DE19636994A1 - Process for the preparation of (2'-fluorophenyl) -3-halopyridines - Google Patents

Abstract

Process for the manufacture of (2'-fluorophenyl)-3-halopyridines having formula (I), characterized in that a 2-fluorophenyl-Grignard compound having formula (II) is made to react with a pyridine derivative having formula (IV) in the presence of a transition metal catalyst.

Description

The invention relates to a new process for the production of (2′-fluorophenyl) -3-halogenopyridines of the formula I,

in which the substituents have the following meaning:
R1 fluorine, chlorine;
R² is hydrogen, alkyl, alkoxy, aryl, aryloxy, aminocarbonyloxy, N-substituted by alkyl and / or aryl radicals, where two alkyl radicals can be linked directly or via an oxygen atom to form a 5- or 6-membered ring, and the radicals among the Reaction conditions can carry inert residues;
R³ alkyl, haloalkyl and
Y chlorine, bromine or iodine.

The compounds I are precursors for pesticides herbicidal activity, but can also be used as herbicides be detected (WO-A 95/02580).

Furthermore, the invention relates to new 2-fluorophenyl zinc halogen Compounds of the formula IIIa,

where X is chlorine or bromine
and a process for the preparation of compounds of formula IIIa. The new intermediates open up an advantageous reaction route for the preparation of the compounds I, but can also be used in organic syntheses for the production of pharmaceuticals, dyes and others.

For coupling heterocyclic systems with substituted benzene Derivatives have recently become transition metal catalysts based reactions applied. Aryl tin compounds, aryl zinc Compounds or arylboronic acids are combined with an aryl halide or aryl triflate converted to mixed biarylene. In DE-A 43 37 321 and WO-A 95/02580 are such reactions wrote. The production of arylboronic acids, starting from the corresponding lithium-organic compounds, is in WO-A 93/15074 taught.

The direct coupling of a fused 2-chloropyridine with 9-An Thrylmagnesium bromide takes place according to J. Org. Chem. 55 (1990) 4789 in an unsatisfactory manner. If you put bromopyridines under 1,2-bis diphenylphosphinoethane / NiCl₂ catalysis with 2-methylbutylmagnesium chloride around, yields in the range of 50-70% were obtained [Helv. Chim. Acta 65 (1982) 2102]. In these literature examples however, the reactants were free of further reactive sub substituents, such as B. Halogens.

Grignard compounds with an ortho-fluorine or ortho Chlorine atoms have only been sporadically described in the literature [G. Lopez et al., Journal of Organometallic Chemistry, 241 (1983) Pp. 269-273; T. Ghosh & H. Hart, Journal of Organic Chemistry, 53 (1988) pp. 3555-3558], since these intermediate stages u. a. because of the slight arine formation are not very stable. That is why the Ausbeu Most of the Grignard reagent was bad. As a special case, this is in Organic Synthesis Coll., Vol. VI, 1988, p. 875 ff To view tafluorophenylmagnesium bromide, its production and Implementation succeeded in a yield of 63 to 80%.

A general procedure for the production of ortho-halogen Grignard compounds that act as precursors for the above-mentioned coupling components are conceivable, there are not for these reasons.

The invention was therefore based on the object, a general reversible manufacturing process for (2'-fluorophenyl) -3-halogenpyri dine of formula I from easily accessible starting materials to sit down. In particular, a procedural path should be found that allows the products I use a stew synthesis without isolation of intermediates, d. H. through an in to make situational implementation accessible.  

Accordingly, a process for the preparation of (2'-fluorine phenyl) -3-halopyridines of the formula I found, the ge is characterized by the fact that a 2-fluorophenyl Grignard compound of formula II with a pyridine derivative of formula IV in the presence a transition metal catalyst.

The substituents of the formulas II and IV have the meaning given for formula I, next to them are:
X for bromine or chlorine and
Z is independent of Y for chlorine, bromine or iodine.

In particular, 2-chloropyridines and 2-bromine come as starting materials IV pyridine in question.

