CH640530A5 - Process for preparing mefloquine - Google Patents

Description

The present invention relates to a process for the preparation of erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) -4-quinoline methanol, which is characterized in that

2,8-bis (trifluoromethyl) -4-bromoquinoline is reacted with n-butyllithium i5, the resulting 2,8-bis (trifluoromethyl) -4-quinolyl-lithium is reacted with pyridine-2-aldehyde and the resulting a Hydrogenated -2-pyridyl-2,8-bis (trifluoromethyl) -4-quinoline-methanol with 3 molar equivalents of hydrogen.

The reaction sequence of the method 20 according to the invention as well as the preparation of the starting material IV from 2- (trifluoromethyl) aniline according to Ohnmacht et al. is shown schematically in the following overview.

Reaction scheme

0'C2H5

+

CF3

IV

CHO

3rd

640530

"O f QJ Ha f

H "H H

oTol @oi i "* CFo TT ^ CB.

cf3

II

While in the Ohnmacht et al. the compound IV, 2,8-bis (trifluoromethyl) -4-bromoquinoline, treated with n-butyllithium and the resulting 4-lithium derivative was carboxylated to the 4-carboxy derivative, which was reacted with 2-lithium pyridyl before the hydrogenation, is carried out according to In the present invention, the compound IV is reacted with n-butyllithium to give 2,8-bis (trifluoromethyl) -4-lithium quinoline, which is then reacted 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 40 mixtures thereof. In a preferred embodiment, the reaction can be carried out in diethyl ether / n-hexane (1: 1, v / v). The <x-2-pyridyl-2,8-bis (trifluoromethyl) -4-quinoline methanol (II) can be obtained from the reaction mixture in a manner known per se, e.g. by crystallization, 45 can be obtained.

In the last stage, the a-2-pyridyl-2,8-bis (trifluoromethyl) -4-quinoline methanol with 3 molar equivalents of hydrogen becomes erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) -4 -quinoline methanol (I) hydrogenated. The hydrogenation can be carried out in a 50 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 60 derivatives of compounds of the formula I, i.e. to compounds in which the quinoline ring is partially or fully hydrogenated. The hydrogen uptake must therefore be carefully observed throughout the reaction and the reaction must be stopped when the theoretically necessary 6s amount of hydrogen, i.e. 3 molar equivalents.

Depending on the acid used in the hydrogenation, the cf3

I.

Compound I obtained in the form of a salt, for example as the hydrochloride. The isolation of the salt, the conversion into the free base and the purification can be carried out in a manner known per se, for example by crystallization, chromatography and treatment with a base, e.g. with sodium methoxide in methanolic solution.

The erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) -4-quinoline methanol is very effective against Plasmodium berghei in mice and against Plasmodium falciparum in Aotus monkeys. In humans, the compound is very effective against chloroquine-sensitive strains of Plasmodium falciparum [Tremmhoolm et al., Science 190, 792 (1975)].

example 1

To 400 ml of dry ether, 23.5 ml of a 2.04 M solution of n-butyllithium in hexane were added. A solution of 16.5 g of 2,8-bis (trifluoromethyl) -4-bromoquinoline in 200 ml of anhydrous ether was added to this solution with stirring at -70 ° C. and under argon so that the temperature did not exceed -70 ° C. rose. After the addition had ended, the mixture was stirred at the same temperature for a further hour and then 5.35 g of freshly distilled pyridine-2-aldehyde in 100 ml of anhydrous ether were slowly added. The mixture was stirred for another hour at -70 ° C., hydrolyzed with 20 ml of water and warmed to room temperature. The organic phase was separated, washed twice with 100 ml of water, dried over sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ether / hexane gave 11.1 g (62%) of a-2-pyridyl-2,8-bis (trifluoromethyl) -4-quinoline-methanol, melting point 135-139 ° C. By sublimation of part of the substance obtained at 135-140 ° C / 0.1 mm, analytically pure material with a melting point of 139-141 ° C could be obtained.

A solution of 1000 ml of ethanol and 10 ml of concentrated hydrochloric acid containing 1 g of platinum oxide was saturated with hydrogen at room temperature and under normal pressure. A solution of 12.5 g of a-2-pyridyl-2,8-bis (trifluoromethyl) -4-quinolinemethanol in 100 ml of ethanol was then added through a septum. The mixture was then hydrogenated under slightly increased pressure and stirring at room temperature until 2340 ml of hydrogen had been absorbed. The catalyst was filtered through

640 530

4th

Celite was removed and the filtrate was evaporated to dryness. 13.2 g of a light yellow residue were obtained, which was recrystallized from acetonitrile and a total of 10.1 g (72.5%) erythro-a-2-piperidyl-2,8-bis- (trifluoromethyl) -4- quinoline methanol hydrochloride, melting point s 259-261 ° C, delivered. An analytically pure sample of the hydrochloride was obtained by further recrystallization from acetonitrile and drying for 20 hours at 100 ° C./0.1 mm; Melting point 259-261 ° C.

