MXPA00004780A - Method for preparing bromomethyl-biphenyl derivatives - Google Patents

Abstract

The invention concerns a method for preparing 4'-bromomethyl-biphenyl derivatives of general formula (I) in which R is as defined in Claim 1, characterised in that it consists in reacting in a biphasic medium and under the effect of light irradiation, a bromination agent selected among bromine, N-bromoacetamide, N-bromophtalimide, N-bromomaleimide, a N-bromosulphonamide, N-bromosuccinimide, 1,3-dibromo-5,5-dimehtylhydantoin and an alkaline metal bromhydric/bromate acid system with a biphenyl derivative of general formula (II) in which R has the same meaning as above, thereby obtaining the desired compound.

Description

PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF BROMÓME TILBIPENILO The present invention refers in a general way to the preparation of bromómetiIbi phenyl derivatives. More precisely, the invention concerns a process for the preparation of 4'-bromomethylbiphenyl of the general formula: In which R represents: • a cyano group • a group: -C02R? or -CON R2R3 in which Ri, R2 and R3, identical or different, represent hydrogen or an alkyl group, linear or branched, with Ci to Ce, which in its case may be substituted by a halogen atom, a hydroxy, amino group , C 1 to C 4 alkoxy or 1 to 3 phenyl groups optionally substituted by 1 to 3 groups selected from the halogen atoms and the hydroxy, nitro, C 1 to C, and C 1 to C 4 alkoxy groups, a tetrazolyl group of the general formula: wherein R4 located at position 1 or preferably at position 2 of the tetrazolyl group represents hydrogen or a protecting group, in particular an alkyl group, linear or branched, from Ci to Ce optionally substituted by one to three phenyl groups which in turn, 1 to 3 groups selected from halogen atoms and hydroxy, nitro, Ci to C alkyl, and Ci to C4 alkoxy groups may be substituted. In particular, R may represent a cyano, tetrazolyl, triphenylmethyl-tetrazolyl group or a group -C02 Ri in which Ri represents hydrogen, a methyl, ethyl or propyl group. Among the compounds of the formula I which can be prepared by the process according to the invention, there may be mentioned: 4 '-bromomethyl-2-cyanobiphenyl 4' -bromometho1-2-tetrazolylbiphenyl 4'-bromomethyl-2-carboxybiphenyl 4'-bromomethyl -2-methoxycarbonylbiphenyl 4'-bromomethyl-2-N-triphenylmethyl tetrazolyl-phenyl. According to a preferential aspect, the invention relates to the preparation of the compound of the formula I in which R represents the cyano group, ie the 4'-bromomethyl-2-cyanobiphenyl. The 4 '-bromomethylbiphenyl derivatives of the formula I are known compounds which have been specifically described in the patent applications European EP 324377 and 553879 or that can be prepared by the procedures described therein. These compounds of the formula I constitute intermediates which are particularly useful in the synthesis of numerous active drug ingredients which act in particular against hypertension by means of an angiotensin II inhibiting mechanism. Recently, different methods for the synthesis of 4'-bromomethyl-2-cyanobiphenyl have been proposed, these methods being based on a radical reaction, initiated chemically. For example, patent applications JP 63-23868, 61-92170 and 62-98683 as well as EP patent applications can be cited. 553879, 595150 and 709369 that all describe, to varying degrees, the bromination of o-tolylbenzonitrile, (hereinafter referred to as OTBN) by means of brominating agents such as N-bromosuccinimide (hereinafter referred to as NBS), dibromodi ethylhydantoin (hereinafter referred to as DBDMH), N-bromophthalimide or bromine, in the presence of a chemical initiator, generally benzoyl or t-butyl peroxide, t-butyl perbenzoate or an azobis derivative such as 2, 2'-azobis (isobutyronitrile) (hereinafter referred to as AIBN) or 2,2'-azobis (2, 4-dimethylvaleronitrile), the solvent being a C5 to C alkane? , a halogenated aliphatic hydrocarbon of Ci to C4 such as dichloromethane or carbon tetrachloride, an alkyl ester of Ci to C4 of acetic acid such as ethyl acetate or also a halogenated aromatic hydrocarbon such as chlorobenzene. On the other hand, these methods carry at the same time certain disadvantages and disadvantages, sometimes sufficient to rule them out of any use on an industrial scale. For example, the implementation of peroxide derivatives becomes very difficult and even dangerous taking into account the explosive nature of this type of product. On the other hand, these procedures appeal to relatively expensive compounds such as chemical initiators from the family of azobis derivatives or also to products that are sources of contamination since they can give rise to reaction byproducts that have not been contemplated or for which it is very difficult perform your recycling. Therefore, the development of 4 '-bromomethyl-2-cyano-biphenyl by radical reaction, not susceptible to contamination, from a minimum of compounds, which above is not very expensive, does not have an unquestionable interest. dangerous and that is done according to a method devoid of major difficulties for its implementation at industrial level. For this purpose, by virtue of the advantages it produces, the photochemical initiation of a radical-based reaction in replacement of a chemical initiation may represent a particularly interesting approach to offer a solution to the problems raised above. In fact, it is known that chemical initiation: a) can be inhibited by the presence of impurities in the starting products, such as a chemical reaction. b) it is dependent on the temperature; As an example, it is pointed out that chemical initiators such as benzoyl peroxide or AIBN require a certain temperature of use, preferably a temperature higher than 60 ° C, particularly for the bromination of the OTBN, c) generates decomposition products and for consequently, it presents risks of contamination of the environment. A radical reaction for the preparation