JP3046401B2 - 6- [1- (N-Alkoxyimino) ethyl] salicylic acid derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivatives and intermediates thereof (also known as 6- [1- (N-alkoxyimino) ethyl). A salicylic acid derivative) and a process for producing the same.

[0002]

BACKGROUND OF THE INVENTION The present inventors have already found that a 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivative has herbicidal activity (Japanese Patent Laid-Open No. 4-140773).
issue).

Among these compounds, for example,

Embedded image Can be produced by reacting 2-[(4,6-dimethoxypyrimidin-2-yl) oxy] -6-acetylbenzoic acid ester with methoxyamine.

However, the above-mentioned acetylated benzoic acid ester used as a starting material for the reaction is difficult to obtain and is hardly soluble in a solvent, so that a large amount of a solvent is required in the reaction operation. Further, a method for industrially obtaining an acetylated benzoate ester with high purity has not been developed yet. Therefore, different from the method using acetylated benzoic acid, 6- [1-
Development of a method for producing (N-alkoxyimino) ethyl] salicylic acid derivatives is expected.

[0005]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned problems, and provides a new method for producing a 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivative useful as a herbicide and its synthesis. An object is to provide an intermediate and an efficient production method thereof.

[0006]

Means for Solving the Problems The present inventors have made intensive studies to overcome the drawbacks of such a method for producing 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivative, and have identified salicylic acid derivatives having the alkoxyiminocarboxylic ethyl group and 4,6-dimethoxy-pyrimidone Jin -2
It has been found that the purpose can be achieved by reacting -yl-methylsulfone, and the present invention has been accomplished based on this finding. That is, the present invention provides (1) reacting a compound represented by the following general formula ( Ia ) with 4,6-dimethoxypyrimidin-2-yl-methylsulfone in the presence of a base; A method for producing a 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivative represented by II).

The general formula (I a )

Embedded image

The general formula (II)

Embedded image (In the formula , R ² and R ³ represent a hydrogen atom or a lower alkyl group.)

[0009] (2) represented by the following following general formula (I) 6-
[1- (N-alkoxyimino) ethyl] salicylic acid derivative.

Formula (I)

Embedded image (Wherein, R ¹ represents a hydrogen atom or a hydroxyl-protecting group;
² and R ³ represent a hydrogen atom or a lower alkyl group. )

(3) The compound represented by the above general formula (I) is obtained by reacting an acetal derivative represented by the following general formula (III) with an alkoxyamine salt. Production method of 1- (N-alkoxyimino) ethyl] salicylic acid derivative.

General formula (III)

Embedded image (Wherein, R ¹ and R ³ are as defined above, and R ⁴ , R ⁵
Represents methoxy, ethoxy or bonded to each other to represent ethylenedioxy, methylethylenedioxy, or propylenedioxy. ).

Hereinafter, the present invention will be described in detail. The 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivative of the present invention represented by the general formula (I) can be synthesized according to the following reaction scheme. The following reaction formula (1) shows the case where R ¹ is a hydrogen atom or a benzyl group and R ³ is a methyl group in the general formula (I).

[0014]

Embedded image (In the above formula, R ² has the same meaning as described above.)

That is, the compound represented by the general formula (VI) is reacted with the compound represented by the general formula (IV) in an inert solvent at a temperature ranging from 0 ° C. to the boiling point of the solvent. To obtain a compound represented by the formula: At this time, as the solvent, for example, hydrocarbon solvents such as toluene, benzene, xylene, halogenated hydrocarbon solvents such as methylene chloride and chloroform, alcohol solvents such as methanol and ethanol, ethyl ether, isopropyl ether, tetrahydrofuran, Ether solvents such as 1,4-dioxane, N, N-dimethylformamide,
An aprotic polar solvent such as N, N-dimethylacetamide and dimethylsulfoxide and an ester solvent such as ethyl acetate can be used. Preferably water or methanol,
It is a lower alcohol such as ethanol. The solvent may be used in an amount of 0.01 to 10 liters, preferably 1.0 to 5.0 liters, per mole of the compound represented by the general formula (IV). Preferred reaction conditions include reflux in a methanol solvent. General formula (I
With respect to the compound represented by V), the compound represented by the general formula (V) may be used in an equal amount or more.

