EP0984935A1

EP0984935A1 - Method for producing substituted thiopyridines

Info

Publication number: EP0984935A1
Application number: EP98929326A
Authority: EP
Inventors: Gerhard Hamprecht; Markus Menges; Olaf Menke; Robert Reinhard; Peter Schäfer; Cyrill Zagar
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1997-05-30
Filing date: 1998-05-15
Publication date: 2000-03-15
Also published as: WO1998054139A1; US6191280B1; JP2002507197A

Abstract

The invention relates to a method for producing thiopyridines of general formula (I), wherein the substituents can have the meaning cited in the description. The inventive method is characterized in that substituted 2-halogen pyridines of formula (II), wherein Hal stands for fluorine, chlorine or bromine, are reacted in a first step with a thio compound of formula (III) HS-R<5> in the presence of a copper catalyst to obtain a pyridine thioether of formula (Ia) which is then gradually oxidized to form sulphoxide (Ib) or sulphone (Ic).

Description

Process for the preparation of substituted thiopyridines

description

The invention relates to a process for the preparation of thiopyridines of the general formula I.

in the

n 0, 1 or 2

R - * -, R ² , R ³ and R ^{4 are the} same or different and are for

Hydrogen, halogen, nitro, cyano; Ci-C _ß alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Cι-C ₆ alkoxy, C ₂ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, Ci-Ce- Alkylthio, C ₂ -C ₆ -alkenylthio, C ₃ -C ₆ -alkynylthio, -C-C ₆ -alkylsulfinyl, C -C ₆ -alkenylsulfinyl, C ₃ -C ₆ -alkynylsulfonyl, Ci-Cg-alkylsulfonyl, C -Cg alkenylsulfonyl, C ₃ -C _G alkynylsulfonyl, where the alkyl, alkenyl and alkynyl parts of these groups can carry up to 6 halogen atoms; one unsubstituted in the phenyl or naphthyl part or by halogen,

Cχ-C ₃ alkyl, -CC ₃ alkoxy, trifluoromethyl, cyano or nitro substituted -CC ₄ alkylenephenyl, phenyl, phenoxy or naphthyl radical; C0R ⁶ , CONR ⁷ R ⁸ , S0NR ⁷ R ⁸ or COR ⁶ ; furthermore, together, in the adjacent position in the pyridine ring, mean a 5- or 6-membered aromatic or aliphatic ring which optionally contains one or more heteroatoms or is substituted by halogen, trifluoromethyl, methyl or methoxy;

R ^{5 is} an unsubstituted or halogen radical,

C 1 -C ₄ -alkoxy-, C - * _- C ₄ -alkoxycarbonyl, di- (C 1 -C ₄ -alkylamino) carbonyl, cyano or nitro-substituted C ₁ -C ₁ -alkyl-, C ₂ -Cι ₀ -alkenyl - or C ₂ -Cι rest ₀ alkynyl, C ₃ -CG-cycloalkyl, phenyl in - unsubstituted or naphthyl moiety or by Ha- lied, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl, cyano or nitro substituted C 1 -C ₄ alkylene phenyl, phenyl or naphthyl radical,

R ⁶ , R ⁷ , R ^{8 are} identical or different from one another and

Hydrogen; C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C -C ₆ -alkenyl, C ₃ -C ₆ -alkynyl, where these groups can carry up to 6 halogen atoms; an unsubstituted in the phenyl moiety or by halogen, Cι-C ₃ -alkyl, C ~ ₃ alkoxy, trifluoromethyl, cyano or nitro substituted phenyl or C ₁ -C ₄ -AI- kylenphenylrest mean.

The thiopyridines I are important intermediates for the production of crop protection agents having a herbicidal action, as are known from WO-A-95/02580.

In the literature, the synthesis of pyridine thioethers from thiols and halopyridines is usually carried out in the presence of bases (J. Chem. Soc, Perkin Trans., Part I (1980) 648; Bull. Soc. Chim. Belg. 101 (1992) 297 ).

In GB-A 2 223 017 the sodium salt of the thio component is reacted with the halopyridine in the presence of copper bronze and supplies the corresponding pyridine thioether in 31% yield.

Finally, EP-A 320448 describes the reaction of a 2 -halogenopyridine with anilines without adding base to the corresponding 2 -arylaminopyridine in 11 or 37% yield. It is also mentioned in the same document that in addition to anilines, thiophenols can also be used. However, EP-A 320 448 does not list a specific exemplary embodiment which describes the reaction of a 2 -halopyridine with a thiophenol.

The object of the present invention was to find a simple and inexpensive process for the preparation of thiopyridine derivatives which, in turn, are suitable as a coupling component for the preparation of substituted phenylpyridines, as are described in WO-A-95/02580.

We have found that this object is achieved by the process defined above for the preparation of thiopyridines of the general formula I which is characterized in that substituted 2-halopyridines of the formula II

in which R ¹ , R ² , R ³ and R ^{4 have} the abovementioned meaning and Hai is fluorine, chlorine or bromine, in a first step with a thio compound of the formula III

HS - R ⁵ III

in which R ^{5 has} the abovementioned meaning in the presence of a copper catalyst first converted to a pyridine thioether of the formula Ia and then stepwise to the sulfoxide Ib or sulfone Ic

la lb Ic

oxidized.

The process according to the invention provides the pyridine thioethers of the formula Ia in a surprisingly high yield. The purity of the formed pyrid thioethers la is so high that they can generally be oxidized to the sulfoxides 1b and 1c without intermediate cleaning with oxidizing agents.

Hydrogen peroxide in acetic acid or acetic acid / trifluoroacetic acid mixtures has proven to be particularly advantageous for the stepwise oxidation of the pyridine thioethers la to the sulfoxides Ib and the sulfones Ic. For the direct oxidation of the Pyrid thioether la to the sulfones Ic is particularly suitable for hypochlorous acid or its alkali salt.