In a preferred embodiment of the Ver driving a pyridine derivative of formula IV is used in which Z stands for bromine.

As transition metal catalysts are iron, cobalt, nickel, Rhodium, platinum or palladium compounds, especially Nickel (0) -, Nickel (II) - Palladium (0) - and Palladium (II) -verbin suitable. Salts such as palladium chloride or Palladium acetate or Pd complexes can be used. Advance is only that the ligands on the palladium under the reac conditions can be displaced from the substrate.

Are particularly well suited for the method according to the invention Phosphine ligands such as aryl alkyl phosphines. Here may be mentioned as examples: methyldiphenylphosphine, isopropyldi phenylphosphine, triarylphosphines such. B. triphenylphosphine, or triphenylphosphines substituted in the phenyl ring, such as trito lylphosphine, trixylylphosphine, or trihetarylphosphines, such as. B. Trifurylphosphine or dimeric phosphines. Still good ge olefinic ligands such as diben are also suitable cylidene acetone or its salts, Cycloocta-1,5-diene or also ter tiary amines, such as trialkylamines, here are examples of triethyl called amine, tetramethylethylenediamine or N-methylmorpholine, or pyridine.  

The complex used can be used directly in the reaction Zen. So you can z. B. with tetrakistriphenylphosphine palladium (0), Bistriphenylphosphine palladium dichloride, bistriphenylphosphine palladium diacetate, a dibenzylidene acetone-palladium (0) complex, Tetrakismethyldiphenylphosphine palladium (0) or bis (1,2-diphe Process nylphosphinoethane) palladium dichloride. You can also get one Palladium salt and additionally use a suitable ligand, which then only form the catalytically active complex in situ.

This procedure offers z. B. in the above Salts and phosphine ligands such as e.g. B. trifurylphosphine or tri tolylphosphine. Palladium complexes such as. B. Tris (dibenzylidene acetone) dipalladium, bis (dibenzylidene acetone) pal ladium or 1,5-cyclooctadiene palladium dichloride by the addition of ligands such as e.g. B. trifurylphosphine or tritolylphosphine be activated further.

Usually 0.001 to 10 mol%, in particular 0.01 to 1 mol% of the palladium compound (salt or complex), based on the raw materials used. Larger quantities are possible, but in usually not required. The molar ratio of pyridine Derivatives of formula IV, based on the reactant, is generally at 0.8 to 2, preferably at 0.95 to 1.3 mole equi valence.

They also come in as solvents for the coupling reaction Grignard reactions usual solvents, for example Tetra hydrofuran, dimethoxyethane, diethyl ether, methyl tert-butyl ether, dibutyl ether, dipropyl ether, 1,4-dioxane, toluene or N-Me thylpyrrolidone into consideration. Tetrahydrofuran or are preferred Dimethoxyethane. There are also amides, such as dimethylformamide or dimethylacetamide, ethers, such as diethyl ether, methyl tert-bu tylether, dimethoxyethane, tetrahydrofuran, dioxane, N-methylpyrro lidon or amines, such as triethylamine, are suitable. It is advantageous often the use of solvent mixtures, e.g. B. from Ethers with amides.

The reaction temperature when coupling the 2-fluorophenyl ver bindings is not critical, it is usually 0 to 200 ° C. The reaction times are usually, depending on the Substi tution and solvent used, between a few minutes and 50 hours, usually 0.5 to 20 hours. A preferred embodiment The form of implementation is the implementation under autogenous pressure in the Autoclaves.

In a preferred embodiment of the Ver a 2-bromopyridine of the formula IV (Z = Br) with a 2-fluorophenyl Grignard compound of formula II with transition  Metal catalysis to phenylpyridines of the formula I implemented. It the above-mentioned catalysts and solutions are suitable medium. The reaction temperature is generally between 0 and 200 ° C, preferably at 20 to 120 ° C.

