Process for the manufacture of a tricyclic compound

Details Process for the manufacture of a tricyclic compound Process for the manufacture of a tricyclic compound

1996-01-04

1999-04-06

Shah, Mukund J.

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

544 66, 544344, 544234, 546156, C07D49806, C07D21558, A61K 31535, C07C24328

Patent

active

058920404

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/00147, filed Jan. 19, 1994.
The present invention relates to a new process for the manufacture of a derivative of the formula ##STR2## and its pharmaceutically acceptable salts. Also included in the present invention are novel intermediates useful in this process.
The compound of formula I, 3,2, 1-ij!-1,3,4-benzoxadiazine-6-carboxylic acid and its pharmaceutically acceptable salts are antibacterially active and useful as effective ingredients in antibacterial agents. They are described in European Patent Specification No. 259 804 together with a process for their manufacture. The process described therein is unpracticable for large scale manufacture, however, in that a multistep process is used which requires high temperatures and untechnical reagents (e.g. 0-(2,4-dinitrophenyl)-hydroxylamine for amination involves danger of explosion) resulting in low over-all yields.
The present invention provides a practical process for manufacturing the compound of formula I in superior yields. Starting from the acid chloride of 2, 3, 4, 5-tetrafluorobenzoic acid, the process can be depicted by the following flow sheet (Scheme I).
Note that Research Disclosure No. 291, 1988, pages 548-551 discloses an alternative route also starting from 2, 3, 4, 5-tetrafluorobenzoic acid. Also that Liebigs Annalen Der Chemie, No. 10, 1987, page 875 discloses the compound 2-(2, 3, 4, 5-tetrafluorobenzoyl)-3-(2-formyl-2-methylhydrazino) acrylic acid-ethyl ester. ##STR3##
In Scheme I R represents alkyl of from one to four carbon atoms, preferably methyl or ethyl, NR.sup.1 R.sup.2 is N,N'-(dicyclohexyl)amino, N-methyi-N'-benzyl-amino or 4-methyl-piperazinyl, M is the cation of an alkali metal hydroxide, and the wavy line () indicates two stereospecific possibilities.
As is seen from the above Reaction Scheme I the manufacture of compound I proceeds over a key intermediate of formula V which is obtained through 3 alternative pathways, the preferable pathways, due to their superior yields, being pathways VII.fwdarw.IVb.fwdarw.V and VII-XI.fwdarw.V.
The various process steps will be discussed in detail hereinbelow.
2,3,4,5-Tetrafluorobenzoic acid chloride VII is converted to the acylated malonic ester VIII via a metal salt of a malonic acid ester, preferably via the magnesium salt of diethyl malonate.
The so-obtained acylated malonic acid ester VIII is subjected to acidic hydrolysis, preferably by refluxing with a sulfonic acid, such as p-toluene sulfonic acid in aqueous medium, to yield the monoester IX.
Said monoester IX is converted to the alkoxyacrylic acid ester IVa by refluxing with a trialkyl orthoformate (preferably triethyl orthoformate) in an organic solvent, which is preferably acetic acid anhydride.
The alkoxyacrylic acid IVa is reacted with N-amino-N-methyl-formamide in an inert organic solvent, preferably toluene at about room temperature to yield product V.
Compound V is cyclized to the 1-(N-methylformamido)-quinoline derivative VI by heating the reaction solution, preferably up to reflux temperature, preferably in the presence of a base, such as a lower trialkyl-amine, e.g. triethylamine, or an alkali metal carbonate, e.g. sodium carbonate.
The compound VI is reacted with N-methylpiperazine to yield the substitution product III, preferably at reflux temperature in the same solvent as the previous reaction and under the same basic conditions.
Compound III is reacted with an alkali metal hydroxide, preferably potassium hydroxide, in an aqueous medium at about 80.degree. C. to 120.degree. C., preferably reflux, for about 20 to 100 hours. In this reaction surprisingly a fluorine/hydroxy exchange is effected in position 8, which goes to practical completion by utilizing at least about 10 mol equivalents of alkali metal hydroxide and increasing the reaction time to about 70 to 100 hours. The alkali metal hydroxide is preferably present in a concentration of about 10 to 20% by weight of the aqueous solution.
The 1-(N-methylamino)-quinoline derivative II obtained in this manner is cyclized to the

REFERENCES:
patent: 4666920 (1987-05-01), Grohe et al.
patent: 4689423 (1987-08-01), Beylin et al.
patent: 4753925 (1988-06-01), Grohe et al.
patent: 4769492 (1988-09-01), Kaieda et al.
patent: 4769493 (1988-09-01), Ito et al.
patent: 4782180 (1988-11-01), Wemple et al.
patent: 4801584 (1989-01-01), Yokose et al.
patent: 4831190 (1989-05-01), Ataka et al.
patent: 4864023 (1989-09-01), Yokose et al.
Research Disclosure, `Process for the manufacture . . . ` No. 291, 1988, New York USA, pp. 548-551.
Grohe, K., et al. `Synthese von . . . ` Liebigs Annalen der Chemie., No. 10, 1987, Weinheim DE, pp. 871-879.
Derwent Abstract 94-062042/08, Katayama Seiyakusho KK (94.01.25).

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