MXPA99002235A - Process for the production of substituted phenylpyridines - Google Patents

Abstract

Process for the production of substituted phenylpyridines having formula (I), characterized by the fact that substituted pyridine having formula (II) is made to react with an aryl compound having formula (III).

Description

PREPARATION OF SUBSTITUTE PHENILPIRIDINES Description The present invention relates to a novel process for preparing substituted phenylpyridines of the formula I where R is hydrogen, fluorine, chlorine or haloalkyl, R is fluorine, chlorine or haloalkyl, R is hydrogen, halogen or an organic radical which is inert under the reaction conditions, R is alkyl, haloalkyl, halogen, alkylsulfonyl, haloalkylsulfonyl or haloalkoxy, and R is hydrogen, halogen, haloalkyl, haloalkoxy, alkylsulfonyl or haloalkylsulfonyl.

The compounds I are intermediates for herbicides, but they can also be used as herbicides themselves (WO-A 95/02580). Different synthetic routes are known for preparing the phenyl substituted heterocycles. For example 1 to 2-bromopyridine can be converted using activated zinc into the corresponding 2-pyridylzinc bromide which can then be coupled with excess benzene iodine in a palladium-catalyzed reaction to obtain 2-phenylpyridine in a moderate yield [THL 33 ( 1992) 5373; J. Org. Chem. 56 (1991) 1445]. This reaction requires bromine heterocycles that are often difficult to obtain; for example, according to JP-A 81/115776, 2-bromo-3-chloro-5-trifluoromethylpyridine is obtained in a yield of only 10%. In addition, expensive iodine building blocks are required as an aromatic component. Finally, due to the high cost of the palladium catalyst, very laborious recovery procedures are required. Another method of coupling a phenyl boronic acid with an aromatic or heterocyclic bromine compound (Synthesis 1995, 1421, WO 95/2580) The disadvantages of this method are the low yield preparation of the aromatic boric acids (Houben Weyl, Methoden der Org. Chemie, IV edition, vol.13 / 3a, p.636), which have to be prepared from organometallic precursors, and the use of costly palladium catalysts In addition to halogens, sulfoxides and sulphones are known as Other leaving groups of heterocycles According to JP-A 61 / 280,474, the 2-sulfonylpyridines can be coupled with aryl magnesium compounds, but an additional halogen substitution in the Grignard portion is not mentioned According to Heterocycles 24 (1986) , p.3337, an additional halogen substitution in pyridyl sulfone reduces the yield of the coupling product, while a substitution of a Grignard reagent donor increases the yield The pyridyl sulfoxides as leaving groups in the coupling not catalyzed with Grignard reagents usually only produce bipyridyls [Bull. Chem. Soc. Jpn. 62 (1989) 2338; THL 25 (1984) 2549]. Only in the case of 2-quinoline sulfoxide can the coupling product be completely isolated, in a yield of 20%. An object of the present invention is to provide a generally applicable process for the preparation of substituted phenylpyridines of the formula I in high yields and purity from easily obtainable starting materials. We have found that this objective is achieved by a process for preparing substituted phenylpyridines of the formula I, which substituted pyridines of the formula II comprise the reaction with an aryl compound of the formula III, which is suitable, in the presence of a metal catalyst of the formula transition.

II III I Substituents of formulas II and III are as defined for formula I; further: n is 1 or 2, and Y is alkyl, alkenyl or alkynyl, each of which may be substituted by halogen or methoxy; or is cycloalkyl or phenylalkyl; or substituted or unsubstituted phenyl or naphthyl, M is magnesium or zinc, and Z is halogen.

