Substituted Fused Ring Tetracycline Compounds

Patent 7-Substituted Fused Ring Tetracycline Compounds 

Nelson etal, US Patent 6,642,270 (November 4, 2003) Assignee Paratek Pharmaceuticals, Inc. 

Sancycline (Ig) was dissolved in 25 ml trifluoroacetic acid, N-iodosuccinimide (1.2 eq) added, and the reaction stirred 40 minutes at 0 °C and 5 hours at ambient temperature. The mixture was concentrated, dissolved in 3 ml methyl alcohol, and precipitated in diethyl ether. The product was purified by treating with activated charcoal, filtering through celite, and isolated in 75% yield. H-NMR and MS data supplied. 

The product from Step 1 (0.3 mmol) was added to palladium(II)acetate (8.4 mg), 5 ml methyl alcohol, and Na2C03 (3 eq) dissolved in 2 ml water. Thereafter 3, 4 -methylenedioxyphenyl boronic acid (2 eq) dissolved in 5 ml methyl alcohol was added, the mixture reacted 2 hours, then concentrated in vacuo to produce the crude product. The mixture was purified by preparative HPLC using divinylbenzene as the solid phase with trifluoroacetic acid (0.1%)/acetonitrile with a gradient of 0-100% acetonitrile over 20 minutes. The fraction was removed, concentrated, the residue dissolved in methyl alcohol, and hydrogen chloride gas introduced. The salt was concentrated and the product isolated in 43% yield. H-NMR and MS data supplied. 

The coupling of 3 4 -methylenedioxyphenyl boronic acid to 7-iodosancycline in the presence of a palladium salt is an example of the Suzuki reaction and is described (1). 

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Tetracyclines [tet ra SYE kleen] are a group of closely related compounds that, as the name implies, consist of 4 fused rings with a system of conjugated double bonds. Their small differences in clinical efficacy reflect a variation in their individual pharmacokinetics due to substitutions on these rings. 

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