Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-03-11
1999-08-17
Dentz, Bernard
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D47104
Patent
active
059395508
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a new and useful process for preparing a naphthyridine carboxylic acid. More particularly, it is concerned with a novel method for preparing ex-3-yl!-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridin e-3-carboxylic acid as a pharmaceutically acceptable acid addition salt. It is especially concerned with the preparation of the corresponding methanesulfonic acid salt of the aforementioned naphthyridine carboxylic acid, which serves as a water-soluble prodrug of the known antibacterial agent uoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1-naphthyridine-3-carboxylic acid.
In accordance with the prior art, there is described in U.S. Pat. No. 5,164,402 to K. E. Brighty a method for preparing ex-3-yl-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine -3-carboxylic acid (prodrug acid) by first reacting oro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid with N-tert.-butoxycarbonyl-L-alanine, to eventually yield the intermediate mono-L-Ala-amino prodrug, followed by an additional reaction of the latter product with still further N-tert.-butoxycarbonyl-L-alanine to ultimately yield the desired prodrug final product. The same patent reference also describes the conversion of oro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid to ex-3-yl!-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridin e-3-carboxylic acid by first reacting the aforesaid N-deprotected drug acid starting material with N-benzyloxycarbonyl-L-alanyl-L-leucine to eventually give the corresponding prodrug acid compound having two different amino acids in the side chain at the 6-position of the molecule. In each instance, the N-deprotected drug acid is obtained from the corresponding N-protected drug ethyl ester by means of acid hydrolysis with hot concentrated hydrochloric acid at reflux temperatures, while the prodrug acid final product obtained in the last step is also achieved in essentially the same manner, but under somewhat milder reactions conditions. In the aforesaid process, it is possible for the unprotected carboxy group of oro-1-(2,4-difluoro-phenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxyli c acid to engage in a number of side reactions of the self-condensation type, thereby leading to somewhat diminished yields of the desired prodrug acid final product of the present invention.
BACKGROUND ART
In accordance with the present invention, there is now provided a new and improved process for preparing the prodrug herein before discussed above, viz., ex-3-yl-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine -3-carboxylic acid as a pharmaceutically acceptable acid addition salt, in pure form and in high yield by a novel three-step method, starting from the appropriate N-protected drug ester that is typically an N-protected o-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid lower alkyl (C.sub.1 -C.sub.4) ester and proceeding through the following sequence of reactions, as outlined in the accompanying reaction scheme. ##STR1##
More particularly, the overall process of the invention involves the steps of:
(a) treating an N-protected oro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic N-protecting group like benzyloxycarbonyl, C.sub.1 -C.sub.4 alkoxycarbonyl or C.sub.1 -C.sub.4 alkanoyl and R" is an alkyl group having from one to four carbon atoms, with a strongly-protic acid to selectively remove the N-protecting group; (III)! in the presence of dehydrating agent to form the corresponding N-protected prodrug ester as the desired condensation product; and formula (I)! in the presence of a pharmaceutically-acceptable strong acid to convert said intermediate N-protected prodrug ester to the corresponding naphthyridinone L-Ala-L-Ala prodrug acid final product pharmaceutically acceptable acid addition salt.
In this way, for example, a compound such as thyridine-3-carboxylic acid ethyl ester is readily converted, via the intermediates uoro-1-(2,4-di
REFERENCES:
patent: 4851418 (1989-07-01), Sanchez
patent: 5164402 (1992-11-01), Brighty
Chemical Abstracts, vol. 111, No. 17, Abstract No. 153779 w (1989).
Braish Tamim F.
Castaldi Michael J.
Watson, Jr. Harry A.
Dentz Bernard
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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