The starting materials for the process according to the invention are pyridine derivatives of the formula II which can be obtained, for example, from 2-halopyridines by reaction with suitable thiolates and the subsequent oxidation. With or without catalysis with transition metals, these react with Grignard reagents or zinc compounds of the formula III to obtain phenylpyridines of the formula I. If R1 in formula III is fluorine, compounds III can, for example, be obtained by forming a Grignard reagent from the corresponding substituted o-fluorobromobenzene with magnesium at -10 to 60 ° C. The molar proportions in which the starting materials II and III are reacted together can, for example, be in the range from 0.9 to 1.5, preferably from 1.0 to 1.2, for the ratio of the phenyl derivative III to the pyridine compound II. The concentration of the initial materials in the solvent is not crucial; it is for example from 0.1 to 5 mol / 1, preferably from 0.5 to 2 mol / 1. Suitable solvents for these reactions are hydrocarbons, such as pentane, hexane, heptane, cyclohexane, toluene or chlorobenzene, and the solvents preferably have the character of electron donors, in particular solvents having one or more ether oxygens, such as diethyl ether. , diisopropyl ether, dibutyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, ethylene glycol dimethyl ether, furan, 5,6-dihydro-4H-pyran, tetrahydrofuran, tetrahydropyran, 1,3-dioxane, 1,4-dioxane, 4-methyl-l, 3-dioxane, anisole, formaldehyde dimethyl acetal, formaldehyde and ethyl acetal, acetaldehyde dimethyl acetal, acetaldehyde diethyl acetal and also triethylamine, hexamethylphosphoric triamide, 1,2-bis (dimethylamino) ethane, N-ethylmorpholine, oxide of tribenzylphosphine, dimethyl sulfide, dimethyl sulfoxide, dimethylsulfone, tetramethylene sulfone, N-methylpyrrolidone or dimethyl acetamide. It is often advantageous to use mixtures, for example, of ethers with amines or amides. It may also be advantageous to mix the polar component, for example from 1 to 3 mol% of tetrahydrofuran, triethylamine or N-ethylmorpholine, as an additive in the less polar component, for example benzene, toluene, xylene or naphthalene. The conversion can be accelerated by the addition of a catalyst, for example a transition metal. Suitable transition metal catalysts are iron compounds, cobalt compounds, nickel compounds, rhodium compounds, palladium compounds or platinum compounds, in particular nickel (0) compounds, nickel (II) compounds, palladium (0) and palladium (II) compounds. In this way, salts such as nickel chloride, palladium chloride, palladium acetate or even complexes can be used. The only precondition is that the palladium ligands can be displaced by the substrate under the conditions of the reaction. Phosphine ligands, for example aryl alkyl phosphines, such as, among others, methyl diphenyl phosphine or isopropyl diphenyl phosphine, triaryl phosphines, such as, among others, triphenyl phosphine, tritolylphosphine or trixylphosphine, and trietarylphosphines, such as trifurylphosphine, or dimeric phosphines, are particularly suitable. Olefinic ligands, such as, among others, dibenzylidene acetone or salts thereof, cyclo-octa-1,5-diene or amines such as trialkylamines, for example triethylamine, tetramethylethylenediamine or N-methylmorpholine) or pyridine are in the same way adequate. If a complex is used, it can be used directly in the reaction. This method can be used for example with bis (triphenyl-phosphine) -lich (II) bromide, bis (triphenyl-phosphine) nickel (II) chloride, [1,3-bis (diphenylphosphine) propane] nickel chloride ( II), [1,2-bis (diphenyl phosphine) ethane] nickel (II) chloride, tetrakis triphenyl phosphine palladium (0), bistriphenylphosphine palladium dichloride, bistriphenylphosphine palladium diacetate, dibenzylidene acetonpalladium (0) complex, tetrakismethyldiphenylphosphine palladium ( 0) or bis (1,2-diphenylphosphinoethane) palladium dichloride. Otherwise, a suitable ligand can be added to a nickel or palladium salt, thereby forming the catalytically active complex in situ. This method is advantageous, for example for the aforementioned phosphine salts and ligands, such as trifurylphosphine or tritolylphosphine. In addition, nickel complexes or palladium complexes, such as tris (dibenzylidene acetone) dipalladium, bis (dibenzylideneaketone) palladium or 1,5-cyclooctadienpalladium dichloride can also be activated by adding ligands such as trifuryl phosphine or tritolylphosphine.