of 4 '-bromomethyl-2-cyanobiphenyl which recurs to a photochemical initiation, was suggested in the patent applications JP 62-98683 and EP 709369. Thus the patent application JP 62-98683 mentions the possibility of a photochemical reaction of the OTBN with a brominating agent at a temperature of from 0 ° to 80 ° C, preferably from 10 ° to 40 ° C and in a fatty acid ester as a solvent, with ethyl acetate particularly mentioned . In aion, the NBS and the DBDMH are designated there as preferred brominating agents and examples are given in said texts. If bromine is mentioned in such text as a brominating agent, on the other hand it does not contain any example for its use. Certain orientation tests carried out in the framework of the preparation of the present invention have revealed some inherent drawbacks of this method by virtue of the nature of the solvent used. In fact it has been observed that parasitic reactions occur, involving the solvent, namely ethyl acetate, which causes a greater consumption of the brominating agent, in particular bromine. Likewise, patent application EP 709369 reports on an OTBN bromination process according to which this compound is reacted with bromine at a temperature of 0 to 100 ° C, preferably 20 to 80 ° C, in the presence of an initiator. chemical, ie an azobis derivative or benzoyl peroxide and a halogenated hydrocarbon or a C5 to C7 alkane, as a solvent. It is also pointed out in said text that the formation of radicals can be ensured by a simple photo irradiation without the use of a radical initiator. On the other hand, no indication of any particular nature is given about the operating conditions for the execution of this procedure, which is not exemplified in any way. Within the framework of the present invention, this photochemical radical reaction has been attempted. Thus it has been observed that bromination of OTBN by bromine with photoirradiation is slow at temperatures below 50 ° C in organic solvents conventionally used for this type of reaction. For example, 40 ° C in dichloromethane, the reaction requires at least 3 hours while at 0 ° C the reaction time is greater than 6 hours. Considering that the selectivity of this bromination of radicals in a monobrominated derivative to the detriment of the corresponding dibrominated derivative increases as the temperature decreases, it is essential to be able to operate at temperatures less than or equal to 45 ° C. Reference is also made to European Patent EP 336567 which relates to a process for the photochemical bromination of an alkane by means of a bromidic acid / hydrogen peroxide in a two-phase medium formed by an aqueous phase and an organic phase and at a temperature of 20 ° C. at 80 ° C, preferably between 60 and 70 ° C. The process of this patent can be applied in particular to the bromination of the alpha carbon of an alkyl group attached to a cyclobenzene which in turn carries a deactivating group as a cyano group. On the other hand it is indicated that the bromination of the OTBN is not even described in said patent. As a result of different preliminary tests carried out during the elaboration of the present invention it has been possible to demonstrate that the procedure of this patent, applied to the bromination of the OTBN, requires a considerable contact time to obtain high conversion yields. However, it has now surprisingly been found that it is possible to obtain the compounds of the formula 1 in particular the 4'-bromomethyl-2-cyanobiphenyl according to a radical-based photochemical bromination reaction, almost instantaneous, and avoiding both the disadvantages and the disadvantages of the previous methods. According to the invention, the biphenyl derivatives of the formula I are obtained by reacting in a biphasic medium and under the effect of a photoirradiation, a brominating agent selected from bromine, N-bromoacetamide, N-bromophthalide, N-bromomaleimide, N-bromosulfonamide, N-bromosuccinimide, 1,3-dibromo-5,5-diraethylhydantoin and an alkali metal bromhydric / bromate acid system with a biphenyl derivative of the general formula: in which R has the same meaning as in the previous case, in particular cyano, which gives rise to the desired compound. The biphasic medium, used in the above procedure, is constituted by water and a number of organic solvents not miscible with water, selected from the solvents generally used in radical-based reactions and which offer little possibility of interaction with the brominating agent. Such solvents can be, for example, halogenated aliphatic hydrocarbons from Ci to C4 such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetraclorethane or halogenated aromatic hydrocarbons from Ce to Cio, such as chlorobenzene or dichlorobenzene. Dichloromethane on the other hand constitutes a preferred organic solvent. The biphasic medium in question usually comprises from 0.1 to 1 volume of water per volume of organic solvent and is used in a proportion of 3 to 30 equivalents in volume per equivalent in weight of the compound of the formula II, in particular the OTBN. As for the brominating agent, it intervenes in the reaction in a proportion of 0.5 to 1.4 molar equivalents for each molar equivalent of the compound of the formula II, preferably in an amount of 0.9 to 1.2 molar equivalents, and even better of 0.95 to 1.1 molar equivalents. Beyond a 1.2 equivalent of brominating agent, the tendency to the formation of the corresponding dibrominated derivative is growing in a marked manner. This brominating agent is bromine or an organic compound containing bromine, selected from N-bromoacetamide, N-bromophthalimide, N-bromomaleimide, an N-bromosulfonamide, N-bromosuccinimide (NBS) and 1,3-dibromo-5 , 5-dimethylhydantoin (DBDMH). It is further considered that NBS, DBDMH or bromine are preferred as preferred brominating agents. Alternatively, the brominating agent may be constituted with an alkali metal bromhydric / bromate acid system, preferably sodium