The invention relates to a process for preparing biaryl compounds using Suzuki type coupling reactions of aryl chlorides with aryl boronic acids in presence of a base and a water-soluble transition metal catalyst in a reaction solvent consisting of water/oil/surfactant. The used surfactant is a non-ionic surfactant of 3-6 wt.% (the percentage is related to the total weight of the reaction solvent) and the oil to water ratio in the reaction solvent is from 10:1 to 1 :10. Using these reaction conditions a three phases system is formed. The reaction product is isolated from the oil phase. The water phase comprises the formed salts. The catalyst is contained in the surfactant phase being between the oil and water phases. The catalyst is recyclable and reusable. Palladium-catalyzed coupling reactions are widely used routes for the formation of carbon-carbon bonds and carbon-heteroatom bonds in particular for the synthesis of biaryl compounds. Besides others well-known coupling reactions of Heck, Sonogashira, Stille and Kumada, the Suzuki synthesis of biaryls is very attractive to synthesize polyolefins, styrenes, and substituted biphenyls by an organic reaction of an aryl- or vinyl-boronic acid with an aryl- or vinyl-halide catalyzed by a palladium complex (Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866). The reaction also works with pseudohalides, such as triflates (OTf), instead of halides, and also with boron-esters instead of boronic acids. In particular, the toleration of many functional groups, which makes an expensive protective technique superfluous, make C-C coupling reactions particularly attractive for fine chemistry and pharmaceutical chemistry.

Aryl iodides, triflates and bromides are easy accessible in Suzuki-type coupling reactions, whereas the accessibility can be described for different halides in the sequence: l>OTf>Br>»CI.

Organoboronic acids are advantageous as reagents in laboratories and industry. They are well manageable, non-toxic as well as stable to water and oxygen. Homogenous Pd catalysts for C-C coupling reactions are well known. The homogeneous catalysts are dissolved in liquid reaction media, which consists beside the solvent also of the substrates and the product, respectively. The transition metal Pd can be used as catalyst for all coupling reactions, mostly in form of a palladium(ll) compound as precursor bearing water-soluble phosphine ligands.

For the coupling of aryl chlorides no generally applicable method could be found to introduce these for the coupling reactions with its various nucleophiles of Heck, Sonogashira, Stille and Kumada and Suzuki to mention some examples. The low reactivity of aryl chlorides makes them to non-favoured partners for the coupling reactions. However it is fact that they are easier accessible and much cheaper than the cost-intensive analogues bromides and iodides.

At the end of the 1990s, synthesis and application of new ligands have improved the methods to couple aryl chlorides. A prominent contribution from industry is the Suzuki coupling of 2-chlorobenzonitrile with p-tolylboronic acid as an intermediate for the production of sartans (US 6,140,265 A). In this reaction, 1 mol/l of 2-chlorobenzonitrile is used with 0.1 mol% catalyst using the ligand tris(3-sulfophenyl)phosphine thsodium salt (TPPTS) and results in approximately 90 % product after a reaction time of 12 to 15 hours.

However, the relatively long reaction time and the temperature of 120 ⁰ C make this process limited economically.

Buchwald introduced in a Pd catalyzed Suzuki coupling reaction electron rich biaryl ligands such as the water soluble 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) ligand (J Am Chem Soc. 2005 Apr 6;127(13):4685-96.). But, if a noble metall catalyst and/or an expensive ligand are used, a catalyst recycling is desired to cut costs. Research on recycling of the catalyst attacks interest but is established in industry only rarely. According to the current prior art, it is impossible to separate off the noble metal catalyst completely. Therefore it was the object of the present invention to provide an advantageous method for preparation of aryl compounds with shortened reaction time and lower reaction temperature and allowing to recycle the catalyst directly and nearly completely after the homogeneous catalyzed coupling reaction. Surprisingly, it has now been found that this problem can be solved with the preparation method of claim 1. Small amounts of a non-ionic surfactant are employed in the Suzuki coupling reaction and besides the non-ionic surfactant concentration the oil to water ratio of the reaction solvent is kept in a defined range described in claim 1. This way, after the complete conversion of the reactants phase separation into three liquid phases is achieved within few minutes. Under these conditions and using the special catalyst described in claim 1 a very simple method is achieved which allows fast product separation, catalyst recycling and removal of the salts.

Accordingly, the present invention provides a process for preparing biaryl compounds by reacting aryl chlorides with aryl boronic acids or their salts in the presence of a base and catalyzed by a complex consisting of a transition metal and an organic ligand and carried out in a reaction solvent consisting of water, oil and surfactant, which is characterized in that the reaction is carried out in a reactor at 35 to 90 ⁰ C and the used catalyst is a complex of a palladium(ll)-compound with 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) as ligand. The ligand is preferably used in its water soluble form for example as sodium 2'- dicyclohexylphosphino-2,6-dimethoxy-1 ,1 '-biphenyl-3-sulfonate. The reaction solvent comprises 3 to 6 wt.% of a non-ionic surfactant (the percentage is related to the total weight of the reaction solvent) and the ratio of oil to water in the reaction solvent is from 10:1 to 1 :10. This way after the homogenously catalyzed chemical reaction a three phases system is formed. This three phases system consists of an oil phase, which is the upper phase and comprises the final biaryl reaction product, a lower water phase comprising formed salts and a surfactant phase between oil and water phase comprising the catalyst. Surprisingly the loss of catalyst by leaching into the water phase is less than 15 ppm. That shows that the catalyst remains nearly completely in the surfactant phase. The formation of three phases allows the reaction product isolation and catalyst recycling in one step as well as the separation of the formed salts. The surfactant phase comprising the catalyst is reusable.

In one embodiment of the invention, based on the three phase system a special setup can be designed to extract water and oil phase from the reactor and to leave the catalyst phase (surfactant phase) within the reactor for further product cycle(s). The aqueous phase can be extracted completely, for example through a bottom valve of the reactor. The pure final product is obtained for example after evaporation of the oil phase and by washing the residue with water.

According to the invention the used palladium(ll) compound as precursor of the catalyst complex is preferably selected from palladium(ll) acetate (Pd(OAc)2), palladium(ll) chloride (PdCI2), palladium(ll) acetylacetonate (Pd(acac)2), palladium(ll) nitrate (Pd(NOs) ₂ ) or palladium(ll) sulfate PdSO ₄ , preferably Pd(OAc) ₂ .

The electron rich ligand SPhos is used for forming the catalyst complex so that water solublility of the catalyst complex is achieved. The ratio of the palladium(ll) compound to the ligand is preferably from 1 :2 to 1 :8. Especially preferred is a ratio of Pd(II) compound : ligand of 1 :5. In particular a catalyst complex consisting of Pd(OAc)2 and SPhos in a ratio of 1 :5 is especially preferred in the preparation process of the invention. Using a catalyst complex comprising ligands other than SPhos for example the known ligand TPPTS in the process of the present invention at low reaction temperatures between 35 and 80 ⁰ C and using the defined reaction solvent no coupling product could be detected. The catalyst can be employed in the process according to the invention with a content of 0.01 to 5 mol% Pd(II) compound based on the aryl chloride. In the reaction solvent consisting of oil, water and non-ionic surfactant the non-ionic surfactant is used in small amounts of a concentration of 3-6 wt.%, especially of 3-5 wt. % according to the invention. These non-ionic surfactants are especially selected from the group consisting of alkyl polyethylene glycols having in the alkyl part of the molecule a C-content < Ciβ. The application of polyethylene glycols as non-ionic surfactants has the advantage that these substances are to approximately 100% biodegradable.

Preferred used non-ionic surfactants are for example alkyl polyethylene glycol ethers commercially available as Marlipal ^® of SASOL, South Africa, nonylphenol polyethylene glycol ethers commercially available as Marlophen ^® of SASOL, South Africa, and narrow range alkyl polyethylene glycol ethers commercially available as Novel ^® of SASOL, South Africa having a sum formula of CH ₃ (CH ₂ )X-O-(CH ₂ -CH ₂ - O) _y H; wherein x is 11 -13 and y is 2-10 as average. Particularly preferred are narrow range alkyl polyethylene glycol ethers with y = 8, especially Novel 8 ^® = Novel 1216CO-8 Ethoxylate (SASOL, South Africa).

The reaction solvent of the invention has preferably the oil to water ratio from 4:1 to 1 :4, more preferred the ratio is 1 :1. The oil component of the reaction solvent is preferably selected from the group consisting of alkanes, cycloalkanes, benzene, toluene and xylene. Especially used are cyclopentane, cyclohexane, cycloheptane, hexane, heptane, octane and decane and toluene, preferably heptane, cyclohexane or toluene. In an especially preferred embodiment of the invention a water/heptane/non-inionic surfactant mixture is used. The presence of a base in a homogenous catalyzed coupling reaction is essential.

