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Step 1: ethyl 1H-benzimidazole-4-carboxylate 2.50 g (15.4 mmol) 1H-benzimidazole-4-carboxylic acid in 100 mL ethanol are combined with 50 mL saturated ethanolic hydrochloric acid solution and refluxed for 15 hours. The reaction mixture is poured into saturated, aqueous potassium carbonate solution and extracted with ethyl acetate. The combined organic phases are dried on sodium sulphate and evaporated down to 50 mL using the rotary evaporator and filtered. 1.80 g (9.46 mmol, 61%) ethyl 1H-benzimidazole-4-carboxylate are obtained as a colourless solid. Rf=0.92 [silica gel, dichloromethane/methanol (80/20)] MS [ESI (M+H)+]]=191
Step 2: ethyl 1-(3-tert-butoxycarbonylamino-3-methyl-butyl)-1H-benzimidazole-4-carboxylate; 0.502 g (12.6 mmol) sodium hydride (60% in mineral oil) are added batchwise at 5 C. to 3.09 g (13.9 mmol) <strong>[167487-83-4]ethyl 1H-benzimidazole-4-carboxylate</strong> in 15 mL dimethylformamide and stirred for 30 minutes at ambient temperature. The reaction mixture is then combined with 1.75 g (9.20 mmol) tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate and 0.310 g (0.840 mmol) tetraabutylammonium iodide and stirred for 24 hours at 60 C. The reaction mixture is poured into ice water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried on sodium sulphate and concentrated by evaporation in the rotary evaporator. The residue is purified by reversed-phase flash column chromatography {Varian Microsorb C18-reverse-phase [acetonitrile (0.1% trifluoroacetic acid)/water (0.13% trifluoroacetic acid)=10:90?100:0], thus obtaining 0.850 g (2.26 mmol, 16%) ethyl 1-(3-tert-butoxycarbonylamino-3-methyl-butyl)-1H-benzim idazole-4-carboxylate. Rf=0.48 [silica gel, dichloromethane/methanol/ammonia (95/5/0.1)]MS [ESI (M+H)+]=376
Into a 100-mL round-bottom flask was placed a suspension of sodium hydride (1.24 g, 31.00 mmol, 1.20 equiv) in DMF (10 mL). Ethyl 1H-1,3-benzodiazole-4-carboxylate (4.9 g, 25.76 mmol, 1.00 equiv) was added to the reaction solution at 0 C. The resulting solution was stirred for 1 h at 0 C. Next, iodomethane (3.66 g, 25.79 mmol, 1.00 equiv) was added to the reaction mixture at 0 C. The resulting solution was allowed to react, with stirring, for an additional 2 h while the reaction mixture temperature was maintained 0 C in an ice bath. Then, the reaction was quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x200 mL of dichloromethane. The combined organic layers were washed with 3x200 mL of H2O. The resulting mixture was concentrated under vacuum and the resulting residue was purified by silica gel column with dichloromethane/methanol (97:3) as eluent to furnish 2.4 g (46%) of ethyl 1-methyl-1H-1,3-benzodiazole-4-carboxylate as a red solid.
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