As is customary, from 0.001 to 12 mol%, in particular from 0.001 to 5 mol% of catalyst is used, based on the initial materials. It is possible to use larger quantities, but this is usually not necessary. The reaction can be carried out under atmospheric or superatmospheric pressure, continuously or intermittently. The treatment after the reaction is carried out in a manner known per se; for example, the reaction mixture is extracted with water to remove the salts, and the organic phase is dried and purified, for example by chromatography or distillation. However, it is also possible to concentrate the organic phase directly and digest the residue in a solvent. The process according to the invention produces the coupling product in high yields, even if both substrates carry more than one halogen substituent - something that the literature has already considered disadvantageous. When substituted pyridyl sulfoxides of the formula II are used (n = 1), the main products of the process according to the invention are the phenylpyridines I and not, as expected from the literature [Bull. Chem. Soc. Jpm. 62 (1989) 2338], bipyridyl coupling products. Essential for the process according to the invention is the presence of a sulfinyl or sulphonyl radical in the pyridine component. This leaving group guarantees a particularly gentle conversion with exceptional high selectivity if R a R are also reactive substituents. A preferred embodiment of the process according to the invention is the reaction of a pyridine derivative of the formula II wherein Y is alkyl or aryl with a Grignard reagent of the formula Illa.

II illa I For convenience, the pyridine compound II is, if appropriate together with a catalyst, initially charged in a solvent and then the Grignard Illa component is added. However, the Grignard reagent can also be initially loaded in one of the aforementioned solvents-advantageously the solvent used in the Grignard synthesis-and the pyridine derivative II can then be added, if appropriate, together with a catalyst. In a specific embodiment of the process according to the invention, the pyridine derivative II is added towards the end of the addition, for example, under the control of the HPLC, until it is the only one to be consumed. In this way, the reaction is carried out under the conditions of a titration and the isolation of the final products from the initial materials is facilitated. For convenience, the addition is carried out at a temperature from -20 to 50 ° C, in particular from 10 to 30 ° C. The reaction time depends, among others, on the choice of solvent and substituents, and is usually from 0.1 to 16 hours, in particular from 0.5 to 6 hours from 10 ° to 140 ° C, in particular from 20 to 80 ° C. A particularly preferred embodiment of the process according to the invention is the coupling of, for example, the 2-alkyl- or 2-arylsulfonyl-3-chloro-5-trifluoromethylpyridine of the formula II 'or the corresponding 2-arylsulfoxides of the Formula II 'with 2-chloro-4-fluoroanisole-5-magnesium Illa' bromide to obtain 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine.

II 'Illa' For convenience, the reaction is carried out in the presence of a solvent at from -20 to 140 ° C, preferably from 20 to 80 ° C, and in an advantageous embodiment of the process according to the invention, using the pyridine derivatives of the formulas lía, Ilb or lie. lia: Y = aryl, n = 2 Ilb: Y = alkyl, n = 1 He: Y = aryl, n = 1 Very high yields of the final products I are obtained even without the use of catalysts. In another embodiment of the process according to the invention, the alkyl- or arylsulfonyl- or sulfinylpyridines of the formula II are reacted with an aryl zinc halogen compound of the formula IIIb.