The method according to the invention deliver on simple and host substituted phenylpyridines. Contrary to the he maintenance is carried out with regard to the transition metal catalyst based coupling between the halopyridine IV and the o-fluorine aryl-Grignard compound II, or the corresponding boronic acid or zinc halide compound III, a selective reaction only a pyridine halogen atom and there is no further reaction already formed end product I with still in the reaction mixture present aryl metal halide.

The method according to the invention is based on ortho-fluorine Grignard Compounds of formula II. For example, to them Production called the following processes:

• 1. Metallic magnesium is in a suitable solvent submitted. It is added, if necessary dissolved in a solvent most, 2-bromofluoroaromatics added. Suitable as a solvent the usual solvents for Grignard reactions for example tetrahydrofuran, dimethoxyethane, diethyl ether, Methyl tert-butyl ether, dibutyl ether, dipropyl ether, 1,4-dioxane, toluene or N-methylpyrrolidone. Are preferred thereby tetrahydrofuran or dimethoxyethane.
• The 2-bromofluoroaromatic is added between -10 and 60 ° C, preferably between 0 and 50 ° C. The reaction temp temperature is kept below 60 ° C. After the jump starts the reaction even at a lower temperature, for example in a room temperature, complete.
• 2. A solution of the 2-bromofluoroaromatic is in a suitable Submitted solvent. A solution of an Alkymag is given nesium halide, e.g. B. isopropyl magnesium chloride or iso propyl magnesium bromide, in addition. Suitable solvents are under 1. mentioned. Advantageous reaction temperatures are between -30 and 60 ° C, preferably between -10 and 30 ° C.

In other preferred embodiments of the invention The process is the 2-fluorophenyl Grignard compound of the formula II with a boric acid ester B (OR⁴) ₃ and subsequent hydrolysis or a Zn (II) compound to a 2-fluorophenyl compound of the formula III implemented, which then or in situ with a  Pyridine derivative of the formula IV in the presence of a transition metal catalyst is converted to the compound of formula I.

A in formula III represents a group B (OR⁴) ₂ or ZnX, wherein R⁴ may be the same or different and be a C₁-C₆ alkyl group indicates or both R⁴ together form a C₂-C₆ alkylene chain form between the two oxygen atoms.

The reaction temperature when coupling the 2-fluorophenyl ver bindings III with the pyridine derivative IV is generally between 0 and 200 ° C, preferably at 40 to 140 ° C.

The 2-fluorophenyl zinc halogen compounds of formula IIIa from the described Grignard connections by: these with zinc (II) compounds, such as. B. zinc bromide or zinc chloride, in a manner known per se in a solution medium implemented.

This reaction can advantageously be carried out directly as a "one-pot synthesis" connect to the establishment of the Grignard connection. The tem Temperature is usually between -40 and 50 ° C, preferred between -15 ° C and 30 ° C.

As a solvent for the preparation of the 2-fluorophenyl zinc halo Gene compounds of formula IIIa come in the making the Grignard connection.

This reaction mixture can also be used directly for the transition metal catalyzed coupling with the pyridine derivative of formula IV be set so that the entire sequence in one reaction vessel can take place.

In another embodiment of the method according to the invention is the 2-fluorophenyl Grignard compound of formula II Boron compounds of the formula IIIb, prepared by using II a boric acid ester B (OR⁴) ₃ in a conventional manner in a solvent, the temperature between -40 and 50 ° C, preferably between -15 ° C and 30 ° C.

The radicals R⁴ can be the same or different and stand for C₁-C₆ alkyl or an optionally branched C₂-C₆ alkylene chain between the two oxygen atoms.

As a solvent for the preparation of the boron compounds Formula IIIb come in the making of the Grignard verb above mentioned.

For cost reasons, one becomes readily available boric acid esters, such as Trialkyl borates, e.g. B. Use trimethyl borate (R⁴ = methyl). The free boronic acids of formula IIIc

are selected under normal conditions by hydrolysis won rend the aqueous work-up of the reaction mixture. They can be isolated in this way, if necessary pure and use for the next reaction step.

When using the boron compounds for coupling with the pyridine derivative IV, it is often useful, preferably 0.9 to 10 equivalents 1 to 3 equivalents of an organic or inorganic base such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, Calcium carbonate, calcium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, sodium phosphate, pyridine or one Add amine such as triethylamine.

In addition, the new 2-fluorophenyl-zincha already mentioned logen compounds formula IIIa,

where R¹, R² and X have the abovementioned meaning.

In the process according to the invention, preference is given to 2-fluorine phenyl-zinc halogen compounds used in formula IIIa, in which R² is bound in the 5-position.

In particular, compounds of the formula IIIa are also preferred in which R¹ is chlorine.

The phenylpyridines of the formula I can be obtained from the zinc Compounds of formula IIIa, as well as from the boron compounds of the formula IIIc, by a transition metal-catalyzed coupling produce with a pyridine derivative of formula IV. Especially be Zn compounds are preferred because they use a one-pot process enable particularly high yields.  

The method according to the invention provides simple and efficient substituted phenylpyridines. Contrary to Expectation is made with regard to the transition metal catalyzed coupling between the halopyridine IV and the o-fluoroaryl metal halide compound II or III a selective Reaction only on a pyridine halogen atom and none occurs Further reaction of end product I already formed with still in the Reaction mixture present aryl metal halide.

Preferred compounds of formula I are those in which R1 is Chlorine stands.

Alkyl generally represents C₁-C₁₀ alkyl, preferably C₁-C₆ alkyl, especially for C₁-C₄ alkyl. This also applies to alkyl combinations nen, such as alkoxy or haloalkyl radicals. The remains can be white tere bear inert under the reaction conditions.

Aryl generally represents phenyl or substituted phenyl, e.g. B. substituted with 1 to 3 halogen atoms, e.g. B. fluorine, chlorine or Bromine, C₁-C₄-alkyl, such as methyl or C₁-C₄-haloalkyl, such as tri fluoromethyl.

Preferred substituents R 2 in compounds of the formula I are:
Alkyl, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-propyl, 1,1-dimethyl-ethyl and higher homologues,
Alkoxy, such as methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, 2-methyl-propoxy, 1,1-dimethyl-ethoxy and higher homologues,
Dialkylaminocarbonyloxy, such as dimethylaminocarbonyloxy, diethyl aminocarbonyloxy, dipropylaminocarbonyloxy and isomers, dibutylaminocarbonyloxy and isomers, (piperidin-1-yl) carbonyloxy, (morpholin-4-yl) carbonyloxy and
Alkylarylaminocarbonyloxy such as N-methyl-N-phenylaminocarbonyloxy, N-ethyl-N-phenylaminocarbonyloxy and higher homologues.

As possible substituents of the groups R² and / or R³ in the formula I come into question under the described reaction conditions are stable. These are preferably alkoxy radicals, in particular ders the aforementioned C₁-C₄ alkoxy radicals, of which more can be located on one carbon atom.

Substituents R³ are, for example, alkyl, as for R² individually NEN called, and haloalkyl, such as trihaloalkyl, z. B. Dichlorofluoromethyl, chlorodifluoromethyl, trifluoromethyl or trichloromethyl or dihaloalkyl, e.g. B. dichloromethyl, difluoromethyl, chlorine fluoromethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-difluoro  propyl, 2,3-difluoropropyl, 2,3-dichloropropyl or 1- (bromine methyl) -2-bromethyl, or monohalalkyl.

With regard to the intended use of the connections I are processes for the preparation of compounds of formula Ib and Ic particularly preferred

in which
R² for OCH₃ or di-C₁-C₃-alkylaminocarbonyloxy and
R³ represents CH₃ or halomethyl.

The following examples illustrate the Ver drive.

Examples 1) Preparation of 4-chloro-2-fluoro-5-methoxyboronic acid

60.0 g (0.25 mol) of 5-bromo-2-chloro-4-fluoroanisole was added in 250 ml Tetrahydrofuran (THF) dissolved. Approx. 15 ml of this solution were mixed with 6.5 g (0.275 mol) of magnesium shavings are placed in a stirred flask and heated to 28 ° C. After adding 2 drops of ethyl bromide the temperature rose slowly with stirring. At 33 to 35 ° C the rest of the solution of the anisole in THF was removed within 45 mi grooves added dropwise with cooling. Then 40 Mi at 35 ° C. grooves stirred.

26.0 g (0.25 mol) of trimethyl borate were removed within about 5 mi grooves added dropwise at 0 to 2 ° C. After stirring for 15 minutes 250 ml of 4% hydrochloric acid were added within about 30 minutes given. The organic phase was separated and the aqueous Phase extracted with 100 ml of methyl tert-butyl ether (MTBE). The organic phases were concentrated and the residue in 20 ml  Diisopropyl ether digested, suction filtered, the suction filter with 10 ml Washed and dried diisopropyl ether.

37 g (72.5% of theory based on anisole) of pure boronic acid were obtained receive.

2) Preparation of 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine (variant 1)

2.8 g (0.013 mol) of 2,3-dichloro-5-trifluoromethylpyridine, 5 ml of THF and 2.6 g (0.013 mol) of 4-chloro-2-fluoro-5-methoxyboronic acid (from Example 1) were placed in a stirred flask. There were 0.024 g (0.034 mmol) bis (triphenylphosphine) palladium (II) chloride, 3.3 g (0.04 mol) sodium hydrogen carbonate, and 0.23 g (0.013 mol) Water added and heated to boiling with stirring. The Wed was refluxed until the boronic acid was full was constantly implemented (HPLC control). The reaction mixture was worked up with MTBE / water. After narrowing the orga nical phase, 4.4 g of product (purity approx. 90%) remained. This corresponds to a yield of approx. 90% of theory

Any cleaning can be done by entering the hot product tes in methanol / water (approx. 2: 1) and then cooling or by recrystallization from cyclohexane.

3) Preparation of 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine (variant 2)

2 ml of THF and 2 ml of a solution of 3.0 g (12.5 mmol) of 5-bromo-2-chloro-4-fluoroanisole in 5 ml of THF were carefully added to 0.45 g (18.8 mmol) of magnesium under nitrogen added. After the exothermic start of the reaction (31 ° C.), the mixture was cooled to 10 ° C. and the remainder of the solution of the anisole and 13 ml of THF were metered in continuously at this temperature and the mixture was stirred at 0 to 5 ° C. for 35 min. 1.3 g (12.5 mmol) of trimethyl borate were added dropwise at 5 ° C., the mixture was stirred for a further 20 minutes, acidified at 0 ° C. with 10% hydrochloric acid, filtered, and the precipitate was washed with 35 ml of tetrahydrofuran. The aqueous phase was separated off after addition of a little sodium chloride solution and discarded. The organic solution thus obtained was treated with 2.5 g (29.4 mmol) of sodium hydrogen carbonate in 15 ml of water, 180 mg (0.16 mmol) of tetrakistriphenylphosphine palladium (0) and 2.11 g (9.8 mmol) 2 , 3-dichloro-5-trifluoromethyl pyridine were added and the mixture was heated at 100 ° C. in an autoclave for 3 h. After cooling, the organic phase was separated off, 10 ml of sodium chloride solution were added to the aqueous phase, the mixture was extracted with 40 ml of THF, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo.
Yield: 2.6 g.

4) Preparation of 4-chloro-2-fluoro-5-methoxybenzeneboronic acid from a Grignard compound

5.0 g of 5-bromo-2-chloro-4-fluoroanisole in 50 ml of anhydrous THF were initially introduced under protective gas. After the dropwise addition of 11.5 ml of a 2.0 M solution of isopropylmagnesium chloride in THF, the mixture was stirred at 20.degree. C. for 6.5 h, cooled to -20.degree. C., mixed with 6.5 g of trimethylborate and 16 h at 20.degree C stirred. Then 50 ml of 10% hydrochloric acid were added dropwise, extracted with methyl tert-butyl ether (MTBE) and the combined extracts were extracted with 10% sodium hydroxide solution. The alkaline solution was acidified with ice-cooling with half-concentrated hydrochloric acid (pH 1) and extracted with MTBE. The extract was dried and concentrated in vacuo.
Yield: 2.8 g (66%) white crystals (purity <95%).
1 H-NMR (DMSO-d₆): δ = 3.83 (s, 3H); 7.25 (d. 1H); 7.29 (d. 1H); 7.80-8.80 (broad, 2H).

5) Preparation of 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine Ic using an organic zinc intermediate

4 ml of THF and 3 ml of a solution of 6.0 g (25.1 mmol) of 5-bromo-2-chloro-4-fluoroanisole in 10 ml of THF were added to 0.76 g (31.7 mmol) of magnesium under nitrogen . After the exothermic jump to the reaction (40 ° C), the rest of the solution of the anisole and 25 ml of THF were continuously added at a maximum of 55 ° C. 4.1 g (30 mmol) of water-free zinc chloride, dissolved in 30 ml of THF, were then added dropwise at -5 to 0 ° C., and the mixture was mixed with 740 mg (0.64 mmol) of tetrakistriphenylphosphine palladium (0) after warming to room temperature, and 6.5 g (30 mmol) of 2,3-dichloro-5-trifluoromethylpyridine were added and the mixture was heated under reflux for 16 h. After cooling, 150 ml of dilute phosphoric acid were added, the precipitate which had precipitated was filtered off, the filtrate was mixed with 30 ml of concentrated sodium chloride solution and extracted with 200 ml of THF, and the organic phase was dried and concentrated in vacuo. The residue (10 g) was digested with diethyl ether, filtered and the filter cake was dried in vacuo.
Yield: 8.2 g of yellow solid. Purity: 69.2% (GC, NMR).

Other ingredients: 2,3-dichloro-5-trifluoromethylpyridine (9.2%), 2-chloro-4-fluoroanisole (4.3%), 3- (4-chloro-2-fluoro-5- methoxyphenyl) -2-chloro-5-trifluoromethylpyridine (2.1%), 4,4'-di chloro-2,2'-difluoro-5,5'-dimethoxybiphenyl (3.3%), and tri phenylphosphine oxide.

This corresponds to an overall yield of 66.5% across all levels i.e. the

6) Preparation of 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine-Ic using an organic zinc intermediate

0.43 g of isopropyl bromide in 1 ml of THF was added to 0.84 g (35 mmol) of magnesium under nitrogen. Then 3 ml of a solution of 6.0 g (25.1 mmol) of 5-bromo-2-chloro-4-fluoroanisole in 10.0 ml of THF and 4 ml of THF were carefully added. After the reaction had started exothermically (40 ° C.), the rest of the anisole solution, such as 30 ml of THF, was metered in continuously, the temperature rising to 53 ° C. The mixture was then allowed to cool to room temperature within 30 minutes. At -5 to 0 ° C 3.4 g (25.1 mmol) of water-free zinc chloride dissolved in 30 ml of THF were added dropwise and then allowed to warm up to room temperature. 116 mg (0.1 mmol) of tetrakistriphenylphosphine palladium (0) and 5.4 g (25.1 mmol) of 2,3-dichloro-5-lrifluoromethylpyridine were then added and the mixture was heated under reflux for 16 h. After cooling, 60 ml of dilute phosphoric acid were added, the mixture was stirred for 10 min, extracted with ethyl acetate, the organic phase was washed with 50 ml of sodium chloride solution, dried and concentrated in vacuo.
Yield: 7.5 g of yellow solid. Purity: <80% (GC, NMR).

