TW201946902A - Method for preparing nitrogen-containing heterocycles - Google Patents

Abstract

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

Description

Method for preparing nitrogen-containing heterocyclic compound

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

Compounds of formula (I) and their insecticidal properties are known (see WO 2017/005673 A1 and European Patent Application No. 17204401.8).

To date, such compounds have been synthesized by multi-step unsatisfactory yield of the obtained (see, e.g. [1- [6-trifluoromethyl-pyridin-3-yl] -2- (1 H) pyridylene Synthesis of cyanamide, WO 2017/005673 A1). As an intermediate product in this case, substituted [1 (2H), 3'-bipyridine] -2-thione and its preparation are known.

The disadvantages of the previously known methods are unsatisfactory overall yields and, if necessary, the isolation and purification of intermediate products, because the method makes considerable efforts in terms of time, yield loss, and cost on the preparation scale .

WO 2017/005673 A1 describes the preparation of compounds of the formula

Where the structural unit of the formula

For example, optionally substituted 2 (1H) -pyridine subunit (for example, A1, A2, A3, A4 = CH), which is substituted at the N position by a group R, and wherein W-R1 is a group = N-CN The halogen is activated by cyanamide exchange (Scheme 1).
Process 1 :

In particular, WO2017 / 005673 A1 describes the preparation of [1- [6-trifluoromethyl-pyridin-3-yl] -2 (1H) -pyridinyl] cyanamide (compound (3)), which is a compound Starting with 6'-trifluoromethyl- [1 (2H), 3'-bipyridyl] -2-one (1) and phosphonium chloride as the starting material, the second one contains N, N-dimethylformamide Bipyridine synthesized in the presence of methyl chloride (see Scheme 2).
Process 2 :

In this case, 5 times the equivalent molar amount of phosphonium chloride was added to 6'-trifluoromethyl- [1 (2H), 3'-bipyridine] -2-one (1), and The isolated 2-chloro-1- (6-trifluoromethylpyridin-3-yl) pyridinium chloride (2) is reacted with an equimolar amount of cyanamide in the presence of acetonitrile of potassium carbonate. The desired product (3) was obtained in a yield of 28%.

The method described in WO2017 / 005673 A1 is disadvantageous because the halogen atoms are not sufficiently exchanged with the only weakly basic amine group of cyanamide. This resulted in a low yield of only 28%.

European Patent Application No. 17204401.8 describes the preparation of various compounds of formula (Ia) by exchanging activated methylthio with sodium cyanamide (Scheme 3).
Process 3 :

Specifically, the preparation of [1- [6-difluoromethylpyridin-3-yl] -2 (1H) pyridinyl] cyanamide (compound (7)) is described. Synthesized in the presence of 1,4-dioxane using 6'-difluoromethyl- [1 (2H), 3'-bipyridine] -2-one and phosphorus pentasulfide as starting materials and then using methyl iodide S-methylation was performed in acetonitrile (Scheme 4).
Process 4 :

In this case, sodium bicarbonate in an amount equal to 10 times the molar amount is added to the compound (4), and vulcanization is performed in the presence of 5 times the equivalent amount of phosphorus pentasulfide. The isolated and purified 6'-difluoromethyl- [1 (2H], 3'-bipyridine] -2-thione (5) is then reacted with 10 times the equivalent molar amount of methyl iodide, and then The isolated [1- [6-difluoromethylpyridin-3-yl] -2- (methylthio) pyridinium iodide (6) and 2 times the equivalent molar amount of sodium cyanamide were mixed in acetonitrile. At first, 6'-difluoromethyl- [1 (2H)], 3'-bipyridyl] -2-thione (5) was obtained in a yield of 68%, and then it was passed through in a yield of 91.5%. Conversion to get the desired product.

The method described in European Patent Application No. 17204401.8 for preparing compounds of formula (Ia) is disadvantageous because the compounds of formula (IVa) must be isolated and purified before S-methylation. In addition, for reasons of atomic economy, the use of P ₄ S ₁₀ is uneconomical because it results in a large amount of phosphorus and sulfur waste. This resulted in a loss of overall yield with only 68% yield of the sulfur compound.

In addition, the method described in the European patent application with application number 17204401.8 requires the use of iodomethane that is harmful to health in excess of 10 times the molar amount.