The thiopyridines I are particularly preferably obtained if sub * substituted 2-halopyridines of the formula II

in which R ² , R ⁴ and shark have the aforementioned meaning in a first step with a thio compound of the formula III

HSR ⁵ III

in which R ^{5 has} the abovementioned meaning first in the presence of 0.001 to 1 mol% of a copper catalyst to give a pyridine thioether of the formula Ia and then this stepwise to give the sulfoxide Ib

or sulfone Ic oxidized.

Particularly preferred compound II is 2,3,5-trichloropyridine, 5-chloro-2,3-difluoropyridine, 2,3-dichloro-5-difluoromethylpyridine, 2,3-dichloro-5 - (3,3,3-trifluoropropyl ) -pyridine, 2,3-dichloro-5-tri-fluoromethylpyridine or 2,3-dichloro-5-pentafluoroethylpyridine.

The preparation of the compounds I is exemplified by the reaction described in the following scheme, starting from 2,3-dichloro-5-trifluoromethylpyridine and thiophenol as the nucleophile using hydrogen peroxide as the oxidizing agent.

Instead of hydrogen peroxide, the oxidizing agents mentioned below can also be used analogously.

Preferred embodiments of the method are mentioned below:

The reaction of the 2-halopyridines II with a thiol III is advantageously carried out in the presence of a solvent at temperatures in the range from 80-250 ° C., preferably 120-200 ° C., particularly preferably 140-180 ° C.

Depending on the temperature range, the solvents used for these reactions are hydrocarbons such as toluene, xylene, chlorinated hydrocarbons such as 1, 2-dichloroethane, 1, 1, 2, 2-tetrachloroethane, chlorobenzene, 1,2-, 1,3- or 1, 4-dichlorobenzene, ethers such as 1,4-dioxane, anisole, glycol ethers such as dirnethyl glycol ether, diethyl glycol ether, diethylene glycol dimethyl ether, esters such as ethyl acetate, propyl acetate, methyl isobutyrate, isobutyl acetate, carboxamides such as DMF, N-methylpyrrolidone, nitrocarbons, hydrocarbons such as tetraethyl urea, tetrabutyl urea, dimethyl ethylene urea, dimethyl propylene urea, sulfoxides such as dimethyl sulfoxide, sulfones such as dimethyl sulfone, diethyl sulfone, tetramethylene sulfone, nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; Water or mixtures of individual solvents.

Execution in the melt without the use of a solvent is particularly preferred.

The molar ratios in which the starting compounds are reacted with one another are generally 0.9-1.4, preferably 0.95-1.1, particularly preferably 0.98-1.04, for the ratio of thiol to 2-halopyridine II. tration of the starting materials in the solvent is 0.1-5 mol / 1, preferably 0.2-2 mol / 1.

Suitable catalysts are copper oxide, salts such as copper (II) chloride, copper sulfate, copper nitrate, copper acetate, copper carbonate. It is particularly preferred to use metallic copper in fine distribution, e.g. B. copper powder or copper - bronze. The molar amount of catalyst based on the 2-halopyridine II is 0.001-10, preferably 0.001-1 mol% and particularly preferably 0.001 to 0.1 mol%.

The reaction is preferably carried out under acidic conditions, in which the hydrogen halide split off in the reaction is removed from the reaction mixture by means of an inert gas, for example nitrogen, or is allowed to escape into a washing device under autogenous pressure.

The 2-halopyridine II is advantageously added for 10 to 60 min. to a mixture of the thiol III and the catalyst at 20-80 ° C and then stirred to complete the reaction for 0.5 to 12 hours, preferably 1 to 8 hours at 140-180 ° C.

However, the thiol III can also be added to a mixture of 2-halopyridine II and catalyst and the reaction can then be completed as above.

In the case of low-boiling 2-halopyridines II or thiols III, the reaction can also be carried out in an autoclave.

If only one of the two starting components has a low boiling point, the higher-boiling component can be introduced together with the catalyst and the lower-boiling component - depending on its consumption - directly at the reaction temperature of preferably 120-200 ° C., particularly preferably 140-180 ° Add C or introduce in gaseous form.

Finally, the reaction can also be carried out in an aqueous two-phase system, preferably in the presence of phase transfer catalysts such as quaternary ammonium or phosphonium salts. The reaction conditions described in EP-A-556 737 are suitable for the two-phase reaction.

The reaction can be carried out under pressure or under pressure, continuously or batchwise. The oxidation of the pyridine thioethers of the formula Ia to the sulfoxides Ib and sulfones Ic can preferably be carried out with hydrogen peroxide, the sulfoxides Ib being obtained with approximately equivalent amounts of oxidant and the sulfones Ic being obtained with approximately twice molar amounts.

Water, acetonitrile, carboxylic acids such as acetic acid, trifluoroacetic acid, propionic acid, alcohols such as methanol, ethanol, isopropanol, tert. -Butanol, chlorinated hydrocarbons such as methylene chloride, 1, 1, 2, 2-tetrachloroethane or ketones such as acetone or methyl ethyl ketone can be used. Water, methanol, acetic acid and trifluoroacetic acid are particularly preferred.

In a particularly preferred variant, the reaction can also be catalyzed by adding stronger acids such as trifluoroacetic acid or perchloric acid. However, metal compounds are also suitable as catalysts, e.g. B. transition metal oxides such as vanadium pentaoxide, sodium tungstate, potassium dichromate, iron oxide tungstate, sodium tungstate-molybdic acid, osmic acid, titanium trichloride, selenium dioxide, phenyleneselenic acid, oxovanadinyl-2, 4-pentanedionate.

