CH640531A5 - Alpha-2-pyridyl-2,8-bis-(trifluoromethyl)-4-quinolinemethanol - Google Patents

Abstract

alpha -2-Pyridyl-2,8-bis-(trifluoromethyl)-4-quinolinemethanol, its preparation by reacting 2,8-bis-(trifluoromethyl)-4-bromoquinoline with n-butyllithium and reacting the resulting 2,8-bis-(trifluoromethyl)-4-quinolyllithium with pyridine-2-aldehyde. The compound is an intermediate in the preparation of mefloquine.

Description

640531

2nd

PATENT CLAIMS

1. a-2-pyridyl-2,8-bis (trifluoromethyl) -4-quinoline-methanol.

2. Process for the preparation of a-2-pyridyl-2,8-bis (tri-fluoromethyl) -4-quinoline methanol, characterized in that 2,8-bis (trifluoromethyl) -4-bromoquinoline with n-butyllithium and the resulting 2,8-bis (trifluoro-

methyl) -4-quinolyllithium with pyridine-2-aldehyde to react.

3. Use of a-2-pyridyl-2,8-bis (trifluoromethyl) -4-quinoline-methanol for the preparation of mefloquine or one of its physiologically tolerable salts by hydrogenation with 3 molar equivalents of hydrogen.

Mefloquine, erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) - Ohnmacht et al., J. Med. Chem. 14,926 (1971)]. 4-quinoline-methanol (I), a known compound which belongs to the The present invention relates to a new intermediate

Treatment of malaria has been used to produce mefloquine, namely that previously in a 6-step synthesis from 2-trifluoromethylaniline a-2-pyridyl-2,8-bis (trifluoromethyl) -4-quinoline methanol of over 2, 8-bis (trifluoromethyl) -4-bromoquinoline prepared [CJ is formula ii

The new process for the preparation of mefloquine, in which the compound II is an intermediate, is characterized in that 2,8-bis (trifluoromethyl) -4-bromo-quinoline (IV) is reacted with n-butyllithium, the resulting 2nd , 8-bis (trifluoromethyl-4-quinolyllithium (III) with pyridine-2-aldehyde to react and the resulting a-2-pyridyl

2,8-bis (trifluoromethyl) -4-quinoline methanol (II) hydrogenated with 3 molar equivalents of hydrogen.

40 The individual reactions of this process as well as the preparation of the starting material IV from 2- (trifluoromethyl) aniline according to Ohnmacht et al. are shown schematically in the following overview.

Reaction scheme oh o: c2h5

oTö

Cfv,

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Reaction scheme (continued)

n-C4H!> Li

IV

cho

O O

3Hz

While in the Ohnmacht et al. the compound IV, 2,8-bis- (trifluoromethyl) -4-bromoquinoline, treated with n-butyllithium and the 4-lithium derivative obtained was carboxylated to the 4-carboxy derivative, which was reacted with 2-lithium pyridyl before the hydrogenation, according to the The method outlined above reacted the compound IV with n-butyllithium to give 2,8-bis (trifluoromethyl) -4-lithium quinoline, which is then reacted, if appropriate in situ, with pyridine-2-aldehyde. This reaction sequence is preferably carried out at a low temperature, in a range from about -30 ° C. to about -70 ° C., in particular at -70 ° C. or below, depending on the solvent. Suitable solvents are ether, such as tetrahydrofuran or diethyl ether, or hydrocarbons, such as hexane, and mixtures thereof. In a preferred embodiment, the reaction can be carried out in diethyl ether / n-hexane (1: 1, v / v). The ct-2-pyridyl-2,8-bis (trifluoromethyl) -4-quinoline methanol (II) can be made from

55

6 «

the reaction mixture in a manner known per se, e.g. by crystallization.

In the last stage, the a-2-pyridyl-2,8-bis (trifluoromethyl) -4-quinoline methanol according to the invention is converted into erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) with 3 molar equivalents of hydrogen. 4-Quinoline methanol (I) hydrogenated. The hydrogenation can be carried out in an alkanol, such as ethanol, containing 1% of a concentrated strong acid, such as hydrochloric acid, sulfuric acid or trifluoroacetic acid, over a catalyst which can usually be used in such hydrogenations, such as a platinum catalyst, preferably at room temperature. The pressure at which the reaction is carried out is not critical; normal pressure is preferred.

It must be pointed out that the hydrogenation does not remain at the stage of the compound I, but that further hydrogenation with excess hydrogen leads to derivatives of compounds of the formula I, i.e. to compounds in which the quinoline ring is partially or wholly

640531

4th

is hydrated. Hydrogen uptake must therefore be carefully observed during sation of the white residue from 1.5 ml of benzene. The reaction- 150 mg (68.5%) erythro-a-2-piperidyl-2,8-bis- (trifluoro- Tung be stopped when the theoretically necessary methyl) -4-quinoline methanol, melting point 174-176 ° C.

