JPS5935380B2 - Phenyl acetic acid derivative and its manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R1 is a lower alkenyl group, R2 is a lower alkyloxy group, a lower alkylthio group, or a phenylthio group).

) and a method for producing the same. The compound represented by the general formula (1) is a new compound, but by reducing this compound, it can be converted into a useful compound having antipyretic, anti-inflammatory, analgesic, and spasmodic effects (Japanese Patent Publication No. 1973 -7421). Conventionally, methods for producing this type of compound with anti-inflammatory and analgesic effects include (1) a method in which the corresponding phenol derivative is chloromethylated and hydrolyzed via the nitrile form (Japanese Patent Publication No. 7421/1983); (2)
Method of alkylating and then hydrolyzing 4-hydroxyphenylacetic acid derivatives (Japanese Patent Publication No. 7421/1983), (3
) A method in which the corresponding 4-hydroxyphenylacetamide is alkylated and then hydrolyzed (JP-A-49-2624
No. 4), (4) A method of preparing a Grignard compound of 4-alkoxybenzyl chloride, reacting it with carbon dioxide gas, and then hydrolyzing it (Japanese Unexamined Patent Publication No. 48-94643), etc. are known.

However, method (1) tends to involve side reactions in the chloromethylation step, making it difficult to selectively obtain only the target compound. In method (2), the method for producing the 4-hydroxyphenylacetic acid derivative serving as the starting material is itself complicated, and is difficult to adopt as an industrial production method. Further, the method (3) is a modification of the method (1), and cannot avoid the flaws of the method (1). Furthermore (
In method 4), a Grignard compound is a reaction intermediate, and due to the nature of this compound, completely anhydrous conditions are essential for its preparation, so it cannot be adopted as an industrial method. The present inventors have discovered that the compound of the general formula (1) can be easily synthesized from a phenol derivative and trihaloacetaldehyde, both of which are available as industrial raw materials, through a two- to three-step reaction, and this compound is synthesized under reducing conditions. The inventors have discovered that the above-mentioned useful compounds can be directly derived by subjecting them to the following steps, and have completed the present invention.

Next, examples of compounds represented by the general formula (1) are as follows.

4-allyloxy-3-chloro-α-methoxyphenylacetic acid, 4-allyloxy-3-chloro-α-ethoxyphenylacetic acid, 4-allyloxy-3-chloro-α-isopropoxyphenylacetic acid, 4-allyloxy-3-chloro-α-isopropoxyphenylacetic acid Chloro-α-methylthiophenyl acetic acid, 4-allyloxy-3-
Chloro-alpha-ethylthiophenyl acetic acid, 4-allyloxy-3-chloro-alpha-phenylthiophenyl acetic acid, 3-
Chloro-4-crotyloxy-α-methoxyphenylacetic acid, 3-chloro-4-crotyloxy-α-4-crotyloxy-α-phenylthiophenylacetic acid, 3-chloro-4-methacryloxy-α-methoxyphenyl acetic acid,
3-chloro-4-methallyloxy-α-methylthiophenyl acetic acid, 3-chloro-4-methallyloxy-α-phenylthiophenyl acetic acid, 3-chloro-4-methallyloxy-α-dimethylaminophenyl acetic acid, 3-chloro -4-
(prenyloxy)-α-methoxyphenylacetic acid, 3-
Chloro-4-(prenyloxy)-α-methylthiophenyl acetic acid, 3-chloro-4-(prenyloxy)-α-
Phenylthiophenyl acetic acid.

The method for producing the compound of the present invention is shown in the following reaction formula.

(In the formula, R1 and R2 are the same as above, X is a chlorine or bromine atom, and Y is a halogen atom or an arylsulfonyloxy group.

) First step The phenol derivative represented by the general formula () used as a raw material in this step is a compound that can be easily produced by reacting the corresponding phenol with chloral in the presence of a base [Austria Patent 1411
59 (1935): Chem. Abst. , 29, 40
21 (1935)] (see reference examples below).