The catalysts are generally used in an amount of 0.5 to 10%, but because of the easy filterability and recovery of the inorganic catalysts, stoichiometric amounts can also be used.

Another preferred oxidizing agent is peracetic acid or hydrogen peroxide / acetic anhydride, optionally also the peracetic acid present in equilibrium in a hydrogen peroxide / acetic acid mixture.

A preferred oxidizing agent also provides the Pertrifluor- acetic acid or the mixture of hydrogen peroxide / trifluoroacetic acid ^¬ or the mixture of hydrogen peroxide / anhydride is Trifluoracet-.

Oxidation with hydrogen peroxide in glacial acetic acid is generally very selective, but often slow. By adding

Trifluoroacetic acid can generally shorten the reaction time. Oxidation with hydrogen peroxide in pure trifluoroacetic acid frequently leads, as also described in Chimia 29 (1975) 466, to the formation of the corresponding N-oxides. A rapid and selective oxidation of the pyridine thioethers la to the corresponding sulfoxides Ib and sulfones Ic is possible, for example, with solutions of hydrogen superoxide in mixtures of acetic acid and trifluoroacetic acid in a volume ratio of 10: 1 to 1: 1, in particular 6: 1 to 4: 1. These mixtures are therefore particularly preferred as solvents.

Petroleum ether, the abovementioned solvents and the catalysts listed above can also be used as solvents.

In addition to peracetic acid and pertrifluoroacetic acid, perbenzoic acid, monoperphthalic acid or 3-chloroperbenzoic acid can also advantageously be used in chlorinated hydrocarbons such as methylene chloride or 1,2-dichloroethane.

Chlorine and bromine are also very suitable for the oxidation of the thiols to sulfoxides or sulfones. Favorable solvents are water, acetonitrile, dioxane, two-phase systems such as aqueous potassium hydrogen carbonate solution / dichloromethane and, in the case of pyridine alkyl thioether, also acetic acid.

As a source of active halogen can also tert. -Butyl hypochlorite, hypochlorous and bromonic acid, the salts thereof, and also N-halogen compounds such as N-bromine and N-chlorosuccinimide or sulfuryl chloride.

Nitrogen tetroxide, e.g. in the process-technically simple variant with air / nitrogen dioxide or trioxide and, for example, osmium (VIII) oxide as catalyst. In addition, the oxidation can also be carried out directly with nitric acid, with acetic anhydride, acetic acid as additional solvents and copper (I) and (IΙ) bromide and chloride as catalysts.

Photosensitized oxygen transfer is also suitable for the oxidation, chlorophyll, protoporphyrin, Rose Bengal or methylene blue being recommended as photosensitizers. Inert solvents are hydrocarbons such as pentane, hexane, heptane, cyclohexane, chlorinated hydrocarbons such as methylene chloride, 1, 2-dichloroethane, 1, 1, 2, 2-tetrachloroethane, alcohols such as methanol, ethanol, n-propanol or isopropanol, ketones such as acetone , Methyl ethyl ketone, polar aprotic solvents such as acetonitrile, propionitrile or aromatic hydrocarbons such as benzene, toluene, chlorobenzene or xylene are suitable. Instead of oxygen, it is also possible to use ozone in the abovementioned solvents, in addition to ether, 1,4-dioxane or THF. In addition to photosensitization, catalysts are also recommended for oxygen oxidation. B. oxides and sulfides of nickel, copper, aluminum, tungsten, chromium, vanadium, ruthenium, titanium, »manganese, molybdenum, magnesium and iron.

Depending on the stoichiometry of the oxidizing agents used, either pyridine sulfoxides Ib or their pyridine sulfones Ic are obtained. The molar ratios in which the starting compounds are reacted with one another are generally 0.9-1.8, preferably 1.05-1.3 for the ratio of pyridine thioether la to oxidizing agent in the case of oxidation to pyridine sulfoxide and in general 1.9-3.5, preferably 2.05-2.9 in the case of oxidation to pyridine sulfone.

The concentration of the starting materials in the solvent is generally 0.1-5 mol / 1, preferably 0.2-2 mol / 1.

Advantageously, the pyridine thioether or the pyridine sulfoxide, if appropriate with one of the abovementioned catalysts, is initially introduced in one of the abovementioned solvents, and the oxidizing agent is then added with stirring for 0.25-20 hours. The addition and reaction temperature depends on the optimal efficiency of the respective oxidizing agent and the avoidance of side reactions. If photosensitized oxygen is used, the procedure is generally from -20 to 80 ° C, but metal-catalyzed generally from 50 to 140 ° C and when using ozone generally from -78 to 60 ° C. Because of the limited solubility of the oxygen derivatives, these must be continuously gassed into the reaction mixture over a longer period (up to 20 hours) until the oxidation at the sulfoxide or sulfone stage is complete. If air / nitrogen dioxide or trioxide is used, work is preferably carried out at 15 - 150 ° C for 1 - 15 hours.Liquid or easily soluble oxidizing agents such as hydrogen superoxide, the peracetic acid or peracetic acid formed together with acetic anhydride or in equilibrium with acetic acid or trifluoroacetic acid Pertrifluoroacetic acid, hypochlorous or bromonic acid, tert-butyl hypochlorite, chlorine or bromine, N-chloro- or N-bromosuccinimide or nitric acid can, depending on the exothermic nature of the reaction, be in a shorter period of time during 0.25 - Add 6 hours to the reaction mixture of pyridine thioether or sulfoxide to complete the reaction after another 1-60 hours. A staggered addition of the liquid or dissolved oxidizing agent is also preferred. In the case of hydrogen superoxide and peracetic acid or pertrifluoroacetic acid, work is generally carried out at 0 - 90 ° C with tert. -Butyl hypochlorite in general at - 78 to 30 ° C, with N-halogen compounds in generally at 0 - 30 ° C and with nitric acid generally at 20 to 140 ° C. In the case of chlorine or bromine, a reaction temperature of 0 - 40 ° C is recommended.