II IIIb The reactions are carried out as already described, and in an advantageous embodiment of the process according to the invention, using the pyridine derivatives of the formulas lia, Ilb or lie, very high yields of the final products I are obtained even without the use of catalysts. The compounds I I Ib are prepared from the aryl-Grignard Illa compounds already described, which are reacted in a manner known per se with zinc bromide or zinc chloride. This reaction can be advantageously carried out as a "one-step synthesis" directly after the formation of the Grignard compound, the temperature being from -40 to 50 ° C, in particular from 15 to 30 ° C. This mixture can then be used directly for the coupling, which may or may not be catalyzed by transition metal, so that the entire sequence can be carried out in a reaction vessel. For reasons of cost, the non-substituted derivatives easily obtainable will be preferred. The Y substituents are not crucial for the process according to the invention. In the definitions of the compounds stated at the beginning, general terms are used which represent the following radicals: Aliphatic radicals are, for example, alkyl, cycloalkyl, alkenyl or alkynyl. Alkyl is generally C 1 -C 6 alkyl, preferably C 1 -C 6 alkyl and in particular C 1 -C 4 alkyl. This also applies to combinations of alkyls, such as alkoxy or haloalkyl. The radicals can also carry inert substituents under the reaction conditions. Cycloalkyl is C3-C6 cycloalkyl. Alkenyl is C2-C6 alkenyl and alkynyl is C2-C6 alkynyl. This also applies to combinations such as alkenyloxy or alkynyloxy. The radicals can carry other inert substituents under the reaction conditions. Aryl is generally phenyl or naphthyl or substituted phenyl or substituted naphthyl, for example substituted with 1 to 3 halogens, Ci to C4 alkyl such as methyl or halomethyl, such as trifluoromethyl and / or Ci to C alkoxy. Phenylalkyl is benzyl, 1- or 2-phenylethyl. With respect to the proposed use of the phenylpyridines of the formula I, these compounds are preferred where R 3 have the following meanings: Hydrogen, halogen, an aliphatic or cycloaliphatic radical or aryl, where the mentioned organic radicals can be linked through sources of CH 2 , C (O), C (0) 0, O, S, C (0) NR6 or NR6 and where R6 is hydrogen, alkyl, alkenyl, alkynyl or aryl and two alkyl radicals can be linked by a bond or an oxygen to form a 5 or 6 member ring. For R3, particular preference is given to: hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio or alkynylthio; cycloalkyl; CH = CR5R7; alkylsulfonyloxy; haloalkylsulfonyloxy; Arylsulfonyloxy; dialkylaminosulfonyloxy; alkoxysulfonyl; dialkylaminosulfonyl; aryloxysulfonyl or arylalkylaminosulfonyl; alkoxycarbonyl; dialkylaminocarbonyl; CR (U-alkyl) (V-alkyl); U-P- (V) -WR9XR10; aryl, aryloxy or arylthio; alkylarylamino-, alkenylarylamino- or alkynylarylaminocarbonyloxy; dialkylamino-, alkylalkenylamino-, alkylalquinylamino-, dialkenylamino- or dialkylamino-aminocarbonyloxy, where, in the case of dialkylaminocarbonyloxy, the two radicals can be linked by a bond or an oxygen to form a 5- or 6-membered alkyl-, alkenyl-, alkynylcarbonyloxy ring or alkoxy-; alkenyloxy- or alkynyloxycarbonylalkoxy, NR10Rn or NR1: LOR10, where: Rd is halogen or alkyl, R7 is formyl, alkoxycarbonyl or P (V) WRXR10, R8 is hydrogen or alkyl, R9 is alkyl, R10 is alkyl, alkenyl, alkynyl or aryl , R 11 is alkyl, alkenyl, alkynyl, formyl, alkanoyl, alkylsulfonyl or arylsulfonyl, U, V are independently of each other oxygen and / or sulfur and W, X are independent of each other oxygen, sulfur and / or alkylamino. The aforementioned meanings for the substituents R1 to R11 in the formula I are collective terms for a detailed list of the individual group members. All hydrocarbon chains, that is, all the alkyl, alkenyl, alkynyl, haloalkyl and haloalkoxy portions, can be straight or branched chains. The substituents for the phenylpyridines of the formula I are in particular the following: Halogen fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine; - alkyl, for example, C? -C6 alkyl, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1, 1-dimethylethyl; - alkenyl, for example C2-C6 alkenyl, such as ethenyl, prop-1-en-l-yl, prop-2-en-l-yl, 1-methylethyl, n-buten-1-yl, n-buten- 2-yl, n-buten-3-yl, 1-methylprop-1-en-1-yl, 2-methylprop-1-en-1-yl, 1-methylprop-2-en-1-yl and 2- methylprop-2-en-l-yl, n-penten-1-yl, n-penten-2-yl, n-penten-3-yl, n-penten-4-yl, 1-methylbut-l-en- l -yl, 2-methylbutyl-en-l-yl, 3-methylbut-1-en-l-yl, l-methylbut-2-en-l-yl, 2-methylbut-2-en-l-yl, 3-methylbut-2-en-l-yl, i-methylbut-3-en-l-yl, 2-methylbut-3-en-l-yl, 3-methylbut-3-en-l-yl, 1, 1- dimethylprop-2-en-l-yl, 1,2-dimethylprop-l-en-l-yl, 1,2-dimethylprop-2-en-l-yl, l-ethylprop-l-en-2 ilo, 1-ethyl-prop-2-en-l-yl, n-hex-1-en-l-yl, n-hex-2-en-l-yl, n-hex-3-en-l- ilo, hex-4-en-l-yl, hex-5-en-l-yl, 1-methyl-pent-1-en-l-yl, 2-methylpent-l-en-l-yl, 3- methylpent-l-en-l-yl, 4-methylpent-l-en-l-yl, l-methylpent-2-en-l-yl, 2-methylpent-2-en-l-yl, 3-methylpentyl- 2-en-l-yl, 4-methylpent-2-en-l-yl, l-methylpent-3-en-l-yl, 2-methylpent-3-en-l-yl, 3-me tilpent-3-en-l-yl, 4-methylpent-3-en-l-yl, l-methylpent-4-en-l-yl, 2-methylpent-4-en-l-yl, 3-methylpent- 4-en-l-yl, 4-methylpent-4-en-l-yl, 1, l-dimethylbut-2-en-l-yl, 1,1-dimethylbut-3-en-l-yl, 1, 2-dimethylbut-l-en-l-yl, 1,2-dimethylbut-2-en-l-yl, 1, 2-dimethylbut-3-en-l-yl, 1,3-dimethylbut-3-enyl l-yl, 1,3-dimethylbut-2-en-l-yl, 1,3-dimethylbut-3-en-l-yl, 2,2-dimethylbut-3-en-l-yl, 2, 3- dimethylbut-1-en-l-yl, 2,3-dimethylbut-2-en-l-yl, 2,3-dimethylbut-3-en-l-yl, 3, 3-dimethylbut-l-en-l- ilo, 3, 3-dimethylbut-2-en-l-yl, 1-ethylbut-l-en-l-yl, 1-ethylbut-2-en-l-yl, l-ethylbut-3-en-l- ilo, 2-ethylbut-l-en-l-yl, 2-ethylbut-2-en-l-yl, 2-ethylbut-3-en-l-yl, 1, 1, 2-trimethylprop-2-enyl l -yl, l-ethyl-l-methylprop-2-en-l-yl, l-ethyl-2-methylprop-l-en-l-yl and l-ethyl-2-methylprop-2-en-1- ilo, preferably ethenyl and prop-2-en-1-yl; - alkynyl, for example C2-C6 alkynyl, such as ethynyl, prop-1-yn-l-yl, prop-2-yn-3-yl, n-but-l-yn-yl, n-but- l-in-4-yl, n-but-2-yn-l-yl, n-pent-l-yn-1-yl, n-pent-l-in-3-yl, n-pent-l- in-4-yl, n-pent-1-in-5-yl, n-pent-2-yn-l-yl, n-pent-2-yn-4-yl, n-pent-2-in 5-yl, 3-methylbut-l-in-l-yl, 3-methylbut-l-in-3-yl, 3-methylbut-l-in-4-yl, n-hex-1-in-l- ilo, n-hex-l-in-3-yl, n-hex-l-in-4-yl, n-hex-l-in-5-yl, n-hex-l-in-6-yl, n-hex-2-in-l-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n- hex-3-in-l-yl, n-hex-3-yn-2-yl, 3-methylpent-l-in-l-yl, 3-methylpent-l-yn-3-yl, 3- methylpent- l-in-4-yl, 3-methylpent-l-in-5-yl, 4-methylpent-1-yn-l-yl, 4-methylpent-2-yn-4-yl and 4-methylpent-2- in-5-yl, preferably prop-2-yn-l-yl and l-methylprop-2-yn-l-yl; Haloalkyl, for example haloalkyl of C? -Cd, as alkyl as mentioned above which is partially or completely substituted by fluorine, chlorine and / or bromine, ie, for example chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, trifluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2, 2- dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoro propyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl , 2-bromopropyl, 3-bromopropyl, 3, 3, 3-trifluoropropyl, 3, 3, 3-trichloropropyl, 2, 2/3, 3, 3-pentafluoropropyl, heptafluoropropyl, 1- (fluoromethyl) -2-fluoroethyl, 1- (chloromethyl) -2-chloroethyl, 1- (bromomethyl) -2-bromoethyl, 4-fluorobutyl, 4- chlorobutyl or 4-bromobutyl; Alkoxy, for example Ci-Cβ alkoxy, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, n-hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbut-oxy, 