WO2019215076A1 - Process for preparing nitrogen-containing heterocycles - Google Patents

Abstract

The present invention relates to an improved process for preparing nitrogen-containing, heterocyclic compounds of formula (I).

Description

 Process for the preparation of nitrogen-containing heterocycles

The present invention relates to an improved process for the preparation of nitrogen-containing heterocyclic compounds of formula (I) shown below.

Compounds of the formula (I) and their pesticidal properties have already been disclosed (see WO 2017/005673 A1 and European patent application with the application number 17204401.8).

So far, these compounds have been obtained in an unsatisfactory yield by a multi-step synthesis (see, for example, the synthesis of 1 1 - [6 -I ri GI uormct liy I -py ri di n-3-y 11 -2- (IH) py ridi ny I idcuc | cy an am id, WO 2017/005673 Al). Substituted [1 (2 H), 3'-bipyridine] -2-thiones and their preparation have become known as intermediates. A disadvantage of the previously known process is the unsatisfactory overall yield and, if appropriate, the isolation and purification of the intermediates, because this is associated with considerable expenditure of time, yield loss and costs on a preparative scale.

In WO 2017/005673 Al, the preparation of compounds of the formula

described in which the structural unit of the formula

for example, optionally substituted 2 (I //) -pyridiny I i den (eg, Al, A2, A3, A4 = CH), which is substituted in the N position by an R radical and wherein WR ^{1 is} the group = N-CN, by replacing the activated halogen with cyanamide (Scheme 1). Scheme 1:

H, WR ¹

 Reaction Step 1 Reaction Step 2

(Halogenierung) (Hai Austausch)

(Halogenation) (shark exchange)

Konkret beschreibt W02017/005673 Al die Herstellung von 1 1 -[ 6- I ri GI uormctlryl -pyridi n-3-yl | -2( I H)- pyridinyl idcn |cyananiid (Verbindung (3)), das ausgehend von 6’ - I ri GI uormctlryl - [ I (2/7), 3‘-bipyridin]- 2-on (1) und Phosphorylchlorid in Gegenwart von W- Dimethylformamid in Dichlormethan synthetisiert wird (siehe Schema 2). Schema 2:

Specifically, W02017 / 005673 Al describes the preparation of 1 1 - [6 -IrI GI urormctlryl-pyridin-3-yl | -2 (IH) - pyridinyl idcn | cyanide (Compound (3)), starting from 6 '- I ri GI uormctlryl - [I (2/7), 3'-bipyridin] -2-one (1) and phosphoryl chloride in the presence of W-dimethylformamide in dichloromethane (see Scheme 2). Scheme 2:

 6'-Trifluoromethyl [l (2H), 3'-bipyridin] -2-one (1) is thereby added with 5 times the equimolar amount of phosphoryl chloride and the isolated 2-chloro-l- (6-trifluoromethyl-pyridine 3-yl) -pyridinium chloride (2) is reacted with the equimolar amount of cyanamide in the presence of potassium carbonate in acetonitrile. The desired product (3) was obtained in a yield of 28%.

The method described in WO2017 / 005673 A1 is disadvantageous, since the halogen atom can be exchanged badly against the only weakly basic amino group of the cyanamide. This leads to the low yield of only 28%.

In the European patent application with the application number 17204401.8 the preparation of various compounds of formula (Ia) is described by replacing the activated methylthio group by means of Natriumhydrogencyanamid (Scheme 3).

Scheme 3:

 Concretely, the preparation of 1 1 - [6-l) i II uormet liy I -py ridi 11 -3 -y 11-2 (I / V) -py r idi idy I iden | cyan on id (compound (7) described starting from 6'-!) ifluomicthyl- | 1 (2/7), 3'-bipyridin] -2-one and diphosphorus pentasulfide were synthesized in the presence of sodium bicarbonate in 1,4-dioxane followed by methylation with methyl iodide in acetonitrile (Scheme 4).

Scheme 4:

 The compound (4) was mixed with 10 times the equimolar amount of sodium bicarbonate and thionated in the presence of 5 times the equimolar amount of diphosphorus pentasulfide. The isolated and purified 6'-l) illuormcthyl- | 1 (2/7], 3'-bipyridine] -2-thione (5) was then reacted with 10 times the equimolar amount of methyl iodide and the isolated [1- [6-difluoromethylpyridin-3-yl] -2 (Methylthio) -pyridinium iodide (6) was then reacted with 2-fold equimolar amounts of sodium hydrogen-cyanamide in acetonitrile to afford the 6'-l) illuormcthyl- I (2 //, 3'-bipyridine] -2-thione (5) in a yield of 68%, which was then converted in a yield of 91.5% to the desired product.