Therefore, there is a need to find a method for preparing a specified compound that is cost-effective and can be used on an industrial scale. There is also a need to obtain these compounds in high yields and high purity so that they do not have to undergo any other complicated purification.

A simplified method for the preparation of certain nitrogen-containing heterocyclic compounds has been found which avoids the disadvantages of the known methods and is simple to implement and cost-effective and can be used industrially.

Accordingly, the present invention relates to a method for preparing a compound of formula (I)
,
Where the structural unit of the formula

(α) is a group A in the following series

Where these groups carry m substituents X,
X is a group in the following series: halogen, cyano (CN), nitro, alkyl, alkoxy, alkylthio, alkylthiooxy, alkanesulfonyl, haloalkyl, haloalkoxy, Haloalkylthio, haloalkylsulfonyl, alkoxycarbonyl, alkylcarbonyl and cycloalkylcarbonyl,
m is a value in the 0, 1 and 2 series,
R is a group B in the following series

Where these groups carry n substituents Y and the dashed line represents the bond with the nitrogen atom in group A,
Y is a group in the following series: halogen, cyano, nitro, amine, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio , Alkylthiooxy, haloalkylthiooxy, alkylsulfonyl, haloalkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, alkylamino, dialkylamino, alkyl Alkylaminosulfonyl, dialkylaminosulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkoxyalkylcarbonylamino, haloalkylcarbonylamino, In the case, optionally substituted aryl and heteroaryl,
n is a value in the 0, 1 and 2 series, or
(β) is a group
,
R is a group
,
Where the dotted line represents the bond with the nitrogen atom in the group A-1, and
Y ₁ is a group of the following series: a cyano-substituted haloalkyl, C ₁ -C ₄ - haloalkoxy, C ₁ -C ₄ - haloalkyl group, C ₁ -C ₄ - alkylimino halo Sulfonyl, C ₁ -C ₄ -haloalkanesulfonyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl optionally substituted with halogen, C _1- C ₄ -Alkylthio-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylsulfinamilide _- C _1- C ₄ -alkyl, C ₁ -C ₄ -alkylsulfonyl- C ₁ -C ₄ -alkyl; and cycloalkyl substituted with halogen, cyano, alkyl or haloalkyl,
It is characterized in that in the first step, the compound of formula (II)
,
Where R, A ¹ , A ² , A ³ and A ⁴ have the above definitions,
Conversion to a compound of formula (III) by means of a halogenating agent
,
Where Hal is a halogen atom and X ^- is a halide anion,
And then these compounds are reacted with an alkyl thiolate of formula (IV) in a second reaction step
R ¹ -S ^- M ⁺ (IV),
Where R ¹ is an alkyl group and M ⁺ is a cation,
To obtain a compound of formula (V),

And these compounds are then reacted in the third reaction step in the presence of cyanamide and optionally in the presence of a base to obtain a compound of formula (I).

Preference is given to the preparation of compounds of formula (I)
,
Where the structural unit of the formula

(α) is a group A in the following series

Where these groups carry m substituents X,
X is a group in the following series: halogen, cyano, nitro, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₄ -alkylthiooxy, C ₁ -C ₄ -alkylsulfonyl, halo-C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkoxy, halo-C ₁ -C ₄ -alkylthio, halo-C ₁ -C ₄ -alkanesulfonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -alkylcarbonyl and C ₃ -C ₆ -ring Alkylcarbonyl,
m is a value in the 0, 1 and 2 series,
R is a group B in the following series

