Method for preparing 4-methyl-biphenyl derivatives

Details Method for preparing 4-methyl-biphenyl derivatives Method for preparing 4-methyl-biphenyl derivatives

1999-07-14

2002-06-18

Higel, Floyd D. (Department: 1613)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C558S378000

Reexamination Certificate

active

06407253

ABSTRACT:

The present invention relates to a process for the preparation of substituted biphenyls. More particularly, the subject-matter of the invention is a process for the preparation of substituted 4-methylbiphenyls of general formula:
in which R is a cyano group or a tetrazolyl group of formula:
in which R
1
, situated at the 1 position or preferably at the 2 position of the tetrazolyl group, is a protective group.
In particular, R
1
can be:
a (C
1
-C
4
) alkyl group
a (C
1
-C
4
) alkyl group monosubstituted or polysubstituted by an aryl group itself optionally monosubstituted or polysubstituted by a (C
1
-C
4
) alkyl or (C
1
-C
4
) alkoxy group
a (C
1
-C
4
) alkyl group substituted by (i) a (C
1
-C
4
) alkoxy group or (ii) an aryloxy group optionally monosubstituted or polysubstituted by a (C
1
-C
4
) alkyl or (C
1
-C
4
) alkoxy group or else (iii) an arylalkyloxy group which is optionally monosubstituted or polysubstituted by a (C
1
-C
4
) alkyl or (C
1
-C
4
) alkoxy group and in which the alkyl part is (C
1
-C
4
)
a (C
1
-C
4
) alkyl group substituted by a (C
1
-C
4
) alkylthio group
a 2-tetrahydropyranyl, allyl or silyl group.
In the above formula I, “aryl” means, for example, phenyl or pyridyl, whereas “silyl” corresponds in particular to a silyl group trisubstituted by a (C
1
-C
4
) alkyl group.
By way of examples, R
1
can be in particular a tert-butyl, benzyl, p-methoxybenzyl, 2-phenyl-2-propyl, diphenylmethyl, di(p-methoxyphenyl)methyl, trityl, (p-methoxyphenyl)diphenylmethyl, diphenyl(4-pyridyl)methyl, benzyloxymethyl, methoxymethyl, ethoxymethyl, methylthiomethyl, 2-tetrahydropyranyl, allyl, trimethylsilyl or triethylsilyl group.
The substituted 4-methylbiphenyls of formula I are known compounds which are particularly of use as intermediates in the synthesis of numerous medicinal active principles which act in particular against hypertension by a mechanism in which angiotensin II is inhibited.
Thus, the substituted tetrazolyls of formula I were disclosed in WO 96/13489, while the substituted cyano of formula I, that is to say o-(p-tolyl)benzonitrile, hereinafter denoted more briefly as ortho-tolylbenzonitrile or OTBN, was disclosed for the first time in EP 253,310.
A number of processes for the synthesis of OTBN have recently been provided. The process which seems to be the most appropriate is disclosed in EP 566,468 and consists of the reaction of an o-halobenzonitrile with a p-tolylmagnesium halide in the presence of a manganous salt, preferably MnCl
2
, this reaction generally taking place in an ether, such as tetrahydrofuran, dibutyl ether or dioxane.
This method, with respect to those previously known, has the advantage of taking place in a single stage with yields of approximately 70% before crystallization. However, it gives 4,4-dimethylbiphenyl as a reaction byproduct resulting from the condensation of p-tolylmagnesium halide with itself.
Furthermore, results of orientation tests for the preparation of OTBN from p-tolylmagnesium bromide and 2-chlorobenzonitrile have been reported in EP 566,468 in question, the reaction being carried out in tetrahydrofuran in the presence or absence of various catalysts comprising a transition metal, namely PdCl
2
, NiCl
2
, or Pd(PPh
3
)
4
. These tests showed poor, even zero, yields of OTBN, depending on the methods used, such as yields varying from 0 to 27%.
It has now been found, surprisingly, that, when the coupling between the o-halobenzonitrile and the p-tolylmagnesium halide is carried out in the presence of a linear or branched polyether and of traces of a catalyst comprising a transition metal, OTBN is obtained with a yield of at least approximately 92%, while the 4,4′-dimethylbiphenyl impurity falls below approximately 3.5%.
Such results, however, could not be observed when the linear or branched polyether is completely replaced by a cyclic diether in which the two endocyclic oxygens form part of the same ring, in this case dioxane.
Thus, the subject-matter of the present invention is a process for the preparation of the compounds of formula I in general and of o-(p-tolyl)benzonitrile in particular, characterized in that a halobenzene of formula
in which Hal is a halogen atom, preferably bromine, and R has the same meaning as above, is reacted with a p-tolylmagnesium halide in the presence of a linear or branched polyether and of a catalyst comprising a transition metal.
Linear or branched polyether is understood to denote any organic compound comprising at least two ether functions forming part of a ring or of a linear or branched hydrocarbon chain, with the exception of compounds in which all the ether functions are endocyclic and form part of the same ring.
According to a preferred embodiment, the linear or branched polyether is a linear or branched diether, the two ether functions of which, when they are both endocyclic, do not form part of the same ring.
The linear or branched diether is advantageously such that its two ether functions are incorporated in a linear or branched, preferably (C
2
-C
12
), better still (C
2
-C
6
), hydrocarbon chain.
The coupling reaction according to the invention is carried out in a medium composed of a linear or branched polyether, to which has optionally been added a solvent of the monoether type, such as methyl tert-butyl ether or dibutyl ether, or alternatively a cyclic mono- or diether, such as dioxane or tetrahydrofuran, it being possible for the reaction temperature to vary from −10 to 65° C. depending on the medium employed.
In fact, it has been found that, in order to improve the progress of the reaction in question, it is essential to carry out the reaction in the presence of a polyether of this type, generally a glycolic diether. According to the invention, a glycolic ether is a glycol ether in which the glycol is composed of a linear or branched, preferably (C
2
-C
12
), better still (C
2
-C
6
), dihydroxylated hydrocarbon chain. Ethers of 1,2-glycol and in particular diethylene glycol are more particularly advantageous.
In this respect, diethoxyethane and, preferably, dimethoxyethane have proved to be particularly advantageous.
This coupling reaction results in the transient formation of a complex, which is hydrolysed according to the usual procedures, for example by means of an acid, such as hydrochloric acid.
The transition metal forming the catalyst is advantageously cobalt, nickel, platinum, manganese or, in particular, palladium.
Use is preferably made, as catalyst comprising a transition metal, of a palladium(II) salt, in particular the nitrate, chloride, acetate, bromide, sulphate or the like, the chloride (PdCl
2
) and the acetate (CH
3
—COO—Pd—OOC—CH
3
) being particularly advantageous. The palladium salt is preferably complexed, for example with at least one organophosphorus compound comprising trivalent phosphorus. More particularly, use is made of palladium complexes, such as bis(triphenylphosphine)dichloro-, bis(tributylphosphine)dichloro-, bis(tricycloheylphosphine) dichloro-, diallyltriphenylphosphinedichloro-, triphenylphosphinepiperidinodichloro-, bis(cyclohexyloxime)dicarbonyl-, 1,5,9-cyclododecatrienedichloro-, bis(triphenylphosphine)dicarbonyl-, bis(triphenylphosphine)diacetate-, bis(triphenylphosphine)sulphate- or (2,4-pentanedione), tetrakis(triphenylphosphine) palladium. Among these, palladium(II) complexes are particularly advantageous 1,3-bis(diphenylphosphino)propane (dppp) complex with palladium(II) chloride or palladium(II) acetate being preferred.
The palladium salts and the organophosphorus compounds can be added separately to the reaction mixture. In this case, the amount of organophosphorus compound is preferably sufficient to form the catalyst in situ in the form of a complex with the palladium present.
The said complex is generally prepared so that the P/Pd ratio is approximately 1/1 but such a ratio can vary between 0.5/1 and 2/1 without having a significant detrimental effect on the result of the process.
This catalyst is present in very small amounts in the reaction mixture, namely from 0.001 to 2 molar % per mole of s

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