The process for the preparation of compounds of the formula (Ia) described in the European patent application with the application number 17204401.8 is disadvantageous because the compounds of the formula (IVa) must be isolated and purified before .S'-Mcthylicrung. In addition, the use of P4S10 is uneconomical due to the atom economy, as it can lead to larger amounts of phosphorus and sulfur containing wastes. This results in an overall yield loss, the yield of thionated compounds was only 68%. Moreover, the process described in European Patent Application No. 17204401.8 requires the use of the harmful methyl iodide in a 10-fold equimolar excess.

There was therefore the need to find a process for the preparation of said compounds, which is inexpensive and can be used on an industrial scale. Also, it is desirable to obtain these compounds in high yield and in high purity, so that they need not be subjected to further complex purification.

A simplified process for the preparation of certain nitrogen-containing, heterocyclic compounds has now been found which avoids the disadvantages of the known processes, is simple and inexpensive to carry out and can be used industrially. The present invention thus relates to a process for the preparation of compounds of the formula

(D

worin die Struktureinheit der Formel

wherein the structural unit of the formula

(a) for a residue A from the series

steht, wobei diese Reste m Substituenten X tragen,

where these radicals carry m substituents X,

X is a radical selected from halogen, cyano (CN), nitro, alkyl, alkoxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, m is a number from the series 0, 1 and 2 stands,

R for a rest B from the series

B-7 B-8 B-9 B-10 B-1 1 B-12

 B-13 B-14 B-15 B-16, where these radicals carry n substituents Y and the dashed line denotes the bond to the nitrogen atom in the radical A,

Y is a radical selected from halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfoxyl,

Haloalkylsulfoxyl, alkylsulfonyl, haloalkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, alkylamino, dialkylamino, alkylaminosulfonyl, dialkylaminosulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkoxyalkylcarbonylamino, haloalkylcarbonylamino, in each case optionally substituted aryl and hetaryl, n is a number from the series 0, 1 and 2 stands, or (ß) for the rest

 R for the rest

 B-3 stands. wherein the dashed line represents the bond to the nitrogen atom in the radical A-1, and

Yi substituted for a radical from the series cyano- haloalkyl, Ci-C _t haloalkoxy, Ci- C _t haloalkylthio, Ci-C4-haloalkylsulfinyl, Ci-C4-haloalkylsulfonyl, optionally halogen-substituted Ci-C4-alkoxy-Ci C4-alkyl, optionally by halogen substituted C 1 -C ₄ -alkylthio-C 1 -C ₄ -alkyl, C 1 -C ₄ -alkylsulfinyl-C 1 -C ₄ -alkyl, C 1 -C ₄ -alkylsulfonyl-C 1 -C ₄ -alkyl and cycloalkyl which is substituted by halogen, cyano, alkyl or halogenoalkyl, which is characterized in that, in a first step, compounds of the formula (II)

in which R, A ¹ , A ² , A ³ and A ^{4 have} the abovementioned meanings, with the aid of a halogenating agent in compounds of the formula (III)

 Hai c - in which Hal is a halogen atom and X is a halide anion, transferred and then in a second reaction step with an alkyl thiolate of the formula (IV)

R ^ SM ^ IV), wherein R ^{1 is} an alkyl radical, and M ^{+ is} a cation, to compounds of formula (V)

reacted, and then reacted in a third reaction step in the presence of a cyanamide and optionally in the presence of a base to compounds of formula (I).

hergestellt, worin die Struktureinheit der Formel Preference is given to compounds of the formula (I)

prepared, wherein the structural unit of the formula

 (a) for a residue A from the series

 A-7 A-8 A-9 A-10 A-1 1, where these radicals carry m substituents X,

X is a radical from the series halogen, cyano, nitro, Ci-C _t -alkyl, C _t -alkoxy, C _t alkylthio, Ci-C _t alkylsulfoxyl, Ci-C _t alkylsulfonyl, halogen Ci-C ₄ alkyl, halogen-Ci-C ₄ alkoxy, _{halo-Ci-C4-alkylthio, halo-Ci-C4-alkylsulfonyl,} Ci-C ₄ alkoxycarbonyl, C ₁ -C ₄ - alkylcarbonyl, and C ₃ -C ₆ -cycloalkylcarbonyl, m is a number from the series 0, 1 and 2,

R for a rest B from the series

 B-13 B-14 B-15 B-1 6, where these radicals carry n substituents Y and the dashed line denotes the bond to the nitrogen atom in the radical A,

Y is a radical from the series halogen, cyano, nitro, amino, Ci-C _t -alkyl, C ₂ -C ₄ alkenyl, C ₂ - C _t -alkynyl, halo-Ci-C _t-alkyl, Ci-C _t -alkoxy, halogen-Ci-C _{t-alkoxy, Ci-C4-alkylthio, halo-Ci-C4-alkylthio, Ci-C4-alkylsulfoxyl, halo-Ci-C4-alkylsulfoxyl,} C ₁ -C ₄ - alkylsulfonyl, _{halo-Ci-C4-alkylsulfonyl,} Ci-C ₄ alkoxycarbonyl, Ci-C ₄ alkylcarbonyl, C ₃ - ( 'e, - (' ycloal kylcarhonyl, Ci-C ₄ alkylamino, di (C C ₄ alkyl) amino, C 1 -C ₄ alkylaminosulfonyl,

