JPH0236151A - Racemization of optically active alpha-isopropyl-p-chlorophenylacetic acid esters - Google Patents

Abstract

PURPOSE:To readily and efficiently racemize the title compound useful as an intermediate for agricultural chemical by treating a mixture of optically active alpha-isopropyl-p-chlorophenylacetic acid esters and both antipodes with an organic strong base. CONSTITUTION:A compound expressed by the formula (X1-X3 are halogen or two of X1-X3 are halogen and the other is H or lower alkyl; * is asymmetric carbon) is treated with an organic strong base such as 1,8-diazabicyclo [5,4,0]7- undecene or 1,5-diazabicyclo[ 4,3,0]-5-nonene to racemize the compound expressed by the formula. The organic strong base is used normally at amount of 0.1-10 times in mol based on the compound expressed by the formula. The reaction is carried out in an inert solvent such as chloroform, methylene chloride or benzene.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for racemizing logolue p-chlorophenylacetic acid esters.

<Background of the Invention and Problems to be Solved by the Invention> Optically active α-isopropyl-p-chlorophenylacetic acid (hereinafter abbreviated as ICPA), especially its (+) substance, can be used to treat pyrethroid insecticides such as fenvalerate. It is well known that it is useful as a carboxylic acid component, and it is extremely important to industrially advantageously produce the optically active ICPA.

Generally, optically active ICPA is produced by an optical resolution method using racemic ICPA and an optically active amine (
The diastereoisomer salt method) is known, but the above production method is not necessarily industrially advantageous because the optically active amine is expensive. The present inventors proposed a method for producing optically active ICPA that does not use expensive optically active amines, using the general formula (1) (wherein, X, X, and x3 are all halogen atoms or Racemic α-isopropyl-p-chlorophenylacetic acid esters (hereinafter abbreviated as ICP 8-ethyl ), then the racemic ICPA ester (
A new compound) is converted into an optically active ICPA ester (a new compound) having the desired configuration by preferential crystallization,
We have developed a process to hydrolyze this into optically active ICPA (Japanese Patent Application No. 62-3o6'f (No. 8, Patent Application No. 3111r32-1982 and Patent Application No. 31-3-2)
? moss).

However, even if an optically active ICPA ester with the desired steric configuration is produced by preferential crystallization, it cannot be said to be an industrially completed process by itself, and the enantiomers separated and removed (having a steric configuration opposite to the desired steric configuration) can only be considered a useful technique if an effective use is found.

That is, the present invention provides a method for effectively utilizing these separated and removed enantiomers.

A last resort to solving problems The present invention provides general formula (II) ×.

(In the formula, X, X2 and X are all halogen atoms, or two of them are halogen atoms and the other one is a hydrogen atom or a lower alkyl group,
This is a racemization method characterized by treating an optically active α-isopropyl-p-chlorophenylacetic acid ester represented by an asterisk (* indicates an asymmetric carbon atom) with a strong organic base.

The present invention will be explained in detail below.

The present inventors discovered that the optically active ICPA of the general formula (n)
As a result of extensive research into methods for racemizing esters, the present invention was completed by discovering that racemization can be easily and efficiently achieved by treating the compound with a strong organic base in a solvent.

Examples of the optically active ICPΔ ester of the general formula (II) include (+)-2,4,6-dolichlorophenyl ester, (+)-2,4,6-tribromophenyl ester, (+)- 2,6-dichloro-p-)lyl esters or their enantiomers, or even the mother of both enantiomers ≠
Examples include right-handed mixtures and the like.

Examples of strong organic bases used in the present invention include amidine, 1,8-diazabicycloC5,4゜0]7-undece〉' (hereinafter referred to as DBU), 15-diazabicyclo(4,3,0)5- Nonen (hereinafter referred to as DBN),
Examples include 1,4-diazabicycloC2,2,2) octane (hereinafter referred to as DBO), and the amount used is not particularly limited; It is 0.1 to 10 times the amount by mole.