The compound represented by the general formula (VII) can be obtained by catalytic hydrogenation of the thus obtained intermediate represented by the general formula (VI) in an inert solvent in the presence of a solvent. The solvent used here is the same as described above. The catalyst used is not particularly limited, and examples thereof include Raney nickel and palladium carbon. Preferred conditions include hydrogenation in a methanol solvent in the presence of palladium carbon.

On the other hand, an intermediate represented by the general formula (VIII) is obtained by catalytically hydrogenating a compound represented by the general formula (IV) in an inert solvent in the presence of a catalyst. The reaction conditions, solvent, catalyst and the like used here are the same as those for (VI). The compound represented by the general formula (VII) can also be obtained by reacting the thus obtained intermediate represented by the general formula (VIII) with the amine salt represented by the general formula (V). The solvent and reaction conditions used here are the same as those used in formula (IV). In addition, the general formula
The compound represented by (VII) can also be obtained by reacting a compound represented by the general formula (IX) with an amine salt represented by the general formula (V) in an inert solvent. The general formula (V
The compound represented by II) can also be synthesized after reacting a compound of the general formula (V) with a compound of the general formula (X) to obtain a compound of the general formula (VI).

The solvent and the reaction temperature are the same as those used in the above formula (IV) or (VIII), but in some cases, a base may be used. As the base,
Such as alkali metal or alkaline earth metal carbonates especially sodium and mosquito Liu arm as magnesium and calcium, bicarbonate, acetate, alcoholate, hydroxide, hydroxide or oxide or the like can be used. Further, an organic base such as pyridine or triethylamine.
Secondary amines can also be used. Preferred conditions include methanol reflux in the presence of potassium acetate and chloroform reflux in the presence of triethylamine.

In the general formula (V) of the reaction formula (1), HD represents an acid corresponding to a salt with an amine, for example, a sulfate or a hydrochloride. As such an amine salt, methoxyamine hydrochloride is preferable, and it can be used in any form of a solid or an aqueous solution. When an aqueous solution of an alkoxyamine hydrochloride is used, an excess of hydrogen chloride is often mixed therein, and it is preferable to use a base to neutralize the excessive amount of hydrogen chloride. General formula (V)
Is used in an amount of 1.0 mol or more, preferably 1.1 to 2.0 mol, per 1 mol of the compound represented by the general formula (IV). In the above operation, since the pH changes depending on the generated acid, an alkali hydroxide may be appropriately added on the way.

The starting material represented by the general formula (IV) used in the present production method is described in the specification of Japanese Patent Application No. 2-251755. Further, the starting materials represented by the general formulas (IX) and (X) are described in the above patents, but can also be produced by the method of Pharmaceutical Journal Vol. 74, p. 466.

In the general formula (I), a protecting group R ^{1 for a} hydroxyl group
Is not particularly limited as long as it is a protecting group usually used for the purpose. For example, benzyl group, substituted benzyl group, t-
A butyldimethylsilyl group, a methoxymethyl group, an ethoxyethyl group, a methyl group and the like are used.

The reaction temperature is 0 to 150 ° C., preferably 5 to 150 ° C.
The reaction is performed in the range of 0 to 80 ° C, and after the completion of the reaction, extraction, washing,
By distilling off the solvent, a 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivative represented by the general formula (I) having high purity can be easily obtained. The obtained 6- [1-
The (N-alkoxyimino) ethyl] salicylic acid derivative is deprotected under acidic conditions or hydrolysis and used in the next reaction.

Next, Tables 1 to 3 show examples of the above-mentioned raw material compounds and target compounds of the present invention.

[0024]

Embedded image

[0025]

[Table 1]

[0026]

Embedded image

[0027]

[Table 2]

[0028]

Embedded image

[0029]

[Table 3]

The 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivative represented by the general formula (I) obtained above, when R ¹ is a protecting group, removes the protecting group.
To give a compound represented by the general formula (Ia)
In the presence of a base, according to the following reaction formula (2), 4,6
-Dimethoxypyrimidin-2-yl-methylsulfone is reacted with a compound represented by the general formula (II):
[1- (N-Alkoxyimino) ethyl] salicylic acid derivative is obtained in good yield.

[0031]

Embedded image (Above formulas odor Te ^{R 2} and R have the same meanings as ³ above.)

