Ether, iodomethyl ethyl

More recently, Kim and coworkers have developed a novel radical alkylation reaction of organic nitro derivatives 16a-d via bis(silyloxy)enamines 17a-d (Scheme 16). This method enables not only P -alkylation to the nitro gronp, bnt also the conversion of the nitro group (16a-d) into an oxime ether fnnctionahty (18a-d). The irradiation of a solntion of 16a-d with iodomethyl phenyl snlfone (or ethyl iodoacetate) and hexamethylditin in benzene at 300 nm give the oxime ethers 18a-d in good yields. 

A mixture of 7-[(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxilate (4.5 g, 4.83 mmoles) and N-methylpyrrolidine (0.65 ml, 6.28 mmoles) in CH2CI2 (45 ml) was stirred at room temperature for 20 min. Ether (300 ml) was added to the mixture to separate the quaternary salt of the blocked cephalosporin, which was collected by filtration and treated with 90% trifluoroacetic acid (TFA) (40 ml) at room temperature for 1 hour. The mixture was then evaporated under reduced pressure below 20°C. The residue was triturated with ether to give the TFA salt of 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate (2.40 g), which was dissolved in methanol (5 ml) and treated with 1 M solution of sodium-2-ethylhexoate in ethyl acetate (8 ml) at room temperature for 30 min. After the addition of ethyl acetate (100 ml), the precipitate (1.94 g) formed was collected by filtration. HPLC analysis showed that the crude product was 7% pure with a 1 8 ratio of the S3 isomer to the S2 isomer. Purification of the product by HPLC was repeated three times (Lichrosorb RP-18, eluted with 5% aqueous methanol or 0.01 M ammonium phosphate buffer (pH 7.2 containing 5% of methanol) to give 35 mg (1.5%) of the title product as a colorless powder of 7-[(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate. Estimated purity (by HPLC) 90%. M.p. 150°C (dec.). 

Step 2 Preparation of iodomethyl-2-(trimethylsilyloxy)ethyl ether... 

R ace the mixture obtai ned i n step 1 i nto a dry i ce/acetone bath, and then add 100 mi 11 i I iters of dry cyd ohexene, and then 60 milliliters of dry 1,3-dioxolane. During the additions, rapidly stir the reaction mixture. After the addition, stirthereadion mixture for 1 hour. After stirring for 1 hour, keepthereadion mixture containing the iodomethyl-2-(trimethylsilyloxy)ethyl ether in the dry ice/acetone bath for step 3. 

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