JPH0662505B2 - α-Isopropyl-p-chlorophenylacetic acid esters and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention provides a compound represented by the general formula (I): (Wherein X ₁ , X ₂ and X ₃ are all halogen atoms, or two of them are halogen atoms and other 1
Wherein each is a hydrogen atom or a lower alkyl group) and α-isopropyl-p-chlorophenylacetic acid esters thereof and a method for producing the same.

<Prior Art> The α-isopropyl-p-chlorophenylacetic acid ester represented by the above general formula (I) is a novel compound synthesized by the present inventors for the first time, and has never been known.

By the way, the formula It is well known that the optically active α-isopropyl-p-chlorophenylacetic acid (hereinafter referred to as ICPA), especially the (+)-form, is useful as a carboxylic acid component of a pyrethroid insecticide such as fenvalerate. (Japanese Patent Application Laid-Open No. 55-136245), it is extremely important to industrially produce this.

As a method for producing such an optically active ICPA, a method of optically resolving racemic 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.

When performing such optical resolution, the desired optical activity I
The salt of the optically active ICPA and amine of the antipode, which is recovered after the salt of CPA and the amine is separated and obtained, is usually unnecessary. Therefore, this is racemized and optically resolved again for the purpose. Obtaining an optically active substance is an industrially essential requirement.

<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, so that a desired salt of optically active ICPA and an amine is separated. After that, the salt of the optically active ICPA of the antipode and the amine, which is recovered later, cannot be racemized as it is. In order to obtain the desired optically active ICPA from the salt again, the salt is A complicated operation of once decomposing to obtain a free optically active ICPA (an enantiomer with respect to the desired optically active ICPA), which has to be racemized, then again to form a salt with an amine and then optically resolved. There is a problem that requires.

In addition, the method (A) uses an expensive resolving agent,
Moreover, there is a problem that a resolving agent having high optical purity must be prepared in order to obtain ICPA having high optical purity.

In order to solve such a problem, optical resolution by preferential crystallization is possible, and the recovered optically active substance is usually stable, but it can be easily racemized under specific conditions, and is easy. A compound capable of being an optically active ICPA is required, but such a compound has never been known.

<Means for Solving Problems> The present invention solves the above problems and provides a compound represented by the above general formula (I) as a novel compound capable of industrially advantageously producing optically active ICPA. -Isopropyl-p
-Chlorophenylacetic acid esters (hereinafter referred to as ICPA esters) are provided.

The ICPA ester of the present invention can be optically resolved by preferentially crystallizing it to separate and obtain a desired optically active ICPA ester, and by hydrolyzing this, an optically active ICPA can be easily obtained, Further, an optically active ICPA ester which is an antipode to the desired optically active ICPA ester after optical resolution is treated with an organic base such as diazabicycloundecene to easily racemize the ester. Therefore, it can be advantageously reused as a raw material for producing the target optically active ICPA.

Such optically active ICPA ester (I) has the general formula (II) (Wherein R represents a hydroxyl group or a halogen atom), and α-isopropyl-p-chlorophenylacetic acid represented by the general formula (III) (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 raw material α-isopropyl-p-chlorophenylacetic acid (II), ICPA or its acid halide (for example, acid chloride, acid bromide) is used, but from the viewpoint of reactivity, acid halide is used. More preferable.

Conventionally known general methods are applied to prepare the acid halide from ICPA. For example, ICPA is prepared 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 with a halogenating agent such as thionyl chloride.

The other raw material, halogenated phenols (III)
As, for example, 2,4,6-trichlorophenol, 2,
Examples are 4,6-tribromophenol and 2,6-dichloro-p-cresol.

The esterification reaction between α-isopropyl-p-chlorophenylacetic acid (II) and halogenated phenol (III) 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,
Benzene, toluene, n-hexane, petroleum ether, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, etc. are exemplified, and the amount used is not particularly limited, but generally α -Isopropyl-p-chlorophenylacetic acid (I
It is 1 to 10 times the weight of I). Further, a mixture of the above solvent and water is also used as a reaction solvent.

When an 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. , Lithium hydroxide, lithium carbonate, etc.) are used, and the amount used is usually I
It is 1 to 5 equivalent times with respect to the acid halide of CPA.

When a mixture of water and a solvent such as toluene or tetrahydrofuran is used as a reaction solvent, a quaternary ammonium salt such as benzyltriethylammonium chloride or tetra-n-butylammonium bromide can be used as a catalyst.

