Process for the preparation of oxazolidinones and method of use thereof
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example 1
[0106] This example illustrates the preparation of (S)-5-trityloxymethyl-2-oxazolidinone using the process disclosed in U.S. Pat. No. 6,288,239 B1 to Hollingsworth and Wang.
[0107] In a flask, (S)-3,4-dihydroxybutyramide (11.9 g, 0.10 moles) was dissolved in 50 mL of tetrahydrofuran (THF) to which 50 mL of dimethylformamide and 10 mL pyridine was added followed by 30.6 g (0.11 moles) of trityl chloride. A drying tube filled with calcium chloride was used to exclude moisture. The reaction mixture was stirred for 36 hours at room temperature. Afterwards, the reaction mixture was filtered to remove the solids. The liquid was concentrated under reduced pressure to remove most of the solvent. The concentrate was poured into ice water, stirred for about half an hour, and then the water layer was removed from the organic layer containing the 3-Hydroxy-4-trityloxy butyramide. The product was a semi-crystalline liquid which was dried in vacuo. Afterwards, the excess trityl chloride was washe...
example 2
[0109] This comparative example illustrates the N-arylation of 5-trityloxymethyl-2-oxazolidinone to produce (S)-3-(2-nitro)phenyl-5-trityloxymethy)-2-oxazolidinone using the procedure disclosed in Shakespeare, Tetrahedron Lett. 40: 2035-2038 (1999).
[0110] To 36 mg of 5-trityloxymethyl-2-oxazolidinone, 30 mg (1.5 equivs) 1-bromo-2-nitrobenzene, 2.4 mg (0.1 equivs) palladium (II) acetate, 5.5 mg (0.1 equivs) 1,1′-bis(diphenylphosphino)-ferrocene, 16 mg (0.15 equivs) potassium t-butoxide, and 1 mL toluene were added under a nitrogen atmosphere. The mixture was heated at 110° C. for 14 hours after which time the mixture was resolved by thin-layer chromatography (TLC) comprising silica with dichloromethane as the eluant.
[0111] The TLC indicated complete conversion to a single product: (S)-3-(2-nitro)phenyl-5-trityloxymethyl-2-oxazolidinone. The mixture was cooled and diluted with dichloromethane. The dark brown organic solution was washed with 5% sodium carbonate, concentrated, and chr...
example 3
[0113] This example illustrates the preparation of a library of substituted 2-oxazolidinones, which are members of Family II, according to the process of the present invention. In this example, (S)-5-trityloxymethyl-2-oxazolidinone is N-acylated with 2,5-dimethoxyphenacyl bromide, detritylated, and then acylated with ten different acyl halides or anhydrides to produce a library of n=10 3-(2,5-dimethoxyphenacyl)-5-(substituted methyl)-2-oxazolidinones.
[0114] In the first step (FIG. 1A), (S)-3-(2,5-dimethocyphenacyl)-5-trityloxymethyl-2-oxazolidinone was produced in a reaction comprising (S)-5-trityloxymethyl-2-oxazolidinone and the aryl bromide: 2,5-dimethoxyphenacyl bromide. To a solution of 3.59 g (10 mmoles) of(S)-5-trityloxymethyl-2-oxazolidinone (MW 359.2) in 40 mL THF at 4° C., 400 mg (10 mmoles) NaH (MW 24) as a 60% suspension in hexane was added. The reaction mixture was stirred for about 10 minutes under nitrogen at 0° C. and then warmed up to room temperature and stirred f...
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