JPS58117886A - Manufacture of 4-substituted phenylacetic acids - Google Patents

Abstract

PURPOSE:To manufacture 4-substituted phenylacetic acid of high purity by by simple operation under mild reaction conditions in a high yield by electrolytically reducing a 4-substituted phenylacetic acid deriv. CONSTITUTION:A 4-substituted phenylacetic acid deriv. represented by formulaI(where R<1> is hydroxyl or lower alkoxy, and R<2> is H or lower alkyl), e.g., hydroxymandelic acid is electrolytically reduced in an electrolytic cell composed of an anode chamber and a cathode chamber divided by a central diaphragm, preferably a cation exchange membrane to manufacture 4-substituted phenylacetic acid represented by formula II (where R<1> is hydroxyl or lower alkoxy, and R<2> is H or lower alkyl), e.g., 4-hydroxyphenylacetic acid. At this time, the anode chamber is composed of a sulfuric acid soln. and an anode, and the cathode chamber is composed of the phenylacetic acid deriv., and org. solvent, an electrolyte and a cathode. A 1-20% aqueous sulfuric acid soln. is used as the sulfuric acid soln., and a quat. ammonium salt such as tetramethylammonium citrate is used as the electrolyte. The electrolytic reduction is carried out at 0-60 deg.C, especially 30-50 deg.C.

Description

[Detailed description of the invention] The present invention relates to a method for producing 4-substituted phenylacetic acids.

More specifically, the present invention is based on the general formula % (2) [wherein R1 represents a hydroxyl group or a lower alkoxy group, and R1 represents a hydrogen atom or a lower alkyl group, respectively].

The present invention relates to a novel method for producing 4-11-substituted phenylacetic acids represented by:

The 4-substituted phenyl acetate represented by the above general formula (2) is highly reactive and useful as a raw material for physiologically active substances, and is widely used as a raw material for pharmaceuticals and other ingredients. For example, 2-(4-hydroxyphenyl)-8-amino-1-glopanol, which has a bronchodilator effect, can be easily derived from 4-substituted phenylacetic acids represented by general formula (2) (West German Patent Publication No. (See No. 2621090)
.

Among the 4-substituted phenylacetic acids represented by the above general formula (2), the method for producing 4-hydroxyphenylacetic acid is as follows:
For example, 4-hydroxyacetophenone is produced from phenol by Friedel-Krach reaction, and then 4-
A method for obtaining 4-hydroxyphenylacetic acid by subjecting hydroxyacetophenone to Willgerott reaction (J, Sci,
Ind, Hes.

(New Delhj)8ect,B,,21,2
84 (1962)], 4-hydroxymandelic acid and its esters and 8-halogeno-4-hydroxymantelic acid and its esters are reduced to produce 4-hydroxyphenyl acetic acid r! ! How to obtain I [Unexamined Patent Application @54-1256f35
Publications No. 1, No. 54-148746, etc.] are known. However, in the former method, the objective 4
-Hydroxyacetic acid is at most 801! This method is insufficient for industrial use. Even in the latter method, the reduction reaction must be carried out under harsh conditions at high temperature and pressure, and even in such cases, the target compound can only be obtained in low yield and purity. Also, among the 4-substituted phenylacetic acids represented by the above general formula (2), 4-lower alkoxyphenyl acid r! R is merely produced by alkylating the 4-hydroxyphenylacetic acid obtained above using an alkylating agent such as dimethyl sulfuric acid.

The present inventors have conducted intensive research to develop an industrially advantageous method for producing 4-fill-converted 7-ethyl acetic acids represented by general formula (2), and have finally completed the present invention. 9.

That is, the present invention is directed to the general formula [where R1 represents a hydroxyl group or a lower alkoxy group, and R1 represents a water bulk atom or a lower alkyl group, respectively]. ] A 4-11 substituted phenyl acetic acid derivative represented by the formula % is electrolytically reduced to give the general formula % (2) [wherein R1 and R1 are the same as above. ] It concerns on the manufacturing method of 4-substituted phenylacetic acid characterized by obtaining the 4-substituted phenylacetic acid represented by these.

According to the method of the present invention, the desired 4-substituted phenyl acetic acid aIIaIt can be produced in high yield and purity under simple operations and mild reaction conditions. The process is carried out in an electrolytic cell consisting of an anode chamber and a cathode chamber.

As the diaphragm, in addition to the cation exchange membrane, asbestos, ceramic, etc. can also be used, but the cation exchange membrane is preferred. The anode chamber usually consists of a sulfuric acid solution and an anode, and the anode chamber usually consists of a 4-substituted phenylacetic acid derivative represented by general formula (1), an organic solvent, an electrolyte, and a cathode.

The concentration of the 4A acid solution in the anode chamber is not particularly limited and can be appropriately selected from a wide range, but is usually 1 to 201,
Preferably, a 5-10% sulfuric acid aqueous solution or alcohol solution is used. Any known anode can be used as long as it is not dissolved by the sulfuric acid solution, such as lead, lead alloy, platinum, nickel, nickel alloy,
Zinc, zinc alloy, cadmium, etc. can be mentioned.

Among these, it is preferable to use lead or platinum.

