HK1066225B - Processes for preparing pesticidal intermediates - Google Patents

Description

Process for preparing pesticidal intermediates

The present application is a division of the parent application entitled "Process for the preparation of pesticidal intermediates", application number 00805760.5.

Technical Field

The present invention relates to a novel process for the preparation of intermediates (in particular certain arylamine compounds and arylhydrazine derivatives) useful in the preparation of pesticides.

Background

Published european patent nos. 0295117 and 0234119 describe the preparation of pesticidally active phenylpyrazole compounds and 5-amino-1-aryl-3-cyanopyrazole intermediate compounds for use in their synthesis.

Various methods for the preparation of these compounds are known. The present invention is directed to improved or more economical methods of preparing these pesticides and the intermediate compounds used to prepare them. 4-trifluoromethylaniline, 2-chloro-4-trifluoromethylaniline and 2, 6-dichloro-4-trifluoromethylaniline are valuable compounds for the synthesis of pesticidally active phenylpyrazole compounds. Various methods are known for preparing these compounds. However, their process costs are high, and the compounds are difficult to prepare, requiring multiple synthetic procedures. For example, published U.S. Pat. No. 4096185 describes the preparation of 4-trifluoromethylaniline from 4-chlorotrifluoromethyltoluene and ammonia in the presence of potassium fluoride and cuprous chloride in a Hastelloy vessel at 200 ℃. There remains a need to develop new methods for obtaining these compounds.

Disclosure of Invention

The applicants of the present invention have unexpectedly discovered a novel process for the preparation of certain substituted aromatic amines and aromatic hydrazines, thereby providing a novel process for the preparation of the important compound 5-amino-1-aryl-3-cyanopyrazole, which is a valuable intermediate for the preparation of pesticides.

Thus, the present invention provides a process (a) for preparing a compound of formula (I) or an acid addition salt thereof:

wherein R is¹Is haloalkyl (preferably trifluoromethyl), haloalkoxy (preferably trifluoromethoxy) or-SF₅；

W is N or CR³(ii) a And

R²and R³Each is hydrogen or chlorine;

the process comprises the hydrogenolysis of a compound of formula (II) or an acid addition salt thereof with a metal or metal compound (e.g. metal salt) under reducing conditions:

certain compounds of formula (I) and (II) are novel and therefore form a feature of the present invention.

In the present invention, unless otherwise specified, "haloalkyl" and "haloalkoxy" are each a straight-chain or branched alkyl or alkoxy group having 1 to 3 carbon atoms substituted with one or more halogen atoms selected from fluorine, chlorine and bromine.

The acid addition salts referred to in the present invention are preferably salts formed with strong acids, such as mineral acids, for example sulfuric acid or hydrochloric acid.

Hydrogenolysis can be carried out using a metal or metal salt selected from the group consisting of: raney nickel (a nickel-aluminum alloy) optionally in the presence of iron, manganese, cobalt, copper, zinc or chromium, stannous chloride, zinc in the presence of acetic acid, and molybdenum (III) salts. The reaction may also be carried out in the presence of hydrogen using raney nickel, platinum or palladium (which may be supported on carbon or other inert material). When the reaction is carried out under hydrogen, a pressure of from 2 to 20 bar (preferably from 5 to 10 bar) is generally employed. The hydrogenolysis is preferably carried out using raney nickel.

The reaction is generally carried out in a solvent which may be selected from alcohols such as methanol or ethanol, ethers and aromatic hydrocarbons (methanol and ethanol being preferred solvents).

The reaction temperature is usually 20 to 150 ℃, preferably 20 to 90 ℃, more preferably 50 to 80 ℃. Although a smaller amount of catalyst generally gives satisfactory results when the reaction is carried out under a hydrogen atmosphere, the amount of catalyst used is generally 0.01 to 3 molar equivalents (preferably 0.05 to 2 molar equivalents).

In the formulae (I) and (II) and in the formulae¹Preferably represents trifluoromethyl, trifluoromethoxy or-SF₅More preferably trifluoromethyl.

Particularly preferred compounds of the formula (I) are 2, 6-dichloro-4-trifluoromethylaniline, 2-chloro-4-trifluoromethylaniline and 4-trifluoromethylaniline. Process (A) seeks to be able to obtain the arylamine compounds of formula (I) in high yields from readily available starting materials. Furthermore, the reaction can be carried out simply and economically and the isolated product can be obtained directly. Another advantage of this process is that the compounds of formula (I) can be prepared at moderate temperatures and pressures, whereas the prior art processes require high temperatures.

If desired, the compounds of formula (I) may be purified by crystallization, for example from petroleum ether, to remove undesired isomeric products which may be present in minor amounts. In addition, crystallization at a later stage of the synthesis process is also effective.

The compound of formula (II) can be obtained by process (B) wherein a compound of formula (III) is reacted with hydrazine or an acid addition salt thereof or a source thereof:

the compounds of the formula (III) are known and can be prepared by known methods.

According to another characteristic of the invention, process (A) can be combined with process (B) to prepare the compound of formula (I) from the compound of formula (III).

Hydrazine hydrate is preferably used in process (B).

When an acid addition salt of hydrazine is used, a base such as a trialkylamine (e.g. triethylamine) is optionally present.

Particularly preferred compounds of the formula (II) are 2, 6-dichloro-4-trifluoromethylphenylhydrazine, 2-chloro-4-trifluoromethylphenylhydrazine and 4-trifluoromethylphenylhydrazine.

Process (B) may be carried out in a solvent selected from the group consisting of: cyclic or aliphatic ethers, such as tetrahydrofuran, 1, 4-dioxane or 1, 2-dimethoxyethane, N-methylpyrrolidone, dimethyl sulfoxide, N-dimethylformamide, tetramethylene sulfone, N' -tetramethylurea, aromatic hydrocarbons which may be substituted by one or more alkyl or chlorine atoms, such as chlorobenzene or xylene, alcohols, such as isopropanol, and pyridine. Preferred solvents include pyridine, tetrahydrofuran, N' -tetramethylurea and 1, 4-dioxane (pyridine and tetrahydrofuran are particularly preferred). The amount of solvent used is generally from 1 to 10ml (preferably from 4 to 8ml) per gram of compound of formula (III).

Process (B) is generally carried out in an autoclave or other sealed vessel. The pressure generally used is from 1 to 8 bar (preferably from 2 to 6 bar).

The reaction temperature for the process (B) is generally from 50 to 250 ℃ and preferably from 120 to 180 ℃. The reaction temperature is most preferably 120 ℃ to 150 ℃ where corrosion of the vessel and thermal decomposition of the products is minimized.

The reaction is generally carried out using from 1 to 20 molar equivalents (preferably from 4 to 8 molar equivalents) of hydrazine starting material.

Optionally, a catalyst may be used in process (B), which catalyst, when used, is typically selected from alkali and alkaline earth metal fluorides, such as potassium fluoride. The amount of the catalyst to be used is usually 0.05 to 2 molar equivalents (preferably 0.5 to 1 molar equivalent). The reaction can also be carried out in the presence of copper or copper salts, preferably copper (I) chloride.

According to another characteristic of the invention, process (A) or combined processes (A) and (B) give the compound of formula (I) which is purified by precipitation of the salt formed by treatment with a strong acid in the presence of an organic solvent.

The combination of processes (A) and (B) according to the invention is particularly valuable when used to prepare and react the important intermediate 2-chloro-4-trifluoromethylphenylhydrazine, since process (B) is carried out in high yield and, together with the other processes according to the invention, provides a process which is effective for obtaining the important insecticidal phenylpyrazole compounds. However, the preparation of 2-chloro-4-trifluoromethylphenylhydrazine often forms small amounts of undesirable contaminants of 2-chloro-5-trifluoromethylphenylhydrazine in addition to the desired isomer. It was found that this mixture can be used directly in the process (A) described below, followed by purification. Purification of 2-chloro-4-trifluoromethylaniline can be achieved by precipitation of a salt formed with a strong acid, preferably the hydrochloride salt, in the presence of an organic solvent. The hydrochloride can be obtained using hydrogen chloride gas or aqueous hydrochloric acid. The solvent is generally an alcohol, preferably ethanol, or a halogenated aromatic compound, preferably chlorobenzene, or a mixture thereof. This procedure enables the precipitation of the desired isomer as 2-chloro-4-trifluoromethylaniline hydrochloride salt, thereby efficiently removing the undesired 2-chloro-5-trifluoromethylaniline isomer in high yield and high purity.

According to a preferred feature of the invention, process (A) or processes (A) and (B) in combination, wherein R¹Is trifluoromethyl, W is CR³，R²Is chlorine, R³Is hydrogen, to give the compound of formula (I) which is purified by precipitation of the salt formed by treatment with a strong acid in the presence of an organic solvent.

In addition, when the method (B) is used for preparing 4-trifluoromethylphenylhydrazine, in which the reactant (4-chlorotrifluoromethylene) is particularly inactive, the reaction process has excellent regioselectivity. In addition, it was found that the use of a catalyst can increase the reaction rate. In this case, no product isomer exists, and therefore, when this method is combined with the subsequent step, a more useful method for obtaining an important pesticidal phenylpyrazole compound can be provided.

As described aboveIt is a particular advantage of the present invention that it is effective in the preparation of compounds of formula (I) wherein R is²And R³One or two of (a) represents a hydrogen atom.

According to a preferred feature of the invention, process (A) or combined processes (A) and (B) is followed by process (C) which comprises a compound of formula (I) (wherein W is N or CR)³，R²And R³One or two of which represent a hydrogen atom) with a chlorinating agent to replace R²And R³The or each hydrogen atom represented and forming the corresponding compound of formula (I), wherein R²And R³Each represents a chlorine atom. The chlorination can be carried out using chlorine gas or sulfuryl chloride in an inert solvent, such as a halogenated hydrocarbon (e.g., dichloromethane), according to known processes.

According to a further feature of the invention, process (a) or combined processes (a) and (B), processes (a) and (C), or (a), (B) and (C), can be combined with a further processing step (D) in which the compound of formula (I) is diazotized to form the compound of formula (IV):

wherein X is an anion, typically hydrogen sulfate or chloride, which is reacted with a compound of formula (V):

wherein R is⁴Is C_1-6Alkyl, and optionally with a base, to form a compound of formula (VI):

wherein R is¹、R²And W is as defined above.

The above-described process for preparing the compounds of the formula (VI) according to the invention in combination with the above-described reaction step for converting the compounds of the formula (III) into the compounds of the formulae (II) and (I) provides an advantageous novel synthetic route.

According to a further feature of the present invention, the combined processes (A) and (D), (A), (C) and (D), (A), (B) and (D), or (A), (B), (C) and (D), can be combined with a further processing step (E) to prepare a compound of formula (VII):

wherein R is alkyl or haloalkyl and n is 0, 1 or 2. Particularly preferred compounds of the formula (VII) are 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfinylpyrazole (fipronil) and 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-ethylsulfinylpyrazole (ethiprole). This process step (E) is known, for example, as described in published European patent Nos. 0295117 and 0374061 and published U.S. patent No. 5814652.

The compounds of the formula (I) obtained by process (A) according to the invention are particularly suitable for preparing 5-amino-1-aryl-3-cyanopyrazole derivatives of the formula (VII) having insecticidal activity, which are obtained, for example, from intermediate compounds of the formula (VI) according to the following reaction sequence:

wherein R is¹、R²、R³And R⁴Is as defined above.

The following non-limiting examples illustrate the invention. Each of the products shown is consistent with the compound samples already mentioned.

Example 1

Preparation of 4-trifluoromethylaniline

Raney nickel (2g) was added to a solution of 4-trifluoromethylphenylhydrazine (1g) in methanol (5ml) and heated at reflux for 1 hour. The cooled mixture was filtered and evaporated to afford the title compound in 100% yield.

Example 2

Preparation of 2-chloro-4-trifluoromethylaniline

The procedure of example 1 was repeated but using 2-chloro-4-trifluoromethylphenylhydrazine to give the title compound in 100% yield.

Example 3

Preparation of 4-trifluoromethylaniline

The procedure of example 1 was repeated, but using a catalytic amount of raney nickel in methanol (8-10ml for 4-trifluoromethylphenylhydrazine per mmole) and stirring at 20 ℃ for 2 hours under an atmosphere of hydrogen (5 bar). The mixture was filtered and evaporated to afford the pure title compound in 75% yield (not optimized).

In the same manner, also with similar results:

2-chloro-4-trifluoromethylaniline; and

2, 6-dichloro-4-trifluoromethylaniline.

Example 4

Preparation of 4-trifluoromethylphenylhydrazine

4-Chlorotrifluorotoluene (1.08g), hydrazine hydrate (1.8g, 6 molar equivalents) and pyridine (5ml) were heated at 180 ℃ for 6 hours in an autoclave (purged with argon). The mixture was cooled, excess hydrazine was decanted off and the organic phase was evaporated under reduced pressure. The residue was crystallized from petroleum ether to form the title compound in 20% yield. This indicates that the reaction proceeds with high selectivity using 20% of the starting material.

Example 5

Preparation of 4-trifluoromethylphenylhydrazine using potassium fluoride as catalyst

The procedure of example 4 was repeated, but potassium fluoride (0.8 molar equivalent) was added to give the title compound in 30% yield. This indicates that the reaction proceeds with high selectivity using 30% of the starting material.

The above reaction was repeated, but using N, N' -tetramethylurea as a solvent, to give the title compound in 40% yield. This indicates that the reaction proceeds with high selectivity using 40% of the starting material.

Example 6

Preparation of 4-trifluoromethylphenylhydrazine Using Potassium fluoride and copper (I) chloride as catalysts

The procedure of example 4 was repeated, but potassium fluoride (0.1 molar equivalent) and copper (I) chloride (0.1 molar equivalent) were added to afford the title compound in 14% yield. This indicates that the reaction proceeds with high selectivity using 14% of the starting material.

Example 7

Preparation of 2-chloro-4-trifluoromethylphenylhydrazine

The procedure of example 4 was repeated, but using 3, 4-dichlorotrifluorotoluene. After work-up, the title compound is isolated in 95% yield. This indicates that 100% of the starting material is used and the reaction proceeds with high selectivity and high yield.

The above reaction was repeated, but various other solvents were used. The following title compound was obtained in yield:

solvent(s)	Yield%
		Tetrahydrofuran (THF)	90
1, 4-dioxane	93
		N, N, N ', N' -tetramethylurea	72

Example 8

Two-step preparation and purification of 2-chloro-4-trifluoromethylaniline starting from 3, 4-dichlorotrifluorotoluene

(a)3, 4-Dichlorobenzotrifluoride (48g), hydrazine hydrate (65g) and pyridine (240g) were stirred and heated at 150 ℃ for 6 hours in an autoclave at a pressure of 4 bar. The cooled mixture was quenched with sodium hydroxide solution and the organic layer was evaporated under reduced pressure. The residue was dissolved in ether, washed (water) and the ether evaporated to give an 95/5 mixture of 2-chloro-4-trifluoromethylphenylhydrazine and 2-chloro-5-trifluoromethylphenylhydrazine (36 g).

(b) Raney nickel (0.7g) was added to an ethanol solution of the above isomer mixture (35.85g) in a hydrogenation reactor, and the mixture was allowed to stand at 50 ℃ under a hydrogen atmosphere at a pressure of 5 bar for 5 hours. The mixture was cooled, filtered and evaporated to give an 95/5 mixture (33.1g) of 2-chloro-4-trifluoromethylaniline and 2-chloro-5-trifluoromethylaniline. Hydrogen chloride gas was added to the ethanol and chlorobenzene solution of the above mixture over 0.5 hour, cooled to 0 deg.C, filtered to make 2-chloro-4-trifluoromethylaniline hydrochloride (33.5g) with a purity of over 99%. The overall yield calculated from 3, 4-dichlorotrifluorotoluene was 85%.

Claims (5)

1. A process for preparing a compound of formula (VI):

in formula (VI):

R¹is a halogenated alkyl group or a halogenated alkoxy group,

w is N or CR³And are and

R²and R³Each is hydrogen or chlorine;

the process comprises diazotizing a compound of formula (I) to form a compound of formula (IV):

r in the formulae (I) and (IV)¹、R²And R³Is as defined for formula (VI), X is an anion, which is reacted with a compound of formula (V):

wherein R is⁴Is C_1-6Alkyl, and which is optionally reacted with a base, to produce a compound of formula (VI).

2. The method of claim 1, wherein R is¹Is trifluoromethyl or trifluoromethoxy.

3. The method of claim 2, wherein R is¹Is trifluoromethyl.

4. The process of claim 1, wherein the compound of formula (VI) is converted to a compound of formula (VII) in a known manner:

wherein R is alkyl or haloalkyl and n is 0, 1 or 2.

5. The process of claim 4, wherein the compound of formula (VI) is 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-trifluoromethylsulfinylpyrazole or 5-amino-1- (2, 6-dichloro-4-trifluoromethylphenyl) -3-cyano-4-ethylsulfinylpyrazole.