JPS61106533A - Preparation of 2-(4'-isobutylphenyl)-propionic acid, and novel dioxolane compound - Google Patents

Abstract

PURPOSE:To produce the titled substance useful as a medicine, in high yield, by using novel 2-(1'-halogenoethyl)-2-(4'-isobutylphenyl)-4-methyl-1,3-dio-xolane as a raw material, and hydrolyzing the compound in the presence of zinc salicy late. CONSTITUTION:The compound of formula II can be prepared by using 2-(1'- halogenoethyl)-2-(4'-isobutylphenyl)-4-methyl-1,3-dio-xolane of formula I (X is halogen) as a raw material, heating the material is toluene or ethylene dichloride in the presence of zinc salicylate, and hydrolyzing the reaction product. A cata lytic amount of zinc salicylate is sufficient for the purpose, however, it can be used up to equimolar amount to the raw material, if necessary. The com pound of formula I used as the raw material is a novel compound, and can be synthesized by adding propylene glycol, toluene and p-toluenesulfonic acid to the compound of formula III and heating under refluxing while removing the produced water from the system.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel compounds 2-(1'-halogenoethyl)-2-(4'-isobutylphenyl)-4-methyl-
1,3-dioquinrane is heated and hydrolyzed in the presence of zinc salicylate to produce 2-(4'-isobutylphenyl)-propionic acid at a high yield unmatched by conventional methods. 2-(1'-halogenoethyl)-2-(4'-isobutylphenyl)-4-methyl-1,3-dioxolane, which is the new raw material compound used in the method and the present production method. .

The production method of the present invention is represented by the following reaction formula.

CH3, Δ (1) (■) (In the formula, X represents a halogen atom.) That is, Af
2-(1'-halogenoethyl)-2- denoted by Il
(4'-isobutylphenyl)-i 4
- Methyl-1,3-dioquinrane is easily immersed with zinc salicylate in toluene or ethylene dichloride for several hours and hydrolyzed in an alkaline aqueous solution. '-Inbutylphenyl)-propionic acid is obtained in high yield. Post-reaction work-up and purification can be carried out using conventional methods such as crystallization, recrystallization, extraction,
This is done by concentration, filtration, activated carbon treatment, etc. The amount of zinc salicylate used is usually a catalytic amount, but if necessary, it can be used in the same molar amount as the starting compound represented by the formula fl. Further, the zinc salicylate is preferably anhydrous, but a hydrated form can also be used.

Originally, 2-(4'-isobutylphenyl)-propionic acid represented by formula (3), which is the target substance of the production method of the present invention, was
It is a useful medicinal substance as an anti-inflammatory, analgesic, and antipyretic agent, but
Conventionally, the manufacturing method is 2-(1'-halogenoethyl)-2-(4'-isobutylphenyl)-1,3-
Dioquinrane, 2- (1'-halogenoethyl) -
Dioxolanes such as 2-(4'-isobutylphenyl)-4,5-dimethyl-1°3-dioxolane or 2-(1'-bromoethyl)-2-(4'-isobutylphenyl)-1,3-dioxane A method is known in which a compound or a dioxane compound is treated with zinc chloride or zinc acetate and then hydrolyzed to obtain a compound of the formula tm (Japanese Patent Application Laid-Open No. 135423/1983, etc.), but the present invention # etc. As a result of extensive research into a more industrially advantageous production method for the compound of formula 5), a novel raw material compound represented by formula +II was treated with the zinc chloride or zinc acetate used in the conventional method, and then
Even when hydrolyzed, many by-products are produced and it is not possible to isolate ml of the target substance, but when zinc salicylate is used as a catalyst for the new raw material compound I11, no product is produced and the target substance is isolated. The present invention was completed by discovering that it is possible to isolate the compound in a high yield unmatched by conventional methods.

Next, the new raw material compound α) used in the production method of the present invention
An example of the method for producing the new raw material compound II) is as follows.

CH.

(In the formula, X represents a halogen atom.) That is, 2-halogeno-1-(4'-
imbutylphenyl)-propan-1-one (I[D(
Literature: K, Fu4tt @tJLI1. .

