JPH0717560B2 - Process for producing optically active α-isopropyl-p-chlorophenylacetic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention provides a compound represented by formula (I): (In the formula, * indicates an asymmetric carbon) and relates to a method for producing an optically active α-isopropyl-P-chlorophenylacetic acid.

The optically active α-isopropyl-p-chlorophenylacetic acid (hereinafter referred to as ICPA) represented by the above general formula (I), especially its (+)-form, is useful as a carboxylic acid component of a pyrethroid insecticide such as fenvalerate. It is well known that it exists (Japanese Patent Application Laid-Open No. 55-136245), and it is extremely important to produce it industrially advantageously.

<Prior Art> As a method for producing such an optically active ICPA, a method of optically resolving a ceramic ICPA, for example, (A) an optically active amine [eg α-phenyl-β-
(P-Tolyl) ethylamine, α-phenethylamine]
(B) A salt with an achiral amine (for example, diethylamine) is formed by a preferential crystallization method by forming a diastereomeric salt with the compound (JP-A-50-25544 and JP-A-59-80627). Optical resolution method [Agric.Bio
l. Chem., 46 1421 (1982)] and the like are known.

However, when performing such optical resolution, even if it is relatively easy to decompose the salt obtained by optical resolution to obtain the target optically active ICPA, the target optically active ICPA and amine The salt of the optically active ICPA of the antipode and the amine, which is recovered after the salt is separated and obtained, is usually unnecessary for a specific purpose, so it is racemized and re-optically resolved. It is very important for industrially advantageous production of optically active ICPA to recycle it as a desired optically active substance.

<Problems to be Solved by the Invention> However, in the case of the above-mentioned known method, racemization on the ICPA side in a salt state is very slow, and thus the desired optically active ICPA salt and amine salt are separated. After that, the salt of the optically active ICPA of the antipode and the salt of amine cannot be racemized as it is, and in order to obtain the desired optically active ICPA from the salt again, the salt is Once decomposed to obtain free optically active ICPA (an enantiomer with respect to the desired optically active ICPA), it is necessary to racemize it, form a salt with an amine again, and then perform optical resolution. There is a problem that it requires operation, and in addition,
The method (A) has a problem that an expensive resolving agent is used, and a resolving agent having high optical purity must be prepared in order to obtain ICPA having high optical purity, which is industrially advantageous for optically active ICPA. There was a problem as a manufacturing method.

In order to solve such a problem, an optically active salt recovered after optical resolution or an optically active compound corresponding thereto can be easily racemized, and can be decomposed to easily give an optically active compound. A method via an optically active salt capable of being ICPA or an optically active compound corresponding to the same is required, but such a method has not been heretofore known at all.

<Means for Solving Problems> The present invention is to solve the above problems and is represented by the general formula (I
I) (Wherein X ₁ , X ₂ and X ₃ are all halogen atoms, or two of them are halogen atoms and other 1
Is a hydrogen atom or a lower alkyl group. (* Is the same as above) In the above general formula (I), which consists of hydrolyzing the optically active α-isopropyl-p-chlorophenylacetic acid ester (hereinafter referred to as ICPA ester) represented by It provides a method for making the indicated optically active ICPA.

The sterically retentive hydrolysis of the optically active ICPA ester is usually carried out under acidic conditions, especially in the presence of an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid or nitric acid, and such an acid is usually contained in an amount of 10 to 50% by weight. Used as a concentrated aqueous solution.

This reaction is carried out in the presence of water. Although water is used in the form of an aqueous solution of the above acid, the presence of an organic solvent may be present as long as it does not particularly affect the reaction.

The amount of water used is at least 1 equivalent of the optically active ICPA ester, and the upper limit is not particularly limited.

The reaction temperature is in the range of 20 ° C to the boiling point of the solution.