As the base used in the above reaction,
For example, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide and the like are used.

Further, 6- [1-
(N-alkoxyimino) ethyl] salicylic acid derivative, 4,6-dimethoxypyrimidin-2-yl-methylsulfone and the base are used in a molar ratio of 1: 1 to 2: 0.5 to
2, preferably 1: 1 to 1.1: 1 to 1.2.

As the solvent, any solvent which is inert to the reaction may be used. For example, aprotic polar solvents, acetones and alcohols are used. Above all, N, N-
Dimethylformamide, N, N-dimethylacetamide, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, ethanol, water and the like can be used alone or in combination. The reaction temperature is 0 to 150 ° C., preferably 25 to 100 ° C., and the reaction time may be sufficient for the reaction to proceed sufficiently, and may be 2 to 5 hours.

[0035]

The present invention will be described in detail with reference to the following examples.

Reference Example 1 "Synthesis of 3-hydroxy-2-methoxycarbonylacetophenone ethylene acetal" 1.64 g (0.005 mol) of 3-benzyloxy-2-methoxycarbonylacetophenone ethylene acetal was dissolved in 60 ml of tetrahydrofuran. % Palladium on carbon was added and hydrogenated for 3 hours. After filtering off the catalyst, the solvent was distilled off, and the resulting crystals were washed with isopropyl ether to obtain 1.10 g of 3-hydroxy-2-methoxycarbonylacetophenone ethylene acetal as colorless crystals (yield 92.0%). . Melting point 142-
143 ° C.

Example 1 "Production of methyl 2-benzyloxy-6- [1- (N-methoxyimino) ethyl] benzoate" 3-benzyloxy-2-methoxycarbonylacetophenone ethylene acetal (330 mg, 1. 0 mmol) and methoxyamine hydrochloride (170 mg, 2.0 mmol) were refluxed for 2 hours in 8 ml of methanol. After cooling, the solvent was distilled off under reduced pressure, 20 ml of 10% sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After concentrating the solvent, the residue was purified by column chromatography to give 2-benzyloxy-6- [1-
(N-methoxyimino) ethyl] methyl benzoate in 30
0 mg was obtained. The yield is 95.8% and the refractive index (20
° C.: Na-D line) ^was 20 _D n 1.5719.

[0038] are shown below the same constant data. IR (neat) 1730, 1565, 1440, 13
20, 1255, 1050 cm ^-1 . NMR (CDCl
₃ ) δ 2.2 (s, 3H), 3.9 (s, 3H),
4.0 (s, 3H), 5.2 (s, 2H), 6.9-
7.6 (m, 8H)

Example 2 "Production of methyl 6- [1- (N-methoxyimino) ethyl] salicylate" In a 500 ml four-necked flask, 3-hydroxy-2-methoxycarbonylacetophenone ethylene acetal (1
1.9 g, 50 mmol) and a 21% aqueous methoxyamine hydrochloride solution (23.9 g, 60 mmol), and 10%
The pH was adjusted to 6 with aqueous sodium hydroxide. 150 ml of methanol was added thereto, and the mixture was stirred at 67 to 68 ° C for 4 hours. During this time, the pH of the reaction solution was adjusted appropriately with a 10% aqueous sodium hydroxide solution so as to be around 6. After completion of the reaction, methanol was distilled off under reduced pressure, and toluene was added thereto, followed by extraction, washing with water, and drying.
(N-methoxyimino) ethyl] methyl salicylate 1
0.5 g (92% yield) was obtained. Gas chromatography analysis indicated a product purity of 97.4% and an E / Z isomer ratio of 89/11.

[0040] are shown below the same constant data. GC-MS m / z 223 (M +). 1H-NMR
_{(CDCl 3) δ2.09 (s,} 3H), 3.90
(S, 3H), 3.94 (s, 3H), 6.4-7.7.
(M, 3H), 10.82 (bs, 1H).

Example 3 "Production of methyl 2-benzyloxy-6- [1- (N-methoxyimino) ethyl] benzoate" 3-Benzyloxy-2-methoxycarbonylacetophenone dimethyl acetal And subjected to post-treatment in the same manner as in Example 1 to give 2-benzyloxy-6-
280 mg (yield 89.4%) of methyl [1- (N-methoxyimino) ethyl] benzoate was obtained. NMR and IR were consistent with those of Example 1.

