Triethylamine → benzyl (3R)-4-(5-cyano-2-benzyloxyphenoxy)-3-[(1-(pyridine-4-yl)piperidine-4-carbonyl)amino]butanoate

Participants

Reaction Steps

2.1 g (4.07 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-(5-cyano-2-benzyloxyphenoxy)butanoate was dissolved in 20 ml of 4 N solution of hydrogen chloride in dioxane, and they were stirred at room temperature for 4 hours. The solvent was evaporated and the obtained crude product was dissolved in 20 ml of DMF. 1.08 g (1.03 mmol) of 1-(4-pyridyl)-4-piperidinecarboxylate hydrochloride, 1.03 g (6.11 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 1.7 ml (61.6 mmol) of triethylamine were added to the obtained solution, and they were stirred for 16 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography. 1.0 g (1.66 mmol) (of 2.0 g in total) of the obtained product was dissolved in a mixture of 20 ml of 4 N solution of hydrogen chloride in dioxane and 4 ml of ethanol, and the obtained solution was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure, and the obtained crude product was dissolved in 20 ml of ethanol. 1.0 g of ammonium carbonate was added to the obtained solution, and they were stirred at room temperature overnight. The solvent was evaporated, and the obtained crude product was dissolved in 10 ml of ethanol. 100 mg of 10% palladium/carbon was added to the obtained solution, and they were stirred in the presence of hydrogen overnight. The reaction liquid was filtered through Celite, and the solvent was evaporated. The obtained crude product was dissolved in 28 ml of 6 N aqueous hydrogen chloride solution, and the obtained solution was stirred at 60° C. for 2 hours. The solvent was evaporated, and the obtained crude product was treated in the same manner as that in step 9 in Example 1 to obtain the title compound.

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