JPH04368361A - 6-(1-(n-alkoxyimino)ethyl)salicylic acid derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a compound useful as a herbicide in high purity and yield by reacting a specific salicylic acid derivative having methoxyiminoethyl group with 4,6-dimethoxypyridin-2-yl-methyl s u if one. CONSTITUTION:A compound expressed by formula I (R<1> is H or protecting group of OH; R<2> and R<3> are H or lower alkyl) is reacted with 4,6- dimethoxypyridin-2-yl-methyl sulfone in the presence of a base (e.g. NaOH) in a solvent such as methanol at 0-150 deg.C to afford the objective compound expressed by formula II. The compound expressed by formula I can be obtained by reacting an acetal derivative expressed by formula III (R<4> and R<5> are methoxy or ethoxy or mutually bound to form ethylenedioxy or propylenedioxy, etc.) with an alkoxyamine salt.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present inventor has developed a method for producing 6-[1-(N-alkoxyimino)ethyl]salicylic acid derivatives and intermediates thereof (also known as 6-[1-(N-alkoxyimino)ethyl). ] salicylic acid derivative) and its production method.

0002

BACKGROUND OF THE INVENTION The present inventors have already revealed that 6-[1-(N-alkoxyimino)ethyl]salicylic acid derivatives have herbicidal activity (Japanese Patent Application No. 2-413991).

Among these compounds, for example,

embedded image can be produced by reacting 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-acetylbenzoate and methoxyamine.

However, the acetylated benzoic acid ester used as a raw material for this reaction is difficult to obtain and is poorly soluble in a solvent, so a large amount of solvent is required for the reaction operation. Moreover, a method for obtaining acetylated benzoic acid ester with high purity industrially has not yet been developed. Therefore, 6-[1-
The development of a method for producing (N-alkoxyimino)ethyl]salicylic acid derivatives is expected.

[0005]

The present invention solves the above problems and provides a new method for producing 6-[1-(N-alkoxyimino)ethyl]salicylic acid derivatives useful as herbicides and a method useful for the synthesis thereof. The purpose is to provide an intermediate and an efficient method for producing the same.

[0006]

[Means for Solving the Problems] As a result of intensive research to overcome the drawbacks of the method for producing 6-[1-(N-alkoxyimino)ethyl]salicylic acid derivatives, the present inventors have found a specific The inventors discovered that the object could be achieved by reacting a salicylic acid derivative having a methoxyiminoethyl group with 4,6-dimethoxypyridin-2-yl-methylsulfone, and based on this knowledge, the present invention was accomplished. .

Specifically, the present invention provides (1) the following general compound, which is characterized by reacting a compound represented by the following general formula (I) 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 formula (II).

General formula (I)

[C6]

General formula (II)

[Formula 7] (wherein, R1 represents a hydrogen atom or a hydroxyl group-protecting group,
R2 and R3 represent a hydrogen atom or a lower alkyl group. )

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

(3) 6- A method for producing a 1-(N-alkoxyimino)ethyl]salicylic acid derivative.

General formula (III)

[Image Omitted] (In the formula, R1 and R3 have the same meanings as above, and R4
, R5 are methoxy, ethoxy or bonded to each other to represent ethylenedioxy, methylethylenedioxy or propylenedioxy. ).

The present invention will be explained in detail below. 6-[1-(N
-Alkoxyimino)ethyl]salicylic acid derivatives can be synthesized according to the following reaction scheme. The following formula (1) is shown for the case where R1 is a hydrogen atom or a benzyl group and R3 is a methyl group in the general formula (I).

[0014]

[Chemical formula 9] (In the above formula, R2 has the same meaning as above.)

[
That is, by reacting a compound represented by general formula (IV) with a compound represented by general formula (V) in an inert solvent at a temperature ranging from 0°C to the boiling point of the solvent, a compound represented by general formula (VI) is obtained. The represented compound is obtained. At this time, examples of the solvent include hydrocarbon solvents such as toluene, benzene, and 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, N,
Aprotic polar solvents such as N-dimethylacetamide and dimethyl sulfoxide, and ester solvents such as ethyl acetate can be used. Preferably it is water or a lower alcohol such as methanol or ethanol. The amount of solvent used is 0.0 per mole of the compound represented by general formula (IV).
It may be used in a range of 1 to 10 liters, preferably 1.0 to 5.0 liters. Preferred reaction conditions include reflux in methanol solvent. The compound represented by general formula (V) may be used in an equal or larger amount to the compound represented by general formula (IV).