2 ml of a 2.7 N methanolic solution of sodium methoxide were added to a solution of 0.224 g of erythro-a-2-piperidyl-2,8-bis-io (trifluoromethyl) -4-quinoline methanol hydrochloride in 5 ml of methanol. The solution was evaporated to dryness under reduced pressure and the residue taken up in 10 ml of anhydrous ether. Insoluble material was removed by filtration and the filtrate was brought to dryness under reduced pressure. Crystallization of the white residue from 1.5 ml of benzene gave 150 mg (68.5%) of erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) -4-quinoline methanol, melting point 174-176 ° C. 20th

The starting material was obtained as follows:

64.4 g of 2-trifluoromethylaniline were slowly added to a mixture of 73.6 g of 4,4,4-trifluoroacetoacetic acid ethyl ester in 400 ml of polyphosphoric acid at 100 ° C. with stirring. The mixture became 25 with constant stirring

first heated to 140-150 ° C for 1 Vi hours, kept at room temperature overnight and then poured onto 1200 g of ice. It was stirred vigorously until the ice melted. The crystalline precipitate was separated by filtration and dissolved in 21 chloroform. The organic phase was washed with 11 water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure until crystallization began. The crystalline material was filtered off and gave 67.14 g (60%) of 2,8-bis (trifluoromethyl) -4-quinolinol, melting point 35

129-131 ° C. An analytically pure sample of the quinolinol was obtained by recrystallization from chloroform; Melting point 130-131 ° C (white needles).

A suspension of 25.5 g of 2,8-bis (trifluoromethyl) -4-quinolinol in 50 ml of phosphorus tribromide 40 heated to 70 ° C

70 g (25 ml) of phosphorus oxibromide were added all at once. The temperature was raised to 140 ° C. The mixture was kept at this temperature for 4 hours, cooled to room temperature and then carefully poured onto 1 liter of ice with vigorous stirring. Additional ice was added as necessary until the exothermic reaction was complete. The solution was then made alkaline with 12 N sodium hydroxide with the addition of ice again for cooling. The yellow precipitate was filtered off and air dried overnight. Sublimation at 50 ° C / 0.2 mm gave 28.6 g (92%) of 2,8-bis (trifluoromethyl) -4-bromoquinoline, melting point 57-58 ° C. 1 g of this material was recrystallized from 95% ethanol and gave 0.7 g of 2,8-bis (trifluoromethyl) -4-bromoquinoline with a melting point of 59-60 ° C.

Example 2

In a 601 kettle, a solution of 61 butyl-lithium in 301 dry n-hexane, cooled to -70 ° C., was added dropwise with a likewise cooled solution of 1800 g of 2,8-bis (trifluoromethyl) - under an argon atmosphere and good stirring. 4-bromoquinoline in 41 dry ether.

After stirring for one hour with constant cooling, a solution of 1170 g of pyridine-2-aldehyde was added to the mixture within 45 minutes and, after a further hour, a total of 251 ether and 11 water were added to the resulting suspension. The solution obtained was extracted with 101 water, the aqueous phase was washed with 101 ether and the entire ether phase was washed neutral with 2x101 water, 1010.5 N hydrochloric acid and twice with 101 water each. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product obtained (1996 g) was treated with 5 l of petroleum ether for cleaning and dried. 1709 g (87.5%) of pure a-2-pyridyl-2,8-bis (trifluoromethyl) -4-quinoline methanol, mp.

140-142 ° C.

The compound was then hydrogenated in a manner analogous to Example 1 to give erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) -4-quinoline methanol.

B

Claims (4)

640530 PATENT CLAIMS 1. Process for the preparation of erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) -4-quinoline methanol, characterized in that 2,8-bis (trifluoromethyl) -4-bromo-quinoline with reacts n-butyllithium, the resulting 2,8-bis (trifluoromethyl) -4-quinolyllithium reacts with pyridine-2-aldehyde and the resulting a-2-pyridyl-2,8-bis (trifluoromethyl) -4 -quinoline methanol hydrogenated with 3 molar equivalents of hydrogen. 2. The method according to claim 1, characterized in that 2,8-bis (trifluoromethyl) -4-quinolyllithium is reacted in situ with the pyridine-2-aldehyde. 3. The method according to claim 1 or claim 2, s characterized in that the hydrogenation takes place in the presence of a noble metal catalyst. 4. The method according to any one of claims 1-3, characterized in that the hydrogenation is carried out in the presence of a platinum catalyst. Mefloquine, erythro-a-2-piperidyl-2,8-bis (trifluoromethyl) -4-quinoline-methanol (I), a known compound that can be used to treat malaria, has so far been synthesized from 2 in a 6-step process -Trifluoromethylaniline over 2,8-bis (trifluoromethyl) -4-bromoquinoline prepared [CJ Ohnmacht et al., J. Med. Chem. 14,926 (1971)].