CN1524070A - Preparation method of Z-alpha-alkoxyiminophenylacetic acid derivatives - Google Patents

Abstract

A process for producing a Z- alpha -alkoxyiminophenylacetic acid derivative represented by the general formula (I) (wherein R represents C>1-6< alkyl), characterized by reacting a compound represented by the general formula (II) (wherein R is the same as defined above) with benzoylformic acid, which is represented by the formula (III), at -40 to 0[deg.]C.

Description

Preparation method of Z-alpha-alkoxyiminophenylacetic acid derivatives

technical field

The present invention relates to the preparation method of Z-alpha-alkoxyiminophenylacetic acid derivatives.

Background technique

Z-alpha-alkoxyiminophenylacetic acid derivatives as physiologically active substances such as insecticidal milbemycin derivatives described in JP-A-8-259570 or JP-A-2000-44571 Synthetic intermediates are useful.

The production method of Z-α-alkoxyiminophenylacetic acid derivatives has been disclosed in JP-A-48-4487 or JP-A-54-135792. However, the rate of formation of the Z-isomer was not high. Moreover, in order to further selectively obtain the Z-type isomer, it is necessary to derivatize the oxime carboxylic acid obtained by oximation into methyl ester or ethyl ester, and then use silica gel column chromatography to separate the Z-type isomer and the E-type isomer, Finally the ester is hydrolyzed. In addition, the Journal of the Chemical Society of Japan, May 1981, page 800 also describes a method for producing Z-α-alkoxyiminophenylacetic acid, but the production rate of the Z-isomer is not high.

invention disclosure

In view of the importance of Z-α-alkoxyiminophenylacetic acid derivatives, the present inventors have carefully studied the method for selectively preparing Z-type isomers, and found that salts of alkoxyamine derivatives After being neutralized with a base, reacting with benzoylformic acid under cooling conditions can selectively prepare the Z isomer, thereby completing the present invention.

The present invention is a method for preparing Z-alpha-alkoxyiminophenylacetic acid derivatives represented by the following general formula (I), characterized in that the alkoxyamine derivatives represented by the following general formula (II) It is reacted with benzoylformic acid represented by the following general formula (III) at -40°C to 0°C.

(In the formula, R represents an alkyl group having 1 to 6 carbon atoms) RO-NH ₂ , (II) (In the formula, R represents the same meaning as above)

In addition, the object compound Z-alpha-alkoxyiminophenylacetic acid derivative of the present invention is represented by the following general formula (I), which is characterized in that the geometric isomer of the imino group is Z-type, on the other hand, the corresponding Geometric isomer Type E refers to a geometric isomer represented by the following general formula (IV).

(wherein, R represents an alkyl group having 1 to 6 carbon atoms)

(In the formula, R represents the same meaning as above)

In the compounds represented by the above-mentioned general formulas (I) and (II), as "a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms" in the definition of R, such as methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl , isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl base, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl, preferably Methyl, ethyl, n-propyl or n-butyl, more preferably methyl or ethyl, particularly preferably methyl.

The preparation method of the present invention can be carried out in the presence or absence of a solvent, and is preferably carried out in the presence of a solvent.

The usable solvent is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as hexane, benzene, or toluene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane Ethers; Amides such as N,N-dimethylformamide or N,N-dimethylacetamide; Halogenated hydrocarbons such as chloroform, dichloromethane or dichloroethane; Methanol, ethanol, isopropanol or alcohols such as n-butanol; esters such as ethyl acetate, isopropyl acetate or butyl acetate; sulfoxides such as dimethyl sulfoxide; or water; and mixed solvents obtained by mixing these solvents, preferably dioxygen A mixed solvent obtained by mixing hexacyclo, N,N-dimethylformamide, methanol or water with these solvents, more preferably methanol or a mixed solvent of methanol and water.

The reaction temperature is preferably carried out in the range of -40°C to 0°C, more preferably in the range of -30°C to 10°C.

The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 72 hours, preferably 30 minutes to 24 hours, more preferably 1 hour to 8 hours.

After completion of the reaction, the compound represented by the above general formula (I) can be obtained from the reaction mixture according to a conventional method. For example, if necessary, the reaction mixture is concentrated under reduced pressure, an acid such as dilute hydrochloric acid or dilute sulfuric acid aqueous solution is added, and extraction is performed with a solvent immiscible with water. After the extract is dried over anhydrous sodium sulfate or the like, the solvent is distilled off to obtain the compound represented by the above general formula (I). The obtained compound can be purified by a conventional method such as recrystallization, distillation or sublimation as necessary.

