JP3018480B2 - Method for producing substituted 2-oxa-7-aminoindan derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing a substituted 2-oxa-7-aminoindan derivative. For further details, see JP-A-2-1314.
The present invention relates to a method for producing a substituted 2-oxa-7-aminoindan derivative which can be a useful intermediate in producing an acid amide compound which is an active ingredient of an agricultural and horticultural fungicide described in the specification such as No. 81. It is.

The substituted 2-oxa-7-aminoindan derivative which is the object of the method of the present invention can be obtained by using the general formula (I) which is useful as an active ingredient of an agricultural and horticultural fungicide by the following reaction route described in, for example, JP-A-2-131481. The compound is useful as an intermediate because it can lead to the acid amide compound represented by the formula (1).

Wherein, R ^2, R ³ and R ⁴ represents a lower alkyl group, R ⁵
Represents a lower alkyl group or a trifluoromethyl group, and R ⁶ represents a lower alkyl group, a halogen atom or a hydrogen atom. <Conventional Technology> Conventionally, as a method for producing a substituted 2-oxa-7-aminoindan derivative, for example, Journal of the American Ch
emical Society, 69 , 1909 (1947), Compt. rend. 231 , 911
(1950), a method as described in JP-A-2-131481 is known.

Wherein R ¹ , R ² and R ³ have the same meaning as described above. That is, a phthalic anhydride derivative is obtained by reacting a nitrobenzene derivative with hydrogen in an alcoholic solvent such as methanol or ethanol in the presence of a catalytic amount of palladium carbon and acetic acid under heating at 110 ° C to 120 ° C. Further, the phthalic anhydride derivative is reduced in an alcoholic solvent such as methanol or ethanol or an acetic acid solvent in the presence of zinc metal and hydrochloric acid to obtain a lactone derivative. Further, the lactone derivative is reacted with a lower alkyl Grignard reagent such as methylmagnesium iodide in an ether solvent such as diethyl ether or tetrahydrofuran to obtain a diol form. Next, the diol is reacted with activated manganese dioxide to obtain a substituted 2-oxa-7-aminoindan derivative.

<Problems to be Solved by the Invention> However, in the above-described production method, there is a problem in treating manganese residues generated by the reaction. In addition, the yield is low, the reaction operation is complicated, and an expensive metal catalyst is used many times.

<Means for Solving the Problems> In view of such circumstances, the present inventors have conducted intensive studies on a method for producing a substituted 2-oxa-7-aminoindan derivative, and found that the general formula [In the formula, R ¹ and R ² represent a lower alkyl group. Is reacted with a lower alkyl Grignard reagent represented by the formula: [Wherein, R ² represents the same meaning as described above, and R ³ represents a lower alkyl group. ] It has been found that the substituted 2-oxa-7-aminoindan derivative represented by the formula (1) can be industrially efficiently produced, and the present invention has been accomplished.

By reacting the anilide derivative represented by the general formula (II) with a lower alkyl Grignard reagent, the general formula (III)
The reaction for obtaining the substituted 2-oxa-7-aminoindan derivative represented by is usually performed in a solvent, and examples of the solvent used include ethers such as tetrahydrofuran,
Examples thereof include hydrocarbons such as toluene, halogenated hydrocarbons such as monochlorobenzene, and mixtures thereof.

Examples of the lower alkyl Grignard reagent used in the above reaction include organomagnesium compounds such as alkylmagnesium halides and organolithium compounds such as alkyllithium.

The amount of the reagent used in the above reaction is about 3 to about 10 times, preferably about 4 to about 6 times, the molar amount of the lower alkyl Grignard reagent based on the anilide derivative represented by the general formula [II].
It is twice the molar amount.

The reaction temperature ranges usually from about -70 ° C to about 50 ° C, preferably from about -10 ° C to room temperature, and the reaction time is usually from about 1 hour to about 24 hours.

After completion of the reaction, for example, ammonium chloride, dilute hydrochloric acid,
After treatment with dilute sulfuric acid or the like, extraction with an organic solvent such as ethyl acetate, toluene, or monochlorobenzene, and concentration under reduced pressure give the desired substituted 2-amino compound represented by the general formula [III].
An oxa-7-aminoindan derivative can be obtained. Further, if necessary, it can be further purified by a usual method such as recrystallization, chromatography and the like.

