JP2000191612A - Production of benzoic acid amides - Google Patents

Abstract

PROBLEM TO BE SOLVED: To reduce the consumption of noble metal catalysts such as expensive palladium and produce benzoic acid amides useful as an intermediate for medicines and agrochemicals by reacting a specific aromatic compound with carbon monoxide and ammonia in the presence of a specific catalyst. SOLUTION: This method for producing benzoic acid amides comprises a step for reacting (A) an aromatic compound represented by the formula Ar-X [Ar is a (substituted) aromatic group; X is a halogen, trifluoromethanesulfonate or the like] with (C) carbon monoxide and (D) ammonia in the presence of (B) a catalyst comprising palladium and phosphines, a step for separating at least benzoic acid amides represented by the formula from the above reactional system and a step for adding the components A, C and D into the reactional system separated from the amides and carrying out the reaction. Furthermore, a palladium-phosphine complex compound is preferably recovered from the reactional system of the components A, C and D and the recovered complex compound is preferably used as the catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing benzoic acid amides useful as intermediates for medical and agricultural chemicals.

[0002]

2. Description of the Related Art Generally, benzoic acid amides (benzoamides) can be produced by reacting benzoic acid halides or benzoic acids with ammonia.

Reference (J. Org. Chem., 39, 3318 (1974))
Report that an aromatic carboxylic acid ester can be obtained under mild conditions from an aryl halide, carbon monoxide, a tertiary amine, an alcohol and a catalytic amount of a triphenylphosphine-palladium salt complex.

It has also been reported that a similar reaction can be carried out on primary or secondary amines instead of alcohols to give the corresponding secondary or tertiary amides (J. Org.
Chem., 39, 3331 (1974)).

[0005]

In order to produce benzoic acid amides, benzoic acid halides are used in the literature (J. Org. C).
hem., 39, 3318 (1974)), a method is known in which an ester is once obtained, hydrolyzed to benzoic acid, and then converted to an amide with ammonia. there were. Thus, the present inventors have found a method for producing benzoic acid amides from aromatic halides by using carbon monoxide in a single-step reaction, and have already filed an application. Since the process uses noble metals as catalysts as in other carbon monoxide reactions, reducing its use is of great economical interest.

Accordingly, an object of the present invention is to provide a method for producing benzoic acid amides, which can reduce consumption of expensive noble metal catalysts such as palladium.

[0007]

The present inventors have made a general formula (1) Ar-X (1) (where Ar is an aromatic group which may have a substituent, X
Represents an aromatic compound represented by halogen (fluorine, chlorine, bromine or iodine), a trifluoromethanesulfonate group, an alkylsulfonate group having 1 to 4 carbon atoms or an arylsulfonate group in the presence of palladium and phosphines General formula (2) by reacting carbon and ammonia,

[0008]

Embedded image In the process of producing benzoic acid amides represented by the formula (where Ar is the same as described above), it has been found that a palladium-containing substance recovered from a reaction solution can be applied to the same reaction, and the present invention has been achieved.

Hitherto, noble metal catalysts are expensive, and various studies have been made on their recovery. However, the catalyst is usually in a state of being mixed with the reaction product, and since the post-reaction of the reaction and the purification operation of the product are performed with a primary focus on recovering the product in good yield therefrom, the catalyst has an activity. It is difficult to recover the catalyst, and it is general that the catalyst is recovered in a state where the catalyst activity has been lost.

However, the method of the present invention is based on the surprising finding that the produced benzoamides can be recovered in good yield, and that the catalyst can be recovered in an active state without any activation treatment. That is, the present invention is a method for producing benzoic acid amides including the following three steps.

General formula (1) Ar—X (1) (wherein, Ar is an aromatic group which may have a substituent, X
Represents an aromatic compound represented by halogen (fluorine, chlorine, bromine or iodine), a trifluoromethanesulfonate group, an alkylsulfonate group having 1 to 4 carbon atoms, or an arylsulfonate group in the presence of a catalyst comprising palladium and phosphines A step of reacting lower carbon monoxide with ammonia.

At least a compound represented by the general formula (2)

[0013]

Embedded image (Wherein Ar is the same as above).

A step of adding an aromatic compound represented by the general formula (1), ammonia, and carbon monoxide to a reaction system in which at least benzoic acid amides are separated in the step, and reacting them.

Further, the present invention provides a method for producing benzoic acid amides, which comprises the following two steps in place of the steps in this production method.

From the reaction system of the step
Recovering the phosphine complex compound.

Using the palladium-phosphine complex compound recovered in the step as a catalyst.