Where these groups carry n substituents Y and the dashed line represents the bond with the nitrogen atom in group A,
Y is a group in the following series: halogen, cyano, nitro, amine, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, halo- C ₁ -C ₄ - alkyl, C ₁ -C ₄ - alkoxy, halo -C ₁ -C ₄ - alkoxy, C ₁ -C ₄ - alkylthio, halo -C ₁ -C ₄ - alkylthio, C ₁ -C ₄ - alkylthio group, halo -C ₁ -C ₄ - alkylthio group, C ₁ -C ₄ - alkylsulfonyl group, halo -C ₁ - C ₄ -alkanesulfonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -alkylcarbonyl, C ₃ -C ₆ -cycloalkylcarbonyl, C ₁ -C ₄ -alkylamino, Di (C ₁ -C ₄ -alkyl) amino, C ₁ -C ₄ -alkylaminosulfonyl, di (C ₁ -C ₄ -alkyl) aminosulfonyl, C ₁ -C _4- Alkylaminocarbonyl, di (C ₁ -C ₄ -alkyl) aminocarbonyl, C ₁ -C ₄ -alkylcarbonylamino, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl Carbonylamino, halo-C ₁ -C ₄ -alkylcarbonylamino, optionally substituted aryl in each case, and 5- to 6-membered heteroaryl, and
n is a value in the 0, 1 and 2 series, or
(β) is a group
, And
R is a group
,
among them
Y ₁ is a group in the following series: cyanofluoromethyl, cyanodifluoromethyl, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2 -Trifluoroethoxy, difluoromethylthio, trifluoromethylthio, difluoromethylsulfinyl, trifluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethyl Sulfosulfenyl, H ₃ COF ₂ C, H ₃ CSF ₂ C, H ₃ CS (O) -F ₂ C, H ₃ CO ₂ SF ₂ C, H ₃ CSH ₂ C, H ₃ CS (O) -H ₂ C, H ₃ CO ₂ SH ₂ C, 1-fluorocyclopropyl, 1-cyanocyclopropyl and 1-trifluoromethylcyclopropyl.

Particular preference is given to the preparation of compounds of formula (I)
,
Where the structural unit of the formula

(α) is a group A in the following series

Where these groups carry m substituents X,
X is a group in the following series: halogen, cyano, C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkyl,
m is a value in the 0, 1 and 2 series,
R is a group B in the following series
,
Where these groups carry n substituents Y and the dashed line represents the bond with the nitrogen atom in group A,
Y is a group in the following series: halogen, cyano, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, halo-C ₁ -C _4- Alkyl, halo-C ₁ -C ₄ -alkoxy, halo-C ₁ -C ₄ -alkylthio, C ₁ -C ₄ -alkylthiooxy, halo-C ₁ -C _4- alkylthio group, C ₁ -C ₄ - alkylsulfonyl groups, halo -C ₁ -C ₄ - alkylsulfonyl group optionally substituted by the following series of five heteroaryl group obtained: Halo, cyano, C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkoxy, halo-C ₁ -C ₄ -alkanesulfide group, C ₁ -C ₄ - alkylthio group, halo -C ₁ -C ₄ - alkylthio group, C ₁ -C ₄ - alkyl sulfonic acyl, halo -C ₁ -C ₄ - alkoxy Sulfonyl, where heteroaryl represents, for example, N -pyrazolyl, N -imidazolyl, or N -1,2,4-triazolyl, and
n is a value in the 0, 1 and 2 series, or
(β) is a group
, And
R is a group
,
among them
Y ₁ is a group in the following series: cyanofluoromethyl, cyanodifluoromethyl, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2 -Trifluoroethoxy, difluoromethylthio, trifluoromethylthio, difluoromethylsulfinyl, trifluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethyl Sulfonyl, H ₃ COF ₂ C, H ₃ CSF ₂ C, H ₃ CS (O) -F ₂ C, H ₃ CO ₂ SF ₂ C, H ₃ CSH ₂ C, H ₃ CS (O) -H ₂ C, H ₃ CO ₂ SH ₂ C, 1-fluorocyclopropyl, 1-cyanocyclopropyl and 1-trifluoromethylcyclopropyl.

Very particular preference is given to the preparation of compounds of formula (I)
,
Where the structural unit of the formula

(α) is a group A-1

Where these groups carry m substituents X,
X is a group in the following series: fluorine, chlorine, methyl, ethyl, trifluoromethyl and difluoromethyl,
m is a value in the 0, 1 and 2 series,
R is a group in the following series

Where these groups carry n substituents Y and the dashed line represents the bond with the nitrogen atom in group A,
Y is a group in the following series: fluorine, chlorine, bromine or iodine, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluorochloromethyl, difluorobromomethyl, 2 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, difluoro Methylsulfinyl, trifluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, N-triazolyl, and pyrazolyl, the pyrazolyl is optionally as follows Substituents in the series: fluorine, chlorine, iodine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, and methylthio,
n is a value in the 0, 1 and 2 series, or
(β) is a group
, And
R is a group
,
among them
Y ₁ is a group of the following families: cyano fluoromethyl, difluoromethyl cyano, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2 -Trifluoroethoxy, difluoromethylthio, trifluoromethylthio, difluoromethylsulfinyl, trifluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfonyl Fluorenyl, H ₃ COF ₂ C, H ₃ CSF ₂ C, H ₃ CS (O) -F ₂ C, H ₃ CO ₂ SF ₂ C, H ₃ CSH ₂ C, H ₃ CS (O) -H ₂ C , H ₃ CO ₂ SH ₂ C, 1-fluorocyclopropyl, 1-cyanocyclopropyl, and 1-trifluoromethylcyclopropyl.