7) Preparation of 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine by Grignard coupling

A Grignard solution of 0.6 g (24.2 mmol) of magnesium and 5.3 g (22 mmol) of 1-bromo-4-chloro-2-fluoro-5-methoxybenzene in 16 ml of THF was added within 10 min with stirring 60 ° C to a mixture of 4.4 g (17 mmol) of 2-bromo-3-chloro-5-trifluoromethylpyridine and 2 g (1.7 mmol) of tetrakistriphenylphosphine palladium (0) in 20 ml of THF. The reaction mixture was stirred under reflux for 2.5 h and, after cooling, was treated with an ice water / ammonium chloride solution, then extracted with methylene chloride. After washing with 1N hydrochloric acid, water and drying over magnesium sulfate, the organic phase was chromatographed on silica gel and concentrated.
Yield: 2.9 g (50.7% of theory), mp: 88 to 93 ° C.

Claims (14)

1. Process for the preparation of (2'-fluorophenyl) -3-halopyri dynes of the formula I, where the substituents have the following meaning:
R1 fluorine, chlorine;
R² is hydrogen, alkyl, alkoxy, aryl, aryloxy, aminocarbonyl oxy, N-substituted by alkyl and / or aryl radicals, where two alkyl radicals can be linked directly or via an oxygen atom to form a 5- or 6-membered ring and the radicals below the reaction conditions can carry inert residues;
R³ alkyl, haloalkyl and
Y chlorine, bromine or iodine,
characterized in that a 2-fluorophenyl Grignard compound of the formula II, in which
X represents bromine or chlorine,
with a pyridine derivative of the formula IV, in which Y and Z independently of one another represent chlorine, bromine or iodine,
in the presence of a transition metal catalyst. 2. The method according to claim 1, characterized in that one uses a pyridine derivative of formula IV in which Z is bromine stands. 3. The method according to claim 1, characterized in that the 2-fluorophenyl Grignard compound of formula II according to claim 1 first with a boric acid ester B (OR⁴) ₃ and then hydrolysis or a Zn (II) compound to one 2-fluorophenyl compound of the formula III, in the
A represents a group B (OR⁴) ₂ or ZnX,
in which the radicals R⁴ can be identical or different and stand for C₁-C₆-alkyl or an optionally branched C₂-C₆-alkylene chain between the two oxygen atoms,
reacted and III subsequently or in situ with a pyridine derivative of the formula IV. 4. The method according to claim 3, characterized in that a 2-fluorophenyl Grignard compound of the formula II according to claim 1 with a Zn (II) compound to 2-fluorophenyl-zinc halogen compounds of the formula IIIa implements. 5. The method according to claim 4, characterized in that one the 2-fluorophenyl zinc halogen compound of the formula IIIa without Intermediate insulation implemented with the pyridine derivative IV. 6. The method according to claims 1 to 5, characterized in net that as a catalyst in the implementation of the 2-fluorine phenyl compounds of formula II or III with a pyridine derivative of formula IV a palladium (O) - or palla dium (II) compound used. 7. The method according to claims 1 to 6, characterized in net that the rest R² is bound in the 5-position. 8. The method according to claims 1 to 7, characterized in net that R¹ is chlorine. 9. The method according to claims 1 to 8, characterized in net that R¹ for chlorine, R² for methoxy or dialkylaminocarbo nyloxy and R³ is methyl or halomethyl. 10. The method according to claims 1 to 9, characterized in net that R¹ for chlorine, R² for methoxy and R³ for trifluor methyl stands. 11. Process for the preparation of 4-chloro-2-fluorophenyl zinc halogen compounds of the formula IIIa according to claim 4, characterized in that a 2-fluorophenyl Grignard Reacts compound of formula II with a Zn (II) compound. 12. 2-fluorophenyl zinc halogen compounds of the formula IIIa according to Claim 4. 13. 2-fluorophenyl zinc halogen compounds of the formula IIIa according to Claim 4, characterized in that the rest R² in 5-position is bound. 14. 2-fluorophenyl zinc halogen compounds of the formula IIIa according to Claim 4 or 9, characterized in that R¹ is chlorine stands.