Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-05-08
2004-08-03
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S418000
Reexamination Certificate
active
06770781
ABSTRACT:
The present invention relates to a process for the preparation of meta or para-substituted &agr;-arylalkanoic acids.
More particularly, the invention relates to a process for the preparation of compounds of formula (I)
wherein
R is hydrogen, C
1
-C
6
alkyl; R
1
is hydrogen, straight or branched C
1
-C6 alkyl, phenyl, p-nitrophenyl, a cation of an alkali or alkaline-earth metal cation or of a pharmaceutically acceptable ammonium salt; A is C
1
-C
4
alkyl, aryl, aryloxy, arylcarbonyl, 2-, 3- or 4-pyridocarbonyl, aryl optionally substituted with one or more alkyl, hydroxy, amino, cyano, nitro, alkoxy, haloalkyl, haloalkoxy; A is at the meta or para positions; starting from compounds of formula (II)
in which P is straight or branched C
1
-C
6
alkyl, phenyl, p-nitrophenyl.
Different strategies are at present used for removing the phenolic hydroxyl of arylalkanoic acids derivatives, based on the derivatization and subsequent elimination of the derivative by reduction, but in most cases such procedures suffer from drawbacks such as high-cost reagents or lack of selectivity.
British Patent 2025397 (Chinoin), discloses the use of various derivatives of the phenolic hydroxyl, such as phenylaminocarbonyl, 1-phenyl-5-tetrazolyl, 2-benzoxazolyl, —SO
2
OMe, and the reduction of the derivative with hydrogen on Pd/C catalyst.
WO 98/05632 application, in the Applicant's name, discloses the use of perfluoroalkanesulfonates, in particular trifluoromesylate, followed by reduction with formic acid and triethylamine in the presence or palladium acetate/triohenylphosphine complex.
It has now been found a process for the preparation of arylpropionic acids starting from the corresponding &agr;-hydroxylated derivatives, using inexpensive reagents and keeping intact any reducible groups, such as esters or ketones, present on the side chains of the starting molecules.
According to the process of the invention, the compounds of formula (I) are prepared through the following steps:
a) transformation of compounds of formula (II) into compounds of formula (III):
wherein R
a
and R
b
are C
1
-C
6
alkyl, preferably methyl;
b) thermal rearrangement of compound (III) to give (IIIb)
c) catalytic hydrogenation of (IIIb) to give (IIIc)
d) transformation of (IIIc) into (I).
The compounds of formula (II) can be prepared as described in WO 98/05623. Briefly, starting from arylolefins of formula (IV)
wherein A and R have the same meanings as defined above, by Claisen rearrangement, compound (V) is obtained
which can be subsequently subjected to oxidative cleavage, for example by ozonolysis or with potassium permanganate in phase transfer conditions, thus yielding the corresponding carboxylic acid product. The latter can be transformed into compound (II) by esterification with a suitable alcohol.
Step a) can be carried out in two ways.
In the first case, compound of formula (II) is reacted with
wherein R
a
and R
b
are as defined above, in the presence of an inorganic base such as an alkali or alkaline-earth carbonate, or an organic one, such as triethylamine or pyridine.
Alternatively, compound of formula (II) is reacted first with thiophosgene,
to obtain compound (IIIa)
which is subsequently reacted with HNR
a
R
b
in which R
a
and R
b
are as defined above.
The conversion of the phenol in O-aryl-dialkylthiocarbamate by reaction with R
b
R
a
NCSCl, and the subsequent thermal rearrangement (step b) of the O-aryl dialkylthiocarbamate to give compound (IIIb), are described in Newman and Karnes, “The conversion of phenols”, J. Org. Chemistry, Vol. 31, 1966, 3980-3982.
On the ocher hand, as for the preparation of the O-aryl-dialkylthiocarbamate by reacting the phenol with thiophosgene and subsequently the resulting product with amine R
a
R
b
NH, the method reported in Can. J. Chem., 38, 2042-52 (1960) can be followed.
In step c), the catalytic hydrogenation of S-aryl-dialkylthiocarbamate (IIIb) to give (IIIc) can be carried out with Ni-Raney as catalyst.
Compound (IIIc) is easily converted to (I) through conventional procedures for the hydrolysis of the ester group and optional subsequent reesterification or salification of the carboxylic group.
The process of the invention proved to be particularly advantageous when group A in general formula (I) is an optionally substituted aroyl group, in that the carbonyl function is preserved during the reduction of the thiocarbamoyl derivative. For example, when A is benzoyl, no reduction of the ketone under the used experimental conditions is observed. Furthermore, as already mentioned, the process of the invention is based on the use of low cost reagents, provides good yields, requires no purifications of the intermediates and has a low environmental impact.
REFERENCES:
patent: 4605758 (1986-08-01), Schloemer
patent: 4910337 (1990-03-01), Chiu et al.
patent: 5061629 (1991-10-01), Coffen et al.
patent: 971700 (1964-09-01), None
patent: 2025397 (1980-01-01), None
patent: 1586798 (1981-03-01), None
patent: 9805623 (1998-02-01), None
McKay et al.,Can. J. Chem., 38, pp.2042-2052 (1960).
Newman et al., Journal of Organic Chemistry, vol. 31, No. 12, pp. 3980-3984 (1966).
Allegretti Marcello
Cesta Maria Candida
Mantovanini Marco
Nicolini Luca
Dompe′ S.p.A
Oh Taylor V
Trinh Ba K.
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