GB1579016A - 1-phenylethanols and their derivatives - Google Patents

Description

(54) 1-PHENYLETHANOLS AND THEIR DERIVATIVES (71) We, SAGAMI CHEMICAL RESEARCH CENTER, a Japanese Company, of No. 45, Marunouchi, l-chome, Chiyoda-ku, Tokyo, Japan, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to certain intermediates which are useful for preparing phenylacetic acid derivatives.

Phenylacetic acid derivatives having an alkenyloxy group or an alkynyloxy group at the 4-position of the phenylacetic acid represented by the formula (I)

wherein R1 and R2 each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen atom, and R3 represents an alkenyl group having 2 to 4 carbon atoms or an alkynyl group having 2 to 4 carbon atoms, are known to have useful pharmacological activities such as antipyretic, anti-inflammatory, analgesic and antispasmodic activities as disclosed in Japanese Patent Publication (examined) No. 7421/1973.

This invention relates to novel phenylethanol derivatives which are useful as intermediates for preparing the above compounds represented by the formula (I).

More particularly, these novel intermediates are 2,2,2 - trihalo - 1 - arylethanols represented by the formula (III)

wherein R', R2 and R3 are as defined above and X represents a chlorine atom or a bromine atom; and phenylacetic acid derivatives represented by the formula (IV)

wherein R1, R2 and R3 are as defined above and R4 represents an alkoxy group having 1 to 4 carbon atoms, a hydroxy group, an alkylthio group having 1 to 4 carbon atoms or an arylthio group.

Hitherto, the phenylacetic acid derivatives represented by the formula (I) above have been prepared, typically, by one of the following methods: 1) chloromethylating a corresponding phenol derivative and converting the chloromethyl derivative into a nitrile compound followed by hydrolysis, as described in Japanese Patent Publication (examined) No. 74215/1973, 2) alkylating a 4-hydroxyphenylacetic acid compound followed by hydrolysis, as described in Japanese Patent Publication (examined) No. 74215/1973, 3) alkylating a corresponding 4-hydroxyphenylacetamide followed by hydrolysis, as described in Japanese Patent Application Publication (OPI, unexamined) No. 26244/1974, and 4) reacting a Grignard reagent of a 4-allyloxybenzyl chloride with carbon dioxide followed by hydrolysis, as described in Japanese Patent Application Publication (OPI, unexamined) No. 94643/1973.

However, the above conventional methods are not considered advantageous since they are not able to produce the desired compounds of the formula (I) above in high yield or they are not applicable to the production of the desired compounds of the formula (I) on an industrial scale. That is, the above method 1) tends to cause side reactions in the chloromethylation step thereby making it very difficult to produce selectively the desired compounds the above method 2) cannot be applied to the production of the desired compounds on an industrial scale since the production of starting materials, 4-hydroxyphenylacetic acid compounds, is very cumbersome and not expedient; the above method 3) is a modification of the method 1) and, therefore, it still has disadvantages associated in the method 1); and the above method 4) requires a Grignard reagent which is very difficult to be produced on an industrial scale since it requires absolutely anhydrous condition from the standpoint of the nature of Grignard reagents.

The present inventors have found that the phenylacetic acid derivatives represented by the formula (I) above can easily be prepared from phenol compounds and a trihaloacetaldehyde, which are easily available as industrial raw materials, through novel intermediates represented by the formulae (III) and (IV) as hereinafter described, and the present invention is based on the above finding.

The process for preparing the phenylacetic acid derivatives of the formula (I) from an intermediate product of the present invention can be illustrated by the following reaction scheme:

R1 llOe CIICX3 (11) R OM 1st Step | R3Y (II') R1 R3-O ( t 3 (III) R 2nd Step i R411 (III') I R3 - o t Cll - CO2H (IV) ,14 3rd Step { Reduction (I) wherein R', R2, R3, R4 and X are as defined above, and Y represents a halogen atom or an arylsulfonyloxy group.

The process of the present invention is further illustrated below in greater detail.

Ist Step The 1st step comprises reacting a phenol derivative represented by the formula (II) with a halide or an arylsulfonic acid ester represented by the formula (II') in the presence of a base.

The phenyl derivatives of the formula (II) used as starting materials can be easily obtained by reacting a corresponding phenol compound and chloral in the presence of a base, as described in, for example, Austrian Patent No. 141159(1935) and Chem. Abst., 29, 4021 (1935). Typical examples of the preparation of the starting materials of the formula (II) are shown in Reference Examples hereinafter described.

Representative examples of halides or arylsulfonic acid esters of the formula (II') used as a reactant in the above reaction are allyl chloride, allyl bromide, cortyl chloride, crotyl bromide, propargyl bromide" methallyl chloride, methallyl bromide, prenyl chloride, prenyl bromide, allyl tosylate and methallyl tosylate, which can be easily available as raw materials in chemical industry. These halides or arylsulfonic acid esters can be used in an amount approximately equimolar amount to a slightly molar excess relative to the phenol derivative of the formula (if).

The reaction in the 1st step is generally carried out in the presence of a base.

