FR2766821A1 - 1,3-OXAZOLINYL-BIPHENYL DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS SYNTHESIS INTERMEDIATES - Google Patents

Abstract

The invention concerns 1,3-oxazolin-2-yl-1,1'biphenyl derivatives of general formula (I) in which R represents hydrogen or the methyl radical.

Description

 The present invention relates generally to novel oxazolin-2-yl-1,1'-biphenyl derivatives, to their process of preparation and to their use as synthesis intermediates.

dans laquelle R représente l'hydrogène ou méthyle.More specifically, the subject of the invention is the 2- (1,3-oxazolin-2-yl) 4'-phthalimidomethyl-1,1'-biphenyl derivatives of the general formula:

wherein R is hydrogen or methyl.

 The compound of formula I wherein R is methyl may be considered a preferred compound.

The compounds of the invention have proved to be particularly useful as intermediates especially for the preparation of 4'-aminomethyl-2-cyano-1,1'-biphenyl of formula:

dans laquelle Am représente un groupement spirocyclopentane-cétoimidazolinyle, I H-imidazolyle ou I H-benzimidazolyie, ce groupement comportant lui-même un ou plusieurs substituants sélectionnés parmi des atomes d'halogène, des groupements alkyle en C1-04 alkoxy en C1-C4 et carboxylique.The latter can itself be widely used as synthesis intermediate for example for the preparation of various pharmacologically active compounds. As such, mention may be made of biphenyl antagonist derivatives of angiotensin II receptors corresponding to the general formula:

in which Am represents a spirocyclopentane-ketoimidazolinyl, 1H-imidazolyl or 1H-benzimidazolyie group, this group itself comprising one or more substituents selected from halogen atoms, C 1 -C 4 -alkoxy C 1 -C 4 -alkyl groups; and carboxylic.

représente un groupement Am préféré.The 2-n-butyl-4-spirocyclopentane-5-keto-2-imidazolin-1-yl group of formula:

represents a preferred Am group.

 The compounds of formula Ib, which can be used in the treatment of cardiovascular diseases, such as hypertension or cardiac defaeciency, have been described in particular in patents US 5,138,069, 5,196,444 and 5,529,233.

Among the biphenyl derivatives of formula Ib that are most interesting are 2-butyl-3- [p- (2- (1H-tetrazol-5-yl) phenyl} benzyl] -1,3-diazaspiro. [4,4] no I -ên-
4-one or irbesartan - 2-ethoxy-1- [4- [2- (1H-tetrazol-5-yl) phenyl] benzyl] 1H-benzimidazole-7-one
carboxylic acid or candesartan - 2-butyl-4-chloro-1 - [[2 '- (1H-tetrazol-5-yl) -111'-biphenyl-4yl] methyl] H-
imidazole-5-methanol or losartan.

 Irbesartan, however, is a preferred compound of formula I b.

 Most of the known processes for the preparation of the biphenyl derivatives of formula Ib or analogs thereof are carried out through the formation of a common intermediate, namely 4'-bromomethyl-2-cyano-1, biphenyl.

 However, this brominated derivative has the major drawbacks of being lachrymatory and aliergene therefore requiring handling precautions such as, for example, containment or use in solution.

 The search for a process for the preparation of the biphenyl derivatives of formula I b, or analogs thereof, while not having the disadvantages reported above, therefore remains of undeniable interest.

 It has surprisingly been found, according to the invention, that the 2- (1,3-oxazolin-2-yl) -4'-phthalimidomethyl-1,1'-biphenyl derivatives of formula I make it possible to prepare the compounds of formula I b or the like according to a method devoid of the drawbacks mentioned above, in that it avoids the passage through intermediate 4'-bromomethyl-2-cyano-1,1'-biphenyl in favor of 4'-aminomethyl-2 -cyano-1,1'-biphenyl. This 4'-aminomethyl derivative, which can advantageously be prepared starting from the compounds of formula I since the yields obtained are of the order of 70% to 80%, therefore offers the possibility of synthesizing the active ingredients of formula I b and their analogues, in a new and original way.

dans un milieu approprié, tel qu'un solvant aprotique, par exemple le chlorure de méthylène, d'abord avec le chlorure d'oxalyle, ensuite avec le 2-amino-2méthylpropanol ou le DL-2-amino-l -propanol et finalement avec le chlorure de thionyle, pour donner un dérivé de 2-(1, 3-oxazolin-2-yi)-i , l'-biphényle de formule générale:

According to the invention, the oxazolin-2-yl-1,1'-biphenyl derivatives of formula I are prepared by carrying out the following steps: a) treating biphenyl-2-carboxylic acid of formula:

in a suitable medium, such as an aprotic solvent, for example methylene chloride, first with oxalyl chloride, then with 2-amino-2-methylpropanol or DL-2-amino-1-propanol and finally with thionyl chloride to give a 2- (1,3-oxazolin-2-yl) -1,3-biphenyl derivative of the general formula:

wherein R has the same meaning as above; b) the thus obtained 1,2-biphenyl derivative is reacted with phthalimide;
presence of formaldehyde polymerized or not, such as paraformaldehyde or
trioxane, and in the presence of a strong acid as a catalyst, to form the
desired compound of formula I.

 This latter reaction can be carried out directly in the strong acid in question, generally a sulfonic acid such as methanesulfonic acid which then plays the additional role of solvent, or alternatively in an organic solvent containing this strong acid.

In this case, an aliphatic carboxylic acid such as acetic or propionic acid or a nitroaliphatic or nitroaryl derivative, such as nitromethane or nitrobenzene, is generally preferred as the appropriate organic solvent, the strong acid being generally a sulphonic acid such as than above, or a mineral oxacid such as sulfuric acid
This is usually used in a proportion of 1 to 3 equivalents by volume relative to the solvent, preferably 3 equivalents.

 The reaction in question takes place in most cases at room temperature or by heating at a temperature not exceeding 60 ° C while phthalimide is used at 1 to 2 molar equivalents relative to the compound of formula III .

en présence d'une base alcaline telle qu'un hydroxyde de métal alcalin, de préférence l'hydroxyde de sodium ou de potassium, puis traitement du sel obtenu par un acide fort pour obtenir finalement l'acide souhaité de formule Il. As for the biphenyl-2'-carboxylic acid of formula II, it can be obtained according to known methods, for example by heating the fluorenone of formula:

in the presence of an alkaline base such as an alkali metal hydroxide, preferably sodium or potassium hydroxide, and then treatment of the salt obtained with a strong acid to finally obtain the desired acid of formula II.

 As indicated previously, the 2- (1,3-oxazolin-2-yl) -4'-phthalimidomethyl-1,1'-biphenyl derivatives of formula I can be used for the preparation of 4'-aminomethyl-2-cyano 1-biphenyl of formula la.

 Accordingly, the invention relates to compounds of formula I as intermediates for the final synthesis of the compound of formula Ia, especially the compound of formula I wherein R is methyl.

For example, this compound of formula Ia can be prepared from compounds of formula I by carrying out a process comprising the following steps: a) treating the compound of formula I with oxychloride of phosphorus in a
polar solvent such as pyridine, which provides 4'-phthalimidomethyl-2
cyano-i, biphenyl of formula:

This reaction is usually carried out at a temperature of the order of 80 ° C. to 90 ° C. in the presence of an excess of phosphorus oxychloride, that is to say up to 2 molar equivalents per molar equivalent of compound of formula
I, thereby providing the desired compound in yields of about 90%.

b) the phthalimido derivative of formula V is then reacted with ethylenediamine
or a hydrazine / acetic acid buffered solution, to obtain the 4 '
desired aminomethyl-2-cyano-1 '-biphenyl.

The reaction in question is carried out in the presence of an excess of reagents
up to 2 molar equivalents of ethylenediamine or 2
molar equivalents of hydrazine buffered with a molar equivalent
acetic acid, relative to the compound of formula V, which allows
to obtain the desired compound in yields ranging from 60 to 85%.

 As indicated above, the compounds of formula I can be used for the synthesis of the compound of formula itself intermediate for the preparation of biphenyl derivatives of formula Ib.