The aromatic compound represented by the general formula (1) used in the present invention includes an aromatic group which may have a substituent, a halogen, a trifluoromethanesulfonate group, an alkylsulfonate group having 1 to 4 carbon atoms, It is a compound to which an arylsulfonate group is bonded. Practically preferred are halides whose raw materials are easily available. Halogen is fluorine,
Chlorine, bromine or iodine, with bromine or iodine being more preferred.

The aromatic group is a carbocyclic group such as a phenyl group or a naphthyl group, or a heterocyclic group such as a pyridyl group or a quinolyl group, which may have a substituent.
(Aromatic group) represented by the general formula (7)

[0020]

Embedded image (Wherein R ² represents a trifluoromethyl group, a trifluoromethyloxy group, a halogen (fluorine, chlorine, bromine or iodine)), a nitro group, an acetyl group, a cyano group, an alkyl group having 1 to 4 carbon atoms, Represents an alkoxy group having 1 to 4 carbon atoms or an alkoxycarbonyl group having 2 to 5 carbon atoms;
Represents 0 or an integer of 1 to 5. ) Is preferably a monovalent aromatic group. Examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, an n-propyl group and an i-propyl group, and examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group and n Examples of the -propoxy group, i-propoxy group, and alkoxycarbonyl group having 2 to 5 carbon atoms include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, and an i-propoxycarbonyl group.

More preferably, at least one of R ² is a trifluoromethyl group. As the aromatic compound represented by the general formula (1), general formula (8),

[0022]

Embedded image (Wherein, Y represents bromine or iodine)
Examples of the aromatic compound having only one trifluoromethyl group other than the halogen represented by are 1-bromo-2- (trifluoromethyl) benzene and 1-bromo-3- (trifluoromethyl) benzene , 1-bromo-
4- (trifluoromethyl) benzene, 1-iodo-2
-(Trifluoromethyl) benzene, 1-iodo-3-
(Trifluoromethyl) benzene, 1-iodo-4-
(Trifluoromethyl) benzene and the like.

Further, 1-bromo-2-chloro-3- (trifluoromethyl) benzene, 1-bromo-2-chloro-3 as the aromatic compound having a substituent described above.
-(Trifluoromethyl) benzene, 1-bromo-2-
Fluoro-3- (trifluoromethyl) benzene, 1-
Bromo-2-fluoro-4- (trifluoromethyl) benzene, 1-bromo-3-fluoro-5- (trifluoromethyl) benzene, 1-bromo-2-iodo-3-
(Trifluoromethyl) benzene, 1-bromo-4-chloro-2- (trifluoromethyl) benzene, 1-bromo-4-fluoro-2- (trifluoromethyl) benzene, 1-chloro-2-iodo-3 -(Trifluoromethyl) benzene, 1-fluoro-4-iodo-2- (trifluoromethyl) benzene, 2-bromo-1-chloro-
3- (trifluoromethyl) benzene, 2-bromo-1
-Chloro-4- (trifluoromethyl) benzene, 2-
Bromo-1-fluoro-3- (trifluoromethyl) benzene, 2-bromo-1-fluoro-4- (trifluoromethyl) benzene, 2-chloro-1-iodo-4-
(Trifluoromethyl) benzene, 4-bromo-1-chloro-2- (trifluoromethyl) benzene, 4-chloro-1-iodo-2- (trifluoromethyl) benzene and the like; 1-bromo-2-methyl- 3- (trifluoromethyl) benzene, 1-bromo-3-methyl-5- (trifluoromethyl) benzene, 1-iodo-2-methyl-
4- (trifluoromethyl) benzene, 1-iodo-
4,5-dimethyl-2- (trifluoromethyl) benzene, 2-bromo-1-methyl-4- (trifluoromethyl) benzene, 2-bromo-3,4-dimethyl-1-
(Trifluoromethyl) benzene, 2-bromo-4-methyl-1- (trifluoromethyl) benzene, 2-iodo-1-methyl-4- (trifluoromethyl) benzene, 4-bromo-1-methyl-2 -(Trifluoromethyl) benzene and the like; 1-bromo-2-methoxy-4-
(Trifluoromethyl) benzene, 1-bromo-2-ethoxy-4- (trifluoromethyl) benzene, 1-bromo-4-ethoxy-2- (trifluoromethyl) benzene, 1-bromo-4-methoxy-2 -(Trifluoromethyl) benzene, 1-iodo-2-methoxy-4-
(Trifluoromethyl) benzene, 2-bromo-1-methoxy-4- (trifluoromethyl) benzene, 2-iodo-1-methoxy-4- (trifluoromethyl) benzene, 4-bromo-2-methoxy-2 -(Trifluoromethyl) benzene, etc .; 1-bromo-2-trifluoromethoxybenzene, 1-bromo-3-trifluoromethoxybenzene, 1-bromo-4-trifluoromethoxybenzene, etc .; 1-bromo-2-nitro -3- (trifluoromethyl) benzene, 1-bromo-2-nitro-4
-(Trifluoromethyl) benzene, 1-bromo-4-
Nitro-2- (trifluoromethyl) benzene, 1-iodo-2-nitro-4- (trifluoromethyl) benzene, 1-iodo-3-nitro-5- (trifluoromethyl) benzene, 1-iodo-4 -Nitro-2- (trifluoromethyl) benzene, 2-bromo-1-nitro-4
-(Trifluoromethyl) benzene, 4-bromo-1-
Nitro-2- (trifluoromethyl) benzene and the like; 2
-Bromo-4- (trifluoromethyl) benzonitrile, 2-bromo-5- (trifluoromethyl) benzonitrile, 2-fluoro-5-iodo-3- (trifluoromethyl) benzonitrile, 4-bromo-2 -(Trifluoromethyl) benzonitrile, 4-chloro-3-iodo-5- (trifluoromethyl) benzonitrile, 4-
Iodo-2- (trifluoromethyl) benzonitrile,
4-iodo-3- (trifluoromethyl) benzonitrile and the like; 2-bromo-3- (trifluoromethyl) benzenamine, 2-bromo-4- (trifluoromethyl)
Benzenamine, 2-bromo-5- (trifluoromethyl) benzenamine, 2-bromo-6- (trifluoromethyl) benzenamine, 2-iodo-4- (trifluoromethyl) benzenamine, 2-iodo-5 -(Trifluoromethyl) benzenamine, 3-bromo-4-
(Trifluoromethyl) benzenamine, 3-bromo-
5- (trifluoromethyl) benzenamine, 4-bromo-3- (trifluoromethyl) benzenamine, 4-
Iodo-2- (trifluoromethyl) benzenamine,
4-Iodo-3- (trifluoromethyl) benzenamine, 5-bromo-2- (trifluoromethyl) benzenamine, 5-bromo-2- (trifluoromethyl) benzenamine and the like can be exemplified. Not limited.