Compounds included in RlY represented by the general formula (γ) include allyl chloride, allyl bromide, crotyl chloride, crotyl bromide, methallyl chloride, methallyl bromide, prenyl chloride, prenyl bromide, allyl tonlate, methallyl tosylate, These compounds are easily available as raw materials for the chemical industry.The first step is
It is an essential requirement to carry out the reaction in the presence of a base, and bases include inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide; metal alkoxides such as sodium alkoxide and potassium alkoxide; trimethylamine, triethylamine,
A wide variety of organic amines such as dimethylaniline can be used. The use of inorganic bases is recommended because they are inexpensively available as industrial raw materials and have high reaction selectivity. As for the amount of these bases used, it is sufficient if they are used in equimolar to slightly excessive amounts. In carrying out the first step, it is preferable to use a solvent, such as ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, ethers such as diethyl ether and tetrahydrofuran, benzene, toluene, and hexane. Examples include hydrocarbons.

Although the reaction generally proceeds at room temperature,
In order to obtain the target compound in high yield, it is desirable to carry out the reaction at the reflux temperature of the solvent. Under such conditions, the general formula (
) 2,2,2-trihalo-1-arylethanol can be formed in high yield.

This compound can be isolated or used in the next step without isolation. Second step This step consists of 2.2.2- represented by the general formula ().
Trihalo-1-arylethanol and the compound represented by the general formula (γ) are reacted.

Compounds represented by the general formula (X include methanol,
Alcohols such as ethanol, isopropanol, butanol, methyl mercaptan, ethyl mercaptan,
Examples include thiols such as isopropyl mercaptan, thiopropyl mercaptan, and thiol. Although this second step requires the use of an alkali or alkaline earth metal hydroxide as a condensation aid, the use of sodium hydroxide or potassium hydroxide is preferred from an industrial standpoint.

The amount of these bases to be used is preferably at least 3 times the molar amount of the compound (), and generally, by using 3 to 4 times the molar amount, the target compound can be selectively produced. can. In carrying out the reaction, inexpensive solvents other than hydrocarbons among the solvents used in the first step can be suitably used.

For example, when the compound represented by the general formula (γ) is an alcohol, alcohol can be used in excess to act as a solvent.Also, when the compound represented by the general formula (γ) is a thiol, Alcohols may be used as a solvent, and in this case, thiols or amines react preferentially due to the difference in reaction rate.The reaction proceeds at room temperature as in the first step. However, in order to accelerate the reaction and selectively obtain only the target compound, it is preferable to operate at the reflux temperature of the solvent.
As is clear from the above explanation of the first and second steps, when using alcohol as a solvent and an alkali or alkaline earth metal hydroxide as a base in the first step, first By reacting the hydroxide with RlY to convert it into the compound of the general formula (), and then introducing an excess amount of the hydroxide and, if desired, the compound of the general formula R2H into the reaction system, an intermediate It is also possible to directly produce the phenylacetic acid derivative represented by the general formula (1) without isolating the compound.

The present invention will be explained in more detail with reference to Reference Examples and Examples below. Reference example 1 25.707 (0,2
m01e) and 44.227 (0
．． 3m01e) of chloral was added and stirred at room temperature.

1.4f (0.001m01e) of potassium carbonate was added to this mixed solution and stirred. 1.4'i more after 1 hour
1 liter of potassium carbonate in an oil bath kept below 40°C.
The mixture was heated and stirred for 2 hours.

After the reaction solution was cooled to room temperature, 50 ml of water was added and further diluted with 200 ml of chloroform. 1N hydrochloric acid was added to this mixture to make the solution acidic and extracted with chloroform. The aqueous layer was extracted again with 200 ml of chloroform, and the extracts were combined and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residual liquid was distilled under reduced pressure to obtain 1-(3-chloro-4-hydroxyphenyl)- having a boiling point of 128°C/0.1 mmHg.
46.01y of 2,2,2-trichloroethanol was obtained. Yield 83% o product nuclear magnetic resonance absorption (CCl4) δ
:390 (d, 1H), 5.16 (d, 1H), 6.1
5 (SllH), 6.9-7.7 (Ml3H). Reference Example 2 1.387 (10 mm01e) of potassium carbonate was added to 80 ml of benzene, and o-chlorophenol (
1.297, 10mm01e) of benzene (10TfL
0 solution was added dropwise and stirred at room temperature.

After 1 hour, the mixture was heated to 50°C and chloral (1.
A solution of 617, 11mm01e) in benzene (10m0) was added, and the mixture was heated and stirred for 15 hours.

The reaction mixture was cooled to room temperature, acidified with 1N hydrochloric acid, and then the benzene layer was separated. Furthermore, the aqueous layer was extracted with benzene, and the extracts were combined and dried over anhydrous magnesium sulfate.
After distilling off the solvent, 1.24y of 1-(3-chloro4-hydroxyphenyl)-2,2,2-trichloroethanol was obtained as a crude product. Example 1 1-(3-chloro-4-
The crude product of (hydroxyphenyl)-2,2,2-trichloroethanol was mixed with 200ml of acetone. It was dissolved in 1.

Potassium carbonate 27.647 (0, 20m01
e), 25.07 (0.20 m01e) of allyl bromide was added and stirred at room temperature for 3 hours, then the reaction mixture was heated to 40°C and stirring was continued for 12 hours. After cooling the mixture to room temperature, add 5 liters of water.
After adding 0me to dissolve the inorganic salt, acetone was distilled off and concentrated under reduced pressure. The mixture was acidified with 1N hydrochloric acid and extracted with chloroform.

After drying the extract, the solvent is distilled off and the resulting residual liquid is distilled under reduced pressure to a boiling point of 146-148℃/0.2 Hg.
1-(4-allyloxy-3-chlorophenyl)-2,2,2-trichloroethanol 36,37 having the following were obtained. Yield 57.5% (0420m0 used as raw material
1 o-chlorophenol reference) Nuclear magnetic absorption spectrum (CDCl3) δ: 3.65 (d, J-4Hz, 1H)
, 4.60 (BrOadd.J4Hz, 2H), 5.1
0 (D.J-4Hz, 1H), 5.00-5.67 (M
l2H), 5.67-6.43 (MllH), 6.70
Infrared absorption spectrum of ~7.73(Ml3H) product (
Liquid film? -1): 350013075, 29001161
0, 1505, 1265, 1060, 995, 930,
8200 Example 2 1-(3-chloro4-hydroxyphenyl)-2.2 was prepared by the method of Reference Example 1 using 0.20 m01e of o-chlorophenol, 0.30 m01e of chloral, and a catalytic amount of potassium carbonate.・2-Trichloroethanol 45.
477 was obtained as a crude product.

Dissolve this in 200 ml of acetone, add 27.64 y of potassium carbonate, and replace allyl bromide with 1 ml of allyl chloride.
5.3 t was added, and the reaction mixture was heated to 30-40°C and continued stirring for 12 hours. The crude product obtained by post-treatment in the same manner as in Example 1 was quantified using gas chromatography (1m Dias01idZS, 16'C). As a result, 1-(4-allyloxy-
It was found that 3-chlorophenyl)-2,2,2-trichloroethanol was produced. Example 3 1-(3-chloro-4-hydroxyphenyl)-2,2,2-trichloroethanol 6.3 in 50ml of acetone
8y was dissolved, 3.57y of potassium carbonate and 3.02y of allyl bromide were added to this solution, and the mixture was stirred at room temperature for 3 hours.
Warming to ˜40° C. and continued stirring for an additional 15 hours.

After diluting the reaction solution with 50 ml of water, acetone was distilled off under reduced pressure, and the remaining solution was acidified with 1N hydrochloric acid and extracted with chloroform. After drying and concentrating the extract, the remaining liquid was subjected to column chromatography (silica gel, ethyl acetate: n-hexane = 1:
9) to give pure 1-(4-allyloxy-
3-chloro)-2,2,2-trichloroethanol6.
I got 147.

