Triethylamine → 2-(benzyloxy)acetamide

Participants

Reaction Steps

Starting with the 3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenyl]-5-hydroxymethyl-oxazolidin-2-one which was formed as an intermediate in Example 3, the procedure of Example 1 was repeated to produce an azide compound in a yield of 90%. The azide compound (1.5 g) was reduced with triphenylphosphine/tetrahydrofuran/water by the same method as in Example 10 to provide a primary amine compound. The amine compound and triethylamine (1.2 ml) were added to dry dichloromethane (20 ml) and benzyloxyacetyl chloride (1.20 g) was subsequently added at 0° C. The reaction mixture was stirred overnight at room temperature and the resulting precipitate was filtered off. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (methanol/dichloromethane=5/95) to afford a benzyloxyacetamide compound (2.7 g) in a yield of 100%. The benzyloxyacetamide compound (1.9 g) was dissolved in a mixed solvent consisting of methanol (30 ml) and dichloromethane (5 ml). To the solution, 10% palladium hydroxide/carbon (340 mg) was added and the mixture was stirred for 2 days under 3 atm hydrogen atmosphere. The palladium hydroxide was filtered off and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol/dichloromethane=7/93) to afford an α-hydroxyacetamide compound (780 mg) in a yield of 49%. To a tetrahydrofuran solution (10 ml) of the α-hydroxyacetamide compound (530 mg), p-toluenesulfonyl fluoride (450 mg) and tetrabutylammonium fluoride (1.0M tetrahydrofuran solution; 3.3 ml) were added and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/acetone=2/3) to afford a monofluoroacetamide compound (562 mg) in a yield of 100%. To 10 ml of an acetone solution of the monofluoroacetamide compound, p-toluenesulfonic acid monohydrate (580 mg) and water (3 ml) were added and the mixture was heated under reflux for 2.5 h. The reaction mixture was cooled to room temperature, neutralized with solid sodium hydrogencarbonate, and concentrated under vacuum. Water was removed by azeotropy with toluene and the residue was purified by silica gel column chromatography (hexane/acetone=1/1) to afford the title compound (408 mg) in a yield of 81%.

Provenance & Evidence