The aromatic compound represented by the general formula (1) is more preferably an aromatic halide having two or more trifluoromethyl groups. General formula (9)

[0025]

Embedded image (Wherein, Y represents bromine or iodine) Examples of the compound having only two trifluoromethyl groups in addition to the halogen represented by Y represented by 1-bromo-2,
4-bis (trifluoromethyl) benzene, 1-iodo-2,4-bis (trifluoromethyl) benzene, 1-
Bromo-3,5-bis (trifluoromethyl) benzene [3,5-bis (trifluoromethyl) bromobenzene], 1-iodo-3,5-bis (trifluoromethyl) benzene [3,5-bis ( Trifluoromethyl) iodobenzene], 2-bromo-1,3-bis (trifluoromethyl) benzene, 2-iodo-1,3-bis (trifluoromethyl) benzene, 2-bromo-1,4-bis ( Trifluoromethyl) benzene, 2-iodo-1,
4-bis (trifluoromethyl) benzene, 4-bromo-1,2-bis (trifluoromethyl) benzene, 1,
2-dibromo-4,5-bis (trifluoromethyl) benzene, 1,4-dibromo-2,5-bis (trifluoromethyl) benzene and the like can be mentioned.

Further, the compound having a substituent described above includes 1-bromo-2,3,4-tris (trifluoromethyl) benzene, 1-bromo-2,4,5-tris (trifluoromethyl) benzene , 1-iodine-2,
3,5-tris (trifluoromethyl) benzene, 1-
Iodo-2,4,5-tris (trifluoromethyl) benzene, 2-bromo-1,3,5-tris (trifluoromethyl) benzene, 5-bromo-1,2,3-tris (trifluoromethyl) Benzene, 5-iodo-1,
2,3-tris (trifluoromethyl) benzene, 2-
Iodo-1,3,4,5-tetrakis (trifluoromethyl) benzene, 1,2-dibromo-3,4,5-tris (trifluoromethyl) benzene and the like; 1,3-dichloro-5-iodo-2 1,4-bis (trifluoromethyl) benzene, 1,2-dibromo-4,5-bis (trifluoromethyl) benzene, 1,4-dibromo-2,5
-Bis (trifluoromethyl) benzene, 1-bromo-
2-chloro-3,5-bis (trifluoromethyl) benzene [2-chloro-3,5-bis (trifluoromethyl) bromobenzene], 1-bromo-2-methoxy-
3,5-bis (trifluoromethyl) benzene, 1-iodo-2-methoxy-3,5-bis (trifluoromethyl) benzene, 2-bromo-1-iodo-3,5-bis (trifluoromethyl) Benzene, 2-bromo-1-nitro-3,5-bis (trifluoromethyl) benzene,
2-bromo-3,4-dichloro-1,5-bis (trifluoromethyl) benzene, 5-bromo-2-chloro-
Examples thereof include 1,3-bis (trifluoromethyl) benzene, but are not limited thereto.

