Process for preparing 4-(4′-carboxyphenyl)pyridine

Details Process for preparing 4-(4′-carboxyphenyl)pyridine Process for preparing 4-(4′-carboxyphenyl)pyridine

2001-02-15

2002-05-21

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06392051

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a novel process for preparing 4-(4′-carboxyphenyl)-pyridine of the formula (I).
BACKGROUND OF THE INVENTION
4-(4′-Carboxyphenyl)pyridine of the formula (I) and the corresponding esters and acid chlorides are important intermediates in the synthesis of active compounds for the pharmaceutical and agrochemical industries.
Possible synthetic routes to compounds of the formula (I) are the Suzuki coupling of 4-halopyridines with suitable organometallic reagents, for example 4-carboxyphenylboronic acid or 4-carboxyphenylboronic esters. However, such pyridines, for example, 4-bromopyridine or 4-chloropyridine, are firstly very expensive and difficult-to-obtain raw materials which are also unstable in pure form and can be used only in the form of derivatives, for example as hydrochloride. Secondly, they are very corrosive and place high demands on the materials of construction used.
It is an object of the present invention to develop a process for preparing 4-(4′-carboxyphenyl)pyridine of the formula (I) which makes it possible to obtain the target compound in very few, technically simple steps starting from readily available and inexpensive raw materials. Furthermore, the process to be developed has to give the target product in a good total yield and in a purity sufficient for pharmaceutical applications.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
It has surprisingly been found that the compound of the formula (I) can be prepared in good total yields and in good purity in few steps starting from pyridine. The individual steps can each be carried out in a technically simple manner and use only commercially available and inexpensive reagents, solvents and catalysts.
The present invention provides a process for preparing 4-(4′-carboxyphenyl)pyridine, which comprises oxidizing a 4-phenyl-N-acyldihydropyridine of the formula (II)
where
R
1
is a bulky alkyl, alkylaryl, arylalkyl or alkoxy group and
R
2
is a straight-chain or branched, substituted or unsubstituted alkyl radical having from 1 to 8 carbon atoms,
by means of an oxidizing agent selected from the group consisting of permanganates, nitric acid, Cr(VI) compounds, oxygen and air to give the compound of the formula (I)
where M is a cation, preferably hydrogen, ammonium or an alkali metal cation.
Preferred radicals R
1
are tert-butyl, isopropyl, (dimethyl)phenylmethyl, methyl(diphenyl)methyl, trityl, diphenylmethyl, triethylmethyl, tert-butoxy and isopropoxy.
Preferred radicals R
2
are straight-chain or branched alkyl radicals which have from 1 to 4 carbon atoms and may be unsubstituted or substituted by one or more hydroxy or C
1
-C
4
-alkoxy radicals; particular preference is given to methyl, ethyl, n-propyl, i-propyl, n-butyl, methoxymethyl and hydroxymethyl, most preferably methyl.
The preparation of dihydropyridines of the formula (II) from pyridine by addition of organometallic compounds, for example Grignard compounds, cannot be carried out directly; prior activation of the pyridine ring is necessary. This can be achieved, for example, by N-acylation (Scheme 1). The N-acylpyridinium salts which can be obtained in this way do react with Grignard compounds, but the reaction gives mixtures of 2- and 4-aryldihydropyridines which are difficult to separate. According to Akiba et al., Tetrahedron Lett. 23, 4, 429-432, 1982, a high selectivity to the 4-aryldihydropyridines can be achieved by using bulky radicals on the pyridine nitrogen and using equimolar amounts of organocopper compounds. However, for a number of reasons, the preparation and handling of organocopper compounds is problematical for industrial processes.
X can be Cl or Br.
