MXPA00009304A - Methyl-phenyl derivatives, preparation method and use - Google Patents

Abstract

The invention concerns:a) methyl-phenyl derivatives of general formula (I) wherein R1 represents OH, C3-C7 alkyl, or C3-C7 cycloalkyl, said compounds being in the form of individual isomers or mixtures thereof;b) the method for preparing them by reacting:either a hydroxylamine salt with an N-substituted o-(p-tolyl)-benzaldimine to obtain o-(p-tolyl)-benzaldoxime;or an N-substituted 2-halobenzaldimine with a p-tolylmagnesium halide in the presence of a manganese mineral derivative, to obtain the compounds of formula (I) wherein R1 represents C3-C7 alkyl or C3-C7 cycloalkyl;c) their use for preparing o-(p-tolyl)-benzonitrile, intermediate in the synthesis of medicines.

Description

DERIVATIVES OF METHYL-BIFENYL. METHOD OF PREPARATION AND USE The present invention relates, in a general manner, to a new methyl biphenyl derivative, to its preparation method and to its use as synthesis intermediate. More precisely, the invention has as its object the o-tolyl-benzaldoxime of the formula: . this compound is considered in the form of its individual isomers or mixtures thereof. The oxime derivative of the formula I, herein designated by OTBO, is particularly useful as an intermediate product especially for the preparation of o- (p-tolyl) -benzonitrile, referred to in the present OTBN. The latter can be used as a particularly interesting intermediary since it is the key intermediary in the synthesis of numerous active drugs that act especially against hypertension by an inhibiting mechanism of angiotensin II. O- (p-tolyl) -benzonitrile has been described for the first time in Patent EP 253310 and a number of methods have recently been proposed for its synthesis. One of the procedures that seems most suitable for the preparation of o- (p-tolyl) -benzonitrile was described in Patent EP 566488. This consists of the reaction between an o-halobenzonitrile with a p-tolylmagnesium halide in the presence of a magnesium salt, preferably MCCI2. However, this method provides as a by-product of the reaction of 6.5 to 10 weight percent of 4,4'-di-ethyl biphenyl, in the present so-called bis-tolyl, resulting from the condensation of the p-tolylmagnesium halide on itself. In the context of the invention, it has been investigated, in order to solve the above problem, the possibility of preparing the o- (p-tolyl) -benzonitrile by means of one of its potential precursors in the occurrence of o- (p- tolyl) -benzaldoxime. With this effect, an attempt has been made to apply a procedure analogous to that of Patent EP 253310 also using p-tolylmagnesium bromide. However, of the tests carried out starting from 2-chlorobenzaldoxime and 3.5 equivalents of p-tolylmagnesium bromide, the reaction takes place in the presence of 0.36 equivalents of MnCl2 in tetrahydrofuran at 90 ° C and for 8 hours, it has not allowed to observe the expected coupling reaction but the massive production of bis-tolyl. The investigation of a process for the preparation of o- (p-tolyl) -benzonitrile from, for example, the corresponding oxime advantageously obtained and exempt from the drawbacks mentioned above, has an unquestionable interest. Now, it has surprisingly been found that o- (p-tolyl) -benzaldoxime can be obtained in excellent yield and less than 6 percent by-product of bis-tolyl by the coupling reaction using p-tolylmagnesium bromide and not the 2-chlorobenzaldoxime but an N-substituted 2-halogenobenzalimine so as to form an N-substituted o- (p-tolyl) -benzaldimine easily transformable at the desired oxime. According to the invention, this oxime of formula I is obtained by the reaction of a hydroxylamine salt, with a benzaldimine derivative of the general formula: li. wherein R represents an alkyl group, linear or branched, with 3 to 7 carbon atoms or cycloalkyl with 3 to 7 carbon atoms, this compound of formula II being considered as individual isomers or mixtures of these, what supplies the desired compounds.