Examples of bases which can be used are inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like, metal alkoxides such as sodium alkoxides or potassium alkoxides, organic amines such as trimethylamine, triethylamine or dimethylaniline. From the standpoint of availability as industrial materials and high selectivity in the reaction, it is preferred to use inorganic bases. These bases can be used in an amount of an approximately equimolar amount to a slightly molar excess relative to the phenol derivative of the formula (II).

In carrying out the reaction of the 1st step, an inert organic solvent is preferably used. Examples of such solvents are ketones such as acetone or methyl ethyl ketone, alcohols such as methanol or ethanol, ethers such as diethyl ether or tetrahydrofuran and hydrocarbons such as benzene, toluene or hexane.

The reaction proceeds smoothly at room temperature, but is preferably conducted at a refluxing temperature of the solvent used in order to promote the reaction and to improve the yield of the desired product. The reaction time varies depending upon the reaction temperature used, but is generally from about 3 to about 24 hours.

Under the reaction conditions described above, the novel compounds, 2,2,2 trihalo - 1 - arylethanols represented by the formula (III) can be produced in high yield. The resulting compounds can be isolated from the reaction mixture or can be directly used in the following step without isolation from the reaction mixture.

Examples of the 2,2,2 - trihalo - 1 - arylethanoles thus obtained are (List A) 2,2,2 - trichloro - I - (4 - allyloxy - 3 - chlorophenyl)ethanol, 2,2,2 - trichloro - - - propargyloxy - 3 - chlorophenyl)ethanol, 2,2,2 - trichloro - 1 - (4 - crotyloxy - 3 - chlorophenyl)ethanol, 2,2,2 - trichloro - 1 - (4 - prenyloxy - 3 chlorophenyl)ethanol, 2,2,2 - trichloro - 1 - (4 - methallyloxy - 3chlorophenyl)ethanol, 2,2,2 - trichloro - 1 - (4 - allyloxy - 3 methylphenyl)ethanol, 2,2,2 - trichloro - 1 - (4 - allyloxy - 3,5 dichlorophenyl)ethanol, 2,2,2 - trichloro - 1 - (4 - allyloxy - 3,5 dimethylphenyl)ethanol, 2,2,2 - trichloro - 1 - (4 - allyloxy - 3,5 dimethoxyphenyl)ethanol and 2,2,2 - tribromo- 1 - (4 - allyloxy - 3 chlorophenyl)ethanol.

2nd Step The 2nd step comprises reacting the 2,2,2 - trihalo - 1 - arylethanol of the formula (II) obtained as described above with a compound of the formula (III').

Examples of compounds of the formula (III') are water (R4=OH), alcohols such as methanol, ethanol, isopropanol or butanol (R4=alkoxy), thiols such as methyl mercaptan, ethyl mercaptan, isopropyl mercaptan, thiophenol or tolyl mercaptan (R4=alkylthio or arylthio).

The reaction in the 2nd step is generally carried out in the presence of an alkali metal or alkaline earth metal hydroxide as a condensing agent which is preferably sodium hydroxide or potassium hydroxide from the economical standpoint.

The condensing agent can preferably be used in an amount of at least 3 mols, most preferably 3 to 4 mols, per mol of the compound of the formula (III) in order to produce the desired compound of the formula (IV) in high selectivity.

In carrying out the reaction in the 2nd step, it is advantageous from the economical standpoint that the same type of solvents as those used in the 1st step other than the hydrocarbon solvents can be used. For example, when the compounds of the formula (III') are alcohols (R4=alkoxy), these alcohols can be used in an excess amount so as to serve as both the reactant and the solvent. When the compounds of the formula (III') are thiols (R4=alkylthio or arylthio), alcohols can also be used as solvent since these thiols react more predominantly with the compound of the formula (III) than the alcohols used as solvents.

The reaction proceeds smoothly at room temperature, but can also be conducted at a refluxing temperature of the solvent used in order to promote the reaction and to improve the yield of the desired product. The reaction time varies depending upon the reaction temperature used, but is generally from about 3 to about 24 hours.

Again, the resulting compounds of the formula (IV) can be isolated from the reaction mixture or can be used directly in the subsequent step without isolation from the reaction mixture.

