تفاعل #72838

معادلة التفاعل

lithium hydroxide

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

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

potassium carbonate

→

desired product

المردود 12.0%

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

المردود 12.0%

المذيبات

tetrahydrofuran

water

N,N-Dimethylformamide

ظروف التفاعل

المعالجة

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

الإجراء التجريبي

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-(1-bromoethyl)-3-chloro-2-methylbenzene (0.339 g, 1.453 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 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) (20-50%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (36.1 mg, 0.087 mmol, 12.01% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.04-2.10 (m, 6H) 2.88 (s, 3H) 2.98-3.17 (m, 4H) 3.87 (s, 4H) 5.95-6.06 (m, 1H) 6.70-6.77 (m, 1H) 7.35-7.42 (m, 1H) 7.51-7.57 (m, 1H) 7.60-7.67 (m, 1H) 7.71-7.77 (m, 1H). MS (ES+) m/e 413.8 [M+H]+.

المصدر