This reaction usually takes place at a temperature between 0 ° C and 10 ° C, preferably between 0 ° C and 5 ° C in an aprotic solvent. By "aprotic solvent" is meant, within the scope of the present invention, a solvent such as an ether, generally an aliphatic or alicyclic ether, for example tetrahydrofuran, methyl tertiarybutylether, dibutyl ether or dioxane, an aliphatic or aromatic hydrocarbon such as benzene, toluene or a xylene or a halogenated hydrocarbon such as dichloromethane, dichloroethane, chloroform or tetrachloroethane. However, it is preferred to use an ether as a solvent, for example tetrahydrofuran. On the other hand, the hydroxylamine salt, such as the hydrochloride or, preferably, the sulphate, intervenes at a ratio of 1.5 to 2.5 molar equivalents per molar equivalent of the benzaldimine derivative of the formula II. According to this method, o-tolyl-benzaldoxime can be obtained in yields of the order of 90 to 93 weight percent. The methyl biphenyl derivatives of formula II are novel and, in this way, it is another object of the invention that these are in the form of individual isomers or mixtures of these. Accordingly, the invention also relates, in terms of novel intermediates, to the benzaldimine derivatives of formula II in which R represents an alkenyl group, linear or branched, with 3 to 7 carbon atoms or a cycloalguyl group with of 3 to 7 carbon atoms, these benzaldimine derivatives are in the form of individual isomers or mixtures thereof. Among these compounds of formula II, those in which R represents a tert-butyl group or better a cyclohexyl group constitute the preferred compounds. The compounds of formula II can be prepared by reacting, in the presence of a manganese mineral derivative, a benzaldimine derivative of the general formula: lll. wherein R has the same meaning as above and Hal represents a halogen atom such as chlorine or bromine, this compound is in the form of individual isomers or mixtures thereof, with a p-tolylmagnesium halide such as chloride or bromide of p -Tolylmagnesium, which supplies the desired compounds. Generally this coupling reaction is carried out in a suitable solvent at a temperature between -10 ° C and the reflux temperature, preferably the reflux temperature of the reaction medium. As the solvent, an ether-type compound such as an aliphatic or alicyclic ether, for example tetrahydrofuran, methyl tertiarybutylether, dibutyl ether or dioxane, is usually considered. However, tetrahydrofuran constitutes a preferred solvent. In addition, the p-tolyl magnesium halide, in particular excess in particular, is generally used at a ratio of 1 to 2 molar equivalents per molar equivalent of compound of formula II, usually at a ratio of approximately 1.5 equivivalent. The mineral derivative of manganese intervenes in the reaction at a ratio of 0.1 to 0.5 molar equivalent by molar equivalent of benzaldimine derivative of formula II, preferably from 0.15 to 0.30 molar equivalent. It is generally a salt or a manganese oxide but in particular a manganous salt or manganese oxide. However, the manganese preferably corresponds to MnCl 2 or MnCl L ^, the latter being able to be formed at the site by the addition of two molar eguivalents of LiCl and a molar equivalent of MnCl 2 - In this way, the compounds of formula II can be obtain with yield of less than 85 percent and with less than 6 percent of bis-tolyl derivative. For example, the preparation of o- (p-tolyl) -N-cyclohexyl-benzaldimine from 0.4 moles of 2-chloro-N-cycloalkyl-benzaldimine, 0.15 molar equivalent of MnCl2 and 1.5 molar equivalent of p-chloride tolylmagnesium in tetrahydrofuran for 1 hour did not produce, in addition to an excellent yield in o- (p-tolyl) -benzonitrile, more than 5.5 percent of bis-tolyl with respect to the start imine. As for the benzaldimine derivatives of formula III, these can be prepared by reaction at a temperature between room temperature and reflux temperature and in an