JP2606291B2 - Method for producing 2-nitrotoluene derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel method for producing a 2-nitrotoluene derivative useful as a synthetic intermediate of pyrrolenitrin known as an antifungal agent, And so on.

[Prior Art] The synthetic intermediate [VIII] of pyrrolenitrin, which is useful as an antifungal agent, has been conventionally produced by the following method.

That is, 2-chloro-6-methylaniline [VII] is oxidized to give 2-chloro-6-methylnitrobenzene [VII].
I].

[Problems to be Solved by the Invention] 2-Chloro-6-methylaniline [VII] which is a starting material of the above-mentioned known method is a 4-chloro-2-metal conventionally obtained by chlorinating 2-methylaniline. Aniline The production was stopped as 4-chloro-2-enylaniline [IX] was considered as a risk of inducing bladder cancer.
Chloro-6-methylaniline [VII] has also become difficult to obtain.

A general synthetic method of 2-chloro-6-methylaniline [VII] is described in Journal of the American Chemical Society (J. Am. Chem. Soc.) Vol. 77, No. 57.
It is described on pages 00 to 5702 (1955), and its outline is as follows.

However, in this synthesis method, when removing the sulfonic acid group in the last step, it is necessary to blow heated steam into the reaction solution, which is extremely difficult as an industrial operation,
Due to the problem of poor yield, the conventional compound [VI
Instead of the method of oxidizing I] to obtain compound [VIII], compound [V] is obtained by a new total route without using compound [VII].
III].

[Means for Solving the Problems] The inventors of the present invention have conducted intensive studies on an industrial production method of a 2-nitrotoluene derivative, and as a result, as shown below, a compound [I] was used as a starting material, and an intermediate [ II], [I
The present invention has been completed by finding that a 2-nitrotoluene derivative [VI] useful as a synthetic intermediate of pyrrolenitrin can be produced via V] and [V].

(Wherein, R ¹ and R ² each represent a cyano group or an esterified carboxy group, and X represents a halogen atom, respectively.) Preferable examples of the “halogen atom” in the present invention include chlorine, bromine, iodine and A fluorine atom.

Preferred examples of "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples include linear alkyl groups such as tertiary butyl, pentyl, hexyl and the like.

Suitable "esterified carboxy groups" include:
For example, lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and tert-butoxycarbonyl, for example, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl ,
Mono (or di or tri) phenyl (lower) alkoxycarbonyl groups which may have a nitro group, such as trityloxycarbonyl, are exemplified.

The salt of the raw material compound [V] in the present invention is not particularly limited. Examples thereof include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, arginine salt, aspartate salt, and the like. Examples include amino acid salts such as glutamate.

The method for producing the 2-nitrotoluene derivative [VI] obtained according to the present invention will be described in detail below.

(I) Production of Compound [II] Compound [II] can be produced by oxidizing Compound [I].

This oxidation reaction is carried out by a conventional method for oxidizing an amino group to obtain a nitro group, for example, by reacting compound [I] with a nitrite compound such as sodium nitrite in the presence of an inorganic acid such as hydrochloric acid or sulfuric acid. After obtaining the salt, the reaction can be carried out by reacting the above-mentioned nitrite compound in the presence of a copper compound such as cuprous oxide.

The reaction is, for example, water, methanol, ethanol,
It is carried out in a conventional solvent such as tetrahydrofuran, dioxane, methylene chloride, chloroform, benzene, dimethylformamide, dimethylsulfoxide.

The reaction temperature is not particularly limited, and the reaction can be performed under cooling or normal temperature.

This oxidation reaction is carried out by using an oxidizing agent such as m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, ozone, hydrogen peroxide, periodate, permanganate, or perborate. Can also be done.

This reaction is usually performed in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, and ethyl acetate, but may be performed in any other solvent that does not adversely affect the reaction. it can.

The reaction temperature is not particularly limited, but the reaction is preferably performed under cooling or at room temperature.

The compound [II] obtained by this reaction can be isolated by a conventional method, but may be subjected to the next reaction without isolation.

(Ii) Production of Compound [IV] Compound [IV] can be produced by reacting compound [II] with compound [III].

Preferred examples of the compound [III] include, for example, cyanoacetates such as methyl cyanoacetate and ethyl cyanoacetate;
Active methylene compounds such as malonic acid diesters such as dimethyl malonate and diethyl malonate are exemplified.

This reaction is preferably performed in the presence of a base. Examples of the base used include sodium hydride, alkali metal hydrides such as potassium hydride, calcium hydride, and the like.
Alkaline earth metal hydrides such as magnesium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate Bicarbonate, potassium fluoride, alkali metal fluorides such as cesium fluoride, sodium methoxide,
Alkali metal alkoxides such as sodium ethoxide, potassium tert-butoxide, trialkylamines such as trimethylamine and triethylamine, picoline, 1,5-
Organic or inorganic bases such as diazaicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane may be mentioned.

This reaction is usually performed in a solvent such as, for example, tetrahydrofuran, acetonitrile, dioxane, toluene, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone.

The reaction temperature is not particularly limited, but the reaction is usually performed under heating or heating.

The compound [IV] obtained by this reaction can be isolated by a conventional method, but may be subjected to the next reaction without isolation.

(Iii) Production of compound [V] Compound [V] or a salt thereof can be produced by hydrolyzing compound [IV].

This reaction can be performed by a conventional method, and is usually performed in the presence of an acid or a base.

Suitable acids include, for example, organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

Suitable bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate.

This reaction is generally performed in an aqueous solution, but a liquid acid can be used as a solvent.

The reaction temperature is not particularly limited, but the reaction is usually carried out at normal temperature, under heating or under heating.

(Iv) Production of Compound [VI] Compound [VI] can be produced by subjecting compound [V] or a salt thereof to a decarboxylation reaction.

This reaction is usually performed in a solvent such as dimethylformamide, quinoline, pyridine, N, N-dimethylaniline.

Although the reaction temperature is not particularly limited, it is usually carried out under heating or heating.

The compound [VI] thus obtained can be converted into pyrrolnitrin or an analog thereof by the following known steps.

That is, first, compound [VI] is cooled or heated in a solvent such as tetrahydrofuran, butanol, dioxane, toluene, dimethylformamide, dimethylsulfoxide, or N-methylpyrrolidone in a base (eg, sodium ethoxide, potassium Reaction with di (lower) alkyl oxalate (eg, dimethyl oxalate, diethyl oxalate, etc.) in the presence of tertiary butoxide, etc.
Nitrophenylpyruvate derivatives (Wherein X represents a halogen atom and R ³ represents a lower alkyl group, respectively).

Subsequently, through a ring-closing step using an aminoacetal, a chlorination step, a hydrolysis step and a decarboxylation step, pyrrolenitrin or an analog thereof (Wherein, X represents a halogen atom).

[Effect] According to the present invention, a compound [VII] which is obtained as a by-product when producing the carcinogenic substance [IX] or which is industrially difficult to synthesize and has a low yield is used as a starting material. Without use, 2-nitrotoluene derivative [VI]
Can be produced with high yield.

EXAMPLES Hereinafter, the present invention will be described with reference to Examples and Reference Examples.

Example 1 (1) 35% hydrochloric acid (1000 g) and water (1000 ml) were placed in a three-necked flask, and 2,6-dichloroaniline (500 g) was added.
And cool. Sodium nitrite (277g) in water (75
0 ml) is added dropwise at -5 to 5 ° C over 30 minutes and stirred at the same temperature for 1 hour.

On the other hand, sodium nitrite (1280
g) and water (5000 ml) were added and dissolved, and then cuprous oxide (150 g) and ethyl acetate (1500 ml) were added, and the mixture was added at -10 ° C.
Cool. The above diazotization reaction solution is added dropwise to this aqueous nitrous acid solution at -10 to 0 ° C, and the mixture is stirred at the same temperature for 1 hour.

After completion of the reaction, the ethyl acetate layer is separated. The aqueous layer is further extracted with ethyl acetate (500ml). Combine the ethyl acetate layers and 17.
Wash with 5% hydrochloric acid (1000 ml), saturated saline (1000 ml), saturated aqueous sodium bicarbonate (1000 ml) and saturated saline (1000 ml).

Ethyl acetate layer containing 2,6-dichloronitrobenzene
Transfer to a three-necked flask with dimethylformamide (500
0 ml), ground potassium carbonate (853 g) and methyl cyanoacetate (612 g) are added and heated at 105-110 ° C for 6 hours.

After completion of the reaction, the mixture is cooled to room temperature, water (4500 ml) and ethyl acetate (1500 ml) are added, the pH of the reaction solution is adjusted to 2 to 3 with 17.5% hydrochloric acid (about 1500 ml), and the ethyl acetate layer is separated. The aqueous layer is further extracted with ethyl acetate (1000ml). The ethyl acetate layers are combined, washed with a saturated saline solution (1500 ml), and concentrated to dryness under reduced pressure.

Acetic acid (2000 ml) and 35% hydrochloric acid (2000 ml) are added to the concentrated residue containing methyl 2-cyano-2- (3-chloro-2-nitrophenyl) acetate, and the mixture is heated under reflux for 5 hours. After completion of the reaction, water (2000 ml) and methyl isobutyl ketone (2500 ml) were added, and methyl isobutyl ketone (2500 ml) was added.
And the methyl isobutyl ketone layer is separated. The aqueous layer is further extracted with methyl isobutyl ketone (1500 ml). Combine the methyl isobutyl ketone layers and add water (2000 ml) and 24
Aqueous layer was separated after adding 12% aqueous sodium hydroxide solution (1500 ml) to adjust the pH to 12-13. Methyl isobutyl ketone layer is 10
Extract with 1% aqueous sodium hydroxide (1500 ml). The aqueous layers are combined, and 17.5% hydrochloric acid (about 3500 ml) is added dropwise to adjust the pH to 2.5 to precipitate crystals. After cooling to 10 ° C or less, the precipitated crystals were filtered, washed with water (1500 ml), dried in vacuo, and dried.
-Chloro-2-nitrophenylacetic acid (448.5 g) is obtained.

IR (Nujol): 1720, 1530, 1360, 1230 cm ^-1 NMR (CDCl ₃ , δ): 7.6 to 7.3 (3H, m), 3.8 (2H, s) (2) 3-chloro obtained in (1) Dimethylformamide (2000 ml) was added to -2-nitrophenylacetic acid (384 g), and the mixture was heated at 125 to 130 ° C for 3 hours, and dimethylformamide was distilled off under reduced pressure. Concentrated oil in dichloromethane (1344
ml) and washed with water to remove residual dimethylformamide. The dichloromethane layer is distilled off under reduced pressure, and the residual oil is distilled under vacuum to obtain oily 3-chloro-2-nitrotoluene (269.5 g).

Boiling point: 68-70 ° C./0.2 mmHg NMR (CDCl ₃ , δ): 2.38 (3H, s), 7.23-7.45 (3H, m) Reference Example 1 3-chloro- obtained in Example 1- (2) 2-nitrotoluene (240 g) and dimethylformamide (1200 m
l) into a three-necked flask of 5 and cool to room temperature,
After this reaction, diethyl oxalate (410 g) was added, and then sodium ethoxide (190.4 g) was added in four portions.
React at 3030 ° C. for 4 hours.

The reaction solution was treated with water (2400 ml), methanol (240 ml), 17.5
It takes 1 hour to a solution of hydrochloric acid (960 ml) at a temperature of 25 ° C. or lower. After the dropwise addition, the mixture is cooled to 0 to 10 ° C., and the precipitated crystals are filtered.

After washing with water (480 ml) and drying in vacuo, ethyl 3-chloro-2-nitrophenylpyruvate (368.6 g) is obtained.

IR (Nujol): 3360,1700,1660,1540,1420,1370,125
0 cm ^-1 NMR (CDCl ₃ ): 8.4-8.1 (1H, m), 7.6-7.3 (2H, m), 7.0 (1H, s), 6.3 (1H, s), 4.4 (2H, q), 1.36 ( 3H, t)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location C07C 255/41 8927-4H C07C 255/41

Claims (1)

(57) [Claims] (1) General formula (Wherein, X represents a halogen atom) by oxidizing a compound represented by the general formula (Wherein X has the same meaning as before) to obtain a compound of the general formula (Wherein R ¹ and R ² each represent a cyano group or an esterified carboxy group) (Wherein R ¹ , R ² and X have the same meanings as before), and then subjected to a hydrolysis reaction to give a compound of the general formula (Wherein X has the same meaning as described above) or a salt thereof, and further subjected to a decarboxylation reaction to obtain a compound represented by the general formula (Wherein, X has the same meaning as before). A method for producing a 2-nitrotoluene derivative represented by the formula: