Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1999-06-08
2000-09-05
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544183, 544217, 544218, 544235, 544240, 544241, 544253, 544313, 544315, 544319, 544353, 544408, 546290, 546345, C07D21302, C07D21518, C07D21520, C07D23712, C07D23714
Patent
active
061145246
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to an industrially advantageous process for producing halogenated heteroaryl compounds useful in the chemical industries especially in the field of pharmaceuticals.
BACKGROUND ART
Heretofore, halogenated heteroaryl compounds have been produced by reacting hydroxyheteroaryl compounds with thionyl halides, phosphorus oxyhalides, phosphorus trihalides or phosphorus pentahalides. These prior processes of production, however, require so severe conditions as industrially undesirable. For instance, John B. Pain III [J. Heterocyclic Chem., Vol. 24, Page 351 (1987)] and others produced halogenated heteroaryl compounds by adding a hydroxyheteroaryl compound to boiling phosphorus tribromide (bp. 173.degree. C.). However, it is difficult to control the reaction because this reaction causes a violent generation of heat. In addition, water must be added for the sake of post treatment after the reaction has been completed, which is accompanied by a generation of heat and a large quantity of hydrogen bromide. Further, the phosphorus compounds are in danger of spontaneous ignition. For these reasons, this process is undesirable as an industrial process. Thus, it has been desired to develop a process for producing halogenated heteroaryl compounds under mild conditions.
It is an object of the present invention to develop a process by which halogenated heteroaryl compounds can be produced under mild conditions.
DISCLOSURE OF INVENTION
With the aim of solving the problems mentioned above, the present inventors conducted extensive studies to find a process for producing halogenated heteroaryl compound which comprises reacting a hydroxyheteroaryl compound with a quaternary ammonium halide in the presence of phosphorus pentoxide. Based on this finding, the present invention has been accomplished.
Thus, the present invention relates to a process for producing a compound represented by the following general formula [II]: ##STR3## wherein X is a halogen atom, each of A.sup.1, A.sup.2 and A.sup.3 may be identical or different, is a carbon atom or a nitrogen atom, provided that at least one of A.sup.1, A.sup.2 and A.sup.3 is a nitrogen atom, and each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may be identical or different, is a hydrogen atom, a lower alkyl group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a halogen atom, a nitro group, a hydroxyl group or an amino-(lower alkyl) group, provided that in cases where R.sup.1 and R.sup.2 are adjacent to each other, R.sup.1 and R.sup.2 may be combined with each other to form a 5- or 6-membered ring which may carry on the ring thereof one substituent selected from the group consisting of a lower alkyl group, a nitrile group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a halogen atom, a nitro group, a hydroxyl group and an amino-(lower alkyl) group; comprises reacting a compound represented by the following general formula [I]: ##STR4## wherein A.sup.1, A.sup.2, A.sup.3, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above, with a quaternary ammonium halide in the presence of phosphorus pentoxide.
Next, meanings of the technical terms used in the present specification are explained below.
As used in the present specification, the term "lower alkyl group" means a branched or straight-chain alkyl group having 1 to 6 carbon atoms, of which examples include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, an isohexyl group or the like.
The term "lower alkoxycarbonyl group" means an alkoxycarbonyl group having 1 to 7 carbon atoms, of which examples include a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group, an isopropoxycarbonyl group, a n-butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, a n-pentyloxycarbonyl group, an isopentyloxycarbonyl group, a n-hexyloxycarbonyl group, an isohexyloxycarbonyl
REFERENCES:
patent: 4404388 (1983-09-01), h et al.
patent: 4739057 (1988-04-01), Leoney-Bay
Paquette In Encyclopedia of Reagents for Organic Synthesis. Vol. 6, p. 4127-4129, 1995.
Journal of Heterocyclic Chemistry: J.B. Paine, "A Conversion of Nicotinate Esters from 3-Cyanopyridones". Vol. 24, No. 2, p. 351 (references cited in the description. particularly p. 351).
Ishikawa Kiyofumi
Okada Shigemitsu
Ushijima Ryosuke
Balasubramanian Venkataraman
Banyu Pharmaceutical Co. Ltd.
Raymond Richard L.
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