MXPA99002145A - Method for preparing a cyanobiphenyl - Google Patents

Abstract

The invention concerns a method for preparing o-(p-tolyl)benzonitrile characterised in that one o-halobenzonitrile is treated with one halogenide of p-tolylmagnesium in presence of one manganese salt and one co-catalyst containing a transition metal.

Description

PROCEDURE FOR THE PREPARATION OF A CYANOPHENYLENE DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of a cyanobiphenyl. More particularly, the object of the invention is a process for the preparation of o- (p-tolyl) benzonitrile of the formula I which is the key intermediary in the synthesis of numerous active drugs that act mainly against hypertension, through a mechanism of inhibition of angiotensin II.

REF .: 29604 The o- (p-tolyl) benzonitrile, hereinafter more briefly referred to as orthotolylbenzonitrile or OTBN, was first described in European Patent EP-253310 and a number of procedures have recently been proposed for its application. synthesis. The procedure that seems to be the most appropriate for the preparation of the OTBN is described in European Patent EP-566,468 and cons in the reaction between an o-halobenzoni trile with a p-tolylmagnesium halide in the presence of a manganous salt, preferably MnCl 2 . This method, in relation to those previously known, has the advantage of developing in a single stage with a yield of approximately 70% before crystallization. However, as a by-product of reaction, 4,4'-dimethyl-phenyl occurs as a result of the condensation of the p-tolylmagnesium halide thereon. It has now been found that if the reaction between the p-tolylmagnesium halide and the o-hal-obenzonitrile is carried out in the presence of a manganous salt and traces of a palladium (II) salt, the OTBN is obtained with a yield of at least about 92%, while the impurity of 4, '-dimethylbiphenyl falls below about 2.5%. The object of the present invention is therefore a process for the preparation of o- (p-tolyl) benzonyl trile, characterized in that an o-halobenzonitrile, preferably an o-bromobenzonitrile, is treated with a p-tolyl magnesium halide in the presence of of a manganous salt and a co-catalyst containing 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, and the reaction temperature can vary from -10 to 60 ° C. , according to the solvent used. This reaction leads transiently to the formation of a complex which is hydrolyzed according to known processes, for example by means of an acid such as hydrochloric acid. As for the manganous salt, it is preferably MnCl2 or MnCl4Li2, the latter being able to be formed by adding two molar equivalents of LiCl and one molar equivalent of MnCl2. This manganous salt intervenes in the reaction at a ratio of 0.5 to 1.3 molar equivalents per molar equivalent of starting o-halobenzoni tryl. The transition metal forming the co-catalyst is advantageously nickel, cobalt, platinum or principally palladium. As the co-catalyst containing a transition metal, a palladium (II) salt, preferably nitrate, chloride, acetate, bromide, sulfate or the like, is preferably used.

(PdCl2) and acetate (CH3-C00-Pd-00C-CH3) which is particularly advantageous. Preferably, the palladium salt is complexed, for example, with at least one organophosphorus compound comprising trivalent phosphorus. More particularly, palladium complexes, such as bis (triphenylphosphine) dichloro-, bis (tributylphosphine) dichloro, can be mentioned. , bis (tricyclohexylphosphine) dichloro. , diallyltriphenylphosphindichloro-, triphenylphospiperidinedi chloro-, bis (cyclohexyloxime) dicarbonyl-, 1, 5, 9-cyclododecatriendichloro-, bis (triphenylphosphine) dicarbonyl-, bis (triphenylphosphine) diacetate-, bis (triphenylphosphine) -sulfate-, 2, 4 -pentandione, tetra is (triphenylphosphine) -palladium. Between these, the palladium (II) complexes are particularly advantageous. 1,3-bis (di-phenyl-phosphino) propane (dppp) complexed with palladium (II) chloride or palladium (II) acetate is preferred. The palladium salts and the organophosphorus compounds can be added separately to the reaction medium. In this case, the amount of organophosphorous compound is preferably sufficient to form in si t? the co-catalyst in the form of complex with the palladium present. Said complex is generally prepared so that the P / Pd ratio is about 1/1, but a ratio of this type can vary between 0.5 / 1 and 2/1 without significantly altering the result of the procedure. This co-catalyst is present in very small amounts in the reaction mixture namely 0.001 to 2 mol% per mol of starting o-halobenzonitrile. According to a preferred mode of operation, the p-tolyl magnesium halide is in equimolar amounts or in a small excess (from 1 to 1.5 mol) relative to o-halobenzonitrile. In addition, the preferred manganese catalyst (MnCl4Li2) is formed, either in itself, in equimolar amounts or in a small excess (from 1 to 1.5 mol) relative to o-halobenzonitrile, either extemporaneously or before the addition to the medium. of reaction. The MnCl4Li is prepared by reacting an equivalent of MnCl2 with two equivalents of LiCl. The reaction can be conducted in tetrahydrofuran by adding, at the temperature of 10 ° C, the co-catalyst and the o-halobenzonitrile optionally in solution in tetrahydrofuran to a solution of tetrahydrofuran containing p-tolylmagnesium halide and the manganese catalyst. This reaction, which is exothermic, can be controlled by regulating the rate of addition of the benzonitrile derivative and the co-catalyst, so as to keep it below 35 ° C.

