914-00-1

Rondomycin ,Pfizer ,UK ,1963

Methacycline is a semi-synthetic tetracycline prepared by dehydration of the 6-hydroxy group of oxytetracycline to yield an exocyclic 6-methylene. Like all tetracyclines, methacycline shows broad spectrum antibacterial and antiprotozoan activity and acts by binding to the 30S and 50S ribosomal subunits, blocking protein synthesis. Methacycline has been extensively cited in the literature with over 400 references.

ChEBI: A tetracycline that is the 6-methylene analogue of oxytetracycline, obtained by formal dehydration at position 6.

To a stirred solution of 4.6 g (0.01 mol) of anhydrous oxytetracycline in 40 ml of dry tetrahydrofuran is added 3.5 g (0.021 mol) of pyridine-sulfur trioxide complex. After 16 hours of stirring at room temperature, the resulting suspension is filtered, and the solid is slurried with 25 ml of 2% hydrochloric acid for 10 minutes, filtered and thoroughly washed with methanol followed by ether. The pale yellow crystalline 5-oxytetracycline-6,12-hemiketal-12-sulfuric acid ester melts at 210°C.
500 mg 5-oxytetracycline-6,12-hemiketal-12-sulfuric acid ester, prepared as described, is added to 4 ml dry liquid hydrogen fluoride, and the mixture is stirred for 1.5 hours at ice bath temperature. The hydrogen fluoride is then evaporated in a stream of nitrogen and the resulting gummy solids are triturated with about 15 ml ether and filtered. The resulting solid hydrofluoride salt is further purified by suspending in water, adjusting the pH to about 4, and extracting the 6-methylene-5-oxytetracycline free base from the aqueous phase with ethyl acetate. The extract is separated and evaporated to dryness under reduced pressure. The resulting residue is triturated with ether and filtered, and the solid is recrystallized from methanol-acetone-etherconcentrated hydrochloric acid to obtain the product as a purified hydrochloride, according to US Patent 3,026,354.

Rondomycin (Medpointe).

Antibiotic

6-Methylene-5-hydroxy-tetracycline. A semisynthetic derivative supplied as the hydrochloride for oral administration.
Mean peak plasma concentrations of 2–6 mg/L are found about 4 h after a 300 mg oral dose. Both food and milk reduce uptake by half. Protein binding is 80–90%. The plasma elimination half-life varies between 7 and 15 h and increases to 44 h in severe renal impairment. It is widely distributed, producing lung concentrations similar to, or greater than, the simultaneous plasma concentration. About one-third is excreted in the urine.
Gastrointestinal intolerance is reported to be less frequent than with other tetracyclines, largely because of the lower dosages used. There are no unique adverse drug reactions, although skin and conjunctival pigmentation have been reported.

Methacycline, 4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10, 12,12a-pentahydroxy-6-methylen-1,11-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–sulfotetrahydrofuran derivative intermediate (32.3.5), which when reacted with hydrofluoric acid forms methacycline (32.3.6).