Examples of the phenylacetic acid derivatives of the formula (IV) thus obtained are 3 - chloro - 4 - allyloxy - a - methoxyphenylacetic acid, 3 - chloro 4- allyloxy - cr- ethoxyphenylacetic acid, 3 - chloro - 4- allyloxy - a - isopropoxyphenylacetic acid, 3 - chloro - 4 - allyloxy - a - methylthiophenylacetic acid, 3 - chloro - 4 - allyloxy - a - ethylthiophenylacetic acid, 3 - chloro - 4 - allyloxy - a - phenylthiophenylacetic acid, 3 - chloro - 4 allyloxy - a - hydroxyphenylacetic acid, 3 - chloro - 4 - propargyloxy - a - methoxyphenylacetic acid, 3 - chloro - 4 - propargyloxy - a - methylthiophenylacetic acid, 3 - chloro - 4 - propargyloxy - a - phenylthiophenylacetic acid, 3 - chloro -4 - crotyloxy - a - methoxyphenylacetic acid, 3 - chloro - 4 - crotyloxy - a - methylthiophenylacetic acid, 3 - chloro - 4 crotyloxy - a - phenylthiophenylacetic acid, 3 - chloro - 4 - methallyloxy - a methoxyphenylacetic acid, 3 - chloro - 4 - methallyloxy - a methylthiophenylacetic acid, 3 - chloro - 4 - methallyloxy - aphenylthiophenylacetic acid, 3 - methoxy - 4 - allyloxy - a methoxyphenylacetic acid, 3 - methoxy - 4 - allyloxy - a - methylthiophenylacetic acid, 3 - methoxy - 4 - allyloxy - a - phenylthiophenylacetic acid, 3 - methyl - 4 - allyloxy - a - methoxyphenylacetic acid, 3 - methyl - 4 - allyloxy - a - methylthiophenylacetic acid, 3 - methyl - 4 allyloxy - a - phenylthiophenylacetic acid, 3 - bromo - 4 - allyloxy - a - methoxyphenylacetic acid, 3 - bromo - 4 - allyloxy - a - methylthiophenylacetic acid, 3 - bromo - 4 - allyloxy - a - phenylthiophenylacetic acid, 3,5 - dichloro 4 - allyloxy - a - methoxyphenylacetic acid, 3,5 - dichloro - 4 - allyloxy - a methylthiophenylacetic acid, 3,5 - dichloro - 4 - allyloxy - - phenylthiophenylacetic acid, 3,5 - dimethyl - 4 - allyloxy - a - methoxyphenylacetic acid, 3,5 - dimethyl - 4 - allyloxy - a - methylthiophenylacetic acid, 3,5 - dimethyl - 4 - allyloxy - a phenylthiophenylacetic acid, 3 - chloro - 4 - (3,3 - dimethylallyloxy) - a - methoxyphenylacetic acid, 3 - chloro - 4 - (3,3 - dimethylallyloxy) - - methylthiophenylacetic acid, 3 - chloro - 4 - (3,3 - dimethylallyloxy)- aphenylthiophenylacetic acid.

3rd Step The 3rd step comprises a reduction of the phenylacetic acid derivative of the formula (IV). This reduction can be carried out by alternative procedures depending upon the type of the substituent R4 of the compound of the formula (IV).

That is, when R4 is an alkoxy group, the reduction can be conducted in the presence of a catalyst which is generally used for the catalytic hydrogenation of a benzyl ether, for example, nickel catalysts such as Raney nickel, palladium catalysts such as palladium black or platinum catalysts. Examples of solvents which can be used in the above reduction are water, acetone, hydrocarbons, ethers, etc.

The reduction can be carried out at ambient temperature under atmospheric pressure. In order to improve the selectivity of the reduction, inorganic acids such as hydrochloric acid or sulfuric acid, or inorganic or organic bases such as sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, triethylamine or pyridine can be used, although the use of such acids or bases is not essential.

Alternatively, a usual reduction reaction using a hydrogen halide can also be used in place of the above-described catalytic hydrogenation. For example, the reduction reaction can be carried out using hydrogen iodide, a combination of red phosphorus and hydrogen iodide (or iodine), or a combination of red phosphorus and hydrochloric acid. This reduction can be carried out in water or acetic acid as a solvent, but other solvents which do not take part in the reduction, for example, hydrocarbon and ether solvents may be used in conjunction with water or acetic acid. The reduction can be completed by heating the reaction system at a refluxing temperature for about 1 to about 24 hours.

When R4 is a hydroxy group, the reduction reaction can be conducted by the catalytic hydrogenation and the reduction procedure described above for the compounds wherein R4 is an alkoxy group. In addition, the reduction can also be achieved by a usual reduction procedure using, for example, a combination of tin or stannous chloride and hydrochloric acid, or a catalytic hydrogenation using, for example, copper, chromic oxides, molybdenum sulfides, etc.

When R4 is an alkylthio group or an arylthio group, a conventional reductive desulfurization of a-thiocarboxylic acid can be used. That is, the reduction can be carried out using nickel catalysts such as Raney nickel; a combination of zinc and acetic acid, hydrochloric acid,- sulfuric acid or nitric acid; or amalgams such as aluminum amalgam, zinc amalgam, sodium amalgam, etc.

In carrying out the reduction, it is important that any substituents on the aromatic moiety of the phenylacetic acid derivatives of the formula (IV) are not adversely affected under the reduction conditions used. From this standpoint, it is practically preferred to use a combination of zinc and acetic acid, hydrochloric acid, sulfuric acid or nitric acid, or sodium amalgam in an alcohol when R4 of the phenylacetic acid derivatives is an alkylthio group or an arylthio group.

The reaction proceeds smoothly at room temperature, but can also be conducted at a refluxing temperature of the solvent used in order to promote the reaction and to improve the yield of the desired product. The reaction time varies depending upon the reaction temperature used, but is generally from about 1 to about 24 hours.

The present invention is further illustrated by the following Reference Examples and Examples, but they are given for illustrative purposes only and are not to be construed as limiting the present invention. Unless otherwise indicated, all parts, percents, ratios are by weight.

Preparation Example 1 25.70 g (0.02 mol) of o-chlorophenol and 44.44 g (0.03 mol) of chloral were stirred in a 200 ml three-necked flask at room temperature, and 1.4 g (0.001 mol) of potassium carbonate was added to the mixture followed by stirring. After one hour, an additional 1.4 g of potassium carbonate was added to the mixture and the resulting mixture was further stirred in an oil bath maintained at a temperature below 40"C for 12 hours. After allowing the reaction mixture to cool to room temperature, 50 ml of water was added to the mixture which was then diluted with 200 ml of chloroform. The resulting mixture was rendered acidic with 1 N hydrochloric acid and extracted with chloroform. The aqueous layer was extracted with 200 ml of chloroform, and the combined chloroform extract was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation, and the residue was distilled under reduced pressure to obtain 46.01 g (83 /" yield) of 1 (3 - chloro - 4 - hydroxyphenyl) - 2,2,2 - trichloroethanol having a boiling point of 128"C/0.1 mmHg.

NMR Absorption Spectrum (CCl4) b: 3.90 (d, 1 H), 5.16 (d, 1 H), 6.15 (s, 1 H), 6.9-7.7 (m, 3 H).

Preparation Example 2 1.38 g (10 mmols) of potassium carbonate was added to 80 ml of benzene, and a solution of 1.29 g (10 mmols) of o-chlorophenol dissolved in 10 ml of benzene was added dropwise to the mixture at room temperature followed by stirring. After one hour, the mixture was heated to a temperature of 50"C, and a solution of 1.61 g (11 mmols) of chloral in 10 ml of benzene was added to the mixture which was then heated for 15 hours while stirring. After allowing the reaction mixture to cool to room temperature, the mixture was rendered acidic with 1 N hydrochloric acid and the benzene layer was separated. The aqueous layer was extracted with benzene, and the combined benzene extract was dried over an hydros magnesium sulfate.

The solvent was removed by distillation to obtain 1.24 g 1 - (3 - chloro - 4 hydroxyphenyl) - 2,2,2 - trichloroethanol as a crude product.

Example I 10.5 g (0.1 mol) of prenyl chloride and 15.0 g (0.1 mol) of sodium iodide were dissolved in 16 ml of acetone and the resulting solution was stirred at room temperature for 45 hours. 27.6 g (0.1 mol) of 1 - (3 - chloro - 4 - hydroxyphenyl) 2,2,2 - trichloroethanol dissolved in 40 ml of acetone and 6.91 g (0.05 mol) of potassium carbonate were added to the above solution, and the resulting mixture was stirred while heating at a temperature of 55"C for 24 hours. Thereafter, 1.05 g (0.01 mol) of prenyl chloride and 2.0 g of potassium carbonate were added to the mixture followed by stirring at that temperature (550C) for 2 hours. After allowing the reaction mixture to cool to room temperature, any precipitated substance was removed by filtration, and the filtrate was concentrated under reduced pressure.

Diethyl ether and dilute hydrochloric acid were added to the concentrate, and the ether layer was separated, washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue (34.0 g) was purified by column chromatography to obtain 23.4 g (68.1 yield) of 1 - (3 - chloro - 4 - prenyloxyphenyl) - 2,2,2 - trichloroethanol.

IR Absorption Spectrum (cm-1): 3450, 2925, 1610, 1503, 1386, 1290, 1265, 1200, 1063, 990, 920, 820.

NMR Absorption Spectrum (CDCl3) 8: 1.75 (br, s, 6 H), 3.53 (d, J=4 Hz, 1 H), 4.57 (d, J=6 Hz, 2 H), 5.06 (d, J=4 Hz, 1 H), 5.25-5.65 (br, t, J=6 Hz, 1 H), 6.78- 7.58 (m, 3 H).

Elementary Analysis for C,3H14C1402 Found: C,45.49; H,4.24 (%) Calc'd: C, 45.38; H,4.10(0/,) Example 2 The crude product of 1 - (3 - chloro - 4- hydroxyphenyl)- 2,2,2 - trichloroethanol obtained as described in Reference Example 1 was dissolved in 200 ml of acetone. 27.64 g (0.20 mol) of potassium carbonate and 25.0 g (0.20 mol) of allyl bromide were added to the solution, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was heated to a temperature of 40"C and stirred for 12 hours. After allowing the reaction mixture to cool to room temperature, 50 ml of water was added to the mixture to dissolve any inorganic salt, and the mixture was concentrated by distilling off the acetone under reduced pressure. The residue was rendered acidic with 1 N hydrochloric acid and extracted with chloroform. The extract was dried and the residue obtained after distilling off the solvent was distilled under reduced pressure to obtain 36.3 g (57.5% yield based on 0.20 mol of o-chlorophenol used as a starting material) of 1 (3 - chloro - 4 - allyloxyphenyl) - 2,2,2 - trichloroethanol having a boiling point of 146--148"C/0.2 mmHg.

NMR Absorption Spectrum (CDCl3) 8: 3.65 (d, J=4 Hz, 1 H), 4.60 (broad d, J=4 Hz, 2 H), 5.10 (d, J=4 Hz, 1 H), 5.005.67 (m, 2 H), 5.67-6.43 (m, 1 H), 6.70 7.73 (m, 3 H).

IR Absorption Spectrum (liquid film, cm-1): 3500, 3075, 2900, 1610, 1505, 1265, 1060, 995, 930, 820.

Example 2 In the same manner as described in Reference Example 1, 45.47 g of a crude product of 1 - (3 - chloro - 4 - hydroxyphenyl) - 2,2,2 - trichloroethanol was prepared from 0.20 mol of o-chlorophenol and 0.30 mol of chloral in the presence of a catalytic amount of potassium carbonate. The crude product thus obtained was dissolved in 200 ml of acetone, 27.64 g of potassium carbonate and 15.3 g of allyl chloride in place of the allyl bromide used in Example 1 were added to the solution.

The reaction mixture was heated to a temperature of 30-400C and stirred for 12 hours. The mixture was then worked up in the same manner as described in Example 1 and the resulting crude product was quantitatively analyzed by gas chromatography (1 m Diasolid ZS, 1600). The above gas chromatography analysis showed that 1 - (3 - chloro - 4 - allyloxyphenyl) - 2,2,2 - trichloroethanol was produced in 41 /" yield.

Example 3 6.38 g of 1 - (3 - chloro - 4 - hydroxyphenyl) - 2,2,2 - trichloroethanol was dissolved in 50 ml of acetone, and 3.5 g of potassium carbonate and 3.02 g of allyl bromide were added to the solution. The mixture was stirred for 3 hours at room temperature and, thereafter, heated to a temperature of 340"C followed by stirring for 15 hours. The reaction mixture was diluted with 50 ml of water, and the acetone was removed by distillation. The residue was rendered acidic with 1 N hydrochloric acid and extracted with chloroform. The extract was dried and concentrated, and the resulting residue was purified by column chromatography [silica gel, eluted with ethyl acetate:n-hexane (1:1 by volume)] to obtain 6.14 g (84 /n yield) of pure 1 - (3 - chloro - 4 - allyloxyphenyl) - 2,2,2 - trichloroethanol.

Example 4 3.72 g (13.5 mmol) of 1 - (3 - chloro - 4 - hydroxyphenyl) - 2,2,2 trichloroethanol and 1.64 g (13.5 mmol) of allyl bromide were dissolved in 40 ml of acetone, and the solution was stirred vigorously while cooling with water and stirring for 48 hours in the presence of 1.87 g (13.5 mmol) of potassium carbonate.

After completion of the reaction, most of the solvent was removed from the reaction mixture by distillation under reduced pressure, and diethyl ether was added to the mixture. The reaction mixture was then decomposed with dilute hydrochloric acid, and the ether layer was separated, washed with water and dried over anhydrous magnesium sulfate. After filtration of the organic layer, the filtrate was concentrated to obtain 3.30 g (77% yield) of 1 - (3 - chloro - 4 - allyloxyphenyl) - 2,2,2 - trichloroethanol as a viscous oily substance.

Example 5 6.37 g (114 mmol) of potassium hydroxide was dissolved in 40 ml of methanol, and 5.93 g (18.8 mmol) of 1 - (3 - chloro - 4 - allyloxyphenyl)- 2,2,2 - trichloroethanol dissolved in 5 ml of methanol was added to the solution in an argon atmosphere while cooling with ice-water and stirring. The temperature of the resulting mixture was then elevated slowly and, after 30 minutes, the mixture was heated under refluxing for 2 hours. Thereafter, the reaction mixture was allowed to cool to room temperature, and most of the solvent was removed by distillation.

Diethyl ether was added to the residue and the mixture was then decomposed with dilute hydrochloric acid. The ethanol layer was separated, washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed from the filtrate by distillation under reduced pressure to obtain 4.05 g of a methoxy - 3 - chloro - 4 - allyloxy - phenylacetic acid as a viscous oily substance.

A portion of the resulting product was distilled to obtain a pure product having a boiling point of 1500C/0.7 mmHg as an oily substance which crystallized upon allowing to stand to give a solid product having a melting point of 65-670C. Crude Yield, 84.

IR Absorption Spectrum (cm-1): 3075, 1725, 1645, 1603, 1500, 1260, 1200, 1100, 1057, 990, 93, 810.

NMR Absorption Spectrum (CDCl3) 8: 3.34 (s, 3 H), 4.54 (broad d, J=4 Hz, 2 H), 4.64 (s, 1 H), 5.04-5.54 (m, 2 H), 5.75-6.22 (m, 1 H), 6.72-7.48 (m, 3 H), 10.06 (broad s, 1 H).

The following Examples are not of the process of the invention, but show production of compounds of formula (I).

Example 6 1.0 g (18 mmol) of potassium hydroxide was dissolved in 5 ml of methanol, and 364 mg (3.3 mmol) of thiophenol was added to the solution in an argon atmosphere while cooling with ice-water and stirring. After 10 minutes, 948 mg (3 mmols) of 1 (3 - chloro - 4 - allyloxyphenyl) - 2,2,2 - trichloroethanol (product of Example 4) dissolved in 1.5 ml of methanol was added to the mixture, and the resulting reaction mixture was heated under refluxing for 2.5 hours. The reaction mixture was allowed to cool to room temperature, and most of the solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue and the mixture was decomposed with dilute hydrochloric acid. The ether layer was separated, washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 870 mg of a - phenylthio - 3 chloro - 4 - allyloxy - phenylacetic acid as an oily substance. Crude yield, 87%.

IR Absorption Spectrum (cm-1): 3060, 1712, 1645, 1600,1500, 1262,1060, 995, 930, 807, 745, 690.

NMR Absorption Spectrum (CDCl3) b: 4.57 (broad d, J=4 Hz, 2 H), 4.77 (s, 1 H), 5.105.63 (m, 2 H), 5.73-6.47 (m, 1 H), 6.67-7.65 (m, 3 H), 10.40 (broad s, 1 H).

Example 7 A 20% aqueous solution of 2.0 g (5.70 mmols) of a sodium salt of methyl mercaptan and 670 mg (12 mmols) of potassium hydroxide were added to 5 ml of methanol. 948 mg (3 mmols) of 1 - (3 - chloro - 4 - allyloxyphenyl) - 2,2,2 trichloroethanol dissolved in 1.5 ml of methanol was then added to the mixture in an argon atmosphere while cooling with ice-water and stirring, and the resulting reaction mixture was heated while refluxing for 2.5 hours. The reaction mixture was then allowed to cool to room temperature, and most of the solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue and the mixture was decomposed with dilute hydrochloric acid. The ether layer was separated, washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give 670 mg (82 /" yield) of a - methylthio - 3 - chloro - 4 - allyloxy - phenylacetic acid as crystals. For analysis, a portion of the product thus obtained was purified by recrystallization from a mixture of ethyl acetate and n-hexane to give a product having a melting point of 94--95"C.

IR Absorption Spectrum (KBr, cm-1): 1720, 1700, 1647, 1570, 1500, 1290, 1262, 1174, 1000, 987, 922, 914.

NMR Absorption Spectrum (CDCl3) 8: 2.07 (s, 3 H), 4.35 (s, 1 H), 4.54 (broad d, J=4 Hz, 2 H), 5.14-5.51 (m, 2 H), 5.806.29 (m, 1 H), 6.787.51 (m, 3 H), 10.75 (broad s, 1 H).

Example 9 40 mg (1.3 mmol) of red phosphorus, 30 mg of 57 /" hydroiodic acid and 256 mg (1 mmol) of a - methoxy - 3 - chloro - 4 - allyloxy - phenylacetic acid were added to 1 ml of acetic acid, and the resulting mixture was heated for 5 hours while refluxing and vigorous stirring. After allowing the mixture to cool to room temperature, diethyl ether and water were added thereto and the organic layer was separated. The organic layer was washed with water, and any acidic substance contained in the organic layer was transferred to an aqueous layer using an aqueous sodium hydroxide solution. The aqueous layer was separated, rendered acidic with dilute hydrochloric acid, and extracted with diethyl ether. The ether layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography to obtain 113 mg (50 /O yield) of 3 - chloro - 4 - allyloxy phenylacetic acid (alclofenac).

Example 10 400 mg (1.2 mmol) of the crude product of a - phenylthio - 3 - chloro - 4 allyloxy - phenylacetic acid prepared as described in Example 6 was dissolved in 2 ml of acetic acid, and 235 mg (3.6 mmols) of zinc powder was added to the solution followed by heating for 4.5 hours while refluxing and vigorous stirring. After allowing the reaction mixture to cool to room temperature diethyl ether and water were added thereto, and the organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The organic layer was filtered and the filtrate was concentrated to give 256 mg (94 S yield) of 3 - chloro - 4 - allyloxy phenylacetic acid (alclofenac) as crystals. The product thus obtained was recrystallized from a mixture of ethyl acetate and n-hexane to give a pure product having a melting point of 91--92"C. (The melting point of the authentic compound reported in literature is 92--94"C).

Example 11 417 mg (1.53 mmol) of the crude a - methylthio - 3 - chloro - 4 - allyloxy phenylacetic acid prepared as described in Example 7 was dissolved in 2 ml of acetic acid, and 300 mg (4.6 mmols) of zinc powder was added to the solution followed by heating for 4.5 hours while refluxing and vigorous stirring. After allowing the reaction mixture to cool to room temperature, diethyl ether and water was added thereto, and the organic layer was separated. The organic layer was washed with water, and any acidic substance contained in the organic layer was transferred to an aqueous layer using an aqueous potassium hydroxide solution.

The aqueous layer was separated, rendered acidic with dilute hydrochloric acid and extracted with diethyl ether. The ether layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 246 mg (71 /" yield) of 3 - chloro - 4 - allyloxy - phenylacetic acid (alclofenac) as crystals. The product had a melting point of 91--92"C after recrystallization from a mixture of ethyl acetate and n-hexane.

Example 12 7.33 g (21.3 mmols) of 1 - (3 - chloro - 4 - prenyloxyphenyl) - 2,2,2 trichloroethanol was dissolved in 22 ml of methanol, and a solution of 18.3 g (12.8 mmols) of potassium hydroxide dissolved in 22 ml of methanol was added dropwise over a period of 2 hours while heating at 500C and stirring. After stirring the mixture for an additional one hour at 500 C, the reaction mixture was allowed to cool to room temperature, and stirred overnight. The reaction mixture was filtered and the residue on the filter was washed with methanol. The combined filtrate and the methanol washing was concentrated, and the concentrate was dissolved in a small amount of water. The resulting solution was washed with diethyl ether and decomposed with hydrochloric acid. The organic layer was extracted with diethyl ether, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting crude crystals (5.74 g, 94.60/, yield) was recrystallized from a mixture of n-hexane and ethyl acetate to obtain 4.02 g (66.2 /n yield) of a - methoxy - 3 - chloro - 4 - prenyloxy - phenylacetic acid having a melting point of 88--89"C.

Ir Absorption Spectrum (KBr, cm-1): 3050, 1770, 1735, 1675, 1605, 1505, 1470, 1450, 1400, 1295, 1270, 1250, 1180, 1100, 1060, 990, 820, 750, 690.

NMR Absorption Spectrum (CDCl3) b: 1.72 (broad s, 6 H), 3.30 (s, 3 H), 4.53 (broad d, J=6 Hz, 2 H), 4.63 (s, 1 H), 5.43 (broad t, J=6 Hz, 1 H), 6.75-7.43 (m, 3 H), 8.95 (broad s, I H).

Elementary Analysis for C14H17CIO4 Found: C, 59.11; H,6.12() Calc'd: C, 59.06; H, 6.02 ( /n) Example 13 4.9 g (101 mmols) of methyl mercaptan was blown through a glass tube into a solution of 12.5 g (224 mmols) of potassium hydroxide dissolved in 56 ml of ethanol in an argon atmosphere while cooling with ice-water whereby methyl mercaptan was dissolved in the solution. After allowing the mixture to stand for several minutes, 11.6 g (33.7 mmols) of 1 - (3 - chloro - 4 - prenyloxyphenyl) - 2,2,2 trichloroethanol dissolved in 20 ml of ethanol was added to the solution. The resulting mixture was stirred at room temperature for 2 days, and the reaction mixture was rendered acidic with hydrochloric acid while cooling with ice-water.

The mixture was extracted with diethyl ether, washed with water and rendered basic with 1.90 g (34 mmols) of potassium hydroxide. The aqueous layer was separated and washed with diethyl ether. The aqueous layer was again rendered acidic, and the organic layer was extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium hydroxide and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting crystals (9.3 g, 92.1 /n yield) were purified by column chromatography (8.1 g, 80.2 /n yield). The product thus obtained was further purified by recrystallization from n-hexane to obtain pure a - methylthio 3 - chloro - 4 - prenyloxy - phenylacetic acid having a melting point of 83--85"C in a yield of 69.7.

IR Absorption Spectrum (KBr, cm-1): 2900, 1690, 1600, 1500, 1465, 1435, 1400, 1290, 1255, 1180, 1060, 1000, 915, 810, 745, 685.

NMR Absorption Spectrum (CDCl3) b: 1.68 (s, 3 H), 1.74 (s, 3 H), 2.06 (s, 3 H), 4.36 (s, 1 H), 4.52 (d, J=3.5 Hz, 2 H), 5.41 (broad t, J=3.5 Hz, 1H), 6.78-7.46 (m, 3 H), 11.14 (s, 1 H).

Elementary Analysis for C14H17CISO3 Found: C, 55.98; H, 5.68 ( /n) Calc'd: C, 55.90; H, 5.70 ( z/n) Example 14 1.79 g (6 mmols) of a - methylthio - 3 - chloro - 4 - prenyloxy - phenylacetic acid was dissolved in 10 ml of ethanol, and 8 g of 6% sodium amalgam was added to the solution followed by vigorous stirring at room temperature for 24 hours. Water was added to the mixture to dissolve any solid substance, and the mixture was suction filtered to remove mercury. Ethanol was removed from the filtrate by distillation under reduced pressure and the residue was decomposed with dilute hydrochloric acid. The organic layer was extracted with diethyl ether, and the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting crystals (1.51 g) were purified by silica gel column chromatography (eluted with a mixture of ethyl acetate and n-hexane in 1:4 by volume) to obtain 1.39 g (91 /n yield) of 3 - chloro - 4 - prenyloxy - phenylacetic acid. The product thus obtained was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 1.02 g (67% yield) of a pure product having a melting point of 81--82"C.

IR Absorption Spectrum (KBr, cm-1): 3100--2500, 1700, 1605, 1500, 1415, 1390, 1300, 1270,1250, 1200, 1170, 1055, 995, 810.

NMR Absorption Spectrum (CCl4) 6: 1.75 (broad s, 6 H), 3.47 (s, 2 H), 4.47 (d, J=6.5 Hz, 2 H), 5.43 (broad t, J=6.5 Hz, 1 H), 6.6-7.27 (m, 3 H), 11.8 (s, 1 H).

Elementary Analysis for C13H1sCIO3 Found: C,61.51; H, 5.96 ( /n) Calc'd: C, 61.30; H, 5.94 (%) Example 15 6.5 g (116 mmols) of potassium hydroxide, 3.84 g (34.9 mmoles) of thiophenyl and 8.0 g (23 mmols) of I - (3 - chloro - 4 - prenyloxyphenyl)- 2,2,2 trichloroethanol were dissolved in 50 ml of ethanol, and the solution was stirred at room temperature for 24 hours. The mixture was rendered acidic with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 5.42 g (64% yield) of a - phenylthio - 3 chloro - 4 - prenyloxyphenyl acetic acid having a melting point of 92--94"C.

IR Absorption Spectrum (KBr, cm-1): 3100--2500, 1705, 1600, 1500, 1466, 1436, 1380,1280, 1255, 1055, 975, 750, 685.

NMR Absorption Spectrum (CCl4) 6: 1.70 (s, 1 H), 1.76 (s, 3 H), 4.44 (d, J=7 Hz, 2 H), 4.59 (s, I H), 5.39 (broad t, 1 H), 6.62-7.40 (m, 8 H), 11.50 (broad s, 1 H).

Elementary Analysis for C19H19CIO3S Found: C, 62.80; H, 5.23 (%) Calc'd: C, 62.89; H, 5.20 (%) WHAT WE CLAIM IS: 1. A 2,2,2 - trihalo - 1 - arylethanol represented by the formula (III)

wherein R1 and R2 each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen atom, R3 represents an alkenyl group having 2 to 4 carbon atoms or an alkynyl group having 2 to 4 carbon atoms, and X represents a chlorine atom or a bromine atom.

2. Any of the compounds as claimed in Claim 1 which are specifically named herein in List A.

3. A process of preparing a 2,2,2 - trihalo - 1 - arylethanol represented by the formula (III) as claimed in Claim 1 or 2, which comprises reacting in the presence of a base, a phenol compound represented by the formula (II)

wherein R1 and R2 are as defined in Claim 1, and X represents a chlorine atom or a bromine atom, with a halide or an arylsulfonic acid ester represented by the formula (II') R3Y (tri')

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (5)

**WARNING** start of CLMS field may overlap end of DESC **. extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting crystals (1.51 g) were purified by silica gel column chromatography (eluted with a mixture of ethyl acetate and n-hexane in 1:4 by volume) to obtain 1.39 g (91 /n yield) of 3 - chloro - 4 - prenyloxy - phenylacetic acid. The product thus obtained was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 1.02 g (67% yield) of a pure product having a melting point of 81--82"C. IR Absorption Spectrum (KBr, cm-1): 3100--2500, 1700, 1605, 1500, 1415, 1390, 1300, 1270,1250, 1200, 1170, 1055, 995, 810. NMR Absorption Spectrum (CCl4) 6: 1.75 (broad s, 6 H), 3.47 (s, 2 H), 4.47 (d, J=6.5 Hz, 2 H), 5.43 (broad t, J=6.5 Hz, 1 H), 6.6-7.27 (m, 3 H), 11.8 (s, 1 H). Elementary Analysis for C13H1sCIO3 Found: C,61.51; H, 5.96 ( /n) Calc'd: C, 61.30; H, 5.94 (%) Example 15 6.5 g (116 mmols) of potassium hydroxide, 3.84 g (34.9 mmoles) of thiophenyl and 8.0 g (23 mmols) of I - (3 - chloro - 4 - prenyloxyphenyl)- 2,2,2 trichloroethanol were dissolved in 50 ml of ethanol, and the solution was stirred at room temperature for 24 hours. The mixture was rendered acidic with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 5.42 g (64% yield) of a - phenylthio - 3 chloro - 4 - prenyloxyphenyl acetic acid having a melting point of 92--94"C. IR Absorption Spectrum (KBr, cm-1): 3100--2500, 1705, 1600, 1500, 1466, 1436, 1380,1280, 1255, 1055, 975, 750, 685. NMR Absorption Spectrum (CCl4) 6: 1.70 (s, 1 H), 1.76 (s, 3 H), 4.44 (d, J=7 Hz, 2 H), 4.59 (s, I H), 5.39 (broad t, 1 H), 6.62-7.40 (m, 8 H), 11.50 (broad s, 1 H). Elementary Analysis for C19H19CIO3S Found: C, 62.80; H, 5.23 (%) Calc'd: C, 62.89; H, 5.20 (%) WHAT WE CLAIM IS:

1. A 2,2,2 - trihalo - 1 - arylethanol represented by the formula (III)

wherein R1 and R2 each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen atom, R3 represents an alkenyl group having 2 to 4 carbon atoms or an alkynyl group having 2 to 4 carbon atoms, and X represents a chlorine atom or a bromine atom.

2. Any of the compounds as claimed in Claim 1 which are specifically named herein in List A.

3. A process of preparing a 2,2,2 - trihalo - 1 - arylethanol represented by the formula (III) as claimed in Claim 1 or 2, which comprises reacting in the presence of a base, a phenol compound represented by the formula (II)

wherein R1 and R2 are as defined in Claim 1, and X represents a chlorine atom or a bromine atom, with a halide or an arylsulfonic acid ester represented by the formula (II') R3Y (tri')

wherein R3 is as defined in Claim 1 and Y represents a halogen atom or an arylsulfonyloxy group.

4. A process as claimed in Claim 3, substantially as herein described in any of Examples I to 5.

5. A 2,2,2 - trihalo - 1 - arylethanol made by a process as claimed in Claim 3 or 4.