bromate. In this case, the alkali metal bromate is used in a proportion of 0.3 to 0.4 molar equivalents per molar equivalent of the compound of the formula I I. The reaction according to the present invention is usually carried out at a temperature comprised between 0 ° C and 45 ° C. On the other hand, a temperature between 0 ° C and room temperature (of the order of 20 to 25 ° C), in particular a temperature between 0 ° C and 15 ° C, is preferred. Beyond 50 to 60 ° C, a relatively significant decrease in the selectivity of the compound of the formula I in favor of the corresponding dibrominated compound is noted. In order to cause the formation of bromine as radical, necessary for the initiation of the reaction according to the invention, the photoirradiation of the reaction mixture is ensured from an appropriate light source emitting radiation of a wavelength below 600 nm . A significant proportion of effective radiation can be obtained from lamps whose main emission is in the range of 350 to 600 nm. Thus, for example, a mercury vapor lamp can be used, at medium pressure, which mainly emits its rays in this wavelength range. The reactor model used for the practical application of the method according to the invention also contributes significantly to the effectiveness of the irradiation including some other factors such as the ratio of the reaction volume to the illuminated air surface or the distance of the light source relative to the reaction medium. The choice of the geometry of this reactor is also linked with the possibility of arranging the lamp in such a way that optimal conditions for irradiation are achieved. Depending on the case, it is possible, for example, to design the reactor in the form of a simple angled U-tube or a spiral tube in such a way that the lighting system can be placed in the immediate vicinity of this reactor. Preferably, a type of reactor is chosen that offers the possibility of arranging the lamp coaxially, for example a reactor in the form of a coil or with an annular tubular structure. In order to further reduce the losses in light radiation, reflectors can also be added. Above it is imperative to take into account certain factors capable of affecting the efficiency of the luminous flux per unit area that must be radiated, and this by resorting to reactors whose model is adapted in the most appropriate manner possible. Accordingly, the device intended for the practical application of the method according to the invention will be chosen or modified in such a way that the volumes of reaction mixture that do not directly receive the light radiation will be minimized or eliminated. For this reason, the choice of the reactor will preferably be directed towards the ring-type or serpentine-type models in order to place the lamp in coaxial position. A system capable of producing an effective agitation or turbulence of the reaction mixture will also be provided to increase the possibilities of this mixture passing through an illuminated area of the reactor. The process of the invention thus described is carried out in a period of about 1 to 2 hours depending on the reaction temperature applied and the duration of the phase of introduction of the reagents, and in most cases in a period of about 1 hour and a half. Thus, at temperatures of the order of 35 ° C to 45 ° C, the reaction ends in 1 hour which is equivalent to the duration of the introduction into the reaction medium of the reagent0 of the reagents, namely the brominating agent or a mixture of brominating agent and compound of the formula II. On the other hand, at temperatures that vary from approximately 0 ° C to approximately 15 ° C, the reaction is reached in approximately 1 and a half hours if the duration of the introduction of the reagents also corresponds to the order of 1 hour. Accordingly, it is observed that the reaction according to this invention is almost instantaneous at temperatures of the order of 35 ° C to 45 ° C especially at the reflux temperature of dichloromethane. In addition, at temperatures of 0 ° C to 15 ° C, approximately, the duration of the reaction remains compatible with an industrial development. By way of comparison, the photobromination of the OTBN with bromine was carried out at a temperature of 40 ° C either in dichloromethane alone or in a two-phase medium according to the invention, that is, constituted by water and dichloromethane, for the purpose of forming 4 '-bromomethyl-2-cyanobiphenyl, hereinafter referred to as Compound A. In both cases, the same reaction conditions were respected and the introduction of bromine into the reaction medium containing OTBN requires about 1 hour. The following results expressed in% of OTBN, of Compound A and of 4 '-dibromomethyl-2-cyanobiphenyl (hereinafter referred to as "dibrominated compound") obtained in the reaction medium were obtained: a) in dichloromethane alone b) in the two-phase medium according to the invention These results show: • That the reaction according to the invention is instantaneous at the temperature used since the final yield is obtained practically at the moment of finishing the introduction of the reagents; • That the process according to the current state of the art requires at least 3 hours to obtain a yield as regards Compound A that approaches that yield obtained after 1 hour by the application of the method according to the invention. Other comparative tests of OTBN photobinding were carried out at 10 ° C in a biphasic medium of water and dichloromethane with a system of bromhydric acid and sodium bromate as a brominating agent in comparison with a system of hydrobromic acid and peroxide. hydrogen. The results showed that the reaction with the hydrobromic acid and hydrogen peroxide system only leads to a 20% conversion of OTBN to Compound A after 1.5 hours. On the other hand, under the same conditions, an 85% conversion rate of OTBN in Compound A was also recorded after 1 hour and a half. Furthermore, bromination