Di- (Ci-C ₄ alkyl) aminosulfonyl, Ci-C ₄ alkylaminocarbonyl, di- (Ci-C ₄ alkyl) aminocarbonyl, C ₁ -C ₄ - alkylcarbonyl amino or C ₁ -C ₄ - alkoxy C ₁ -C ₄ -alky lcarbony lamino, halo-C ₁ -C ₄ - alkylcarbonylamino, each optionally substituted aryl and 5- to 6-membered hetaryl, and n is a number from the series 0, 1 and 2, or

(β) for the rest

 A-1 stands, and

R for the rest

 B 3 stands. Yi is a radical from the series cyano-fluoromethyl, cyano-difluoromethyl, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, difluoromethylthio, trifluoromethylthio, difluoromethylsulfinyl, trifluoromethylsulfinyl, difluoromethylsulfonyl,

Trifluoromethylsulfonyl, H3C-O-F2C, H3C-S-F 2 C H ₃ CS (0) -F ₂ C, H3C-O2S-F2C, H3C-H2C-S, H ₃ CS (0) -H ₂ C, FI ₃ C-O ₂ S-FI ₂ C, 1-fluorocyclopropyl, 1-cyanocyclopropyl and 1-trifluoromethylcyclopropyl.

Particular preference is given to compounds of the formula (I)

hergestellt, worin die Struktureinheit der Formel

prepared, wherein the structural unit of the formula

(a) für einen Rest A aus der Reihe

(a) for a residue A from the series

 A-1 A-2 A-3 A-4 A-5

 where these radicals carry m substituents X,

X is a radical from the series halogen, cyano, Ci-C _t alkyl, halo-Ci-C _t -alkyl, m is a number from the series 0, 1 and 2, B is a radical from the series

wobei diese Reste n Substituenten Y tragen und die gestrichelte Linie die Bindung zum Stickstoffatom im Rest A bedeutet,

these radicals bear n substituents Y and the dashed line denotes the bond to the nitrogen atom in the radical A,

Y is a radical from the series halogen, cyano, Ci-C _t -alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ -alkynyl, _{halo-Ci-C4-alkyl,} halo-Ci-C ₄ - alkoxy, _{halo-Ci-C4-alkylthio, Ci-C4-alkylsulfoxyl,} halo-C i -C ₄ alkylsulfoxyl, C ₁ -C ₄ - alkylsulfonyl, halo-C ₁ -C ₄ -alkylsulfony 1, optionally with a Substituents from the group halogen, cyano, C 1 -C ₄ -alkyl, halogeno-C 1 -C ₄ -alkyl, halogeno-C 1 -C ₄ -alkoxy, halogeno-C 1 -C ₄ -alkylthio, C 1 -C ₄ -alkylsulfoxyl,

Halogen-C 1 -C ₄ -alkylsulfoxyl, C 1 -C ₄ -alkylsulfonyl, halogen-C 1 -C ₄ -alkylsulfonyl-substituted 5-membered hetaryl, where hetaryl is, for example, / V-pyrazolyl, / V-imidazolyl or N-1,2,4 - Triazolyl means, stands, and n is a number from the series 0, 1 and 2, or

(β) for the rest

 A-1 stands, and

R for the rest

steht, worin

stands in which

Yi is a radical from the series cyano-fluoromethyl, cyano-difluoromethyl, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, difluoromethylthio, trifluoromethylthio, difluoromethylsulfinyl, trifluoromethylsulfinyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, H ₃ C-0 -F ₂ C, H ₃ CSF ₂ C, H ₃ CS (0) -F ₂ C, H ₃ C-0 ₂ SF ₂ C, H ₃ CSH ₂ C,

H ₃ CS (0) -H ₂ C, H ₃ C-O ₂ SH ₂ C, 1-fluorocyclopropyl, 1-cyanocyclopropyl and 1-

Trifluoromethylcyclopropyl stands.

Very particular preference is given to compounds of the formula (I)

hergestellt, worin die Struktureinheit der Formel

prepared, wherein the structural unit of the formula

 (a) for the radical A-1

 A-1, where these radicals m carries substituents X, X is a radical from the series fluorine, chlorine, methyl, ethyl, trifluoromethyl and difluoromethyl, m is a number from the series 0, 1 and 2,

R for a rest of the series

steht, wobei diese Reste n Substituenten Y tragen und die gestrichelte Linie die Bindung zum Stickstoffatom im Rest A bedeutet,

where these radicals carry n substituents Y and the dashed line denotes the bond to the nitrogen atom in the radical A,

Y is a radical selected from fluorine, chlorine, bromine or iodine, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluorochloromethyl, difluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio , Trifluoromethylthio, difluoromethylsulfinyl, trifluoromethylsulfinyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, N-triazolyl and / V-pyrazolyl optionally substituted by a substituent selected from fluorine, chlorine, iodine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy and methylthio, n is a number from the series 0, 1 and 2, or

(β) for the rest

 A-1 stands, and

R for the rest

steht. worin Yi für einen Rest aus der Reihe Cyano-fluormethyl, Cyano-difluormethyl, Difluormethoxy, Trifluormethoxy, 2,2-Difluorethoxy, 2,2,2-Trifluorethoxy, Difluormethylthio, Trifluormethylthio, Difluormethylsulfinyl, Trifluormethylsulfinyl, Difluormethylsulfonyl,

stands. Yi is a radical from the series cyano-fluoromethyl, cyano-difluoromethyl, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, difluoromethylthio, trifluoromethylthio, difluoromethylsulfinyl, trifluoromethylsulfinyl, difluoromethylsulfonyl,

Trifluoromethylsulfonyl, H3C-O-F2C, H3C-S-F 2 C H ₃ CS (0) -F ₂ C, H3C-O2S-F2C, H3C-H2C-S, H ₃ CS (0) -H ₂ C, FI ₃ C-O ₂ S-FI ₂ C, 1-fluorocyclopropyl, 1-cyanocyclopropyl and 1-trifluoromethylcyclopropyl.

Very particular preference is given to compounds of the formula (I)

hergestellt, worin die Struktureinheit der Formel

prepared, wherein the structural unit of the formula

für den Rest A-l

for the rest Al

 A-1 stands,

R for the rest

 B 3 is and Y 2 is a radical from the series, difluoromethyl, trifluoromethyl, difluorochloromethyl, difluorbrommethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl.

The compounds of the formula (I) can be prepared in good yields using the process according to the invention.

The reaction sequence according to the invention for the preparation of compounds of the formula (I) is shown in Scheme 5:

Scheme 5

 Reaction Step 1 Reaction Step 2

 O (halogenation) (shark exchange)

(II) (III)

 Reaction Step 3

(R ¹ -S exchange)

und R die oben genannten Bedeutungen. Hai steht für ein Halogenatom wie Chlor oder Brom. X steht für ein Halogenidion wie Chlorid oder Bromid. M⁺ steht für Natrium⁺, Kalium⁺, Caesium⁺, Vi Calcium⁺⁺ oder für ein Tetramethylammonium-ion, Tetraethylammonium-ion oder ein Tetraphenylphosphonium- ion. R¹ steht für (YCe, Alkyl, bevorzugt Methyl oder Ethyl, oder für Benzyl. In Reaction Scheme 5, the structural unit

and R is the same as above. Hal is a halogen atom such as chlorine or bromine. X is a halide ion, such as chloride or bromide. M ⁺ stands for sodium ⁺ , potassium ⁺ , cesium ⁺ , Vi calcium ⁺⁺ or for a tetramethylammonium ion, tetraethylammonium ion or a tetraphenylphosphonium ion. R ¹ is (YCe, alkyl, preferably methyl or ethyl, or benzyl.

In the process according to the invention, the compounds of the formula (II) react in a first reaction step in the presence of a suitable halogenating agent to form activated halogen compounds of the formula (III), which are then reacted in a second reaction step to give compounds of the formula (V) which are subsequently react in a third reaction step to compounds of formula (I).

The compounds of the formula (II) in which R, Al, A2, A3 and A4 have the abovementioned meanings and their preparation are known (cf., WO 2017/005673 A1 and European patent application with the application number 17204401.8).

Is in the process of the invention as a compound of formula (II) 6'-Tnfluomicdiyl- | 1 (2/7), 3'-bipyridin] -2-one (Al, A2, A3, A4 = CH, R = 6-trifluoromethyl-pyridin-3-yl) (II-1) is used, is formed by reaction with a chlorinating reagent, first 2-chloro-1- (6-trifluoromethylpyridin-3-yl) -pyridinium chloride (III-1) (Hai = CI, X = Cl), which in the second reaction step, for example with sodium methylthiolate (IV - 1), to give [1- [6-trifluoromethyl-pyridin-3-yl] -2- (methylthio) -pyridinium chloride (VI) (X = Cl). Subsequent reaction with cyanamide leads to [1- [6-trifluoromethyl-pyridin-3-yl] -2 (1H) -pyridinylidene] -cyanamide (R = 6-trifluoromethylpyridin-3-yl; Al, A2, A3; A4 = CH) of the formula (1-1) (Scheme 6, compare Preparation Example 1).

Scheme 6

Reaction Step 1

According to the invention, the activation (halogenation, reaction step 1) is carried out with halogenating agents such as thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, phosphoryl chloride, phosphorus pentachloride and phosphoryl bromide. Preference is given to phosphoryl chloride and thionyl chloride. When phosphoryl bromide or phosphorus pentabromide is used, the corresponding substituted pyridinium bromides (X = Br) are formed. The halogenation step is accelerated by the addition of catalysts. Suitable catalysts are VV-dimethylformamide, / V, / V-dibutylformamide, pyridine or picoline. The reaction step 1 is usually carried out under atmospheric pressure. It is also possible to carry out the reaction under pressure z. When using phosgene or thionyl chloride. In the reaction step 1, the molar ratio of the halogenating agent used to the compound of the formula (II) may be, for example, in the range of about 12 to about 1. Preferably, it is in the range of about 10 to about 2, more preferably in the range of about 6 to 2. The use of larger amounts of halogenating agent is basically possible, but generally uneconomical.

Suitable solvents or diluents for reaction step 1 are methylene chloride, dichloroethane, chloroform, toluene, chlorobenzene, isopropyl acetate and acetonitrile.

The reaction step 1 is usually carried out in a temperature range of 20 ° C to 120 ° C and optionally in the presence of a solvent or diluent. Preferably, the reaction is carried out at about 80 ° C without solvent or diluent.

Reaction step 2

In the second reaction step, the compounds of the formula (III) are reacted by reaction with alkyl thiolates of the formula (IV) to give compounds of the formula (V). In the reaction step 2, the molar ratio of the alkylthiolate (IV) to the halogen compound of the formula (III) may be in the range of about 6 to about 1. Preferably, it is in the range of about 4.5 to about 1.5, more preferably in the range of about 3.5 to 2. The use of larger amounts of alkyl thiolate (IV) is basically possible, but generally uneconomical.

Suitable alkyl thiolates are sodium methyl or ethyl thiolates (eg NaSMe, NaSEt), potassium methyl or ethyl thiolates (eg KSMe, KSEt) or PhCI ESNa. It is also possible to use the thio compounds (R ¹ S 11) in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methylate or sodium ethylate, sodium or potassium ieri butanolates. Alkylthiols and alkylthiolates are commercially available. In reaction step 2, the molar ratio of the alkyl thiolate (IV) to the base may range from about 1 to 0.5. Preferably, the bases and alkylthiolates are used in stoichiometric amounts.

The duration of the reaction for the reaction step 2 is in the range of about 2 to about 25 hours, preferably in the range of 4 to 20 hours.

The reaction step 2 is usually carried out in a temperature range of 0 ° C to 40 ° C. Preferably, the reaction is carried out at room temperature in a solvent or diluent.

Reaction Step 3

In reaction step 3, the molar ratio of the cyanamide to the compound of formula (V) may range from about 5 to about 1. Preferably, it is in the range of about 4 to about 1.5, more preferably in the range of about 3 to 2. The use of larger amounts of cyanamide is basically possible, but generally uneconomical.

Reaction step 3 is usually carried out in the presence of a base. Suitable are inorganic bases such as lithium, sodium, potassium, sodium, potassium, sodium, potassium, sodium, ethanol Pyridines, alkylpyridines (picolines), phosphazenes and 1,8-diazabicyclo [5.4.0] undecenes (DBUs). Preference is given to sodium carbonate, potassium carbonate, potassium acetate and sodium methoxide,

In step 3 cyanamide of the formula NH 2 CN is used. It is also possible to prepare sodium or potassium hydrogen cyanamide (NaNHCN or KNHCN) separately and to use it without additional base in reaction step 3. The reaction step 3 is usually carried out in a temperature range of 0 ° C to 40 ° C. Preferably, the reaction is carried out at room temperature in a solvent or diluent.

Suitable solvents or diluents for reaction steps 1, 2 and 3 are all inert organic solvents under the reaction conditions, for example aliphatic or aromatic hydrocarbons (such as petroleum ether, toluene), halogenated hydrocarbons (such as chlorotoluene, dichloromethane, chloroform, 1.2 Dichloroethane), ethers (such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane), esters (such as ethyl acetate or methyl ester), nitrohydrocarbons (such as nitromethane, nitroethane, nitrobenzene), nitriles (such as acetonitrile, benzonitrile), amides (e.g. N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, hexamethylphosphoric acid triamide) and dimethyl sulfoxide or water or mixtures of said solvents.

Preferred solvents or diluents for reaction step 1 are methylene chloride, dichloroethane, chloroform, toluene, chlorobenzene, isopropyl acetate, tetrahydrofuran and acetonitrile.

The reaction time of the reaction for the reaction step 3 is in the range of about 1 to about 4 hours. A longer reaction time is possible, but economically not usually useful.

For working up the reaction mixture, the solvent or diluent is separated off and the remaining residue is stirred with water. The compounds of the formula (I) can then be isolated, for example by separating off the precipitated crystals (cf. Preparation Example 1) or by chromatographic purification.

The compounds of the formula (I) are obtained by the process according to the invention in good yields and in high purity. Significantly better yields can be achieved with the process according to the invention than with the processes described in WO 2017/005673 A1 or the European patent application with the application number 17204401.8.