In addition, very particular preference is given to the preparation of compounds of formula (I)
,
Where the structural unit of the formula

For group A-1
,
R is a group
And
Y ₂ is a group in the following series: difluoromethyl, trifluoromethyl, difluorochloromethyl, difluorobromomethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl base.

Compounds of formula (I) can be prepared in good yields by the method according to the invention.

The reaction sequence for preparing a compound of formula (I) according to the present invention is shown in Scheme 5:
Process 5

In Reaction Scheme 5, the structural unit

And R has the definition given above. Hal is a halogen atom such as chlorine or bromine. X ^- is a halide ion, such as a chloride ion or a bromide ion. M ⁺ is sodium ⁺ , potassium ⁺ , cesium ⁺ , ½ calcium ⁺⁺ , or tetramethylammonium ion, tetraethylammonium ion or tetraphenylphosphonium ion. R ¹ is C ₁ -C ₆ alkyl, preferably methyl or ethyl, or benzyl.

According to the method of the present invention, a compound of formula (II) is reacted in a first reaction step in the presence of a suitable halogenating agent to form an activated halogen compound of formula (III), which is then converted into a second reaction step into A compound of formula (V) which is reacted in a third reaction step to obtain a compound of formula (I).

Compounds of formula (II) (wherein R, A1, A2, A3 and A4 have the above definitions) and their preparation are known (see WO 2017/005673 A1 and European Patent Application No. 17204401.8).

If in the method according to the present invention, 6'-trifluoromethyl- [1 (2H), 3'-bipyridyl] -2-one (A1, A2, A3, A4 = CH; R = 6-trifluoro Methylpyridin-3-yl) (II-1) is used as a compound of formula (II), and initially 2-chloro-1- (6-trifluoromethylpyridin-3-yl) pyridinium chloride (III-1 ^{) (Hal = Cl, X -} = Cl -) by reaction with a chlorinating agent to form, in a second reaction step, the chlorinating agent used, for example sodium methanethiolate (IV-1) reacted to give [1- [6-trifluoromethyl-pyridin-3-yl] -2- (methylthio) pyridinium chloride ^{(V-1) (X -} = Cl -). And then reacted with cyanamide to obtain [1-6-trifluoromethylpyridin-3-yl] -2 (1H) -pyridinyl] cyanamide (R = 6-trifluoromethylpyridine) of formula (I-1) -3-yl); A1, A2, A3, A4 = CH) (Scheme 6, see Preparation Example 1).
Flow 6

Reaction step 1:

According to the present invention, activation is performed using a halogenating agent such as thionyl chloride, phosgene, diphosgene, triphosgene, ethylene dichloride, phosphorous chloride, phosphorus pentachloride, and phosphorous bromide (halogenation, reaction step 1) . Preference is given to phosphonium chloride and thionyl chloride. When phosphorus or phosphorus pentabromide acyl bromo, to form the corresponding substituted pyridinium bromide (X ^- = Br ^-). The halogenation step is accelerated by adding a catalyst. Suitable catalysts are N, N -dimethylformamide , N, N -dibutylformamide, pyridine or formidine. Reaction step 1 is usually carried out under standard pressure. The reaction can also be performed under pressure, such as when using phosgene or thionyl chloride. In reaction step 1, the molar ratio of the halogenating agent to the compound of formula (II) is, for example, in the range of about 12 to about 1. The ratio is preferably in the range of about 10 to about 2, and particularly preferably in the range of about 6 to 2. Large amounts of halogenating agents can be used in principle, but are generally not economical.

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

The reaction step 1 is usually performed in a temperature range of 20 ° C to 120 ° C, and optionally in the presence of a solvent or a diluent. The reaction is preferably carried out at about 80 ° C without solvents or diluents.
Reaction step 2:

In a second reaction step, a compound of formula (III) is converted by reaction with an alkyl thiolate of formula (IV) to obtain a compound of formula (V).