Yield 84% o Example 4 1-(3-chloro-4-hydroxyphenyl)-2.2
・2-Trichloroethanol (3.727, 13.5W
! 77! MOl), allyl bromide (1.64t113.5
TrLm01) was dissolved in acetone (40m0), potassium carbonate (1.87y1135mm01) was added, and the mixture was vigorously stirred for 48 hours while cooling with water.

After most of the solvent was distilled off under reduced pressure, ether was added, followed by dilute hydrochloric acid to decompose and separate the ether layer. The organic layer is washed with water and dried over anhydrous magnesium sulfate. After filtration,
Concentration gave 3.307 g of 1-(4-allyloxy3-chlorophenyl)-2,2,2-trichloroethanol as a viscous oil. Yield 77%. Example 5 Dissolve potassium hydroxide (6.377, 114 mm01) in methanol (40 m0).

Under an argon atmosphere, while cooling with ice water and stirring, 1-(4
-allyloxy-3-chlorophenyl)-2,2,2-
Trichloroethanol (5.937, 18,8mm01
) is dissolved in methanol (5 m0) and added. Gradually raise the temperature for 30 minutes, then continue heating under reflux for 2 hours. Cool to room temperature,
After most of the solvent was distilled off under reduced pressure, ether was added and the mixture was decomposed with dilute hydrochloric acid. The ether layer is separated, washed with water, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 4.057 4-allyloxy-3-chloro-α-methoxyphenylacetic acid as a viscous oil. When a portion is taken out and distilled, it has a boiling point of 15'C.
A pure product was obtained as an oily substance exhibiting a temperature of /0.7 mmHg.
Crude yield: 84%.

Infrared absorption spectrum ((V7l-1): 3075, 17
25, 1645, 1603, 150011260112
001110011057, 990, 9301810.

Nuclear magnetic absorption spectrum (CDCl3) δ: 3.34 (s
, 3H), 4.54 (BrOadd..J-4Hz12
H), 4.64 (SllH), 5.04-5.54 (M
l2H), 5.75-6.22 (m, 1H), 6.72
~7,48 (Ml3H), 10.06 (BrOadsl
lH). Example 6 Potassium hydroxide (1.07, 18
mm01) is dissolved.

Under an argon atmosphere, thiophenol (364Tf19, 3.3 mm01) is added while stirring and cooling with ice water. 1
After 0 minutes, 1-(4allyloxy-3-chlorophenyl)-2,2,2-trichloroethanol (948w,
3mm01) was dissolved in methanol (1.5m0) and added,
The reaction mixture was then heated to reflux for 2.5 hours.

After cooling to room temperature, most of the solvent is distilled off under reduced pressure, ether is added, diluted hydrochloric acid is added to decompose, and the ether layer is separated. The organic layer is washed with water and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated to obtain 4-allyloxy-3-chloro-α-phenylthiophenyl acetic acid of 870 η as a viscous oil. Crude yield: 87% Infrared absorption spectrum (CrrL-1): 3060, 17
12, 11645, 16001150011262, 1
060, 995, 930, 807, 745, nuclear magnetic absorption spectrum (CDCl3) δ: 4.57 (BrOadd
．． J-4Hz, 2H), 4.77 (SllH), 5.1
0-5.63 (m, 2H), 5.73-6.47 (m,
1H), 6.67-7.65 (m, 3H), 10.40
(BrOads, 1H).

Example 7 To methanol (5 ml) is added a 20% aqueous sodium methyl mercaptan solution (2.07, 5.70 mm 01) and potassium hydroxide (670 w, 12 mm 01).

Under an argon atmosphere, cool with ice water and continue with stirring.
(4-allyloxy-3-chlorophenyl)-2.2.
2-Trichloroethanol (948 ml, 3 mmOl) dissolved in methanol (1.5 ml) was added, and the reaction mixture was then heated to reflux for 2.5 hours. After cooling to room temperature, most of the solvent is distilled off under reduced pressure, ether is added, diluted hydrochloric acid is added to decompose, and the ether layer is separated.
The organic layer is washed with water and dried over anhydrous magnesium sulfate. After filtration and concentration, 670 Watts of 4-allyloxy-3-chloro-α-methylthiophenyl acetic acid was obtained as crystals. A specimen for elemental analysis was purified by recrystallization from ethyl acetate:n-hexane. Yield: 82% o Melting point: 9
4-95°C Infrared absorption spectrum (KBr,.(:FIL-1): 1
7201170011647, 15701150011
29011262, 1174, 1000, 987922
914 Nuclear magnetic absorption spectrum (CDCl3) δ: 2.07 (S
l3H), 435 (SllH), 4,54 (BrOad
d. J-4Hz, 2H), 5.14-5.51 (m, 2
H), 5.80-6.29 (MllH), 6.78-7
．． 51 (Ml3H), 10.73 (BrOadsllH
). Example 8 Prenyl chloride (10.57, 0.1 m01) and sodium iodide (15.07, 0.1 m01) were added to acetone (16WLI) and stirred at room temperature for 45 minutes.

Next, 1-(3-chloro-4-hydroxyphenyl)-2,2,2-trichloroethanol (27.
67, 0.1 m01) dissolved in acetone (40 m1) and potassium carbonate (6.917, 0.05 m
01) was added, and the mixture was heated and stirred at 55°C for 24 hours. After this, prenyl chloride (1.057, 0.01m01
) and potassium carbonate (2.07) were further added, and the mixture was heated and stirred at the same temperature for 2 hours. After cooling to room temperature, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. Ether and dilute hydrochloric acid were added to the residue, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the residue (34.07) was concentrated under reduced pressure and purified by column chromatography to give 1-(3-chloro4-prenyloxyphenyl)-2,2,2-trichloroethanol (23.07).
47) was obtained. Yield: 68.1%. Infrared absorption spectrum: 3450, 2925, 1610, 1503, 1386
, 1290, 120011265, 1063, 990,
9201820? -1 Nuclear magnetic absorption spectrum (CDCl3) δ: 1.75 (B
rsl6H), 3.53 (D,.J-4Hz, 1H),
4.57 (D.J-6Hz, 2H), 5.06 (D.J
-4Hz, 1H), 5.25 to 5.65 (Brt,.J
-6Hz11H), 6.78-7.58 (Ml3H).
Elemental analysis: Actual value: Cl45.49:Hl4.24%. Calculated value: C
, 45.38; H, 4.10%. Example 91-(3-
Chloro-4-prenyloxyphenyl)-2,2,2-
Trichloroethanol (7.337, 21.3mm01
) was dissolved in methanol (22m0), heated and stirred at 50°C, and a solution of potassium hydroxide (8.3f112.8mm01) in methanol (22m1) was added dropwise over 2 hours.

After further stirring at 50°C for 1 hour, the mixture was returned to room temperature and stirred overnight.

The reaction solution was filtered, and the methanol solution from which the residue was washed and the filtrate were concentrated together. The mixture was dissolved in a small amount of water, washed with ether, decomposed with hydrochloric acid, and the organic layer was extracted with ether. After washing with saturated brine, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude crystals (5.747, yield 94
, 6%) was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 4.02f of 3-chloro-4-prenyloxy-α-methoxyphenylacetic acid. Yield: 66.2%. Melting point: 88-89°C. Infrared absorption spectrum (KBr): 305011770,
1735, 1675, 1605, 1505, 1470,
1450, 1400, 1295, 1270, 1250,
1180, 1100, 10601990, 820, 75
0,690Cf11. Nuclear magnetic absorption spectrum (CDCl
3) δ: 1.72 (Brsl6H), 3.30 (Sl3
H), 4.53 (Brd,.J-6Hz12H), 4.
63 (s, 1H), 5,43 (Brt.J-6Hz11
H), 6.75-7.

43 (Ml3H), 8.95 (BrsllH). Elemental analysis: Actual value: Cl59. ll:Hl6. l2%. Calculated value: C
l59. O6:Hl6. O2%. Example 10 Potassium hydroxide (12.57, 224 mm01) in ethanol (
While cooling the 56m0 solution with ice water, methyl mercaptan (4,97, 101 mm01) was blown into the solution through a glass tube and dissolved under an Ar atmosphere.

After a few minutes, 1-(3-chloro-4prenyloxyphenyl)-2,2,2-trichloroethanol (11.67,
A solution of 33.7 mmOle) in ethanol (20 ml) was added. After stirring at room temperature for 2 days, the reaction solution was made acidic with hydrochloric acid while cooling with ice water, and extracted with ether. After washing with water, the solution was made basic again with potassium hydroxide (1.90f, 34mm01), and the aqueous layer was separated and washed with ether.
The aqueous layer was made acidic again, and the organic layer was extracted with ether and washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain crystals (9.3v, yield 92.1
%) was purified by column chromatography. (8.11
, 80.2%). Further, this was recrystallized from n-hexane to obtain pure 3-chloro-4-prenyloxy-α-methylthiophenyl acetic acid. Yield: 69.7%, melting point: 83-85°C. Infrared absorption spectrum (KBr): 2900, 1690,
160011500, 1465, 1435, 1400,
129011255, 1180, 1060, 10001
915, 810, 745, 685C7TL-1.

Nuclear magnetic absorption spectrum (CDCl3) δ: 1.68 (S
l3H), 1.74 (Sl3H), 2.06 (s, 3H
), 4.36 (SllH), 4.52 (D,.J-3.
5Hz12H), 5.41(Brt..J-3.5Hz
11H), 6.78-7.46 (Ml3H), 11.1
4 (SllH). Elemental analysis: Actual value; C, 55.98:H, 5.68%. Calculated value: C
155.9O: H15.7O%. Example 11 Potassium hydroxide 4 (6.57, 116 mm01), thiophenol (3.847, 34.9 mm01), 1-(3-chloro-4-prenyloxyJ-G-nyl)-2.2.2- Trichloroethanol (8.0y123mm01) was added to ethanol (50TL0) and stirred at room temperature for 24 hours.

The mixture was made acidic with dilute hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. After filtration, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5.427 3-chloro-4-prenyloxy-α-phenylthiophenyl acetic acid. Yield: 64%. Melting point: 92-9'C. Infrared absorption spectrum: 3100-250011705,
160011500, 1466, 1436, 1380,
1280, 1255, 1055, 975, 750168
5? -1. Nuclear magnetic absorption spectrum (CCl4) δ: 1.
70 (S, 1H), 1.76 (Sl3H), 4,44 (
D. J-7Hz, 2H), 4.59(s, 1H), 5
, 39 (Brt, 1H), 6.62-7.40 (m, 8
H), 11.50 (BrsllH). Elemental analysis: Actual value: Cl62.8O; H15, 23%. Calculated value; C
l62.89; Hl5.2O%. Reference example 3 Red phosphorus (40η, 1.3mm01) in acetic acid (1ml),
57% hydriodic acid (30η), 4-allyloxy-3
-Chloro-α-methoxyphenylacetic acid (256▼, 1m
m01) was added, and the mixture was heated under reflux for 5 hours with vigorous stirring.

After cooling to room temperature, add ether and water and separate the organic layer. After washing the organic layer with water, the acidic substance is transferred to the aqueous layer using an aqueous sodium hydroxide solution. Separate the aqueous layer and make it acidic by adding dilute hydrochloric acid. Extract with ether, wash the ether layer with water and dry with anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography to obtain 4-allyloxy-3-chlorophenylacetic acid (Alcrophenylacetate) having a concentration of 113η. Yield 50% o Reference Example 4 Crude 4-allyloxy 3-chloro-α-phenylthiophenyl acetic acid prepared in Example 6 (400η, 1.2 m
m01) was dissolved in acetic acid (2 m) and zinc powder (235 m) was dissolved in acetic acid (2 m).
ヮ, 3.6mm01) and stirred vigorously.
．． The mixture was heated under reflux for 5 hours.

After cooling to room temperature, add ether and water, and separate the organic layer.

After washing with water, dry with anhydrous magnesium sulfate. After filtration and concentration, 256η of 4-allyloxy-3-chlorophenylacetic acid (Arclophenylacetic acid) was obtained as crystals (yield: 94%). This is ethyl acetate: n-
Literature value 92-9'C) which gave a pure product with a melting point of 91-92°C by recrystallization from hexane. Reference Example 5 Crude 4-allyloxy-3-chloro-α-methylthiophenyl acetic acid (417η, 1.53m
m01) was dissolved in acetic acid (2ml), and zinc powder (300η
, 4.6mm01) and stirred vigorously.
The mixture was heated to reflux for an hour.

After cooling to room temperature, add ether and water, separate the organic layer, wash with water, and transfer the acidic substance to the aqueous layer using an aqueous potassium hydroxide solution. Separate the aqueous layer and make it acidic by adding dilute hydrochloric acid. Extract with ether, wash the ether layer with water and dry with anhydrous magnesium sulfate. Concentrated after filtration to 246m
9, 4-allyloxy-3-chlorophenylacetic acid (Arclophenylacetic acid) was obtained as crystals (yield 71%). This product showed a melting point of 91-92°C after one recrystallization from ethyl acetate:n-hexane. Reference example 6 3-chloro-4-prenyloxy-α-methylthiophenyl acetic acid (1.797, 6mm01) was dissolved in ethanol (1
0 ml) dissolved in 6% sodium amalgam (87)
was added and stirred vigorously at room temperature for 24 hours.

After adding water to dissolve the solids, the mixture was filtered under suction to remove mercury. Ethanol in the filtrate was distilled off under reduced pressure and decomposed with dilute hydrochloric acid. The organic layer was extracted with ether, washed with water, and dried over anhydrous magnesium sulfate. Crystals obtained by concentration (1.
517) was purified by silica gel column chromatography (ethyl acetate: n-hexane 1:4) to obtain 3-chloro-4-prenyloxyphenylacetic acid (1.397, yield 91%). . This was recrystallized from a mixed solvent of ethyl acetate and n-hexane to produce a pure product (1.02V, yield 67%).
I got it. Melting point: 81-82°C. Infrared absorption spectrum (KBr): 3100-25001
1700, 1605, 150011415, 1390,
130011270, 1250, 1200, 1170,
1055, 995, 810? -1.

Nuclear magnetic absorption spectrum (CCl4) δ: 1.75 (Brs, 6H), 3.47 (Sl2H), 4
．． 47 (D.J=6.5Hz12H), 5.43 (Br
t,. J=6.5Hz11H), 6.6~7.27(m
, 3H), 11.8 (SllH). Elemental analysis;

Claims (1)

[Claims] 1 A phenylacetic acid derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc.▼ (wherein R^1 is a lower alkenyl group, R^2 is a lower alkyloxy group,
It is a lower alkylthio group or a phenylthio group. ). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ 2,2,2-trihalo-1-arylethanol represented by and a compound represented by the general formula R^2H are combined in the presence of an alkali or alkaline earth metal hydroxide. A method for producing a phenylacetic acid derivative represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R^1 is a lower alkenyl group, R^2 is a lower alkyloxy group, lower alkylthio group or phenylthio group, X represents a chlorine or bromine atom). 3 A phenol derivative represented by the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ and a halide or arylsulfonic acid ester represented by the general formula R^1Y are reacted in the presence of a base to form the general formula ▲ mathematical formula, chemical formula , tables, etc. ▼ Form 2,2,2-trihalo-1-arylethanol represented by A method for producing a phenylacetic acid derivative represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ characterized by reacting with a compound (in the formula, R^1 is a lower alkenyl group, R^2 is a lower (alkyloxy group, lower alkylthio group, or phenylthio group, X is a chlorine or bromine atom, Y is a halogen atom or an arylsulfonyloxy group)