CH667267A5 - METHOD FOR PRODUCING (2,8-BIS- (TRIFLUORMETHYL) -4-CHINOLYL) -2-PYRIDINYL-METHANONE. - Google Patents

Description

DESCRIPTION

The present invention relates to a new, productive process for the preparation of [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone by reacting 2,8-bis (trifluoromethyl) -4-quinolyl- Lithium with 2-cyanopyridine.

[2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl-metha-non is an important intermediate for the production of MEFLOQUIN ((R, S) - (±) -alpha-2-piperidinyl-2 , 8-bis- (trifluoromethyl) -4-quinoline-methanol), an important chemotherapy drug recommended by the World Health Organization (WHO) for the treatment of malaria.

Processes for the preparation of [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone have already been described in the literature.

One method consists in reacting 2,8-bis (trifluoromethyl) quinoline-4-carboxylic acid with 2-pyridinyl-lithium or with 2-pyridinyl-magnesium bromide (cf. J. Med. Chem. 14, 926 (1971) and European Patent 26 894).

The yields are unsatisfactory and the reagents required 2-pyridinyl-lithium and 2-pyridinyl-magnesium-bromide are expensive, rather difficult to obtain and difficult to handle.

Another method is that 2,8-bis (trifluoromethyl) -4-bromo-quinoline with a compound of formula I

,, - ÈJÛ

3 N

wherein R, a cyan or triphenylphosphoranmethino group and R4 represents a hydrogen atom or an acetal radical, first to a 2,8-bis (trifluoromethyl) -4-quino-linmethane derivative of the formula II

reacted and then oxidized the compound of formula II obtained to [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridynyl methanone. Compare European Patent 49 776. A disadvantage of this method is the high price or the relatively difficult accessibility of the reagents.

There is therefore a need for a simple and efficient process for the preparation of [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone which does not require reagents which are difficult to obtain or relatively expensive.

It has now surprisingly been found that the desired [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone is obtained by reacting 2,8-bis (trifluoromethyl) -4-15 quinolyl lithium can be obtained with 2-cyanopyridine in a high yield of more than 80% of theory.

It’s amazing and it wasn’t foreseeable

that such a procedure would be sufficiently productive.

Based on relevant literature, much more had to be expected with a very bad result.

Ping-Lu Chien et al., I. Med. Chem. 19, 170/171 (1976) note regarding the preparation of the isomeric [2,8-bis (trifluoromethyl) -4-quinolyl] -3-pyridinyl-methanone: The one-25 step reaction of the corresponding 4-quinolyl-lithium compound with 3-cyanopyridine to form the ketone was also studied, but the yield was unsatisfactory. Also in Houben-Weyl's well-known «Methods of Organic Chemistry», volume 13/1 on pages 188-189, 30 it is noted that the addition of organic lithium compounds to nitriles has no significance as a ketone synthesis because side reactions occur.

2,8-Bis- (trifluoromethyl) -4-quinolyl-lithium is produced by reacting 2,8-bis- (trifluorom-35 thyl) -4-bromo- or -4-chloro-quinoline with alkyl-lithium preferably with butyl lithium or better an alkyl lithium complex such as the butyl lithium TMEDA complex. TMEDA stands for N, N, N ', N'-tetramethylethylenediamine (= 1,2-bis (dimethylamino) ethane). Butyl lithium itself has become a cheap reagent. Today it is produced on an industrial scale and transported by tanker.

The 2,8-bis- (trifluoromethyl) -4-quinolyl-lithium obtained is usually not isolated, but after its largely quantitative formation has been analytically determined, is further reacted in situ with 2-cyano-pyridine.

For the largely quantitative formation of 2,8-bis (trifluoromethyl) -4-quinolyl-lithium, it is necessary to use an excess of the lithium reagent, for example butyl-lithium and / or in the form of a particularly reactive butyl-lithium complex such as the particularly easily accessible butyl-lithium-TMEDA complex.

The yield of [2,8-bis- (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone is improved if the second reagent 2-cyano-pyridine is used in excess.

The reaction is carried out in a dry solvent which is inert with respect to the reaction to be carried out, for example in diethyl ether, diisopropyl ether, di-n-butyl ether, methyl t-butyl ether, 1,2-dimethoxyethane, 60 tetrahydrofuran, methylal, 1,4-dioxane, Hexane, heptane, benzene or toluene. Hexane, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and toluene are preferred as solvents.

The process according to the invention for the preparation of 65 [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone is accordingly characterized in that 2,8-bis (tri-fluoromethyl) -4-quinolyl -Lithium reacted with 2-cyanopyridine.

The 2,8-bis- (trifluoromethyl) -4-quinolyl-lithium formed with an excess of alkyl-lithium and / or with an alkyl-lithium complex in practically quantitative yield is in situ with an excess of 2-cyano- pyridine in a dry solvent inert to the intended reaction.

Butyl lithium is preferred as alkyl lithium and the butyl lithium TMEDA complex is preferred as alkyl lithium complex.

Example I

A solution of 440 ml of 1.6 molar butyl lithium (0.7 mol) in hexane at −65 ° C. while stirring with a solution of 138 g of 2,8-bis- (trifluoromethyl) -4- bromo-quinoline (0.4 mol) in 600 ml of diethyl ether.

After a few hours of reaction, 73 g of 2-cyano-pyridine (0.7 mol) are added to the reaction solution and the mixture is left to react overnight.

The suspension of the ketimide thus obtained is broken down by adding aqueous hydrochloric acid or sulfuric acid.

The organic phase is separated off, the aqueous phase is extracted with a water-immiscible organic solvent. The organic phase and the extract are combined and evaporated to dryness. Pure [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl-metha-non can be isolated from the residue by boiling with hexane.

Yield 123 g [2,8-bis- (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone, that is 83% of theory.

Example 2

A solution of 440 ml of 1.6 molar butyl lithium in hexane (ie 0.7 mol) is stirred under protective gas with 81.3 g (0.7 mol) of N, N, N ', with stirring at a maximum of 20 ° C. N'-tetramethylethyleniamine (TMEDA) (= 1,2-bis- (dimethylaminoethane) is added. The solution of the butyl-lithium-TMEDA complex formed in the process is cooled with 206 g of 2,8-bis- (trifluoromethyl) -4 -bromo-chi-nolin (0.6 mol) was added to 500 ml of dry tetrahydrofuran and after a few hours 73 g (0.7 mol) of 2-cy-

667 267

an-pyridine to the reaction solution and allowed to react overnight. Working up is carried out similarly to that described in Example 1. 193.6 g of [2,8-bis (trifluoromethyl) -4-quinolylJ-2-pyridinyl-methanone are obtained, that is 87% of theory.

Example 3

0.7 mol of butyl-lithium-TMEDA complex are reacted with 0.6 mol of 2,8-bis (trifluoromethyl) -4-bromoquinoline in hexane.

After stirring overnight, 0.7 mol of 2-cyanopyridine is added and the mixture is stirred until the reaction has come to a standstill according to thin-layer chromatographic control.

After working up, 190 g of [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone are obtained, which is 85% of theory.

Example 4

0.55 mol of butyl-lithium-TMEDA complex in hexane are mixed with 0.5 mol of 2,8-bis (trifluoromethyl) -4-bromoquinoline and with 600 ml of dry toluene and stirred until the bromine -quinoline compound has fully implemented.

Now add 0.6 mol of 2-cyanopyridine and allow to react. This gives [2,8-bis- (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone with a yield of 81% of theory.

Examples 5-8

The procedure is as described in Example 4, but the toluene is replaced by

5. Diethyl ether

6. 1,2-dimethoxyethane

7. 1,4-dioxane

8. Hexane

Yields of [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl methanone: 75-85% of theory.

2,8-bis (trifluoromethyl) -4-bromo-quinoline can also be replaced by 2,8-bis (trifluoromethyl) -4-chloro-quinoline.

3rd

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15

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Claims (3)

667 267 PATENT CLAIMS 1. A process for the preparation of [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone, characterized in that 2,8-bis (trifluoromethyl) -4-quinolyl lithi to react with 2-cyanopyridine. 2. A process for the preparation of [2,8-bis (trifluoromethyl) -4-quinolyl] -2-pyridinyl-methanone, characterized in that from 2,8-bis (trifluoromethyl) -4-bromo- or -4-chloro-quinoline with an excess of alkyl-lithium or with an alkyl-lithium complex in practically quantitative yield forms 2,8-bis- (trifhiormethyl) -4-quinolyl-lithium in situ and this with an excess 2-cyanopyridine in a dry solvent inert to the intended reaction. 3. The method according to claim 2, characterized in that the butyl lithium TMEDA complex is used as the alkyl lithium butyl lithium and as the alkyl lithium complex.