Ethyl chloroformate → 4-amino-N-[{4-[(1-(tert-butoxycarbonyl)-4-piperidinyl)methyl]-2-morpholinyl}-methyl]-5-chloro-2-methoxybenzamide

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Reaction Steps

To a suspension of 4-amino-5-chloro-2-methoxybenzoic acid (27.6 g) in chloroform (200 ml) was added dropwise TEA (16.6 g) at room temperature with stirring. The internal temperature of the reaction solution was ice-cooled, and then thereto was slowly added dropwise ethyl chloroformate (16.3 g) so that the internal temperature did not rise over 5° C. After completion of addition, the mixture was stirred at internal temperature of 0 to 5° C. for 1 hour. To the reaction solution was slowly added dropwise a solution of 2-aminomethyl-4-[1-(tert-butoxycarbonyl)-4-piperidinylmethyl]morpholine (Reference Example 12) (42.9 g) in chloroform (50 ml) so that the internal temperature did not rise over 5° C., and after completion of addition, the mixture was stirred overnight without an ice bath. The reaction solution was sequentially washed with water, 5% aqueous potassium hydroxide solution, water, 5% aqueous solution of citric acid, water and brine. The solution was dried over anhydrous magnesium sulfate, and then the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the titled compound (32.4 g) as an amorphous solid.

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