The amount of these catalysts used is usually 0.1 to 20 mol% based on the halogenated phenol (III).

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

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 optically active α-isopropyl-p-chlorophenylacetic acid esters (I) can be obtained in good yield.

<Effects of the Invention> The α-isopropyl-p-chlorophenylacetic acid esters (I) of the present invention are optically crystallized by preferential crystallization thereof to separate and obtain a desired optically active ICPA ester, which is then hydrolyzed. An optically active ICPA can be easily obtained by decomposing, and the desired optically active ICPA ester after optical resolution is the optically active ICPA of an enantiomer.
The ester can be easily racemized as it is by treating the ester with an organic base such as diazabicycloundecene.
It can be advantageously reused as a raw material for producing CPA.

<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 143 g and triethylamine 43.8 g
Was dissolved in 1200 ml of chloroform, and the chloroform solution prepared above was added dropwise to this solution at room temperature over 30 minutes,
Then, stirring is performed 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 to 107 ° C. ¹ H-NMR: (CDCl ₃ ) δ: 0.75 (d, 3H, J = 6Hz), 1.15 (d, 3H, J = 6Hz), 1.9 to 2.8
(m, 1H), 3.45 ( d, 1H, J = 10Hz), 7.4 (S, 4H), 7.6 (s, 2H) IR (CHCl 3): 1760cm -1 Example 2 2,4,6-tribromo The reaction and post-treatment were carried out in the same manner as in Example 1 except that 2,4,6-trichlorophenol was used instead of phenol to obtain 2,4,6-trichlorophenyl ester of α-isopropyl-p-chlorophenylacetic acid. .

Yield: 71.8% Melting point: 79-80 ° C ¹ H-NMR: (CDCl 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 (CHCl 3): in place of the 1760 cm ^-1 Example 3 2,4,6-tribromophenol 2,6 -Dichloro-
The reaction was carried out according to Example 1 except that p-cresol was used,
Post-treatment was carried out to obtain 2,6-dichloro-p-tolyl ester of α-isopropyl-p-chlorophenylacetic acid.

Yield: 58.7% Melting point: 66 ° C. ¹ H-NMR: (CDCl ₃ ) δ: 0.75 (d, 3H, J = 6Hz), 1.15 (d, 3H, J = 6Hz), 2.0 to 2.7
(m, 1H), 2.25 (s, 3H), 3.5 (d, 1H, J = 10Hz), 7.1 (s, 2H),
7.3 (s, 4H) IR (CHCl ₃ ): 1750 cm ⁻¹ Reference Example 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.

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

Then, the precipitation result is collected by filtration and dried under reduced pressure to obtain (+)-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] Reference Example 2 2,4,6-tribromophenyl ester of (+)-α-isopropyl-p-chlorophenylacetic acid obtained in Reference Example 200
mg was refluxed in 4 ml of 6N hydrochloric acid for 1 hour. 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, the alkaline aqueous layer was adjusted to pH 2 with 6N hydrochloric acid, and then extracted with toluene. The toluene layer was washed with water and concentrated under reduced pressure to give (+)-α-isopropyl-p-chlorophenylacetic acid 72.9 mg (yield 90.1
%) Was obtained.

[[Α ▲] ²⁵ _D ▼ + 40.9 ° (c = 1.01, CHCl ₃ ), 86.2%
ee] Reference Example 3 The filtrate [(-)-α-isopropyl-p- obtained in Reference Example 1
A mixture of 0.82 g of diazabicycloundecene was added to [containing 2,4,6-tribromophenyl ester of chlorophenylacetic acid] and heated at 50 ° C. 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 desiccant, 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.

Mp: 106-107 ° C. [[alpha ▲] ²⁵ _D ▼ + 0.0 DEG (c = 1.03, hexane)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07C 51/493 57/58 (56) References JP-A-60-81144 (JP, A) JP Sho 56-158732 (JP, A) Japanese Patent Sho 56-11692 (JP, B1)

Claims (2)

[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
Each is a hydrogen atom or a lower alkyl group), α-isopropyl-p-chlorophenylacetic acid esters. 2. General formula (Wherein 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
A general formula characterized by reacting halogenated phenols represented by (In the formula, X ₁ , X ₂ , and X ₃ have the same meanings as described above.) A method for producing α-isopropyl-p-chlorophenylacetic acid esters.