Process for the preparation of aryl-pyridinyl compounds

Details Process for the preparation of aryl-pyridinyl compounds Process for the preparation of aryl-pyridinyl compounds

2002-04-11

2004-07-20

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

06765097

ABSTRACT:

Arylpyridines are generally used in organic synthesis as intermediates for the preparation of various kinds of compound; of these, 4-(2′-pyridyl)benzaldehyde is a useful intermediate in the preparation of antiviral drugs and, in particular, of HIV protease inhibitors, such as, for example, the azahexane heterocyclic derivatives described in international patent application WO 97/40029, which is incorporated herein by reference; among the antiviral drugs concerned, one of particular interest is, for example, that indicated by the abbreviation BMS-232632 in
Drugs of the Future
1999, 24(4):375, the structural formula of which is given below:
Arylpyridines can be prepared by aryl-aryl cross-coupling reactions (Lohse et al.;
Synlett.
1999, Vol. 1; 45-48. Minato et al.,
Tetrahedron Letters,
Vol. 22, no. 52, pp. 5319-5322. 1981. Ei-ichi Negishi et al. Heterocycles 1982, Vol. 18; 117-122), or coupling reactions between two aryl compounds in accordance with the scheme given below:
ArMeX+PyY→ArPy+MeXY
wherein:
Ar represents an aryl compound and Py represents a pyridine compound; Me represents a metal selected from Mg, Zn and Sn, and X represents Br, Cl, I; or, alternatively, Me and X, together, represent B(OH)
2
or BR
2
(wherein R is an alkyl group); Y represents Br, Cl or I.
In particular, 4-(2′-pyridyl)benzaldehyde is normally prepared starting from 4-bromobenzaldehyde and 2-bromopyridine (Bold et al.;
J.Med.Chem.
1998, 41, 3387 and WO 97/40029), according to the scheme given in FIG.
1
.
The method provides for the conversion of 4-bromobenzaldehyde into the corresponding acetal and then into the Grignard reagent BrMgC
6
H
4
CH(OR)
2
(compound 1). The Grignard reagent is then reacted with 2-bromopyridine (compound 2) in the presence of NiCl
2
and 1,3-bis(diphenylphosphine)propane (
Inorg. Chem.
1966, 1968) to give, after the conversion of the acetal group into an aldehyde group, by treatment in an acidic aqueous medium, 4-(2′-pyridyl)benzaldehyde (compound 3).
However, that method has disadvantages of not inconsiderable importance, such as the use of a toxic and carcinogenic catalyst such as the nickel salt and, above all, poor reproducibility, which is all the greater the smaller the amount of catalyst employed.
The object of the work which resulted in the present invention was therefore to find a novel and reliable aryl-aryl cross-coupling process based on the use of metals that are both other than nickel and capable of leading to the formation of arylpyridines, and in particular 4-(2′-pyridyl)benzaldehyde, with reproducible and industrially satisfactory yields, even in the presence of very small amounts of catalyst.
It has now been found that a zinc salt can be used in a catalytic amount and in combination with palladium to catalyse efficiently the formation of arylpyridines by aryl-aryl cross-coupling reactions. In particular, as will be seen hereinafter, it has been found that the zinc salt in combination with palladium catalyses with optimum yields, a high level of productivity and, above all, with a high degree of catalyticity the reactions for the synthesis of arylpyridines according to the general scheme given below
wherein A and B, which are the same or different from one another, represent H; a linear or branched C
1
-C
8
alkyl; an optionally substituted acetal group; an aryl or a benzyl, which are optionally substituted by groups that do not interfere with a Grignard reaction; and X
1
and X
2
, which are the same or different from one another, represent Cl, Br or I.
The subject-matter of the present invention is particularly interesting bearing in mind that coupling reactions catalysed by palladium and mediated by zinc salts have already been described in Jetter et al.,
SYNTHESIS, June
1998, 829-831. However, in that article the zinc salt was used in amounts of approximately 2 equivalents with final yields of 70-80%; by increasing the concentration of the zinc salt to 3 equivalents it was possible to obtain a substantial increase in the yield which, however, fell by 40% when only one equivalent of the zinc salt was used.
With the present invention, it has, however, surprisingly been found that the use of a catalytic amount of the zinc salt in the presence of a catalytic amount of palladium leads to the formation of arylpyridines with yields ranging from 84 to 99.5%, depending on the conditions, and also to a substantial reduction in the amount of catalyst; in this connection, among other things, it was also observed that, in the presence of a catalytic amount of the zinc salt, the palladium can be used in an amount of up to 1 mole for every 10,000 moles of arylpyridine product, which is undoubtedly surprising bearing in mind that, in the already mentioned WO 97/40029, the catalyticity was approximately 0.6 mole of nickel per 100 moles of bromopyridine. It is important to remember that the extremely high cost of palladium makes its use in an industrial process economically disadvantageous if it is employed in molar ratios with respect to the substrate of from 1:20 to 1:200.
In this connection, it should be noted that the use of catalytic amounts of zinc salts in combination with catalysts based on nickel or palladium had already been described by Miller and Farrell in
Tetrahedron Letters,
Vol. 39, 1998, 7275-8, and in the corresponding U.S. Pat. No. 5,922,898. However, those documents describe a method which permits the coupling of Grignard compounds with aryl halides containing groups reactive towards the Grignard compounds, such as, for example, esters, ketones and nitrites, the presence of the zinc salt as a co-catalyst in this case makes it possible to avoid the protection and deprotection of the groups reactive towards the Grignard compounds. In the documents in question, the ratio of the catalyst (Pd or Ni) to the aryl halide is normally approximately 1:20 and, in any case, is never less than 1:100; those documents also give examples demonstrating a high degree of inhibition of the coupling reaction in the presence of a molar ratio of 1:1 between the arylmagnesium reagent and ZnCl
2
. The fairly high yields are also promoted by the presence of electron-attracting groups on the aryl halides, which increases the reactivity thereof in the aryl-aryl cross-coupling reactions (V. V. Grushin, H. Alper
Chem. Rev.,
1994, 94, 1047-1062).
In contrast, the subject-matter of the present invention is represented by a process for the preparation of arylpyridines in which an arylmagnesium halide is reacted with a halopyridine in the presence of a catalytic amount of a zinc salt and a catalytic amount of palladium, wherein the molar ratio of the palladium to the halopyridine is less than 1:100 and, normally, less than 1:1000.
In order to avoid any undesired secondary reactions, the arylmagnesium halide and the halopyridine should not contain other substituents capable of interfering with the Grignard reaction or, if such substituents are present, they should be in a suitably protected form; any carbonyl groups can be protected, for example, by being converted beforehand into the corresponding acetals.
According to its preferred embodiment, the process according to the present invention can thus he represented in the following scheme.
wherein: R
1
, R
2
and R
3
, which are the same or different from one another, represent H; a linear or branched C
1
-C
6
alkyl; an aryl, preferably phenyl, optionally substituted by a linear or branched C
1
-C
6
alkyl; or, alternatively, R
1
and R
2
represent an optionally cyclic acetal group; and X
1
and X
2
, which are the same or different from one another, represent Cl, Br or I.
In its more preferred embodiment, the process consists (a) in reacting an arylmagnesium halide of formula:
wherein X
1
represents Cl, Br or I; R
1
and R
2
, which are the same or different from one another, represent linear or branched C
1
-C
6
alkyls, preferably methyls, or alternatively, R
1
and R
2
together represent a single C
1
-C
8
alkyl or alkylene group; R
3
represents hydrogen or a linear

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