The formylation of benzyl 6beta-aminopenicillanate (I) with formic acid and dicyclohexylcarbodiimide in ethyl acetate gives the corresponding formamido derivative (II), which is treated with phosgene in methylenechloride containing triethylamine to yield benzyl 6beta-isocyanopenicillanate (III). The reaction of (III) with methyl methoxycarbonyl disulfide (A) by means of K2CO3 in DMF affords benzyl 6beta-isocyano-6alpha-methylthiopenicillanate (IV), which is treated with p-toluenesulfonic acid hydrate in CHCl3, giving benzyl 6beta-amino-6alpha-methylthiopenicillanate (V). The treatment of (V) with HgCl2 pyridine in methanol yields benzyl 6beta-amino-6alpha-methoxypenicillanate (VI) , which is condensed with 2-benzyloxycarbonyl-2-(thien-3-yl)acetyl chloride (VII) by means of pyridine in methylene chloride to afford benzyl 6beta-[2-(benzyloxycarbonyl)-2-(thien-3-yl)acetamido]-6alpha-methoxypenicillanate (VIII). Finally, this compound is debenzylated by hydrogenolysis with H2 over Pd/C in aqueous ethanol, and treated with NaHCO3.
The reaction of p-nitrobenzyl 6beta-[2-(p-methylphenoxycarbonyl)-2-(thien-3-yl)acetamido]penicillanate (IX) with PCl5 and pyridine in benzene gives p-nitrobenzyl 6beta-[2-(p-methylphenoxycarbonyl)-2-(thien-3-yl)ketenimino]penicillanate (X), which is treated with Cl2 (or Br2) at -70 C in THF, followed by addition of lithium methoxide (or NaHCO3) in methanol to yield p-nitrobenzyl 6beta-[2-(p-methylphenoxycarbonyl)-2-(thien-3-yl)ketenimino]-6alpha-methoxypenicillanate (XI). The treatment of (XI) with H3PO4 in THF yields p-nitrobenzyl 6beta-[2-(p-methylphenoxycarbonyl)-2-(thien-3-yl)acetamido-6alpha-methoxypenicillanate (XII), which is debenzylated with H2 over Pd/C in ethanol to the corresponding free penicillanate (XIII). Finally, the p-methylphenyl ester is hydrolyzed with Na2B4O7 in water and treated with sodium 2-ethylhexanoate in isobutyl ketone (B).