The solvent used is one that is inert to the reaction and dissolves the reaction raw materials, such as chloroform, methylene chloride, benzene, toluene, n-hexeno, petroleum ether, ethyl ether, isopropyl ether, tetrahydrofuran, etc. Examples include dioxane, acetone, methyl ethyl ketone, NlN-dimethylformamide, and dimethyl sulfoxide. There is no particular restriction on the amount used, but in general, the higher the concentration of the racemizing agent, the faster the racemization rate, but if the concentration is too high, side reactions tend to occur. For example, when using DBU, It is desirable that DBU be in a range of 20 to 100 times the weight of DBU.

The reaction temperature is not particularly limited, but as mentioned above, the higher the temperature, the faster the racemization rate, but if it is too high, side reactions are likely to occur, so for example, use a solvent 20 to 100 times the weight of DBU. In this case, the racemization temperature is 0 to 120°C, preferably 120 to 100°C.

After completion of the racemization reaction, - after-ship treatment, for example, if the solvent is poorly soluble in water, the reaction mass is washed with an acidic aqueous solution, dried with a desiccant, and then the solvent is removed. ) can be obtained as a racemate of the ICPΔ ester.

<Effects of the Invention> Thus, according to the method of the present invention, when racemic CPA ester is optically resolved by the preferential crystallization method, the desired optical activity remaining on the filtrate side is the optically active ICPA of the enantiomer.
It becomes possible to racemize the ester (II) back to the racemic ICPA ester (1) before the preferential crystallization treatment, and thereby, after esterifying the racemic ICPA to the racemic ICPA ester, This means that a series of industrially advantageous processes have been completed in which an optically active ICPA ester having a desired steric configuration is obtained by a preferential crystallization method, and then an optically active ICPA is obtained by hydrolysis.

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

Example 1 2.4.6-11J bromophenyl ester of (+)-α-isopropyl-p-chlorophenylacetic acid [[α] name' +85.8° (C.1.00.hexane), optical 10
After cooling to ℃, the mixture was washed successively with 2N hydrochloric acid and water, and the organic layer was dried over anhydrous magnesium sulfate. After filtering the desiccant, the solvent was distilled off under reduced pressure to obtain 0.498 g of (±)-α-isopropyl-p-chlorophenyl acetic acid I1[)2,4.6-dribromophenyl ester.

[α]ru 5-0.1 (C・1.00.hexane) Example 2 (+)-α-isopropyl-p-chlorophenylacetic acid 2, 4, 6-) IJ Bromophenyl ester [[α]o5+85 .8° (c=1.00. hexane), optical purity 100%ee] 0.500 g was dissolved in 10 ml of toluene, 27 g of DBUo was added, and the mixture was heated at 50° C. for 1 hour and 30 minutes. After cooling to room temperature, 2N
It was washed with hydrochloric acid and then water, and the organic layer was dried over magnesium sulfate. After filtering the desiccant, the solvent was distilled off under reduced pressure (±)-
α-isopropyl-p-chlorophenyl i[[D2,4
゜6-)'J dibromogenyl ester 0.499g wo4.

[α] A5+ 0.1” (c=1.00.hexane) Example 3 (+)-α-inpropyl-p-chlorophenylacetic acid R(
D2.4.6-) dichlorophenyl ester [Ca]
g'+99. Oo (c=1.00. hexane),
Optically heated. After cooling to room temperature, the mixture 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 (±)-α-inpropyl-p.
-2.4°6-drichlorophenyl ester of chlorophenylacetic acid 0.497 g) Fc obtained:.

[α]a5+ 0.0° (c=1.00. hexane)
Example 4 2,6-dichloro-p-tolyl ester CCa of (+)-α-isopropyl-p-chlorophenylacetic acid] g5
Optically pure heating was performed at +90.0° (c=1.00.hexane). After cooling, the mixture 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 2,6-dichloro-p-tolyl ester of (±)-α-inpropyl-p-chlorophenylacetic acid.
495g:.

[α['-o, pi (c=1.00.hexane) Reference example 1 α-isopropyl-p-chlorophenyl ff191°9
g was dissolved in 160 μm of toluene, and 48 μβ of T-picoline was added thereto. Add thionyl chloride 3 to this solution at 40°C.
8- was added dropwise over 5 minutes, and then stirred at the same temperature for 3 hours.

