JP3473254B2 - Method for producing aminonitrobenzoic acids - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing aminonitrobenzoic acids.

[0002]

2. Description of the Related Art Aminonitrobenzoic acids are known as extremely important compounds as raw materials or intermediates for medicines, agricultural chemicals, dyes, additives, etc. because they are precursors of diaminobenzoic acids. As an industrial production method of such aminonitrobenzoic acids, conventionally, a method of reducing the nitro group of nitrobenzoic acids, acylating and protecting the obtained amino compound, and then deprotecting by nitration or nitrobenzenedicarboxylic acid A method of deriving an acyl azide or a carboxylic acid amide from a derivative and synthesizing it through Curtius rearrangement or Hoffmann rearrangement, respectively (for example, JP-A-4-36).
No. 4171) and the like are known, but these methods have a problem that they require a multi-step process.

[0003]

From the above, the present inventors have conducted studies to develop a method for producing aminonitrobenzoic acids from nitrobenzoic acids in a short process in a simple manner. As a result, nitrobenzoic acids and O The inventors have found that the desired aminonitrobenzoic acids can be easily obtained in one step by reacting with a -substituted hydroxylamine, and have reached the present invention.

[0004]

That is, the present invention provides a general formula [2]. [In the formula, R ₁ and R ₂ are the same or different and each is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an aryl group, a di-lower alkylamino group, a lower group which may be substituted with a halogen or a lower alkoxyl group. Alkyl group, lower alkoxyl group optionally substituted by halogen or lower alkoxyl group, aryloxy group, lower alkylthio group, arylthio group, carboxyl group, lower alkylsulfonyl group, arylsulfonyl group, sulfonic acid lower alkyl ester group, or An alkenyl group which may be substituted with a lower alkyl group or an aryl group is shown. Further, when R ₁ and R ₂ are bonded to the aromatic ring at the ortho position to each other, R ₁ and R ₂ together form a cycloalkyl group, -O- (CX ₂ ) _n -O- group, -CX ₂ -O-CX ₂ -group (where X is
Represents a hydrogen atom or a halogen atom, and n represents 1 or 2. ), An aromatic condensed carbocycle or a heterocycle may be formed. ] And the nitrobenzoic acids represented by the general formula [3] (In the formula, R ₃ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aralkyl group, and R ₄ represents a lower alkyl group or an aralkyl group.), And an O-substituted hydroxylamine or a salt thereof, General formula [1] characterized by reacting in the presence of a base (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as described above.)
The present invention provides a method for producing an aminonitrobenzoic acid compound represented by:

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. Examples of the nitrobenzoic acid represented by the general formula [2] used as a raw material in the present invention include o
-Nitrobenzoic acid, m-nitrobenzoic acid, p-nitrobenzoic acid, 2-chloro-6-nitrobenzoic acid, 5-chloro-2-nitrobenzoic acid, 4-chloro-2-nitrobenzoic acid, 2-chloro -3-Nitrobenzoic acid, 2-chloro-5
-Nitrobenzoic acid, 3-chloro-5-nitrobenzoic acid,
4-chloro-3-nitrobenzoic acid, 2-chloro-4-nitrobenzoic acid, 3-chloro-4-nitrobenzoic acid, 2-
Bromo-4-nitrobenzoic acid, 2,6-dichloro-4-
Nitrobenzoic acid, 2-cyano-4-nitrobenzoic acid,
2,4-dinitrobenzoic acid, 2-nitro-5-phenylbenzoic acid, 3-dimethylamino-6-nitrobenzoic acid,
3-t-butyl-6-nitrobenzoic acid, 3-trifluoromethyl-6-nitrobenzoic acid, 2-methoxy-5-nitrobenzoic acid, 5-methoxy-2-nitrobenzoic acid, 3
-Methoxy-4-nitrobenzoic acid, 4,6-dimethoxy-2-nitrobenzoic acid, 2-trifluoromethoxy-5
-Nitrobenzoic acid, 2- (2-methoxyethoxy) -4
-Nitrobenzoic acid, 2-nitro-5-phenoxybenzoic acid, 2-methylthio-6-nitrobenzoic acid, 2-nitro-5-phenylthiobenzoic acid, 4-nitrophthalic acid, 3
-Nitrophthalic acid, 2-methylsulfonyl-5-nitrobenzoic acid, 3-phenylsulfonyl-5-nitrobenzoic acid, 3-methoxysulfonyl-5-nitrobenzoic acid, 3
-(1-Propenyl) -5-nitrobenzoic acid, 3,4-
Methylenedioxy-6-nitrobenzoic acid, 4-nitro-
1-naphthalenecarboxylic acid, 6-nitro-1,1,3,
Examples thereof include, but are not limited to, 3-tetrafluoro-1,3-dihydro-5-isobenzofurancarboxylic acid and the like.