The alkoxyamine derivative used in the present invention is preferably a compound obtained by neutralizing a salt of an alkoxyamine derivative with a base.

The above "salt of alkoxyamine derivative" is not particularly limited as long as it is a stable salt of the above alkoxyamine derivative, for example, an alkoxyamine derivative and hydrochloric acid, sulfuric acid, perchloric acid, Inorganic acids such as chloric acid, chlorous acid, chloric acid or bromic acid, nitric acid; organic carboxylic acids such as formic acid, acetic acid, propionic acid, isobutyric acid, pivalic acid or trifluoroacetic acid; trifluoromethanesulfonic acid or p-toluenesulfonic acid Acid addition salts formed by sulfonic acids such as glutamic acid or aspartic acid or amino acids such as glutamic acid or aspartic acid. Preferred are salts formed of the above-mentioned alkoxyamine derivatives and inorganic acids or organic acids, more preferably salts of the above-mentioned alkoxyamine derivatives and inorganic acids, most preferably hydrochlorides or sulfates of the above-mentioned alkoxyamine derivatives .

As the above-mentioned "base", as long as it is a base and/or its solution that can be used in a general chemical reaction, there is no particular limitation, such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, lithium carbonate, lithium bicarbonate, Inorganic bases such as cesium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide and their aqueous solutions; alcoholates such as sodium methoxide, sodium ethoxide, potassium ethoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide and their alcoholic solutions ( As the alcohol, for example, an alcohol having 1 to 6 carbon atoms such as methanol, ethanol, propanol or isopropanol); or an organic base such as triethylamine or pyridine. Preferred are inorganic bases and their aqueous solutions, or alcoholates and their alcoholic solutions, more preferably aqueous sodium hydroxide solutions or alcoholic solutions of sodium methoxide.

The reaction temperature is preferably carried out in the range of -40°C to 0°C, more preferably in the range of -30°C to -10°C.

The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 72 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 8 hours.

Among the above-mentioned preparation methods, a preferred embodiment is the preparation method of Z-alpha-alkoxyiminophenylacetic acid derivatives represented by the following general formula (I), characterized in that, the following general formula (II) represents The salt formed by the alkoxyamine derivative and inorganic acid, in the presence of dioxane, N,N-dimethylformamide, methanol or water and the mixed solvent obtained by mixing these solvents, use sodium hydroxide After neutralizing the aqueous solution of sodium methoxide or the alcohol solution of sodium methoxide, it reacts with benzoylformic acid represented by the following formula (III) at -40°C to 0°C.

(wherein, R represents an alkyl group having 1 to 6 carbon atoms)

RO-NH ₂

(II)

(In the formula, R represents the same meaning as above)

A further preferred embodiment is a method for preparing Z-alpha-alkoxyiminophenylacetic acid derivatives represented by the following general formula (I), characterized in that the alkoxy group represented by the following general formula (II) The hydrochloride or sulfate of amine derivatives, in the presence of methanol or a mixed solvent obtained by mixing water and methanol, is neutralized with an aqueous solution of sodium hydroxide or an alcoholic solution of sodium methoxide, and is represented by the following formula (III): The benzoylformic acid reacts at -30°C to -10°C.

(wherein, R represents an alkyl group having 1 to 6 carbon atoms)

RO-NH ₂

(II)

(In the formula, R represents the same meaning as above)

BEST MODE FOR CARRYING OUT THE INVENTION

The method of the present invention is specifically described below in conjunction with embodiment, but the present invention is not limited by these

Limitations of the Examples.

[Example 1]

Preparation of Z-α-methoxyiminophenylacetic acid (R=methyl)

A methanol (80 ml) solution of 6.13 g (71.9 mmol) of O-methylhydroxylamine hydrochloride was cooled to -20°C and stirred. To this solution was added dropwise a solution of sodium methoxide in methanol (about 28%) for neutralization, using a pH meter, until the pH reached 7. Next, a methanol (40 ml) solution of 9.5 g (63.3 mmol) of benzoylformic acid was added dropwise to this solution, followed by stirring at -20°C for 8 hours. After the reaction was completed, it was concentrated under reduced pressure, poured into a mixture of saturated brine and 1N hydrochloric acid aqueous solution, and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to obtain 11.5 g of a crude product of the target product. NMR spectrum: (200MHz, CDCl3δppm): 10.3 (1H, br), 7.60-7.72 (2H, m), 7.32-7.45 (3H, m), 4.03 (3H, s).