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

This acid chloride of α-isopropyl-p-chlorophenylacetic acid is dissolved in chloroform.

Separately, 143 g of 2,4.5-)libromophenol and 43.8 g of triethylamine were dissolved in 1200 rnl of chloroform, and the previous chloroform solution was added dropwise to this solution over 30 minutes at room temperature, followed by stirring for 1 hour. I do.

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

After crystallizing the obtained oil by hexane treatment,
The crude crystals were recrystallized from hexane to give α-isopropyl-p.
-Chlorophenyl vinegar [)2.4゜6-) 195g of colorless crystals of IJ dibromoenyl ester (yield: 85.5%)
) was obtained.

Melting point °106-107 °C H-NMR: (CD(1,) δ: 0.75 (d, 3H, J = 6Hz), 115
(d, 3H, J=6flz), 1.9-2.8 (m,
lH), 3.45 (d, LH, J=10Hz),
7.4(s, 4)1), 7.6(s, 2N) I R(CHCR3) + 1760cm-' α above
-isopropyl-p-chlorophenylacetic acid 2.4.6
-) 1.88 g of ribromophenyl ester in 4 hexane
0m1! After heating and dissolving the mixture, the mixture was cooled to 25°C.

2.4.6-1-ribromophenyl ester of (+)-α-isopropyl-p-chlorophenylacetic acid CCa]a' +85,8° (c=1.00. 2.4.6-)ribromophenyl ester of (+)-α-inpropyl-p-chlorophenylacetic acid 251 mg 4.

[Ca”J R5+76.2° (c=1.16.hexane), 88.8%ee) Example 5 DBUo, 8 was added to the filtrate obtained in Reference Example 1 after crystallization treatment.
The mixture to which 2 g was added was heated to 50° C. and kept warm for 3 hours. After cooling, the mixture 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 (±) = 2.4.6-dribromophenyl ester of α-isopropyl-p-chlorophenylacetic acid 1.70
G It's 4.

Melting point: 106-107°C [α]:' 0.0° (c=I, 0].hexane)] Reference Example 2.4 of (±)α-isopropyl-p-chlorophenylacetic acid obtained in Example 5 .1.6 g of 6-dribromophenyl ester was optically resolved in the same manner as in Reference Example 1 to obtain (+)-
2. of α-inpropyl-p-chlorophenylacetic acid. ．． 4
．． 6-) 30 mg of IJ dibromienyl ester was obtained.

C[a]g5+78.1' (c=1.02.hexane), 91.0%ee) Next, 24,6-tribromophenyl ester of α-isopropyl-p-chlorophenylacetic acid obtained above 500 mg of a mixture of 2.4°6-tribromophenyl ester of α-isopropyl-p-chlorophenylacetic acid obtained in Reference Example 1 was refluxed in 8 ml of 6N hydrochloric acid for 1 hour. The reaction mixture was cooled to room temperature, extracted with toluene, and washed with water. The organic layer was reduced to 0. Extracted with 8 d of IN sodium hydroxide, and purified this alkaline aqueous layer with 6N hydrochloric acid.
After adjusting to H2, extraction was performed with toluene. After washing the toluene layer with water, it was concentrated under reduced pressure to obtain 182.2 mg (yield: 90.1%) of (+)-α-isopropyl-p-chlorophenylacetic acid.

CL a 'J R5+42,7° (c=1.01.
This (+)-α-inpropyl-p-chlorophenylacetic acid was recrystallized twice from hexane.

[[α) o' +46.5° (C・1.01.C)
ICL), 98.0%ee] (margin below)

Claims (3)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, all of X_1, X_2 and X_3 are halogen atoms, or two of them are halogen atoms and is a hydrogen atom or a lower alkyl group, and the mark * indicates an asymmetric carbon atom), or a mixture of both enantiomers, is treated with an organic strong force. A racemization method characterized by treatment with a base. (2) Strong organic base is 1,8-diazabicyclo[5,4,
0]7-Undecene.The racemization method according to claim 1. (3) Strong organic base is 1,5-diazabicyclo[4,3,
0]5-Nonene. The racemization method according to claim 1.