It has also been found that the process according to the invention can be carried out in a preferred embodiment as a one-pot process. In this case, the intermediates of the formulas (III) and (V) are not isolated and optionally purified. It is also possible to carry out the process so as to isolate the intermediate of the formula (III), but not the intermediate of the formula (V). It is also possible to carry out the process in such a way that the intermediate of the formula (III) is not isolated, but the intermediate of the formula (V) is. Explanation of processes and intermediates

The products were characterized by I-NMR spectroscopy and / or LC / MS (Liquid Chromatography Mass Spectrometry).

The determination of the logP values was carried out according to OECD Guideline 117 (EC Directive 92/69 / EEC) by HPLC (High Performance Liquid Chromatography) on reversed-phase (RP) columns (CI 8), using the following methods:

[a] The determination with the LC-MS in the acidic range is carried out at pH 2.7 with 0.1% aqueous formic acid and acetonitrile (containing 0.1% formic acid) as eluent; linear gradient from 10% acetonitrile to 95% acetonitrile.

[b] The determination with the LC-MS in the neutral range is carried out at pH 7.8 with 0.001 molar aqueous ammonium bicarbonate solution and acetonitrile as eluent; linear gradient from 10% acetonitrile to 95% acetonitrile.

The calibration is carried out with unbranched alkan-2-ones (with 3 to 16 carbon atoms) whose logP values are known (determination of the logP values by means of the retention times by linear interpolation between two consecutive alkanones).

The NMR spectra were determined on a Bruker Avance 400 equipped with a flowhead probe (60 pl volume). In individual cases the NMR spectra were measured with a Bruker Avance II 600.

Examples:

The present invention will be explained in more detail with reference to the following examples, without limiting the invention to these.

Example 1: (according to the invention)

[1- [6-trifluoromethyl-pyridin-3-yl] -2- (1/7) -pyridinylidenes] cyanamide (1-1)

 Step 1: Synthesis of Compounds of Formula (III)

2-chloro-1- (6-trifluoromethylpyridin-3-yl) pyridinium chloride (III-1)

1.0 g (4.16 mmol) of 6'-trifluoromethyl- [l (2 //), 3'-bipyridin] -2-one (II-1) (for the preparation see WO 2017/005673 A1) with 4.93 g (32.18 mmol, 3.0 ml) of phosphoryl chloride at 80 ° C for 1.5 hours. The reaction mixture was then concentrated to dryness in vacuo and the obtained 2-chloro-l- (6-trifluoromethyl-pyridin-3-yl) -pyridinium chloride (II-1) reacted further in step 2 directly.

Step 2: Synthesis of Compounds of Formula (V)

[1- [6-trifluoromethylpyridin-3-yl] -2- (methylthio) pyridinium chloride (V-1)

1.23 g (4.16 mmol) of 2-chloro-1- (6-trifluoromethyl-pyridin-3-yl) -pyridinium chloride (III-1) were initially charged in 20 ml of acetonitrile, with 0.87 g (12 , 48 mmol) sodium methylthiolate (IV-1) and stirred for 18 hours at room temperature. Subsequently, the reaction mixture without isolation of the formed [l- [6-trifluoromethyl-pyridin-3-yl] -2- (methylthio) -pyridinium-chloride (V-l) according to step 3 was further reacted directly.

Step 3: [1- [6-Trifluoromethylpyridin-3-yl] -2 (1/7) pyridinylidenes] cyanamide (1-1)

1.28 g (4.16 mmol) of [1- [6-trifluoromethylpyridin-3-yl] -2- (methylthio) -pyridinium chloride (VI) from step 2, dissolved in 20 ml of acetonitrile, were charged with 0 , 53 g (8.31 mmol) Natriumhydrogencyanamid added and stirred for 2 hours at room temperature. For workup, the reaction mixture was concentrated in vacuo and the remaining residue was stirred with water. The precipitated crystals were separated and dried. 981 mg (93.1% purity, 89.27% yield) of [1- [6-trifluoromethyl-1-pyridin-3-yl] -2 (I A7) -pyridinyl-idcuc were obtained cyanamide (I-1).

Example 2: (described in WO 2017/005673 A1)

[1- [6-trifluoromethyl-pyridin-3-yl] -2- (1/7) -pyridinylidenes] cyanamide (3)

Synthesis of 2-chloro-1- (6-trifluoromethyl-pyridin-3-yl) -pyridinium chloride (2)

To 1.0 g (4.16 mmol) of 6'-trifluoromethyl- [l (2 //), 3'-bipyridin] -2-one (1) dissolved in 40 ml of dichloromethane was added 1.9 ml ( 20.8 mmol) of phosphoryl chloride and a drop / V, / V dimethylformamide. Thereafter, the reaction mixture was stirred at reflux temperature for 6 hours. The reaction mixture was then concentrated to dryness in vacuo and the isolated 2-

Chloro- (6-trifluoromethyl-pyridin-3-yl) -pyridinium chloride (2) further reacted according to step 3 directly.