Mass Spectrum (m/z): 179(M+), 134, 119, 103.

The ratio of Z-type isomer to E-type isomer=20:1 (the formation ratio is determined by liquid chromatography under the following conditions)

Liquid Chromatography Conditions

Column: puresil C18 (φ6.0×150mm, pore size 120 Å, average particle size 5μm) solvent: 0.1M KH ₂ PO ₄ aqueous solution/MeOH=84/16

Temperature: room temperature

Flow rate: 1.0ml/min

Detection: UV240nm

Retention time: about 10 minutes for the Z-type isomer, about 13 minutes for the E-type isomer

[Example 2]

Preparation of Z-α-methoxyiminophenylacetic acid (R=methyl)

Preparation of Z-α-methoxyiminophenylacetic acid (R=methyl)

A methanol (80 ml) solution of 6.81 g (79.9 mmol) of O-methylhydroxylamine hydrochloride was cooled to 0° C. and stirred. To this solution, 8N aqueous sodium hydroxide solution was added dropwise for neutralization until the pH reached 7 using a pH meter. Next, a methanol (40 ml) solution of 10.0 g (66.6 mmol) of benzoylformic acid was added dropwise to this solution, followed by stirring at 0° C. for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, poured into a mixture of saturated brine and 1N hydrochloric acid aqueous solution, and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to obtain 11.8 g of a crude product of the target product.

The ratio of Z-type isomer and E-type isomer=16: 1 (generation ratio adopts liquid chromatography to determine under the same conditions as Example 1)

[Example 3]

Preparation of Z-α-methoxyiminophenylacetic acid (R=methyl)

1.42 g (corresponding to O-methylhydroxylamine 8.0 mmol) of O-methylhydroxylamine sulfate aqueous solution was dissolved in methanol (11.5 ml), phenolphthalein was added, cooled to -20° C., and stirred. To this solution was added dropwise sodium methoxide in methanol (about 28%) until the color of the solution turned reddish purple. Next, an aqueous solution of O-methylhydroxylamine sulfate was added dropwise to the solution until the color of the solution disappeared. After slowly adding 1.00 g (6.7 mmol) of benzoylformic acid to this solution, it stirred at -20 degreeC for 3 hours. The reaction solution was poured into a mixture of saturated brine and 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to obtain 1.13 g of a crude product of the target product.

The ratio of Z type isomer and E type isomer=19: 1 (generation ratio adopts liquid chromatography to determine under the conditions with embodiment 1 and)

[Example 4]

Preparation of Z-α-methoxyiminophenylacetic acid (R=methyl)

A methanol (60 ml) solution of 6.81 g (79.9 mmol) of O-methylhydroxylamine hydrochloride was cooled to 0° C. and stirred. Sodium methoxide in methanol (ca. 28%) was added dropwise to this solution until the pH reached 7 using a pH meter. After stirring at 0°C for 30 minutes, the precipitated sodium chloride was removed by filtration. A methanol (35 ml) solution of 10.0 g (66.6 mmol) of benzoylformic acid was added dropwise to the filtrate, followed by stirring at 0° C. for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, poured into a mixture of saturated brine and 1N hydrochloric acid aqueous solution, and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to obtain 12.0 g of a crude product of the target product.

The ratio of Z-type isomer and E-type isomer=16: 1 (generation ratio adopts liquid chromatography to determine under the same conditions as Example 1)

[Example 5]

Preparation of Z-α-methoxyiminophenylacetic acid (R=methyl)

A solution of 31.22 g (366 mmol) of O-methylhydroxylamine hydrochloride in methanol (300 ml) was cooled to -10°C and stirred. To this solution was added dropwise 8N aqueous sodium hydroxide solution until the pH reached 7 using a pH meter. Next, a methanol (100 ml) solution of 50.0 g (333 mmol) of benzoylformic acid was added dropwise to this solution, followed by stirring at -10°C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, poured into a mixture of saturated brine and 1N hydrochloric acid aqueous solution, and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to obtain 59.89 g of a crude product of the target product.