Examples of the O-substituted hydroxylamine represented by the general formula [3] used in the present invention include O-methylhydroxylamine, O-ethylhydroxylamine, Ot-butylhydroxylamine, N, O. -Dimethylhydroxylamine, O-benzylhydroxylamine, N-cyclohexyl-O-methylhydroxylamine, N-benzyl-O-methylhydroxylamine and the like can be mentioned, but O-methylhydroxylamine is particularly preferably used. Such O-substituted hydroxylamine may be used as it is, but may also be used as a salt thereof, for example, an inorganic acid salt such as a hydrochloride or a sulfate. Any of these O-substituted hydroxylamines or salts thereof can be easily and relatively inexpensively produced from hydroxylamine.

The base is not particularly limited and, for example, alkali metal hydroxide, alkali metal hydride, alkali metal amide, alkali metal alkoxide and the like are preferably used. Specific examples of such a base include sodium hydroxide, potassium hydroxide, sodium hydride, sodium amide, lithium amide, lithium diisopropylamide, sodium methoxide, sodium ethoxide, potassium-t-butoxide, sodium-t. -Butoxide and the like.

In the method of the present invention, a metal catalyst is preferably used, and by using this, the yield of aminonitrobenzoic acids can be improved. As such a metal-based catalyst, for example, a metal such as copper, manganese, iron, nickel, cobalt, silver, chromium, zinc, or a metal compound thereof is used, and as such a metal compound, a halide or oxidation of the metal as described above is used. Compounds, sulfides, hydroxides, carboxylates, nitrates, sulfates, carbonates, sulfonates, phosphates, thiocyanates, chromates, perchlorates, alkoxides, cyanides, acetylacetonates Are exemplified. As such a metal-based catalyst, copper or a copper compound is particularly preferable, and specific examples of the copper compound include copper (I) chloride and copper chloride (I
I), copper (I) bromide, copper (II) bromide, copper (I) iodide
Such as copper halides, copper carboxylates such as copper acetate (II), copper (I) oxide, copper (II) oxide, copper sulfide (I
I), copper nitrate (II), copper sulfate (II), copper carbonate (I
I), copper (II) hydroxide, copper (I) cyanide, copper (I
I) Acetylacetonate, copper (II) phosphate, copper (I) thiocyanate, copper (II) chromate, copper perchlorate (I
I), copper (I) methoxide and the like, but particularly copper halide, copper carboxylate, copper nitrate, copper (II)
Acetylacetonate and the like are preferable. Further, these metal compounds can be used without problems even if they contain water of crystallization.

In the method of the present invention, the amount of O-substituted hydroxylamine or a salt thereof used is usually 0.8 to 5 mol times, preferably 1 to 3 mol times, relative to the nitrobenzoic acid. The amount of the base used is usually 2 to 20 mol times, preferably 4 to 10 mol times, of the O-substituted hydroxylamine or its salt. When a metal-based catalyst is used, its amount is usually 0.001 to nitrobenzoic acid.
Although it is 1 mol times, in many cases 0.005 to 0.2 mol times is suitable.

A solvent is usually used in the reaction, and as such a solvent, an aprotic polar solvent such as N, N-dimethylformamide or dimethylsulfoxide, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran or diethoxy is used. Examples include ether solvents such as methane, aromatic solvents such as benzene, toluene and chlorobenzene, aliphatic hydrocarbon solvents such as hexane and heptane, alcohol solvents such as t-butanol, and liquid ammonia. You may use it as a mixed solvent of 1 or more types. The amount of such a solvent to be used is usually 1 to 200 times by weight that of the nitrobenzoic acid as a raw material.

The reaction temperature is usually in the range of -40 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

From the reaction mixture after completion of the reaction, the usual means,
For example, the desired aminonitrobenzoic acid can be easily isolated and purified by operations such as distillation, extraction, recrystallization or various chromatography. At the same time, unreacted nitrobenzoic acids can be recovered,
It can again be used in the method of the invention.

[0013]

According to the method of the present invention, aminonitrobenzoic acids can be easily produced in a short process.