1, 2- trimethylpropoxy, 1, 2, 2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy, Haloalkoxy, for example Ci-Cß haloalkoxy, as alkoxy as mentioned above, which are partially or completely substituted by fluorine, chlorine, bromine and / or iodine, ie, for example difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, 2- fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2, 2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2, 2- dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy; pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 2, 2-difluoropropoxy, 2,3-difluoropropoxy, 2,3-dichloropropoxy, 3,3,3- trifluoropropoxy, 3, 3, 3-trichloropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy 1- (fluoromethyl) -2-fluoroethoxy, 1- (chloromethyl) -2-chloroethoxy or 1- (bromomethyl) -2 -bromoethoxy, 2,2,3,3,4,4,4-heptafluorobutoxy, nonafluorobutoxy, 2-chlorofluorobutoxy, 3-chlorobutoxy or 4-chlorobutoxy, alkylthio, for example Cι-C 6 alkylthio, such as methylthio, ethylthio, n-propylthio, 1-methylethylthio, n-butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio, -alkylsulfinyl, for example C-alkylsulfinyl. -C6 such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, 1-methyl-ethylsulfinyl, n-butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylsulfinyl or 1,1-dimethylethylsulfinyl, - alkylsulfonyl, for example C 1 -C 6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, 1-methylethylsulphonyl, n-butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl or 1,1-dimethylethylsulfonyl; - alkenyloxy, for example C2-C6 alkenyloxy, such as et-1-en-l-yloxy, prop-1-en-l-yloxy, prop-2-en-l-yloxy, 1-methylenyloxy, n-buten- 1-yloxy, n-buten-2-yloxy, n-buten-3-yloxy, 1-methyl-rop-l-en-l-yloxy, 2-methylprop-l-en-1-yloxy, l-methylprop 2-en-l-yloxy or 2-methylprop-2-en-1-yloxy; - alkynyloxy, for example C2-C6 alkynyloxy, such as prop-1-yn-l-yloxy, prop-2-yn-l-yloxy, n-but-l-yn-l-yloxy, n-but-l- in-3-yloxy, n-but-l-in-4-yloxy or n-but-2-yn-4-yloxy; cycloalkyl for example, C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; - alkylamino, for example Ci-Cd alkylamino, such as methylamino, ethylamino, n-propylamino, 1-methylethylamino, n-butylamino, 1-methylpropylamino, 2-methylpropylamino and 1, 1-dimethylethylamino, preferably methylamino and ethylamino; Dialkylamino, for example di (C?-C5 alkyl) amino, such as N, N-dimethylamino, N, N-diethylamino, N, N-dipropylamino, N, N-di (1-methylethyl) amino, N, N -dibutylamino, N, N-di (l-methylpropyl) amino, N, N-di (2-methylpropyl) amino, N, N- di (1,1-dimethylethyl) amino, N-ethyl-N-methylamino, N -methyl- N-propyl-amino, N-methyl-N- (1-methylethyl) amino, N-butyl-N-methylamino, N-methyl-N- (1-methylpropyl) amino, N-methyl-N- ( 2-methylpropyl) amino, N- (1,1-dimethylethyl-N-methylamino, N-ethyl-N-propylamino, N-ethyl-N- (1-methylethyl) amino, N-butyl-N-ethylamino, N-ethyl-N- (1-methylpropyl) amino, N-ethyl-N- (2 -methylpropyl) amino, N-ethyl-N- (1, 1- dimethylethyl) amino, N- (1-methylethyl) -N-propylamino, N-butyl-N-propylamino, N- (1-methylpropyl) -N- propylamino, N- (2-methylpropyl) -N-propylamino N- (1,1-dimethylethyl) -N-propylamino, N-butyl-N- (1-methylethyl) amino, N- (1-methylethyl) -N- (1-methylpropyl) mino, N- (1-methylethyl) -N- (2-methylpropyl) amino, N- (1,1-dimethylethyl) -N- (1-methylethyl) amino, N-butyl-N- ( 1-methylpropyl) amino, N-butyl-N- (2-methylpropyl) amino, N-butyl-N- (1, 1- di-ethylethyl) amino, N- (1-methylpropyl) -N- (2-methylpropyl) amino, N- (1, 1-dimethylethyl) -N- (1-methylpropyl) amino and N- (1,1-dimethylethyl) -N- (2-methylpropyl) amino, preferably dimethylamino and diethylamino; cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, 1,2-, 1,3- or 1,4-oxazino.