Example 4 "Method for producing methyl 6- [1- (N-methoxyimino) ethyl] salicylate" In a 500 ml four-necked flask, 3-hydroxy-2-methoxycarbonylacetophenone dimethyl acetal (1
2.0 g, 50 mmol) and a 21% aqueous solution of methoxyamine hydrochloride (23.9 g, 60 mmol) and 10%
The pH was adjusted to 6 with aqueous sodium hydroxide. To this, 150 ml of methanol was added, and the mixture was stirred at 20 to 30 ° C. for 8 hours. During this time, the pH of the reaction solution was adjusted appropriately with a 10% aqueous sodium hydroxide solution so as to be around 6. After completion of the reaction, methanol was distilled off under reduced pressure, and toluene was added thereto, followed by extraction, washing with water, and drying.
(N-methoxyimino) ethyl] methyl salicylate9.
5 g (85% yield) were obtained. The purity of the product was 98.0% by gas chromatography analysis, and the E / Z isomer ratio was 92%.
/ 8. In addition, NMR and IR agreed with the product of Example 2.

Example 5 Synthesis of methyl 6- [1- (N-methoxyimino) ethyl] salicylate (1) 188 mg of methyl 2-benzyloxy-6- [1- (N-methoxyimino) ethyl] benzoate (0 mg) .0006 mol) was dissolved in 5 ml of methanol, 40 mg of 10% palladium on carbon was added, and hydrogenated for 2 hours. After filtering off the catalyst, the solvent was distilled off and 6- [1- (N-methoxyimino) ethyl]
130 mg of methyl salicylate was obtained as a colorless oil (yield 97.0%). Refractive index 1.5423.

Example 6 Synthesis of methyl 6- [1- (N-methoxyimino) ethyl] salicylate (2) 170 mg (0.0006 mol) of 3-benzyloxy-2-methoxycarbonylacetophenone ethylene acetal and 100 mg of methoxyamine hydrochloride (0.0012 mol) was heated to reflux in 4 ml of methanol for 2 hours. After cooling, 40 mg of 10% palladium carbon was added and hydrogenated for 2 hours. After the solvent was filtered off, the solvent was distilled off, and 10 ml of water was added.
The mixture was extracted with ether, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained mixture was separated and purified by column chromatography (Wakogel C-200, eluent: n-hexane / ethyl acetate = 4/1) to give 6- [1- (N- Methoxyimino)
Ethyl] methyl salicylate (121 mg) was obtained as a colorless oil (yield: 90.4%). Refractive index 1.5423.

Example 7 "Synthesis of methyl 6- [1- (N-methoxyimino) ethyl] salicylate" 3-benzyloxy-2-methoxycarbonylacetophenone ethylene acetal 0.197 g (0.0006)
Mol) and methoxyamine hydrochloride 0.10 (0.0012
Mol) was heated to reflux for 2 hours in 4 ml of methanol. After cooling, 40 mg of 10% palladium on carbon was added, and hydrogenation was continued for 2 hours.
Time went. After the catalyst was removed by filtration, the solvent was distilled off, 10 ml of water was added, the mixture was extracted with ether, washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by column chromatography (Wakogel C-200, n-hexane / ethyl acetate = 4/1) to give 6- [1- (N-methoxyimino). ) Ethyl] methyl salicylate (0.12 g) was obtained as a colorless oil (yield 90.4%). Refractive index 1.5423.

Example 8 "Synthesis of methyl 6- [1- (N-methoxyimino) ethyl] salicylate" Methyl 6-acetylsalicylate (1.2 g, 0.006)
2 mol), methoxyamine hydrochloride (1.3 g, 0.016
Mol) and potassium acetate (1.5 g, 0.015 mol) were added to 30 ml of methanol and allowed to stand overnight. The reaction solution was poured into water, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with an aqueous sodium hydrogen carbonate solution and water in that order, dried,
The oily substance obtained by concentration was purified by column chromatography to obtain the desired product. 1.15 g (83% yield). Refractive index 1.5423.