Alternatively, the reaction can also be conducted by adding the p-tolylmagnesium halide in, for example, tetrahydrofuran to a mixture of o-halobenzonitrile, co-catalyst and manganous catalyst in, for example, tetrahydrofuran. In this case, the reaction temperature can be better controlled and the addition of the p-tolylmagnesium halide can be carried out even at a higher temperature, of the order of 50 to 55 ° C, in order to decrease the duration of the reaction and the amount of co-catalyst used. In order to improve the development of the reaction, it can be advantageous, however, to add a co-solvent to the medium containing the manganese catalyst. This co-solvent is preferably another ether or di-ether, for example dimethoxyethane. According to the above preferred mode of operation, the hydrolysis is carried out in itself with hydrochloric acid and the OTBN formed in this way is isolated according to conventional techniques, for example by extraction with a suitable solvent, evaporation of the solvent and purification by Crystallization in ethanol or by chromatography. The OTBN is obtained in this way with very high yields, from 92 to 98% according to the proportions of the reagents used. It contains very small amounts of 4,4'-dimethylbiphenyl, generally less than 2.5%. The amount of 4,4'-dimethylbiphenyl that is formed according to the process of the present invention has been compared to that which is formed according to the process described in European Patent EP-566,468. Operating in this way: according to European Patent EP-566,468, namely using MnCl 2 as a catalyst, in a series of tests under the same conditions, the by-product 4,4'-dimethylbiphenyl was obtained with a yield from 8 to 12% relative to p-tolylmagnesium bromide, or from 6.5 to 10% by weight of 2- (p-tolyl) benzonitrile as final product; according to the present invention, namely using MnCl2 and PdCl2 / dppp as a catalyst and co-catalyst, in a series of tests under the same conditions, the by-product 4, 4'-dimethylbiphenyl was obtained in a yield of 0.5 to 1. % relative to p-tolylmagnesium bromide, or a maximum of 0.65% by weight of final product. The co-catalyst containing a transition metal can also be a cobalt, nickel, or platinum salt, as indicated above. In the case of a co-catalyst containing nickel, a nickel (II) salt such as chloride, or nickel acetylacetonate, is generally used. This salt is preferably formed in complex 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 separately to the reaction medium. This nickel-containing co-catalyst is advantageously pretreated with a reducing agent such as a hydride, for example dibutylaluminum hydride or diisobutylaluminum hydride or even with a methylmagnesium halide, for example methylmagnesium chloride, so as to form catalysts containing Ni (O) such as Ni [P (C6H5) 3] 4.

Systems comprising nickel acetylacetonate, triphenylphosphine and diisobutylaluminum hydride are particularly interesting. The following non-limiting examples illustrate the invention. In these examples, the molar percentages of the co-catalyst are calculated in relation to the amount of the ortho-halobenzonitrile.

EXAMPLE 1 Under nitrogen atmosphere and at room temperature, 2 ml of anhydrous tetrahydrofuran, MnCl 2 (0.65 g, 5.14 mol) and LiCl (0.44 g, 10.28 mmol) are added successively. The mixture is stirred until the salts dissolve (formation of MnCl4Li2). A solution of p-tolylmagnesium chloride in tetrahydrofuran (1.80 N, 2.86 ml, 5.14 mmol) is then added so that the temperature is maintained between -10 ° C and 0 ° C. The dimethoxyethane (1 ml, 10.28 mmol) is then rapidly added at 0 ° C and the organomanganous compound obtained in this way is kept under stirring for 5 minutes at + 10 ° C.

The PdCl2 / dppp is then added: 1/1 (0.023 g, 1 mol%) then the o-bromobenzonitrile (0.72 g, 3. 955 mmol). The temperature rises from +10 to + 30 ° C in 15 minutes, and then slowly decreases to + 25 ° C. After 3 hours of stirring at room temperature, the reaction mixture is hydrolyzed with the aid of a 1N hydrochloric acid solution (15 ml). After extraction with ethyl ether, the organic phase is dried over potassium carbonate, filtered and then evaporated in vacuo. It is then purified by chromatography (silica: 20 g, eluent petroleum ether / ethyl acetate = 95/5) the oil formed in this way. The o- (p-tolyl) benzonitrile obtained in this way is then collected, in the form of whitish crystals, with a yield of 96%. Melting point: + 48 ° C XH NMR (CDC13) d 2.42 (s, 3 H, CH 3) 13 C NMR (CDCl 3) d 21.03; 110.85; 118.70; 127.09; 128.39; 129.22; 129.74; 132.60; 133.47; 135.03; 138.43; 145.20.