Examples of the organic solvent in the cathode chamber include lower 141 aliphatic alcohols such as methanol, ethanol and propatool, nitriles such as acetonitrile, and cyclic ethers such as tetrahydrofuran and dioxane. The amount of such an organic solvent to be used is not particularly limited and can be appropriately selected from a wide range, but it is usually about 6 to 201, preferably 6 to 101, organic solvent per mole of raw material compound Wt. Further, as the electrolyte, any ordinary quaternary ammonium salt can be used, and specifically, tetramethylammonium tosylate, tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium tosylate, tetraethylammonium chloride, tetraethylammonium bromide, Examples include tetrabutylammonium tosylate and tetrabutylammonium chloride. Among these, tetramethylammonium tosylate, tetramethylammonium chloride and tetramethylammonium bromide are preferred. The amount of such electrolyte to be used is not limited to the percentage and can be selected as appropriate from a wide range.
Normal raw material conversion 1: t = 100 to 800 electrolyte per mole
It is good to use about P, preferably 200 to 250F. Moreover, lead, zinc, etc. are suitable for the cathode.

In the electrolytic reduction of the present invention, the electrolysis method is I'J' t4 in both the constant voltage method and the constant current tIL method, but it is preferable to use the constant flow method. When the constant It flow method is employed, the current density is usually l-toQmA/-root bark, preferably 80 to 60 mA/-. As for the sensitivity required for electrolytic reaction, the shape of the 1ts tank, the type of electrode,
Although IJ-y does not depend on the substrate concentration, substrate reactivity, etc., it is usually sufficient to apply a current of about 5 to 6 mol/F. The electrolytic reduction is usually carried out at a temperature of 0 to 60°C, preferably 80 to 50°C.

Examples are listed below.

Example 1 4-hydroxymandelic acid 0.5F and tetramethylammonium tosylate 0.75Fk methanol 2011
9 and put this solution into an anode chamber of an electrolytic cell separated by a T-diaphragm (cation exchange membrane, Selemion CMV, manufactured by Asahi Glass), and 20 d of a 10-chlorine sulfuric acid methanol solution was poured into the anode chamber. Using zinc as the cathode material and platinum as the anode material, a constant current current (80 mA/7) was applied at 50° C., and a current of 45 F/mo1 was applied to conduct the reaction. After the reaction was completed, methanol in the catholyte was distilled off, 6 d of water was added, and 107
The extract was extracted six times with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue is separated and purified using a silica gel column to obtain 4-hydroxyphenylacetic acid 0.40F.

NMR data (solvent CDCI) of the obtained compound is shown below.

ff (ppm) -8,50 (8,2H) -6,60~7
．． 18(m, 4H) -5,26(S, IH) Example 2 The same operation as Example 1 was performed except that methyl 4-hydroxymandelate 0.5P was used instead of 4-hydroxymandelic acid, and 4 -Methyl hydroxyphenylacetate 0.
41Pf! r get.

NMR data (solvent CDCl) of the obtained compound is shown below.

acppm) -8,54(8,2H) -8,68(S,8H) -6,60-7.20(m,4H) -7,80(S,LH) Example 8 4-hydroxymandelic acid The same operation as in Example 1 was carried out using methyl 4-methoxymandelate 0.5F instead of 8.
It was carried out at a temperature of 0 DEG C. and 0.48 g of 4-methoxyphenylacetate was added.

The NMI (data (mmedian CDCls)) is shown below.

'7(1)m)-8,50(g,2H)-8,60(S
, 8J -8,75(8,8)1) =6.70~7.25(m, 4H) Example 4 Sulfuric acid aqueous solution instead of sulfuric acid methanol solution, lead instead of platinum, lead instead of zinc, Tetramethylammonium chloride) 0.75 Using tetramethylammonium chloride instead of f, the same operation as in Example 1 was carried out, and 4
-Hydroxyphenylacetic acid 0,88P is obtained.

The NMR data of the resulting compound are consistent with those of Example 1.

Example 6 All operations were performed in the same manner as in Example 1, except that acetonitrile was used instead of methanol in the catholyte, and tetramethylammonium bromine 0.45F was used instead of tetramethylammonium tosylate 0.759, and 4-hydroxyphenyl Acetic acid 0.87jFtn.

NMI of the resulting compound (data consistent with that of Example 1).

(that's all)

Claims (1)

[Claims] ■ General formula [In the formula, R1 represents a hydroxyl group or a lower alkoxy group t, and R2 represents a hydrogen atom or a lower alkyl group, respectively. A 4-substituted phenylacetic acid conductor represented by the following formula is electrolytically reduced to form a compound of the general formula [wherein R1 and R2 are the same as above]. ] A method for producing 4-substituted phenylacetic acids, which comprises obtaining 4-fit-substituted phenylacetic acids represented by: ■ Using a diaphragm type electrolytic cell in which the cathode chamber is composed of a 4-substituted phenyl acetate conductor represented by the general formula (1), an organic solvent, an electrolyte, and a cathode, and the anode chamber is composed of a sulfur solution and an anode. The method according to claim 1, which carries out electrolytic reduction. (2) The method according to claim 1 or ts2, in which lead or platinum is used as the anode and zinc or lead is used as the cathode. (2) The method according to any one of claims 1 to 8, wherein the diaphragm is a cation exchange membrane. (2) The method according to any one of claims 1 to 4, wherein the electrolyte is tetramethylammonium tosylate, tetramethylammonium chloride, or tetramethylammonium bromide.