JPS6058741B2 - Method for producing metatoluidine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing metatoluidine, which is useful as a dye intermediate, an intermediate for producing organic compounds, and particularly as a pharmaceutical intermediate.

Traditionally, metatoluidine has been produced by obtaining it from the dry distillate of coal, but this method has the disadvantage that it cannot be produced in large quantities due to quantitative limitations on the dry distillate of the raw material. be.

It is also generally obtained by mononitrating toluene and then reducing the corresponding metanitrotoluene. However, while ortho-toluidine and para-toluidine can be obtained relatively easily, meta-toluidine has an extremely low yield of several percent due to the low production rate of meta-nitrotoluene, which is nitrated at the 3-position by mononitration of toluene. There are drawbacks that can only be obtained by Recently, as shown in the reaction scheme below, orthohalogenotoluene or parahalogenotoluene is nitrated, and about 20 to 35% of the resulting halogenomononitrotoluene is produced. - A method has been proposed in which metatoluidine is obtained by separating halogenotoluene from other halogen mononitrotoluenes produced in large amounts, and subjecting this to catalytic reduction and dehalogenation (Japanese Patent Application Laid-open No. 50-151-828). .

(Conventional method) However, in this conventional method, 2-halogeno-3-nitrotoluene or 3-nitro-4-halogenotoluene, which is nitrated at the 3-position by the nitration reaction of orthohalogenotoluene or parahalogenotoluene, is selectively used. Since it cannot be produced, there is a drawback that the target metatoluidine cannot be produced in high yield.

After the nitration reaction, the 3-nitro form, which is only a few tens of percent produced, is produced in large quantities by-product, the 2-nitro form.
Unless it is separated from the nitro and/or 4-nitro bodies by precision distillation, it has the disadvantage that the target metatoluidine cannot be produced with high purity through the reduction and dehalogenation reactions in the next step.

That is, after nitration of orthohalogenotoluene or parahalogenotoluene and further reduction/dehalogenation reaction without a separation step, the desired metatoluidine is obtained from the resulting mixture of orthotoluidine, metatoluidine, and paratoluidine. This is because separation is extremely difficult because the boiling points of each product are close to each other.

Therefore, a separation step after the nitration reaction is essential, and a precision distillation method must be used as the separation method. These drawbacks cannot be overcome as long as orthohalogenotoluene or parahalogenotoluene is used as the starting material. The present inventors have conducted various studies in order to efficiently produce metatoluidine in high yield. As a result, we have adopted a 4-halogenobenzylamine compound as a starting material, and by nitration of this compound, we can selectively produce 3-
It was discovered that a nitro-4-halogenobenzylamine compound can be produced, and that when it is further reduced, the amination reaction of the nitro group, dehalogenation, and cleavage and reduction of the C-N bond are carried out in one step, and the present invention has been completed. I came to the conclusion.

That is, the present invention is based on the general formula (where R1 represents a hydrogen atom, an alkyl group, or a phenyl group, R2 represents a hydrogen atom or an alkyl group, and x represents a halogen atom).

) is a method for producing metatoluidine, which is characterized by nitrating a 4-halogenobenzylamine compound and then reducing it.

As shown in the following reaction scheme, the production method of the present invention first nitrates the 4-nogenobenzylamine compound represented by the general formula [1], and then selectively converts the 3-position by the nitration reaction. The 3-nitro-4-halogenobenzylamine compound [■] produced by nitration is reduced, and the nitro group is aminated, denotated, and 1°C H2--N<
The target metatoluidine [■] is produced by cutting and reducing the C--N bond of the group in one step.