[0014]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 334 mg (2 mmol) of p-nitrobenzoic acid and O
-188 mg (4 mmol) of methylhydroxylamine
The solvent (ethylene glycol dimethyl ether) 12m
Dissolved in 1 l, metal-based catalyst [copper (II) acetate] 36 mg
(0.2 mmol) and 1568 mg (14 mmol) of base (potassium-t-butoxide) in 8 ml of ethylene glycol dimethyl ether suspension at 27 ° C.
The solution was added dropwise over a period of 1 minute, and then stirred at the same temperature for 4 hours. Then, water was added, and 2N hydrochloric acid was added to make the mixture acidic, and ethyl acetate was added for extraction treatment. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and silica gel thin-layer chromatographic treatment (developing solution: chloroform / methanol / acetic acid = 100/100/1) was performed.
Amino-4-nitrobenzoic acid 187 mg (51% yield)
And at the same time unreacted p-nitrobenzoic acid 134 mg
(Recovery rate 40%) was recovered.

Examples 2 to 9 As Example 1 except that the type of metal catalyst, the amount thereof, the amount of O-methylhydroxylamine, the amount of base and the type of solvent were changed as shown in Table 1. By the same operation, 3-amino-4-nitrobenzoic acid was obtained, and at the same time, unreacted p-nitrobenzoic acid was recovered. 3-amino-4-
Table 1 shows the yield of nitrobenzoic acid and the recovery rate of p-nitrobenzoic acid.

[0017]

[Table 1] CuCl: Copper (I) chloride Cu (OAc) ₂ : Copper (II) acetate t-BuOK: Potassium-t-butoxide DMF: N, N-Dimethylformamide DEM: Diethoxymethane DME: Ethylene glycol dimethyl ether

Example 10 167 mg (1 mmol) of o-nitrobenzoic acid and O
-Dissolving 94 mg (2 mmol) of methylhydroxylamine in 5 ml of ethylene glycol dimethyl ether,
2 ml of a 5 ml suspension of ethylene glycol dimethyl ether containing 18 mg (0.1 mmol) of copper (II) acetate and 784 mg (7 mmol) of potassium t-butoxide.
The mixture was added dropwise at 7 ° C over 5 minutes and then stirred at the same temperature for 2 hours. Next, water was added and the mixture was acidified by adding 2N hydrochloric acid, and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and silica gel thin-layer chromatographic treatment (developing solution: chloroform / methanol / acetic acid = 100/100/1) was performed.
-Amino-2-nitrobenzoic acid 64 mg (yield 35%)
And 62 mg (yield 34%) of 5-amino-2-nitrobenzoic acid, and at the same time unreacted o-nitrobenzoic acid 22
mg (recovery rate 13%) was recovered.

Example 11 m-Nitrobenzoic acid 167 in place of o-Nitrobenzoic acid
By the same procedure as in Example 10 except that mg (1 mmol) was used, 2-amino-3-nitrobenzoic acid 38 mg
(Yield 21%) and simultaneously 111 mg (yield 61%) of a mixture of 4-amino-3-nitrobenzoic acid and 2-amino-5-nitrobenzoic acid, and at the same time unreacted m-nitrobenzoic acid. 20 mg (recovery rate 12%) was recovered.

Example 12 The procedure of Example 10 was repeated except that 197 mg (1 mmol) of 2-methoxy-5-nitrobenzoic acid was used in place of o-nitrobenzoic acid, and 2-amino-6-methoxy- was used.
45 mg of 3-nitrobenzoic acid (yield 21%) and 4-
Amino-2-methoxy-5-nitrobenzoic acid 93 mg
(Yield 44%) and at the same time unreacted 2-methoxy-5
-37 mg of nitrobenzoic acid (recovery rate 19%) was recovered.

Example 13 The procedure of Example 10 was repeated except that 197 mg (1 mmol) of 5-methoxy-2-nitrobenzoic acid was used in place of o-nitrobenzoic acid, and 3-amino-5-methoxy-
180 mg of 2-nitrobenzoic acid (yield 85%) was obtained, and at the same time, 10 m of unreacted 5-methoxy-2-nitrobenzoic acid was obtained.
g (recovery rate 5%) was recovered.

Example 14 The procedure of Example 10 was repeated except that 197 mg (1 mmol) of 3-methoxy-4-nitrobenzoic acid was used in place of o-nitrobenzoic acid, and 3-amino-5-methoxy-
85 mg of 4-nitrobenzoic acid (yield 40%) was obtained, and 96 mg of unreacted 3-methoxy-4-nitrobenzoic acid was obtained at the same time.
(Recovery rate 49%) was recovered.

