6-Methylene-5-oxytetracycline

Hydrogen was introduced into a standard hydrogenation vessel containing 10 grams 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline hydrochloride (methacycline), 150 ml methanol and 5 grams 5% rhodium on carbon. The pressure was maintained at 50 psi while agitating at room temperature for 24 hours. The catalyst was then filtered off, the cake washed with methanol and the combined filtrates were evaporated to dryness. The dry solids were slurried in ether, filtered and the cake dried. The resulting solids exhibited a bioactivity of 1,345 units per mg versus K. pneumoniae. 

Hydrogen was introduced into a standard hydrogenation vessel containing 10 grams 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline hydrochloride... 

Some other members of the tetracycline family may conveniently be named as follows Methacycline 6-Methylene-5-oxytetracycline ... 

Methylenetetracycline > tetracycline > 6-deoxy-5-oxytetracycline > 5-oxytetracycline > 6-methylene-5-oxytetracycline Ref. 

Demethyl-6-deoxy-6-methylene-5-oxytetracycline was obtained in 90% yield by dehydration of lla-chloro-5-oxytetracycline-6,12-hemiketal or its salts by treatment with a mixture of chlorosulfonic and formic acid in dichloromethane at... 

The three tetracyclines most recently marketed were made by a semisynthetic pathway. The first of these were methacycline (6-methylene oxytetracycline) (5), C22H22N2OS. and its reduction product doxycycline (6). C22H24CIN2O2- The latter compound is a potent antibiotic which is well-absorbed and slowly excreted, thus allowing small and infrequent (once or twice a day) dosage schedules. Finally, the most recent addition to the commercial tetracyclines is minocycline (7). C21H27N3O7. which is also well-absorbed and slowly excreted. 

Methacycline Methacycline, 4-dimethylamino-l,4,4a,5,5a,6,ll,12a-octahydro-3,6,10, 12,12a-pentahydroxy-6-methylen-l,ll-dioxo-2-naphthacencarboxamide (32.3.6), is synthesized from oxytetracycline (32.3.2), which is reacted with a sulfur trioxide— pyridine complex, resulting in an oxidation reaction. Simultaneous sulfonation gives a naphthacen-snlfotetrahydrofuran derivative intermediate (32.3.5), which when reacted with hydrofluoric acid forms methacycline (32.3.6) [222-225]. 

Structural susceptibilities and structure/activity studies have both inspired a large amount of semi-synthetic vrork to find more stable compounds without loss of antibacterial activity. The less active 6p methyl isomer of doxycycline (6) has been derived from oxytetracycline (3 R = OH) by catalytic reduction.. Treatment of (3) with N-chlorosuccinimide followed by hydrofluoric acid gave the chloro compound (X) which upon catalytic reduction afforded doxycycline (6), the 6a compound together with the less active 6p isomer (refs.250, 251) by saturation of the methylene group and removal of chlorine from (X). Reductive treatment of (X) with sodium hydrosulphite produced methacycline (5). The corresponding 5-deoxy analogues have likewise been derived by using tetracycline (3 R = H) in the same reaction sequences. 

Several workers (28-29) reported an increase in the methylene blue reduction time when 0.05-0.5 lU Penicillin were present per milliliter of milk. Similarly, Manokidis et al. (30) noted that Penicillin and Oxytetracycline were responsible for a false positive phosphatase test in pasteurized or partially pasteurized milk while Streptomycin, Erythromycin and Neomycin inhibited the phosphatase test to some extent in partially pasteurized milk, but not in raw milk. Although raw milk containing antibiotic residues was never mistakenly identified as pasteurized, these authors suggested that as a "precaution" antibiotic assays be run in conjunction with the phosphatase test. 

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