JPS60100536A - Preparation of 2-(p-isobutylphenyl)propionic acid - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a drug having analgesic characteristics, etc. by simple operation by a few processes in high yield, by subjecting p-isobutylacetophenone as a raw material to electrolytic reduction and reacting it with CO2, subjecting the reaction product to hydrogenolysis. CONSTITUTION:A supporting electrolyte is dissolved in an aprotic solvent to give a solution, which is divided equally and put in an electrolytic reaction bath with a permeable membrane equipped with an anode and a cathode, p-isobutylacetophenone shown by the formula I is dissolved in the cathode side of the reaction bath, the solution is saturated with CO2, electricity is applied to the electrodes at room temperature with stirring under stream of CO2 or under pressure, so that the compound is electrically reduced and reacted with CO2 to give a reaction product, which is treated with an acid, to give 2-(p-isobutylphenyl)-2-hydroxypropionic acid shown by the formula II, which is reduced or subjected to hydrogenolysis at normal pressure in a hydrogen stream or under hydrogen pressure, to give the desired compound shown by the formula III. EFFECT:Inexpensive raw materials are used, the reactions are carried out under mild conditions, and this process is industrially advantageous.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for producing 2-(1'-isobutylphenyl)propionic acid using p-isobutylacetophenone as the starting material η.

It is already known that 2-(P-inbutylphenyl)propionic acid represented by the following formula has anti-inflammatory, analgesic, and antipyretic properties and is used as a useful pharmaceutical.

CI-13-1 Conventionally, such compounds used isobutylbenzene, P-inbutylacetophenone, P-inbutylhalobenzene, and P-isobutylphenylene as starting materials.

A well-known synthesis method using P-isobutylacetophenone, a typical starting material, is (1) dehydration condensation with a thiazoline derivative to produce 5-(1-(P
-Inbutylphenyl)ethylidene] A method for synthesizing a thiazoline derivative via first hydrolysis, then dehydration, and oxidative decarboxylation (Japanese Patent Publication No. 54-22338). (2) A method in which a lithio salt of formaldehyde mercaptal-8-oxide is added and the resulting lithio compound is acetylated, deaceticated, and hydrolyzed (Japanese Patent Publication No. 53-50137). (
3) A method of reacting an enamine produced by reacting a secondary amine with trichloroacetic acid, followed by hydrogen reduction and heating and hydrolysis (Japanese Patent Publication No. 111.535 of 1982) (4) A method of reacting with cyanacetic acid ester 2-cyano-3-
After methyl-3-(P-isobutylphenyl)acrylation and Grignard reaction, the aldehyde is converted into oxime and deammoniated.
53). (6) After the Dalzen condensation reaction, hydrolysis,
A method of carrying out thermal decarboxylation and oxidation or loform reaction of the aldehyde produced (Japanese Patent Publication No. 49-I'1
l (07IO, 5+-65730). (7) A method in which a dialkylmethylsulfonium salt is reacted in the presence of a base, the resulting 2-(1'-isobutylphenyl)-2-methyloxirane is treated with an acid, and then oxidized (Japanese Patent Publication No. 53
-18535). (8) A method in which dimethylsulfonium methylide is reacted in the presence of a base, resulting in total rearrangement and oxidation of 2-(P-inbutylphenyl)-1°2-epoxypropane (Japanese Patent Publication No. 51-100040). (9) Oxidation of 2-(P-inbutylphenyl)-2-anilinopropionitrile produced by reacting aniline and potassium anhydride.

How to disassemble and restore door gzk (% Kosho 52-13903
7°! - A method of hydrogenolyzing by reacting hydrogen with phosphoric acid (Japanese Patent Publication No. 51-95035). (11) / A method of reacting potassium anhydride and ammonium carbonate to form a hydantoin derivative, followed by hydrolysis and reductive deamidation/conversion (
Tokuko Sho 5] -65731). (12) VC reaction of chloroform under phase transfer catalyst conditions produces 2-(P
A method for catalytically reducing (isobutylphenyl) acrylic acid (Japanese Patent Publication No. 52-11] 534).

53-90237). (13) A method of producing 2-(p-inbutylphenyl)-2-hydroxypropionic acid under the same conditions as in (12) and hydrogenolyzing it (
Special Publication No. 53-37I744). etc. are known.

However, in these conventional methods, methods (1) to (6) have long reaction steps of 4 to 6 steps, the total yield from the starting material is low even if these steps are included, and special reagents characterized by Grignard reagents are required. It has the disadvantage that it requires the use of chemicals that are dangerous to handle during the reaction. Methods (9) to (I[) are dangerous because they involve the use of sodium cyanide or potassium cyanide and hydrochloric acid, or produce toxic cyanide gas as a by-product during the reaction. Method(]
]2, (13) is the most useful method as the number of reaction steps is as short as 2, but it has drawbacks in terms of reaction conditions and yield in intermediate synthesis.

The present inventors have solved all the problems of each building of J double series, and produced 2-(P-inbutylphenyl)propion by an industrially easy method with ease of operation, simplification of process, and good yield. h
The present invention was established as a result of extensive research into λ1 (01).

That is, the method of the present invention can be comprehensively expressed by the following reaction formula.