Among the compounds exemplified above, the compound represented by the general formula (8)
Or halogeno-bis (trifluoromethyl) benzene represented by the general formula (9), or hydrogen on the benzene ring of these compounds is substituted with another functional group. Compounds are particularly preferred.

As the halide represented by the general formula (1), among the above-listed compounds, aromatic halides in which at least one of R is a trifluoromethyl group because of the remarkable usefulness of the product And an aromatic halide in which at least two of R are trifluoromethyl groups is more preferable.

Furthermore, from the remarkable usefulness of the product, 3,5-bis (trifluoromethyl) bromobenzene or 3,5-bis (trifluoromethyl) iodobenzene, and hydrogen of these benzene nuclei is halogen. 2-chloro-3,5-bis (trifluoromethyl) substituted with
Bromobenzene and the like are more preferred. In this case, before 2
When the compound is used as a starting material, 3,5-bis (trifluoromethyl) benzoic acid amide is obtained, and from the latter, 2-chloro-3,5-bis (trifluoromethyl) benzoic acid amide is obtained.

When the method of the present invention is applied to the aromatic compound represented by the general formula (1), generally, only the halogen bonded to the aromatic ring is converted to a carbamoyl group, and the substituent represented by R remains unchanged. Things are obtained. Compounds having a plurality of different halogens on the aromatic ring generally include iodine, bromine,
It reacts preferentially in the order of chlorine and fluorine, but may differ depending on the position and type of substituent on the ring.

Next, a method for producing a benzoic acid amide represented by the general formula (2) will be described in detail.

In the step of the general formula (1), Ar—X (1) (where Ar is an aromatic group which may have a substituent, X
Represents an aromatic compound represented by halogen (fluorine, chlorine, bromine or iodine), a trifluoromethanesulfonate group, an alkylsulfonate group having 1 to 4 carbon atoms, or an arylsulfonate group in the presence of a catalyst comprising palladium and phosphine This is a step of reacting carbon monoxide and ammonia.

The amount of ammonia used is usually 1 mol or more per 1 mol of the aromatic compound represented by the general formula (1), preferably 1 to 10 mol, more preferably 2 to 5 mol. If the amount of ammonia used is less than 1 mol, the reaction is not completed. On the other hand, if it exceeds 10 mol, there is no problem in terms of the reaction yield, but it is not preferable because it is useless.

The carbon monoxide may be a pure gas, but does not necessarily have to be of high purity, and is used after being diluted with an inert gas such as nitrogen gas, argon gas, or carbon dioxide gas. May be. The amount of carbon monoxide used may be 1 mol or more per 1 mol of the aromatic compound represented by the general formula (1). The pressure of carbon monoxide is usually above normal pressure and 15
0 kg / cm ² or less is appropriate, and preferably 50 kg / cm ² or less.
/ Cm ² or less.

The palladium used in the step is the palladium-phosphine complex compound obtained in the step or as described below. That is, although palladium metal alone can be used, it can also be used by being supported on a carrier such as graphite, silica gel, alumina, silica alumina, and molecular sieve. It can also be used as a metal salt, and is used as acetate, carbonate, nitrate, chloride, bromide and the like. Specific examples of the metal salt include palladium acetate, palladium chloride, palladium bromide and the like.

Further, a palladium complex compound may be used. As the ligand, the general formula (3) P (R ¹ ) ₃ (3) (wherein R ¹ independently represents a lower alkyl group, a phenyl group, or a lower alkyl group-substituted phenyl group) or a general formula ( 7) (R ¹ ) ₂ PQP (R ¹ ) ₂ (4) (wherein, R ¹ independently represents a lower alkyl group, a phenyl group, a lower alkyl group-substituted phenyl group, and Q represents a divalent group. A phosphine represented by the following formula: Wherein Q is _{- (CH 2) m - (} m is an integer of 2-8), or the like alkylene group represented by. A lower alkyl group having about 1 to 4 carbon atoms is preferred. Specific examples of such phosphines include, for example, triphenylphosphine, tri-o-tolylphosphine, tri-m-tolylphosphine, tri-p-tolylphosphine, 1,1′-bis (diphenylphosphino) ferrocene, , 4-bis (diphenylphosphino) butane, 1,3-bis (diphenylphosphino) propane, 1,2-bis (diphenylphosphino) ethane, tri-n-butylphosphine, triethylphosphine and the like. Other ligands include acetonitrile, benzonitrile, carbon monoxide and the like. Of these, phosphines are preferred,
Phosphines having a phenyl group or a lower alkyl-substituted phenyl group are more preferred.

