Quinoline derivatives and processes for the preparation thereof

Details Quinoline derivatives and processes for the preparation thereof Quinoline derivatives and processes for the preparation thereof

1991-03-19

1992-11-24

Springer, David B.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546152, 546167, C07D40306

Patent

active

051663546

DESCRIPTION:

BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATION

This application is a national phase of PCT/HU90/00050 filed Jul. 20, 1990 and based upon Hungarian national application A3736/89 filed Jul. 25, 1989 and modified Jul. 3, 1990, under the International Convention.


FIELD OF THE INVENTION

The present invention is directed to a process for the preparation of quinoline derivatives of the formula (I) ##STR3## wherein R.sup.1 stands for hydrogen or a group of the formula (II) ##STR4## by reacting a halogen quinoline derivative of the formula (III) ##STR5## wherein X stands for chlorine or bromine with picoline oxide of the formula (IV) ##STR6## in the presence of alkali-t-alkylate, preferably potassium-t-butylate or b) oxidizing a compound of the formula (V). ##STR7## The definition of the substituents is as follows: R.sup.1 stands for hydrogen or a group of the formula (II)
The novel compounds according to the present invention are important intermediates for the preparation of pharmaceutically active compounds. Thus, for instance the novel compounds are valuable intermediates of erythro-alpha-2-piperidyl-2,8-bis(trifluoro-methyl)-quinoline-4-methanol-h ydrochloride (meflokin) or mefloquin. This latter active ingredient can be successfully used in pharmaceutically active compositions against malaria.


BACKGROUND OF THE INVENTION

Meflokin has been first prepared (see J. Med. Chem. 14, 926 (1971)) by reacting a 2,8-bis(trifluoro-methyl)-quinoline-4-carboxylic acid synthesized in three steps with 2-lithio-pyridine and by hydrating the obtained 2-pyridyl-2,8-bis(trifluor-methyl)-quinolyl-ketone ("Ketone") above Adams-catalyst. From the above quinoline carboxylic acid intermediate the ketone was obtained also by reacting it with 2-bromo-magnesiumpyridine (DOS 29 40443), and by hydrogenating the "ketone" analogously to meflokin above a platina charcoal catalyst. The unisolated intermediate of the reduction step (2-pyridyl)-2,8-bis(trifluor-methyl)-quinoline-4-methanol is referred to hereinafter as "Oxy-methane". This compound can be obtained also by reacting 4-lithio-quinoline derivatives obtained from 2,8-bis(trifluoro-methyl)-4-bromo-quinoline by lithiation with 2-pyridine-aldehyde (DOS 28066909). According to a newer technical solution the metallation step is eliminated and thereby a less expensive starting material can be used compared to the so far known quinoline intermediates. When reacting 2,8-bis(trifluoro-methyl)-4-chloro-quinoline with 2-pyridyl-acetonitrile or with 2-pyridyl-methyl-phosphonium salt the obtained intermediate results in ketone by oxidation. According to the authors in these cases in order to subject the halogen of the quinoline in 4-position to nucleophilic substitution the pyridine reactant has to contain on the methyl group an electron withdrawing substituent (see the above mentioned carbonitrile or phosphonium group) (EP0049776).
In EPA 0049 776 in Example 1 the aromatic nucleophilic substitution of 2-methyl-pyridine-N-oxide has been mentioned and was carried out with sodium amide in dimethoxy-ethane, but the structure of the obtained product has not been determined, no physical-chemical data were given and the reference was cancelled from the granted patent.
The above mentioned processes have several disadvantages, such as the already mentioned metallation steps or the expensive quinoline intermediates (such as 2,8-bis(trifluoro-methyl)-4-bromo-quinoline or the corresponding quinoline-4-carboxylic acid) and the pyridine derivatives are expensive and not easily accessible.
These disadvantages could be successfully eliminated by using a quinoline intermediate of the formula (III) and 2-methyl-pyridine-N-oxide. The quinoline intermediate of the formula (III) is prepared by our method disclosed in U.S. Pat. No. 4,599,345 and U.S. Pat. No. 4,659,834 which is also suitable for the industrial synthesis of 2,8-bis(trifluoro-methyl)-4-chloro-quinoline. We have now found that as opposed to the teaching of EP 0 049 776 the electron withdrawing substituent is not necessary on the methyl group of picoline

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