The problem is solved more elegantly by Comins et al., J. Org. Chem. 1982, 47, 4315-4319. The authors react Grignard compounds with pyridine and pivaloyl chloride in the presence of catalytic amounts of CuI and obtain yields of somewhat above 60% in this way. The amounts of Cu required do not stand in the way of industrial utilization. However, such a low yield combined with the disposal problems associated with the sometimes problematical by-products resulting from the starting materials not converted into product makes the viability of the overall process questionable.
It has surprisingly been found that the addition of palladium or nickel salts or complexes or of metallic Pd or Ni as cocatalysts leads to a significant increase in yield in the preparation of a dihydropyridine of the formula (II). Yields of usually above 90%, based on the organometallic reagent used, are then achieved.
In a preferred embodiment of the process of the invention, the compound of the formula (II) is therefore prepared by acylating pyridine by means of a compound of the formula (IV) to give a compound of the formula (VI), or using a compound of the formula (VI), and coupling the compound of the formula (VI) with a Grignard compound of the formula (V) in the presence of from 0.01 to 10 mol %, preferably from 0.1 to 5 mol %, based on the Grignard compound, of a Cu compound, and in the presence of a Pd or Ni cocatalyst,
where X is Cl or Br.
Suitable solvents for the coupling of the compound of the formula (IV) with (V) are, for example, aliphatic or aromatic ethers or hydrocarbons, preferably THF or THF/toluene mixtures. The coupling can be carried out at temperatures in the range from −80° C. to the boiling point of the solvent used. However, the proportion of the 2-substitution product increases at the expense of the desired 4-substitution product at high temperatures, so that temperatures of from −70 to +60° C. are preferred. Particular preference is given to temperatures of from −50 to +50° C., particularly preferably from −35 to +40° C. Suitable Cu compounds are Cu(I) and Cu(II) compounds, preferably CuI, CuBr, CuCl or CUCl
2
.
Suitable cocatalysts for the coupling reactions are salts, complexes or the metallic form of nickel or palladium. The amounts employed can be from 10
−5
to 10 mol %, preferably from 10
−4
to 7.5 mol %, in particular from 10-3 to 5 mol %, based on the Grignard compound.
Particular preference is given to salts or complexes of nickel or palladium and also metallic forms, if desired on a suitable support, e.g. Pd on C or on BaSO
4
, very particularly preferably PdCl
2
(dppf), PdCl
2
(PPh
3
)
2
, PdCl
2
(dppe), PdCl
2
(dppp), PdCl
2
(dppb), Pd(PPh
3
)
4
, Pd(OAc)
2
, PdCl
2
, PdBr
2
or NiCl
2
(PPh
3
)
2
, where “dppf” is 1,2-bis(diphenylphosphino)ferrocene, “dppe” is 1,2-bis(diphenylphosphino)ethane, “dppp” is 1,2-bis(diphenylphosphino)propane, “dppb” is 1,2-bis(diphenylphosphino)butane, “Ph” is phenyl and “Ac” is acetyl.
The conversion of the dihydropyridine of the formula (II) into 4-(4′-carboxyphenyl)-pyridine of the formula (I) is achieved according to the invention by oxidation using an oxidizing agent selected from the group consisting of permanganates, e.g. sodium or potassium permanganate, nitric acid, chromium(VI) reagents, e.g. alkali metal chromates or alkali metal dichromates, oxygen and air, particularly preferably by air oxidation.
According to Comins et al., it is possible to convert N-acylated 4-aryldihydropyridines into the corresponding 4-arylpyridines by heating with elemental sulfur.
However, large amounts of hydrogen sulfide and other sulfur compounds are formed in the treatment with sulfur and, furthermore, high temperatures are required, resulting in a very impure, black product. This is very cumbersome to purify to the extent required for further oxidation.
It has surprisingly been found that the dihydropyridine of the formula (II) can be oxidized in a single step to give a very pure product of the formula (I). Despite the successive oxidations of the N-acyl group, of the dihydropyridine to give the pyridine and of the aromatic alkyl group to give the acid group, good yields of a pure product are obtained.
The oxidation can be carried out by means of permanganates, nitric acid, air, O
2
, or chromium(VI) reagents; however, oxidation by mea

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