Example 15 The procedure of Example 10 was repeated except that 202 mg (1 mmol) of 5-chloro-2-nitrobenzoic acid was used instead of o-nitrobenzoic acid, and 3-amino-5-chloro- 2-
169 mg of nitrobenzoic acid (yield 78%) was obtained, and at the same time, 16 mg of unreacted 5-chloro-2-nitrobenzoic acid (recovery rate 8%) was recovered.

Example 16 The procedure of Example 10 was repeated except that 202 mg (1 mmol) of 2-chloro-4-nitrobenzoic acid was used in place of o-nitrobenzoic acid, and 3-amino-2-chloro- 4-
134 mg of nitrobenzoic acid (yield 62%) and 17 mg of 3-amino-6-chloro-4-nitrobenzoic acid (yield 8
%), And at the same time, 30 mg of unreacted 2-chloro-4-nitrobenzoic acid (recovery rate 15%) was recovered.

Example 17 197 mg (1 mmol) of 2-methoxy-5-nitrobenzoic acid and 94 mg of O-methylhydroxylamine.
(2 mmol) was dissolved in 5 ml of dimethylsulfoxide and then added to a suspension of 5 ml of dimethylsulfoxide containing 181 mg (1 mmol) of copper (II) acetate and 784 mg (7 mmol) of potassium t-butoxide.
The mixture was added dropwise at 5 ° C over 5 minutes, and then stirred at the same temperature for 2 hours. After that, water was added and 2N hydrochloric acid was added to make the mixture acidic, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel thin layer chromatographic treatment (developing solution: chloroform / methanol / acetic acid = 100/10/1) to give 2-amino-6. -Methoxy-3-nitrobenzoic acid 1
9 mg (yield 9%) and 4-amino-2-methoxy-5-
Nitrobenzoic acid 85 mg (yield 40%) was obtained, and unreacted 2-methoxy-5-nitrobenzoic acid 20 mg was obtained at the same time.
(Recovery rate 10%) was recovered.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI B01J 31/04 B01J 31/04 X C07B 61/00 300 C07B 61/00 300 (58) Fields investigated (Int.Cl. ⁷ , DB name) C07C 227/06 C07C 229/56 C07C 229/60 C07C 229/64 C07C 209/02 C07C 213/02

Claims (3)

(57) [Claims] 1. A general formula [2] [In the formula, R ₁ and R ₂ are the same or different and each is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an aryl group, a di-lower alkylamino group, a lower group which may be substituted with a halogen or a lower alkoxyl group. Alkyl group, lower alkoxyl group optionally substituted by halogen or lower alkoxyl group, aryloxy group, lower alkylthio group, arylthio group, carboxyl group, lower alkylsulfonyl group, arylsulfonyl group, sulfonic acid lower alkyl ester group, or An alkenyl group which may be substituted with a lower alkyl group or an aryl group is shown. Further, when R ₁ and R ₂ are bonded to the aromatic ring at the ortho position to each other, R ₁ and R ₂ together form a cycloalkyl group, -O- (CX ₂ ) _n -O- group, -CX ₂ -O-CX ₂ -group (where X is
Represents a hydrogen atom or a halogen atom, and n represents 1 or 2. ), An aromatic condensed carbocycle or a heterocycle may be formed. ] And the nitrobenzoic acids represented by the general formula [3] (Wherein R ₃ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aralkyl group, and R ₄ represents a lower alkyl group or an aralkyl group), and an O-substituted hydroxylamine or an inorganic acid salt thereof. The copper, copper halogen
Oxide, copper carboxylate, copper nitrate or copper acetate
A metal selected from at least one of cetyl acetonates
General formula [1] characterized in that the reaction is carried out in the presence of a base catalyst in an amount of 4 to 10 times the molar amount of the substrate (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as described above.)
A method for producing an aminonitrobenzoic acid represented by: 2. The O-substituted hydroxylamine represented by the general formula [3] is O-methylhydroxylamine, O-ethylhydroxylamine, Ot-butylhydroxylamine, O-benzylhydroxylamine or N, O.
-The method for producing aminonitrobenzoic acid according to claim 1, which is dimethylhydroxylamine. 3. The method for producing aminonitrobenzoic acid according to claim 1 or 2, wherein the inorganic acid salt is a hydrochloride or a sulfate.