GB2078743A

GB2078743A - 2-Phenoxyphenylacetic acids

Info

Publication number: GB2078743A
Application number: GB8119344A
Authority: GB
Original assignee: Ihara Chemical Industry Co Ltd
Current assignee: Ihara Chemical Industry Co Ltd
Priority date: 1980-06-27
Filing date: 1981-06-23
Publication date: 1982-01-13
Also published as: GB2078743B; JPS5714554A

Abstract

2-(Substituted phenoxy) phenylacetic acid having the formula <IMAGE> wherein R represents hydrogen or a halogen atom or an alkyl, an alkoxy or trifluoromethyl group; and n represents 0 or an integer of 1 to 4 and R' represents hydrogen or a halogen atom or an alkyl group and represents 0 or an integer of 1 to 2 is produced by reacting a phenol having the formula <IMAGE> wherein R and n are defined above with a phenylacetic acid derivative having the formula <IMAGE> wherein R' and m are defined above and X represents a halogen atom in the presence of a base in a polar solvent.

Description

SPECIFICATION Process for producing 2-(substituted phenoxy) phenylacetic acids BACKGROUND OF THE INVENTION Field of the invention The present invention relates to a process for producing 2-(substituted phenoxy) phenylacetic acids.

Description of the prior arts 2-(Substituted phenoxy) phenylacetic acids are useful as antiinflammatory compounds. It has been known to produce the compounds by the following three steps: in Japanese Unexamined Patent Publication No. 4971/1971.

First step:

Second step:

Third step:

The process disadvantageously requires many steps and low yield of 1 5 to 35% Summary of the invention It is an object of the present invention is to overcome these disadvantages and to produce 2 (substituted phenoxy) phenylacetic acid derivative by reaching a phenol with a phenylacetic acid in the presence of a base in a polar solvent by one step in high yield.

The foregoing and other objects of the present invention have been attained by providing a process for producing 2-(substituted phenoxy) phenylacetic acid having the formula

wherein R represents hydrogen or a halogen atom or an alkyl, an alkoxy or trifluoromethyl group; and n represents 0 or an integer of 1 to 4 and R' represents hydrogen or a halogen atom or an alkyl group and m represents 0 or an integer of 1 to 2 which comprises reacting a phenol having the formula

where R and n are defined above with a phenylacetic acid derivative having the formula

wherein R' and n are defined above and X represents a halogen atom in the presence of a base in a polar solvent.

Detailed description of the preferred embodiments The phenols having the formula

used in the present invention can be the compounds which have the substituent R which can be hydrogen atom or a halogen atom such as fluorine, chlorine, bromine and iodine atoms (hereinafter, a halogen atom means the same); alkyl groups such as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert-butyl, heptyl, hexyl, nonyl, decyl, undecyl and dodecyl groups (hereinafter, an alkyl group means the same); alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy and butoxy groups or trifiuoromethyl group at any position of benzene ring and n of number of the substituent R is 0 or an integer of 1 to 4; and R can be the same of different.

The phenylacetic acid derivatives having the formula

can be the compounds which have the substituent R' which can be hydrogen atom or a halogen atom or an alkyl group at any position of benzene ring and m of number of substituent R' is 0 or an integer of 1 or 2; and R' can be the same or different and X represents a halogen atom.

The base can be alkali metal or alkaline earth metal hydroxides, carbonates or alcoholates.

The solvents used for the reaction are polar solvents, for example, they are preferably water, N,Ndimethylformamide, N,N-dimethylacetamide, tetramethylurea, dimethylsulfoxide, N-methylpyrrolidone, diethylacetamide, hexamethylphosphoric triamide, sulfolane, methanol, ethanol, ethyl acetate, ethyleneglycol, triethyleneglycol, triethanolamine, and glycerine.

The use of a copper compounds such as metallic copper, copper oxide, chloride and other halide imparts certain improvement of purity and yield without any trouble in the reaction in an inert gas environment.

In the present invention, the phenol and phenylacetic acid salt can be separately produced or simultaneously produced to react them (the phenylacetic acid esters can be used without any conventional).

Amounts of the phenol, the phenylacetic acid derivative and the base can be stoichiometric amounts. Either of the phenol or the phenylacetic acid derivative can be excess.

An amount of the polar solvent is not critical and can be to maintain a desired stirring condition of the reaction mixture.

When the catalyst is used, an amount of the catalyst is preferably in a range of 1 to 5 mole % based on the phenol.

The reaction of the phenol, the phenylacetic acid derivative and the base at said ratios is carried out at lower than 2500C preferably 100 to 2000 C. The reaction time is dependent upon the elimination of the starting material and is usually longer than 30 minutes especially 1 to 48 hours. When the solvent and the catalyst are used, a reaction temperature is selected depending upon the kinds of them.

The reaction can be carried out under any condition of a reduced pressure,the atmospheric pressure or higher pressure.

In accordance with the present invention, the reaction of the phenol, the phenylacetic acid derivative and the base is carried out in the polar solvent whereby 2-(substituted phenoxy) phenylacetic acids as useful compounds for medicine can be produced at high yield in high purity.

In comparison with the conventional process of the three steps to give the low yield, excellent effect is imparted. The present invention provides the process for producing 2-(substituted phenoxy) phenylacetic acids as the effective industrial process.

The present invention will be further illustrated by certain examples and references which are provided for purposes of illustration only and are not intended to be limiting the present invention.

EXAMPLE 1 In a 200ml, four necked flask equipped with a stirrer, a thermometer, a nitrogen gas inlet and Dean Stark device, 34.2g. (0.2 mol) of o-chlorophenylacetic acid, 32.6g. (0.2 mol) of 2,4 dichlorophenol, 1 6g. (0.4 mol) of sodium hydroxide, 100ml. of dimethylsulfoxide and 50ml. of toluene were charged and the mixture was heated with stirring.

The resulting water was separated by azeotropic distillation of toluene and water at 80 to 1000C and then, the reaction mixture was heated to 1 400C to completely distill off toluene. Dean Stark device was replaced to a reflux condenser and 0.6g. of cupric cloride was added and a reaction was carried out at 1.400C for 24 hour under nitrogen gas flow. After the reaction, dimethylsulfoxide was distilled off under a reduced pressure. The residue was moved into a 500ml. Erlenmeyer flask and 200g. of water and 1 50ml. of toluene were added to extract the neutral by-product formed in the reaction. The unreacted 2,4-dichlorophenoxide and sodium o-chlorophenylacetate were separated by pH cut to obtain 42.7g. of 2-(2,4-dichlorophenoxy) phenylacetic acid (yield of 72%).

EXAMPLES 2 to 29 In accordance with the process of Example 1 except changing kinds of the phenol, the phenylacetic acid derivative and the base, each reaction was carried out. The results are shown in Table 1.

TABLE 1

Test Phenylacetic No. Phenol acid derivative Base 2 2-chlorophenol 2-chlorophenyl- KOH acetic acid 3 2,6-dichlorophenol " " 4 3,4-dichlorophenol " " 5 2,3,5-trichlorophenol Sl 6 4-chloro-o-cresol " 7 2,4-dichloro-3,5-dimethylphenol " 8 2,4-di ch lorophenol 2-bromo-5-ch loro phenylacetic acid 9 4-chloro-o-cresol " " 10 2-chloro-4,5-dimethylphenol " " 11 2,4-dichloro-3,5-dimethylphenol " " 12 4-chloro-o-cresol 2-chloro-5-methyl- methyl phenylacetic acid alcoholate 13 2,3,5-trimethylphenol " NaOH 14 2-ethyl-4-chlorophenol 15 2,4-diethylphenol 16 2,4-dichloro-3,5-dimethylphenol " " 17 2-i sop ropy l-4-ch I oro-5-methy phenol ,, | " 18 2-chloro-4-t-butylphenol " ethyl alcoholate 19 2-chloro-4-n-hexyphenol " " 20 2-chloro-4-n-decylphenol " " 21 2-chloro-4n-dodecylphenol .. ., 22 2-methoxy-4-chlorophenol " " 23 2-chloro-5-trifluoromethyl " " 24 2-chloro-4n-butylphenol .. ., 25 2-chloro-4-sec-butylphenol 26 2-chloro-n-nonylphenol 'I 27 2-chloro-4-undecylphenol " " 28 2-chloro-ethylphenol 2-chglorophenyl-v Ca(OH)2 acetic acetic acid 29 2,4-di bromophenol ,, K2CO3 TABLE 1'

Test Physical Yield No. Produc: Aryl acetic acid property ( C) (%) 2 2-(2-chlorophenoxy)phenylacetic acid m.p. 72 119 - 121 3 2-(2,6-dichlorophenoxy)phenyl- mp. 53 acetic acid 152.5 - 154 4 2-(3,4-dichlorophenoxy)phenyl- mp. 59 acetic acid 114.5-116 5 2-(2,3,5-trichlorophenoxy)phenyl- mp. 50 acetic acid 118 - 120 6 2-(2-methyl-4-chlorophenoxy)phenyl- mp. 43 acetic acid 104 - 107 7 2-(2,4-dichloro-3,5-dimethylphenoxy)- mp. 40 phenylacetic acid 159 - 162 8 2-(2,4-dichlorophenoxy)-5-chloro- mp. 72 phenylacetic acid 106-108 9 2-(2-methyl-4-chlorophenoxy)-5- mp. 68 chlorophenylacetic acid 94 - 96 10 2-(2-ch loro-4,5-dimethylphenoxy)-5- mp. 53 chlorophenylacetic acid 134 - 135.2 11 2-(2,4-dichloro-3,5-dimethylphenoxy)- mp. 42 5-chlorophenylacetic acid 168 - 169 12 2-(2-methyl-4-chlorophenoxy)-5- mp. 63 methylphenylacetic acid 96.5 - 97.5 13 2-(2,3,5-trimethylphenoxy)-5- mp. 58 methylphenylacetic acid 125 - 126.5 14 2-(2-ethy i-4-ch lorophenoxy)-5 mp. 63 methylphenylacetic acid 114 - 117 15 2-(2,4di ethy Iphenoxy)-5sethyl- mp.

phenylacetic acid 6- - 64 16 2-(2,4-dichlorophenoxy-3,5-dimethylphenoxy)- mp. 38 5-methylphenylacetic acid 153 - 154 17 2-(2-i-propyl-4-chloro-5-methyl- mp. 44 phenoxy)-5-methylphenylacetic acid 104.5 - 106 18 2-(2-ch loro-4-t-butyl phenoxy)-5- mp. 63 methylphenylacetic acid 133 - 134 19 2-(2-ch loro-4-n-hexy lphenoxy)-5- mp. 65 methylphenylacetic acid 71 - 73 20 2-(2-chloro-4-n-decylphenoxy)-5- mp. 46 methylphenylacetic acid 58 - 60 TABLE 1' (Continued)

Test Physical Yield No. Produc: Aryl acetic acid property ( C) (%) 21 2-(2-chloro-4-n-decylphenoxy)-5- mp. 51 methylphenylacetic acid 56 - 58 22 2-(2-methoxy-4ehlorophenoxy)-5 - mp. 47 methylphenylacetic acid 104 - 105.5 23 2-(2-ch loro-5-tri fI uoromethy Iphenoxy)- mp. 45 5-methylphenylacetic acid 123-124 24 2-(2-ch loro-4-n-butylphenoxy)-5- mp. 59 methylphenylacetic acid 70 - 71.3 25 2-(2-methyl-4-sec-butylphenoxy)-5- mp. 62 methyphenylacetic acid 53 - 54 26 2-(2-chloro-4-nonylphenoxy)-5- mp. 52 methylphenylacetic acid 60 - 61 27 2-2-chloro-4-undecylphenoxy)-5- mp. 56 methylphenylacetic acid 59 - 61 28 2-(2-chloro-4-ethylphenoxy) mp. 61 phenylacetic acid 117 - 119 29 2-(2,4-dibromophenoxy) phenyl- mp. 69 acetic acid 146-148

Claims

1. A process for producing 2-(substituted phenoxy) phenylacetic acid having the formula

wherein R represents hydrogen or a halogen atom or an alkyl, alkoxy or trifluoromethyl group; and n represents 0 or an integer of 1 to 4 and R' represents hydrogen or a halogen atom or an alkyl group and m represents 0 or an integer of 1 to 2 which comprises reacting a phenol having the formula

wherein R and n are defined above with a phenylacetic acid derivative having the formula

wherein R' and m are defined above and X represents a halogen atom in the presence of a base in a polar solvent.

2 A process according to claim 1 substantially as herein described with reference to any one of the Examples.