In reaction step 2, the molar ratio of the alkyl thiolate (IV) to the halogen compound of formula (III) may be, for example, in the range of about 6 to about 1. The ratio is preferably in the range of about 4.5 to about 1.5, and particularly preferably in the range of about 3.5 to 2. Large amounts of alkylthiolates (IV) can be used in principle, but are generally not economical.

Suitable alkyl thiolates are sodium methanethiolate or sodium ethanethiolate (eg, NaSMe, NaSEt), potassium methanethiolate or potassium ethanethiolate (eg, KSMe, KSEt) or PhCH ₂ SNa. It is also possible to use a thiol compound (R ¹ SH) in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide. Alkyl mercaptans and alkyl mercaptans are commercially available. In reaction step 2, the molar ratio of the alkyl thiolate (IV) to the base may be, for example, in the range of about 1 to 0.5. The base and alkyl thiolate are preferably used stoichiometrically.

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

Reaction step 2 is usually carried out in a temperature range of 0 ° C to 40 ° C. The reaction is preferably carried out in a solvent or diluent at room temperature.
Reaction step 3:

In reaction step 3, the molar ratio of the cyanamide to the compound of formula (V) may be, for example, in the range of about 5 to about 1. The ratio is preferably in the range of about 4 to about 1.5, and particularly preferably in the range of about 3 to 2. Large amounts of cyanamide can be used in principle, but are generally not economical.

Reaction step 3 is usually carried out in the presence of a base. Suitable are inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, cesium hydroxide, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide , Sodium tert-butoxide, potassium tert-butoxide or potassium fluoride), or organic bases (such as trialkylamine, pyridine, alkylpyridine (methylpyridine)), phosphazene, and 1,8-diaza Heterobicyclo [5.4.0] undecene (DBU). Preference is given to sodium carbonate, potassium carbonate, potassium acetate and sodium methoxide.

In step 3, the formula NH ₂ CN cyanamide. It is also possible to separately prepare sodium or potassium cyanamide (NaNHCN or KNHCN) and use it in reaction step 3 without the need for an additional base.

Reaction step 3 is usually carried out in a temperature range of 0 ° C to 40 ° C. The reaction is preferably carried out in a solvent or diluent at room temperature.

Suitable solvents or diluents for reaction steps 1, 2 and 3 under reaction conditions include all inert organic solvents such as aliphatic or aromatic hydrocarbons (such as petroleum ether, toluene), halogenated hydrocarbons (such as chlorotoluene, dichloride Methane, chloroform, 1,2-dichloroethane), ethers (such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane), esters (such as ethyl acetate or methyl acetate), nitrate Hydrocarbons (such as nitromethane, nitroethane, nitrobenzene), nitriles (such as acetonitrile, benzonitrile), amidine (such as N, N-dimethylformamide, N, N-dimethyl Acetamide, N-methylformanilide, N-methylpyrrolidone, hexamethylphosphamide), and dimethylsulfine or water or a mixture of the solvents mentioned.

The preferred solvents or diluents in reaction step 1 are dichloromethane, dichloroethane, chloroform, toluene, chlorobenzene, isopropyl acetate, tetrahydrofuran and acetonitrile.

The reaction duration of reaction step 3 is in the range of about 1 to about 4 hours. Longer reaction times are possible, but generally uneconomical.

To work up the reaction mixture, the solvent or diluent is separated off and the remaining residue is stirred with water. The compound of formula (I) can then be isolated, for example, by isolating the precipitated crystals (see Preparation Example 1) or by purification by chromatography.

The method according to the invention provides the compound of formula (I) in good yields and high purity. With the method according to the invention, significantly better yields can be obtained than the method described in WO 2017/005673 A1 or the European patent application with application number 17204401.8.

It has also been found that the method according to the present invention can be implemented as a one-pot process in a preferred embodiment. In this case, the intermediate products of formulae (III) and (V) are not isolated and purified as appropriate. This method can also be implemented to isolate an intermediate product of formula (III), but not an intermediate product of formula (V). This method can also be implemented so as not to isolate the intermediate product of formula (III), but to isolate the intermediate product of formula (V).
Description of methods and intermediates

The product is characterized by ¹ H NMR spectroscopy and / or LC-MS (liquid chromatography mass spectrometry).