The anilide derivative represented by the general formula (II) is represented by the general formula [Wherein, R ¹ has the same meaning as described above. A nitrobenzene derivative represented by the general formula (R ² CO) ₂ O [V] wherein R ² has the same meaning as described above. The reaction can be carried out by reacting a carboxylic acid anhydride represented by the following formula:

The reaction is usually performed in an alcohol solvent such as methanol or ethanol, an ethyl acetate solvent, an acetic acid solvent or a mixture thereof.

In the above reaction, as a method for reduction under a hydrogen atmosphere, for example, a catalytic reduction method can be mentioned, and as a catalyst to be used, palladium carbon, a platinum compound and the like can be mentioned.

In the above reaction, after performing a reduction reaction with the nitrobenzene derivative represented by the general formula [IV] alone, it can be reacted with a carboxylic anhydride represented by the general formula [V].
The nitrobenze derivative represented by the general formula [IV] can be reacted in the presence of a carboxylic anhydride represented by the general formula [V] in advance.

The amount of the reagent used in the above reaction is 1 to 5 times the molar amount of the carboxylic anhydride represented by the general formula [V] with respect to the nitrobenzene derivative represented by the general formula [IV]. The catalyst used in the catalytic reduction method is a usual catalyst amount, for example, 0.0001 to 0.1 times mol based on the nitrobenzene derivative represented by the general formula [IV].

Although the reaction temperature cannot be generally specified, for example, about 0
C. to about 50.degree. C., preferably about 0.degree. C. to about 30.degree.

The reaction time varies depending on the reaction temperature, the amount of the catalyst, and the like, and cannot be specified unconditionally.

After completion of the reaction, the catalyst used in the catalytic reduction method is separated by filtration and then concentrated under reduced pressure, for example, to obtain a desired anilide derivative represented by the general formula [II]. Further, if necessary, it can be further purified by a usual method such as recrystallization, chromatography and the like.

The nitrobenzene derivative represented by the general formula [IV]
-Nitrophthalic acid and the general formula R ¹ OH [VI] wherein R ¹ represents a lower alkyl group. ] In the presence of an acid.

In the reaction, for example, commonly used solvents include lower alcohols represented by the general formula [VI] such as methanol and ethanol, hydrocarbons such as toluene, halogenated hydrocarbons such as monochlorobenzene, and mixtures thereof. No.

Examples of the acid used in the above reaction include sulfuric acid.

The above reaction is usually carried out under heating.

The amount of the reagent used in the above reaction is about 1 to about 100 times, preferably about 1 to 20 times, the molar amount of the lower alcohol represented by the general formula [VI] with respect to 3-nitrophthalic acid. .

The above reaction is usually carried out under heating. The reaction temperature is usually from room temperature to about 200 ° C, preferably about 5 ° C.
The temperature ranges from 0 ° C to about 150 ° C, and the reaction time is usually about 1 hour to about 48 hours.

After completion of the reaction, the reaction mixture is poured into water, extracted with an organic solvent such as toluene or ethyl acetate, and concentrated under reduced pressure to obtain a desired nitrobenzene derivative represented by the general formula [IV]. Also, if necessary,
Further purification can be performed by ordinary methods such as recrystallization and chromatography.

From the anilide derivative represented by the general formula [II] to the substituted 2-oxa-7-aminoindan derivative represented by the general formula [III], the general formula Wherein R ² , R ³ and R ⁴ have the same meaning as described above. ] Can be continuously performed in the same reaction vessel without changing the reaction vessel for each reaction. That is, the general formula (III)
After completion of the synthesis reaction of the substituted 2-oxa-7-aminoindan derivative represented by, for example, ethyl acetate, toluene after treatment with ammonium chloride, diluted hydrochloric acid, diluted sulfuric acid, or the like,
Normal post-treatment such as extraction with an organic solvent such as monochlorobenzene is not required.

In addition, 3-nitrophthalic acid is, for example, Organic Synt
The phthalic anhydride can be synthesized by reacting phthalic anhydride with nitric acid in the presence of an acid such as sulfuric acid by the method described in Hesis, 7 , 74 (1927).