from bromhydric acid and sodium bromate turned out to be almost instantaneous. They also showed the results that at the end of the reaction the selectivity in Compound A is better with the system of bromhydric acid and sodium bromate than with the system of hydrobromic acid and hydrogen peroxide. Finally, it is pointed out that the monobrominated derivatives of the formula I, obtained according to the process of the invention described here, can be further separated from the reaction medium according to the classical methods, for example by decanting the organic phase, removing the solvent and optionally recrystallization in a suitable medium or also by chromatographic methods. The method according to the invention can be applied in different ways by resorting to some cases to intermittent or continuous type techniques. For example, the preparation of the compounds of the Formula I according to the invention can be contemplated, starting from applications in intermittent phase that implies the following: 1) either the total charge to the reactor of the various constituents of the two-phase medium as well as the reagents, namely the substrate of formula II and the brominating agent, to then carry out the irradiation of the reaction medium; 2) or the loading of the different constituents of the two-phase medium and then, within this medium maintained under irradiation, the introduction of a mixture of the reactants, optionally in solution or suspension in the organic solvent, 3) or also, in contrast to the foregoing, the introduction by casting of the brominating agent optionally into solution or suspension in the organic solvent, and This is carried out in the reaction medium maintained under irradiation, which is constituted by the biphasic mixture containing the substrate of the formula II. In the case of a brominating agent formed by hydrobromic acid and alkali metal bromate, it is also possible to contemplate the introduction by pouring of the hydrobromic acid into a reaction medium under light irradiation, which is constituted by the biphasic mixture based on bromate of alkali metal and the substrate of formula II. For the application of the process according to the invention in accordance with a method called intermittent or discontinuous, it is possible to resort to the device that carries a reactor of classic type provided with a double heating or cooling envelope and which has been designed in such a way that preferably allow the immersion of the light source in the reaction medium. In the context of the effective application of the process according to the invention, it has been possible to observe an increase in the selectivity for the monobrominated derivative of the formula I when the reaction temperature decreases but also when the reactants are mixed in their entirety before being introduced into the the reactor. On the other hand, the application of the process according to the invention by introducing the mixture of the reagents as provided in the intermittent techniques 2) and 3) described above requires an almost perfect control of the amount of photochemical initiator to master the kinetics of the reaction. Since the power of the sources responsible for this photochemical initiation is not adjustable, it turns out to be necessary to irradiate small volumes of this medium so that the temperature will be more easily controlled. In consideration of these limitations, the development of the method of the invention in continuous phase can be favorably contemplated. Thus, it is possible to resort, for this bromination reaction, to continuous phase applications based on a circulation of the reagents constituted by the brominating agent and by the biphenyl derivative of the formula II, in a tubular reactor with piston-type runoff ("plug-flow reactor"), ie with a runoff such that each element of the fluid will pass through the reactor without mixing with the previous or subsequent material, this reactor being photo-irradiated and maintained at a temperature comprised between 0 ° C and 45 ° C , for example at a temperature between 0 ° C and room temperature, preferably at a temperature between 0 ° C and 15 ° C. For this purpose, a suitable device that allows, for example, the introduction with a controlled flow and in a two-phase medium, of a solution or suspension of substrate of the formula II and of the brominating agent optionally in the organic solvent can be advantageously used. selected, regulating the flow through a set consisting of a dosing pump and a flow regulator coupled to a balance. This device is also completed with a reactor that carries an inlet to introduce the various constituents of the reaction medium and an outlet to collect the products generated by the reaction. This reactor, intended to receive the two-phase medium, is constituted by a tube, for example of glass or quartz, preferably in the form of a spiral, submerged in a heating or cooling fluid, for example a glycolated water bath or not. , whose temperature is controlled with a cryothermostat. In this device, when it takes a spiral reactor, the lamp or the necessary focus for carrying out the photoirradiation of the reaction medium, which can be for example a mercury vapor focus, can be placed outside or preferably inside the volume tubular formed by this reactor but on the other hand in the immediate vicinity of the latter. Certain brominating agents, used in the process according to the invention, can give rise to certain water-soluble by-products. Such is the case especially of the DBDMH which provides 5,5-dimethylhydantoin (hereinafter referred to as DMH) water-soluble but which otherwise crystallizes in the medium when the conversion rate of the compound of the formula II into the monobrominated compound of Formula I is greater than 80%. This crystallization therefore entails certain phenomena of congestion of the tubular reactor which disturb the piston-type runoff of the reaction medium.

