JPS6257631B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Erythro α- useful in the treatment of malaria
Mefloquine, which is 2-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol () and is a known compound, was described by CJOhnmacht et al., J.
As described in Med . has been manufactured.

The present invention involves reacting 2,8-bis(trifluoromethyl)-4-bromoquinoline () with n-butyllithium, and the reaction of the 2,8-bis(trifluoromethyl)-4-quinolyllithium (). The product is treated with 2-pyridinecarboxaldehyde and the resulting α-2-pyridyl-2.
Erythro-alpha-2-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol () consisting of hydrogenation of 8-bis(trifluoromethyl)-4-quinolinemethanol () to give the desired erythroα-2-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol. α-2-piperidyl-2,8-
The present invention relates to a method for producing bis(trifluoromethyl)-4-quinolinemethanol.

In another aspect, the invention provides the formula α-2-Pyridyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol useful as an intermediate in the process of the invention, characterized by:

The reaction route of the present invention and the Ohnmacht described above
The preparation of the starting material from 2-(trifluoromethyl)-aniline according to et al. is described in the reaction scheme below.

In the method according to Ohmacht et al., the compound 2,8-bis(trifluoromethyl)-4
- treatment of bromoquinoline with n-butyllithium and carboxylation of the resulting 4-Li derivative to give a 4-carboxy derivative, which was reacted with 2-lithium pyridyl prior to hydrogenation, According to the invention, the compound is treated with n-butyllithium to yield 2,8-bis(trifluoromethyl)-4-lithioquinoline, and this compound is then reacted in situ with 2-pyridinecarboxaldehyde. The reaction order is preferably, depending on the solvent used,
It is preferred to carry out at low temperatures ranging from about -30°C to about -70°C, most preferably about -70°C or less. As solvents, ethers such as tetrahydrofuran or diethyl ether, or hydrocarbons such as hexane, and mixtures thereof may be used. In a preferred embodiment, the reaction can be carried out in diethyl ether/n-hexane (1:1 υ/υ). α-2-pyridyl-2,8-
Bis(trifluoromethyl)-4-quinolinemethanol, a compound of formula, can be recovered from the reaction mixture using conventional methods, such as crystallization.

As a final step, α-2-pyridyl-2,8-
Bis(trifluoromethyl)-4-quinolinemethanol is hydrogenated with 3 molar equivalents of hydrogen to yield erythro α-2-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol, a compound of formula Close. The hydrogenation may be carried out over a catalyst commonly used in such hydrogenations, such as a platinum catalyst, preferably at room temperature, in an alkanol such as ethanol containing 1% of a concentrated strong acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, etc. can. The pressure at which the reaction is carried out is not critical; however, atmospheric pressure is preferred.

It should be noted that the hydrogenation does not stop at the stage of the compound, but continued hydrogenation with excess hydrogen gives derivatives of the compound of formula in which the quinoline ring is partially or completely reduced. Therefore, the absorption of hydrogen during the reduction must be closely monitored and the reaction should be carried out after the stoichiometric amount of hydrogen has been absorbed, i.e.
After a mole of hydrogen has been absorbed, cessation is performed to obtain the compound.

Depending on the nature of the acid used in the hydrogenation step, the compound is recovered as a salt, for example as a hydrochloride. Isolation of the salt, conversion to the free base and purification can be carried out using conventional methods such as crystallization, chromatography and treatment with a base such as sodium methoxide in methanolic solution.

Erythro α-2-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol has been shown to be effective against Plasmodium berghei in rodents and Plasmodium falciparum in Aotus monkeys. It was shown to be highly active against Plasmodium falciparum). In humans, the compound was highly effective against Chloroquine-sensitive strains of P. falciparum [Tremholme et al.,
Science 190 , 792 (1975)].

The invention is further illustrated by the following examples. All temperatures are in degrees Celsius.

Example 1 n in hexane for 400 ml of anhydrous ether
- 23.5 ml of a 2.04M solution of butyllithium was added.
200 g of anhydrous ether to the resulting stirred solution.
A solution of 16.5 g of 2,8-bis(trifluoromethyl)-4-bromoquinoline dissolved in 100 ml of 2.8-bis(trifluoromethyl)-4-bromoquinoline at -70° under argon was added in such proportions as to maintain the temperature at -70°. After the addition was complete, stirring was continued for 1 hour at the same temperature, followed by 100 ml of anhydrous ether.
5.35 g of freshly distilled 2-pyridinecarboxaldehyde dissolved in the solution were slowly added. The mixture was stirred for a further 1 hour at -70°, hydrolyzed with 20 ml of water and warmed to room temperature. The organic layer was separated, washed with 2 x 100 ml of water, dried over sodium sulfate and evaporated to dryness under reduced pressure. By crystallizing the residue from ether-hexane, 11.1 g (62%) of α-2-pyridyl-
2,8-bis(trifluoromethyl)-4-quinoline methanol, melting point 135-139°, was obtained. A portion of this crystalline material was sublimed at 135-140°/0.1 mm to produce analytically pure α-2-pyridyl-2.
8-bis(trifluoromethyl)-4-quinoline methanol, melting point 139-141°, was obtained.

