Process for the preparation of rufloxacin and salts thereof

Details Process for the preparation of rufloxacin and salts thereof Process for the preparation of rufloxacin and salts thereof

1996-04-24

1998-03-24

Shah, Mukund J.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

544362, 544363, C07D51300, C07D27908, C07D27902, C07D27914

Patent

active

057314330

DESCRIPTION:

BRIEF SUMMARY
The present invention concerns a process for the preparation of rufloxacin and salts thereof. More particularly, the invention relates to a process for the preparation of rufloxacin hydrochloride starting from a new quinolone disulfide, to novel intermediates in such a preparation and to the hydrolysis of rufloxacin esters to rufloxacin hydrochloride.
Rufloxacin is the International Non-proprietary Name of ##STR2## which is a quinolone antibiotic having a broad and powerful antibacterical activity on Gram-positive and Gram-negative microorganisms as well as a low toxicity and favorable pharmacokinetics.
In clinical trials rufloxacin is used in form of its hydrochloride salt; it is described by V. Cecchetti et al. in J. Med. Chem. 1987, 30, 465-473.
The most convenient method described heretofore for the preparation of rufloxacin hydrochloride is the one-pot synthesis of V. Cecchetti et al., Synthetic Communications, 1991, 21(22) 2301-2308 which, starting from ethyl 2,3,5-trifluoro-4-(4-methyl-1-piperazinyl) benzoylacetate, leads to the desired compound in a 61% total yield.
It has now been found that, starting from a quinolone disulfide, rufloxacin hydrochloride can be obtained one-pot in very high yields. Since the starting quinolone disulfide is, in its turn, obtained in high yield from an ester of 2,3,5-trifluoro-4-(4-methyl-1-piperazinyl) benzoylacetic acid, the obtention of rufloxacin hydrochloride occurs in a safer manner and in higher yields in respect of the known methods.
More particularly, it has been found that, starting from a quinolone disulfide of formula (II) ##STR3## in which R represents an alkyl group of from 1 to 4 carbon atoms, more particularly methyl or, preferably, ethyl, rufloxacin hydrochloride is obtained according to the following reaction scheme: ##STR4## wherein R is as defined above, in a yield of at least 75%.
Thus, it is an object of the present invention to provide a process for the preparation of rufloxacin hydrochloride which comprises reacting a quinolone disulfide of formula (II), wherein R is an alkyl group of from 1 to 4 carbon atoms with a reducing agent, cyclizing the mercaptane of formula (III) with a base in an organic solvent, saponifying the rufloxacin ester of formula (IV) and isolating rufloxacin as hydrochloride.
In step (a), the reduction is carried out with a reducing agent such as sodium hydride, sodium metabisulfite, triphenylphosphine and an acid such as acetic acid or zinc and hydrochloric acid according to conventional methods.
In step (b), the cyclization is carried out with a base, such as sodium or potassium carbonate and sodium hydride, in an organic solvent, preferably N,N-dimethylformamide.
In step (c), the rufloxacin ester (IV) is subjected to a saponification, for example in acidic medium or with a base, such as sodium hydroxide as described by V. Cecchetti et al. in Chemical Communication, 1991, 21(22), 2301-2308.
More particularly, it has been found that, by treating the rufloxacin ester (IV), or a salt thereof, with hydrochloric acid, rufloxacin hydrochloride is isolated in a pure state in practically quantitative yield.
Thus, it is a further object of the present invention to provide a process for converting a rufloxacin (C.sub.1 -C.sub.4) alkyl ester into rufloxacin hydrochloride, which comprises reacting said rufloxacin ester of formula (IV), or a salt thereof, with hydrochloric acid. This hydrolysis takes place using concentrated hydrochloric acid, diluted with water or with glacial acetic acid as solvents, preferably at the boiling point of the reaction mixture, and rufloxacin hydrochloride is isolated by adding a precipitating solvent, preferably acetone. The yield is almost quantitative. After a purification with ethanol/water, the yield is from 88 to 95% of the theoretical in rufloxacin hydrochloride for pharmaceutical use.
Beside the improved yields, the acid hydrolysis of the ester according to the present invention has the advantage over the known saponification in a basic medium, of being carried out without any need of monitorin

REFERENCES:
patent: 4772605 (1988-09-01), Naik et al.

Affiliated with

Also associated with

Rating

Process for the preparation of rufloxacin and salts thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of rufloxacin and salts thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of rufloxacin and salts thereof will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2289857