Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-06-23
1991-04-30
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
544 94, 564218, 568 29, 568 36, 568 43, 568335, C07D215316, C07C23315
Patent
active
050119311
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for the preparation of certain quinolone compounds.
UK Patent 2047691 describes quinolone compounds having therapeutic activity as antihypertensive agents and also describes various processes for their manufacture. EP 149519 also describes some of these quinolone compounds having therapeutic activity in the treatment of heart failure.
UK 2047691 discloses that certain quinolones may be prepared by reacting 8-ketosulphoxides of the general formula ##STR3## in which R.sub.1 ' is lower alkyl, with a tri(lower alkyl)orthoformate.
We have now prepared valuable novel compounds useful in a process to produce some of the quinolones described in UK 2047691. These novel compounds have an inherent property not possessed by the above-described .beta.-ketosulphoxides, namely that they will undergo intramolecular cyclisation to produce said quinolone compounds.
The present invention provides a process to prepare compounds of formula I, ##STR4## in which n is 0, 1 or 2, comprising the cyclisation of compounds of formula II, ##STR5## in which n is 0, 1 or 2.
Compounds of formula I have valuable therapeutic activity in the treatment of cardiovascular diseases, especially in the treatment of hypertension and heart failure. A specific compound of formula I provided by a process according to the present invention is 7-fluoro-1-methyl-3-methylthio-4-quinolone. This compound may be oxidised by known methods to give 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone, (flosequinan), for example by reaction with 3-chloroperoxybenzoic acid (see, for example UK 2047691). Flosequinan has especially valuable therapeutic activity in the treatment of heart failure and hypertension.
It has been found that the yields provided in a process according to the present invention are generally greater than 60%, with preferred processes providing a yield in excess of 80%. The yields are reproducible and are unexpectedly high, particularly in view of the potential for forming side-products, for example by deformylation of compounds of formula II before the cyclisation reaction has been completed.
The cyclisation reaction may be effected in the presence of an organic or inorganic base, for example triethylamine, sodium ethoxide or sodium hydroxide, or by heating the compound of formula II in a suitable liquid, inert to the conditions of the reaction, to a temperature in the range 40.degree.-160.degree. C. The liquid is preferably a solvent for the compound of formula II, e.g an alcoholic solvent such as isopropyl alcohol, 1-octanol or 2-methoxyethanol.
It has been observed that particular process advantages are obtained in a process according to the invention when n is 1 or 2, especially when n is 2.
Preferably the cyclisation reaction in a basic medium is effected in the presence of an amine or an ion selected from hydroxide ion, alkoxide ion or thiolate ion. Particularly suitable bases useful in the cyclisation reaction are sodium hydroxide, sodium ethoxide, triethylamine and pyridine. Preferably the base is sodium hydroxide in aqueous solution.
The thermal cyclisation of compounds of formula II represents a preferred feature of the invention as particularly valuable yields of the product are obtained. The thermal cyclisation of compounds of formula II to compounds of formula I in which n is 1 or 2 is especially preferred as yields in excess of 95% may be obtained. Advantageously the compounds of formula II are cyclised in separate temperature ranges according to the oxidation state of the compound. When n is O, the cyclisation reaction is preferably carried out at a temperature in the range 130.degree.-160.degree. C., especially 140.degree.-160.degree. C.; when n is 1 the cyclisation reaction is preferably carried out at a temperature in the range 80.degree.-160.degree. C., especially 120.degree.-140.degree. C.; when n is 2 the cyclisation reaction is preferably carried out at a temperature in the range 40.degree.-160.degree. C., especially 90.degree.-140.degree. C. This reaction is preferably carried out at atmo
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Barron Kenneth
Harrison Albert E.
MacLean Lachlan
Nichol Kenneth J.
Roberts David L.
Bernhardt E.
Shah Mukund J.
The Boots Company PLC
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