The oxidations can be operated without pressure or under pressure, continuously or batchwise.

The multistage reaction can advantageously also be carried out as a one-pot process, the pyridethioethers la obtained in the first synthesis step in the reaction of the 2-halopyridines II with the thiols III being converted directly to the sulfoxides Ib or the sulfones Ic without isolation and purification. Accordingly, the reaction product 1 a is allowed to cool to 90 to 20 ° C., if appropriate, a solvent is optionally added, for. B. trifluoroacetic acid, preferably acetic acid and / or water and now adds the oxidizing agent according to its consumption. Hydrogen peroxide, particularly sodium hypochlorite, is preferred as the oxidizing agent for the one-pot process.

For working up, the end products I are generally taken up in a water-immiscible solvent, acidic impurities or oxidizing agents are extracted with dilute alkali metal or water, dried and the solvent is removed under reduced pressure.

These processes can preferably be used to obtain the new substituted thiopyridines of the formula I '

in the

n 1 or 2;

R ² chlorine, -CC ₃ fluoroalkyl, cyano or methylsulfonyl;

R ^{4 is} fluorine or trifluoromethyl;

R ^{5 is} an unsubstituted or substituted by halogen, C 1 -C ₄ -alkoxy-, C 1 -C ₄ -alkoxycarbonyl, di- (C 1 -C ₄ -alkylamino) carbonyl, cyano or nitro C ₁ -C -o ~ alkyl, C ₂ -Cιo alkenyl or C -Cι ₀ alkynyl group, a C ₃ -C ₈ ~ cycloalkyl radical, an unsubstituted or in the phenyl moiety by halogen, Cχ-C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl, cyano or nitro substituted C 1 -C ₄ alkylenephenyl, phenyl or naphthyl radical.

The meanings given above for the substituents R ² to R ⁵ in the formula I 'are collective terms for individual lists of the individual group members. All carbon chains, that is to say all alkyl, alkenyl, alkynyl or alkoxy parts, can be straight-chain or branched. Halogenated substituents preferably carry 1-6 identical or different halogen atoms.

Specifically, for example:

Halogen fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine;

Cχ-C ₃ alkyl

Methyl, ethyl, n-propyl, 1-methylethyl;

Cχ-C ₁₀ alkyl

Cχ-C ₃ alkyl as mentioned above, and n-butyl, 1-methylpropyl, 2-methylpropyl and 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl , 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl , 1, 3-dimethylbutyl, 2, 2-dimethylbutyl, 2,3-dimethylbutyl, 3, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1-ethyl-l-methylpropyl and l -Ethyl-2-methylpropyl; n-heptyl, n-octyl, n-nonyl, n-decyl, 1-methylhexyl, 1-ethylhexyl, 1-methyl-heptyl, 1-methyl-octyl, 1-methyl-nonyl;

C -Cχo alkenyl

Ethenyl, prop-1-en-l-yl, prop-2-en-l-yl, 1-methylethenyl, n-buten-1-yl, n-buten-2-yl, n-buten-3-yl, 1-methylprop-l-en-l-yl, 2-methylprop-l-en-l-yl, l-methylprop-2-en-l-yl, 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-methylbut-l- en-l-yl, 3-methylbut-l-en-l-yl, l-methylbut-2-en-l-yl, 2-methylbut-2-en-l-yl, 3-methylbut-2- en-l-yl, l-methylbut-3-en-l-yl, 2-methylbut-3-en-l-yl, 3-methylbut-3-en-l-yl, 1, 1-dimethyl-prop- 2-en-1-yl, 1, 2-dimethylprop-1-en-1-yl, 1, 2-dimethyl-prop-2-en-1-yl, 1-ethylprop-1-en-2-yl, l-ethylprop-2-en-l-yl, n-hex-1-en-l-yl, n-hex-2-en-l-yl, n-hex-3-en-l-yl, n- Hex-4-en-l-yl, n-hex-5-en-l-yl, 1-methylpent-l-en-l-yl, 2-methylpent-1-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-methyl pent-2-en-l-yl, 4-methylpent-2-en-l-yl, l-methylpent-3-en-l-yl, 2-methylpent-3-en-l-yl, 3-methylpent- 3-en-l-yl, 4-methyl-pent-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, 1-dimethyl-but-2-en-l-yl, 1, l-dimethylbut-3-en-l-yl, 1, 2-dimethylbut-1-en-l-yl, 1, 2-dimethylbut-2-en-l-yl, 1, 2-dimethylbut-3-en-l-yl, 1, 3- Dimethylbut-l-en-l-yl, 1, 3-dimethyl-but-2-en-l-yl, 1, 3-dimethylbut-3-en-l-yl, 2, 2-dimethyl - but-3- en-l-yl, 2,3-dimethylbut-l-en-l-yl, 2,3-dimethyl-but-2-en-l-yl, 2,3-dimethylbut-3-en-l-yl, 3,3-dimethyl-but-1-en-l-yl, 3,3-dimethylbut-2-en-l-yl, 1-ethylbut-l-en-l-yl, l-ethylbut-2-en- l-yl, l-ethylbut-3-en-l-yl, 2-ethylbut-l-en-l-yl, 2-ethylbut-2-en-l-yl, 2-ethylbut-3-en-l- yl, 1, 1, 2-trimethylprop-2-en-l-yl, l-ethyl-l-methylprop-2-en-l-yl, l-ethyl-2-methylprop-1-en-l-yl and l-ethyl-2-methylprop-2-en-l-yl, hept-2-en-1-yl,

Oct-2-en-l-yl, non-2-en-l-yl, dec-2-en-l-yl, preferably ethenyl and prop-2-en-l-yl;