Bases, which are preferably used in the process according to the invention are alkali metal and alkaline earth metal hydroxides or salts, alkali metal and alkaline earth metal carbonates, alkali metal bicarbonates.

Preferably used bases are Na ₂ CO ₃ , Cs ₂ CO ₃ or K ₂ CO ₃ . The base can be employed in the process according to the invention in a proportion of 100 - 500 mol% based on the aryl chloride compound. To carry out the process, the starting materials, the base and the catalyst complex are mixed in the reaction solvent at temperatures of up to 95°C, especially at a temperature of 15 ⁰ C to 95 ⁰ C, preferably at 45 to 80 ⁰ C, more preferred 60 ⁰ C. The reaction time for a conversion of the reactants in good yields (that means more than 95%) is very fast preferred between 10 minutes and 240 minutes.

As already mentioned, after converting the reactants into the final product, oil and water phases can be separated from the reactor and the catalyst complex-containing surfactant phase remains inside the reactor for further reactions cycle(s) surprisingly with consistent activity. That means new substrates except catalyst and ligand dissolved already in fresh oil and water, respectively, were delivered to the reactor to start a further reaction. The time between first and second cycle, including phase separation and the exchange of all phases, takes few minutes only and can be decreased further using automatic control techniques.

Furthermore, the expensive noble catalyst can be recovered nearly completely, contamination of the final product with noble metal is avoided and the salts as byproducts can be easily removed from the water phase.

Because a small loss of Pd and P for the catalyst complex is not avoidable (the loss of Pd after the first cycle is only 1 %), the yields in the next cycle(s) are decreased. However, it could be pointed out that also in further cycles a yield of more than 30% can be achieved if the amount of surfactant is always maintained of 3 wt. %. An addition of further catalyst complex is not necessary.

Aryl chlorides and aryl boronic acids, which can be used as starting material in the presented method depends on the desired reaction products. The process is used for producing active compounds for pharmaceuticals and components of liquid crystal mixtures as well as intermediates for their production.

The starting materials usable in the Suzuki type reaction are either known or can be prepared by known methods as for example described in Houben Weyl, Methoden der Organischen Chemie, Georg Thieme Verlag, Stuttgart, Volume 5. It is well known, that electron poor (what means 'activated') aryl halides undergo coupling reactions more easily than neutral or extremely electron-rich aryl halides. Therefore aryl chlorides including heteroaryl chlorides as starting material are especially activated aryl chlorides with additional electron withdrawing groups and substituents, for example aryl chlorides having electron withdrawing groups selected from the groups comprising F, CN, NO ₂ , C=O-R, CH=O, COOR, NH ₃ ⁺ . These groups are preferably in o- or p-position to the chlorine atom.

Preferred aryl chlorides are o- or p-chloro-benzonithles, o- or p-chloro- acetophenones, o-or p-chloro-thfluoromethylbenzenes.

Aryl boronic acids are also well known for the person skilled in the art as starting materials in the Suzuki reaction. In the reaction of the present invention electron-rich as well as electron-deficient boronic acids can be used, preferably substituted or unsubstituted phenyl, tolyl or naphthyl boronic acids. In particular 2- or 4-methyl- benzene-boronic acid, 3-thfluoromethylbenzene- or 3-nitrobenzene-boronic acid are used.

For example the preparation of 4'-methyl-2-biphenylcarbonitrile which is an important intermediate for the synthesis of angiotensin Il antagonists used for the treatment of hypertension is obtainable by a reaction of the present invention using the starting materials 2-chlorobenzonitrile and 4-methylbenzeneboronic acid. The coupling of 4- chloroacetophenon and 4-methylbenzeneboronic acid result in 4-acetyl-4'- methylbiphenyl. According to the present invention the biaryl products are prepared very fast (preferably within 20 and 180 minutes) and in high yields (in particular > 97%) from the oil phase using the cheaper and easier accessible aryl chlorides as starting reactants. The final product is then obtainable very fast from the oil phase. The following examples illustrate the invention. Example 1

Synthesis of 4'-methyl-2-biphenylcarbonitrile

According to the invention 4'-methyl-2-biphenylcarbonitrile is obtainable starting with

2-chlorobenzonitrile and 4-methylbenzeneboronic acid according to the following schemata:

Preparation of the catalyst solution

6 mg (2.67 ^* 10 ^"5 mol) Pd(OAc)2 and 68 mg (1.33 ^* 10 ^"4 mol) of the SPhos ligand were placed in a schlenk tube and purged with nitrogen. Subsequently, 1.5 ml of deaerated water was added to the catalyst mixture by a syringe in a counterflow of nitrogen. The catalyst solution was stirred over night (15 hours) to ensure complete complexation of the ligand to the metal before the reaction. The colour of the catalyst solution changed during stirring time from bright yellow to orange, indicating that the active complex has been formed within this time.