Example 9 "Synthesis of methyl 6- [1- (N-ethoxyimino) ethyl] salicylate" Methyl 6-acetylsalicylate (1.9 g, 0.010
Mol), ethoxyamine hydrochloride (1.1 g, 0.011
Mol) and potassium acetate (1.1 g, 0.011 mol) were added to 30 ml of methanol and refluxed for 3 hours. The reaction solution was poured into water, acidified with acetic acid, and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and water in that order, dried and concentrated, and the obtained oil was purified by column chromatography to obtain the desired product. 1.5 g (63% yield).
Refractive index 1.5326.

Example 10 "2-[(4,6-dimethoxypyrimidin-2-yl)"
Oxy] -6- [1- (N-methoxyimino) ethyl]
Preparation of methyl benzoate "In a 100 ml four-necked flask, methyl 6- [1- (N-methoxyimino) ethyl] salicylate (10.3 g, 46.
2 mmol), 4,6-dimethoxypyrimidin-2-yl-methylsulfone (11.09 g, 50.8 mmol), potassium carbonate (3.83 g, 27.7 mmol)
And 15 ml of N, N-dimethylformamide, and 9
The mixture was stirred at 0 ° C for 3.5 hours. After completion of the reaction, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration.
-Methyl [-[(4,6-dimethoxypyrimidin-2-yl) oxy] -6- [1- (N-methoxyimino) ethyl] benzoate was obtained. E / E by gas chromatography analysis
The mixture had a Z isomer ratio of 90/10. This was dissolved in ethyl acetate, washed with water, concentrated, and then concentrated in ethyl acetate.
Recrystallized with a mixed solvent of hexane (1: 2), 12.2 g
(73%) of 2-[(4,6-dimethoxypyrimidine-
Methyl 2-yl) oxy] -6- [1- (N-methoxyimino) ethyl] benzoate was obtained as white crystals. E
/ Z isomer ratio is 98/2. 102-105 ° C.

[0049]

According to the method of the present invention, a 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivative having a high herbicidal activity and represented by the general formula (II) can be efficiently produced by suppressing the formation of by-products. Can be synthesized. The 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivative represented by the general formula (I) of the present invention is easy to synthesize,
It can be used as a synthetic intermediate of the compound represented by the above general formula (II).

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Fumiaki Takabe 408-1, Shioda, Fukuda-cho, Iwata-gun, Shizuoka Pref. Inside the KI Research Institute, Inc. (72) Inventor Masatoshi Tamaru Shioshin, Fukuda-cho, Iwata-gun, Shizuoka 408 No. 1 in the K.I. Research Institute Co., Ltd. (72) Inventor Keisuke Igusumi 2256 Nakanosato, Fujikawa-cho, Fujiwara-cho, Anbara-gun, Shizuoka Prefecture In-laboratory of Ihara Chemical Industry Co., Ltd. 2256, Nakanosato, Kawamachi, Ihara Chemical Industry Co., Ltd. (72) Inventor Tomonori Miyazaki 2256, Nakanosato, Fujikawa-cho, Anbara-gun, Shizuoka Pref. Address Ihara Chemical Industry Co., Ltd. Laboratory (56) References JP-A-4-134073 (J , A) (58) investigated the field (Int.Cl. ^7, DB name) CA (STN) REGISTRY (STN )

Claims (3)

(57) [Claims] 1. A compound represented by the following general formula ( Ia ) and 4,6-dimethoxypyrimidine-2-one in the presence of a base.
Reacting yl-methyl sulfone,
A method for producing a 6- [1- (N-alkoxyimino) ethyl] salicylic acid derivative represented by the following general formula (II). General formula (I a ) General formula (II) (In the formula , R ² and R ³ represent a hydrogen atom or a lower alkyl group.) 2. A compound represented by the following general formula (I):
-(N-alkoxyimino) ethyl] salicylic acid derivative. General formula (I) (Wherein, R ¹ represents a hydrogen atom or a hydroxyl-protecting group;
² and R ³ represent a hydrogen atom or a lower alkyl group. ) 3. The compound according to claim 2, wherein an acetal derivative represented by the following general formula (III) is reacted with an alkoxyamine salt to obtain a compound represented by the general formula (I). (N-alkoxyimino) ethyl] method for producing salicylic acid derivative. General formula (III) (Wherein, R ¹ and R ³ are as defined above, and R ⁴ , R ⁵
Represents methoxy, ethoxy or bonded to each other to represent ethylenedioxy, methylethylenedioxy, or propylenedioxy. )