The compound represented by general formula (VII) can be obtained by subjecting the thus obtained intermediate represented by general formula (VI) to catalytic hydrogenation 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, but
Examples include Raney nickel and palladium on carbon. Preferred conditions include hydrogenation in methanol solvent in the presence of palladium on carbon.

On the other hand, by subjecting the compound represented by general formula (IV) to catalytic hydrogenation in an inert solvent in the presence of a catalyst, an intermediate represented by general formula (VIII) is obtained. The reaction conditions, solvent, catalyst, etc. used here are (VI
). The general formula thus obtained (
The compound represented by general formula (VII) can also be obtained by reacting the intermediate represented by general formula (VIII) with an amine salt represented by general formula (V). The solvent and reaction conditions used here are the same as those used for general formula (IV). Furthermore, the compound represented by the general formula (VII) can be added to the compound represented by the general formula (IX) by the general formula (V
The amine salt represented by II) can also be obtained by reacting in an inert solvent. Further, the compound represented by the general formula (VII) is added to the compound of the general formula (X) by the general formula (V
) may be reacted to obtain a compound of general formula (VI) before synthesis.

The solvent and reaction temperature are the same as those used for the above general formula (IV) or (VIII), but
In some cases, a base may be used. Bases include, for example, alkali metals or alkaline earth metals,
In particular, carbonates, bicarbonates, acetates, alcoholates, hydroxides, hydroxides or oxides of sodium and caulim, as well as magnesium and calcium, can be used. Furthermore, it is also possible to use organic bases, for example pyridine or tertiary amines such as triethylamine. 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 above formula (I), HD
indicates the corresponding acid when it forms a salt with an amine, such as a sulfate or a hydrochloride. Such amine salts include
Methoxyamine hydrochloride is preferred and can be used in either solid or aqueous form. When an aqueous alkoxyamine hydrochloride solution is used, excess hydrogen chloride is often mixed in, and it is preferable to use a base to neutralize the excess hydrogen chloride. The amount of the compound represented by general formula (V) to be used is 1.0 mol or more, preferably in the range of 1.1 to 2.0 mol, per 1 mol of the compound represented by general formula (IV). . In addition, in the above operation, the pH changes due to the acid produced, so
It is advisable to add alkali hydroxide appropriately during the process.

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

In the general formula (I), the hydroxyl protecting group R1
There is no particular restriction as long as it is a protecting group that is normally used for that purpose. For example, benzyl group, substituted benzyl group, t
-Butyldimethylsilyl group, methoxymethyl group, ethoxyethyl group, methyl group, etc. are used.

[0022] The reaction temperature is 0 to 150°C, preferably 5°C.
It is carried out in the range of 0 to 80℃, and after the reaction is completed, extraction, washing with water,
By distilling off the solvent, a highly purified 6-[1-(N-alkoxyimino)ethyl]salicylic acid derivative represented by general formula (I) can be easily obtained. Furthermore, the obtained 6-[1-
The (N-alkoxyimino)ethyl]salicylic acid derivative is deprotected by 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]

[Chemical formula 10]

[0025]

[Table 1]

[0026]

[Chemical formula 11]

[0027]

[Table 2]

[0028]

[Chemical formula 12]

[0029]

[Table 3]

The above-obtained 6-[1-(N-alkoxyimino)ethyl]salicylic acid derivative represented by the general formula (I) can be converted to 4 in accordance with the following formula (2) in the presence of a base.
, 6-dimethoxypyrimidin-2-yl-methylsulfone, a 6-[1-(N-alkoxyimino)ethyl]salicylic acid derivative represented by general formula (II) can be obtained in good yield.

[0031]

embedded image (In the above formula, R1, R2 and R have the same meanings as 3 above.)

The base used in the above reaction is as follows:
For example, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, etc. are used.

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

Note that any solvent that is inert to the reaction may be used. For example, aprotic polar solvents, acetones, and alcohols are used. Among them, N, N-
Dimethylformamide, N,N-dimethylacetamide, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone, ethanol, water, etc. can be used alone or in combination. The reaction temperature is 0 to 150°C, preferably 25 to 100°C, and the reaction time is sufficient as long as it is enough time for the reaction to proceed, and 2 to 5 hours is sufficient.

[0035]

[Examples] The present invention will be explained in detail with reference to Examples below.

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 purified 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℃.

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 o-methylhydroxylamine hydrochloride (170 mmol)
g, 2.0 mmol) was heated under reflux for 2 hours in 8 ml of methanol. After cooling, the solvent was distilled off under reduced pressure, and the residue was
After adding 20 ml of 0% sodium hydrogen carbonate, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate. After concentrating the solvent, the residue was purified by column chromatography to obtain 2-benzyloxy-6-[1-(N-methoxyimino)ethyl]
300 mg of methyl benzoate was obtained. Yield is 95.8%
The refractive index was 20Dn 1.5719.

Fixed data is shown below. IR (neat) 1730, 1565, 1440, 13
20,1255,1050 cm-1. NMR (CD
Cl3) δ2.2 (s, 3H), 3.9 (s, 3H)
, 4.0 (s, 3H), 5.2 (s, 2H), 6.9-
7.6 (m, 8H)

Example 2 "2-Hydroxy-6-[1-(N-methoxyimino)"
3-Hydroxy-2-methoxycarbonylacetophenone ethylene acetal (1
1.9 g, 50 mmol) and 21% aqueous O-methylhydroxylamine hydrochloride solution (23.9 g, 60 mmol)
was added, and the pH was adjusted to 6 with a 10% aqueous sodium hydroxide solution. Add 150ml of methanol to this and add 67~6
The mixture was stirred at 8°C for 4 hours. During this time, the pH of the reaction solution was adjusted to around 6 with a 10% aqueous sodium hydroxide solution. After the reaction was completed, methanol was distilled off under reduced pressure.
After adding toluene, extraction, washing with water, and drying, the solvent was distilled off to obtain 10.5 g (92% yield) of methyl 2-hydroxy-6-[1-(N-methoxyimino)ethyl]benzoate. Gas chromatography analysis shows that the purity of the product is 9.
The E/Z isomer ratio was found to be 7.4% and 89/11.

Fixed data is shown below. GC-MS m/z 223 (M+). 1H-NM
R(CDCl3)δ2.09(s,3H),3.90
(s, 3H), 3.94 (s, 3H), 6.4-7.7
(m, 3H), 10.82 (bs, 1H).

0041
Example 3 "Method for producing methyl 2-benzyloxy-6-[1-(N-methoxyimino)ethyl]benzoate" 3-benzyloxy-2-methoxycarbonylacetophenone dimethyl acetal was used as a raw material. The reaction and post-treatment were carried out in the same manner as in Example 1 to obtain 280 mg (yield: 89.4%) of methyl 2-benzyloxy-6-[1-(N-methoxyimino)ethyl]benzoate. NMR and IR were consistent with those of Example 1.

Example 4 "2-Hydroxy-6-[1-(N-methoxyimino)"
3-Hydroxy-2-methoxycarbonylacetophenone dimethyl acetal (1
2.0 g, 50 mmol) and 21% aqueous O-methylhydroxylamine hydrochloride solution (23.9 g, 60 mmol)
was added, and the pH was adjusted to 6 with a 10% aqueous sodium hydroxide solution. Add 150ml of methanol to this and add 20~3
The mixture was stirred at 0°C for 8 hours. During this time, the pH of the reaction solution was adjusted to around 6 with a 10% aqueous sodium hydroxide solution. After the reaction was completed, methanol was distilled off under reduced pressure.
After adding toluene, extraction, water washing, and drying, the solvent was distilled off to obtain 9.5 g (85% yield) of methyl 2-hydroxy-6-[1-(N-methoxyimino)ethyl]benzoate. The purity of the product was 98 by gas chromatography analysis.
．． 0%, and the E/Z isomer ratio was found to be 92/8. Furthermore, N
MR and IR were consistent with the product of Example 2.

Example 5 Synthesis of methyl 6-[1-(N-methoxyimino)ethyl]salicylate (1) Methyl 2-benzyloxy-6-[1-(N-methoxyimino)ethyl]benzoate 188 mg (0 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 to obtain 130 g of methyl 6-[1-(N-methoxyimino)ethyl] salicylate as a colorless oil (yield: 97.0%). Refractive index 1.5423.