Accordingly, the invention also relates to compounds of the formula
As intermediates for the final synthesis of biphenyl derivatives of formula Ib, especially for the synthesis of irbesartan.

For example, these compounds of formula Ib can be prepared from the carbonitrile derivative of formula la obtained according to the invention from compounds of formula I, by carrying out a process comprising the following steps. after: (a) the carbonitrile derivative of formula la is condensed with a compound of formula
general:
H-Am VI
in which Am has the same meaning as before, in the presence
of a suitable catalyst to obtain the cyano-biphenyl derivatives of
general formula:

 in which Am has the same meaning as before.

 This reaction is generally carried out by heating the reactants in the presence at a temperature above 100 ° C., for example 100 ° C. to 130 ° C., in a suitable solvent which is usually an aprotic solvent such as a particular ether. dibutyl ether or in an aromatic compound such as a halobenzene for example chlorobenzene or an aromatic hydrocarbon such as toluene or xylene.

 The coupling of the aminonitrile compound of formula la with the compound of formula VI is carried out in the presence of a catalyst containing a transition metal, more particularly a metal of the lanthanide or rare earth group, namely ytterbium or praseodymium.

 Among the catalysts which have proved effective, mention may be made of ytterbium salts and of praseodymium salts, for example praseodymium (III +) acetate, but more particularly and, preferentially, ytterbium (III +) trifluoromethanesulphonate and praseodymium trifluoromethanesulfonate (here +).

 In this way, the compounds of formula VII can be obtained in particularly advantageous yields.

 For example, aminonitrile of formula la coupled to 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one in the presence of praseodymium trifluoromethanesulfonate (III +) or ytterbium (III +) provides the corresponding compound of formula VII with yields of around 65%.

(b) the nitrile group of the compound of formula VII is then converted into a
tetrazolyl group optionally protected for example by means of a
trityl group by treating the compound of formula VII with the
an azide derivative, for example tributyltin azide or sodium azide
and deprotect, if necessary, by acid hydrolysis to finally give
desired compounds of formula Ib.

The following nonlimiting examples illustrate the invention. These examples mention infra-red spectra (IR) and nuclear magnetic resonance (NMR) spectra in which the abbreviations "s" and "m" respectively have the meanings of "singlet" and "multiplet"
PREPARATIONS a) 2- (4,4-Dimethyl-3-oxazolin-2-yl) -1,4'-biphenyl
To a solution of 11.9 g (60 mmol) of biphenyl-2-carboxylic acid in 60 ml of dry methylene chloride, cooled to 0 ° C., 6.2 ml (72 mmol) of sodium chloride are added dropwise. oxalyl. The mixture is stirred for 12 hours at room temperature and then at 35 ° C. for 4 hours, the solvent and the excess oxalyl chloride are removed under vacuum and the residue is dissolved in 50 ml of methylene chloride. then this solution dropwise to a cooled solution of 10.7 g (0.12 mole) of 2-amino-2-methylpropanol in 50 ml of methylene chloride.The mixture is stirred for 10 to 12 hours at room temperature, filtered and evaporated under empty.

 The oily residue is diluted with 10 ml of methylene chloride and treated, with stirring, with 6.6 ml (90 mmol) of thionyl chloride. After 30 minutes, 100 ml of water are carefully added, then the aqueous phase is separated off, neutralized to a pH of about 7 by addition of a 20% aqueous solution of sodium hydroxide and extracted with 3 times 100 ml of water. diethyl ether. The organic fractions are combined, washed with water and then dried over anhydrous sodium sulphate.

Evaporation of the solvent in vacuo gave 14.49 (yield: 96%) of the desired product as a yellowish oil of satisfactory purity (98% by high pressure liquid chromatography).

If necessary, it is further purified by distillation (for example 135-140 ° C./0.6 mmHg) which gives 13.89 of 2- (4,4-dimethyl-1,3-oxazolin-2-yl) -1, the biphenyl.