The following examples illustrate the invention. 1) Preparation of 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine One-fifth of the solution of 5.3 g (22 mmol) of 1-bromo-4-chloro-2-fluoro-5-methoxybenzene in 11 ml of tetrahydrofuran (THF) was added to 0.6 g (24.2 mmol) of magnesium . After the start of the reaction, the temperature is maintained at 29 to 31 ° C. The rest of the solution was added dropwise within one hour and stirring was continued at 30 ° C for another 40 minutes. The excess magnesium was separated from the solution and washed with THF. At 0 ° C, this solution was added over 10 minutes to a mixture of 5.8 g (0.02 mol) of 3-chloro-2-n-propylsulfonyl-5-trifluoromethylpyridine and 0.65 g (1 mmol) of bis ( triphenylphosphine) -nickel (II) in 25 ml of THF. The mixture was then kept under stirring at 25 ° C for another 14 hours. 50 g of ice and 150 ml of a saturated solution of ammonium chloride were added to the reaction mixture, the solution was extracted and the organic phase was washed with saturated ammonium chloride solution. After being dried and concentrated, the organic phase was chromatographed on silica gel using methylene chloride to give 8.2 g of the colorless crystalline material containing 3.73 g (54.9%) of the title compound according to GC and NMR. -NMR (CDC13), d = 8.06 (s, ÍH), 8.6 (s, ÍH, pyridine), 6.97 (d, ÍH), 7.25 (d, 1H, phenyl) 2) Preparation of 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine from lia A solution of 5.3 g (22 mmol) of 4-chloro-2-fluoro-5-methoxyphenylmagnesium bromide in 11 ml of THF, freshly prepared by the method of example 1, was added with stirring at 0 ° C for 5 minutes to a mixture of 6.4 g (0.02 mol) of 3-chloro-2-phenyl-sulfonyl-5-trifluoromethyl pyridine and 0.065 g (0.1 mmol) of bis (triphenylphosphine) nickel (II) chloride in 25 ml of THF. Then the stirring was continued at 25 ° C for one hour, another 0.065 g (0.1 mmol) of catalyst was added and the mixture was stirred at 25 ° C for another 14 hours. After treatment by the method of Example 1, 7.9 g of a crystalline material containing 4.4 g (64.7%) of the title compound was obtained according to GC and NMR analysis. 3) Preparation of 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine from Ilb 2. 64 g (0.01 mol) of a Grignard solution of 4-chloro-2-fluoro-5-methoxyphenylmagnesium bromide in 30 ml of THF, freshly prepared by the method of example 1, were added at -15 ° C for 15 minutes to a mixture of 2.55 g (0.01 mol) of 3-chloro-2-n-propyl-sulfinyl-5-trifluoromethylpyridine in 10 ml of THF, causing the mixture to warm to -5 ° C. After heating the mixture to 25 ° C, stirring was continued for 2.5 h while the reaction was monitored using HPLC. The reaction mixture was then treated with 50 g of ice and 100 ml of saturated ammonium chloride solution and extracted with ether. The extract was washed with saturated ammonium chloride solution, dried and filtered through neutral aluminum oxide and completely eluted with methylene chloride. After concentration, 2.2 g of a viscous oil containing 1.9 g (56% of theory) of the title compound were obtained by NMR and GC analysis. 4) Preparation of 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine from At 20 ° C, 5 ml of a solution of 13.8 g (57.5 mmol) of 1-bromo-4-chloro-2-fluoro-5-methoxybenzene in 25 ml of THF were added to 1.46 g (60.4 mmol) of magnesium under nitrogen, after the start of the reaction, the rest of the aforementioned solution was added at 28 to 30 ° C for 20 minutes. After rinsing with THF, the mixture was stirred at 30 to 25 ° C for 2 hours, initially with cooling. The Grignard solution obtained in this way was added with nitrogen at 20 to 25 ° C for 15 minutes to a mixture of 15.1 g (47 mmol) of 3-chloro-2-phenylsulfonyl-5-trifluoromethylpyridine in 45 ml of THF . The progress of the reaction was monitored using HPLC, and after stirring for 2.5 hours at 23 to 24 ° C, the reaction mixture was concentrated under reduced pressure. The residue was taken up in methylene chloride and extracted with IN hydrochloric acid, IN aqueous sodium hydroxide solution and water. The organic phase was concentrated under reduced pressure and distilled at 130-135 ° C / 0.5 mbar. 14.9 g of product of melting point 100-102 ° C containing 13.7 g of pure title compound were obtained by GC analysis. Yield: 84.1% based on pyridine, 70.1% based on anisole ) Preparation of 2- (4-chloro-2-fluoro-5-methoxyphenyl) -3-chloro-5-trifluoromethylpyridine from At 20 to 25 ° C, a solution of 13.9 g (43.9 mmol) of 3-chloro-2-phenylsulfinyl-5-trifluoromethylpyridine in 25 ml of THF was added over 15 minutes to a Grignard solution of 1.3 g (52.9 mmol) of magnesium and 12.1 g (50.4 mmol) of l-bromo-4-chloro-2-fluoro-5-methoxybenzene prepared by the method of Example 1. After the mixture was stirred for 2 hours at 24 ° C, the solution The reaction mixture was drained on ice water, acidified with 4N hydrochloric acid and extracted with methylene chloride. The organic phase was washed with an aqueous IN solution of sodium hydroxide and water, dried and filtered through silica gel. 16.3 g of a mixture of 87 to 90 ° C melting point containing 12.1 g of the title compound was obtained by GC analysis. Yield: 84.1% based on pyridine, 70.1% based on anisole.