A solvent mixture of 1000 ml of ethanol and 10 ml of concentrated hydrochloric acid containing 1 g of platinum oxide was presaturated with hydrogen at room temperature and atmospheric pressure. A solution of 12.5 g of α-2-pyridyl-2,8-bis(trifluoromethyl)-4-quinoline methanol dissolved in 100 ml of ethanol was injected into the reaction flask through a septum. The stirred mixture was hydrogenated at room temperature under slightly positive pressure until 2340 ml of hydrogen was consumed. The catalyst was removed by filtration through Celite and the liquid was evaporated to dryness to give 13.2 g of a pale yellow solid. Recrystallization of this material from acetonitrile yielded a total of 10.1 g (72.5%) of erythroα-2-piperidyl-2,8-bis(trifluoromethyl)-
4-quinoline methanol hydrochloride, melting point 259-261°, was obtained. An analytical sample of the hydrochloride salt was obtained by recrystallization from acetotrile and drying at 100°/0.1 mm for 20 hours. Melting point 259-261℃.

0.224g of erythro alpha-2 in 5ml of methanol
- a solution of piperidyl-2,8-bis(trifluoromethyl)-4-quinoline methanol hydrochloride,
Combined with 2 ml of 2.7N methanolic solution of sodium methoxide. The solution was evaporated to dryness under reduced pressure and the residue was taken up in 10 ml of absolute ether. Insoluble material was removed by filtration and the liquid was evaporated to dryness under reduced pressure. Slow crystallization of the white solid residue from 1.5 ml of benzene yielded 140 mg (68.5 %) was obtained.

The starting material was prepared as follows: 64.4 g of 2-trifluoromethylaniline was added to a stirred mixture of 73.6 g of ethyl 4,4,4-trifluoroacetoacetate in 400 ml of polyphosphoric acid.
was added slowly at 100°. After the addition was complete, the mixture was heated at 140-150° with continuous stirring for 1.5 hours and kept at room temperature overnight, stirring continued until the ice melted. The crystalline precipitate was collected by filtration and dissolved in chloroform 2. The organic layer was washed with 1 portion of water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until crystallization was observed. Collect the crystalline substance by filtration,
67.14 g (60%) of 2,8-bis(trifluoromethyl)-4-quinolinol, melting point 129-131°, was obtained. An analytical sample of this quinolinol was obtained by recrystallization from chloroform, melting point 130-131° (white needles).

A suspension of 25.5 g of 2,8-bis(trifluoromethyl)-4-quinolinol in 50 ml of phosphorus tribromide was heated to 70°. Phosphoryl bromide 70g (25ml)
was added at once. The temperature was increased to 140° and the mixture was maintained at this temperature for 4 hours. The mixture was cooled to room temperature and carefully added to crushed ice 1 with vigorous stirring. Additional ice was added as needed until the exothermic reaction ceased. The solution was made alkaline with 12N sodium hydroxide while adding ice again for cooling. A yellow solid precipitate was collected by filtration and air dried overnight.
Sublimation at 50°/0.2 mm yielded 28.6 g (92%) of 2,8-bis(trifluoromethyl)-4-bromoquinoline, mp 57-58°. Recrystallize 1 g of the sublimated substance from 95% ethanol to give 0.7 g.
A bromoquinoline with a melting point of 59-60° was obtained.

Example 2 A solution of n-butyllithium 6 in dry n-hexane 30 is placed in a 60 vessel and cooled to -70° with effective stirring under argon, then 2,8-bis in dry ether 4 A precooled solution of 1800 g of (trifluoromethyl)-4-bromoquinoline was added dropwise to react. After stirring for 1 hour with constant cooling, a solution of 1170 g of 2-pyridinecarboxaldehyde was added over a period of 45 minutes; after a further hour, 25 ether and 1 water were added dropwise to the resulting suspension. The solution thus obtained is diluted with 10 ml of water.
The aqueous phase was washed with 10 ml of ether, and the entire ether phase was washed with 2×10 ml of water until neutral.
Washed twice with 10 g of 0.5N hydrochloric acid and 10 g each time with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product obtained (1996 g) was purified by treatment with petroleum ether 5 and drying. Thus 1709g
(87.5%) pure α-2-pyridyl-2,8-
Bis(trifluoromethyl)-4-quinoline methanol, melting point 140-142°, was obtained.

This compound is then hydrogenated to form erythroα-
2-Piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol was obtained in a similar manner as described in Example 1.

Claims (1)

[Claims] 1 2,8-bis(trifluoromethyl)-4-
Bromoquinoline is reacted with n-butyllithium, and its 2,8-bis(trifluoromethyl)-
The 4-quinolyl lithium reaction product is treated with 2-pyridinecarboxaldehyde and the resulting α-2-pyridyl-2,8-bis(trifluoromethyl)-4-quinoline methanol is treated with 3 moles of hydrogen per mole. to obtain the desired erythro-α
-2-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol erythro α-2-piperidyl-
A method for producing 2,8-bis(trifluoromethyl)-4-quinolinemethanol. 2 2,8-bis(trifluoromethyl)-4-
Claim 1: Reacting quinolyl lithium with 2-pyridylcarboxaldehyde in situ
The method described in section. 3. The method according to claim 1 or 2, wherein the hydrogenation is carried out in the presence of a noble metal catalyst. 4. The method according to any one of claims 1 to 3, wherein the hydrogenation is carried out in the presence of a platinum catalyst.