Thionyl Chloride → HCID 67405110, compound

Participants

Reaction Steps

The conversion of the alcohol to chloromethyl derivative and the subsequent alkylation were done using similar procedure as described in the synthesis of tert-butyl 4-(((5-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (5) and tert-butyl 4-(((6-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate. (6-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methanol (25 mg, 0.072 mmol) was converted to chloromethyl derivative as described in the synthesis of tert-butyl 4-(((5-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate and tert-butyl 4-(((6-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate using thionyl chloride (0.030 mL, 5.7 eq) and the crude chloromethyl derivative was alkylated with tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (25.2 mg, 1.2 eq) using sodium hydride (9 equiv) in tetrahydrofuran (3 mL) at ambient temperature for 3 days. The crude product was purified by silica gel chromatography using a gradient of 10%-80% ethyl acetate in dichloromethane. Fractions containing required compound were combined and evaporated in vacuo to give tert-butyl 4-phenyl-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (25 mg) containing required product and piperidinyl alcohol reagent in the ratio of 2:3 by proton NMR. Material used without additional purification. LC/MS (HPLC method 8): tR=3.8 min, 642(MNa)+.

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