5ynth@sis, 1983.444) + Propyl l/7 glycol, toluene and para-toluene sulfonic acid were added and heated under reflux for several hours while removing the water produced, and a new raw material compound (Il was easily produced in high yield. can get.

Next, the present invention will be explained in detail by giving Examples.

Example 2-P0-t-1-(4'-isobutylphenyl)-
Propan-1-one 26.9 g, propionic acid 1
7: 7.6 g of I-L and 0.76 g of balatoluenesulfonic acid e-hydrate were added to 55 liters of toluene, followed by Dean-Stark addition, and the mixture was heated to reflux with stirring for 7 hours to complete the reaction. After the reaction, 150ml of water and 50ml of toluene were added, followed by 10% hydroxylation.
Add an aqueous solution of aluminum to make it slightly alkaline, and separate the toluene layer. The separated toluene layer was washed with water, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure.
32.7 g light brown oil of methyl-1,3-dioquinrane
(100% yield).

Elemental analysis value t%+ Theoretical value as 016H2302 0
, 58.72; H, 7,08° actual value 0, 5
8.68; li, 7.111, R1X vector (Neat, oIll) 2940, 2910.28
55,1685.1607.1505,1465.14
45.1410.1380.13・□(0°1°8"9
) /L= (ODO"°・"su0°92(゛・6H
), 1.12-1.42(3,3H)S 1.58 (
d, 3H), 1.77-2.01 (Maro,
IH), 2.48 (d, 2H)
, 3.21-4.55 (+, 4H), 7.08-7
．． 48 (@, 4H).

Next, the obtained 2-(1'-bromoethyl)-2-(
13.1 g of 4'-isobutylphenyl)-4-methyl-1,3-dioxolane and 0 zinc salicylate anhydride.
．． 54 g was added to 20.1 g of ethylene dichloride and heated to 2F under stirring. After heating under reflux for a while, the reaction solvent was distilled off under reduced pressure, 20.1 g of water and 3.2 g of sodium hydroxide were added to the residue, and the mixture was heated under reflux for 1 hour to complete the reaction. After cooling, toluene is added to the reaction solution to separate the aqueous layer. The separated aqueous layer is made mayy by adding concentrated salt, and then extracted with toluene. The toluene extract was washed with water, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the remaining oil, 23 liters of 65% aqueous methanol solution was added, and the precipitated crystals were separated and dried. Colorless crystals of 2-(4〆-inbutylphenyl)-propionic acid shown 7.83
g (95% yield) is obtained.

Elemental analysis value (%10 engineering 3H engineering, theoretical value as 0.0
, 75.69; H, 8,79; 0, 15.51 Actual value 0, 75.74; H, 8,83; 0
, 15.46 1, R, spectrum (Nujol, am) 2
720.

2630.1720.1・420,1235°1180
．． 935,865,780,665°Njt, R, spectrum (0DO13, ppm) 0.92 (d.

6H), 1.50 (d, 3H), 1.64-1.98 (
m, IH), 2.44 (d, 2H), 3.70 (q, I
H), 7.02-8.26 (q, 41i), 10.
82 (8, I I(').

Patent applicant: Hamari Pharmaceutical Industry Co., Ltd. Agent Patent Attorney Italian NIA Takashi Nobu-23';

Claims (1)

[Claims] 1. 2-(1'-halogenoethyl)-2-(4'
-Isobutylphenyl)-4-methyl-1,3-dioxolane is hydrolyzed after heating in the presence of zinc salicylate. A method for producing -(4'-isobutylphenyl)-propionic acid. 2. The method for producing 2-(4'-isobutylphenyl)-propionic acid according to claim 1, wherein zinc salicylate is an anhydride. 3. The method for producing 2-(4'-isobutylphenyl)-propionic acid according to claim 1, wherein zinc salicylate is a hydrate. 4. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a halogen atom.) 2-(1'-halogenoethyl)-2-(4'
-isobutylphenyl)-4-methyl-1,3-dioxolane.