Yield: 92%
Using the same procedure as described above, but replacing 2-amino-2-methylpropanol with DL-2-amino-1-propanol, 2- (4-methyl-1,3-oxazolin-2-yl) was obtained. ) -1,1'-biphenyl after purification by chromatography on silica (eluent: heptane / ethyl acetate 4/1) and distillation (145-150 ° C./0.6 mm)
Hg).

Yield: 46%
EXAMPLE I 2- (4,4-Dimethyl-1,3-oxazolin-2-yl) -4-phthalimidomethyl-1,1 '-biphenyl
To a cooled solution of 0.7549 (3 mmol) 2- (4,4-dimethyl-1,3-oxazolin-2-yl) -1,1'-biphenyl and 0.4869 (3.3 mmol) of phthalimide in 4.2 ml of nitromethane, 0.0999 (1.1 mmol) of trioxane and 1.8 ml of 96% sulfuric acid are added dropwise. The mixture is stirred for 20 hours at room temperature, diluted with 20 ml of ethyl acetate and poured into a saturated aqueous solution of sodium bicarbonate. The organic layer is separated and the aqueous phase is extracted with twice 30 ml of ethyl acetate. The extracts are combined, dried over anhydrous sodium sulphate and evaporated under vacuum.

In this manner, 1.25 g of 2- (4,4-dimethyl-1,3-oxazolin-2-yl) -4'-phthalimidomethyl-1,1'-biphenyl are obtained in the form of a white powder which is purified on a silica column (eluent: hexane / ethyl acetate)
Yield: 0.989 or 80%
PF: 115-119 ° C (methanol)
IR (KBr): 2964, 2927, 1716, 1654, 1393, 1349 cm1 1H NMR (CDCl3, 200MHz), δ, ppm: 1.27 (s, 6H); 3.79 (s, 2H); 4.89 (s, 2H); 7.297.51 (m, 7H); 7.66 to 7.78 (m, 3H); 7.81 to 7.91 (m, 2H).

 3C NMR (CDCl3, 50MHz), ppm: 168.0; 163.6; 141.0; 140.6; 135.2; 133.9; 132.0; 130.4; 130.1; 130,0128,6; 128.2; 127.8; 127.1; 123.3; 79.4; 67.4; 41.3; 27.9.

EXAMPLE II 2- (4,4-Dimethyl-1,3-oxazolin-2-yl) -4'-phthalimidomethyl-1'-biphenyl
To a cooled solution of 0.7549 (3 mmol) 2- (4,4-dimethyl-1,3-oxazolin-2-yl) -1,1'-biphenyl and 0.4869 (3.3 mmol) of phthalimide in the solvent, 0.0999 (1.1 mmol) of trioxane and dropwise strong acid.

 The mixture is stirred for H hours at the temperature T, diluted in 20 ml of ethyl acetate and poured into a saturated aqueous solution of sodium bicarbonate. The organic layer is separated and the aqueous phase is extracted with twice 30 ml of ethyl acetate. The extracts are combined, dried over anhydrous sodium sulphate and evaporated under vacuum.

 In this manner, 2- (4,4-dimethyl-1,3-oxazolin-2-yl) -4'-phthalimidomethyl-1,1'-biphenyl is collected and purified on a silica column (hexane / acetate eluent). ethyl).