Accordingly, it can be envisaged to advantageously complete the process according to the invention by means of a continuous extraction operation of the water-soluble by-products generated by the brominating reaction, its evacuation or withdrawal of the reaction medium and, if necessary, carrying out its recovery. Therefore, and in accordance with a preferred application of the process of the invention, the bromination reaction and the extraction of the water-soluble by-products generated by this reaction are carried out simultaneously and in continuous phases, byproducts which are then removed from the reaction medium. For this purpose, a tubular reactor with a piston-type drainage system, which is constituted by a liquid / liquid extraction column, is advantageously used. These operations can be handled according to a technique involving on the one hand the bromination reaction in continuous phase by circulating the reaction mixture formed by the organic solvent and the reactants in a tubular reactor with piston-type runoff constituted by a column liquid / liquid extraction, photo-irradiated and maintained at a temperature comprised between 0 ° C and 45 ° C, for example at a temperature comprised between 0 ° C and room temperature, preferably at a temperature between 0 ° C and 15 ° C and on the other hand the simultaneous and continuous extraction of the water-soluble by-products, operated with water from the biphasic medium circulating countercurrently with respect to the reaction mixture in the column as well as the removal of the water-soluble by-products in question, from the reaction medium. This method makes it possible in particular to increase the selectivity of the bromination reaction and to improve the thermal control thereof by eliminating, if necessary, the heat evolved by the focus and by the reaction. Another object of the invention thus relates to a photobroming device for the application of the process according to the invention in a continuous phase, which carries a tubular reactor with a piston-type runoff constituted by a liquid / liquid extraction column photo-irradiated and maintained at a temperature between 0 ° C and 45 ° C, for example at a temperature between 0 ° C and room temperature, preferably at a temperature between 0 ° C and 15 ° C. Other characteristics and advantages will stand out in the course of the following description which refers to an embodiment of the device according to the invention that is presented by way of non-limiting example, and with reference to the attached drawing in which the figure represents a schematic view of such a continuous photobroming device. The device described is particularly adapted to the application of a process that uses, by way of organic solvents not miscible with water, aliphatic hydrocarbons or halogenated aromatics. Referring to this figure, the device carries a reactor (1) forming a liquid / liquid extraction column, for example glass or quartz. This reactor is constituted by an annular enclosure (2), with its vertical axis, delimited by an internal wall (3) and an external wall (4), separated. In its upper and lower parts respectively, the enclosure (2) carries two decanters (2a) and (2b) or a rest area that allows the separation of the two phases. Two disks (7) and (5) respectively close the lower end and the upper end of the enclosure (2). The external wall (4) is in its central part in contact with a heat exchanger (6). According to a preferred embodiment of the invention, the ring enclosure (2) is provided in its outer central part with a double envelope in which circulates a cooling or heating liquid, such as for example a glycolous aqueous solution. The inner wall (3) and the discs (7) and (5) delimit an interior enclosure (9) in which a photochemical lamp (10) is arranged, which can be, for example, a mercury vapor focus, equipped with a double envelope (not shown) in which a cooling liquid circulates, which can be deionized water, as an alternative the photochemical lamp (10) of such a double envelope is left out . In this case the cooling of its focus can be ensured by means of the circulation of a liquid provided for this purpose in the enclosure (9). The lamp (10) passes through the disc (5) to which it is anchored. The reactor also comprises a feed conduit (12) for loading the reagents and the organic solvent located at the head of the column as well as a water supply conduit (13) which is located at the foot of the column. The water supply conduit (13) passes through the disc (7) and opens into the lower decanter (2b) of the enclosure (2) below the level of the lamp (10). The feeding conduit (12) passes through the disc (5) and opens into the upper decanter (2a) of the enclosure (2). The reactor further comprises a withdrawal outlet of the aqueous solution (14) for the dislodging of water-soluble by-products. This outlet is located at the head of the column and consists for example of a withdrawal conduit that passes through the external wall (4) of the enclosure (2) present in the upper decanter (2a). Otherwise, the disc (7) is traversed by a withdrawal conduit (15) of the products of the reaction. The faces in front of the inner (3) and external (4) walls of the enclosure (2) preferably comprise protruding parts, ie cantilevers, which are constituted, for example, by imbricate half-discs, arranged along the central part of the enclosure (2) , forming deviators (18). These half-discs are made of an inert material, for example a suitable plastic material such as polytetrafluoroethylene. As an alternative, the lining is formed in the form of crowns or disc diverters supported by rods (not shown) secured in the discs (5) and (7), the space between these crowns or discs being adjustable by shelves of a defined height.