EXAMPLES 2 and 3 Operating as described in Example 1, using 0.5 equivalents of MnCl4Li2 and 1.3 equivalents of p-tolylmagnesium chloride for an equivalent of o-halobenzonitrile and varying the amount of PdCl2 / dppp: 1/1, yields have been obtained in o- (p-tolyl) benzonitrile indicated in Table 1.

TABLE 1 EXAMPLE 4 At room temperature, a suspension of MnCl 2 (0.25 g, 1.98 mmol) and LiCl (0.17 g, 3,955 mmol) is stirred in a mixture of 2 ml of anhydrous tetrahydrofuran and 0.38 ml of dimethoxyethane (3,955 mmol). After about 30 minutes of stirring, a homogeneous mixture is obtained. The PdCl2 / dpp is then added: 1/1 (0.023 g, 1 mol%) and o-bromobenzonitrile (0.72 g, 3.955 mmol), and then a solution of sodium chloride is added in 2 hours at room temperature. p-tolylmagnesium in tetrahydrofuran (1.80N, 2.86 mL, 5.14 mmol). After 90 minutes of stirring the reaction mixture is treated as described in Example 1. O- (p-tolyl) benzonyl trilo was thus obtained with a yield of 95% isolated product.

EXAMPLE 5 The procedure is exactly as described in Example 4, replacing the PdCl2 / dppp complex with a 1: 1 mixture of palladium (II) acetate and dppp. O- (p-tolyl) benzonitrile is thus obtained with a yield of 94% isolated product.

EXAMPLE 6 The procedure is exactly as described in Example 4, but the PdCl2 / dppp complex is replaced with a mixture of PdCl? * 2LiCl and dppp 1: 1. O- (p-tolyl) benzonitrile is thus obtained with a yield of 95% isolated product.

EXAMPLE 7 At room temperature, a suspension of MnCl 2 (0.25 g, 1.98 mmol) and LiCl (0.17 g, 3,955 mmol) is stirred in a mixture of 2 ml of anhydrous tetrahydrofuran and 0.38 ml of dimethoxyethane. (3.955 mmol) until obtaining, after approximately 30 minutes, a homogeneous mixture. The PdCl2 / dppp complex is then added (0.0023 g, 0.1 mol%) and o-bromobenzonitrile (0.72 g, 3.955 mmol), then a solution of p-tolylmagnesium chloride in tetrahydrofuran (1.80N, 2.86 mL, 5.14 mmol) is added in 30 minutes. After 30 minutes of stirring, the reaction mixture is treated as described in Example 4.

O- (p-tolyl) benzonitrile is thus obtained with a yield of 95% isolated product. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (17)

1. A process for the preparation of o- (p-tolyl) benzonitrile, characterized in that it is an o-halobenzonitrile with a p-tolylmagnesium halide in the presence of a manganous salt and a co-catalyst containing a transition metal.

2. The process according to claim 1, characterized in that the o-halobenzonitrile is o-bromobenzonitrile.

3. The process according to claim 1 or 2, characterized in that the manganous salt is MnCl2 or MnCl4Li2.

4. The process according to any of claims 1 to 3, characterized in that the co-catalyst containing transition metal is a palladium salt, a cobalt salt, a nickel salt or a platinum salt.

5. The process according to any of claims 1 to 3, characterized in that the co-catalyst containing transition metal is a palladium salt (I "I).

6. The process according to claim 5, characterized in that the palladium (II) salt is palladium chloride (II) or palladium (II) acetate.

7. The process according to any of claims 4 to 6, characterized in that the palladium salt is added to the reaction medium with an organophosphorous compound comprising trivalent phosphorus.

8. The process according to any of claims 4 to 7, characterized in that the palladium salt is in the form of a complex with an organophosphorus compound comprising a trivalent phosphorus.

9. The process according to claim 8, characterized in that the palladium salt is in the form of a complex between 1,3-bis (diphenylphosphino) propane and palladium chloride or acetate (II).

10. The process according to claim 4, characterized in that the nickel salt is nickel acetylacetonate.

11. The process according to any of claims 4 to 10, characterized in that the nickel salt is added to the reaction medium with an organophosphorus compound comprising trivalent phosphorus.

12. The process according to any of claims 4, 10 or 11, characterized in that the nickel salt is in the form of a complex with an organophosphorus compound comprising trivalent phosphorus.

13. The process according to any of claims 4, 10, 11 or 12, characterized in that the nickel salt is pretreated with a reducing agent.

14. The process according to any of claims 1 to 13, characterized in that the reaction is conducted in a solvent of the ether type.

15. The process according to claim 14, characterized in that the solvent is tetrahydrofuran.

16. The process according to any of claims 1 to 15, characterized in that the reaction is conducted in a solvent of the ether type and a co-solvent of the diether type.

17. The process according to claim 16, characterized in that the solvent is tetrahydrofuran and the co-solvent is dimethoxyethane.