Amount of hydrogen, i.e. 3 molar equivalents, taken up The starting material was obtained as follows:

has been. s

Depending on the acid used in the hydrogenation, a mixture of 73.6 g of 4,4,4-trifluoroacetoacetic acid compound I is obtained in the form of a salt, for example ethyl ester in 400 ml of polyphosphoric acid was used as the hydrochloride. The isolation of the salt, the conversion, stirring at 100 ° C., slowly 64.4 g of 2-trifluoromethylaniline into the free base and the purification in itself. The mixture was carried out with constant stirring in a known manner, for example by first heating to 140-150 ° C for 1 Vi hours, crystallization, chromatography and treatment overnight with one kept at room temperature and then on 1200 g of ice base, e.g. with sodium methoxide in methanolic solution. poured. It was stirred vigorously until the ice melted

The erythro-a-2-piperidyl-2,8-bis ~ (trifluoromethyl) -4- was. The crystalline precipitate was separated by filtration from quinoline methanol and is very effective against Plasmodium and dissolved in 21 chloroform. The organic berghei on mice and against Plasmodium falciparum on phase was washed with 11 water, over anhydrous Aotus monkey. In humans, the compound is very effectively dried, filtered, and concentrated under reduced pressure against chloroquine-sensitive strains of Plasmodium falci until crystallization begins. The kri-parum [Tremmhoolm et al., Science 190, 792 (1975)]. stalline material was filtered off and gave 67.14 g (60%)

2,8-bis (trifluoromethyl) -4-quinolinol, melting point Example 1 20 129-131 ° C. An analytically pure sample of quinolinol

To 400 ml of dry ether, 23.5 ml of a 2.04 M was obtained by recrystallization from chloroform; Solution of n-butyllithium in hexane. This solution melting point 130-131 ° C (white needles).

a solution of 16.5 g of 2,8-bis- (trifluoromethyl) -4-bromoquinoline in 200 ml of a suspension of 25.5 g of 2.8- heated to 70 ° C. was stirred at −70 ° C. and under argon. Bis-anhydrous ether added so that the temperature did not rise above -70 ° C to 25 (trifluoromethyl) -4-quinolinol in 50 ml phosphorus tribromide. After the addition had ended, a further 70 g (25 ml) of phosphorus oxibromide were stirred at the same temperature for an hour and then set. The temperature was raised to 140 ° C. The mixture slowly 5.35 g of freshly distilled pyridine-2-aldehyde in 100 ml was kept at this temperature for 4 hours, added on room water-free ether. A temperature was cooled again and then carefully, stirred under a strong hour at -70 ° C., hydrolyzed with 20 ml of water and stirred for 30 hours, poured onto 1 liter of ice. Additional ice was warmed to room temperature as far as possible. The organic phase was added until the exothermic reaction had ended, separated, washed twice with 100 ml of water, and was over. The solution was then dried with 12 N sodium hydroxide sodium sulfate and made alkaline under reduced pressure, with the addition of ice again to make it dry. Crystallization of the residue from cooling. The yellow precipitate was filtered off and 11.1 g (62%) of a-2-pyridyl-2,8-bis (triflu- 35 air-dried overnight over ether / hexane. Sublimation at 50 ° C./0.2 mm ormethyl) -4-quinoline methanol, melting point 135-139 ° C. gave 28.6 g (92%), 2,8-bis (trifluoromethyl) -4-bromo-by sublimation of part of the substance obtained with quinoline, melting point 57-58 ° C. 1 g of this material was 135-140 ° C / 0.1 mm analytically pure material was recrystallized with 95% ethanol and gave 0.7 g of a melting point of 139-141 ° C was obtained. 2,8-bis (trifluoromethyl) -4-bromoquinoline with a melting

A solution of 100 ml ethanol and 10 ml concentrated 40 point of 59-60 ° C.

Hydrochloric acid, containing 1 g of platinum oxide, was saturated with hydrogen at room temperature and under normal pressure. Example 2 A solution of 12.5 g was then passed through a septum. In a 601 kettle, the mixture was brought to a temperature of -70.degree cooled solution of 61 butyl-100 ml of ethanol was added. The mixture was then dropwise hydrogenated under 45 lithium in 301 dry n-hexane with a slightly increased pressure and stirring at room temperature so also cooled solution of 1800 g 2,8-bis (trifluoro-long until 2340 ml hydrogen was absorbed methyl) -4-bromoquinoline were added to 41 dry ether. The catalyst was removed by filtration over Celite. After stirring for 1 hour with constant cooling, the was removed and the filtrate was evaporated to dryness. A mixture of 1170 g was obtained within 45 minutes. 13.2 g of a light yellow residue were obtained, which was recrystallized from pyridine-2-aldehyde and, after a further hour, the de-acetonitrile and a total of 10.1 g of the suspension in portions 251 ether (72.5%) erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) -4- and 11 water were added. The solution obtained in this way was extracted with 101 water, quinoline methanol hydrochloride, melting point 259-261 ° C., which gave the aqueous phase with 101 ether. An analytically pure sample of the hydrochloride was washed and the entire ether phase with 2 × 101 by further recrystallization from acetonitrile and 20 hours water, 1010.5 N hydrochloric acid and twice with 101 water drying at 100 ° C / 0.1 mm received; Washed to neutral melting point. The organic phase was over water-259-261 ° C. Free sodium sulfate dried and concentrated to dryness under reduced pressure to a solution of 0.224 g of erythro-a-2-piperidyl-2.8 bis. The crude product obtained (trifluoromethyl) -4-quinoline methanol hydrochloride in 5 ml (1996 g) was treated with 51 petroleum ether for cleaning. Methanol, 2 ml of a 2.7 N methanolic solution 60 and dried. 1709 g (87.5%) of pure a-2-pyridyl of sodium methoxide were added. The solution was concentrated to dryness under mixed 2,8-bis- (trifluoromethyl) -4-quinoline-methanol, mp. Reduced pressure and the residue was obtained at 140-142 ° C.

taken up in 10 ml of anhydrous ether. Insoluble The compound then became more analogous to Example 1

Material was removed by filtration and the filtrate way to erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) -4-

brought to dryness under reduced pressure. Crystalline quinoline-methanol hydrogenated.

B