In addition, the photobroming device upstream of the supply duct (12) can be equipped with a reservoir (8) which is intended for the storage of the reagents and the organic solvent and, downstream of the withdrawal duct (15) with a second reservoir (16) which serves to store after its extraction, brominated products formed in the course of the reaction. Advantageously, this device comprises a hydraulic protector (17) located immediately at the outlet of the column, downstream of the withdrawal conduit (15) and mounted in series with the reservoir (16). This hydraulic protector is intended to maintain the organic phase continuously inside the enclosure (2) to perform the photobroming with runoff of the piston type, in which the water constitutes the dispersed phase. This dispersion, obtained thanks to the deviators, on the other hand is improved by a pulsation of the reaction mixture caused by a metering pump (11) for example a membrane pump, connected to the lower decanter (2b) of the enclosure (2). During use of this device, the enclosure (2) is first filled with organic solvent, the bulb (10) is turned on and its cooling circuit is channeled, and if it is present, the dosing pump is put into service (11). ) to ensure the pulsation of the reaction mixture inside the enclosure (2), the enclosure (2) is then brought to the desired temperature by means of the corresponding heating or cooling system. continuous use of the column with water on the one hand and with an organic solution of the reagents on the other The use of the simultaneous bromination and extraction device, which is thus conceived for the application of the process according to the invention in continuous phase, made it possible to obtain the monohydrate derivatives of the formula I with excellent selectivity The rate of conversion of the compound of the formula II into the desired compound is particularly high. The conversion of the OTBN into '-bromomethyl-2-cyanobiphenyl is greater than or equal to 90% and the selectivity for the desired compound is between 85% and 90% while the rate of the corresponding dibrominated compound is less than 10% and general is of the order of 5 to 7%. Among the by-products generated by the reaction, those coming from the decomposition of the brominating agent can be advantageously recovered, and retransformed and recycled for example to the process of the invention. Such is the case, in particular of the DMH, water-soluble product generated by the decomposition of the DBDMH. This product, after its retransformation in DBDMH, for example by treatment with bromine in a basic medium, can be recycled especially to the point of continuous application of the process according to the invention. For example, at 10 ° C, such treatment, in the presence of sodium hydroxide or sodium carbonate, provides 91% to 92% of DBDMH with a purity greater than 99%. This possibility of recovery and recycling of the reaction by-products after their retreatment increases the interest represented by the use of the process according to the invention in continuous phase, as described above, and when recourse is made to a liquid / liquid extraction column. as a bromination reactor with the piston type drip system. The following non-limiting Examples illustrate the invention. In these Examples, the controls were made in the course of the reaction by high performance liquid chromatography, hereinafter referred to as CLAR, in the reaction medium diluted in acetonitrile. Also, hereby designated by "dibrominated compound" is the 4'-dibromomethyl-2-cyanobiphenyl also produced during the course of the bromination reaction. EXAMPLE 1 4 '-bromomethyl-2-cyanobiphenyl In a glass reactor with a capacity of 2 liters provided with a double envelope and connected to a cryothermostat for regulating the internal temperature, and which bears a turbine-type stirrer as well as a medium-pressure mercury vapor lamp (power: 150 watts) located in a submerged tube cooled by a water circulation in a double envelope, 200 g (1.036 moles) are introduced of OTBN, 1000 ml of dichloromethane and 500 ml of water and then the whole is subjected to a stirring system. The bulb is switched on, the reaction medium is heated with the aforesaid focus until boiling and while the feed flow rate is regulated, a suspension of 162.2 g (0.567 mol) of DBDMH in 200 ml of dichloromethane is introduced in 1 hour. . The medium is maintained in a reflux system during the introduction and then for an additional 1 hour. The reaction mixture is cooled to between 29 and 25 ° C, stirring is stopped and it is left to decant for 30 minutes. The upper aqueous phase is removed and 2 washes of the organic phase are carried out by 2000 ml of water. A control with CLAR chromatography provides the following results: OTBN Desired compound Dibrominated compound 3.5% 86% 10.5! The desired compound is then isolated after partial removal of dichloromethane, 250 ml of methyl ether and tertiary butyl ether are added, the elimination of dichloromethane is effected by keeping the volume constant by successive additions of 250 ml fractions of diethyl ether. methyl and tertiary butyl (final% of dichloromethane < 2.5), cooling to 20 ° C, filtration, drying, washing with 150 ml and then 70 ml of methyl ether and tertiary butyl ether and drying in the oven at 50 ° C under vacuum. In this way, 224.5 g of 4'-bromomethyl-2-cyanobiphenyl are obtained in the form of a beige powder. Yield: 79.6% EXAMPLE 2 4'-bromomethyl-2-cyanobiphenyl In a glass reactor equipped as described in Example 1, 150 g (0.776 mole) of OTBN, 700 ml of dichloromethane and 300 ml of water are introduced and then the whole assembly is subjected to a stirring system at 300 revolutions per minute. The mercury vapor source is turned on and then, while regulating the feed rate, a solution of 124 g (0.776 mol) of bromine in 200 ml of dichloromethane is introduced in about 1 hour. The medium is maintained in a reflux system during the total time of introduction. A control by CLAR carried out after 57 minutes shows that the medium contains: OTBN Desired Compound Dibromo Compound .44% 3.92% 7.64: The medium is maintained in reflux condition for an additional 1 hour and then cooled between 20 and 25 ° C. Agitation is stopped and left to decant for 30 minutes. The upper aqueous phase is removed and two washes of the organic phase are carried out by water. A new control by means of CLAR provided the results that follow, once the 2 hours of reaction have been completed: OTBN Desired compound Dibrominated compound 84.18% 7.42% EXAMPLE 3 4'-bromomethyl-2-cyanobiphenyl In a glass reactor equipped as in the Example 1, 200 g (1.036 moles) of OTBN are introduced, 900 ml of dichloromethane and 400 ml of water and then the entire assembly is placed under agitation at 380 revolutions per minute. The medium is cooled to a temperature between 0 ° C and 5 ° C and then the mercury vapor source is turned on while maintaining the reaction medium at the same temperature. While regulating the feed flow rate, a solution of 165.4 g (1.03 mol) of bromine in 300 ml of dichloromethane is then introduced over a period of about 1 hour. The medium is maintained at a temperature between 0 ° C and 5 ° C during the total time of introduction. At the end of the introduction, ie after 58 minutes, a control by means of CLAR of the colored reaction medium shows that it contains: OTBN Desired compound Dibrominated compound 34.05% 64.66% 1.29% Stirring is continued, which provides 30 minutes after the end of the introduction, an orange medium containing: OTBN Desired Compound Dibromo Compound 14. 