The following results were obtained

<tb> Example <SEP> Solvent <SEP> Acid <SEP> Strong <SEP> H <SEP> T <SEP> Yield
<tb><SEP> (ml) <SEP> (mi) <SEP> (Time) <SEP> (C) <SEP> (%)
<tb><SEP> It <SEP> acid <SEP> acid <SEP> sulfuric acid <SEP> 3 <SEP> 60 <SEP> 60
<tb><SEP> propionic <SEP> 98%
<tb><SEP> 1.8ml <SEP> 1.8ml
<tb><SEP> III <SEP> acid <SEP> acid <SEP> sulfuric acid <SEP> 24 <SEP> 45 <SEP> 65
<tb><SEP> propionic <SEP> 96%
<tb><SEP> 1.8ml <SEP> 1.8ml
<tb><SEP> IV <SEP> acid <SEP> methanesulfonic acid <SEP> 20 <SEP> 20-25 <SEP> 70
<tb><SEP> 4.2ml
<tb><SEP> V <SEP> nitrobenzene <SEP> acid <SEP> sulfuric acid <SEP> 20 <SEP> 20-25 <SEP> 70
<tb><SEP> 5.4ml <SEP> 96%
<tb><SEP> 1.8ml <SEP>
EXAMPLE VI 2- (4-Methyl-1, 3-oxazolin-2-yl) -4'-phthalimidomethyl-1,1'-biphenyl
To a cooled solution of 0.237 g (1 mmol) 2- (4-methyl-1,3-oxazolin-2yl) -1,1'-biphenyl and 0.2219 (1.5 mmol) phthalimide in 1, 5 ml of nitromethane, 0.0459 (1.5 mmol) of paraformaldehyde and 0.5 ml of 96% sulfuric acid dropwise dropwise.

 The reaction mixture is kept at ambient temperature for 5 hours and the process is continued as described in Example I.

 The desired compound is then purified on a silica column (eluent hexane / ethyl acetate) to give 0.2879 (yield: 72%) of 2- (4-methyl-1,3-oxazolin-2-yl) -4 ' -phthalimidomethyl-1,1'-biphenyl which is recrystallized from methanol.

PF 125-127 ° C
IR (KBr): 3027, 2965, 2891, 1770, 1715, 1652, 1428, 1393.1348 cmH NMR (CDCl3, 200MHz), δ, ppm: 1.18-1.30 (m, 6H); 3.56-3.72 (m, 1H); 4.103.33 (m, 2H); 4.89 (s, 2H); 7.29-7.52 (m, 7H); 7.66-7.77 (m, 3H); 7.81-7.90 (m, 2H).

3 C NMR (CDCl3, 50 MHz), ppm: 168.1; 164.9; 141 .2; 140.8; 135,3134,1; 132.2; 130.6; 130.3; 130.2; 128.7; 128.3; 127.7; 127.2; 123.4; 74.4; 62.0; 41.4; 21.2.

EXAMPLE VII 4 '- (2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-on-1-yl) methyl-2-cyano-1, biphenyl a) 4'-phthalimidomethyl-2-cyanl, 1 '-biphenyl
To a solution of 11,289 (27.5 mmol) of 2- (4,4-dimethyl-1,3-oxazolin-2-yl)
4'-phthalimidomethyl-1,1'-biphenyl in 30 ml of anhydrous pyridine is added
under cooling and drip, 5.1 ml (56 mmol) of
phosphorus. With stirring, the mixture is then heated to 85-90 ° C for 3 hours.
hours. After cooling, the dark solution is poured into iced water
thus obtained and extracted with 3 times 200 ml of methylene chloride.

The organic layers are combined, washed with water, with an aqueous solution of
5% hydrochloric acid, again with water and then twice with
saturated aqueous solution of sodium bicarbonate. Dry on sulfate
anhydrous sodium and the solution is filtered through neutral alumina.

 The filtrate is evaporated in vacuo yielding 8.49 of desired product.

(Yield: 90%)
In this way, 7.69 of 4'-phthalimidomethyl-2-cyano-1 is obtained.
pure biphenyl after recrystallization from acetic acid. A sample
analytic can be obtained by recrystallization from methanol.

Mp 178-179 ° C b) 4'-Aminomethyl-2-cyano-1, 1-biphenyl
6,769 (20 mmol) of 4 'are heated under reflux for 6 hours.
phthalimidomethyl-2-cyano-1,1'-biphenyl, 2ml (40 mmol) of monohydrate
of hydrazine and 1.2ml of acetic acid dissolved in a mixture of 100ml of
tetrahydrofuran and 100 ml of isopropanol. The cooled suspension is filtered,
Wash the precipitate with 50 ml of methanol and treat the filtrate with 100 ml of
5% sodium hydroxide solution. After 15 minutes, add 200ml
of an aqueous solution of sodium chloride and the mixture is extracted with 3
100 ml of a 3/1 diethyl ether / tetrahydrofuran mixture.