The LogP value is determined according to OECD Guideline 117 (EC Directive 92/69 / EEC) by HPLC (High Performance Liquid Chromatography) using a reversed-phase (RP) column (C18) according to the following method:
[a] Using 0.1% formic acid aqueous solution and acetonitrile (containing 0.1% formic acid) as eluents, perform LC-MS measurement in acidic range at pH 2.7; linear gradient from 10% acetonitrile to 95% acetonitrile.
[b] LC-MS measurement in the neutral range with 0.001 mol aqueous ammonium bicarbonate solution and acetonitrile as eluent at pH 7.8; linear gradient from 10% acetonitrile to 95% acetonitrile.

Calibration was performed using an unbranched alkane-2-one (having 3 to 16 carbon atoms) with a known logP value (logP value determined based on residence time by linear interpolation between two consecutive alkaneones).

NMR spectra were measured using a Bruker Avance 400 equipped with a flow probe (60 µl in volume). In individual cases, Bruker Avance II 600 was used to measure the NMR spectrum.

Example :
The invention is illustrated in more detail by the following examples, without limiting the invention to these examples.

Examples 1 : (Inventive)
[1- [6- Trifluoromethylpyridine -3- base ] -2 (1 H )- Pyridine subunit ] Cyanamide (I-1)

step 1 : formula (III) Synthesis of compounds
2- chlorine -1- (6- Trifluoromethylpyridine -3- base ) Pyridinium chloride (III-1)

1.0 g (4.16 mmol) of 6'-trifluoromethyl- [1 (2 H ), 3'-bipyridyl] -2-one (II-1) (for preparation, see WO 2017 / 005673A1) and 4.93 g (32.18 mmol; 3.0 ml) of phosphonium chloride was continuously stirred at 80 ° C for 1.5 hours. The reaction mixture was then concentrated to dryness under reduced pressure, and the 2-chloro-1- (6-trifluoromethylpyridin-3-yl) pyridinium chloride (II-1) obtained was further directly according to step 2 reaction.

step 2 : formula (V) Synthesis of compounds
[1- [6- Trifluoromethylpyridine -3- base ]-2-( Methylthio ) Pyridinium chloride (V-1)

At first, 1.23 g (4.16 mmol) of 2-chloro-1- (6-trifluoromethylpyridin-3-yl) pyridinium (III-1) chloride was charged into 20 ml of acetonitrile, and 0.87 g (12.48 mmol) was added. ) Sodium methyl mercaptan (IV-1), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then further reacted directly according to step 3 without isolating [1- [6-trifluoromethylpyridin-3-yl] -2- (methylthio) pyridinium chloride (V-1).

step 3 : [1- [6- Trifluoromethylpyridine -3- base ] -2- (1 H )- Pyridine subunit ] Cyanamide (I-1)
To 1.28 g (4.16 mmol) of [1- [6-trifluoromethylpyridin-3-yl] -2- (methylthio) pyridinium chloride (V- 1) 0.53 g (8.31 mmol) of sodium cyanamide was added, and the mixture was stirred at room temperature for 2 hours. For work-up, the reaction mixture was concentrated under reduced pressure, and the remaining residue was stirred with water. The precipitated crystals were separated and dehydrated. This gave 981 mg (93.1% purity, 89.27% yield) of [1- [6-trifluoromethylpyridin-3-yl] -2 (1H ) -Pyridylidene] cyanamide (I-1).

Examples 2 : (Described in 2017 / 005673A1)
[1-6- Trifluoromethylpyridine -3- base ] -2 (1 H )- Pyridine subunit ] Cyanamide (3)

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

To 1.0 g (4.16 mmol) of 6'-trifluoromethyl- [1 (2 H ), 3'-bipyridyl] -2-one (1) dissolved in 40 ml of methylene chloride was added 1.9 ml in sequence (20.8 mmol) of phosphonium chloride and a drop of N, N-dimethylformamide. The reaction mixture was then stirred at reflux temperature for 6 hours. The reaction mixture was then concentrated to dryness under reduced pressure, and the isolated 2-chloro-1- (6-trifluoromethylpyridin-3-yl) pyridinium chloride (2) was further reacted directly according to step 3.