16% 82.60% 3.24% After 60 minutes after completing the introduction, this same yellow medium becomes and at that moment contains: OTBN Desired compound Dibrominated compound 6.53% 42% 5.05% EXAMPLE 4 4'-Bromomethyl-2-cyanobiphenyl In a 2 liter glass reactor equipped in the manner described in Example 1, 250 g (1.29 mol) of OTBN, 1000 ml of dichloromethane and 500 ml of water are introduced and then the whole assembly is subjected to an agitation at 300 revolutions per minute. The medium is cooled to 10 ° C by circulating glycol water in the double envelope and then 64.9 g (0.43 mol) of sodium bromate are added. The mercury vapor source is turned on and the introduction of 222 g of hydrobromic acid at 47% (corresponding to 104.4 g of 100% acid or 1.29 mol) is initiated by a metering pump and a flow regulator (flow: 222g / h). At the end of the introduction of the broithhydric acid, that is after 60 minutes, the orange colored medium contains: OTBN Desired Compound Dibrominated Compound 32.27 I 66.27% 1.46% This medium is maintained at 10 ° C under agitation for an additional 60 minutes and thus a mixture is obtained which contains: OTBN Desired compound Dibrominated compound 5.62% 02% 6.36% EXAMPLE 5 4'-bromomethyl-2-cyanobiphenyl a) Preparation In a tank 100 kg of OTBN and 81.2 kg (1.1 equivalents) of DBDMH are charged and then 2000 1 of dichloromethane are added. The whole is subjected to agitation at 60 to 80 revolutions per minute and this material is maintained at 20 ° C at 25 ° C until complete dissolution is reached. b) Photobrushing For this operation, a device is used comprising an annular tubular reactor with a piston-type runoff in the form of a liquid / liquid extraction column, as illustrated in the attached figure. This column is filled with dichloromethane, the power of the lamp is regulated to 8 kw, a pressure of 0.3 bar is applied and then its specific cooling circuit is put into service with deionized water. The bulb is switched on and the pulsation system of the reaction mixture in the column is put into service, regulating the pulsation frequency at 30% (= 15Hz) and the rate at 20%. The circulation of glycol water is put into service within the double envelope of the pulsed column and the flow rates of glycolized water are regulated until obtaining a temperature of 10 ° C in the dichloromethane medium. At this time, the continuous feeding of the column pulsed first with deionized water at a rate of 300 kg / h and then with a solution of OTBN / DBDMH in dichloromethane, prepared according to paragraph a) above, with a speed of 600 kg / h. These operating conditions are maintained until the solution of the reagents in the dichloromethane is exhausted and then the tank containing this solution is rinsed through the transfer line to the column, charging the latter with 200 1 dichloromethane. An analysis by CLAR shows that the mixture at the end of the reaction contains: OTBN Desired compound Dibrominated compound 5.7% 87.5% 6.8% c) Isolation At that time, the desired compound is isolated by washing the solution of the photobrominated products in dichloromethane by means of a dilute aqueous solution of sodium bisulfite, recovery of the organic phase by decantation, preconcentration of this organic phase, elimination of dichloromethane. by successive additions of methyl ether and tertiary butyl, crystallization of the suspension at 0 ° C to 3 ° C, filtration, filtration to the tube or mechanical drying of the suspension, washing of the product obtained with methyl ether and tertiary butyl and dried at 40 to 45 ° C. In this way, pure 4 '-bromomethyl-2-cyanobiphenyl is obtained with a yield of 78% by weight relative to the OTBN.

Claims (17)

1. CLAIMS; A process for the preparation of 4 '-bromomethyl-biphenyl derivatives of the general formula: wherein R represents: • a cyano group • a group: -C0Rx or -CON R2R3 in which R, R2 and R3, identical or different represent hydrogen or an alkyl group, linear or branched, with Ci to C6, same as in its case may be substituted by a halogen atom, a hydroxy, amino, alkoxy group of Ci to C4, or by 1 to 3 phenyl groups optionally substituted by 1 to 3 groups selected from the halogen atoms and the hydroxy, nitro groups, Ci to C alkyl, and Ci to C4 alkoxy, • a tetrazolyl group of the general formula: wherein R4 located at the 1 or 2 position of the tetrazolyl group represents hydrogen or a protecting group, characterized in that it is reacted in a biphasic medium and under the effect of a photoirradiation, a brominating agent selected from bromine, N-bromoacetamide , N-bromophthalimide, N-bromomaleimide, N-sulfonamide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin and a system of hydrobromic acid and alkali metal bromate with a biphenyl derivative of the general formula: in which R has the same meaning as indicated above, which generates the desired compound.
2. 2. The process according to claim 1 characterized in that R represents a tetrazolyl group in which R4 represents an alkyl group, linear or branched with Ci to e and optionally substituted by 1 to 3 phenyl groups which in turn can be substituted by 1 to 3 groups
3. 3. The process according to claim 1 or 2, characterized in that R represents a cyano, tetrazolyl, triphenylmethyl-tetrazolyl group or a -CO 2 group in which formula R x represents hydrogen as a methyl, ethyl or propyl group.
4. 4. The process according to any of claims 1 to 3, characterized in that R represents the cyano group.
5. 5. The process according to any of claims 1 to 4, characterized in that the two-phase medium is constituted by water and 1 or several organic solvents immiscible with water.