As a specific example of the palladium complex compound,
For example, PdCl_Two[P (o-Me-Ph)_Three]_Two, PdCl_Two
[P (m-Me-Ph)_Three]_Two, PdCl_Two[P (p-M
e-Ph)_Three]_Two, PdCl_Two(PMe_Three)_Two, PdCl
_Two(PPh_Three)_Two, PdBr_Two(PPh_Three)_Two, Pd (PPh
_Three)_Four, PdCl_Two[P (Ph)_TwoCH_TwoCH_TwoP (P
h)_Two], PdCl_Two[P (Ph)_TwoCH_TwoCH_TwoCH_TwoCH
_TwoP (Ph)_Two], PdCl_Two(PhCN) 2, Pd (C
O) (PPh_Three)_Three, PhPdI (PPh_Three)_Two, PhPd
Br (PPh_Three)_Two, PhPdBr (PMePh_Two)_Two, P
dCl_Two(PMePh_Two) _Two, PdCl_Two(PEt_TwoP
h)_Two, PdCl_Two(PMe_TwoPh)_Two, Pd_TwoBr_Four(PP
h_Three)_Two, PdCl_Two(PEt_Three)_Two, PdCl_Two(Bpy)
_TwoAnd the like. Here, Me is a methyl group, Et is
A tyl group and Ph represent a phenyl group.

In general, it is not clear what kind of intermediate state or activated state the catalyst is in the reaction system, but in view of the intention of the present invention to manufacture the target product, these metals,
It is clear that the form of the metal compound, ligand, and metal complex to be initially charged into the reaction system is not particularly limited as long as the ligand and the reagents involved in the reaction can be in a state of being active under the reaction conditions of the present invention. It is.

The ligand may be used in an amount larger than that which forms a metal complex with the metal in the reaction system. For example, usually palladium 1
It may be adjusted to 2 moles of triphenylphosphine and added to the reaction system with respect to moles, but it may be preferable to use 2 moles or more. The metal and ligand may be added separately or as a complex to the reaction system. The amount of palladium used is usually 0.00001 to 0.5 mol, preferably 0.00005 to 0.1 mol, more preferably 0 mol, as a metal per 1 mol of the aromatic compound represented by the general formula (1). .
0001-0.05 mol. If it is less than 0.00001 mol, the progress of the reaction is slow and it is not practical because it is not practical. On the other hand, if it is more than 0.5 mol, there is no problem in terms of the reaction, but it is economically disadvantageous, so it is not preferable.

The step can be carried out without using water, an organic solvent or the like, or using an organic solvent. As the organic solvent, the aromatic compound itself represented by the general formula (1), which is a substrate, can be used as the solvent. In addition, ethers such as diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, benzene, Aromatic hydrocarbons such as toluene, xylene, nitrobenzene and chlorobenzene, nitriles such as acetonitrile and benzonitrile, N, N-dimethylacetamide, N, N-dimethylformamide;
Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide, hexamethylphosphamide, and the like, and one or more of these can be used. The amount of the solvent is not particularly limited from the viewpoint of the reaction, but using too much is not preferable because it causes an increase in the size of the apparatus.

The process of the present invention can be carried out extremely easily by allowing water to be present in the reaction system. Ammonia has a high vapor pressure and generally requires a high pressure to increase its concentration in a system containing only an organic solvent, but because of its high solubility in water, the presence of water in the reaction system makes it possible to significantly increase the reaction system. Pressure drop can be achieved. In addition, since the salt generated as a result of the reaction easily moves to the aqueous layer, it contributes to the promotion of the reaction and also has the effect of facilitating the purification operation. When water is used as the solvent, ammonia can be introduced into the reaction system as an aqueous solution. When water is used as the solvent, it is preferable to use a solvent that dissolves an amide that is appropriately formed as a combined solvent, and each of the above-mentioned solvents can be used. The reaction may be promoted by adding a phase transfer catalyst such as a quaternary ammonium salt or crown ether. The amount of water used is not particularly limited, but it is preferable to use an amount sufficient to form two layers of a reaction system mainly composed of water and a layer mainly composed of an organic liquid.
The reaction temperature is usually 10 to 200 ° C, preferably 10 to 200 ° C.
150 ° C. The reaction time is usually 0.1 to 30 hours,
Preferably, 0.5 to 10 hours is good.