C ₂ -Cχo-alkynyl ethynyl and C ₃ -C ₆ -alkynyl such as prop-1-in-l-yl, prop-2-in-3-yl, n-but-1-in-l-yl, n- But-l-in-4-yl, n-but-2-in-l-yl, n-pent-1-in-l-yl, n-pent-l-in-3-yl, n-pent l-in-4-yl, n-pent-l-in-5-yl, n-pent-2-in-l-yl, n-pent-2-in-4-yl, n-pent-2- in-5-yl, 3-methyl-but-1-in-l-yl, 3-methyl-but-l-in-3-yl, 3-methyl-but-l-in-4-yl, n- Hex-1-in-l-yl, n-hex-l-in-3-yl, n-hex-l-in-4-yl, n-hex-1-in-5-yl, n-hex l-in-6-yl, n-hex-2-in-l-yl, n-hex-2-in-4-yl, n-hex-2-in-5-yl, n-hex-2- in-6-yl, n-hex-3-in ~ l-yl, n-hex-3-in-2-yl, 3-methylpent-l-in-l-yl, 3-methyl-pent-l- in-3-yl, 3-methylpent-l-in-4-yl, 3-methylpent-l-in-5-yl, 4-methyl-pent-1-in-l-yl, 4-methylpent-2- in-4-yl and 4-methylpent-2-in-5-yl, hept-2-in-l-yl, oct-2-in-l-yl, non-2-in-l-yl, Dec- 2-in-1-yl, preferably prop-2-in-1-yl, 1-methylprop-2-in-1-yl;

Cχ-C ₃ fluoroalkyl

Cχ-C ₃ alkyl as mentioned above, where 1-5 hydrogen atoms are replaced by fluorine, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2 -trifluoroethyl , Pentafluoroethyl, 3, 3, 3 -trifluoropropyl, preferably difluoromethyl, trifluoromethyl, 2, 2, 2 -trifluoroethyl, pentafluoroethyl, 3, 3, 3 -trifluoropropyl, particularly preferred is trifluoromethyl;

Cχ-Cχo-haloalkyl Cχ-Cχ ₀ -alkyl as mentioned above, where in each case 1-6 hydrogen atoms are replaced by fluorine, chlorine and / or bromine, for example chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, Difluoromethyl, 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 and 3-chloropropyl, preferably trifluoromethyl;

C ₂ -Cχo haloalkenyl

C ₂ -Cχo-alkenyl as mentioned above, where in each case 1-6 hydrogen atoms are replaced by fluorine, chlorine and / or bromine;

C ₂ ^_ Co-haloalkynyl

C ₂ ^_ Cχo-alkynyl as mentioned above, where one to six hydrogen atoms are replaced by fluorine, chlorine and / or bromine;

C ₃ -C ₈ cycloalkyl

Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and

Cyclooctyl, preferably cyclopropyl, cyclopentyl and cyclohexyl;

Cyano- (Cχ-Cχ ₀ ) alkyl

Cχ-Cχo ~ alkyl as mentioned above, wherein each hydrogen is ^¬ atom replaced by the cyano group, eg cyano - methyl, 1-Cyanoeth-l-yl, 2-Cyanoeth-l-yl, 1-cyanoprop-l-yl , 2-cyanoprop-l-yl, 3-cyanoprop-l-yl, l-cyanoprop-2-yl, 2-cyano-prop-2-yl, 1-cyanobut-l-yl, 2-cyanobut-l-yl , 3-cyanobut-l-yl, 4-cyanobut-l-yl, l-cyanobut-2-yl, 2-cyanobut-2-yl, 1-cyano-but-3-yl, 2-cyanobut-3-yl , l-cyano-2-methyl-prop-3-yl, 2-cyano-2-methyl-prop-3-yl, 3-cyano-2-methyl-prop-3-yl, and 2-cyanomethyl-prop- 2-yl, 6-cyanohex-l-yl, 7-cyanohept-l-yl, 8-cyanooct-l-yl, 9-cyanonon-l-yl, 10-cyanodec-l-yl; preferably cyanomethyl, 1-cyano-l-methylethyl;

Cχ-C ₄ alkoxy and the alkoxy parts of Cχ-C ₄ alkoxycarbonyl, methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy and 1, 1-dimethylethoxy, preferably Methoxy, ethoxy and 1-methylethoxy;

Di- (Cχ-C ₄ alkyl) aminocarbonyl

N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N, N-dipropylaminocarbonyl, N, N-di- (1-methylethyl) aminocarbonyl,

N, N-dibutylaminocarbonyl, N, N-di- (1-methylpropyl) aminocarbonyl, NN-di- (2-methylpropyl) aminocarbonyl, N, N-di- (1, 1-dimethylethyl) aminocarbonyl, N-ethyl -N-methylaminocarbonyl, N-methyl-N-propylaminocarbonyl, N-methyl-N- (1-methylethyl) aminocarbonyl, N-butyl-N-methylaminocarbonyl, N-methyl-N- (1-methylpropyl) - aminocarbonyl, N- Methyl-N- (2-methylpropyl) aminocarbonyl, N- (1, 1-dimethylethyl) -N-methylaminocarbonyl, N-ethyl-N-propyl- aminocarbonyl, N-ethyl-N- (1-methylethyl) aminocarbonyl, N-butyl-N-ethylaminocarbonyl, N-ethyl-N- (1-methylpropyl) aminocarbonyl, N-ethyl-N- (2-methylpropyl ) aminocarbonyl, N-ethyl-N- (1, 1-dimethylethyl) aminocarbonyl, N- (1-methylethyl) -N-propylamino - carbonyl, N-butyl-N-propylaminocarbonyl, N- (1-methylpropyl) -