6. 6. The process according to claim 5, characterized in that the organic solvent is a halogenated aliphatic hydrocarbon or a halogenated aromatic hydrocarbon. The process according to claim 5 or 6, characterized in that the organic solvent is dichloromethane. The process according to any of claims 1 to 7, characterized in that the two-phase medium comprises 0.1 to 1 volume per water per volume of organic solvent. The process according to any of claims 1 to 8, characterized in that the biphasic medium is used in a proportion of 3 to 30 equivalents in volume per equivalent in weight of biphenyl derivative of the formula II. The process according to any of claims 1 to 9, characterized in that the brominating agent is bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin or a system of hydrobromic acid and alkali metal bromate. The process according to any of claims 1 to 10, characterized in that the brominating agent is used in a proportion of 0.5 to 1.4 molar equivalents per molar equivalent of the biphenyl derivative of the formula II. 12. The process according to claim 11, characterized in that the brominating agent is used in a ratio of 0.95 to 1.1. molar equivalents per molar equivalent of biphenyl derivative of formula II. The process according to any of claims 11 or 12, characterized in that the alkali metal bromate is used in a proportion of 0.3 to 0.4 molar equivalents per molar equivalent of the biphenyl derivative of the formula II. The process according to any of claims 1 to 13, characterized in that the reaction is conducted at a temperature comprised between 0 ° C and 45 ° C. 15. The method according to claim 14, characterized in that the reaction is conducted at a temperature between 0 ° C and room temperature. 16. The process according to claim 14 or 15, characterized in that the reaction is conducted at a temperature comprised between 0 ° C and 15 ° C. 1
7. 7. The method according to any of claims 1 to 16, characterized in that the photoradiation is obtained from a light source that emits radiation from 350 to 600 nm. lß. The process according to any of claims 1 to 17, characterized in that the bromination reaction proceeds in continuous phase and comprises the continuous circulation of the reactants constituted by the brominating agent and the biphenyl derivative of the formula II in a tubular reactor with piston-type runoff, a photo-irradiated reactor and maintained at a temperature between 0 ° C and 45 ° C, which provides the desired compound and eventually water-soluble byproducts. The process according to claim 18, characterized in that the bromination reaction and the extraction of the water-soluble by-products which are then removed from the reaction medium are carried out simultaneously and in continuous phases. 20. The process according to claim 19, characterized in that the reaction, extraction and removal are carried out in a reactor with a piston-type runoff constituted by a liquid / liquid extraction column. The process according to any of claims 18 to 20, characterized in that it comprises, on the one hand, the bromination reaction in continuous phase by circulation of the mixture formed by the organic solvent and the reactants, in a tubular reactor with a piston-type runoff. consisting of a liquid / liquid extraction column photo-irradiated and maintained at a temperature between 0 ° C and 45 ° C and, on the other hand, the simultaneous and continuous extraction of the water-soluble by-products operated with water from the biphasic medium circulating in countercurrent with with respect to the mixture present in the column, followed by the removal of said water-soluble byproducts from the reaction medium 22. The process according to any of claims 18 to 21, characterized in that the temperature is between 0 ° C and room temperature . 23. The process according to any of claims 18 to 22, characterized in that the temperature is comprised between 0 ° C and 15 ° C. 24. Photobroming device for the application of the continuous phase process according to any of claims 18 to 23, characterized in that it comprises a tubular reactor with piston-type runoff, photo-irradiated and maintained at a temperature comprised between 0 ° C and 45 ° C . 25. The device according to claim 24, characterized in that the tubular reactor with run-off of the piston type is constituted by a liquid / liquid extraction column. 26. The device according to claim 24 or 25, comprising (i) a reactor (1) constituted by an annular enclosure (2) with vertical axis, delimited by an internal wall (3) and an external wall (4), spaced apart and closed with a disc (7) located at the level of the lower decanter (2b) of the enclosure (2), and with a disc (5) located at the level of the upper decanter (2a) of the enclosure (2), (ii) a lamp photochemical (10) provided with a double cooling envelope, disposed inside the enclosure (9) delimited by the internal wall (3) of the enclosure (2) and by the disc (5), passing through the disc (5) in the direction of the thickness, (iii) a feeding duct (12) for the loading of the reagents and the organic solvent, which is placed at the head of the column that crosses the disc (5) and which empties into the upper decanter ( 2a) of the enclosure (2), (iv) a water supply conduit (13) located at the foot of the column that passes through the disc (7) and that empties into the l lower decanter (2b) of the enclosure (2), (v) a duct for withdrawing the aqueous solution (14) located at the head of the column passing through the external wall (4) of the enclosure (2) at the level of the upper decanter (2a) and (vi) a withdrawal conduit (15) of the products of the reaction located at the foot of the column, which passes through the disc (7), being equipped the ring enclosure (2) in its central part with a heat exchanger (6) arranged in contact with its external wall (4) and the inner (3) and external (4) walls of the enclosure (2) being provided in its central part of diverters (18). 27. The device according to claim 25 or 26, characterized in that it is equipped upstream of the supply conduit (12) with a reservoir (8) intended for the storage of the reactants and the organic solvent, and, downstream of the withdrawal conduit (15), with a reservoir (16). ) for the storage after removal of the brominated products formed in the course of the reaction, the enclosure (2) being connected at the level of the lower decanter (2b) to a dosing pump (11) intended to press the reaction medium. The device according to any of claims 26 to 27, characterized in that the run-off of the piston type is ensured by a hydraulic protector (17) disposed immediately at the outlet of the column, downstream of the withdrawal duct (15) and mounted in series with the tank (16). 29. The device according to any of claims 26 to 30, characterized in that the reactor is maintained at a temperature comprised between 0 ° C and room temperature. 30. The device according to any of claims 26 to 31, characterized in that the reactor is maintained at a temperature comprised between 0 ° C and 15 ° C. SUMMARY The invention relates to a process for the preparation of 4'-bromomethyl-biphenyl derivatives of the general formula (I) in which R represents what is defined in claim 1, characterized in that it consists in reacting in a biphasic medium and under the effect of photoirradiation, a brominating agent selected from bromine, N-bromoacetamide, N-bromophthalimide, N-bromomaleimide, an N-sulfonamide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin and a system of hydrobromic acid / alkali metal bromate with a biphenyl derivative of the general formula (II) wherein R has the same meaning as above, thus obtaining the desired compound.