, 2.179 mmol) and potassium carbonate (0.452 g, 3.27 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 was 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 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 grey solid was purified by reversed phase HPLC 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 desried product (120.1 mg, 0.277 mmol, 25.4% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.53 (s, 3H) 2.88 (s, 3H) 3.15-3.23 (m, 4H) 3.79-3.88 (m, 4H) 5.84 (s, 2H) 7.06 (s, 1H) 7.27 (d, J=2.27 Hz, 1H) 7.51-7.58 (m, 1H) 7.59-7.64 (m, 1H) 7.86 (d, 1H). MS (ES+) m/e 433.8 [M+H]+.

출처