(In the formula, Rl, R2 and
n-propyl group, i-propyl group, n-butyl group, i-
butyl group, n-amyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, phenyl group or substituted phenyl group, and R2 is a hydrogen atom, methyl group, ethyl group, n-propyl group, n- amyl group, hexyl group, heptyl group, octyl group, nonyl group, or decyl group, etc., and X is a chloro atom, a bromine atom, or a fluorine atom 4
-halogenobenzylamine compounds, typical starting materials include 4-chloro or 4-bromobenzylamine, -N-methylbenzylamine, -N-ethylbenzylamine, -N-n-propylbenzylamine,
-N-1-propyl peneyl amine, -N-n-butylbenzylamine, -N-n-amylbenzylamine,
-N-n-hexylbenzylamine, -N-n-heptylbenzylamine, -N-n-octylbenzylamine, -N-n-nonylbenzylamine, -N-decylbenzylamine, -N-phenylbenzyl Amine, -N
, N-diethylbenzylamine, -N,N-di-n-propylbenzylamine, -N,N-di-1-propylbenzylamine, N,N-dibutylbenzylamine, -N
, N-diamylbenzylamine, -N-methyl-N-phenylbenzylamine, -N-ethyl-N-phenylbenzylamine, and the like.

The nitration reaction of the present invention is carried out by a conventional nitration method using a mixed acid of nitric acid and sulfuric acid or concentrated nitric acid as a nitration agent. ~1.5 mol, preferably 1.1~
1.3 moles of nitric acid and 2.5 to 5 moles, preferably 3 to 4
mol of concentrated nitric acid is reacted with stirring at a temperature range of 0°C to 50°C, preferably 10°C to 40°C, for 2 to 5 hours, or 1 mol of 24-halogenobenzylamine compound per 1 mol of the 24-halogenobenzylamine compound. ~7 mol, preferably 2-3 mol of concentrated sulfuric acid is mixed at 0°C to 40°C, preferably 15°C to 30°C to form the 4-halogenobenzylamine compound into a sulfate salt, and then the 4-halogenobenzylamine compound used 1 to 1.5 mol, preferably 1.1 to 1 mol per mol of halogenobenzylamine compound
．． 3 moles of fuming nitric acid and 0.5 to 5 moles, preferably 1 to 3
mol of concentrated sulfuric acid (however, the total amount of concentrated sulfuric acid is 1.5 to 9 mol, preferably 3 to 6 mol, per 1 mol of the 4-halogenobenzylamine compound) at 09C to 50°C.
The reaction is preferably carried out at a temperature range of 10°C to 40'C with stirring for 1 to 4 hours.

After the nitration reaction, ammonia, potassium hydroxide,
By neutralizing with a hexa-alkali such as sodium hydroxide or sodium carbonate and washing with water, a 3-nitro-4-halogenobenzylamine compound with a purity of 98% can be obtained in a yield of 90% or more.

In post-treatment after the reaction is complete, add an inert solvent such as benzene, xylene, toluene, etc. to obtain the desired product! There is no problem even if it is extracted, neutralized, and washed with water. In the present invention, by-products such as 2-nitro-4-halogenobenzylamine compounds in which the 2-position is nitrated are hardly produced, so the 3-nitro-4-halogenobenzylamine compounds obtained through the nitration reaction It is also possible to carry out the next reduction reaction without isolating and purifying.

The nitration reaction of the present invention can be carried out by any of the above methods, but if method 2 is employed, the purity and yield can be improved.

For the reduction reaction of the present invention, a commonly used catalytic reduction reaction using hydrogen in the presence of a reduction catalyst can be applied, and catalysts such as platinum, nickel, and palladium can be used as the reduction catalyst. Although the catalyst can be used as a metal, it is usually supported on the surface of a carrier such as carbon black or activated carbon, and the amount used is 0 as a metal relative to the 3-nitro-4-halogenobenzylphamine compound. .2~0.
Heel weight % Preferably 0.3 to 0.5 weight is used. Although the reaction can be carried out either in the presence or absence of an inert solvent, it is preferable to carry out the reaction in a solvent that is inert to the reaction in order to allow the reaction to proceed smoothly. For example, alcohols such as methanol, ethanol, propanol, butanol are preferably used, and the amount used is 1 to 7 times, preferably 4 to 5 times by weight, relative to the 3-nitro-4-halogenobenzylamine compound.

Surprisingly, the amination, dehalogenation, and C-N bond scission/reduction reactions of the 3-nitro-4-halogenobenzylamine compound in the present invention proceed satisfactorily even at room temperature and pressure. do not need.

When a palladium catalyst is used as a catalyst, if the reaction is carried out at an unnecessarily high temperature condition, the resulting complex of metatoluidine and palladium may be a by-product, resulting in a decrease in yield. However, in order to shorten the reaction time, the reaction temperature may be heated to 30'C to 70C. Further, hydrogen may be used in a stoichiometric amount. After the completion of the reduction reaction, by treating with a conventional method, mator-f-dine with a purity of 98% or higher is converted to 95% of the 3-nitro-4-halogenobenzylamine compound (based on the starting material 4-halogenobenzylamine compound). 76 to 94%), and at the same time, it is possible to efficiently co-produce and recover amine compounds useful as raw materials for various industrial products. For example, after the completion of the reduction reaction, the used catalyst is separated by a three-passage method, etc., then a solvent such as benzene, toluene, xylene, etc. is added to the three liquids, stirred thoroughly and extracted, and metatoluidine is extracted by washing with water. A solvent layer containing a solvent layer and an amine compound (
The aqueous solution layer containing amine hydrochloride) is separated, metatoluidine is obtained from the solvent layer by a distillation separation method, and the aqueous solution layer is neutralized with an alkali and then rectified to obtain an amine compound. Next, to explain the features and advantages of the method of the present invention, firstly, a 4-halogenobenzylamine compound is employed as a starting material, and by nitration of this compound, 3-nitro-4-halogenobenzylamine is selectively produced. A compound is obtained, and when this nitro compound is further reduced, the nitro group selectively substituted at the 3-position of the 4-halogenobenzylamine compound is reduced to an amino group, and the halogen J at the 4-position is reduced in one step.
and one CH2-N atom is eliminated and reduced.

Since the bond is cut and reduced, the target metatoluidine can be selectively and efficiently produced with high purity and high yield.

Since the nitration of the second starting material 4-halogenobenzylamine compound selectively produces 3-nitro-4-halogenobenzylamine compound in high yield, it can be used in the following manner without isolation and purification. It is also possible to continue the reduction reaction. Third, in the conventional method of reducing halogenomononitrotoluene to produce metatoluidine, the hydrochloric acid by-product of dehalogenation produces metatoluidine hydrochloride, which has a high melting point and is difficult to use as a reaction solvent. , a catalyst precipitated during the reaction; since this may cause a decrease in activity, the reaction must be carried out at a high temperature above the melting point of metatoluidine-hydrochloride or above the temperature required to dissolve it in the reaction solvent. However, in the reduction reaction of the present invention, the hydrochloric acid by-produced by dehalogenation is
A salt is preferentially formed with the amine HN<8, which is produced by the cleavage and reduction of the C-N bond of the N Since the reaction is easily carried out, the reaction can proceed sufficiently even at low temperatures, and the reaction operation is also easy. Fourth
The 4-halogenobenzylamine compound used as a starting material in the present invention can be easily obtained by the reaction of 4-halogenobenzyl halide with an amine. Since compounds can be efficiently co-produced and recovered, they can be effectively reused as raw materials for various industrial chemicals. Next, in order to further clarify the contents of the present invention, examples will be shown.

I will explain in detail. 3 Example 1) Nitration reaction 75.6 g (1.2 mol) of fuming nitric acid and 370 g (3.7 mol) of concentrated sulfuric acid were charged into a 500 ml flask, and while stirring while cooling to below 20°C, 4-Chloru N,
197.6 g (1.0 mol) of N-diethylbenzylamine was added dropwise.

After completion of the dropwise addition, the mixture was further stirred at 30°C to 35°C for 3 hours to react. After the reaction was completed, the reaction solution was neutralized with a 24% aqueous sodium monohydroxide solution, and the upper organic layer was separated and washed with water.

After washing with water, the obtained organic layer was analyzed by gas chromatography to determine the purity of 3-nitro-4-chloro-N,N-diethylbenzylamine.

As a result of the analysis, 8.23% of unreacted 4-chloro-N,N-diethylbenzylamine, 0.23% of unknown substances,
The desired intermediate 3-nitro-4-chloro-N,N-
Diethylbenzylamine was 90.65%.

Next, the organic layer was rectified under reduced pressure, with a boiling point of 138-140℃/5
194.9 g (yield 80.36%) of 3-nitro-4-chloro-N,N-diethylbenzylamine (purity 98.5%) of wnHg was obtained.

2) Reduction reaction 3-nitro-4-chloro-N,N-diethylbenzylamine 123. obtained by the nitration reaction in (1) above.
2 g (0.5 mol) and 500 g of ethanol were charged into a 1e volume flask, and 4.92 g of 10% Pb-C was added, and hydrogen gas was blown into the flask under stirring at 50°C to 55°C under normal pressure.
The reaction was allowed to proceed for 6 hours until the theoretical amount of hydrogen gas was absorbed.

After the reaction was completed, the reaction solution was filtered three times to separate and remove the catalyst, and concentrated under reduced pressure to distill off ethanol.

Next, 100 ml of toluene was added to the obtained concentrate and thoroughly stirred, and further 50 ml of water was added and stirred, and then a toluene solution layer and an aqueous layer were separated and collected. Next, the toluene solution layer was washed with a 10% aqueous sodium monohydroxide solution and water, the toluene was distilled off under reduced pressure, and then rectified under reduced pressure.
~100℃/20wnHg metatoluidine (purity 99
．． 4%) (yield: 95.0% of the theoretical yield based on 3-nitro-4-chloro-N,N-diethylbenzylamine) starting material 4-chloro-N,N-
7 for the theoretical yield based on diethylbenzylamine
6.4%) was obtained. On the other hand, 48% sodium monohydroxide aqueous solution was added to the separated and collected aqueous layer to neutralize it, and then distilled under normal pressure to obtain diethylamine (purity 98.2%) with a boiling point of 53-55 C.
) was obtained (recovery rate: 90% of the theoretical recovery rate based on 3-nitro-4-chloro-N,N-diethylbenzylamine).

Example 2 300g of 98% monoconcentrated sulfuric acid was placed in a 500mt flask (3.
0 mol) and stirred at 25°C to 30°C, 197.6 g (1 mol) of 4-chloro-N,N-diethylbenzylamine
．． After adding dropwise 75.8 g (1.2 mol) of fuming nitric acid and 98
A mixed acid consisting of 100 g of 1% concentrated sulfuric acid (1 mono(c)) was added dropwise.

After the completion of the dropwise addition, the mixture was stirred at 30°C to 35°C for 3 hours to react.
After the reaction was completed, the reaction solution was neutralized with a 24% aqueous sodium monohydroxide solution, and the upper organic layer was collected and washed with water.

After washing with water, the obtained organic layer was analyzed by gas chromatography to determine the purity of 3-nitro-4-chloro-N,N-diethylbenzylamine.

*1 As a result of analysis, unreacted 4-chloro-N,N-diethylbenzylamine was 13.9%, and the target intermediate 3-nitro-4-chloro-N,N-diethylbenzylamine was 98.61%. Yes, no unknown substances were produced as by-products. (2) Reduction reaction The organic layer obtained by the nitration reaction in (1) above and the total amount of 970 g of ethanol were placed in a 2 F flask, 9.7 g of 10% Pb-C was added, and the mixture was heated at 50°C under normal pressure.
Hydrogen gas was blown into the reactor at 55°C with stirring, and the reaction was continued for 6 hours until the theoretical amount of hydrogen gas was absorbed.

After the reaction was completed, 100.3 g of metatoluidine (purity 99.5%) was added to the same treatment as in (2) reduction reaction of Example 1.
The yield was 93.0% of the theoretical yield based on the starting material 4-chloro-N,N-diethylbenzylamine.

Example 3 Using various 4-halogenobenzylamine compounds as starting materials, a nitration reaction was carried out in the same manner as in Example 2, followed by a reduction reaction by blowing in hydrogen gas for 6 hours to obtain metatoluidine.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. A method for producing metatoluidine, which comprises nitrating and then reducing a 4-halogenobenzylamine compound represented by