N-propylaminocarbonyl, N- (2-methylpropyl) -N-propylamino-carbonyl, N- (1, 1-dimethylethyl) -N-propylaminocarbonyl, N-butyl-N- (1-methylethyl) aminocarbonyl, N- (1- Methylethyl) -N- (1-methylpropyl) aminocarbonyl, N- (1-methylethyl) -N- (2-methylpropyl) aminocarbonyl, N- (1, 1-dimethylethyl) -N- (1-methylethyl) aminocarbonyl, N- Butyl- N- (1-methylpropyl) aminocarbonyl, N-butyl-N- (2-methylpropyl) - aminocarbonyl, N-butyl-N- (1, 1-dimethylethyl) amino-carbonyl, N- (1-methylpropyl) - N- (2-methyl-propyl) aminocarbonyl, N- (1, 1-dimethylethyl) -N- (1-methylpropyl) aminocarbonyl and N- (1, 1-dimethyl-ethyl) -N- (2-methylpropyl) aminocarbonyl , preferably dimethylaminocarbonyl and diethylaminocarbonyl;

Cχ-C ₄ alkylene

Methylene, ethylene, propylene, 1-methylethylene, butylene, 1,2-dimethylethyl and 1-ethylethylene;

optionally halogen, Cχ-C ₃ alkyl, Cχ-C ₃ alkoxy, trifluoromethyl,

Cyano or nitro substituted phenyl

2-, 3-, 4-chlorophenyl, 2-, 3-, 4-tolyl, 2-chloro-4-methylphenyl, 2, 4-dichlorophenyl, 2, 4, 6-trichlorophenyl, 2, 6-dichloro-4- methyl - phenyl, 2-, 3-, 4-methoxyphenyl, 2-chloro-4-methoxyphenyl, 3-chloro-4-methoxyphenyl, 2-, 3-, 4-trifluoromethylphenyl, 2-, 3-, 4- Cyanophenyl, 2-, 3-, 4-nitrophenyl, 2-methyl-4-nitrophenyl, 2-chloro-4-trifluoromethylphenyl, 2-chloro-4-nitrophenyl and unsubstituted phenyl.

The process according to the invention is particularly preferably suitable for the preparation of compounds I in which

n 1 or 2;

R ^{2 is} chlorine or trifluoromethyl;

R ⁴ fluorine and

R ^{5 is} an unsubstituted or substituted by halogen, Cχ-C ₄ alkoxy Cχ-Cs-alkyl, C ₂ -C ₈ alkenyl or C ₃ -Cs alkynyl radical, an unsubstituted C ₃ -C ₈ cycloalkyl radical or is a benzyl or phenyl radical which is unsubstituted in the phenyl moiety or substituted by halogen, Cχ-C ₃ alkyl, Cχ-C ₃ alkoxy, nitro, cyano or trifluoromethyl. and particularly preferably of compounds I in which

n 2;

R ^{2 is} chlorine or trifluoromethyl;

R ^{5 is} an unsubstituted or substituted by chlorine or methoxy Cχ-C ₈ alkyl radical, a benzyl or phenyl radical unsubstituted in the phenyl part or substituted by chlorine, methyl, methoxy or trifluoromethyl.

The thiopyridines I 'according to the invention are valuable precursors for the production of crop protection agents, in particular herbicides from the class of the phenylpyridines, as are described in WO-A 95/02580.

Scheme 1

A particularly advantageous process for the preparation of herbicidal phenylpyridines based on the sulfoxides Ib and sulfones Ic prepared by the process according to the invention is described in DE Application No. 197 226 60.4 and in DE Application No. 196 36995.9 (see Scheme 1). . In addition, the thiopyridines I 'but also as intermediates in organic syntheses for the production of pharmaceuticals, dyes and. a. be used.

Process examples

Production of the pyridine thioethers la

example 1

3-chloro-2-octylthio-5-trifluoromethylpyridine

17.6 g (0.1166 mol) of n-octanethiol were removed within 5 min. while stirring at 23 ° C. to a mixture of 25 g (0.1132 mol) of 97.8% 2,3-dichloro-5-trifluoromethylpyridine and 7 mg (0.1 mol%) of copper powder and 4 h at 185 ° C stirred. After cooling, the reaction mixture was partitioned between methylene chloride and water and the organic phase dried and concentrated. You got

35.4 g (96.1% of theory) of the title compound with n ?, = 1.4985.

Example 2

3 -Chlor -2 -benzylthio- 5 - trifluoromethylpyridine

14.6 g of 99% benzyl mercaptan were stirred analogously to Example 1, only with 0.7 mg (0.01 mol%) of copper powder at 180 ° C. for 4 h. 32.4 g (94.3% of theory) of the title compound with n ^ ⁴ "= 1.5645 were obtained.

Example 3

3-chloro-2-phenylthio-5-trifluoromethylpyridine

26 g (0.233 mol) 98.7% thiophenol, 50 g (0.226 mol) 97.8% 2, 3-dichloro-5-trifluoromethylpyridine and 14.7 mg (0.23 mmol) copper powder were reacted analogously to Example 1 However, the reaction time was only 1 h and the reaction temperature was 160-170 ° C. The yield was 99%;

Example 4

3 -Fluor -2 -phenylthio- 5 - trifluoromethylpyridine

59.6 g (0.326 mol) of 2,3-difluoro-5-trifluoromethylpyridine were converted into 37.7 g (0.338 mol) of 98.7% thiophenol and 2.1 mg within 2.5 at 148-156 ° C. (0.01 mol%) copper powder added and stirred at 156-164 ° C for 2 hours. After cooling, the residue was taken up in methylene chloride, washed with 0.5N sodium hydroxide solution and with water, dried over magnesium sulfate and concentrated in vacuo. 88.9 g (100% of theory) of the title were obtained -

24 compound with n ^ = 1.5539.