Thus, the desired optically active ICPA ester can be easily obtained from the optically active ICPA ester. The optically active ICPA ester (II), which is a raw material for this reaction, has not been known at all until now, and the first time by the present inventors. A new compound found, for example having the general formula (III) (Wherein X ₁ , X ₂ and X ₃ are the same as above), and the racemic form of the ICPA ester represented by or one of the optically active forms thereof is present in excess relative to the optically active form of the antipode. The optically active mixture can be easily produced by performing the crystallization treatment under the condition that the degree of supersaturation in the crystallization treatment is 150% or less.

In the present invention, supersaturation means a state in which the ICPA ester as a solute is present in a saturated amount or more in the organic solvent at the crystallization temperature, and whether the total amount of the ICPA ester present is dissolved in the solvent. The supersaturated solution, whether or not, means the organic solvent solution in the supersaturated state.

Further, the degree of supersaturation indicates the ratio of the total amount of solutes present in the solution to the amount of solute in the saturated solution at the crystallization temperature.For example, the degree of supersaturation of 150% is necessary to form a saturated solution. It means a state in which a solute of 1.5 times the weight of the solute is present regardless of the presence or absence of dissolution.

The supersaturated solution used in the present invention is obtained by saturating an optically active mixture in which the racemic form of ICPA ester or one of the optically active forms of ICPA ester is present in excess over the optically active form of the antipode thereof, at the crystallization treatment temperature. It can be obtained by adding and mixing to an organic solvent so that the amount is equal to or more than that, that is, supersaturated.

The organic solvent used for this purpose is not particularly limited as long as it has a suitable solubility in ICPA ester, for example, aromatic hydrocarbons such as benzene and toluene, pentane, hexane, heptane, cyclohexane,
Aliphatic hydrocarbons such as petroleum ether, methylene chloride,
Chloroform, carbon tetrachloride, halogenated hydrocarbons such as chlorobenzene, ethyl ether, isopropyl ether, tetrahydrofuran, ethers such as dioxane, acetone, methyl ethyl ketone, N, N-dimethylformamide, aprotic polar solvents such as dimethyl sulfoxide, Examples thereof include alcohols such as methanol, ethanol, n-propanol and isopropanol, ethers such as ethyl acetate, and mixed solvents thereof.

The concentration of the solution must be supersaturated at the time of crystallization, but if the degree of supersaturation is too high, the optically active substance opposite to the target optically active substance is crystallized at the same time, and the optical activity of the obtained target crystal is obtained. Since the purity will decrease, an appropriate degree of supersaturation, usually 150% or less at the time of crystallization, preferably 145%
It is particularly preferable to prepare the following. Also,
The lower limit of the degree of supersaturation is not particularly limited, but is usually 110%, and if it is less than that, the crystallization efficiency tends to be poor.

The crystallization treatment itself is carried out, for example, by heating a mixture of an ICPA ester and an organic solvent prepared so as to be in the supersaturated state at the time of crystallization, making this a solution, and then, at a predetermined crystallization temperature, a supersaturation degree of 150% or less. Or let it cool
Alternatively, the solution is concentrated, or in some cases, these methods are combined.

At this time, seed crystals are inoculated if necessary, but usually, when a racemic ICPA ester is used as a raw material, crystals do not precipitate even at a predetermined crystallization temperature, and a supersaturated solution in the usual sense is obtained. Therefore, the optically active substance to be precipitated is induced by inoculating the same optically active ICPA ester crystal as the desired optically active substance as a seed crystal.

However, when an optically active mixture in which one optically active substance is present in excess as compared to the other optically active substance as the raw material ICPA ester is used, it is left as it is or cooled, or by concentrating the solution, it becomes excessive. Since the existing optically active substance spontaneously crystallizes and the optical resolution proceeds, it is usually unnecessary to add a seed crystal.

When seed crystals are added, the addition amount and particle size are not particularly limited, but it is usually preferable to use crushed crystals corresponding to 1 to 10% by weight based on the ICPA ester in the solution.

The crystallization temperature is not particularly limited and is arbitrarily selected according to each condition.

Thus, an optically active ICPA ester can be obtained, and if necessary, it can be purified by a method such as recrystallization.