Synthesis of [1- [6-trifluoromethyl-pyridin-3-yl] -2 (1 //) -pyridinylidenenes] cyanamide (3) 1.2 g (4.16 mmol) of 2-chloro-1- (6-trifluoromethyl -pyridin-3-yl) -pyridinium chloride (2) were dissolved in 80 ml

Stirred acetonitrile, with 192.4 mg (4.57 mmol) of cyanamide and 661.1 mg (4.78 mmol) of potassium carbonate and stirred for about 18 hours at room temperature. For workup, the precipitated salts were filtered off. Subsequently, the entire reaction mixture was concentrated in vacuo and the remaining crude product by column chromatography on silica gel (mobile phase: Cy clohexan - acetone gradient). This gave 310 mg (99.04% purity, 28.2% yield) of [1- [6-trifluoromethyl-1-pyridin-3-yl] -2 (1H) -pyridinylidenes] cyanamide.

Example 3: (according to the invention)

[1- [6-Difluoromethyl-pyridin-3-yl] -2- (1/7) -pyridinylidenes] cyanamide (1-2)

Schritt 1: Synthese von Verbindungen der Formel (III) 2-Chlor-l-(6-difluormethyl-pyridin-3-yl)-pyridinium-chlorid (III-2)

Step 1: Synthesis of compounds of the formula (III) 2-chloro-1- (6-difluoromethyl-pyridin-3-yl) -pyridinium chloride (III-2)

1.08 g (4.87 mmol) of 6'-difluoromethyl- [l (2 //), 3'-bipyridin] -2-one (II-2) (for the preparation see European patent application with the application number 17204401.8) were stirred with 5.77 g (37.65 mmol, 3.0 ml) of phosphoryl chloride at 80 ° C for 1.5 hours. The reaction mixture was then concentrated to dryness in vacuo to give 1.35 g (99.9% of theory) of 2-chloro-1- (6-difluoromethylpyridin-3-yl) -pyridinium chloride (III-2 ), which was implemented directly in accordance with step 2. Step 2: Synthesis of Compounds of Formula (V)

[1- [6-Difluoromethylpyridin-3-yl] -2- (methylthio) pyridinium chloride (V-2)

1.35 g (4.87 mmol) of 2-chloro-1- (6-difluoromethyl-pyridin-3-yl) -pyridinium chloride (III-2) were initially charged in 30 ml of acetonitrile, with 0.68 g (9 , 73 mmol) sodium methyl thiolate (IV-1) and stirred for 18 hours at room temperature. After filtration of the reaction mixture was eingeingt and the formed 1.41 g (99.8% of theory) of [l- [6-difluoromethylpyridin-3-yl] -2- (methylthio) pyridinium chloride (V-2) implemented directly in accordance with step 3.

Step 3: [1- [6-Difluoromethyl-pyridin-3-yl] -2 (1/7) -pyridinylidenes] cyanamide (1-2)

1.40 g (4.86 mmol) of [1- [6-difluoromethyl-pyridin-3-yl] -2- (methylthio) -pyridinium chloride (V-2) from step 2 dissolved in 15 ml of acetonitrile 0.62 g (8.31 mmol) Natriumhydrogencyanamid and stirred for 2 hours at room temperature. For workup, the reaction mixture was in Concentrated vacuum and the residue remaining on kieselguhr and purified by column chromatography on silica gel (mobile phase: cyclohexane - acetone gradient). This gave 510 mg (99.4% purity, 42.3% yield) of 1 1 - [6-l] i 11 uormctliyl-pyridine n-3-yl -2 (I //) - pyridmylidecnc | cyanamide (1-2). Example 4: (described in the European patent application with the application number 17204401.8)

[1- [6-Difluoromethyl-pyridin-3-yl] -2- (1/7) -pyridinylidenes] cyanamide (7)

Synthesis of 6'-I) ifluoromethyl [1 (2 //), 3'-bipyridine] -2-thione (5)

1,20 g (5,4 mmol) 6‘-Difluormethyl-[l(2//), 3‘-bipyridin]-2-on (4) und 4,53 g (54,0 mmol)

1.20 g (5.4 mmol) of 6'-difluoromethyl [l (2 //), 3'-bipyridin] -2-one (4) and 4.53 g (54.0 mmol)

Sodium bicarbonate was stirred in 40 ml of 1,4-dioxane. After addition of 6.00 g (27.0 mmol) of diphosphorus pentasulfide, the reaction mixture was stirred at 80 ° C. for about 18 hours. For workup, the reaction mixture was filtered after cooling over Celite, it was rinsed with dichloromethane and concentrated in vacuo to dryness. The remaining residue was purified by column chromatography on silica gel (gradient: cyclohexane-acetone). There were obtained 0.88 g (68.3% of theory) of ethyl acetate (1: 1, 2'-bipyridine) -2-thione (5).