The extracts are combined, washed with 2 times 100 ml of an aqueous solution of
sodium chloride and dried over anhydrous sodium sulfate. We evaporate
solvents under vacuum and distilled, which provides 3.39 g of 4'-aminomethyl-2
cyano-1'1-biphenyl (yield: 82%) as a viscous oil
slowly solidifying at rest.

Mp: 110-101C c) 4 '- (2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-on-1-yl) methyl-2-cyano-1,1'
biphénvle
To a solution of 1.04 g (5 mmol) of 4'-aminomethyl-2-cyano-1,
biphenyl in 15 ml of dibutyl ether, 0.971 g (5 mmol) of 2-n
butyl-4-spirocyclopentane-2-imidazolin-5-one then 0.3g (about 0.48
mmol) of hydrated ytterbium trifluoromethanesulfonate (III +). We shake
then the mixture under argon for 22 hours at 110-115 ° C then, after
cooling, the solution is washed first with water and then with a solution
aqueous sodium chloride. Dry over anhydrous sodium sulphate and
evaporate under vacuum.

The residue is chromatographed on a silica column (eluent: heptane / acetate
2/1), which gives 1.25 g of 4 '- (2-n-butyl-4-spirocyclopentane-2
imidazolin-5-on-1-yl) methyl-2-cyano-1,1'-biphenyl.

Yield: 65%
EXAMPLE VIII 2-n-Butyl-4-spirocyclopentane-1 - [(2 '- (tetrazol-5-yl) -4-biphenylyl) methyl] -2-imidazolin-5-one or irbesartan a) 2-n-Butyl 4-spirocyclo-pentane-1 - [(2 '- (triphenylmethyl-tetrazol-5-yl) -4-biphenylyl) methyl-2-imidazolin-5-one
Refluxed for 66 hours, 1.56 g of 4 '- (2-n-butyl-4-spirocyclopentane-2-imidarolin-5-on-1-yl) methyl-2-cyano-1,1'-biphenyl,
2.6g of tributyltin azide and 30ml of xylene. We evaporate the xylene and we
dissolves the residue in 20 ml of dichloromethane and 5 ml of tetrahydrofuran
by adding 0.8ml of 1N sodium hydroxide solution. After 30
minutes of stirring, 2.5 g of trityl chloride are introduced and left under
stirring for 26 hours. After evaporation of the solvents, take up the
residue in ethyl acetate and washed with water, with a solution of sulphate
3% potassium acid and with water. Dry and evaporate. We
chromatography then the residue on alumina, eluting on the mixture
hexane / ethyl acetate (9/1 v / v).

 In this way, 1.97 g of desired compound are obtained.

PF: 150-152C (b) irbesartan
10 ml of methanol and 10 ml of tetrahydrofuran, 1.96 g of
compound obtained in step a) above. After cooling the medium
at 5 ° C., 1.5 ml of 4N hydrochloric acid are added and the mixture is stirred
for 3 hours at room temperature and 1 hour at 30 ° C.
evaporation of the solvents, the residue is taken up in water and
pH = 12 by addition of 10N sodium hydroxide.

The aqueous phase is extracted with diethyl ether, toluene and
again with diethyl ether.

The aqueous phase is acidified to pH = 2 by adding hydrochloric acid
1N, then extracted with methyl acetate, dried and evaporated. Dry
then at 50 ° C under 0.05mm Hg the white solid obtained.

 In this way, 0.840 g of irbesartan is collected.

 M.p .: 180-181 ° C

Claims (19)

