~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 --
. . .
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 : <IMG> 3100 - 2600, 1718. 1238. 780 cm-1.
* Trade Mark