<Effect of the Invention> The present invention is directed to production of a substituted 2-oxa-7-aminoindane derivative represented by the general formula [III] useful as an intermediate of the acid amide compound represented by the general formula [I] having bactericidal activity. With respect to the method, the target substance can be advantageously produced by the method of the present invention.

<Examples> Next, the present invention will be described in more detail with reference to Production Examples, but the present invention is not limited to only the following Production Examples.

Production Example 1 2.37 g of 2-methoxycarbonyl-6-acetylaminobenzoic acid was dissolved in 50 ml of tetrahydrofuran, and 20 ml of a 3M solution of methylmagnesium chloride in tetrahydrofuran was slowly added dropwise on ice. After the dropwise addition, the temperature was gradually raised to room temperature, and the mixture was stirred and reacted overnight. After the completion of the reaction, the reaction mixture was poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. The obtained extract was concentrated under reduced pressure to obtain 1.86 g of the desired 3,3-dimethyl-7-acetaminophthalide.
Obtained.

Yield 85.0% mp 129-131 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm 1.6 (6H, S), 2.2 (3H, s), 7.0 (1H, d, J = 8.0 Hz),
7.6 (1H, dd, J = 8.0Hz), 8.5 (1H, d, J = 8.0Hz), 9.7
(1H, bs) Production Example 2 2.25 g of 2-methoxycarbonyl-6-nitrobenzoic acid
Then, 1.53 g of acetic anhydride and 1.53 g of acetic anhydride were dissolved in 100 ml of methanol, and a catalytic amount of 10% palladium carbon was added thereto, followed by a reaction under a hydrogen atmosphere at room temperature for 5 hours. After the reaction, palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure to obtain 2.18 g.
Of 2-methoxycarbonyl-6-acetylaminobenzoic acid was obtained.

Yield 92.0% mp 175 ° C ¹ H-NMR (DMSO-d) δ ppm 2.2 (3H, s), 3.9 (3H, S), 7.4 to 8.2 (3H, m) 7.6 (1
(H, bs) 9.8 (1H, bs) Production Example 3 1.36 g of sulfuric acid was slowly dropped at room temperature into a solution of 2.26 g of 3-nitrophthalic acid dissolved in 22.6 g of methanol. After the addition, the reaction was carried out for 24 hours under reflux with heating. After completion of the reaction, the reaction mixture was poured into cold water and extracted with ethyl acetate. By concentrating the obtained extract under reduced pressure, 2
2.17 g of -methoxycarbonyl-6-nitrobenzoic acid was obtained.

Yield 90.0% mp 164-165 ° C ¹ H-NMR (CDCl ₃ ) δ ppm 3.9 (3H, s), 7.7 (1H, dd), 8.1-8.4 (2H, m), 11.
5 (1H, bs) Comparative Production Example 1 Journal of the American chemical Society, 69 , 1909
(1947) 3-acetaminophthalic anhydride was produced according to the method described in (1947).

200 g of 2-methoxycarbonyl-6-nitrobenzoic acid and 430 g of acetic anhydride were dissolved in 920 g of acetic acid, and a catalytic amount was added thereto.
After adding 10% palladium carbon, under hydrogen atmosphere, 110 ° C
Reduced at ~ 120 ° C for 3 hours. After the reaction, palladium carbon was filtered off, and the filtrate was cooled to obtain crystals. The resulting crystals were separated by filtration to obtain 157 g of 3-acetaminophthalic anhydride.

Yield 80.8% mp 186-190 ° C. Comparative Production Example 2 According to the method described in Compt. Rend. 231 , 911 (1950), 3
-Acetaminophthalic anhydride and acetic anhydride were dissolved in acetic acid, and a catalytic amount of zinc powder was added thereto in the presence of hydrochloric acid, followed by vigorous shaking. After the reaction, zinc was filtered off, and the filtrate was purified to obtain 4-acetaminophthalide.