Incidentally, the optically active ICPA ester obtained as crystals on the filtrate side after the above crystallization treatment is the optically active ICPA of the antipode.
Although an ester is present, the optically active ICPA ester is a racemating agent such as diazabicycloundecene (DB
U), diazabicyclononenene (DBN) or diazabicyclooctane (DBO) and the like can be easily racemized using an organic strong base.

In this racemization reaction, the filtrate is generally treated as it is, but in some cases, the optically active substance in the filtrate is
After separating the ICPA ester, it may be dissolved in a suitable organic solvent for racemization.

In this racemization, the concentration of the racemizing agent in the treatment liquid varies depending on the kind of the racemizing agent, but generally, the higher the concentration, the faster the racemization rate, but if it is too high, side reactions tend to occur. From somewhere, for example DB
When U is used, a concentration range of 1 to 5% by weight is selected.

Similarly, the higher the racemization temperature, the faster the racemization rate, but if it is too high, side reactions tend to occur.

In this racemization, the faster the racemization rate is, the more preferable, but from the viewpoint of suppressing side reactions, it is preferable to reduce the concentration of the racemizing agent and carry out the racemization at a temperature up to the boiling point of the treatment liquid.

Thus, the racemized ICPA ester is optically resolved by the above-mentioned crystallization treatment to form an optically active ICPA ester,
This can be sterically retained and hydrolyzed to give the optically active ICPA of interest.

The ICPA ester used in the crystallization treatment is also a novel compound first discovered by the present inventors,
ICPA ester has the general formula (IV) (Wherein R represents a hydroxyl group or a halogen atom) and α-isopropyl-P-chlorophenylacetic acid represented by the general formula (V) (Wherein X ₁ , X ₂ and X ₃ have the same meanings as described above), and can be easily produced by reacting a halogenated phenol.

Here, as the α-isopropyl-p-chlorophenylacetic acid used as a raw material, ICPA or its acid halide (for example, acid chloride or acid bromide) is used, but it is more preferable to use the acid halide from the viewpoint of reactivity.

Conventionally known general methods are applied to prepare the acid halide from optically active ICPA, for example, in the presence of a catalyst such as γ-picoline in a suitable solvent such as benzene, toluene and n-hexane. It is carried out by reacting ICPA with a halogenating agent such as thionyl chloride.

Examples of the halogenated phenols as the other raw material include 2,4,6-trichlorophenol, 2,4,6-tribromophenol, and 2,6-dichloro-p-cresol.

The esterification reaction of α-isopropyl-p-chlorophenylacetic acid and halogenated phenols is usually carried out by reacting in a solvent in the presence or absence of a neutralizing agent.

As a solvent, it is inert to the reaction and has a property of dissolving the reaction raw materials, for example, chloroform, methylene chloride,
Examples include benzene, toluene, n-hexane, petroleum ether, ethyl ether, isopropyl ether, terahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, N, N-dimethylformamide, dimethyl sulfoxide, etc. Although not particularly limited, it is generally 1 to 10 times by weight relative to α-isopropyl-p-chlorophenylacetic acid.

When the acid halide of ICPA is used as a raw material, a neutralizing agent (for example, organic base such as triethylamine, pyridine, tripropylamine, tributylamine, collidine, picoline, sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide) is usually used. Inorganic bases such as lithium hydroxide and lithium carbonate) are used, and the amount thereof is usually 1 to 5 equivalent times with respect to the acid halide of ICPA.

The reaction temperature is generally -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
Is.

After completion of the reaction, by general post-treatment such as removal of the solvent, if necessary by purification by recrystallization and the like,
The desired α-isopropyl-p-chlorophenylacetic acid ester can be obtained in good yield.

<Effects of the Invention> As described above, an optically active ICPA can be easily obtained by hydrolytically hydrolyzing an optically active α-isopropyl-p-chlorophenylacetic acid ester,
Further, since an optically active ICPA ester which is an antipod to the desired optically active ICPA ester after optical resolution can be easily racemized as the ester, it is advantageous as a raw material for producing an optically active ICPA. Can be reused for
The method for producing an optically active α-isopropyl-p-chlorophenylacetic acid using the optically active α-isopropyl-p-chlorophenylacetic acid esters of the present invention is a very industrially advantageous method.

