Methyl-quinoline derivatives as mefloquin intermediates and proc

Details Methyl-quinoline derivatives as mefloquin intermediates and proc Methyl-quinoline derivatives as mefloquin intermediates and proc

1991-03-19

1992-12-29

Springer, David B.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546174, C07D40306

Patent

active

051752972

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to a process for the preparation of methyl-quinoline derivatives of the formula (I) ##STR3## and salts thereof. The compounds of the formula (I) can be prepared by rearranging an N-oxide derivative of the formula (III) ##STR4## with an organic carboxylic acid derivative containing halogen, preferably with a halogene substituted C.sub.1-8 aliphatic or aromatic carboxylic anhydride or carboxylic acid halide and by reducing the obtained ester of the formula (IV) ##STR5## after or before solvolizing the ester group. The definition of the substituents in the present application is as follows: ##STR6## R.sup.2 stands for acyloxy or hydroxyl, R.sup.3 stands for a group of the formula (II) and
The compounds prepared according to the present invention are novel important intermediates for the preparation of pharmaceutically active compounds. Thus erythro-alfa-2-piperidyl-2,8-bis(trifluoro-methyl)-quinoline-4-methanol-hy drochloride (meflocin) can be prepared from the above compounds. This active ingredient can be used as antimalaria substance.


BACKGROUND OF THE INVENTION

Meflocin has been first prepared (J. Med. Chem. 14 926 (1971)) by hydrating 2-pyridyl-2,8-bis(trifluoro-methyl)-quinolyl-ketone ("Ketone" hereinafter) above Adams catalyst and 2-pyridyl-2,8-bis(trifluor-methyl)-quinolyl-ketone is obtained from 2,8-bis(trifluoro-methyl)-quinoline-4-carboxylic acid synthetized in three steps with 2-lithio-pyridine. Starting from the above quinoline carboxylic acid intermediate "ketone" has been obtained also by reacting same with 2-bromo-magnesium-pyridine (DOS 29 40443) which analogously was hydrogenated to mefloquin in the presence of platina-charcoal catalyst. (2-pyridyl)-2,8-bis(trifluoro-methyl)-quinoline-4-methanol which is an unisolated intermediate of the reduction step is called hereinafter "Oxy-methane". This Oxy-methane can be also obtained by subjecting 2,8-bis(trifluoro-methyl)-4-bromo-quinoline to lithiation and by reacting the formed 4-lithio-quinoline derivative with 2-pyridine-aldehyde (DOS 28066909). According to a recent approach the metallation step is eliminated so that the use of less expensive starting material than quinoline intermediates became possible. By reacting 2,8-bis(trifluoro-methyl)-4-chloro-quinoline with 2-pyridyl-aceto-nitrile or 2-pyridyl-methyl-phosphoniumsalt "ketone" is obtained by oxidizing the formed intermediate. According to the authors for the nucleophilic substitution of the halogen of the quinoline in the four-position the pyridine derivative has to contain an electron withdrawing substituent on the methyl group (such as the above mentioned carbonitrile or phosphonium group) (EP 0049776).
The industrial realization of the above described processes has several disadvantages, such as the mentioned metallation steps and the expensive quinoline intermediates, such as 2,8-bis(trifluoro-methyl)-4-bromo-quinoline or the corresponding quinoline-4-carboxylic acid (due to the use of the expensive and not easily available pyridine derivatives as disclosed above.


DESCRIPTION OF THE INVENTION

These disadvantages are eliminated by the process of the invention, according to which quinoline intermediate of the formula (III) obtained by our method disclosed in U.S. Pat. No. 4,599,345 and U.S. Pat. No. 4,659,834 suitable for the industrial synthesis of 2,8-bis(trifluoro-methyl)-4-chloro-quinoline and 2-methyl-pyridine-N-oxide.
In the course of our experiments we have found that as opposed to the above said teaching in EP 0 049 776 there is no need to have an electron withdrawing substituent on the methyl group of picoline and a less expensive and more readily available 2-methyl-pyridine-N-oxide can be reacted without this substituent. The preparation of the N-oxide compounds is described in our Hungarian patent application No. .3736/89, 3736/89 (corresponding to PCT/HU90100080 and U.S. application Ser. No. 671,916 whereas according to the present invention the oxymethane derivative is obtained by rearranging the above compounds.

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