The ratio of Z-type isomer and E-type isomer=19: 1 (generation ratio is determined by liquid chromatography under the same conditions as in Example 1)

[Comparative Example 1]

Preparation of Z-α-methoxyiminophenylacetic acid (R=methyl)

According to the method described in Preparation Example 1 of JP-A No. 54-135792, at room temperature, in methanol (40ml) solution of O-methylhydroxylamine hydrochloride 6.0g (70.4mmol), add dropwise methanol of sodium methoxide solution (approximately 28%) until pH 7 was reached using a pH meter. After stirring at room temperature for 30 minutes, the precipitated sodium chloride was removed by filtration. A methanol (40 ml) solution of 10.0 g (66.6 mmol) of benzoylformic acid was added dropwise to the filtrate, followed by heating under reflux for 2.5 hours. After the reaction was completed, it was concentrated under reduced pressure, poured into a mixture of saturated brine and 1N hydrochloric acid aqueous solution, and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to obtain 12.0 g of a crude product of the target product.

The ratio of Z-type isomer and E-type isomer=10:1 (generation ratio is determined by liquid chromatography under the same conditions as in Example 1)

[Comparative Example 2]

Preparation of Z-α-methoxyiminophenylacetic acid (R=methyl)

According to the method described on page 800 of the May, 1981 issue of the Journal of the Chemical Society of Japan, at room temperature, in methanol (15 ml) solution of 0.62 g (7.33 mmol) of O-methylhydroxylamine hydrochloride, a methanol solution of sodium methoxide was added dropwise. (approximately 28%), neutralize until pH 6-8 is reached. After stirring at room temperature for 30 minutes, the precipitated sodium chloride was removed by filtration. 1.0 g (6.66 mmol) of benzoylformic acid was added to the filtrate, followed by stirring at room temperature for 2.5 hours. After the reaction was completed, it was concentrated under reduced pressure, poured into a mixture of saturated brine and 1N hydrochloric acid aqueous solution, and extracted with ethyl acetate. The extract was dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to obtain 1.1 g of a crude product of the target product.

The ratio=11:1 of Z-type isomer and E-type isomer (generation ratio is determined by liquid chromatography under the same conditions as in Example 1)

Industrial Applicability

According to the production method of the present invention, Z-α-methoxyiminophenylacetic acid useful as a synthetic intermediate of bioactive substances such as insecticidal milbemycin derivatives can be easily and selectively produced.

Claims (5)

1. the preparation method of the Z-alpha-alkoxy base imino-phenyl acetic acid derivatives of following general formula (I) expression is characterized in that, the alkoxylamine derivative of following general formula (II) expression and the benzoyl formic acid of following formula (III) expression are reacted down at-40 ℃ to 0 ℃,

In the formula, R represents to have the alkyl of 1 to 6 carbon atom,

RO-NH ₂

(II)

In the formula, R represents implication same as described above,

2. the preparation method of Z-alpha-alkoxy base imino-phenyl acetic acid derivatives as claimed in claim 1, wherein the alkoxylamine derivative is the alkoxylamine derivative that the salt of alkoxylamine derivative is obtained with the alkali neutralization.

3. the preparation method of Z-alpha-alkoxy base imino-phenyl acetic acid derivatives as claimed in claim 1 or 2, wherein temperature of reaction is-30 ℃ to-10 ℃.

4. the preparation method of the Z-alpha-alkoxy base imino-phenyl acetic acid derivatives of following formula general formula (I) expression, it is characterized in that, make the alkoxylamine derivative of following general formula (II) expression and the salt that mineral acid forms, at dioxane, N, under the condition that the mixed solvent that dinethylformamide, methyl alcohol or water and these solvent obtain exists, with in the alcoholic solution of the aqueous solution of sodium hydroxide or sodium methylate and after, with the benzoyl formic acid of following formula (III) expression-40 ℃ to 0 ℃ reactions down

In the formula, R represents to have the alkyl of 1 to 6 carbon atom,

RO-NH ₂

(II)

In the formula, R represents implication same as described above,

5. the preparation method of the Z-alpha-alkoxy base imino-phenyl acetic acid derivatives of following formula general formula (I) expression, it is characterized in that, make the hydrochloride or the vitriol of the alkoxylamine derivative of following general formula (II) expression, under the condition that the mixed solvent that methyl alcohol or water and methanol mixed obtain exists, with in the alcoholic solution of the aqueous solution of sodium hydroxide or sodium methylate and after, react down at-30 ℃ to-10 ℃ with the benzoyl formic acid of following formula (III) expression

In the formula, R represents to have the alkyl of 1 to 6 carbon atom,

RO-NH ₂

(II)

In the formula, R represents implication same as described above,