In addition, the optically active α-isopropyl-identified in the present invention
By combining a crystallization treatment method (optical resolution method) for producing p-chlorophenylacetic acid esters and a production method for α-isopropyl-p-chlorophenylacetic acid esters, which is a raw material thereof, industrially more advantageous purposes can be achieved. The optically active α-isopropyl-p-chlorophenylacetic acid can be produced.

<Examples> Hereinafter, the present invention will be described with reference to Examples, but it goes without saying that the present invention is not limited thereto.

Example 1 91.9 g of α-isopropyl-p-chlorophenylacetic acid was dissolved in 160 ml of toluene, and 48 μl of γ-picoline was added thereto. To this solution, 38 ml of thionyl chloride was added dropwise at 40 ° C over 5 minutes, and then stirred at the same temperature for 3 hours.

After completion of the reaction, the reaction solution was cooled and washed successively with water, 10% sodium carbonate and water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain a pale yellow oily α-
An acid chloride of isopropyl-p-chlorophenylacetic acid was obtained.

The acid chloride of α-isopropyl-p-chlorophenylacetic acid is dissolved in 300 ml of chloroform. Separately 2,4,6-
Tribromophenol 143g and triethylamine 43.8g 1
It is dissolved in 200 ml of chloroform, and the above chloroform solution is added dropwise to this solution at room temperature over 30 minutes, followed by stirring for 1 hour.

After completion of the reaction, the reaction solution was washed successively with water, saturated sodium hydrogen carbonate and water. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

After the obtained oily substance was crystallized by hexane treatment,
The crude crystal was recrystallized from hexane to obtain α-isopropyl-p.
195 g (yield 85.5%) of colorless crystals of 2,4,6-tribromophenyl ester of -chlorophenylacetic acid were obtained.

Melting point: 106-107 ° C ¹ H-NMR: (CDC1 ₃ ) δ: 0.75 (d, 3H, J = 6Hz), 1.15 (d, 3H, J = 6Hz), 1.9-
2.8 (m, 1H), 3.45 (d, 1H, J = 10Hz), 7.4 (S, 4H), 7.
6 (s, 2H) IR (CHC1 ₃ ): 1760 cm ⁻¹ α-isopropyl-p-chlorophenylacetic acid 2,4,6-
Tribromophenyl ester (1.88 g) was dissolved by heating in 40 ml of hexane and then cooled to 25 ° C.

To this solution, 2,4,6-tribromophenyl ester of (+)-α-isopropyl-p-chlorophenylacetic acid [▲ [α] ²⁵ _D ▼ + 85.8 ° (c = 1.00, hexane), 100% ee] 188 mg of crystals were inoculated and left at 25 ° C. for 1 hour.

Then, the precipitated crystals were collected by filtration, dried under reduced pressure, and then (+)-α-
251 mg of 2,4,6-tribromophenyl ester of isopropyl-p-chlorophenylacetic acid was obtained.

[▲ [α] ²⁵ _D ▼ + 76.2 ° (c = 1.16, hexane) 88.8%
ee] 200 mg of this (+)-α-isopropyl-p-chlorophenylacetic acid 2,4,6-tribromophenyl ester was added to 6N hydrochloric acid.
Reflux for 1 hour in 4 ml. The reaction mixture was cooled, extracted with toluene, and washed with water. The organic layer was extracted with 4 ml of 0.1N sodium hydroxide, and the alkaline aqueous layer was adjusted to pH 2 with 6N hydrochloric acid.
After adjusting to, extraction was performed with toluene. The toluene layer was washed with water and then concentrated under reduced pressure to obtain (+)-α-isopropyl-p-chlorophenylacetic acid 72.9 mg (yield 90.1%).

[▲ [α] ²⁵ _D ▼ + 40.9 ° (c = 1.01, CHC1 ₃ ), 86.2% e
e] This (+)-α-isopropyl-p-chlorophenylacetic acid was recrystallized twice from hexane.

[▲ [α] ²⁵ _D ▼ + 45.5 ° (c = 1.01, CHC1 ₃ ), 96.0% e
e] Example 2 A mixture obtained by adding 0.82 g of diazabicycloudecene to the filtrate after the crystallization treatment obtained in Example 1 was heated to 50 ° C and kept warm for 3 hours. After cooling, it was washed with 2N hydrochloric acid and then with water, and the organic layer was dried over magnesium sulfate.

After filtering the drying agent, the solvent was distilled off under reduced pressure to obtain 1.70 g of 2,4,6-tribromophenyl ester of (±) -α-isopropyl-p-chlorophenylacetic acid.

Melting point: 106 to 107 ° C. [▲ [α] ²⁵ _D ▼ 0.0 ° (c = 1.03, hexane) 1.6 g of this (±) -α-isopropyl-p-chlorophenylacetic acid 2,4,6-tribromomphenyl ester. Was optically resolved according to Example 1 to obtain 303 mg of 2,4,6-tribromomphenyl ester of (+)-α-isopropyl-p-chlorophenylacetic acid.

[▲ [α] ²⁵ _D ▼ + 78.1 ° (c = 1.02, hexane), 91.0
% Ee] Next, 250 mg of 2,4,6-tribromomumephenyl ester of (+)-α-isopropyl-p-chlorophenylacetic acid was hydrolyzed according to Example 1 to obtain (+)-α-isopropyl- 92 mg (yield 91.1%) of p-chlorophenylacetic acid was obtained.

[▲ [α] ²⁵ _D ▼ + 44.0 ° (c = 1.01, CHC1 ₃ ) Example 3 Example 1 except that 2,4,6-trichlorophenol was used in place of 2,4,6-tribromophenol. The reaction and post-treatment were carried out according to the above procedure to obtain 2,4,6-trichlorophenyl ester of α-isopropyl-p-chlorophenylacetic acid.

Yield: 71.8% ^{mp: 79~80 ℃ 1 H-NMR:} (CDC1 3) δ: 0.75 (d, 3H, J = 6Hz), 1.15 (d, 3H, J = 6Hz), 2.1~
2.8 (m, 1H), 3.45 (d, 1H, J = 10Hz), 7.3 (S, 6H) IR (CHC1 ₃ ): 1760 cm ⁻¹ This α-isopropyl-p-chlorophenylacetic acid 2,4,
9.64 g of 6-trichlorophenyl ester was dissolved in 50 ml of hexane by heating and then cooled to 25 ° C.

To this solution, 2,4,6-trichlorophenyl ester of (+)-α-isopropyl-p-chlorophenylacetic acid [▲
[Α] ²⁵ _D ▼ + 99.0 ° (c = 1.01, hexane), 100% e
Inoculated with 964 mg of the crystals of [e] and kept at 25 ° C., the crystals are collected by filtration and dried under reduced pressure to give (+)-α-isopropyl-p-
1.97 g of 2,4,6-trichlorophenyl ester of chlorophenylacetic acid was obtained.

[▲ [α] ²⁵ _D ▼ + 90.9 ° (c = 1.10, hexane), 91.8
% Ee] 1.8 g of this (+) ester was hydrolyzed according to Example 1 to obtain 0.88 g of (+)-α-isopropyl-p-chlorophenylacetic acid (yield 90%).

[▲ [α] _{^{25 D ▼ + 43.5 ° (c}} = 1.01, CHC1 3) ] Example 4 2,4,6-tribromophenol in place of 2,6-dichloro -
Reaction as in Example 1, except that P-cresol is used,
Post-treatment was carried out to obtain 2,6-dichloro-p-tolyl ester of α-isopropyl-p-chlorophenylacetic acid.

Yield: 58.7% ^{mp: 66 ℃ 1 H-NMR:} (CDC1 3) δ: 0.75 (d, 3H, J = 6Hz), 1.15 (d, 3H, J = 6Hz), 2.0~
2.7 (m, 1H), 2.25 (s, 3H), 3.5 (d, 1H, J = 10Hz), 7.
1 (S, 2H), 7.3 (s, 4H) IR (CHC1 ₃ ): 1750cm ^-1 2,6 of this α-isopropyl-p-chlorophenylacetic acid
-Dichloro-p-tolyl ester 11.2 g hexane 50 ml
After heating and melting at 25 ° C., the mixture was cooled to 25 ° C.

To this solution, 2,6-dichloro-p-tolyl ester of (+)-α-isopropyl-p-chlorophenylacetic acid [▲
Crystals of [α] ²⁵ _D ▼ + 91.5 ° (c = 1.04, hexane)]
1.0 g was inoculated and left at 25 ° C.

Then, the precipitated crystals were collected by filtration, dried under reduced pressure, and then (+)-α-
2.0 g of 2,6-dichloro-p-tolyl ester of isopropyl-p-chlorophenylacetic acid was obtained.

[▲ [α] ²⁵ _D ▼ + 90.0 ° (c = 1.04, hexane)] 1.8 g of this (+)-ester was hydrolyzed according to Example 1 to give (+)-α-isopropyl-p. -0.93 g (yield 90.0%) of chlorophenylacetic acid was obtained.

[▲ [α] ²⁵ _D ▼ + 44.0 ° (c = 1.01, CHC1 ₃ )]

Claims (3)

[Claims] 1. A general formula (Wherein X ₁ , X ₂ and X ₃ are all halogen atoms, or two of them are halogen atoms and other 1
Is a hydrogen atom or a lower alkyl group, and * indicates an asymmetric carbon.) Optically active α-isopropyl-p-chlorophenylacetic acid ester represented by General formula characterized by (In the formula, the * mark has the same meaning as described above.) A method for producing an optically active α-isopropyl-p-chlorophenylacetic acid. 2. General formula (Wherein X ₁ , X ₂ and X ₃ are all halogen atoms, or two of them are halogen atoms and other 1
Each of which is a hydrogen atom or a lower alkyl group), and a racemic form of α-isopropyl-p-chlorophenylacetic acid ester or one of the optically active substances is contained in excess as compared with the optically active substance of the antipode. The optically active mixture has a general formula (Wherein X ₁ , X ₂ and X ₃ have the same meanings as described above, and * indicates an asymmetric carbon), and thus optically active α-isopropyl-p-chlorophenylacetic acid esters are obtained. , Followed by a general formula characterized by sterically retaining hydrolysis with an aqueous solution of an inorganic acid (In the formula, * has the same meaning as described above.) A method for producing an optically active α-isopropyl-P-chlorophenylacetic acid. 3. General formula (In the formula, R represents a hydroxyl group or a halogen atom) and α-isopropyl-P-chlorophenylacetic acid represented by the general formula (Wherein X ₁ , X ₂ and X ₃ are all halogen atoms, or two of them are halogen atoms and other 1
Is a hydrogen atom or a lower alkyl group) and is reacted with a halogenated phenol represented by the general formula (Wherein X ₁ , X ₂ and X ₃ have the same meanings as described above), and the racemic form of α-isopropyl-p-chlorophenylacetic acid esters or one of the optically active substances is the antipode thereof. An optically active mixture, which is contained in excess of the optically active substance, is crystallized at a supersaturation degree of 150% or less to give a general formula. (Wherein X ₁ , X ₂ and X ₃ have the same meanings as described above, and * indicates an asymmetric carbon), and thus optically active α-isopropyl-p-chlorophenylacetic acid esters are obtained. , Followed by a general formula characterized by sterically retaining hydrolysis with an aqueous solution of an inorganic acid (In the formula, * has the same meaning as described above.) A method for producing an optically active α-isopropyl-P-chlorophenylacetic acid.