One pot synthesis of [2,8-Bis...

Details One pot synthesis of [2,8-Bis... One pot synthesis of [2,8-Bis...

2002-01-30

2002-12-31

Morris, Patricia L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06500955

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of [2,8-bis(trifluoromethyl)-4-quinolinyl]-2-pyridinylmethanone, having structural formula 1, which is an important drug intermediate, more particularly for the preparation of the anti-malarial drug mefloquine having structural formula 2.
BACKGROUND OF THE INVENTION
Malaria ranks third among the major infectious diseases after acute respiratory infections and tuberculosis. About 2.5 million deaths occur per year due to malaria, 90% occurring in Africa mostly caused by
Plasmodium falciparum
. Children under the age of 5 years are hit by malaria. Malaria kills one child every 12 seconds. Human environmental changes such as road building, mining, deforestation and new agricultural and irrigation projects have created new breeding sites and thus contribute to spread of malaria. Malaria has re-emerged in areas where it had been eradicated e.g. Koreas, Central Asian republics.
Wide spread prevalence of malaria and emergence of drug resistant
Plasmodium falciparum
have enhanced the importance of mefloquine as a highly effective anti-malarial agent.
Resistance of
P. falciparum
to chloroquine, one of oldest, cheapest and most commonly used drugs, was first detected in 1960. Resistance of sulfadoxine/pyrimethamine, the main alternative to chloroquine is wide spread in South-east Asia and South America. It is being recommended that combination of drugs should be used to slow down the development of drug resistance. Mefloquine has emerged as an important drug to be used in these combinations. An important intermediate in the preparation of mefloquine is methanone of formula (1).
In the prior art, the methanone (1) has been prepared through various routes, all of which suffer from one or more shortcomings as listed below:
Methanone was first prepared [Ohnmacht, C. J., Palei, A. R. and Lutz, R. E., J. Med. Chem. 14, p. 926, 1971] by the reaction of 2-pyridyl lithium (prepared in situ from 2-bromo pyridine and n-butyl lithium) with 2,8-bis(trifluoromethyl)-quinoline-4-carboxylic acid. Apart from being expensive, the use of butyl lithium on large scale always poses the problems of fire and explosion hazards.
As a variant of this method, 2-pyridylmagnesium bromide was used for the synthesis instead of 2-pyridyl lithium [Hickmann, E., Oeser, H. -G. and Moebius, L. U.S. Pat. No. 4,327,215, 1982]. The organomagnesium complexes also have fire and explosion hazards associated with them.
An alternative to the method taught by Hickmann, E., Oeser, H. -G. and Moebius, L. U.S. Pat. No. 4,327,215 1982, 2,S-bis(trifluoromethyl)-quinoline-4-carboxylic acid has been replaced by 4-cyano-2,8-bis(trifluoromethyl)-quinoline. Methanone of formula 1 was obtained in only moderate yields. [Nagesheswar Y. V. D., Meshram H. M., Prasad A. R., Hashim S. R. and Sattur P. B. R., Indian IN 170919 (1992)]. The method still uses an organometallic reagent which carries fire and explosion hazards on scaleup.
In another process, methanone of structural formula 1 has been obtained by the reaction of 4-lithio-2,8-bis(trifluoromethyl)-quinoline [prepared in situ from 4-bromo-2,8-bis(trifluoromethyl)-quinoline and n-butyl lithium] and 2-cyanopyridine, [Haenni, R. and Kuendig, W., Ger Offen. DE 3709891 (1987)]. The organo lithium intermediate obtained is hazardous.
As a modification of the route described heretofore [Haenni, R. and Kuendig, W., Ger Offen. DE 3709891 (1987)] 2,8-bis(trifluoromethyl)-quinolinylmagnesium bromide [prepared in situ from 4-bromo/iodo-2,8-bis(trifluoromethyl)-quinoline and magnesium] was utilized instead of the 4-lithio derivative. [Nagesheswar Y. V. D., Meshram H. M., Prasad A. R., Hashim S. R. and Sattur P. B. R., Indian IN 170918 (1992)]. The disadvantage of the method includes hazardous nature of organomagnesium intermediate and low yields.
In yet another process 4-bromo-2,8-bis(trifluoromethyl)-quinoline of formula (6) on reaction with 2-pyridylacetonitrile (4) in presence of concentrated NaOH, DMF and tetra butylammonium chloride at an ambient temperature under nitrogen atmosphere furnished &agr;,2-pyridinyl-2,8-bis(trifluoromethyl)-4-quinolineacetonitrile of formula (5). [Hickmann, E. and Oeser, H. -G. U.S. Pat. No. 4,429,130 (1984)]. In the second step, the acetonitrile of formula (5) is converted to methanone of formula (1) by oxidation with hydrogen peroxide in acetic acid. This method suffers from the following disadvantages (1) the first step is carried out in presence of a base and dimethylformamide, whereas second step of oxidation is carried out in acetic acid medium (2) dimethylformamide (DMF) is incompatible with hydrogen peroxide used in the oxidation step [Hickmann, E., Oeser, H. -G. U.S. Pat. No. 4,429,130 (1984)] this necessitating the isolation of intermediate acetonitrile of formula 5.
As a modification of prior art [Hickmann, E. and Oeser, H. -G. U.S. Pat. No. 4,429,130 (1984)] 4-chloro-2,8-bis(trifluoromethyl)quinoline of formula 3, sodium hydride, dry toluene-dry DMF and 0° C.-10° C. temperature conditions were utilized instead of 4-bromide derivative concentrated NaOH, DMF and tetrabutylammonium chloride at room temperature conditions respectively [Solange A., Tetrahedron 47, 7609 (1991)]. Second step reagents were same as in prior art [Hickmann, E., and Oeser, H. -G. U.S. Pat. No. 4,429,130 (1984)]. This method suffers from the following disadvantages (1). The first step requires the use of inert and anhydrous conditions and the use of sodium hydride which can pose problems during scale up operations due to fire and explosion hazard. (2) In order to carry out second step, acetonitrile derivative (5) needs to be isolated.
Thus the prior art has no method whereby the intermediate methanone of formula (1) of the drug mefloquine of formula (2) can be prepared in a single pot and without the use of hazardous chemicals. There was a long felt need in the art to develop a process which is safe, economical and easy to follow.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a one pot, single step simple and economical process for the preparation of methanone of structural formula (1) from haloquinoline of the formula (3) and 2-pyridylacetonitrile of formula (4).
Yet another object of the present invention is to provide a process for the preparation of methanone of formula (1) from an intermediate of formula (5) without the use of hazardous chemicals.
Still another object is to provide an improved process, which obviates the use of expensive anhydrous solvents or hazardous reagents in the preparation of methanone of formula 1.
Another object is to provide a process wherein the intermediate acetonitrile derivative of the formula (5) need not be isolated before oxidation.
Yet another object is to provide a process wherein the steps can be conveniently carried out sequentially in the same reaction vessel making it a one-pot process.
SUMMARY OF THE INVENTION
The invention provides a simple single step process for the preparation of [2,8-bis(trifluoromethyl)-4-quinolinyl]-2-pyridinylmethanone (I), comprising the step of condensing a halo-quinoline with an alpha-picolyl derivative in the presence of a solvent, a base and a phase transfer catalyst at −10° C. to +90° C. to obtain an intermediate acetonitrile derivative of formula (5), which is oxidised in situ to methanone derivative of formula (1).


REFERENCES:
patent: 4327215 (1982-04-01), Hickmann et al.
patent: 4429130 (1984-01-01), Hickmann et al.
patent: 37 09 841 (1988-10-01), None
patent: 170918 (1992-06-01), None
patent: 170919 (1992-06-01), None

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