The steps are as follows: glass, stainless steel, platinum,
It is preferable to use a pressure-resistant container made of a corrosion-resistant material such as a fluororesin. A predetermined amount of the aromatic compound represented by the general formula (1), palladium and phosphine serving as a catalyst, ammonia, water, and, if necessary, a predetermined amount of a solvent are charged into the pressure vessel. At this time, when water is used, ammonia can be charged as ammonia water, which is preferable. However, ammonia may be charged as water and ammonia gas or liquid. The inside of the reactor is replaced with carbon monoxide to set a predetermined carbon monoxide pressure and heating is started. When the internal temperature reaches a predetermined temperature (for example, about 50 ° C. or more, usually about 80 ° C.), the internal pressure is adjusted to the predetermined pressure, and then the internal temperature and the internal pressure are kept constant while adjusting the amount of carbon monoxide introduced. Or adjust to programmed conditions.

The process of the general formula (2)

[0044]

Embedded image (Wherein Ar is the same as in the general formula (1)) is a step of separating and extracting benzoic acid amides represented by the general formula (1).

When the reaction rate of the starting aromatic compound in the reaction solution reached an expected value, heating of the reactor and supply of carbon monoxide were stopped, the reactor was cooled, and gas in the reactor was purged. ,
Remove the reaction solution. When aqueous ammonia or water is used as the solvent, the reaction solution usually has two layers, and the target product is contained in the organic layer. The crude desired product is obtained by distilling off the solvent. This composition can be purified by a conventional method.

In the step (a), an aromatic compound represented by the general formula (1), ammonia and carbon monoxide are added to a reaction system in which at least benzoic acid amides have been separated in the step (b) to cause a reaction. That is, in the step, the reaction product is supplied and reacted without adding new palladium and phosphine to the reaction system from which the target product from the step and the salts which are necessarily generated are removed. It consists of things. At this time, the reaction conditions may be similar to those in the step, but need not be the same, and may be changed as appropriate. Further, palladium and / or phosphine may be newly added to this reaction system, but this is not always necessary.

The step comprises recovering a palladium-phosphine complex compound from a mixture of a product, a solvent and the like obtained in the reaction step. Although it is not clear what form palladium takes in the reaction system, it is presumed that it is a complex compound containing palladium and phosphine. This complex compound present in the reaction system,
Although the palladium-phosphine complex compound obtained in the step is not required to be the same substance, it is thought that it can be easily converted into each other under an environment similar to that of the reaction system.

The recovered palladium-phosphine complex compound is represented by the following general formula (5)

[0049]

Embedded image (In the formula, Ar is the same as in the general formula (1), L is the general formula (3) P (R ¹ ) ₃ (3) (wherein, R ¹ is each independently a lower alkyl group, a phenyl group, a lower An alkyl group-substituted phenyl group) or two bonded to form a group represented by the general formula (4) (R ¹ ) ₂ PQP (R ¹ ) ₂ (4) (wherein R ¹ is independently a lower alkyl group; , A phenyl group or a lower alkyl group-substituted phenyl group, and Q represents a divalent group.) Or a general formula (6)

[0050]

Embedded image (Wherein, Ar and X are the same as in the general formula (1), and L is the same as in the general formula (5)), but the structure is not limited to this. However, the palladium-phosphine complex compound recovered in a different form may be used. These palladium-phosphine complexes are soluble in many organic solvents and are stable in air.

The aromatic compound represented by the general formula (1) is
In the case of 3,5-bis (trifluoromethyl) bromobenzene, Ar is a 3,5-bis (trifluoromethyl) group [3,5-bis (trifluoromethyl) benzoato] 3 ′, 5 '-Bis (trifluoromethyl) phenylbis (triphenylphosphine) palladium (I
I) or bromo [3,5-bis (trifluoromethyl) phenyl] bis (triphenylphosphine) palladium (II) can be easily recovered.

Since the palladium present in the reaction solution is dissolved in the organic solvent together with the product benzoic acid amides, it is necessary to separate the product, but any method may be used. . For the purposes of the present invention, it is sufficient to exclude products and by-products that are necessarily produced from the reaction system. Further, it is not always necessary to completely remove the products or by-products, but it is preferable to remove as much as possible from the viewpoint of throughput. As an operation method, for example, it can be recovered using the difference in solubility between benzoic acid amides and a palladium-phosphine complex in an organic solvent. The benzoic acid amides and palladium-phosphine complex compound taken out as insoluble components in water from the reaction solution are brought into contact with an organic solvent to extract the palladium-phosphine complex compound into the organic solvent,
It can be carried out by removing, for example, distilling off the organic solvent. As the organic solvent, aromatic solvents such as benzene, toluene, xylene, ethylbenzene, mesitylene and the like can be used. These may be used as a mixture, and a part of the solvent may be a hydrocarbon-based solvent; pentane, hexane, heptane or the like; an ester-based solvent; ethyl acetate, butyl acetate or the like.

The recovery operation can be carried out at about 0 to 100 ° C., and depending on the type of the solvent, cooling may be performed to adjust the solubility. However, it may be performed at normal temperature without heating or cooling.

The recovered palladium-phosphine complex compound can be further purified by known means such as recrystallization, but is not particularly required in the method of the present invention.

The step can be carried out by using the same method as described above, using the palladium-phosphine complex compound obtained in the step as all or a part of palladium and phosphine necessary for the reaction.

[0056]

Next, the production method of the present invention will be described in detail with reference to examples, but the present invention is not limited thereto. Unless otherwise noted, pressures in the examples are gauge pressures.

Example 1 400 g of 3,5-bis (trifluoromethyl) bromobenzene and tetrahydrofuran 2 were placed in a 1000 ml stainless steel autoclave.
27 ml, 1.53 g of palladium acetate, 5.37 g of triphenylphosphine, and 371 g of 25% aqueous ammonia were charged. After the stirring was started and the atmosphere was replaced with nitrogen, the initial pressure of carbon monoxide was set to 3 kg / cm ² and heating was started. One hour later, when the internal temperature reached 100 ° C., carbon monoxide was introduced under pressure to adjust the internal pressure to 10 kg / cm ² . During the reaction, the internal temperature was kept at 100 ° C. and the internal pressure was kept at 10 kg / cm ² .

After 11 hours, the reaction vessel was cooled and the internal gas was purged. The reaction solution was taken out into a separating funnel, and the organic layer of the reaction solution separated into two layers was separated and collected. 700 ml of water was added to a separately prepared 2000 ml flask with a stirrer,
The mixture was heated to 80 to 85 ° C. in an oil bath, and the separated organic layer was dropped thereto. When the distillation of tetrahydrofuran was completed, the heating was stopped, the mixture was cooled to room temperature, and the generated crystals were filtered by suction, and then 900 ml of cold water and then 250 ml of toluene.
And washed twice with to obtain 241.3 g of 3,5-bis (trifluoromethyl) benzamide. Melting point (3,5-bis (trifluoromethyl) benzamide): 160-16
2 ℃

Example 2 After about 500 ml of the toluene washing solution obtained in Example 1 was dried over anhydrous magnesium sulfate, the filtrate was concentrated with an evaporator, and the obtained residue was subjected to silica gel column chromatography (developing solvent: n-solvent). Hexane / ethyl acetate = 7/3 (v / v)).
As a result, 6.0 g of colorless crystals were obtained. The crystal is [3,
5-bis (trifluoromethyl) benzoato] 3 ',
5′-bis (trifluoromethyl) phenylbis (triphenylphosphine) palladium (II).

[3,5-bis (trifluoromethyl) benzoato] 3 ', 5'-bis (trifluoromethyl) phenylbis (triphenylphosphine) palladium (I
I) Melting point: 168-170 ° C (decomp.) IR (KBr: cm-1): 3060,2926,1637,1437,1321,1277,1173,
1127,748,697,518 ¹ H-NMR (reference substance: TMS solvent: CDCl ₃ ): δ ppm 6.97 (s, 1
H), 7.09 (s, 2H), 7.20-7.32 (m, 18H), 7.40-7.50 (m, 12H), 7.
53 (s, 2H), 7.62 (s, 1H) ³¹ P-NMR (reference substance: 85% H ₃ PO ₄ solvent: CDCl ₃ ): δppm 2
5.73 (s)

Example 3 200 g of 3,5-bis (trifluoromethyl) bromobenzene and tetrahydrofuran 12 were placed in a 500 ml stainless steel autoclave.
0 ml, palladium complex 3.74 recovered in Example 2
g, and 185 g of 25% aqueous ammonia were further charged. After stirring and purging with nitrogen, the initial pressure of carbon monoxide was raised to 1
The heating was set at kg / cm2 and started. After 1 hour the internal temperature is 1
When the temperature reached 00 ° C., carbon monoxide was introduced under pressure, and the internal pressure was adjusted to 10 kg / cm ² . Internal temperature 100 during the reaction
° C and an internal pressure of 10 kg / cm ² .

After 8 hours, the reaction vessel was cooled and the internal gas was purged. The reaction solution was taken out into a separating funnel, and the organic layer of the reaction solution separated into two layers was separated and collected. 400 ml of water was added to a separately prepared 2000 ml flask equipped with a stirrer, heated to 80 to 85 ° C. in an oil bath, and the separated organic layer was added dropwise thereto. When the distillation of tetrahydrofuran was completed, heating was stopped, the temperature was cooled to room temperature, the resulting crystals were filtered by suction, washed with 500 ml of cold water and then with 300 ml of toluene, and 124 g of 3,5-bis (trifluoromethyl) benzamide was added. Obtained.

[0063]

According to the method of the present invention, benzoic acid amides can be produced in one step from an aromatic compound, carbon monoxide and ammonia, and the amount of expensive catalyst used is greatly reduced. The effect that it can be made to play is produced.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Satoshi Narizuka 2805 Imafukunakadai, Kawagoe-shi, Saitama F-term in Chemical Research Laboratory, Central Glass Co., Ltd. 4G069 AA02 AA03 AA08 BC72A BC72B BE26A BE26B CB25 CB72 CB77 DA08 4H006 AA02 AC53 BA25 BA48 BA83 BA84 BD36 BD52 BE14 BE40 BJ50 BV71 4H039 CA71 CD20 CD90

Claims (7)

[Claims] 1. A method for producing benzoic acid amides comprising the following three steps. General formula (1) Ar-X (1) (wherein, Ar is an aromatic group which may have a substituent, X
Represents an aromatic compound represented by halogen (fluorine, chlorine, bromine or iodine), a trifluoromethanesulfonate group, an alkylsulfonate group having 1 to 4 carbon atoms, or an arylsulfonate group in the presence of a catalyst comprising palladium and phosphines A step of reacting lower carbon monoxide with ammonia. In the reaction system of step (b), at least a compound represented by the general formula (2): (Wherein Ar is the same as above). A step of adding an aromatic compound represented by the general formula (1), ammonia and carbon monoxide to a reaction system in which at least benzoic acid amides have been separated in the step, and reacting them. 2. A method for producing benzoic acid amides comprising the following four steps. General formula (1) Ar-X (1) (wherein, Ar is an aromatic group which may have a substituent, X
Represents an aromatic compound represented by halogen (fluorine, chlorine, bromine or iodine), a trifluoromethanesulfonate group, an alkylsulfonate group having 1 to 4 carbon atoms, or an arylsulfonate group in the presence of a catalyst comprising palladium and phosphines A step of reacting lower carbon monoxide with ammonia. At least a compound represented by the general formula (2) (Wherein Ar is the same as above). Recovering the palladium-phosphine complex compound from the reaction system of the step. Using the palladium-phosphine complex compound recovered in the step as a catalyst. The phosphine is represented by the general formula (3) P (R ¹ ) ₃ (3) (wherein R ¹ independently represents a lower alkyl group, a phenyl group, or a lower alkyl group-substituted phenyl group) or a general formula: (4) (R ¹ ) ₂ PQP (R ¹ ) ₂ (4) (wherein, R ¹ independently represents a lower alkyl group, a phenyl group, a lower alkyl group-substituted phenyl group, and Q represents The method for producing a benzoic acid amide according to any one of claims 1 to 2, which is a phosphine represented by the following formula: 4. The phosphine is triphenylphosphine,
1,3-diphenylphosphinopropane or 1,4-
The method for producing a benzoic acid amide according to any one of claims 1 to 2, which is diphenylphosphinobutan. 5. A palladium-phosphine complex compound represented by the general formula (5): (In the formula, Ar is the same as in the general formula (1), L is the general formula (3) P (R ¹ ) ₃ (3) (wherein, R ¹ is each independently a lower alkyl group, a phenyl group, a lower An alkyl group-substituted phenyl group) or two bonded to form a group represented by the general formula (4) (R ¹ ) ₂ PQP (R ¹ ) ₂ (4) (wherein R ¹ is independently a lower alkyl group; , A phenyl group or a lower alkyl group-substituted phenyl group, and Q represents a divalent group), or a phosphine represented by the following general formula (6): 3. A palladium-phosphine complex compound represented by the formula (wherein, Ar and X are the same as in the general formula (1), and L is the same as in the general formula (5)). For producing benzoic acid amides. 6. The method according to claim 1, wherein the combination of palladium and phosphine is any combination selected from a palladium salt, a phosphine, a palladium complex or a palladium-phosphine complex compound recovered in the step. A method for producing the benzoic acid amides according to the above. 7. Ar is a compound represented by the general formula (7). (Wherein R ² is a trifluoromethyl group, a trifluoromethyloxy group, a halogen (refers to fluorine, chlorine, bromine or iodine), a nitro group, an acetyl group, a cyano group, an alkyl group having 1 to 4 carbon atoms, An alkoxy group of Formulas 1 to 4,
Represents an alkoxycarbonyl group having 2 to 5 carbon atoms, and n is 0
Or, represents an integer of 1 to 5. The method for producing a benzoic acid amide according to any one of claims 1 to 6, which is a monovalent aromatic group represented by the formula: