CA1077960A - Production of phenylpropionic acid derivative - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The specification describes a process for pre-paring 2-(4-isobutylphenyl)propionic acid. The process com-prises reacting isobutylbenzene with a sulfonate of lactic acid in the presence of an acid catalyst.

Description

~al77~f~0 1 This invention relates to a novel process for preparing a-phenylpropionic acid derivatives, particularly, 2-(4-isobutyl-phenyl)propionic acid, which is useful as a drug possessing analgesic, anti-inflammatory and antirheumatic actions.

2-(4-isobutylphenyl~propionic acid, of which the generic name is ibuprofen, is a valuable drug frequently employed as an analgesic, anti-inflammatory and antirheumatic agent. The object of this invention is to offer a more economical and more safe process for preparing this valuable drug than already known processes in the art.
There are many processes for preparing ibuprofen.
For example, (1) according to Japanese Patent Publication Nos. --40-7178 and 40-7491, 4-isobutylbenzyl chloride is reacted with magnesium to yield Grignard reagent, the latter reacted with carbon dioxide to yield 4-isobutylphenylacetic acid, and the latter methylated in an appropriate manner to yield 2-(4-isobutylphenyl)-propionic acid (ibuprofen); (2) according to Japanese Patent Publication No. 43-22297, 2-(4-isobutyl-phenyl)propion-nitrile, -amide, -thioamide, or -acid ester is hydrolyzed to yield the corresponding carboxylic acid;

(3) according to Japanese Patent Publication No. 47-24550,

4~isobutylacetophenone is reacted with ~-halogeno-acetic acid esters to yield corresponding glycidate and the latter ~'1 subjected to hydrolysis, rearrangement and oxidation to yield ibuprofen; (4) according to French Patent No. 1,549,758, hydantoin prepared from 4-isobutylacetophenone in the Bucherer manner is hydrolyzed, N-alkylated and deaminated to yield ibuprofen; (5) according to Japanese Unexamined Patent Publication No. 50-40541, 4-isobutylphenyl magnesium brcmide is reacted with 2-bromopropionic acid to yield . . .

1~77960 1 iboprofen. In addition to the processes as described above, there is a number of tricky processes, but all of them are similar to the aforementioned processes or out of consideration.
In the aforementioned known processes, however for example, the reaction of (1) and (5) is conducted under conditions of the Grignard reaction; such reaction conditions are not proper to industrial scale production. The third process (3) requires an expensive reagent, silver oxide, and the fourth one (4) is effected by catalytic hydrogenation in hydrogen atmosphere; both processes are also inappropriate for industrial scale production.
In the process (2), the scope of demand for patent includes ibuprofen in the general formula, but there is no description for disclosing how to prepare ibuprofen in the detailed explanation of the invention; accordingly, it is not clear whether or not the process is applicable to ibuprofen~
From these points of view, the present inventor inves-, tigated to prepare the said objective compounds from readily available starting materials and reagents under simple and safe conditions in the shortest possible steps. The present invention was completed on the basis of these results.The process in this invention comprises treating isobutylbenzene with the sulfonate of lactic acid in the presence of an acid catalyst of yield 2-(4-isobutylphenyl)-propionic acid.
According to this invention, the objective ibuprofen can be prepared from commercially available inexpensive starting materials in practically one step.
The starting materials employed in this invention are isobutylbenzene, lactic acid and sulfonic acid chloride, and any of them is accessible at low price as industrial raw materials. The sulfonates of lactic acid described above 1077~60 1 are esters formed between the 2-hydroxy group of lactic acid and sulfonic acids which are readily prepared from lactic acid and sulfonic acid chloride. Representative of sulfonates of lactic acid are 2-methylsulfonyloxypropionic - -acid, 2-benzenesulfonyloxypropionic acid, 2-p-toluenesulfonyloxy-propionic acid and the like.
The reaction in this invention may be conducted in conditions for alkylation of aromatic rings effected in the presence of acid catalysts, that is, the conditions for Friedel-Craft reaction. The acid catalysts mean ones employed in the Friedel-Crafts reaction; particularly, aluminum chloride affords a good result. The reaction is carried out in an organic solvent under heating at a temperature higher than 100C (at 100 to 160C; ordinarily at the boiling point of the solvent employed) for a period -of 2 to 10 hours. The result of the reaction is much influenced by the solvent used, and accordingly it is preferable to use high boiling solvents such as nitrobenzene and s-tetrachloro-ethane among other solvents ordinarily employed in the Friedel-Craft reaction. The reaction is preferably carried out in anhydrous conditions like in the Friedel-Crafts reaction, if required, under an innert gas such as nitrogen and argon.
The yield of the objective carboxylic acid (ibuprofen) is ordinarily more than 80% in this process.
The process of this invention is characterized by use of readily available and inexpensive isobutylbenzene and lactic acid used as industrial raw materials which produce ibuprofen in a single step in high yield.
The following example is provided to further illustrate this invention.

.

Example To a suspension of 80 parts by weight of powdered anhydrous aluminum chloride in a mixture of 100 parts by volume of s- tetrachloroethane and 320 parts by volume of isobutylbenzene is added 122 parts by weight of 2-tosyloxy-propionic acid with stirring, and the mixture stirred at 145°C for 4 hours, then mixed with an ice-concentrated hydrochloric acid mixture, and then extracted with benzene.
The benzene layer is washed with water and extracted with

5% sodium hydrogencarbonate aqueous solution.
The aqueous layer containing the carboxylic acid is separated, adjusted to pH 1.5 with concentrated hydro-chloric acid, and re-extracted with benzene. The benzene layer is washed with a water, dried over anhydrous sodium sulfate and evaporated. The product is recrystalized from hexane to yield 87 parts by weight of 2-(4-isobutylphenyl)-propionic acid (ibuprofen) as colourless plates.
mp. 75 - 75.5°C
IR : 3100 - 2600, 1718. 1238. 780 cm-1.
* Trade Mark

Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing 2-(4-isobutylphenyl)-propionic acid which comprises reacting isobutylbenzene with a sulfonate of lactic acid in the presence of an acid catalyst.

2. A process claimed in Claim 1, where the sulfonate of lactic acid is selected from the group consisting of 2-methylsulfonyloxypropionic acid, 2-benzenesulfonyloxy-propionic acid, and 2-p-toluenesulfonyloxypropionic acid.

3. A process claimed in Claim 1, where the acid catalyst is one employed in the Friedel-Crafts reaction.

4. A process claimed in Claim 1, where the acid catalyst is aluminum chloride.

5. A process claimed in Claim 1, where the reaction is carried out in an organic solvent at a temperature of 100 to 160°C for a period of 2 to 10 hours.

6. A process claimed in Claim 5, where the solvent is selected from the group consisting of nitrobenzene and s-tetrachloroethane.