Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-30
2002-12-31
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S255000
Reexamination Certificate
active
06500956
ABSTRACT:
This application is a 371 of PCT /EP99/02788 filed Apr. 24, 1988.
The present invention relates to an improved process for the catalytic preparation of substituted bipyridyl derivatives by converting substituted halopyridine derivatives with a base and a reducing agent in the presence of a palladium catalyst.
Such a process, which for bipyridyls follows the reaction equation
has been described in the publications listed below, the reaction with chloropyridines frequently resulting in low yields, and the use of bromopyridines and iodopyridines, which are significantly more expensive and therefore of lesser interest industrially, resulting in higher yields. The processes known hitherto have cost and/or ecological disadvantages.
Bipyridyls, which are also frequently referred to in the literature as bipyridines, including their derivatives are, for example, important as industrial and medicinal intermediates, as analytical reagents or as ligands for the synthesis of metal complexes having catalytic activity. The use of bipyridyl metal complexes, particularly of ruthenium complexes, is of particular importance due to the use as photosensitizers for sensitizing semiconductor surfaces, as photocatalysts for solar cells, in particular for photovoltaic cells or photoelectrochemical cells, as described, for example, in WO 91/16719 or EP-A-0 333 641, and for photo-induced electrolysis.
The synthesis of substituted bipyridyls from halopyridines usually only takes place with good yields in accordance with the prior art if stoichiometric amounts of a metal compound are used. If catalytic amounts of these metal compounds are used, the yield is, by contrast, low in most cases, and the bromopyridines or iodopyridines are used as initiator materials.
Tiecco and Testaferri describe, in Synthesis 1984, 736 et seq., the synthesis of bipyridyl derivatives using stoichiometric amounts of elemental zinc and nickel chloride and four equivalents of triphenylphosphine in dimethylformamide as solvent at 50° C. Using this process, it is possible, for example, to convert 3-bromo-2-methoxypyridine in a yield of 75% with one equivalent of zinc(II) chloride and one equivalent of nickel(II) chloride as byproduct. In two comparative experiments, in which palladium on activated carbon is used as catalyst, or copper, the product 3,3′-dimethoxy-2,2′-bipyridyl can only be obtained in a yield of 18% or 23%; the experimental conditions are described in Synthesis 1978, 537 et seq. If catalytic amounts of nickel(II) chloride are used, as published by Zembayashi et al. in Tetrahedron Lett. 1977, 4089 et seq., the dehalogenated initiator material is primarily obtained, and the desired product is obtained only in a low yield.
Using the process described by Tiecco and Testaferri it is also possible to convert chloropyridines, although large amounts of heavy metal salts are also produced at the same time, making this process neither ecologically nor economically attractive. For example, 2-chloro-5-methoxypyridine is converted in a yield of 88% to 5,5′-dimethoxy-3,3′-bipyridyl with one equivalent of zinc(II) chloride and one equivalent of nickel(II) chloride as byproduct.
In DE-A-39 21 025, Langhals discloses that the reaction described by Tiecco and Testaferri can also be carried out in the presence of free phenolic hydroxyl groups. At the same time Langhals discloses that the zinc hydroxide produced in the reaction as a byproduct can only be separated off with difficulty in the examples for the synthesis of 3,3′-dihydroxy-2,2′-bipyridyl and 3,3′-dihydroxy-2,2′-biquinoline.
Newcame discloses, in J. Inorg. Nucl. Chem. 1981, Vol. 43, 1529 et seq., the conversion of methyl-substituted bromopicoline to the corresponding bipyridyl with catalysis by palladium on activated carbon and a phase-transfer reagent in the presence of sodium formate as reducing agent in a two-phase system. Using this process, for example, 2-bromo-6-methylpyridine (=2-bromo-6-picoline) can be converted in a yield of 59% to 3,3′-dimethyl-2,2′-bipyridyl. The disadvantage of this method is that it is absolutely obligatory to use a phase-transfer reagent as cocatalyst in addition to palladium. Likewise, only bromopyridines which are usually substituted by alkyl groups are usually used as initiator materials for this method.
The classical Ullmann reaction, as described by Fanta in Synthesis 1974, 9 et seq., requires extremely drastic reaction conditions and the use of stoichiometric amounts of copper as reducing agent. In most cases, it produces only low yields of the desired bipyridyls or of derivatives thereof.
According to Fanta, the Ullmann reaction cannot be used for the synthesis of bipyridyls which are substituted by amino, hydroxyl and/or free carboxyl groups.
The synthesis of carboxy-substituted bipyridyls of the formula (IIa)
currently represents a particular problem. This class of substance is usually obtained by oxidation of the readily accessible dimethyl-substituted bipyridyls with potassium permanganate, as is described, for example, by Bruce in Liquid Crystals, 1996, Vol. 20, pages 183-193.
In DE-A-24 50 100, Shaw discloses that bipyridyls and bipyridyls substituted by alkyl, amino, cyano and/or carboxyl groups can also be made accessible from the corresponding pyridines in yields of only 50% by an electrochemical process. The large number of byproducts prevents an industrial and ecologically and economically attractive realization. Shaw discloses at the same time that in the case of the other known processes for the preparation of bipyridyls, metal derivatives of pyridine, especially sodium derivatives, frequently have to be prepared as intermediates, meaning that the preparation of bipyridyls by such processes is hazardous and relatively expensive.
In J. Chem. Soc. 1956, 616 et seq., Badger and Sasse describe the conversion of 50 g of nicotinic acid with activated nickel prepared from 125 g of nickel alloy to only 1 g of the coupled product. The low yield of this process renders the process uninteresting for the synthesis of this class of substance.
U.S. Pat. No. 3,767,652 teaches that 2,2′-bis(3-pyridinols) can be prepared in low yields up to 35% by oxidative coupling of the corresponding pyridinols with stoichiometric amounts of lead dioxide as oxidizing agent. The use of stoichiometric amounts of lead salts renders this process ecologically unacceptable.
The synthesis of bipyridyls without substituents takes place, according to DE-A-22 30 562, with yields up to 65% by converting chloro- or bromopyridine in methanol in the presence of water, an additive which has a reducing action, such as, for example, hydroxylamine or hydrazine, a base, such as, for example, potassium hydroxide, and supported palladium. The synthesis of bipyridyls containing alkyl groups as substituents, which are referred to in the laid-open specification as inert substituents, was possible, however, only in yields of up to 26% in accordance with the process described. The great disadvantage of the process is the high conversion to dehalogenated pyridines, which can amount to 68%. The dehalogenation appears to be favored by large amounts of water in the reaction medium.
EP-A-0 206 543 discloses the synthesis of bipyridyl by converting a halopyridine in the presence of 0.2 to 3 MPa of carbon monoxide, an alkaline medium and a supported palladium catalyst. The use of carbon monoxide is, however, uneconomical for industrial realization in view of the high safety requirements for handling this highly toxic gas.
Since the processes for the synthesis of substituted bipyridyls hitherto described can only be carried out in good yields with a high ecological impact, there was a great need for a process which makes accessible substituted bipyridyls and, in particular, carboxy-substituted bipyridyls in a high yield and purity in a manner which is ecological and simple to carry out on an industrial scale. The object was to develop such a process.
This object is achieved by a process for the preparation of bip
Geissler Holger
Gross Peter
Axiva GmbH
Connolly Bove & Lodge & Hutz LLP
Davis Zinna Northington
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