(I) (11) 1 Compound (I), P-inbutylacetophenone, is reduced by +1 in a carbon dioxide gas flow or under pressure, and the resulting product is subjected to plate treatment, and then compound (11), 2- (P-inbutylphenyl)-2-hydroxypropion was produced, which was then hydrogenolyzed to form the compound (III).
The present invention relates to a method for producing 2-(P-isobutylphenyl)propion.

A part of the present invention also provides a method for synthesizing imbutylphenyl)-2-hydroxypropionic acid, which is described in the known production method (:D, (] 0), which has disadvantages as the above-mentioned industrial production method. .

In carrying out the present invention, first, the starting material, P-isobutylacetophenone, is electrolytically reduced and reacted with carbon dioxide gas. In this reaction, a solution of a supporting electrolyte dissolved in an aprotic solvent is divided equally into an electrolytic reaction tank equipped with a diaphragm equipped with positive and negative electrodes, and after dissolving P-inbutylacetophenone on the cathode side of the reaction tank, the Saturate with carbon dioxide gas, and while stirring at room temperature, apply a carbon dioxide gas flow Ft (7i + 1F:) and apply a specified amount of electricity to the bottom.

As a supporting electrolyte, an alkali metal or charcoal (preferably iodine salt). At this time, the amount of supporting salt used is preferably high in concentration since it lowers the cell voltage and the migration ability of the reaction intermediate. Desirably, the amount is 5 to 10 times the molar amount per m(1) of the compound.

As the electrode material, it does not matter whether it is a conductive substance or not, but mercury or carbon electrodes can be used as the cathode electrode. Among these, a mercury electrode is preferably used because it improves the reaction yield.

Both a constant potential method and a constant current method are used as the electrolytic method, and the constant current method is preferable because it can shorten the reaction time.

11. Use the optimum current density history. Although it is affected by the type I of the electrode and solvent, the electrolytic reaction is normally 400mA/CrrL2.
It is carried out at a current density in the range ~500 mA/(Xn2).

The reaction temperature in a dimethylformamide solvent using a mercury electrode is -io"c to room temperature, but preferably 03
~10°C.

P-isobutylacetophenone used as a raw material in the present invention can be easily synthesized by Friedelkraff's acetylation of isobutylbenzene, and is an industrially easy chemical, and carbon dioxide gas is an unused resource. It's cheap.

This reaction thus yields 2-(P-inbutylphenyl)-2-hydroxypropionic acid.

Next, this 2-(P-inbutylphenyl)-2-hydroxypropionic acid is converted to 2-(P-inbutylphenyl)-2-hydroxypropionic acid in a VC normal pressure hydrogen stream or under hydrogen pressure -1-' in the presence of a catalyst. ) Propio/produces one prong.

Although this reaction can be carried out in the absence of a solvent, as mentioned above, by employing the method of the present invention, a conventionally known method for producing (1)-isobutylphenyl)propionic acid can be obtained. It is an industrially advantageous production method because the reaction operation is extremely easy compared to the above, the number of steps is small, and it can be produced with a high J-zone ratio using inexpensive raw materials and mild reaction conditions.

The present invention will be explained in more detail with reference to Examples below.

Example 1 Preparation of 2-CP-isobutylphenyl)-2-hydroxypropionic acid.

A solution of 18.4 g of tetrabutylammonium iodide dissolved in 100 ml of dimethylformamide was poured into a glass 1.3 mm inner diameter tube with an internal volume of 200 ml and a glass filter membrane. -1 type electrolytic anti-LrXJa platinum plate (2cm
An anode chamber with a 2 cm x 2 cm) and a cathode chamber filled with 5 ml of mercury were heated under a stream of carbon dioxide while stirring.
A constant current of 3In A/(': IrL2 was used to conduct the reaction at 965 coulombs. After the reaction, the solvent in the cathode chamber solution was distilled off under reduced pressure at 100°C, and the resulting white solid was dissolved in 30 ml of water. After that, if acidified, an oily substance will precipitate, so this is extracted with ether, washed with water, dried over magnesium sulfate7, and when the ether is distilled off, 2-(4
'-isobutylphenyl)-2-hydroxypropionic acid is 0.94. ! 9 was obtained. Yield: 85. When recrystallized from n-hexane, white crystals with a melting point of f10 to 111°C are obtained.

Elemental analysis (as C101-11803') Actual value: C
70,37, II 814 Theoretical value: C70,24・l-18,16I R value (K
Br) 3445cm' (OH), 1.745cm'
(C0ON) to N it value (δ/ppm) 7.47 (d, 21-1.J=8Hz), 7.1
3 (d, 211.J=8Hz), 6.7-5.8
CbB, 2N), 2.46 (d, 211°J'
=7.5Hz), 1.8 (S, 3H),
2.2-1.5 (m, III).

0.9 (d, 6H, J=61-I;) Example 2゜Similarly to Example 1, but changing the solvent to acetonitrile 2
At a reaction temperature of 0 to 25°C,
/cIn2, when 965 coulombs of current was applied at a constant current, 0.76!9 of 2-(L'-inbutylphenyl)-2-hydroxypropionic acid was obtained. Yield 68
Person in charge.

Example 3 Preparation of 2-(P-1 Sotylphenyl)propione.

Claims (1)

[Claims] (1) Method for producing P-isobutylacetophenone by electrolytic reduction.