aprotic solvent, preferably an ether between a 2-chloro- or 2-bromo- benzaldehyde and an amine of the general formula: R-NH7 IV in which R has the same meaning as above, which makes it possible to obtain the desired compounds. This reaction develops with water formation, it may be advantageous to undertake it in the presence of a dehydrating agent of the reaction medium such as anhydrous magnesium sulfate. As indicated above, the oxime derivative of formula I can be used for the preparation of o- (p-tolyl) -benzonitrile. Accordingly, the invention relates to o- (p-tolyl) -benzaldoxime as an intermediate for the final synthesis of o- (p-tolyl) -benzonitrile. In this way, o- (p-tolyl) -benzonitrile can be obtained starting from the oxime derivative of formula I, for example by subjecting it to the action of a dehydrating agent. The resulting reaction is usually carried out at a temperature between room temperature and the reflux temperature of the medium, and in an aprotic solvent, preferably an ether such as tetrahydrofuran. By "dehydrating agent" is meant, within the scope of the invention, an agent capable of transforming the oxime function into a nitrile function such as, for example, formic acid, phosphoric anhydride, phosphorus oxychloride, pyridine or dicyclohexylcarbodiimide. In addition, the dehydration reaction is usually carried out in the aprotic solvent preferably and advantageously in an ether such as, for example, tetrahydrofuran and at a temperature between room temperature and reflux temperature, preferably at the reflux temperature of the reaction medium. . Nevertheless, this dehydration reaction can be undertaken in the absence of solvent, replacing the dehydrating agent with the solvent function. This is particularly the case of formic acid which can be used both as a dehydrating agent and as a solvent in the context of the invention. According to the above method, o- (p-tolyl) -benzonitrile is obtained with yields of the purified and crystallized product greater than 85 percent, generally of the order of 90 to 95 percent from o-tolyl-benzaldoxime. The oxime of formula I and the benzaldimine derivatives of formula II are involved in the final synthesis of o- (p-tolyl) -benzonitrile and can be used after isolation of the reaction medium in which they are formed. Advantageously and preferably, o- (p-tolyl) -benzonitrile is prepared in the same medium where o-tolyl-benzaldoxime is formed without isolation of the latter. Accordingly, the invention also relates to the preparation of o- (p-tolyl) -benzonitrile from a benzaldimine derivative of formula II: either; (a) by reacting this imine in an aprotic solvent, with a hydroxylamine salt at a temperature comprised between 0 ° C and 10 ° C, so that the oxime of the formula I is treated transiently and without isolation. means of a dehydrating agent at a temperature between room temperature and reflux temperature, which provides the desired compound. that is: (b) by reaction of this imine hydroxylamine-O-sulfonic acid (H2N-O-SO3H) in a two-phase medium formed of water and an aprotic solvent and at a temperature between room temperature and reflux temperature for obtaining transiently and without isolation the oxime of formula I in mixture with o- (p-tolyl) -benzonitrile, mixture which is treated by means of a dehydrating agent at a temperature comprised between room temperature and reflux temperature, which supplies the desired compound. This method, which usually develops in an aprotic solvent, first supplies a transient mixture of o- (p-tolyl) -benzonitrile / o-tolyl-benzaldoxime, generally a mixture of 55 to 75 weight percent o- (p-tolyl) ) -benzonitrile / 45 to 25 weight percent o-tolyl-benzaldoxime, then the o- (p-tolyl) -benzonitrile itself with an overall yield greater than 90 percent and less than bis-tolyl compound. or either: (c) by hydrolysis of this imine, in an aprotic solvent, to obtain o- (tolyl) -benzaldehyde which is reacted with a hydroxylamine salt at a temperature between 0 ° C and 10 ° C, which provides transiently and without isolation the oxime of the formula I which is treated, with a dehydrating agent at a temperature comprised between room temperature and the reflux temperature of the medium, which supplies the desired compound. Following alternative practices, o-tolyl-benzaldoxime and consequently o- (p-tolyl) -benzonitrile can be prepared from amine derivatives of formula III without isolation of the intermediates formed. For example, an imine derivative of formula II in question is reacted, in an ether such as tetrahydrofuran, with a p-tolylmagnesium halide in the presence of a manganese mineral derivative and, generally, at a temperature between -10 ° C and reflux temperature, to form a benzaldimine derivative of formula II which is then transformed, without isolation, from its reaction medium into o-tolyl-benzaldoxime of formula I then, into o- (p-tolyl) -benzonitrile according to one of methods (a), (b) or (c) above. The following more limiting examples illustrate the invention. In these examples, the following abbreviations are used: CG: gas chromatography SM: mass spectrum IR: infrared spectrum NMR: nuclear magnetic resonance OTBCI: o-tolyl-N-cyclohexyl-benzaldimine OTBO: o- (p-tolyl) -benzaldoxime OTBA: o- (p-tolyl) -benzaldehyde OTBTBI: o- (p-tolyl) -terthoxybutylbenzaldimine t: retention time PREPARATIONS A) 2-Chloro-N-cydohexyl-benzaldimine In a 50-milliliter double neck flask , loaded with a magnetic stirrer and topped with an upward coolant, 9.70 grams (0.806 moles, 1132 equivalents) of anhydrous magnesium sulfate are charged. A stream of nitrogen is passed for 10 minutes in the flask, then 8 milliliters (10.01 grams, 0.0712 moles, 1 equivivalent) of 2-chloro-benzaldehyde diluted in 20 milliliters of tetrahydrofuran are added. With stirring, the mixture is refluxed for 10 minutes (bath temperature = 90 ° C). 8.15 milliliters (7.07 grams, 0.0713 moles, 1 equivivalent) of cyclohexylamine are then introduced, drop by drop, in 5 minutes so that the reflux that still persists for 2 hours is not interrupted. In this way, there is a solution of 2-chloro-N-cyclohexyl-benzaldimine CG / SM: t (2-chloro-N-cyclohexyl-benzaldimine) = 9.92 min; m / z (ion,%) = 223 (M + / C1 37.10); 222 (M'-H / C1 37.10); 221 (M + / C1 35.30); 221 (M + -H / C1 35.30) IR (CC14): v (cm'-11): 3071 (weak, aromatic CH elongation); 2931 and 2856 (strong, lengthening CH alguilo); 1636 (strong, CN elongation); 1592, 1568, 1470, 1450 and 1440 (medium to strong, aromatic CC elongation); 1383, 1346, 1274 (medium to strong, deformation in the aromatic CH plane). B) 2-Chloro-N-cydohexyl-benzaldimine 11 milliliters (13,728 grams, 0.0977 moles) of 2-chlorobenzaldehyde are diluted in 50 milliliters of toluene, then 12 milliliters (10,404 grams, 0.105 moles, 1.07 equivalent) are added in one go. ) of cyclohexylamine, which causes an exothermic reaction. The temperature rises from 18 ° C to 38 ° C. The reaction mixture is then brought to reflux (bath temperature = 124 ° C). The solution becomes cloudy. The water formed by a Dean-Stark system is eliminated then after 3 hours of reflux the reaction is stopped. The reaction mixture is cooled to room temperature and the toluene is evaporated with the aid of a rotary evaporator, giving 20.22 grams of a brown viscous liquid (0.091 mol with a yield of 93.3 percent) which slowly crystallizes with temperature. In this way, 2-chloro-N-cyclohexyl-benzaldimine is obtained. O 2 -Cloro-N-tert-butyl-benzaldimine In a 50-milliliter double-necked flask, fitted with a magnetic stirrer and an ascending coolant, 11 milliliters (13,728 grams, 0.0977 moles) of 2-chlorobenzaldehyde are added under stirring. and 16 milliliters (11.136 grams, 0.152 moles, 1.56 equivalent) of tertiobutylamine, which gives rise to an exothermic reaction. The temperature rises from 16 ° C to 37 ° C. A red veil then appears in the yellowish solution. Then 15 milliliters of toluene are added, which muddy the solution. The final mixture is then placed at 50 ° C for 2 hours then at 127 ° C for 1 hour in a Dean & Stark so that the water is removed and after 30 minutes of reflux the reaction is stopped. The solution is cooled to room temperature and the toluene is evaporated with a rotary evaporator. In this way, 17.99 grams (0.092 moles) of 2-chloro-N-tert-butyl-benzaldimine are obtained in the form of a yellowish viscous liquid that crystallizes slowly. Yield: 94 percent GC / MS: t = 5.85 min; m / z (ion,%) = 197 (M + / C1 37.1); 196 (M "~ H / Cl 37.1); 195 (M" / C1 35.5); 194 (M "-H / C1 35.5) IR (CC14): v (cm" 1): 3080, 2940 (weak, aromatic CH elongation); 2970 (strong, CH alkyl elongation); 1636 (strong, CN elongation); 1593, 1568, 1471 and 1441 (medium to strong, aromatic CC elongation); 1372 to 1274 (medium to strong, deformation in the aromatic CH plane). EXAMPLE 1 o- (p-Tolyl) -N-cydohexyl-benzaldimine In a 250-milliliter triple neck flask containing 1.34 grams (0.0106 moles, 0.15 equivalent) of manganese chloride, the solution of 1 equivivalent is filtered under nitrogen. of 2-chloro-N-cyclohexyl-benzaldimine obtained by Preparation A and the magnesium sulfate is washed with 58.85 milliliters of anhydrous tetrahydrofuran and under nitrogen. The filtrate obtained is then added to the previous filtrate. Under magnetic stirring, it is then brought to reflux for 10 minutes (bath temperature = 92 ° C), the final suspension thus obtained contains 0.75 moles of 2-chloro-N-cyclohexyl-benzaldimine and is added dropwise in reflux and in 30 minutes, 1.52 equivalent of p-tolylmagnesium chloride. The suspension darkens, passes for an ephemeral green color, turns blood red, then ends with a dark brown. After the magnesium derivative has been drained, the reflux is maintained for 1 hour, then a sample is collected which is treated with a water / ice mixture and the diethyl ether is extracted. The organic phase is then analyzed in gas chromatography, which allows to observe the desired compound as well as the presence of bis-tolyl, traces of p-cresol and possibly OTBA. In this way, a solution of o- (p-tolyl) -N-cyclohexyl-benzaldimine is obtained. CG / SM: t (OTBCl): 13.47 min; m / z (ion,%) = 277 (M +, 20); 276 (M + -H, 100); 194 (M + -cyclohexyl, 70).

Following the same procedure as above but starting from 2-chloro-N-tert-butyl-benzaldimine, the o- (p-tolyl) -N-tert-butyl-benzaldimine was prepared (Example 2) CG / SM: t (0TBTB1): 10.87 min; m / z (ion,%) = 251 (M ", 5); 250 (M + -H, 10); 236 (M + -CH3, 70); 194 (M + -terti? butyl ?, 100); 179 (M + -tert-butyl-CH3, 100) EXAMPLE 3 o- (p-Tolyl) -benzaldoxime The reaction mixture obtained from Example 1 is cooled to room temperature and without stirring in order to decant the inorganic species that precipitate (brown powder). ), then slowly empty under stirring in 150 milliliters of an ice solution (0 ° C to 5 ° C) of 23.37 grams (0.1424 mol, 2 eguivalents) of hydroxylamine sulfate. The biphasic mixture is then stirred vigorously for one hour and allowed to come to room temperature. With stirring, 3 milliliters (2.65 grams, 0.0226 mol, 2 equivalents with respect to manganese chloride) of N, N-diethylethanolamine are then added to the mixture. After 10 minutes, stirring is stopped and the phases are allowed to settle. The upper organic phase is recovered and the aqueous phase is extracted with 3 times 100 milliliters of dichloromethane (pH of the aqueous phase = 4). The whole organic phase is dried over magnesium sulfate, filtered and then evaporated under vacuum with the aid of a rotary evaporator, which supplies 11.00 grams of white flakes (overall yield: 73% from 2-chlorobenzaldehyde, the amount The amount of bis-tolyl in the mixture is 4 percent). To the solid thus obtained, 50 milliliters of petroleum ether (fraction 30-40 ° C) are added and stirred for 15 minutes. The white solid formed is filtered and rinsed cold with 10 milliliters of petroleum ether. In this way, 10.62 grams of o- (p-tolyl) -benzaldoxime are obtained in the form of white flakes which do not contain traces of bis-tolyl. The gross overall yield: 67.5 percent from 2-chlorobenzaldehyde. The oxime thus obtained can be recrystallized (dichloromethane / petroleum ether) to give white flakes. Purity: 100 percent. CG / SM: t (OTBO): 10.97 min; m / z (ion,%) = 211 (M +, 25); 210 (M + -H, 100); 194 (M + -OH, 60). IR (CC14): v (cm "1): 3596 (strong, free OH elongation, diluted solution), 3312 (weak, associated OH elongation), 3061, 3026 and 2924 (weak, aromatic CH elongation); 1516, 1480, 1447 and 1397 (weak to medium, elongation CC aromatic), 1260, 1200 and 1112 (weak to medium, deformation in the CH plane aromatic), 952 (strong, elongation NO). 1 H NMR: (CDCl 3) d (ppm): 2.45 (long, 3H, CH 3); 7.28 (long m, 4H, H8-H9-H11-H12); 7.43 (long m, 3H, H4-H5 and CHN); 7.95 (length m 1H H3); 8.22 (long s, 1H, H2) and 9.27 (long, 1H, OH). 13 C NMR: (CDCl 3) d (ppm): 21.22 (CH 3); 126.20; 127. 53; 129.15; 129.59; 129.69; 129.84 and 130.37 (aromatic CH); 136.56; 137.42 and 142.36 (aromatic C) and 149.85 (CH = NOH). EXAMPLE 4 o (p-Tolyl) -benzaldehyde In a 250-milliliter triple-necked flask containing 1.34 grams (0.0106 mol, 0.15 eguivalent) of manganese chloride, filtered under nitrogen, the solution of 1 equivivalent of 2-chloro- N-cyclohexyl-benzaldimine obtained with Preparation A and the operation is continued as described in Example 1 especially by adding 1.52 eguivalents of p-tolylmagnesium chloride. The reaction is then stopped by introducing into a mixture of 200 milliliters of water / ice and 3 times 100 milliliters of dichloromethane are extracted after filtration under the paper of a very viscous brown deposit. The whole organic phase is dried over magnesium sulfate, filtered and then evaporated under vacuum, which gives 16.29 grams of a brown viscous liquid. The obtained liguid is absorbed on silica and the solid formed is placed at the head of a column of silica prepared with petroleum ether (fraction 30-40 ° C). It is washed with this solvent until all the bis-tolyl is collected. Thus 0.79 gram (4.34 mmoles) of a solution in crystalline form is recovered. It is then washed with a mixture of dichloromethane / petroleum ether 5/95 volume / volume. In this way, 10.05 grams (51.26 mmoles) of o- (p-tolyl) -benzaldehyde are collected in the form of a viscous yellowish liguid. Yield: 72 percent CG / SM: t (OTBA): 8.78 min; m / z (ion,%) = 196 (M +, 75); 195 (M + -H, 50); 181 (M + -CH3, 100); 167 (M + -CHO, 40). IR (CC14): d (cm "1): 3066, 3028, 2924, 2848 and 2751 (weak, aromatic CH elongation); 1598, 1517, 1476, 1445 and 1392 (weak to medium, aromatic CC elongation); 1256 and 1194 (weak to medium, deformation in the aromatic CH plane) NMR: (CDCl 3) d (ppm): 2.44 (s, 3 H, CH 3); 7.26- 7.28 (m, 4H, H8-H9-H11-H12); 7.42-7.52 (m, 2H, H4-H5); 7.59-7.64 (m 1 H 3 H); 8.00-8.05 (m, 1H, H2) and 10.00 (s, 1H, CHO). 13 C NMR: (CDCl 3) d (ppm): 21.21 (CH 3); 127.56; 128. 95; 129.19; 129.87; 130.06; 130.81 and 133.53 (aromatic CH); 133.80; 134.84; 138.04 and 146.01 (aromatic C) and 192.51 (CHO). EXAMPLE 5 o- (p-Tolyl) -benzaldoxime At room temperature, the 10.05 grams of o- (p-tolyl) -benzaldehyde obtained in Example 4 is added to 50 milliliters of tetrahydrofuran, and an aqueous solution of 16.83 grams (0.1025 mol, 2 eguivalents) of hydroxylamine sulfate. The biphasic mixture is stirred violently at room temperature for 1 hour. Gas chromatography analysis indicates the disappearance of OTBA. The upper organic part is recovered and the aqueous part is extracted with 3 times 50 milliliters of dichloromethane (pH of the aqueous phase = 1). The organic phases are combined, dried over magnesium sulphate, filtered on a porous glass and evaporated in vacuo. In this way, 10.07 grams (0.0477 mol) of o- (p-tolyl) -benzaldoxime are obtained. Yield: 93 percent. EXAMPLE 6 o- (p-Tolyl) -benzonitrile In 0.54 grams (2.56 mmoles) of o- (p-tolyl) -benzaldoxime, 5 milliliters of formic acid are added. The suspension obtained is refluxed for one hour and maintained at that temperature for one additional hour (bath temperature: 126 ° C). At the internal temperature of 54 ° C, the assembly dissolves. The solution is cooled to room temperature, and poured into the water and extracted with diethyl ether. The etched phase is washed with a 0.5 N sodium hydroxide solution until the basicity of the washing water (pH about 9) then with water until the neutrality of the washing waters (pH about 7). The organic phase is dried over magnesium sulfate, filtered and evaporated in vacuo to give 0.45 grams (2.33 mmol) of oil which hardens with temperature. In this way, o- (p-tolyl) -benzonitrile is obtained with a yield of 91 percent. Purity: > 95 percent. EXAMPLES 7 TO 9 o- (p-Tolyl) -benzonitrile A molar equivalent of o- (p-tolyl) -N-cyclohexyl-benzaldimine is dissolved in a 1 / l mixture of tetrahydrofuran / water and X molar equivalents of acid are added. aminohydroxysulfonic This mixture is maintained at a temperature T for one hour, which provides a mixture of o-tolyl-benzaldoxime / o- (p-tolyl) -benzonitrile. This mixture is diluted in tetrahydrofuran, then 10 molar equivalents of phosphoric anhydride are added and it is allowed to react for 1 additional hour at room temperature. The dehydrating agent layer turns pink and the o-tolyl-benzaldoxime is recovered in a mixture with the bis-tolyl (< percent mass). After washing the phosphoric anhydride layer with tetrahydrofuran, the solvent is evaporated. According to the starting amounts of the aminohydroxysulfonic acid and the reaction temperature used, o- (p-tolyl) -benzonitrile is obtained with the following yields: EXAMPLES 10 TO 12 o (p-Tolyl) -benzonitrile A molar eguivalent of o- (p-tolyl) -benzaldoxime is dissolved in the chosen solvent and the dehydrating agent is added. The medium is maintained at a temperature T for H hours. The medium is then filtered, then it is introduced into the water and extracted with diethyl ether. The etched phase is washed with a 0.5N sodium hydrogen solution then with water until neutral. Dry over magnesium sulfate, filter and evaporate in vacuo. According to the solvents, dehydrating agent, temperature and duration of the reaction used, o- (p-tolyl) -benzonitrile is obtained with the following yields: * dicyclohexylcarbodiimide ** tetrahydrofuran

Claims (25)

1. CLAIMS Derivatives of methyl biphenyl of the general formula in which R represents an alkyl group, linear or branched with 3 to 7 carbon atoms or a cycloalkyl group with 3 to 7 carbon atoms, these compounds are considered in the form of their individual isomers or mixtures of these.
2. 2. Derivative of methyl biphenyl of formula: this compound is considered in the form of its individual isomers or mixtures thereof.
3. 3. Derivative of methyl biphenyl according to claim 1, characterized in that R represents cyclohexyl.
4. 4. Derivative of methyl biphenyl according to claim 1, characterized by R represents tert-butyl.
5. Process for the preparation of the methyl biphenyl derivative according to claim 2, characterized in that a hydroxylamine salt is reacted with a benzaldimine derivative according to one of claims 1, 3 or 4, which supplies the desired compound.
6. 6. Process according to claim 5, characterized in that the reaction is carried out at a temperature comprised between 0 ° C and 10 ° C.
7. 7. Process according to claim 5 or 6, characterized in that the reaction is carried out in an aprotic solvent.
8. 8. The process according to claim 7, characterized in that the aprotic solvent is an aliphatic or alicyclic ether, an aliphatic or aromatic hydrocarbon or a halogenated hydrocarbon.
9. 9. Process according to claim 7 or 8, characterized in that the aprotic solvent is tetrahydrofuran, methyl tert-butyl ether, dibutyl ether or dioxane.