[1-6- Trifluoromethylpyridine -3- base ] -2 (1 H )- Pyridine subunit ] Cyanamide (3) Of synthesis
Stir 1.2 g (4.16 mmol) of 2-chloro-1- (6-trifluoromethylpyridin-3-yl) pyridinium chloride (2) in 80 ml of acetonitrile and add 192.4 mg (4.57 mmol) of cyanide Amine and 661.1 mg (4.78 mmol) of potassium carbonate, and the mixture was stirred at room temperature for about 18 hours. For processing, the precipitated salt was filtered off. The entire reaction mixture was then concentrated under reduced pressure and the remaining crude product was purified by silica gel column chromatography (mobile phase: cyclohexane-acetone gradient). This gave 310 mg (99.04% purity, 28.2% yield) of [1-6-trifluoromethylpyridin-3-yl] -2 (1H ) -Pyridylidene] cyanamide.

Examples 3 : (Inventive)
[1- [6- Difluoromethylpyridine -3- base ] -2- (1 H )- Pyridine subunit ] Cyanamide (I-2)

step 1 : formula (III) Synthesis of compounds
2- chlorine -1- (6- Difluoromethylpyridine -3- base ) Pyridinium chloride (III-2)

1.08 g (4.87 mmol) of 6'-difluoromethyl- [1 (2 H ), 3'-bipyridyl] -2-one (II-2) (for preparation, see application number 17204401.8 European patent application) and 5.77 g (37.65 mmol; 3.0 ml) of phosphonium chloride were stirred at 80 ° C for 1.5 hours. The reaction mixture was then concentrated to dryness under reduced pressure, and 1.35 g (99.9% of theory) of 2-chloro-1- (6-difluoromethylpyridin-3-yl) pyridinium chloride obtained ( III-2) Further direct reaction according to step 2.

step 2 : formula (V) Synthesis of compounds
[1-6- Difluoromethylpyridine -3- base ]-2-( Methylthio ) Pyridinium chloride (V-2)

Initially, 1.35 g (4.87 mmol) of 2-chloro-1- (6-difluoromethylpyridin-3-yl) pyridinium (III-2) chloride was charged into 30 ml of acetonitrile, and 0.68 g (9.73 mmol) was added. ) Sodium methyl mercaptan (IV-1), and the mixture was stirred at room temperature for 18 hours. After filtration, the reaction mixture was concentrated, and 1.41 g (99.8% of theory) of the formed [1- [6-difluoromethylpyridin-3-yl] -2- (methylthio) pyridinium chloride was formed. (V-2) Further direct reaction according to step 3.

step 3 : [1- [6- Difluoromethylpyridine -3- base ] -2- (1 H )- Pyridine subunit ] Cyanamide (I-2)
To 1.40 g (4.86 mmol) of [1- [6-trifluoromethylpyridin-3-yl] -2- (methylthio) pyridinium chloride (V- 2) 0.62 g (8.31 mmol) of sodium cyanamide was added, and the mixture was stirred at room temperature for 2 hours. For processing, the reaction mixture was concentrated under reduced pressure, and the remaining residue was absorbed onto diatomaceous earth and purified by silica gel column chromatography (mobile phase: cyclohexane-acetone gradient). This gave 510 mg (99.4% purity, 42.3% yield) of [1- [6-difluoromethylpyridin-3-yl] -2 (1H ) -Pyridylidene] cyanamide (I-2).

Examples 4 : (Described in European Patent Application No. 17204401.8)
[1- [6- Difluoromethylpyridine -3- base ] -2 (1 H )- Pyridine subunit ] Cyanamide (7)

6'- Difluoromethyl -[1 (2H), 3'- Bipyridine ]-2- Thione (5) Of synthesis

Stir 1.20 g (5.4 mmol) of 6'-difluoromethyl- [1 (2 H ), 3'-bipyridyl] -2-one (4) and 4.53 g (54.0 mmol) of sodium bicarbonate at 40 in 1,4-dioxane. After adding 6.00 g (27.0 mmol) of phosphorus pentasulfide, the reaction mixture was stirred at 80 ° C. for about 18 hours. For work-up, the cooled reaction mixture was filtered through celite, rinsed with dichloromethane and concentrated to dryness under reduced pressure. The remaining residue was purified by silica gel column chromatography (gradient: cyclohexane-acetone). Thus, 0.88 g (68.3% of theory) of 6'-difluoromethyl- [1 (2 H ), 3'-bipyridine] -2-thione (5) was obtained.

[1- [6- Difluoromethylpyridine -3- base ]-2-( Methylthio ) Pyridinium iodide (6) Of synthesis

At first, 850.0 mg (3.5 mmol) of 6'-difluoromethyl- [1 (2H), 3'-bipyridyl] -2-thione (5) was charged into 50 ml of acetonitrile, and 5063.6 mg (35.6 mmol) of methyl iodide, and the mixture was stirred at room temperature for about 18 hours. LC-MS control showed the reaction was over. The reaction mixture was then concentrated under reduced pressure and the remaining crude product (6) was reacted in the next reaction step without further purification.

[1- [6- Difluoromethylpyridine -3- base ] -2 (1 H )- Pyridine subunit ] Cyanamide (7) Of synthesis
Add 448.1 to 1330.6 mg (3.5 mmol) of [1- [6-difluoromethylpyridin-3-yl] -2- (methylthio) pyridinium iodide (6) dissolved in 50 ml of acetonitrile mg (7.0 mmol) of sodium cyanamide. The reaction mixture was then stirred at room temperature for 18 hours. For processing, the reaction mixture was filtered, the organic phase was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (mobile phase gradient: cyclohexane: acetone gradient). This gave 789.0 mg (91.5% of theory) of [1- [6-difluoromethylpyridin-3-yl] -2 (1H ) -Pyridylidene] cyanamide (7).

Claims (3)

Method for preparing compound of formula (I) Where the structural unit of the formula (α) is a group A in the following series Where these groups carry m substituents X, X is a group in the following series: halogen, cyano (CN), nitro, alkyl, alkoxy, alkylthio, alkylthiooxy , Alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, and cycloalkylcarbonyl, m is in the 0, 1 and 2 series Value, R is the group B in the following series Where these groups carry n substituents Y and the dashed line represents the bond with the nitrogen atom in group A, Y is a group in the following series: halogen, cyano, nitro, amine, alkyl, alkylene Alkyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylthiooxy, haloalkylthiooxy, alkylsulfonyl, haloalkylsulfonyl, Alkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, alkylamino, dialkylamino, alkylaminosulfonyl, dialkylaminosulfonyl, alkylaminocarbonyl, dioxane Alkylaminocarbonyl, alkylcarbonylamino, alkoxyalkylcarbonylamino, haloalkylcarbonylamino, optionally substituted aryl and heteroaryl in each case, n is 0, 1 and 2 series The value in (or (β) is a group , R is a group , Where the dotted line represents the bond with the nitrogen atom in group A-1, and Y ₁ is a group in the following series: cyano-substituted haloalkyl, C ₁ -C ₄ -haloalkoxy, C ₁ -C ₄ -haloalkylthio, C ₁ -C ₄ -haloalkylsulfinyl, C ₁ -C ₄ -haloalkylsulfonyl, C ₁ -C ₄ -alkoxy-C ₁ optionally substituted with halogen -C ₄ -alkyl, optionally 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 substituted with halogen, cyano, alkyl, or haloalkyl, characterized in the first In the reaction step, a compound of formula (II) Where R, A ¹ , A ² , A ³ and A ⁴ have the above definitions and are converted into compounds of formula (III) by means of halogenating agents Wherein Hal is a halogen atom, and X ^- is a halogen anion, and subsequently in a second reaction step of such a compound with the formula (IV) salt of an alkyl mercaptan ^{R 1 -S - M + (IV} ), in which R ¹ Is an alkyl group and M ⁺ is a cation to obtain a compound of formula (V), And these compounds are then reacted in the third reaction step in the presence of cyanamide and optionally in the presence of a base to obtain a compound of formula (I). The method of claim 1 is performed without isolating the compound of formula (III) and the compound of formula (V). Process according to claim 1 or 2 for the preparation of a compound of formula (I) Where the structural unit of the formula For group A-1 R is a group And Y ₂ is a group of the following families: fluoromethyl, difluoromethyl, trifluoromethyl, difluorochloromethyl, difluoromethyl bromomethyl, 2,2-difluoroethyl, 2,2, 2-trifluoroethyl and pentafluoroethyl.