Ammonium Acetate → HCID 70061643, compound

Participants

Reaction Steps

A solution of oxalyl chloride (1.25 g) in methylene chloride (30 ml) is cooled to -78° C. and dimethylsulfoxide (1.16 ml) is slowly added. The reaction mixture is stirred at -78° C. for about 30 minutes and a solution of (R)-N-(4-methoxybenzenesulfonyl)-4-hydroxycyclohexylglycine methyl ester (2.34 g) in methylene chloride (30 ml) is added dropwise. Stirring is continued for 30 minutes at -78° C. and then at 0° C. for 30 minutes. The reaction mixture is again cooled to -78° C., triethylamine (7.3 ml) is added dropwise, and the reaction mixture is stirred at -78° C. for 30 minutes, allowed to warm to room temperature over an hour, diluted with methylene chloride, washed first with 1N hydrochloric acid and then brine. The organic layer is dried over sodium sulfate, evaporated to dryness, and the resulting product is purified by flash chromatography using 50-60% ethyl acetate in hexane to yield (R)-N-(4-methoxybenzenesulfonyl)-4-oxocyclohexylglycine methyl ester as a white solid. Treatment with benzyl bromide in DMF in the presence of potassium carbonate at room temperature yields (R)-N-(4-methoxybenzenesulfonyl)-N-benzyl-4-oxocyclohexylglycine methyl ester as an oil. The ketone (2.2 g) is dissolved in methylene chloride (3 ml) and isopropanol (60 ml). Molecular sieves (3A°, 1.5 g), sodium cyanoborohydride (0.311 g), and ammonium acetate (3.81 g) are added. The reaction mixture is stirred at room temperature overnight, filtered and evaporated to dryness. The residue is partitioned between water and methylene chloride and the product extracted with methylene chloride. The resulting product is purified by flash chromatography using methanol/methylene chloride/0.5% ammonium hydroxide as eluent to yield (R)-N-(4-methoxybenzenesulfonyl)-N-benzyl-4-aminocyclohexylglycine methyl ester. N-Methylation with formic acid/formaldehyde/sodium formate at reflux temperature followed by hydrolysis with 3N hydrochloric acid at reflux temperature yields 2-(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(tran-4-dimethylaminocyclohexyl)-acetic acid.

Provenance & Evidence