Synthesis of 4'-methyl-2-biphenylcarbonitrile

5.5 mmol (757 mg) of 2-chlorobenzonitrile, 6.05 mmol (1.1 equiv., 822 mg) of 4- methylbenzeneboronic acid and 6.87 mmol (1.25 equiv., 950 mg) of K2CO3 were transfered to the reactor with the solvents. For the preparation of the solvent mixture 38.8 g heptane and 2.4 g of non-ionic surfactant being Novel 8 ^® (Novel 1216CO-8 from SASOL, SA) were dissolved to transfer the nonpolar reactants to the reactor quantitatively. Furthermore, 38.8 g of water were used to feed the base quantitatively into the reactor. Afterwards, the reactor was pretreated with a pressure of 150 mbar and purged with nitrogen, alternately three to five times. Then, the reaction temperature was adjusted to 60 ⁰ C (or 80 ⁰ C or 45 ⁰ C). The heating of the reaction mixture was accomplished by a water thermostat, which delivered the heating medium through the jacket of the reactor. The catalyst solution (1.5 ml) of above was added by a syringe setting the starting point of the reaction, when the reaction mixture was heated to reaction temperature.

The progress of the reaction was followed, by taking samples in a range of 5 to 10 minutes, approximately.

After the first run and the appearance of the three phases, the stirrer was stopped to await phase separation. The use of the solvent mixture of 3 wt.-% (2.4 g) Novel 8, 38.8 g heptane and 38.8 g water (oil:water =1 :1 ) has the following volumes at the end of the reaction: 45 ml of heptane phase, 30 ml of aqueous phase and 23 ml of the middle phase, which remain in the reactor. The oil phase was delivered by the lsmatec pump to isolate the product, the aqueous phase was removed by the bottom valve and analysed to determine palladium and phosphor content. The loss of Pd was 1 % and for P 14%.

Reaction time: 100 minutes, yield: 100%

Catalyst recycling

For a next reaction run, the catalyst fraction remains in the reactor, 757 mg of the aryl chloride and 822 mg of the arylboronic acid were dissolved in the solvent mixture, consisting of 28 g of heptane and 0.8 g of Novel 8.

This amount of surfactant (0.8 g), which is needed for the next run, was evaluated. The surfactant is distributed as monomers in the aqueous and oil phase and finally a fraction is taken out after the first cycle, when the oil and the water phase are removed for isolating the product and the removal of the salts, respectively. It should be noted that the estimated value of 0.8 g surfactant corresponds to the value, which is really taken out with the oil and the water phase, because of the same volume fractions of water, oil and middle phase, which are obtained after phase separation of the second and further cycles.

The reaction mixture (heptane, surfactant and coupling reactants) was preheated to reaction temperature in a storage tank. Furthermore, 950 mg of K2CO3 was dissolved in 30 ml of water and also preheated to reaction temperature in a second storage tank. After removing of the water and oil phases of the first run from the reaction vessel, both solvent mixtures from the storage tanks were delivered to the reactor in order to start the second run. During the stirrer was switched on, a sample was taken for estimating the initial concentration of all UVA/IS detectable components in the second run and first recycling reaction, respectively. With the initial concentration of aryl chloride, the conversion was calculated for the second run and with the initial amount of the product 4'-Methyl-2-biphenylcarbonitrile the fraction was observed, which remains in the middle phase from the previous reaction. This amount of the product is approximately 30 % and is also achieved in a next cycle when 3 wt.-% Novel 8 are used. Example 2

Synthesis of 4-acetyl-4'-methylbiphenyl

In analogy to example 1 5.5 mmol (850 mg) of 4-chloroacetophenon was reacted with

6.6 mmol (1.2 equiv., 895 mg) of 4-methylbenzeneboronic acid and 7.5 mmol (1037 mg) of K ₂ CO ₃ to synthesize 4-acetyl-4'-methylbiphenyl.

Reaction time: 3 hours, yield: 97 %.