Example 5

5 -Chlor - 3 - fluoro-2 - henylthio-pyridine

Starting from 93 g (0.508 mol) of 2,3-difluoro-5-chloropyridine, 58.8 g (0.5276 mol) of 98.7% thiophenol and 3.2 mg (0.01 mol%) of copper powder were obtained after stirring for 1.5 h in a pressure apparatus at 185 ° C. and working up according to Example 1, 121.5 g (99.9% of theory) of the title compound as a colorless oil. 1H NMR (ppm, d ₆ DMSO) 8.35 (s / lH), 8.05 (d / lH), 7.4-7.6 (m / 5H).

Production of sulfoxides Ib and sulfones Ic

5

Example 6

3-chloro-2-phenylsulfonyl-5-trifluoromethylpyridine

10 Variant a: starting from 2,3-dichloro-5-trifluoromethylpyridine

26 g (0.233 mol) of 98.7% thiophenol were within 20 min. with stirring at 20 - 40 ° C to a mixture of 50 g (0.226 mol) 97.8%, 2,3-dichloro-5-trifluoromethylpyridine and

15 14.7 mg (0.23 mmol) of copper powder (= 0.1% or pyridine) added. The reaction mixture was within 30 min. heated to 170 ° C. with stirring, with strong HCl evolution starting at 120 ° C. After 40 min. Stirring at 160-170 ° C, the conversion rate was 98.9% according to HPLC.

20th

In the cooled flask, 80 ml of water and 260 ml of glacial acetic acid were then added with stirring and then in 4 portions for 15 minutes each. a mixture of a total of 294 g (0.532 mol) of 13.5% sodium hypochlorite and 300 ml of water was added. To

25 of each addition were 15 min. stirred at 30 ° C with gentle cooling, finally 1 h. The reaction mixture was poured onto 1.5 l of ice water and extracted with methylene chloride. The org. The phase was washed with water and saturated sodium bicarbonate solution, dried and concentrated. 73 g were obtained

30 (100% of theory) of the title compound, mp 86-87 ° C.

In further experiments, the amount of catalyst (amount of copper in the first step of the one-pot synthesis could be reduced to 0.01% without loss of yield. If it was reduced again to 0.003% 35 Cu, the reaction time of the thioether synthesis increased to 6 hours and the yield decreased to 95.1% isolated sulfone.

Variant b: starting from 3-chloro-2-phenylthio-5-trifluoromethylpyridine

40

273.2 g (0.495 mol) of 13.5% sodium hypochlorite solution in 240 ml of water were added to a mixture of 65.2 g (0.225 mol) of 3-chloro-2-phenylthio-5- at 25-30 ° C. in the course of 2 hours. trifluoromethylpyridine in 100 ml of water and 100 ml of glacial acetic acid. After stirring for 2 h

45 25 ° C, 70 ml of glacial acetic acid were added and 84.5 g

(0.153 mol) 13.5% sodium hypochlorite solution within 30 min. fed. After stirring at 25 ° C. for 3 h, the reaction mixture was mixed with Methylene chloride extracted, the organic extract washed with water, saturated sodium bicarbonate solution and again with water. The mixture was then dried over magnesium sulfate and concentrated in vacuo. 70.9 g (98% of theory) of the title - 5 compound, melting point 91 ° C., were obtained. According to the GC examination, the purity was 100%.

Example 7

10 3-chloro-2-n-propylsulfinyl-5-trifluoromethylpyridine

8.4 g (0.124 mol) of 50% hydrogen peroxide were removed within 15 min. at 15 - 20 ° C with stirring to a mixture of 31 g (0.1213 mol) of 3-chloro-2-n-propylthio-5-trifluoromethylpyridine in

15 150 ml of acetic acid were added, the temperature increasing to 27 ° C. within 6 h. After stirring at 25 ° C. for 14 h, the reaction mixture was poured onto ice water and extracted 3 times with methylene chloride. The org. The phase was washed with water and saturated sodium bicarbonate solution, dried and in vacuo

20 concentrated, giving 32 g (97.2% of theory) of the title compound of mp. 51-53 ° C.

Example 8

25 3-chloro-2-n-propylsulfonyl-5-trifluoromethylpyridine

11.7 g (0.172 mol) of 50% hydrogen peroxide were removed within 30 min. with stirring at 20-25 ° C to 20 g (0.0783 mol) of 3-chloro-2-n-propylthio-5-trifluoromethylpyridine in 150 ml of glacial acetic acid

30 given, the temperature rising to 31 ° C within 8 h. After stirring for 60 h while cooling to 25 ° C., the reaction mixture was poured onto ice water and worked up as described. 21 g (93.3% of theory) of the title compound of mp 41-42 ° C. were obtained.

35

Example 9

3-chloro-2-phenylsulfinyl-5-trifluoromethylpyridine

40 11.76 (0.173 mol) 50% hydrogen peroxide were within 20 min. at 25 ° C. to a mixture of 50 g (0.173 mol) of 3-chloro-2-phenylthio-5-trifluoromethylpyridine in 50 ml of trifluoroacetic acid and 250 ml of acetic acid. After stirring for 4 h at 30 to 28 ° C, the reaction mixture was extracted with methylene chloride

45 and the organic phase washed with sodium hydrogen carbonate solution and with water. After drying over magnesium sulfate and concentration in vacuo, 48.5 g of colorless crystals of Mp 67-68 ° C. According to the NMR analysis, they contained 44.9 g

(85% of theory) of the pure title compound and 3.6 g (6.4% of theory) of the corresponding sulfone.