Example 6 Synthesis of methyl 6-[1-(N-methoxyimino)ethyl]salicylate (2) 3-benzyloxy-2-methoxycarbonylacetophenone ethylene acetal 197m
(0.0006 mol) and 100 mg (0.0012 mol) of o-methylhydroxylamine hydrochloride were heated under reflux for 2 hours in 4 ml of methanol. After cooling, 40 mg of 10% palladium on carbon was added and hydrogenated for 2 hours. After filtering off the solvent, the solvent was distilled off, 10 ml of water was added, extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting mixture was separated and purified by column chromatography (Wakogel C
-200, eluent: n-hexane/ethyl acetate = 4/1
) to obtain 121 mg of methyl (N-methoxyimino)ethyl]salicylate as a colorless oil (yield: 90.4
%). Refractive index 1.5423.

Example 7 “2-Hydroxy-6-[1-(N-methoxyimino)
3-benzyloxy-2-methoxycarbonylacetophenone ethylene acetal 0.197 g (0.0006
mol) and methoxyamine hydrochloride 0.10 (0.001
2 mol) was heated under reflux for 2 hours in 4 ml of methanol. After cooling, 40 mg of 10% palladium on carbon was added, and hydrogenation was performed for 2 hours. After filtering off the catalyst, the solvent was distilled off, and 10% of water was added.
ml was added, extracted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by column chromatography (Wakogel C-200, n-hexane/ethyl acetate = 4/1) to obtain 2-hydroxy-6-[1-
(N-methoxyimino)ethyl]methylbenzoate 0.1
2 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, 0.01
6 mol), caulim acetate (1.5 g, 0.015 mol)
was added to 30 ml of methanol and left overnight. The reaction solution was poured into water, acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and then with water, dried, and concentrated. The resulting oil was purified by column chromatography to obtain the desired product. 1.15g (yield 83%)
. 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) was added to 30 ml of methanol and refluxed for 3 hours. The reaction solution was poured into water, made acidic with acetic acid, and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and then with water, dried, and concentrated. The resulting oil was purified by column chromatography to obtain the desired product. 1.5g (yield 6
3%). Refractive index 1.5326.

Example 10 “2-[(4,6-dimethoxypyrimidin-2-yl)
Oxy]-6-[1-(N-methoxyimino)ethyl]
2-Hydroxy-6-[1] in a 100ml four-necked flask.
-(N-methoxyimino)ethyl]methylbenzoate (1
0.3 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 N,N-dimethylformamide 15
ml and stirred at 90°C for 3.5 hours. After the reaction was completed, the reaction solution was poured into ice water, the precipitated crystals were collected by filtration, and 16.7 g of 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-[1-(N- Methyl methoxyimino)ethyl]benzoate was obtained. Gas chromatography analysis revealed that it was a mixture with an E/Z isomer ratio of 90/10. This product was dissolved in ethyl acetate, washed with water, concentrated, and then recrystallized from a mixed solvent of ethyl acetate and hexane (1:2). Methyl 2-yl)oxy]-6-[1-(N-methoxyimino)ethyl]benzoate was obtained as white crystals. E/Z isomer ratio is 98/2. Melting point 102-10
5℃.

[0049]

Effects of the Invention According to the method of the present invention, the 6-[1-(N-alkoxyimino)ethyl]salicylic acid derivative represented by the general formula (II), which has high herbicidal activity, can be used efficiently by suppressing the production of by-products. can be synthesized. Furthermore, the 6-[1-(N-alkoxyimino)ethyl]salicylic acid derivative represented by the general formula (I) of the present invention is easy to synthesize and can be used as a synthetic intermediate for the compound represented by the above general formula (II). can be used.

Claims (3)

[Claims] Claim 1: A compound represented by the following general formula (II), which is characterized by reacting a compound represented by the following general formula (I) 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. General formula (I) [Formula 1] General formula (II) [Formula 2] (wherein, R1 represents a hydrogen atom or a hydroxyl group protecting group,
R2 and R3 represent a hydrogen atom or a lower alkyl group. ) Claim 2: 6-[ represented by the following general formula (I)
1-(N-alkoxyimino)ethyl]salicylic acid derivative. General formula (I) [Formula 3] (wherein, R1 represents a hydrogen atom or a hydroxyl group protecting group,
R2 and R3 represent a hydrogen atom or a lower alkyl group. ) 3. 6-[1- according to claim 2, characterized in that the compound represented by the general formula (I) is obtained by reacting an acetal derivative represented by the following general formula (III) with an alkoxyamine salt. (N-alkoxyimino)
Method for producing ethyl salicylic acid derivatives. General formula (III) [Formula 4] (wherein, R1 and R3 have the same meanings as above, and R4
, R5 are methoxy, ethoxy or bonded to each other to represent ethylenedioxy, methylethylenedioxy or propylenedioxy. )