Yield 32.0% Comparative Production Example 3 α, α-Dimethyl-2-hydroxymethyl-3-acetoaminobenzyl alcohol was produced according to the method described in JP-A-2-131481. Dissolve 7.5 g of 4-acetaminophthalide in 120 ml of tetrahydrofuran, and add a 3M ether solution of methylmagnesium iodide on ice with 13 ml.
0 ml was slowly added dropwise. After the dropwise addition, the temperature was gradually raised to room temperature, and the mixture was stirred and reacted overnight.

After completion of the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride under ice-cooling, and extracted twice with ethyl acetate. After drying the extract, the oily substance obtained by concentration is purified by silica gel column chromatography,
7.2 g of white crystals of α-α-dimethyl-2-hydroxymethyl-3-acetaminobenzyl alcohol were obtained.

Yield 84.5% mp 137.9 ° C ¹ H-NMR (CDCl ₃ ) δ ppm 1.6 (6H, s), 2.1 (3H, s), 3.7 (2H, bs), 5.0 (2H,
s), 7.2 to 7.8 (3H, m), 8.7 (1H, bs) Comparative Production Example 4 3,3-Dimethyl-7-acetaminophthalide was produced according to the method described in JP-A-2-131481. Was.
Dissolve 7.2 g of α, α-dimethyl-2-hydroxymethyl-3-acetaminobenzyl alcohol in 300 ml of chloroform, add 28 g of activated manganese dioxide, and heat for 6 hours.
Refluxed. After completion of the reaction, the reaction mixture was allowed to cool and then filtered through a glass filter covered with celite, and the residue was washed with 100 ml of chloroform. The filtrate and the washing solution were combined and concentrated, and the resulting oil was purified by silica gel column chromatography to obtain the desired 3,3-dimethyl-7-
4.4 g of acetaminophthalide was obtained.

Yield 60.6% mp 124.1 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm 1.6 (6H, s), 2.2 (3H, s) 7.0 (1 H, d, J = 8.0 Hz), 7.
6 (1H, dd, J = 8.0Hz), 8.5 (1H, d, J = 8.0Hz), 9.7 (1
H, bs)

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Tadashi Osumi 4-2-1 Takashi Takarazuka-shi, Hyogo Prefecture Inside Sumitomo Chemical Co., Ltd. (72) Inventor Hidenori Dan 4-2-1 Takashi Takarazuka-shi, Hyogo Prefecture Sumitomo Chemical Industries Co., Ltd. (56) References JP-A-2-131477 (JP, A) JP-A-2-131481 (JP, A) JP-A-4-182460 (JP, A) JP-A-4-182477 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 307/88 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) General formula [In the formula, R ¹ and R ² represent a lower alkyl group. Wherein an anilide derivative represented by the formula (1) is reacted with a lower alkyl Grignard reagent. [Wherein, R ² represents the same meaning as described above, and R ³ represents a lower alkyl group. ] A method for producing a substituted 2-oxa-7-aminoindan derivative represented by the formula: 2. The general formula [In the formula, R ¹ represents a lower alkyl group. A nitrobenzene derivative represented by the general formula (R ² CO) ₂ O wherein R ² represents a lower alkyl group. By reacting a carboxylic acid anhydride represented by the general formula [Wherein, R ¹ and R ² represent the same meaning as described above. Wherein the derivative is reacted with a lower alkyl Grignard reagent. [Wherein, R ² represents the same meaning as described above, and R ³ represents a lower alkyl group. ] A method for producing a substituted 2-oxa-7-aminoindan derivative represented by the formula: 3. Nitrophthalic acid and a lower alcohol represented by the general formula R ¹ OH wherein R ¹ represents a lower alkyl group. Is reacted in the presence of an acid to obtain a compound of the general formula [Wherein, R ¹ has the same meaning as described above. A nitrobenzene derivative represented by the general formula (R ² CO) ₂ O wherein R ² represents a lower alkyl group. By reacting a carboxylic acid anhydride represented by the general formula [Wherein, R ¹ and R ² represent the same meaning as described above. Wherein the derivative is reacted with an alkyl Grignard reagent. [Wherein, R ² represents the same meaning as described above, and R ³ represents a lower alkyl group. ] A method for producing a substituted 2-oxa-7-aminoindan derivative represented by the formula: