Process for the preparation of a cyanobiphenyl

Details Process for the preparation of a cyanobiphenyl Process for the preparation of a cyanobiphenyl

1999-06-30

2002-05-21

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Nitriles

Reexamination Certificate

active

06392080

ABSTRACT:

THIS APPLICATION IS A 371 OF PCT/FR97/01577 FILED SEP. 8, 1997.
The present invention relates to a process for the preparation of a cyanobiphenyl.
More particularly, the subject-matter of the invention is a process for the preparation of o-(p-tolyl)benzonitrile of formula I
which constitutes the key intermediate in the synthesis of numerous active principles of medicines acting in particular against hypertension by a mechanism in which angiotensin II is inhibited.
o-(p-Tolyl)benzonitrile, hereinafter denoted more concisely as orthotolylbenzonitrile or OTBN, was disclosed for the first time in EP 253,310 and a number of processes for its synthesis have recently been provided.
The process which seems to be the most appropriate for the preparation of OTBN 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 method, with respect to those known previously, has the advantage of taking place in a single stage with yields of approximately 70% before crystallization. However, it gives 4,4′-dimethylbipohenyl, resulting from the condensation of the p-tolylmagnesium halide with itself, as reaction by-product.
It has now been found that, if the reaction between the p-tolylmagnesium halide and the o-halobenzonitrile is carried out in the presence of a manganous salt and of traces of a palladium(II) salt, the OTBN is obtained with a yield of at least approximately 92% while the 4,4′-dimethylbiphenyl impurity falls below approximately 2.5%.
Thus, the subject-matter of the present invention is a process for the preparation of o-(p-tolyl)benzonitrile, characterized in that an o-halobenzonitrile, preferably o-bromobenzonitrile, is treated with a p-tolylmagnesium halide in the presence of a manganous salt and of a cocatalyst comprising a transition metal, preferably a palladium(II) salt.
The coupling reaction according to the invention is carried out in a solvent of the ether type, such as methyl t-butyl ether, dibutyl ether, dioxane or tetrahydrofuran, it being possible for the reaction temperature to vary from −10 to 60° C., depending on the solvent employed.
This reaction results in the transient formation of a complex, which is hydrolysed according to known procedures, for example by means of an acid, such as hydrochloric acid.
As regards the manganous salt, it is preferably MnCl
2
or MnCl
4
Li
2
, it being possible for the latter to be formed in situ by addition of two molar equivalents of LiCl and of one molar equivalent of MnCl
2
.
This manganous salt takes part in the reaction in a proportion of 0.5 to 1.3 molar equivalents per molar equivalent of starting o-halobenzonitrile.
The transition metal forming the cocatalyst is advantageously nickel, cobalt, platinum or, in particular, palladium.
Use is preferably made, as cocatalyst 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. Mention may more particularly be made of palladium complexes, such as bis(triphenylphosphine)-dichloro-, bis(tributylphosphine)dichloro-, bis(tri-cyclohexylphosphine)dichloro-, diallyltriphenyl-phosphinedichloro-, triphenylphosphinepiperidine-dichloro-, 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) complexed 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 cocatalyst 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 cocatalyst is present in very small amounts in the reaction mixture, namely from 0.001 to 2 molar % per mole of starting o-halobenzonitrile.
According to a preferred procedure, the p-tolylmagnesium halide is in equimolar amounts or in slight excess (1 to 1.5 mol) with respect to the o-halobenzonitrile. In addition, the preferred manganous catalyst (MnCl
4
Li
2
) is formed either in situ, in equimolar amounts or in slight excess (1 to 1.5 mol) with respect to the o-halobenzonitrile, or at the time of use, before addition to the reaction mixture.
MnC:L
4
Li
2
is prepared by reacting one equivalent of MnCl
2
with two equivalents of LiCl.
The reaction can be carried out in tetrahydrofuran by adding, at a temperature of 10° C., the cocatalyst and the o-halobenzonitrile, optionally in solution in tetrahydrofuran, to a tetrahydrofuran solution comprising the p-tolylmagnesium halide and the manganous catalyst. This reaction, which is exothermic, can be controlled by adjusting the rate of addition of the substituted benzonitrile and of the cocatalyst, so as to maintain it below 35° C.
Alternatively, the reaction can also be carried out by adding the p-tolylmagnesium halide in, for example, tetrahydrofuran to a mixture of o-halobenzonitrile, cocatalyst and manganous catalyst in, for example, tetrahydrofuran. In this case, the reaction temperature can be better controlled and the addition of p-tolylmagnesium halide can be carried out even at a higher temperature, about 50-55° C., so as to decrease the duration of the reaction and the amount of cocatalyst employed.
However, in order to improve the progress of the reaction, it can be advantageous to add a cosolvent to the mixture comprising the manganous catalyst. This cosolvent is preferably another ether or diether, for example dimethoxyethane.
According to the above preferred procedure, hydrolysis is carried out in situ with hydrochloric acid and the OTBN thus formed is isolated according to conventional techniques, for example by extraction with a suitable solvent, evaporation of the solvent and purification by crystallization from ethanol or by chromatography.
The OTBN is thus obtained with very high yields, from 92 to 98% depending on the proportions of the reactants employed. It comprises very small amounts of 4,4′-dimethylbiphenyl, generally less than 2.5%.
The amount of 4,4′-dimethylbiphenyl which is formed according to the process of the present invention was compared with that which is formed according to the process disclosed in EP 566,468. Thus, by carrying out the reaction:
according to EP 566,468, namely by using MnCl
2
alone as catalyst, in a series of tests under the same conditions, the 4,4′-dimethylbiphenyl by-product was obtained with a yield of 8 to 12% with respect to the p-tolylmagnesium bromide, i.e. 6.5 to 10% by weight of 2-(p-tolyl)benzonitrile final product; according to the present invention, namely by using MnCl
2
end PdCl
2
/dppp as catalyst and cocatalyst, in a series of tests under the same conditions, the 4,4′-dimethylbiphenyl by-product was obtained with a yield of 0.5 to 1% with respect to the p-tolylmagnesium bromide, i.e. at most 0.65% by weight of final product.
The cocatalyst comprising a transition metal can also be a cobalt, nickel or platinum salt, as indicated above. In the case of a cocatalyst comprising nickel, use is generally made of a nickel(II) salt, such as nickel chloride or acetylacetonate. This salt is preferably complexed with at least one organophosphorus compound comprising trivalent phosphorus, such as a phosphine, for example triphenylphosphine. The nickel salt and the organophosphorus compound can be added

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