10. Process for the preparation of the methylbiphenyl derivative according to one of claims 1, 3 or 4, characterized in that a benzaldimine derivative of the general formula is reacted in the presence of a mineral or manganese derivative: CH = N-R III. in which R represents an alkyl group, linear or branched, with 3 to 7 carbon atoms or cycloalkyl with 3 to 7 carbon atoms and Hal represents a halogen atom, this compound is in the form of individual isomers or mixtures thereof, with a p-tolylmagnesium halide, which supplies the desired compounds.
11. 11. Process according to claim 10, characterized in that the reaction is carried out at a compressed temperature between -10 ° C and the reflux temperature.
12. 12. Procedure according to one of the claims 10 or 11, characterized in that the reaction is carried out in an aliphatic or alicyclic ether.
13. 13. Process according to one of claims 10 or 11, characterized in that the ether is tetrahydrofuran, methyl tertiary butyl ether, dibutyl ether or dioxane.
14. Process according to one of claims 10 to 13, characterized in that 1 to 2 molar equivalents of p-tolylmagnesium chloride or bromide are used per molar equivalent of benzaldimine derivative of formula III.
15. 15. Process according to one of claims 10 to 14, characterized in that the manganese mineral derivative is a manganous salt or a manganous oxide.
16. 16. Process according to claim 15, characterized in that the manganese salt is a manganous salt and the manganese oxide is a manganous oxide.
17. 17. Process according to claim 16, characterized in that the manganous salt is MnCl or MnCl4Li2.
18. Process according to one of Claims 10 to 17, characterized in that the mineral derivative of manganese is present at a ratio of 0.1 to 0.5 molar equivalent per molar equivalent of benzaldimine derivative of formula III.
19. 19. Process for the preparation of o- (p-tolyl) -benzonitrile, characterized in that the methyl-biphenyl derivative according to claim 2 is subjected to the action of a dehydrating agent.
20. 20. Process according to claim 19, characterized in that the reaction produced is carried out at a temperature comprised between the ambient temperature and the reflux temperature of the medium.
21. 21. Process according to claim 19 or 20, characterized in that the reaction takes place in an aprotic solvent.
22. 22. Method according to claim 21, characterized by the aprotic solvent is an ether.
23. Method according to one of Claims 19 to 22, characterized in that the dehydrating agent is formic acid, phosphoric anhydride, phosphorus oxychloride, pyridine or dicyclohexylcarbodiimide.
24. 24. Process for the preparation of o- (p-tolyl) -benzonitrile according to claim 19, characterized in that a benzaldimine derivative of formula II is converted according to claim 1: either: (a) by reaction with a hydroxylamine salt, in an aprotic solvent and at a temperature comprised between 0 ° C and 10 ° C, so that o- (p-tolyl) -benzaldoxime which is transiently and without isolation is treated by means of a dehydrating agent at a temperature comprised between room temperature and the reflux temperature which supplies the desired compound. that is: (b) by reaction with hydroxylamine-O-sulfonic acid in a two-phase medium formed of water and an aprotic solvent and at a temperature between room temperature and reflux temperature to obtain transiently and without isolation the o- ( p-tolyl) -benzaldoxime in admixture with o- (p-tolyl) -benzonitrile, which mixture is treated by means of a dehydrating agent at a temperature comprised between room temperature and reflux temperature, which provides the desired compound . or either: (c) by hydrolysis in an aprotic solvent, to obtain o- (tolyl) -benzaldehyde which is reacted with a hydroxylamine salt at a temperature comprised between 0 ° C and 10 ° C, which is supplied transiently and without isolation the o- (tolyl) -benzaldoxime which is treated with a dehydrating agent at a temperature between room temperature and the reflux temperature of the medium, which provides the desired compound.
25. 25. Process according to claim 24, characterized in that the benzaldimine derivative of formula II is obtained by the reaction between a benzaldimine derivative of the general formula: wherein R represents an alkyl group, linear or branched, with 3 to 7 carbon atoms or cycloalguilo with 3 to 7 carbon atoms, this compound being in the form of individual isomers or of mixtures thereof, with a halogenide of p-tolylmagnesium in the presence of a magnesium mineral derivative, then transformed without isolation of its reaction medium.