Synthesis of [1- [6-difluoromethylpyridin-3-yl] -2- (methylthio) pyridinium iodide (6)

850,0 mg (3,5 mmol) 6‘-Difluormethyl-[l(2H), 3‘-bipyridin]-2-thion (5) wurden in 50 ml Acetonitril vorgelegt, mit 5063,6 mg (35,6 mmol) Iodmethan versetzt und ca. 18 Stunden bei Raumtemperatur gerührt. Die Kontrolle mittels LC-MS zeigte, dass die Reaktion beendet war. Anschließend wurde der Reaktionsansatz im Vakuum eingeengt und das verbleibende Rohprodukt (6) ohne weitere Reinigung im nachfolgenden Reaktionsschritt umgesetzt.

850.0 mg (3.5 mmol) of 6'-difluoromethyl [l (2H), 3'-bipyridine] -2-thione (5) were initially charged in 50 ml of acetonitrile, with 5063.6 mg (35.6 mmol ) Iodomethane and stirred for about 18 hours at room temperature. Control by LC-MS showed that the reaction was complete. Subsequently, the reaction mixture was concentrated in vacuo and the remaining crude product (6) reacted without further purification in the subsequent reaction step.

Synthesis of [1- [6-Difluoromethylpyridin-3-yl] -2- (l / 7) -pyridinylidenes] cyanamide (7)

To 1330.6 mg (3.5 mmol) of [1- [6-difluoromethylpyridin-3-yl] -2- (methylthio) -pyridinium iodide (6) dissolved in 50 ml of acetonitrile was added 448.1 mg (7.0 mmol) sodium hydrogen cyanamide. Subsequently, the reaction mixture was stirred at room temperature for 18 hours. For workup, the reaction mixture was filtered, the organic phase concentrated in vacuo and the remaining residue purified by column chromatography on silica gel (mobile phase gradient: cyclohexane: acetone gradient). This gave 789.0 mg (91.5% of theory) of [1- [6-difluoromethylpyridin-3-yl] -2 (1 H) -pyridinylidenecyanamide (7).

Claims

claims 1. Process for the preparation of compounds of the formula (I)

wherein the structural unit of the formula

(a) for a residue A from the series

where these radicals carry m substituents X, X is a radical selected from halogen, cyano (CN), nitro, alkyl, alkoxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, Haloalkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, m is a number from the series 0, 1 and 2, R for a rest B from the series

where these radicals carry n substituents Y and the dashed line denotes the bond to the nitrogen atom in the radical A, Y is a radical selected from halogen, cyano, nitro, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfoxyl, haloalkylsulfoxyl, alkylsulfonyl, haloalkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, alkylamino, dialkylamino, alkylaminosulfonyl , Dialkylaminosulfonyl, Alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, Alkoxyalkylcarbonylamino, haloalkylcarbonylamino, each optionally substituted aryl and hetaryl, n is a number from the series 0, 1 and 2, or (β) for the rest

R for the rest

B 3 stands. wherein the dashed line represents the bond to the nitrogen atom in the rest of Al and Yi substituted for a radical from the series cyano- haloalkyl, Ci-C _t haloalkoxy, Ci- _{C4-haloalkylthio, Ci-C4-haloalkylsulfinyl,} Ci-C ₄ haloalkylsulfonyl, optionally substituted by halogen, _{Ci-C4-alkoxy-Ci-C4-alkyl,} optionally substituted by halogen C ₁ -C ₄ - alkylthio-C ₁ -C ₄ -alky 1, C ₁ -C ₄ - alkylsulphinyl -C ₁ -C ₄ alkyl, C ₁ -C ₄ - alkylsulfonyl Ci-C ₄ is substituted alkyl and by halo, cyano, alkyl or haloalkyl, cycloalkyl, which is characterized in that in a first reaction step compounds of the formula (II)

in which R, A ¹ , A ² , A ³ and A ^{4 have} the abovementioned meanings, with the aid of a halogenating agent in compounds of the formula (III) (III)

Hai X ^' in which Hal is a halogen atom and X is a halide anion, and then converted in a second reaction step with an alkyl thiolate of the formula (IV) R ^ SM ⁺ (IV), wherein R ^{1 is} an alkyl radical and M ⁺ for a Cation, to compounds of formula (V)

reacted, and then reacted in a third reaction step in the presence of a cyanamide and optionally in the presence of a base to compounds of formula (I). 2. The method according to claim 1, which is carried out without isolation of the compounds of formulas (III) and (V). 3. Process according to Claim 1 or 2 for the preparation of compounds of the formula (I)

wherein the structural unit of the formula

for the rest Al

 A-1 stands, R for the rest

 B-3 "stands and Y2 is a radical selected from fluoromethyl, difluoromethyl, trifluoromethyl, difluorochloromethyl, difluorobromoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and pentafluoroethyl.