 1. Derivatives of 1,3-oxazolin-2-yl-1,1'biphenyl of general formula:  in which R represents hydrogen or the methyl radical. 2. 2- (4,4-Dimethyl-1,3-oxazolin-2-yl) -4'-phthalimidomethyl-1,1'-biphenyl. 3- (4-Methyl-1,3-oxazolin-2-yl) -4'-phthalimidomethyl-1,1'-biphenyl. 4. Process for the preparation of 1,3-oxazolin-2-yl-1,1'-biphenyl derivatives according to  one of Claims 1 to 3, characterized in that  a) treating biphenyl-2-carboxylic acid of formula

 in a suitable medium first with oxalyl chloride, then with 2-amino-2-methylpropanol or DL-2-amino-1-propanol and finally with thionyl chloride to give a derivative of (1, 3-oxazolin-2-yl) -1,1'-biphenyl of the general formula

 strong as a catalyst, which provides the desired compounds.  solvent and catalyst or in an organic solvent in the presence of an acid  presence of formaldehyde polymerized or not, in a strong acid like  b) the 1,1'-biphenyl derivative thus obtained is reacted with phthalimide in  in which R represents hydrogen or the methyl radical Process according to Claim 4, characterized in that formaldehyde  polymerized is paraformaldehyde or trioxane. Process according to Claim 4 or 5, characterized in that the reaction is  carried out in a strong acid which is a sulfonic acid. Process according to Claim 4 or 5, characterized in that the reaction is  carried out in an organic solvent which is an aliphatic carboxylic acid  or a nitroaliphatic or nitroaryl derivative, and in the presence of a strong acid  which is a sulfonic acid or a mineral oxacid. 8. Process according to one of Claims 4 to 7, characterized in that the acid  sulfonic acid is methanesulfonic acid. 9. Process according to Claim 7, characterized in that the carboxylic acid  Aliphatic is acetic or propionic acid. Process according to Claim 7, characterized in that the derivative  nitroaliphatic is nitromethane and the nitroaryl derivative is the  nitrobenzene.  sulfuric acid.  11.Procédé according to claim 7, characterized in that the mineral oxacid is

 wherein R represents hydrogen or methyl radical, with phosphorus oxychloride in a polar solvent, which provides 4 'phthalimidomethyl-2-cyano-1,1'-biphenyl of formula

 characterized in that a) treating a compound of the general formula

 12. Process for the preparation of 4'-aminomethyl-2-cyano-1,1'-biphenyl of formula  to obtain the deprotected amine desired.  ethylenediamine or a hydrazine / acetic acid buffered solution,  b) the phthalimido derivative thus formed is then reacted with

 general formula: Am in which Am has the same meaning as above, in the presence of a catalyst containing a metal of the lanthanide group, to obtain the cyanobiphenyl derivatives of general formula  c) the carbonitrile derivative thus formed is condensed with a compound of

 to obtain 4'-aminomethyl-2-cyano-1,1'-biphenyl of formula:  ethylenediamine or a hydrazine / acetic acid buffered solution,  b) the phthalimido derivative thus formed is then reacted with

 wherein R is hydrogen or methyl, with phosphorus oxychloride in a polar solvent, which provides the 4 'phthalimidomethyl-2-cyano-1,1'-biphenyl of formula

 in which Am represents a spirocyclopentane-ketoimidazolinyl, 1H-imidazolyl or 1H-benzimidazolyl group, this group having itself one or more substituents selected from halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and carboxylic acid, characterized in that a) a compound of general formula is treated

 13.Procedure for the preparation of biphenyl derivatives of the general formula  wish.  deprotecting, if necessary, by acid hydrolysis, to obtain the compound  by treating the compound of formula VII with an azide derivative and  thus formed, into an optionally protected tetrazolyl group and this,  d) the cyano group of the cyanobiphenyl derivative is finally converted  in which Am has the same meaning as before, 14.Procédé according to claim 13, characterized in that the metal of the group  lanthanides is ytterbium or praseodymium. 15.Process according to Claim 13 or 14, characterized in that the catalyst  is a salt of ytterbium or praseodymium.  praseodymium (III +).  ytterbium trifluoromethanesulfonate (III +) or trifluoromethanesulfonate  Process according to Claim 15, characterized in that the catalyst is the  Tetrazolyl is protected by a trityl group.  Method according to Claim 13, characterized in that the grouping  tributyltin azide or sodium azide.  18. Process according to Claim 13, characterized in that the azide derivative is  represents 2-n-butyl-4-spirocyclopentan e-5-keto-2-imidazolin-1-yl.  19.Process according to one of Claims 13 to 18, characterized in that Am