5 Example 10

3-fluoro-2-phenylsulfinyl-5-trifluoromethylpyridine

20 g (0.0693 mol) of 95% 3-fluoro-2-phenylthio-5-trifluoromethyl-0 pyridine were placed in 100 ml of glacial acetic acid and 20 ml of trifluoroacetic acid and within 5 min. 5.64 g (0.083 mol) of 50% hydrogen superoxide were added with stirring at 22 ° C. and the mixture was stirred at 22 ° C. for 10 h. The reaction mixture was added to 1 1 of ice water, extracted with methylene chloride and the organic phase was washed with saturated sodium bicarbonate solution and with water. After drying, filtering through silica gel and concentrating in vacuo, 19.1 g (95.4% of theory) of the title were obtained -

24 connection with n = 1.5522.

20th

Example 11

3-fluoro-2-phenylsulfonyl-5-trifluoromethylpyridine

25 63.2 g (0.1145 mol) of 13.5% sodium hypochlorite were in 4 portions each within 10 min. while stirring at 25-30 ° C. to a mixture of 13.6 g (0.0498 mol) of the compound from Example 5 in 85 ml of water and 60 ml of glacial acetic acid and stirred for a total of 2.5 h. The reaction mixture was poured onto 1 l of ice water.

Give 30, extracted with methylene chloride and the organic phase washed with saturated sodium bicarbonate solution and with water. After drying and concentrating in vacuo, 15.1 g (98.9% of theory) of the title compound of mp 82-83 ° C. were obtained.

35 Example 12

5-Chloro-3-fluoro-2-phenylsulfinyl-pyridine

33.8 g (0.497 mol) of 50% hydrogen superoxide were removed within 40 15 min. with stirring at 23-28 ° C to a solution of 119 g

(0.497 mol) of the compound from Example 6 in 500 ml of glacial acetic acid and 150 ml of trifluoroacetic acid and stirred at 23 ° C for 14 h. The reaction mixture was poured onto 2 l of ice water and extracted with methylene chloride and the organic phase was washed with saturated sodium bicarbonate solution and with water. After concentration, 123.5 g (97.3% of theory) of the title Compound as colorless crystals. After stirring with ether / pentane 2: 8, 116.1 g (91.6% of theory) of melting point 77-78 ° C. remained.

Claims

claims

1. Process for the preparation of substituted thiopyridines of the general formula I

in the

n 0, 1 or 2

R - * -, R ² , R ³ and R ^{4 are the} same or different and are hydrogen, halogen, nitro, cyano, Cχ-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl ,

Cχ-C ₆ alkoxy, C -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, Cχ-C ₆ alkylthio, C -C ₆ alkenylthio, C ₃ -C ₆ alkynylthio, Cx-Cς- Alkylsulfinyl, C ₂ -C ₆ alkenylsulfinyl, C ₃ -C ₆ alkynylsulfinyl, Cχ-C ₆ alkylsulfonyl, C ₂ -C ₆ alkenylsulfonyl,

C ₃ -C ₆ alkynylsulfonyl, where the alkyl, alkenyl and alkynyl parts of these groups can carry up to 6 halo atoms; one unsubstituted in the phenyl or naphthyl part or by halogen, Cχ-C ₃ alkyl, Cχ-C ₃ alkoxy,

Trifluoromethyl, cyano or nitro substituted Cχ-C ₄ ~ alkylenephenyl, phenyl, phenoxy or naphthyl radical; C0 ₂ R ⁶ , CONR ⁷ R ⁸ , S0 ₂ NR ⁷ R ⁸ or COR ⁶ ; furthermore together, in the adjacent position in the pyridine ring, mean a 5- or 6-membered aromatic or aliphatic ring which optionally contains one or more heteroatoms or is substituted by halogen, trifluoromethyl, methyl or methoxy;

R ^{5 is} an unsubstituted or halogen radical,

Cχ-C ₄ -alkoxy-, Cχ-C ₄ -alkoxycarbonyl, di- (Cχ-C ₄ -alkylamino) carbonyl, cyano or nitro substituted Cχ-Cχo-alkyl-, C ₂ -Cχo-alkenyl- or C ₂ -Cχo alkynyl radical, a C ₃ -Cs cycloalkyl radical, a Cχ unsubstituted in the phenyl or naphthyl part or substituted by halogen, Cχ-C ₃ alkyl, C--C ₃ alkoxy, trifluoromethyl, cyano or nitro Are -C ₄ alkylene, phenyl, phenyl or naphthyl,

R ⁶ , R ⁷ , R ^{8 are the} same or different and are hydrogen Cχ-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C -C ₆ alkenyl, C ₃ -C ₆ alkynyl, these groups up to Can carry 6 halogen atoms; an unsubstituted in the phenyl or ₃ alkoxy, trifluoromethyl, cyano or nitro nyl- Phe- substituted by halogen, Cχ-C ₃ alkyl, Cχ-C or Cχ-C ₄ mean -Alkylenphenylrest,

characterized in that substituted 2-halopyridines of the formula II

HS - R ⁵ III

in which R ^{5 has} the abovementioned meaning first in the presence of a copper catalyst to give a pyridine thioether of the formula Ia and then stepwise to the sulfoxide Ib or sulfone Ic

la Ib Ic

oxidized.

2. The method according to claim 1, characterized in that the 2 -halopyridines II are reacted with a thio compound of the formula III in the presence of 0.001 to 10 mol% of a copper catalyst.

3. The method according to any one of claims 1 or 2, wherein the stepwise oxidation of the pyridine thioethers la to the sulfoxides Ib and sulfones Ic with the aid of hydrogen peroxide in a mixture of acetic acid and trifluoroacetic acid in a volume ratio of 6: 1 to 4: 1.

4. The method according to any one of claims 1 or 2, wherein the oxidation of the pyridine thioether la to the sulfones Ic with the help of hypochlorous acid or its alkali salt.