Claims (9)

1. A process for preparing substituted phenylpyridines of the formula I wherein R is hydrogen, fluorine, chlorine or haloalkyl, R is fluorine, chlorine or haloalkyl, R is hydrogen, halogen or an organic radical that is inert under the conditions of the reaction, 4 R is alkyl, haloalkyl, halogen, alkylsulfonyl, haloalkylsulfonyl or haloalkoxy, and R is hydrogen, halogen, haloalkyl, haloalkoxy, alkylsulfonyl or haloalkylsulfonyl, which consists of the reaction of the substituted pyridines of the formula II wherein R4 and R5 are each as defined above, n is 1 or 2, and Y is alkyl, alkenyl or alkynyl, each of which may be substituted by halogen or methoxy; or cycloalkyl or phenylalkyl; or substituted or unsubstituted phenyl or naphthyl, with an aryl compound of formula III wherein R1, R2 and R3 are each as defined above, and M is magnesium or zinc, and Z is halogen.

The process as recited in claim 1, wherein the reaction is carried out in the presence of a transition metal catalyst.

The process as recited in claim 1 or 2, wherein Y in formula II is alkyl that can be substituted by halogen or methoxy; or is substituted or unsubstituted phenyl.

The process as recited in claim 1 or 2, wherein the aryl compound of the formula III is a Grignard reagent of the formula Illa, wherein R 1 is hydrogen, fluorine, chlorine or haloalkyl, R 2 is fluorine, chlorine or haloalkyl , and R3 is hydrogen, halogen or an organic radical that is inert under the reaction conditions.

The process, as mentioned in claim 1 or 2, wherein the aryl compound of the formula III is a zinc compound of the formula Illb wherein R1 is hydrogen, fluorine, chlorine or haloalkyl, R2 is fluorine, chlorine or haloalkyl, and R3 is hydrogen, halogen or an organic radical that is inert under the reaction conditions.

The process as recited in claim 1 or 2, wherein a Grignard reagent of the formula Illa as set forth in claim 4, is reacted with a pyridine derivative of the formula lia, Ilb or lie: Y = aryl, n = 2 Iib: Y = alkyl, n = 1 He: Y = aryl, n = 1

7. The process as recited in claim 1 or 2, wherein a zinc compound of the formula Illb, as set forth in claim 5, is reacted with a pyridine derivative of the formulas lia, Ilb or lie, as set forth in claim 6.

8. The process, as recited in claim 1, wherein the nickel (0) compounds, the nickel (II) compounds and / or the palladium (0) compounds and also the compounds of palladium (II) are used as catalysts.

9. The process as recited in claim 1, wherein the palladium (0) compounds and / or the palladium (II) compounds are used as catalysts.